A world-wide yearly survey of new data and trends in adverse drug reactions

SIDE EFFECTS OF DRUGS ANNUAL 26

Side Effects of Drugs Annual 26 HONORARY EDITOR Prof. M.N.G. Dukes, Oslo, Norway

ADVISORY EDITORIAL BOARD Prof. F. Bochner, Adelaide, Australia Prof. I.R. Edwards, Uppsala, Sweden Prof. G.P. Velo, Verona, Italy

SIDE EFFECTS OF DRUGS ANNUAL 26 A worldwide yearly survey of new data and trends in adverse drug reactions EDITOR

J. K. ARONSON M.A., D.Phil., M.B.Ch.B., F.R.C.P. Clinical Reader in Clinical Pharmacology University Department of Clinical Pharmacology Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom

2003

ELSEVIER Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo

ELSEVIER SCIENCE B.V. Sara Burgerhartstraat 25 P.O. Box 211, 1000 AE Amsterdam, The Netherlands © 2003 Elsevier Science B.V. All rights reserved. This work is protected under copyright by Elsevier Science, and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone: (+44) 1865 843830, fax: (+44) 1865 853333, e-mail: [email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions’. In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (+1) (978) 7508400, fax: (+1) (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London W1P 0LP, UK; phone: (+44) 207 631 5555; fax: (+44) 207 631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation, but permission of Elsevier Science is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier’s Science & Technology Rights Department, at the phone, fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. First edition 2003 ISBN: 0-444-50999-2 ISSN: 0378-6080 ∞ The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of !

Paper). Printed in The Netherlands.

Contributors M.C. ALLWOOD, B . PHARM ., PH . D . University of Derby, School of Health and Community Studies, Pharmacy Academic Practice Unit, Kingsway House, Derby, DE22 3HL, U.K. E-mail: [email protected] J.K. ARONSON, M . A ., M . B . CH . B ., D . PHIL ., F. R . C . P. University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, U.K. E-mail: [email protected] S. ARROYO, M . D ., PH . D . Medical College of Wisconsin, Froedtert Hospital, Department of Neurology, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, U.S.A. E-mail: [email protected] I. AURSNES, M . D . University of Oslo, Department of Pharmacotherapeutics, P.O. Box 1065 Blindern, N-0316 Oslo, Norway. E-mail: [email protected] A.M. BALDACCHINO, M . D ., M . R . C . PSYCH ., M . PHIL ., DIP. ADD . BEH . Centre for Addiction Studies, St. George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 0RE, U.K. M. BEHREND, M . D ., PH . D . Klinik für Viszeral-, Gefäß-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Str. 41, D-94469 Deggendorf, Germany. E-mail: [email protected] T. BICANIC, M . A ., MB . CH . B ., M . R . C . P. St. George’s Hospital Medical School, Department of Infectious Diseases, Cranmer Terrace, London, SW17 0RE, U.K. C. BOKEMEYER, PH . D ., M . D . Department of Hematology/Oncology/Immunology, Eberhard Karls University Tübingen, UKT - Medical Center II, Department of Hematology, Oncology, Immunology, Rheumatology, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. A. CARVAJAL, M . D ., PH . D . Instituto de Farmacoepidemiologia, Facultad de Medicine, 47005 Valladolid, Spain. E-mail: [email protected] N.H. CHOULIS, M . D ., PH . D . LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania (Attika), Greece. E-mail: [email protected] P. COATES, M . B . B . S ., F. R . A . C . P., F. R . C . P. A . University of Pittsburgh, Department of Endocrinology and Metabolism, 1110 Kaufmann Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, U.S.A. E-mail: [email protected] J. COSTA, M . D . Universitat Autònoma de Barcelona, Hospital Universitari Germans Trias I Pujol, Clinical Pharmacology Department, Ctra de Canyet, 08916 Badalona, Spain. E-mail: [email protected]

v

vi

Contributors

P.J. COWEN, M . D . University Department of Psychiatry, Warenford Hospital, Oxford, OX3 7JX, U.K. E-mail: [email protected] S. CURRAN, B . S . C ., M . B . CH . B ., M . MED . SC ., M . R . C . PSYCH ., PH . D . South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, U.K. E-mail: [email protected] H.J. DE SILVA, M . B . B . S ., M . D ., D . PHIL ., F. R . C . P., F. R . C . P. E ., F. C . C . P. University of Kelaniya, Department of Medicine, Faculty of Medicine, P.O. Box 6, Ragama, Sri Lanka. E-mail: [email protected] F.A. DE WOLFF, M . A ., PH . D ., EUR . CLIN . CHEM ., E . R . T., F. A . T. S . Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Pharmacy and Toxicology, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] A. DEL FAVERO, M . D . Istituto di Medicina Interna e Science Oncologiche, Policlinico Monteluce, 06122 Perugia, Italy. E-mail: [email protected] J. DESCOTES, M . D ., PH . D ., PHARM . D . Hôpital Edouard Herriot, Centre Antipoison – Centre de Pharmacovigilance, 5 Place d’Arsonval, 69347 Lyon cedex 03, France. E-mail: [email protected] S. DITTMANN, M . D ., D . SC . MED . Vice-Chairman, German Advisory Committee on Immunization, 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail: [email protected] M.N.G. DUKES Trosterudveien 19, 0778 Oslo, Norway. E-mail: [email protected] I.R. EDWARDS, M . B ., F. R . C . P., F. R . A . C . P. Uppsala Monitoring Centre, The WHO Collaborating Centre for International Drug Monitoring, Stora Torget 3, S-753 20 Uppsala, Sweden. E-mail: [email protected] H.W. EIJKHOUT, M . D . Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] E. ERNST, M . D ., PH . D ., F. R . C . P. ( EDIN ) University of Exeter, Peninsula Medical School, Department of Complementary Medicine, 25 Victoria Park Road, Exeter, EX2 4NT, U.K. E-mail: [email protected] M. FARRÉ, M . D . Universitat Autónoma de Barcelona, Institut Municipal d’Investigació Mèdica (IMIM-IMAS), Unitat de Farmacologia, Doctor Aiguader 80, 08003 Barcelona, Spain. E-mail: [email protected] D.J. FINNEY, M . A ,. SC . D . 13 Oswald Court, South Oswald Road, Edinburgh, EG9 2HY, U.K. E-mail: [email protected] J.A. FRANKLYN, M . D ., PH . D ., F. R . C . P., F. MED . SCI . University of Birmingham, Queen Elizabeth Hospital, Department of Medicine, Edgbaston, Birmingham, B15 2TH, U.K. E-mail: [email protected]

Contributors

vii

M.G. FRANZOSI, PH . D . Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] A.H. GHODSE, M . D ., PH . D ., F. R . C . P., F. R . C . PSYCH . Centre for Addiction Studies, St. George’s Hospital Medial School, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 0RE, U.K. E-mail: [email protected] G. GILLESPIE, M . B . CH . B . F. R . C . A . Royal Perth Hospital, Department of Anaesthesia and Pain Medicine, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected] A.H. GROLL, M . D . Infectious Disease Research Program, Center for Bone Marrow Transplantation and Division of Hematology/Oncology, Department of Pediatrics, Wilhelms University, Muenster, Germany. E-mail: [email protected] K. HARTMANN, P. SC . PHARM . Swiss Drug Monitoring Center, Neubruchstrasse 37, 7000 Chur, Switzerland. J.T. HARTMANN, PH . D ., M . D . Department of Hematology/Oncology/Immunology, Eberhard Karls University Tübingen, UKT - Medical Center II, Department of Hematology, Oncology, Immunology, Rheumatology, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. E-mail: [email protected] A. IMHOF, M . D . Program in Infectious Disease, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D3-100, Seattle, WA 98109-1024, U.S.A. E-mail: [email protected] PROFESSOR L.L. IVERSEN, M . A ., PH . D . University of Oxford, Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, U.K. E-mail: [email protected] PROFESSOR J.W. JEFFERSON, M . D . University of Wisconsin Medical School, Madison Institute of Medicine, 7617 Mineral Point Road, Madison, WI 53717, U.S.A. E-mail: [email protected] M. JOERGER, M . D . Kantonsspital, Department of Internal Medicine, 9007 St. Gallen, Switzerland. P. JOUBERT, B . SC ., M . B . B . CH ., M . MED . SC ., F. C . P.( SA ), M . D . Honorary Professor of Pharmacology and Therapeutics, Medical University of Southern Africa, Pretoria, South Africa. E-mail: [email protected] H.M.J. KRANS, M . D . Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, Building 1 C4-R, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: [email protected] S. KRISHNA, B . A ., D . PHIL ., F. R . C . P. St. George’s Hospital Medical School, Department of Infectious Diseases, Cranmer Terrace, London, SW17 0RE, U.K. E-mail: [email protected] M. KUHN, M . D . Swiss Drug Monitoring Center, Neubruchstrasse 37, 7000 Chur, Switzerland. E-mail: [email protected]

viii

Contributors

R. LATINI, M . D . Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] M. LEUWER, M . D . The University of Liverpool, University Department of Anaesthesia, The Duncan Building, Daulby Street, Liverpool, L69 3GA, U.K. E-mail: [email protected] H.-P. LIPP, PH . D . Eberhard-Karls-University Tübingen, Department of Clinical Pharmacy, Röntgenweg 9, 72076 Tübingen, Germany. C. LUDWIG, M . D . Abt. Thoraxchirurgie, Universitätsklinikum Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany. P. MAGEE, B . SC ., M . SC ., M . R . PHARM . S . Director of Pharmaceutical Sciences, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, U.K. E-mail: [email protected] A.P. MAGGIONI, M . D . Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] L.H. MARTÍN ARIAS, M . D ., PH . D . Instituto de Farmacoepidemiologia, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] I.R. MCNICHOLL, PHARM . D ., B . C . P. S . WITH ADDED QUALIFICATIONS IN INFECTIOUS DIS EASES

UCSF Positive Health Program, Building 80, Ward 86, San Francisco General Hospital, 995 Potrero Avenue, San Francisco, CA 94110, U.S.A. E-mail: [email protected] M.M.H.M. MEINARDI, M . D ., PH . D . Academic Medical Centre, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: [email protected] R.H.B. MEYBOOM, M . D ., PH . D . Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands. T. MIDTVEDT, M . D ., PH . D . Karolinska Institutet, Laboratory of Medical Microbial Ecology, Von Eulers v. 5, Box 60 400, S-171 77 Stockholm, Sweden. E-mail: [email protected] S.K. MORCOS, F. R . C . S ., F. F. R . R . C . S . I ., F. R . C . R . Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Sheffield, S5 7AU, U.K. E-mail: [email protected] W.M.C. MULDER, M . D ., PH . D . Academic Medical Center, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. S. MUSA, M . B . CH . B ., M . R . C . PSYCH . South West Yorkshire Mental Health NHS Trust, Aberford Centre, Wakefield, U.K.

Contributors

ix

S. OLSSON, M . SCI . PHARM . Uppsala Monitoring Centre, The WHO Collaborating Centre for International Drug Monitoring, Stora Torget 3, S-753 20 Uppsala, Sweden. E-mail: [email protected] J.N. PANDE, M . D ., F. A . M . S . Professor of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. E-mail: [email protected] J.K. PATEL, M . D . University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, U.S.A. E-mail: [email protected] K. PEERLINCK, M . D . University of Leuven, Center for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, B-3000 Leuven, Belgium. E-mail: [email protected] T. PLANCHE, M . R . C . P. St. George’s Hospital Medical School, Department of Infectious Diseases, Cranmer Terrace, London, SW17 0RE, U.K. B.C.P. POLAK, M . D . VU University Medical Center, Department of Ophthalmology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected] H.D. REUTER, PH . D . Siebengebirgsallee 24, D-50939 Köln, Germany. E-mail: [email protected] M. SCHACHTER, M . D . Department of Clinical Pharmacology, St. Mary’s Hospital, London, W2 1NY, U.K. E-mail: [email protected] S.A. SCHUG, M . D ., F. A . N . Z . C . A ., F. F. P. M . A . N . Z . C . A . University of Western Australia, Anaesthesia, School of Medicine and Pharmacology, MRF Building, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected] G. SCREATON, B . M . B . CH ., D . PHIL ., M . R . C . P. Nuffield Department of Clinical Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, U.K. E-mail: [email protected] R.P. SEQUEIRA, PH . D . Arabian Gulf University, College of Medicine and Medial Sciences, Department of Pharmacology and Therapeutics, P.O. Box 22979, Manama, Bahrain. E-mail: [email protected] DOMENIC A. SICA, M . D . Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Medical College of Virginia of Virginia Commonwealth University, Box 980160 MCV Station, Richmond, Virginia 23298-0160, U.S.A. E-mail: [email protected] A. STANLEY, PH . D ., M . R . PHARM . S . Birmingham Oncology Centre, St. Chad’s Unit, City Hospital, Dudley Road, Birmingham, B18 7QH, U.K. E-mail: [email protected] K.J.D. STANNARD, B . SC ., M . B . B . S ., F. R . C . A . Royal Perth Hospital, Department of Anaesthesia and Pain Medicine, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected]

x

Contributors

W.G. VAN AKEN, M . D . Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] G.B. VAN DER VOET, PH . D ., E . R . T. Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Pharmacy and Toxicology, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] P.J.J. VAN GENDEREN, M . D ., PH . D . Habour Hospital and Institute of Tropical Diseases, Department of Internal Medicine, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail: [email protected] R. VERHAEGHE, M . D . University of Leuven, Center for Vascular and Molecular Biology, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] J. VERMYLEN, M . D . University of Leuven, Center for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, B-3000 Leuven, Belgium. E-mail: [email protected] T. VIAL, M . D . Hôpital Edouard Herriot, Centre Antipoison – Centre de Pharmacovigilance, 5 Place d’Arsonval, 69347 Lyon cedex 03, France. E-mail: [email protected] P.J.M. VOSSEBELD, PH . D . Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] G.M. WALSH, M . SC ., PH . D . University of Aberdeen, IMS Building, Department of Medicine & Therapeutics, Foresterhill, Aberdeen, AB25 2ZD, U.K. E-mail: [email protected] T.J. WALSH, M . D . Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A. E-mail: [email protected] E.J. WONG, M . D . Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Boston, MA 02115, U.S.A. E-mail: [email protected] Y. YOUNG, M . B . B . S ., M . R . C . P.( UK ), F. R . C . A . Auckland Hospital, Department of Anaesthesia, Private Bag 92024, Auckland, New Zealand. E-mail: [email protected] O. ZUZAN, M . D . Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, U.K. E-mail: [email protected]

Contents Contributors List of special reviews

v xv

Cumulative index of special reviews

xvii

How to use this book

xxiii

Historical Essay: From thalidomide to pharmacovigilance: a personal account D.J. Finney Essay: How safe is cannabis? L. Iversen

xxv xxxiii

1.

Central nervous system stimulants and drugs that suppress appetite R.P. Sequeira

1

2.

Antidepressant drugs P.J. Cowen

11

3.

Lithium J.W. Jefferson

19

4.

Drugs of abuse E. Wong and J.K. Patel

30

5.

Hypnosedatives and anxiolytics S. Curran and S. Musa

46

6.

Antipsychotic drugs A. Carvajal and L.H.M. Arias

53

7.

Antiepileptic drugs S. Arroyo

70

8.

Opioid analgesics and narcotic antagonists A.H. Ghodse and A.M. Baldacchino

89

9.

Anti-inflammatory and antipyretic analgesics and drugs used in gout A. Del Favero

111

10.

General anesthetics and therapeutic gases Y. Young

131

11.

Local anesthetics S.A. Schug, G. Gillespie, and K.J.D. Stannard

140

xi

xii 12.

Contents

Neuromuscular blocking agents and skeletal muscle relaxants

150

O. Zuzan and M. Leuwer 13.

Drugs that affect autonomic functions or the extrapyramidal system M. Schachter

156

14.

Dermatological drugs and topical agents W.M.C. Mulder and M.M.H.M. Meinardi

168

15.

Antihistamines (H1 receptor antagonists) G.M. Walsh

180

16.

Drugs acting on the respiratory tract M. Kuhn, M. Joerger, and K. Hartmann

186

17.

Positive inotropic drugs and drugs used in dysrhythmias J.K. Aronson

198

18.

Beta-adrenoceptor antagonists and antianginal drugs

223

A.P. Maggioni, M.G. Franzosi, and R. Latini 19.

Drugs acting on the cerebral and peripheral circulations R. Verhaeghe

230

20.

Antihypertensive drugs P. Joubert

233

21.

Diuretics D.A. Sica

238

22.

Metals G.B. van der Voet and F.A. de Wolff

243

23.

Metal antagonists

253

R.H.B. Meyboom 24.

Antiseptic drugs and disinfectants P. Magee

258

25.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines T. Midtvedt

262

26.

Miscellaneous antibacterial drugs A. Imhof

271

27.

Antifungal drugs A.H. Groll and T.J. Walsh

302

28.

Antiprotozoal drugs T. Bicanic, T. Planche, and S. Krishna

315

Contents

xiii

29.

328

Antiviral drugs I.R. McNicholl

30.

Drugs used in tuberculosis and leprosy

339

J.N. Pande 31.

Antihelminthic drugs

344

P.J.J. van Genderen 32.

Vaccines

353

S. Dittmann 33.

Blood, blood components, plasma, and plasma products

363

P.J.M. Vossebeld, H.W. Eijkhout, and W.G. van Aken 34.

Intravenous infusions—solutions and emulsions

374

M.C. Allwood 35.

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

379

K. Peerlinck and J. Vermylen 36.

Gastrointestinal drugs

382

H.J. de Silva 37.

Drugs acting on the immune system

393

T. Vial, J. Descotes, G. Screaton, M. Behrend, and C. Ludwig 38.

Vitamins

416

H.D. Reuter 39.

Corticotrophins, corticosteroids, and prostaglandins

427

J. Costa and M. Farré 40.

Sex hormones and related compounds, including hormonal contraceptives

434

M.N.G. Dukes 41.

Thyroid hormones and antithyroid drugs

457

J.A. Franklyn 42.

Insulin, glucagon, and hypoglycemic drugs

461

H.M.J. Krans 43.

Miscellaneous hormones

477

P. Coates 44.

Drugs that affect lipid metabolism I. Aursnes

486

xiv

Contents

45.

Cytostatic drugs H.-P. Lipp, C. Bokemeyer, J.T. Hartmann, and A. Stanley

490

46.

Radiological contrast agents S.K. Morcos

512

47.

Drugs used in ocular treatment B.C.P. Polak

525

48.

Treatments used in complementary and alternative medicine E. Ernst

528

49.

Miscellaneous drugs, materials, and medical devices N.H. Choulis

540

50.

The WHO International Drug Monitoring Programme I.R. Edwards and S. Olsson

548

Address list of national centres that participate in the WHO Drug Monitoring Programme

559

Index of drugs

xxx

Index of adverse effects

xxx

Special reviews The cognitive effects of MDMA Antipsychotic drugs and weight gain Cognitive effects of topiramate Valproate-associated polycystic ovary syndrome Vigabatrin-related visual abnormalities Managing the adverse effects of morphine An update on NSAIDs and chronic renal disease What is safe prescribing and use of selective COX-2 inhibitors? Comparisons with non-selective NSAIDs Propofol-infusion syndrome Allergic reactions to rocuronium The baclofen withdrawal syndrome Midodrine Sleep disorders with dopamine receptor agonists The cardiotoxic effects of antihistamines CNS effects of second-generation antihistamines Inhaled corticosteroids and growth inhibition in children Systemic availability of inhaled corticosteroids Dofetilide The role of endothelin receptor antagonists in hypertension Tetracyclines and metalloproteinases Adverse effects of the chemically modified tetracyclines (CMTs) Hepatotoxicity of antituberculous agents revisited Surveillance of adverse events following immunization (AEFI) Bioterrorism and prevention through immunization Co-medication and multimedication in users of acetylsalicyclic acid and vitamin E in Germany Could fertility treatments cause malignant melanoma? The third-generation oral contraceptives: a judicial assessment and further evidence Modes of administration of insulin Ovarian hyperstimulation syndrome Platinum compounds Delayed reactions to iodinated water-soluble contrast agents

32 56 78 81 82 98 111 116 135 150 152 157 160 180 182 186 187 208 233 266 268 339 353 354 423 434 442 464 477 490 513

xv

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Cumulative index of special reviews, Annuals 16–25 Index of drugs Note: the format 24.115 refers to SEDA-24, p. 115. ACE inhibitors angio-edema, 22.225 cough, 19.211 indications, 24.233 Alcohol, vitamin A, beta-carotene, interaction, 24.442 Aldosterone antagonists, in heart failure, 24.246 Aluminium, in albumin solutions, 23.359 Aminoglycoside antibiotics, 17.304 deafness, 18.268 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 17.305 Amiodarone, dysrhythmias, 25.211 Amphotericin, liposomal, 17.319 Analgesics headache, 21.95 headaches in children, 23.114 nephropathy, 21.98 Androgens, in women, 24.477 Anesthesia, dental, safety of, 16.122 Anesthetics halogenated, renal damage, 20.106 local, combinations, 20.121 local, neurotoxicity, 21.129, 25.152 ocular, 17.542 Anorectic drugs cardiac valvulopathy 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Anthracyclines, 25.533 Antibiotics allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 17.303 male fertility, 16.262 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 preterm infants, 21.258 prudent use, 25.279 resistance, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273 seizures, 18.261 side chains, 16.264

Anticholinergic drugs, 22.507 Anticonvulsants, see Antiepileptic drugs Antidepressants, during and after pregnancy, 21.17 Antidysrhythmic drugs in atrial fibrillation, 24.197 prodysrhythmic effects, 17.218, 23.196 Antiepileptic drugs comparison, 25.78 death, 23..83 overdosage, 22.84 psychiatric effects, 22.82 Antifungal drugs drug interactions (azoles), 24.318 Pneumocystis carinii pneumonia, 18.289 Antihistamines cardiovascular adverse effects, 17.196, 22.176, 25. 183 drowsiness, 23.171 sedation, 21.170 Antihypertensive drugs, 19.209 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 17.325, 20.257 adjunctive treatments, 24. 330 prophylaxis, 23.304 Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antipsychotic drugs, comparison 25.53 Antitubercular drugs, 16.341 Liver damage, 25.363 Mycobacterium avium–complex infection, 20.278 Appetite suppressants cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Aspirin, 21.100 gastrointestinal effects, 17.95, 18.90 rhinosinusitis/asthma, 17.94 Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Azoles, see antifungal drugs Bambuterol, cardiac failure, 23.181 Benzodiazepines, depression, 17.43

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Cumulative index of special reviews, Annuals 16–25

Beta2 -adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 Beta-carotene alcohol, vitamin A, interaction, 24.442 carcinogenicity, 25.454 Beta-lactams, pregnancy, 25.280

Fertility drugs, ovarian cancer, 24.474 Flecainide, in supraventricular dysrhythmias, 21.200 Fluoroquinolones, 18.271 Fluorouracil, adverse effects, 23.476 Folic acid, dietary supplementation, 19.369 Formoterol, tolerance, 24.187 Fragrances, contact allergy, 20.149

Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carotenoids, carcinogenicity, 25.454 Charcoal, activated, in digitalis overdose, 24.201 Ciclosporin, urinary system, 19.348 Clozapine, agranulocytosis, 22.1359 Co-trimoxazole, hypersensitivity reactions, 20.264 Cocaine cardiovascular effects, 18.5 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151 Contrast agents adverse effects, 24.525 anaphylactoid and allergic reactions, 20.422 in magnetic resonance imaging, 20.419 Corticosteroids bone, 16.447, 22.182, 25.195 contact allergy, 21.158 effective dose and therapeutic ratio, 23.175 inhaled, systemic availability, 24.185 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 19.377, 20.374 preterm infants, 17.445 Cosmetics contact allergy, 16.150, 19.151 ingredient labeling 22.159 COX2 inhibitors, 24.115, 25.126

General anesthetics, see Anesthetics Germanium, 16.545 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 insulin resistance, 24.504 malignancy, 23.468

Deferoxamine, 16.247 bone dysplasia, 23.241 Diamorphine, progressive spongiform leukoencephalopathy, 24.40 Diclofenac, liver damage, 20.91 Digitalis, in atrial fibrillation, 24.197 Digoxin, heart failure in sinus rhythm, 18.196 Diuretics renal cell carcinoma, 23.225 renal insufficiency, 25.250 Ecstasy, deaths, 24.32 EDTA, pseudothrombocytopenia, 21.250 Erythromycin, versus the new macrolides, 21.269 Erythropoietin, status and safety, 16.400 Euxyl K 400, contact allergy, 16.150 Felbamate aplastic anemia, 19.68, 22.86 risk/benefit ratio, 23.86 Fenfluramine cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77

Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Heroin, see diamorphine HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530 Hormones, sex, tumors, 22.465 Hypnotics, 20.30 avoiding adverse effects, 21.37 Immunization adverse effects, 24.364 bioterrorism, 25.378 surveillance after, 22.333, 23.335, 24.364, 25.376 Indomethacin, fetal and neonatal complications, 18.102 Insulin resistance, and growth hormone, 24. 504 synthetic analogs, 24. 489 Isoniazid, prophylactic, toxicity, 24. 352 Ketorolac, risk of adverse effects, 17.110 Lamotrigine, skin rashes, 20.62, 24.88 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183 Lithium adverse effects, prevention and treatment, 17.28 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 18.25 mortality, 19.14 urinary system, 19.16 Local anesthetics, see Anesthetics Lyme disease vaccine, autoimmune disease, 24.366 Macrolides, intestinal motility, 18.269 Malaria vaccines, 22.306 MAO inhibitors, 17.361 Measles immunization autism, 23.350 Crohn’s disease, 23.350 neurological adverse effects, 23.348 Melatonin, 25.523 Metformin, lactic acidosis, 23.459 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151

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Cumulative index of special reviews, Annuals 16–25 Mibefradil, drug interactions, 23.210 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387 Crohn’s disease, 23.350, 25.387 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 intensive care, 19.140

Phentermine, cardiac valvulopathies, 24.4 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 PUVA, malignant melanoma, 22.166

Niacin, extended-release, 16.440 NSAIDs blood pressure, 19.92 children, 19.96 current controversies, 17.102 COX2 inhibitors, 24.115, 25.126 gastrointestinal adverse effects, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 nephrotoxicity, 18.100, 20.89, 24.120 topical, 18.163

Rotashield, intussusception, 23.354

Ocular drugs allergic reactions, 21.486 geriatric patients, 16.542 risk factors for adverse effects, 22.507 Omeprazole, tumors, 16.423 Opioids adverse effects, prevention, 24.100 death, 25.37 obstetric use, 24.102 tolerance in neonates, 23.97 Oral contraceptives antibiotics, and pregnancy, 24.274 formulations, 24.472 third-generation, 25.484 venous thromboembolism, 23.442 Paclitaxel, adverse effects, 21.463 Pancreatic enzyme supplements, fibrosing colonopathy, 20.322 Paracetamol liver damage, 17.98, 18.94 overdose, 23.117 Penicillins, acute desensitization, 23.252 Peritoneal dialysis fluids, effects on peritoneum, 22.381

Salmeterol, tolerance, 24.187 Sex hormones, tumors, 22.465 Specific serotonin reuptake inhibitors, drug interactions, 22.13 Statins, see HMG co-A reductase inhibitors Steroids, see corticosteroids Sumatriptan, 17.171 Suramin, patients with prostate cancer, 20.283 Tetracyclines comparative toxicity, 22.268 in pregnancy, 25.280 in rheumatology, 23.255 therapeutic effects, 24.278 Theophylline, asthma, 17.2, 18.1, 18.2 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 Total parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Vaccines, poliomyelitis, 22.352 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98 Vitamin A, 17.436 alcohol, beta-carotene, interaction, 24.442 in pregnancy, 21.405 Vitamin B6 , debate, 23.420 Vitamin K cancer, 23.424 skin reactions, 25.461 Vitamins, in old age, 22.431

Index of adverse effects Cardiovascular atrial fibrillation, antidysrhythmic drugs, 24.197 atrial fibrillation, digitalis, 24.197 cardiac failure, aldosterone antagonists, 24.246 cardiac failure, bambuterol, 23.181 cardiotoxicity, antihistamines, 17.196, 25.183 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 hypertension, NSAIDs, 19.92

prodysrhythmic effects, antidysrhythmic drugs, 17.218, 23.196 QT interval prolongation, 24.54 valvulopathies, fenfluramine, 22.3, 23.2, 24.4, 25.5 valvulopathies, phentermine, 24.4, 25.5 venous thromboembolism, oral contraceptives, 23.442 Respiratory asthma, aspirin, 17.94 asthma, fenoterol, 23.182

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Cumulative index of special reviews, Annuals 16–25

asthma deaths, beta2 -adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 Churg–Strauss syndrome, leukotriene receptor antagonists, 24. 183 cough, ACE inhibitors, 19.211 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 rhinosinusitis, aspirin, 17.94 Nervous system demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness, antihistamines, 23.171 headache, analgesics, 21.95, 23.114 neuroleptic malignant syndrome, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 poliomyelitis, vaccines, 22.352 progressive spongiform leukoencephalopathy, diamorphine, 24.40 sedation, antihistamines, 21.170 seizures, antibiotics, 18.261 tardive dyskinesia, 20.38 tardive syndromes, 17.54 transient symptoms, intrathecal anesthetics, 25.152 Sensory systems deafness, aminoglycosides, 18.268 eye effects, muscle relaxants, 21.145 visual field defects, vigabatrin, 21.78, 24.95, 25.98 Psychiatric antiepileptic drugs, 22.82 autism, MMR/measles immunization, 23.350, 25.387 depression, benzodiazepines, 17.43 psychosis and abnormal behavior, vigabatrin, 18.71 Endocrine insulin resistance, growth hormone, 24.504 insulin resistance, HIV-protease inhibitors, 22.317 Metabolism lactic acidosis, metformin, 23.459 lipodystrophy, HIV-protease inhibitors, 22.317 polyvinylpyrrolidone storage disease, 22.522 Hematologic agranulocytosis, clozapine, 22.59 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 pseudothrombocytopenia, EDTA, 21.250 Gastrointestinal bleeding, aspirin, 17.95, 18.90 bleeding and perforation, NSAIDs , 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114 cholestasis, total parenteral nutrition, 22.376 colitis, antibiotics, 17.303 Crohn’s disease, MMR/measles immunization, 23.350, 25.387 fibrosing colonopathy, pancreatic enzyme supplements, 20.322 inflammatory bowel disease, NSAIDs, 25.131 intestinal motility, macrolides, 18.269 intussusception, Rotashield, 23.354

Liver hepatotoxicity, alcohol/vitamin A/beta-carotene, 24.442 hepatotoxicity, antitubercular drugs, 25.363 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, paracetamol, 17.98, 18.94 Urinary tract cystitis, tiaprofenic acid, 18.106 nephrotoxicity, aminoglycosides, 17.305 nephrotoxicity, analgesics, 21.98 nephrotoxicity, anesthetics, halogenated, 20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, lithium, 19.16 nephrotoxicity, NSAIDs, 18.100, 20.89, 24.120 renal cell carcinoma, diuretics, 23.225 renal insufficiency, diuretics, 25.250 Skin contact allergy, 23.160 rashes, lamotrigine, 20.62, 24.88 vitamin K1, 25.461 Serosae peritoneum, peritoneal dialysis, 22.381 pleurodesis, 25.189 Musculoskeletal bone, total parenteral nutrition, 22.378 bone dysplasia, deferoxamine, 23.241 bone mineral density, corticosteroids, 25.195 osteoporosis and osteonecrosis, corticosteroids, 16.447, 19.377, 20.374, 21.417, 22,182 Sexual function fertility, male, antibiotics, 16.262 Immunologic allergic reactions, antibiotics, 23.251 angio-edema, ACE inhibitors, 22.225 autoimmune disease, Lyme disease vaccine, 24.366 cocamidopropylbetaine, 19.151 contrast agents, 20.422 corticosteroids, 21.158 cosmetics, 16.150, 19.151 co-trimoxazole, 20.264 desensitization, penicillin, 23.252 Euxyl K 400, 16.150 fragrances, 20.149 methyldibromoglutaronitrile, 16.150, 19.151 ocular drugs, 21.486 propolis, 17.181 red man syndrome, 17.312 Infection risk AIDS, polio vaccine, 23.352 total parenteral nutrition, 22.379 Body temperature malignant hyperthermia, 18.112 Death antiepileptic drugs, 23.83 calcium antagonists, 22.214 ecstasy, 24.32 lithium, 19.14 opiates, 25.37 Drug tolerance antibiotic resistance, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 25.279 opioids in neonates, 23.97 Carcinogenicity alcohol/vitamin A/beta-carotene, 24.442

Cumulative index of special reviews, Annuals 16–25 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474 growth hormone, 23.468 omeprazole, 16.423 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Use in pregnancy affective disorders in, 21.17 antibiotics and the pill, 24.274 beta-lactams, 25.280 opioids, 24.102 tetracyclines, 25.280 vitamin A, 21.405 Teratogenicity tretinoin, topical, 18.164 Fetotoxicity cocaine, 20.24 indomethacin, 18.102 Risk factors children, NSAIDs, 19.96 intensive care, muscle relaxants, 19.140 neonatal complications, indomethacin, 18.102 ocular drugs, 22.507

xxi old age, vitamins, 22.431 preterm infants, beta-lactam antibiotics, 21.258 Drug administration dosage regimens, aminoglycosides, 23.264 formulations, oral contraceptives, 24.472 inhaled corticosteroids, systemic availability, 24.185 labeling problems, cosmetics, 22.159 Drug overdose digitalis, charcoal, 24.201 paracetamol, 23.117 Drug interactions alcohol/vitamin A/beta-carotene, 24.442 antibiotics/the pill, 24.274 antifungal azoles, 24.318 grapefruit juice, 23.519 HMG Co-A reductase inhibitors, 25.530 lithium, 16.13 lithium/specific serotonin reuptake inhibitors, 18.30 mibefradil, 23.210 specific serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods Post-marketing surveillance, 24.274

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How to use this book

THE SCOPE OF THE ANNUAL The Side Effects of Drugs Annual has been published every year since 1977. It is designed to provide a critical and up-to-date account of new information relating to adverse drug reactions and interactions from the clinician’s point of view. It complements the standard encyclopedic work in this field, Meyler’s Side Effects of Drugs, the 14th edition of which was published in November 2000. PERIOD COVERED The present Annual reviews all reports that presented significant new information on adverse reactions to drugs during 2001. During the production of this Annual, some more recent papers have also been included. SELECTION OF MATERIAL In compiling the Side Effects of Drugs Annual particular attention is devoted to publications that provide essentially new information or throw a new light on problems already recognized. In addition, some authoritative new reviews are listed. Publications that do not meet these criteria are omitted. Readers anxious to trace all references on a particular topic, including those that duplicate earlier work, or to cross-check an electronic search, are advised to consult Adverse Reactions Titles, a monthly bibliography of titles from about 3400 biomedical journals published throughout the world, compiled by the Excerpta Medica International Abstracting Service. SPECIAL REVIEWS The special reviews deal in more detail with selected topics, interpreting conflicting evidence and providing the reader with clear guidance. They are identified by the traditional prescription symbol and are printed in italics. This volume includes a Cumulative Index of Special Reviews (SEDA-16 to SEDA-25) and a list of the titles of the Special Reviews published in the current Annual. CLASSIFICATION OF DRUGS Drugs are classified according to their main field of use or the properties for which they are most generally recognized. In some cases a drug is included in more than one chapter (for example, lidocaine may be mentioned in Chapter 11 as a local anesthetic and in Chapter 17 as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their most characteristic component. DRUG NAMES Drugs are usually dealt with under their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combination has a generic combination name (e.g. co-trimoxazole for trimethoprim + sulfamethoxazole) that has been used; in some cases brand names have been used instead.

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How to use this book

SYSTEM OF REFERENCES References in the text are tagged in an extended version of the tagging system that has been used in previous editions; the new tagging system is as follows: M: E: A: R: r: C: c: S:

A meta-analysis or other form of systematic review; An experimental study (animal or in vitro); An anecdote or set of anecdotes (i.e. case histories); A major review, including non-systematic statistical analyses of published studies; A brief commentary (e.g. an editorial or a letter); A major randomized controlled trial or observational study; A minor randomized controlled trial or observational study or a non-randomized study; Official (e.g. Governmental, WHO) statements.

The various editions of Meyler’s Side Effects of Drugs are cited in the text as SED-13, SED-14, etc.; the Side Effects of Drugs Annuals 1–25 are cited as SEDA-1, SEDA-2, etc. INDEXES Index of drugs: this index provides a complete listing of all references to a drug for which adverse effects and/or drug interactions are described. Index of adverse effects: this index is necessarily selective, since a particular adverse effect may be caused by very large numbers of compounds; the index is therefore mainly directed to adverse effects that are particularly serious or frequent, or are discussed in special detail; before assuming that a given drug does not have a particular adverse effect, consult the relevant chapters. American spelling has been used throughout, e.g. anemia, estrogen rather than anaemia, oestrogen.

SIDE EFFECTS OF DRUGS HISTORICAL ESSAY

From thalidomide to pharmacovigilance: a personal account David J. Finney∗ In the beginning After I had been totally out of contact with matters related to adverse reactions to drugs for several years, a chance meeting in the summer of 2002 with Dr Ralph Edwards, Director of the WHO Uppsala Monitoring Centre, brought me an invitation to speak at the forthcoming Conference of the International Society of Pharmacovigilance. As a biometrician without medical education, I found myself cynically wondering what facts and reasoning had governed medical practice before the currency of the now fashionable term “evidence-based medicine”. The essay that follows has been prepared from the talk that I gave at the Conference. The ancient but now discredited “Doctrine of Signatures”, espoused by Paracelsus as an accepted science, must through the ages have encouraged many a priest or doctor to compound a drug from leaves or flowers that bore some resemblance to an ailing bodily organ. As Nelson has concisely stated (1): “The Doctrine relies on the concept that like affects like. Hence plants designed by the Creator for man may be expected to bear each a sign pointing to their special use”. Were adverse reactions to such drug therapy uncommon? I believe that even in the eighteenth century the great Dutch physician Herman Boerhaave recorded serious harm occasionally resulting from standard well-intentioned medication. Yet not until the thalidomide crisis of ∗ David Finney, MA ScD, is Professor Emeritus of Statistics in the University of Edinburgh, UK.

the mid-twentieth century was there widespread public concern or determination to prevent similar tragedies in the future. I shall try to place the birth of pharmacovigilance in perspective with the history of this period. Ignorance will oblige me to place undue emphasis on my personal involvement: I hope to draw attention to a few of the people who have been important to the growth of this discipline, but inevitably I shall omit many worthy names. Inman has written an excellent account of early days in the UK, with much detail that is outside my own memory (2).

Early ideas An academic statistician with long experience in biometry, in 1962 I began my only period of sabbatic leave from university duties. I had accepted an invitation to spend a year in the Statistics Department of Harvard University. I took with me a need to benefit from Harvard’s superior computing facilities in order to advance my research into a problem related to plant breeding. For reasons that are no longer important, my hosts had arranged that for about half my time I should occupy a room in the Department of Preventive Medicine. In one of my first conversations with David D Rutstein, then Professor of Preventive Medicine, he said that he hoped that I could produce ideas on how statisticians might contribute to the early detection of dangers like the thalidomide problem that was then alarming the medical world. At that time, I had never heard of

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xxvi thalidomide or its effects, but Dave referred me to several publications. I read the reports from McBride in Sydney and Lenz in Hamburg. I was fortunately able to visit Frances Kelsey of FDA, whose suspicions had ensured that thalidomide never became a disaster in the USA. I soon began to embody preliminary suggestions in a short paper (3). Naive though these first notions were, Rutstein saw promise in them; he, Louis Lasagna, and others encouraged me to develop proposals in greater detail and to present them in a more formal memorandum. After some months, Rutstein urged me to distribute this memorandum to a selection of national and international health authorities. I had drafted no blueprint for pharmacovigilance, only a common-sense presentation of logical principles, with an outline of how these might be implemented. At a time when noone else had attempted to take a comprehensive view of the general problem, my ideas proved useful; in addition to my private distribution, early publication followed (4, 5). I saw the need for adoption of a terminology that would give precision to discussion of such data as might be collectable and to the kinds of logical inference that could be supported. A subsequent fuller published version (6) has been quite widely quoted. From the earliest days, I have argued that the problem is international and needs to be handled through internationally coordinated sharing of information (7–9). By the 1960s, the stimulus of Bradford Hill and his colleagues was enabling much clinical research to achieve the standards of experimental design and objective statistical assessment that were then expected in non-medical biological research. It was evident that data collectable on adverse reactions would never have the objectivity, mutual independence, and freedom from bias that, as an experienced biometrician, I expect from the records of good wellplanned experiments. Here the word “bias” has the statistician’s sense of a systematic departure of observations from the intended truth, possibly because of faulty instrumentation or unavoidable subjectivity of judgment, and not as implying any reprehensible wish to deceive. Recognition of this was a step on my road to what has become a firmly held belief (10): when faced with a problem of vital importance

David J. Finney

to public health and welfare, and despite severe imperfections in the only available data, a statistician may have an ethical duty to cooperate in cautiously turning whatever relevant skills he possesses to the extracting and interpretation of any usable information.

British drug safety In 1963, the UK Ministry of Health invited Professor Sir Derrick Dunlop to head a new agency, the Committee on Safety of Drugs (CSD), which would advise on measures for the future protection of the community against adverse reactions to therapeutic drugs. One important need was the introduction of a system for the licensing of new drugs. The CSD was to have only a small central medical and administrative Secretariat, but its operations would depend on suitable academics and others who could make their special skills available. This typically British pattern of the quango (Quasi-Autonomous Non-Governmental Organization) was later to be much criticized by political malcontents, but I believe that in this and many other instances it was a successful method of obtaining enthusiastic but normally unpaid help from diverse experts, who would not have been attracted by offers of full-time government employment. From among medical scientists, Dunlop assembled a complex of subcommittees to support his vision for the CSD. At the time I did not know Dunlop, but presumably he had seen my memorandum and thought that I might be helpful to the Subcommittee on Adverse Reactions, so beginning for me a period of over 30 years of fascinated involvement in this subject. The Ministry of Health had written (11) to every British doctor urging alertness to any suspicion that: “an untoward condition in a patient might be the result of drug treatment”. Dunlop hoped that, whether a drug had been prescribed by a physician or purchased over the counter, spontaneously submitted accounts of suspicions would come to the CSD for study by the Adverse Reactions Subcommittee. Reports soon began to reach us. Our first chairman, Professor Leslie Witts, proved an inspiring leader for a group of enthusiasts who, argumentative and often frustrated by bureaucracy, worked well together at learning how to handle their task. Initially we were much helped by Roy Goulding,

From thalidomide to pharmacovigilance: a personal account

who, as Director of the National Poisons Information Service, had valuable experience in handling anecdotal medical evidence. In 1964, Dunlop appointed Dr WHW Inman as a Senior Medical Officer in the CSD Secretariat. This fortunate choice gave Bill, as he was soon known to all, special responsibilities in respect of adverse reactions. We of the Subcommittee were industrious, enthusiastic, and aware of the need to avoid the fallacy of “post hoc ergo propter hoc”, but lacking any formal procedures that could aid interpretation of the suspicions reported to us. During several years, the papers distributed as agenda for each of our regular meetings included standardized listings of all recent reports. These we would scan in advance, noting apparent anomalies or confirmations of previous indications that would need careful scrutiny when we met; a few days later, physicians and pharmacologists would discuss the inherent plausibility of drug causation for each serious suspicion, while my role was more to search for patterns or to play devil’s advocate, by suggesting how an apparent cluster of cases might have resulted from the subjective judgments of the reporting doctors. One evident need was to have a standardized pattern of reporting, rather than informal letters. Inman saw that all practising physicians ought to be encouraged to act promptly, by having on their desks a supply of standard forms on which they could enter the minimal set of relevant facts. He redesigned prototypes already under trial and developed the yellow card that soon became recognized as the main instrument of reporting. The CSD realized that responsible reporting could prove a burden to general practitioners; the cards were therefore made selfsealing and free of postal charges. Although the subsequent 30 years have seen the yellow card undergo many changes and improvements in order to provide fuller information, I believe it to be still the main form of data input to the UK monitoring system.

WHO involvement From the start, my own belief had been that, because the drug industry was a world-wide force, effective action for safety needed international coordination. Late in 1963, I was able

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to visit Geneva in order to talk with Dr Hans H. Halbach of the WHO, who was then facing a novel and difficult task: “In 1962, as a direct consequence of the thalidomide tragedy, it was requested by the Member States that WHO should initiate an international programme for exchanging information on safety and efficacy of drugs” (12). However, there were no guidelines on how to interpret and comply with this request. Hence, despite its evident weaknesses, my memorandum came at a fortunate moment: Halbach quickly became a strong advocate of studying and trying to use its suggestions. The next year saw the first of a long series of small meetings convened by, or associated with, the WHO for the development of international standardized reporting and dissemination of information. Most were held in Geneva, but others were in Washington and Honolulu. Relevant experts and others with national responsibilities for drug safety met for intensive discussion of ways and means. During long days, we argued vigorously but constructively in the quest for ways of creating a viable international centre. WHO secretaries went far beyond their normal duties by working long hours to keep us supplied with successive revisions of daily documents, and even to ensure immediate delivery of drafts to Geneva hotels. In retrospect, I am amazed at how well the ever-changing small group worked together, without pressing special national interests, and even coping with the emotional stress for a Czech and a Russian colleague on the morning that brought news of the USSR army’s entry into Prague. Disagreements scarcely went beyond friendly joking about Ed Napke’s somewhat extravagant claims for the superiority of his pigeon-hole system (13). Today, I sometimes wonder whether Napke’s ability to make rapid visual survey of his accumulated reports might not sometimes be a more effective safeguard than the statistically sophisticated procedures now sometimes advocated without the assurance that they are appropriate to the type of data available. An early realization was the need for a comprehensive dictionary of possible adverse reactions, a purpose for which the existing International Classification of Diseases was too restricted. In excellent cooperation, Inman and Barbro Westerholm of Sweden worked to produce this dictionary. With the benefit of input

xxviii from many who were now operating a diversity of monitoring programmes in their own countries—notably James Crooks of the UK, Juhana Idänpään-Heikkilä of Finland, Garth McQueen of New Zealand, Ronald Meyboom of the Netherlands, and Arthur Ruskin of the USA—our meetings produced advice for Halbach on the creation of a WHO coordinating centre. Encouraged and helped by the USA Food and Drug Administration, a feasibility trial in Virginia gave this a start. In the 1960s, transatlantic data transmission facilities were far from ideal and effective operation was not easy. In 1970, this centre was moved to a more permanent home in Geneva, where it was first directed by Bruce W Royall with valuable assistance from Margaretha Helling and Jan Venulet. Such a novel operation could not become firmly established without time for growth and evolutionary adaptation to its practicability; during the 1970s, however, the WHO was unable to support this growth with adequate staffing and equipment. In 1978, the WHO gratefully accepted an invitation, first suggested by Professor Åke Liljestrand, with support from the Swedish Government, to move the centre to Uppsala. Thus was created the WHO Uppsala Monitoring Centre.

Adverse events From my time at Harvard, I had sensed the need for language and terminology that would facilitate objective discussion of evidence. It was natural for a statistician to be unhappy with the subjectivity of reports that originated in suspicion, not fact. Clearly there could be no question of imposing on physicians a legal requirement to report adverse reactions. Nothing in an episode of jaundice or agranulocytosis or thrombosis announces itself as having been caused by a drug taken 2 weeks previously. A natural reaction for a statistician was to propose that more informative data would be obtained if a cohort of patients beginning to take a nominated drug could be identified and their subsequent medical history recorded in respect of all events of medical importance (14, 15). I think that this suggestion (6) may have been the first introduction of the term “event” in pharmacovigilance. I also stressed (16, 17)

David J. Finney

the need to keep careful account of how patients who experienced adverse events were detected for inclusion in monitoring files. Special difficulties may arise in respect of adverse reactions, such as carcinogenesis, that are detectable only from events that by their nature may be unobservable until long after their cause; I hope that by now there has been much thought given to this type of problem (18). Hershel Jick and his Boston colleagues thought along lines similar to mine, when they planned studies that defined a cohort as a set of admissions to a chosen hospital, thereafter recording each patient’s subsequent history in respect of drugs received and all events or incidents of medical importance. This facilitated the examination of associations between a drug and objectively recorded patient experience, free from any prejudice involving initial suspicion of drug causation. A new Act of Parliament replaced the CSD by the Committee on Safety of Medicines (CSM); this may have meant little change in purpose and duties, but in our Subcommittee it certainly made bureaucracy more evident. Inman had long struggled for improvements in the data-gathering process, but he could not gain official support. Frustrated by indifference and refusal to think ahead, in 1980 he resigned from his position with the CSM Secretariat. By great determination, he obtained minimal financial backing and fortunately found in the University of Southampton a willingness to help him start what was to become the Drug Safety Research Unit (DSRU). From among his personal contacts, he found a small group to join this enterprise as an advisory committee, and eventually to become trustees of what was constituted as a charity (19, 20). I was one of these from the start until 1997. Despite continuing financial stresses, we firmly maintained a principle that Inman saw as vital, namely a refusal to undertake any study sponsored by the pharmaceutical industry, lest loss of independence should in any way constrain our freedom to investigate and publish. The DSRU adopted my idea of defining a cohort as consisting of all persons for whom a named drug is prescribed and then seeking to record a subsequent event history for each of them. Unknown to me until very recently, as early as 1977 in New Zealand, Garth McQueen had been trying a similar procedure that

From thalidomide to pharmacovigilance: a personal account

would later become known as “PrescriptionEvent Monitoring” (PEM). In implementing its form of PEM, the DSRU was able to use a special feature of the British National Health Service. With cooperation from the national agency responsible for handling individual prescription costs, access is possible to all prescriptions of a named drug during a stated period of time. The prescribing physicians can then be asked to provide, in confidence of course, information on events experienced by each patient. For this purpose (21), an event is defined as: “any new diagnosis, any reason for referral to a consultant or admission to hospital (e.g. operation, accident, or pregnancy), any unexpected deterioration (or improvement) in a concurrent illness, any suspected drug reaction, or any other complaint which was considered of sufficient importance to enter in the patient’s notes”. In 1991, a House of Lords committee, with a membership that included several eminent medical scientists, recommended (22) “that the Commission considers the use of Prescription Event Monitoring throughout the [European] Community. Its method of in-depth analysis of a carefully selected group of new products on the basis of data from a large random sample seems both effective and well adapted for Community policy”. Inman had estimated that PEM would cost about £150 000 per drug, a small expense relative to development costs, but apparently this strongly worded recommendation has been ignored.

Computers Today, any medical scientist faced with an accumulating collection of individual case records immediately thinks of entering each into a computer database designed for easy retrieval or later statistical study. Few scientists still under the age of 50 realize that in the mid 1960s this was not possible. During those years, as a member of the UK Computer Board, and for four years its Chairman, I was closely involved in efforts to ensure that every British university had access to a mainframe computer. The Board’s funding related almost solely to the demands of number-crunching for scientific research, with no provision for holding administrative records or handling the communication

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and text-processing tasks that form so large a part of the life of a computer in AD 2003. My first involvement in drug monitoring led me to think of this new subject as a form of operational research. I saw it as demanding imaginative new software for data retrieval and analysis associated with the then rapidly evolving computer technology. I considered the needs to be similar to those of a detective agency responsible for scanning miscellaneous imperfect records for evidence on previously unsuspected crimes (23, 24). Initially, the CSD had no computer support. Inman would transfer the information on each yellow card to a special type of index card; he classified and sorted packs of these by ingenious manipulation of knitting needles pushed through holes in the card edges. This “advanced technology” sufficed for his early successes in using retrospective case-control techniques to understand adverse reactions to oral contraceptives. The total number of stored records soon necessitated better systematic processing of summaries, which could be debated in subcommittees or possibly become the basis for discussion with a drug manufacturer. After a few years, the CSD secured some rights of use on a computer far from London. Each new access of data had to be transported to it by road; if we were lucky, standard tabulations would return to London in time for regular meetings of our Subcommittee. Improvement was slow. The CSM repeatedly inquired into the possibility of obtaining a small computer dedicated to its varied needs, by that time, scarcely an extravagant proposal. In 1980, at almost the last meeting I attended, a civil servant told me firmly that Subcommittee members had no right to be told anything about progress of negotiations on a request for a computer. Inman and I have always been sceptical about applying formal statistical significance tests to an accumulation of records of suspected adverse reactions. Such tests are incorporated into the clever software now readily available on most standard computers, tempting uncritical use by every medical scientist without questioning whether inherent assumptions are satisfied. Nevertheless, discussion on problems met within the CSD encouraged me to try to specify acceptable uses of standard statistical test procedures (25–28). Independently Inman empirically devised an ingeniously simple test of

xxx whether reports of a specific event are more frequent than a natural background rate. Under plausible assumptions of randomness such as seem appropriate to PEM, Andrew et al. have shown a theoretical basis for this “T1/T2 Test” (29). Once a monitoring system has all its data systematically stored within a computer, the computer can be instructed to maintain a continuous watch on a selected measure of association between a drug and a type of event, and to output a warning signal if that measure goes beyond a critical threshold. Napke advanced ideas on this with reference to his pigeon-hole data store (30), and in an internal WHO report, Patwary described another possibility (31). I reviewed the signalling problem more completely (32), but later years have seen many more developments. A modern computer will have no difficulty in checking the value of the chosen measure after each new case enters the database; output of a signal, however, is not in itself proof of adverse reaction to a drug, only a warning that an association merits closer study.

David J. Finney

the raw data was essential. Individual acknowledgment of every report received was scarcely needed, but I believed that the CSD ought to have done more than it did to interact with doctors and the public (33, 34). If we are to have a flow of therapeutic improvements by the introduction of new drugs, adverse reactions that could not have been predicted by a pharmacologist nor always observed during the routine of clinical trials will inevitably sometimes occur. I have emphasized (35) the importance of regular communication between a national monitoring agency, the drug industry, doctors, and the public, in order to increase understanding of problems that are common to all. From early in the life of the DSRU, Inman distributed to all collaborating doctors successive issues of PEM NEWS, booklets filled with information on the studies planned or in progress. I hope that today other drug monitoring operations have analogous practices of feedback.

Language Feedback to doctors and public Within the CSD, when the Adverse Reactions Subcommittee found strengthening evidence of a causal link between a drug and a potentially dangerous reaction, discussion would intensify, aided by consultation with all relevant levels of expertise and possibly with the manufacturer’s technical experts. If the main Committee became convinced that the link was genuine, much attention was given to drafting and distributing a suitable warning. Because this would go to all doctors and would of course reach the public press, avoidance of unduly alarmist tones was important. Errors of judgment were inevitable, but I think that the CSD managed this responsibility well. Whether for a national monitoring agency, or for the Boston hospital studies, or the type of work undertaken by the DSRU, the quality and completeness of the reports on which all inference depends requires the willing cooperation of busy men and women. From early days, I had thought that systematic feedback of information to the medical professionals who provided

I have emphasized the importance to pharmacovigilance of using unambiguous terminology. Inaccurate use of words is today a disease that afflicts speech and writing about quantitative statements in the news media, in popular journalism, and increasingly even in serious technical writing. It may be primarily an Anglophone phenomenon, but it needs to be noted and avoided by all who write on any topic for an international readership. I shall comment on examples from my large collection of horrors. One cause may lie in educational principles, acceptance of a doctrine that creative use of language is inhibited by any insistence on verbal precision. Among a younger generation, the correct words for simple arithmetical operations have almost disappeared because no longer taught, so that even “divisor”, “numerator”, “product”, and “quotient” are unknown; in speech, one may hear a simple multiplication described by a non-existent verb: “I timesed [sic] 15 by 12”. A similar fate has befallen basic grammatical terms, so that “adverb” and “conjunction” cease to be recognized as elements of sentence construction. Is it mere outdated pedantry to regret these losses and object to the consequential errors?

From thalidomide to pharmacovigilance: a personal account

A more damaging source of scientific confusion, not limited to pharmacovigilant or epidemiological contexts, is the frequent miscalculation of percentages in consequence of failure to distinguish numerator and denominator, or to recognize what either quantity represents. Thus, one can find a biologist summarizing an experiment by stating: “The mean weight of the treated animals was reduced by 122%”, and I have recently read that: “Migraines affect approximately 14% of women and 7% of men; that’s one fifth of the population”. In similar vein, a newspaper reported that: “70% of what we die from is the foods we eat” and even the astounding: “Men commit suicide four times more often than women”. Anyone who cannot think more coherently than those who penned these statements would be wise to write in such a way as to avoid all mention of percentages. On any topic that involves probabilistic inferences, one can find journalists and senior scientists writing as though “chance”, “likelihood”, “odds”, “probability”, and “risk” are synonymous. In a serious report of recent medical research, I have read: “If a woman is on HRT and has one of these clotting factors, her chance of having a DVT is increased 80 times”, and elsewhere I found: “The smoking of cannabis increases by five times the risk of dy-

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ing from heart attack in middle age”. Such statements leave uncertain whether “chance” and “risk” are intended as synonyms for probability (in an unspecified population); if they are, multiplications by 80 or 5 may produce some implausible values! I do not imply that pharmacovigilantes are especially liable to the making of such errors: what is important is that they become alert to the danger that the quality of data they must interpret and the meaning of articles they read may be contaminated by adverse effects from those who report numbers ambiguously or meaninglessly. We live in a world that depends critically on numerical facts. Do we need a campaign to eliminate from science and technology the kind of faults that I have illustrated?

Acknowledgments Without the stimulus of Ralph Edwards, this essay would never have existed, but its content owes far more to Bill Inman for years of enjoyable cooperation and for his recent help in recalling important facts and names. This essay is based on a lecture given to the International Society of Pharmacology in Amsterdam, 2002.

REFERENCES 1. Nelson, A. Medical Botany. Edinburgh: E & S Livingstone Ltd, 1951. 2. Inman WHW. Don’t Tell The Patient. Los Angeles: Highland Park Publications, 1999. 3. Finney DJ. An international drug safety program. J New Drugs 1963; 3: 262–5. 4. Finney DJ. An international drug safeguard plan, J Chron Dis 1964; 17: 565–81. 5. Finney DJ. Le contrôle des medicaments et la securité des medicaments. Biométrie-Praximétrie 1964; 5: 3–19. 6. Finney DJ. The design and logic of a monitor of drug use. J Chron Dis 1965; 18: 77–98. 7. Finney DJ. A gyögyszerek pályafutasá. Gyögyszereink 1971; 21: 337–48. 8. Finney DJ. Adverse reactions to therapeutic drugs [in Japanese]. 1977; 29: 706–12. 9. Finney DJ. Theoretical objectives of international collaboration. In: Gross H, Inman WHW (editors). Drug Monitoring. London: Academic Press, 1977: 207–18.

10. Finney DJ. Problems, data, and inference. J R Stat Soc 1974; A137: 1–23. 11. Ministry of Health. Safety of Drugs: An Invitation to all Medical Practitioners. London: Her Majesty’s Stationery Office, 1964. 12. Dunne JF. The World Health Organization, In: Inman WHW (editor). Monitoring for Drug Safety. Lancaster: MTP Press, 1985: 165–72. 13. Napke R. Canada. In: Inman WHW (editor). Monitoring for Drug Safety. Lancaster: MTP Press, 1985: 59–69. 14. Finney DJ. Statistical logic in the monitoring of reactions to therapeutic drugs. Proceedings of the Fourth Conference on Probability Theory, Brasov, 1973: 91–2. 15. Finney DJ. The detection of causation of adverse events. Proceedings of the 39th Session of the International Statistical Institute, 1973; 1: 387–94. 16. Finney DJ. The vital statistics of a drug. Biomet Z 1966; 8: 15–31.

xxxii 17. Finney DJ. Monitoring adverse reactions to drugs—its logic and its weaknesses. Proc Eur Soc Study Drug Tox 1966; 7: 198–207. 18. Finney DJ. Statistical problems in detecting the late consequences of therapy. Cancer 1976; 37: 1226–32. 19. Finney DJ. Statistical aspects of pharmacoepidemiology. Drug Inf J 1996; 30: 987–90. 20. Finney DJ. Postmarketing studies: the work of the Drug Safety Research Unit. Drug Saf 1999; 21: 337–38. 21. Inman WHW, Hawson HSA, Wilton LV. Prescription event monitoring. In: Inman WHW (editor). Monitoring for Drug Safety. Lancaster: MTP Press, 1985: 213–35. 22. House of Lords Select Committee on the European Community. European Medicines Agency and Future Marketing Authorisation Procedures. London: Her Majesty’s Stationery Office, 1991. 23. Finney DJ. Statistical techniques, medicine, and computers. Trab Estadist Invest Operat 1965; 16: 43–61. 24. Finney DJ. Reporting and interpreting adversities that follow drug administration. In: Ducrot H, Goldberg M, Hoigné H, Middleton P (editors). Computer Aid to Drug Therapy and Drug Monitoring. Amsterdam: North-Holland Publishing Company, 1978: 109–14. 25. Finney DJ. Statistical aspects of monitoring for dangers in drug therapy. Methods Inf Med 1971; 10: 1–8. 26. Finney DJ. Statistical logic in the monitoring of reactions to therapeutic drugs, Methods Inf Med 1971; 10: 237–45.

David J. Finney 27. Finney DJ. Statistical aspects of monitoring systems. In: Gent M, Shigematsu I (editors). Epidemiological Issues in Reported Drug-Induced Illnesses—SMON and Other Examples. Hamilton, Ontario: McMaster University Library Press, 1978: 32–39. 28. Finney DJ. Drugs, adverse reactions, and patients. In: Gent M, Shigematsu I (editors). Epidemiological Issues in Reported Drug-Induced Illnesses—SMON and Other Examples. Hamilton, Ontario: McMaster University Library Press, 1978: 311–18. 29. Andrew JE, Prescott P, Smith TMF, Inman WHW, Kubota K. Testing for adverse reactions using Prescription Event Monitoring. Stat Med 1996; 15: 987–1002. 30. Napke E. Drug Adverse Reaction Alerting Program. Can Pharm J 1968; 29: 251–4. 31. Patwary KW. Report on Statistical Aspects of the Pilot Project for International Drug Monitoring. Geneva: World Health Organization, 1969. 32. Finney DJ. Systematic signalling of adverse reactions to drugs. Methods Inf Med 1974; 13: 1–10. 33. Finney DJ. The detection of adverse reactions to therapeutic drugs. Stat Med 1982; 1: 153–61. 34. Finney DJ. Report–Record–Detect–Interpret– Inform. In: Boström H, Ljungstedt N (editors). Detection and Prevention of Adverse Drug Reactions. Skandia International Symposia. Stockholm: Almqvist & Wiksell International, 1984: 121–32. 35. Finney DJ. Drugs and patients: thoughts on communication. Adv Drug React Bull 1976; 56: 192–5.

SIDE EFFECTS OF DRUGS ESSAY

How safe is cannabis? Leslie Iversen∗ Enthusiasm for cannabis in the 1960s and early 1970s was rapidly followed by a wave of reaction in the Western world. Extravagant warnings were issued, suggesting that cannabis was a highly dangerous drug that could cause chromosomal damage, impotence, sterility, respiratory damage, depressed immune system responses, personality changes, psychosis, and permanent brain damage (1R , 2S ). Most of these claims were later proved to be spurious, and balanced reviews (3R –5R ) have shown how effectively many of them have been demolished. Currently cannabis is widely perceived to be relatively safe. Many people believe that there are genuine medical uses for cannabis-based medicines (6R , 7R , 8RS ), and it seems likely that such products will gain official approval in several Western countries. At the same time there is a move towards relaxation of the criminal penalties associated with the recreational use of cannabis, ranging from a proposed downgrading of criminal penalties in the UK to the possibility of full legalization in Canada and Jamaica. In the light of these changes in attitude it is timely to consider again the adverse effects that are associated with the use of cannabis, since no drug can ever be considered completely safe.

Animal toxicology 9 -Tetrahydrocannabinol (THC), the active component in herbal cannabis, is very safe. Laboratory animals (rats, mice, dogs, monkeys) can tolerate doses of up to 1000 mg/kg, equivalent to some 5000 times the human intoxicant dose. Despite the widespread illicit use ∗ Leslie Iversen is Visiting Professor of Pharmacology in the University of Oxford.

of cannabis, there are very few if any instances of deaths from overdose (9R ). Long term toxicology studies with THC were carried out by the National Institute of Mental Health in the late 1960’s (10ER ). These included a 90-day study with a 30-day recovery period in both rats and monkeys and involved not only 9 -THC but also 8 -THC and a crude extract of marijuana. Doses of cannabis or cannabinoids in the range 50–500 mg/kg caused reduced food intake and lower body weight. All three substances initially depressed behavior, but later the animals became more active and were irritable or aggressive. At the end of the study the weights of the ovaries, uterus, prostate, and spleen were reduced and the weight of the adrenal glands was increased. The behavioral and organ changes were similar in monkeys, but less severe than those seen in rats. Further studies were carried out to assess the damage that might be done to the developing fetus by exposure to cannabis or cannabinoids during pregnancy. Treatment of pregnant rabbits with THC at doses up to 5 mg/kg had no effect on birth weight and did not cause any abnormalities in the offspring (10ER ). A similarly detailed toxicology study was carried out with THC by the National Institute of Environmental Health Sciences in the USA, in response to a request from the National Cancer Institute (11E ). Rats and mice were given THC up to 500 mg/kg 5 times a week for 13 weeks; some were followed for a period of recovery over 9 weeks. By the end of the study more than half of the rats treated with the highest dose (500 mg/kg) had died, but all of the remaining animals appeared to be healthy, although in both species the higher doses caused lethargy and increased aggressiveness. The THC-treated animals ate less food and their body weights were consequently significantly lower than those of untreated controls

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xxxiv at the end of the treatment period, but returned to normal during recovery. During this period the animals were sensitive to touch and some had convulsions. There was a trend towards reduced uterine and testicular weights. In further studies rats were treated with doses of THC up to 50 mg/kg and mice with up to 500 mg/kg 5 times a week for 2 years in a standard carcinogenicity test (11E ). After 2 years more treated animals had survived than controls, probably because the treated animals ate less and had lower body weights. The treated animals also had a significantly lower incidence of the various cancers normally seen in aged rodents, in testes, pancreas, pituitary gland, mammary glands, liver, and uterus. Although there was an increased incidence of precancerous changes in the thyroid gland in both species and in the mouse ovary after one dose (125 mg/kg), these changes were not doserelated. The conclusion was that there was “no evidence of carcinogenic activity of THC at doses up to 50 mg/kg”. This was also supported by the failure to detect any genetic toxicity in other tests designed to identify drugs capable of causing chromosomal damage. For example, THC was negative in the so-called “Ames test”, in which bacteria are exposed to very high concentrations of a drug to see whether it causes mutations. In another test, hamster ovary cells were exposed to high concentrations of the drug in tissue culture; there were no effects on cell division that might suggest chromosomal damage. By any standards, THC must be considered to be very safe, both acutely and during longterm exposure. This probably partly reflects the fact that cannabinoid receptors are virtually absent from those regions at the base of the brain that are responsible for such vital functions as breathing and blood pressure control. The available animal data are more than adequate to justify its approval as a human medicine, and indeed it has been approved by the FDA for certain limited therapeutic indications (generic name = dronabinol) (9R ).

Acute adverse effects of cannabis Psychoactive effects Of all the immediate actions of cannabis, its psychoactive effects are

Leslie Iversen

undoubtedly those that give the greatest concern in considering its medical uses (7R , 8RS , 10ER ). All of the CNS effects of THC, both the desired medical actions and the undesired psychological effects, appear to be mediated through a single type of brain receptor, the CB1 cannabinoid receptor. This was illustrated, for example, by a well-controlled study in 63 healthy cannabis users, who received either the CB1 receptor antagonist rimonabant (SR141716A) or placebo and smoked either a THC-containing or a placebo marijuana cigarette (12C ). Rimonabant blocked the acute psychological effects of the active cigarettes, but when given alone (with placebo cigarettes) produced no significant psychological effects. In many of the medical applications that have been assessed to date, unwanted psychological adverse effects have been blamed as the main cause of patients’ rejection of the drug as unacceptable. Patients who have had no prior experience with cannabis often find its intoxicant effects disturbing, and it can cause panic/anxiety attacks in such people. Others may simply not want to be “high” when they go about their daily work. The deleterious effects of cannabis on short-term memory and other aspects of cognition make it especially unacceptable for those whose occupation depends on an ability to remain alert and capable of handling and processing complex information. The medicinal use of cannabis often involves oral administration, but absorption is slow and erratic, leading to the risks of overdosage or underdosage. For this reason smoking is the preferred route of administration, but it carries its own hazards (see below). If improved delivery systems could be devised, it is likely that patients could titrate optimum doses of the drug to avoid some of these unwanted effects, but the therapeutic window between a medically effective dose and an intoxicant one is narrow. A possible acceptable alternative to smoking may be to give cannabis by means of a sublingual spray, and this is currently being tested in clinical trials (13S ). Psychomotor impairment CB1 receptors are expressed in particularly high densities in the basal ganglia and cerebellum, so it is not surprising that cannabinoids have complex effects on psychomotor function (14R ). One of the earliest reports of the effects of cannabis extracts in experimental animals described an awkward

How safe is cannabis?

swaying and rolling gait in dogs, with periods of intense activity provoked by tactile or auditory stimuli, and followed eventually by catalepsy and sleep (15E ). In mice a “popcorn effect” was described: the animals are sedated by THC but will jump in response to auditory or tactile stimuli; as they fall into other animals these in turn jump, resembling popping corn (16R ). These effects of cannabinoids may be due in part to actions at cerebellar or striatal receptors. Tests of specific cerebellar functions have shown that cannabinoids increased gait width and the number of slips on a bar cross test (17E ). Rotorod impairments were also reported in mice after direct injection of synthetic cannabinoids into the cerebellum, but not in animals pretreated with cerebellar injections of an antisense oligonucleotide directed at a sequence in the CB1 receptor (18E ). In humans cannabis caused impaired performance in tests of balance (19E ) or tests that require fine psychomotor control, for example tracking a moving point of light on a screen (20E ). Human cannabis users may also seek isolation and remain immobile for long periods (21R ). Because psychomotor skills are impaired by cannabis intoxication, it is inadvisable for users to drive for some hours after taking the drug, and the ability to carry out any tasks that require manual dexterity is likely to be impaired. Druginduced impairment of balance could also make elderly patients more likely to fall. A comparison of 452 marijuana smokers with a similar number of non-smokers attending the Kaiser Permanente Health Group in California showed that the marijuana smokers had an increased risk of attending out-patient clinics with injuries of various types, perhaps as a result of the acute intoxicant effects of the drug (22C ). Effects on memory One of the well-established effects of acute intoxication with cannabis in man is impairment of short-term memory (21R , 23R –25R ). Many studies have shown significant effects on short-term memory, particularly when tests were used that depend heavily on attention (26E , 27R ). In animals THC, synthetic cannabinoids, and anandamide cause deficits in short-term memory in spatial learning tasks (28ER ). These include delayed matching or non-matching tests in rodents (29E , 30E ), performance in a maze (31E ,

xxxv 32E ), and a fixed-ratio food acquisition task in squirrel monkeys (33E ). The effects of both cannabinoids (32E ) and anandamide (30E ) were reversed by rimonabant, showing that they are mediated by the CB1 receptor. A likely site for these effects is the hippocampus: the effects of cannabinoids on shortterm memory in rats were the same as the effects seen after surgical removal of the hippocampus (29E ). In each case the animals were unable to segregate information between trials in the task because of disruptions to the processing of sensory information in hippocampal circuits. CB1 receptors are expressed in high density in the hippocampus (34E , 35E ) and the mechanisms underlying synaptic plasticity have been studied more intensely in the hippocampus than in any other brain region. In particular the electrophysiological phenomena of longterm potentiation and long-term depression are thought to be involved in memory formation at glutamatergic synapses in the hippocampus. Several studies have shown that cannabinoids inhibit the induction of both long-term potentiation and depression (36R ). Cannabinoids appear to work by reducing glutamate release below the level needed to activate NMDA receptors, a requirement for long-term potentiation and depression (37E , 38E ). Effects on other cognitive functions Like other intoxicant drugs, cannabis causes profound changes in a variety of higher brain functions (9R , 21R , 23R , 25R ). The distribution of CB1 receptors in the neocortex has been described in detail (39E , 40E ). The earlier literature contained several reports of the effects of acute and chronic cannabis use on EEG activity, both in animals (16R ) and man (25R ). Most studies in man have shown EEG changes consistent with a state of drowsiness, with increases in relative and absolute alpha power, particularly in the frontal cortex. In contrast, the CB1 antagonist rimonabant caused EEG changes characteristic of arousal in rats and increased the time spent in wakefulness as opposed to sleep (41E ). There have been many studies of the acute and chronic effects of cannabis on human cognitive function (21R , 23R , 25R ). Performance in a variety of tests is impaired, but by comparison with alcohol the effects of cannabis are subtle. Whereas even moderate doses of alcohol impair

xxxvi reaction time, most studies of cannabis have failed to show consistent effects. Therefore, abnormal cognitive function due to cannabis cannot be due to an inability to respond promptly. Among the types of impairment of cognitive function that have been observed in many, but not all, human studies are: a reduced ability to inhibit responses, impaired vigilance, especially for long and boring tasks, reduced ability to perform complex mental arithmetic, and impairment in tests of complex reaction times. On the other hand, intoxicated subjects can perform simple arithmetic, learn simple lists of words, and recall memories laid down earlier (21R ). Cardiovascular effects Cannabis has profound effects on the cardiovascular system. In inexperienced users it can cause a large increase in heart rate (up to a doubling) and this could be harmful to someone with a previous history of coronary artery disease or heart failure (3R , 4R , 9R ). Such patients should therefore be excluded from clinical trials of cannabis-based medicines. The postural hypotension that can be caused by cannabis could also be distressing or possibly dangerous. These cardiovascular effects usually show rapid tolerance on repeated exposure to cannabis, so for healthy subjects they are not of concern.

Effects of long-term exposure to cannabis Is cannabis neurotoxic? Although there have been claims that chronic cannabis use can permanently damage the brain, there is little scientific evidence to support this (3R , 4R , 5R , 42R ). Some studies have shown modest impairment of the ability to focus attention and filter out irrelevant information in ex-cannabis users (25R ), but other studies have failed to show any long-term impairment in cognitive function (43E ). There is little evidence that cannabis impairs work performance or leads to an “amotivational syndrome” (3R , 42R , 44R ). Nor is there any convincing evidence for neuropathological changes in the brains of cannabis users (3R ). The earlier studies have been complemented by the application of powerful modern neuroimaging methods. For example, in an MRI imaging study 18 current, young adult, frequent

Leslie Iversen

cannabis users were compared with 13 comparable non-users; there was no evidence of cerebral atrophy or regional changes in tissue volumes (45c ). Animal studies have yielded conflicting results. Treatment of rats with high doses of THC given orally for 3 months (46E ) or subcutaneously for 8 months (47E ) produced neural damage in the hippocampal CA3 zone, with shrunken neurons, reduced synaptic density, and loss of cells. But in perhaps the most severe test of all, rats and mice treated on 5 days each week for 2 years had no histopathological changes in the brain, even after 50 mg/kg/day (rats) or 250 mg/kg/day (mice) (11E ). Although claims were made that exposure of a small number of rhesus monkeys to cannabis smoke led to ultrastructural changes in the septum and hippocampus (48E , 49E ), subsequent larger-scale studies failed to show any cannabis-induced histopathology in monkey brain (50E ). Studies of the effects of cannabinoids on neurons in vitro have also yielded inconsistent results. Exposure of rat cortical neurons to THC shortened their survival: twice as many cells were dead after exposure to THC 5 µmol/l for 2 h than in control cultures (51E ). Concentrations of THC as low as 0.1 µmol/l had a significant effect. The effects of THC were accompanied by release of cytochrome c, activation of caspase-3, and DNA fragmentation, suggesting an apoptotic mechanism. All of the effects of THC could be blocked by the antagonist AM-251 or by pertussis toxin, suggesting that they were mediated through CB1 receptors. Toxic effects of THC have also been reported in hippocampal neurons in culture, with 50% cell death after exposure to THC 10 µmol/l for 2 h or 1 µmol/l for 5 days (52E ). The antagonist rimonabant blocked these effects, but pertussis toxin did not. The authors proposed a toxic mechanism involving arachidonic acid release and the formation of free radicals. On the other hand, other authors have failed to observe any damage in rat cortical neurons exposed for up to 15 days to THC 1 µmol/l, although they found that this concentration killed rat C6 glioma cells, human astrocytoma U373MG cells, and mouse neuroblastoma N18TG12 cells (53E ). In a remarkable study, injection of THC into solid tumors of C6 glioma in rodent brain led to increased survival times, and there was complete eradication of the tumors in 20–35% of

How safe is cannabis?

the treated animals (54E ). A stable analogue of anandamide also produced a drastic reduction in the tumor volume of a rat thyroid epithelial cell line transformed by K-ras oncogene, implanted in nude mice (55E ). The antiproliferative effect of cannabinoids has suggested a potential use for such drugs in cancer treatment (56R ). Some authors have reported neuroprotective actions of cannabinoids. WIN55,212-2 reduced cerebral damage in rat hippocampus or cerebral cortex after global ischemia or focal ischemia in vivo (57E ). The endocannabinoid 2AG protected against damage elicited by closed head injury in mouse brain, and the protective effects were blocked by rimonabant (58E ). THC had a similar effect in vivo in protecting against damage elicited by ouabain (59E ). Rat hippocampal neurons in tissue culture were protected against glutamate-mediated damage by low concentrations of WIN55,212-2 or CP-55,940, and these effects were mediated through CB1 receptors (60E ). But not all of these effects seem to require mediation by cannabinoid receptors. The protective effects of WIN55,212-2 did not require either CB1 or CB2 cannabinoid receptors in cortical neurons exposed to hypoxia (57E ), and there were similar findings for the protective actions of anandamide and 2-AG in cortical neuronal cultures (61E ). Both THC and cannabidiol, which is not active at cannabinoid receptors, protected rat cortical neurons against glutamate toxicity (62E ) and these effects were also independent of CB1 receptors. The authors suggested that the protective effects of THC might be due to the antioxidant properties of these polyphenolic molecules, which have redox potentials higher than those of known antioxidants (e.g. ascorbic acid). The mixed reports of neurotoxic and neuroprotective effects of cannabinoids are confusing. While it may be possible to show neurotoxic actions after exposure of neurons to high concentrations of cannabinoids in vitro, there is little evidence for any significant neural damage in vivo after the administration of pharmacologically relevant doses. Cannabis and psychiatric illness There is a long-standing concern that the use of cannabis might precipitate mental illness in some users. There was a lively correspondence in the columns of the British Medical Journal in 1893,

xxxvii for example, as to whether or not the endemic use of hashish in Egypt led to mania and insanity (63r –68r ). There was also concern that the mental asylums in British India were filling with cannabis-induced lunatics, and this was one of the factors that led the British Government to appoint the Indian Hemp Drugs Commission. The Commission undertook a large and painstaking review and concluded that there were virtually no patients in the Indian asylums whose illness could be attributed to cannabis use (69RS ). However, the Commission’s findings were not widely noted, and claims of a relation between cannabis use and insanity continued to be made in India and many other countries. Claims that cannabis causes insanity were used by early advocates of marijuana prohibition in the USA. A temporary form of drug-induced psychosis can occur in some cannabis users. In some of the psychiatric literature this is referred to as “cannabis psychosis” (or “marijuana psychosis”) (21R ). Research psychiatrists, particularly in Britain, have carefully studied this condition (70R –72R ). It nearly always results from taking large doses of the drug, often in food or drink, and may persist for some time, perhaps as the accumulated body load of THC is washed out. The acute toxic psychosis that is sometimes caused by cannabis can be sufficiently serious to lead to hospital admission, and the initial diagnosis can be confused with schizophrenia, with delusions of control, grandiose identity, persecution, thought insertion, auditory hallucinations, changed perception, and blunting of emotions. Not all of these symptoms will occur in every patient, but there can be a considerable similarity to paranoid schizophrenia. This has led some to propose a “cannabinoid hypothesis of schizophrenia”, suggesting that the symptoms of schizophrenic illness might be caused by abnormal overactivity of endogenous cannabinoid mechanisms in the brain (73R ). Several studies have addressed the more contentious question of whether cannabis can precipitate long-term psychiatric illness. The strongest evidence seemed to come from a Swedish study with detailed medical records and information about the social background and drug-taking habits of 45 570 conscripts on entry to the Swedish army at age 18 years and follow-up of their subsequent medical history over 15 years (74C ). A total of 4293 of the

xxxviii conscripts admitted having taken cannabis at least once, but the cannabis users accounted for a disproportionate number of the 246 cases of schizophrenic illness diagnosed in the overall group on follow-up. The relative risk of schizophrenia in those who had used cannabis was 2.4 times greater than in the non-users. And in the small number of heavy users (who had taken the drug on more than 50 occasions) the relative risk of schizophrenia increased to 6.0. The authors concluded that cannabis was an independent risk factor for schizophrenia. There have been other similar reports (71R , 72R , 75R ). Of 232 patients in Germany with first-episode schizophrenia, 13% had a history of cannabis use, a rate twice that of matched healthy controls (76C ). At first sight these findings seem convincing, but they do not prove a cause-and-effect relation with cannabis. It may be that both cannabis use and schizophrenia are related to some common predisposing factor, such as personality. Indeed, some psychologists and psychiatrists believe that they can identify psychological traits that are described as “schizotypy” and may predict an increased risk of clinical psychosis. Some studies in healthy adults have shown that those users of cannabis scored higher on schizotypy scales than non-users (77C , 78C ). Half of the cannabis-users in the original Swedish study (74C ) had used cannabis more than 10 times, and those who subsequently developed schizophrenia had also taken amphetamine, which can cause a schizophreniform psychosis. The cannabis users also came from deprived social backgrounds, another known risk factor for schizophrenia. However, in a more detailed follow-up of some of the original Swedish cohort the authors claimed to have answered some of these criticisms and denied that other drug use or premorbid psychosis could have explained the data (79C , 80C ). In addition, longitudinal studies of large cohorts of young people in New Zealand have added weight to the hypothesis that cannabis dependence is associated with increased rates of psychiatric symptoms, although these were described as “schizophrenia symptoms” or “schizophreniform disorder” rather than schizophrenic illness (81C , 82C ). An Australian study further suggested a relation between heavy cannabis use in adolescents and the subsequent development of symptoms of depression and anxiety, which was particularly marked in adolescent girls (83C ).

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Nevertheless, a causative relation between cannabis use and long-term psychotic illness remains unproven. If cannabis did precipitate schizophrenia one might expect to have seen a large increase in the numbers of sufferers from this illness as cannabis use became more common in the West during the past 30 years. However, a detailed review of the epidemiological evidence up to 1990 has shown that this has not been the case (84R ). But a more recent survey in South-East London showed that there has been a progressive increase in the incidence of schizophrenia (as defined by DSM-III diagnostic criteria) over the period 1965–1997, with more than a doubling over the past three decades, particularly in people under 35 years of age (85C ). Although the question of whether cannabis can cause mental illness remains open, it is clear that it can exacerbate the symptoms of existing psychotic illness. While schizophrenic patients seem to use cannabis and other psychoactive drugs as a form of “self-medication”, cannabis can make the key symptoms of delusions and hallucinations worse, and it tends to counteract the antipsychotic effects of the drugs used to treat the illness (86C , 87C ). On the other hand, in one Swedish study cannabis made schizophrenic patients less withdrawn and more likely to speak (88E ). It would be prudent, nevertheless, to discourage the use of cannabis in patients with existing psychotic illness. Cognitive functions Several studies have addressed the question of whether more severe deficits in cognitive function develop in chronic heavy users of cannabis, or in animals treated for prolonged periods. The human studies are fraught with difficulties (21R ). For example, comparisons have to be made between groups of users and non-users, but it is usually impossible to compare the baseline performances of these groups before cannabis use to see if they are properly matched. Statistical analysis of such data has often been poor, common errors being the use of so many different tests that the likelihood of finding some significant differences is increased, or the use of inadequate sample sizes. Other drug use can also confound the data. Results have been very variable. Some studies in very heavy long-term users of cannabis (10–20 joints/day for more than 10 years) in Jamaica (89C ), and Costa Rica

How safe is cannabis?

(90C ) failed to show any significant difference between users and non-users with a battery of tests of cognitive function, and similar negative results were reported in some studies of US college students (21R ). However, most studies have shown deficits in the performance of complex cognitive tasks in long-term cannabis users, although there is little evidence that these are qualitatively or quantitatively more severe than those seen after acute drug use (21R ). Even more controversial is the question of whether long-term cannabis use can cause irreversible deficits in higher brain function, which persist after drug withdrawal. Many studies have been poorly designed. It is not sufficient to identify a group of cannabis users and test them after withdrawing cannabis. One study, for example, involved 63 current heavy users who had smoked cannabis at least 5000 times in their lives and 72 control subjects (43E ). The subjects underwent a 28-day washout from cannabis use, monitored by urine assays. On days 0, 1, and 7 the heavy users scored significantly less than control subjects on a battery of neuropsychological tests, particularly word recall. However, by day 28 there were virtually no differences between the groups and no significant association between cumulative lifetime cannabis use and test scores. The fact that drug-induced effects on cognitive performance can persist for up to 1 week after withdrawal (perhaps because of the persistence of THC in the body, or because of a subtle withdrawal syndrome) means that many earlier studies that did not allow a sufficiently long washout period may have been invalid. On the other hand, some well-designed studies have shown subtle persistent cognitive deficits in ex-cannabis users. For example, 36 people who had used cannabis regularly for at least 5 years but who had stopped on average 2 years before the experiment were given a very difficult task: they had to listen to a series of tones (some in the right ear some in the left), either long or short (but differing by only 51 ms), and high or low pitch (but differing very little) they had to press a button as fast as possible in response to longer tones of a specified pitch in the correct ear (25R ). Previous research using this paradigm had shown that current regular cannabis users had difficulty in discriminating between tones of this sort. Measurements of event-related potentials also showed small but significant abnormalities in the P300 wave. The

xxxix ex-users continued to make significant errors in the discrimination task, but they had normal P300 waves. The conclusion of these and many other studies in ex-users seems to be that regular cannabis use can cause a small but significant degree of impairment in cognitive function, which may persist after drug withdrawal. Such impairment appears to be associated with longterm heavy use and is unlikely to affect most recreational users. Tolerance and dependence Many animal studies have shown that tolerance develops to most of the behavioral and physiological effects of THC (91R ). Earlier clinical reports also suggested that tolerance occurs after repeated administration of THC in man, although many of these studies were poorly controlled (3R , 23R , 92R ). But for many years cannabis was not considered to be a drug of addiction. Withdrawal did not lead to any obvious physical withdrawal symptoms, either in people or in animals, and animals failed to self-administer the drug, a behavior that is usually associated with drugs of dependence. Attitudes have changed markedly in recent years. The DSM-IV diagnostic manual defines “substance dependence” and “substance abuse” rather than “addiction” (93S ). When the DSMIV criteria are applied to populations of regular cannabis users, surprisingly high proportions appear to be positive by these definitions. In a survey of 10 641 Australians aged 18 years and over almost one-third of regular cannabis users fell within the definitions of “substance abuse” (11%) or “substance dependence” (21%) (94C ). A large-scale survey in the USA showed that some 46% of those interviewed had ever used cannabis and that 9% of such users became dependent (95C ). More carefully controlled studies have shown that a reliable and clinically significant withdrawal syndrome does occur in human cannabis users. The symptoms include craving for cannabis, reduced appetite, difficulty in sleeping, and weight loss; anger, aggression, increased irritability, restlessness, and strange dreams also sometimes occur (96C ). Dependence on cannabinoids in animals is also much more clearly observable, because of the availability of CB1 receptor antagonists, which can be used to precipitate withdrawal. Thus, a behavioral withdrawal syndrome was precipitated by rimonabant in rats treated for

xl only 4 days with THC in doses as low as 0.5–4.0 mg/kg/day (97E ). The syndrome included scratching, face rubbing, licking, wet dog shakes, arched back, and ptosis, many of the signs that are seen in rats undergoing opiate withdrawal. Similar withdrawal signs occurred when rats treated chronically with the synthetic cannabinoid CP-55,940 were given rimonabant (98E ). Rimonabant-induced withdrawal after 2 weeks of treatment of rats with the cannabinoid HU-120 was accompanied by a marked increase in release of the stress-related neuropeptide corticotropin-releasing factor in the amygdala, a result that also occurred in animals undergoing heroin withdrawal (99E ). An electrophysiological study showed that precipitated withdrawal was also associated with reduced firing of dopamine neurons in the ventral tegmental area of rat brain (100E ). These data clearly show that chronic administration of cannabinoids leads to adaptive changes in the brain, some of which are similar to those seen with other drugs of dependence. The ability of THC to cause selective release of dopamine from the nucleus accumbens (101E ) also suggests some similarity between THC and other drugs in this category. Furthermore, although many earlier attempts to obtain reliable self-administration behavior with THC were unsuccessful (91R ), some success has been obtained recently. Squirrel monkeys were trained to self-administer low doses of THC (2 µg/kg per injection), but only after the animals had first been trained to selfadminister cocaine (102E ). THC is difficult to give intravenously, but these authors succeeded, perhaps in part because they used doses comparable to those to which human cannabis users are exposed, and because the potent synthetic cannabinoids are far more water-soluble than THC, which makes intravenous administration easier. Mice could be trained to self-administer intravenous WIN55,212-2, but CB1 receptor knockout animals could not (103E ). Another way of demonstrating the rewarding effects of drugs in animals is the conditioned place preference paradigm, in which an animal learns to approach an environment in which it has previously received a rewarding stimulus. Rats had a positive THC place preference after doses as low as 1 mg/kg (104E ). Some studies have suggested that there may be links between the development of dependence to cannabinoids and to opiates (105E ).

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Some of the behavioral signs of rimonabantinduced withdrawal in THC-treated rats can be mimicked by the opiate antagonist naloxone (106E ). Conversely, the withdrawal syndrome precipitated by naloxone in morphinedependent mice can be partly relieved by THC (107E ) or endocannabinoids (108E ). Rats treated chronically with the cannabinoid WIN55,212-2 became sensitized to the behavioral effects of heroin (109E ). Such interactions can also be demonstrated acutely. Synergy between cannabinoids and opiate analgesics has been described above. THC also facilitated the antinociceptive effects of RB 101, an inhibitor of enkephalin inactivation, and acute administration of THC caused increased release of Met-enkephalin into microdialysis probes placed into the rat nucleus accumbens (110E ). The availability of receptor knockout animals has also helped to illustrate cannabinoid/opioid interactions. CB1 receptor knockout mice had greatly reduced morphine self-administration behavior and less severe naloxone-induced withdrawal signs than wild type animals, although the antinociceptive actions of morphine were unaffected in the knockout animals (103E ). The rimonabantprecipitated withdrawal syndrome in THCtreated mice was significantly attenuated in animals with knockout of the pro-enkephalin gene (111E ). Knockout of the µ-opioid receptor also reduced rimonabant-induced withdrawal signs in THC-treated mice, and there was an attenuated naloxone withdrawal syndrome in morphine-dependent CB1 knockout mice (112E , 113E ). These findings clearly point to interactions between the endogenous cannabinoid and opioid systems in the CNS, although the neuronal circuitry involved is unknown. Whether this is relevant to the so-called “gateway” theory is unclear. In the US National Household survey of Drug Abuse respondents aged 22 years or over who had started to use cannabis before the age of 21 years were 24 times more likely than non-cannabis users to begin using hard drugs (114C ). However, in the same survey the proportion of cannabis users who progressed to heroin or cocaine use was very small (2% or less). Mathematical modelling using the Monte Carlo method suggested that the association between cannabis use and hard drug use need not be causal, but could relate to some common

xli

How safe is cannabis?

predisposing factor, e.g. “drug-use propensity” (115E ). Cannabis in pregnancy In animals THC can cause spontaneous abortion, low birth weight, and physical deformities (5R ). However, these were only seen after treatment with extremely high doses of THC (50–150 times higher than human doses), and only in rodents and not in monkeys. In most studies in which babies born to women who had used marijuana during pregnancy were compared with the babies of women who had not there were no significant differences, but some differences are likely to occur by chance and small differences have been reported in some studies (5R , 21R ). There is a tendency towards a shorter gestation period and smaller birth weight in babies born to mothers who have used marijuana. However, although there was a significantly lower birth weight in the largest such study (involving 12 424 births), when other factors were taken into account (for example, tobacco smoking) there was no relation between marijuana use and low birth weight (116C ). Similarly, there was only a nonsignificant trend towards a higher incidence of birth abnormalities in the marijuana-exposed babies in the same study. If marijuana smoking does cause a reduction in birth weight, this may be to be due to the presence of carbon monoxide in marijuana smoke, as has been suggested for tobacco smoking, although this is speculative. Several studies have examined the development of children born to mothers who were exposed to marijuana during pregnancy, to see whether there were any abnormalities in physical or mental development. While the results of most of these investigations were negative, the few instances in which subtle abnormalities could be detected in subsets of the IQ scale have been used as evidence that marijuana can impair children’s cognitive development. In one of the largest studies of this kind, the Ottowa Prenatal Prospective Study, children whose mothers were exposed to marijuana for the first years of their life were given hundreds of different psychological tests, but there were very few differences between the marijuana-exposed and non-exposed groups (117R ). The investigators, who appeared to be convinced that there must be some abnormalities, tried a new series of cognitive tests when the children were

6 years old, and claimed to have found deficits in frontal lobe “executive” functions. However, the differences in the babies born to mothers who used marijuana were relatively minor by comparison with the consistent cognitive deficits observed in children of all ages born to mothers who had been heavy cigarette smokers during pregnancy.

Special hazards of smoked cannabis Traditionally the use of cannabis both in Oriental and Western medicine involved taking the drug by mouth, but most current use in the West involves the inhalation of cannabis smoke. Unfortunately, although smoking is a remarkably efficient means of delivering an accurately gauged dose of THC it also carries special hazards. Although THC itself appears to be relatively safe, the same cannot be said of marijuana smoke. Cannabis smoke and smoking behavior Although there has been relatively little research on the effects of cannabis smoke, a great deal is known about the toxic components in tobacco smoke and their biological effects. Cannabis smoke is very similar in chemical composition to tobacco smoke, so it is not unreasonable to suggest that our knowledge of the dangers of tobacco can provide useful predictions about the hazards of smoking cannabis. Both cannabis and tobacco smoke contain carbon monoxide and a number of toxic chemicals, several of which are carcinogenic. Two of the most potent carcinogens in tobacco smoke, benzanthracene and benzpyrene, are also present in cannabis smoke (3R , 118R ). The way in which experienced users smoke cannabis tends to enhance the potential dangers of taking the drug by this route. Cannabis smokers usually inhale more deeply than tobacco smokers and tend to hold their breath, in the belief that this increases the absorption of THC by the lungs. The results of these differences in smoking behavior are profound. In a study of the amounts of particulate matter (tar) and carbon monoxide absorbed in 15 volunteers who were regular tobacco and cannabis smokers, smoking cannabis resulted in a fivefold

xlii greater absorption of carbon monoxide than tobacco and 4–5 times more tar was retained in the lungs (119E ). Effects of cannabis smoke on the lungs Since tobacco smoking is known to be the most important cause of chronic obstructive lung disease and lung cancer, it is reasonable to be concerned about the adverse effects of cannabis smoke on the lungs. There have been several attempts to address this question by exposing laboratory animals to cannabis smoke. After such exposure on a daily basis for periods of up to 30 months, extensive damage has been observed in the lungs of rats (120E ), dogs (121E ), and monkeys (122E ), but it is very difficult to extrapolate these findings to man, as it is difficult or impossible to imitate human exposure to cannabis smoke in any animal model. The various studies that have been undertaken in human cannabis smokers seem to be far more relevant, although here the problem is confounded by the fact that many cannabis smokers take the drug with tobacco, making it difficult to disentangle the effects of the two agents. In 144 volunteers who were heavy smokers of cannabis only, 135 who smoked tobacco and cannabis, 70 smokers of tobacco only, and 97 non-smokers, about 20% of both tobacco smokers and cannabis smokers reported the symptoms of chronic bronchitis (chronic cough and phlegm production), even though the cannabis smokers consumed only 3–4 joints a day compared with over 20 cigarettes for the tobacco smokers (123C , 124R ). There were no additive effects in those who smoked both cannabis and tobacco, although additive effects have been reported in other studies of this type. Lung function in the tobacco smokers continued to get worse over 10 years, particularly in the small airways, making them more liable to develop chronic obstructive lung disease later in life (125C ). However, there was no such decline in the cannabis smokers, suggesting that they may be less likely to develop such diseases as emphysema through smoking. At the Kaiser Permanente Health Care Group in California, 452 “daily” cannabis smokers who had never smoked tobacco were compared with 450 non-smokers of either substance; the cannabis smokers had a small increase in the number of out-patient visits for respiratory illness (RR = 1.19; 95% CI = 1.01, 1.41) (22C ).

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In volunteers who were subjected to a saline rinse of their lungs in order to sample the population of white blood cells present, about 2–3 times more macrophages were collected from the lungs of tobacco or cannabis smokers versus non-smokers, suggesting the presence of an inflammatory response (125C , 126C ). The macrophages from both tobacco smokers and cannabis smokers also had significantly impaired ability to kill and engulf yeasts (Candida albicans) or bacteria (Staphylococcus aureus). The macrophages from smokers were also less able to generate some of the chemical toxins (e.g. superoxides) that they normally use to kill invading micro-organisms, or the cytokines that help to activate further inflammatory and immune system responses (126C ). In addition, the macrophages had impaired ability to attack and kill cancer cells (small cell cancers) in vitro. The depressed immune function may be caused by an interaction of THC with the CB2 receptors present on macrophages (126C ). These findings suggest that, like tobacco smokers, cannabis smokers are likely to be more susceptible to respiratory tract infections and possibly less able to defend themselves against the development of lung cancers. An added complication is that some batches of herbal cannabis may be contaminated with fungi (e.g. Aspergillus spp) that could themselves cause lung infections. This could be a particular hazard to patients with AIDS. Cannabis smoking and cancer THC does not appear to be carcinogenic, but there is plenty of evidence that the tar derived from cannabis smoke is. Bacteria exposed to cannabis tar develop mutations in the standard Ames test for carcinogenicity (127E ), and hamster lung cells in tissue culture develop accelerated malignant transformations within 3–6 months of exposure to tobacco or cannabis smoke (128E ). But is there any evidence that this happens in the lungs of cannabis smokers? Bronchoscopic examination of the large airways showed that a large proportion of both cannabis and tobacco smokers had evidence of increased redness and swelling and increased mucus production relative to non-smokers (124R , 125C , 126C ). Biopsies taken from the lining of the airways showed abnormal cell changes in both cannabis and tobacco smokers. These included abnormal proliferation of

How safe is cannabis?

mucus-producing cells and a reduced number of ciliated cells. These changes could explain the chronic cough and overproduction of phlegm reported by tobacco and cannabis smokers. A more sinister observation was the presence of abnormal cells resembling those normally seen in skin (squamous metaplasia) in the lungs of smokers. These changes are thought to represent premalignant precursors. There were even more possible premalignant cells in the lungs of volunteers who smoked both cannabis and tobacco. In lung biopsies from cannabis and tobacco smokers there was evidence of overexpression of genes that control receptors for epidermal growth factor and a nuclear proliferation protein responsible for cell division known as KI-67 in the lungs of smokers (125C , 126C ). Bronchial biopsies from cannabis smokers also showed evidence of overexpression of the enzyme CYP1A1 (125C ), which plays a key role in converting the benz[a]pyrene present in tobacco smoke into a very potent carcinogen. However, the P53 oncogene, which plays a role in 75% of lung cancers, was not activated, except in a single subject who was a combined cannabis and tobacco smoker. These changes may indicate that precancerous changes take place in the lungs of cannabis smokers, similar to those that occur in tobacco smokers, the end result of which may be to increase the likelihood of lung cancer. One of the reasons why we should be seriously concerned about the possible link between cannabis smoking and lung cancer is that it could take a very long time for such a relation to become manifest. Cigarette smoking became common among men in the developed world during the first decades of this century, but it was not until 30–40 years later that the first evidence of a link between tobacco smoking and lung cancer was obtained. Even though cigarette consumption has fallen significantly in many developed countries, deaths from tobacco-related diseases will continue to rise for many years to come, particularly among women, who did not commonly smoke cigarettes until the 1930s or 1940s. The relation between cigarette smoking and lung cancer is very complex. The increased risk of lung cancer depends far more strongly on the duration of cigarette smoking than on the number of cigarettes consumed each day (129CR ). Thus, while smoking three times as many cigarettes a day does increase the lung cancer risk

xliii about threefold, smoking for 30 years as opposed to smoking for 15 years does not simply double the lung cancer risk, it increases it 20fold, and smoking for 45 years as opposed to 15 years increases the risk 100-fold. The reasons underlying the relation between the duration of tobacco smoking and the development of lung cancer are unknown, but they are likely to apply to cannabis smokers as well. Since the widespread use of cannabis as a recreational drug is a fairly recent development in the West, large numbers of people have not yet been exposed to cannabis smoke for long enough for any link to become clear. The following comments on tobacco smoking (129CR ) could well apply also to cannabis: “Among regular cigarette smokers, the excess lung cancer risk depends strongly not only on smoking habits during the past few years, but also on smoking habits during early adult life. Hence, current lung cancer rates in countries where smoking among young adults became widespread less than half a century ago may be serious underestimates of the eventual magnitude of the tobaccoinduced lung cancer hazard.”

One of the few large-scale studies of the health consequences of cannabis smoking was reported in 65 171 men and women undergoing health checks at the Kaiser Permanente Health Care Organization in California between 1979 and 1985 (130C ). The health of these subjects was then followed for an average of a further 10 years. Nearly 27 000 people admitted to being either current or former cannabis users (defined as ever having smoked more than six times). Over the period of the study 182 tobaccorelated cancers were detected, of which 97 were lung malignancies. There were no effects of former or current cannabis use on the risks of any cancers. However, although this study involved large numbers, almost all of the cannabis smokers were young (15–39 years) and the follow-up period was relatively short. Such a study could not have been expected to detect any relation between cannabis and lung cancer if the lag time were comparable to that seen with tobacco. It may not be possible to answer the question of a link between cannabis smoking and lung cancer for another decade or more. Although the added risk of lung cancer that cigarette smoking confers does not go away, the risk becomes much greater with increased duration of exposure, so that those who give

xliv up gain a disproportionate benefit. British doctors who gave up smoking before the age of 35 years had a pattern of survival that did not differ significantly from non-smokers (131C ). Those who gave up at later ages had a survival pattern that was intermediate between continuing smokers and non-smokers. The relevance of this to cannabis smokers is clear. Several surveys have shown that most cannabis smokers are in their teens or twenties and that they tend to give up the habit when they reach their thirties. If the pattern is similar to that seen with tobacco smoking, their risk of developing lung cancer later in life may not be significantly increased. On the other hand, some surveys of current cannabis use have shown that more and more people are continuing to smoke throughout their lives, so the pattern of giving up in mid-life may not hold in the future. Another factor to consider is how much tar cannabis smokers are exposed to compared with cigarette smokers. Although cannabis smokers on average consume no more than 3–4 joints a day, in contrast to the 15–20 cigarettes commonly consumed by tobacco users, each joint is liable to deposit 4–5 times more tar in the lungs than a tobacco cigarette (119E ). Tar exposure is thus similar, except for the large numbers who smoke cannabis with tobacco, for whom the hazards are compounded. When experienced users are given cannabis cigarettes containing different amounts of THC, they adjust their smoking behavior to obtain a similar dose of THC, while depositing less tar in the lungs (132C ). This might paradoxically be an argument in favor of the use of higher THC potency strains of herbal cannabis, which are now increasingly available. At the moment the jury is out on the link between cannabis and cancer, although there has been some concern about reports of an increased number of cancers of the head and neck in young people with a history of heavy cannabis use (63c –68r , 133C ). However, these reports are based on small numbers, and no cause-and-effect relation has been established.

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Conclusions The medical and recreational uses of cannabis are associated with some adverse effects. While the acute toxicity of cannabis is low, longterm use is associated with cognitive impairment and can lead to dependence in a proportion of regular users. The medical uses of cannabis are complicated by the narrow therapeutic window between the desired effects and intoxication. Smoking cannabis involves the additional risks of chronic lung damage and possibly cancer. The adverse effects of cannabis are not sufficient to limit possible medical uses. But the recreational use of cannabis, although less dangerous than heroin or cocaine, carries some risks that should inform public debate on changes to the drug laws. What place, if any, should smoked cannabis have in modern medicine? Because of the potential hazards of chronic respiratory disease and cancer, it is unlikely that smoked cannabis could ever be recommended for the long-term treatment of any illness in which its use might need to be continued on a regular basis for many years. However, the principal groups that currently smoke cannabis consist mainly of patients with life-threatening illnesses. Patients with AIDS, cancer, or multiple sclerosis have a considerably reduced life-expectancy, and it could plausibly be argued that the long-term health risks of smoking cannabis are of little relevance to them. If their illness does not respond to conventional medicine, and their doctor has agreed that smoked cannabis might be beneficial, why should the law stand in their way? The authors of the influential US Institute of Medicine report concluded that although smoked cannabis should generally not be recommended for long-term use, there were certain patients for whom short-term use could be justified (7R ). A similar conclusion was reached by the UK House of Lords enquiry into cannabis (8RS ).

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Reginald P. Sequeira

1

Central nervous system stimulants and drugs that suppress appetite

METHYLXANTHINES

(SED-14, 1; SEDA-23, 1; SEDA-24, 1; SEDA-25, 1)

Caffeine Cardiovascular Guarana is produced from the guarana plant (Paullina cupana), the seeds of which contain 3.6–5.8% caffeine. • A 25-year-old woman, who had pre-existing mitral valve prolapse and a history of having had bouts of palpitation with caffeine, developed intractable ventricular fibrillation after consuming a “natural energy” guarana health drink containing a high concentration of caffeine (1A ). At autopsy, she was found to have sclerosis and myxoid changes in the mitral valve leaflets. The caffeine concentration in her aortic blood was 19 mg/l.

This case highlights the need for more careful regulation of “natural” products, including warning for patients with underlying health problems, and clear labeling to document the presence of any constituents with potentially toxic effects. It also shows the need for medical practitioners to be familiar with the more widely used “natural remedies” and their toxicological profiles. Following the death of this patient, the Western Australian Coroner recommended that Race 2005 Energy Blast should be removed from the local market, and the product was recalled nationally in August 1999. Nervous system Red Bull, a widely consumed “power drink”, a mixture of caffeine, taurine, and inositol, affects mental performance and mood. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

• A 36-year-old man with bipolar I disorder had a second manic episode, after having been in remission for 5 years while taking lithium to maintain a serum lithium concentration of 0.8–1.1 mmol/l (2A ). One week before this episode he drank three cans of Red Bull at night and needed less sleep. Three days later he drank three more cans. After 4 days he was feeling euphoric, hyperactive, and insomniac. He gradually became more hyperactive and had increased libido and irritability. He took no more Red Bull and improved within 7 days.

Based on this report the authors suggested that stimulant beverages containing caffeine might cause cognitive and behavioral changes, especially in vulnerable patients with bipolar illness. Musculoskeletal Caffeine toxicity is an uncommon cause of myopathy, but a history of excessive dietary and pharmaceutical consumption of caffeine should be sought in any patient with unexplained myopathy, particularly if there is concomitant hypokalemia (3A ). • A 21-year-old woman with a 12-month history of progressive muscle weakness, nausea, vomiting, diarrhea, and weight loss had significant worsening of muscle weakness over 2 weeks, associated with exercise-induced muscle stiffness and pain. She had severe hypokalemia and a metabolic acidosis. For the past 1–2 years she had been consuming about 8 liters of cola every day. She stopped drinking the cola and took potassium supplements, after which her hypokalemia and muscle weakness resolved and the serum creatine kinase activity fell. Based on the concentration of caffeine in the cola, it was estimated that she had been consuming at least 1 g/day of caffeine for more than 12 months.

Hypokalemia and myopathy are known effects of caffeine toxicity, and severe hypokalemia and fatigue and hypokalemia with myopathy have been described before (4R ).

1

2 Consumption of methylxanthine-containing products can aggravate the neurological symptoms associated with the glucose transporter type 1 (Glut 1) deficiency syndrome. The human erythrocyte and brain glucose transporters are identical, and the erythrocyte transporter has been used in four patients with individual mutations in the Glut 1 gene to demonstrate that caffeine and theophylline inhibit glucose transport (5E ). The Glut 1 deficiency syndrome represents impaired glucose transport across the blood–brain barrier caused by partial Glut 1 deficiency, which results in hypoglycorrhachia, seizures, and developmental delay. Identifying potential inhibitors of Glut 1 is essential in preventing further impairment of glucose transport in these patients. In addition to phosphodiesterase inhibition and adenosine A1 receptor antagonism by methylxanthines, it is likely that inhibition of glucose transport also contributes to the convulsive effects of methylxanthines in high doses.

Theophylline Risk factors Age Developmental differences in the balance between metabolic and renal elimination pathways determine the unique toxicokinetics of theophylline in neonates. Three premature neonates received inadvertent intravenous doses of theophylline for apnea of prematurity (6A ). All the neonates had sinus tachycardia and agitation. Maximum serum theophylline concentrations were 55–123 mg/l; theophylline-derived caffeine concentrations plateaued at 8.4–13 mg/l and did not fall during the sampling period. The half-life of theophylline was 28–37 hours and the clearance 0.02–0.05 l/kg/h. This study shows that, in contrast to older children, theophylline elimination remains a first-order process during acute intoxication in premature infants, and that large overdoses of theophylline in neonates, while inducing symptoms and signs of overdose, do not uniformly result in life-threatening sequelae and do not necessarily require invasive treatment. Although the literature is rather scanty, the pharmacokinetics of theophylline in premature neonates do not seem to be different from those in full term neonates. Furthermore, toxic

Chapter 1

Reginald P. Sequeira

concentrations in neonates have not been defined. It has been speculated that various factors in neonates, such as low plasma protein binding, metabolic interconversion to caffeine, and limited excretory capacity, make them susceptible to toxicity even at plasma concentrations within the usual adult therapeutic range (SEDA23, 1; SEDA-25, 1). Drug overdose In patients with theophylline overdose, charcoal hemoperfusion is the recommended method for rapid reduction of serum theophylline concentrations. However, access to this technique is limited in most hospitals. Venovenous hemofiltration, which is readily available in many hospitals, appears to be a realistic and practical alternative to charcoal hemoperfusion, in combination with oral activated charcoal, particularly in the hemodynamically unstable patient with severe theophylline toxicity without anticoagulation (7A , 8A ). A higher extraction ratio in neonates than in adults has also been described (8A ). Rhabdomyolysis is a rare complication of theophylline overdose (9A ). • A 73-year-old man took an unknown number of theophylline modified-release tablets and furosemide 40 mg tablets. He developed a tachydysrhythmia, vomiting, and restlessness. His maximum theophylline concentration was 67 mg/l and he had hypokalemia (2.8 mmol/l) and hyponatremia (123 mmol/l). The maximum creatine kinase activity was (32 mol/l [[sic]]) and the serum myoglobin concentration was 3789 µg/l. He was treated with oral activated charcoal, continuous venovenous hemodialysis, intravenous potassium and sodium chloride, forced diuresis, and continuous intravenous metoprolol, and survived without sequelae.

Interference with diagnostic tests Methylxanthines, especially theophylline, in healthy subjects appear to inhibit solute reabsorption in both the proximal nephron and the diluting segment without changing either glomerular filtration rate or renal blood flow appreciably. Accordingly, such a discrepancy between GFR and creatinine clearance has been ascribed to the increase in creatinine clearance in a heavy tea drinker (10A ). Drug interactions Levofloxacin A 59-yearold Japanese man taking theophylline for emphysema had stimulation, insomnia, and tachycardia owing to theophylline toxicity after

Central nervous system stimulants and drugs that suppress appetite

he also took levofloxacin and clarithromycin (11A ). His theophylline clearance returned to normal and his symptoms resolved after withdrawal of levofloxacin, while clarithromycin was continued. Moxifloxacin In a randomized, multiple-dose, period-balanced, three-way, crossover study in healthy non-smoking male volunteers, moxifloxacin did not alter the pharmacokinetics of theophylline (12c ). Tegaserod The effect of tegaserod on the single-dose pharmacokinetics and safety profile of theophylline has been determined in a randomized, open-label, crossover study in 18 subjects (13c ). Tegaserod did not alter the pharmacokinetics of theophylline and the incidence of adverse events was similar after coadministration. However, since in vitro studies have shown that tegaserod inhibits CYP1A2 (14E ), more evidence is needed to claim that no dosage adjustment is required when theophylline is co-administered with tegaserod. Trimethoprim Two episodes of severe hyponatremic symptoms have been described in the same patient, one attributed to theophylline and one to trimethoprim (15A ). The evidence to support an interaction is circumstantial, and the patient was taking multiple medications, making interpretation difficult.

STIMULANT DRUGS

(SED-14, 12; SEDA-23, 2; SEDA-24, 2; SEDA-25, 2)

Amphetamines Cardiovascular The cardiovascular response to an oral dose of d-amphetamine 0.5 mg/kg has been determined in 81 subjects with schizophrenia, eight healthy controls who took amphetamine, and seven subjects with schizophrenia who took a placebo (16c ). Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in the controls. Intramuscular haloperidol 5 mg produced a more rapid fall in systolic blood pressure in

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3

six subjects, compared with 12 subjects who did not receive haloperidol. The authors concluded that increased blood pressure due to amphetamine may have a dopaminergic component. They also suggested that haloperidol may be beneficial in the treatment of hypertensive crises caused by high doses of amphetamine or methamphetamine. Vertebral artery dissection has been described in a previously healthy man with a 3-year history of daily oral amphetamine abuse (17A ). • A 40-year-old man had mild hypertension and a chronic history of heavy cigarette smoking. MRI scans showed infarction of both mesial occipital lobes, the left posteromedial thalamus, and the right superior and left superior cerebellum. Magnetic resonance angiography and fat saturation MRI showed changes consistent with dissection and hematoma. He was treated with anticoagulants and made a partial recovery.

Since this patient had no known risk factors for vertebral artery dissection and had abused amphetamine daily for 3 years with escalating amounts, an association between methamphetamine and vertebral artery dissection cannot be excluded. The local and systemic vascular impacts of amphetamine could have contributed to initial changes (along with smoking), resulting in dissection. Nervous system Methamphetamine-induced neurotoxicity in animals, especially involving effects on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascade, has been comprehensively reviewed (18ER ). Although prior work has focussed primarily on the effects of methamphetamine on dopaminergic neurons, there is evidence that other types of neurons are also affected. Regional brain metabolism has been studied using positron emission tomography after administration of [18 F]-fluorodeoxyglucose in 15 detoxified methamphetamine abusers and 21 controls (19c ). The authors concluded that since the parietal cortex is devoid of any significant dopaminergic innervation, the observed changes in cerebral metabolism resulted from the effects of methamphetamine on circuits other than those modulated by dopamine. These results provide evidence that methamphetamine, in doses abused by humans, produces

4 long-lasting metabolic changes in brain regions neuroanatomically connected with dopaminergic pathways, but also in areas that are not innervated by dopamine. Notwithstanding several confounding factors and limitations of this study, it shows the need to explore whether these changes recover and if they predispose to neurodegenerative diseases. Dopamine transporter reductions in methamphetamine abusers are associated with motor and cognitive impairment. There is therefore growing evidence to support the view that the long-term changes that methamphetamine can cause in the brain have implications in understanding methamphetamine neurotoxicity. However, we do not know whether this reduction in dopamine transporter activity reflects dopaminergic neuronal damage or down-regulation of the dopamine transporter (20c ). Teratogenicity The possible neurotoxic effect of prenatal methamphetamine exposure on the developing brain has been studied using 1 H magnetic resonance spectroscopy in 12 methamphetamine-exposed children and 14 age-matched unexposed controls (21c ). There was an increased creatinine concentration in the striatum, with relatively normal concentrations of N-acetyl-containing compounds in children exposed to methamphetamine. These findings suggest that exposure to methamphetamine in utero causes abnormal energy metabolism in the brains of children. However, there were no differences in reported behavioral problems among methamphetamine-exposed children compared with controls. Risk factors Genetic factors A study in 93 unrelated methamphetamine-dependent subjects and 131 controls did not prove any association between methamphetamine dependence in Caucasians of Czech origin and TaqI A polymorphism of the DRD2 gene, I/D polymorphism of the ACE gene, or M235T polymorphism of the AGT gene (22C ). Drug overdose Concentrations of methamphetamine and its metabolite amphetamine were measured in autopsied brain regions of 14 human methamphetamine abusers (23E ). There was no evidence of variation in the regional distribution of amphetamines in the

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brain. Postmortem redistribution of methamphetamine in the heart and lung has been reported before, although peripheral blood concentrations appear to remain constant (24E , 25E ).

Methylphenidate Two reviews have addressed the diagnosis and management of attention-deficit hyperkinetic disorder (ADHD) and have summarized the effects of stimulants, including those of methylphenidate and adderal (a mixture of equal components of d-amphetamine saccharate, d,lamphetamine aspartate, d-amphetamine sulfate, and d,l-amphetamine sulfate, which seems to be gaining popularity in the treatment of ADHD) (26R , 27R ). The results of the National Institute of Mental Health Collaborative Multimodal Treatment Study of children with attention deficit hyperkinetic disorder have been analysed (28C ). This double-blind, placebo-controlled methylphenidate titration trial identified the optimum dose and replicated previously reported methylphenidate response rates and doserelated adverse events. For parent ratings, the severity of the following adverse events increased as the dose was raised: appetite suppression, dull/listless appearance, stomach ache, tearfulness, and trouble sleeping. For teacher ratings, the only significant drug-related adverse event that had a dose-related trend was reduced appetite. Other adverse events reported by teachers were dull/listless appearance, crabbiness, and buccal movement or chewing. However, these teacher-reported adverse events improved with increased methylphenidate dosage. The authors also emphasized that parents report more dose-related adverse events than teachers do, making them better reporters of safety during dosage titration. A modified-release, once-daily formulation has been evaluated in 282 children with ADHD in a double-blind, placebo-controlled trial for 28 days (29C ). For core ADHD symptoms both once-daily modified-release and thrice-daily immediate-release methylphenidate were superior to placebo and not different from each other. A similar percentage of patients reported

Central nervous system stimulants and drugs that suppress appetite

at least one adverse event with both formulations. The most commonly reported adverse events were headache and upper respiratory infections, followed by abdominal pain, cough, pharyngitis, vomiting, and otitis media. Of these, only headache and abdominal pain were considered to be related to the study medication. One patient withdrew because of depression with modified-release methylphenidate and one because of tics with placebo. Headache occurred in 14%, 5.8%, and 10% of patients taking modified-release methylphenidate, immediate-release methylphenidate, or placebo respectively, and abdominal pain in 6.7%, 5.8%, and 1.0%. Other adverse events included appetite suppression (modified-release methylphenidate) and insomnia (all three). The results of this study suggest that once-daily modified-release methylphenidate provides efficacy superior to placebo and not significantly different from thrice-daily immediate-release methylphenidate. Nervous system Episodes of explosive behavior, apparently due to methylphenidate, masquerading as unmanageable ADHD have been reported (30A ). • A 10-year-old boy developed motor and vocal tics and severe obsessive–compulsive symptoms, predominantly about symmetry. These were not evident before he started taking methylphenidate. At 7 years of age he had begun a regimen of methylphenidate 20 mg/day in divided doses. Paradoxically, his impulsive behavior increased and he began to have explosions of aggressive and violent behavior, during which he would lash out at his family or destroy things. After a year of methylphenidate therapy, the tics subsided spontaneously but other symptoms remained. Eventually, because of severe impairment resulting from obsessive–compulsive symptoms, his parents stopped giving him methylphenidate. A few months later there were no further obsessive– compulsive preoccupations and no tics, and he did not have any explosive behavior.

It is well recognized that methylphenidate can induce or aggravate Tourette’s syndrome in vulnerable individuals, most often characterized by motor tics and occasionally vocal tics (31A ). Moreover, obsessive–compulsive symptoms caused by methylphenidate have also been reported (32A , 33A ). However, it is not clear whether explosive episodes associated with Tourette’s syndrome are an integral part

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of the disorder or occur as part of a co-morbid disorder, predominantly ADHD or obsessive– compulsive disorder. In this case the explosive episodes coincided with a period of treatment with methylphenidate. In view of the extreme, sudden, discrete nature of the outbursts and the temporal relation to treatment, it was concluded that the episodes were behavioral problems caused by methylphenidate, rather than a feature of the underlying ADHD. Drug interactions Ciclosporin Potential drug–drug interactions involving methylphenidate with ciclosporin and amfebutamone (bupropion) with ciclosporin have been described (34A ). A 10-year-old boy with a heart transplantation had a potentially lifethreatening reduction in ciclosporin blood concentrations with amfebutamone. He subsequently had an increase in ciclosporin concentrations while taking methylphenidate. These interactions merit further systematic investigation. Citalopram There is growing interest in using stimulants, particularly methylphenidate, in the management of elderly depressed patients, either alone (35c ) or in combination with antidepressants such as citalopram (36A ). In a preliminary trial in 10 elderly patients a combination of methylphenidate and citalopram was well tolerated. Levodopa Methylphenidate increased some of the motor effects of levodopa in selected patients with Parkinson’s disease (37A ). Changes in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ.

Modafinil Once-daily modafinil for an average of 4.6 weeks has been evaluated in an open-label trial in 11 children aged 5–15 years with ADHD (38c ). This pilot study, with non-blinded ratings, a small number of subjects, and a short duration of treatment, showed significant improvement. Adverse events were responsible for drug withdrawal in one child. The most common adverse event was delayed onset of sleep or sleep disruption, which, in two of three

6 cases, responded to a reduction in dosage. No patient taking modafinil lost weight or had a reduced appetite. A larger-scale, double-blind, placebo-controlled study will be needed to further substantiate the efficacy and safety of modafinil.

Strychnine A 33-year-old man attempted suicide by selfinjection of strychnine intramuscularly (39A ). A few seconds after the first injection he developed dizziness and lightheadedness. Ten minutes after the second injection he had seizures, opisthotonos, and tetany. He was rescued with a benzodiazepine and ventilatory support.

DRUGS THAT SUPPRESS APPETITE (SEDA-22, 3; SEDA-23, 2; SEDA-24, 4; SEDA-25, 5)

Fenfluramines Cardiovascular Further evidence that the prevalence of significant valvular regurgitation is low in patients treated with fenfluramine/phentermine has been reported (40C ). Transthoracic echocardiography was performed in 343 obese patients in a 3-year prospective study that began within 4 months from the withdrawal of fenfluramine and dexfenfluramine from the market. There were 281 women and 62 men, mean age 47 years and mean body mass index 40 kg/m2 . Using the FDA’s criteria, only 21 subjects (6.1%) had significant valvular lesions. Aortic regurgitation was detected in 18 subjects, mitral regurgitation in three, and both aortic and mitral regurgitation in one. Significant valvular disease did not correlate with age, sex, initial or final body mass index, drug dose, or the duration of therapy. In another study, 50 patients with fenfluramine-associated valvular heart disease were followed by serial echocardiography for 6–24 months after withdrawal of therapy (41C ). In most cases valvular heart disease did not

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change, or improved at least by one grade. Mitral and aortic regurgitation improved in some patients, and tricuspid and pulmonic regurgitation improved in most patients after withdrawal. When improvement did occur, regression of regurgitation often involved multiple valves on both the left and right sides of the heart, rather than affecting one valve in isolation. Although most of the patients stabilized or improved, a few had worsening of valvular regurgitation despite withdrawal. Comparable results were also reported in a larger series in another study (42C ). Sequential echocardiographic evaluation 1 year after withdrawal of dexfenfluramine showed a significant reduction in aortic regurgitation. There were no significant changes in mitral regurgitation or any other valvular variables. Although these results can be applied only to the population studied (predominantly middleaged, obese, white women who took dexfenfluramine for 2–3 months), the implications are considerable. Because valvular regurgitation remained stable or improved in most of the patients, surgical referral for patients with severe regurgitation may be delayed. Improvement in valvular regurgitation often occurred within months after drug withdrawal. It remains unclear, however, whether further improvement will continue to occur over longer periods. Watchful waiting, with serial echocardiography, prophylaxis against endocarditis, and medical therapy, may be a reasonable management strategy in patients with severe regurgitation, minimal symptoms, and no evidence of left ventricular dysfunction (41c ). It is not known what factors determine outcome after withdrawal of fenfluramine. Hematologic A clotting disorder has been attributed to fenfluramine–phentermine (fen– phen) (43A ). • A 35-year-old woman developed calf-pain while taking fen–phen. It resolved when the medications were stopped, but her pain returned when fenfluramine was restarted. She had slight rises in aspartate aminotransferase and lactate dehydrogenase activities and a remarkably shortened prothrombin time. The clot was composed of very thin fibrin fibers. All laboratory abnormalities, including the abnormal fibrin structure, completely resolved when fen–phen was stopped.

This is the first report of clotting abnormalities associated with fenfluramine. Thin fibrin

Central nervous system stimulants and drugs that suppress appetite

fibers are more resistant to lysis and can result from a variety of factors and increase the risk of thrombosis. Whether abnormal fibrin structure and an increased thrombotic tendency play a role in patients who develop fenfluramineassociated pulmonary hypertension and valvular heart disease is a question that deserves further investigation.

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Alzheimer’s disease (49M , 50R –52R ). However, these drugs are not expected to alter the neurodegenerative disease process, which is variable and unpredictable. Treatment response was not predicted by the Apo E genotype of six patients (53C ).

Donepezil Sibutramine Although serious adverse events have not been reported, there is no evidence of the longterm safety of sibutramine (44M ). Several new randomized clinical trials have assessed longterm weight reduction efficacy, tolerability, and safety of sibutramine. In a 1-year placebocontrolled study in primary care, sibutramine 10 mg/day (n = 122) or 15 mg/day (n = 123) with dietary advice produced and maintained more weight loss than dietary advice alone (45C ). None of the patients taking sibutramine or placebo (n = 114) was withdrawn because of a raised blood pressure. There were comparable results in 44 patients who took sibutramine 10 mg/day for 12 months in a double-blind, placebo-controlled, crossover design (46C ). After sibutramine withdrawal the patients gained weight but did not reach baseline body weight. There were no significant adverse events of sibutramine withdrawal. Early sibutramine administration produced better effects than late post-diet administration. Cardiovascular risk factors associated with obesity, including dyslipidemia, particularly raised triglyceride and lowered high density lipoprotein concentrations, can be improved with weight loss during sibutramine treatment (45C –47C ). In general, improvements in serum lipids are proportional to the degree of body weight loss, whether that weight loss occurs with sibutramine or with placebo (47C , 48c ).

DRUGS USED IN ALZHEIMER’S DISEASE (SED-14, 435; SEDA-23, 8; SEDA-24, 6; SEDA-25, 7) Cholinesterase inhibitors are currently the mainstay of treatment for mild-to-moderate

The beneficial effect of donepezil on global ratings of dementia symptoms cognition and activities of daily living has been confirmed (53C , 54c ). Donepezil was well tolerated for periods up to 1 year and adverse events were usually mild and transient, lasting only an initial few days, and typically resolved without the need for dosage modification. It has been suggested that patients with Alzheimer’s disease do best while taking donepezil 10 mg/day and when the dosage is maintained at that level without interruption. Donepezil treatment effects that are lost after prolonged withdrawal do not fully recover when the drug is restarted (55c ).

Pemoline Liver Limitations in post-marketing surveillance and public reporting in the USA, particularly in the 1980s, largely accounted for delays in ensuring an appropriate response to pemoline hepatotoxicity (56R ). Several authors have urged that voluntary reporting systems need augmentation (57R , 58r , 59R ), including the addition of an active surveillance system to assess the prevalence of adverse drug reactions and the increased use of public health-oriented information sources to disseminate clearly documented drug risk information to physicians and their patients. The case of pemoline is just one example of this.

Piracetam Piracetam has received significant attention in the media for its purported beneficial effect on cognition in children with Down syndrome. Piracetam 80–100 mg/day for 4 months has

8 been evaluated in a randomized, double-blind, placebo-controlled, crossover study in 25 children with Down syndrome (60c ). Piracetam did not enhance cognition or behavior, but was associated with adverse events: 18 children completed the study, four withdrew, and three were excluded at baseline. The adverse events were CNS related, such as aggression (n = 4), agitation/irritability (n = 2), sexual arousal (n = 2), poor sleep (n = 1), and reduced appetite (n = 1).

Rivastigmine

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Reginald P. Sequeira

while taking rivastigmine (61A ). The time course suggested an association with rivastigmine, and each improved after withdrawal.

Tacrine Liver Tacrine-induced hepatotoxicity was reduced by ursodeoxycholic acid (13 mg/kg/d for 105 days) in a pilot study in 14 patients with Alzheimer’s disease (62c ). Serum activity of AlT in 100 patients taking ursodeoxycholic acid was normal in 93% of cases compared with 69% of patients who had taken tacrine alone.

Psychiatric Three patients with dementia, with no prior psychiatric history, deteriorated

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P.J. Cowen

2

Antidepressant drugs

TRICYCLIC ANTIDEPRESSANTS (SED-14, 44; SEDA-23, 16; SEDA-24, 12; SEDA-25, 13) Cardiovascular At therapeutic doses tricyclic antidepressants can cause postural hypotension, but they are regarded as being safe in patients who require general anesthesia. However, hypotension during surgery has been associated with clomipramine (1A ). • A 57-year-old man due to undergo mitral valve surgery took clomipramine (150 mg at night) up to the night before surgery. His blood pressure before induction with thiopental (250 mg) and fentanyl (250 µg) was 105/65 mmHg, with a heart rate of 70 beats/minute. Anesthesia was maintained with isofluorothane, and 45 minutes after induction, his systolic blood pressure fell to 90 mmHg. Neither ephedrine (30 mg total), phenylephrine (500 µg total), nor dopamine (10 µg/kg/minute) increased the blood pressure. After sternotomy, his systolic blood pressure fell to 55 mmHg and his pulse rate to 60 beats/minute and he had third degree atrioventricular block. Further ephedrine, phenylephrine, and adrenaline were without effect. During cardiopulmonary bypass a noradrenaline infusion was started (0.2 µg/kg/minute) and isofluorothane withdrawn. After he had been weaned from bypass the noradrenaline infusion was continued at a dose of 0.2–0.8 µg/kg/minute, sufficient to maintain the systolic blood pressure at 90–100 mmHg. After the operation clomipramine was withheld and the noradrenaline infusion tapered off, and 3 days later the hypotension had resolved.

The hypotension in this case was severe and refractory to noradrenergic stimulation, perhaps because of the alpha1 -adrenoceptor antagonist properties of clomipramine. The fall in systolic blood pressure was accompanied by a paradoxical fall in heart rate, perhaps because the anticholinergic effect of clomipramine removed the effect of vagal tone on the resting heart rate. It seems likely that the hypotensive effect of © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

clomipramine was potentiated by general anesthesia; however, such a reaction is rare and the underlying cardiac problem may have contributed to this severe adverse reaction. This case reinforces current advice that tricyclic antidepressants are best avoided in patients with significant cardiac disease. Drug interactions There is growing interest in the use of herbal medicines to treat depression, and the propensity of St John’s wort to cause drug interactions has been noted previously (SEDA-24, 12). In 12 patients (nine women, three men) the addition of St John’s wort (900 mg/day) to amitriptyline (150 mg/day) led to a 20% reduction in plasma amitriptyline concentrations, while nortriptyline concentrations were almost halved (2c ). The mechanism is likely to be induction either of hepatic CYP enzymes or the drug transporter P glycoprotein, which causes a net efflux of substrates such as amitriptyline from intestinal epithelial cells into the gut lumen. Amitriptyline can be added to the growing list of drugs (including theophylline, ciclosporin, and warfarin) whose clearance is significantly increased by St John’s wort.

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-14, 67; SEDA-23, 17; SEDA-24, 14; SEDA-25, 14) Severe adverse reactions to SSRIs that had been reported to Health Canada’s database in 1986– 96 have been reviewed (3R ). There were 295 severe adverse reactions with 87 deaths. Of the fatal cases, 65 were due to intentional overdose. The other 22 deaths were due chiefly to other forms of suicide or were accidental or indeterminate (12 cases). Of the rest there were three cases of neuroleptic malignant syndrome and

11

12 individual cases of cardiac or respiratory disease in which the role of SSRIs was less clear. This report shows that the major causes of death in patients taking SSRIs are related to the risks of depression itself, particularly selfharm. SSRIs themselves appear to be relatively safe. It is possible, however, that the cases of neuroleptic malignant syndrome could have been misdiagnosed forms of the serotonin syndrome, which, like the neuroleptic malignant syndrome, can present with hyperthermia and changes in consciousness. I have previously pointed out the risk of SSRI-induced serotonin toxicity, which is usually produced by pharmacodynamic interaction between SSRIs and other serotonin potentiating compounds (SEDA-25, 24). In general, the risks of SSRIs are increased by co-prescription, and fatal overdose with SSRIs usually involves a mixture of psychotropic drugs and/or alcohol. Cardiovascular Generally SSRIs have a benign cardiovascular profile. However, fluoxetine has reportedly caused prolongation of the QTc interval (4A ). • A 52-year-old man had an abnormally prolonged QTc interval of 560 ms, with broad-based T waves. He had taken fluoxetine (40 mg/day) over the previous 3 months, before which an electrocardiogram had shown a normal QTc interval (380 ms). The fluoxetine was withdrawn, and 10 days later the QTc interval was 380 ms. His only other medication was verapamil, which had been started 3 years before for hypertension.

Systematic studies of fluoxetine as monotherapy have not shown evidence of QTc prolongation. It is possible in this case that fluoxetine interacted with verapamil to produce a conduction disorder. The other SSRI that has been associated with cardiovascular abnormalities is citalopram (SEDA-24, 14). These are most commonly apparent in large overdoses, in which a variety of cardiac abnormalities, including QTc prolongation, have been noted. • A 21-year-old woman developed QTc prolongation (457 ms) after taking a fairly modest overdose (400 mg) of citalopram (usual daily dose 20–60 mg) (5A ). The QTc prolongation resolved uneventfully over the next 30 hours.

This case suggests that even modest overdoses of citalopram can cause QTc prolongation

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and that cardiac monitoring should be considered. Based on the pharmacokinetic profile of citalopram and the temporal pattern of QTc change, the authors suggested that the effect of citalopram on the QTc interval was mediated by one of its metabolites, dimethylcitalopram. Nervous system SSRIs can cause extrapyramidal disorders, including Parkinsonism (SEDA-23, 24). In these cases, withdrawal of SSRIs usually results in remission of symptoms. However, occasionally SSRIs can unmask a vulnerability to Parkinson’s disease. • An 81-year-old woman took sertraline 100 mg/day for depression and 6 months later presented with tremor and difficulty in moving her right arm and leg (6A ). A diagnosis of right hemi-parkinsonism was made and the sertraline was withdrawn. Her extrapyramidal symptoms resolved within 3 months, but 14 months later she developed Parkinsonism and was treated with levodopa and carbidopa. • A 70-year-old man developed Parkinsonian symptoms 1 month after starting to take sertraline 100 mg/day (7A ). Withdrawal of sertraline resulted in amelioration but not complete remission of his symptoms, which then required treatment with carbidopa and levodopa.

In these cases presumably the sertraline prematurely precipitated Parkinson’s disease. Fluvoxamine causes increased plasma melatonin concentrations. In an in vitro preparation melatonin was metabolized to 6-hydroxymelatonin by CYP1A2, which was inhibited by fluvoxamine at therapeutic plasma concentrations (8E ). This effect was not shared by other SSRIs or by tricyclic antidepressants which do not have prominent effects on melatonin secretion. Whether increased concentrations of melatonin and loss of its normal circadian rhythm might cause symptoms is unclear. However, melatonin is believed to play a role in the regulation of circadian rhythms, including entrainment of the sleep-wake cycle. There have been 10 cases of circadian rhythm sleep disorder associated with fluvoxamine (9c ). All the patients had delayed sleep-phase syndrome, which is characterized by delayed sleep onset and late awakening. The delay in falling asleep and waking up in the morning was 2.5–4 hours. In nine of the cases withdrawal of fluvoxamine or a reduced dosage led to resolution of the sleep disorder. When the patients were given alternative serotonin

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potentiating agents, such as clomipramine or fluoxetine, the sleep disorder did not recur. SSRIs can cause insomnia and daytime somnolence; however, the symptoms seem to reflect a sleep-wake cycle disorder. It is conceivable that disruptions in the normal pattern of melatonin secretion, particularly a delay in the normal early morning fall in plasma concentrations could be involved in the pathophysiology of these symptoms. The fact that these sleep disorders were seen only with fluvoxamine would also support a role of melatonin. Endocrine SSRIs can cause modest increases in plasma prolactin concentrations, presumably because serotonin pathways in the hypothalamus facilitate the release of prolactin releasing factor. This is rarely associated with obvious clinical sequelae, but hyperprolactinemia and galactorrhoea have been reported. • A 71-year-old woman who had taken fluoxetine (dose unspecified) for a number of weeks noted unilateral galactorrhea and had a raised prolactin of 37 ng/ml (reference range 1.2–24 ng/ml) (8A ). She was also taking estrogen hormonal replacement therapy, benazapril, and occasional alprazolam. Withdrawal of the fluoxetine led to normalization of the prolactin concentration and resolution of the galactorrhea. • A 32-year-old woman taking paroxetine 40 mg/day had a raised prolactin concentration (46 ng/ml) and galactorrhea, both of which resolved a few days after paroxetine withdrawal (9A ).

Estrogens also facilitate prolactin release, and so hormone replacement therapy may have played a part in the first case. Electrolyte balance Reports of hyponatremia with SSRIs continue to appear (12A , 13R ). Hyponatremia is probably more common with SSRIs than tricyclic antidepressants and predominantly but not exclusively affects older patients. Most reports involve fluoxetine but this might represent greater patient exposure. All SSRIs and venlafaxine can produce this adverse effect (SEDA-23, 21; SEDA-25, 14). According to the published reports the median time to onset of hyponatremia is 13 days (range 3–120) and the presentation is of inappropriate secretion of antidiuretic hormone (12A ). Symptoms, such as lethargy and confusion, can be non-specific, so awareness of the possibility of SSRI-induced hyponatremia, particularly in elderly people, is needed.

13 Skin As with other antidepressants, SSRIs have been associated with skin reactions. • A 20-year-old woman taking paroxetine 10 mg/day for obsessive–compulsive disorder developed multiple purple lesions on the fingers of both hands after 15 weeks (14A ). The lesions disappeared after 1 week but returned 2 days after re-challenge with paroxetine.

The skin reaction here was consistent with a vasculitis, a potentially serious adverse reaction that has been previously reported with fluoxetine but not paroxetine. Sexual function SSRIs are usually associated with reduced sexual function, including loss of interest. However, occasionally they are associated with increased sexual desire and behavior. • A 27-year-old married woman with a borderline personality disorder was admitted to hospital with depression and suicidal ideation (15A ). Over 3 weeks she was treated with fluvoxamine in doses up to 150 mg/day, but because of lack of response the dosage was increased to 200 mg/day; 3 days later she reported that her sex drive was greater than it had ever been before and that she felt she could not control it. There was no evidence of mania. Within a week of withdrawal of fluvoxamine her sexual desire had returned to its previous level.

Patients with borderline personality disorder may behave in a sexually disinhibited manner and have mood swings. In this patient, however, it did not appear as though the hypersexuality was part of a manic syndrome, and she was clear that the sexual feelings were unusually great for her. Support for a role of the SSRI in this adverse effect comes from a series of five patients (four taking citalopram and one paroxetine) who had an unusual increase in sexual interest, with preoccupation with sexual thoughts, promiscuity, and excessive interest in pornography (16A ). In some of the cases symptoms such as diminished need for sleep suggested the possibility of a manic syndrome. These reports suggest that occasionally SSRIs can be associated with increased sexual desire and behavior. This might be associated with mood instability, for example in a manic or mixed affective state, but in some people personality factors are likely to be important. Unlike most other antidepressants, SSRIs can cause ejaculatory delay and even complete anorgasmia in both men and women (SEDA23, 18). This adverse effect has been used

14 with benefit in men with premature ejaculation. However, laboratory studies in such patients have shown that fluvoxamine differs from paroxetine, sertraline, and fluoxetine in not delaying the time to ejaculation. The effect of citalopram to delay ejaculation is also relatively modest (17r ). There are, however, many other ways in which SSRIs can interfere with sexual function, for example by causing loss of sexual interest and erectile difficulties. In an open, prospective study of 1000 Spanish patients taking a variety of antidepressants, there was an overall incidence of sexual dysfunction of 59% (18R ). The highest rates, 60–70%, were found with SSRIs (including fluvoxamine) and venlafaxine. The lowest rates were found with mirtazepine (24%), nefazodone (8%), and moclobemide (4%). Spontaneous resolution of this adverse effect was uncommon—80% of subjects had no improvement in sexual function over 6 months of treatment. This study suggests very high rates of sexual dysfunction in patients taking SSRIs and venlafaxine. However, in investigations of this nature it can be difficult to tease out the effect of the drug from that of the underlying disorder. Nevertheless, while depressive symptoms should improve in most patients over 6 months of treatment, the sexual dysfunction in these subjects tended not to remit, suggesting that the antidepressant was the main culprit. Lactation The benefit : harm ratio of breast feeding during antidepressant treatment is difficult to compute and must be done on an individual basis. In general, breast-feeding with SSRIs is regarded as safe, as the amount of drug ingested by the infant is very low. However, adverse effects in the child are reported occasionally (SEDA-25, 15) and it is difficult to exclude completely the possibility of longterm effects on brain development in the infant. Clearly the lower the concentration of SSRI in the infant the less likely are problems of acute and longer-term toxicity. In two cases treatment of breast-feeding mothers with fluvoxamine (300 mg/day) was associated with undetectable concentrations of fluvoxamine (below 2.5 ng/ml) in the plasma of both infants (19A ). These results are encouraging, but further data will be needed before it can be concluded that fluvoxamine has an advantage over other SSRIs in this respect.

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Drug interactions Olanzapine is an atypical antipsychotic drug, which is increasingly being used in combination with SSRIs in the management of both depression and schizophrenia with secondary depression. It is metabolized by CYP1A2, which is inhibited by fluvoxamine. • A 21-year-old woman with schizophrenia and depression, who had been taking fluvoxamine (150 mg/day) and olanzapine (15 mg/day) for several months, developed an extrapyramidal movement disorder, including rigidity and tremor (20A ). The plasma fluvoxamine concentration was 70 µg/l (usual target range 20–500 µg/l), while that of olanzapine was 120 µg/l (usual target range 9–25 µg/l). The dosage of olanzapine was reduced to 5 mg/day and the plasma olanzapine concentration fell to 38 µg/l, with resolution of the tremor and rigidity. When fluvoxamine was replaced with paroxetine (20 mg/day) the olanzapine concentration fell further to 22 µg/l.

Of the SSRIs, fluvoxamine is the most potent inhibitor of CYP1A2 and is therefore likely to increase plasma olanzapine concentrations. The extrapyramidal effects in this case were presumably due excessive blockade of dopamine D2 receptors by raised olanzapine concentrations. Fluvoxamine also inhibits CYP2C9 and CYP2C19, the enzymes responsible for the metabolism of phenytoin. • A 45-year-old woman taking phenytoin (300 mg/day) had a plasma phenytoin concentration of 66 µmol/l (21A ). When she became depressed fluvoxamine (50 mg/day) was added. A month later her depressive symptoms had improved but she was ataxic and the plasma phenytoin concentration was 196 µmol/l. The fluvoxamine was withdrawn and the phenytoin dose reduced to 150 mg/day. Her plasma phenytoin concentration fell to 99 µmol/l, with resolution of the ataxia.

In vitro studies suggest that fluvoxamine is the most potent SSRI in terms of its ability to inhibit phenytoin metabolism. Inhibition of CYP2C19 or CYP2C9 could be responsible, although in vitro studies suggest that fluvoxamine is a relatively weak inhibitor of CYP2C9. However, in 14 healthy volunteers treatment with fluvoxamine (150–300 mg/day) for 5 days significantly reduced the clearance of tolbutamide (22C ). This suggests that fluvoxamine should be used with caution when it is co-administered with drugs such as tolbutamide, phenytoin, and warfarin, which are substrates for CYP2C9.

Antidepressant drugs

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Chapter 2

Like olanzapine, risperidone is a atypical antipsychotic that is frequently combined with SSRI treatment. Risperidone is metabolized mainly by CYP2D6. As might be expected, the addition of paroxetine (20 mg/day) to risperidone (4–8 mg/day) in 10 patients with schizophrenia produced a 45% increase in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (23C ). An increase in risperidone concentrations of this magnitude is likely to be clinically significant, and one of the patients developed signs of drug-induced Parkinson’s disease following the addition of paroxetine. Another case of severe parkinsonism with urinary retention occurred when fluoxetine (20 mg/day) was added to risperidone treatment (2 mg/day) in a 46-year-old man with schizophrenia. Risperidone had been prescribed at this dose for 1 month without any adverse effects, and the authors considered that a pharmacokinetic interaction between fluoxetine and risperidone was the most likely mechanism (24A ). Co-prescription of citalopram, which does not inhibit CYP2D6, has been reported not to alter plasma risperidone concentrations (SEDA23, 18). In a study treatment with citalopram (40 mg/day) for 4 weeks also failed to alter the pharmacokinetics of digoxin (1 mg orally) (25C ). Digoxin is not a CYP substrate, so an interaction with SSRIs is unlikely, but the authors cited a report that showed that fluoxetine increased plasma digoxin concentrations. Caution has been advocated when SSRIs such as fluoxetine are combined with the triptan drugs used to treat acute episodes of migraine (SEDA-24, 16). Triptans are metabolized mainly by monoamine oxidase, which makes pharmacokinetic interactions with SSRIs unlikely. However, there are case reports of symptoms suggestive of serotonin toxicity when fluoxetine has been combined with sumatriptan, perhaps because the SSRI can potentiate the 5-HT1B/1D agonist effects of the triptan (SEDA22, 14). The effect of fluoxetine 60 mg/day for 8 days on the pharmacokinetics of almotriptan has been studied in 14 healthy volunteers (26C ). Fluoxetine produced a significant increase in the peak concentration of almotriptan, but the AUC was not altered. These results suggest that CYP2D6 plays a minor role in the metabolism of almotriptan. The combined treatment was reported to be well tolerated, but this does not

exclude the possibility of occasional cases of serotonin toxicity in some individuals.

OTHER ANTIDEPRESSANTS Amfebutamone (bupropion) (SED-14, 60; SEDA-23, 20; SEDA-24, 16; SEDA-25, 17) Death The anti-smoking drug amfebutamone has been linked to 41 deaths (27Ar ). From the reports of suspected adverse events received by the Netherlands Pharmacovigilance Foundation, it appears that more than half of these cases concerned patients at risk of developing smoking-related diseases. In 15 cases there had been simultaneous use of amfebutamone with another antidepressant (10 patients), theophylline (one patient), or insulin (four patients). These combinations may lead to an increase in the risk of seizures. Furthermore, two patients reported having taken antiepileptic drugs, despite the fact that amfebutamone is contraindicated in patients with a seizure disorder. These results suggest that the guidelines described in the product information are not being adhered to in some cases. Although amfebutamone is useful new aid for patients who are trying to quit smoking, the contraindications should be carefully evaluated. Drug overdose A major concern about amfebutamone has been the risk of seizures (SEDA-23, 20), although this appears to be low with the modified-release formulation that is licensed in the UK for the treatment of nicotine dependence. However, it appears that seizure is a significant risk in amfebutamone overdose. • An 18-year-old man attempted suicide by taking bupropion 7.5 g (50 × 150 mg tablets) (28A ). On assessment 90 minutes later he was agitated and aggressive, with a resting pulse of 160 beats/minute and a blood pressure of 142/63 mmHg. He quickly developed a persistently low blood pressure (65/40 mmHg), followed by three generalized tonic–clonic seizures, which were controlled by diazepam. He was ventilated and a metabolic acidosis was corrected with sodium bicarbonate. Despite this, his blood pressure remained persistently low (70/40 mmHg) with a sinus tachycardia (150 beats/minute). Dopamine was ineffective and adrenaline was required. After

16 24 hours he was extubated and made a full recovery over the next 3 days. • A 14-year-old boy took 1.5–3.0 g of amfebutamone and had a persistent tachycardia, seizures, and brief agitation and aggression (29A ). He also had visual hallucinations, disorientation, and confusion but recovered about 24 hours after ingestion.

These cases show that overdose of amfebutamone can be serious.

Nefazodone

(SED-14, 64; SEDA-23, 20; SEDA-24, 17; SEDA-25, 17)

Liver There has been previous concern about rare but severe hepatic reactions to nefazodone (SEDA-24, 25). The cumulative incidence of hepatic adverse reactions associated with antidepressant treatment has been estimated through spontaneous reports to the Spanish Pharmacovigilance System (30c ). For classical tricyclic antidepressants and SSRIs the estimated rate of adverse hepatic reactions was 1.28–4.00 per 100 000 patient years. However, the rate with nefazodone was much higher (29 per 100 000 patient years). This report supports concerns that nefazodone may be more hepatotoxic than other antidepressants. Significant hepatic reactions to nefazodone are relatively rare but can be serious. Drug interactions Nefazodone is a potent inhibitor of CYP3A4 and raises plasma concentrations of drugs that are substrates for this enzyme, such as benzodiazepines, carbamazepine, and ciclosporin. A previous report suggested that nefazodone did not increase plasma concentrations of the atypical antipsychotic drug clozapine, suggesting that CYP3A4 may not play a major role in the metabolism of clozapine (SEDA-24, 17). However, in one case the addition of nefazodone appeared to produce clozapine toxicity (31A ). • A 40-year-old man had taken clozapine 450 mg/day and risperidone 6 mg/day for several years. Nefazodone (200 mg/day) was added in an attempt to improve persistent negative symptoms, and after a week the dosage was increased to 300 mg/day. One week later he reported anxiety and dizziness and was hypotensive. The combined concentrations of clozapine and its active metabolite norclozapine had increased from 309 ng/ml

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before nefazodone to 566 ng/ml. The nefazodone dosage was reduced to 200 mg/day and the anxiety, dizziness, and hypotension resolved over the next 7 days. At the same time plasma concentrations of clozapine and norclozapine fell to 370 ng/ml.

These results suggest that in some individuals CYP3A4 plays a significant role in the metabolism of clozapine and that the combination of nefazodone and clozapine should therefore be used with caution. It is possible that in this case concomitant treatment with risperidone may have increased the effect of nefazodone to reduce the clearance of clozapine. Drugs that inhibit CYP3A4 inhibit the clearance of terfenadine, an antihistamine that can prolong the QTc interval. This can cause potentially dangerous interactions. In a doubleblind, placebo-controlled study of the effect of nefazodone (600 mg/day for 1 week) on the pharmacokinetics of terfenadine (120 mg/day for 14 days) and another antihistamine, loratadine (20 mg/day for 14 days), in 67 healthy volunteers, nefazodone significantly reduced the clearance of terfenadine and prolonged the mean QTc interval (32C ). In addition, nefazodone produced a similar but smaller decrease in the clearance of loratadine and combined treatment also significantly increased the QTc interval. This effect of nefazodone on the clearance of terfenadine is expected, as is the increase in QTc interval. Loratadine is also partly metabolized by CYP2D6, which probably explains the lesser effect of nefazodone on loratadine clearance. Loratadine by itself does not increase the QTc interval significantly, but the current data suggest that cardiotoxicity might be a possibility when it is combined with nefazodone.

Venlafaxine

(SED-14, 66; SEDA-23, 20; SEDA-24, 18; SEDA-25, 18)

Hair SSRIs can cause occasional, idiosyncratic hair loss in some patients (SEDA-19, 10), and this has also been attributed to venlafaxine (33A ). • A 50-year-old woman took venlafaxine (75 mg/day) for depression, and the dose was increased to 150 mg/day after 2 weeks. After 4 weeks she noted increased hair loss when brushing or washing her hair. After 3 months she stopped taking

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17

venlafaxine and 1 month later her hair loss stopped completely. However, 10 months later she developed another depressive episode and was again successfully treated with venlafaxine. Once again she noted excessive hair loss. She was subsequently treated with sertraline (50 mg/day), which helped her depression without causing hair loss.

enced after sudden withdrawal of tricyclic antidepressants). The fact that they were relieved by a serotonin but not a noradrenaline re-uptake inhibitor suggests that venlafaxine-induced withdrawal symptoms are indeed mediated by serotonergic mechanisms.

The fact sertraline did not cause hair loss in this patient suggests that the mechanism was not related to serotonin re-uptake blockade.

Drug overdose Venlafaxine has been associated with occasional reports of cardiac conduction disturbances at both therapeutic doses and in overdose (SEDA-24, 19).

Drug withdrawal Both SSRIs and venlafaxine can cause troublesome withdrawal symptoms (SEDA-22, 12, 17). Because venlafaxine blocks the re-uptake of both serotonin and noradrenaline the mechanism of venlafaxineinduced abstinence symptoms is not clear. • A 72-year-old woman taking venlafaxine (150 mg/day) for depression was abruptly switched to the noradrenaline re-uptake inhibitor maprotiline 75 mg/day and 1 day later had agitation, sweating, nausea, vomiting, tinnitus, and insomnia (34A ). These symptoms continued for another week, but were abolished on the second day of sertraline treatment 50 mg/day.

The symptoms experienced by this patient were typical of venlafaxine and SSRI withdrawal (although they could also be experi-

• A 44-year-old woman took an overdose of venlafaxine of 3 g. An electrocardiogram showed sinus rhythm and incomplete right bundle branch block (35A ). She was monitored in an intensive care unit and 10 hours later a further electrocardiogram showed atrial fibrillation with wide QRS complexes. Both of these abnormalities resolved with sodium bicarbonate (100 ml of a 1 M solution). No further conduction disturbances were noted over the following days.

The authors suggested that the effect of venlafaxine on cardiac conduction was mediated by its ability to block the fast inward sodium current in cardiac myocytes. This might promote membrane stabilizing effects in a similar way to tricyclic antidepressants. They recommended that the management of venlafaxine overdose should include cardiac monitoring.

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24. Bozikas V, Petrikis P, Karavatos A. Urinary retention caused after fluoxetine-risperidone combination. J Psychopharmacol 2001; 15: 142–3. 25. Larsen F, Priskorn M, Overø KF. Lack of citalopram effect on oral digoxin pharmacokinetics. J Clin Pharmacol 2001; 41: 340–6. 26. Fleishaker JC, Ryan KK, Carel BJ, Azie NE. Evaluation of the potential pharmacokinetic interaction between almotriptan and fluoxetine in healthy volunteers. J Clin Pharmacol 2001; 41: 217–23. 27. Bhattacharjee C, Smith M, Todd F, Gillespie M. Bupropion overdose: A potential problem with the new ‘miracle’ anti-smoking drug. Int J Clin Pract 2001; 55: 221–2. 28. Ayers S, Tobias JD. Bupropion overdose in an adolescent. Pediatr Emerg Care 2001; 17: 104–6. 29. Carvajal García-Pando A, García del Pozo J, Sánchez AS, Velasco Martín A, Rueda de Castro AM, Lucena MI. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002; 63: 135–7. 30. Khan AY, Preskorn SH. Increase in plasma levels of clozapine and norclozapine after administration of nefazodone. J Clin Psychiatry 2001; 62: 375–6. 31. Abernethy DR, Barbey JT, Franc J, Brown KS, Feirrera I, Ford N, Salazar DE. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001; 69: 96–103. 32. Pitchot W, Ansseau M. Venlafaxine-induced hair loss. Am J Psychiatry 2001; 158: 1159–60. 33. Luckhaus C, Jacob C. Venlafaxine withdrawal syndrome not prevented by maprotiline, but resolved by sertraline. Int J Neuropsychopharmacol 2001; 4: 43–4. 34. Combes A, Peytavin G, Theron D. Conduction disturbances associated with venlafaxine. Ann Intern Med 2001; 134: 166–7. 35. Wagena EJ, De Graaf L, Chavannes NH, Van Groothiest AC, Van Schayck CP. Onrust over de veiligheid van bupropion als middel om te stoppen met roken onterecht. Ned Tijdschr Geneeskd 2001; 145: 1489–92.

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3 A review of the comparative efficacy and tolerability of drug treatments for bipolar disorder included tolerability comparisons of lithium versus carbamazepine, lithium versus valproate semisodium, and lithium versus other medications (1R ). When 60 patients (22 men, 38 women) who had taken lithium for 1 year or more (mean 6.9 years; mean serum concentration 0.74 mmol/l) were interviewed about adverse effects, 60% complained of polyuria–polydipsia syndrome (serum creatinine concentrations were normal) and 27% had hypothyroidism requiring treatment (2c ). Weight gain was more common in women (47% vs. 18%) as were hypothyroidism (37% vs. 9%) and skin problems (16% vs. 9%), while tremor was more common in men (54% vs. 26%). Weight gain of over 5 kg in the first year of treatment was the only independent variable predictive of hypothyroidism. How knowledgeable 123 patients in a lithium clinic (mean treatment duration 12.1 years) were about lithium has been assessed with 63 questions based on the Lithium Knowledge Test. About two-thirds of the questions were answered correctly, and knowledge about lithium was not related to diagnosis, education, or sex. There was a negative association between increasing age and knowledge, and this was independent of the duration of lithium treatment (3C ). Even in a specialized lithium clinic, it seems that patient education could be improved upon, with the hope of a positive outcome on the effectiveness and safety of treatment.

ORGANS AND SYSTEMS Cardiovascular Investigators who used a Bayesian confidence propagation network to © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Lithium mine the World Health Organization International Drug Monitory Database for information on antipsychotic drugs and heart muscle disorders found 17 case reports involving lithium (4R ). There was a significant association with lithium and cardiomyopathy, but not with myocarditis. However, a causal relation could not be established. Two reviews of drug-related congenital malformation briefly mentioned lithium and cardiovascular teratogenesis, but no new information was provided (5r , 6r ). Likewise, two reviews of the cardiac effects of psychotropic drugs briefly mentioned lithium and dysrhythmias, with a focus on sinus node dysfunction (7r , 8r ). Case reports of adverse cardiovascular effects of lithium have included the following: • a 52-year-old man who took an overdose of lithium (serum concentration 4.58 mmol/l) and developed asymptomatic sinus bradycardia with sinus node dysfunction and multiple atrial extra beats, which resolved after hemodialysis (9A ); • a 59-year-old woman with syncope and sick sinus syndrome, which remitted when lithium was withdrawn, recurred when lithium was restarted, and then persisted despite lithium withdrawal; after a pacemaker was implanted she was treated successfully with lithium for 7 years (10A ); • a 66-year-old woman with pre-existing first-degree AV block who, about 2 weeks after beginning lithium therapy, developed sinus bradycardia, a junctional rhythm, a prolonged QT interval, and syncopal episodes (serum lithium concentration 1.4 mmol/l in a 40-hour sample); she was treated successfully with a pacemaker and a lower dose of lithium (11A ); • a 36-year-old man who became hypomanic after lithium was withdrawn because of symptomatic first-degree atrioventricular block (although how first-degree block could have caused symptoms is unclear) (12A ); • a 59-year-old man who was noted to have tachycardia, a shortened QT interval, and non-specific ST-T changes while hospitalized with lithium-associated hypercalcemia (13A ); • a 13-year-old boy in whom lithium induced a “pseudo-myocardial infarct pattern” on the electrocardiogram (this may have been an overinterpretation of non-specific T-wave changes) (14A );

19

20 • a 44-year-old woman with atropine-resistant but isoprenaline-sensitive bradycardia (36 bpm), thought to be due to sinus node dysfunction related to lithium, fentanyl, and propofol (15A ).

Respiratory A 60-year-old woman with bipolar disorder since the age of 29 developed idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis) after having taken lithium for 9 years (16A ). Whether lithium played a causal role is at best highly speculative. Nervous system (see also Drug overdose) A case-control study of delirium in 22 psychiatric in-patients showed that lithium was one of the risk factors (adjusted odds ratio of 2.23) (17c ). Four of 17 patients who had paroxetine added to lithium as an adjunctive antidepressant developed symptoms suggestive of emerging serotonin syndrome (e.g. nausea, vomiting, diarrhea, sweating, anxiety, oversleeping) (see also Drug interactions) (18c ). Although the English abstract of a Polish review concluded that there is no evidence of significant cognitive deficits caused by lithium (19r ), others would take issue with this conclusion (20M ). Case reports of adverse nervous system effects of lithium have included the following: • permanent cerebellar sequelae in a 36-year-old man after intoxication at therapeutic lithium concentrations (21A ); • a prolonged seizure after ECT in a 45-year-old man taking lithium, amfebutamone, and venlafaxine (see also Drug interactions) (22A ); • worse stuttering in a 48-year-old man while taking lithium with improvement when he was switched to valproate (23A ); • severe essential tremor, which was at first mistaken for tardive dyskinesia in an 80-year-old woman taking lithium; it resolved almost completely when lithium was withdrawn (24A ).

Neuromuscular Lithium has been implicated in impaired athletic prowess in two cases (25A ). • A 21-year-old man had muscular incoordination while fast bowling (cricket), which improved when he switched to valproate. • A 71-year-old woman was unable to serve properly at tennis until she stopped taking lithium.

Endocrine Thyroid The prevalence of thyroperoxidase antibodies was higher in 226 bipolar patients (28%) than in population control

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and psychiatric control groups (3–18%). While there was no association with lithium exposure, the presence of antibodies increased the risk of lithium-induced hypothyroidism (26C ). When 22 men and 38 women who had taken lithium for at least a year (mean 6.9 years) for bipolar disorder were evaluated for adverse effects, hypothyroidism requiring thyroid supplementation was found in 16 (14 women and two men); nine had a goiter (2C ). The area from which some of the patients came was known to have a high background incidence of thyroid dysfunction. In 1989, 150 patients at different stages of lithium therapy had thyroid function assessed and subsequently, 118 were reassessed at least once and 54 completed a 10-year follow-up (27C ). The annual rates of new thyroid dysfunction were subclinical hypothyroidism 1.7%, goiter 2.1%, and autoimmunity 1.4%. While these figures were little different from those found in the general population, the authors acknowledged that lithium was a potential cause of thyroid dysfunction. Serum TSH concentrations were raised (to 10 mU/l or more) in 13 of 61 children aged 5–17 years taking lithium and valproate for up to 20 weeks (28c ). Of 42 bipolar patients who had taken lithium for 4–156 months, three had subclinical hypothyroidism, three had subclinical hyperthyroidism, and one was overtly hyperthyroid (29C ). Goiter by ultrasonography was present in 38% and mild thyroid dysfunction was suggested in 48% because of an apparent increased conversion of free T4 to free T3 . There was no correlation between the duration of lithium therapy and thyroid abnormalities. A retrospective record review of 300 patients with Graves’ disease and 100 with silent thyroiditis who had undergone thyroid scans showed that the likelihood of lithium exposure was 4.7 times higher in the latter, suggesting a link between lithium and thyrotoxicosis caused by silent thyroiditis (30C ). Case reports of adverse thyroid effects of lithium have included the following: • 56-year-old man taking lithium whose TSH concentration was abnormally high (50 mU/l) (31A ); • a 44-year-old woman who had taken lithium for 10 years and who developed swelling of the right lobe of the thyroid and hypothyroidism (15A );

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• a 63-year-old woman taking long-term lithium who developed subclinical hypothyroidism and primary hyperparathyroidism (32A ); • a 30-year-old man taking long-term ciclosporin and prednisolone following a bone-marrow transplant and long-term lithium for bipolar disorder who developed subacute thyroiditis, but without a clear relation to lithium (33A ); • a 27-year-old man who developed thyrotoxicosis while taking lithium (34A ).

Parathyroid Links between lithium and parathyroid dysfunction abound. Total serum calcium and intact parathyroid hormone concentrations were measured in 15 patients taking long-term lithium and 10 lithium-naïve patients; both were significantly higher in the lithium group (35c ). While the number of lithium patients with abnormally high concentrations was not stated, mean intact parathyroid hormone concentrations were almost twice the upper limit of the reference range (102 vs. 55 pg/ml). Parathyroid tumors from nine patients with lithium-associated hyperparathyroidism (six multiglandular, three uniglandular) have been compared with 13 non-lithium-associated sporadic parathyroid tumors with regard to gross genomic alterations (36c ). Gross chromosomal alterations were absent in most of the lithium group and were more common in the sporadic group. A lithium chloride solution caused changes in gravicurvature, statocyte ultrastructure, and calcium balance in pea root, believed to be due to effects of lithium on the phosphoinositide second messenger system (37E ). The implications with regard to human parathyroid function are obscure. Case reports of adverse parathyroid effects of lithium have included the following: • three cases of hyperparathyroidism among 26 cases of chronic lithium poisoning (see also Drug overdose) (38A ); • a 78-year-old man who had taken lithium for 30 years who presented with dehydration, azotemia, hypernatremia, hypercalcemia, and increased parathyroid hormone concentrations (39A ); • a 63-year-old woman taking long-term lithium therapy who had primary hyperparathyroidism (32A ); • a woman who had taken lithium for 15 years who became hypercalcemic and stopped taking lithium, but 2 years later had two parathyroid adenomas removed surgically (40A );

21 • a 42-year-old man who had taken lithium for 17 years and who had raised serum calcium and parathyroid hormone concentrations, which normalized after removal of a parathyroid adenoma (41A ); • a 59-year-old man with hypercalcemia and increased parathyroid hormone concentrations 3 months after starting lithium, which normalized after lithium was withdrawn (13A ); • three cases of lithium-related hyperparathyroidism from Denmark (42A ) and one from Spain (43A ).

Diabetes insipidus Two of 10 patients taking long-term lithium therapy were thought to have hypothalamic diabetes insipidus, because of a positive response to desmopressin (44c ). Metabolic It has been reported that diabetes mellitus is three times more common in bipolar patients than in the general population (45r ). However, the authors of this review also pointed out that data are conflicting with regard to the effects of lithium on blood glucose concentrations. An increased lithium dosage requirement in a hyperglycemic 40-year-old woman was attributed to the osmotic diuretic effect of glycosuria, increasing lithium excretion (46A ). In two cases of lithium intoxication, type 2 diabetes mellitus was felt to be a contributing factor (47A ). Electrolyte balance Potassium A 25-yearold man had a single episode of generalized flaccid hypokalemic paralysis while taking lithium. He responded to intravenous potassium, lithium was stopped, and 1 year later there were no further episodes (48A ). While the authors believed that lithium had been the cause, without confirmation by rechallenge this remains far from conclusive. Sodium Hypernatremia can occur secondary to dehydration in patients taking lithium and is not uncommon in association with lithium poisoning. Lithium-induced diabetes insipidus is often a contributing factor (see also Urinary tract and Drug overdose). Hematologic The effects of lithium on hemopoiesis have been studied in 100 patients who had developed chronic granulocytopenia after cancer chemotherapy or radiotherapy (49C ). The mean leukocyte count rose by 46%, but there were no changes in platelet or erythrocyte counts. However, there was a significant

22 increase in platelet count in those whose baseline values were below 150 × 109 /l. Lithium was well tolerated (mean serum concentration 0.59 mmol/l). Granulocyte counts and granulocyte colonystimulating factor (G-CSF) concentrations were measured in 18 patients before and after 1 and 4 weeks of lithium treatment, and compared with values in 20 patients taking long-term lithium (50c ). At week 4, the granulocyte count was significantly higher than at baseline or at week 1, or in the long-term group. There was only a non-significant increase in G-CSF concentration at weeks 1 and 4. The granulocyte count in those taking long-term lithium did not differ significantly from the baseline values in the other group. Mouth and teeth The issue has been raised of whether oral lithium therapy was responsible for failure of titanium dental implants in a 62-year-old man (51A ). Pancreas All cases of drug-induced pancreatitis (n = 47) reported to the Danish Committee on Adverse Drug Reactions between 1968 and 1999 have been analysed; one involved lithium (plus a neuroleptic drug) (52C ). Whether lithium was causally involved is not known. Urinary tract In a retrospective study, 114 patients who had taken lithium for 4–30 years were compared with 94 unmedicated age- and sex-matched controls with regard to changes in creatinine concentrations (53C ). Of the patients taking lithium 21% had blood creatinine concentrations that had increased gradually and were now over the top of the reference range. This finding was associated with episodes of lithium intoxication and with diseases and other medications that could also affect glomerular function. Sex, psychiatric diagnosis, duration of treatment, cumulative dose, and serum lithium concentrations did not predict an abnormal creatinine concentration. Renal function has been assessed in 10 patients taking long-term lithium (over 3 years, mean 80 months), 10 taking short-term lithium (3 years or less, mean 16 months), and 10 lithium-naïve patients (44C ). Serum BUN and creatinine concentrations were within the reference ranges and did not differ among the

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groups, but 24-hour creatinine clearance was significantly lower in those taking long-term lithium (73 vs. 125 and 150 ml/min). There were no significant differences among the groups in urine osmolality after 8-hour water deprivation and desmopressin, but partial nephrogenic diabetes insipidus was diagnosed in four long-term and two short-term patients and hypothalamic diabetes insipidus in two long-term patients. The authors concluded that long-term lithium therapy is a risk factor for renal impairment. There have been several case reports of lithium-related nephrogenic diabetes insipidus, sometimes associated with dehydration and lithium intoxication (39A , 54A –57A ). For example, a 77-year-old woman who had taken lithium for 10 years developed delirium, hypernatremia, prerenal azotemia, and a serum lithium concentration of 1.4 mmol/l; her condition was attributed to dehydration related to partial nephrogenic diabetes insipidus (54A ). An 83-year-old man developed nephrotic syndrome while taking lithium (58A ). Two studies in rats have potential implications for humans. In rats with mild to severe lithium-induced nephropathy, urine N-acetyl-bD-glucosaminidase (NAG) was an early indicator of renal insufficiency (59E ). Both 6 Li and 7 Li caused reduced urine concentrating ability and increased urine volume and renal tubular lesions, but 6 Li was more nephrotoxic (60E ). The authors suggested that eliminating 6 Li from pharmaceutical products might reduce nephrotoxicity (although 6 Li accounts for only about 7% of the lithium in such products). Skin Six months after beginning lithium, a man in his late twenties developed severe truncal acne, which worsened over 5 years, at which time lithium was withdrawn (61A ). Nevertheless, the lesions were still present 4 years later, leading to the conclusion that lithium had caused irreversible acne. Of course, the association could have been coincidental. Skin and hair A 55-year-old man (erroneously reported by me in SEDA-25 to be a woman), who had taken lithium and haloperidol for 11 years, developed hyperkeratotic follicular papules on his scalp, extremities, and trunk, which on biopsy were suggestive of follicular mycoses fungoides (62A ). He also had a

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1-year history of scalp, axillary, and pubic hair loss. Following replacement of lithium with valproate, his hair regrew and the papules cleared almost completely in 3 months. Hair When a split hair sample from a healthy volunteer was sent to six commercial laboratories in the USA for trace mineral analysis, marked variations in results were found (including lithium concentrations), leading to the conclusion that such analyses were unreliable (63c ). Sexual function A 17-year-old man had taken risperidone for 2 years without adverse effects, but 12 weeks after lithium was added he reported prolonged erections (lasting 1–3 hours) 2–5 times daily; risperidone was tapered and withdrawn and the problem resolved (64A ). Reproductive system In an in vitro study, LY294002, a phosphatidylinositol-3-kinase inhibitor, overcame impaired human sperm motility induced by lithium chloride (65E ). At blood concentrations within the human target range, oral lithium caused degenerative changes in testicular morphology in spotted munia (Lonchura punctulata), a seasonally breeding sub-tropical finch (66E ). How this might relate to effects in men is open to question. Immunologic Lithium has complex effects on immune function, as suggested by a study of 10 healthy volunteers who had increases in interleukin-4 and interleukin-10 concentrations, and falls in interleukin-2 and interferon concentrations (67c ). The clinical implications of these findings are unclear. Death Evidence continues to accrue that long-term lithium therapy reduces suicidal behavior. A retrospective study divided high-risk patients into excellent, moderate, and poor responders to lithium and showed that no further suicide attempts occurred in 93%, 83%, and 49% respectively (68C ). The substantial reduction in suicidal tendency in the poor responder group suggested an antisuicidal effect of lithium beyond its mood stabilizing properties, although the psychosocial benefits of lithium clinic treatment could have been contributing factors. For deaths related to lithium toxicity, see Drug overdose.

LONG-TERM EFFECTS Withdrawal Of 30 patients with major depressive disorder who had responded to lithium augmentation for antidepressant-resistant depression, 15 were switched to placebo over 1–7 days (69c ). Two became manic, and it was suggested that lithium withdrawal may have uncovered latent bipolar disorder (70r ). When 21 elderly patients with a major depressive episode who had responded to lithium augmentation had lithium withdrawn gradually (over 2–12 weeks), nine relapsed but none became manic (71c ). Whether gradual withdrawal protected against withdrawal mania or whether there were no latent bipolar patients in the study is unknown.

SECOND-GENERATION EFFECTS Pregnancy and lactation The treatment of bipolar disorder during pregnancy and lactation has been reviewed, with reference to lithiumrelated maternal, fetal, and neonatal toxicity, morphological and behavioral teratogenicity, carcinogenicity and mutagenicity, and miscellaneous effects (72R ). Elsewhere the effects of lithium, valproic acid, and carbamazepine during pregnancy (73R ), and drug-induced congenital defects (with only a brief mention of lithium) (6r ) have been reviewed. A more specific review dealing with the use of drugs during pregnancy in women with renal disease mentioned the need for lithium dosage reduction in such cases (74r ). A 37-year-old woman with severe bipolar disorder, who continued to take lithium throughout pregnancy, had a normal delivery but was not allowed to breast-feed (75A ). In a review of the use of psychotropic drugs during breast-feeding it was briefly mentioned that lithium was not advisable but was justified under certain circumstances (76r ). Lithium was also briefly discussed in a review of xenobiotics and breast-feeding (77r ).

RISK FACTORS Age In a cross-sectional study of 12 octogenarians (average age 84 years) who had

24 taken lithium for an average of 54 months (mean serum concentration 0.42 mmol/l), none became toxic and none had to stop treatment because of adverse effects. Transient renal function abnormalities were noted, one patient developed nephrogenic diabetes insipidus, and one became hypothyroid (78c ). For lithium therapy in very old people the authors advised close monitoring in a specialized setting.

DRUG ADMINISTRATION Drug formulations Brain lithium concentrations (measured by magnetic resonance spectroscopy) after the use of a modified-release formulation (Lithobid SR) or an immediaterelease formulation have been compared in a crossover design (79c ). There were higher brain concentrations with the modified-release formulation, but whether this has clinical implications requires further study. Formulations of lithium carbonate tablets with various binding substances have been discussed (80c ). Drug additives Gelatin is derived from natural pork and beef products and is present in some lithium formulations. Since certain religions forbid the consumption of gelatin, knowing that it is present in Eskalith capsules and Eskalith CR and absent in Eskalith tablets (not available in the USA) and Lithobid SR might influence prescribing practices under certain circumstances (81r ). The same would apply to other lithium products. Drug dosage regimens In an open-label pilot study of rapid administration of slow-release lithium (20 mg/kg/day in two divided doses) for acute mania, five of 15 patients completed 10 days of treatment, seven improved sooner and were discharged, and two withdrew because of adverse effects (bradycardia in one and tremor, fatigue, and diarrhea in the other; one patient appears not to have been accounted for); two other patients also had asymptomatic bradycardia (82c ). A review of loading strategies in acute mania included a section on lithium (83r ). A small study of brain lithium concentrations measured by magnetic resonance spectroscopy showed higher brain:serum lithium

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concentration ratios in subjects taking a single daily dose (n = 5) than in those taking a twicedaily regimen (n = 3) (84c ). Even to speculate about the possible clinical implications of this finding would be premature. Drug administration route To determine the safety of using lithium chloride dilution to measure cardiac output, the pharmacokinetic and toxic effects of intravenous lithium chloride have been studied in six conscious healthy Standardbred horses (85E ). The mean peak serum concentration was 0.56 mmol/l. There were no toxic effects nor significant changes in laboratories studies, electrocardiograms, or gastrointestinal motility. Three horses had increased urine output. A similar study was performed in patients undergoing cardiac surgery and healthy volunteers; the highest dose of LiCl was 0.6 mmol given intravenously five times at 2-minute intervals (86c ). Unfortunately, no mention was made of tolerability or adverse effects. Drug overdose There are three forms of lithium overdose: • acute (abrupt overdose in a drug-naïve person); • chronic (gradual accumulation, reaching toxic concentrations); • acute-on-chronic (abrupt overdose by a person already taking lithium). Overdose secondary to drug interactions is discussed in that section. The 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System listed six lithium-related deaths (four cases of intentional suicide and two of therapeutic error) and two other deaths in which lithium was not listed as the primary cause (87R ). A total of 4663 lithium-related exposures were reported, in which death was the outcome in 13 and a major life-threatening event or cause of significant disability in 267. A retrospective study of 97 cases of lithium poisoning treated at a regional center in Australia over 13 years found severe neurotoxicity in 28 (26 were cases of chronic poisoning and two were acute-on-chronic) (38C ). Risk factors were nephrogenic diabetes insipidus, older age,

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abnormal thyroid function, and impaired renal function. In a retrospective study of 114 patients admitted to a toxicological ICU with suspected lithium intoxication, 81 had definite intoxication; 78% were deliberate overdoses and 22% were accidental (due, for example, to renal insufficiency, dehydration, drug interactions, poor compliance, drunkenness). Most were treated conservatively with gastric lavage and forced diuresis; hemodialysis was used only in 3–6%. Two of those who took a deliberate overdose and one of those who took an accidental overdose died (88C ). Cases of lithium toxicity in a municipal hospital over a 10-year period involved eight women (mean age 66 years); neurological symptoms were the most common presentations (89c ). Two were acute overdoses and the rest were chronic intoxications. There was one death (group not specified). A 64-year-old woman had a two-week history of daily bilateral holocranial headache as the presenting complaint of lithium toxicity (serum concentration 2.5 mmol/l); dosage reduction resolved the headache and the extrapyramidal and cerebellar findings (90A ). Another toxic patient presented with nonconvulsive status epilepticus and a serum lithium concentration of 1.9 mmol/l (91A ). Non-reversible lithium neurotoxicity continues to be reported (92A , 93A ), including a case of lithium overdose (serum lithium concentration 3.9 mmol/l) with persistent severe ataxia for 9 months that improved markedly when inadvertently treated with high-dose buspirone (120–160 mg/day) (94A ). Hemodialysis (56A , 95A , 96A ), sometimes with additional continuous venovenous hemofiltration dialysis (97A , 98A ), continues to be described as a successful intervention for lithium poisoning. Peritoneal dialysis is a far less efficient way to clear lithium from the body. One patient treated in this way had permanent neurological abnormalities and another died; a third toxic patient who also had diabetic ketoacidosis died after treatment with hydration and insulin (99A ). On the other hand, a 51-yearold woman who took fifty 450 mg slow-release lithium carbonate tablets had a serum lithium concentration of 10.6 mmol/l 13 hours later, but no evidence of neurotoxicity or nephrotoxicity. She was treated conservatively with intravenous

fluids and recovered fully (100A ). Acute lithium overdose is often tolerated better than chronic intoxication. An 85-year-old woman became gradually toxic (serum lithium 2.9 mmol/l) in a nursing home (101A ). Despite only conservative management, there was slow but complete resolution of severe neurological symptoms, including coma, fixed pupils, and Cheyne–Stokes respiration.

DRUG INTERACTIONS In a review of the pharmacokinetics of mood stabilizers and new anticonvulsants, lithium drug interactions were only briefly mentioned (102r ). Anesthetics Sinus bradycardia (36 bpm) developed in a 44-year-old woman taking lithium, fentanyl, and propofol (15A ) (see also Cardiovascular). Antibiotics A 40-year-old woman developed nausea, malaise, impaired concentration, trembling, unsteadiness, diarrhea, and muscle spasm in association with a serum lithium concentration of 2.1 mmol/l while taking trimethoprim 300 mg/day (103A ). The interaction was attributed to the amiloride-like diuretic effect of the latter, causing lithium retention. Anticonvulsants In a review of pharmacokinetic interactions between antiepileptic drugs and psychotropic drugs, there were no clinically significant interactions of lithium with gabapentin, lamotrigine, valproate, or topiramate, although serum lithium concentrations were reduced slightly by topiramate (104r ). Lithium intoxication in a 33-year-old man was attributed to carbamazepine-induced renal insufficiency (105A ). Antidepressants Of 17 patients who took paroxetine as an adjunct to lithium therapy, retrospectively evaluated, four developed symptoms suggestive of an evolving serotonin syndrome that remitted when either drug was withdrawn (see also Nervous system) (18c ). A 45-year-old man taking lithium, amfebutamone, and venlafaxine developed a prolonged

26 seizure after ECT, thought to have been caused by a lowering of the seizure threshold due to amfebutamone (although a role of the other two drugs could not be excluded) (22A ). Antipsychotic drugs A 59-year-old man taking lithium, haloperidol, and carbamazepine had impaired memory, impaired attention, and an encephalopathy-like pattern on EEG that normalized when haloperidol was withdrawn (106A ). Olanzapine 5 mg/day was added, and 3 weeks later he became disoriented. Surprisingly, the olanzapine was continued and he remained disoriented. A 13-year-old boy with rhabdomyolysis ascribed to olanzapine was also taking lithium, so that a drug interaction could not be excluded (14A ). Diuretics A 26-year-old woman had been stable on lithium (serum concentration 1.1 mmol/l), but after taking herbal diuretics for 2–3 weeks

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developed manifestations of lithium toxicity (serum concentration 4.5 mmol/l) (107A ). NSAIDs A man of unspecified age developed cognitive impairment and a serum lithium concentration of 2.4 mmol/l after taking ibuprofen for shoulder pain (108A ). In a review of celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor, increased serum lithium concentration was mentioned as a possibility, but no specifics were provided (109r ). A 44-year-old woman taking nimesulide, a COX-2 inhibitor, and ciprofloxacin developed lithium intoxication (serum concentration 3.23 mmol/l) complicated by renal insufficiency; the interaction was attributed to nimesulide (110A ). Xanthines There have been case reports of caffeine withdrawal leading to increased serum lithium concentrations, assumed to be due to reduced renal lithium clearance (111r ).

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9. Newland KD, Mycyk MB. Hemodialysis reversal of lithium overdose cardiotoxicity. Am J Emerg Med 2002; 20: 67–8. 10. Terao T. Lithium therapy with pacemaker. Pharmacopsychiatry 2002; 35: 35. 11. Delva NJ, Hawken ER. Preventing lithium intoxication. Guide for physicians. Can Fam Phys 2001; 47: 1595–600. 12. Montes JM, Ferrando L. Gabapentin-induced anorgasmia as a cause of noncompliance in a bipolar patient. Bipolar Disord 2001; 3: 52. 13. Rifai MA, Moles JK, Harrington DP. Lithiuminduced hypercalcemia and parathyroid dysfunction. Psychosomatics 2001; 42: 359–61. 14. Rosebraugh CJ, Flockhart DA, Yasuda SU, Woosley RL. Olanzapine-induced rhabdomyolysis. Ann Pharmacother 2001; 35: 1020–3. 15. Uchiyama Y, Nakao S, Asai T, Shingu K. A case of atropine-resistant bradycardia in a patient on long-term lithium medication [Japanese]. Jpn J Anesthesiol 2001; 50 1229–31. 16. Bhandari S, Samellas D. Bipolar affective disorder and idiopathic pulmonary fibrosis. J Clin Psychiatry 2001; 62: 574–5. 17. Patten SB, Williams JVA, Petcu R, Oldfield R. Delirium in psychiatric inpatients: a case–control study. Can J Psychiatry 2001; 46: 162–6. 18. Fagiolini A, Buysse DJ, Frank E, Houck PR, Luther JF, Kupfer DJ. Tolerability of combined treatment with lithium and paroxetine in patients

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with bipolar disorder and depression. J Clin Psychopharmacol 2001; 21: 474–8. 19. Suwalska A, Lojko D, Rybakowski J. Wplyw lekow normotymicznych na czynnosci poznawcze. Psychiatr Pol 2001; 35: 245–56. 20. Arts BMG, Honig A, Riedel WJ, Ponds RWHM. Cognitive effects of lithium; a metaanalysis and proposal for screening. Tijdschr Psychiatr 1998; 40: 466–8. 21. Van der Steenstraten IM, Achilles RA. Irreversibele neurologische schade na een lithiumintoxicatie bij therapeutische concentraties. Tijdschr Psychiatr 2001; 43: 271–5. 22. Conway CR, Nelson LA. The combined use of bupropion, lithium, and venlafaxine during ECT: a case of prolonged seizure activity. J ECT 2001; 17: 216–18. 23. Netski AL, Piasecki M. Lithium-induced exacerbation of stutter. Ann Pharmacother 2001; 35: 961. 24. Davis JM. Lithium intoxication and pontine haemorrhage. Acta Psychiatr Scand 2001; 103: 401. 25. Grounds D. Connection between lithium and muscular incoordination. Aust NZ J Psychiatry 2002; 36: 142–3. 26. Kupka RW, Nolen WA, Post RM, McElroy SL, Altshuler LL, Denicoff KD, Frye MA, Keck PE, Leverich GS, Rush AJ, Suppes T, Pollio C, Drexhage HA. High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol Psychiatry 2002; 51: 305–11. 27. Bocchetta A, Mossa P, Velluzzi F, Mariotti S, Del Zompo M, Loviselli A. Ten-year follow-up of thyroid function in lithium patients. J Clin Psychopharmacol 2001; 21: 594–8. 28. Gracious BL. Elevated TSH in bipolar youth prescribed both lithium and divalproex sodium. Int Drug Ther Newslett 2001; 36: 94–5. 29. Çayköylü A, Çapoglu I, Ünüvar N, Erdem F, Çetinkaya R. Thyroid abnormalities in lithiumtreated patients with bipolar affective disorder. J Int Med Res 2002; 30: 80–4. 30. Miller KK, Daniels GH. Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Clin Endocrinol (Oxf) 2001; 55: 501–8. 31. Bermudes RA. Psychiatric illness or thyroid disease? Don’t be misled by false lab tests. Curr Psychiatry 2002; 1: 51–2, 57–61. 32. Mira SA, Gimeno EJ, Díaz-Guerra GM, Carranza YFH. Alteraciones tiroideas y paratiroideas asociadas al tratamiento crónico con litio. A propósito de un caso. Rev Esp Enferm Metab Oseas 2001; 10: 153–6. 33. Obuobie K, Al-Sabah A, Lazarus JH. Subacute thyroiditis in an immunosuppressed patient. J Endocrinol Invest 2002; 25: 169–71. 34. Scanelli G. Tireotossicosi da litio. Descrizione di un caso e revisione della letteratura. Recenti Prog Med 2002; 93: 100–3. 35. Turan MT, Esel E, Tutus A, Sofuoglu S, Gönük AS. Lithium-induced alterations in parathormone function in patients with bipolar disorder. Bull Clin Psychopharmacol 2001; 11: 96–100. 36. Dwight T, Kytölä S, Teh BT, Theodosopoulos G, Richardson AL, Philips J, Twigg S, Delbridge L.

27 Marsh DJ, Nelson AE, Larsson C, Robinson BG. Genetic analysis of lithium-associated parathyroid tumors. Eur J Endocrinol 2002; 146: 619–27. 37. Belyavskaya NA. Lithium-induced changes in gravicurvature, statocyte ultrastructure and calcium balance of pea roots. Adv Space Res 2001; 27: 961– 6. 38. Oakley PW, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust NZ J Psychiatry 2001; 35: 833–40. 39. Krastins MG, Phelps KR. Nephrogenic diabetes insipidus and hyperparathyroidism in a patient receiving chronic lithium therapy. J Am Geriatr Soc 2002; 50: S140. 40. Dieserud F, Brun AC, Låhne PE, Normann E. Litiumbehandling og hyperparatyreoidisme. Tidsskr Nor Laegeforen 2001; 121: 2602–3. 41. Pieri-Balandraud N, Hugueny P, Henry JF, Tournebise H, Dupont C. Hyperparathyroïdie induite par le lithium. Un nouveau cas. Rev Med Interne 2001; 22: 460–4. 42. Valeur N, Andersen RS. Lithium-induced dysfunction of the parathyroid hormone. Ugeskr Laeg 2002; 164: 639–40. 43. Catalá JC, Rubio AB, Fernández CC, Ballester YAH. Hiperparatiroidismo asociada al tratamiento con litio. Rev Esp Enferm Metab Oseas 2001; 10: 157–8. 44. Turan T, Esel E, Tokgöz B, Aslan S, Sofuoglu S, Utas C, Kelestimur F. Effects of short- and long-term lithium treatment on kidney functioning in patients with bipolar mood disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 651–5. 45. Cassidy F. Diabetes mellitus in manicdepressive patients. Essent Psychopharmacol 2001; 4: 49–57. 46. Cyr M, Guia MAC, Laizure SC. Increased lithium dose requirement in a hyperglycemic patient. Ann Pharmacother 2002; 36: 427–9. 47. Uzu T, Ichida K, Ko M, Tsukurimichi S, Yamato M, Takahara K, Ohashi M, Yamauchi A, Nomura M. Two cases of lithium intoxication complicated by type 2 diabetes mellitus [Japanese]. J Jpn Diabetes Soc 2001; 44: 767–70. 48. Chémali KR, Suarez JI, Katirji B. Acute hypokalemic paralysis associated with long-term lithium therapy. Muscle Nerve 2001; 24: 297–8. 49. Hager ED, Dziambor H, Höhmann D, Winkler P, Strama H. Effects of lithium on thrombopoiesis in patients with low platelet cell counts following chemotherapy or radiotherapy. Biol Trace Elem Res 2001; 83: 139–48. 50. Esel E, Özdemir MA, Turan MT, Bastürk M, Kiliç H, Köse K, Gönül AS, Sofuoglu S. Effects of lithium treatment on granulocytes and granulocyte colony-stimulating factor in patients with bipolar affective disorder. Bull Clin Psychopharmacol 2001; 11: 28–32. 51. Corica M, Borcese R, Savoldi E. Can the lithium therapy cause titanium implant failure? J Dent Res 2001; 80: 1246. 52. Andersen V, Sonne J, Andersen M. Spontaneous reports on drug-induced pancreatitis in Den-

28 mark from 1968 to 1999. Eur J Clin Pharmacol 2001; 57: 517–21. 53. Lepkifker E, Sverdlik A, Iancu I, Ziv R. Renal failure in long-term lithium treatment. Bipolar Disord 2001; 3 Suppl 1: 45. 54. Mukhopadhyay D, Gokulkrishnan L, Mohanaruban K. Lithium-induced nephrogenic diabetes insipidus in older people. Age Ageing 2001; 30: 347–50. 55. Eustatia-Rutten CFA, Tamsma JT, Meinders AE. Lithium-induced nephrogenic diabetes insipidus. Neth J Med 2001; 58: 137–42. 56. Laßnig E, Berent R, Wallner M, Jagsch C, Auer J, Eber B. Manisch-depressive Patientin mit Polyurie unter Lithiumtherapie. Intensivmedizin 2001; 38: 26–30. 57. Waise A, Fisken RA. Unsuspected nephrogenic diabetes insipidus. Br Med J 2001; 323: 96–7. 58. Herrero-Mendoza MD, Caramelo C, BellverÁlvarez TM, Lopez-Cubero L. Sindrome nefrotico y tratamiento con litio. Med Clin (Barc) 2001; 116: 758–9. 59. Ida S, Yokota M, Ueoka M, Kiyoi K, Takiguchi Y. Mild to severe lithium-induced nephropathy models and urine N-acetyl-b-D-glucosaminidase in rats. Methods Find Exp Clin Pharmacol 2001; 23: 445–8. 60. Stoll PM, Stokes PE, Okamoto M. Lithium isotopes: differential effects on renal function and histology. Bipolar Disord 2001; 3: 174–80. 61. Öztas P, Aksakal AB, Öztas MO. Severe acne with lithium. Ann Pharmacother 2001; 35: 961–2. 62. Francis GJ, Silverman AR, Saleh O, Lee GJ. Follicular mycosis fungoides associated with lithium. J Am Acad Dermatol 2001; 44: 308–9. 63. Seidel S, Kreutzer R, Smith D, McNeel S, Gilliss D. Assessment of commercial laboratories performing hair mineral analysis. J Am Med Assoc 2001; 285: 67–72. 64. Owley T, Leventhal B, Cook EH. Risperidoneinduced prolonged erections following the addition of lithium. J Child Adolesc Psychopharmacol 2001; 11: 441–2. 65. Luconi M, Marra F, Gandini L, Filimberti E, Lenzi A, Forti G, Baldi E. Phosphatidylinositol 3kinase inhibition enhances human sperm motility. Hum Reprod 2001; 16: 1931–7. 66. Banerji TK, Maitra SK, Dey M, Hawkins HK. Gametogenic responses of the testis in spotted munia (Lonchura punctulata; aves) to oral administration of lithium chloride. Endocr Res 2001; 27: 345–56. 67. Rapaport MH, Manji HK. The effects of lithium on ex vivo cytokine production. Biol Psychiatry 2001; 50: 217–24. 68. Ahrens B, Müller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry 2001; 34: 132–6. 69. Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry 2000; 157: 1429–35.

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70. Faedda GL, Tondo L, Baldessarini RJ. Lithium discontinuation: uncovering latent bipolar disorder? Am J Psychiatry 2001; 158: 1337–8. 71. Fahy S, Lawlor BA. Discontinuation of lithium augmentation in an elderly cohort. Int J Geriatr Psychiatry 2001; 16: 1004–9. 72. Davis LL, Shannon S, Drake RG, Petty F. The treatment of bipolar disorder during pregnancy. In: Yonkers KA, Little BB, editors. Management of Psychiatric Disorders in Pregnancy. London: Arnold, 2001: 122–33. 73. Iqbal MM, Sohhan T, Mahmud SZ. The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. Clin Toxicol 2001; 39: 381–92. 74. Keller F, Griesshammer M, Häussler U, Paulus W, Schwarz A. Pregnancy and renal failure. The case for application of dosage guidelines. Drugs 2001; 61: 1901–20. 75. Retamal PC, Cantillano VA. Tratamiento de la enfermedad bipolar durante el embarazo y puerperio. Caso clinico. Rev Med Chil 2001; 129: 556–60. 76. Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E. The use of psychotropic medications during breast-feeding. Am J Psychiatry 2001; 158: 1001–9. 77. Howard CR, Lawrence RA. Xenobiotics and breastfeeding. Pediatr Clin North Am 2001; 48: 485–504. 78. Fahy S, Lawlor BA. Lithium use in octogenarians. Int J Geriatr Psychiatry 2001; 16: 1000–3. 79. Henry ME, Moore CM, Demopolas C, Cote J, Renshaw PF. A comparison of brain lithium levels attained with immediate and sustained release lithium. Biol Psychiatry 2001; 49 Suppl 8: 119S. 80. Gazikolovic E, Obrenovic D, Nicovic Z. Formulation of lithium carbonate tablets with various binding substances [Serbo-Croatian]. Vojnosanit Pregl 2001; 58: 641–4. 81. Sattar SP, Pinals DA. When taking medications is a sin. Psychiatr Serv 2002; 53: 213–14. 82. Keck PE, Strakowski SM, Hawkins JM, Dunayevich E, Tugrul KC, Bennett JA, McElroy SL. A pilot study of rapid lithium administration in the treatment of acute mania. Bipolar Disord 2001; 3: 68–72. 83. Carroll BT, Thalassinos A, Fawver JD. Loading strategies in acute mania. CNS Spectrums 2001; 6: 919–22, 30. 84. Soares JC, Boada F, Spencer S, Mallinger AG, Dippold CS, Wells KF, Frank E, Keshavan MS, Gershon S, Kupfer DJ. Brain lithium concentrations in bipolar disorder patients: preliminary 7 Li magnetic resonance studies at 3T. Biol Psychiatry 2001; 49: 437–43. 85. Hatfield CL, McDonell WN, Lemke KA, Black WD. Pharmacokinetics and toxic effects of lithium chloride after intravenous administration in conscious horses. Am J Vet Res 2001; 62: 1387–92. 86. Jonas MM, Linton RAF, O’Brien TK, Band DM, Linton NWF, Kelly F, Burden TJ, Chevalier SFA, Thompson RPH, Birch NJ, Powell JJ. The pharmacokinetics of intravenous lithium chloride in patients and normal volunteers. J Trace Microprobe Techn 2001; 19: 313–20.

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87. Litovitz TL, Klein-Schwartz W, White S, Cobaugh DJ, Youniss J, Omslaer JC, Drab A, Benson BE. 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001; 19: 337–95. 88. Montagnon F, Saïd S, Lepine JP. Lithium: poisonings and suicide prevention. Eur Psychiatry 2002; 17: 92–5. 89. Meltzer E, Steinlauf S. The clinical manifestations of lithium intoxication. Isr Med Assoc J 2002; 4: 265–7. 90. Bigal ME, Bordini CA, Speciali JG. Daily headache as a manifestation of lithium intoxication. Neurology 2001; 57: 1733–4. 91. Kuruvilla PK, Alexander J. Lithium toxicity presenting as non-convulsive status epilepticus (NCSE). Aust NZ J Psychiatry 2001; 35: 852. 92. García-Resa E, Blasco-Fontecilla H, ValbuenaBriones A. Sindrome de neurotoxicidad irreversible por litio. Med Clin (Barc) 2001; 116: 357. 93. Roy M, Fond L, Ratrema M, Convers Ph, Lutz MF, Cathébras P. Intoxication au lithium: complications neurologiques sevères. Presse Med 2001; 30: 900–1. 94. Megna J, O’Dell M. Ataxia from lithium toxicity successfully treated with high-dose buspirone: a single-case experimental design. Arch Phys Med Rehabil 2001; 82: 1145–8. 95. Peces R, Pobes A. Effectiveness of haemodialysis with high-flux membranes in the extracorporeal therapy of life-threatening acute lithium intoxication. Nephrol Dial Transplant 2001; 16: 1301–3. 96. Danel V, Rhodes AS, Saviuc P, Hanna J. Intoxication grave par le lithium: à propos de deux cas. JEUR 2001; 14: 134–6. 97. Meyer RJ, Flynn JT, Brophy PD, Smoyer WE, Kershaw DB, Custer JR, Bunchman TE. Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis 2001; 37: 1044–7. 98. Beckmann U, Oakley PW, Dawson AH, Byth PL. Efficacy of continuous venovenous hemodialy-

29 sis in the treatment of severe lithium toxicity. Clin Toxicol 2001; 39: 393–7. 99. Suraya Y, Yoong KY. Lithium neurotoxicity. Med J Malaysia 2001; 56: 378–81. 100. Nagappan R, Parkin WG, Holdsworth SR. Acute lithium intoxication. Anaesth Intensive Care 2002; 30: 90–2. 101. Dolamore MJ. Case report: lithium toxicity in a nursing home patient. Ann Long-Term Care 2001; 9: 56–61. 102. Wang PW, Ketter TA. Pharmacokinetics of mood stabilizers and new anticonvulsants. Psychopharmacol Bull 2002; 36: 44–66. 103. De Vries PL. Lithiumintoxicatie bij gelijktijdig gebruik van trimethoprim. Ned Tijdschr Geneeskd 2001; 145: 539–40. 104. Spina E, Perucca E. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia 2002; 43 Suppl 2: 37–44. 105. Mayan H, Golubev N, Dinour D, Farfel Z. Lithium intoxication due to carbamazepineinduced renal failure. Ann Pharmacother 2001; 35: 560–2. 106. Swartz CM. Olanzapine–lithium encephalopathy. Psychosomatics 2001; 42: 370. 107. Pyevich D, Bogenschutz MP. Herbal diuretics and lithium toxicity. Am J Psychiatry 2001; 158: 1329. 108. Joseph DiGiacomo. Interview with F Flach. Risk management issues associated with psychopharmacological treatment. Essent Psychopharmacol 2001; 4: 137–50. 109. Davies NM, Gudde TW, De Leeuw AWC. Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert Opin Pharmacother 2001; 2: 139–52. 110. Bocchia M, Bertola G, Morganti D, Toscano M, Colombo E. Intossicazione da litio e uso di nimesulide. Recenti Prog Med 2001; 92: 462. 111. Donovan JL, DeVane CL. A primer on caffeine pharmacology and its drug interactions in clinical psychopharmacology. Psychopharmacology Bull 2001; 35: 30–48.

Eileen Wong and Jayendra K. Patel

4 AMPHETAMINES

(SED-14, 100; SEDA-23, 34; SEDA-24, 32; SEDA-25, 34)

Amphetamine Cardiovascular Two new cases of myocardial infarction following use of amphetamine have been reported (1Ar , 2Ar ). • A 34-year-old man who smoked a pack of cigarettes a day took amphetamine for mild obesity. He developed an acute myocardial infarction 1 week later. Echocardiography showed inferior left ventricular hypokinesia and a left ventricular ejection fraction of 50%. Coronary cineangiography showed normal coronary arteries, but confirmed the inferior left ventricular hypokinesia. Blood and urine toxicology were positive only for amphetamine. • A 31-year-old man developed generalized discomfort after injecting four doses of amphetamine and methamphetamine over 48 hours, but no chest pain or tightness or shortness of breath. Electrocardiograms showed inverted T waves and left bundle branch block. Echocardiography showed reduced anterior wall motion.

The authors reviewed other reported cases of myocardial infarction associated with amphetamine. The patients were in their mid-thirties and most were men. The interval from the use of amphetamines to the onset of symptoms varied from a few minutes to years. No specific myocardial site was implicated. Coronary angiography in most cases showed non-occlusion. The cause of myocardial ischemia in these cases was uncertain, even though coronary artery spasm followed by thrombus formation was considered the most likely underlying mechanism. Some have suggested that electrocardiographic and biochemical cardiac marker testing should be considered in every patient, with or without symptoms suggesting acute coronary syndrome, after the use of amphetamines. Others © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

30

Drugs of abuse have suggested that calcium channel blockers may play an important role in the treatment of myocardial infarction due to amphetamine use or abuse. In one patient, administration of betablockers caused anginal pain, suggesting that they should be avoided. All the patients except one had a good outcome. Nervous system Vertebral artery dissection has been reported in a patient taking amphetamine and methamphetamine (3Ar ). • A healthy 40-year-old right-handed man presented with a 3-day history of an occipital headache and imbalance. He had a 3-year history of daily oral amphetamine abuse with escalating quantities, the last occasion being 12 hours before the onset of the symptoms. He had a history of “speed” abuse and a 20-pack-year history of tobacco use. He had mild right arm dysmetria without ataxia. His brain CT scan without contrast was normal. He then developed nausea, vomiting, visual loss, and progressive obtundation. He had hypertension (160/90 mmHg), bilateral complete visual loss, right lower facial weakness, mild dysarthria without tongue deviation, divergent gaze attenuated by arousal, bilateral truncal and appendicular dysmetria with inability to stand and walk, and generalized symmetrical hyper-reflexia with extensor plantar reflexes. His urine screen was positive for methamphetamine. A brain MRI scan showed infarction of both medial temporal lobes, the left posteromedial thalamus, and the right superior and left inferior cerebellum. Magnetic resonance angiography and fat saturation MRI showed reduced flow in the left vertebral artery and a ring of increased signal within its lumen, consistent with hematoma and dissection.

The authors suggested that there was a possible association between the use of amphetamines and vertebral artery dissection.

Methamphetamine Psychiatric Methamphetamine is difficult to control legally, as it is easily manufactured

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in a small laboratory. Chronic methamphetamine use is associated with psychiatric symptoms, such as psychosis and anxiety. Methamphetamine increases the activity of dopamine, mainly by inhibiting the dopamine transporter. However, this does not explain why psychosis persists even when the methamphetamine is no longer present in the body (4R ). Chronic methamphetamine use has been reported to reduce dopamine transporter density in the caudate/putamen and nucleus accumbens. However, previous studies have been criticized for not controlling for other drug use. Dopamine transporter density in the brain has been investigated during a period of abstinence in 11 methamphetamine monodrug users and nine healthy subjects, all men (5C ). The dopamine transporter density of methamphetamine users was significantly lower in the caudate/putamen, nucleus accumbens, and prefrontal cortex than in the controls. The severity of psychiatric symptoms correlated with the duration of methamphetamine use. The reduction in dopamine transporter density in the caudate/putamen and nucleus accumbens was significantly associated with the duration of methamphetamine use and closely related to the severity of persistent psychiatric symptoms. The reduction in dopamine transporters may be long lasting, even if methamphetamine is withdrawn. Only some methamphetamine users develop psychosis, not all (4R ). In laboratory animals, methamphetamine is toxic to dopamine terminals. In 15 subjects (six men and nine women, mean age 32 years), who met the criteria for methamphetamine abuse, and 18 healthy volunteers (12 men and six women), there was a significant reduction in the number of dopamine transporters in detoxified methamphetamine abusers compared with controls (mean values of 28% in the caudate and 21% in the putamen) (6C ). This was associated with poor motor and memory performance. The reductions in dopamine transporters in the methamphetamine abusers were smaller than those found in patients with Parkinson’s disease and occurred in subjects who had been abstinent for 11 months. Since significant reductions in dopamine transporters occur with both age and methamphetamine use, it is possible that methamphetamine will be associated with a higher risk of parkinsonian symptoms in abusers later in life.

31 Glucose metabolism in the brain has been studied using positron emission tomography, to look for evidence of functional changes in regions other than those innervated by dopamine neurons in 15 detoxified methamphetamine abusers and 21 controls (7C ). Whole-brain metabolism in the methamphetamine abusers was 14% higher than in the controls. The difference was largest in the parietal cortex (20%), but there was significantly lower metabolism in the thalamus (17%) and striatum (12% caudate and 6% putamen). The authors suggested that methamphetamine, in doses abused by humans, causes long-lasting metabolic changes in brain regions connected with dopamine pathways, but also in areas that are not innervated by dopamine. The effects of protracted abstinence on loss of dopamine transporters in the striatum in 5 methamphetamine abusers has been evaluated during short-term abstinence and then retested during protracted abstinence (12–17 months) (8C ). The dopamine transporters increased in number, providing hope for effective treatment; however, this regeneration was not sufficient to provide complete functional recovery, as measured by neuropsychological tests. Drug dependence The role of dopamine in the addictive process has been explored (9C ). The authors raised the possibility that the orbitoprefrontal cortex is linked to compulsive drug abuse. They recruited 15 methamphetamine users and 20 non-drug user controls. The methamphetamine abusers had significantly fewer dopamine D2 receptors than the controls. There was an association between lower numbers of dopamine D2 receptors and metabolism in the orbitofrontal cortex in the methamphetamine users. These findings are similar to those observed in cocaine, alcohol, and heroin users. The authors suggested that D2 receptormediated dysregulation of the orbitofrontal cortex could be a common mechanism underlying loss of control and compulsive abuse of drugs.

Methylenedioxymethamphetamine (ecstasy, MDMA) Concern has been raised about the increasing use of ecstasy in Europe in the last 10

32 years (10Cr ), particularly the UK and the Netherlands. MDMA and drugs such as its Ndemethylated derivative (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), N-methylbenzodioxazolylbutamine (MBDB), and 4bromo-2,5-dimethoxyphenylethylamine (2-CB or Nexus) are often grouped together as “ecstasy”. Some have used the term “enactogen”, meaning “touching within”, to describe MDMA. The patterns and trends of substance use among college students have been evaluated over a 30-year period (11C ). Alcohol use remained stable, but illicit drug use peaked in 1978 and fell sharply over the next 20 years. MDMA was the exception: its use rose from 4.1% in 1989 to 10% in 1999. MDMA was the second most frequently tried illicit drug after marijuana.

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Respiratory Pneumomediastinum after MDMA has been reported (13c ). • A 16-year-old boy took six ecstasy tablets over 2 hours. A period of vomiting ensued and he developed chest pain and swelling in the neck. A chest X-ray showed pneumomediastinum. He was managed conservatively and his emphysema settled uneventfully within 2 days.

The authors reported that five such cases have been reported in the past 4 years in the British literature; the respiratory complications were thought to be due to severe physical exercise or secondary to vomiting. It is therefore possible that this complication may not be due to a direct effect of MDMA, but rather a consequence of repeated Valsalva maneuvers associated with the dance habits of ecstasy users or vomiting induced by the drug.

Cardiovascular Cardiotoxicity following ecstasy use has been reported (12Ar ). • A 16-year-old boy took three tablets of ecstasy and amphetamine 0.3 g and several hours later had convulsions and a temperature of 40.9◦ C. His heart rate was 210 and his blood pressure 100/75 mmHg. His creatine kinase activity was raised and he had myoglobinuria, renal impairment, hyperkalemia, and hypocalcemia. An electrocardiogram showed ventricular and supraventricular tachycardias but no myocardial ischemia. A diagnosis of serotonin syndrome due to ecstasy ingestion with associated hyperpyrexia and rhabdomyolysis was made. Following active treatment, his condition stabilized, with restoration of sinus rhythm and normal urine output. However, 12 hours later he developed jaundice, raised liver enzymes, and coagulopathy, suggesting acute liver failure due to ecstasy. With supportive treatment, his liver function improved. However, another 12 hours later, he developed shortness of breath associated with right-sided chest signs and X-ray changes compatible with aspiration pneumonia, and required emergency intubation 4 days later. He developed pulmonary edema, his pulmonary artery was occluded, and an echocardiogram showed globally impaired left ventricular function with an ejection fraction of 30–35%; there was electrocardiographic T wave inversion. Primary myocardial damage causing cardiac dysfunction was investigated using serial creatine kinase and troponin measurements. He recovered completely with treatment and an echocardiogram showed an ejection fraction of 60%.

The authors reported that this was the first case report of clinical, radiological, biochemical, and echocardiographic evidence of myocardial damage and cardiac dysfunction following ecstasy and amphetamine use.

The cognitive effects of MDMA Recently, several studies have focused on the cognitive effects of MDMA, and a review of the adverse effects of MDMA in animals has raised concerns about potential toxicity in humans (14R ). MDMA can selectively damage brain serotonin (5-HT) neurons in animal brains, even at doses within the range of those typically used recreationally. In many studies lasting reductions in various brain 5-HT markers have been reported in MDMA-treated animals. Axons of 5-HT neurons were damaged in MDMA-treated animals, including monkeys, and neurotoxic effects of MDMA have been observed in every animal species studied so far. In non-human primates, the toxic dose of MDMA closely approaches the dose used by humans. In 30 regular ecstasy users (drug use ten or more times per month) and 31 ecstasy-free controls, prospective memory—the process of remembering to do things at some future time— was assessed using a self-report questionnaire (15C ). Ecstasy users reported global impairment in prospective memory, even after controlling for the use of other drugs. The authors observed that their finding of impairment of cognitive functions, especially memory, in regular ecstasy users is similar to findings in other recent studies. They postulated that serotonergic toxicity secondary to chronic MDMA exposure

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can cause cognitive impairment, as serotonergic pathways are involved in memory function. More support for a relation between memory impairment, serotonin neurotoxicity, and chronic MDMA use has come from a study of cognitive performance and serotonin function in two groups of 21 men with moderate or heavy MDMA use and a control group of 20 men who had not used MDMA (16R ). Ecstasy users had a broad spectrum of statistically significant but clinically subtle impairment of memory and prolonged reaction times. Heavy users had larger effects than moderate users. Serotonergic function was assessed in a double-blind crossover challenge with dexfenfluramine 30 mg or placebo. Release of cortisol, but not prolactin, after dexfenfluramine was significantly reduced in both groups of ecstasy users compared with controls. According to the authors, these neuroendocrine findings are similar to those observed in animals and humans. Recent exposure to ecstasy, psychosocial profiles, and the use of other drugs did not explain the differences. As mentioned above, animal studies have shown reductions in various serotonin markers in the brain. The density of serotonin transporters (SERTs) in humans can be measured by neuroimaging techniques, such as SPECT and PET. Two groups of ecstasy users (22 recent but abstinent and 16 ex-users) were compared with ecstasy-naïve controls (17C ). In subjects who had stopped using MDMA more than 1 year before the study, cortical densities of SERTs did not differ from those of controls. However, recent MDMA users had global reductions in SERTs. In addition, individuals who had stopped using MDMA had a deficit in verbal memory similar to that in current MDMA users. Higher lifetime doses of MDMA were associated with greater impairment of immediate verbal memory. The authors suggested that the absence of reductions in SERT densities in exMDMA users suggested reversibility of MDMAinduced changes in brain SERTs. Thus, MDMA use can lead to neurotoxic changes in human cortical 5-HT brain neurons, but these changes may be reversible. However, functional consequences of MDMA on cortical brain 5-HT neurons may not be reversible, as seen by impaired memory function in this group, similar to that in current MDMA users. The amino acid N-acetylaspartate is a robust, non-specific marker of neuronal loss or

33 brain dysfunction. It is detectable by proton magnetic resonance spectroscopy (MRS). The ratio of creatine to phosphocreatine, another marker that remains stable in many brain diseases, can also be assessed using MRS. In a recent study, the ratio of N-acetylaspartate to creatine/phosphocreatine was used to determine whether there are memory deficits in MDMA users and whether there are changes in specific brain regions (18C ). Eight men with a history of MDMA use and seven MDMA-naïve male controls took part. The findings included a significant difference in delayed recall between MDMA users and MDMA-naïve controls. There was a strong association between impaired memory function in MDMA users and neuronal pathology, specific to the prefrontal cortex. Poorer performance on verbal memory testing was associated with greater neuronal loss or dysfunction in MDMA users. These findings implicate MDMA as a cause of serotonergic neuronal damage and memory impairment. Another group has assessed cognitive function in 80 subjects who were non-users, novice users, regular users, or currently abstinent users of MDMA (19C ). Compared with the nonusers, all three groups of MDMA users had significantly poorer verbal fluency and immediate and delayed prose recall. Days since last use and total lifetime consumption of MDMA made separate contributions to the variance in recall scores. Novice and currently abstinent users likewise had significantly poorer immediate recall than non-users. The novice users had milder impairment than the regular users, while those who were currently abstinent performed at a similar level to regular users. These deficits were not attributable either to differences in general reasoning ability or to impairment of working memory. The authors expressed concern that increased use of MDMA in large numbers of young people and its enduring effects on memory are under-appreciated consequences. However, cognitive impairment and MDMA use is a complex association to study, with difficult confounding variables. For example, MDMA users may consume cannabis to relieve the negative experience that occurs when MDMA-related euphoria diminishes. In a recent study the concurrent use of cannabis was controlled by the recruitment of 31 drug-naïve controls, 11 MDMA/cannabis users, and 18 cannabis users (20C ). Users were instructed

34 to abstain from drug use for 48 hours before testing. The MDMA/cannabis user group had deficits in learning, memory, verbal word fluency, speed of processing, and manual dexterity compared with the healthy controls. The authors suggested that the deficits in the drug group were not related to MDMA. They observed that the study group did not perform poorly compared with those who used cannabis only. Moreover, the finding that the MDMA/cannabis group was no different from the cannabis group suggested that MDMA does not cause significant cognitive deficits. The poorer performance of the MDMA/cannabis users was very little affected by the frequency of use or total MDMA consumption. However, co-varying for indices of cannabis consumption removed most of the significant differences between the groups. On the other hand, MDMA did affect the measures of working memory, such as forward and backward digit span. The authors raised the question of whether previous evaluations of the effects of MDMA on cognition had been confounded by the concomitant use of cannabis. Risk factors Sex differences in subjective experiences of MDMA use have been reported. Three previously published controlled studies of the acute effects of MDMA in healthy subjects with no or single previous MDMA experience have been summarized (21M ). There were 74 subjects (54 men and 20 women), aged 20– 49 (mean 27) years, of whom 69 were ecstasynaïve and five had used it on one or two occasions before. All had been screened using a semi-structured interview, and anyone with a personal or family history of mood disorders, schizophrenia, or other psychiatric disorders was excluded. The analysis included psychological and physiological effects of MDMA in controlled settings. Generally, subjective effects of MDMA were more intense in women then men. Women had especially higher scores for MDMA-induced perceptual changes, anxiety, and adverse effects. In contrast, men were slightly activated by MDMA compared with women and had significantly higher increases in systolic blood pressure. The authors suggested that women may be more sensitive to the effects of MDMA. Many previous studies have suggested sex differences in markers for serotonergic activity in ecstasy users, with sugges-

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tions that serotonergic function is relatively impaired in women compared with men. The authors, based on their findings coupled with data from previous reports, raised the question of whether women might be more susceptible to MDMA-induced depletion of serotonin. Psychiatric Psychosis, both acute and chronic, has been reported following the use of ecstasy. A 26-year-old man without previous psychopathology (except social phobia) unknowingly consumed ecstasy with alcohol and developed an acute psychosis 12 hours later. The authors reported that 12 cases of acute psychosis have previously been reported after the use of ecstasy once or twice. Based on a previously suggested hypothesis, they proposed that the psychosis was probably due to the indirect effects of MDMA on the dopaminergic system, secondary to serotonergic deregulation. Most patients who went on to develop a chronic psychosis were either chronic ecstasy users or multiple substance users. However, in the case mentioned here, after 6 months the patient still had symptoms of psychosis. The authors further suggested that genetically slow metabolizers of ecstasy are probably more vulnerable to this adverse effect, even with a single exposure. Past reports have suggested that MDMA use is associated with increased scores on selfreport measures of depression. The long-term effects of MDMA consumption on depression have been examined in 29 individuals who had consumed large quantities of the drug in the past, but were now leading relatively drug-free lives (22C ). They had taken an average of 1.5 ecstasy tablets in the last month, 8.4 in the last 6 months, and 23.3 in the last 12 months. None had taken it in the last 14 days. The former chronic ecstasy users had not taken ecstasy for an average of 26 weeks. The female former users had taken ecstasy more recently than the men (15 versus 31 weeks respectively). The levels of depression, as measured by Beck’s depression inventory (BDI), were significantly increased compared with a matched non-drug using control group. The depression scores were independent of alcohol and cannabis use. Peak usage (maximum ecstasy usage in 12 hours) and current levels of perceived stress together significantly predicted depression scores. Thus, former chronic ecstasy users may be at a high risk of developing more severe depression.

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Liver A case of MDMA-associated hepatotoxicity has been reported (23Ar ). • A 17-year-old girl developed progressive jaundice and weight loss. Four months before, she had had malaise, anorexia, a sore throat, and tender cervical lymph nodes. Two months later she reported eating “hallucinogenic mushrooms”. Five weeks before admission she observed blood clots in her stool. Three weeks later, she ate more mushrooms. She then developed progressive jaundice, with vomiting, dark urine, light colored stools, and raised aminotransferases. She drank alcohol in binges and reported marijuana use since the age of 15. She had used MDMA on several occasions during the previous 2 months. She had a minimally tender enlarged liver. Her viral hepatitis screen was negative. Genetic, metabolic, and autoimmune disorders were also ruled out. A urine screen for drugs was positive only for cannabinoids. Abdominal ultrasound showed periportal edema and contraction of the gall bladder, but no gallstones or dilated bile ducts. A CT scan showed moderate amounts of free fluid in the abdomen and pelvis and periportal hepatic edema. Percutaneous liver biopsy showed acute cholestatic hepatitis with cholangitis, eosinophils, and histiocytes, strongly suggesting a hypersensitivity reaction. There was no evidence of chronic liver disease. Within 24 hours after the liver biopsy, her liver enzymes and coagulopathy had begun to improve.

Two cases of successful liver transplantation after ecstasy-induced hepatotoxicity have been reported (24Ar , 25Ar ). • A 19-year-old man with no significant past history of medical problems took 1½ tablets of ecstasy and some alcohol. Within 2–4 days he developed tiredness, nausea, malaise, and vomiting and on the fifth day weakness and anorexia; 12 days later he was admitted to hospital with marked jaundice and weight loss. He deteriorated and developed hepatomegaly and an abnormal prothrombin time; his total bilirubin was 571 (reference range 5–17) µmol/l, AsT 213 (14–50) U/l, and AlT 336 (11– 60) U/l. By day 20, his condition had deteriorated, with increased jaundice, somnolence, mild disorientation, and altered glucose metabolism. His total bilirubin was 654 µmol/l, AsT 1290 U/l, and AlT 1932 U/l. A liver biopsy showed swollen hepatocytes, patches of necrosis, and patchy cholestasis. Two days later, he developed a grade III encephalopathy and further disturbances of coagulation. Abdominal ultrasonography showed hepatic atrophy and a liver biopsy showed massive necrosis. Serological tests for viral infections were negative. The probable diagnosis was toxic hepatitis secondary to MDMA. On day 31, he had a right auxiliary liver transplantation, but there was no clinical and laboratory improvement during the next 48 hours. Histopathology of the transplanted liver showed massive liver necrosis consistent with

35 a “diagnosis of primary non-function”. A second liver transplant on day 33 was successful. • A 17-year-old woman with no history of drug abuse took two tablets of ecstasy at a disco 10 days apart, and reported malaise, constipation, and icterus 6 days after taking the second. She had severe acute hepatic failure. Viral hepatitis was ruled out. Following rapid clinical and neurological deterioration (encephalopathy grade I–II), she had an urgent liver transplant and made a good recovery. In the affected liver there was submassive centrilobular hemorrhagic necrosis (75–80%) with massive periportal and lobular lymphocytic infiltration (CD 8+) and moderate fatty changes.

Many cases of hepatotoxicity and some deaths have occurred in drug-naïve subjects after the ingestion of relatively small amounts of MDMA. The authors reported that more than 70 deaths have been reported world wide between 1990 and 1998 after the onset of severe hepatic damage from ecstasy. Although many patients died after liver transplantation, a significant number recovered. The authors suggested that in emergency care the use of ecstasy should be suspected in young people who present with unexplained jaundice, hepatomegaly, or altered liver function, in the absence of other known substance exposure. Early referral for liver transplantation may be significantly beneficial. The prognosis may be better with grade I–II encephalopathy than grade III–IV, which is usually associated with rapid deterioration and a poor prognosis. Pregnancy Workers in Canada have tried to characterize women who reported gestational exposure to ecstasy (26C ). The Motherisk Program is a large Teratogen Information Service based in Toronto and receives over 150 calls daily about exposure to various agents during pregnancy. The authors reviewed the data from 1998 to 2000. The study group consisted of all pregnant women who had been exposed to MDMA. The control group was randomly selected pregnant women who visited the Motherisk Clinic during the same week as the subject who called about MDMA. The 132 MDMAexposed women were significantly younger, earlier in gestational age, and weighed less than the non-exposed controls. The MDMA users had had significantly fewer pregnancies and live births and had a higher rate of therapeutic abortions but not spontaneous abortions. Significantly more MDMA users reported unplanned

36 pregnancies and were more likely to be single and white. The MDMA users were more likely than controls to have had alcohol exposure in pregnancy, and significantly more drank heavily. The MDMA-exposed women were more likely to binge drink and smoke cigarettes during pregnancy, and more were significantly heavy smokers. MDMA users also had a greater tendency to use marijuana, cocaine, amphetamines, ketamine, gamma-hydroxybutyrate, and psilocybin. Of the 132 women who reported MDMA use, 129 had used it during pregnancy, of whom 101 reported previous use of MDMA before their pregnancy, but had discontinued it. The mean gestational age of last MDMA exposure was 5.0 weeks (range 1–24 weeks). All but three used tablets: two snorted and one used a liquid formulation. The mean dose taken on one occasion was 1.24 tablets. Of the 122 patients whose data were included in the analysis, most (57%) had only one exposure to MDMA during pregnancy; 10 women had more than five exposures. One 15-year-old girl did not realize she was pregnant until 24 weeks gestation and had used two tablets of MDMA four times a day. Only seven of the MDA group reported exposure to MDMA alone. MDMA associated adverse events were reported by 33 of 77 respondents. The physical adverse effect most commonly reported was vomiting (23%). The authors raised significant concerns about the potential teratogenic effects in these women, due to clustering of risk factors. Drug contamination It is not uncommon for people to be deceived into consuming other substances, believing them to be MDMA. At dance parties and “raves” for young adults compounds passed as ecstasy may be more lethal than MDMA, either because they contain more potent amphetamines than MDMA or because of adulteration with other substances. In three fatal cases reported in the USA the victims (two men aged 19 and 24 and a woman aged 18) believed that they were using MDMA but had in fact taken paramethoxyamphetamine (PMA), a more potent central stimulant with structural and pharmacological similarities to MDMA (27c ). They became agitated and developed bruxism, severe hyperthermia, convulsions, and hemorrhages. The presence of PMA was confirmed by enzyme immunoassay, and

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MDMA was not detected. PMA is not a contaminant of MDMA.

CANNABINOIDS

(SED-14, 95; SEDA-23, 41; SEDA-24, 36; SEDA-25, 43) The adverse effects of cannabis are discussed in detail in the Side Effects of Drugs Essay in this volume (pp. xxxiii–xlviii), in the context of the question of whether cannabis should be made available for medical use. The essay contains many references to experimental data in animals, not usually a feature of these volumes. Cardiovascular Marijuana has several effects on the cardiovascular system, and can increase resting heart rate and supine blood pressure and cause postural hypotension. It is associated with an increase in myocardial oxygen demand and a decrease in oxygen supply. Marijuana use is most popular among young adults (18–25 years old). However, with a generation of post-1960s smokers growing older, the use of marijuana in the age group that is prone to coronary artery disease has increased. Nevertheless, it is not known whether marijuana can precipitate myocardial infarction. Investigators in the Determinants of Myocardial Infarction Onset Study recently reported that smoking marijuana is a rare trigger of acute myocardial infarction (28C ). Interviews of 3882 patients (1258 women) were conducted an average of 4 days after infarction. Reported use of marijuana in the hour preceding the first symptoms of myocardial infarction was compared with use in matched controls. Among the patients, 124 reported smoking marijuana in the previous year, 37 within 24 hours, and nine within 1 hour of cardiac symptoms. The risk of myocardial infarction was increased 4.8 times over baseline in the 60 minutes after marijuana use and then fell rapidly. The authors emphasized that in a majority of cases, the mechanism that triggered the onset of myocardial infarction involved a ruptured atherosclerotic plaque secondary to hemodynamic stress. It was not clear whether marijuana has direct or indirect hemodynamic effects sufficient to cause plaque rupture.

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Paroxysmal atrial fibrillation has been reported in two cases after marijuana use (29A ). • A healthy 32-year-old doctor, who smoked marijuana 1–2 times a month, had paroxysmal tachycardia for several months. An electrocardiogram was normal and a Holter recording showed sinus rhythm with isolated supraventricular extra beats. He was treated with propranolol. He later secretly smoked marijuana while undergoing another Holter recording, which showed numerous episodes of paroxysmal atrial tachycardia and atrial fibrillation lasting up to 2 minutes. He abstained from marijuana for 12 months and maintained stable sinus rhythm. • A 24-year-old woman briefly lost consciousness and had nausea and vomiting several minutes after smoking marijuana. She had hyporeflexia, atrial fibrillation (maximum 140 beats/min with a pulse deficit), and a blood pressure of 130/80 mmHg. Echocardiography was unremarkable. Within 12 hours, after metoprolol, propafenone, and intravenous hydration with electrolytes, sinus rhythm was restored.

The authors discussed the possibility that delta-9-tetrahydrocannabinol, the active ingredient of marijuana, can cause intra-atrial reentry by several mechanisms and thereby precipitate atrial fibrillation. Nervous system Marijuana can interact with the neurotransmitter dopamine, and the effects of marijuana on the brain in schizophrenia have been studied by single photon emission computerized tomography (SPECT) (30A ). • A 38-year-old man with schizophrenia secretively smoked marijuana during a neuroimaging study. A comparison of two sets of images, before and after marijuana inhalation, showed a 20% reduction in the striatal dopamine D2 receptor binding ratio, suggestive of increased synaptic dopaminergic activity.

On the basis of this in vivo SPECT study, the authors speculated that marijuana may interact with dopaminergic systems in brain reward pathways.

COCAINE

(SED-14, 106; SEDA-23, 37; SEDA-24, 37; SEDA-25, 40) Cardiovascular Chest pain is a frequent emergency presenting complaint of cocaine

37 users. Myocardial infarction is the most serious cause, but other causes for pain must be considered, including aortic rupture and dissection (SEDA-18, 36; SEDA-19, 26; SEDA-21, 29; SEDA-22, 31). A first case of intramural hematoma of the ascending aorta has been reported in a cocaine user (31A ). • A healthy 39-year-old man developed retrosternal chest pain radiating to the back with nausea and sweating. About 10–15 minutes before he had inhaled cocaine for 2 hours and then smoked crack cocaine. He had an aortic dissection, which was repaired surgically.

The authors identified hypertension secondary to the use of cocaine as the risk factor for this complication. Coronary artery dissection associated with cocaine is rare. The first case was reported in 1994 (32A ), and two new cases have been reported (33A , 34A ). • A healthy 33-year-old man with prior cocaine use had a small myocardial infarction, and 36 hours later, having inhaled cocaine, developed a dissection of the left main coronary artery, extending distally to the left anterior descending and circumflex arteries. There was marked anterolateral and apical hypokinesis. • A 23-year-old man with a history of intravenous drug abuse and hepatitis C was found unconscious, hypoxic, and hypotensive. A urine drug screen was positive for cocaine metabolites, benzodiazepines, and opiates. An electrocardiogram suggested a myocardial infarction, verified by raised troponin I and the MB fraction of creatine kinase. He had severe hypokinesia with a left ventricular ejection fraction of 10%, falling to less than 5%. He became septic, developed multiorgan system failure, and died. The post-mortem findings included dissection of the left anterior descending artery with complete occlusion of the true lumen and thrombosis of the false lumen. The left ventricle showed extensive transmural myocardial necrosis with adjacent contraction band necrosis. He also had deep vein thromboses in veins in the neck and abdomen and multiple pulmonary infarctions.

Cocaine is associated with vascular complications, including pulmonary, musculoskeletal, intestinal, and placental. Cocaine-induced ischemic finger necrosis has been reported (35A ). • A healthy 36-year-old man, who had used intranasal crack cocaine daily in increasing doses for 2 weeks, developed pain, numbness, swelling, and cyanosis of the fingers and toes aggravated by cold and an ulcer on one finger. Ultrasound Doppler of

38 the hand confirmed ischemic finger necrosis. He was treated unsuccessfully with aspirin, diltiazem, and heparin, but responded to intravenous infusions of iloprost for 5 days.

Respiratory Pulmonary complications associated with cocaine use include exacerbation of asthma, lung infiltrates, pulmonary infarction, pneumothorax, and end-stage lung disease (SEDA-20, 21; SEDA-21, 25; SEDA-22, 31; SEDA-23, 37; SEDA-25, 41). A case of severe bullous emphysema in a cocaine smoker has been described (36A ). • A 40-year-old man with cough, shortness of breath, and fever progressed to respiratory failure. He had smoked cocaine for the past 17 years. His tobacco history was not known. His medical history included recurrent respiratory tract infections. A chest X-ray and CT scan showed findings consistent with bilateral bullous emphysema with a right lung abscess. He was ventilated and given antibiotics but died from respiratory failure secondary to pneumonia. Sputum cultures were positive for Enterobacter cloacae and Streptococcus species. Alpha-1 antitrypsin deficiency was ruled out.

Spontaneous pneumomediastinum has been reported (37R ). • A 20-year-old obese Hispanic man awoke with severe, continuous retrosternal chest pain radiating to the neck and back. The pain was aggravated by deep breathing and local chest pressure. He denied substance abuse and gave a history of a flu-like illness 2 months before. His respiratory rate was 19/minute. He had a two-component pericardial rub. Laboratory blood testing ruled out myocardial infarction. His arterial blood gases and pH, electrocardiogram, chest X-ray, and echocardiogram were unremarkable. A later chest X-ray showed air in the mediastinum and chest CT confirmed the diagnosis of pneumomediastinum. Urine toxicology was positive for cocaine and cannabinoids. On further questioning, he admitted to substance use and performing a Valsalva maneuver during inhalation.

Ear, nose, throat Intranasal cocaine can damage the sinonasal tract, causing acute and chronic inflammation, necrosis, and osteocartilaginous erosion (SEDA-17, 36). These conditions occur secondary to the combined effects of direct trauma from instrumentation, vasoconstriction of small blood vessels with resultant ischemic necrosis, and chemical irritation from adulterants. Intranasal cocaine users can develop septal perforation, saddle-nose deformities, and sinonasal structural damage (38A ).

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• A 43-year-old woman with a past history of chronic heavy cocaine use and osteomyelitis of the hard palate and nasal cavity 10 years before had required continuous follow-up for recurrent ethmoid and sphenoid sinusitis. Endoscopy showed an absent nasal septum, middle turbinates, anterior twothirds of the inferior turbinates, and lateral nasal wall.

In another case there was progression of septal perforation to secondary bone infection in a chronic cocaine user (39A ). • A 56-year-old chronic intranasal cocaine abuser with a visible nasal defect presented with a hole in the roof of his mouth. He had been reportedly drug free for 2 weeks. He had an oronasal fistula with adjacent black necrotic areas and erosive destruction of the nasal septum, turbinates, and antrum, with mucoperiosteal thickening of the sphenoid and maxillary sinuses. Treatment included antibiotics and a prosthesis plate construction to cover the defect. Two years later, having continued to inhale cocaine, he had progressive destruction of his sinonasal tract, a fistula between his oral and nasal cavity, a saddle-nose deformity with total cartilage loss, and a complete palatal defect. Biopsy of the nasal septum showed acute osteomyelitis and extensive bacterial overgrowth (including anerobic Actinomyces-like organisms). He was given intravenous antibiotics for 6 weeks followed by longterm oral antibiotics.

Nervous system Cocaine has been associated with movement disorders, such as acute dystonias, choreoathetosis, and akathisia. Chronic pancerebellar dysfunction occurred in a cocaine user with schizophrenia treated with risperidone (40A ). • A 38-year-old man was found comatose in a crack house. The ambient temperature was 13◦ C. He had earlier abused cocaine. His temperature was 43◦ C, heart rate 115, blood pressure 144/89 mmHg, and oxygen saturation 97% on air. His general muscle tone was flaccid. He had a mild leukocytosis and hypophosphatemia. Urine toxicology was positive for benzoylecgonine, a cocaine metabolite. He was mechanically ventilated, cooled, and given intravenous fluids. His temperature fell to 38◦ C, but he later developed acute disseminated intravascular coagulation and rhabdomyolysis. After 5 days he developed nystagmus, intention tremor, truncal ataxia, dysarthria, ocular dysmetria, and dysmetria of the arms and legs. There were no sensory or motor deficits. Finger-to-nose and heelto-knee tests were slowed and uncoordinated. He could not stand. Brain imaging studies (CT and MRI scans) were unremarkable. He was given thiamine, propranolol, clonazepam, primidone, and baclofen every 8 hours without improvement. After 1 year he still had nystagmus, intention tremor,

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ataxic gait, and dysmetria were. He could walk short distances slowly.

Cocaine and neuroleptic drugs can both cause hyperthermia and the authors proposed that the combination of cocaine and risperidone may have caused this problem. Cocaine-induced delirium with severe acidosis has been reported (41A ). • A 25-year-old man with agitation and paranoia who had consumed a lot of alcohol with cocaine the night before had a clonic seizure lasting 1 minute. In the emergency room, he responded to pain and made incomprehensible sounds. His pulse rate was 116, blood pressure 100/40 mmHg, respiratory rate 28, and temperature 38.3◦ C. He was acidotic (pH 6.53), with a PaCO2 of 13.1 kPa, a base deficit of 36 mmol/l, a serum potassium concentration of 7 mmol/l, and sodium 153 mmol/l. He was hyperventilated and given sodium bicarbonate, dantrolene, and passive cooling. His acidosis quickly corrected and his temperature fell to 37.6◦ C within 1 hour.

The association between cocaine use and aneurysmal subarachnoid hemorrhage has previously been reported (SEDA-18, 36; SEDA21, 26). New research has identified cocaine as a risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (42M ). In a retrospective analysis of the medical records of 440 patients who presented to a neurosurgery unit between 1992 and 1999 with aneurysmal subarachnoid hemorrhage, 27 patients (6.1%) had either a positive urine screen for cocaine metabolites (n = 20) or a history of cocaine use within 72 hours of subarachnoid hemorrhage (n = 7). Cocaine users were more likely to have cerebral vasospasm from 3 to 16 days after subarachnoid hemorrhage than non-exposed patients (63% versus 30%). They were also more likely to be younger and to have aneurysms of the anterior circulation than the control group (97% versus 84%). Cocaine use has been associated with a reduced inhibitory response of the P50 auditory evoked response, attributed to catecholaminergic neurotransmission secondary to cocaine (43A ). In a double-blind, placebo-controlled study, 11 cocaine users in the first and third weeks of detoxification had electrophysiological testing 10 minutes before and 30 minutes after taking nicotine gum 6 mg. Nicotine briefly reversed the inhibitory deficit.

39 Psychological Chronic substance use has been associated with long-lasting changes in brain function (44c ). Five brain regions that may be affected (the orbitofrontal gyrus, rectal gyrus, anterior cingulate gyrus, basal ganglia, and thalamus) were selected for analyses of cerebral glucose metabolism by positron emission scanning in controls, cocaine users, and alcoholics (17 in each group), who performed the Stroop test, which assesses cognitive interference and response inhibition. In controls, higher brain glucose metabolism in the orbitofrontal gyrus correlated with poorer performance. In contrast, in substance users, higher brain glucose metabolism was associated with better performance. Chronic abuse appears to be associated with altered function of the orbitofrontal gyrus. Urinary tract Cocaine can cause acute renal insufficiency (SEDA-21, 19, SEDA-24, 38). A recent study has suggested that it can also cause chronic renal insufficiency (45C ). Of hemodialysis patients from an urban center in California, 55 who reported a history of significant cocaine use were compared with 138 non-users. A diagnosis of hypertension-related end-stage renal disease was reported in 49 of the 55 cocaine users (89%) and 64 of the 138 non-users (46%). Of 113 patients with endstage renal disease, 49 had a history of cocaine use. The patients who had used cocaine had hypertension for a shorter duration (5.3 vs. 12.7 years). They were also younger (41 vs. 54 years). The authors proposed that this outcome had been caused by several mechanisms: renal vasoconstriction or stenosis, resulting in ischemic nephropathy and secondary hypertension, direct renal damage with progressive renal insufficiency, and recurrent episodes of accelerated hypertension, vasculitis, acute tubular necrosis, and rhabdomyolysis. Renal infarction is an uncommon adverse effect of cocaine (46A ). • After using intranasal cocaine, a 25-year-old African man developed fever and progressive right flank pain over 4 days. He had a temperature of 38.3◦ C, a blood pressure of 106/54 mmHg, and severe tenderness in the right flank and right lower quadrant of the abdomen. His urine contained cocaine. A CT scan showed reduced uptake in the lower pole of the kidney, confirming renal infarction. Other causes were ruled out.

40 Sexual function Priapism has been reported in men who have used cocaine by inhalation or applied it topically to the glans penis or intraurethrally (SEDA-19, 26; SEDA-23, 24, SEDA24, 38). Priapism associated with intracavernosal injection of cocaine has now also been reported (47A ). • A 43-year-old man developed persistent painful erection after intracavernosal injection of cocaine. He had previously administered cocaine in this way to prolong erections. Cavernosal aspiration resulted in partial detumescence, but the condition recurred. Urine screen was positive for cocaine. Aspiration and irrigation fully alleviated the condition.

During penile erection, nitric oxide is released from the endothelium of the cavernous spaces and from nerve endings (non-adrenergic and non-cholinergic). Nitric oxide stimulates guanylate cyclase, which is involved in the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP); the latter relaxes the smooth muscle in the corpora cavernosa, allowing influx of blood for erection. The authors suggested that cocaine directly applied to the cavernosal endothelium can cause nitric oxide production. Drug abuse A rare case of polysubstance abuse, which unmasked myasthenia and caused complete external ophthalmoplegia, has been reported (48A ). • A 29-year-old woman, who used cocaine 2 g/day, heroin 1 g/day, and methadone 40 mg/day, developed abscesses caused by drug injection. She had had generalized weakness, difficulty in swallowing, and lagging eyelids for 1 week. There was bilateral ptosis, and a diagnosis of myasthenia was made. Edrophonium 10 mg relieved the ptosis and improved ocular movements.

Fetotoxicity The prevalence rate of cocaine use during pregnancy is 10–45% in some centers in North America. As cocaine use is increasing and widespread, information on the possible adverse effects secondary to fetal cocaine exposure continue to amass in case reports and studies. Fetal microcephaly has been attributed to cocaine abuse during pregnancy (49A ). Urine toxicology confirmed the presence of morphine, benzoylecgonine, barbiturates, paracetamol, and propoxyphene. Analyses of amniotic fluid, placenta, and fetal serum and urine

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were also positive for these substances. The authors suggested that vascular disruption was the likely major mechanism of anomalies, both behavioral and malformative, due to prolonged exposure to cocaine in utero. However, in a prospective, large-scale, longitudinal study there was no association between prenatal cocaine exposure and congenital anomalies in 272 offspring of 154 cocaineusing mothers and 154 non-using matched controls (50C ). The cocaine-exposed group had significantly more premature infants, who were significantly smaller in birth weight, length, and head circumference than the control infants. However, there were no differences in the type or number of abnormalities. The impact of prenatal exposure to cocaine on fetal growth and fetal head circumference has been studied in 476 African–American neonates, including 253 full term infants prenatally exposed to cocaine (with or without alcohol, tobacco, or marijuana) and 223 noncocaine exposed infants (147 drug-free, 76 exposed to alcohol, tobacco, or marijuana) (51C ). The cocaine-associated deficit in fetal growth was 0.63 standard deviations and for gestational age 0.33 standard deviations. There were also cocaine-associated deficits in birth weight and length, but no evidence of a disproportionate effect on head circumference. There have been two studies of the adverse effect of prenatal cocaine on behavior of the offspring. In the first, 31 cocaine-exposed, very low birth weight infants and matched very low birth weight controls followed longitudinally were assessed at 3 years (52C ). The cocaineexposed children had delayed cognitive, motor, and language development compared with the controls. Of the exposed children 45% scored in the range of mental retardation compared with 16% of the controls. Infants in the exposed group during the neonatal period were less responsive in their interactions and their mothers were less nurturing and less emotionally available. In contrast, in a second study there were few differences in interactive behaviors between prenatally cocaine-exposed and non-exposed 12-month-old infants and their mothers (53c ). Videotapes recorded African–American infants and their mothers engaged in interactions (49 cocaine-exposed, 63 non-exposed). Children

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who were prenatally exposed to cocaine ignored their mother’s departure during separation significantly more often than controls. Mothers who abused cocaine used more verbal behavior with their children than non-abusers. The effects of prenatal cocaine exposure on later learning abilities, including language, have been further investigated in 265 infants aged 1 year (134 cocaine-exposed and 131 matched non-exposed), who were tested using the Preschool Language Scale-3 (PLS-3) by blinded examiners (54C ). The infants were assigned to three cocaine exposure groups: (as defined by maternal self-report and infant meconium assay): non-exposure (n = 131), heavier exposure (n = 66), and lighter exposure (n = 68). Fetal cocaine exposure was associated with deficits in developmental precursors of speech/language skills. At 1 year of age, more heavily exposed infants had poorer auditory comprehension than the non-exposed infants and worse total language performance than lighter and non-exposed infants. The more heavily exposed infants were also more likely to be classified as mildly delayed than nonexposed infants. Moreover, the degree of cocaine exposure had an inverse relation to auditory comprehension. Prenatal cocaine exposure has been associated with subependymal hemorrhage and subependymal cyst formation in term neonates and more recently in preterm neonates (<36 weeks of gestation) (55M ). Medical records and cranial sonograms obtained during 1 year on 122 premature infants showed an increased incidence of subependymal cysts in preterm cocaine-exposed infants (8 of 18) compared with non-exposed infants (8 of 99). There was no increase in the incidence of major structural abnormalities. All subependymal cysts resolved by 4 months of age. The authors noted that the neurodevelopmental implications of such cyst formation are unknown. Prenatal cocaine exposure appears to have short-term effects on respiratory function in very low birth weight infants. In a retrospective study of 149 such infants, 48 cocaine-exposed and 101 non-exposed, the cocaine-exposed infants had transiently improved respiratory status at time of delivery; they needed surfactant treatment in lower doses and at a lower frequency and intubation less often (56c ). At 24 and 48 hours there was no significant difference

41 between the treatment requirements in the two groups. The development of bronchopulmonary dysplasia was also similar. The authors suggested that prenatal cocaine exposure affects the fetus by two mechanisms: indirectly through reduced uterine blood flow with placental insufficiency and directly through an adrenergic effect on the fetus. The fetus may experience cocaine as a stressor that leads to accelerated fetal lung maturity. The relation between prenatal cocaine exposure and early childhood outcome has been reviewed (57M ). Prospective longitudinal studies of perinatal cocaine exposure and associated outcomes were studied in a survey of 36 of 74 reports, published from 1984 to October 2000, in which the examiners were blinded to cocaine exposure. Prenatal cocaine exposure did not alter physical growth, developmental test scores, or receptive and expressive language among children aged 6 years or less. The authors concluded that there is no convincing evidence that prenatal cocaine exposure is associated with effects on a child’s physical or behavioral development, and that many findings once thought to be specific effects of in utero cocaine exposure instead correlated with factors such as the quality of the child’s environment and prenatal exposure to tobacco, marijuana, or alcohol. This review generated responses from other authorities in the field. Some commented that the conclusions may be premature, given the age of the subjects, and drew attention to several studies that have shown subtle but consistent deficits in cognitive and attentional processes in 6- and 7-year-old children (58r ). These effects may become more prominent as development continues and may persist into adulthood. Others criticized the attempt to isolate cocaine exposure from all other associated risk factors; from a public health perspective, prenatal cocaine exposure clusters with other risk factors, such as poor care-giving, child maltreatment, domestic violence, and prenatal exposure to other substances (59r ). Furthermore, the selection criteria narrowed the total articles reviewed to under half of the 74 articles found. Others suggested that the study had been misinterpreted (60r ). Pregnancy In a attempt to replicate the conclusions of an earlier study, there was no association between cocaine use during preg-

42

Chapter 4

nancy and acute thrombocytopenia in 326 patients (61M ). There were similar prevalences of thrombocytopenia in cocaine-using women (13/160) and non-using women (11/160) during pregnancy. Thrombocytopenia occurred more often in the third trimester in both groups.

OPIATES

(SED-14, 198; SEDA-24, 36;

SEDA-25, 37)

Diamorphine (heroin) Nervous system Reflex sympathetic dystrophy, in which there is an excessive or abnormal sympathetic nervous system response in a limb, has been associated with rhabdomyolysis secondary to heroin abuse (62A ). • A 37-year-old male heroin smoker developed teacolored urine and pain, swelling, and tenderness in both feet. He had acute renal insufficiency and rhabdomyolysis and was treated with hemodialysis. Urine toxicology was negative. He also had persistent burning pain in both feet, with cool, pale, thin skin on both legs, a mild reduction in sensation on the lateral aspects of the lower legs and diminished bilateral knee and ankle reflexes. Walking was restricted, with limited range of movement owing to the severe pain. His feet would swell and redden after a 5 meter walk, suggesting loss of sympathetic regulation. Nerve conduction velocity studies of the tibial, peroneal, and sural nerves were abnormal. Radiographs showed mildly reduced bone mineralization in the legs. Three-phase bone scintigraphy showed diffusely increased radiotracer accumulation over both feet in all three phases, as found in reflex sympathetic dystrophy. The diagnosis was confirmed by local anesthetic sympathetic blockade. Nasal calcitonin spray led to pain relief 2 months later. A follow-up threephase bone scintigram showed less radiotracer uptake, consistent with a good response to calcitonin therapy.

Sensory systems Profound reversible hearing loss and vestibular dysfunction has been attributed to heroin abuse (63A ). • A 47-year-old man with a history of chronic heroin abuse (up to 1 g/day) and oral methadone maintenance (85 mg/day) relapsed after 3 weeks of full abstinence and injected 0.25 g of black tar heroin intravenously. He was unconscious for about 20 minutes and awoke with profound hearing loss and loud tinnitus. He had profound bilateral symmetrical sensorineural hearing loss and severe vestibulopathy. He recovered gradually over the next 3 weeks.

Eileen Wong and Jayendra K. Patel

The authors pointed out that bilateral deafness after heroin relapse after prolonged abstinence had been reported in two previous cases, suggesting resensitization of a tolerized opioid system or prolonged hypersensitization of a system in withdrawal. Drug abuse Smoked heroin by heating the free base over tin foil and inhaling the vapors is known as “chasing the dragon”, a method that probably originated in Southeast Asia. Some are using this to reverse the stimulant effects of ecstasy. In a study of 102 patients (55 men and 47 women, mean age 21 years) interviewed at four clinics in Dublin, Ireland, three subgroups of opiate users were identified: (a) those who had ever used opiates to come off ecstasy, who were compared with those who had never used opiates for this purpose, (b) those whose first use of opiates had been to come off ecstasy, and (c) those who had started opiates by “chasing” and then did or did not move to injecting (64C ). Of the 102 patients, 92 reported having taken ecstasy, 68 of whom reported having taken opiates to come off it, and the remaining 24 of whom had not. The 68 patients who reported taking opiates to come off ecstasy had significantly heavier ecstasy use, in terms of the number of nights per week and number of tablets taken per night. Of 36 who reported that their first ever experience of using opiates was in the context of “chasing” to come off ecstasy, 28 reported this as their main reason for starting to use opiates and the other eight reported that they would probably have tried opiates independent of their ecstasy use. Of the 86 patients whose initial route of use of heroin was “chasing”, 61 reported changing to injecting, 23 continued to smoke heroin, and two switched to an oral formulation of methadone or morphine. When those who came to inject heroin were compared with those who did not (61 vs. 23), the injectors had begun illicit drug use earlier, had started heroin at a younger age, were younger at the time of interview, and had been more likely to have a history of ecstasy use. Despite the younger age of onset of illicit drug use in those who came to inject, they had not been using illicit drugs for longer at the time of interview. This study confirmed the authors’ previous findings that heroin smoking was associated with ecstasy use.

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43

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14. Ricaurte GA, McCann UD. Experimental studies on 3, 4-methlenedioxymethamphetamine (MDMA, Ecstasy) and its potential to damage brain serotonin neurons. Neurotoxic Res 2001; 3: 85–99. 15. Heffernan TM, Ling J, Scholey AB. Subjective ratings of prospective memory deficits in MDMA (’ecstasy’) users. Hum Psychopharmacol 2001; 16: 339–44. 16. Verkes RJ, Gijsman HJ, Pieters MSM, Schoemaker RC, Visser S, Kuijpers M, Pennings EJM, Bruin D, Wijngaart GV, Va Gerven JMA, Cohen AF. Cognitive performance and serotonergic function in users of ecstasy. Psychopharmacology 2001; 153: 196–202. 17. Reneman L, Lavalaye J, Schmand B, de Wolff FA, van den Brink W, den Heeten GJ, Booij J. Cortical serotonin transporter density and verbal memory in individuals who stopped using 3, 4-methylenedioxymethamphetamine (MDMA or ”Ecstasy”). Arch Gen Psychiatry 2001; 58: 901–6. 18. Reneman L, Majoie CBLM, Schmand B, Van den Brink W, Den Heeten GJ. Prefrontal Nacetylaspartate is strongly associated with memory performance in (abstinent) ecstasy users: preliminary report. Biol Psychiatry 2001; 50: 550–4. 19. Bhattachary S, Powell JH. Recreational use of 3, 4-methylenedioxymethamphetamine (MDMA) or ’ecstasy’: evidence for cognitive impairment. Psychol Med 2001; 31: 647–58. 20. Croft RJ, Mackay AJ, Mills ATD, Gruzelier JGH. The relative contributions of ecstasy and cannabis to cognitive impairment. Psychopharmacology 2001; 153: 373–9. 21. Liechti ME, Gamma A, Vollenweider FX. Gender differences in the subjective effects of MDMA. Psychopharmacology 2001, 154: 161–8. 22. MacInnes N, Handley SL, Harding GFA. Former chronic Methylenedioxymethamphetamine (MDMA or ecstasy) users report mild depressive symptoms. J Psychopharmacol 2001; 15: 181–6. 23. Jonas MM. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. New Engl J Med 2001; 344: 591–9. 24. Garbino J, Henry JA, Mentha G, Romand JA. Ecstasy ingestion and fulminant hepatic failure: liver transplantation to be considered as a last therapeutic option. Vet Hum Toxicol 2001; 43: 99–102. 25. De Carlis L, De Gasperi A, Slim AO, Giacomoni A, Corti A, Mazza E, Di Benedetto F, Lauterio A, Arcieri K, Maione G, Rondinara GF, Forti D. Liver transplantation for ecstasy-induced fulminant hepatic failure. Transplant Proc 2001; 33: 2743–4. 26. Ho E, Karimi-Tabesh L, Koren G. Characteristics of pregnant women who use ecstasy (3, 4-methylenedioxymethamphetamine). Neurotoxicol Teratol 2001; 23: 561–7. 27. Kraner JC, McCoy DJ, Evans MA, Evans LE, Sweeney BJ. Fatalities caused by the MDMArelated drug paramethoxyamphetamine (PMA). J Anal Toxicol 2001; 25: 645–8.

44 28. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation 2001; 103: 2805–9. 29. Kosior DA, Krzysztof J, Filipiak, Przemyslaw S, Grzegorz O. Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association. Int J Cardiol 2001; 78: 183–4. 30. Voruganti LN, Slomka P, Zabel P, Mattar A, Awad AG. Cannabis induced dopamine release: an in-vivo SPECT study. Psychiatry Res 2001; 107: 173–7. 31. Neri E, Toscano T, Massetti M, Capannini G, Frati G, Sassi C. Cocaine-induced intramural hematoma of the ascending aorta. Tex Heart Inst J 2001; 28: 218–19. 32. Jaffe BD, Broderick TM, Leier CV. Cocaineinduced coronary-artery dissection. New Engl J Med 1994; 330: 510–11. 33. Eskander KE, Brass NS, Gelfand ET. Cocaine abuse and coronary artery dissection. Ann Thorac Surg 2001; 71: 340–1. 34. Steinhauer JR, Caulfield JB. Spontaneous coronary artery dissection associated with cocaine use: a case report and brief review. Cardiovasc Pathol 2001; 10: 141–5. 35. Balbir-Gurman A, Braun-Moscovici Y, Nahir AM. Cocaine-induced Raynaud’s phenomenon and ischaemic finger necrosis. Clin Rheumatol 2001; 20: 376–8. 36. Van der Klooster JM, Grootendorst AF. Severe bullous emphysema associated with cocaine smoking. Thorax 2001; 56: 982–3. 37. Goel P, Flaker GC. Cardiovascular complications of cocaine use. New Engl J Med 2001; 22: 1575–6. 38. Gupta A, Hawrych A, Wilson W. Cocaineinduced sinonasal destruction. Otolaryngol Head Neck Surg 2001; 124: 480. 39. Talbott JF, Gorti GK, Koch RJ. Midfacial osteomyelitis in a chronic cocaine abuser: a case report. Ear Nose Throat J 2001; 80: 738–43. 40. Tanvetyanon T, Dissin J, Selcer UM. Hyperthermia and chronic pancerebellar syndrome after cocaine abuse. Arch Intern Med 2001; 161: 608–10. 41. Allam S, Noble JS. Cocaine-excited delirium and severe acidosis. Anaesthesia 2001; 56: 385–6. 42. Conway JE, Tamargo RJ. Cocaine use is an independent risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2001; 32: 2338–43. 43. Adler LE, Olincy A, Cawthra E, Hoffer M, Nagamoto HT, Amass L, Freedman R. Reversal of diminished inhibitory sensory gating in cocaine addicts by a nicotinic cholinergic mechanism. Neuropsychopharmacology 2001: 25: 796. 44. Goldstein RZ, Volkow ND, Wang GJ, Fowler JS, Rajaram S. Addiction changes orbitofrontal gyrus function: involvement in response inhibition. NeuroReport 2001; 12: 2595–9. 45. Norris KC, Thornhill-Joynes M, Robinson C, Strickland T, Alperson BL, Witana SC, Ward HJ. Cocaine use, hypertension, and end-stage renal disease. Am J Kidney Dis 2001; 38: 523–8. 46. Saleem TM, Singh M, Murtaza M, Singh A, Kasubhai M, Gnanasekaran I. Renal infarction: a rare

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complication of cocaine abuse. Am J Emerg Med 2001; 19: 528–9. 47. Mireku-Boateng AO, Tasie B. Priapism associated with intracavernosal injection of cocaine. Urol Int 2001; 67: 109–10. 48. Valmaggia C, Gottlob I. Cocaine abuse, generalized myasthenia, complete external ophthalmoplegia and pseudotonic pupil. Strabismus 2001; 9: 9–12. 49. Kesrouani A, Fallet C, Vuillard E, JacqzAigrain E, Sibony O, Oury JF, Blot P, Luton D. Pathologic and laboratory correlation in microcephaly associated with prenatal cocaine exposure. Early Hum Dev 2001: 63: 79–81. 50. Behnke M, Eyler FD, Garvan CW, Wobie K. The search for congenital malformations in newborns with fetal cocaine exposure. Pediatrics 2001; 107: E74. 51. Bandstra ES, Morrow CE, Anthony JC, Churchill SS, Chitwood DC, Steele BW, Ofir AY, Xue L. Intrauterine growth of full-term infants: impact of prenatal cocaine exposure. Pediatrics 2001; 108: 1309–19. 52. Singer LT, Hawkins S, Huang J, Davillier M, Baley J. Developmental outcomes and environmental correlates of very low birthweight cocaineexposed infants. Early Human Dev 2001; 64: 91– 103. 53. Ukeje I, Bendersky M, Lewis M. Mother-infant interaction at 12 months in prenatally cocaineexposed children. Am J Drug Alcohol Abuse 2001; 27: 203–24. 54. Singer LT, Arendt R, Minnes S, Salvator A, Siegel AC, Lewis BA. Developing language skills of cocaine-exposed infants. Pediatrics 2001; 107: 1057–64. 55. Smith LM, Qureshi N, Rensio R, Sinow RM. Prenatal cocaine exposure and cranial sonographic findings in preterm infants. J Clin Ultrasound 2001; 29: 72–7. 56. Hand IL, Noble L, McVeigh TJ, Kim M, Yoon JJ. The effects of intrauterine cocaine exposure on the respiratory status of the very low birth weight infant. J Perinatol 2001; 21: 372–5. 57. Frank DA, Augustyn M, Knight WG, Pell T, Zuckerman B. Growth, development and behavior in early childhood following prenatal cocaine exposure: a systematic review. J Am Med Assoc 2001; 285: 1613–25. 58. Stanwood GD, Levitt P. Prenatal cocaine exposure as a risk factor for later developmental outcomes. J Am Med Assoc 2001; 286: 45. 59. Singer LT, Arendt R. Prenatal cocaine exposure as a risk factor for later developmental outcomes. J Am Med Assoc 2001; 286: 45–6. 60. Delaney-Black V, Covington CY, NordstromKlee B, Sokol RJ. Prenatal cocaine exposure as a risk factor for later developmental outcomes. J Am Med Assoc 2001; 46. 61. Miller JM Jr, Nolan TE. Case-control study of antenatal cocaine use and platelet levels. Am J Obstet Gynecol 2001; 184: 434–7. 62. Lee BF, Chiu NT, Chen WH, Liu GC, Yu HS. Heroin-induced rhabdomyolysis as a cause of reflex

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sympathetic dystrophy. Clin Nucl Med 2001; 26: 289–92. 63. Ishiyama A, Ishiyama G, Baloh RW, Evans CJ. Heroin-induced reversible profound deafness and vestibular dysfunction. Addiction 2001; 96: 1363–4.

45 64. Gervin M, Hughes R, Bamford L, Smyth BP, Keenan E. Heroin smoking by “chasing the dragon” in young opiate users in Ireland: stability and associations with use to “come down” off “ecstasy.” J Subst Abuse Treat 2001: 20: 297–300.

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5

Hypnosedatives and anxiolytics

Hypnotics and sedatives are commonly prescribed drugs, especially in older people. The ideal hypnotic would induce sleep rapidly, keep patients asleep without disrupting sleep architecture, have no adverse effects, produce no next-morning sedation, lack dependence and rebound insomnia, and be safe in the medically unwell and in overdose. Although the newer drugs, including zaleplon, zolpidem, and zopiclone, satisfy many of these criteria, it is unlikely that the perfect drug will ever be developed.

BENZODIAZEPINES

(SED-14, 122; SEDA-23, 44; SEDA-24, 46; SEDA-25, 47) Trauma In a case-control study of whether benzodiazepines are associated with a higher risk of hip fractures in the elderly 245 cases were matched to 817 controls (1C ). Benzodiazepines as a group were not associated with a higher risk of hip fracture, but patients who used lorazepam or two or more benzodiazepines had a significantly higher risk.

Alprazolam Drug withdrawal Catatonia has been attributed to alprazolam withdrawal (2A ). • A woman with paranoid schizophrenia developed catatonia 5 days after the abrupt withdrawal of olanzapine and alprazolam. The catatonic symptoms included mutism, prostration, waxy flexibility, oculogyric movements, and an inability to swallow. Her symptoms disappeared after the administration of alprazolam and haloperidol, and there was no recurrence. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

46

Drug interactions The effect of alosetron 1 mg bd on the pharmacokinetics of a single oral dose of alprazolam 1 mg has been determined in an open, randomized, crossover study in 12 healthy men and women; alosetron did not effect the pharmacokinetics of alprazolam (3c ).

Bromazepam Drug overdose A non-fatal overdose of bromazepam has been reported (4A ). • A 42-year-old woman with a history of depression was found unconscious, lying near her car. The lower part of her body was undressed and there were multiple purple spots and excoriations on her body, suggesting a sexual assault. She was hypothermic (core temperature 28.4◦ C). Her plasma bromazepam concentration was 7.7 mg/l, the highest concentration reported in a case of non-fatal intoxication.

Drug withdrawal Catatonia has been described as an effect of bromazepam withdrawal (5A ). • A 51-year-old man who had been taking bromazepam for 9 years in a dosage that he had gradually increased to 18 mg/day abruptly stopped taking it. He initially developed psychotic symptoms and on day 5 after withdrawal became mute and was posturing. A provisional diagnosis of a catatonic syndrome was made, and he was given oral lorazepam 3 mg and risperidone 4 mg. It was later concluded that the catatonia had most probably been due to benzodiazepine withdrawal, the risperidone was withdrawn, and diazepam was substituted for lorazepam and slowly tapered. He had no recurrence of catatonic or psychotic symptoms and had some improvement in his fatigue.

Chlordiazepoxide Hematologic A 68-year-old man who had been taking lorazepam, perphenazine, and amitriptyline for many years, developed acute thrombocytopenic purpura after combination

Hypnosedatives and anxiolytics

47

Chapter 5

therapy of chlordiazepoxide 5 mg and clidinium 2.5 mg tds for irritable bowel syndrome (6A ). His disease improved after withdrawal of chlordiazepoxide and clidinium and treatment with intravenous prednisolone. In this case it was not clear which of the two compounds caused the purpura; it is possible that it was due to the combination. Drug formulations The California State Health Director has warned consumers to stop using the herbal product Anso Comfort capsules immediately, because the product contains the undeclared prescription drug chlordiazepoxide (7A ). Anso Comfort capsules, available by mail or telephone order from the distributor in 60-capsule bottles, are clear with dark green powder inside. The label is yellow with green English printing and a picture of a plant. An investigation by the California Department of Health Services Food and Drug Branch and Food and Drug Laboratory showed that the product contains chlordiazepoxide. The ingredients for the product were imported from China and the capsules were manufactured in California. Advertising for the product claims that the capsules are useful for the treatment of a wide variety of illnesses, including high blood pressure and high cholesterol, in addition to claims that it is a natural herbal dietary supplement. The advertising also claims that the product contains only Chinese herbal ingredients and that consumers may reduce or stop their need for prescribed medicines. No clear medical evidence supports any of these claims. The distributor, NuMeridian (formerly known as Top Line Project), is voluntarily recalling the product nationwide.

• A 52-year-old white woman developed a burning mouth. She had previously taken alprazolam for anxiety, but this was changed to clonazepam because of increased anxiety and panic. Clonazepam relieved her symptoms, but after 4 weeks of therapy she continued to have a constant, mild, oral burning sensation. Examination of the mouth was normal and laboratory tests were unremarkable. The dose of clonazepam was reduced and her symptoms abated but remained intolerable. Clonazepam was withdrawn and her symptoms completely resolved. Since no other medications relieved her anxiety and panic she took clonazepam again, but again developed an intolerable burning mouth. Clonazepam was again withdrawn and her symptoms resolved.

Drug interactions The mutual interaction of clonazepam and carbamazepine has been investigated in 183 children and adults with epilepsy during routine clinical care (9C ). Carbamazepine increased the clearance of clonazepam by 22% and clonazepam reduced the clearance of carbamazepine by 21%.

Diazepam Nervous system Five neonates who suffered an unexpected long period of respiratory failure, muscular hypotonia, and drowsiness have been retrospectively investigated (10c ). Unusually high doses of diazepam had been given by intravenous bolus injection and serum concentrations of diazepam and its active metabolites were high. The authors emphasized the persistence of the very long-acting N -desmethyldiazepam, particularly in neonates and even more exaggeratedly in premature infants, owing to reduced capacity of hepatic biotransformation.

Drug interactions A San Francisco woman with a history of diabetes and high blood pressure was hospitalized in January 2001 with a life-threatening low blood sugar concentration after she consumed Anso Comfort capsules (7A ). The hospitalization may have been necessitated by a drug interaction of chlordiazepoxide and the prescribed medications for her other medical conditions.

Drug overdose A 54-year-old man took 2 g of bulk laboratory diazepam and was treated with activated charcoal, diuresis, and flumazenil infusion (11A ). He wakened, but had drowsiness, dysarthria, diplopia, and dizziness for 9 days. Blood concentrations of diazepam and its main metabolite, N -desmethyldiazepam, remained high for over 4 weeks.

Clonazepam

Lorazepam

Mouth A sensation of a burning mouth has been attributed to clonazepam (8A ).

Nervous system The effects of lorazepam and diazepam on false memories and related

48 states of awareness have been investigated in 36 healthy volunteers, randomly assigned to one of three groups (placebo, diazepam 0.3 mg/kg, lorazepam 0.038 mg/kg) (12C ). The results suggested that diazepam and lorazepam cause impaired conscious recollection associated with true, but not false, memories. The effects of lorazepam on three neuropsychiatric measures of attention and psychomotor performance have been investigated in 40 patients, 20 of whom were given placebo, 10 were given lorazepam 1 mg, and 10 were given lorazepam 2.5 mg (13C ). Performance on digit cancellation, digit-symbol substitution, and the Paced Auditory Serial Addition Task was significantly impaired by lorazepam (2.5 mg) and this was significantly worse in the middle-aged subjects compared with the younger. These results suggest that older people are more susceptible to these adverse effects. The psychomotor and amnesic effects of single oral doses of etifoxine (50 mg and 100 mg) and lorazepam (2 mg) have been studied in 48 healthy subjects in a double-blind, placebocontrolled, randomized, parallel-group study (14C ). Etifoxine is a non-benzodiazepine drug, which is licensed in France for psychosomatic manifestations of anxiety. Its effects were assessed by a battery of subjective and objective tests that explored mood and vigilance, attention, psychomotor performance, and memory. Whereas vigilance, psychomotor performance, and free recall were significantly impaired by lorazepam, neither dose of etifoxine (50 mg and 100 mg) produced such effects. The results suggested that 50 mg and 100 mg single doses of etifoxine do not induce amnesia and sedation compared with lorazepam.

Chapter 5

Stephen Curran and Shabir Musa

Drug administration route The pharmacokinetics of intranasal lorazepam compared with oral administration have been evaluated in 11 volunteers in a randomized, crossover study (16c ). Lorazepam had favorable pharmacokinetics for intranasal administration compared with standard methods. Intranasal delivery could provide an alternative non-invasive delivery route for lorazepam.

Mexazolam The anxiolytic effects of mexazolam have been compared with those of alprazolam in 64 outpatients with generalized anxiety disorder in a multicenter, double-blind, parallel-group, randomized trial (17C ). Five mexazolam and nine alprazolam recipients reported mild adverse events: drowsiness in three patients in each group; dizziness in one taking mexazolam and two taking alprazolam; blurred vision in one patient taking mexazolam; and weight gain, nausea, and insomnia in one patient taking alprazolam. Both drugs were anxiolytic and both were well tolerated.

Oxazepam Passiflora incarnata extract has been compared with oxazepam in a double-blind, randomized trial in 26 out-patients with DSM-IV generalized anxiety disorder (18C ). Both were effective but oxazepam had a more rapid onset of action; oxazepam caused significantly more problems relating to work performance.

Metabolism Metabolic acidosis and hyperlactatemia have been attributed to lorazepam (15A ). • A 34-year-old woman with a history of renal insufficiency induced by long-term use of cocaine developed respiratory failure and was intubated and sedated with intravenous lorazepam (65 mg, 313 mg, and 305 mg on 3 consecutive days). After 2 days she had a metabolic acidosis with hyperlactatemia and hyperosmolality. Propylene glycol, a component of the lorazepam intravenous formulation, was considered as a potential source of the acidosis, as she had received more than 40 times the recommended amount over 72 hours. Withdrawal of lorazepam produced major improvements in lactic acid and serum osmolality.

Temazepam Nervous system In a randomized, crossover study, psychomotor performance and memory were tested and mood assessed for 3 hours after single doses of placebo, temazepam 20 mg, or temazepam 30 mg in six healthy women aged 21–23 years (19C ). Psychomotor speed and explicit memory showed dose-dependent slowing and impairment, but there was no change in short-term memory.

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Chapter 5

OTHER HYPNOSEDATIVES AND ANXIOLYTICS (SED-14, 133; SEDA-23, 46; SEDA-24, 49; SEDA-25, 49)

Buspirone In a 21-day, open, multicenter, dose-escalation study, 13 children and 12 adolescents with anxiety disorder and 14 healthy adults, took buspirone 5–30 mg bd titrated over 3 weeks (20c ). Buspirone was generally safe and well tolerated at doses up to 30 mg in adolescents and adults and in most of the children. The most common adverse events in children and adolescents were light-headedness (68%), headache (48%), and dyspepsia (20%); two children withdrew from the study at the higher doses (15 mg and 30 mg bd) owing to adverse effects. In adults the most common adverse event was somnolence (21%); mild light-headedness, nausea, and diarrhea were also reported. Drug formulations A single dose of buspirone ER (extended-release) 30 mg has been compared with two doses of buspirone IR (immediate-release) 15 mg given 12 hours apart to assess differences in tolerability in an open, crossover, randomized study in 18 healthy men (21c ). Blood samples were obtained at 22 times. Seven subjects reported a total of 13 adverse events during the study, but none of the events recorded was unexpected. All were mild and resolved by the end of the study without medical intervention. Three adverse events (rhinitis, headache, and light-headedness) were categorized as unrelated to the study drug. The other 10 adverse events included drowsiness, dizziness, depression, tinnitus, and increased blood pressure. There were no significant differences between the two formulations.

Clomethiazole Drug interactions The safety of the thrombolytic drug alteplase (tPA) plus clomethiazole in patients with acute ischemic stroke has been assessed in a randomized, double-blind study (22C ). All received alteplase 0.9 mg/kg beginning within 3 hours of stroke onset and then either intravenous clomethiazole 68 mg/kg

(n = 97) over 24 hours, or placebo (n = 93) beginning within 12 hours of stroke onset. During follow-up for 90 days the number of serious adverse event reports was 47 in the clomethiazole group and 48 in the placebo group. There were 15 deaths in those given clomethiazole and nine in those given placebo, but this was not significantly different. Sedation was also greater with clomethiazole (42%) than placebo (13%).

Zaleplon Zaleplon is a relatively new non-benzodiazepine sleep medication that induces sleep comparable to other hypnotics but with significantly fewer residual effects (23R ). In addition, evaluations of psychomotor or memory function at zaleplon peak plasma concentrations show much less impairment than noted with other hypnotics, suggesting an improved benefit : harm profile for zaleplon compared with older agents. Zaleplon can be used to treat symptoms of insomnia with little next-day psychomotor or memory impairment. However, further research is needed. Psychiatric A 25-year-old unmarried Asian woman with high intellectual functioning and superior psychosocial adjustment, with no current or prior medical or psychiatric history, developed illusions and hallucinations and a feeling of depersonalization within several minutes of taking zaleplon 10 mg (24A ). The illusions and visual hallucinations resolved after 15 minutes, but she continued to have lightheadedness and fatigue, which gradually resolved by the next day. Drug interactions The effects of alcohol combined with either zaleplon or triazolam have been studied in 18 healthy volunteers (25c ). Triazolam, with and without ethanol, impaired digit symbol substitution, symbol copying, simple and complex reaction times, and divided attention performance compared with placebo. Zaleplon without ethanol impaired only digit symbol substitution and divided attention tracking, but when it was combined with ethanol all measures were impaired. However, zaleplon without ethanol was consistently better than triazolam alone. Zaleplon produced less performance impairment and a shorter period of ethanol potentiation than triazolam.

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Zolpidem Zolpidem has been investigated in a multicenter, double-blind, placebo-controlled, parallelgroup, randomized study in 138 adults, who were experienced air travelers (26C ). They were randomized to zolpidem 10 mg or placebo for three (optionally four) consecutive nights, starting with the first night-time sleep after travel. Sleep was assessed with daily questionnaires. Compared with placebo, zolpidem was associated with significantly improved sleep, longer total sleep time, reduced numbers of awakenings, and improved sleep quality. It was not associated with improvement in sleep latency. No unexpected or serious adverse events were reported and the most common adverse event was headache in both groups. Nervous system Zolpidem 10 mg, temazepam 15 mg, and placebo have been compared in 630 healthy adults in a multicenter study (27C ). They were given 15 minutes before lights out, with polysomnographic monitoring for 7.5 hours. Subjective questionnaires and performance tests, including digit symbol substitution and symbol copying, were administered before and after sleep. Neither drug significantly reduced objective sleep latency, but zolpidem reduced awakenings compared with temazepam. Both improved sleep efficiency and most subjective sleep measures, and zolpidem was superior to temazepam in five of six subjective outcome measures. Symbol copying, morning sleepiness, and morning concentration were not altered. Zolpidem 10 mg provided greater subjective hypnotic efficacy than temazepam 15 mg in this model of transient insomnia, with reduced polysomnographic awakenings. Zolpidem was identified in the blood of 29 subjects arrested for impaired driving (28c ). In those in whom zolpidem was present with other drugs and/or alcohol, the symptoms reported were generally those of CNS depression and included slow movements and reactions, slow and slurred speech, poor co-ordination, lack of balance, flaccid muscle tone, and horizontal and vertical gaze nystagmus. In five subjects in whom zolpidem was the only drug detected, signs of impairment included slow and slurred speech, slow reflexes, disorientation, and lack of balance and co-ordination. Therapeutic doses of zolpidem can affect driving adversely, and

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concentrations above the target range further impair consciousness and driving ability. The acute effects of zolpidem and triazolam have been compared in 10 non-drug-abusing subjects using a Digit-Enter-and-Recall task with varying delay intervals (9, 10, and 20 seconds) (29c ). Zolpidem and triazolam impaired performance as a function of dose after all intervals. However, zolpidem produced significantly less impairment than triazolam after the longest delay (20 seconds). Zolpidem and triazolam produced comparable dose-related impairment of the digit symbol substitution, circular lights, and picture recall/recognition tasks. The results suggested that zolpidem may have less potential than triazolam to impair recall, which may be due to differences between these compounds in terms of their benzodiazepine-receptor binding profiles. Zolpidem 10 mg/day and zopiclone 7.5 mg/day, given at night, have been compared in a 14-day, double-blind study in 479 chronic primary insomniacs (30C ). With zolpidem 68% of the patients were rated at least “moderately improved”, versus 62% with zopiclone. However, with zolpidem sleep-onset latency improved in significantly more patients (86 versus 78%). In addition, significantly fewer patients who took zolpidem had drug-related adverse events (31 versus 45%); bitter taste accounted for 5.8% of such complaints with zolpidem compared with 40% with zopiclone. In conclusion, zolpidem was at least as effective as zopiclone but showed significantly less rebound on withdrawal; overall it was better tolerated. Psychiatric An 86-year-old white woman with headaches and diplopia took zolpidem 5 mg and about 2 hours later became restless, disoriented, and physically agitated (31A ). She was given haloperidol and needed restraining for her own safety. Her symptoms resolved by day 5 and she had no recollection of the incident. Rechallenge was not attempted. Drug abuse There is a risk of abuse/dependence from chronic use of zolpidem in high doses (32A ). • A 67-year-old Caucasian woman, who had previously been treated for depression, anxiety, and insomnia, as well as alcohol, barbiturate, and benzodiazepine dependence, was given zolpidem 10 mg at bedtime for insomnia. She increased the dose

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without the knowledge of her physicians, using up to 100 mg/day for the previous 1.5 years, alternating it with various benzodiazepines obtained from multiple physicians when zolpidem was unobtainable. She developed severe generalized tremor, psychomotor agitation, facial flushing, and anxiety, despite taking chlordiazepoxide 300 mg in divided doses during the first 24 hours of detoxification. A tapering dose of zolpidem was initiated and the chlordiazepoxide was tapered. Her symptoms completely subsided within 30 minutes of a single dose of zolpidem 15 mg.

the first night after withdrawal of triazolam. After withdrawal from zopiclone or zolpidem there were slight but not significant rebound effects. Self-rating scales showed minimal rebound insomnia after withdrawal of all three hypnotics. In the placebo group there were no changes in sleep. These results suggest that the risks of tolerance and dependency are low after short-term zopiclone or zolpidem in the recommended doses.

Drug overdose A 44-year-old white man, who had had major depression and anxiety disorder for 25 years, became drowsy after swallowing 20 tablets (10 mg) of zolpidem (33A ). He was not taking any other medications at the time. A few hours later he became unresponsive and comatose and developed respiratory depression with hypoxia and mild hypercapnia. He subsequently made a full recovery after appropriate medical support.

Drug overdose A 72-year-old with respiratory debilitation due to bronchogenic carcinoma died after taking zopiclone about 200–350 mg (35A ).

Zopiclone Nervous system The acute polysomnographic effects of withdrawal of standard doses of zopiclone (n = 11), zolpidem (n = 11), triazolam (n = 10), and placebo (n = 7) have been studied in healthy men (34C ). They took zopiclone 7.5 mg, zolpidem 10 mg, triazolam 0.25 mg, or placebo for 4 weeks in double-blind, randomized order. Sleep EEG was performed. Total sleep time and sleep efficiency were lower in

Drug interactions An 86-year-old white woman taking nefazodone for depression started to take zopiclone for insomnia, but subsequently had morning drowsiness (36A ). The concentration of plasma zopiclone was measured 8 hours after administration on two occasions, during and after nefazodone therapy. After withdrawal of nefazodone, the plasma concentration of the S-enantiomer of zopiclone fell from 107 to 17 ng/ml, while the plasma concentration of the R-enantiomer fell from 21 to 1.5 ng/ml. The substantial fall in plasma zopiclone concentrations after withdrawal of nefazodone probably reflects a drug interaction. Despite the normally short half-life of zopiclone, the residual sedation initially observed in this case suggests that the interaction had clinical significance.

REFERENCES 1. Pierfitte C, Macouillard G, Thicoipe M, Chaslerie A, Pehourcq F, Aissou M, Martinez B, Lagnaoui R, Fourrier A, Begaud B, Dangoumau J, Moore N. Benzodiazepines and hip fractures in elderly people: case-control study. Br Med J 2001; 322: 704–8. 2. Roberge C, Mosquet B, Hamel F, Crete P, Starace J. Catatonie après sevrage d’un traitement par olanzapine et alprazolam. J Clin Pharm 2001; 20: 163–5. 3. D’Souza DL, Levasseur LM, Nezamis J, Robbins DK, Simms L, Koch KM. Effect of alosetron on the pharmacokinetics of alprazolam. J Clin Pharmacol 2001; 41: 452–4.

4. Michaud K, Romain N, Giroud C, Brandt C, Mangin P. Hypothermia and undressing associated with non-fatal bromazepam intoxication. Forensic Sci Int 2001; 124: 112–14. 5. Deuschle M, Lederbogen F. Benzodiazepine withdrawal-induced catatonia. Pharmacopsychiatry 2001; 34: 41–2. 6. Alexopoulou A, Michael A, Dourakis SP. Acute thrombocytopenic purpura in a patient treated with chlordiazepoxide and clidinium. Arch Int Med 2001; 161: 1778. 7. Anonymous. Herbal medicine. Warning: found to contain chlordiazepoxide. WHO Pharm Newslett 2001; 1: 2–3.

52 8. Culhane NS, Hodle AD. Burning mouth syndrome after taking clonazepam. Ann Pharmacother 2001; 35: 874-6. 9. Yukawa E, Nonaka T, Yukawa M, Ohdo S, Higuchi S, Kuroda T, Goto Y. Pharmacoepidemiologic investigation of a clonazepam–carbamazepine interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients. J Clin Psychopharmacol 2001; 21: 588–93. 10. Peinemann F, Daldrup T. Severe and prolonged sedation in five neonates due to persistence of active diazepam metabolites. Eur J Pediatr 2001; 16: 378– 81. 11. De Haro L, Valli M, Bourdon J-H. Diazepam poisoning with one-month monitoring of diazepam and nordiazepam blood levels. Vet Hum Toxicol 2001; 43: 174–5. 12. Huron C, Servais C, Danion J-M. Lorazepam and diazepam impair true, but not false, recognition in healthy volunteers. Psychopharmacology 2001; 155: 204–9. 13. Fluck E, Fernandes C, File SE. Are lorazepaminduced deficits in attention similar to those resulting from aging? J Clin Psychopharmacol 2001; 21: 126–30. 14. Micallef J, Soubrouillard C, Guet F, Le Guern ME, Alquier C, Bruguerolle B, Blin O. A double blind parallel group placebo controlled comparison of sedative and amnesic effects of etifoxine and lorazepam in healthy subjects. Fundam Clin Pharmacol 2001; 15: 209–16. 15. Cawley MJ. Short-term lorazepam infusion and concern for propylene glycol toxicity: case report and review. Pharmacotherapy 2001; 21: 1140–4. 16. Wermeling DPH, Miller JL, Archer SM, Manaligod JM, Rudy AC. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol 2001; 41: 1225–31. 17. Vaz-Serra A, Figueira ML, Bessa-Peixoto A, Firmino H, Albuquerque R, Paz C, Dolgner A, VazSilva M, Almeida L. Mexazolam and alprazolam in the treatment of generalised anxiety disorder. Clin Drug Invest 2001; 21: 257–63. 18. Akhondzadeh S, Naghavi HR, Vazirian M, Shayeganpour A, Rashidi H, Khani M. Passionflower in the treatment of generalized anxiety: a pilot double-bind randomized controlled trial with oxazepam. J Clin Pharm Ther 2001; 26: 363–7. 19. Begg A, Drummond G, Tiplady B. Effects of temazepam on memory and psychomotor performance: a dose-response study. Hum Psychopharmacol 2001; 16: 475–80. 20. Salazar DE, Frackiewicz EJ, Dockens R, Kollia G, Fulmor E, Tigel PD, Uderman HD, Shiovitz TM, Sramek JJ, Cutler NR. Pharmacokinetics and tolerability of buspirone during oral administration to children and adolescents with anxiety disorder and normal healthy adults. J Clin Pharm 2001; 41: 1351–8.

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21. Sakr A, Andheria M. Pharmacokinetics of buspirone extended-release tablets: a single-dose study. J Clin Pharm 2001; 41: 783–9. 22. Lyden P, Jacoby M, Schim J, Albers G, Mazzeo P, Ashwood T, Nordlund A, Odergren T, for the CLASS IHT Investigators. The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Neurology 2001; 57: 1199–205. 23. Mangano RM. Efficacy and safety of zaleplon at peak plasma levels. Int J Clin Pract Suppl 2001; 116: 9–13. 24. Bhatia SC, Arora M, Bhatia SK. Perceptual disturbances with zaleplon. Psychiatr Serv 2001; 52: 109–10. 25. Roehrs T, Rosenthal L, Koshorek G, Mangano RM, Roth T. Effects of zaleplon or triazolam with or without ethanol on human performance. Sleep Med 2001: 323–32. 26. Jamieson AO, Zammit GK, Rosenberg RS, Davis, JR, Walsh JK. Zolpidem reduces the sleep disturbance of jet lag. Sleep Med 2001; 2: 423–30. 27. Erman MK, Erwin CW, Gengo FM, Jamieson AO, Lemmi H, Mahowald MW, Regestein QR, Roth T, Roth-Schechter B, Scarf MB, Vogel GW, Walsh JK, Ware JC. Comparative efficacy of zolpidem and temazepam in transient insomnia. Hum Psychopharmacol 2001; 16: 169–76. 28. Logan BK, Couper FJ. Zolpidem and driving impairment. J Forensic Sci 2001; 46: 105–10. 29. Rush CR, Baker RW. Zolpidem and triazolam interact differentially with a delay interval on a digit-enter-and-recall task. Hum Psychopharmacol 2001; 16: 147–57. 30. Tsutsui S. A double-blind comparative study of zolpidem versus zopiclone in the treatment of chronic primary insomnia. J Int Med Res 2001; 29: 163–77. 31. Brodeur MR, Stirling AL. Delirium associated with zolpidem. Ann Pharmacother 2001; 35: 1562– 4. 32. Madrak LN, Rosenberg M. Zolpidem abuse. Am J Psychiatry 2001; 158: 1330–1. 33. Hamad A, Sharma N. Acute zolpidem overdose leading to coma and respiratory failure. Intensive Care Med 2001; 27: 1239. 34. Voderholzer U, Riemann D, Hornyak M, Backhaus J, Feige B, Berger M, Hohagen F. A doubleblind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin Neurosci 2001; 251: 117– 23. 35. Bromness JG, Arnestad M, Karinen R, Hilberg T. Fatal overdose of zopiclone in an elderly woman with bronchogenic carcinoma. J Forensic Sci 2001; 46: 1247–9. 36. Alderman CP, Gebauer MG, Gilbert AL, Condon JT. Possible interaction of zopiclone and nefazodone. Ann Pharmacother 2001; 35: 1378–80.

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6

Antipsychotic drugs

GENERAL In the last few years there has been an overall increase in the use of antipsychotic drugs worldwide—mainly of those considered as atypical. Atypical antipsychotic drugs are regarded as being safer and sometimes more effective than typical drugs, although cost is an important issue. Nevertheless, the real advantages of atypical antipsychotic drugs have not been definitively established (SEDA-25, 53). Typical and atypical (second-generation) antipsychotic drugs have recently been compared in the treatment of chronic refractory schizophrenia (1M ). Clozapine was compared with typical antipsychotic drugs in seven studies (n = 1124). Of the 10 comparisons of second-generation versus typical antipsychotic drugs (n = 1801), there was a significant difference in six favoring second-generation antipsychotic drugs on measures of treatment efficacy; in the other four there was no significant difference between treatments. ANCOVA with the baseline score as a co-variate was performed to compare the efficacy of clozapine with that of typical antipsychotic drugs in terms of BPRS total score; there was a significant reduction in psychopathology in those who took clozapine, and the reduction was greater among those with higher BPRS scores. When the assessment was performed with other scales (BPRS positive symptom subscale, SANS) there were no significant treatment effects for clozapine over typical antipsychotic drugs. The subjects who took clozapine had significantly fewer extrapyramidal effects; tardive dyskinesia occurred equally in the two groups. Weight gain was reported in patients who took chlorpromazine (1%) and clozapine (7.1%), but in none of those who took haloperidol. There were problems in concentrating in patients taking © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

chlorpromazine (3.4%) or clozapine (2.9%), but in none of those taking haloperidol. Other adverse events reported in patients taking clozapine included neutropenia (2.0%), enuresis (1.0%), and seizures (0.4%); neuroleptic malignant syndrome developed in 0.5% of the patients who took chlorpromazine. Completion rates were higher for clozapine (70%; n = 400) than for the typical antipsychotic drugs (56%; n = 398). Despite the superior efficacy of clozapine in the treatment of resistant patients, the extent of this in terms of scope (symptoms improved) and magnitude (effect size) was variable. Using what might be regarded as a non-stringent criterion of a 20–30% reduction in total psychopathology scores, under half of the patients responded in most of the studies. The effects of risperidone and haloperidol in preventing relapse in 365 patients with schizophrenia have been compared (2C ). The patients were randomly assigned to receive risperidone (n = 177; median duration 364 days; mean dose 4.9 mg/day) or haloperidol (n = 188; median duration 238 days; mean dose 11.7 mg/day). Primary analyses were performed on all subjects who underwent randomization and were assessed at least once during drug treatment. The risk ratio for relapse with haloperidol was 1.93 (95% CI = 1.33, 2.80), and early withdrawal for any reason was more frequent among haloperidol-treated patients (RR = 1.52; 95% CI = 1.18, 1.96). Patients who took risperidone had greater reductions in mean severities of both psychotic symptoms and extrapyramidal adverse effects than those who took haloperidol. There were adverse events in 90% of those who took risperidone and 91% of those who took haloperidol. Events that were reported in more than 10% of subjects in at least one group were somnolence (14% with risperidone; 25% with haloperidol), agitation (10% and 18%), and hyperkinesia (5% and 20%). There was a mean weight gain of 2.3 kg in those who took risperidone—similar in magnitude to the weight gain seen in short-term

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studies—and a mean loss of 0.73 kg in those who took haloperidol. It has been suggested that the apparent advantage of risperidone in some trials may be explained by the use of doses of conventional drugs that are more than optimal, leading to poorer tolerability and effectiveness (3r ). Cardiovascular Particular attention has been devoted to QTc interval prolongation, torsade de pointes, and sudden death, which have accordingly been revised in depth (SEDA-24, 54). Evidence linking QTc interval prolongation, potassium channels, and torsade de pointes to antipsychotic drugs has been newly addressed (4R ). It is prudent to ask apparently healthy patients if they have had syncope, if they have relatives with the long QT syndrome, or if they have relatives who died suddenly at a young age. Intravenous haloperidol is often prescribed to treat agitation, and torsade de pointes has on occasions occurred (SEDA-20, 36). In a crosssectional cohort study QTc intervals were measured before the intravenous administration of haloperidol plus flunitrazepam, and continuous electrocardiographic monitoring was performed for at least 8 hours after (n = 34) (5c ); patients who received only flunitrazepam served as controls. The mean QTc interval after 8 hours in those who were given haloperidol was longer than in those who were given flunitrazepam alone; four patients given haloperidol had a QTc interval of more than 500 msec after 8 hours. However, none developed ventricular tachydysrhythmias. In a study of the electrocardiographic effects of various drugs used to treat schizophrenia, ziprasidone increased the QTc interval by an average of 9–14 msec more than risperidone, olanzapine, quetiapine, and haloperidol, but about 14 msec less than thioridazine (6r ). Although ziprasidone is approved for the treatment of schizophrenia, the product labelling allows “the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia”. Cardiomyopathy is a matter of concern with antipsychotic drugs (SEDA-24, 62; SEDA-25, 61). The relation between antipsychotic drug therapy and myocarditis and cardiomyopathy has been examined using the international database on adverse drug reactions run by the World

Alfonso Carvajal and Luis H. Martín Arias

Health Organization (7C ). Myocarditis and cardiomyopathy were reported rarely as suspected adverse drug reactions, and accounted for under 0.1% (n = 2121) of almost 2.5 million reports. The association of clozapine with those adverse reactions was statistically significant (231 reports out of 24 730), as was the association with “other antipsychotics” (89 of 60 775). Nervous system Seizures Convulsions in patients taking typical neuroleptic drugs are relatively rare (SED-14, 142). However, they are more common with clozapine (SEDA-22, 57) and are said to occur in 0.9% of patients taking olanzapine (SEDA-24, 67; SEDA-25, 64). Olanzapine has been reported to cause a lowered seizure threshold (8A ). • A 30-year-old man with paranoid psychosis for 5 years and seizures for 12 years (two generalized seizures a year) was switched to olanzapine 10 mg/day; he was also taking zuclopenthixol and valproate. He then had more frequent seizures, culminating in a generalized tonic–clonic seizure, which resulted in bilateral humeral head fractures. There were no metabolic or electrolyte disturbances. An electroencephalogram showed multifocal generalized epileptiform discharges similar to those seen with clozapine. They resolved on withdrawal of olanzapine and reintroduction of zuclopenthixol.

Akathisia Akathisia is common, afflicting 25– 75% of patients taking oral neuroleptic drugs (SED-14, 143). The agents that are currently available for the treatment of neurolepticinduced akathisia (beta-blockers, anticholinergic drugs, and benzodiazepines) have only modest efficacy, and new treatments have been tried. Prochlorperazine is a high-potency dopamine receptor antagonist that causes extrapyramidal adverse effects, such as akathisia. In 100 adults who were randomly assigned to receive a 3-minute infusion of diphenhydramine or placebo after receiving intravenous prochlorperazine 10 mg for nausea/vomiting or headache, akathisia developed in 18 of 50 subjects in the control group and in 7 of 50 subjects in the diphenhydramine group (9c ). The only adverse effect of diphenhydramine was sedation. Diphenhydramine may be effective in akathisia by more than just an anticholinergic mechanism, since it crosses the blood–brain barrier and blocks central muscarinic, 5-HT, and H1 histamine receptors, and

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α-adrenoceptors. This is claimed to be the first randomized controlled study of the efficacy of single-dose adjuvant diphenhydramine in preventing intravenous drug-induced akathisia. The same authors have also tried a slow infusion of prochlorperazine in 160 patients randomly assigned to two groups; akathisia developed in 31 of 84 who were given a 2-min infusion and in 18 of 76 patients who were given a 15-min infusion (10C ). Finally, mirtazapine was successfully used in a 28-year-old man with akathisia who was taking haloperidol 10 mg/day for schizophrenia and who complained of leg restlessness, an inability to sit still, and a constant urge to move (11A ). Biperiden (4 mg bd for 5 days) with the subsequent addition of diazepam (10 mg/day for 3 days) had no effect. Mirtazapine (15 mg/day for 5 days) produced substantial relief of the subjective component of the akathisia, and the abnormal movements disappeared. Mirtazapine is a tetracyclic antidepressant, similar to mianserin, and is a potent 5-HT2A/2C receptor antagonist. Apart from mianserin, other 5-HT2A/2C receptor antagonists, such as ritanserin and cyproheptadine, have also been used to treat akathisia. Tardive dyskinesia Pharmacogenetic assessments of antipsychotic drug-induced tardive dyskinesia have been reviewed (12R ). The dopamine D3 receptor (DRD3 ) gene has a single nucleotide polymorphism that results in a serine to glycine amino acid substitution (Ser9Gly) in the N terminal and gives rise to allelic differences in dopamine affinity (SED-14, 145); the glycine variant has been associated with tardive dyskinesia. The severity of tardive dyskinesia was greater in homozygotes for the glycine variant of DRD3 than in serine/serine homozygotes or serine/glycine heterozygotes. Another polymorphism has been identified in intron 1 of the CYP1A2 gene; similarly, there is an association between the severity of tardive dyskinesia and one of the corresponding genotypes. It is said that CYP1A2 may be important in antipsychotic drug metabolism after CYP2D6 saturation during long-term treatment. According to the authors of the review, who also carried out the experimental studies, a combined pharmacogenetic analysis of pharmacokinetic and pharmacodynamic targets for antipsychotic drugs should improve our ability

55 to identify subpopulations that differ in drug safety profiles. In dealing with the whole problem of dyskinesia, the pre-eminent role of prevention must be emphasized, particularly because treatment is so unrewarding (SED-14, 145). This has led to studies of many other compounds, such as hormones, antiparkinsonian drugs, benzodiazepines, and vitamin E, and techniques such as electroconvulsive therapy, dietary control, and biofeedback training (SEDA-18, 49; SEDA-23, 53). A 41-year-old man had dramatic relief from tardive dyskinesia and akathisia with highdose piracetam (13A ). Neuroleptic malignant syndrome There have been reports of neuroleptic malignant syndrome precipitated by promethazine 100 mg/day to treat neuroleptic drug-induced extrapyramidal symptoms and lorazepam 6 mg/day to treat agitation (14A ), after the addition of intramuscular haloperidol 23 mg to atypical antipsychotic drugs (15A ), and in other instances in children and adolescents (16A ). Stuttering Stuttering, a rare adverse effect of antipsychotic drugs, has been attributed to risperidone (17A ). • A 32-year-old Korean man with delusions took oral risperidone 1.0 mg/day and lorazepam 0.5 mg bd. The dose of risperidone was increased to 4 mg/day over 4 days. On day 5, he began to stutter and could not articulate what he wanted to say without stuttering. The dose of risperidone was increased to 8 mg/day and the stuttering became more pronounced. However, after 1 year of continuous treatment, he did not stutter any more.

The authors suggested that since the patient had a history of stuttering risperidone had reactivated the speech pattern. Sensory systems Chlorpromazine-induced ocular pigmentation has often been reported (SED-14, 151). A 46-year-old schizophrenic patient who had taken chlorpromazine 200 mg/day for 9 years and then 400 mg/day for 7 years developed ocular pigmentation (18A ). The interesting thing about this report was its striking photographs, in which multiple, small, dark pigment deposits in the conjunctiva were seen; in addition, the cornea had multiple, small, discrete, yellowish specks, and both lenses had anterior capsular opacities.

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Endocrine Antipsychotic drugs cause increased serum prolactin concentrations (SED14, 148; SEDA-23, 55). Sex differences in hormone concentrations have been now investigated in 47 patients (21 men and 26 women) with schizophrenia or related psychoses, and using different antipsychotic drugs (19c ). The median daily dose and the median body weightadjusted daily dose were twice as high in men as in women. However, antipsychotic druginduced hyperprolactinemia was more frequent and occurred at a lower daily dose in women. The growth hormone concentration was normal in all patients. Some patients who take clozapine take another antipsychotic drug, and the consequences of this practice in terms of prolactin have been studied in five patients (20c ). After the addition of haloperidol (4 mg/day) to clozapine the mean prolactin concentration increased from 9.7 µg/l to 16 µg/l at week 4 and 19 µg/l at week 6. Each subject had an increase in the percentage of D2 receptor occupancy, and the group mean increased from 55% at baseline to 79% at week 4; the increased prolactin concentrations correlated with receptor occupancy. Metabolism In a recent cross-sectional study in 44 men, olanzapine has been shown to have a worse metabolic risk profile than risperidone (21c ). The men (mean age 29 years) took olanzapine (n = 22; mean duration 18 months; mean dose 13 mg/day) or risperidone (n = 22; mean duration 17 months; mean dose 2.8 mg/day). Those who took olanzapine had significantly higher plasma triglyceride concentrations, significantly higher very low density lipoprotein cholesterol concentrations, a trend to a lower HDL cholesterol concentration, and a trend to a higher cholesterol/HDL cholesterol ratio. Despite similar mean body weights (olanzapine 84 kg vs. risperidone 81 kg), 32% of those who took olanzapine were characterized by the atherogenic metabolic triad (hyperinsulinemia and raised apolipoprotein B and small-density LDL concentrations) compared with only 5% of those who took risperidone.

Antipsychotic drugs and weight gain Shortly after the conventional antipsychotic drugs were introduced in the 1950s, marked in-

Alfonso Carvajal and Luis H. Martín Arias

creases in body weight were observed; in fact, excessive weight gain has been reported in up to 50% of patients receiving long-term antipsychotic drug treatment (22R , 23M ) and has often been addressed in this series (SEDA-22, 62; SEDA-23, 67; SEDA-24, 58 and 69). However, changes in weight during psychosis are also related to the condition; Kraepelin wrote, “The taking of food fluctuates from complete refusal to the greatest voracity . . . Sometimes, in quite short periods, very considerable differences in the body weight are noticed . . .” (24R ). It was observed early on that food intake and weight often fell as psychosis worsened, but eating and weight returned to normal or increased when an acute psychotic episode abated. However, since the start of the neuroleptic drug era in the 1950s, a new pattern of sustained increased weight has commonly been detected. The question of whether weight gain is associated with efficacy is important; in one study there was no obvious relation between the magnitude of weight gain and therapeutic efficacy (25c ). Epidemiology While concerns about extrapyramidal symptoms and tardive dyskinesia are less with the atypical antipsychotic drugs, excessive weight gain has been recently noted as an important shortcoming. Several reviews have addressed this issue (26R –30R ). It has been pointed out that comparison of different studies of weight gain during treatment with atypical antipsychotic drugs is hampered by problems with study design, recruitment procedures, patient characteristics, measurement of body weight, co-medications, and duration of therapy. These problems have to be considered when assessing this type of information, particularly figures collected in accordance with the last-observation-carried-forward technique, which is one of the most common approaches taken; this type of analysis can produce marked underestimates of the magnitude of weight gain. Many studies have shown weight gain among individuals taking various antipsychotic drugs, and there has been one comprehensive meta-analysis including over 80 studies and over 30 000 patients (31M ). Most antipsychotic drugs cause some degree of weight gain, but clozapine and olanzapine are associated with the largest effect, around 4 kg; ziprasidone was not associated with weight gain.

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The percentages of patients who gain more than 7% of their baseline body weight are highest for olanzapine (29%) and lowest for ziprasidone (9.8%). Although these figures are useful for comparing different drugs, they do not illustrate how weight increases over time nor the total gain. Body weight tends to increase at first but reaches a plateau by about 1 year; with olanzapine 12.5–17.5 mg/day patients gained, on average, 12 kg (32c ). Risperidone and olanzapine, the two most commonly used atypical drugs, have been compared in trials; patients who took olanzapine gained almost twice as much weight (4.1 kg) as those who took risperidone (2.3 kg) (33C ). In a new study changes in body weight were examined in two groups of in-patients, who took either risperidone (n = 50) or olanzapine (n = 50) for schizophrenia (34c ). The mean body weight at baseline was 83 kg in the risperidone group and 85 kg in the olanzapine group; after 4 months of treatment, the mean body weights were 83 kg and 87 kg respectively. The increase in body weight with olanzapine was statistically significant. Risk factors In general, people with schizophrenia have a greater tendency to be overweight and obese than those who do not have schizophrenia (35c ). The evidence suggests that weight gain will progress most rapidly during the first 3–20 weeks of treatment with secondgeneration antipsychotic drugs; there is little evidence that dose affects weight gain. There are no sex differences, but there is a positive correlation between weight gain and age. Smokers treated with antipsychotic drugs may gain less weight than non-smokers (36c , 37R ). Patients in hospital are more likely to gain weight than those in the community, perhaps because they have an unrestricted diet and limited physical activity; there is some evidence that those with a lower baseline BMI are likely to gain more weight (27R ). Clinical features Obesity is associated with increased risks of dyslipidemia, hypertension, type 2 diabetes mellitus, cardiovascular disease, osteoarthritis, sleep apnea, and numerous other disorders; all these conditions have been associated with increased mortality. In the EUFAMI (European Federation of Associations of Families of Mentally Ill People) Patient Survey

57 undertaken in 2001 across four countries and involving 441 patients, treatment-induced adverse effects were a fundamental problem; of the 91% of patients who had adverse effects, 60% had weight gain, and of these more than half (54%) rated weight gain as the most difficult problem to cope with (38C ). Furthermore, weight gain may adversely affect patients’ adherence to medication, undermining the success of drug treatment for schizophrenia. A report has illustrated how extreme the problem of weight gain associated with antipsychotic drugs can be (39AR ). • A 32-year-old man with schizophrenia taking antipsychotic drugs was switched to olanzapine 20 mg/day for better control. He weighed 101 kg and his BMI was 31 kg/m2 . After 6 months he had gained 4.5 kg and after 1 year 17 kg. Because of poor control, risperidone 4 mg/day was added and 16 months later he had a 34.6 kg increase from baseline and had a BMI of 42 kg/m2 (i.e. in the range of severe obesity). He had both increased appetite and impaired satiety. His serum triglycerides were 4.0 mmol/l, and his fasting blood glucose was 6.7 mmol/l. He and his physician agreed on a goal of losing 12 kg over 12 months and he was referred to a dietitian. Over the next 5 weeks, he lost 2.7 kg and after 2 years his BMI was 38 kg/m2 and 1 year later 39 kg/m2 . He was given nizatidine 300 mg bd and 1 year later his weight was 95 kg (BMI 29 kg/m2 ). His triglycerides and fasting blood glucose concentrations were within the reference ranges.

Mechanisms The mechanisms of weight gain are not known. Olanzapine, for example, affects at least 19 different receptor sites, may have reuptake inhibition properties, and may affect hormones such as prolactin. Animal models do not help to elucidate mechanisms, since they have not shown clear results: some studies have shown weight gain with antipsychotic drugs in rats and others have not. Most of the atypical drugs, which most commonly cause weight gain, interact with 5-HT2C receptors; however, ziprasidone also binds to 5-HT2C receptors with high affinity and does not cause weight gain or does so to a lesser extent. In 152 patients treated with clozapine, Cys23Ser polymorphism of the 5-HT2C receptor did not explain the weight gain that occurred (40E ). Nor was there an association between specific alleles of the dopamine D4 receptor gene (41E ). In contrast, in 19-year-old monozygotic twins who gained around 40 kg after taking mainly clozapine, weight gain was related to an unspecified genotype (42A ).

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Management Behavioral treatment of obesity has given good results in patients taking antipsychotic drugs (43c ). More dubious is the use of antiobesity drugs, as some of them can cause psychotic reactions. Good results have been reported with amantadine, which increases dopamine release (44c ). In 12 patients with a mean weight gain of 7.3 kg during olanzapine treatment, amantadine 100– 300 mg/day over 3–6 months produced an average weight loss of 3.5 kg without adverse effects. In contrast, calorie restriction did not lead to weight loss in 39 patients with mental retardation who were taking risperidone, 37 of whom gained weight, the mean gain being 8.3 kg over 26 months (45c ). Gastrointestinal The possibility of fatal intestinal dilatation, although very rare, warrants careful evaluation of persistent complaints of constipation, particularly in patients who also have vomiting and abdominal pain, distension, or tenderness (SED-14, 150). Acute intestinal pseudo-obstruction (Ogilvie’s syndrome) has now been reported in a patient taking haloperidol plus benzatropine (46A ). • A 64-year-old woman started to take oral haloperidol 0.5 mg tds, and 3 days later was given intravenous benzatropine 2 mg for dystonia plus a second dose 1 hour later because she had not responded to the first dose. Her dystonia improved, but she started to develop abdominal distension and discomfort, and within the next 3–4 hours her whole abdomen had become significantly distended. Haloperidol and benzatropine were withdrawn and she was treated with hydration, nasogastric suction, a rectal tube, and frequent change of position. With this conservative therapy, her abdominal distension resolved completely in 24 hours.

Skin A 55-year-old man who had been treated for a manic-depressive disorder for about 5 years developed toxic epidermal necrolysis after being given carbamazepine and haloperidol (47A ). Body temperature Although antipsychotic drugs can cause neuroleptic malignant syndrome, whose main feature is fever, they commonly cause a reduction in body temperature (SEDA-25, 59). Hypothermia, defined as a body temperature lower than 35◦ C, has been reported.

Alfonso Carvajal and Luis H. Martín Arias

• A 73-year-old woman with diabetes mellitus and schizophrenia was given haloperidol 8 mg/day instead of zuclopenthixol; she also took levomepromazine 75 mg at night; 10 days later she was found unconscious with a rectal temperature of 31.5◦ C (48A ). A few weeks later, she had two further episodes, first with olanzapine 10 mg/day (rectal temperature 31.7◦ C) and then with thioridazine 40 mg/day (rectal temperature 34◦ C). She was therefore given dixyrazine 150 mg/day and alimemazine 20 mg at night, and had no more episodes of hypothermia. • An 83-year-old woman developed a rectal temperature of 33.1◦ C 3 weeks after starting to take olanzapine 5 mg/day (49A ). • A 68-year-old schizophrenic woman with type 1 diabetes mellitus developed a body temperature of 33.4◦ C 1 week after starting to take quetiapine 100 mg bd (49A ).

In the two last cases, the most common causes of hypothermia, such as hypothyroidism, infection, and cold exposure, were ruled out. Drug overdose Suicide is the leading cause of premature death among patients with schizophrenia. The lifetime incidence of completed suicide among patients with schizophrenia is about 10% (50R ) and 18–55% of patients with schizophrenia make suicide attempts (51R ), sometimes with neuroleptic drugs. In autopsies and toxicological analyses in Vienna from 1991 to 1997, 97 neuroleptic compounds were detected in 85 fatal intoxications (52c ). Of these, 17 fatal poisonings were attributed to a single compound, three were due to two neuroleptic drugs, 57 to a combination of one neuroleptic drug with other drugs, seven to two neuroleptic drugs with other drugs, and in one case three neuroleptic drugs combined with other drugs. Relating the number of deaths by a drug to the number of Defined Daily Doses, a fatality index (f -value) was estimated. At the top of the rating were levopromazine, prothipendyl, and chlorprothixene, which had f -values significantly higher than the mean. However, since the estimates were not adjusted for age or condition, these data should be taken with caution.

INDIVIDUAL DRUGS Amisulpride

(SEDA-23, 58; SEDA-24;

60) Cardiovascular Sinus bradycardia and QT interval prolongation occurred in a 25-year-

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old man taking amisulpride 800 mg/day (53A ). The dosage of amisulpride was reduced to 600 mg/day and the electrocardiogram normalized within a few days.

Clozapine

(SED-14, 140; SEDA-23, 59; SEDA-24, 61; SEDA-25, 60) Cardiovascular Clozapine can cause prolongation of the QT interval (54A ). • In a 30-year-old man taking clozapine there were minor electrocardiographic abnormalities, including a prolonged QT interval. A power spectrum analysis of heart rate variability showed marked abnormalities in autonomic nervous system activity. When olanzapine was substituted, power spectrum analysis studies showed that his heart rate had improved significantly and that his cardiovascular parameters had returned to normal. Serial electrocardiograms showed minimal prolongation of the QT interval.

Clozapine has been associated with cardiomyopathy, including myocarditis, and partial data have suggested an incidence of 1 in 500 in the first month (SED-14, 142; SEDA-24, 62; SEDA-25, 61). Now the first case of clozapine rechallenge after myocarditis has been described (55A ). • A 23-year-old man with no history of cardiac disease was given clozapine 12.5 mg/day, increasing to 200 mg/day over 3 weeks; 5 weeks later he complained of shortness of breath and non-specific aches and pains in his legs and body. There was marked ST segment depression and T wave inversion in the lateral and inferior leads of the electrocardiogram. There was no eosinophilia, and creatine kinase activity was not raised. An echocardiogram showed a hyperdynamic heart and left ventricular size was at the upper limit of normal. The heart valves were normal. Clozapine was withdrawn, but his mental state and quality of life deteriorated, and 2 years later clozapine was restarted because other drugs had not produced improvement. The dose of clozapine was built up to 225 mg at night and he remained well and free from cardiac adverse effects.

In this case a consultant cardiologist diagnosed myocarditis secondary to clozapine, as no other confounding co-morbidity was identified. However, the negative rechallenge suggests that either the clozapine was not responsible or that there was tolerance to the effect.

59 Electrocardiographic changes have been associated with clozapine (SEDA-23, 60; SEDA24, 62; SEDA-25, 61), as has sudden cardiac death with fatal myocarditis and cardiomyopathy (SEDA-24, 62). The reports of sudden death associated with clozapine and the possibility that it may have direct prodysrhythmic properties have been reviewed (56R ). Classical neuroleptic drugs have been associated with an increased risk of venous thromboembolism (57C ). It has also been suggested that the use of clozapine is associated with thromboembolism, through unknown mechanisms, with a risk of 1 per 2000–6000 patients (SEDA-25, 61). Fatal pulmonary embolism occurred in a 29-year-old man who was not obese, did not smoke, and had not had recent surgery, after he had taken clozapine 300 mg/day for 6 weeks (58A ). Several cases of hypertension have been associated with clozapine, and alpha2 -adrenoceptor blockade has been proposed as a possible mechanism (SEDA-23, 59). Four patients developed pseudopheochromocytoma syndrome associated with clozapine (59A ); all had hypertension, profuse sweating, and obesity. The authors suggested that clozapine could increase plasma noradrenaline concentrations by inhibiting presynaptic reuptake mediated by alpha2 adrenoceptors. Metabolism Hyperglycemia has been reported in patients taking clozapine (SEDA-23, 60; SEDA-24, 64), and the effects of clozapine and haloperidol on blood glucose metabolism have recently been studied (60c ). Of 17 patients taking clozapine, six had impaired glucose tolerance and eight had a glycemic peak delay, whereas of 10 taking haloperidol none had impaired glucose tolerance and only one had a glycemic peak delay. Hematologic The problem of agranulocytosis with clozapine has been extensively discussed, and some of the available postmarketing data on clozapine-induced agranulocytosis from different countries have been published (SEDA-23, 62; SEDA-24, 62). About 10 000 patients have been treated with clozapine in Australia since its introduction in 1993, and the Clozaril monitoring system has ensured that since that time there have been no deaths from agranulocytosis in patients taking clozapine (61r ). A recent report has suggested that

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clozapine-induced blood dyscrasias can persist when an atypical neuroleptic replaces clozapine: granulocytopenia, presumably induced by clozapine, persisted in a 53-year-old woman after she switched from clozapine to quetiapine (62A ). Agranulocytosis due to clozapine has previously been associated with different types of human leukocyte antigen (HLA), and in Jewish patients with agranulocytosis there was a higher frequency of the HLA B38 antigen (SEDA-23, 63). In a further open study in 31 German schizophrenic patients with clozapine-induced agranulocytosis and 77 schizophrenic controls, agranulocytosis was significantly associated with HLA-Cw*7, DQB*0502, DRB1*0101, and DRB3*020 (63c ). No other antigens were associated with agranulocytosis, but age was another major risk factor. In another study in two groups of Finnish patients, 19 “clozapine responders” and 26 patients with a history of non-fatal clozapine-induced granulocytopenia or agranulocytosis, the frequency of the HLA-A1 allele in the latter was low (12%), whereas HLA-A1 was associated with a good therapeutic response at an allele frequency of 58% (the frequency of HLA-A1 being 20% in the Finnish population) (64c ). The first report of concordant clozapineinduced agranulocytosis in monozygotic twins has appeared; in both twins there was a low leukocyte count after 9 weeks of treatment (65A ). Serological typing of the HLA system showed identical patterns in the twins: HLA-A: 28, 26; HLA-B: 49, 63; DR: 2 (vs 16), 12, 52; DQ: 1. The authors pointed out that these data suggest that genetic factors may participate not only in the time of onset of schizophrenia, but also in the emergence and timing of agranulocytosis in response to clozapine. On the other hand, an example of a false sense of security gained by relying on monitoring monthly blood counts in patients taking clozapine has been published (66A ). • A 61-year-old man who had taken clozapine for 3 years had normal blood counts. However, one day, his hemoglobin was 8.5 g/dl, having previously been 13 g/dl, following a steady asymptomatic fall over 6 months that had been documented but had gone unnoticed. He subsequently underwent investigation and treatment for anemia.

Alfonso Carvajal and Luis H. Martín Arias

Salivary glands Hypersalivation is a common and well-known adverse effect of clozapine (SEDA-25, 63). A comprehensive review has been published on the evidence of the benefit of using antimuscarinic agents, adrenoceptor antagonists, and adrenoceptor agonists in treating clozapine-induced hypersalivation (67R ). There is a lack of good-quality controlled trials, most papers having reported series of uncontrolled cases dependent on subjective measures of improvement reported by patients; however, the authors suggested that the most effective treatment may be a combination of terazosin and benzhexol. The authors of a recent study claimed to have considerable evidence implicating alphaadrenoceptors in hypersalivation caused by clozapine, and tested the hypothesis that a biallelic polymorphism in the promoter region of the alpha2 -adrenoceptor gene confers susceptibility to schizophrenia, which is associated with a clozapine-induced favorable therapeutic response and/or clozapine-induced hypersalivation (68c ). However, the results in 97 patients showed that the alpha2 -adrenoceptor gene polymorphism did not play a major role in susceptibility to hypersalivation or the therapeutic response of patients with schizophrenia. Liver Hepatitis associated with clozapine has been reported (SEDA-23, 61), and a new case has been published in a 49-year-old woman (69A ). The dosage of clozapine was titrated to 300 mg/day and she developed lethargy, anorexia, fever, eosinophilia, leukocytosis, and abnormal liver function tests. The serum clozapine concentration was 8595 nmol/l. Clozapine was withdrawn and after 8 days her condition stabilized and low-dose clozapine treatment was successfully restarted with serum monitoring. Drug interactions Clozapine plasma concentrations increase when risperidone is introduced. The effects of risperidone 3.25 mg/day on cytochrome P450 isozymes have therefore been assessed in eight patients by determination of the metabolism of caffeine (for CYP1A2), dextromethorphan (for CYP2D6), and mephenytoin (for CYP2C19) (70c ). The results suggested that risperidone is a weak in vivo inhibitor of CYP2D6, CYP2C19, and CYP1A2. The authors concluded that inhibition

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Chapter 6

by risperidone of those isozymes is an unlikely mechanism to explain increased clozapine concentrations.

Loxapine Hematologic Three cases of leukocytosis attributed to loxapine have been reported; all resolved when loxapine was withdrawn (71A ).

Olanzapine

(SEDA-23, 64; SEDA-24, 66;

SEDA-25, 64) There have been no adequate comparisons of olanzapine with clozapine (SEDA-23, 64; SEDA-25, 53). The aim of a recent study by Lilly Research Laboratories was to compare olanzapine with clozapine after 18 weeks of double-blind treatment in 220 schizophrenic patients eligible for treatment with clozapine; conclusions were based on the one-sided lower 95% confidence limit of the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale (PANSS) total score) (72C ). The two drugs were comparably effective in neuroleptic drug-resistant patients. Significantly fewer olanzapine-treated patients (4%) withdrew owing to adverse effects than their clozapine-treated counterparts (14%). Among spontaneously reported adverse effects, increased salivation, constipation, dizziness, and nausea were reported significantly more often by patients taking clozapine, whereas only dry mouth was reported more often by patients taking olanzapine. The efficacy and safety of olanzapine have previously been studied (SEDA-24, 67; SEDA25, 64). A multicenter, double-blind, placebocontrolled study in patients with Alzheimer’s disease and symptoms of agitation/aggression and/or psychosis but few or no psychotic symptoms at baseline, and data from a subgroup of patients have now been analysed (73C ). Three subsets of patients were identified on the basis of their symptoms at baseline: those with no clinically significant hallucinations, those with no clinically significant delusions, and those with no clinically significant delusions or

61 hallucinations. Of the patients without hallucinations or delusions at baseline (n = 75), the placebo-treated patients had significantly more of these symptoms than olanzapine-treated patients. Similarly, among the patients without baseline hallucinations (n = 153), the placebotreated patients had higher hallucination scores than olanzapine-treated patients, whereas patients without baseline delusions (n = 87) had no significant treatment effects. Abnormal gait, a term comprising leaning, limp, stooped posture, and unsteady gait, occurred in a higher incidence among olanzapine-treated patients (14/72) than placebo-treated patients (0/33). Somnolence was also reported at higher rates with olanzapine (27/72) than placebo (3/33). The efficacy and safety of olanzapine and clozapine have been studied in an open 12week study in 18 patients with Parkinson’s disease and dopaminergic drug-induced psychosis (74c ). All the patients who took clozapine (mean dosage 13 mg/day) completed the study, despite reporting a number of adverse effects, including somnolence, falls, orthostatic hypotension, and syncope. In contrast, early withdrawal was required in three of the nine patients who took olanzapine, owing to severe gait deterioration and drowsiness (mean dosage 3.9 mg/day). Psychotic symptoms improved in both groups. However, parkinsonism improved in the clozapine group according to the Cornell University Rating Scale (with a 20% fall in raw score and a 7.9% fall in weighted score), while the six patients who took olanzapine and who finished the study had worse parkinsonian symptoms (with a 26% worsening in raw score and a 25% worsening in weighted score). Cardiovascular QT interval prolongation, torsade de pointes, and sudden death associated with antipsychotic drugs were reviewed in SEDA-24 (p. 54). It has also been suggested that olanzapine often causes QT interval prolongation (SEDA-25, 64). Now electrocardiograms, obtained as part of the safety assessment of olanzapine in four controlled randomized trials (n = 2700), have been analysed (75C ). The incidence of maximum QTc prolongation beyond 450 msec during treatment was approximately equal to the incidence of prolongation of the QTc beyond 450 msec at baseline. The authors therefore suggested that olanzapine does not contribute to QTc prolongation. This

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has been supported by the report of a patient in whom QTc prolongation while he was taking clozapine reversed when he switched to olanzapine (54A ). Nervous system Neuroleptic malignant syndrome associated with olanzapine therapy has previously been reported (SEDA-23, 66; SEDA-24, 68; SEDA-25, 64). Now there has been another report associated with severe hypernatremia. • A 30-year-old man who had taken olanzapine 20 mg/day for 10 days developed typical neuroleptic malignant syndrome with raised body temperature (39.7◦ C), obtundation, tremor, rigidity, sweating, fluctuating pupillary diameter, tachycardia, labile hypertension, raised serum creatine kinase activity, and severe hypernatremia (190 mmol/l) (76A ).

Psychiatric Mania has been previously associated with olanzapine (SEDA-23, 66; SEDA24, 68; SEDA-25, 65), and a new case has been reported (77A ). • A 36-year-old woman with paranoid schizophrenia was given olanzapine 15 mg/day and 3 weeks later she had a hypomanic episode (Young Mania Rating Scale, YMRS, score 30). The dosage of olanzapine was reduced to 10 mg/day and then to 5 mg/day, with minimal improvement of her manic symptoms (YMRS score 27). Olanzapine was withdrawn and a conventional antipsychotic drug given instead. The manic episode resolved over the next 4 days (YMRS score 5).

Metabolism Hyperglycemia and diabetes have been associated with olanzapine, and published cases have suggested that these adverse effects may be caused by a mechanism related to weight gain (SEDA-23, 67; SEDA-24, 69; SEDA-25, 65). Other risk factors, such as family history, obesity, and concomitant medications can predispose an individual taking olanzapine to diabetes mellitus. New-onset diabetes mellitus developed after olanzapine was given to a 31-year-old man and a 44-year-old man (78A ). In both cases, the family history included diabetes mellitus, type unknown. The patients were taking various psychotropic drugs. In the first case body weight increased by about 12 kg (BMI 32 kg/m2 ) 6 weeks after starting olanzapine, when his diabetes mellitus started; in the second case (BMI 26 kg/m2 , weight 81 kg) the previous weight was unknown.

Alfonso Carvajal and Luis H. Martín Arias

Olanzapine-induced non-ketotic hyperglycemia has also been reported in the absence of obesity (79A ). • A non-obese 51-year-old man without a history of diabetes mellitus had a serum glucose concentration of 89 mmol/l and was non-ketotic. Olanzapine had been begun under 6 months before; about 2 months before the event his blood glucose concentration was 6.0 mmol/l, and 8 days after withdrawal the glucose concentration returned to normal; he no longer required insulin nor any other hypoglycemic drug.

The authors suggested that olanzapine can cause hyperglycemia by a mechanism other than weight gain. Glucose concentrations have been studied in 47 patients with non-responsive schizophrenia taking olanzapine (80c ). Three of them, who had taken olanzapine for 3–6 months, had persistently high blood glucose concentrations. However, this is similar to what would be expected on the basis of the prevalence of diabetes mellitus in US adults. On the other hand, seven cases of asymptomatic lowered blood glucose concentrations have also been reported in patients with Tourette’s syndrome who were taking olanzapine (mean dose 12 mg/day) during an 8-week, open-label trial (81c ). The mean serum glucose concentration was 4.8 mmol/l at baseline and 4.1 mmol/l during the study; the average weight gain was 4.5 kg. The authors suggested that increased insulin release may have been responsible for the changes observed; however, non-insulin mechanisms, such as a low carbohydrate intake, may also have played a role. Hematologic Olanzapine is relatively free of hematological adverse effects (SEDA-24, 69), but several cases of neutropenia, prolonged granulocytopenia, and agranulocytosis, and an isolated case of thrombocytopenia have been reported (SEDA-23, 67; SEDA-25, 65). Three new cases of leukopenia with olanzapine have recently been reported (82A ). In each case, the leukopenia was dose-dependent, and a reduction in dose was followed by normalization of the leukocyte count and allowed continued treatment. Two of the patients had a previous history of neutropenia and agranulocytosis associated with typical antipsychotic drugs and the third developed neutropenia for the first time while taking olanzapine.

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Pancytopenia associated with exacerbation of motor disability induced by olanzapine (10 mg/day) in a patient with Parkinson’s disease has been reported (83A ). Olanzapine withdrawal increased the neutrophil, total granulocyte, erythrocyte, and platelet counts to normal in 3 weeks, while the motor disability improved only moderately. There is some evidence for an association of human leukocyte antigen (HLA) type with clozapine-induced agranulocytosis, and perhaps also with olanzapine-induced agranulocytosis; however, if there is an HLA association for olanzapine, it seems to be different from the HLA antigens incriminated for clozapine (SEDA-25, 66). In a 46-year-old man taking olanzapine 10 mg/day leukopenia and neutropenia were associated with HLA types A1 24, B7, B35, DRB1*15, DRB1*11, DRB3*0103, DRB5*01-02, a haplotype distinct from that previously observed in clozapine-induced hemotoxicity (84A ). Pancreas Acute pancreatitis has previously been reported (SEDA-25, 66), and was subsequently discussed (85r , 86r ). The main points of debate were the interpretation of attributability and the use of the Naranjo probability scale in a case in which the patient was taking another drug that could not be completely excluded as at least a partial contributor to the acute pancreatitis. Sexual function Priapism has previously been attributed to olanzapine (SEDA-23, 68; SEDA-24, 70; SEDA-25, 66), and new cases have been reported. • A 26-year-old man, who had previously taken a variety of psychotropic medications, including typical antipsychotic drugs and risperidone, without sexual adverse effects, took olanzapine 10 mg at bedtime (87A ). Soon after he developed priapism; 24 hours after withdrawal of olanzapine, the adverse effect disappeared. • A 51-year-old man developed priapism 16 hours after attempting suicide by taking olanzapine 100 mg and gabapentin 1500 mg (88A ). Detumescence was produced by two injections of lidocaine and 8 hours later an intracorporeal shunt.

Immunologic Hypersensitivity syndrome has been defined as a drug-induced complex consisting of fever, rash, and internal organ involvement; a case associated with olanzapine has been reported, purportedly for the first time (89A ).

• A 34-year-old man took clozapine for several months, but developed a cardiomyopathy. Clozapine was withdrawn and olanzapine 20 mg/day was given instead; 60 days later he developed a recurrent high fever, rash, and pruritus. There was bilateral periorbital edema and generalized erythroderma without target lesions or bullae and no mucosal involvement. He also had an eosinophilia and hepatitis.

Drug interactions Olanzapine is metabolized by CYP1A2 and there have been reports that fluvoxamine, which inhibits CYP1A2, increases plasma olanzapine concentrations (SEDA-24, 71). A 21-year-old woman had a very high olanzapine plasma concentration (120 µg/l) during co-administration of fluvoxamine 150 mg/day and olanzapine 15 mg/day; her symptoms included slight tremor, rigid movements, and general discomfort (90A ).

Quetiapine

(SEDA-22, 65; SEDA-23, 68; SEDA-24, 71; SEDA-25, 66)

Nervous system In a study funded by AstraZeneca, the marketing authorization holder of quetiapine, 25 patients with schizophrenia were randomly assigned double-blind to quetiapine 300–600 mg/day (n = 13) or haloperidol 10–20 mg/day (n = 12) for 6 months; 11 completed the study, eight with quetiapine three with haloperidol (91c ). After Bonferroni correction for 34 comparisons, only the beneficial effect of quetiapine on the revised Wechsler Adult Intelligence Scale (WAIS-R) was significant. Three patients had weight gain with quetiapine versus one with haloperidol. Two patients had raised hepatic enzymes with quetiapine. One patient taking quetiapine had tiny subcapsular blebs, which were apparent at baseline as small dots and appeared larger after 8 weeks of treatment.

Risperidone

(SEDA-23, 68; SEDA-24,

71; SEDA-25, 67) The efficacy and safety of risperidone have been previously examined in special groups of patients, such as those with mental retardation (SEDA-23, 69) and young people with

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behavioral disorders (SEDA-23, 69; SEDA-25, 67 and 68). Recently the efficacy and safety of risperidone (mean dose 2.9, range 1.5–4 mg/day) have been examined in a double-blind, randomized, parallel-group, 6-week study of the treatment of aggression in 35 adolescents with a primary diagnosis of disruptive behavior disorder and subaverage intelligence (92C ). Risperidone significantly improved aggression, and extrapyramidal symptoms were absent or very mild; there was transient tiredness in 11 of the 19 drug-treated subjects compared with one of the 16 placebo-treated subjects; other adverse effects were sialorrhea (n = 4 for risperidone, n = 0 for placebo), nausea (n = 3 for risperidone, n = 0 for placebo), and weight gain (mean of 3.5% of body weight with risperidone). There were no clinically important changes in laboratory parameters, electrocardiography, heart rate, or blood pressure. Risperidone (n = 26, mean dosage 3.8 mg/day) has been compared with pimozide (n = 24, mean dosage 2.9 mg/day) in a 12week, multicenter, double-blind, parallel-group study in patients with Tourette’s disorder (93C ). Tics significantly improved in both groups, as measured by the Tourette’s Symptom Severity Scale (TSSS) and there was also significant improvement in scales of Global Assessment of Functioning and Clinical Global Impressions, and in symptoms of anxiety and depressive mood; however, obsessive–compulsive behavior was significantly improved only by risperidone. Fewer patients who took risperidone reported extrapyramidal adverse effects (n = 4) compared with those who took pimozide (n = 8), and depression, fatigue, and somnolence were the most prominent adverse effects in both groups. In a double-blind, placebo-controlled study of the addition of low-dose risperidone (mean dosage 2.2 mg/day) to a 5-HT reuptake inhibitor in refractory obsessive–compulsive disorder in 70 adults, 18 of 20 risperidone-treated patients had at least one adverse effect (94C ). The adverse effects in both groups included sedation (n = 17 for risperidone, n = 8 for placebo), increased appetite (6 and 3), restlessness (6 and 6), and dry mouth (5 and 5). Patients with bipolar disorder may benefit from risperidone, but this conclusion comes from open studies with small sample sizes (SEDA-23, 69). In a 6-week open study of

Alfonso Carvajal and Luis H. Martín Arias

risperidone (mean dosage 4.7 mg/day) in combination with mood-stabilizing treatments (usually lithium, carbamazepine, or valproate) for the treatment of schizoaffective disorder in 102 patients, 95 of whom completed the trial, at week 4 most patients had improved symptom severity and 9.3% were completely symptomfree (95c ). There were no statistically significant differences between baseline and week 4 in the severity of extrapyramidal symptoms, as measured by the UKU Side Effect Rating Scale subscale for neurological adverse effects; other adverse effects included depressive symptoms (n = 13), exacerbation of mania (n = 5), drowsiness (n = 3), and impotence (n = 2). The results of two major controlled clinical trials of risperidone in patients with dementia have not been conclusive, but risperidone is more effective than placebo in agitated and demented patients (SEDA-25, 68). The longterm data have recently been reviewed (96R ). The data suggest that although in the two pivotal previous comparisons of risperidone with placebo, the risk of adverse events was similar in the two groups when risperidone was given in the optimal dosage (1 mg/day), during a 12-month open extension of these studies, the incidence of de novo tardive dyskinesia was very low, and there were no clinically important adverse events or changes in vital signs or laboratory signs. Nervous system A qualitative analysis of extrapyramidal effects has been performed using Extrapyramidal Symptom Rating Scale (ESRC) data reported in 11 double-blind risperidone comparisons with haloperidol or placebo (97M ). Between-group comparisons showed no differences between placebo and risperidone 1–2 mg/day, but parkinsonism, tremor, akathisia, and sialorrhea were more likely to occur with haloperidol 1–6 mg/day than with placebo or risperidone. At risperidone dosages of more than 8 mg/day, the severity of acute extrapyramidal effects lay between those of placebo and haloperidol; the severity of tardive dyskinesia was greater with placebo than with either drug. The long-term effect of risperidone on basal ganglia volume, measured by MRI scanning, has been studied in 30 patients with a first episode of schizophrenia who took risperidone, 12 patients taking long-term typical antipsychotic drugs, and 23 healthy controls (98c ).

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Treatment with risperidone for 1 year (mean dosage 2.7, range 1–6 mg/day) did not alter basal ganglia volume, although there were movement disorders in both groups of treated patients, suggesting effects of both illness and medications. Endocrine Hyperprolactinemia, galactorrhea, and/or gynecomastia have previously been reported with risperidone in both men and women (SEDA-23, 71; SEDA-24, 72; SEDA25, 70). A 17-year-old man developed galactorrhea and breast tenderness within weeks of starting to take risperidone; the authors suggested that patients who have galactorrhea, amenorrhea, or both while taking risperidone should be gradually switched to olanzapine, quetiapine, or clozapine (99A ). Salivary glands Hypersalivation or sialorrhea has been reported with all antipsychotic drugs, and has been associated with risperidone as one of the most frequently mentioned adverse effects in patients with disturbing extrapyramidal symptoms during previous neuroleptic drug treatment (SEDA-25, 68). Hypersalivation is a troublesome adverse effect that can contribute to non-adherence, but it can be treated with clonidine, as happened in a 22-year-old man whose hypersalivation was rapidly and markedly reduced by clonidine 0.1 mg bd over 3 days (100A ). Liver Hepatotoxicity has been associated with risperidone (SEDA-23, 71; SEDA-24, 73), and there has been a recent case of risperidoneinduced cholestatic jaundice in a 37-year-old man (101A ). Sexual function Risperidone can cause erectile dysfunction (SEDA-24, 71) and priapism (SEDA-25, 70). Ejaculatory dysfunction has also been associated with risperidone in two cases. • A 21-year-old patient with bipolar schizoaffective disorder developed absent ejaculation with normal orgasm 3 weeks after starting to take risperidone (102A ). • A 37-year-old man with paranoid schizophrenia had ejaculatory difficulty during sexual intercourse with his wife, compatible with retrograde ejaculation, 1–2 weeks after starting to take risperidone (103A ). He reported complete failure to emit semen but a normal desire, erection, and sense of

65 orgasm. Semen was seen in postcoital urine. The dosage of risperidone was reduced to 3 mg/day and anterograde ejaculation was partially restored.

Drug overdose A 15-year-old who took 110 mg of risperidone in a suicide attempt developed only transient lethargy, hypotension, and tachycardia without any other significant effects (104A ). Drug interactions Several cases of interactions of risperidone with paroxetine have been published (SEDA-25, 71). The effects of paroxetine 20 mg/day for 4 weeks on steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone have been studied in 10 patients taking risperidone 4–8 mg/day (105c ). During paroxetine administration, mean plasma risperidone concentrations increased significantly, while 9hydroxyrisperidone concentrations fell slightly but not significantly; after 4 weeks, the sum of the risperidone and 9-hydroxyrisperidone concentrations increased significantly by 45% over baseline, and the mean plasma risperidone/9hydroxyrisperidone concentration ratio was also significantly changed; however, the drug combination was generally well tolerated, with the exception of one patient, who developed parkinsonian symptoms during the second week, and whose total plasma risperidone and 9-hydroxyrisperidone concentrations increased by 62%. A potential pharmacokinetic interaction of risperidone with carbamazepine has previously been described (SEDA-23, 72), and it has been suggested that induction of CYP3A4a markedly reduces the plasma concentrations of risperidone and 9-hydroxyrisperidone, an interaction that is likely to be clinically important (SEDA-25, 70). In a 50-year-old man with deficient CYP2D6 activity, the addition of carbamazepine to pre-existing risperidone therapy resulted in a marked reduction in the plasma concentrations of risperidone and 9-hydroxyrisperidone and in acute exacerbation of his psychosis (106A ). Risperidone increases plasma clozapine concentrations. The effects of risperidone 3.25 mg/day on cytochrome P450 isozymes have therefore been assessed in eight patients by determination of the metabolism of caffeine (for CYP1A2), dextromethorphan (for CYP2D6),

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and mephenytoin (for CYP2C19) (70c ). The results suggested that risperidone is a weak in vivo inhibitor of CYP2D6, CYP2C19, and CYP1A2. The authors concluded that inhibition by risperidone of those isozymes is an unlikely mechanism to explain increased clozapine concentrations.

Sertindole Sertindole was suspended in January 2000, following concerns about reports of cardiac dysrhythmias and sudden death (SEDA-22, 71; SEDA-25, 71). To gather further information, data collected for prescription-eventmonitoring (PEM) studies have been analysed (107c ). Patients taking sertindole (n = 462; 5482 months of observation) were compared with patients taking risperidone or olanzapine (n = 16 542; 139 987 months of observation). There were seven deaths in the sertindole group and 415 in the other, and the death rates were not significantly different, although the confidence intervals were wide because of the small number of patients in the sertindole group.

Alfonso Carvajal and Luis H. Martín Arias

There were six cases of prolonged QTc interval in the patients taking sertindole and one in the controls. The authors concluded that the sertindole group was too small to rule out an association between sertindole and cardiovascular deaths. On 28 June 2001 an ad hoc expert committee was convened to review the available clinical and preclinical data related to the cardiovascular activity of sertindole and to consider whether such data supported the then current marketing authorization status of sertindole (108S ). Based on a re-evaluation of all the available data, including additional data submitted by the Marketing Authorization Holder, it was concluded that the re-introduction of sertindole could be supported by further clinical safety data, strong safeguards (including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias), a reduction in the recommended maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive electrocardiographic monitoring before and during treatment. In the first instance, reintroduction should be limited to patients participating in two new post-marketing studies.

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Santiago Arroyo

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GENERAL TOPICS (SED-14, 164; SEDA-23, 83; SEDA-24, 82; SEDA-25, 78) Psychiatric The appropriate methods and timing in assessing cognitive and behavioral adverse events during drug development programs have been thoroughly reviewed (1R ). Endocrine Thyroid The effects of antiepileptic drugs on thyroid function have been studied in an open prospective study in 90 men with epilepsy (40 taking carbamazepine, 29 taking oxcarbazepine, and 21 taking valproate monotherapy) and 25 control subjects (2C ). Serum thyroxine (T4 ) and/or free T4 concentrations were below the reference ranges in 45% of men taking carbamazepine and 24% of men taking oxcarbazepine. Thyroid peroxidase and/or thyroglobulin concentrations were increased in 13% of those taking carbamazepine, 17% of those taking oxcarbazepine, and 6% of controls, but these changes were not associated with altered serum thyroid hormone concentrations. Serum triiodothyronine and thyrotropin concentrations in those taking carbamazepine or oxcarbazepine were normal. In men taking valproate, the concentrations of thyroid hormones, thyrotropin, and antithyroid antibodies were normal. Thus, low serum thyroid hormone concentrations appear to be frequent in men taking carbamazepine or oxcarbazepine and are probably not due to liver enzyme induction or activation of immunological mechanisms. The clinical significance of these changes is uncertain: serum TSH was not affected and all the patients were clinically euthyroid. Similar results have been obtained in a retrospective study in 37 children taking valproate or carbamazepine (3C ). © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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Reproductive Reproductive endocrine disorders and sexual dysfunction have often been attributed to epilepsy itself, but antiepileptic drugs can cause various alterations in endocrine functions. Reproductive endocrine function has been prospectively evaluated in 90 men taking valproate (n = 21), carbamazepine (n = 40), or oxcarbazepine (n = 29) as monotherapy for epilepsy, and in 25 healthy controls (4C ). There were increased serum androgen concentrations in 60% of those who took valproate. Carbamazepine had an opposite effect: men had mean low serum concentrations of dehydroepiandrosterone and a high sex hormone binding globulin concentration. Moreover, 18% of men taking carbamazepine for epilepsy reported reduced libido, impaired potency, or both. Low daily doses of oxcarbazepine (under 900 mg/day) did not have any effects on serum concentrations of reproductive hormones, but men taking high doses of oxcarbazepine (over 900 mg/day) had increased serum testosterone, gonadotropin, and sex hormone binding globulin concentrations. Serum insulin concentrations were high in all patients. Thus, the three antiepileptic drugs affected the serum concentrations of reproductive endocrine hormones in men with epilepsy, but in different ways. Valproate directly affects steroid synthesis or metabolism. Oxcarbazepine and carbamazepine differ in their effects, despite their close structural homology: oxcarbazepine does not reduce the activity of androgens, whereas carbamazepine does. The relevance of these hormonal changes to reproductive or sexual function remains to be demonstrated. In another study changes in reproductive hormones associated with valproate or carbamazepine were prospectively analysed in 17 women and 22 men with recently diagnosed epilepsy (5C ). There were no clinical signs of hormonal disorders or weight gain during follow-up at 1 and 3 months. Valproate and carbamazepine caused alterations in reproductive hormonal function during the first

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month of treatment, and these changes were stable or progressive during the next 2 months. Serum testosterone concentrations increased in half of the women taking valproate; mean serum concentrations of gonadotropins and sex hormone binding globulin also increased, but the concentrations of serum dehydroepiandrosterone sulfate fell. On the other hand, in men after 3 months of valproate treatment, serum FSH concentrations were low and serum progesterone and dehydroepiandrosterone sulfate concentrations were high. Carbamazepine increased serum concentrations of sex hormone binding globulin and dehydroepiandrosterone sulfate, while the free-androgen index fell. Thus, valproate was associated with increased serum androgen concentrations, but the profiles of hormonal changes were different in men and women. On the other hand, carbamazepine was associated with reduced sex steroid function in both sexes. Although these results are of interest, the study was not randomized and a large number of statistical comparisons were performed, so that no firm conclusions can be drawn. Metabolism Changes in body weight associated with anticonvulsants have been extensively reviewed, including the effects of the antiepileptic drugs that have been most commonly associated with this adverse effect (valproic acid, carbamazepine, vigabatrin, and gabapentin) (6R ). Musculoskeletal Bone metabolism has been assessed in 27 children aged 3–17 years taking long-term valproate and lamotrigine (7C ). Valproate and lamotrigine were associated with short stature, low bone mineral density, and reduced bone formation. The effect was larger when the two drugs were used together. However, these results need further corroboration, as the level of physical activity could have been the major factor in producing these deficits and not the drugs themselves. Death The risk of sudden death associated with antiepileptic drugs has been assessed in a retrospective case-control study in 6880 patients with epilepsy, from whom 57 cases of sudden death and 171 controls (living with the patients with epilepsy) were selected (8C ). Polytherapy, frequent dosage changes, and high

71 carbamazepine concentrations were identified as risk factors for sudden death, all pointing to risks associated with unstable severe epilepsy. Because the study was retrospective it is difficult to know whether antiepileptic drugs in themselves are associated with sudden death, or if the higher risk is a result of uncontrolled seizures. Teratogenicity In 128 049 women at time of delivery three groups of infants were identified: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (controls) (9C ). The aim was to determine whether the major malformations associated with antiepileptic drugs are related to maternal epilepsy or exposure to anticonvulsant drugs. The infants were examined systematically for major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 controls (21% vs. 8.5%; OR = 2.8; 95% CI = 1.1, 9.7). The frequency of anticonvulsant embryopathy was also higher in 93 infants exposed to two or more anticonvulsant drugs than in controls (28% vs. 8.5%; OR = 4.2; 95% CI = 1.1, 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of malformations than the control infants. Thus, fetal malformations in women with epilepsy are associated with the drugs rather than the epilepsy. The developmental outcome in children of women exposed to antiepileptic drugs has been assessed in a retrospective survey that included 150 women on monotherapy, 74 on polytherapy, and 176 not exposed to any antiepileptic drugs (10C ). The odds ratio of additional educational needs in children exposed to antiepileptic drugs in utero compared with those not exposed was 1.49 (95% CI = 0.83, 2.67). Those exposed to valproate monotherapy had an odds ratio of 3.4 (95% CI = 1.63, 7.10), significantly higher than in those exposed to carbamazepine (OR = 0.26; 95% CI = 0.06, 1.15). Although the authors concluded that valproate during pregnancy impairs development in children exposed in utero, the fact that this was a

72 retrospective study means that firm conclusions are not possible.

Benzodiazepines

(SED-14, 186; SEDA-23, 84; SEDA-24, 84; SEDA-25, 81) (see also Chapter 5) The use of intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus has been evaluated in a double-blind, randomized trial in 205 adults (11C ). The patients presented either with seizures lasting 5 minutes or more or with repetitive generalized convulsive seizures and were randomized to receive intravenous diazepam 5 mg, lorazepam 2 mg, or placebo. Status epilepticus was controlled on arrival at the hospital in significantly more patients taking benzodiazepines than placebo (lorazepam 59%, diazepam 43%, placebo 21%). The rates of respiratory or circulatory complications related to drug treatment were 11% with lorazepam, 10% with diazepam, and 23% with placebo, but these differences were not significant. Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.3 mg/kg have been compared in a prospective randomized study in 47 children (aged 6 months to 5 years) with prolonged (over 10 min) febrile seizures (12C ). Intranasal midazolam controlled seizures significantly earlier than intravenous diazepam. None of the children had respiratory distress, bradycardia, or other adverse effects. Electrocardiography, blood pressure, and pulse oximetry were normal in all children during seizure activity and after cessation of seizures. Drug overdose Of 149 patients, 10 received an overdose of rectal diazepam indicated for acute repetitive seizures (51 overdoses in total) (13C ). There were no untoward events in 40 cases, and the adverse events were most often not drug-related. No patient had bradypnea or apnea.

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tients withdrawn from carbamazepine powerspectrum analysis of RR interval variability has been used to investigate changes in sympathetic/parasympathetic autonomic equilibrium (14C ). Abrupt withdrawal of carbamazepine altered the sympathovagal balance during nonREM sleep, shifting the sympathovagal balance toward sympathetic predominance. However, analysis of the before and after withdrawal cardiac Holter recordings showed no serious cardiac dysrhythmias in any patient. Psychiatric The cognitive effects of carbamazepine and gabapentin have been compared in a double-blind, crossover, randomized study in 34 healthy elderly adults, of whom 19 subjects withdrew (15 while taking carbamazepine, probably due to excessively rapid dosage titration) (15C ). The primary outcome measures were standardized neuropsychological and mood state tests, yielding 17 variables. Each subject had cognitive testing at baseline (pre-drug), at the end of the first drug phase, the end of the second drug phase, and 4 weeks after completion of the second drug phase. Adverse events were frequently reported with both antiepileptic drugs, although they were more common with carbamazepine. There were significant differences between carbamazepine and gabapentin for only one of 11 cognitive variables, with better attention/vigilance for gabapentin, although the effect was modest. Both carbamazepine and gabapentin can cause mild cognitive deficits in elderly subjects, and gabapentin has a slightly better profile. Metabolism Some antiepileptic drugs have been associated with low serum and erythrocyte folate concentrations and high total plasma homocysteine concentrations in some patients. The concentrations of folate and homocysteine have been measured in 42 patients taking carbamazepine and 42 matched healthy controls (16C ). Patients taking carbamazepine had significantly lower serum and erythrocyte folate concentrations. There was hyperhomocystinemia (over 15 µmol/l) in 24% of the patients and 5% of the controls.

Carbamazepine

(SED-14, 172; SEDA-23, 85; SEDA-24, 84; SEDA-25, 81) Cardiovascular Carbamazepine occasionally causes cardiac dysrhythmias. In 12 pa-

Electrolyte balance Hyponatremia is a wellknown adverse effect of carbamazepine. In 117 patients with chronic epilepsy taking carbamazepine in residential care the retrospective

Antiepileptic drugs

prevalence of hyponatremia was 42% compared with 9.4% in controls (17C ). Higher doses and serum concentrations of carbamazepine were associated with a higher risk of hyponatremia. Skin Carbamazepine and phenytoin have previously been associated with lymphoproliferative disorders, including dermatopathic lymphadenitis, atypical lymphoid proliferation, and cutaneous pseudolymphoma. In most reported cases, regression follows withdrawal of treatment with the causative drug. However, rarely true lymphoma can develop. • A 13-year-old girl who had taken carbamazepine for about 8 months developed multiple painless reddish skin nodules, which grew and quickly ulcerated (18A ). The nodules were on the neck, trunk, and arms and varied in size. Neither lymphadenopathy nor splenomegaly was detected. Histology showed a CD30, primary, cutaneous, anaplastic, large-cell lymphoma. Carbamazepine was withdrawn, she received radiotherapy, and the lesions regressed. At 3 years after diagnosis she was still in complete remission.

Drug interactions In dogs concurrent administration of lamotrigine had no significant effect on the pharmacokinetics of carbamazepine or the plasma concentration ratio of carbamazepine epoxide to carbamazepine (19E ). Teratogenesis The Israeli Teratogen Information Service has prospectively followed 210 pregnancies with exposure to carbamazepine in the first trimester (20C ). The outcomes were compared with those in two overlapping groups of matched controls (n = 629) who had been exposed to non-teratogens. There was a twofold increase in the rate of major congenital anomalies in the women who had used carbamazepine (12/160 on carbamazepine versus 18/560 controls; RR = 2.24; 95% CI = 1.10, 4.56) and a reduction in birth weight of about 250 g after in utero exposure to carbamazepine. There were no neural tube defects. These results are to be interpreted with caution, as they were obtained from a questionnaire in 87% of cases.

Felbamate

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(SED-14, 187; SEDA-23, 86;

SEDA-24, 85) An open trial with 3-year follow up has been conducted in 36 patients with catastrophic

childhood onset epilepsy (21C ). The overall responder rate (more than a 50% reduction in seizure frequency) fell with time: 69% at 3 months, 66% at 6 months, 47% at 1 year, and 41% at the end of the study. The most frequent adverse effects were anorexia, weight loss, urinary retention, somnolence, nervousness, and insomnia. Urinary tract Urolithiasis has been associated with felbamate (22A ). • A 15-year-old boy with Lennox–Gastaut syndrome treated with felbamate (3000 mg/day), topiramate (200 mg/day), and lorazepam developed painful hematuria, bilateral urethral obstruction, and urinary retention. Kidney, bladder, and urethral stones were found. The stone material was identified as felbamate by chemical analysis. However, as the patient was also taking topiramate the association with felbamate was uncertain.

Gabapentin

(SED-14, 188; SEDA-23, 87; SEDA-24, 86; SEDA-25, 84)

In 237 children aged 3–12 years with refractory partial seizures gabapentin 24–70 mg/kg/day was used as add-on therapy over 6 months (23C ). There was a more than 50% reduction in partial seizures in 34% of the children. Somnolence was the most common adverse event related to gabapentin. Emotional lability and hostility were related to gabapentin in 3.4% and 3.0% of the patients respectively. Gabapentin and lamotrigine have been compared in an open, parallel-group, add-on, randomized study in 109 patients with uncontrolled partial epilepsy and learning disabilities (24C ). The two drugs were similarly efficacious, with similar incidences of adverse events and serious adverse events. Neither lamotrigine nor gabapentin exacerbated any of the challenging behaviors observed in these patients. The most common adverse effect of gabapentin was somnolence, which was mostly reported during the initial titration phase. Nervous system Two cases of gabapentinrelated dyskinesia have been reported (25A ). The patients were 60 and 41 years old and took gabapentin 900–1200 mg/day for generalized anxiety. Generalized dyskinetic movements and facial tics appeared after 3 days and disappeared after 2 days of withdrawal.

74 Psychiatric Gabapentin has been associated with hostility, especially in children. Two cases of aggression in adults taking gabapentin for bipolar disorder have been reported (26A ). Neither patient had a history of aggression. In one the symptoms appeared after 3 days of treatment (1200 mg/day), and in the other after 48 hours (600 mg/day). In the second case, aggression was associated with auditory hallucinations. It is hard to associate new antiepileptic drugs with psychiatric adverse effects in patients with severe psychiatric disorders, and rechallenge with the offending drug should ideally have been tried before postulating a causal relation. Urinary tract Patients on chronic hemodialysis are at risk of gabapentin toxicity. A patient undergoing hemodialysis and taking gabapentin 400 mg/day developed a very high serum concentration (56 mg/l) and clinical toxicity manifested by stupor (27A ). A subsequent pharmacokinetic analysis suggested that in patients undergoing chronic hemodialysis gabapentin should be started at 300 mg/day and posthemodialysis dosing should be reduced to 100 mg/day, at least in some patients. Immunologic A hypersensitivity syndrome secondary to gabapentin has been described in a 72-year-old patient after 9 days (28A ). The symptoms (altered mental status, fever, diffuse macular rash, and an enlarged spleen) resolved after withdrawal. However, the concomitant use of levofloxacin made the association of gabapentin with the hypersensitivity syndrome unclear. Drug withdrawal Three cases of withdrawal symptoms after abrupt withdrawal of highdose gabapentin have been reported in adults with psychiatric conditions (29A ). The patients were restless and anxious, with sweating and tachycardia. The symptoms improved after gabapentin was reintroduced. Drug administration Two different regimens of add-on gabapentin have been compared in a double-blind, randomized trial (30C ). In 574 patients randomized to either slow initiation (300 mg on day 1, 600 mg on day 2, then 900 mg/day) or rapid initiation (900 mg/day immediately after the placebo lead-in), the four

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most common adverse events, which occurred equally in the two groups, were somnolence, dizziness, ataxia, and fatigue. The frequency of adverse events in a subgroup of elderly patients was similar to that in younger adults.

Lamotrigine

(SED-14, 188; SEDA-23, 87; SEDA-24, 87; SEDA-25, 85) The adverse effects of lamotrigine have been surveyed retrospectively in 2701 patients in five tertiary referral epilepsy centers in the UK; 1326 were excluded because lamotrigine and/or comparators had been begun outside the study centers (31C ). The most common adverse events were rash (10%), dizziness, ataxia, and diplopia. There were four cases of lifethreatening adverse events: one case each of hepatic insufficiency, acute exacerbation of ulcerative colitis, disseminated intravascular coagulation, and renal insufficiency caused by rhabdomyolysis and myoglobinuria. The mortality rate was 1.7 per 100 patient years and the standard mortality ratio was 10.4, similar to other antiepileptic drugs (gabapentin and vigabatrin). No deaths were directly attributable to lamotrigine. In an open randomized trial in 417 patients over 2 years old who took lamotrigine or carbamazepine monotherapy for new-onset epilepsy there was similar efficacy (65% were free of seizures with lamotrigine and 73% with carbamazepine) (32C ). Although the patients taking lamotrigine tended to have fewer adverse events than those taking carbamazepine (52% versus 60%), the difference was not significant. Somnolence was the only adverse event reported at an incidence of over 5% and it was more frequent in patients taking carbamazepine (11% vs. 4% with lamotrigine). Psychiatric The cognitive and behavioral effects of lamotrigine 150 mg/day have been compared with those of carbamazepine 696 mg/day in 25 healthy adults in a double-blind, crossover, randomized study with two 10week treatment periods (33C ). Lamotrigine had significantly fewer cognitive and behavioral adverse effects than carbamazepine, and 48% of the variables favored lamotrigine. The differences encompassed cognitive speed, memory,

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graphomotor coding, neurotoxic symptoms, mood, sedation, perception of cognitive performance, and other quality-of-life perceptions. The cognitive and behavioral changes favored lamotrigine over carbamazepine, but the magnitude of the observed effects was modest, although it could be relevant in some patients. Metabolism In a prospective evaluation of the effect of lamotrigine 3.5–14.2 mg/kg on growth in 103 children and adolescents aged 1.6–16 years with epilepsy treated with lamotrigine monotherapy for 6–71 months, the children had normal growth, although there were several methodological shortcomings (34C ). Drug overdose Severe encephalopathy due to lamotrigine overdose has been reported (35A ). • A 55-year-old woman taking lamotrigine and valproate for partial epilepsy took an overdose of lamotrigine and became stuporose. A CT scan was unremarkable and the cerebrospinal fluid was normal. Electroencephalography showed generalized slowing without epileptiform activity. The serum valproate concentration was 65 µg/ml and the lamotrigine concentration 32 µg/ml. A toxicology screen was negative. Lamotrigine was withheld and she remained unresponsive for 3 days, when she awoke disoriented. On day 5 she was alert and fully oriented (serum lamotrigine 15 µg/ml).

Dug interactions Plasma concentrations of lamotrigine were reduced in seven women taking an oral contraceptive (mean reduction 49%, range 41–64%), probably through induction of glucuronide conjugating enzymes (36A ).

Levetiracetam

(SED-14, 190; SEDA-24,

90; SEDA-25, 88) The safety profile of levetiracetam has been reviewed (37M ). The authors assessed the integrated summary of safety report submitted for regulatory review in order to obtain information about abnormal laboratory tests values and adverse events collected during the overall levetiracetam development program. The analysis included 3347 patients exposed to levetiracetam in clinical trials for epilepsy, cognition, and anxiety disorders. Safety data from

75 all the studies showed a similar pattern of adverse effects, predominantly somnolence, weakness, and dizziness, which occurred most often during the first month of treatment. Laboratory tests that changed significantly in placebocontrolled trials nevertheless stayed in the reference ranges. The incidences of any types of allergic reactions were similar between levetiracetam and placebo (0.3% and 0.2%). Cases of common cold and upper respiratory infection were significantly more frequent with levetiracetam than placebo (13% vs. 7.5%), but were not preceded by low neutrophil counts that might have suggested impaired immunological status. There was worsening of seizures (>25% increase) in 14% of patients taking levetiracetam and 26% of patients taking placebo. There were nine sudden unexplained deaths; the overall mortality rates and standardized mortality rates were higher in the placebo group (1.8 levetiracetam vs. 2.5 placebo). Behavioral problems occurred in 5.2–14% of those taking levetiracetam and 4.1–6.0% in those taking placebo. There were higher incidences of adverse effects, particularly behavioral effects, among patients with epilepsy than in elderly patients with cognitive disorders or in patients with anxiety disorders. The long-term retention rate, efficacy, and safety of levetiracetam have been evaluated in all patients with epilepsy exposed to the drug during its developmental program (n = 1422) (38C ). The retention rate was 60% after 1 year and 32% after 5 years. Seizures were reduced by over 50% in 39% of the patients, and 13% became seizure free for at least 6 months. The commonest treatment-emergent adverse events requiring withdrawal were convulsions (3.4%), somnolence (2.0%), weakness (0.6%), depression (0.6%), dizziness (0.5%), and headache (0.5%). There was no evidence of idiosyncratic adverse effects or any serious hematological or biochemical abnormalities during exposure to levetiracetam. Eight patients died suddenly and unexpectedly, about one death per 300 patients years, which is within the expected range in patients with refractory epilepsy. Psychiatric Psychiatric adverse events, most often hostility and irritability, have been reported in children taking levetiracetam. Four cases of acute psychosis have also been reported (39A ).

76 • A 5-year-old girl with refractory epilepsy treated with a ketogenic diet was given levetiracetam 250 mg bd (25 mg/kg/day). She had a history of mild mental retardation and was receiving special education. Two weeks later she started to have visual hallucinations, became agitated, bit relatives, and could not sleep. Levetiracetam was withdrawn and her symptoms resolved within 24 hours and did not recur.

Drug interactions Two placebo-controlled studies in healthy subjects have shown no interactions of levetiracetam with digoxin (40C ) or warfarin (41C ).

Oxcarbazepine

(SED-14, 190; SEDA-23, 88; SEDA-24, 90; SEDA-25, 90)

Two doses of oxcarbazepine have been compared in a double-blind, parallel-group, randomized trial in patients with uncontrolled partial-onset epilepsy who had previously taken carbamazepine monotherapy (42A ). After two open phases in 143 patients, 96 were randomized to oxcarbazepine 300 or 2400 mg/day for 126 days. The time to meet an exit criterion was significantly in favor of oxcarbazepine 2400 mg/day. In all, 24 of the 47 non-randomized patients withdrew because of an adverse event, most commonly dizziness, ataxia, headache, nausea, vomiting, or fatigue. Three withdrew because of laboratory abnormalities, one each with leukopenia, hyponatremia, and hyperglycemia. Headache, dizziness, and nausea were the only adverse events that occurred in more than 10% in either group. Similar adverse events were reported in the randomized patients, but none withdrew. Electrolyte balance Hyponatremia is a frequent, but usually not severe, adverse effect of oxcarbazepine (43R ). Changes in serum electrolyte balance and underlying regulatory mechanisms have been evaluated in ten men with epilepsy 2 and 6 months after long-term carbamazepine monotherapy had been replaced with oxcarbazepine (44C ). Serum sodium concentrations fell in four patients (in two below the reference range) and remained unaltered in six. Serum aldosterone rose in the six patients whose serum sodium concentrations did not fall, but not in those with low sodium concentrations during oxcarbazepine. The serum

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concentration of the N-terminal fragment of pro-atrial natriuretic peptide fell in all patients, reflecting the reduced serum sodium concentrations. Thus, compensatory aldosterone release may prevent hyponatremia in some patients taking oxcarbazepine. Drug interactions A possible interaction of oxcarbazepine with ciclosporin has been reported after renal transplantation in a 32-yearold man (45A ). The ciclosporin trough serum concentration and serum sodium concentration fell after oxcarbazepine was added.

Phenytoin and fosphenytoin (SED-14, 180; SEDA-23, 89; SEDA-24, 90; SEDA-25, 90) Immunologic Hypersensitivity to phenytoin (which had been previously well tolerated) after a hypersensitivity reaction to carbamazepine has been reported (46A ). • A 19-year-old man with partial epilepsy took phenytoin 300 mg/day for over 6 months. Carbamazepine was introduced and after about 6 weeks (while taking phenytoin 300 mg/day and carbamazepine 600 mg/day), he developed fever, anorexia, a sore throat, bloody diarrhea, a diffuse, erythematous, maculopapular rash and palatal petechiae, tender cervical lymphadenopathy, and mild splenomegaly. His liver enzymes were raised and he had a leukocytosis with eosinophilia. Phenytoin and carbamazepine were withdrawn, and he was given prednisone and sodium valproate 1000 mg/day. The rash resolved, as did other manifestations of what was thought to be a hypersensitivity reaction. About a year later phenytoin was reintroduced starting at 100 mg/day. He developed a sore throat after taking the first dose and a widespread rash after the second dose. There was no evidence of hepatic or hematological dysfunction. Phenytoin was withdrawn and the rash resolved in 1 week.

Cross-sensitivity among aromatic antiepileptic drugs occurs in about 50% of patients with a hypersensitivity reaction. It has previously been described on first exposure to each of the offending drugs (47R ). However, this patient developed an allergic rash on his second exposure to phenytoin, having previously tolerated it for 6 months. This suggests that carbamazepine altered his response to phenytoin.

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Skin The incidence of purple glove syndrome associated with intravenous phenytoin has been assessed in a prospective review of 179 consecutive exposures (48C ). There were only three mild cases (1.7%). Drug administration route The extent of absorption and tolerability of intramuscular fosphenytoin has been assessed in an double-blind study in which patients received 10 mg/kg dose of intramuscular fosphenytoin in one gluteus and intramuscular saline in the other (49C ). More than half the patients had serum concentrations in the target range at 30 minutes. There was no pain at either the fosphenytoin or saline injection sites in 46% of patients and no difference in pain at 60 minutes and thereafter.

Remacemide

(SEDA-25, 91)

The efficacy of adjunctive therapy with remacemide has been evaluated in 11 children (50C ). Remacemide was well tolerated in doses up to 13.5 mg/kg/day. The most common adverse events were dizziness, ataxia, and gastrointestinal events. One patient died after a suspected seizure, which was unlikely to have been related to remacemide.

Tiagabine

(SED-14, 190; SEDA-23, 89; SEDA-24, 91; SEDA-25, 92) The efficacy and safety of tiagabine have been assessed in a study with an open screening phase (in which patients were titrated to the optimal tiagabine dose) followed by a double-blind, placebo-controlled, crossover phase (51C ). Of the 88 patients who entered the double-blind phase, seizure frequency was significantly reduced in 44, and there was an over 50% reduction of partial seizures in 33%. There were adverse events in 77% of the patients during the screening phase and 22% during the double-blind phase. The most frequent adverse events were dizziness (32%), somnolence (30%), and weakness (19%). Two patients taking tiagabine withdrew during the double-blind phase because of adverse events.

77 Nervous system Three patients had transient dystonic reactions while taking tiagabine 20– 30 mg/day in addition to carbamazepine (52A ). The dystonic reactions occurred during the first few weeks of treatment. The patients each had a different type of dystonia: focal limb dystonia, oromandibular dystonia, and writer’s cramp. In each case the dystonia resolved spontaneously without withdrawal of tiagabine and without any other treatment. Although paroxysmal dystonic movements have been well described with carbamazepine, these patients had been taking carbamazepine for years without this adverse effect. There have previously been reports of tiagabine-related non-convulsive status epilepticus (53A ). Now the frequency of status during tiagabine trials has been compared with the occurrence of status epilepticus in four large epidemiological cohorts from Rochester (Minnesota), Turku (Finland), New York, and New Haven (Connecticut) (54R ). Review of 13 cases with non-convulsive status showed that most of them had had generalized discharges on prior electroencephalography. Only three had encephalographic evidence of status during tiagabine treatment. In the placebo-controlled trials, there was no difference in the frequency of status or complex partial status between patients taking tiagabine or placebo (0.8–1.0% vs. 1.5%). In long-term safety studies, which included 2248 patients, there was a 5% frequency of status and a 3% frequency of complex partial status in the tiagabine-treated patients, which was similar to the rates of occurrence in the four external cohorts. Thus, tiagabine does not appear to increase the risk of status or nonconvulsive status. Drug dosage regimens Two different dosage regimens (twice or three times a day) of addon tiagabine have been compared in a multicenter, open, randomized, parallel-group study in 347 patients (55C ). The tiagabine dosage was titrated over 12 weeks to a target of 40 mg/day. The patients were followed for a further 12 weeks. Significantly more patients in the thrice-daily group completed the titration period (81% versus 73%). The proportion of responders during the last 8 weeks of the flexible phase was similar in the two groups (42% for twice-daily and 47% for thrice-daily administration). Thus, although both regimens

78 appear to offer similar efficacy, significantly more patients completed the study in the thricedaily group, probably because tolerability is less when high doses are given undivided.

Topiramate

(SED-14; 191; SEDA-23, 90; SEDA-24, 92; SEDA-25, 93)

Topiramate has been used for the treatment of psychiatric disorders, especially bipolar disease. The adverse events profile is similar to that in patients with epilepsy. In a retrospective assessment of 76 patients taking topiramate for bipolar spectrum disorders there was mild improvement in 47% and moderate-to-marked improvement in 13% (56C ). Responders took a significantly higher mean dose (180 mg/day) than non-responders (83 mg/day). There was weight loss (mean 6.4 kg) in 50% of the patients; the dose was significantly higher in patients who lost weight. Other adverse events were reported by 82% of patients: cognitive effects, sedation, paresthesia, nausea, insomnia, headache, and dizziness. Adverse effects led to withdrawal in 36% of the total patient population. Similar anecdotal experiences in the treatment of bipolar disorders have been reported by others (57A , 58C ).

Cognitive effects of topiramate All antiepileptic drugs have been associated with adverse cognitive events, and many, sometimes contradictory, studies of classical antiepileptic drugs have been published (59R ). Cognitive adverse effects are large for phenobarbital, and possibly larger for phenytoin than for carbamazepine or valproic acid (59R ). Most often cognitive adverse events result in mild general psychomotor slowing. Although the severity of cognitive adverse effects is considered mild to moderate for most antiepileptic drugs, their impact may be substantial in some patients, especially in those with pre-existing impaired cognitive function. There is relatively little reliable information on cognitive adverse events of new antiepileptic drugs. Most of the published studies are on polytherapy and there

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is little information about healthy volunteers (60C ). Topiramate has been specifically associated with cognitive complaints. Two patients had neuropsychological deficits during topiramate treatment and cognitive improvement after withdrawal (61A ). One patient was assessed during and after topiramate withdrawal and the other before, during, and after. The cognitive adverse effects of gabapentin, lamotrigine, and topiramate in healthy volunteers have been compared in a randomized, single-blind, parallel-group study (60C ). Neurobehavioral testing was conducted at baseline, during the acute oral dosing period 3 hours after medication administration, and at 2 and 4 weeks during chronic dosing. Acutely, those who took topiramate (2.8 mg/kg) performed significantly worse than those who took gabapentin (17 mg/kg) or lamotrigine (3.5 mg/kg) on tasks of letter and category word fluency and visual attention; cognitive effects were not different between those who took gabapentin or lamotrigine. The doses were then increased to topiramate 5.7 mg/kg/day, lamotrigine 7.1 mg/kg/day, and gabapentin 35 mg/kg/day. At 2 and 4 weeks, those taking topiramate had significant verbal memory deficit and slow psychomotor speed compared with baseline; those taking gabapentin and lamotrigine did not. However, the clinical impact of the trial was limited, owing to the small sample size (17 patients) and the very rapid topiramate titration, much faster than is currently recommended (62C ). There has been a retrospective analysis of neuropsychological scores before and after the use of topiramate 125–600 mg/day for at least 3 months in 18 patients (63C ). Topiramate was associated with significant deterioration in verbal IQ, learning, and fluency. Withdrawal or dosage reduction was associated with significant improvement. There was no correlation between individual topiramate dose and the change in test score. This study was retrospective and the patients were selected because they had cognitive problems; the resultant bias makes it difficult to generalize these results to wider populations. A group of 14 US epilepsy centers has published the results of a post-marketing surveillance study of 701 patients taking topiramate (64C ). Although 41% of the patients reported

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cognitive adverse events at any time during treatment, only 5.8% of them discontinued for that reason. Cognitive effects were the most frequent reason for withdrawal because of adverse events (41/170 or 24% of those who discontinued). The central nervous system-related adverse effects profile in these patients included psychomotor slowing, fatigue, slurred speech, irritability, behavioral changes, confusion, inappropriate laughter, and hallucinations. Only 2.4% of the patients were taking monotherapy, and the mean dose of topiramate at 6 months was 385 mg/day, with a mean weekly dose during titration of 35.5 mg/day. Risk factors for discontinuation were evaluated. A slow titration rate (slower than 25 mg/week), but not the total dose at discontinuation, was significantly associated with a lower discontinuation rate. There was no specific population, dose titration, or concomitant antiepileptic drug that increased the risk of treatment discontinuation because of cognitive complaints. Psychomotor slowing was the most common complaint, but most patients elected to continue treatment because of improved seizure control. The effects of topiramate and valproate, when added to carbamazepine, on cognitive status in adults have been compared in a randomized, observer-blinded, parallel-group study (65C ). Topiramate was introduced slowly at a starting dose of 25 mg/day and increased weekly by 25 mg/day increments over 8 weeks to a minimum dosage of 200 mg/day. The target dosages were 200–400 mg/day for topiramate and 1800 mg/day for valproate. There were significant differences between topiramate and valproate in short-term verbal memory— worsening with topiramate and improvement with valproate—but the differences were small. There were no effects on mood disorders, psychiatric symptoms, or motor and mental speed and language tests. These results suggest that if the dose of topiramate is slowly titrated cognitive adverse events can be minimized. However, although most patients tolerated topiramate if properly titrated and dosed, a subset of patients had clinically significant deficits, possibly as an idiosyncratic reaction. In another multicenter, parallel-group, randomized study there were similar results when topiramate or valproate was added to carbamazepine (66C , 67C ). In conclusion, topiramate can cause cognitive adverse effects in some patients. Those

79 affected often have impaired verbal learning and fluency. Slow titration reduces the likelihood of cognitive adverse events. Sensory systems On 26 September, 2001 OrthoMacneil/Jansen-Cilag issued a “Dear Doctor” letter about an ocular syndrome in patients taking topiramate. The syndrome is characterized by acute myopia and secondary angle closure glaucoma. Several case reports have been published (68A –70A ). As of 17 August, 2001 there have been 23 reported cases (22 adults and one child) out of 825 000 patients. Symptoms typically occur within the first month of therapy, and the patients report acutely reduced visual acuity and/or ocular pain. There is myopia, redness, swelling of the anterior chamber, and raised ocular pressure, with or without pupil dilatation. Supraciliary effusion can displace the lens and iris anteriorly, secondarily causing angle closure glaucoma. The symptoms are reversible if topiramate is withdrawn. Acute myopia has been described as a rare idiosyncratic reaction to other sulfonamides. It has been postulated that the pathogenic mechanism is related to partial inhibition of carbonic anhydrase and to ciliary body swelling. Psychiatric Three patients treated with topiramate for bipolar disorder developed substantial depression (71A ). The symptoms began or increased within 1 week of topiramate treatment (25 mg/day) or with an increase in dosage to 50 mg/day. All had significant relief from depression 1–2 weeks after withdrawal of topiramate. The close association with the onset of the most severe depression these patients had ever experienced suggests an adverse effect of topiramate. However, all these patients had bipolar disorder, so the onset of depression could have been coincidental. Moreover, their depression might also have been due to a synergistic interaction between topiramate and their other medications. A single case report of new-onset panic attacks in a 24 year-old woman with a history of bipolar disorder and binge eating has been described (72A ). She had a history of “isolated” panic attacks 8 years before and the attacks subsided 14 days after topiramate withdrawal. Because she had a history of psychiatric diseases and panic attacks, the relation of these symptoms to topiramate was doubtful.

80 Acid-base balance Two children developed symptomatic metabolic acidosis while taking topiramate (73A ). • An 11-year-old boy with refractory partial epilepsy who had been taking topiramate 300 mg/day for 13 months developed hyperventilation. He had a hyperchloremic metabolic acidosis with partial respiratory compensation. The hyperventilation and acidosis resolved after the administration of sodium bicarbonate and reduction of the dose of topiramate. • A 16-month-old girl developed increasing irritability associated with topiramate; it resolved promptly on withdrawal. Venous blood showed a metabolic acidosis.

The authors postulated that the mechanism of topiramate-induced acidosis is inhibition of carbonic anhydrase in the proximal renal tubule, resulting in impaired proximal bicarbonate reabsorption. Blood gases should be obtained in patients taking topiramate who develop hyperventilation and changes in mental status. Body temperature Reduced sweating, heat and exercise intolerance, and fever have been associated with topiramate. Three patients (aged 17 months, 9 years, and 16 years) developed hyperthermia because of reduced sweating capacity during the summer and/or during exercise 2–3 months after reaching the target dose of topiramate (74A ). A reduction in the dosage of topiramate did not correct the symptoms, which disappeared on topiramate withdrawal. This adverse effect may be related to carbonic anhydrase inhibition by topiramate, as it has been described with zonisamide (another carbonic anhydrase inhibitor). • A 9-year-old boy with partial epilepsy taking topiramate (4 mg/kg/day) developed hyperthermia, reduced sweating, and tiredness after exercise 4 months after the start of treatment (74A ). Sudomotor function showed 180 sweat glands/cm2 (normal 286, fifth percentile 221). After topiramate withdrawal he became asymptomatic and 5 weeks later he had 392 sweat glands/cm2 .

Drug administration Slow dosage titration of topiramate has been advocated by clinicians for improving tolerability. In a multicenter, double-blind trial in adults with refractory partial epilepsy 188 patients were randomized to add-on topiramate by either “slow” titration (initial dose 50 mg/day increased

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weekly by 50 mg/day) or “fast” titration (initial dose 100 mg/day increased weekly by 100– 200 mg/day) (62C ). The maximum dosage of 400 mg/day in both groups was achieved by 3 weeks or 8 weeks. Efficacy was comparable, but slow titration was significantly associated with a lower frequency of adverse events or withdrawals because of adverse events.

Valproate sodium

(SED-14, 182; SEDA-23, 90; SEDA-24, 93; SEDA-25, 95) Nervous system Valproate can occasionally cause aggravation of absence seizures in children (75A ). Eight patients with typical and myoclonic absence epilepsy and electroencephalography that showed generalized 3-Hz spike-and-wave had an increase in the frequency of absence seizures within days of valproate introduction. Dosage increments resulted in further aggravation. Serum concentrations of valproate were within the target range in all cases. All the children improved on valproate withdrawal; in five valproate was reintroduced, resulting in further seizure aggravation. Metabolism A randomized, double-blind study was conducted for 32 weeks to analyse weight change in patients taking lamotrigine (n = 65; mean age 35 years; target dosage 200 mg/day) and valproate (n = 68; mean age 30 years; target dosage 20 mg/kg/day) (76C ). Weight remained stable in the patients taking lamotrigine. However, there was significant weight gain in the patients taking valproate by the 10th week of treatment, and weight continued to increase throughout the study. After 32 weeks, mean weight gain was significantly higher in those taking valproate (5.8 kg) compared with lamotrigine (0.6 kg). Similar proportions of patients taking lamotrigine (29%) or valproate (26%) were seizure-free. The frequencies of adverse events were similar in the two groups. Liver Valproate is often associated with mild asymptomatic rises in liver enzymes. The association between valproate and raised transaminases has been studied in a retrospective review of the medical records of patients positive for

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hepatitis C virus (77C ). Of 214 patients 28 were taking valproate and 186 were not. The controls and those who had been hepatitis-positive for longer were significantly more likely to have worse hepatotoxicity. Valproate, either alone or in the presence of other potential hepatotoxins, was not associated with raised transaminases. Skin Cutaneous pseudolymphoma has been attributed to valproate (78A ). • A 41-year-old man presented with an erythematous papule, histologically mimicking a nonepidermotropic T cell lymphoma. Polymerase chain reaction in the skin biopsy showed monoclonal rearrangement of the T cell receptor gamma gene. Withdrawal of valproate was followed by regression of the lesion, but 5 months after substitution by carbamazepine, two further papules appeared, with similar histological features. Carbamazepine was withdrawn and the lesions disappeared without relapse over 4 years.

Valproate-associated polycystic ovary syndrome There is evidence that polycystic ovary syndrome (polycystic ovaries, hyperandrogenism, obesity, hirsutism, anovulatory cycles, and menstrual disorders) is more common in women with epilepsy. Valproate has been associated with alterations in reproductive hormonal function beginning in the first month of treatment. Serum androgen concentrations increase in patients taking valproate but the profile of hormonal changes is different in women and men (5C ). Animal studies have corroborated the adverse ovarian and endocrine effects of valproate (79E ). Four review articles have recently been published dealing with this reported adverse event, highlighting controversial views (80R , 81R –83R ). The estimated prevalence of polycystic ovary syndrome in patients with epilepsy is 13–25%, compared with 4–6% in the general population (80R ). Polycystic ovary syndrome has been described in women with epilepsy taking valproate, especially those who start treatment before 20 years of age (84C , 85C ), and the frequency is high: in a cross-sectional study of 22 women taking valproate monotherapy, 59% were obese and 64% had polycystic ovaries, hyperandrogenism, or both (85C ).

81 In a prospective study of polycystic ovary syndrome in 52 controls and 72 women with epilepsy (37 taking valproate monotherapy and 35 carbamazepine monotherapy), the frequency of polycystic ovaries, hyperandrogenism, or both was significantly higher in those taking valproate than in the controls (70% vs. 19%) (86C ). They occurred in 20% of the patients taking carbamazepine. The obese women taking valproate who had polycystic ovaries or hyperandrogenism or both had hyperinsulinemia and associated unfavorable changes in serum lipid concentrations consistent with insulin resistance. In both obese and lean women, polycystic ovaries and related hyperandrogenism were similarly found. Most of the abnormalities were reversed when valproate was withdrawn (87C ). Although the association between polycystic ovary syndrome and valproate treatment appears to be established, current published studies are limited owing to small sample sizes and diverse definitions of polycystic ovary syndrome. Thus, the true clinical relevance and frequency of the association needs further investigation in large, multicenter, prospective studies. Women taking valproate should be asked about menstrual disorders. The presence of a menstrual disorder, hirsutism, or weight gain should trigger thorough evaluation and, if necessary, valproate withdrawal. Infection risk In vitro tests have shown that valproate can increase the viral burden in HIVinfected individuals by potentiating replication of the virus (88E ). In a retrospective review of 11 HIV-positive patients with behavioral disturbances taking valproate HIV-1 viral load did not increase in six of the nine patients who had measurements between the first week and 3.5 months after the start of valproate treatment; no follow-up was available for the other three (89C ). These data suggest that, contrary to in vitro data, HIV-1 viral load is not adversely affected by valproate in the presence of effective antiretroviral therapy. Body temperature Hypothermia related to valproate has been reported in a child (90A ). There have been five previously described cases in adults or elderly patients (91A ). • A 2-year-old boy was admitted after a prolonged febrile seizure that stopped only after he was given

82 several doses of benzodiazepines plus phenobarbital. A CT scan showed a right arachnoid cyst. He was given valproate 13 mg/kg/day and 2 days later developed hypothermia (33.8–34.5◦ C). He was lethargic and irritable. Valproate was withdrawn. His lethargy improved within 48 hours and the temperature slowly returned to normal over the course of 1 week.

Fetotoxicity Fetal valproate syndrome comprises a number of typical dysmorphic features and major organ system anomalies (92R ). In a case file review of 2220 children with craniosynostosis, detailed maternal health information was obtained in 1676 cases (93C ). Of these, 17 mothers had taken valproate monotherapy during pregnancy. All 17 children had trigonocephaly (caused by premature fusion of the metopic suture). Their IQs were 45–100 (mean 75). IQs were significantly higher in patients who underwent surgery before 6 months of age. This is the first study to have reported trigonocephaly associated with fetal valproate syndrome. Five patients with fetal valproate syndrome and autism have been described (94A ).

Vigabatrin

(SED-14, 192; SEDA-23, 92; SEDA-24, 94; SEDA-25, 98)

In a single-blind, randomized trial of vigabatrin for 2 weeks in children with newly diagnosed infantile spasms the children were randomly assigned to low-dose vigabatrin (18– 36 mg/kg/day) or high-dose vigabatrin (100– 148 mg/kg/day) (95C ). The time to response was evaluated during the first 3 months, and safety was evaluated during the entire study. Eight of 75 children who took low-dose vigabatrin and 24 of 67 who took high-dose vigabatrin responded. The time to response was significantly shorter in those who took high-dose vigabatrin and in those with tuberous sclerosis. The most common treatment-related adverse events were sedation (42/167), insomnia (15/167), and irritability (15/167). There were no dose-related adverse events, and adverse event rates were similar in the low-dose and high-dose groups. Only nine patients withdrew because of adverse events. Vigabatrin efficacy and tolerability have been evaluated for a mean of 16 months in

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children in a retrospective study of 73 patients (mean age 87 months) (96C ). In 16% of the children vigabatrin was given as monotherapy and patients with both partial or generalized seizures were included. Vigabatrin was highly effective in 30 children (over 90% seizure reduction) and partially effective in four (50– 90% seizure frequency reduction). There were adverse effects in 24%, the commonest being irritability, aggression, opposition/defiance, self-injurious behaviors, and deterioration in behavioral control. There was seizure deterioration in 7% of the children; worsening of myoclonic seizures was most common. Visual field testing by perimetry was possible in only 12 of the children; two had visual field constriction.

Vigabatrin-related visual abnormalities Visual field defects Visual field constriction associated with vigabatrin has continued to be the focus of attention in many reports (SEDA24, 95; SEDA-25, 98; 97R , 98R ). Prevalence and risk factors The prevalence of visual field defects has been analysed in several studies and has varied from study to study: 60% (99C ), 40% (100C ), or 19% (101C ). These different rates have probably been related to the diverse methods of patient inclusion and visual field testing. The longer the duration of vigabatrin treatment and the higher the dose the greater the probability of field defects (99C , 101C , 102C ). In a cohort study of 99 patients taking vigabatrin, the prevalence of visual field defects increased significantly with increasing total vigabatrin dose. The prevalence ranged from four of 51 patients who had been exposed to 1 g/day or less to six of eight patients taking a total dose of 3–5 g/day (101C ). Reversibility Several studies have suggested that vigabatrin-associated visual field defects are irreversible (101C , 102C ). In one study, 12 vigabatrin-treated patients with visual field defects were re-examined 2–10 years after vigabatrin withdrawal, and all still had visual field defects (101C ). In five cases there was apparent worsening. Exceptional cases of reversible visual field defects have been reported in children (103A ). However, perimetry assessment in children is burdened with multiple methodological problems that usually preclude reliable results.

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Pathophysiology The pathophysiology of vigabatrin-related visual field defects is not known. Recent evidence suggests that they might be related to accumulation of GABA in the retina. In rats treated either with vigabatrin or tiagabine, vigabatrin reduced the activity of GABA transaminase and increased GABA concentrations in the brain, but these effects were more pronounced in the retina, in which vigabatrin concentrations are as much as fivefold higher than in the brain (104E ). On the other hand, tiagabine concentrations are considerably lower in the retina than in the brain. Tiagabine has not been associated with visual field defects. The pathological features of visual field constriction have been described in a patient taking vigabatrin (105A ).

some cases to assess the reliability of the apparent worsening or improvement experienced by some patients. In a study in 60 adults with partial epilepsy, progression or reversibility of vigabatrin-associated visual field defects were examined (102C ). The patients had taken vigabatrin for 7 months to 14 years as monotherapy or addon therapy and were examined with repeated kinetic Goldmann perimetry. A follow-up examination was performed after 4–38 months in 55 patients. There was vigabatrin-associated visual field constriction in 40%, and in 13% the defect was severe. During follow-up after withdrawal of vigabatrin, there was no significant recovery of visual fields in any patient. Conversely, there was no progression in those who continued therapy.

• A 41-year-old man who had taken vigabatrin for 2 years in doses of 3–6 g/day developed bilateral concentric visual field defects, with greater loss in the nasal fields, and vigabatrin was withdrawn. Later he had a cardiopulmonary arrest and died. At post-mortem there was peripheral retinal atrophy with loss of ganglion cells, severe in the peripheral retina and less severe in the maculae. There was loss of nerve fibers in the optic nerves, chiasm, and tracts. There was no evidence of intramyelin edema.

Assessment The value of electroretinography and electro-oculography in the early diagnosis of vigabatrin-associated visual field defects has been assessed in 30 patients with temporal lobe epilepsy (107C ). The patients were stratified into three groups: (A) concentric contraction of the visual field associated with vigabatrin (n = 15), (B) normal visual field with vigabatrin use (n = 11), and (C) normal visual field without vigabatrin (n = 4). There were abnormal electrophysiological results in 50% of the patients in group A. The electro-oculographic Arden ratio was lowered in 57%. The amount of visual field loss and the total dose of vigabatrin used correlated only weakly with the results of electroretinography and electro-oculography. These results suggest that ocular electrophysiology is not a good method for detecting patients at risk of vigabatrin-related visual field defects. Regular visual field examination remains the cornerstone in screening. This has been confirmed by a retrospective, comparative case series in which the degree of electroretinal dysfunction was analysed using electroretinography in 40 patients taking vigabatrin, 24 as monotherapy (108C ). There was no statistically significant relation between the frequency of electrodiagnostic abnormalities and the duration of use or the total cumulative dosage of vigabatrin. In conclusion, the relatively high prevalence and the irreversibility of the vigabatrin-related visual field constriction suggest that vigabatrin

These findings suggest that vigabatrin may be directly associated with direct retinal injury (to the ganglion cells). The degree of cell loss suggested that the visual field loss was irreversible. Long-term safety The safety of continuing vigabatrin therapy in adults who have taken prolonged treatment (over 2 years) has been assessed by serially monitoring changes in visual function over 1 year of continued therapy (106C ). Fifteen patients who continued to take vigabatrin had visual function testing (visual acuity, color vision, and kinetic and static perimetry) every 3 months for 1 year. Nine had normal visual fields and six had visual field constriction. During follow-up, they showed no worsening of visual acuity, color vision, or visual field constriction, beyond that measured in the initial test. This study showed that mild changes in visual function after long-term vigabatrin generally remain stable with continued treatment. However, patient consistency was variable and repeated testing was necessary in

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should be used only as a last resort in most patients with epilepsy. In Europe, vigabatrin is being used mostly in children, especially those with infantile spasms. For this indication, vigabatrin has high efficacy and causes fewer severe adverse effects than ACTH (95C , 109C , 110R ). However, the long-term retinal effects of vigabatrin in children are unknown, and visual field testing is usually impossible. Recent evidence has suggested that a short course of vigabatrin (6 months) in children with infantile spasms may be sufficient (111C ) and minimizes the potential for visual adverse effects. Retinal dysfuntion Retinal dysfunction has been retrospectively assessed in 29 children taking vigabatrin 25–114 mg/kg/day for 6.5 years (112C ). Ophthalmic examination was performed before treatment and every 6 months thereafter. Four children developed eye changes (retinal pigmentation, hypopigmented retinal spots, vascular sheathing, and optic atrophy). Visual evoked potentials were abnormal in 16. Electroretinography and electro-oculography were not performed. Color vision changes Changes in color vision have been investigated in healthy volunteers who took a single oral dose of either vigabatrin or carbamazepine in a single-blind, placebocontrolled, randomized trial (113C ). All underwent color visual-evoked potential testing and color perimetry at baseline and after taking placebo, vigabatrin (2000 mg), or carbamazepine (400 mg). Carbamazepine caused mild overall impairment of the chromatic and achromatic systems. Vigabatrin caused selective blue impairment, consistent with GABAergic inhibition in the retina. The relation of this change in color perception to visual field defects, if any, is unknown.

Zonisamide

(SED-14, 193; SEDA-25,

100) In a double-blind, placebo-controlled, add-on, randomized trial of zonisamide 400 mg/day in 203 patients over 14 years of age with refractory partial-onset seizures, the response

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rate was 42% (114C ). The most common treatment-emergent adverse events were somnolence, anorexia, rhinitis, dizziness, nausea or vomiting, ataxia, fatigue, and headache. With zonisamide, 22% of the patients lost over 2.3 kg compared with 10% on placebo. In a Cochrane Collaboration meta-analysis of trials of zonisamide, levetiracetam, oxcarbazepine, and remacemide, there were no significant differences in efficacy among the four drugs (115M ). The relative risks for treatment withdrawal were also not significantly different. Immunologic Zonisamide-induced lupus erythematosus has been reported in a 5-year-old child taking zonisamide and ethosuximide (116A ). He had raised titers of antinuclear antibodies and anti-DNA antibodies and presented with fever, pericarditis, pleurisy, and arthralgia. Clinical recovery and a reduction in the anti-DNA-antibody titer promptly followed withdrawal. A lymphocyte transformation test against zonisamide was positive. Body temperature Children have a higher risk of zonisamide-associated oligohidrosis and hyperthermia (117R ). Elan Pharma have recently issued a “Dear Doctor” letter reporting this adverse event (June 2002). During the zonisamide development program in Japan one case of oligohidrosis was reported among 403 children (an incidence of 1/285 patient-years of exposure). There were no cases reported in the US or European development programs, although under 100 children were included in those programs. In the first 11 years of marketing in Japan, 38 cases have been reported (about 1 per 10 000 patient-years). In the first year in the USA, two cases were reported (an estimated reporting rate of 12/10 000 patient-years). This rate might be an underestimate, owing to underreporting. There has been one report of heat stroke in an 18-year-old patient in the USA. Children treated with zonisamide should be monitored closely for evidence of reduced sweating and increased body temperature, especially in warm or hot weather and when taking other drugs that predispose to this (carbonic anhydrase inhibitors, anticholinergic drugs, topiramate).

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cognitive effects of carbamazepine and gabapentin in healthy senior adults. Epilepsia 2001; 42: 764– 71. 16. Apeland T, Mansoor MA, Strandjord RE, Vefring H, Kristensen O. Folate, homocysteine and methionine loading in patients on carbamazepine. Acta Neurol Scand 2001; 103: 294–9. 17. Kelly BD, Hillery J. Hyponatremia during carbamazepine therapy in patients with intellectual disability. J Intellect Disabil Res 2001; 45: 152–6. 18. Di Lernia, V, Viglio A, Cattania M, Paulli M. Carbamazepine-induced, CD30+, primary, cutaneous, anaplastic large-cell lymphoma. Arch Dermatol 2001; 137: 675–6. 19. Matar KM, Nicholls PJ, Bawazir SA, Al Khamis KI, Al Hassan MI. Effect of lamotrigine on the pharmacokinetics of carbamazepine and its active metabolite in dogs. Eur J Drug Metab Pharmacokinet 2001; 26: 149–53. 20. Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies. Neurology 2001; 57: 321–4. 21. Cilio MR, Kartashov AI, Vigevano F. The longterm use of felbamate in children with severe refractory epilepsy. Epilepsy Res 2001; 47: 1–7. 22. Sparagana SP, Strand WR, Adams RC. Felbamate urolithiasis. Epilepsia 2001; 42: 682–5. 23. Appleton R, Fichtner K, LaMoreaux L, Alexander J, Maton S, Murray G, Garofalo E. Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study. Dev Med Child Neurol 2001; 43: 269–73. 24. Crawford P, Brown S, Kerr M. A randomized open-label study of gabapentin and lamotrigine in adults with learning disability and resistant epilepsy. Seizure 2001; 10: 107–15. 25. Norton JW, Quarles E. Gabapentin-related dyskinesia. J Clin Psychopharmacol 2001; 21: 623– 4. 26. Pinninti NR, Mahajan DS. Gabapentinassociated aggression. J Neuropsychiatry Clin Neurosci 2001; 13: 424. 27. Bassilios N, Launay-Vacher V, Khoury N, Rondeau E, Deray G, Sraer JD. Gabapentin neurotoxicity in a chronic haemodialysis patient. Nephrol Dial Transplant 2001; 16: 2112–13. 28. Ragucci MV, Cohen JM. Gabapentin-induced hypersensitivity syndrome. Clin Neuropharmacol 2001; 24: 103–5. 29. Norton JW. Gabapentin withdrawal syndrome. Clin Neuropharmacol 2001; 24: 245–6. 30. Fisher RS, Sachdeo RC, Pellock J, Penovich PE, Magnus L, Bernstein P. Rapid initiation of gabapentin: a randomized, controlled trial. Neurology 2001; 56: 743–8. 31. Wong IC, Mawer GE, Sander JW. Adverse event monitoring in lamotrigine patients: a pharmacoepidemiologic study in the United Kingdom. Epilepsia 2001; 42: 237–44.

86 32. Nieto-Barrera M, Brozmanova M, Capovilla G, Christe W, Pedersen B, Kane K, O’Neill F. A comparison of monotherapy with lamotrigine or carbamazepine in patients with newly diagnosed partial epilepsy. Epilepsy Res 2001; 46: 145–55. 33. Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Perrine KR, Vazquez BR, Kiolbasa T. Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology 2001; 56: 1177–82. 34. Ueberall MA. Normal growth during lamotrigine monotherapy in pediatric epilepsy patients—a prospective evaluation of 103 children and adolescents. Epilepsy Res 2001; 46: 63–7. 35. Sbei M, Campellone JV. Stupor from lamotrigine toxicity. Epilepsia 2001; 42: 1082–3. 36. Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res 2001; 47: 151–4. 37. French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res 2001; 47: 77–90. 38. Krakow K, Walker M, Otoul C, Sander JWAS. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology 2001; 56: 1772–4. 39. Kossoff EH, Bergey GK, Freeman JM, Vining EP. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001; 42: 1611–13. 40. Levy RH, Ragueneau-Majlessi I, Baltes E. Repeated administration of the novel antiepileptic agent levetiracetam does not alter digoxin pharmacokinetics and pharmacodynamics in healthy volunteers. Epilepsy Res 2001; 46: 93–9. 41. Ragueneau-Majlessi I, Levy RH, Meyerhoff C. Lack of effect of repeated administration of levetiracetam on the pharmacodynamic and pharmacokinetic profiles of warfarin. Epilepsy Res 2001; 47: 55–63. 42. Sachdeo R, Beydoun A, Schachter S, Vazquez B, Schaul N, Mesenbrink P, Kramer L, D’Souza J. Oxcarbazepine (Trileptal) as monotherapy in patients with partial seizures. Neurology 2001; 57: 864–71. 43. Schmidt D, Arroyo S, Baulac M, Dam M, Dulac O, Friis ML, Kalviainen R, Kramer G, Van Parys J, Pedersen B, Sachdeo R. Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view. Acta Neurol Scand 2001; 104: 167–70. 44. Isojarvi JIT, Huuskonen UEJ, Pakarinen AJ, Vuolteenaho O, Myllyla VV. The regulation of serum sodium after replacing carbamazepine with oxcarbazepine. Epilepsia 2001; 42: 741–5. 45. Rosche J, Froscher W, Abendroth D, Liebel J. Possible oxcarbazepine interaction with cyclosporine serum levels: a single case study. Clin Neuropharmacol 2001; 24: 113–16. 46. Klassen BD, Sadler RM. Induction of hypersensitivity to a previously tolerated antiepileptic drug by a second antiepileptic drug. Epilepsia 2001; 42: 433–5. 47. Arroyo S, De la Morena A. Life-threatening adverse events of antiepileptic drugs. Epilepsy Res 2001; 47: 155–74.

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48. Burneo JG, Anandan JV, Barkley GL. A prospective study of the incidence of the purple glove syndrome. Epilepsia 2001; 42: 1156–9. 49. Pryor FM, Gidal B, Ramsay RE, DeToledo J, Morgan RO. Fosphenytoin: pharmacokinetics and tolerance of intramuscular loading doses. Epilepsia 2001; 42: 245–50. 50. Besag FM, Newton RE, Blakey GE, Dean AD. Safety, tolerability, and pharmacokinetics of remacemide in children. Pediatr Neurol 2001; 24: 352–6. 51. Crawford P, Meinardi H, Brown S, Rentmeester TW, Pedersen B, Pedersen PC, Lassen LC. Tiagabine: efficacy and safety in adjunctive treatment of partial seizures. Epilepsia 2001; 42: 531–8. 52. Wolanczyk T, Grabowska-Grzyb A. Transient dystonias in three patients treated with tiagabine. Epilepsia 2001; 42: 944–6. 53. Fitzek S, Hegemann S, Sauner D, Bonsch D, Fitzek C. Drug-induced nonconvulsive status epilepticus with low dose of tiagabine. Epileptic Disord 2001; 3: 147–50. 54. Shinnar S, Berg AT, Treiman DM, Hauser WA, Hesdorffer DC, Sackellares JC, Leppik I, Sillanpaa M, Sommerville KW. Status epilepticus and tiagabine therapy: review of safety data and epidemiologic comparisons. Epilepsia 2001; 42: 372– 9. 55. Biraben A, Beaussart M, Josien E, Pestre M, Savet JF, Schaff JL, Tourniaire D, Sevestre M, Renault-Djouadi J. Comparison of twice- and three times daily tiagabine for the adjunctive treatment of partial seizures in refractory patients with epilepsy: an open label, randomised, parallel-group study. Epileptic Disord 2001; 3: 91–100. 56. Ghaemi SN, Manwani SG, Katzow JJ, Ko JY, Goodwin FK. Topiramate treatment of bipolar spectrum disorders: a retrospective chart review. Ann Clin Psychiatry 2001; 13: 185–9. 57. Davanzo P, Cantwell E, Kleiner J, Baltaxe C, Najera B, Crecelius G, McCracken J. Cognitive changes during topiramate therapy. J Am Acad Child Adolesc Psychiatry 2001; 40: 262–3. 58. Chengappa KN, Gershon S, Levine J. The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder. Bipolar Disord 2001; 3: 215–32. 59. Aldenkamp AP. Effects of antiepileptic drugs on cognition. Epilepsia 2001; 42 Suppl 1: 46–9. 60. Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, Sinclair K, Gilliam F, Faught E. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999; 52: 321– 7. 61. Rorsman I, Kallen K. Recovery of cognitive and emotional functioning following withdrawal of topiramate maintenance therapy. Seizure 2001; 10: 592–5. 62. Biton V, Edwards KR, Montouris GD, Sackellares JC, Harden CL, Kamin M. Topiramate titration and tolerability. Ann Pharmacother 2001; 35: 173–9. 63. Thompson PJ, Baxendale SA, Duncan JS, Sander JW. Effects of topiramate on cognitive func-

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tion. J Neurol Neurosurg Psychiatry 2000; 69: 636– 41. 64. Tatum WO, French JA, Faught E, Morris GL III, Liporace J, Kanner A, Goff SL, Winters L, Fix A. Postmarketing experience with topiramate and cognition. Epilepsia 2001; 42: 1134–40. 65. Aldenkamp AP, Baker G, Mulder OG, Chadwick D, Cooper P, Doelman J, Duncan R, Gassmann-Mayer C, De Haan GJ, Hughson C, Hulsman J, Overweg J, Pledger G, Rentmeester TW, Riaz H, Wroe S. A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures. Epilepsia 2000; 41: 1167–8. 66. Meador KJ, Hulihan JF, Karim R. Cognitive function in adults with epilepsy; effect of topiramate and valproate added to carbamazepine. Epilepsia 2001; 42 Suppl 2: 75. 67. Meador KJ. Effects of topiramate on cognition. J Neurol Neurosurg Psychiatry 2001; 71: 134–5. 68. Sankar PS, Pasquale LR, Grosskreutz CL. Uveal effusion and secondary angle-closure glaucoma associated with topiramate use. Arch Ophthalmol 2001; 119: 1210–11. 69. Rhee DJ, Goldberg MJ, Parrish RK. Bilateral angle-closure glaucoma and ciliary body swelling from topiramate. Arch Ophthalmol 2001; 119: 1721–3. 70. Banta JT, Hoffman K, Budenz DL, Ceballos E, Greenfield DS. Presumed topiramate-induced bilateral acute angle-closure glaucoma. Am J Ophthalmol 2001; 132: 112–14. 71. Klufas A, Thompson D. Topiramate-induced depression. Am J Psychiatry 2001; 158: 1736. 72. Goldberg JF. Panic attacks associated with the use of topiramate. J Clin Psychopharmacol 2001; 21: 461–2. 73. Ko CH, Kong CK. Topiramate-induced metabolic acidosis: report of two cases. Dev Med Child Neurol 2001; 43: 701–4. 74. Arcas J, Ferrer T, Roche MC, MartinezBermejo A, Lopez-Martin V. Hypohidrosis related to the administration of topiramate to children. Epilepsia 2001; 42: 1363–5. 75. Lerman-Sagie T, Watemberg N, Kramer U, Shahar E, Lerman P. Absence seizures aggravated by valproic acid. Epilepsia 2001; 42: 941–3. 76. Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology 2001; 56: 172–7. 77. Lott RS, Helmboldt KM, Madaras-Kelly KJ. Retrospective evaluation of the effect of valproate therapy on transaminase elevations in patients with hepatitis C. Pharmacotherapy 2001; 21: 1345–51. 78. Cogrel O, Beylot-Barry M, Vergier B, Dubus P, Doutre MS, Merlio JP, Beylot C. Sodium valproateinduced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol 2001; 144: 1235–8. 79. Roste LS, Tauboll E, Berner A, Isojarvi JIT, Gjerstad L. Valproate, but not lamotrigine, induces ovarian morphological changes in Wistar rats. Exp Toxicol Pathol 2001; 52: 545–52.

87 80. Herzog AG, Schachter SC. Valproate and the polycystic ovarian syndrome: final thoughts. Epilepsia 2001; 42: 311–15. 81. Isojarvi JIT, Tauboll E, Tapanainen JS, Pakarinen AJ, Laatikainen TJ, Knip M, Myllyla VV. On the association between valproate and polycystic ovary syndrome: a response and an alternative view. Epilepsia 2001; 42: 305–10. 82. Genton P, Bauer J, Duncan S, Taylor AE, Balen AH, Eberle A, Pedersen B, Salas-Puig X, Sauer MV. On the association between valproate and polycystic ovary syndrome. Epilepsia 2001; 42: 295–304. 83. Duncan S. Polycystic ovarian syndrome in women with epilepsy: a review. Epilepsia 2001; 42 Suppl 3: 60–5. 84. Isojarvi J, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. New Engl J Med 1993; 329: 1383–8. 85. Isojarvi JIT, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllyla VV. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996; 39: 579–84. 86. Isojarvi JIT, Tauboll E, Pakarinen AJ, van Parys J, Rattya J, Harbo HF, Dale PO, Fauser BCJM, Gjerstad L, Koivunen R, Knip M, Tapanainen JS. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med 2001; 111: 290–6. 87. Isojarvi JIT, Rattya J, Myllyla VV, Knip M, Koivunen R, Pakarinen AJ, Tekay A, Tapanainen JS. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998; 43: 446–51. 88. Jennings HR, Romanelli F. The use of valproic acid in HIV-positive patients. Ann Pharmacother 1999; 33: 1113–16. 89. Maggi JD, Halman MH. The effect of divalproex sodium on viral load: a retrospective review of HIV-positive patients with manic syndromes. Can J Psychiatry 2001; 46: 359–62. 90. Nagarajan L, Johnston K, Williams S. Hypothermia and thermoregulatory derangements induced by valproic acid. Neurology 2001; 56: 139. 91. Zachariah SB, Zachariah A, Ananda R, Stewart JT. Hypothermia and thermoregulatory derangements induced by valproic acid. Neurology 2000; 55: 150–1. 92. Kozma C. Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet 2001; 98: 168–75. 93. Lajeunie E, Barcik U, Thorne JA, Ghouzzi VE, Bourgeois M, Renier D. Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg 2001; 95: 778–82. 94. Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 2001; 43: 202–6. 95. Elterman RD, Shields WD, Mansfield KA, Nakagawa J. Randomized trial of vigabatrin in patients with infantile spasms. Neurology 2001; 57: 1416–21.

88 96. Prasad AN, Penney S, Buckley DJ. The role of vigabatrin in childhood seizure disorders: results from a clinical audit. Epilepsia 2001; 42: 54–61. 97. Spence SJ, Sankar R. Visual field defects and other ophthalmological disturbances associated with vigabatrin. Drug Saf 2001; 24: 385–404. 98. Kalviainen R, Nousiainen I. Visual field defects with vigabatrin: epidemiology and therapeutic implications. CNS Drugs 2001; 15: 217–30. 99. Toggweiler S, Wieser HG. Concentric visual field restriction under vigabatrin therapy: extent depends on the duration of drug intake. Seizure 2001; 10: 420–3. 100. Nousiainen I, Mantyjarvi M, Kalviainen R. No reversion in vigabatrin-associated visual field defects. Neurology 2001; 57: 1916–17. 101. Malmgren K, Ben Menachem E, Frisen L. Vigabatrin visual toxicity: evolution and dose dependence. Epilepsia 2001; 42: 609–15. 102. Hardus P, Verduin WM, Engelsman M, Edelbroek PM, Segers JP, Berendschot TT, Stilma JS. Visual field loss associated with vigabatrin: quantification and relation to dosage. Epilepsia 2001; 42: 262–7. 103. Vanhatalo S, Alen R, Riikonen R, Rantala H, Aine MR, Mustonen K, Nousiainen I. Reversed visual field constrictions in children after vigabatrin withdrawal – true retinal recovery or improved test performance only? Seizure 2001; 10: 508–11. 104. Sills GJ, Patsalos PN, Butler E, Forrest G, Ratnaraj N, Brodie MJ. Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina. Neurology 2001; 57: 196–200. 105. Ravindran J, Blumbergs P, Crompton J, Pietris G, Waddy H. Visual field loss associated with vigabatrin: pathological correlations. J Neurol Neurosurg Psychiatry 2001; 70: 787–9. 106. Paul SR, Krauss GL, Miller NR, Medura MT, Miller TA, Johnson MA. Visual function is stable in patients who continue long-term vigabatrin therapy: implications for clinical decision making. Epilepsia 2001; 42: 525–30.

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107. Hardus P, Verduin WM, Berendschot TT, Kamermans M, Postma G, Stilma JS, Van Veelen CW. The value of electrophysiology results in patients with epilepsy and vigabatrin associated visual field loss. Acta Ophthalmol Scand 2001; 79: 169– 74. 108. Coupland SG, Zackon DH, Leonard BC, Ross TM. Vigabatrin effect on inner retinal function. Ophthalmology 2001; 108: 1493–6. 109. Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain Dev 2001; 23: 649–53. 110. Nabbout R. A risk-benefit assessment of treatments for infantile spasms. Drug Saf 2001; 24: 813–28. 111. Nabbout R, Melki I, Gerbaka B, Dulac O, Akatcherian C. Infantile spasms in Down syndrome: good response to a short course of vigabatrin. Epilepsia 2001; 42: 1580–3. 112. Koul R, Chacko A, Ganesh A, Bulusu S, Al Riyami K. Vigabatrin associated retinal dysfunction in children with epilepsy. Arch Dis Child 2001; 85: 469–73. 113. Mecarelli O, Rinalduzzi S, Accornero N. Changes in color vision after a single dose of vigabatrin or carbamazepine in healthy volunteers. Clin Neuropharmacol 2001; 24: 23–6. 114. Faught E, Ayala R, Montouris GG, Leppik IE. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology 2001; 57: 1774–9. 115. Marson AG, Hutton JL, Leach JP, Castillo S, Schmidt D, White S, Chaisewikul R, Privitera M, Chadwick DW. Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001; 46: 259–70. 116. Mutoh K, Hidaka Y, Hirose Y, Kimura M. Possible induction of systemic lupus erythematosus by zonisamide. Pediatr Neurol 2001; 25: 340–3. 117. Glauser TA, Pellock JM. Zonisamide in pediatric epilepsy: review of the Japanese experience. J Child Neurol 2002; 17: 87–96.

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8

Opioid analgesics and narcotic antagonists

OPIOID RECEPTOR AGONISTS Alfentanil

(SED-14, 211; SEDA 23, 98; SEDA-24, 104; SEDA 25, 110) Alfentanil is a potent short-acting opioid with a rapid onset and short duration of action. It is therefore the ideal analgesic for focused and ambulatory interventions. In a prospective, uncontrolled study in three consecutive groups of out-patients undergoing shock-wave lithotripsy, group 1 (152 patients) had an induction dose of a combination of propofol 0.8 mg/kg and alfentanil 8 µg/kg; in group 2 (78 patients) and group 3 (250 patients), the induction dose was reduced by 20% (1C ). For all three groups the maintenance dose was a mixture of propofol 0.25 mg/kg and alfentanil 5 µg/kg given via a PCA device with a lock-out time of 5 minutes. In groups 1 and 2 the lithotripter was equipped with a standard electromagnetic shock-wave emitter (the EMSE 200), while in group 3 an upgraded EMSE F150 was used. Analgesic consumption was lower in the patients treated with the EMSE 150; groups 2 and 3, with a 20% reduction in induction dose, did not compensate by using more PCA. Groups 2 and 3 also had a significant reduction in the incidence of oxygen desaturation. The intravenous administration of a mixture of alfentanil and propofol, using the updated EMSE F150 device as in group 3, was therefore considered to be safe and reliable, with good patient tolerance and rapid recovery. Nervous system Simultaneous scalp and depth electrode recordings were performed on five patients with complex partial epilepsy who © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

underwent alfentanil anesthesia induction before depth electrode removal (2c ). Five equal bolus doses of alfentanil 100 µg were given to each patient at 60-second intervals (total 500 µg alfentanil). Epileptiform activity was increased in three of the five, but without clinical evidence of seizure activity. Gastrointestinal A 30-year-old woman with multiple body injuries required five general anesthetics in under 7 days for reconstructive surgery and dressing changes. In order to avoid further general anesthesia she was given a target-controlled infusion of alfentanil 10 mg in 50 ml of 0.9% sodium chloride (a total dose of 5.04 mg alfentanil over 35 minutes). There was one self-limiting episode of nausea with no vomiting. Oxygen saturation was 93–98% on air. There were no episodes of hypotension, cardiac dysrhythmias, or sedation (3A ).

Codeine

(SED-14, 212; SEDA-23, 98; SEDA-25, 110) Nervous system Patients with migraine who use daily codeine or other opioids may be more susceptible to chronic daily headaches; this is evident in opiate overuse. In a pilot questionnaire study of 32 patients who used codeine or other opioids for control of their bowel motility after colectomy, chronic daily headaches occurred in those who were misusing opioids, but only if they had pre-existing migraine (4c ). The study had significant limitations, including the small sample size, diagnosis by means of a mailed questionnaire, a short duration of overuse of opioids, and the fact that it was uncontrolled.

89

90 Skin Rashes have been attributed to codeine. • A 72-year-old man developed a generalized maculopapular rash 12 hours after taking co-codamol (codeine 10 mg plus paracetamol 500 mg) (5A ). The lesions persisted for 7 days, became scaly, and disappeared. He later reported a similar skin condition after having taken a combination of acetylsalicylic acid, codeine, and caffeine. Patch tests gave a positive result for codeine, suggesting a type IV allergic reaction. • A 58-year-old man developed a maculopapular rash on the dorsal aspects of the hand and upper body 6 days after taking codeine as an analgesic for hemoptysis secondary to tuberculosis; on withdrawal of codeine, the rash subsided after 48 hours (6A ).

Drug abuse Recreational use and abuse of codeine cough syrup is becoming more frequent. In a literature search of scientific journals and news media, complemented with in-depth interviews of 12 professionals working in the law enforcement or treatment aspects of drug abuse and 25 adults who reported using codeine syrup in the 30 days before their interview, the information provided useful insights into the different types of cough formulations, the reported reasons for their use, and the various types of administration (7MC ). The effects of cough syrup, including their adverse effects, were reported. The most frequently mentioned negative effects included taste disturbance, prolonged sedation beyond the desired effect, loss of co-ordination, lethargy, constipation, and urinary retention. This qualitative study cannot be described as authoritative or representative, because of its limited nature, involving as it did only a small number of individuals living in the Houston area.

Dextromethorphan

(SED-14, 212; SEDA-23, 99; SEDA-24, 104; SEDA-25, 111) The effect of dextromethorphan premedication on postoperative analgesic requirements, pain scores, and adverse effects has been examined in two double-blind, randomized studies (8C , 9C ). In the first study, 60 adults scheduled for elective upper abdominal surgery were randomly allocated to three equal groups (8C ). One group received intramuscular dextromethorphan 120 mg 30 minutes before

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skin incision (pre-incisional group); the second group received placebo (intramuscular saline) 30 minutes before skin incision and intramuscular dextromethorphan 120 mg 30 minutes before the end of surgery (post-incisional group); the third group received placebo 30 minutes before skin incision and 30 minutes before the end of surgery (control group). Pre-incisional intramuscular dextromethorphan 120 mg provided pre-emptive analgesia, reduced the need for postoperative analgesic supplements, and had a minimal and non-significant adverse effects profile. In the second study oral dextromethorphan 90 mg was compared with placebo given 90 minutes preoperatively to patients undergoing laparoscopic cholecystectomy or inguinal hernioplasty under general anesthesia (9C ). Pain intensity and sedation were significantly reduced in the experimental group, with sparing of postoperative analgesics for up to 24 hours. Dextromethorphan 90 mg also abolished postoperative thermal-induced hyperalgesia and hyperpathia. No adverse effects were recorded in either group. A randomized, double-blind, placebo-controlled study of oral dextromethorphan and PCA morphine has been performed in 66 patients undergoing knee surgery (10C ). The study was in two parts. The first was a dose escalation study in 25 postoperative patients to determine the maximum tolerated oral dose of dextromethorphan. The second involved giving less than the maximum tolerated dose divided into three increments at 8-hour intervals. The maximum tolerated dose of dextromethorphan was 750 mg. One patient, who was given 800 mg of dextromethorphan, had adverse effects, including severe slurred speech and lightheadedness followed by deep sedation. In the second part of the study 66 patients were intended to receive dextromethorphan 800 mg in three doses of 400, 200, and 200 mg. The treatment group was subsequently reduced to 22 patients, compared with 34 in the placebo group, because of unexpected nausea and vomiting in five patients given dextromethorphan 400 mg. Dextromethorphan 200 mg 8-hourly caused a significant increase in nausea 2–24 hours after the first dose. One patient given dextromethorphan had mild hallucinations on one occasion only. There was an associated modest reduction in postoperative morphine consumption (29%),

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with no other benefits. The study failed to provide evidence that the maximum tolerated dose of dextromethorphan 200 mg 8-hourly is useful in the treatment of postoperative pain after knee surgery. Three double-blind, crossover, randomized, placebo-controlled studies of the role of dextromethorphan in neurological pain conditions in 40 adults with diabetic neuropathy, postherpetic neuralgia, and non-specific neuropathic pain syndromes have been reviewed (11M ). Dextromethorphan dosages varied from 13.5 mg tds on alternate days to 120 mg qds. High-dose dextromethorphan significantly reduced pain in diabetic neuropathy with no effect in post-herpetic neuralgia. Sedation (58%) and dizziness (25%) were the most commonly reported adverse effects. Neuromuscular Dextromethorphan has been implicated in a case of movement disorder (12A ). • An 8-year-old boy complained of abnormal facial movements and hallucinations. One day before these symptoms, he had been given his sister’s Cordec DM droplets (carbinoxamine maleate 2 mg, pseudoephedrine hydrochloride 25 mg, and dextromethorphan 4 mg) for a cold. He had facial dyskinesia, dilated pupils, pyrexia, tachycardia, and reduced bowel sounds and responded to a benzodiazepine.

Pregnancy In 184 pregnancies exposed to dextromethorphan (128 exposures in the first trimester) there were 172 live births, 10 spontaneous abortions, one therapeutic abortion, and one stillbirth (13C ). There were three major malformations and seven minor malformations in the children of women who had used dextromethorphan in the first trimester. In the control group there were 174 live births, eight spontaneous abortions, and two therapeutic abortions; there were five major and l8 minor malformations. This small study did not show that dextromethorphan used during pregnancy increases the rates of major malformations above the expected baseline rate of 1–3%.

Diamorphine (heroin)

(SED-14, 214;

SEDA-24, 105; SEDA-25, 112) Combined spinal–epidural anesthesia for mobile analgesia in labor is now widely used. It

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offers the advantage of rapid onset of analgesia with the flexibility of epidural top-ups later in labor. In 62 women who asked for regional analgesia in labor and who were randomized to an intrathecal injection of either bupivacaine 2.5 mg with fentanyl 25 µg or bupivacaine 2.5 mg with diamorphine 250 µg, the diamorphine provided longer analgesia (14C ). There were significant differences in adverse effects between the groups. There were no instances of nausea or vomiting, but pruritus was more common in those who received fentanyl. The dose of diamorphine was deliberately low, and more studies are needed to confirm these findings. High-dose intrathecal diamorphine for analgesia after elective cesarean section has been studied in 40 women who were randomized to diamorphine 0.5 mg or 1 mg (15C ). All also received diclofenac 100 mg at the end of the cesarean section and morphine via a patient-controlled analgesia system. Postoperative analgesia was more prolonged and reliable in those who were given diamorphine 1 mg, who needed significantly less morphine. There was postoperative nausea in just under half of the patients in each group, and most of the patients (93%) had mild to moderate pruritus. There were no cases of excessive sedation or oxygen desaturation. High-dose diamorphine has been compared with morphine in a double-blind, crossover, randomized study in 39 intravenous opioid users who were allocated to either morphine 3% solution or diamorphine 2% solution, gradually increased up to an individual maintenance dose adjusted to meet the patient’s subjective needs (16C ). Those who started with diamorphine and subsequently switched to morphine terminated prematurely owing to excessive histamine reactions, all of which occurred during crossover to morphine. Symptoms included severe pruritus, flushing, swelling, urticaria, severe headaches, nausea, general malaise, hypotension, and tachycardia. Only 44% of the original cohort finished the 6-week study (14 getting diamorphine at the end and three getting morphine). Average daily doses were 491 mg for diamorphine and 597 mg for morphine. These results suggest that diamorphine produces fewer adverse effects than morphine and may be preferable for high-dose maintenance prescription. However, the study was very small and subject selection was biased,

92 as were the variables used to determine a successful outcome. The result was contrary to all the well established pharmacological facts, and the authors did not mention the risks associated with high doses of short-acting opioids. Nasal diamorphine is as effective as intramuscular morphine and is much better tolerated by children, with no apparent increased risk of adverse effects (17M , 18C ). In a multicenter, randomized, controlled study, 404 children aged 3–16 years with a fracture of an arm or leg were given either nasal diamorphine 0.1 mg/kg or intramuscular morphine 0.2 mg/kg. The onset of pain relief was faster with nasal diamorphine, and there were no serious adverse effects. The frequencies of mild opioid-related adverse effects were similar in the two groups. Nervous system Demyelination has been attributed to diamorphine (19A ). • A 41-year-old chronic diamorphine user developed an unsteady gait and dysarthria over 2 weeks, followed by severe cerebellar ataxia and moderate dysmetria of the arms and legs. An MRI scan suggested myelin damage, with symmetrical involvement of the cerebellar hemispheres and decussation of the superior cerebellar peduncles, the corticospinal tracts, and the centrum semiovale, suggesting spongiform leukoencephalopathy. Two years later having taken no more diamorphine he was improved, with minor regression of the MRI lesions, especially the white matter lesions.

Sensory systems Profound reversible deafness with vestibular dysfunction has been described in a 47-year-old intravenous opiate user 24 hours after he had injected illicit diamorphine (20A ). He developed bilateral symmetrical sensorineural hearing loss, ear fullness, and loud tinnitus 20 minutes after injecting about 0.25 g of diamorphine after a period of abstinence. His symptoms gradually subsided with no sequelae after 3 weeks.

Dihydrocodeine Dihydrocodeine is an opioid analgesic related to codeine, in which the double bond in the 7th position is saturated. It has an analgesic potency 2–3 times that of codeine. A modified-release formulation extends the duration of action from 2–4 hours to 12 hours. In 12 volunteers who

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took modified-release dihydrocodeine 60 mg or 120 mg and 120 minutes later lactulose 40 mg diluted in 100 mg of water the orocecal transit time was significantly prolonged by dihydrocodeine compared with placebo (21c ). Dihydrocodeine also significant suppressed the pupillary light reflex. Both dosages caused similar adverse effects. Tiredness and dry mouth were reported in 80%, vertigo in 5%, and headache in 1%.

Fentanyl

(SED-14, 213; SEDA-23, 100; SEDA-24, 105; SEDA-25, 113) Fentanyl can be used transdermally because of its high solubility in both fat and water, low molecular weight, high analgesic potency, and fewer adverse effects, especially gastrointestinal symptoms (22C ). It is easy to administer and can be given at 3-day intervals. Transdermal fentanyl in chronic cancer pain control has been extensively reviewed (23M ). Data from non-blinded, randomized trials suggest that it is as effective as modified-release oral morphine and that the most common adverse effects include nausea, vomiting, and constipation. The most serious adverse effect reported was hypoventilation, which occurred in about 2% of patients. Skin reactions occurred in 1–3%. A number of non-comparative trials have described the use of transdermal fentanyl for periods of at least a year without serious adverse effects. In a follow-up study of 78 patients with cancer who participated in a cross-over, randomized study of transdermal fentanyl (mean final dose 100 µg/hour) and oral morphine for 4 weeks, the incidences of skin reactions and gastrointestinal symptoms were low (24C ). Other adverse effects reported were breakthrough pain, light-headedness, and diarrhea. In the original randomized study, which lasted 15 days, there was significantly less constipation with fentanyl than with morphine (25C ). These results suggest that many patients have stable analgesic requirements with transdermal fentanyl up to the time of death with no need for additional medication. In a questionnaire survey of 1005 patients only 11 had chronic pain from nonmalignant disease while taking transdermal

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fentanyl (26C ). Their physicians were asked to provide information about their reasons for switching to transdermal fentanyl and the patients were then surveyed until withdrawal of fentanyl because of death, change in analgesic regimen, or serious adverse effects. Modifiedrelease morphine (median dose 90 mg/day) was used in 72% of patients before switching to fentanyl. More than 20% of the cohort had received no continuous opioid medication before the start of transdermal therapy. Most of the patients were switched to fentanyl because of inadequate analgesia or opioid-induced gastrointestinal symptoms. The simplicity of administration and patients’ wishes were also contributory factors. Transdermal fentanyl was discontinued primarily because patients died (46%); other reasons included inadequate pain relief (10%), pain relief with another analgesic regimen (10%), adverse effects (5%), rejection of transdermal therapy by the patient (6%), and other unspecified causes, such as pathological fractures and anemia (16%). There were opioidrelated adverse effects in 26% of the patients. Serious neurotoxic effects, such as hallucinations (0.2%), withdrawal symptoms (0.1%), or convulsions (0.1%), were rare. Under controlled conditions transdermal fentanyl is a useful option for direct conversion from mild to strong opioids in cancer patients. In addition, 25 µg/hour daily incremental steps of transdermal fentanyl can be made by palliative care specialists, if it is required for cancer pain management (27C ). Transdermal fentanyl for chronic non-cancer pain control has been studied in two open trials (28C , 29C ). In a multicenter, open, randomized study of 256 patients with a history of chronic non-cancer pain, 65% preferred transdermal fentanyl, whereas 28% preferred modified-release oral morphine. Subjective pain control and quality of life were significantly better in the patients who used transdermal fentanyl. Despite a preference for transdermal fentanyl, more patients withdrew because of adverse effects in the first fentanyl period (16%) than in the first morphine period (9%). The difference could have been related to patients’ previous experience of morphine, with enhanced tolerance of its adverse effects. In the second study, 35 patients with severe AIDS-related chronic pain were recruited

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in a prospective, open, before/after comparison of the analgesic efficacy and adverse effects profile of a stable dose of transdermal fentanyl (25–300 µg/h) or oral morphine (less than 45 mg/day) for 15 consecutive days (29C ). Transdermal fentanyl alleviated chronic pain and those who were already dependent on an opioid needed less fentanyl for the same analgesic result. The addition of fentanyl 1 µg/ml to ropivacaine 7.5 mg/ml did not improve nerve blockade by axillary brachial plexus anesthesia in a double-blind, randomized study in 30 patients undergoing orthopedic procedures (30C ). In another double-blind, randomized study, 60 patients receiving axillary brachial plexus blockade were given 0.25% bupivacaine 40 mg, 0.25% bupivacaine 40 mg plus fentanyl 2.5 µg/ml, or 0.125% bupivacaine 40 mg plus fentanyl 2.5 µg/ml (31C ). The addition of fentanyl 2.5 µg/ml prolonged sensory and motor blockade without any improvement in the onset of anesthesia and no significant increase in adverse effects. These two studies have reaffirmed the current position of conflicting results in studies of the benefits of adding fentanyl to local anesthetics for peripheral nerve blockade. In 100 patients undergoing arthroscopic outpatient surgery minidose spinal lidocaine plus fentanyl (0.5% lidocaine 20 mg plus fentanyl 20 µg) has been compared with traditional spinal anesthesia (1% lidocaine 30 ml with titrated intravenous propofol infusion) (32C ). The study was randomized and prospective but unblinded. Whereas those given local anesthesia were more likely to have pain requiring analgesic medication before discharge (44% vs. 20%), those given spinal anesthesia group were more likely to have nausea (8% vs. 22%) or pruritus (8% vs. 68%). Both techniques provided a high degree of patient satisfaction, with comparable efficacy both intraoperatively and postoperatively. Fentanyl 2 µg/ml has been used in combination with another local anesthetic, ropivacaine 2 mg/ml, to determine its impact on the quality of postoperative analgesia and the incidence of adverse effects after colonic surgery in 155 patients scheduled for elective colonic surgery in a multicenter, double-blind, randomized study (33C ). The incidences of hypotension and pruritus in those given fentanyl were significantly increased, although they had better analgesic

94 control. They also had an increased incidence of serious adverse effects affecting the respiratory, cardiovascular, and genitourinary systems. Further studies are required to evaluate the role of adding epidural opioids to local anesthetic infusions in major abdominal surgery. The relations between fentanyl and local anesthetics and their adverse effects profiles in epidural analgesia (34MC ) further demonstrate the need for well-controlled, double-blind studies (35C , 36C ). Respiratory Cough has been attributed to fentanyl (37A ). • A 7-year-old boy with trisomy 21 (Down syndrome) had explosive coughing 30 seconds after fentanyl 50 µg (2 µg/kg) had been injected and flushed through an intravenous cannula. The cough was unproductive and persisted in spasmodic bursts for a further 2–3 minutes until anesthesia was induced with propofol 60 mg and atracurium 15 mg intravenously. The coughing immediately ceased. A petechial rash in the conjunctivae and periorbital regions was subsequently noted and disappeared by the end of the first postoperative day.

Urinary tract There have been two cases of urinary retention leading to renal pelvocalyceal dilatation as a result of continuous infusion of fentanyl (3 µg/kg/h) in premature neonates (38A ). In both cases the problem was resolved by inserting an indwelling catheter. Skin A rash has been attributed to fentanyl (39A ). • A 70-year-old man with metastatic cancer of the colon was given transdermal fentanyl 50 mg for analgesia. After 10 days he developed an itchy pustular eruption on the trunk and limbs. The lesions subsided on withdrawal of fentanyl. When he restarted transdermal fentanyl 2 months later the skin lesions reappeared and became more generalized. The pustules were scattered, sparse, and superficial, and included the tongue and buccal mucosa, but not the conjunctivae or genitalia. A history of eosinophilia suggested an immunoallergic origin.

Drug formulations A woman suffered sedation, localized erythematous lesions on the hands, and reduced appetite with weight loss after removing transdermal fentanyl patches from her daughter’s skin and replacing them without wearing protective gloves (40A ). She had severe headaches, night sweats, irritability, nausea,

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and insomnia. When she used gloves her weight gradually increased and the sedation abated. A 57-year-old woman using transdermal fentanyl (75 µg/h) developed a reduced respiratory rate and bilateral pinpoint pupils when an upper body warming blanket was used as a normal postoperative procedure (41A ). The resultant increase in skin temperature significantly enhanced skin perfusion, and increased the systemic absorption of fentanyl from the intracutaneous fentanyl depot, leading to symptoms of opioid overdose. She recovered after removal of the fentanyl patch and the intravenous administration of naloxone 60 µg.

Hydromorphone

(SEDA-24, 106)

Intolerable adverse effects or inadequate analgesia occur in 10–15% of patients with chronic pain given continuous intrathecal morphine. Hydromorphone is a semisynthetic derivative of morphine used extensively in the management of cancer pain. It is more soluble than morphine, has a slightly shorter duration of action, and is about five times more potent when given systemically. In a retrospective review of 37 patients with chronic non-malignant pain (mostly from failed lumbosacral spine surgery) treated with intrathecal hydromorphone there was an analgesic response in six of the 16 patients who were switched from morphine to hydromorphone because of poor pain relief (42C ). Opioid-related adverse effects, such as nausea, vomiting, pruritus, and sedation, were also reduced by hydromorphone in the 21 patients who were switched to hydromorphone because of morphine-related adverse effects, especially 1 month after use. These results should be treated cautiously, because of the limitations of a retrospective study that lacks strict inclusion criteria, with obvious population bias and under-reporting, and without standardized procedures for rotation to hydromorphone.

Methadone

(SED-14, 214; SEDA-23, 103; SEDA-24, 106; SEDA-25, 115) Methadone is increasingly being used as an analgesic for chronic pain. It is an attractive

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alternative mu opioid analgesic because of its lack of neuroactive metabolites, a clearance that is independent of renal function, good oral systemic availability, a longer half-life with fewer doses needed per day, and extremely low cost. In a prospective, open, uncontrolled study 50 patients with a history of cancer taking daily oral morphine (90–800 mg) but with uncontrolled pain with or without severe opioid adverse effects, were switched to oral 8-hourly methadone in a dose ratio of 1 : 4 for patients receiving less than 90 mg of morphine daily, 1 : 8 for patients receiving 90–300 mg daily, and 1 : 12 for patients receiving more than 300 mg daily (43C ). Methadone was effective in 80% of the patients when comparing analgesic response with opioid-related adverse effects. Ten patients were switched because of uncontrolled pain, eight because of moderate or severe adverse effects in the presence of acceptable pain control, and 32 because of uncontrolled pain with morphine-related adverse effects. In the last 32 there were significant improvements in pain intensity, nausea and vomiting, constipation, and drowsiness, with a 20% increase in methadone dose over and above the recommended starting dose. A similar effect was shown in a prospective uncontrolled study of intrathecal methadone in 24 patients with a history of intractable chronic non-malignant pain (44C ). Methadone was a better analgesic than morphine, with improved quality of life and no adverse effects in 13 patients. The final rates of methadone infusion were 20% higher than the preceding morphine rates. Several methadone studies have focused on opioid-dependent or opioid-abusing subjects. For example, six opioid-dependent individuals maintained on methadone subsequently developed cancer and continued to use methadone, but in a higher dose as an analgesic (45c ). The first five were partly refractory to the analgesic effects of opioids other than methadone, but all six achieved adequate analgesia without sedation or respiratory depression from aggressive upward intravenous methadone titration using an infusion of 100 mg/hour. Methadone was given in divided doses every 6–12 hours rather than once daily, as is customary in maintenance therapy for opioid dependence. The reasons for increasing the methadone dosage and frequency of administration are cross-tolerance to

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other opioids and the presence in methadonemaintained individuals of hyperalgesia to pain (a low pain tolerance to pain detection ratio) (46C ). These issues are also relevant to determining whether other drugs are more effective than morphine in managing acute pain in these patients. Cardiovascular The use of methadone/dihydrocodeine has been linked to an acute myocardial infarction (47A ). • A 22-year-old man with a 6-year history of intravenous heroin use was maintained on methadone 60 mg/day and dihydrocodeine 0.5 g/day. He had an extensive anterior myocardial infarction as a result of occlusion of the left anterior descending coronary artery, which was reopened by percutaneous transluminal coronary angioplasty.

This case presents circumstantial evidence only, and the association was probably not a true one. There has been a report of five cases of episodes of syncope and an electrocardiogram showing ventricular tachydysrhythmias with prolonged QT intervals and episodes of torsade de pointes; all the patients were taking high doses of methadone (270–660 mg/day) with no previous history of cardiac disease (48A ). Torsade de pointes also occurred when high doses (3 mg/kg) of the long-acting methadone derivative, levomethadyl acetate HCl (LAAM), were given to a 41-year-old woman with a history of heroin dependence (49A ). She was also taking fluoxetine and intravenous cocaine, which can prolong the QT interval, and fluoxetine and marijuana, which inhibit the activity of CYP3A4, which is responsible for the metabolism of LAAM and its active metabolite. Respiratory In ten stable methadone-maintained patients (50–120 mg/day) and nine healthy subjects assessed using polysomnography, the methadone-maintained patients had more abnormalities of sleep architecture, with a higher prevalence of central sleep apnea (50C ). Methadone depresses respiration, probably by acting on the mu receptors in the ventral surface of the medulla and possibly on other receptor sites in the lung and spinal cord. All patients taking methadone also used benzodiazepines and cannabis, which may have influenced the above findings.

96 Nervous system Spastic paraparesis has been attributed to methadone (51A ). • A 43-year-old patient taking methadone for pain secondary to a squamous cell carcinoma of the larynx, which progressed despite surgery and radiation therapy, developed reversible spastic paraparesis with prominent extensor spasms in the legs while receiving an infusion of high-dose intravenous methadone 100 mg/h. On the second day, after 5 hours on 100 mg/h, he noted weakness in both legs, uncontrollable trembling, bilateral tinnitus, and generalized anxiety. Dexamethasone 6 mg intravenously every 6 hours was started and the methadone was reduced to 60 mg/h. Dexamethasone was withdrawn when an MRI scan confirmed the absence of metastases in the thoracic and cervical spinal cord. Because of persistent spastic paraparesis, methadone was switched to levorphenol 40 mg/h intravenously, and there was complete resolution of symptoms 24 hours later.

Neuromuscular Methadone can cause movement disorders characterized by tremor, choreiform movements, and a gait abnormality (52A ). • A 41-year-old woman with a 15-year history of chronic neuropathic pain was given methadone 5 mg tds and then qds. One month after the final increase she had bilateral tremor spreading from her arm up to her neck, followed by choreiform movements of the torso, a broad-based gait, and staccato-like speech. She was switched from methadone to modified-release oxycodone 60 mg/day, with complete resolution after 3 weeks.

Psychological In a randomized, double-blind, crossover study of 20 patients on a stable methadone regimen, a single dose of methadone caused episodic memory deficits (53C ). This was significant in patients with a history of diamorphine use averaging more than 10 years duration. Such deficits can be avoided by giving methadone in divided doses. Risk factors From a literature search and subsequent analysis of data on the relation between methadone prescribing and mortality, it was concluded that (54M ): • 69% of deaths attributed to methadone occurred in subjects who had not previously received methadone; • 51% of deaths attributed to methadone occurred during the dose-stabilizing period of methadone maintenance treatment;

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• the dose of illicit methadone exceeded that prescribed for methadone maintenance therapy; • deaths were attributed to discharge from prison and immediate intravenous injection of methadone in people who had lost their tolerance to high doses of methadone when incarcerated. Subsequent advice related to the above identifiable risk factors included: • restriction of take-home prescriptions with daily supervised consumption of methadone in pharmacy premises; • meticulous evaluation of substance abuse history; • slowing down of increases and tolerance testing during the stabilization period of methadone maintenance; • enhanced psychosocial assistance during the first months out of prison; • use of naloxone as an adjunct to methadone syrup. Drug interactions Methadone is predominantly metabolized by CYP3A4. Antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (e.g. efavirenz, abacavir, and nevirapine) and/or a protease inhibitor (e.g. amprenavir) will induce the metabolism of methadone. This therapeutic combination is becoming increasingly common in HIV-positive substance misusers. Two studies have explicitly shown a significant reduction of methadone concentration in 28–87%. In the first study, 11 patients taking methadone maintenance therapy were given efavirenz and had a mean increase in methadone dosage requirement of 22% (55c ). In the second study five methadonemaintained opioid-dependent individuals were given a combination of abacavir and amprenavir; the methadone concentration fell to 35% of the original concentration within 14 days (56c ). In a prospective study of 54 patients taking antiretroviral drugs who also took methadone and a further 154 patients who did not take methadone there were similar clinical, virological, and immunological outcomes after 12 months (57C ). These results support the usefulness of methadone in the management of intravenous drug users with HIV infection.

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Morphine

(SED-14, 215; SEDA-23, 103; SEDA-24, 107; SEDA-25, 115) Morphine is the benchmark “step 3” opioid analgesic based on the WHO’s concept of an analgesic ladder (58S ). Revised recommendations for the use of morphine in cancer pain have been published by the European Association for Palliative Care’s Expert Working Group on Opioid Analgesics (59M ). In summary, oral morphine is still the opioid of first choice for moderate to severe cancer pain, every 4 hours for normal-release morphine and 12- or 24-hourly for modified-release morphine. If patients are not able to take morphine orally the preferred alternative is subcutaneous infusion, especially in patients who require continuous parenteral morphine. A small proportion of patients develop intolerable adverse effects with oral morphine, and a change to an alternative opioid (e.g. hydromorphone, oxycodone, methadone, transdermal fentanyl) or a change in the rate of administration should be considered. If despite optimal use of systemic opioids and non-opioids a patient still has intolerable adverse effects or inadequate analgesia, spinal (epidural or intrathecal) administration of an opioid analgesic in combination with a local anesthetic or clonidine should be considered. In a 7-year, retrospective, multicenter, observational study, 95 children aged 1–19 years with cancer pain and treated with long-acting morphine were investigated for adverse effects and age-dependent analgesic effects (60C ). The adverse effects most frequently reported were constipation (10 patients at the beginning of treatment, 20 patients during the course of therapy, and three patients at the end of data collection), followed by vomiting (five, eight, and two patients) and nausea (two, six, and three patients), especially in children aged 7 years or more. Some of the children repeatedly complained of pruritus (five, eleven, and two patients). There were no cases of respiratory depression. Oral long-acting morphine proved to be safe and effective, even in very young patients with a history of malignancy. There have been another two studies of the analgesic effect of intrathecal morphine in children (61C , 62C ). In a prospective, double-blind study, 30 children (aged 9–19 years) scheduled for spinal fusion were randomly allocated

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to a single dose of saline or intrathecal morphine 2 or 5 µg/kg; after surgery, a PCA device provided access to additional intravenous morphine (61C ). The doses of 2 µg/kg and 5 µg/kg had similar analgesic effectiveness and adverse effects profiles (nausea, vomiting, pruritus). There were no episodes of severe respiratory depression. Low-dose intrathecal morphine supplemented with PCA morphine provides better analgesia than PCA morphine alone. In a smaller prospective, open, uncontrolled study, 12 children (3–6 years of age) were given either intermittent intrathecal morphine 5 µg/kg qds or a continuous infusion of a mixture of bupivacaine (40 µg/kg/h) and morphine (0.6 µg/kg/h) for intense postoperative pain after selective dorsal rhizotomy (62C ). The bupivacaine/morphine mixture provided better analgesia with fewer adverse effects. The incidence of pruritus was 83% with morphine compared with 33% with bupivacaine/morphine. Otherwise the adverse effects were similar. Two retrospective reviews looked at the effect of using intrathecal morphine (63C ) or intrathecal hydromorphone (42C ) in the management of chronic non-malignant pain. Eightyeight patients were originally evaluated followed by 67 patients 6 months later (63C ). At the time of follow-up mean pain relief was 60%, and 74% of respondents reporting increased activity. There were frequent reports of opioid adverse effects, including sexual dysfunction and menstrual disturbances. The reported adverse effects in descending order of frequency were: excessive sweating (62%), weight gain (52%), difficulty in concentrating, thinking, and memory (48%), nausea and vomiting (42%), arthralgia (25%), peripheral edema (25%), and pruritus (21%). Despite these adverse effects, most of the patients expressed satisfaction with intrathecal opioid therapy. The results were limited owing to the retrospective nature of the study, differing rates of response to specific questions, and the lack of objective measures. Pregnancy In a double blind, randomized, controlled study of analgesia in labor, the addition of morphine 150 µg to an intrathecal combination of fentanyl (25 µg) and bupivacaine (2.5 mg) significantly prolonged analgesia to more than 4 hours without increasing opioidrelated adverse effects (64C ).

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Managing the adverse effects of morphine The strategies used in managing the adverse effects of oral morphine have been reassessed in another special article compiled by the Expert Working Group of the European Association of Palliative Care Network (65M ). Factors that predict opioid adverse effects include: • Drug-related factors: there is little evidence suggesting that any one opioid agonist has a substantially better adverse effects profile than any other. • Route-related factors: there is limited evidence to suggest differences in adverse effects associated with specific routes of systemic administration. • Patient-related factors: there is evidence to suggest that there is inter-individual variability in sensitivity to opioid-related adverse effects; the variables include genetic susceptibility, the presence of co-morbidity, and age. • Dose-related factors: a dose-response relation is most evident with the CNS adverse effects of sedation, cognitive impairment, hallucinations, myoclonus, and respiratory depression, although there is still inter-individual variability in dose responsiveness to these effects; nausea and vomiting are common at the start of therapy but are then unpredictable. • Starting doses and escalation: the adverse effects of morphine, especially cognitive impairment, occur transiently and abate spontaneously; there are no reports of a relation between the starting dose of morphine or dose escalation and the occurrence of nausea, vomiting, or delirium. • Drug interactions: adverse effects of concurrent medications may be synergistic or cumulative with those associated with opioids. The reviewers also stressed the importance of differentiating opioid-related adverse effects from other causes of co-morbidity that might mimic opioid-induced adverse effects. Examples include cerebral metastases, stroke, metabolic changes, septicemia, bowel obstruction, and iatrogenic factors (other drugs or radiotherapy).

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Four different approaches to the management of opioid adverse effects were described in the review: 1. Dosage reduction. A reduction in the dosage of the systemic opioid is usually enough to relieve adverse effects. If dosage reduction is accompanied by loss of pain control, a non-opioid analgesic (e.g. an NSAID) can be added. Specific therapy, such as radiotherapy, chemotherapy, or surgery, that targets the cause of the pain can be helpful, as can a regional anesthetic or neuroablative intervention (e.g. celiac plexus blockade in patients with pancreatic cancer). 2. Symptomatic management of the adverse effects. 3. Opioid rotation. 4. Switching the route of administration. The reviewers also examined the symptomatic management of specific adverse effects and commented that most approaches are based on cumulative anecdotal evidence and that there have been few prospective evaluations of the efficacy and toxicity of these approaches over a long period of use. Polypharmacy adds to the burden of adverse effects and drug interactions. The authors of two related double-blind, randomized, placebo-controlled studies of the use of dexamethasone prophylaxis for nausea and vomiting after epidural morphine for post-cesarean or post-hysterectomy analgesia concluded that 5 mg of dexamethasone is an effective dose (66C , 67C ). Meanwhile, ADL 8-2698, a trans-3,4-dimethyl-4-piperidine that is a novel opioid antagonist, produced improved gastrointestinal transit time (peripherally mediated opioid activity) without affecting centrally mediated opioid analgesia (68C ). This contrasts with naloxone or nalmefene, which tend to antagonize central opioid effects, resulting in withdrawal symptoms in up to 50% of patients when used to treat constipation. Gabapentin has been used to treat morphineinduced myoclonus in a 54-year-old patient with gall bladder cancer (69A ). Effective pain control was maintained with morphine 300 mg, but after 24 hours the patient developed generalized muscular movements while asleep. Gabapentin 300 mg bd produced complete resolution of symptoms after 12 hours. In another

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case gabapentin 600 mg/day was used to treat a 1-month history of spontaneous jerking of both wrists after an increase in the dose of morphine to 120 mg/day; the myoclonus disappeared over the next 24 hours (69A ).

Oxycodone

(SED-14, 216; SEDA-23, 104; SEDA-24, 107; SEDA-25, 116) A double-blind, randomized, crossover comparison of modified-release or immediate-release oxycodone has been carried out in 30 patients with cancer pain (70C ). There were no significant differences between the two groups with respect to pain intensity or acceptability of therapy. More than 80% of the patients did not require rescue medication. Adverse effects were similar with the two formulations and occurred in relatively low numbers compared with previous morphine studies. The greatest difference in adverse effects was in the incidence of vomiting, which occurred in 6% of those given immediate-release morphine, and none of those given modified-release morphine. The modified-release formulation provided equal analgesia with the benefit of less frequent dosing.

Pethidine (meperidine)

(SED-14, 217; SEDA-24, 107; SEDA-25, 117) In a double-blind, randomized, controlled study, 17 patients undergoing gastrectomy were given epidural PCA pethidine (10 mg bolus and a 4-hourly maximum dose of 3 mg/kg) and were compared with 20 post-gastrectomy patients who were given the same regimen intravenously (71C ). The mean pethidine consumption in the first 24 hours was 33% less in the epidural group than in the intravenous group. Pain scores, adverse effects profiles, patient satisfaction, and patient outcome were similar. However, the sample size was small, and even though the study was intended to be double-blind, the route of pethidine administration and the patient’s perception of an intravenous and epidural injection might have caused bias.

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Drug abuse The interaction between the drug-dependent patient and health professional has been investigated in a retrospective study of the medical records of 20 patients with chronic organic pain and perceived as being dependent on pethidine (72C ). The fact that the patients were perceived as being addicted may have influenced the adequate management of their chronic intractable pain, precipitated poor staff–patient relationships, created a lower pain threshold or tolerance due to anxiety and depression, and led to overuse of placebo, leading to inadequate analgesia. All of these factors may then have led to craving-like behavior and demands for more analgesics, further fuelling the negative stereotyped perception of the addicted personality. The authors suggested that people with dependence-related problems should be evaluated for suicidal intent; concurrent psychiatric illnesses should be treated; and precipitating factors that make pain worse should be identified. Medical and other staff should be educated about the use of opiate analgesics and concepts of dependence, in order to reduce negative judgmental attitudes and misconceptions. Drug overdose Cardiac arrest occurred after pethidine overdose (73A ). • Cardiac arrest occurred in a 2-month-old boy when he was given a combination of pethidine, promethazine, and chlorpromazine in 10 times the recommended dose by the wrong route (intravenously rather than intramuscularly). Within seconds he became apneic and stiff. Cardiopulmonary resuscitation was instituted, including two intravenous doses of adrenaline 0.06 mg and naloxone 0.6 mg, with recovery 7 minutes after the incident and complete resolution 24 hours later.

Remifentanil

(SED-14, 217; SEDA-23, 105; SEDA-24, 108; SEDA-25, 118) Remifentanil is a relatively pure mu receptor opioid agonist with conventional pharmacodynamic properties. Seven randomized controlled trials and one descriptive trial using infused remifentanil as part of an anesthetic technique in children between 1997 and 2000 have been reviewed (74M ). The general consensus is that a bolus dose of remifentanil 0.5–1 µg/kg appears to be well tolerated when it is given over

100 at least 60 seconds. However, a loading dose is not required if the infusion can be started at least 10 minutes before the skin incision is made. Infusion rates of 0.25–0.5 µg/kg/min provide hemodynamic stability when propofol or a volatile agent is also given. The authors advised that infants who receive remifentanil should be paralysed and mechanically ventilated, because of the possible risk of respiratory depression due to chest wall rigidity in non-paralysed patients. Remifentanil is liable to cause respiratory depression in children (74M , 75c ), as well as muscle rigidity, hypotension and bradycardia, without increasing the incidence of gastrointestinal symptoms (76c ). The adverse effects profiles of remifentanil in neonates and infants undergoing pyloromyotomy have been investigated (77C , 78C ). The hemodynamic responses, recovery profiles, and perioperative and postoperative respiratory patterns in 38 children given remifentanil plus nitrous oxide and 22 given halothane plus nitrous oxide have been studied in a multicenter, open, randomized comparison. There were no cases of bradycardia or dysrhythmias. There were hypertensive responses at the time of incision in 24% of those given remifentanil and 18% of those given halothane and vomiting in 34% and 45% respectively. None of those who were given remifentanil developed newonset postoperative apnea compared with three of those who were given halothane. All other adverse effects had similar incidences in the two groups. Remifentanil 0.1 µg/kg/min by infusion was safe and efficacious in 55 patients (aged 2 months to 12 years) undergoing cardiac catheterization (79C ). In a double-blind, randomized, placebocontrolled study in 28 adults undergoing carotid endarterectomy, remifentanil provided adequate analgesia, and supplementary local anesthetics were not needed (80C ). The remifentanil infusion rate was as low as 0.04 µg/kg/min and there were no episodes of respiratory depression or hemodynamic instability. Intravenous remifentanil 0.3 µg/kg with propofol 2 µg/ml has been compared with propofol 2 µg/ml alone in a double-blind, randomized study in 86 day-case adults undergoing elective orthopedic surgery (81C ). The study was designed to assess whether remifentanil improves conditions for laryngeal mask

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airway insertion. Those given remifentanil had a better quality of airway patency, with minimal cardiorespiratory changes. Remifentanil by infusion (n = 49) has been compared with titrated boluses of pethidine (n = 51) in a randomized, double-blind study in 100 patients undergoing out-patient colonoscopy (82C ). The incidences of tachycardia, hypotension, and nausea were significantly less with remifentanil than with pethidine, but there were higher anxiety and pain scores with remifentanil. However, the study was a comparison of two opioids with different pharmacokinetic profiles, which makes it very difficult to achieve equipotent doses for the purpose of comparison. Remifentanil by infusion has been compared with another opioid, fentanyl, in two studies (83C , 84C ). In a prospective multicenter, double-blind, randomized study in 297 patients undergoing elective coronary artery bypass surgery, remifentanil infusion 1 µg/kg/min was compared with a loading dose of fentanyl 15 µg/kg. The most common adverse effects were nausea and vomiting, which occurred equally often in the two groups. Hypertension and shivering were significantly more common with remifentanil (83C ). In a smaller randomized study, remifentanil 0.5 µg/kg/min was compared with fentanyl 2 µg/kg in 22 patients undergoing rigid bronchoscopy (84C ). The results suggested that remifentanil attenuated the hemodynamic response to bronchoscopy without significantly increasing the incidences of hypotension or bradycardia. Four patients given remifentanil developed ST segment depression compared with eight patients given fentanyl. Mixtures of remifentanil and sevoflurane have been used in two prospective, open, randomized studies (85C , 86C ), which showed that adding remifentanil results in a reduced requirement for sevoflurane for maintenance of anesthesia, leading to faster and easier recovery. Remifentanil has been successfully combined with general anesthetics, as shown in the above studies, but there are few experimental demonstrations of its analgesic properties. Three studies have now focused on the analgesic use of remifentanil (87C –89C ). In a double-blind, crossover, randomized study 20 healthy volunteers received an infusion of either remifentanil or saline (87C ). Thermal sensory

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testing of the heat pain threshold was performed every 5 minutes and the dose of remifentanil was increased by 0.01 µg/kg/minute every 5 minutes. Remifentanil produced a dosedependent increase in the heat pain threshold, and a dose of 0.05 µg/kg/min was suggested as an effective and safe increment in healthy volunteers. The rate of adverse effects (nausea, vomiting, and pruritus) was comparable with previous reports; there were no cardiovascular adverse effects. The postoperative analgesic efficacy and safety of two continuous constant-dose intravenous remifentanil infusions have been investigated in a double-blind, randomized study in 30 patients scheduled to undergo elective abdominal or thoracic surgery (89C ). The patients were randomly assigned to intravenous remifentanil 0.05 µg/kg/min or 0.1 µg/kg/min. There were no cases of respiratory depression, and nausea and vomiting occurred in one patient in each group. There was adequate analgesia in 75% and 78% of the patients in the low-dose and high-dose groups respectively and pethidine rescue analgesia was required in 26% and 6% respectively. Remifentanil 0.1 µg/kg/min was therefore effective and safe for postoperative pain. Further studies are needed to determine the role of remifentanil infusion for severe postoperative pain. Cardiovascular Asystole has been attributed to remifentanil (90A ). • A 78-year-old man with laryngeal cancer developed asystole 1 minute after an intravenous bolus of remifentanil 0.5 µg/kg followed by a continuous infusion of 0.5 µg/kg/h. The asystole was unresponsive to intravenous atropine 1 mg. The remifentanil infusion was stopped and cardiac sinus rhythm resumed after two precordial thumps.

The authors postulated that rapid-sequence induction of anesthesia with sevoflurane had blunted sympathetic tone and allowed uncompensated parasympathetic activation by remifentanil. Nervous system Seizures have been attributed to remifentanil (91A ). • A 42-year-old woman asked for an intravenous opioid as analgesia during paracervical block and was given an intravenous infusion of remifentanil

1.0 µg/kg/min. After 3 minutes she became unresponsive, with upward deviation of gaze and tonic– clonic contractions of the arms. The infusion was discontinued and after another 3 minutes of generalized seizure activity she was given intravenous propofol 80 mg and intravenous succinylcholine 60 mg; she recovered completely 15 minutes later.

Pregnancy Six patients admitted at 36 weeks pregnancy with pre-eclampsia received patientcontrolled intravenous analgesia with remifentanil for labor (88C ). Remifentanil was delivered as continuous background infusion of 0.05 µg/kg/min and 25 µg boluses with a 5-minute lockout period. The procedure did not cause maternal or neonatal adverse effects and this small uncontrolled study suggests that patient-controlled intravenous analgesia with remifentanil might be an effective alternative when epidural analgesia is contraindicated.

Sufentanil

(SED-14, 217; SEDA-23, 105; SEDA-24, 109; SEDA-25, 118)

Sufentanil 1 µg/ml plus 0.1% ropivacaine by epidural infusion has been compared with intravenous patient-controlled analgesia with piritramide in a double-blind, randomized study in 24 patients undergoing elective total hip replacement (92C ). The PCA group had significantly more adverse effects than the epidural group, including hypotension, nausea, and vomiting. There were no cases of respiratory depression, pruritus, hypertension, or dysrhythmias in either group. Epidural sufentanil was a better analgesic. The analgesic efficacy of intrathecal sufentanil with or without lidocaine has been examined in two groups of out-patients undergoing lithotripsy or gynecological laparoscopy in order to determine optimal analgesia with rapid recovery and discharge (93C , 94C ). In a retrospective case-record study of 62 shock-wave lithotripsy procedures, the 25 cases performed using intrathecal sufentanil alone had better outcomes, significantly shorter post-anesthesia care unit time, and time for ambulation compared with 37 procedures performed with intrathecal lidocaine; pruritus was significantly more common with sufentanil (93C ).

102 A double-blind, randomized study in 13 patients undergoing gynecological laparoscopy, who received either lidocaine 10 mg with sufentanil 10 µg or intrathecal sufentanil 20 µg, was terminated early owing to unacceptably frequent adverse effects and inferior analgesia in those given intrathecal sufentanil (94C ). In a double-blind, randomized, placebocontrolled study in 80 patients of the analgesic efficacy of different subarachnoid applications of sufentanil and/or bupivacaine using a microcatheter for easy postoperative pain relief, sufentanil 10 µg, bupivacaine 5 mg, or a combination of sufentanil 2.5 µg and bupivacaine 2.5 mg provided immediate and adequate postoperative analgesia for 2–3 hours (95C ). The group who received only sufentanil had the highest incidence of pruritus and respiratory depression. The limitations of this study were highlighted in a letter, which questioned the value of the above procedure when other tried and tested perioperative pain management methods are available (96r ). Pregnancy In a double-blind, randomized study the analgesic efficacy of sufentanil 0.25 µg/ml with 0.125% bupivacaine was compared with fentanyl 2 µg/ml with 0.125% bupivacaine in 226 patients in labor with a patient-controlled epidural analgesic device (97C ). Overall analgesia was good, with no observed difference between the two groups. There was a significant difference in the occurrence of mild pruritus, with 10 cases in the fentanyl group (n = 105) and only two in the sufentanil group (n = 101). There were no gastrointestinal adverse effects. Sufentanil was deemed preferable owing to a lower incidence of adverse effects for equal analgesic potency. An epidural mixture of sufentanil with ropivacaine has been used in a double-blind, randomized study in 100 women in the first stage of labor (98C ). They were randomized to receive 0.2% ropivacaine 12 mg either alone or with sufentanil 5 µg, 10 µg, or 15 µg. With combined sufentanil plus ropivacaine the duration of analgesia was about 40 minutes longer than with ropivacaine alone. There were no differences in analgesic efficacy or the incidence of opioid-related adverse effects in the three sufentanil groups. Sufentanil 5 µg plus ropivacaine 0.2% was therefore recommended.

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Tramadol

(SED-14, 218; SEDA-23, 107; SEDA-24, 109; SEDA-25, 119)

The postoperative analgesic efficacy of tramadol 2 mg/kg has been studied in 80 children (aged 1–3 years) undergoing day-case adenoidectomy without premedication in a doubleblind, randomized, placebo-controlled study (99C ). General anesthesia was induced with intravenous alfentanil 10 µg/kg plus lidocaine followed by propofol and mivacurium. The children received intravenous tramadol 2 mg/kg or placebo immediately after induction of anesthesia. Those given tramadol required fewer pethidine rescue medication doses than those given placebo. In fact, 45% of the children who were given tramadol did not require postoperative analgesia at all, compared with 15% of the children who were given placebo. The incidences of adverse effects were similar in the two groups. The use or addition of tramadol in children undergoing lower abdominal surgery has been examined in three studies (100C –102C ). In a double-blind, randomized, controlled study, 125 children undergoing inguinal herniorrhaphy were allocated to receive tramadol 2 mg/kg or morphine sulfate 0.03 mg/kg before surgery; the control group received morphine sulfate 0.03 mg/kg at the end of surgery (100C ). Caudal tramadol 2 mg/kg provided reliable postoperative analgesia and there were no inter-group differences in postoperative adverse effects or quality and duration of pain relief. In a randomized, controlled study in 60 boys (aged 1–7 years) undergoing unilateral herniorrhaphy, caudal 0.25% bupivacaine 1 mg/kg plus tramadol 1.5 mg/kg resulted in superior analgesia (quality and duration) with no significant increase in opioid-related adverse effects compared with children who received 0.25% bupivacaine 1 mg/kg alone or caudal tramadol 1.5 mg/kg in 0.9% saline alone (101C ). Thirty children (1–5 years old) in an open, controlled study were randomly given caudal block with 0.25% bupivacaine 0.8 mg/kg or tramadol 0.8 or 2 mg/kg (102C ). The duration of analgesia was longer (9.1 hours) in those given tramadol but the incidences of opioidrelated adverse effects (gastrointestinal effects and sweating) were significantly higher. In a double-blind, randomized study in 120 patients scheduled to undergo out-patient hand

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surgery with intravenous regional anesthesia, tramadol 100 mg was compared with either metamizol 1 g or paracetamol 1 g, all 6-hourly (103C ). Seven patients given tramadol withdrew because of severe nausea and dizziness. Tramadol was the most effective analgesic, but none of the drugs alone provided effective analgesia in all patients and 40% needed rescue analgesia. In another double-blind study 150 patients with post-traumatic musculoskeletal pain were allocated to either tramadol 100 mg, with possible increases to a total of 200 mg, or morphine 5 mg or 10 mg with a total increase to 20 mg (104C ). Analgesic efficacy and adverse effect profiles were similar in the two groups. Tramadol has been compared with a paracetamol derivative in a double-blind, randomized, controlled study in 80 patients undergoing elective thyroidectomy (105C ). They were randomly assigned to propacetamol (an injectable prodrug of paracetamol) 2 g or intravenous tramadol 1.5 mg/kg. A single dose of tramadol provided better analgesia than propacetamol during the first 6 hours after surgery, but failed to ensure optimal analgesia subsequently. The incidences of nausea, vomiting, and sedation were comparable in the two groups. Tramadol and non-steroidal anti-inflammatory drugs have been compared in two studies of patients with joint pain associated with osteoarthritis (106C , 107C ). In an open, randomized study 60 patients with osteoarthritis taking NSAIDs were given either modified-release tramadol 100 mg 8-hourly or modified-release dihydrocodeine 60 mg 8-hourly for 4 days; the controls were 30 patients who took an NSAID alone (106C ). Both opioids provided adequate analgesic adjuncts to NSAIDs, but tramadol caused significantly more minor initial adverse effects. In a similar study of 129 patients with severe joint pain associated with osteoarthritis tramadol was significantly more effective than placebo, but 26 patients taking tramadol and 43 taking placebo withdrew because of ineffectiveness or adverse effects; the main adverse effects of tramadol were nausea and constipation (107C ). In a 4-week, double-blind, multicenter, randomized study tramadol plus paracetamol (37.5 mg/325 mg) was as effective as codeine plus paracetamol (co-codamol 30 mg/300 mg)

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in chronic non-malignant low back pain and osteoarthritis pain, with acceptable tolerability (108C ). The use of modified-release tramadol in chronic malignant pain has been examined in an open, prospective study in 146 patients with moderate to severe cancer pain; 90 patients completed the 6-week trial (109C ). Drop outs were due to opioid adverse effects (20%), inadequate pain relief (9%), or both (2.5%). There was at least one adverse effect in 86%. Overall, 433 adverse effect events were reported but some reduced in frequency over the 6 weeks. Modified-release tramadol (400 mg/day) provided fast and efficient pain relief in almost 60% of patients both during initial dosing and long-term treatment. Drug dependence Seizures followed by opioid withdrawal symptoms have been reported in a patient taking tramadol (110A ). • A 29-year-old woman took tramadol 50 mg 6-hourly for pain associated with the carpal tunnel syndrome. She slowly increased the dose of tramadol and obtained it from several physicians and different hospitals, so that after 3 years she was taking 30 tramadol 50 mg tablets daily. She had two generalized seizures and stopped taking tramadol; 1 day later she developed severe opioid withdrawal symptoms, including diarrhea, headache, insomnia, and blurred vision. She was detoxified with tapering doses of tramadol and discharged after 6 days.

Drug overdose A 26-year-old male nurse died of tramadol intoxication (111A ). The peripheral blood concentration of tramadol was 9.6 mg/l (target concentration 0.1–0.3 mg/l). There was no objective evidence at post mortem of any pre-existing disease or use/overuse of ethanol or other drugs that could have contributed to or caused death. Drug interactions Tramadol dosage requirements for patient-controlled analgesia increased when ondansetron was given as a prophylactic antiemetic in 40 patients undergoing lumbar laminectomy in an open, controlled study (112C ). During the first 4 hours postoperatively tramadol consumption increased by about 30% in those given ondansetron and remained 22–25% higher thereafter. A single dose of ondansetron 4 mg given during induction did not reduce the 24-hour incidence of nausea or vomiting.

104 Serotonin syndrome and mania occurred in a 72-year-old woman taking fluoxetine 20 mg/day and tramadol 150 mg/day 18 days after she started to take the combination (113A ). Inhibition of CYP2D6 may have played a part (114M ).

PARTIAL OPIOID AGONISTS Buprenorphine

(SED-14, 220; SEDA-23, 108; SEDA-24, 110; SEDA-25, 120)

The use of buprenorphine to treat opioiddependent individuals has been the subject of several studies. In a double-blind randomized comparison of sublingual buprenorphine tablets with oral methadone in a 6-week trial in 58 patients using a flexible dosing procedure the retention rate was significantly better in those using methadone (90 vs. 50%) (115C ). Those who completed the study had a similar number of opioid-positive urine samples, with a mean stabilization dose of 11 mg/day of buprenorphine and 70 mg/day of methadone. This study had several limitations: 6 weeks is too short a period to determine any intermediate or long-term treatment outcomes, the sample size was too small, and the comparison of nonequivalent doses makes interpretation difficult. In another study two doses (8 mg and 16 mg) of sublingual buprenorphine were compared in a 6-week double-blind, placebo-controlled in-patient study of the reinforcing effects of intravenous diamorphine (116C ). Only eight diamorphine-dependent men were recruited and the authors could only postulate that doses over 16 mg might be more effective in blocking the reinforcing effects of diamorphine. Liver Intravenous buprenorphine abuse precipitated acute on chronic hepatitis in a 25-yearold woman who was hepatitis C positive with a history of chronic diamorphine dependence (117A ). Four former opiate-dependent individuals with confirmed hepatitis C virus were given substitution therapy with sublingual buprenorphine. After injecting buprenorphine together with their sublingual doses, they had a marked increase in serum AsT activity (13–50 times

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the upper limit of the reference range), resulting in jaundice (118A ). Another patient who was hepatitis C and HIV positive developed jaundice with panlobular liver necrosis and microvesicular steatosis after using sublingual buprenorphine and small doses of paracetamol and aspirin (118A ). Death Two series of 39 and 78 deaths attributed to buprenorphine have been reported in Strasbourg and 13 other French forensic centers respectively between 1996 and 2000 (119M ). The risks incurred by the misuse of buprenorphine seem to arise through a combination of (a) the concomitant use of other psychotropic drugs (especially benzodiazepines and neuroleptic drugs) and (b) the improper use of tablets for intravenous administration and/or massive oral doses. The total recorded number of buprenorphine-related deaths is largely underestimated, because the very low concentrations require sensitive immunoassay techniques, making them difficult to detect; furthermore different cut-off points are used by different forensic pathology laboratories in diagnosing drug-related deaths.

Nalbuphine

(SED-14, 222; SEDA-24, 100; SEDA-25, 120) Intravenous nalbuphine 3 mg (n = 101) has been compared with intravenous propofol 20 mg (n = 90) in a double-blind, randomized study, to determine efficacy in the treatment of intrathecal morphine-induced pruritus after cesarean delivery 10 minutes after the drug was administered (120C ). Nalbuphine was significantly more effective, especially in cases of moderate but not severe pruritus. Adverse effects such as reduced analgesia and increased nausea, vomiting, sedation, and dizziness were not significantly different between the two groups. Drug abuse A 53-year-old man with no past psychiatric history was found by the police walking aimlessly, unclothed, and responding to auditory hallucinations (121A ). He had slurred speech and generalized tremors. Lumbar puncture, a CT head scan, and urine drug

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screen were all normal. He responded to risperidone 1 mg bd with dramatic improvement after 2 days. He reported chronic use of nalbuphine, with recent increased use.

OPIATE ANTAGONISTS Nalmefene

(SED-14, 219; SEDA-23, 109; SEDA-24, 110; SEDA-25, 121) The efficacy and safety of intravenous nalmefene 0.1 mg/ml has been studied in an open trial in 115 children given fentanyl (122C ). An initial dose of 0.25 µg/kg (maximum 10 µg) was infused over 15 seconds, and another dose of 0.25 µg/kg (maximum 10 µg) was given if there was no response after 1.75 minutes. Further doses were given every 2 minutes until a response occurred or a maximum dose of 1 µg/kg (maximum 40 µg) was reached. Nalmefene was effective and safe, especially in a mean dose of 0.55 µg/kg; the median number of doses was two. The limitations of this study included the small study sample and the use of a short-acting opioid, fentanyl, so that re-sedation was unlikely even without the use of an antagonist.

Naloxone

(SED-13, 179; SEDA-18, 86;

SEDA-21, 92) The use of naloxone has been studied in an open study in 43 patients having combined thoracic epidural and general anesthesia for subtotal gastrectomy, who were randomly assigned to receive a bolus dose of epidural morphine 3 mg followed by a continuous infusion of 3 mg in 0.125% bupivacaine 100 mg with either no naloxone (n = 18) or naloxone 0.208 µg/kg/hour (n = 25) for 48 hours (123C ). The time to the first postoperative passage of flatus and feces (indicating restoration of bowel function) and pain intensity (using a visual analogue scale) were assessed. The results suggested that naloxone 0.208 µg/kg/hour adequately reverses hypomotility induced by epidural morphine. The preliminary results of two pilot schemes to provide take-home naloxone to opiate users have suggested that this provision may save

105

lives (124C ). This observation needs corroboration by a prospective case-control study of adequate sample size and response rate, with the ability to collate objective data robust enough for analysis (125r ).

Naltrexone

(SED-14, 200; SEDA-23, 100; SEDA-24, 111; SEDA-25, 121) A systematic review and meta-analysis of seven double-blind, randomized, placebo-controlled out-patient studies of naltrexone used in the treatment of alcohol dependence between 1976 and 2001 has shown that naltrexone was no more toxic than placebo and was not associated with a significantly greater number of withdrawals because of adverse effects (126M ). Naltrexone was more effective than placebo in reducing relapses to heavy drinking and improving alcohol abstinence in the short term, considering that the studies lasted for only 12 weeks. Additional long-term follow-up studies, with the possibility of studying outcomes of naltrexone treatment programs after stopping the drug and with suitable comparison groups, are necessary. Similar results with similar conclusions were seen in a 12-week randomized controlled trial in 55 alcohol-dependent men treated with naltrexone 50 mg or placebo (127C ). In an open, single-blind randomized study naltrexone (50 mg/day) and acamprosate (1665– 1998 mg/day) were used for 1 year by 157 recently detoxified alcohol-dependent men with moderate dependence (128C ). The time to first relapse was 63 days (naltrexone) and 42 days (acamprosate); after 1 year 41% of those given naltrexone and 17% of those given acamprosate had not relapsed. Adverse effects were more common with naltrexone and were worse during the first 2 weeks of treatment. They included nausea (25% vs. 4%), abdominal pain (23% vs. 4%), drowsiness (35% vs. 2%), headache (13% vs. 6%), and nasal congestion (23% vs. 7%). To examine the relation between adverse effects profiles, study retention, and treatment outcomes in alcohol-dependent individuals receiving naltrexone for relapse prevention, 92 subjects had their adverse effects monitored weekly and categorized as either neuropsychiatric or gastrointestinal (129C ). The neuropsychiatric adverse effects had little effect on

106 medication compliance but reduced the length of study retention. In contrast, the gastrointestinal adverse effects significantly affected medication compliance but not study retention. Drug abuse Three opiate-dependent individuals abused intravenous naltrexone, believing it to be diamorphine, and developed acute opiate withdrawal symptoms; they were managed with a combined regimen of diazepam, prochlorperazine, and hyoscine (130A , 131A ).

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postoperative intravenous patient-controlled analgesia with morphine either alone or in combination with nefopam (20 mg 4-hourly) or propacetamol (2 g 6-hourly) (132C ). Nefopam plus morphine was the most effective treatment. Adverse effects, especially sedation, were comparable in the three groups, but there was significantly more nausea in the morphine group and more sweating in the nefopam group (requiring early drug withdrawal in three cases). Tachycardia was seen more often in the nefopam group but did not reach significance.

MISCELLANEOUS Nefopam In an open trial 120 patients undergoing elective hepatic resection were randomized to receive REFERENCES 1. Tailly GG, Marcelo JB, Schneider IA, Byttebier G, Daems K. Patient-controlled analgesia during SWL treatments. J Endourol 2001; 15: 465–71. 2. Ross J, Kearse LA, Barlow MK Jr, Houghton KJ, Cosgrove GR. Alfentanil-induced epileptiform activity. A simultaneous surface and electroencephalographic study in complex partial epilepsy. Epilepsia 2001; 42: 220–5. 3. Gallagher G, Rae CP, Watson S, Kinsella J. Target-controlled alfentanil analgesia for dressing change following extensive reconstructive surgery for trauma. J Pain Symptom Manage 2001; 21: 1–2. 4. Wilkinson SM, Becker WJ, Heine JA. Opiate use to control bowel motility may induce chronic daily headache in patients with migraine. Headache 2001; 41: 303–9. 5. Estrada JL, Alvarez Puebla MJ, Ortiz De Urbina JJ, Matilla B. Generalised eczema due to codeine. Contact Dermatitis 2001; 44: 185. 6. Rodriguez Arroyo LA, Ortiz de Saracho J, Pantoja Zarza L. Reaccion adversa cutanea tras administracion de codeina. Aten Prim 2001; 27: 444–6. 7. Elwood WN. Sticky business: Patterns of procurement and misuse of prescription cough syrup in Houston. J Psychoact Drugs 2001; 33: 121–33. 8. Helmy SAK, Bali A. The effect of the preemptive use of the NMDA receptor antagonist dextromethorphan on post-operative analgesic requirements. Anesth Analg 2001; 92: 739–44. 9. Weinbroum AA, Gorodezky A, Niv D, BenAbraham R, Rudick V, Szold A. Dextromethorphan attenuation of post-operative pain and primary and secondary thermal hyperalgesia. Can J Anaesth 2001; 48: 167–74. 10. Wadhura A, Clarke D, Goodchild CS, Young D. Large dose oral dextromethorphan as an adjunct

to patient-controlled analgesia with morphine after knee surgery. Anesth Analg 2001; 92: 448–54. 11. Generali J, Cada DJ. Dextromethorphan: neuropathy. Hosp Pharm 2001; 36: 421–5. 12. Nairn SJ, Diaz JE. Cold-syrup induced movement disorder. Pediatr Emerg Care 2001; 17: 191–2. 13. Einarson A, Lyszkiewicz D, Koren G. The safety of dextromethorphan in pregnancy: results of a controlled study. Chest 2001; 119: 466–9. 14. Vaughan DJA, Ahmed N, Lillywhite NK, Lewis N, Thomas D, Robinson PN. Choice of opioid for initiation of combined spinal epidural analgesia in labour—fentanyl or diamorphine. Br J Anaesth 2001; 86: 567–9. 15. Stacey RGW, Jones R, Kar G, Poon A. Highdose intrathecal diamorphine for analgesia after caesarian section. Anaesthesia 2001; 56: 54–60. 16. Haemmig RB, Tschacher W. Effects of high dose heroin versus morphine in intravenous drug users: a randomised double-blind cross over study. J Psychoact Drugs 2001; 33: 105–10. 17. Davies M, Crawford I. Nasal diamorphine for acute pain relief in children. Emerg Med J 2001; 18: 271. 18. Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. Br Med J 2001; 322: 261–5. 19. Koussa S, Tamraz J, Nasnas R. Leucoencephalopathy after heroin inhalation: a case with partial regression of MRI lesions. J Neuroradiol 2001; 28: 268–71. 20. Ischiyama A, Ishiyama G, Baloh RW, Evans CJ. Heroin-induced reversible profound deafness

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and vestibular dysfunction. Addiction 2001; 96: 1363–4. 21. Freye E, Boranowski J, Latasch L. Dose-related effects of controlled release dihydrocodeine on orocaecal transit and pupillary light reflex. A study in human volunteers. Arzheim-Forsch Drug Res 2001: 51: 60–6. 22. Varvel JR, Shafer SL, Hurang SS, Coen PA, Stanski DR. Absorption characteristics of transdermally administered fentanyl. Anesthesiology 1989; 70: 928–34. 23. Muijsers RBR, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs 2001; 61: 2289–307. 24. Nugent M, Davis C, Brooks D, Ahmedzai SH. Long-term observations of patients receiving transdermal fentanyl after a randomised trial. J Pain Symptom Manage 2001; 21: 385–91. 25. Ahmedzou S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy and quality of life. J Pain Symptom Manage 1997; 13: 254–61. 26. Radbruch L, Sabatowski R, Petzke F, BrunschRedbruch A, Grond S, Lehmann KA. Transdermal fentanyl for the management of cancer pain: a survey of 1005 patients. Palliative Med 2001; 15: 309–21. 27. Mystakidou K, Befon S, Kouskouni E, Gerolymatos K, Georgaki S, Tsiuka E, Vlanos L. From codeine to transdermal fentanyl for cancer pain control: a safety and efficacy clinical trial. Anticancer Res 2001; 21: 2225–30. 28. Allan L, Hays H, Jensen N-H, Le Polain De Waroux B, Bolt M, Donald R, Kalso E. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. Br Med J 2001; 322: 1154–8. 29. Newshan G, Lefkowitz M. Transdermal fentanyl for chronic pain in AIDS: a pilot study. J Pain Symptom Manage 2001; 21: 69–77. 30. Fanelli G, Cesati A, Magistris L, Berti M, Albertin A, Scarioni M, Torri G. Fentanyl does not improve the nerve block characteristics of axillary brachial plexus anaesthesia performed with ropivacaine. Acta Anaesthesiol Scand 2001; 45: 590–4. 31. Karakaya D, Buyukgoz F, Baris S, Guildogus F, Tur A. Addition of fentanyl to bupivacaine prolongs anaesthesia and analgesia in axillary brachial plexus block. Reg Anesth Pain Med 2001; 26: 434–8. 32. Ben-David B, De Meo PJ, Lucyk C, Solosko D. A comparison of minidose lidocaine-fentanyl spinal anaesthesia and local anaesthesia/propofol infusion for outpatient knee arthroscopy. Anesth Analg 2001; 93: 319–25. 33. Finucane BT, Ganapathy S, Carli F, Pridham JN, Ong BY, Shukla RC, Kristoffersson AHM, Huizak KM, Nevin K, Ashten KG. Canadian Ropivacaine Research Group. Prolonged epidural infusions of ropivacaine (2 mg/ml) after colonic surgery: the impact of adding fentanyl. Anesth Analg 2001; 92: 1276–85. 34. Niemi G, Brevik H. Epidural fentanyl markedly improves thoracic epidural analgesia in a low-dose

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infusion of bupivacaine, adrenaline and fentanyl: a randomised double-blind crossover study with and without fentanyl. Acta Anesthesiol Scand 2001; 45: 221–32. 35. Wigfull J, Welchew E. Survey of 1057 patients receiving post-operative patient-controlled epidural analgesia. Anaesthesia 2001; 56: 70–5. 36. Løvstad RZ, Støen R. Postoperative epidural analgesia in children after major orthopaedic surgery. A randomised study of the effect on PONV of two anaesthetic techniques: low and high dose i.v. fentanyl and epidural infusions with and without fentanyl. Acta Anaesthesiol Scand 2001; 45: 482–8. 37. Tweed WA, Dakin D. Explosive coughing after bolus fentanyl injection. Anesth Analg 2001; 92: 1442–3. 38. Das UG, Basidharan P. Bladder retention of urine as a result of continuous intravenous infusion of fentanyl: 2 case reports. Pediatrics 2001; 108: 1012–15. 39. Mancuso G, Berdondini RM, Passarini B. Eosinophilic pustular eruption associated with transdermal fentanyl. J Eur Acad Dermatol Venereol 2001; 15: 70–2. 40. Gardner-Nix J. Caregiver toxicity from transdermal fentanyl. J Pain Symptom Manage 2001; 21: 447–8. 41. Frälich M, Giannotti A, Modell JH. Opioid overdose in a patient using a fentanyl patch during treatment with a warming blanket. Anesth Analg 2001; 93: 647–8. 42. Yeh H-M, Chen L-K, Shyu M-K, Lin C-J, Sun W-Z, Wang M-J, Mok MS, Tsai S-K. The addition of morphine prolongs fentanyl–bupivacaine spinal analgesia for the relief of labour pain. Anesth Analg 2001; 92: 665–8. 43. Mercandante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari P, Gebbia V, Ripamonti C. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 2001; 19: 2898– 904. 44. Mironer YE, Tollison CD. Methadone in the intrathecal treatment of chronic nonmalignant pain resistant to other neuraxial agents: the first experience. Neuromodulation 2001; 4: 25–31. 45. Manfredi PL, Gonzales GR, Cheville AL, Kornick C, Payne R. Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy. J Pain Symptom Manage 2001; 21: 169–74. 46. Doverty M, Somogyl AA, White JM, Bochner F, Beare CH, Menelaou A, Ling W. Methadone maintenance patients are cross tolerant to the antinociceptive effects of morphine. Pain 2001; 93: 155–63. 47. Backmund M, Meyer K, Zwehl W, Nagengast O, Eichenlaub D. Myocardial infarction associated with methadone and/or dihydrocodeine. Eur Addict Res 2001; 7: 37–9. 48. Hays H, Woodroffe MA. High dosing methadone and a possible relationship to serious cardiac arrhythmias. Pain Res Manage 2001; 6: 64.

108 49. Deamer RL, Wilson DR, Clark DS, Prichard JG. Torsades de pointes associated with high dose levomethadyl acetate (ORLAAM). J Addict Dis 2001; 20: 7–14. 50. Teichtahl H, Prodromidis A, Miller B, Cherry G, Kronborg I. Sleep-disordered breathing in stable methadone programme patients: a pilot study. Addiction 2001; 96: 395–403. 51. Manfredi PL, Gonzales GR, Payne R. Reversible spastic paraparesis induced by high-dose intravenous methadone. J Pain 2001; 2: 77–9. 52. Clark JD, Elliott J. A case of a methadoneinduced movement disorder. Clin J Pain 2001; 17: 375–7. 53. Curran HV, Kleckham J, Bearn J, Strang J, Wanigaratne S. Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: a dose-response study. Psychopharmacology 2001; 154: 153–60. 54. Vormfelde SV, Poser W. Death attributed to methadone. Pharmacopsychiatry 2001; 34: 217–22. 55. Bart PA, Rizzardi PG, Gallant S, Golay KP, Baumann P, Pantaleo G, Eap CB. Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir. Ther Drug Monit 2001; 23: 553–5. 56. Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. The pharmacokinetics of methadone in HIV-positive patients receiving non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001; 51: 213–17. 57. Moreno A, Perez-Elias MJ, Casado JL, Munoz V, Antele A, Drondo F, Naves E, Moreno S. Longterm outcomes of protease inhibitor-based therapy in antiretrovival treatment-naïve HIV-infected injecting drug users on methadone maintenance programmes. AIDS 2001; 15: 1068–70. 58. World Heath Organization. Cancer Pain Relief. 2nd edition. Geneva: WHO, 1996. 59. Hanks GW, De Conna F, Cherny N, Hanna M, Kelso E, McQuay HJ, Mercadante S, Meynardier J, Poulain P, Ripamonti C, Redbruch L, Casas JR, Sawe J, Twycross RG, Ventafridda V. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001; 84: 587–93. 60. Zernikow B, Lindena G. Long-acting morphine for pain control in paediatric oncology. Med Pediatr Oncol 2001; 36: 451–8. 61. Gall O, Aublneau J-V, Bernier J, Desjeux L, Murat I. Analgesic effect of low-dose intrathecal morphine after spinal fusion in children. Anesthesiology 2001; 94: 447–52. 62. Hesselgard K, Stromblad LG, Reinstrup P. Morphine with or without a local anaesthetic for postoperative intrathecal pain treatment after selective dorsal rhizotomy in children. Paediatr Anaesth 2001; 11: 75–9. 63. Anderson VC, Cooke B, Burchiel KJ. Intrathecal hydromorphone for chronic nonmalignant pain: a retrospective study. Pain Med 2001; 2: 287–97. 64. Roberts LJ, Finch PM, Goucki CR, Price LM. Outcome of intrathecal opioids in chronic noncancer pain. Eur J Pain 2001; 5: 353–61.

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65. Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, Mercadante S, Pasternak G, Ventafridde V. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001; 19, 2542–54. 66. Wang J-J, Ho S-T, Wong C-S, Tzeng J-I, Liu H-S, Ger L-P. Dexamethasone prophylaxis of nausea and vomiting after epidural morphine for postcesarean analgesia. Can J Anesth 2001; 48: 185–90. 67. Ho S-T, Wang J-J, Tzeng J-I, Liu H-S, Ger LP, Liaw W-J. Dexamethasone for preventing nausea and vomiting associated with epidural morphine: a dose-raging study. Anesth Analg 2001; 92: 745–8. 68. Liu SS, Hodgson PS, Carpenter RL, Fricke JR Jr. ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without effecting analgesia. Clin Pharmacol Ther 2001; 69: 66–71. 69. Mercadante S, Villari P, Fulfaro F. Gabapentin for opioid-related myoclonus in cancer patients. Supportive Care Cancer 2001; 9: 205–6. 70. Stambaugh JE, Reder RF, Stambaugh MD, Stambaugh H, Davis M. Double-blind randomised comparison of the analgesic and pharmacokinetic profiles of controlled and immediate release oral oxycodone in cancer patients. J Clin Pharmacol 2001; 41: 500–6. 71. Chen PP, Cheam EW, Ma M, Lam KK, Ngan Kee WD, Gin T. Patient-controlled pethidine after major upper abdominal surgery: comparison of the epidural and intravenous routes. Anaesthesia 2001; 56: 1006–112. 72. Hung C-I, Liu C-Y, Chen C-Y, Yang C-H, Yen E-K. Meperidine addiction or treatment frustration? Gen Hosp Psychiatry 2001; 23: 31–5. 73. Brown ET, Corbett SW, Green SM. Iatrogenic cardiopulmonary arrest during pediatric sedation with meperidine, promethazine and chlorpromazine. Pediatr Emerg Care 2001; 17: 351–3. 74. Booker PD, Whyte SD. Paediatric applications of concentration-oriented anaesthesia. Baillière’s Best Pract Res Clin Anaesthesiol 2001; 15: 97–111. 75. Keidan I. Berkenstadt H, Sidi A, Perel A. Propofol/remifentanil versus propofol alone for bone marrow aspiration in paediatric haematooncological patients. Paediatr Anaesth 2001; 11: 297–301. 76. Thees Ch, Frenkel Ch, Hoeft A. Remifentanil in der Neuroanasthesie—eine multizentrische Anwendungsbeobachtung. Anästhesiol Intensivmed 2001; 42: 205–11. 77. Davis PJ, Galinkin J, McGowan FX, Lynn AM, Yaster M, Robb MF, Krane EJ, Kurth D, Blum RH, Maxwell L, Orr R, Szmur P, Hechtman D, Edwards S, Henson LG. A randomised multicentre study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles. Anesth Analg 2001; 93: 1380–6. 78. Galinkin JL, Davis PJ, McGowan FX, Lynn AM, Robb MF, Yaster M, Henson LG, Blum R, Hechtman D, Maxwell L, Szmuk P, Orr R, Krane EJ, Edwards S, Kurth CD. A randomised multicentre study of remifentanil compared with

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halothane in neonates and infants undergoing pyloromyotomy. II Perioperative breathing patterns in neonates and infants with pyloric stenosis. Anesth Analg 2001; 93: 1387–92. 79. Donmez A, Kizilkan A, Berksun H, Varan B, Tokel K. One center’s experience with remifentanil infusions for pediatric cardiac catheterization. J Cardiothorac Vasc Anesth 2001; 15: 736–9. 80. Marrocco-Trischitta MM, Baniera G, Camilli S, Stilla F, Cirielli C, Giverrini P. Remifentanil conscious sedation during regional anaesthesia for carotid endarterectomy: rationale and safety. Eur J Vasc Endovasc Surg 2001; 22: 405–9. 81. Grewal K, Samsoon G. Facilitation of laryngeal mask airway insertion: effects of remifentanil administered before induction with target-controlled propofol infusion. Anaesthesia 2001; 56: 897–901. 82. Greilich PE, Virella CD, Rich JM, Kurada M, Roberts K, Warren JF, Harford WV. Remifentanil versus meperidine for monitored anesthesia care: a comparison study in older patients undergoing ambulatory colonoscopy. Anesth Analg 2001; 92: 80–4. 83. Mollhoff T, Herregods L, Moerman A, Blake D, MacAdams C, Demeyere R, Kirno K, Dybvik T, Shaikh S, and the Remifentanil Study Group. Comparative efficacy and safety of remifentanil and fentanyl in “fast track” coronary artery bypass graft surgery: a randomised double-blind study. Br J Anaesth 2001; 87: 718–26. 84. Prakash N, McLeod T, Gao Smith F. The effects of remifentanil on haemodynamic stability during rigid bronchoscopy. Anaesthesia 2001; 56: 576–80. 85. Breslin DS, Reid JE, Mirakhuk RK, Hayes AH, McBrien ME. Sevoflurane–nitrous oxide anaesthesia supplemented with remifentanil. Effect on recovery and cognitive function. Anaesthesia 2001; 56: 114–19. 86. Joo HS, Perks WJ, Belo SE. Sevoflurane with remifentanil allows rapid tracheal intubation without neuromuscular blocking agents. Can J Anesth 2001; 48: 646–50. 87. Gustorff B, Felleiter P, Nahlik G, Brannath W, Hoerauf KH, Spacek A, Kress HG. The effect of remifentanil on the heat pain threshold in volunteers. Anesth Analg 2001; 92: 369–74. 88. Roelants F, De Franceschi E, Veyckemans F, Lavand’homme P. Patient-controlled intravenous analgesia using remifentanil in the parturient. Can J Anesth 2001; 48: 175–8. 89. Calderón E, Pernie A, Antonia De P, CalderónPla E, Torres L-M. A comparison of two constantdose continuous infusions of remifentanil for severe post-operative pain. Anesth Analg 2001; 92: 715–19. 90. Kurdi O, Deleuze A, Marret E, Bonnet F. Asystole during anaesthetic induction with remifentanil and sevoflurane. Br J Anaesth 2001; 87: 943. 91. Haber GW, Litman RS. Generalised tonic– clonic activity after remifentanil administration. Anesth Analg 2001; 93: 1532–3. 92. Kampe S, Randebrock G, Kiencke P, Hunseler U, Cranfield K, Konig DP, Diefenbach C. Comparison of continuous epidural infusion of ropivacaine

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and sufentanil with intravenous patient-controlled analgesia after total hip replacement. Anaesthesia 2001; 56: 1189–93. 93. Nelson CP, Francis TA, Wolf JS Jr. Comparison of shockwave lithotripsy outcomes in patients receiving sufentanil or lidocaine spinal anaesthesia. J Endourol 2001; 15: 473–7. 94. Henderson CL, Schmid J, Vaghadia H, Fowler C, Mitchell GWE. Selective spinal anesthesia for outpatient laparoscopy III: sufentanil vs lidocaine–sufentanil. Can J Anesth 2001; 48: 267–72. 95. Standl TG, Horn E-P, Luckmann M, Burmeister M-A, Wilhelm S, Schulteam Esch J. Subarachnoid sufentanil for early postoperative pain management in orthopaedic patients: a placebo-controlled, double-blind study using spinal microcatheters. Anesthesiology 2001; 94: 230–8. 96. Gebhard RE, Fenelli G, Matuszczak M, Doehn M. Subarachnoid sufentanil for early postoperative pain management in orthopaedic patients: more disadvantages than benefit? Anesthesiology 2001; 95: 1531–3. 97. Gven Le H, Roy D, Branger B, Ecoffey C. Comparison of fentanyl and sufentanil in combination with bupivacaine for patient-controlled epidural analgesia during labor. J Clin Anesth 2001; 13: 98– 102. 98. Debon R, Allaouchiche B, Duflo F, Boselli E, Chassard D. The analgesic effect of sufentanil combined with ropivacaine 0.2% for analgesia a comparison of three sufentanil doses. Anesth Analg 2001; 92: 180–3. 99. Viitanen H, Annila P. Analgesic efficacy of tramadol 2 mg kg−1 for paediatric day-case adenoidectomy. Br J Anaesth 2001; 86: 572–5. 100. Ozcengiz D, Gunduz M, Ozbek H, Isik G. Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy. Paediatr Anaesth 2001; 11: 459–64. 101. Senel AC, Akyol A, Dohmann D, Solak M. Caudal bupivacaine–tramadol combination for postoperative analgesia in pediatric herniorrhaphy. Acta Anaesthesiol Scand 2001; 45: 786–9. 102. Eren GA, Cinar SO, Oba S, Zoylan G. Pediyatrik alt batin cerrahisinde postoperatif analjezi amacli kaudal tramadol kullanimi. Turk Anesteziyol Reanim 2001; 29: 39–43. 103. Rawal N, Allvin R, Amilon A, Ohlsson T, Hallen J. Postoperative analgesia at home after ambulatory hand surgery: a controlled comparison of tramadol, metamizol and paracetamol. Anesth Analg 2001; 92: 347–51. 104. Vergnion M, Degesves S, Garcet L, Magotteaux V. Tramadol, an alternative to morphine for treating post traumatic pain in the prehospital situation. Anesth Analg 2001; 92: 1543–6. 105. Dejonckheere M, Desjeux L, Deneu S, Ewalenko P. Intravenous tramadol compared to propacetamol for postoperative analgesia following thyroidectomy. Acta Anaesthesiol Belg 2001; 52: 29–33. 106. Smith-Wilder CH, Hill L, Spargo K, Kalla A. Treatment of severe pain from osteoarthritis with

110 slow-release tramadol or dihydrocodeine in combination with NSAIDs: a randomised study comparing analgesia, antinociception and gastrointestinal effects. Pain 2001; 91: 23–31. 107. Fleischmann RM, Caldwell JR, Roth SH, Tesser JRP, Olson W, Kamin M. Tramadol for the treatment of joint pain associated with osteoarthritis: a randomised double-blind, placebo-controlled trial. Curr Ther Res 2001; 62: 113–28. 108. Mullican WS, Lacy JR. Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial. Clin Ther 2001; 23: 1429–45. 109. Petzke F, Radbruch L, Sabatowski R, Karthaus M, Mertens A. Slow-release tramadol for treatment of chronic malignant pain—an open multicenter trial. Supportive Care Cancer 2001; 9: 48–54. 110. Yates WR, Nguyen MH, Warnock JK. Tramadol dependence with no history of substance abuse. Am J Psychiatry 2001; 158: 964. 111. Musshoff F, Madea B. Fatality due to ingestion of tramadol alone. Forensic Sci Int 2001; 116: 197–9. 112. De Witte JL, Schoenmaekers B, Sesster DI, Deloof T. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg 2001; 92: 1319–21. 113. Gonzalez-Pinto A, Imaz H, De Heredia JLP, Gutierrez M, Maco JA. Mania and tramadol– fluoxetine combination. Am J Psychiatry 2001; 158: 964–5. 114. Ingelman-Sundberg M. Genetic susceptibility to adverse effects of drugs and environmental toxicants. The role of the CYP family of enzymes. Mutat Res Fundam Mol Mech Mutagen 2001; 482: 11–19. 115. Petitjean S, Stohler R, Déglon J-J, Livoti S, Waldvogel D, Vehlinger C, Ladewig D. Double-blind randomised trial of buprenorphine and methadone in opiate dependence. Drug Alcohol Depend 2001; 62: 97–104. 116. Comer SD, Collins ED, Fischman MW. Buprenorphine sublingual tablets. Effects on IV heroin self-administration by humans. Psychopharmacology 2001; 154: 28–37. 117. Wisniewski B, Perlemuter G, Buffet C. Hepatite aiguë liée a l’injection intraveineuse de buprenorphine chez une toxicomane substituée. Gastroenterol Clin Biol 2001; 25: 328–9. 118. Berson A, Gervais A, Cazals D, Boyer N, François D, Bernuau J, Marcellin P, Degott C, Valla D, Pessayre D. Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol 2001; 34: 346–50.

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119. Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int 2001; 121: 65–9. 120. Charuluxananan S, Kyokong O, Somboonviboon W, Lertmaharit S, Ngamprasertwong P, Nimcharoendee K. Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritus after caesarian delivery. Anesth Analg 2001; 93: 162–5. 121. Camacho A, Matthews SC, Dimsdale JE. “Invisible” synthetic opiates and acute psychosis. New Engl J Med. 2001; 345: 469. 122. Chumpa A, Kaplan RL, Burns MM, Shannon MW. Nalmefene for elective reversal of procedural sedation in children. Am J Emerg Med 2001; 19: 545–8. 123. Lee J, Shim JY, Choi JH, Kim ES, Kwow OW, Moon DE, Choi JH, Bishop MJ. Epidural naloxone reduces intestinal hypomotility but not analgesia of epidural morphine. Can J Anaesth 2001; 48: 54–8. 124. Dettmer K, Saunders B, Strang J. Take home naloxone and the prevention of deaths from opiate overdose: two pilot schemes. Br Med J 2001; 322: 895–6. 125. Mountain D. Big conclusions are drawn from little evidence. Br Med J 2001; 323: 934–5. 126. Streeton C, Whelan G. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomised controlled trials. Alcohol Alcohol 2001; 36: 544–52. 127. Morris PLP, Hopwood M, Whelan G, Gardiner J, Drummond E. Naltrexone for alcohol dependence: a randomised controlled trial. Addiction 2001; 96: 1565–73. 128. Rubio G, Jimenez-Arriero MA, Ponce G, Palamo T. Naltrexone versus acamprosate: one year follow-up of alcohol dependence treatment. Alcohol Alcohol 2001; 36: 419–25. 129. Oncken C, Van Kirk J, Kranzler HR. Adverse effects of oral naltrexone: analysis of data from two clinical trials. Psychopharmacology 2001; 154: 397–402. 130. Bristow K, Meek R, Clark N. Acute opioid withdrawal in the emergency department: Inadvertent naltrexone abuse? Emerg Med 2001; 13: 359–63. 131. Quigley MA, Boyce SH. Unintentional rapid opioid detoxification. Emerg Med J 2001; 18: 494–5. 132. Mimoz O, Incagnoli P, Josse C, Gillon MC, Kuhlman L, Mirand A, Soilleux H, Fletcher D. Analgesic efficacy and safety of nefopam vs propacetamol following hepatic resection. Anaesthesia 2001; 56: 520–5.

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Anti-inflammatory and antipyretic analgesics and drugs used in gout

An update on NSAIDs and chronic renal disease The relation between long-term heavy exposure to analgesics and the risk of chronic renal disease has been the object of intensive toxicological and epidemiological research for many years (SEDA-24, 120; 1R ). Most of the earlier reports suggested that phenacetincontaining analgesics probably cause renal papillary necrosis and interstitial nephritis. In contrast, there is no convincing epidemiological evidence that non-phenacetin-containing analgesics (including paracetamol, aspirin, mixtures of the two, and NSAIDs) cause chronic renal disease. Moreover, findings from epidemiological studies should be interpreted with caution, because of a number of inherent limitations and potential biases in study design (2R ). Two recent methodologically sound studies have provided more information on this topic. The first was the largest cohort study conducted thus far to assess the risk of renal dysfunction associated with analgesic use (3C ). Details of analgesic use were obtained from 11 032 men without previous renal dysfunction participating in the Physicians’ Health Study (PHS), which lasted 14 years. The main outcome measure was a raised creatinine concentration defined as 1.5 mg/dl (133 μmol/l) or higher and a reduced creatinine clearance of 55 ml/min or less. In all, 460 men (4.2%) had a raised creatinine concentration and 1258 (11%) had a reduced creatinine clearance. Mean creatinine concentrations and creatinine © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

clearances were similar among men who did not use analgesics and those who did. This was true for all categories of analgesics (paracetamol and paracetamol-containing mixtures, aspirin and aspirin-containing mixtures, and other NSAIDs) and for higher risk groups, such as those aged 60 years or over or those with hypertension or diabetes. These data are convincing, as the large size of the PHS cohort should made it possible to examine and detect even modest associations between analgesic use and a risk of renal disease. Furthermore, this study included more individuals who reported extensive use of analgesics than any prior case-control study. However, the study had some limitations, the most important being the fact that the cohort was composed of relatively healthy men, most of whom were white. These results cannot therefore be generalized to the entire population. However, the study clearly showed that there is not a strong association between chronic analgesic use and chronic renal dysfunction among a large cohort of men without a history of renal impairment. The second study was a Swedish nationwide, population-based, case-control study of early-stage chronic renal insufficiency in men whose serum creatinine concentration exceeded 3.4 mg/dl (300 μmol/l) or women whose serum creatinine exceeded 2.8 mg/dl (250 μmol/l) (4C ). In all, 918 patients with newly diagnosed renal insufficiency and 980 controls were interviewed and completed questionnaires about their lifetime consumption of analgesics. Compared with controls, more patients with chronic renal insufficiency were regular users of aspirin (37% vs 19%) or paracetamol (25% vs 12%). Among subjects who did not use aspirin regularly, the regular use of paracetamol was associated with a risk of chronic renal insufficiency

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112 that was 2.5 times as high as that for non-users of paracetamol. The risk increased with increasing cumulative lifetime dose. Patients who took 500 g or more over a year (1.4 g/day) during periods of regular use had an odds ratio (OR) for chronic renal insufficiency of 5.3 (95% CI = 1.8, 15). Among subjects who did not use paracetamol regularly, the regular use of aspirin was associated with a risk of chronic renal insufficiency that was 2.5 times as high as that for non-users of aspirin. The risk increased significantly with an increasing cumulative lifetime dose of aspirin. Among the patients with an average intake of 500 g or more of aspirin per year during periods of regular use, the OR for chronic renal insufficiency was 3.3 (1.4, 8.0). Among patients who used paracetamol in addition to aspirin, the OR for chronic renal insufficiency was 2.2 (1.4, 3.5) when regular aspirin users served as the reference group, and 1.6 (0.9, 2.7) when regular paracetamol users were used as controls. There was no relation between the use of other analgesics (propoxyphene, NSAIDs, codeine, and pyrazolones) and the risk of chronic renal insufficiency. Thus, the regular use of paracetamol, or aspirin, or both was associated dose-dependently with an increased risk of chronic renal insufficiency. The OR among regular users exceeded 1.0 for all types of chronic renal insufficiency, albeit not always significantly. These results are consistent with exacerbating effects of paracetamol and aspirin on chronic renal insufficiency, regardless of accompanying disease. How can we explain the contrasting results of these two studies? A possible explanation lies in the different populations studied. In PHS relatively healthy individuals were enrolled while in the Swedish study all the patients had preexisting severe renal or systemic disease, suggesting that such disease has an important role in causing analgesic-associated chronic renal insufficiency. People without pre-existing disease who use analgesics may have only a small risk of end-stage renal disease. Pregnancy and teratogenicity NSAIDs are among the commonest drugs prescribed for pregnant woman (5C ). However, the risk of adverse birth outcomes in women who take NSAIDs other than aspirin during pregnancy is largely unknown. Now a Danish study has provided important information (6C ).

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The study was conducted in a Danish county (population about 490 000) and included data on all women who between 1991 and 1998 had a live birth or a stillbirth after the 28th week of gestation, or who had a miscarriage (including missed abortions). The researchers performed a cohort study and a case-control study using data from the Danish birth registry, the county hospital discharge registry, and the county’s prescriptions database. The risk of an adverse birth outcome (congenital abnormality, low birth weight, and preterm birth) was examined in the cohort study and the risks of miscarriage were examined in the case-control study. The cohort study included 1462 women who gave birth after 28 weeks and who had filled a prescription for an NSAID, a total of 1742 prescriptions. The control group consisted of 17 259 pregnant women who did not take any drugs during pregnancy. The case-control study involved 4268 women who had had their first miscarriage, 63 of whom had filled a prescription for an NSAID in the 12 weeks before being discharged from hospital after the miscarriage, and 29 750 primiparous controls who had live births. There was no significant association between the uptake of prescriptions for NSAIDs during pregnancy and the risks of congenital abnormalities, low birth weight, or preterm births. However, there was a significant association with miscarriage in the case-control study. The OR for miscarriage was 7.0 (2.8, 17) when the prescription for the NSAID was filled during the week before the miscarriage and 2.6 (1.8, 4.0) when it was filled at 7–9 weeks before the miscarriage. The validity of these findings has been challenged on the grounds of possible bias and other methodological problems (7r , 8r ). However, according to a statement issued by the UK Royal College of Obstetricians and Gynaecologists (RCOG) NSAIDs should be avoided by women who know that they are pregnant. According to the RCOG, although the study did not establish a causative link between NSAID use and miscarriage, pregnant women should avoid NSAIDs and in the mean time prefer to use effective alternative drugs, such as paracetamol (9c ). As NSAIDs are widely used, even a small increase in the risk of adverse effects can have major implications for public health. Further

Anti-inflammatory and antipyretic analgesics and drugs used in gout

studies therefore need to be conducted on the association between NSAIDs and miscarriage before definitive conclusions can be drawn.

INDIVIDUAL DRUGS AND CLASSES Acetylsalicylic acid (aspirin) and related compounds (SED-14, 233; SEDA-23, 116; SEDA-24, 121; SEDA-25, 132) Gastrointestinal The question of whether the risk of gastrointestinal complications with the long-term use of aspirin is dose-related is controversial (SEDA-21, 100; SEDA-25, 132). A systematic review of 17 epidemiological studies conducted between 1990 and 2001 has provided further data on this topic (10M ). The effect of aspirin dosage was investigated in five studies. There was a greater risk of gastrointestinal complications with aspirin in dosages over 300 mg/day than in dosages of 300 mg/day or less. However, users of low-dose aspirin still had a two-fold increased risk of such complications compared with non-users, with no clear evidence of a dose-response relation at dosages under 300 mg/day, confirming previous findings (11M ). The study also addressed the question of whether the aspirin formulation affects gastrotoxicity. The pooled relative risks of gastrointestinal complications in four studies were 2.4 (95%; CI = 1.9, 2.9) for enteric-coated aspirin, 5.3 (3.0, 9.2) for buffered formulations, and 2.6 (2.3, 2.9) for plain aspirin, compared with non-use. These data confirm those from previous studies (SEDA-21, 100; 11M ), which negate any protective effect of the most frequently used aspirin formulations. Furthermore, there were higher relative risks, compared with non-use, for gastrointestinal complications in patients who used aspirin regularly (RR = 3.2; CI = 2.6, 5.9) than in patients who used it occasionally (2.1; 1.7, 2.6), and during the first month of use (4.4; 3.2, 6.1) compared with subsequent months (2.6; 2.1, 3.1). Liver The use of aspirin in children has been associated with Reye’s syndrome. Its cause is not known and it occurs in children and young

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adults up to 20 years of age. Diagnosis is particularly difficult, and so the estimated frequency varies from country to country. During 1980 initiatives were taken in the UK and USA to warn parents not to give aspirin to their children (under 12 years of age). Over the last 20 years in the USA the incidence of Reye’s syndrome has fallen significantly—since this advice was introduced there have been 25 reported cases, but 15 were in adolescents aged 12–17 years, and 8% of cases occurred in patients aged 15 years or over (12C ). In the UK, in view of these findings, the Commission on Safety of Medicines (CSM) has now amended its original statement and has advised that aspirin should be avoided in febrile illnesses or viral infections in patients aged up to 15 years. However, the appropriateness of this decision has been challenged (13r ). This is because the incidence of Reye’s syndrome is already low and is falling; furthermore, restricting the use of aspirin leaves paracetamol and ibuprofen as the only available therapeutic alternatives, and their safety is not absolutely guaranteed and might be even worse than that of aspirin.

ANILINE DERIVATIVES

(SED-14, 240; SEDA-23, 116; SEDA-24, 122; SEDA-25, 132)

Paracetamol Hematological Two patients developed immune thrombocytopenia attributed to metabolites of paracetamol (14A ). • A 30-year-old man and a 66-year-old woman had taken paracetamol 1 g intermittently for headaches and other non-specific indications. Routine blood testing showed thrombocytopenia (50 × 109 and 45 × 109 /l respectively). They both stopped taking paracetamol, and their platelet counts rose to normal within 7–10 days. Their sera contained antibodies (IgG or IgA) that recognized normal platelets in the presence of the metabolite paracetamol sulfate.

This suggests that in patients with druginduced immune thrombocytopenia, tests for metabolite-dependent antibodies can be helpful in identifying the responsible agent.

114 Drug overdose On 16 September 1998 legislation was introduced in the UK limiting the pack size of paracetamol; at the same time nearly all formulations became available only in blister packs. The justification for this legislation was that analgesic self-poisoning is highly impulsive and is associated with both low suicidal intent and limited knowledge of the possible consequences; it was expected that the number of cases of paracetamol overdose might be reduced by limiting its availability. The impact of this legislation on mortality from paracetamol overdose has been assessed in a prospective study of mortality from paracetamol overdose before and after the new legislation (15C ). The evaluation included the number of patients referred to liver units or listed for liver transplantation, the number of episodes of overdose and tablets taken, the plasma concentration of paracetamol, and sales of paracetamol to pharmacies. In the years after the legislation the number of tablets of paracetamol formulations per packet fell markedly, as did the number of deaths from self-poisoning with paracetamol, the number of liver transplants and admissions to liver units with hepatic damage after paracetamol poisoning, and the number of episodes of overdose in which a large number of tablets was taken. On the basis of these results it seems that the legislation was relatively successful. The results suggested that the main factor was the reduction in the number of tablets per pack available for impulsive self-poisoning. However, the study had some limitations. The period assessed may have been too short for a full assessment of the impact of the legislation (16r ) and the effect of legislation on self-poisoning with other drugs was not examined (17r ). It may be that limiting access to one type of drug simply increases the incidence of overdose with other potentially more dangerous medicines. Because restricting the packet size cannot completely resolve the problem of paracetamol overdose, alternative measures have been proposed (SEDA-22, 114). Acetylcysteine, which provides the thiol groups necessary to replenish glutathione depleted by paracetamol, is used to treat paracetamol overdose. It has therefore been suggested that toxicity caused by paracetamol overdoses, whether intentional or not, could be prevented by formulating paracetamol with added acetylcysteine. It has been estimated

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that including 200 mg acetylcysteine for every 500 mg of paracetamol would prevent toxicity (18r , 19r ). Methionine has previously been added to oral paracetamol formulations for the same reason. For example, Paradote, contains paracetamol 500 mg and methionine 100 mg and the combination is called co-methiamol. However, adding methionine to every paracetamol tablet prompted contrasting opinions (SEDA-22, 114; 20r , 21r ). Pameton (500 mg paracetamol, 250 mg methionine) was voluntarily withdrawn in the UK because of safety concerns, before any evaluation of its impact on overdose had been carried out (20r ). Paradote remains available in the UK, but similar formulations are not currently available in the rest of Europe or the USA. Drug interactions Alcohol Alcohol abuse can aggravate hepatotoxicity, not only in individuals who take excessive doses of paracetamol, but also in moderate social drinkers who take regular paracetamol (SEDA-20, 96; SEDA-24, 122). The theory behind this interaction involves induction by alcohol of CYP2E1, which metabolizes about 5% of a typical dose of paracetamol, producing the reactive hepatotoxic metabolite named N-acetylparabenzoquinone-imine (NAPQI). The rest of a therapeutic dose of paracetamol is conjugated to non-toxic forms of glucuronide and sulfate. Ingestion of alcohol induces the activity of CYP2E1 and therefore predisposes the alcoholic patient to injury even at therapeutic doses of paracetamol (22C ). Despite this theory, the evidence that therapeutic doses of paracetamol can produce liver injury in alcoholics is scanty (23M , 24r ). There has been only one study of the hepatotoxicity of paracetamol in therapeutic doses in alcoholic patients, a double-blind, randomized, placebo-controlled study in which 200 long-term alcoholic patients took placebo or paracetamol 1 g qds on 2 consecutive days (25C ). Paracetamol was not given until alcohol had been eliminated from the body. Liver injury, documented by increased serum transaminases, was not detected. Mean (SD) AsT activity on day 4 was 38 (27) u/l with paracetamol and 38 (28) u/l with placebo. Only five patients who took placebo and four who took paracetamol had an increase in serum AsT to greater than 120 u/l, and the AsT did not exceed 200 u/l in any patient. Thus, repeated administration

Anti-inflammatory and antipyretic analgesics and drugs used in gout

of the maximum recommended daily doses of paracetamol to alcoholic patients was not associated with liver damage. An older report also provided evidence that alcoholic patients are not at risk from therapeutic doses of paracetamol (26C ). The researchers concluded that the usual recommendations that alcoholic patients should use reduced doses of paracetamol or avoid it entirely are not based on firm evidence. However, the study had some limitations, as paracetamol was given for only 2 days in doses that did not exceed the maximum therapeutic daily dose. Moreover, the alcoholic patients enrolled in the study may not have been representative of those who would be at increased risk of paracetamol toxicity (27r –29r ). It therefore seems wise to suggest that caution is still warranted with paracetamol in alcoholic patients. Rifampicin The addition of rifampicin in patients taking paracetamol can reportedly cause liver failure and encephalopathy, and this has been reported again (30A ). • A 32-year-old woman, who had been taking paracetamol 2–4 g/day for several weeks, took rifampicin (600 mg bd), and 2 days later developed agitation, confusion, and laboratory abnormalities indicative of severe liver injury. Both rifampicin and paracetamol were withdrawn and she was given acetylcysteine. Her liver dysfunction resolved.

The severe hepatotoxicity in this case was probably due to induction of CYP3A4 by rifampicin, but rifampicin-induced liver damage could not be excluded.

ARYLALKANOIC ACID DERIVATIVES (SED-14, 268; SEDA-23, 119; SEDA-24, 122; SEDA-25, 133)

Aceclofenac Skin After starting twice-daily topical application of a cream containing aceclofenac, a woman developed acute eczema affecting the sun-exposed areas of her legs (31A ). Aceclofenac can therefore be added to the long list of NSAIDs that cause photosensitivity.

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Diclofenac Electrolyte balance NSAIDs can cause hyperkalemic acidosis and should be used with caution in the presence of renal impairment (32A ). • A 76-year-old woman developed quadriparesis associated with hyperkalemia after taking diclofenac 100 mg/day for 10 months for gouty arthritis. She had a metabolic acidosis with a normal anion gap and mild renal impairment. Her weakness resolved after withdrawal of diclofenac and correction of the hyperkalemia.

Ibuprofen Drug interactions Aspirin Patients with arthritis and vascular disease sometimes take both low-dose aspirin and other NSAIDs. However, concomitant treatment with ibuprofen may limit the cardioprotective effects of aspirin, according to the results of a study of the effects of ibuprofen, diclofenac, coxibs, and paracetamol on the antiplatelet activity of aspirin (33C ). The following combinations of drugs were used: aspirin (81 mg every morning) 2 hours before ibuprofen (400 mg every morning) or in the reverse order; aspirin 2 hours before rofecoxib (25 mg every morning or in the reverse order); enteric-coated aspirin 2 hours before ibuprofen (400 mg tds); and enteric-coated aspirin 2 hours before modified-release diclofenac (75 mg bd). Inhibition of the formation of serum thromboxane B2 (an index of COX-1 activity in platelets) and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. Diclofenac, paracetamol, and rofecoxib did not affect the pharmacodynamics of aspirin. These results suggest that ibuprofen, but not diclofenac, paracetamol, or rofecoxib, antagonizes the irreversible inhibition of platelet COX-1 by aspirin and can therefore limit the cardioprotective effects of aspirin. Sulfonylureas Ibuprofen (150 mg, 3 doses) for arthralgias was associated with hypoglycemia in a 72-year-old man who was taking glibenclamide 2.5 mg/day for type 2 diabetes mellitus; after the last dose he lost consciousness and his blood glucose concentration was under 2.2 mmol/l (34A ).

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Ketoprofen Respiratory Even topical formulation of NSAIDs should be avoided in patients with a history of analgesic-induced asthma (35A ). • A 74-year-old woman with a history of sinusitis, nasal polyps, and analgesic-induced asthma had a sudden life-threatening attack of asthma 2 hours after the application of a 2% ketoprofen adhesive tape. Asthma had not previously occurred when she had used a 0.3% ketoprofen adhesive patch.

Loxoprofen Gastrointestinal In a retrospective study of NSAID-induced colonic ulceration related to NSAID therapy, five of 14 patients were taking loxoprofen (36c ). However, this finding does not prove that loxoprofen is more ulcerogenic than other NSAIDs.

• Ischemic colitis occurred in a 49-year-old woman 10 days after she started to take meloxicam 15 mg/day for osteoarthritis; meloxicam was withdrawn and her symptoms completely resolved within 1 week (37A ).

Although meloxicam is considered to be a preferential COX-2 inhibitor, its safety profile is not much different from other traditional NSAIDs, especially in high doses (38R ). Immunologic Meloxicam may be relatively safe when given to patients with NSAIDinduced urticaria/angio-edema (39C , 40C ). Of 148 NSAID-sensitive subjects with an unequivocal history of urticaria with or without angio-edema, who were challenged with increasing oral doses of meloxicam (1–7 mg/day) in a single-blind placebo-controlled trial, only two had a positive test (urticaria in one and urticaria/angio-edema in the other); both had chronic idiopathic urticaria (41C ).

SELECTIVE COX-2 INHIBITORS

Naproxen

(SEDA-25, 122)

Hematologic Three men, aged 56, 57, and 71 years developed extensive purpuric hemorrhages involving their legs (3), arms (2), and abdomen (1) 10–20 days after having taken naproxen 250 mg tds for musculoskeletal disorders (14A ). One patient also had gastrointestinal bleeding. They all had severe thrombocytopenia (platelet counts below 3 × 109 /l). Naproxen was withdrawn and prednisone started. The platelet counts normalized within a week. The prednisone was withdrawn and the thrombocytopenia did not recur during follow up. Analysis of their sera showed the presence of IgG antibodies that recognized normal platelets in the presence of the metabolite naproxen glucuronide.

OXICAM DERIVATIVES

A. Del Favero

(SED-14,

286; SEDA-24, 122)

Meloxicam Gastrointestinal Colitis has been described as an adverse effect of meloxicam (SEDA-20, 94).

At least 11 selective COX-2 inhibitors have been launched or are under development (42r ), but published information is to date available only for celecoxib, parecoxib, and rofecoxib.

What is safe prescribing and use of selective COX-2 inhibitors? Comparisons with non-selective NSAIDs Although the scientific literature has been flooded by articles and reviews on the use of selective COX-2 inhibitors (coxibs) in the last 2 years, the safe prescribing and use of these compounds is controversial (43r , 44R , 45M , 46r ). This topic was considered in previous Annuals (SEDA-24, 115; SEDA-25, 126), but further comments are warranted. Much information on celecoxib and rofecoxib has come from two large pivotal randomized clinical trials, the CLASS and VIGOR studies, in which the efficacy and safety of the two coxibs and various non-selective NSAIDs were compared (47 C , 48C ).

Anti-inflammatory and antipyretic analgesics and drugs used in gout

Cardiovascular In VIGOR rofecoxib 50 mg/day was associated with a higher rate of non-fatal myocardial infarction (0.4%) than the non-selective COX-2 inhibitor naproxen 500 mg bd (0.1%) (RR = 0.2; CI = 0.1, 0.7) (48C ). In CLASS there was no difference in the rates of myocardial infarction in patients taking celecoxib (0.5%) and those taking ibuprofen or diclofenac (0.4%). However, the protocols of the two studies differed substantially with respect to the use of aspirin. In VIGOR the patients were not allowed to take aspirin or any other antiplatelet drug, while in CLASS onefifth of the patients took aspirin. A re-analysis of CLASS for cardiovascular thromboembolic events, including myocardial infarction, stroke, cardiovascular deaths, and peripheral events, showed no significant increase with celecoxib versus NSAIDs (49R ). However a different conclusion was reached in an analysis of FDA data, which suggested an increase in serious cardiac events with celecoxib (45M ). The incidence of serious cardiac adverse events (myocardial infarction, combined anginal events, and atrial dysrhythmias) was 0.6% higher with celecoxib than with other NSAIDs (RR = 1.55; CI = 1.04, 2.30). The reasons for these inconsistencies are not clear and would require an independent meta-analysis using individual patient data. The cardiovascular results in VIGOR may have occurred simply by chance, given the low number of events, or because naproxen may have a cardioprotective effect similar to that of aspirin, or because rofecoxib 50 mg/day could have prothrombotic effects, especially in the absence of concomitant COX-1 inhibition in patients at increased risk of cardiovascular thromboembolic events. Because there was no untreated group in VIGOR, we do not know whether this finding suggests a protective effect of naproxen or a harmful effect of rofecoxib. All three explanations are plausible, and they are not mutually exclusive. It has been suggested that the increase in thrombotic cardiovascular events in rofecoxibtreated patients probably represents the antiplatelet effect of naproxen (50M , 51R , 52r ). Naproxen has a long pharmacodynamic halflife and inhibits platelet aggregation by 88% for up to 8 h (53C ). In VIGOR (45M , 48C ) the incidence of confirmed thrombotic cardiovascular events was

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0.6% higher with rofecoxib than with naproxen (RR = 2.4; 95% CI = 3.9, 4.0). Some recently published data may help to answer the important question of whether the relative difference in the incidence of myocardial infarction in VIGOR was due to a harmful effect of rofecoxib or a beneficial effect of naproxen. Although contrasting data have been published (54R ), the hypothesis that naproxen has a cardioprotective effect has gained wider support (55r ). Only one of the four most recently published studies negated a potential cardioprotective effect of naproxen. In an 11-year observational study in a new users of non-selective, non-aspirin NSAIDs (n = 181 441) and an equal number of nonusers there was no evidence of a protective effect of naproxen (56C ). During 532 634 personyears of follow-up there were 6382 cases of serious coronary heart disease (11.9 per 1000 person-years). Multivariate-adjusted rate ratios for current and former use of non-aspirin NSAIDs, were 1.05 (95% CI = 0.97, 1.14) and 1.02 (0.97, 1.08) respectively. Rate ratios for ibuprofen, naproxen, and other NSAIDs were 1.15 (1.02, 1.28), 0.95 (0.82, 1.09), and 1.03 (0.92, 1.16) respectively. There was no protection in long-term users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1.05 (0.91, 1.21). When naproxen was directly compared with ibuprofen, the rate ratio in current users was 0.83 (0.69, 0.98). This study therefore seems to have shown no cardioprotective effect of naproxen. However, the study had a number of important limitations, including: lack of information about some important confounders (smoking, obesity), possible exposure misclassification, and lack of information about over-the-counter use of aspirin. Opposite evidence has emerged from three recent case-control studies from the USA, Canada, and the UK, which showed that the rates of myocardial infarction in patients taking naproxen were lower than in patients not taking any NSAIDs (57C , 58C ) and those taking other NSAIDs (59C ). In the first study 4425 patients hospitalized with acute myocardial infarction who used NSAIDs were compared with 17 700 controls in a large health-care database in the USA (57C ). Multivariate models were constructed to control for potential confounders. A quarter of the

118 cases and controls had also filled a prescription for an NSAID in the 6 months before the study. Overall, the NSAID users had the same risk of acute myocardial infarction as non-users, but naproxen users had a significantly lower risk of acute myocardial infarction compared with those who were not taking NSAIDs (adjusted OR = 0.84; 95% CI = 0.72, 0.98). The cardioprotective effect of naproxen was very modest compared with aspirin (a 44% reduction in the risk of acute myocardial infarction in the Physician Health Study (60C )). The second study was a case-control study sponsored by Merck & Co (the manufacturers of celecoxib), in which the risk of acute thromboembolic cardiovascular events among 16 937 patients aged 40–75 years with rheumatoid arthritis using naproxen was examined using the British General Practice Research Database (58C ). Each patient with a first thromboembolic event (n = 809: 435 myocardial infarctions, 347 strokes, 27 sudden deaths) was matched with four controls. The results suggested that patients with rheumatoid arthritis who currently use naproxen have a significantly lower risk of thromboembolic events relative to those who have not used naproxen in the past year (RR = 0.61; 0.39, 0.94). However, the risk was not lower with previous use of naproxen, suggesting that any effect of naproxen is likely to be short-lived. Moreover, the significantly lower risk of myocardial infarction with current naproxen was not found when myocardial infractions were analysed separately (RR = 0.57; 0.3, 1.06). There was no protective effect for thromboembolic events with current use of nonnaproxen NSAIDs. The third study was also sponsored by Merck & Co and was designed to examine the association between the use of naproxen and other non-selective NSAIDs and hospitalization for acute myocardial infarction (59C ). In a database of 14 163 patients aged 65 years or older who were hospitalized for acute myocardial infarction and an equal number of age-matched controls, concurrent exposure to naproxen had a protective effect against myocardial infarction compared with the other non-selective non-aspirin NSAIDs (RR = 0.79; 0.63, 0.99). This effect was present only with concurrent naproxen exposure and was stronger in longterm users. However, this study also had several limitations: some important risk factors, such

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as smoking and obesity, could not be assessed, patients who died of myocardial infarction before reaching the hospital were not included, and there was uncertainty about concurrent use of over-the-counter drugs, especially aspirin. In conclusion, although these three studies suggest that patients who take naproxen have a lower incidence of myocardial infarction than those who take other NSAIDs or who do not take NSAIDs, the data do not provide definitive evidence that naproxen is cardioprotective. The data therefore raise a cautionary flag about the risk of severe cardiovascular events with COX2 inhibitors and again call for more studies. As many users of NSAIDs or COX-2 inhibitors are at risk of coronary artery disease, it has been suggested that a COX-2 inhibitor be used together with low-dose aspirin in order to avoid severe cardiovascular events. However, this might cause more gastrointestinal toxicity and loss of the benefit offered by COX-2 inhibition. This has already been shown with celecoxib, and the benefit of using a combination of rofecoxib with aspirin requires further study. COX-2 selectivity may be a double-edged sword. Because the cardiovascular risk outweighs the gastrointestinal risk in adults with rheumatoid arthritis or osteoarthritis, the harm would outweigh the benefits in most clinical settings. This means that the total number of serious adverse events would be increased by COX-2 selective NSAIDs compared with nonselective NSAIDs. COX-2 selectivity, which is an appealing theoretical concept, might be a clinical failure (45M ). Respiratory Most people tolerate aspirin well, but not patients with asthma, of whom there is a subgroup in whom aspirin precipitates asthmatic attacks (61R , 62C ). This is a distinct clinical syndrome, called aspirin-induced asthma, which affects about 10% of adults with asthma (63R ). Aspirin-induced asthma is usually accompanied by naso-ocular symptoms and can by triggered not only by aspirin, but by several NSAIDs, a fact that makes immunological cross-reactivity most unlikely. The propensity of an NSAID to precipitate an attack of asthma is probably related to inhibition of cyclo-oxygenase (63R ). There is evidence that potent inhibitors of COX-1 (such as ibuprofen, indomethacin, and naproxen) are

Anti-inflammatory and antipyretic analgesics and drugs used in gout

more likely to precipitate bronchoconstriction than NSAIDs that inhibit COX-2 preferentially (such as meloxicam and nimesulide) (39C , 64C ). A widely accepted hypothesis is that in patients with asthma and aspirin intolerance, NSAID-induced COX inhibition results in increased products from the 5-lipoxygenase pathway, the leukotrienes, which are both potent bronchoconstrictors and also inducers of mucous hypersecretion and airway edema. The leukotrienes implicated in aspirin intolerance are cysteinyl leukotrienes (61R , 63R ), but leukotriene release is probably not the only pathogenic mechanism. The hypothesis that in aspirin-induced asthma the attacks are triggered by inhibition of COX-1 and not COX-2 has been tested in three small studies, two of which were double-blind and placebo-controlled (65C –67 C ). In the first study (65C ) 12 patients with aspirin-induced asthma were challenged with increasing doses of rofecoxib (1.25–25 mg/day for 5 days); no patients had any adverse symptoms, and biochemical markers that reflect intolerance to aspirin in asthma (urinary leukotriene E4 and 9a-11b-PGF2 ) were unchanged. In the second study, 60 aspirin-sensitive asthmatics were challenged with oral rofecoxib (12.5 and 25 mg/day for 2 days) (66C ). There were no signs or symptoms of asthma in any patient and no reductions in FEV1 . In the third study, 27 patients with stable chronic asthma in whom inhalation of lysine aspirin caused a 20% fall in FEV1 were challenged with increasing doses of oral celecoxib (from 10 to 200 mg/day); they did not develop bronchoconstriction or other extrapulmonary reactions (67 C ). So is the safety of COX-2 inhibitors in patients with aspirin-induced asthma sufficiently well documented? Avoidance of NSAIDs is crucial in patients with asthma who have aspirin sensitivity, and hitherto two alternative analgesic options have been available: paracetamol and non-acetylated salicylates. Paracetamol is a generally safe substitute; however, it is a weak COX inhibitor and, albeit very rarely, patients who are sensitive to aspirin have an adverse reaction to high-dose paracetamol (68C ). Choline magnesium salicylate and salicylic acid are also weak COX inhibitors and should therefore be used with care in these patients. The results of the above-mentioned studies suggest that rofecoxib and celecoxib can be taken safely by

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patients with aspirin-induced asthma. However, this conclusion must be treated with caution, as only a few patients were studied and this does not exclude COX-2 inhibitors from participating in other types of reactions, including immune recognition after prior treatment. Gastrointestinal The results of CLASS and VIGOR showed, according to the investigators, similar efficacy with less risk of upper gastrointestinal complications. Unfortunately, when the FDA analysed the data from the entire study period, not just the first 6 months (as had been presented in the published article), CLASS did not show that celecoxib was associated with a significantly lower incidence of upper gastrointestinal complications than ibuprofen or diclofenac. Serious criticism was aimed at the authors on the grounds of design, data analysis, and misleading presentation of the results. They were charged with having published and circulated overoptimistic short-term pooled data from different protocols, and of omitting disappointing long-term data. They replied to these criticisms, but their explanations were not considered to be convincing (69r –71r ). Furthermore, Pharmacia, the manufacturers of celecoxib, continue to present inappropriately pooled short-term results from different protocols performed in different continents with different comparator drugs for the SUCCESS 1 trial, the successor to CLASS (69r –71r ). Problems have also occurred in interpreting the results of VIGOR (48C ). There were significantly fewer upper gastrointestinal adverse events with rofecoxib compared with naproxen, but an unexpected substantial excess of serious cardiovascular events, making the overall safety of rofecoxib uncertain. When the complete data from VIGOR were presented and all serious adverse events were included (not just gastrointestinal events) the patients who took naproxen had fewer overall serious events: 9.3% of the patients who took rofecoxib had a serious adverse event compared with 7.8% of those who took naproxen (RR = 0.81; 95% CI = 0.62, 0.97). The reasons for the discrepancy between celecoxib and rofecoxib in the frequency of upper gastrointestinal complications are not clear, but some hypotheses have been proposed. First, aspirin was used concomitantly with celecoxib

120 (20% of patients) in CLASS but not in VIGOR, increasing the risk of gastrointestinal damage. Secondly, diclofenac (which has greater COX2 selectivity than naproxen) was used as a comparator in CLASS. Thirdly, the dosages of celecoxib were too high and at the doses studied in CLASS celecoxib might not have had true selectivity for COX-2. Finally, the selectivity of celecoxib for COX-2 is probably lower than that of rofecoxib. Therefore, given major differences in study design and data analysis between the two trials, a valid comparison of the two coxibs is not possible from these data alone; a headto-head comparison in a large outcome study is needed (72r ). Two recently published articles have helped to clarify this point: a systematic review of randomized clinical trials on the upper gastrointestinal safety of celecoxib (73M ) and a population-based retrospective cohort comparison of the rate of upper gastrointestinal hemorrhages in over 40 000 NSAID-naïve elderly users of non-selective NSAIDs, celecoxib, or rofecoxib with the rate in 100 000 patients who had not been exposed to NSAIDs (74C ). In the systematic review all published and unpublished randomized clinical trials that compared at least 12 weeks of celecoxib treatment with placebo or a traditional NSAID (diclofenac, ibuprofen, naproxen) were analysed. Nine of 17 trials fulfilled the inclusion criteria (a total of 15 187 patients). Withdrawals because of drug-related gastrointestinal adverse effects, ulcers detected at endoscopy, and complicated ulcers were used as measures of gastrointestinal tolerability. Compared with those taking non-selective NSAIDs, the patients who took celecoxib had a lower rate of withdrawals because of adverse gastrointestinal effects at 12 weeks (3.2% vs 6.2%), but there was no significant difference between celecoxib and NSAIDs in the incidence of withdrawals for all adverse events. The incidence of ulcers detected at routine endoscopy at 12 weeks was also lower in patients who took celecoxib compared with those who took non-selective NSAIDs (6.2% vs 23%). In four trials that provided information on the incidence of ulcers detected by endoscopy according to whether or not patients were taking concomitant aspirin up to 325 mg/day, the benefit provided by celecoxib was greater in patients not taking aspirin. The incidences of ulcers were as follows:

Chapter 9

• • • •

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celecoxib alone 6.2%; celecoxib + aspirin 12%; non-selective NSAID alone 25%; non-selective NSAID + aspirin 26%.

However, these results must be treated with great caution, as the total number of patients who took prophylactic aspirin was small (150 taking celecoxib and 140 taking non-selective NSAIDs) and the largest number of patients came from a single trial (CLASS). The same warning applies to evaluation of the incidence of complicated ulcers (bleeds, perforation, and obstructions). The incidence of these serious events with celecoxib was 2.7% (11 events) versus 5% (20 events) in patients taking diclofenac or ibuprofen, a nonsignificant difference. This meta-analysis has provided further evidence that celecoxib has better upper gastrointestinal tolerability that some traditional NSAIDs when withdrawal from trials due to drug-related adverse effects or ulceration detected during routine endoscopy are used as measures of tolerability. However, not all ulcers detected by endoscopy progress to a serious event, and many probably heal spontaneously; the clinical relevance of this measure is therefore controversial. On the other hand, there is a consensus that ulcer complications, the prime cause of concern with NSAIDs, should be the primary end-point of outcome studies aimed at evaluating the gastrointestinal toxicity of NSAIDs. Unfortunately, this consensus is counterbalanced by the problems of doing such studies, as they need to be very large to achieve even marginal power and there are also problems in evaluating the clinical outcomes (72r ). Another recent study that deserves attention was an observational study of upper gastrointestinal hemorrhage in over 40 000 elderly patients taking COX-2 selective drugs (rofecoxib, celecoxib) or non-selective NSAIDs with and without misoprostol, compared with 100 000 non-NSAID users (74C ). Of about 1.3 million potential subjects aged 65 years and over, 364 686 (28%) were given an NSAID during the study period (about 1 year). From the total elderly population, the authors identified 5391 users of non-selective NSAIDs, 5087 users of diclofenac plus misoprostol, 14 583 users of rofecoxib, 18 908 users of celecoxib, and 100 000 controls. Most of the users of non-selective

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NSAIDs were taking naproxen (32%), ibuprofen (23%), or diclofenac (20%). During over 55 000 person-years of follow-up, there were 187 hospitalizations for upper gastrointestinal hemorrhage. Relative to the non-users, there was a significantly greater risk of upper gastrointestinal hemorrhage in the patients who took non-selective NSAIDs (adjusted risk ratio 4.0; 95% CI = 2.3, 6.9), diclofenac plus misoprostol (3.0; 1.7, 5.6), or rofecoxib (1.9; 1.3, 2.6), but not celecoxib (1.0; 0.7, 1.6). There were also significant differences in the risks of upper gastrointestinal hemorrhage. Relative to celecoxib users, there was a higher risk of hospitalization for upper gastrointestinal hemorrhage, not only among users of non-selective NSAIDs and diclofenac plus misoprostol but also among users of rofecoxib. This study has provided further evidence that the risk of upper gastrointestinal hemorrhage with COX-2 inhibitors is significantly lower than with conventional NSAIDs, whether or not they are taken with misoprostol. The apparently greater risk of gastrointestinal hemorrhage with rofecoxib than with celecoxib needs confirmation, as the study had some limitations, of which the most important were the low absolute number of events in the study group and the retrospective design. What are the implications of these data on the use of the coxibs? Overall they suggest that COX-2 selective inhibitors are less likely to cause upper gastrointestinal damage than some traditional NSAIDs. This advantage is measured by a lower number of events that represent a composite end-point of gastrointestinal toxicity, such as endoscopically detected symptomatic ulcers and serious ulcer complications (perforation, obstruction, bleeding). However, this may not be true in all patients, especially in those who simultaneously take aspirin. This question is of major clinical importance, as many patients with osteoarthritis or rheumatoid arthritis use low-dose aspirin for cardiovascular prophylaxis. We do not know whether gastrointestinal safety is preserved with the use of such combinations, nor whether a proton pump inhibitor should be added in this situation. Furthermore, the data on which of the coxibs has better gastrointestinal tolerability are inconclusive. Large outcome studies will be necessary to solve these questions. A final consideration is worth while. To focus attention only on gastrointestinal events

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may provide an incomplete picture of the benefit/harm profile of the COX-2 inhibitors. Metaanalysis of mortality and morbidity outcomes from CLASS and VIGOR has suggested that total mortality was higher with coxibs than with non-selective NSAIDs, although the difference was not statistically significant (45M ). Moreover, if one takes into account the incidence of serious adverse events (including death, admission to hospital, and any life-threatening event or events leading to serious disability) as a combined measure of harm, the incidence was significantly higher with COX-2 selective compounds than with other NSAIDs, and complicated gastrointestinal ulcers accounted for only a small proportion of total serious adverse events. Non-gastrointestinal serious adverse events call for more attention. Immunologic There is considerable difficulty and controversy in identifying and classifying these allergic reactions to NSAIDs, for many reasons (75R ). First, the difficulty in making a definite diagnosis in patients who have these reactions without provocative challenge with the suspected drug and other NSAIDs. Secondly, reactions are characterized by a large spectrum of target organ responses to NSAIDs, and the same drug may cause different types of reactions in different organs in the same or different individuals. Thirdly, a patient can have a similar reaction to a structurally different NSAID. Finally, reports of these reactions include different, often imprecise, terms, making interpretation difficult. It is worth evaluating the safety of new coxibs in patients who cannot tolerate non-selective NSAIDs. Although the celecoxib and rofecoxib package inserts warn about their use in patients who cannot tolerate aspirin and NSAIDs, there is little information about whether or not they cross-react. Some recent information on this topic may be of interest. Anaphylaxis Among the anaphylactic reactions to NSAIDs that result in different types of reaction (urticaria, angio-edema, asthma, or hypotension), there have been very few reports of anaphylactic shock. However, this life-threatening reaction has been described in patients taking celecoxib (76 A , 77 A ) or rofecoxib (78A ). Rofecoxib caused this reaction in a patient who had had a similar reaction to diclofenac, suggesting that COX-2 inhibitors may

122 be not safe in all individuals who have adverse reactions to non-selective COX inhibitors. It also suggests that different mechanisms may be involved in patients with asthma and in those with anaphylactoid reactions to NSAIDs. Sulfonamide-like allergic adverse reactions Concerns that COX-2 inhibitors may be associated with an increased risk of allergic reactions in patients with a history of sulfonamide hypersensitivity arise from the molecular structures of these compounds (SEDA-24, 119; 79R ). A sulfur component is necessary for the receptor binding of both celecoxib and rofecoxib, but their structures differ and they have different potentials for causing allergic reactions. Consequently, celecoxib is thought to be contraindicated in patients with a history of allergy to sulfonamides. The available data on the immunological tolerability profile of celecoxib and rofecoxib are scanty but merit attention. Sulfonamide-like adverse drug reactions seem to occur more frequently with celecoxib than with rofecoxib, according to a recent report from Sweden (80C ). The investigators identified a profile of 19 typical sulfonamide-like adverse reactions from published papers and the WHO Adverse Drug Reactions database from 1968 to 2000, and compared this profile with reported adverse drug reactions associated with celecoxib and rofecoxib. The WHO database contained 11 514 reports about celecoxib describing 21 292 suspected adverse drug reactions and 10 200 reports about rofecoxib describing 18 585 suspected drug reactions. The relative reporting rate of sulfonamide-like adverse drug reactions was almost twice as high for celecoxib as for rofecoxib (1.8; 95% CI = 1.6, 1.9) for all reports and for reports that listed a COX-2 inhibitor as the only suspected drug. The reporting rate for 15 of the 19 sulfonamide-like adverse drug reactions was higher for celecoxib than for rofecoxib, with significant differences for rash (relative reporting rate 2.3; 2.0, 2.6), urticaria (2.0; 1.6, 24), Stevens–Johnson syndrome (3.6; 1.4, 12), and photosensitivity (2.4; 1.5, 4.0). Fatal adverse drug reactions fitting the typical sulfonamide profile also occurred more often with celecoxib than with rofecoxib (1.8; 0.9, 4.0). Even though serious sulfonamide reactions are rare, their clinical impact warrants close monitoring as more data become available,

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and physicians should be aware of possible sulfonamide allergy when prescribing COX-2 inhibitors, in particular celecoxib. There have been single case reports of sulfonamide-like allergic reactions in patients taking celecoxib (see below), and in two cases sulfonamide allergy was ignored and was discovered only after an adverse reaction to celecoxib (81A ) or rofecoxib (82A ). Urticaria and angio-edema Of 110 patients with a history of urticaria and angio-edema triggered by one or more non-selective NSAIDs, who were submitted to 184 single-blind placebocontrolled oral challenges with the suspected NSAID, patients with a positive challenge underwent further oral challenge with various COX-2 inhibitors (celecoxib and rofecoxib, but also nimesulide and meloxicam, which are relatively selective COX-2 inhibitors) (83C ). The maximal challenge doses were celecoxib 200 mg, rofecoxib 25 mg, meloxicam 15 mg, and nimesulide 100 mg. Reactions (expressed as a percentage of tested patients with a positive test) varied among the COX-2 inhibitors: 33% (10/30) for celecoxib, 21% (16/75) for nimesulide, 17% (8/46) for meloxicam, and 3% (1/33) for rofecoxib. This suggests that the degree of cross-reactivity of COX-2 inhibitors was related to the degree of in vitro COX1 inhibition since meloxicam, nimesulide, and celecoxib inhibit COX-1 to a similar extent (84R ). The results also suggested that the most selective COX-2 inhibitor (rofecoxib) might be relatively safe in a patient with NSAID-induced urticaria/angio-edema. In another study, 34 patients with a history of urticaria and/or angio-edema after ingestion of at least two chemically unrelated non-selective NSAIDs, 22 of whom also had chronic urticaria, all underwent a single-blind, placebo-controlled oral tolerance test with rofecoxib (12 and 25 mg 1 h apart) (85C ). Rofecoxib caused urticaria and/or angio-edema in 6/34 patients (18%), with no difference between patients with or without a history of chronic urticaria. There was even better tolerability of rofecoxib in another study in 33 patients with documented urticaria/angio-edema after ingestion of two different NSAIDs (86C ). The patients underwent provocative tests with increasing doses of rofecoxib (from 6.25 mg to 25 mg); at the end of the challenge all tolerated rofecoxib 25 mg.

Anti-inflammatory and antipyretic analgesics and drugs used in gout

Other single case reports have supported the evidence of better tolerability of COX-2 selective inhibitors (in particular rofecoxib) in patients with a history of urticaria/angio-edema (39C , 87 C ). However, contrasting data have shown cross-reactivity of celecoxib with other NSAIDs and between celecoxib and rofecoxib (88c ). Why are COX-2 selective drugs better tolerated? The mechanisms underlying intolerance to chemically unrelated NSAIDs are unknown, but it has been hypothesized that intolerant patients may have exaggerated sensitivity to the effects of leukotrienes, which are more active than histamine in inducing wheal and flare reactions. Blockade of both COX-1 and COX-2 by non-selective NSAIDs increases the production of leukotrienes by the lipoxygenase pathway, whereas COX-2 selective agents do not increase the production of LTB4 or cysteinyl LTS . However, this may not be the only pathogenic mechanism, as some drugs probably trigger histamine release from mast cells and basophils non-specifically, and others may trigger immunological cross-reactivity. Overall, the above-mentioned studies and clinical experience suggest that urticaria and angioedema can occur with COX-2 inhibitors, albeit with a lower frequency than with non-selective NSAIDs. When prescribing COX-2 inhibitors one must be aware of possible cross-reactivity with non-selective NSAIDs or between celecoxib and rofecoxib. Reproductive system Many reproductive processes (ovulation, fertilization, implantation, decidualization, and parturition) depend on prostaglandin ligand–receptor interactions. It is therefore not surprising that selective COX2 inhibition has a negative local effect on ovulation, resulting in delayed follicular rupture and infertility, without affecting peripheral hormonal cyclicity (89R , 90C ). There have been several case reports that non-selective NSAIDs (diclofenac, naproxen, piroxicam) can cause infertility, attributed to “luteinized unruptured ovarian follicles” syndrome (91c –93c ). Now the syndrome has been documented in a double-blind, randomized, placebo-controlled study, in which women were assessed over two menstrual cycles while taking rofecoxib (90C ). Women who are trying

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to become pregnant should avoid taking any NSAIDs if possible, and those who need one for a chronic rheumatic disorder should be aware of possible infertility; in such cases further investigation is not required, as withdrawal of the drug restores fertility. Other effects on human reproduction by COX-2 inhibitors are uncertain and need further attention.

Celecoxib Psychiatric There have been two reports of visual hallucinations in patients taking celecoxib. • A 79-year-old woman presented to her optometrist with a 2-day history of seeing orange spots in both visual fields 2 months after starting to take celecoxib 100 mg/day (94A ). Physical examination and a CT scan were normal. Celecoxib was withdrawn and her symptoms resolved within 3 days. • An 81-year-old woman took celecoxib 100 mg/day, and over the next 2 weeks developed delirium and auditory and visual hallucinations (95A ). Celecoxib was withdrawn and her symptoms resolved over several days. She took a few doses of rofecoxib 12.5 mg/day 6 months later without any problem. She began to take rofecoxib regularly again 2 months later, and after 1 month developed agitation, confusion, and hallucinations. Physical examination suggested no cause of the delirium other than rofecoxib. A CT scan was negative. The rofecoxib was withdrawn, and over the next 2 days her symptoms resolved.

Auditory hallucinations have been previously reported in a patient taking celecoxib (SEDA-25, 134) but are probably uncommon. Gastrointestinal Celecoxib reportedly exacerbated inflammatory bowel disease in two patients (96A ). • An 80-year-old woman with ulcerative colitis started taking celecoxib for arthritic pain, and 3 days later developed abdominal pain and diarrhea. Celecoxib was withdrawn and her symptoms improved. • A 35-year-old woman with ileal and perianal Crohn’s disease took four doses of celecoxib for an orthopedic injury, and had rectal bleeding, severe abdominal pain, and worse diarrhea. Celecoxib was withdrawn and her symptoms returned to baseline within 5 days.

The possible association of NSAIDs with inflammatory bowel disease is a matter of controversy (SEDA-25, 131), and there is little

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clinical experience with the selective COX-2 inhibitors. Coxibs should not be prescribed for patients with chronic inflammatory bowel disease until more experience has accumulated.

the non-selective NSAIDs. Most of these renal adverse reactions occur in patients with risk factors associated with prostaglandin-dependent renal function (100A –102A ).

Liver There have been three case reports of acute cholestatic hepatitis in patients taking celecoxib.

Skin Stevens–Johnson syndrome occurred in a 58-year-old man taking celecoxib (103A ). He recovered promptly after withdrawal. The reaction recurred 1 month later, after one dose of celecoxib. Sweet’s syndrome can be associated with several drugs. A case involving celecoxib has now been reported (104A ).

• A 55-year-old non-alcoholic obese woman, who was allergic to sulfa drugs, presented with a 5day history of jaundice, malaise, and a pruritic rash that began 3 weeks after she started to take celecoxib 200 mg/day for radicular pain (97A ). There were marked increases in liver enzymes and bilirubin and a peripheral eosinophilia. Liver biopsy showed marked intrahepatocyte cholestasis with eosinophil-rich inflammation, consistent with a drug reaction. Her symptoms and laboratory abnormalities completely resolved after withdrawal of celecoxib but took a long time (4 months) to normalize. • A 54-year-old woman took celecoxib 200 mg/day for sacroiliac pain (98A ). After 4 days her pain resolved, but she developed generalized pruritus, which resolved when celecoxib was withdrawn. A week later the pain recurred and celecoxib was restarted; 2 days later she again developed pruritus associated with dark urine and 5 days later jaundice and raised bilirubin and liver enzymes. Her eosinophil count was raised. On withdrawal of celecoxib her liver function tests improved and her symptoms resolved. • A 49-year-old man with alcoholic cirrhosis developed jaundice, fatigue, and choluria after he started to take celecoxib 200 mg/day for musculoskeletal pain (99A ). There were increases in transaminases, alkaline phosphatase, and bilirubin (to 547 µmol/l). Liver biopsy showed cirrhosis and marked hepatocellular cholestasis. On withdrawal of celecoxib the bilirubin began to fall very slowly; 1 year later he was well, with a total bilirubin concentration of 44 µmol/l.

• A 57-year-old man developed the typical cutaneous erosions and plaques of Sweet’s syndrome after taking celecoxib 100 mg bd for 1 week for bursitis. Celecoxib was withdrawn and the mucocutaneous lesions began to clear. However the bursitis recurred and he restarted celecoxib. The cutaneous lesions worsened dramatically. After withdrawal of celecoxib for the second time the lesions cleared completely.

Drug interactions Co-administration of celecoxib and clopidogrel can increase the hemorrhagic potential of clopidogrel, possibly by a pharmacokinetic interaction involving CYP2C9 (105A ). However this possibility requires confirmation, as serious, sometimes fatal, hemorrhage has been reported during the postmarketing use of clopidogrel alone (106A ).

Parecoxib Parecoxib sodium is an injectable COX-2 inhibitor developed for the treatment of acute pain. It is a pro-drug of a sulfonamidebased COX-2 inhibitor, valdecoxib, a potent anti-inflammatory and analgesic drug. The published information on this compound is inadequate to draw any conclusion about its tolerability. Single-dose and multiple-dose studies have not shown any safety problems compared with placebo (42r , 107c –109c ). In small shortterm endoscopic studies parecoxib was much better tolerated than the non-selective NSAID ketorolac (110c , 111c ).

The histories, clinical findings, and laboratory tests in these cases all suggested celecoxibinduced acute cholestatic hepatitis. The first case suggested that a sulfonamide-like allergic reaction was the pathogenic mechanism, and the same mechanism cannot be excluded in the other two patients, as sulfonamide allergy is often ignored and is discovered only when an adverse reaction occurs (see also the special review above). Celecoxib should not be given to patients who are allergic to sulfa drugs.

Rofecoxib

Urinary tract As more experience accumulates it appears clear that COX-2 inhibitors have a nephrotoxic potential similar to that of

Nervous system Aseptic meningitis is a rare adverse effect of non-selective NSAIDs in patients with or without connective tissue disease

Anti-inflammatory and antipyretic analgesics and drugs used in gout

or rheumatological disease. Rofecoxib has been implicated in five patients (four women and one man), in each case occurring within 12 days of the start of rofecoxib therapy (112A ). The clinical presentations and cerebrospinal fluid findings were typical of aseptic meningitis. One patient had rheumatoid arthritis. After drug withdrawal and recovery, two consecutive rechallenges in one patient led to relapses. Urinary tract Acute renal insufficiency has been reported after the use of rofecoxib in patients with predisposing conditions, such as chronic renal insufficiency, renal transplantation, heart disease, liver cirrhosis, and dehydration (113A –116A ). COX-2 inhibitors should be used with great caution, if at all, in patients with medical problems that are associated with prostaglandin-dependent renal function. From this point of view they do not differ from traditional NSAIDs (117A ). Rofecoxib 12.5 mg bd for arthritic pain was associated with biopsy-proven acute tubulointerstitial nephritis in a 67-year-old woman; another 16 cases of possible tubulointerstitial nephritis have been reported to the manufacturers of celecoxib between its launching in 1999 and July 2001, but the diagnosis was not confirmed in 12 of these cases (118Ar ). Drug interactions Methotrexate Methotrexate is often prescribed for the management of rheumatoid arthritis, and some NSAIDs have been reported to interact, causing increased plasma concentrations associated with impaired renal function. The safety of concurrent rofecoxib and oral methotrexate has been studied for 3 weeks in 25 patients with rheumatoid arthritis (119c ). Rofecoxib 12.5–50 mg/day had no effect on the plasma concentrations or renal clearance of methotrexate, but supratherapeutic doses of rofecoxib (75 and 250 mg) caused a significant increase in the plasma methotrexate AUC and reduced renal clearance. Warfarin Significant increases in International Normalized Ratio (INR) have been reported in patients who took rofecoxib and warfarin; in some, the increase in INR was accompanied by a bleeding event (120A , 121A ). Careful monitoring of the INR in patients taking warfarin and concomitant rofecoxib is mandatory.

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MISCELLANEOUS COMPOUNDS Nimesulide Liver Further reports of the potential hepatotoxicity of nimesulide continue to appear (SEDA-25, 135; 122A –124A ). A wide range of types of liver damage have been documented (125A ). Some patients have required liver transplantation (126A ) and deaths have occurred (127A ). The pathogenic mechanism of these unpredictable, sometimes severe, reactions is uncertain (128r , 129r ). In recent months in some countries nimesulide has been withdrawn from the market or its use has been restricted.

DRUGS USED-IN THE TREATMENT OF GOUT

(SED-14, 310; SEDA-23, 122; SEDA-25, 135)

Allopurinol Nervous system A 60-year-old man developed aseptic meningitis after taking allopurinol on two separate occasions (130A ). Immunologic Hypersensitivity may preclude the use of allopurinol. One way to overcome this problem is desensitization (SEDA-25, 135). A protocol for selected patients who have skin reactions has been described (131C ). The standard desensitization protocol consisted of an initial allopurinol dosage of 50 µg/day, increasing every 3 days to a target of 50–100 mg/day. The interval between dosage increases was extended to 5 days or more in elderly patients with multiple co-morbidity. Desensitization was successful in 25/32 patients (78%); 28 patients completed the desensitization protocol and 21 did so without requiring deviation from the standard dosage schedule and without adverse effects. During follow-up for 902 patient-months, seven of the 28 patients had recurrent skin eruptions after completing the desensitization protocol and after rechallenge with allopurinol. Desensitization to allopurinol is not recommended for all patients, but it can be useful

126 in selected patients who have had a pruritic maculopapular eruption during treatment with

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allopurinol and who cannot be treated with other drugs.

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45. Wright JM. The double-edged sword of COX2 selective NSAIDs. Can Med Assoc J 2002; 167: 1131–7. 46. McCormack JP, Rangno R. Digging for data from the COX-2 trials. Can Med Assoc J 2002; 166: 1649–50. 47. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomised controlled trial. J Am Med Assoc 2000; 284: 1247–55. 48. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Bosi Ferraz M, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. New Engl J Med 2000; 343: 1520–8. 49. White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, Geis GS, Lefkowith JB. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002; 89: 425–30. 50. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. J Am Med Assoc 2001; 286: 954–9. 51. FitzGerald GA, Cheng Y, Austin S. COX-2 inhibitors and the cardiovascular system. Clin Exp Rheumatol 2001; 19: S31–6. 52. Wooltorton E. What’s all the fuss? Safety concerns about COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex). Can Med Assoc J 2002; 166: 1692–3. 53. Van Hecken A, Schwartz JI, Depre M, De Lepeleire I, Dallob A, Tanaka W, Wynants K, Buntinx A, Arnout J, Wong PH, Ebel DL, Gertz BJ, De Schepper PJ. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40: 1109–20. 54. Cleland JGF. No reduction in cardiovascular risk with NSAIDs – including aspirin? Lancet 2002; 359: 92–3. 55. Dalen JE. Selective COX-2 inhibitors, NSAIDs, aspirin, and myocardial infarction. Arch Intern Med 2002; 162: 1091–2. 56. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 350: 118–23. 57. Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002; 162: 1099–104. 58. Watson DJ, Rhodes T, Bing Cai MS, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002; 162: 1105–10. 59. Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute

128 myocardial infarction. Arch Intern Med 2002; 162: 1111–15. 60. Anonymous. Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. New Engl J Med 1989; 321: 129–35. 61. Levy S, Volans G. The use of analgesics in patients with asthma. Drug Saf 2001; 24: 829–41. 62. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. Eur Respir J 2000; 16: 432–6. 63. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 1999; 104: 5–13. 64. Bianco S, Robuschi M, Petrigni G, Scuri M, Pieroni MG, Refini RM, Vaghi A, Sestini PS. Efficacy and tolerability of nimesulide in asthmatic patients intolerant to aspirin. Drugs 1993; 46 Suppl 1: 115–20. 65. Szczeklik A, Nizankowska E, Bochenek G, Nagraba K, Mejza F, Swierczynska M. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy 2001; 31: 219–25. 66. Stevenson DD, Simon RA. Lack of crossreactivity between rofecoxib and aspirin in aspirinsensitive patients with asthma. J Allergy Clin Immunol 2001; 108: 47–51. 67. Dahlén B, Szczeklik A, Murray JJ. Celecoxib in patients with asthma and aspirin intolerance. New Engl J Med 2001; 344: 142–3. 68. Settipane RA, Stevenson DD. Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma. J Allergy Clin Immunol 1989; 84: 26– 33. 69. Geis GS. CLASS clarification: reaffirms the medical importance of the analyses and results. Br Med J USA 2002; 2: 522–3. 70. Juni P, Rutjes AWS, Dieppe P. Pharmacia addresses June 1 editorial regarding CLASS study: authors’ response. Br Med J 2002; 324: 1287–8. 71. Budenholzer BR, Geis GS, Mamdani M, Juurlink DN, Anderson GM, Stover RR, Juni P, Rutjes AWS, Dieppe P. Are selective COX 2 inhibitors superior to traditional NSAIDs? Br Med J 2002; 325: 161. 72. Hawkey CJ. Outcomes studies of drug induced ulcer complications: do we need them and how should they be done? Br Med J 2000; 321: 291–3. 73. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Br Med J 2002; 325: 619–28. 74. Mamdani M, Rochon PA, Juurlink DN, Kopp A, Andersons GM, Naglie G, Austin PC, Laupacis A. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional nonsteroidal anti-inflammatory drugs. Br Med J 2002; 325: 624–7. 75. Stevenson DD, Sanchez-Borges M, Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclooxygenase en-

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zymes. Ann Allergy Asthma Immunol 2001; 87: 177–80. 76. Levy MB, Fink JN. Anaphylaxis to celecoxib. Ann Allergy Asthma Immunol 2001; 87: 72–3. 77. Habki R, Vermeulen C, Bachmeyer C, Charoud A, Mofredj A. Anaphylactic shock induced by celecoxib. Ann Med Interne 2001; 152: 355. 78. Schellenberg RR, Isserow SH. Anaphylactoid reaction to a cyclooxygenase-2 inhibitor in a patient who had a reaction to a cyclooxygenase-1 inhibitor. New Engl J Med 2001; 345: 1856–7. 79. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of ‘sulfa’ allergy. Drug Saf 2001; 24: 239–47. 80. Wiholm BE. Identification of sulfonamide-like adverse drug reactions to celecoxib in the World Health Organization database. Curr Med Res Opin 2001; 17: 210–16. 81. Anonymous. COX-2 inhibitor-induced rash. Consultant 2001; 41: 1338. 82. Kaur C, Sarkar R, Kanwar AJ. Fixed drug eruption to rofecoxib with cross-reactivity to sulfonamides. Dermatology 2001; 203: 351. 83. Borges MS, Capriles-Hulett A, CaballeroFonseca F, Perez CR. Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions. Ann Allergy Asthma Immunol 2001; 87: 201–4. 84. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 1999; 96: 7563–8. 85. Asero R. Tolerability of rofecoxib. Allergy Eur J Allergy Clin Immunol 2001; 56: 916–17. 86. Berges-Gimeno MP, Camacho-Garrido E, Garcia-Rodriguez RM, Alfaya T, Martin Garcia C, Hinojosa M. Rofecoxib safe in NSAID hypersensitivity. Eur J Allergy Clin Immunol 2001; 56: 1017–18. 87. Enrique E, Cistero-Bahima A, San MiguelMoncin MM, Alonso R. Rofecoxib should be tried in NSAID hypersensitivity. Allergy Eur J Allergy Clin Immunol 2000; 55: 1090. 88. Kelkar PS, Butterfield JH, Teaford HG. Urticaria and angioedema from cyclooxygenase-2 inhibitors. J Rheumatol 2001; 28: 2553–4. 89. Norman RJ. Reproductive consequences of COX-2 inhibition. Lancet 2001; 358: 1287–8. 90. Pall MS, Friden BE, Brannstrom M. Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. Hum Reprod 2001; 16: 1323–8. 91. Smith G, Roberts R, Hall C, Nuki G. Reversible ovulatory failure associated with the development luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs. Br J Rheumatol 1996; 35: 458–62. 92. Akil M, Amos RS, Stewart P. Infertility may sometimes be associated with NSAID consumption. Br J Rheumatol 1996; 35: 76–8.

Anti-inflammatory and antipyretic analgesics and drugs used in gout 93. Mendonca LL, Khamashta MA, Nelson-Piercy C, Hunt BJ, Hughes GR. Non-steroidal antiinflammatory drugs as a possible cause for reversible infertility. Rheumatology 2000; 39: 880–2. 94. Lund BC, Neiman RF. Visual disturbance associated with celecoxib. Pharmacotherapy 2001; 21: 114–15. 95. MacKnight C, Rojas-Fernandez CH. Celecoxib- and rofecoxib-induced delirium. J Neuropsychiatry Clin Neurosci 2001; 13: 305–6. 96. Bonner GF. Exacerbation of inflammatory bowel disease associated with use of celecoxib. Am J Gastroenterol 2001; 96: 1306–8. 97. Galan MV, Gordon SC, Silverman AL. Celecoxib-induced cholestatic hepatitis. Ann Intern Med 201: 134: 254. 98. O’Beirne JP, Cairns SR. Drug Points: cholestatic hepatitis in association with celecoxib. Br Med J 2001; 323: 23. 99. Alegria P, Lebre L, Chagas C. Celecoxibinduced cholestatic hepatotoxicity in a patient with cirrhosis. Ann Intern Med 2002: 137: E75. 100. Graham MG. Acute renal failure related to high-dose celecoxib. Ann Intern Med 2001; 135: 69–70. 101. Pfister AK, Crisalli RJ, Carter WH. Cyclooxygenase-2 inhibition and renal function. Ann Intern Med 2001; 134: 1077. 102. Alkhuja S, Menkel RA, Alwarshetty M, Ibrahimbacha AM. Celecoxib-induced nonoliguric acute renal failure. Ann Pharmacother 2002; 36: 52–4. 103. Gill S, Hermolin RH. Case report of a Stevens–Johnson type reaction to celecoxib. Can J Hosp Pharm 2001; 54: 146. 104. Fye KH, Crowley E, Berger TG, LeBoit PE, Connolly MK. Celecoxib-induced Sweet’s syndrome. J Am Acad Dermatol 2001; 45: 300–2. 105. Fisher AA, Le Couteur DG. Intracerebral hemorrhage following possible interaction between celecoxib and clopidogrel. Ann Pharmacother 2001; 35: 1567–9. 106. Irish Medicines Board. Clopidogrel (Plavix). Newsletter National Pharmacovigilance Center 2001; Sep: 2–3. 107. Cheer SM, Goa KL. Parecoxib (parecoxib sodium). Drugs 2001; 61: 1133–41. 108. Karim A, Laurent A, Slater ME, Kuss ME, Qian J, Crosby-Sessoms BA, Hubbard RC. A pharmacokinetic study of intramuscular (IM) parecoxib sodium in normal subjects. J Clin Pharmacol 2001; 41: 1111–19. 109. Daniels SE, Grossman EH, Kuss ME, Talwalker S, Hubbard RC. A double-blind, randomised comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and placebo in a post-oral surgery pain model. Clin Ther 2001; 23: 1018–31. 110. Stoltz RR, Harris SI, Kuss ME, LeCompte D, Talwalker S, Dhadda S, Hubbard RC. Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects. Am J Gastroenterol 2002; 97: 65–71. 111. Harris SI, Kuss M, Hubbard RC, Goldstein JL. Upper gastrointestinal safety evaluation of pare-

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coxib sodium, a new parenteral cyclooxygenase2-specific inhibitor, compared with ketorolac, naproxen, and placebo. Clin Ther 2001; 23: 1422–8. 112. Barclay L. Aseptic meningitis cases linked to rofecoxib. Arch Intern Med 2002; 162: 713–15. 113. Woywodt A, Schwarz A, Mengel M, Haller H, Zeidler H, Kohler L. Nephrotoxicity of selective COX-2 inhibitors. J Rheumatol 2001; 28: 2133–5. 114. Ofran Y, Bursztyn M, Ackerman Z. Rofecoxib-induced renal dysfunction in a patient with compensated cirrhosis and heart failure. Am J Gastroenterol 2001; 96: 1941. 115. Wahba AL, Soper C. Acute, anuric renal failure associated with two doses of a cyclooxygenase 2-inhibitor. Nephron 2001; 89: 239. 116. Meador R, Kolasinski S. Acute renal failure can occur with inappropriate use of a coxib. J Clin Rheumatol 2001; 7: 413–14. 117. Rocha JL, Fernandez-Alonso J. Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 2001; 357: 1946–7. 118. Demke D, Zhao S, Arellano RM. Interstitial nephritis associated with celecoxib. Lancet 2001; 358: 1726–7. 119. Schwartz JI, Agrawal NGB, Wong PH, Bachmann KA, Porras AG, Miller JL, Ebel DL, Sack MR, Holmes GB, Redfern JS, Gertz BJ. Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients. J Clin Pharmacol 2001; 41: 1120–30. 120. Anonymous. Interaction of rofecoxib with warfarin. Aust Adv Drug React Bull 2002; 21 (Feb): 3. 121. Stading JA, Skrabal MZ, Faulkner MA. Seven cases of interaction between warfarin and cyclooxygenase-2 inhibitors. Am J Health-Syst Pharm 2001; 58: 2076–80. 122. Sbeit W, Krivoy N, Shiller M, Farah R, Cohen HI, Struminger L, Reshe R. Nimesulide-induced acute hepatitis. Ann Pharmacother 2001; 35: 1049– 52. 123. Dumortier J, Borel I, Delafosse B, Vial T, Scoazed JY, Boillot O. Subfulminant hepatitis associated with nimesulide treatment requiring liver transplantation. Gastroenterol Clin Biol 2002; 26: 415–16. 124. Ferreiro C, Vivas S, Jorquera F, Dominguez AB, Espinel J, Munoz F, Herrera A, Fernandez MJ, Olcoz JL, Ortiz de Urbina J. Toxic hepatitis caused by nimesulide, presentation of a new case and review of the literature. Gastroenterol Hepatol 2000; 23: 428–30. 125. Macia MA, Carvajal A, Del Pozo JG, Vera E, Del Pino A. Hepatotoxicity associated with nimesulide: data from the Spanish Pharmacovigilance System. Clin Pharmacol Ther 2002; 72: 596–7. 126. Rodrigo L, de Francisco R, Perez-Pariente JM, Cadahia V, Tojo R, Rodriguez M, Lucena MI, Andrade RJ. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation. Scand J Gastroenterol 2002; 37: 1341–3.

130 127. Merlani G, Fox M, Oehen HP, Cathomas G, Renner EL, Fattinger K, Schneemann M, KullakUblick GA. Fatal hepatotoxicity secondary to nimesulide. Eur J Clin Pharmacol 2001; 57: 321–6. 128. Boelsterli UA. Mechanisms of NSAIDinduced hepatotoxicity: focus on nimesulide. Drug Saf 2002; 25: 633–48. 129. Rainsford KD. Relationship of nimesulide safety to its pharmacokinetics: assessment of ad-

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verse reactions. Rheumatology (Oxford) 1999; 38: 4–10. 130. Greenberg LE, Nguyen T, Miller SM. Suspected allopurinol-induced aseptic meningitis. Pharmacotherapy 2001; 21: 1007–9. 131. Fam AG, Dunne SM, Iazzetta J, Paton TW. Efficacy and safety of desensitisation to allopurinol following cutaneous reactions. Arthritis Rheum 2001; 44: 231–8.

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GENERAL TOPICS In a Canadian multicenter, open, randomized trial in 156 patients to determine whether sedation with propofol would lead to shorter times to tracheal extubation and length of stay in ICU than sedation with midazolam, the patients who received propofol spent longer at the target sedation level than those who received midazolam (60% vs 44% respectively) (1C ). Propofol allowed clinically significantly earlier tracheal extubation than midazolam (6.7 vs 24.7 hours). However, this did not result in earlier discharge from the ICU. Nervous system Hypertension and tachycardia during coronary angiography can cause significant problems. In a double-blind, randomized, placebo-controlled study during coronary angiography in 90 patients, midazolam with or without fentanyl under local anesthesia provided better hemodynamic stability than placebo (2C ). Clinical electrophysiological procedures can be very complex and prolonged, requiring safe and effective conscious sedation. A study in 700 patients has shown that intermittent midazolam plus fentanyl in electrophysiological procedures is safe and efficacious (3C ). All the staff were ACLS certified and had successfully completed conscious sedation training courses, but none was an anesthetist; one team member was dedicated to monitoring conscious sedation and providing rescue defibrillation if required. Gastrointestinal Several small clinical trials have suggested that total intravenous anesthesia with propofol reduces the incidence of postoperative nausea and vomiting and results in © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

shorter emergence times. However, a systematic review (4M ) and a meta-analysis (5M ) have shown that most studies were small, did not have follow-up for more than 6 hours postoperatively, and were sponsored by industry. The results were difficult to combine owing to heterogeneous definitions of postoperative nausea and vomiting. The risk of postoperative nausea and vomiting has been studied in a randomized, controlled trial of total intravenous anesthesia with propofol versus inhalational anesthesia with isoflurane and nitrous oxide in 2010 patients (6C ). It was accompanied by an economic analysis. Propofol total intravenous anesthesia reduced the absolute risk of postoperative nausea and vomiting up to 72 hours postoperatively from 61% to 46%, in in-patients (NNT = 6) and from 46% to 28%, in out-patients (NNT = 5). Both anesthetic techniques were otherwise similar. Anesthesia drug costs were more than three times higher for propofol total intravenous anesthesia (as propofol is substantially more expensive than isoflurane–nitrous oxide). However, the patients preferred propofol. Middle ear surgery is associated with high rates of postoperative nausea and vomiting. Propofol in subhypnotic doses is a potent antiemetic. In a double-blind, randomized study a small dose of propofol (0.5 mg/kg) was compared with droperidol (20 µg/kg) or metoclopramide (0.2 mg/kg) given at the completion of surgery performed in 90 patients under standard anesthesia with thiopental, fentanyl, and sevoflurane (7C ). Follow up was to 24 hours. The incidence of emesis at 24 hours was significantly lower in those who received propofol (10% vs 33% and 40% for droperidol and metoclopramide respectively). Because population measures of anesthetic dosages do not consider the individual’s anesthetic needs, anesthetists often err on the side

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132 of relative overdosage during balanced anesthesia, in order to prevent the devastating consequences of unintentional awareness during surgery. This excessive depth of anesthesia contributes to delayed recovery and more adverse effects, which is particularly important in ambulatory surgery. Monitoring of the bispectral index-processed electroencephalogram has enabled anesthetists to monitor the depth of anesthesia and has brought greater precision to the administration of intravenous and inhaled anesthetics and opioids. The hypothesis that titration of the maintenance dose of sevoflurane during out-patient gynecological surgery using bispectral index monitoring reduces postoperative vomiting and improves recovery has been tested in a randomized, controlled study in 22 patients (8C ). The monitored patients had significantly less vomiting than the controls (16% versus 40%).

ANESTHETIC VAPORS

(SED-14, 318; SEDA-23, 126; SEDA-24, 128; SEDA-25, 139)

Halothane Nervous system The effect of increasing and decreasing concentrations of halothane on the cerebral circulation in 11 young children (aged 4 months to 3.5 years) undergoing minor urological surgery under general relaxant and caudal anesthesia has been studied (9c ). Cerebral blood flow velocity was measured in the middle cerebral artery using transcranial Doppler ultrasound. There was significantly increased cerebral blood flow velocity when the dose was increased from 0.5 to 1.0 minimum alveolar concentration (MAC) and from 0.5 to 1.5 MAC, but not when it was increased from 1.0 to 1.5 MAC. When the halothane concentration was reduced from 1.5 to 1.0 MAC cerebral blood flow velocity fell significantly, whereas there was no effect when the concentration was reduced from 1.0 to 0.5 MAC. These results suggest that there is cerebrovascular hysteresis in response to increasing and decreasing concentrations of halothane. Further comparative studies with sevoflurane are recommended.

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Sevoflurane Cardiovascular Congenital or acquired forms of the long QT syndrome can result in ventricular tachycardia (torsade de pointes). Many drugs, including inhalational anesthetics, alter the QT interval, and sevoflurane prolongs the rate-corrected QT interval (QTc ). In a randomized study of whether sevoflurane-associated QTc prolongation was rapidly reversed when propofol was used instead, 32 patients were randomly allocated to one of two groups (10c ). All received sevoflurane induction and maintenance for the first 15 minutes. In one group, sevoflurane was then withdrawn, and anesthesia was maintained with propofol for another 15 minutes; the other group continued to receive sevoflurane for 30 minutes. Sevofluraneassociated QTc prolongation was fully reversed within 15 minutes when propofol was substituted. Respiratory Inhalational induction of anesthesia is common in children. Sevoflurane is pleasant to breathe and has a rapid onset and offset of action and is challenging the tradition of halothane induction in children. Deep anesthesia with sevoflurane can be obtained rapidly, and recovery is also faster than with halothane. In a randomized study of the respiratory effects of high concentrations of halothane and sevoflurane in 21 healthy boys undergoing inguinal or penile surgery, there was similar respiratory depression with each agent (11C ). Minute ventilation fell by about 50% as a result of a reduction in tidal volume, despite an increase in respiratory rate. Nervous system Convulsions during anesthesia are of concern, because they can be masked by muscle relaxants. They can also cause postoperative delirium. Sevoflurane can cause epileptiform activity on the electroencephalogram, especially during emergence from anesthesia. It has also been associated with epileptiform discharges in volunteer studies, but convulsions appear to be very rare. Epileptiform activity has been reported during sevoflurane anesthesia, but not with propofol in the same individual (12A ). • A 62-year-old woman with no personal or family history of seizures had general relaxant anesthesia for plastic surgery using a total intravenous

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anesthetic technique with propofol, remifentanil, and cisatracurium, after benzodiazepine premedication. Routine EEG monitoring showed continuous slowing followed by burst suppression (consistent with very deep anesthesia), but no epileptiform activity. At a second procedure, and following identical benzodiazepine premedication and induction with propofol, anesthesia was maintained with sevoflurane (plus remifentanil for analgesia and cisatracurium for neuromuscular blockade). During the procedure, sevoflurane was increased from 2 to 8%. After 5 minutes, at an end-tidal concentration of 5.9%, there was epileptiform activity on the EEG. There were no hemodynamic changes.

Epileptiform activity on the electroencephalogram in association with sevoflurane induction has also been reported in a prospective study of 20 non-premedicated healthy children in whom EEG monitoring was started before sevoflurane induction (13c ). At 2 MAC there was epileptiform activity in two boys, with spontaneously resolving myoclonic movements. These cases show that clinicians need to be aware of the possibility of generalized seizures, especially in patients who are predisposed to seizures. Psychiatric Sevoflurane often causes postoperative delirium and agitation in children, and this may be severe. The effect of intravenous clonidine 2 µg/kg on the incidence and severity of postoperative agitation has been assessed in a double-blind, randomized, placebo-controlled trial in 40 boys who had anesthetic induction with sevoflurane after oral midazolam premedication (14C ). There was agitation in 16 of those who received placebo and two of those who received clonidine; the agitation was severe in six of those given placebo and none of those given clonidine. The effect of a single bolus dose of midazolam before the end of sevoflurane anesthesia has been investigated in a double-blind, randomized, placebo-controlled trial in 40 children aged 2–7 years (15C ). Midazolam significantly reduced the incidence of delirium after anesthesia. However, when it was used for severe agitation midazolam only reduced the severity without abolishing agitation. The authors concluded that midazolam attenuates, but does not abolish agitation after sevoflurane anesthesia. Liver and urinary tract Debate still surrounds the effect of sevoflurane on perioperative renal and liver function. Renal impairment

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often follows cardiac surgery, but in a randomized trial in elective coronary artery surgery in 354 patients sevoflurane did not produce greater increases in serum creatinine concentrations than isoflurane or propofol (16C ). It has been suggested that prolonged lowflow closed-circuit anesthesia with sevoflurane may maximize exposure to the haloalkene degradation product Compound A, which causes nephrotoxicity and hepatotoxicity in rats, particularly if barium hydroxide lime is used. In a randomized study of the renal and hepatic effects of prolonged low-flow anesthesia with sevoflurane or isoflurane in patients undergoing prolonged operations (over 8 h), using a technique that maximized Compound A production, there were no significant differences between the groups in serum creatinine or urea concentrations, creatinine clearance, or urinary protein or glucose excretion at 24 or 72 h (17C ). Proteinuria and glycosuria were common in both groups. There was no correlation between exposure to Compound A and any measure of renal function. There were no differences in markers of hepatocellular injury. There was no evidence of nephrotoxicity of sevoflurane even at high degrees of exposure to Compound A for as long as 17 h. The effect on renal function of minimalflow (as opposed to low-flow) anesthesia with sevoflurane and isoflurane has been examined in another randomized trial in 76 patients (18C ). There were no significant differences between the groups in blood chemistry markers of renal or hepatic function or in urinary markers of tubular injury, despite high exposure to Compound A in the patients who received sevoflurane. Plasma alpha-glutathione S-transferase activity (α-GT) is a more sensitive and specific marker of hepatocellular injury than aminotransferase activity and it correlates better with hepatic histology. Anesthesia with halothane leads to transiently raised α-GT activity, but propofol and isoflurane do not. In a randomized study of plasma α-GT activity during and after low-flow anesthesia with sevoflurane or isoflurane there were no significant differences in α-GT activities between the two groups during or after anesthesia (19C ). Thus, the evidence suggests that sevoflurane is as safe as isoflurane in low-flow anesthesia with respect to renal and liver dysfunction.

134 Urinary tract Sevoflurane may contribute to the development of renal insufficiency, perhaps due to toxicity from either the haloalkene degradation product Compound A or inorganic fluoride ions. Compound A is produced in carbon dioxide absorbers (soda lime and barium hydroxide lime in particular) and is nephrotoxic in rats but not humans. Fluoride ions are produced through metabolism of sevoflurane and can reach high concentrations after prolonged anesthesia. • Transient renal tubular dysfunction has been reported in a patient with asthma requiring mechanical ventilation who received sevoflurane for 9 days (20A ). Soda lime was not used, and the cumulative dose was 298 MAC-hours. Serum and urinary inorganic fluoride concentrations reached maximum concentrations of 71 and 2047 µmol/l respectively. Markers of renal tubular injury were also greatly raised (urinary N-acetyl-b-D-glucosaminidase and b2 -microglobulin). However, urine volume, creatinine clearance, and serum creatinine and urea concentrations were unaffected.

Musculoskeletal Malignant hyperthermia triggered by sevoflurane has been reported in two cases (21A , 22A ). The second case was remarkable, in that the specific treatment dantrolene was not available, and yet the patient survived with aggressive active cooling and general supportive measures, including sodium bicarbonate. Drug interactions Ketorolac, which can cause renal vasoconstriction by inhibiting cyclo-oxygenase, is often given to patients anesthetized with sevoflurane, which is also potentially nephrotoxic. The effect of ketorolac has been assessed in a placebo-controlled randomized study in 30 women undergoing breast surgery with sevoflurane anesthesia (23C ). There were no differences in several markers of renal injury in those who did or did not receive ketorolac. The effect of the uricosuric agent probenecid in prolonged sevoflurane anesthesia has been examined in 64 patients randomized to receive high-flow or low-flow anesthesia with sevoflurane with or without preoperative oral probenecid (24C ). There were no differences in urea, creatinine, or creatinine clearance among the treatments. However, patients who received low-flow sevoflurane had some evidence of renal tubular injury (raised urinary markers) compared with those who received either high-flow anesthesia or probenecid.

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Trichloroethylene Carcinogenicity The incidence of cancer among 803 Danish workers exposed to trichloroethylene has been evaluated (25c ). There was no overall increase. However, the standardized incidence ratio was significantly higher in men with non-Hodgkin’s lymphoma or esophageal cancer and in women with cervical cancer. The carcinogenic association was not dose related.

NITROUS OXIDE

(SED-14, 325; SEDA-23, 129; SEDA-24, 132; SEDA-25, 142) Cardiovascular Nitrous oxide inhibits methionine synthase, thereby preventing the conversion of homocysteine to methionine. A high homocysteine concentration has been identified as an independent risk factor for coronary artery, cerebrovascular, peripheral vascular, and venous thromboembolic disease. The effect of nitrous oxide on homocysteine concentrations and perioperative myocardial ischemia/infarction has been extensively reviewed (26R ). Nitrous oxide causes acute rises in postoperative homocysteine concentrations temporally associated with postoperative myocardial ischemia. Preoperative oral folate and vitamins B6 and B12 blunt nitrous oxideinduced postoperative increases in plasma homocysteine (27c ). Nervous system Two cases of polyneuropathy and myelopathy associated with chronic nitrous oxide abuse have been reported (28A , 29A ). Teratogenicity The teratogenicity of nitrous oxide has been extensively reviewed (30R ). Nitrous oxide is the only inhalational anesthetic that has definitely been shown to be teratogenic in experimental animals, but epidemiological studies have suggested that it is not teratogenic in humans.

XENON Xenon anesthesia has been reviewed (31R ). Xenon is receiving renewed interest, because it

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has many characteristics of the ideal anesthetic. In addition to its lack of effects on the cardiovascular system, it has low solubility, enabling faster induction of and emergence from anesthesia. Although its high cost limits its use, the development of closed rebreathing systems has led to further interest. A European multicenter trial is under way.

INTRAVENOUS AGENTS MISCELLANEOUS NON-BARBITURATE ANESTHETICS Ketamine (SED-14, 329; SEDA-23, 130; SEDA-24, 134; SEDA-25, 143) Nervous system There have been several attempts to understand the pathophysiology of schizophrenia using subanesthetic doses of ketamine to probe glutaminergic function in healthy and schizophrenic volunteers; no longterm adverse consequences were attributable to ketamine (32C ). Endocrine In a double-blind, randomized, placebo-controlled comparison of the effects of ketamine and memantine in 15 male volunteers in a three-way crossover trial ketamine increased serum prolactin and cortisol concentrations, whereas memantine and placebo did not (33C ).

Etomidate

(SED-14, 329; SEDA-23, 130)

Endocrine Adrenocortical function has been assessed in a randomized trial after intravenous etomidate in 30 patients who required rapid-sequence induction and tracheal intubation (34C ). The controls received midazolam. Etomidate caused adrenocortical dysfunction, which resolved after 12 hours. Hematologic Platelet hyperaggregablity after general anesthesia has been reported in patients undergoing vascular surgery. The effect of etomidate and thiopental on platelet function has now been examined in 46 patients undergoing

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infrainguinal vascular surgery (35C ). Etomidate caused significant platelet inhibitory effects, whereas the effects of thiopental were minor. This may affect the choice of anesthetic in patients with compromised hemostasis. Immunologic Two cases of anaphylactoid reactions to etomidate have been reported (36A ). The first patient also had a myocardial infarction. Both incidents were successfully managed with intravenous adrenaline and fluids.

Propofol

(SED-14, 330; SEDA-23, 132; SEDA-24, 135; SEDA-25, 144) Cardiovascular The cardiovascular effects of propofol 2.5 mg/kg have been examined a randomized study in 40 healthy subjects using transthoracic echocardiography (37C ). In both groups, global and segmental ventricular function was unchanged, but there was markedly reduced end-systolic quotients, presumably related to reduced afterload. With the higher infusion rate there was a significant reduction in fractional shortening, thought to be related principally to reduced preload. Respiratory Two cases of propofol induced bronchconstriction have been reported (38A ). Both patients had allergic rhinitis and had taken antihistamines during the spring, but were otherwise healthy.

Nervous system A generalized tonic–clonic seizure has been attributed to propofol in a patient with tonic–clonic seizures after surgery for subarachnoid hemorrhage (39A ).

Propofol-infusion syndrome The propofol-infusion syndrome consists of a metabolic acidosis, rhabdomyolysis, and cardiovascular collapse. It occurs after prolonged infusion of propofol (over 48 hours) and has generally been reported in children but also occasionally in adults. Propofol-infusion syndrome mimics the mitochondrial myopathies, in which there are

136 specific defects in the mitochondrial respiratory chain. The clinical features of mitochondrial myopathy result from a disturbance in lipid metabolism in cardiac and skeletal muscle. These patients generally remain well until stressed by infection or starvation, although subclinical biochemical abnormalities of mitochondrial transport can be demonstrated. It has been suggested that early management of critically ill children may not include adequate calorific intake to balance the increase in metabolic demands, and that in susceptible children the diversion of metabolism to fat substrates may cause the propofol-infusion syndrome. It is unclear if the dose or duration of propofol infusion alters this effect. As adults have larger carbohydrate stores and require lower doses of propofol for sedation, this may account for the relative rarity of the syndrome in adults. The authors suggested that adequate early carbohydrate intake may prevent the propofol-infusion syndrome (40AR ). Five adults with head injuries inexplicably had fatal cardiac arrests in a neurosurgical intensive care unit after the introduction of a sedation formulation containing an increased concentration of propofol (41A ). There were striking similarities with the previously reported syndrome of myocardial failure, metabolic acidosis, and rhabdomyolysis in children who received high-dose propofol infusions for more than 48 hours. In a subsequent retrospective cohort analysis the odds ratio for the propofol-infusion syndrome was 1.93 (95% CI = 1.12, 3.32) for every 1 mg/kg/h increase in mean propofol dose above 5 mg/kg/h. The authors suggested that propofol infusion at rates over 5 mg/kg/h should be discouraged for longterm sedation. Reports of the propofol-infusion syndrome in children have continued to appear. • A 13-year-old girl with a head injury who received a high-dose infusion of propofol for 4 days developed the propofol-infusion syndrome (42A ). In an accompanying editorial aspects of the propofolinfusion syndrome were reviewed and the author suggested that prolonged high-dose propofol infusions (over 4.8–6.0 mg/kg/hr for over 48–72 hours) should be avoided and that if high-dose metabolic suppression is required for more than 3 days in head injury, the alternative of a barbiturate should be considered (43r ). However, these long-acting agents have well known potent myocardial depressant effects of their own, which are difficult to manage.

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• A 2-year-old boy with a gunshot head injury developed the propofol-infusion syndrome after receiving propofol in an average dosage of 5.2 mg/kg/h for 72 hours (40AR ). On the fourth day he became oliguric, with raised potassium, urea, and creatinine concentrations, and then developed a nodal bradycardia (28 beats/min). Propofol was withdrawn and an isoprenaline infusion was started, but only emergency transvenous pacing restored his heart rate. Hemofiltration was begun on the basis of another case report, and the acidosis cleared and cardiovascular function was restored. In a blood sample taken before hemofiltration malonylcarnitine, C5-acylcarnitine, creatine kinase, troponin T, and myoglobinemia were raised. The child made a complete recovery and 9 months later all markers of fatty-acid oxidation were normal.

These findings are consistent with impaired fatty-acid oxidation: reduced mitochondrial entry of long-chain acylcarnitine esters due to inhibition of the transport protein (carnitine palmityl transferase 1) and failure of the respiratory chain at complex II. Another previously reported abnormality of the respiratory chain in propofol-infusion syndrome is a reduction in cytochrome C oxidase activity, with reduced complex IV activity and a reduced cytochrome oxidase ratio of 0.004. Propofol can also impair the mitochondrial electron transport system in isolated heart preparations. Liver Hepatocellular injury has been reported after the sole use of propofol for outpatient anesthesia (44A ). • A young woman with multiple allergies underwent femoral hernia repair and the next day developed acute hepatitis, with severe nausea and vomiting and diffuse abdominal tenderness. She had very high transaminase activities and the prothrombin time was slightly raised. No viral cause could be demonstrated. Antinuclear antibody and smooth muscle antibody titers were not raised and the ceruloplasmin concentration was normal. Abdominal ultrasound did not show gallstones or any other abnormality. The urine was normal and there was no evidence of porphyrins or porphobilinogen. She recovered spontaneously and refused liver biopsy.

Pancreas Acute pancreatitis has been attributed to propofol (45A ). • A healthy 35-year-old man developed acute pancreatitis a few hours after receiving a 15-minute propofol anesthetic for laser treatment of a urethral stricture. He spent 3 weeks in an intensive care unit, requiring both respiratory and renal support. There was no evidence of gallstones on abdominal imaging. There was no defect of lipid metabolism.

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BENZODIAZEPINES

(SED-14, 327; SEDA-23, 131; SEDA-24, 133; SEDA-25, 145; see also Chapter 5)

Diazepam Nervous system Severe and prolonged sedation has been reported in five neonates in a neonatal ICU, due to persistence of diazepam metabolites (46A ). The persistence of the very long acting metabolite of diazepam, Ndesmethyldiazepam, in full-term and preterm neonates, due to reduced capacity of the hepatic microsomal enzyme uridine diphosphate glucuronyl transferase, appears to have been responsible for the severe prolonged sedation.

Midazolam Cardiovascular The incidence of hypotension with the use of midazolam for pre-hospital rapid-sequence intubation of the trachea has been assessed in a retrospective chart review (47c ). The rapid-sequence protocols for the two aeromedical crews who serviced the authors’ region were identical, except for the dose of midazolam. The northern crews used 0.1 mg/kg for all patients without a maximum dose and the southern crews used 0.1 mg/kg up to a maximum dose of 5 mg. This meant that of patients over 50 kg, those from the north received higher doses of midazolam; they also had a higher incidence of hypotension. This relation was also present in patients with traumatic brain injury,

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thus potentially compromising cerebral perfusion at a critical time. Nervous system Midazolam can cause paradoxical reactions, including increased agitation, poor co-operation, and aggressive or violent behavior. Often other drugs are required to continue the procedure successfully. Reversal by flumazenil, a benzodiazepine antagonist, has been reported in a cohort study of 58 patients undergoing surgery under spinal or epidural anesthesia (48c ). Flumazenil 0.1 mg over 10 s abolished the agitation without reversing sedation (total dose range 0.1–0.5 mg). Adverse effects of flumazenil were not reported. Care must be taken when considering flumazenil for reversal of midazolam-induced agitation, as these data are anecdotal and no controlled trials have been published. Myoclonic-like movements associated with midazolam in three full-term newborns were reversed by flumazenil (49A ). Further studies are recommended to provide guidelines. Temperature regulation Midazolam premedication caused exaggerated perioperative hypothermia in 15 elderly surgical patients compared with 15 young patients (50c ). The same group also showed that atropine prevents midazolam-induced core hypothermia in 40 elderly patients (51c ). The thermoregulatory effects of benzodiazepine agonists and cholinergic inhibitors oppose each other, and the combination leaves core temperature unchanged.

REFERENCES 1. Hall RI, Sandham D, Cardinal P, Tweedale M, Moher D, Wang X. Propofol vs midazolam for ICU sedation: a Canadian multicenter randomised trial. Chest 2001; 119: 1151–9. 2. Baris S, Karakaya D, Aykent R, Kirdar K, Sagkan O, Tur A. Comparison of midazolam with or without fentanyl for conscious sedation and haemodynamics in coronary angiography. Can J Cardiol 2001; 17: 277–81. 3. Pachulski RT, Adkins DC, Mirza H. Conscious sedation with intermittent midazolam and fentanyl in electrophysiology procedures. J Intervent Cardiol 2001; 14: 143–6.

4. Tramer M, Moore A, McQuay H. Propofol anaesthesia and postoperative nausea and vomiting: Quantitative systematic review of randomised controlled trials. Br J Anaesth 1997; 78: 247–55. 5. Sneyd JR, Carr A, Byrom WD, Bilski AJ. A meta-analysis of nausea and vomiting following maintenance of anaesthesia with propofol or inhalational agents. Eur J Anaesth 1998; 15: 433–45. 6. Visser K, Hassink EA, Bonsel GJ, Moen J, Kalkman CJ. Randomized controlled trial of total intravenous anesthesia with propofol versus inhalational anesthesia with isoflurane–nitrous oxide. Anesthesiology 2001; 95: 616–26.

138 7. Fujii Y, Tanaka H, Kobayashi N. Prevention of postoperative nausea and vomiting with antiemetics in patients undergoing middle ear surgery: comparison of a small dose of propofol with droperidol or metoclopramide. Arch Otolaryngol Head Neck Surg 2001; 127: 25–8. 8. Nelskyla KA, Yli-Hankala AM, Puro PH, Kortilla KT. Sevoflurane titration using bispectral index decreases postoperative vomiting in phase II recovery after ambulatory surgery. Anesth Analg 2001; 93: 1165–9. 9. Paut O, Bissonnett B. Effect of halothane on the cerebral circulation in young children: a hysteresis phenomenon. Anaesthesia 2001; 56: 360–5. 10. Kleinsasser A, Loekinger A, Lidner KH, Keller C, Boehler M, Puehringer F. Reversing sevofluraneassociated Q-Tc prolongation by changing to propofol. Anaesthesia 2001; 56: 248–50. 11. Walpole R, Olday J, Haetzman M, Drummond GB, Doyle E. A comparison of the respiratory effects of high concentrations of halothane and sevoflurane. Paediatr Anaesth 2001; 11: 157–60. 12. Schultz B, Schultz A, Grouven U, Korsch G. Epileptiform EEG activity: occurrence under sevoflurane and not during propofol application. Anaesthetist 2001; 50: 43–5. 13. Conreux F, Best O, Preckel MP, Lhopitault C, Beydon L, Pouplard F, Granry JC. Electroencephalographic effects of sevoflurane in paediatric anaesthesia: a prospective study of 20 cases. Ann Fr Anesth Réanim 2001; 20: 438–45. 14. Kulka PJ, Bressem M, Tryba M. Clonidine prevents sevoflurane-induced agitation in children. Anesth Analg 2001; 93: 335–8. 15. Kulka PJ, Bressem M, Wiebalck A, Tryba M. Midazolam prophylaxis for post-sevoflurane agitation. Anaesthetist 2001; 50: 401–5. 16. Story DA, Poustie S, Liu G, McNicol PL. Changes in plasma creatinine concentration after cardiac anesthesia with isoflurane, propofol, or sevoflurane: a randomised clinical trial. Anesthesiology 2001; 95: 842–8. 17. Kharasch ED, Frink EJ Jr, Artru A, Michalowski P, Rooke AG, Nogami W. Longduration low-flow sevoflurane and isoflurane effects on postoperative renal and hepatic function. Anesth Analg 2001; 93: 1511–20. 18. Goeters C, Reinhardt C, Gronau E, Wusten R, Prien T, Baum Jvrana S, Van Aken H. Minimal flow sevoflurane and isoflurane anaesthesia and impact on renal function. Eur J Anaesthesiol 2001; 18: 43–50. 19. Higuchi H, Adachi Y, Wada H, Kanno M, Satoh T. Comparison of plasma alpha glutathione transferase concentrations during and after low-flow sevoflurane or isoflurane anaesthesia. Acta Anaesthesiol Scand 2001; 45: 1226–9. 20. Ishikawa M, Miyazaki M, Ohta Y. Transient renal tubular dysfunction in a patient with severe asthmatic attack treated with sevoflurane. J Anesth 2001; 15: 49–52. 21. Massaro F, De Klerk DYJ, Snoeck MMJ. A case of malignant hyperthermia during use of sevoflurane. Ned Tijdschr Anesthesiol 2001; 14: 71–3.

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22. Baris S, Karakaya D, Guldogus F, Sarihasan B, Tekat A. A case of malignant hyperthermia during sevoflurane anesthesia. Turk J Med Sci 2001; 31: 171–3. 23. Laisalmi M, Eriksson H, Koivusalo A-M, Pere P, Rosenberg P, Lindgren L. Ketorolac is not nephrotoxic in connection with sevoflurane anesthesia in patients undergoing breast surgery. Anesth Analg 2001; 92: 1058–63. 24. Higuchi H, Wada H, Usui Y, Goto K, Kanno M, Satoh T. Effects of probenecid on renal function in surgical patients anesthetized with sevoflurane. Anesthesiology 2001; 94: 21–31. 25. Hansen J, Raaschou-Nielsen O, Christensen JM, Johansen I, McLaughlin JK, Lipworth L, Blot WJ, Olsen JH. Cancer incidence among Danish workers exposed to trichloroethylene. J Occup Environ Med 2001; 43: 133–9. 26. Badner NH, Spence JD. Homocyst(e)ine, nitrous oxide and atherosclerosis. Ballière’s Best Pract Res Clin Anesthesiol 2001; 15: 185–93. 27. Badner NH, Freeman D, Spence JD. Preoperative oral B vitamins prevent nitrous oxideinduced postoperative plasma homocysteine increases. Anesth Analg 2001; 93: 1507–10. 28. Iwata K, O’Keefe GB, Karanas A. Neurologic problems associated with chronic nitrous oxide abuse in a non-healthcare worker. Am J Med Sci 2001; 322: 173–4. 29. Eichorn M, Watson M, Wurst F. Polyneuropathy and myelopathy after nitrous oxide abuse. Psychiatr Prax 2001; 28: 204–5. 30. Fujinaga M. Teratogenicity of nitrous oxide. Ballière’s Best Pract Res Clin Anesthesiol 2001; 15: 363–75. 31. Leclerc J, Nieuviarts R, Tavernier B, Vallet B, Schpereel P. Xenon anaesthesia: from myth to reality. Ann Fr Anesth Réanim 2001; 20: 70–6. 32. Lahti AC, Warfel D, Michaelidis T, Weiler MA, Frey K, Tamminga C. Long term outcome of patients who receive ketamine in research. Biol Psychiatry 2001; 49: 869–75. 33. Hergovich N, Singer E, Agneter E, Eichler HG, Graselli U, Simhandl C, Jilma B. Comparison of the effects of ketamine and memantine on prolactine and cortisol release in men: a randomised doubleblind placebo-controlled trial. Neuropsychopharmacology 2001; 24: 590–3. 34. Schenarts CL, Burton JH, Riker RR. Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med 2001; 8: 1–7. 35. Gries A, Weis S, Herr A, Graf BM, Seelos R, Martin E, Bohrer H. Etomidate and thiopental inhibit platelet function in patients undergoing infrainguinal vascular surgery. Acta Anaesthesiol Scand 2001; 45: 449–57. 36. Moorthy SS, Laurent B, Pandya P, Fry V. Anaphylactoid reaction to etomidate: report of a case. J Clin Anesth 2001; 13: 582–4. 37. Bilotta F, Fiorani L, La Rosa I, Spinelli F, Rosa G. Cardiovascular effects of propofol administered at two infusion rates: a transthoracic echocardiographic study. Anaesthesia 2001; 56: 266–71.

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38. Nishiyama T, Hanaoka K. Propofol induced bronchconstriction: two case reports. Anesth Analg 2001; 93: 645–6. 39. Iwasaki F, Mimura M, Yamazaki Y, Hazama K, Sato Y, Namiki A. Generalized tonic–clonic seizure induced by propofol in a patient with epilepsy. Jpn J Anesthesiol 2001; 50: 168–70. 40. Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001; 357: 606–7. 41. Cremer OL, Moons KGM, Bouman EAC, Kruijswijk JE, De Smet AMGA, Kalkman C. Long-term propofol infusion and cardiac failure in adult headinjured patients. Lancet 2001; 357: 117–18. 42. Cannon ML, Glazier SS, Bauman LA. Metabolic acidosis, rhabdomyolysis and cardiovascular collapse after prolonged propofol infusion. J Neurosurg 2001; 95: 1053–6. 43. Kelly DF. Propofol-infusion syndrome. J Neurosurg 2001; 95: 925–6. 44. Anand K, Ramsay MA, Crippin JS. Hepatocellular injury following the administration of propofol. Anesthesiology 2001; 95: 1523–4. 45. Betrosian AP, Balla M, Papanikolaou M, Kofinas G, Georgiadis G. Postoperative pancreatitis after propofol administration. Acta Anaesthesiol Scand 2001; 45: 1052.

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46. Peinemann F, Daldrup T. Severe and prolonged sedation in five neonates due to persistence of diazepam metabolites. Eur J Pediatr 2001; 160: 378– 81. 47. Davis DP, Kimbro TA, Vilke GM. The use of midazolam for pre-hospital rapid-sequence intubation may be associated with a dose-related increase in hypotension. Prehosp Emerg Care 2001; 5: 163–8. 48. Weinbroum AA, Szold O, Ogorek D, Flaisshon R. The midazolam-induced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature. Eur J Anaesthesiol 2001; 18: 789–97. 49. Zaw W, Knoppert DC, Da Silva O. Flumazenil’s reversal of myoclonic-like movements associated with midazolam in term newborns. Pharmacotherapy 2001; 21: 642–6. 50. Matsukawa T, Ozaki M, Nishiyama T, Imamura M, Kumazawa T. Exaggerated perioperative hypothermia in elderly surgical patients. Anesth Resusc 2001; 37: 53–7. 51. Matsukawa T, Ozaki M, Nishiyama T, Imamura M, Iwamoto R, Iijima T, Kumazawa T. Atropine prevents midazolam-induced core hypothermia in elderly patients. J Clin Anesth 2001; 13: 504–8.

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Local anesthetics

EFFECTS RELATED TO MODES OF USE

they often have concomitant coronary artery disease, hypertension, and diabetes. Brachial plexus block is often used: as well as avoiding systemic effects it enhances regional blood flow. However, high doses of local anesthetic are required, and this block carries one of the highest rates of seizures. In this study, following axillary block with mepivacaine 650 mg, plasma concentrations were greater than the threshold of 6 µg/ml, above which signs of CNS toxicity reportedly occur. The authors suggested that the absence of CNS signs may have been due to slow systemic absorption of the local anesthetic. Peak concentrations occurred after 60–90 min, but were still high at 150 min, raising the question of more prolonged monitoring after these blocks. Horner’s syndrome is a well-recognized complication of interscalene brachial plexus block, stellate ganglion block, and occasionally epidural blockade. It occurs when the local anesthetic reaches the cervical sympathetic trunk and is usually transient. However, persistent Horner’s syndrome is a rare complication, and may represent traumatic interruption of the cervical sympathetic chain. Two cases of prolonged Horner’s syndrome related to prevertebral hematoma formation at the site of continuous interscalene blockade have been described (3A ).

Brachial plexus anesthesia Respiratory Brachial plexus blockade is often used in patients with cardiorespiratory disease undergoing upper limb surgery. However, the procedure carries certain significant risks, one being blockade of the phrenic nerve, resulting in paralysis of the ipsilateral hemidiaphragm. This can rarely cause severe respiratory compromise, depending on pre-existing lung dysfunction. In unpremedicated patients who underwent supraclavicular brachial plexus block for upper limb surgery, blocks were performed using a peripheral nerve stimulator and 0.5 ml/kg of bupivacaine 0.375% (1c ). Spirometric and ultrasonographic assessments of diaphragmatic function were made at intervals. Of 30 patients, 15 had complete paralysis of the hemidiaphragm, five had reduced diaphragmatic movement, and 10 had no change. Those with complete paralysis all had significant reductions in pulmonary function and those with reduced or normal movement had minimal changes. Only one of the patients had respiratory symptoms and the oxygen saturation remained unchanged. This may not be the case, however, in patients with significant pre-existing respiratory disease or in obese people; the authors therefore suggested caution in choosing this approach as a safer alternative to general anesthesia in such individuals. Nervous system Mepivacaine toxicity has been studied in 10 patients with end-stage chronic renal insufficiency undergoing vascular access surgery (2c ). These patients represent a high-risk group for general anesthesia, as © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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• A 48-year-old obese woman had a 22G interscalene catheter inserted under local anesthesia via a short-bevel stimulating needle. Anesthesia was achieved using 0.6% ropivacaine 40 ml followed by an infusion of ropivacaine 0.2% for effective analgesia. On day 3 she reported blurred vision and a painful neck swelling. She had developed a hematoma around the catheter insertion site (confirmed by ultrasound) and had an ipsilateral Horner’s syndrome, including myosis, ptosis, enophthalmos, ipsilateral anhidrosis, and conjunctival hyperemia. • An interscalene catheter was inserted in an awake 20-year-old woman for analgesia after shoulder surgery. Analgesia was achieved with ropivacaine 0.2% as a 30 ml bolus followed by an infusion of the same solution. One day later she had visual

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disturbance and neck swelling, due to a hematoma between the prevertebral and scalene muscles.

Neither patient was taking NSAIDs, aspirin, or anticoagulants. Catheters were removed immediately on diagnosis of hematoma formation. There was no neurological or sympathetic fiber damage to the upper limb in either patient, as tested by electroneuromyography and sympathetic skin response. Remission in both cases occurred within 1 year. There has been one previous report of prolonged Horner’s syndrome in the absence of any obvious technical complication (4A ). Further studies into the use of interscalene catheters are needed to assess their propensity to cause this rare complication. In 60 patients receiving patient-controlled interscalene analgesia with either ropivacaine 0.2% or bupivacaine 0.15%, there was a significant reduction in hand motor function and an increased incidence of paresthesia in the bupivacaine group, with no difference in pain scores (5C ). This finding contrasts with that in a comparison of epidural bupivacaine or ropivacaine, in which there was no difference in motor function between the two groups (6C ).

Caudal, epidural, and spinal anesthesia

(8C ). They randomly received 0.25% bupivacaine 0.5 ml/kg or the same dose of bupivacaine plus midazolam 50 µg/kg. There were no untoward events in either group. Fewer required additional analgesia in the first 6 hours postoperatively in the bupivacaine plus midazolam group than with bupivacaine alone: 27% compared with 60%. Midazolam prolonged analgesia with no increase in adverse effects. Cardiovascular There has been a report of T wave changes on the electrocardiogram during caudal administration of local anesthetics (9A ). • A 4.2 kg 2-month-old baby was given a caudal injection under general anesthesia for an inguinal hernia repair. A mixture of 1% lidocaine 2 ml and 0.25% bupivacaine 2 ml was injected. Every 1 ml was preceded by an aspiration test and followed by 20 s observation for electrocardiographic changes. On administration of the third 1 ml dose, there was a significant increase in T wave amplitude. The aspiration test was repeated and was positive for blood. The caudal injection was stopped and the electrocardiogram returned to normal after 35 s. The patient remained cardiovascularly stable with no postoperative sequelae.

Previous reports have suggested that an increase in T wave amplitude could result from inadvertent intravascular administration of adrenaline-containing local anesthetics. This is the first case report of local anesthetics alone causing a significant T wave changes.

Caudal anesthesia Caudal block with bupivacaine in children provides adequate analgesia in the early postoperative period, but additional analgesia is often required as the block wears off. Two studies have looked at adjuvants to prolong the analgesic effect. The first was a randomized, controlled trial in 60 boys undergoing unilateral herniorrhaphy (7C ). They received 0.25% bupivacaine 1 ml/kg or the same dose of bupivacaine plus 1.5 mg/kg tramadol, or tramadol 1.5 mg/kg alone made up to the same volume. Caudal administration of bupivacaine plus tramadol resulted in more effective analgesia, with a longer period without demand for additional analgesia postoperatively without increases in any adverse effects. The second was a study of the addition of midazolam to caudal bupivacaine in 30 children undergoing genitourinary surgery

Epidural anesthesia Patient-controlled epidural analgesia is increasingly being used, as it reduces the need for adjustment of epidural infusion rates by anesthetic personnel. In a retrospective survey of 1057 patients who received postoperative patientcontrolled epidural analgesia using bupivacaine 0.1% plus fentanyl 5 micrograms/ml, on the first postoperative day 93% of the patients had adequate analgesia and 96% reported no nausea; two patients had an episode of respiratory depression and one patient was unrousable (10C ). Hypotension occurred in 4.3%, but there were no cases of epidural hematoma or abscess. Despite these adverse events, the authors concluded that patient-controlled epidural analgesia was effective and safe on surgical wards.

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The large amount of fentanyl in the solution they used is most probably the reason for the rare, potentially life-threatening adverse effects. The amount of bupivacaine with fentanyl used in patient-controlled epidural analgesia was significantly less than with a continuous infusion of the same mixture in a group of 54 patients (mean age 71 years) after total knee arthroplasty (11C ). However, 10% of the patients were too confused to use the PCEA device. Despite the advantages of analgesic dosage reductions, a constant infusion may prove more appropriate in this age group. Epidural infusions of bupivacaine are often used in children. However, there are concerns about the increased incidence of adverse effects in infants, owing to reduced hepatic clearance and serum protein binding. In 22 infants aged 1–7 months who received a continuous infusion of bupivacaine 0.375 mg/kg/hour for 2 days during and after surgery, the unbound and total serum concentrations of bupivacaine were measured, along with presurgical and postsurgical concentrations of alpha1 acid glycoprotein (12c ). The concentrations of alpha1 acid glycoprotein increased markedly after surgery. However, because of reduced clearance unbound concentrations of bupivacaine increased to over 0.2 µg/ml in two infants younger than 2 months. The authors propose a maximum dosage rate of 0.25 mg/kg/h in infants younger than 4 months and 0.3 mg/kg/h in older infants.

Intrathecal (spinal) anesthesia Nervous system Transient radicular irritation, often also incorrectly named transient neurological syndrome, has been previously reported as varying transient pain or dysesthesia following intrathecal administration of local anesthetics. While lidocaine is generally implicated in its causation, a randomized study with isobaric mepivacaine 2% administered intrathecally to patients undergoing surgery in the supine position recently showed an incidence of 7.5% compared with 2.5% with isobaric lidocaine 2% (13C ). Even bupivacaine and tetracaine have been shown to have toxic effects on chick neuron cultures in vitro (14E ).

Early ambulation has previously been implicated in transient radicular irritation. However, in a randomized trial there was no difference between early and late mobilization in patients who received spinal lidocaine 2% for inguinal hernia repair; the incidence was 23% in both groups (15C ). Procaine has been suggested as an alternative to lidocaine for spinal use in ambulatory surgery, as it also has a short duration of action. In a randomized, double-blind comparison of procaine 10% or lidocaine 5% in glucose 7.5% for spinal anesthesia transient radicular irritation occurred in 27% of the lidocaine group compared with none of the patients in the procaine group (16C ). However, the failure rate in the procaine group was 14%. This was perhaps a reflection of the fact that the procaine was glucose-free, but further studies are required with procaine to evaluate its use in this context. Intrathecal hyperbaric lidocaine 1.5% has been compared with hyperbaric bupivacaine 0.75% for outpatient transvaginal oocyte retrieval (17C ). The time to voiding of urine and the time to discharge were significantly longer in the bupivacaine group, despite the fact that there were no differences in the time to recovery of sensory and motor function. The incidence of transient radicular irritation in the lidocaine group was 5%, compared with none of the women in the bupivacaine group. The authors concluded that bupivacaine was a useful alternative to lidocaine in outpatient spinal anesthesia. There have been two recent studies of transient radicular irritation in the obstetric population. One was a randomized, double-blind comparison of intrathecal hyperbaric lidocaine 5% or bupivacaine 0.75% for postpartum tubal ligation (18C ). All the patients were supine for surgery. The incidence of transient radicular irritation was 3% with lidocaine and 7% with bupivacaine. The other was a prospective follow-up study of patients who had cesarean sections under spinal anesthesia using hyperbaric 0.5% bupivacaine; the incidence of transient radicular irritation was 8.8% (19c ). The addition of vasoconstrictors, such as phenylephrine and adrenaline, has previously been implicated in the causation of transient radicular irritation. However, a randomized study in 64 patients undergoing urological, gynecological, or lower limb surgery showed

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no significant difference in the incidence of transient neurological symptoms between hyperbaric tetracaine 0.5% with and without phenylephrine 0.025% (8C ). In fact, the neurological symptoms that were described (in 6.7% of the patients) occurred in the group without phenylephrine and could possibly have been explained by the patient’s position or by the effects of plaster-cast compression postoperatively. Recent animal studies have highlighted the potential toxic effects of adding adrenaline to local anesthetics for intrathecal injection. In one study the effects of adding 0.01% adrenaline to intrathecal tetracaine 1% and 2% was investigated in rabbits (20E ). Although adrenaline had no neurotoxic effects when given alone, there was worsening of neurotoxicity when it was given in combination with tetracaine. The same group had previously shown an increase in glutamate concentrations in the CSF and dose-dependent neurotoxicity with tetracaine injected intrathecally in rabbits (21E ). In another study they looked at the effects of intrathecal lidocaine 5% with and without adrenaline 0.02% on the spinal cord and nerve roots of rats (21E ). They showed that lidocaine 5% caused persistent sensory impairment and histological damage that was significantly exacerbated by the addition of adrenaline. Several explanations for the increased neurotoxicity of vasoconstrictors in combination with local anesthetics have been offered: • Adrenaline may reduce the absorption of local anesthetics and thereby increase anesthetic exposure intrathecally. • A reduction in blood flow caused by adrenaline may cause ischemia in the spinal cord. • Bisulfite, used as a preservative in adrenaline formulations, has previously been implicated in neurological deficits. It may have a role in the toxicity seen, but that would not explain the lack of toxicity seen with adrenaline alone. Further studies are required to attempt to clarify the cause of transient radicular irritation, in particular as it remains unclear if it is an expression of true neurotoxicity, as observed in these animal experiments. The reasons for these doubts are the temporary nature of the symptoms and the lack of any neurological deficits in patients with transient radicular irritation.

Cauda equina syndrome has previously been described in patients receiving intrathecal hyperbaric lidocaine 5% (SEDA-24, 146). • Cauda equina syndrome occurred in a 55-yearold woman who underwent spinal anesthesia with a 22 g needle in the L4–5 interspace (22A ). On needle insertion, she felt radiating pain in her right leg. The needle was immediately withdrawn and repositioned. Pain-free intrathecal injection of 2.0 ml of hyperbaric dibucaine 0.24% with adrenaline 66 micrograms resulted in block to L1. Surgery was carried out in the supine position. Three days postoperatively, she had enuresis and reduced perineal sensation, without bowel dysfunction or lower limb symptoms. There was sensory loss at S2–S5. The symptoms persisted, required self-catheterization and systemic steroids, and disappeared on the 19th postoperative day.

The cause of this transient neurological deficit was unclear, but the authors suggested that the following factors may have contributed: • direct nerve damage; • local anesthetic toxicity; • adrenaline effects.

Infiltration anesthesia Nervous system Two cases of medullary injury after injections of local anesthetics intraoperatively have been reported (23A ). • A 4-year-old child received injections of lidocaine plus adrenaline into the anterior tonsillar pillars and nasopharynx during adenotonsillectomy. After the procedure he became agitated and dysarthric, vomited, and had abnormal eye movements. He was unable to stand and walk, owing to ataxia. An MRI scan showed a cavity in the right paramedian medulla. • A 7-year-old boy underwent tonsillectomy, with an injection of lidocaine plus adrenaline into the operative field. After surgery he was lethargic, and during the next 24 hours he developed respiratory distress requiring mechanical ventilation. He was pyrexial (41.8◦ C) and had cardiomegaly and a left hemiparesis. A cranial MRI scan showed a hemorrhagic lesion in the right paramedian medulla.

Both patients had lesions in the medial medulla supplied by branches of the anterior spinal and vertebral arteries, and although such cases are rare it seems wise, in the light of these reports, to avoid the routine use of adrenaline as an adjunct to local anesthesia for adenotonsillectomy.

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Intravenous regional anesthesia It has previously been suggested that ropivacaine is a good choice for intravenous regional anesthesia because of its longer duration of action and lower risk of toxicity. In 20 patients scheduled for upper limb surgery who received 40 ml of either ropivacaine 0.2% or lidocaine 0.5% for intravenous regional anesthesia, both agents provided same onset and quality of surgical anesthesia, but ropivacaine gave longerlasting analgesia in the immediate postoperative period (24c ). Additionally, one patient in the lidocaine group had tinnitus on release of the tourniquet, while there were no adverse effects in the ropivacaine group.

Topical anesthesia A recent meta-analysis of the use of EMLA cream in the elderly (over 65) showed that the technique is generally safe, with only mild transient effects (pallor, redness, and edema) at the application site; there were no systemic effects (25M ). Hematologic High doses of EMLA cream can cause neonatal methemoglobinemia as a result of prilocaine toxicity (SEDA-22, 141). • A 3-year-old girl with multiple lesions of molluscum contagiosum had EMLA applied to the lesions before curettage (26A ). She became lethargic and hypoactive 2 hours later, with periorbital discoloration and cyanosed lips. Her SaO2 was 85%, systolic blood pressure 185 mmHg, pulse 144 beats/minute, and her methemoglobin concentration was 21%. Her caregiver had applied about 25 g of cream to her entire torso, a massive dose of prilocaine (about 625 mg).

This report reinforces previously described problems arising from carers’ lack of understanding of instructions when using EMLA in children or babies. Skin The first report of hyperpigmentation following the use of EMLA cream has appeared (27A ), although hypopigmentation has previously been reported. • A 12-year-old black child developed a patch of hyperpigmentation on his forehead where EMLA

cream had been used for cutaneous anesthesia before local infiltration with lidocaine for removal of a nevus. This persisted, although fading, for at least 4 months. No other cause could be found.

The authors concluded that the constituents of EMLA had been responsible.

INDIVIDUAL COMPOUNDS Articaine

(SED-14, 350)

Articaine is an amide local anesthetic. It was synthesized in 1969 but only registered in the USA in 2000. It is 4-methyl-3[2-(propylamino)propionamido]-2-thiophenecarboxylic acid, methyl ester hydrochloride. The thiophene group increases its lipid solubility while the ester group enables it to undergo plasma esterase hydrolysis as well as hepatic enzyme metabolism. It is formulated as a 4% solution with adrenaline. The safety of articaine has been studied in a series of three randomized trials (28C ). The adverse effects deemed to be related to articaine were headache, paresthesia/hyperesthesia after injection, infection, and rash. There was one case of mouth ulceration. The overall incidence of adverse effects was comparable to that of lidocaine.

Benzocaine

(SED-14, 351; SEDA-23, 143; SEDA-24, 151; SEDA-25, 155) Hematologic Four cases of methemoglobinemia have again been described after the use of benzocaine spray for topical anesthesia of the airways. • A 42-year-old woman received superior laryngeal nerve block with lidocaine, topical anesthesia with benzocaine spray, and intravenous midazolam for awake fiberoptic intubation (29A ). Her SpO2 fell from about 85% to about 30%, and despite highfrequency jet ventilation with 100% oxygen she had persistent SpO2 readings in the low 80s. Her arterial blood was chocolate-brown in color, with a PaO2 of 330 mmHg and an oxyhemoglobin saturation (SaO2 ) of 51%. This discrepancy between PaO2 and SaO2 suggested methemoglobinemia, and co-oximetry showed a concentration of 51%.

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Methylene blue 140 mg produced an immediate improvement in her color, and her SaO2 improved over the next 10 minutes. • An elderly man received benzocaine 20% spray to the throat in preparation for transesophageal echocardiography. He became unwell 1 hour later, with lethargy, central cyanosis, hypoxia, dyspnea, tachypnea, and tachycardia (30A ). His arterial blood was burgundy-colored and the methemoglobin concentration was 41%. He was treated with two doses of methylene blue 2 mg/kg and was weaned from oxygen within 10 h. • Significant methemoglobinemia occurred in a 65-year-old man on re-exposure to topical 20% benzocaine spray for anesthesia of the airways in preparation for awake fiberoptic intubation (31A ). This occurred despite exposure 3 days before to 14% benzocaine for the same procedure. During attempted intubation, he suddenly desaturated to 80% and had significant hypotension and bradycardia, necessitating external cardiac massage and cricothyroid puncture. His SaO2 did not improve significantly, despite seemingly adequate resuscitation with 100% oxygen and intravenous adrenaline. His arterial methemoglobin concentration was 55%. Methylene blue 100 mg intravenously led to rapid improvement in the SaO2 , allowing surgery to continue. • A 57-year-old man developed severe methemoglobinemia after receiving topical benzocaine spray and lidocaine jelly during awake fiberoptic intubation (32A ). After intubation, his oxygen saturation fell to 65% on 100% oxygen. He was cyanosed and had dark arterial blood sample with normal gas tensions. His methemoglobin concentration was 60% and treatment with methylene blue was successful.

These cases illustrate the importance of co-oximetry on grounds of clinical suspicion. Methemoglobin concentrations of 10–15% can cause dark-colored blood and cyanosis. Concentrations of 20–45% can cause lethargy, dizziness, headache, and collapse. Higher concentrations (50–70%) can cause seizures, dysrhythmias, coma, and death. Skin Allergic contact dermatitis has been attributed to local benzocaine (33A ). • A 72-year-old woman was treated for thoracic Herpes zoster with oral aciclovir and topical benzocaine 20% ointment. She subsequently developed painful pruritic erythematous dermatitis in the area of the lesions, spreading to her arm. The dermatitis was initially misdiagnosed as aciclovir resistance, but on patch testing she had a positive reaction to benzocaine.

The authors highlighted the problem in diagnosing allergic contact dermatitis in patients

who have other skin lesions in that area. They emphasized the importance of patch testing to identify the causative agent.

Chlorprocaine Nervous system Prolonged neuromuscular blockade has been reported after epidural 2chlorprocaine (34A ). • A 29-year-old woman in labor was given an epidural infusion of bupivacaine 0.04% plus fentanyl 1.66 micrograms/ml running at 15 ml/h for 7 h. She then required an urgent cesarean section and 15 ml of chlorprocaine 3% was given, followed 20 min later by 12 ml of 2% lidocaine. Half an hour later she showed signs of high epidural blockade with dyspnea followed by unresponsiveness, and required immediate intubation with succinylcholine. She then developed prolonged neuromuscular blockade with a first-twitch response occurring after 1.75 hours. It took 3.75 hours before she could be extubated. Her plasma cholinesterase activity was low immediately post-partum, with a concentration of 1.3 units/ml (reference range 2.8– 11), returning to normal within 7 weeks.

The authors believed that the high epidural blockade and the prolonged neuromuscular block had resulted from reduced pseudocholinesterase activity. Reduced pseudocholinesterase activity has been described both in pregnancy and with magnesium therapy. As most ester local anesthetics (with the exception of cocaine) are metabolized by this enzyme, caution should be exercised when using ester local anesthetics in pregnancy, especially with the increasing use of magnesium sulfate in this field.

Cinchocaine

(SED-14, 352)

Skin Two cases of allergic contact dermatitis have been described after the use of cinchocaine formulations. • A 71-year-old Japanese man, who was using an over-the-counter formulation, Makiron, for minor wounds, developed an itchy rash with seropapules and erosions on his right leg at the site of application (35A ). Makiron contains 0.1% cinchocaine hydrochloride and chlorpheniramine maleate as well as naphazoline hydrochloride and benzethonium chloride. On patch testing, he was positive to both chlorpheniramine and cinchocaine.

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• A 79-year-old man presented with a 10-day history of weeping dermatitis affecting the perianal skin, buttocks, and proximal thighs (36A ). He had used Proctosedyl ointment topically for the preceding 3 weeks. Proctosedyl is an over-the-counter topical formulation for use as an antihemorrhoidal agent. It contains cinchocaine 5%, hydrocortisone, and lanolin. Patch testing was strongly positive to cinchocaine.

The authors highlighted the potential limitations of the International Contact Dermatitis Research Group (ICDRG) standard series for topical anesthetics. Benzocaine is the only topical anesthetic in the series and it will not detect contact allergy to amide agents; crosssensitivity can also exist. They suggested that patch testing should include agents from both groups. DoloPosterine N is an ointment for topical application in the treatment of hemorrhoids. Its active ingredient is cinchocaine. Although cinchocaine is a known contact sensitizer, as described above, systemic contact dermatitis is rare. • A 62-year-old woman, who had applied DoloPosterine N ointment topically to the perianal skin and rectal mucosa for several days, developed erythematous vesicular lesions in the perianal area and an erythematous edematous rash of the face, axillae, elbow flexures, and inner thighs (37A ). This abated on withdrawal of the drug and the administration of oral prednisolone for 10 days. Patch testing was positive to cinchocaine.

Levobupivacaine Hematologic The effects of the low molecular weight heparin enoxaparin in combination with levobupivacaine on coagulation have been studied in vitro (38E ). Whole blood from 10 patients treated with enoxaparin was mixed with levobupivacaine to concentrations of 2.5 µg/ml and 2.5 mg/ml, followed by thromboelastography. Levobupivacaine produced a dosedependent reduction in clotting. The clinical implications of these findings are yet to be acknowledged; larger, in vivo studies are required.

Lidocaine

(SED-14, 349; SEDA-23, 144;

SEDA-24, 152) Cardiovascular In 23 patients there was a significant dose-dependent reduction in blood pressure following submucosal infiltration of lidocaine plus adrenaline compared with saline plus adrenaline for orthognathic surgery (39c ). The study was randomized but small; larger studies are needed to confirm effects that could easily have been due to multifactorial causes in patients undergoing general anesthesia. Hematologic Although methemoglobinema has previously been described in patients exposed to benzocaine and prilocaine, the association with lidocaine is not well defined. Three cases of lidocaine-induced methemoglobinemia have been reported in patients undergoing topical anesthesia of the airway and oropharynx (40A ). • A 26-year-old woman undergoing bronchoscopy received lidocaine jelly 2% to each nostril, lidocaine solution 2% sprayed on the throat, and 10 ml of lidocaine solution 2% into the trachea. She was also given intravenous diazepam 5 mg and pethidine 75 mg and intramuscular atropine 0.6 mg. She developed dyspnea and cyanosis after the procedure and despite 100% oxygen her SpO2 was 85%. Her methemoglobin concentration was 14%. • A 61-year-old woman was given 15 ml of lidocaine solution 2% and lidocaine spray 4% for topical anesthesia of the throat and oropharynx before upper gastrointestinal endoscopy. She was also sedated with intravenous midazolam 2 mg and pethidine 75 mg. She became cyanosed and desaturated (SpO2 78%) immediately after the procedure. Her SpO2 did not recover, despite 100% oxygen. Her methemoglobin concentration was 37%. • In preparation for transesophageal echocardiogram, a 73-year-old woman was given 15 ml of lidocaine solution 2% and lidocaine spray 4% to anesthetize the oropharynx, plus intravenous midazolam 1 mg and pethidine 12.5 mg. She very rapidly became cyanosed, but remained symptomatic, with an SpO2 of 85% on oxygen 2 l/minute. Her methemoglobin concentration was 25%.

Skin Dermatitis has been attributed to lidocaine (41A ). • A 60-year-old woman was given infiltration anesthesia with lidocaine hydrochloride for removal of a melanoma. She developed an itchy dermatitis over the area 36 h later. Conventional patch testing was negative at 48 and 72 h to lidocaine

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and mepivacaine (both amides), as was intracutaneous testing with lidocaine 2%, mepivacaine 2%, and bupivacaine 0.5%. However, intradermal testing at 1/100 dilutions was positive, with itching and erythema at 48 h with lidocaine and mepivacaine, suggesting delayed hypersensitivity to these drugs, but not with bupivacaine.

It has previously been reported that lidocaine and mepivacaine have a high degree of crossreactivity not seen with bupivacaine. In a phase IV trial 66% patients with postherpetic neuralgia gained relief from a 5% lidocaine patch applied to the most painful area of the body (42C ). The lidocaine patch was well tolerated, a rash being the most common adverse effect, in 14% of patients. Drug interactions A potentially beneficial effect of lidocaine has been studied in a randomized, double-blind, placebo-controlled study of the effects of pre-instillation of lidocaine on tropicamide-induced mydriasis (43c ). Pupillary diameter was significantly increased by the instillation of lidocaine before tropicamide. It was thought that lidocaine may enhance intraocular penetration and hence potentiate the effect of tropicamide.

Oxybuprocaine Skin There have been two reports of patients scheduled for tonometry who developed periorbital dermatitis following the topical instillation of local anesthetic eye drops (44A ). The first patient reacted strongly positive on patch testing to Thilorbin AT (oxybuprocaine, fluorescein, phenylmercuric borate, polysorbate 20, mannitol) and also to oxybuprocaine alone. The second reacted to Conjucain EDO (oxybuprocaine, sorbitol, sodium hydroxide) and to oxybuprocaine alone. The authors believed these to be the only described cases of a delayed hypersensitivity reaction to oxybuprocaine, an ester local anesthetic commonly used for topical anesthesia in the eye.

ing procaine, lidocaine, or bupivacaine in combination with fentanyl for spinal anesthesia for a variety of different surgical procedures (45C ). Procaine plus fentanyl and bupivacaine plus fentanyl produced a higher incidence of pruritus than lidocaine plus fentanyl. The severity of pruritus was also greater in those given procaine plus fentanyl. The incidence and severity of pruritus was not related to the dose of fentanyl. Although this may represent an interaction between fentanyl and ester local anesthetics that differs from the synergy occurring between fentanyl and amide local anesthetics, this was an observational study and was neither randomized nor blinded. Furthermore, the doses of local anesthetic or fentanyl were not standardized. Further prospective randomized studies are therefore required to confirm or refute these claims.

Proparacaine

(SEDA-24, 152)

Skin Allergic contact dermatitis of the ophthalmic mucous membranes has previously been reported. Now sensitization to proparacaine via the cutaneous route has also been described (46C ). • An ophthalmologist developed chronic finger pad dermatitis with fissuring and scaling, which mainly affected his thumbs for 3 years. Patch testing confirmed that “ophthetic solution” (proparacaine hydrochloride 0.5%, glycerine, and benzalkonium chloride 0.01%) was the sensitizing agent. He was instructed to change to tetracaine, to which he had had a negative patch test. However, 2 years later his symptoms recurred and a repeat patch testing was carried out. This was now positive to both tetracaine 1% and proparacaine 0.5%.

Cross-sensitization between proparacaine and tetracaine is thought to be rare. Moreover, the chemical structure of proparacaine is sufficiently different from tetracaine to make crossreactivity unlikely. These cases suggest, however, that some degree of cross-sensitization can occur.

Ropivacaine Procaine

(SED-14, 353)

Skin The incidence of pruritus has been evaluated in a retrospective study of patients receiv-

(SED-14, 353; SEDA-23, 145; SEDA-25, 156) Nervous system A single seizure after epidural ropivacaine has been reported (47A ).

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• A 26-year-old primigravid woman in labor had epidural anesthetic with ropivacaine (a background infusion of 18 mg/h and three bolus doses totalling 44 mg, followed by an infusion of 24 mg/hour). She failed to progress and another three boluses totaling 150 mg were given. She received a total of 279 mg of ropivacaine over 5 hours. Immediately after the final bolus she developed oculogyric movements and slurred speech and then twitching of her face and arms. The seizure ceased with thiopental and the operation was carried out uneventfully under general anesthesia. Her serum ropivacaine concentration 1 hour later was 3.5 mg/l; in previous studies, symptoms of toxicity during intravenous infusions occurred at plasma concentrations of 1–2 mg/l.

This shows that CNS toxicity is a potential problem with ropivacaine; it is important to leave adequate time between bolus doses to detect adverse effects. It also confirms that with ropivacaine CNS adverse effects occur before or without severe cardiovascular toxicity, as there have now been several similar reports of CNS toxicity, but not yet one with severe or fatal cardiotoxicity. This reinforces the claim of increased safety from cardiovascular toxicity with this enantiomeric local anesthetic compared with racemic bupivacaine.

REFERENCES 1. Mak PH, Irwin MG, Ooi CG, Chow BF. Incidence of diaphragmatic paralysis following supraclavicular brachial plexus block and its effect on pulmonary function. Anaesthesia 2001; 56: 352–6. 2. Rodriguez J, Quintelat O, Lopez-Rivadulla M, Barcena M, Diz C, Alvarez J. High doses of mepivacaine for brachial plexus block in patients with end-stage chronic renal failure. A pilot study. Eur J Anaesthesiol 2001; 18: 171–6. 3. Ekatodramis G, Macaire P, Borgeat A. Prolonged Horner syndrome due to neck hematoma after continuous interscalene block. Anesthesiology 2001; 95: 801–3. 4. Sukhani R, Barclay J, Aasen M. Prolonged Horner’s syndrome after interscalene block: a management dilemma. Anesth Analg 1194; 79: 601–3. 5. Borgeat A, Kalberer F, Jacob H, Ruetsch YA, Gerber C. Patient-controlled interscalene analgesia with ropivacaine 0.2% versus bupivacaine 0.15% after major open shoulder surgery: the effects on hand motor function. Anesth Analg 2001; 92: 218–23. 6. Rodriguez Lopez JM, Sanchez-Conde P, Nicolas J, Garcia-Castano M, Del Barrio E, Muriel C. Estudio comparativo entre ropivacaina y bupivacaina en analgesia epidural del parto. Rev Esp Anestesiol Reanim 2001; 48: 199–203. 7. Senel AC, Akyol A, Dohmann D, Solak M. Caudal bupivacaine-tramadol combination for postoperative analgesia in pediatric herniorrhaphy. Acta Anaesthesiol Scand 2001; 45: 786–9. 8. Mahajan R, Batra YK, Grover VK, Kajal J. A comparative study of caudal bupivacaine and midazolam-bupivacaine mixture for post-operative analgesia in children undergoing genitourinary surgery. Int J Clin Pharmacol Ther 2001; 39: 116–20. 9. Tanaka M, Nitta R, Nishikawa T. Increased T-wave amplitude after accidental intravascular injection of lidocaine plus bupivacaine with-

out epinephrine in sevoflurane-anesthetized child. Anesth Analg 2001; 92: 915–17. 10. Wigfull J, Welchew E. Survey of 1057 patients receiving postoperative patient-controlled epidural analgesia. Anaesthesia 2001; 56: 70–5. 11. Silvasti M, Pitkanen M. Patient-controlled epidural analgesia versus continuous epidural analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 2001; 45: 471–6. 12. Meunier J-F, Goujard E, Dubousset AM, Samii K, Mazoit JX. Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia. Anesthesiology 2001; 95: 87–95. 13. Salazar F, Bogdanovich A, Adalia R, Chabas E, Gomar C. Transient neurologic symptoms after spinal anaesthesia using isobaric 2% mepivacaine and isobaric 2% lidocaine. Acta Anaesthesiol Scand 2001; 45: 240–5. 14. Saito S, Radwan I, Obata H, Takahashi K, Goto F. Direct neurotoxicity of tetracaine on growth cones and neurites of growing neurons in vitro. Anesthesiology 2001; 95: 726–33. 15. Lindh A, Andersson AS, Westman L. Is transient lumbar pain after spinal anaesthesia with lidocaine influenced by early mobilisation? Acta Anaesthesiol Scand 2001; 45: 290–3. 16. Le Truong HH, Girard M, Drolet P, Grenier Y, Boucher C, Bergeron L. Spinal anesthesia: a comparison of procaine and lidocaine. Can J Anaesth 2001; 48: 470–3. 17. Tsen LC, Schultz R, Martin R, Datta S, Bader AM. Intrathecal low-dose bupivacaine versus lidocaine for in vitro fertilization procedures. Reg Anesth Pain Med 2001; 26: 52–6. 18. Philip J, Sharma SK, Gottumukkala VNR, Perez BJ, Slaymaker EA, Wiley J. Transient neurologic symptoms after spinal anesthesia with lidocaine in obstetric patients. Anesth Analg 2001; 92: 405–9.

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19. Rorarius M, Suominen P, Haanpaa M, Puura A, Baer G, Pajunen P, Tuimala R. Neurologic sequelae after caesarean section. Acta Anaesthesiol Scand 2001; 45: 34–41. 20. Oka S, Matsumoto M, Ohtake K, Kiyoshima T, Nakakimura K, Sakabe T. The addition of epinephrine to tetracaine injected intrathecally sustains an increase in glutamate concentrations in the cerebrospinal fluid and worsens neuronal injury. Anesth Analg 2001; 93: 1050–7. 21. Ohtake K, Matsumoto M, Wakamatsu H, Kawai K, Nakakimura K, Sakabe T. Glutamate release and neuronal injury after intrathecal injection of local anesthetics. Neuroreport 2000; 11: 1105–9. 22. Akioka K-L, Torigoe K, Maruta H, Shimizu N, Kobayashi Y, Kaneko Y, Shiratori R. A case of cauda equina syndrome following spinal anesthesia with hyperbaric dibucaine. J Anesth 2001; 15: 106–7. 23. Kang PB, Phuah HK, Zimmerman RA, Handler SD, Dure LS, Ryan SG. Medial medullary injury during adenoidectomy. J Pediatr 2001; 138: 772–4. 24. Atanassoff PG, Ocampo CA, Bande MC, Hartmannsgruber MWB, Halaszynski TM. Ropivacaine 0.2% and lidocaine 0.5% for intravenous regional anesthesia in outpatient surgery. Anesthesiology 2001; 95: 627–31. 25. Wahlgren C-F, Lillieborg S. Split-skin grafting with lidocaine–prilocaine cream: a meta-analysis of efficacy and safety in geriatric versus nongeriatric patients. Plast Reconstr Surg 2001; 107: 750–6. 26. Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol 2001; 44 Suppl: 399–400. 27. Godwin Y, Brotherston M. Hyperpigmentation following the use of Emla cream. Br J Plast Surg 2001; 54: 82–3. 28. Malamed SF, Gagnon S, Leblanc D. Articaine hydrochloride: a study of the safety of a new amide local anesthetic. J Am Dent Assoc 2001; 132: 177– 85. 29. Singh RK, Kambe JC, Andrews LK, Russell JC. Benzocaine-induced methemoglobinemia accompanying adult respiratory distress syndrome and sepsis syndrome: case report. J Trauma 2001; 50: 1153–7. 30. Ramsakal A, Lezama JL, Adelman HM. A potentially fatal effect of topical anesthesia. Hosp Pract 2001; 36: 13–14. 31. Udeh C, Bittikofer J, Sum-Ping STJ. Severe methemoglobinemia on reexposure to benzocaine. J Clin Anesth 2001; 13: 128–30. 32. Lorelli DR, Morris DE, Lewis JW Jr. Druginduced methemoglobinemia during thoracoscopic lung biopsy. Ann Thorac Surg 2001; 71: 703–5. 33. Roos TC, Merk HF. Allergic contact dermatitis from benzocaine ointment during treatment of Herpes zoster. Contact Dermatitis 2001; 44: 104.

149 34. Monedero P, Hess P. High epidural block with chloroprocaine in a parturient with low pseudocholinesterase activity. Can J Anaesth 2001; 48: 318–19. 35. Hayashi K, Kawachi S, Saida T. Allergic contact dermatitis due to both chlorpheniramine maleate and dibucaine hydrochloride in an overthe-counter medicament. Contact Dermatitis 2001; 44: 38–9. 36. Kearney CR, Fewings J. Allergic contact dermatitis to cinchocaine. Australas J Dermatol 2001; 42: 118–19. 37. Eredmann SM, Sachs B, Merk HF. Systemic contact dermatitis from cinchocaine. Contact Dermatitis 2001; 44: 260–1. 38. Leonard SA, Lydon A, Walsh M, Fleming C, Boylan J, Shorten GD. Does prior administration of enoxaparin influence the effects of levobupivacaine on blood clotting? Assessment using the Thrombelastograph. Br J Anaesth 2001; 86: 808–13. 39. Enlund M, Mentell O, Krekmanov L. Unintentional hypotension from lidocaine infiltration during orthognathic surgery and general anaesthesia. Acta Anaesthesiol Scand 2001; 45: 294–7. 40. Karim A, Ahmed S, Siddiqui R, Mattana J. Methemoglobinemia complicating topical lidocaine used during endoscopic procedures. Am J Med 2001; 111: 150–3. 41. Scala E, Giani M, Pirrotta L, Guerra EC, Girardelli CR, De Pita O, Puddu P. Simultaneous [correction of Spontaneous] allergy to ampicillin and local anesthetics. Allergy Eur J Allergy Clin Immunol 2001; 56: 454–5. 42. Anonymous. Lidocaine patch shown to relieve postherpetic neuralgia. J Pharm Technol 2001; 17: 154. 43. Ghose S, Garodia VK, Sachdev MS, Kumar H, Biswas NR, Pandey RM. Evaluation of potentiating effect of a drop of lignocaine on tropicamideinduced mydriasis. Invest Ophthalmol Vis Sci 2001; 42: 1581–5. 44. Blaschke V, Fuchs T. Periorbital allergic contact dermatitis from oxybuprocaine. Contact Dermatitis 2001; 44: 198. 45. Mulroy MF, Larkin KL, Siddiqui A. Intrathecal fentanyl-induced pruritus is more severe in combination with procaine than with lidocaine or bupivacaine. Reg Anesth Pain Med 2001; 26: 252–6. 46. Dannaker CJ, Maibach HI, Austin E. Allergic contact dermatitis to proparacaine with subsequent cross-sensitization to tetracaine from ophthalmic preparations. Am J Contact Dermatitis 2001; 12: 177–9. 47. Bisschop DY, Alardo JP, Razgallah B, Just BY, Germain M-LY, Millart HG, Trenque TC. Seizure induced by ropivacaine. Ann Pharmacother 2001; 35: 311–13.

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Neuromuscular blocking agents and skeletal muscle relaxants

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 371; SEDA-23, 150; SEDA-24, 159; SEDA-25, 160)

Rapacuronium In the aftermath of the withdrawal of rapacuronium from the market, a paper addressing its effects on respiratory function has been published. In their study, which was performed while rapacuronium was still on the market in the USA, the authors observed statistically significant reductions in peak inspiratory flow rate, peak expiratory flow rate, and dynamic compliance and increases in peak inflating pressure when rapacuronium 1.5 mg/kg was given under steady-state conditions to patients who were already anesthetized, intubated, and ventilated (1C ). In five of the 10 patients these changes amounted to more than 25% from baseline and were considered clinically relevant. As rapacuronium is no longer available this has no direct clinical impact. However, while discussing the mechanisms of rapacuroniuminduced bronchospasm the authors speculated that differential effects of the drug on several subtypes of muscarinic acetylcholine receptors might be responsible. As raised histamine concentrations were not found in seven patients with rapacuronium-induced bronchospasm in another study (2C ), they reckoned that histamine release was an unlikely explanation. Referring to the observation that pipecuronium, another non-steroidal muscle relaxant, blocked © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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pilocarpine-stimulated prejunctional M2 receptors in vitro (3E ), they suggested that a similar effect might result in rapacuronium-induced bronchospasm. Prejunctional M2 receptors are thought to have a role in negative feedback and inhibition of further acetylcholine release, thereby reducing smooth muscle relaxation. These aspects will need to be taken into account when new substances are considered for clinical use.

Allergic reactions to rocuronium During the last few years several allergic reactions to rocuronium have been reported. Based on data from the UK, Australia, and France, it had been suggested that the incidence of such reactions after rocuronium administration paralleled its frequency of use, as assessed by its market share, implying that rocuronium did not have unusual allergenic properties (4C –6C ). Also, the incidence of hypotension, tachycardia, or reduced oxygen saturation (which might suggest an anaphylactoid reaction) was relatively low after rocuronium administration compared with other muscle relaxants in a computerized analysis of 47 295 anesthetic records in one hospital (7c ). Recently, however, the French Group on the Study of Perianesthetic Anaphylactoid Reactions (GERAP) has reported that the proportion of anaphylactoid reactions to rocuronium was similar to succinylcholine in relation to the individual market shares of these agents (8C ). This would make rocuronium look unfavorable, taking into account the fact that succinylcholine is believed to trigger anaphylactoid reactions

Neuromuscular blocking agents and skeletal muscle relaxants

more often than any non-depolarizing neuromuscular blocker. The authors assumed that their figures might have been partly due to anesthetists’ paying more attention to the effects of drugs that had become available more recently, especially in cases of mild reactions. Reporting bias has also been offered as one possible explanation of 29 reports of anaphylaxis to rocuronium among 150 000 patients in Norway, in contrast to eight cases among 800 000 patients in the other Scandinavian countries (9Cr ). This observation has prompted the Norwegian Medicines Agency to recommend that rocuronium be temporarily withdrawn from routine practice and that it be used for rapid-sequence induction only. It is difficult to understand why such an increase in the number of reported cases should only be observed in France and Norway and not in other countries in which rocuronium is widely used. For the time being, it is not possible to decide whether anaphylactoid reactions are more common with rocuronium than with other non-depolarizing muscle relaxants. To get a clearer picture, a large longitudinal survey would be needed (10R ), which is unlikely to be performed, owing to the large number of cases that would be required. We shall probably have to rely on national surveys, like the French one cited above. International networking and pooling of data might be the way forward. All of this will depend on clinicians chasing every case of a suspected anaphylactoid reaction by immunological testing and reporting all confirmed cases to appropriate bodies. For reasons of completeness it should be mentioned that reports of anaphylactoid reactions to newer muscle relaxants other than rocuronium also continue to be published (11c – 13c ).

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 361; SEDA-23, 150; SEDA-24, 158; SEDA-25, 161) Nervous system Patients with severe head injuries require endotracheal intubation and controlled ventilation. Rapid sequence intubation using an intravenous anesthetic plus succinylcholine is the standard technique for this, as

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the patient may have a full stomach. For a couple of years, however, succinylcholine has been suggested by some to have a negative effect by causing increased intracranial pressure. The literature on this has been reviewed (14R ). The authors found only two studies that specifically addressed the effects of succinylcholine on intracranial pressure in patients with head injuries (15C , 16C ). In both studies succinylcholine was given to patients who were already being ventilated in the intensive care unit. There were no adverse effects of succinylcholine on intracranial pressure or cerebral perfusion pressure. However, when succinylcholine was given to lightly anesthetized patients undergoing resection of intracranial tumors there were significant increases in intracranial pressure (17C , 18C ). These could be prevented by pretreatment with a small dose of a non-depolarizing muscle relaxant (18C ). The importance of an adequate level of anesthesia for intubating patients at risk of intracranial hypertension should be stressed. A lightly anesthetized patient will have large increases in intracranial pressure during intubation, no matter which muscle relaxant is used, because of a stress response that includes venous vasoconstriction and a massive increase in central venous pressure, resulting in impaired venous outflow from the cranium and thereby increased intracranial blood volume. Electrolyte balance The underlying mechanisms of and mortality from succinylcholineassociated hyperkalemic cardiac arrest have been reviewed (19R ). The author concluded that hyperkalemia during rapid acute rhabdomyolysis is more likely to result in unsuccessful resuscitation than is the potassium efflux that results from up-regulation of acetylcholine receptors. It should be stressed that almost all reported cases of hyperkalemic cardiac arrest considered to result from rhabdomyolysis occurred in children and adolescents with underlying muscular dystrophies. The use of succinylcholine in intensive care units has been critically reviewed (20r ). The author concluded that its use is obsolete in this setting, referring to the increased risk of succinylcholine adverse effects in intensive care patients. Of particular concern is the growing number of cases of hyperkalemic cardiac arrest that occurred when succinylcholine was given to critically ill patients after a period of immobilization. As stated in last year’s edition

152 (SEDA-25, 161), we think that succinylcholine should be regarded as being contraindicated in critically ill patients who have been immobilized in an intensive care unit for more than 48 hours. Having said that, we still regard succinylcholine as the muscle relaxant of first choice for rapid sequence intubation in emergencies, if risk factors such as prolonged immobilization, pre-existing hyperkalemia, or neuromuscular disorders, are absent. Recently, the authors of yet another report of succinylcholine-induced fatal hyperkalemic cardiac arrest in an intensive care unit assumed that severe mucositis after cancer chemotherapy might have contributed to the hyperkalemic response (21c ). • A 37-year-old woman with acute myelogenous leukemia was admitted to an intensive care unit (ICU) with mental status changes and progressive dyspnea due to pneumonia. Intubation was performed before ICU admission using a sedative without neuromuscular blockade. She had received chemotherapy with cytarabine, daunorubicin, and intrathecal methotrexate for CNS metastases. After chemotherapy and before ICU admission her course was complicated by continuous neutropenic fevers and by painful mucositis causing dysphagia and bleeding. After 10 days of ventilator treatment in the ICU and treatment with ceftazidime, gentamicin, metronidazole, vancomycin, G-cerebrospinal fluid, amphotericin, and aciclovir, her condition improved, allowing withdrawal of ventilator support and extubation. A few hours later, however, she gradually developed severe respiratory distress and required re-intubation. The serum potassium concentration before intubation was 4.3 mmol/l. For endotracheal intubation she received intravenous etomidate 14 mg and succinylcholine 100 mg. Immediately after intubation she developed a broad-complex tachycardia and her blood pressure could not be measured. Chest compression and advanced cardiac life support were started. Her serum potassium concentration was 13.1 mmol/l. Intravenous calcium chloride, sodium bicarbonate, and insulin/glucose were therefore given. The serum potassium fell to 6.5 mmol/l but rose to 7.4 mmol/l 15 minutes later, despite additional antihyperkalemic treatment. She finally died.

Despite this having been a case of succinylcholine-induced hyperkalemic cardiac arrest after several days of ventilator treatment on the intensive care unit, the authors did not believe that upregulation and extrajunctional spread of acetylcholine receptors were the underlying mechanisms. They implied that mobilization and daily physiotherapy would have both prevented these typical denervation-like changes

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and ruled out a neuromuscular disorder. Rather they suggested that severe generalized mucositis had resulted in a state that they compared to an “internal burns injury”. However, these speculations were not substantiated by additional data. In particular, they gave no information on the pre-succinylcholine neuromuscular state of the patient. Some form of polyneuropathy and/or myopathy could have been present, and this was not ruled out by the fact that the patient could breathe spontaneously and sit in a chair. While it is true that severe mucositis represents a state of widespread cellular damage similar to severe burn injuries, it is not clear why this itself should result in hyperkalemia after succinylcholine. To our knowledge succinylcholine only has effects on excitable cells. Even in patients with severe thermal injuries, no case of hyperkalemia after succinylcholine has been reported within the first 48 hours after the accident, and succinylcholine-induced hyperkalemia in burned patients is believed to result from upregulation of acetylcholine receptors, owing to thermal damage of nerve fibres (structural denervation) and immobilization (functional denervation) (22R ). Apart from immobilization due to the severity of the illness it is very unlikely that mucositis should have similar effects. Mucositis itself should therefore not be regarded as a risk factor for succinylcholine-associated hyperkalemia.

SKELETAL MUSCLE RELAXANTS (SED-14, 390; SEDA-23, 152; SEDA-24, 159; SEDA-25, 163)

The baclofen withdrawal syndrome Long-term administration of baclofen is widely used in patients with muscle spasticity resulting from a variety of cerebral and spinal chord lesions. As with other GABA receptor agonists, withdrawal reactions will occur if it is stopped abruptly. Patients can present with different symptoms, not all of which would be considered classical of drug withdrawal. Some interesting aspects of withdrawal symptoms after baclofen administration have been highlighted in three recent reports.

Neuromuscular blocking agents and skeletal muscle relaxants

Clinical presentation There is a proposed similarity between baclofen withdrawal and the neuroleptic malignant syndrome. • A 36-year-old man with paraplegia after a spinal cord injury became disoriented (23A ). He had been taking baclofen 10 mg at night for several years. He had marked rigidity in both arms and legs, he was sweating and pyrexial (38◦ C), and his heart rate was 112 beats/min. His serum creatine kinase was raised at 2668 U/l and rose to 2982 U/l on day 3. At that time, baclofen was restarted. Within 3 days he was fully oriented. Over 2 weeks his creatine kinase activity gradually fell to normal and his temperature settled. It turned out that he had neglected to take any medication for several days before admission.

The authors believed that symptoms in this case resembled the neuroleptic malignant syndrome, based on the combination of muscle rigidity, pyrexia, signs of autonomic disturbance, and altered consciousness. They did not think that the raised serum creatine kinase activity was associated with rhabdomyolysis, stating that there was no evidence from urinalysis to suggest this. Unfortunately, they did not specify whether there was myoglobin in the urine or not. Creatine kinase activities up to 40 000 U/l have been noted during baclofen withdrawal (24c ), compared with which creatine kinase activity in this case was much lower, suggesting only moderate muscle damage. One might assume that muscle damage after baclofen withdrawal correlates with the duration and intensity of muscular hyperactivity. In addition, prolonged muscular hyperactivity may be expected to be followed by an increase in both body temperature and heart rate, owing to hypermetabolism and sympathetic activation. Sweating will result from sympathetic activation and a thermoregulatory response to hyperthermia and is not necessarily an autonomic disturbance. Disorientation is also an expected symptom of baclofen withdrawal. In conclusion, this patient’s combination of symptoms could have been explained by baclofen withdrawal alone. Assuming that disturbances in central dopaminergic systems could have been involved, as in neuroleptic malignant syndrome, is speculative. This is not the first report of similarities between the neuroleptic malignant syndrome and baclofen withdrawal (24c , 25cr , 26c ). In addition, hyperthermia seems to be common in baclofen withdrawal (25cr ).

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If a patient stops taking baclofen, a blood sample for baclofen serum concentration measurement should be taken if possible, to confirm the diagnosis post hoc if hyperthermia occurs. If a patient taking long-term baclofen presents with similar symptoms, baclofen withdrawal should be considered and baclofen should be given. If this is not effective and the patient deteriorates, with hyperthermia, increasing creatine kinase activity, and metabolic sequelae, dantrolene can be given. Dantrolene is lifesaving in malignant hyperthermia associated with volatile anesthetics and succinylcholine and is also the drug of choice for the treatment of neuroleptic malignant syndrome. In one case of baclofen withdrawal, dantrolene was given with success (24c ). It should be stressed that baclofen withdrawal is a potentially fatal emergency requiring intensive care. The effects of renal impairment Baclofen is cleared predominantly by renal excretion. Thus, if a patient taking baclofen has deteriorating renal function one would expect relative baclofen overdose and would reduce the dosage. • An 82-year-old man with left ventricular dysfunction and gout had worsening renal function (27A ). He was taking lisinopril, furosemide, naproxen, allopurinol, and baclofen 20 mg tds. As no reason could be found for the use of baclofen the dose was halved and then stopped 10 days later. The next day he had visual hallucinations, confusion, and agitation, and required sedation with diazepam. He was afebrile, with normal inflammatory markers, and a CT scan of the brain showed only cerebral atrophy. Baclofen was reintroduced, with complete resolution of neuropsychiatric symptoms within 48 hours.

A reduced dosage of baclofen may be necessary in patients with renal insufficiency. On the other hand underdosing can result in withdrawal symptoms and an inadequate therapeutic effect. Both overdosing and underdosing will cause significant morbidity and a prolonged hospital stay. Measuring baclofen serum concentrations in problem patients could be helpful for dosage adjustments and might be cost effective. Withdrawal from baclofen should be performed with extreme caution. In selected patients, hospital admission for this purpose may be justified, for example in elderly patients who live on their own without someone looking after them.

154 Fetotoxicity Convulsions have been attributed to baclofen withdrawal after in utero exposure (28A ). • A 7-day-old baby was admitted to hospital with generalized convulsions, which did not respond to phenobarbital, phenytoin, clonazepam, lidocaine, or pyridoxine. A variety of investigations all gave negative results. Electroencephalography 4 days later showed prolonged episodes of epileptic activity. At that time baclofen withdrawal was suspected, as the paraplegic mother had been taking baclofen 20 mg tds throughout pregnancy. The baby was given baclofen 0.25 mg/kg qds and 30 minutes after the first dose the convulsions stopped. The baclofen was then slowly withdrawn over 2 weeks. An MRI scan of the brain on day 17 suggested a hypoxic ischemic insult in the perinatal period, which was considered to have been secondary to convulsions.

This is the first published case of baclofen withdrawal after intrauterine exposure. As convincingly presented by the authors, baclofen withdrawal was the most likely explanation for the convulsions. In discussing the possible mechanisms of the delayed onset of convulsions

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the authors assumed that a secondary increase in baclofen serum concentration due to redistribution might have prevented earlier onset of the withdrawal symptoms. This is of course speculative; nothing is known about baclofen pharmacokinetics in neonates. On the other hand, the authors stated that the mother had noted some abnormal movements starting on the second day post-partum, which might have represented the first signs of withdrawal. The half-life of baclofen in adults is 3–6 hours, and adults usually become symptomatic 24–72 hours after baclofen is reduced or withdrawn (25cr ). In conclusion, baclofen withdrawal should be suspected if postnatal convulsions occur after intrauterine exposure. The first priority in such a case is to rule out other causes, such as infections, electrolyte disturbances, and intracranial pathology, and to prevent secondary brain damage due to prolonged convulsions. Baclofen should probably be considered at an early stage, as it might be the most effective anticonvulsant in such cases.

REFERENCES 1. Tobias JD, Johnson JO, Sprague K, Johnson G. Effects of rapacuronium on respiratory function during general anesthesia: a comparison with cisatracurium. Anesthesiology 2001; 95: 908–12. 2. Levy JH, Pitts M, Thanopoulos A, Szlam F, Bastian R, Kim J. The effects of rapacuronium on histamine release and hemodynamics in adult patients undergoing general anesthesia. Anesth Analg 1999; 89: 290–5. 3. Zappi L, Song P, Nicosia S, Nicosia F, Rehder K. Do pipecuronium and rocuronium affect human bronchial smooth muscle? Anesthesiology 1999; 91: 1616–21. 4. Rose M, Fisher M. Rocuronium: high risk of anaphylaxis? Br J Anaesth 2001; 86: 678–82. 5. Watkins J. Incidence of UK reactions involving rocuronium may simply reflect market use. Br J Anaesth 2001; 87: 522. 6. Laxenaire MC. Epidémiologie des réactions anaphylactoïdes peranesthésiques. Quatrième enquête multicentrique (Juillet 1994–Décembre 1996). Ann Fr Anesth Reanim 1999; 18: 796–809. 7. Booij LHDJ, Houweling PJ. Rocuronium: high risk for anaphylaxis? Br J Anaesth 2001; 87: 805–6. 8. Laxenaire MC, Mertes PM. Anaphylaxis during anaesthesia. Results of a two-year survey in France. Br J Anaesth 2001; 87: 549–58.

9. Laake J, Rottingen J. Rocuronium and anaphylaxis—a statistical challenge. Acta Anaesthesiol Scand 2001; 45: 1196–203. 10. Fisher M, Baldo BA. Anaphylaxis during anaesthesia: current aspects of diagnosis and prevention. Eur J Anaesthesiol 1994; 11: 263–84. 11. Krombach J, Hunzelmann N, Koster F, Bischoff A, Hoffmann-Menzel H, Buzello W. Anaphylactoid reactions after cisatracurium administration in six patients. Anesth Analg 2001; 93: 1257–9. 12. Legros CB, Orliaguet GA, Mayer MN, Labbez F, Carli PA. Severe anaphylactic reaction to cisatracurium in a child. Anesth Analg 2001; 92: 648–9. 13. Briassoulis G, Hatzis T, Mammi P, Alikatora A. Persistent anaphylactic reaction after induction with thiopentone and cisatracurium. Paediatr Anaesth 2000; 10: 429–34. 14. Clancy M, Halford S, Walls R, Murphy M. In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a competitive neuromuscular blocking agent improve outcome? A literature review. Emerg Med J 2001; 18: 373–5. 15. Kovarik WD, Mayberg TS, Lam AM, Mathisen TL, Winn HR. Succinylcholine does not change intracranial pressure, cerebral blood flow velocity, or the electroencephalogram in patients with neurologic injury. Anesth Analg 1994; 78: 469–73.

Neuromuscular blocking agents and skeletal muscle relaxants 16. Brown MM, Parr MJ, Manara AR. The effect of suxamethonium on intracranial pressure and cerebral perfusion pressure in patients with severe head injuries following blunt trauma. Eur J Anaesthesiol 1996; 13: 474–7. 17. Minton MD, Grosslight K, Stirt JA, Bedford RF. Increases in intracranial pressure from succinylcholine: prevention by prior nondepolarizing blockade. Anesthesiology 1986; 65: 165–9. 18. Stirt JA, Grosslight KR, Bedford RF, Vollmer D. “Defasciculation” with metocurine prevents succinylcholine induced increases in intracranial pressure. Anesthesiology 1987; 67: 50–3. 19. Gronert GA. Cardiac arrest after succinylcholine: mortality greater with rhabdomyolysis than receptor upregulation. Anesthesiology 2001; 94: 523–9. 20. Booij LHDJ. Is succinylcholine appropriate or obsolete in the intensive care unit? Crit Care 2001; 5: 245–6. 21. Al-Khafaji AH, Dewhirst WE, Cornell CJ Jr, Quill TJ. Succinylcholine-induced hyperkalemia in a patient with mucositis secondary to chemotherapy. Crit Care Med 2001; 29: 1274–6. 22. Martyn J, White D, Gronert G, Jaffe R, Ward J. Up-and-down regulation of skeletal muscle

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acetylcholine receptors. Anesthesiology 1992; 76: 822–43. 23. Turner MR, Gainsborough N. Neuroleptic malignant-like syndrome after abrupt withdrawal of baclofen. J Psychopharmacol 2001; 15: 61–3. 24. Khorasani A, Peruzzi WT. Dantrolene treatment for abrupt intrathecal baclofen withdrawal. Anesth Analg 1995; 80: 1054–6. 25. Green LB, Nelson VS. Death after acute withdrawal of intrathecal baclofen: case report and literature review. Arch Phys Med Rehabil 1999; 80: 1600–4. 26. Reeves RK, Stolp-Smith KA, Christopherson MW. Hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation associated with baclofen pump catheter failure. Arch Phys Med Rehabil 1998; 79: 353–6. 27. O’Rourke F, Steinberg R, Ghosh P, Khan S. Withdrawal of baclofen may cause acute confusion in elderly patients. Br Med J 2001; 323: 870. 28. Ratnayaka BD, Dhaliwal H, Watkin S. Drug points. Neonatal convulsions after withdrawal of baclofen. Br Med J 2001; 323: 85.

Michael Schachter

13

Drugs that affect autonomic functions or the extrapyramidal system

It is not by choice that this chapter gets longer every year—the number of references has increased steadily since SEDA-20. Anyone who reads the lay press will see that the adverse effects of drugs are increasingly the subject of news reports. Indeed, at the time of writing the possible toxic effects of Ephedra may be the subject of criminal investigations in the USA, although this does not fall within the scope of this edition. Once again the many problems associated with the treatment of Parkinson’s disease form the most prominent feature of this chapter, while the widespread use of anticholinergic drugs to mitigate bladder dysfunction has also drawn considerable attention. This year the chapter includes, in addition to the usual survey of the past year, a review of the safety and tolerability of midodrine, an alpha1 -adrenoceptor agonist used in some countries in the management of postural hypotension.

10 mg have been compared with oral doses of (−)ephedrine 50 mg in 16 healthy Caucasian men with no drug/alcohol/nicotine abuse or dependence (1c ). Intranasal ephedrine caused an increase in blood pressure but associated orthostatic hypotension. The growing controversy about the toxic effects of Ephedra can be seen in the correspondence section of the New England Journal of Medicine. With reference to an earlier paper a pathologist, who is also consultant to the Ephedra Education Council, has questioned the involvement of Ephedra in the deaths of eight patients, pointing out that several had preexisting conditions such as chest pain and hypertension (2r ). The authors responded, surely justifiably, that these were contraindications to the use of Ephedra in the first place, and they cast doubt on the adequacy of the warnings provided (3r ). In the same issue of the Journal a group from the New York City Poison Control Center have reported a case of myocardial infarction attributed to Ephedra (4A ).

DRUGS THAT STIMULATE BOTH ALPHA- AND BETA-ADRENOCEPTORS

• A previously healthy 19-year-old man took tablets containing a total of 24 mg of Ephedra alkaloids and 100 mg of caffeine, and 15 minutes later developed severe chest pain radiating down the left arm. An electrocardiogram showed an inferolateral myocardial infarct, confirmed by creatine kinase and troponin I measurements. He made a full recovery, and coronary angiography showed only minimal atherosclerotic disease of the left anterior descending artery.

(SED-14, 414; SEDA-23, 155; SEDA-24, 163; SEDA-25, 166)

Ephedra, ephedrine, and pseudoephedrine Cardiovascular The cardiovascular effects, subjective effects, and abuse potential of single intranasal doses of ephedrine 5 mg and © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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The authors emphasized the dangers of Ephedracontaining over-the-counter formulations, even in fit young people. Severe hypertension has been attributed to pseudoephedrine abuse (5A ). • A 36-year-old man with hypertension taking no less than seven antihypertensive drugs had outpatient systolic pressures of over 190 mmHg.

Drugs that affect autonomic functions or the extrapyramidal system Investigations for primary causes of hypertension were negative and there was increasing suspicion of treatment non-compliance or factitious hypertension. Urine screening showed the presence of pseudoephedrine, which the patient could not explain. When he was given his normal antihypertensive drugs under close supervision his systolic blood pressure fell to 70 mmHg and his serum creatinine doubled. His blood pressure became normal when his medication was briefly suspended but he continued to deny any deliberate attempt to alter his blood pressure and discharged himself soon afterwards.

The authors concluded that this represented factitious hypertension due to pseudoephedrine, the first such case reported and a very unusual example of Munchausen’s syndrome. Psychiatric Pseudoephedrine is often used by scuba divers to avoid ear barotrauma. The psychometric and cardiac effects of pseudoephedrine have been evaluated at one atmosphere (100 kPa, sea level) and three atmospheres (30 kPa, 20 m) in a double-blind, placebo-controlled, crossover study in 30 active divers in a hyperbaric chamber (6C ). Pseudoephedrine did not cause significant alterations in psychometric performance at 3 atmospheres. Gastrointestinal Ischemic colitis has been attributed to pseudoephedrine abuse (7A ).

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• A 21-year-old man developed acute myocardial ischemia. Smoking was the only risk factor for coronary artery disease and he denied using cocaine. Angiography showed normal coronary arteries. He had recently started to take amfebutamone for smoking cessation and pseudoephedrine as a non-prescription influenza remedy.

The authors postulated that the combination of two sympathomimetics had caused acute coronary artery vasospasm. This is the first report linking amfebutamone to acute coronary syndrome, and one of a few cases associated with pseudoephedrine. It is also possible that erythromycin, which this patient was also taking, could have impaired the hepatic metabolism of amfebutamone.

DRUGS THAT PREDOMINANTLY STIMULATE ALPHA-ADRENOCEPTORS (SED-14, 417; SEDA-23, 155; SEDA-24, 164; SEDA-25, 167)

Methoxamine

• A 51-year-old woman presented for the second time in 4 months with abdominal pain. On this as on the previous occasion, emergency laparotomy was needed and she was found to have patchy infarction of the terminal ileum and the ascending colon. It emerged that she had been taking pseudoephedrine for 2 years, because she found that it relieved her headaches. In fact she had often noticed abdominal pain and distention, with occasional bloody diarrhea, after taking pseudoephedrine. Before each of her two admissions she had been taking the remarkably high dose of 900 mg/day, and on many other occasions had taken as much as 600 mg/day. She made a good recovery and was said to have stopped taking pseudoephedrine.

Methoxamine, a relatively selective alpha1 adrenoceptor agonist, has been used to a limited extent in the management of urinary stress incontinence. Its effects have been examined in a double-blind placebo-controlled trial in only six women (9c ). There was little effect on maximum urethral pressure, the surrogate end-point used in the trial. The drug was given by intravenous infusion at a maximum dose of 1.0 mg/70 kg/min. There was a significant rise in systolic blood pressure of about 13 mmHg and a fall in pulse rate of some 18 beats/minute. All subjects taking methoxamine had headache, cold extremities, and piloerection. The authors understandably concluded that this is not a very promising treatment for stress incontinence.

The authors quoted seven other published cases of pseudoephedrine-related ischemic colitis, all occurring at much lower dosages, at most 240 mg/day.

Midodrine

Drug interactions Acute coronary syndrome has been attributed to a combination of pseudoephedrine with amfebutamone (bupropion) (8A ).

Orthostatic hypotension forms a potentially very disabling component of several types of autonomic disturbance. It is relatively common in all age groups, but the cause varies. It

158 is commonly due to drugs (such as diuretics, antihypertensive drugs, and neuroleptic drugs) and to neurocardiogenic or vasovagal syncope, which occurs at all ages, usually without any obvious triggers. Hypotension can also form part of autonomic neuropathies, such as those associated with diabetes and less commonly with amyloid. It is also associated with neurodegenerative diseases such as multiple system atrophy and can occur after spinal cord injury, during hemodialysis, and in astronauts. It has also been suggested that orthostatic hypotension is an essential element of the chronic fatigue syndrome in most or all affected individuals, but this is controversial. One relatively common cause of orthostatic hypotension is iatrogenic, in which case withdrawal of the causative drugs solves the problem. In other cases, or when hypotensive drugs cannot be withdrawn, a very wide range of therapies have been tried, reflecting their relative lack of efficacy. Extracellular fluid expansion, with salt and mineralocorticoids, such as fludrocortisone, is of low efficacy and considerable risk, and can lead to cardiac failure or supine hypertension. An alternative approach involves increasing peripheral resistance pharmacologically: ergot alkaloids are among the agents used for this, but their toxicity needs no elaboration. Midodrine is a potential alternative that has now been extensively tested in several of the orthostatic hypotension syndromes, including: neurogenic hypertension due to autonomic neuropathies (10c , 11c ); neurocardiogenic syncope (12c , 13C , 14c , 15M , 16C ); the controversial syndrome of orthostatic hypotension and tachycardia that may be associated with chronic fatigue (17M , 18c ); the hypotension seen during hemodialysis (19M ); and hypotension due to neuroleptic drugs (20c ). Midodrine is a prodrug, whose active metabolite is relatively selective for vascular post-junctional alpha1 -adrenoceptors and therefore increases peripheral resistance by arteriolar constriction, with some venoconstriction in capacitance vessels (21M ). It has minimal activity in the central nervous system, since it does not cross the blood–brain barrier. It can be given orally and has a systemic availability of over 90% by this route. The half-life of the active deglycinated metabolite is relatively short (2–3 hours). The dosage range is 2.5–10 mg tds, and is usually towards the upper end of this range.

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Few of the above-mentioned studies have systematically addressed problems of safety and adverse effects, but on the whole the effects described are predictable from the adrenergic properties of the drug and are dose-related. The most common adverse effect, in up to 15% of patients, is piloerection, with or without paresthesia especially of the scalp and face, most commonly in the form of pruritus. Urinary urgency, increased frequency, and even retention have also been recorded; when they occur they constitute the single most common reason for withdrawal. Less common but more serious is the problem of supine hypertension in up to 3% of subjects, although it is not clear how the underlying pathology of the hypotension influences the likelihood of this reaction. An unexpected reaction has been described in a 33year-old schizophrenic woman who took midodrine 4 mg/day because of postural hypotension due to risperidone 6 mg/day (22A ). She developed an acute dystonic reaction, which recurred several times on rechallenge, and the dose of risperidone had to be halved to minimize the hypotension. Overall, midodrine is a relatively efficacious drug with good tolerability, but with some adverse effects that can usually be anticipated. Monitoring of supine blood pressure is essential.

Phenylpropanolamine Nervous system Cerebral hemorrhage has been attributed to phenylpropanolamine (23A ). • A 37-year-old woman took an over-the-counter formulation containing phenylpropanolamine 100 mg. About 90 minutes later she developed very severe bilateral headache resistant to analgesics. Her blood pressure was 180/100 mmHg but fell rapidly to 110/70 mmHg. A CT scan showed multiple small frontal and parietal hemorrhages, and angiography showed extensive segmental vasospasm. She was treated with nimodipine and prednisolone, followed by verapamil. She made an uneventful recovery and there was angiographic resolution of the vascular lesions.

The authors reviewed a number of other case reports of phenylpropanolamine-induced cerebral vasospasm associated with hemorrhages

Drugs that affect autonomic functions or the extrapyramidal system

and drew a parallel with similar effects of amphetamines.

DRUGS THAT STIMULATE PREDOMINANTLY BETA1 -ADRENOCEPTORS (SED-14, 420; SEDA-23, 156; SEDA-24, 165; SEDA-25, 167) There are still some concerns about the safety of dobutamine stress testing, especially if an accelerated protocol is used. In 47 consecutive patients (mean age 64 years, 46 men) with three or more cardiovascular risk factors, intravenous dobutamine was given at a rate of 40 micrograms/kg/min until the target heart rate was achieved, which took a mean of 11.6 minutes (24c ). Subjective sensations occurred in 49% of the patients (palpitation 21%, chest pain 6%, nausea 6%, headache 6%, dizziness 13%), while half the patients had abnormal cardiac rhythms (ventricular extra beats 38%, supraventricular tachycardia 10%, nonsustained ventricular tachycardia 2%). The authors concluded that the safety and tolerability of this procedure is comparable to that of standard dobutamine stress testing, although its specificity and selectivity are still uncertain. Cardiovascular Even in the absence of overt clinical effects there might be concern that dobutamine may damage the myocardium. In 47 patients in Mannheim (mean age 61 years, 34 men) dobutamine echocardiography was carried out, with blood sampling immediately before and after the procedure and then at 1, 2, 4, 6, and 12 hours (25c ). Assays were carried out for creatine kinase-MB, troponins I and T, myoglobin, and fibrin monomer antigen. There were no significant increases in these markers of myocardial damage and coagulation, regardless of the outcome of the stress test. These findings have confirmed those of an earlier study, although the data do not absolutely exclude abnormal findings in a minority of individuals (26c ). Dobutamine does of course have therapeutic as well as diagnostic uses. Cardiac dysrhythmias have been reported.

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• A 74-year-old man with idiopathic dilated cardiomyopathy was given dobutamine (5 mg/kg/min) to determine whether it would produce a positive inotropic effect (27A ). After 14 minutes he developed asymptomatic pulsus alternans, which resolved with 20 minutes of withdrawal.

A much more serious complication of dobutamine therapy is ventricular dysrhythmias. Of 305 patients with acutely decompensated congestive heart failure, 58 were given dobutamine (although it is difficult to ascertain the dose), 44 were given other standard inotropic drugs such as milrinone, and 203 were treated with brain natriuretic peptide (nesiritide, 0.015 or 0.03 µg/kg/min) (28C ). Of those given dobutamine 7% had sustained ventricular tachycardia, 17% had non-sustained ventricular tachycardia, and 5% had a cardiac arrest. In contrast, the figures for nesiritide were 1, 11, and 0% respectively. There was no analysis of other outcomes but these results certainly do not encourage the use of dobutamine in these very vulnerable patients.

DRUGS THAT ACT ON DOPAMINE RECEPTORS

(SED-14, 421; SEDA-23, 156; SEDA-24, 165; SEDA-25, 168)

Levodopa and dopamine receptor agonists Cardiovascular Dopamine receptor agonists can cause postural hypotension. The efficacy of domperidone in preventing this has been reported in patients taking a dopamine receptor agonist, CQA 206-291, that was never marketed but is said to be as effective as currently used agents (29c ). Apomorphine, one of the oldest and most potent of dopamine receptor agonists, is being increasingly used in patients with severe motor fluctuations in Parkinson’s disease. It is usually given by subcutaneous infusion, but this is associated with the development of persistent nodules, causing major problems in about 10% of patients after 3 or more years. One solution is to give the drug intravenously using an indwelling cannula. Six patients, who

160 had responded well to subcutaneous apomorphine before nodules developed, had such cannulae inserted (30c ). The apomorphine was given at a mean rate of 9.0 mg/hour to a total mean dose of 257 mg/day, very similar to the subcutaneous dosage. The intravenous therapy virtually abolished “off” periods, reduced oral antiparkinsonian drug dosages by 59%, and produced a marked (but unquantified) reduction in dyskinesias and an improved quality of life. However, there were major problems. Two patients receiving high doses of apomorphine (450 and 290 mg/day, in the latter case a deliberate overdose) developed thromboembolic complications, following crystal formation, in one case to the right lung and in the other with obstruction to the superior vena cava. Both required surgical intervention. Both recovered fully, but the authors understandably commented that this therapeutic approach still needs further development. Respiratory Pleuropulmonary disease, especially with a fibrotic component, has been reported with all the ergot alkaloids after longterm use. • A 65-year-old man, who had been taking pergolide 3.5 mg/day for 3 years to treat restless legs syndrome, presented with progressive weight loss, fatigue, and dyspnea (31A ). The history was of at least 2 years duration. A chest X-ray showed a loculated right hydropneumothorax, and a bloody pleural exudate was aspirated with no cytological evidence of malignancy. An open biopsy showed inflammatory changes and fibrosis. After withdrawal of pergolide and a short course of corticosteroids he made a full clinical and radiological recovery.

Nervous system In the USA bromocriptine has not been licensed for the suppression of lactation since 1994. Up to that time there had been no reports of intracranial hemorrhage associated with bromocriptine, but since the withdrawal of the license for this indication there have been 15 case reports of this disastrous adverse effect. • Three women aged 22, 24, and 40 years took bromocriptine 2.5 mg bd for 2–5 days post-partum and complained of headache; two lost consciousness (32A ). One subsequently died and another had a residual neurological deficit. In all three cases intracerebral hemorrhage, confirmed by CT or MRI scans, occurred on the sixth day of administration. Maximal recorded blood pressures were 200/100, 173/120, and 180/118 mmHg.

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It hardly needs emphasis that the use of bromocriptine to suppress lactation is difficult to justify, given these potentially catastrophic, if rare, consequences. The successful use of ergot derivatives to shrink macroprolactinomas can have unwanted neurological consequences, and this has been described in two case reports. • Three Italian men aged 39, 42, and 53 years with invasive prolactinomas took cabergoline 1.0–3.0 mg/week and all developed CSF rhinorrhea after 2–7 months (33A ). This was clearly a consequence of loss of the “stopper” effect of the tumor, owing to shrinkage, and in each case was successfully treated by endoscopic trans-sphenoidal surgery. • A 42-year-old Spanish man took cabergoline (up to 3 mg/day) for a large prolactinoma causing hypopituitarism and symptomatic chiasmal compression (34A ). After 18 months there was only a minimal tumor remnant on the floor of the sella turcica, but there was chiasmal herniation. However, there were no clinical effects of this, and in particular the visual fields were normal.

A much less well-known adverse effect of levodopa and dopamine receptor agonists is impairment of proprioception (35c ). In 17 Parkinsonian patients three tests of proprioception were carried out 1 hour after the administration of levodopa or a dopamine receptor agonist. Although data were not provided for individual patients, there was an overall 11–31% deterioration in the mean scores in all three of the tests. There was no difference between patients with and without dyskinesias, but the authors suggested that abnormal proprioception may be a factor in drug-induced dyskinesia.

Sleep disorders with dopamine receptor agonists The apparent association of some newer dopamine agonists with “sleep attacks” continues to attract a great deal of interest. Some remarkable case reports have previously been published (SEDA-25, 169) and reports continue to appear, supplemented by prospective studies and other analyses. For instance, 11 studies involving ropinirole or pramipexole in a total of 2066 patients have been reviewed (36M ). Four of these (two each with ropinirole and pramipexole) were placebo-controlled.

Drugs that affect autonomic functions or the extrapyramidal system

The pooled relative risk of somnolence was 4.98 compared with placebo: there was a nonsignificant trend for greater somnolence with ropinirole, but the confidence intervals were much wider than with pramipexole. In the other studies levodopa alone was compared with levodopa plus the newer drugs; the relative risk was 2.06 compared with levodopa alone. It must be borne in mind that somnolence and sleep attacks may be separate phenomena, although this is controversial. The whole field of sleep disorders in Parkinson’s disease has been reviewed in a consecutive series of 320 patients from Houston, with analysable data from 303 (sex distribution unknown) (37C ). The mean age was 67 years and the mean duration of the disease was 9.1 years. All the patients completed the Epworth Sleepiness Scale and answered specific questions about falling asleep while driving and about the restless legs syndrome. The mean sleepiness score was 11.1, values greater than 10 being regarded as abnormal. As one would expect, just over half the patients had scores at that level. Higher scores correlated with longer duration and greater severity of the disease, with male sex, and with the use of dopamine receptor agonists. There was no apparent difference in this regard between the three most commonly prescribed drugs in these patients (pergolide, ropinirole, and pramipexole, the last being the most frequent). Among those currently driving, 23% reported falling asleep in the car and nearly 20% had features of the restless legs syndrome. This study has therefore reinforced the view that sleep disorders are common in Parkinson’s disease, especially in its advanced stages, and are exacerbated by dopamine agonists as a class. However, one can draw no conclusions about individual drugs from this review. The effects of pramipexole, cabergoline, and levodopa on daytime sleepiness have been assessed in three groups of patients with Parkinson’s disease (38c ). The first group was 19 patients taking pramipexole (mean age 60 years, mean dosage 4.5 mg/day, eight as monotherapy, the remainder with levodopa); the second group was 22 patients taking cabergoline (mean age 63 years, mean dosage 4.1 mg/day, 10 as monotherapy); the third group was 14 patients taking levodopa (mean age 69 years, mean dosage 789 mg/day) as monotherapy.

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The scores on the Epworth Sleepiness Scale were virtually identical (8.0, 8.1, 8.1). Scores of greater than 16, indicating excessive daytime sleepiness, were also evenly distributed across the three groups, and were attributed to only four individuals; there were no reports of sleep attacks. These results have been supported by a study in 160 patients with Parkinson’s disease (mean age 66 years) divided into four equal groups and taking levodopa alone, levodopa with bromocriptine, levodopa with ropinirole, or levodopa with pramipexole (39C ). They were compared with 40 healthy younger controls (mean age 58 years). All the subjects were evaluated using the Epworth sleepiness scales. All the drug regimens were associated with increased sleepiness compared with the controls but there were no distinct sleep attacks. The authors noted that all the drug regimens produced similar levels of sedation, although the data appeared to show a trend towards greater somnolence with ropinirole and more particularly pramipexole. However, these are not uncontested findings. In a study that was described as prospective, but was strictly speaking not, 236 patients (106 men, 130 women, mean age 67 years) were questioned (40C ). All but one was in Hoehn– Yahr stages II–IV. Sleep attacks were reported by 72 patients, of whom 70% were considered to have autonomic dysfunction. The authors concluded that the highest risk was attributable to ropinirole (OR = 7.35), followed by bromocriptine (5.78) and lisuride (5.68); for comparison, the figure for levodopa was 0.61. No patients took pramipexole. Again, it is uncertain whether sleep attacks can truly be distinguished from “ordinary” sleepiness, but the results emphasize the sedative potential of dopamine receptor agonists. On the other hand, these results have been disputed in another report, with authors in common with the previous report. They presented four case studies, three men and one woman, aged 49–87 years, who had had Parkinson’s disease for 8–17 years; the longest duration was in the youngest patient (41A ). All four were taking levodopa (300–1500 mg/day) plus a decarboxylase inhibitor. All four reported sudden irresistible sleep episodes, even during conversations: two also complained of sleepiness distinct from these attacks. Two of the patients

162 also had definite autonomic disturbances. The authors concluded that sleep attacks do occur and may be associated with levodopa as well as with dopamine receptor agonists. The sedative potential of levodopa has been examined in 16 healthy volunteers (mean age 25 years, eight men), although of course this represents a very different neuropsychological context from Parkinson’s disease (42c ). They were given levodopa 200 mg or a placebo as a single dose, with domperidone to minimize peripheral adverse effects, followed by the active drug or control in a cross-over design. Sedation was assessed using a visual analogue scale and reaction time by the response to a light stimulus. There was no overall change in reaction time, but this concealed considerable interindividual variation. Four subjects complained of nausea and one of excitation after levodopa and all had slower reaction times without complaining of sedation. However, seven subjects reported a greater level of sedation with levodopa than placebo, and this correlated (r = 0.7) with their reaction times. In other words, levodopa can cause sedation in normal young people but does not necessarily do so, at least after a single dose. The extent to which these results can be extrapolated to elderly Parkinsonian patients is debatable. Overall, therefore, the current evidence suggests that sedation is a class effect of all dopaminergic drugs, including levodopa. It may be more severe with the newer synthetic agents pramipexole and ropinirole, but this cannot yet be stated with certainty. The existence of discrete sleep attacks also remains controversial, although on balance one would conclude that they can occur. Psychiatric In a prospective study of 89 patients with Parkinson’s disease, of whom 60 were free of hallucinations at entry, though most of these had disturbed sleep patterns, after 4 years 50% of the original non-hallucinators were experiencing hallucinations, while only 14% of those with hallucinations at entry were no longer affected by them (43C ). Those classified as having severe hallucinations increased from 10% at entry to 35% after 4 years. The development or worsening of hallucinations was not associated with levodopa dosage but was strongly correlated with the use of dopamine receptor agonists in combination

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with levodopa: some 59% of patients with hallucinations were taking agonists as against 33% of non-hallucinators. Drug interactions Ropinirole has been reported to enhance the effects of warfarin (44A ). • A 63-year-old man taking co-careldopa and warfarin 4 mg/day (it is not entirely clear why) was also given ropinirole 0.75 mg/day to allow levodopa sparing. After 9 days of ropinirole his INR had increased to 4.6 from a previously stable value of 1.8–2.1, little changed in 2 years. There was no clinical evidence of bleeding. Warfarin was withheld for 4 days and then restarted at 25% of its previous dose. The ropinirole was then withdrawn because of gastrointestinal adverse effects and the warfarin dosage was restored to its previous level.

The mechanism of this interaction has not been elucidated. Ropinirole is metabolized by CYP1A2, but that is not the major isoform involved in warfarin metabolism.

OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY (SED-14, 424; SEDA-24, 167; SEDA-25, 171)

Amantadine Nervous system The popularity of amantadine has waned in recent years, but it is still used in many Parkinsonian patients, especially the more elderly. A new adverse effect has been described in three Japanese women aged 78–87 years (45A ). They had taken amantadine 100–200 mg/day for 1 month to 5 years, in two cases together with co-careldopa. All three developed multifocal myoclonus and two were confused. Amantadine concentrations were high in the two patients in whom they were measured, at over 3000 ng/ml; a concentration over 1000 ng/ml is regarded as toxic. Amantadine was withdrawn and the myoclonus disappeared within 1–2 weeks and did not recur. Cortical myoclonus has also been described with levodopa and bromocriptine, but the mechanism is not known.

Drugs that affect autonomic functions or the extrapyramidal system

Catechol-O-methyl transferase inhibitors Tolcapone was very effective but was withdrawn in 1998 because of liver toxicity. It has been replaced by entacapone, which appears to lack this serious adverse effect, although some neurologists also consider it to be less effective. In 40 patients (mean age 64 years, 22 men) who took tolcapone for 3–7 months and were given entacapone in dosages titrated to 800–2000 mg/day after a transition period of 3–6 months with co-beneldopa, the improvements in “on” and “off” times were less impressive than they had been with tolcapone and there were more adverse effects (46c ). One patient had diarrhea and orthostatic hypertension with both drugs, but another six patients had increased dyskinesias and hallucinations and one developed myoclonus. There was no evidence of liver toxicity with either drug. The authors pointed out that entacapone, unlike tolcapone, not only increases the half-life of levodopa but also its peak concentration, causing significantly enhanced levodopa-related adverse effects. There is therefore a paradox: entacapone appears to be safer but overall causes more adverse effects. The safety issue has been specifically addressed in a Finnish study in 326 patients (mean age 62 years, 217 men) taking levodopa plus a decarboxylase inhibitor (47C ). Two-thirds were randomized to take entacapone 200 mg/day and the remainder to placebo. The withdrawal rate due to adverse events was 14% with entacapone compared to 11% with placebo. Dyskinesias were greatly increased in the former (29% vs 11%) and entacapone was also associated with increased incidences of diarrhea (9.2% vs 1.9%), dry mouth (6.0% vs 0), and discolored urine (6.9% vs 0). However, there was no evidence of liver toxicity with entacapone.

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Cardiovascular Vasospasm is a well-known adverse effect of ergot alkaloids. • A 48-year-old woman developed a cold pulseless right leg and no measurable blood pressure at the right ankle (48Ar ). She was a migraine sufferer and had been taking over-the-counter medications, some of which contained ergot derivatives, although the nature and quantity were not specified. Arteriography showed severe stenosis of the superficial femoral artery, with no identifiable tibial vessels. There was an initial improvement with intra-arterial glyceryl trinitrate infusion, and sustained normalization of the circulation in the leg after administration of sodium nitroprusside, nifedipine, prazosin, and heparin. She made a full recovery.

The authors reviewed the pharmacology of the ergot alkaloids and the acute and subclinical ischemic syndromes that they can produce. They pointed out that in some countries, notably in Latin America, ergot-containing formulations are freely available without a prescription. • A 34-year-old woman has a myocardial infarction after being given ergonovine for an atonic uterus after cesarean section (49A ). Within minutes she became unresponsive, with bradycardia and then asystole followed by ventricular fibrillation during cardiopulmonary resuscitation. An electrocardiogram showed an acute anterior infarct and coronary angiography showed diffuse spasm of the circumflex and left anterior descending arteries, with subtotal occlusion of the latter. The spasm was reversed with intracoronary glyceryl trinitrate but she required ventilation for another 2 days and was eventually discharged 11 days after the infarct, with a borderline left ventricular ejection fraction of 45%.

The authors commented that the patient was of Asian origin and that such individuals are thought to have increased susceptibility to the vasoconstrictor effects of ergot derivatives. Any vascular bed is susceptible to the vasospastic effects of ergot alkaloids.

SEDA-23, 157; SEDA-24, 168; SEDA-25, 171)

• A 50-year-old woman developed ischemic necrosis of the stomach wall after taking up to 5 mg/day of ergotamine tablets for 10 years because of daily headaches (50A ). The necrosis was on the greater curvature and was about 10 cm in diameter. She required laparotomy because of peritonitis and there was a 4 cm area of full-thickness necrosis within the ischemic area. She made a full recovery.

Ergot-related adverse effects are still remarkably frequent and severe.

The authors noted that this is an extremely rare manifestation of ergot-induced ischemia.

THE ERGOT ALKALOIDS AND RELATED AGENTS (SED-14, 431;

164 Drug interactions It is important to remember that ergot derivatives are subject to metabolism by cytochrome P450 and hence to drug interactions. This has been highlighted by two cases of interactions, one with clarithromycin the other with ritonavir. • A 41-year-old woman presented with pain and pallor in the leg and a sensation of coolness exacerbated by exercise (51A ). For many years she had been taking a formulation containing ergotamine 1 mg plus caffeine 100 mg, at a dose of one or two tablets daily, for both prophylaxis and treatment of migraine. For 7 days she had also taken clarithromycin (dose is not stated) for a chest infection. Her legs were cool and cyanosed, with no palpable popliteal or foot pulses and an ankle–brachial index of only 0.6 (normal > 0.8). The authors concluded that her symptoms had been precipitated by the introduction of clarithromycin, a cytochrome P450 inhibitor like the other macrolide antibiotics. However, she was also taking omeprazole, another inhibitor, which may have contributed to the problem. All drugs were withdrawn and nifedipine was given, with full recovery within a couple of days. • A 37-year-old woman with AIDS who had been taking ritonavir developed acute dysphasia and right-sided weakness having taken a total of 10 mg of ergotamine in suppository form for severe headaches that were presumed to be migraine (52A ). Transcranial Doppler and angiography showed multiple stenoses in vessels in the circle of Willis, and an MRI scan showed watershed infarcts in the right and left hemispheres. It was presumed that she had had ergotamine-induced vasospasm due to inhibition of ergotamine metabolism by ritonavir. She was treated with “hemodilution, hypertension and hypervolemia”, and her cerebral flow velocities normalized over the next 18 days and the angiographic appearances by day 90. She was left with a slight right expressive dysphasia and weakness in the right leg.

DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SED-14, 436; SEDA-23, 158; SEDA-24, 168; SEDA-25, 172)

Acetycholinesterase inhibitors Cardiovascular The cholinesterase inhibitors are potentially very dangerous drugs, as two American case reports of asystole have testified.

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• A 67-year-old man underwent left upper lobectomy for a presumed malignancy 11 years after cardiac transplantation (53A ). He had had no cardiac symptoms since his transplant. Succinylcholine was used as a muscle relaxant and was reversed with glycopyrrolate 0.8 mg and neostigmine 4 mg. Within a few minutes he developed asystole, which lasted for about 45 seconds. He subsequently made a full recovery.

The authors speculated that some degree of cardiac re-innervation may have occurred; they recommended that this type of response should be anticipated in future anesthesia in such patients and that therapeutic measures, such as a beta-adrenoceptor agonist, should be available. Another case of asystole has been reported with the very short-acting cholinesterase inhibitor edrophonium (54A ). • A 49-year-old woman was given intravenous edrophonium chloride 2 mg as part of the investigation of an acute myopathy following gastrointestinal surgery. She had also received a total of 60 mg of intravenous labetalol in the 14 hours before the edrophonium was given: presumably this was for a raised blood pressure, but that was not specified. Labetalol caused transient but severe bradycardia (heart rate about 20 beats/min). Immediately after the injection of edrophonium she developed asystole, which was treated immediately with atropine and recovered in 10 seconds.

Such reactions are extremely rare, but in this case the risk was undoubtedly enhanced by previous beta-blockade.

Anticholinergic drugs The adverse effects of the antimuscarinic anticholinergic drugs in patients with incontinence and bladder overactivity has been emphasized in several recent reviews (55M , 56C , 57M , 58C ). The findings are not unexpected: dry mouth is by far the most commonly reported adverse effect, with a frequency of about 40% in patients taking 2 mg of the immediate-release formulation bd. The next most common effects are consistently headache, constipation, and abdominal discomfort. Hallucinations and tachycardia have also been reported. It is agreed that higher doses should not be used because of the risk of urinary retention. About 5% of patients stopped taking tolterodine because of adverse effects and in about 10% the dosage

Drugs that affect autonomic functions or the extrapyramidal system

was reduced. In one comparison of tolterodine 2 mg bd with 4 mg od in an modified-release formulation the latter produced about a 23% lower incidence of dry mouth, with increased efficacy (59C ). Cardiovascular Non-sustained ventricular tachycardia has been attributed to orphenadrine (60A ). • A 57-year-old woman had been taking a formulation containing orphenadrine 15 mg and paracetamol 450 mg bd for musculoskeletal pain. She was also taking propafenone 600 mg/day for paroxysmal atrial fibrillation. After 5 days she developed severe palpitation. Holter monitoring showed frequent brief episodes not only of atrial fibrillation but also of non-sustained ventricular tachycardia. After the orphenadrine was withdrawn the palpitation ceased.

The authors pointed out the potential problems of anticholinergic drugs like orphenadrine in patients taking antidysrhythmic drugs. Possible precipitation of acute myocardial infarction has been discussed by two American emergency medicine specialists (61A ). • A 62-year-old woman developed chest pain and sinus bradycardia (41 beats/min). She had thirddegree heart block and was given atropine 1 mg intravenously. Three minutes later her chest pain increased and the electrocardiogram now showed

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an acute inferior myocardial infarction, confirmed by serum markers. Angioplasty recanalized the right coronary artery.

The authors discuss the possibility, suggested by others, that atropine can precipitate acute myocardial infarction in an ischemic setting. They concluded that while this may be true, on the whole the advantages of successfully correcting bradycardia outweigh the risks of this rare complication. Salivary glands The reference drug for tolterodine is oxybutynin, and there have been several comparisons of the two. All agree that the older drug, in its standard formulation at a dose of 5 mg bd, while of similar efficacy, produces significantly more adverse effects (62C ). The incidence of dry mouth reached 60%, and over 75% in patients taking the highest dose of 5 mg tds. Direct measurements of saliva production confirmed that oxybutynin 5 mg/day reduces saliva output significantly more than tolterodine 2 mg or a modified-release formulation of oxybutynin 10 mg, all given as single doses (63c ). In over 300 patients modifiedrelease oxybutynin once daily produced less dry mouth (28% vs 33%) than immediate-release tolterodine 2 mg bd (64C ).

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baric environment. S Pac Underw Med Soc J 2001; 31: 50–7. 7. Klestov A, Kubler P, Meulet J. Recurrent ischaemic colitis associated with pseudoephedrine use. Intern Med J 2001; 31: 195–6. 8. Pederson KJ, Kuntz DH, Garbe GJ. Acute myocardial ischaemia associated with ingestion of bupropion and pseudoephedrine in a 21-year-old man. Can J Cardiol 2001; 17: 599–601. 9. Radley SC, Chapple CR, Bryan NP, Clarke DE, Craig DA. Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, doubleblind crossover study. Neurourol Urodyn 2001; 20: 43–52. 10. Low PA, Gilden JL, Freeman R, Sheng K-N, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. J Am Med Assoc 1997; 277: 1046–51.

166 11. Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med 1995; 99: 604–10. 12. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management of neurocardiogenic syncope. Heart 1998; 79: 45–9. 13. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a doubleblind, placebo-controlled study with midodrine. Am J Med 1993; 95: 38–48. 14. Sra J, Maglio C, Biehl M, Dhala A, Blanck Z, Deshpande S, Jazayeri MR, Akhtar M. Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 1997; 8: 42–6. 15. Calkins H. Pharmacologic approaches to therapy for vasovagal syncope. Am J Cardiol 1999; 84: 20Q–25Q. 16. Perez-Lugones A, Schweikert R, Pavia S, Sra J, Akhtar M, Jaeger F, Tomassoni GF, Saliba W, Leonelli FM, Bash D, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 2001; 12: 935–8. 17. Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. Am J Med 1998; 105: 14S–21S. 18. Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance and cognitive impairment in adolescents. PACE 2000; 23: 344–51. 19. Perazella MA. Pharmacologic options available to treat symptomatic intradialytic hypotension. Am J Kidney Dis 2001; 38 Suppl 4: S26–S36. 20. Gairard A-C, Cordonnier A-L, Charles A, Viala A, Patri E, Germain C, Lafay N, Gury C. Recherche de la dose efficace de la midodrine dans l’hypertension orthostatique iatrogène à partir d’une étude pilote. J Pharm Clin 2000; 19: 256–9. 21. Mauro VF. Focus on midodrine: an oral peripheral-acting alpha-agonist for the treatment of orthostatic hypotension. Formulary 1997; 32: 225–31. 22. Takahashi H. Acute dystonia induced by adding midodrine, a selective alpha 1 agonist, to risperidone in a patient with catatonic schizophrenia. J Neuropsychiatry Clin Neurosci 2000; 12: 285–6. 23. Yeyrac G, Huguenin H, Guillon B, Chiffoleau A, Thajte N, Bourin M, Jolliet P. Hémorragie cérébroméningée et angiopathie cérébrale aiguë associées à la prise de phénylopropanolamine: un noveau cas. Thérapie 2001; 56: 321–7. 24. Lu D, Greenberg MD, Little R, Malik Q, Fernicola DJ. Accelerated dobutamine stress testing: safety and feasibility in patients with known or suspected coronary artery disease. Clin Cardiol 2001; 24: 141–5. 25. Pfleger S, Scherhag A, Latsch A, Dempfle CE, Simonis B, Haux P, Voelker W, Gaudron P. Safety of dobutamine echocardiography: no signs of myocardial cell damage or activation of the coag-

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ulation system. Dis Manage Clin Outcomes 2001; 3: 15–19. 26. Beckmann S, Bocksch W, Muller C, Schartl M. Does dobutamine stress echocardiography induce damage during viability diagnosis of patients with chronic regional dysfunction after myocardial infarction? J Am Soc Echocardiogr 1998; 11: 181–7. 27. Kahn JHL, Starling MR, Supiano MA. Transient dobutamine-mediated pulsus alternans. Can J Cardiol 2001; 17: 203–5. 28. Burger AJ, Elkayam U, Neibaur MT, Haught H, Ghali J, Horton DP, Aronson D. Comparison of the occurrence of ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide therapy. Am J Cardiol 2001; 88: 35–9. 29. Lang AE. Acute orthostatic hypotension when starting dopamine agonist therapy in Parkinson disease: the role of domperidone therapy. Arch Neurol 2001; 58: 835. 30. Manson AJ, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, Lees AJ. Intravenous diamorphine therapy in Parkinson’s disease. Clinical and pharmacokinetic observations. Brain 2001; 124: 331–40. 31. Danoff SK, Grasso ME, Terry PB, Flynn JA. Pleuropulmonary disease due to pergolide use for restless legs syndrome. Chest 2001; 120: 313–16. 32. Kirsch C, Iffy L, Zito GE, McArdle JJ. The role of hypertension in bromocriptine-related puerperal intracranial hemorrhage. Neuroradiology 2001; 43: 302–4. 33. Cappabianca P, Lodrini S, Felisati G, Peca C, Cozzi R, Di Sarno A, Cavallo LM, Giombini S, Colao A. Cabergoline-induced CSF rhinorrhea in patients with macroprolactinoma. J Endocrinol Invest 2001; 24: 183–7. 34. Marcos L, De Luis DA, Botella I, Hurtado A. Tumour shrinkage and chiasmal herniation after successful cabergoline treatment for a macroprolactinoma. Clin Endocrinol 2001; 54: 126–7. 35. O’Suilleabhain P, Bullard J, Dewey RB. Proprioception in Parkinson’s disease is acutely depressed by dopaminergic medications. J Neurol Neurosurg Psychiatry 2001; 71: 607–10. 36. Etminan M, Samii A, Takkouche B, Rochon PA. Increased risk of somnolence with the new dopamine agonists in patients with Parkinson’s disease. A meta-analysis of randomised controlled trials. Drug Saf 2001; 24: 863–8. 37. Ondo WG, Vuong KD, Khan H, Atassi F, Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology 2001; 57: 1392–6. 38. Pal S, Bhattacharya KF, Agapito C, Chaudhuri KR. A study of excessive daytime sleepiness and its clinical significance in three groups of Parkinson’s disease patients taking pramipexole, cabergoline and levodopa mono and combination therapy. J Neural Transm 2001; 108: 71–7. 39. Sanjiv CC, Schulzer M, Mak E, Fleming J, Martin WRW, Brown T, Calne SM, Tsui J, Stoessl AJ, Lee CS, Calne DB. Daytime somnolence in patients with Parkinson’s disease. Parkinsonism Relat Disord 2001; 7: 283–6.

Drugs that affect autonomic functions or the extrapyramidal system 40. Montastruc J-L, Brefel-Courbon C, Senard J-M, Bagheri H, Ferreira J, Rascol O, Lapeyre-Mestre M. Sleep attacks and antiparkinsonian drugs: a pilot prospective pharmacoepidemiologic study. Clin Neuropharmacol 2001; 24: 181–3. 41. Ferreira JJ, Thalamas C, Monastruc JL, CastroCaldas A, Rascol O. Levodopa monotherapy can induce “sleep attacks” in Parkinson’s disease patients. J Neurol 2001; 248: 426–7. 42. Micallef-Roll J, Rihet P, Hasbroucq T, Possamaï C, Blin O. Levodopa-induced drowsiness in healthy volunteers: results of a choice reaction time test combined with a subjective evaluation of sedation. Clin Neuropharmacol 2001; 24: 91–4. 43. Goetz CG, Leurgans S, Pappert EJ, Raman R, Stemer AB. Prospective longitudinal assessment of hallucinations in Parkinson’s disease. Neurology 2001; 57: 2078–82. 44. Bair JD, Oppelt TF. Warfarin and ropinirole interaction. Ann Pharmacother 2001; 35: 1202–4. 45. Matunaga K, Uozomi T, Qingrui L, Hashimoto T, Tsuji S. Amantadine-induced cortical myoclonus. Neurology 2001; 56: 279–80. 46. Onofrj M, Thomas A, Iacono D, Di Iorio A, Bonanni L. Switch-over from tolcapone to entacapone in severe Parkinson’s disease patients. Eur Neurol 2001; 46: 11–16. 47. Myllylä VV, Kultalahti E-R, Haapaniemi H, Leinonen M. Twelve-month safety of entacapone in patients with Parkinson’s disease. Eur J Neurol 2001; 8: 53–60. 48. Zavaleta EG, Fernandez BB, Grove MK, Kaye MD. St Anthony’s fire (ergotamine induced leg ischemia). A case report and review of the literature. Angiology 2001; 52: 349–56. 49. Tsui BCH, Stewart B, Fitzmaurice A, Williams R. Cardiac arrest and myocardial infarction induced by postpartum intravenous ergonovine administration. Anesthesiology 2001; 94: 363–4. 50. Papalampros EL, Salakou SG, Felekouras ES, Scopa C, Tsamandas AC, Bastounis E. Ischemic necrosis of gastric wall after long-term ergotamine pill abuse. Case report and review of the literature. Dig Dis Sci 2001; 46: 981–4. 51. Ausband SC, Goodman PE. An unusual case of clarithromycin associated ergotism. J Emerg Med 2001; 21: 411–13. 52. Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W. Cerebral ergotism under treatment

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with ergotamine and ritonavir. Neurology 2001; 57: 743–4. 53. Bjerke RJ, Mangione MP. Asystole after intravenous neostigmine in a heart transplant recipient. Can J Anesth 2001; 48: 305-7. 54. Okun MS, Charriez CM, Bhatti MT, Watson RT, Swift TR. Asystole induced by edrophonium following beta blockade. Neurology 2001; 57: 739. 55. Clemett D, Jarvis B. Tolterodine. A review of its use in the treatment of the overactive bladder. Drugs Aging 2001; 18: 277–304. 56. Abrams P, Malone-Lee J, Jacquetin B, Wyndaele J-J, Tammela T, Jonas U, Wein A. Twelvemonth treatment of overactive bladder. Efficacy and tolerability of tolterodine. Drugs Aging 2001; 18: 551–60. 57. Crandall C. Tolterodine: a clinical review. J Women’s Health Gender Med 2001; 10: 735–43. 58. Layton D, Pearce GL, Shakir SAW. Safety profile of tolterodine as used in general practice in England. Drug Saf 2001; 24: 703–13. 59. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 2001; 57: 414–21. 60. Dilaversi P, Pantazis A, Vlasseros J, Gialafos J. Non-sustained ventricular tachycardia due to lowdose orphenadrine. Am J Med 2001; 111: 418–19. 61. Brady WJ, Perron AD. Administration of atropine in the setting of acute myocardial infarction: potentiation of the ischaemic process? Am J Emerg Med 2001; 19: 81–3. 62. Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol 2001; 165: 1452–6. 63. Chancellor MB, Appell RA, Sathyan G, Gupta SK. A comparison of the effects on saliva output of oxybutynin chloride and tolterodine tartrate. Clin Ther 2001; 23: 753–60. 64. Appell RA, Sand P, Dmochowski R, Anderson R, Zinner N, Lama D, Roach M, Miklos J, Saltzstein D, Boone T, Staskin DR, Albrecht D. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT study. Mayo Clin Proc 2001; 76: 358–63.

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14

Dermatological drugs and topical agents

CONTACT ALLERGY Miscellaneous reports of contact allergy to ingredients of topical drugs and cosmetics are listed in Table 1.

Antiviral drugs Topical antiviral drugs rarely cause contact dermatitis. Skin reactions are mostly mild and transitory, including pruritus, pain, rashes, contact dermatitis, and photoallergic contact dermatitis. However, serious reactions occasionally occur (31R ). Antiviral drugs that have been implicated include topical aciclovir, cidofovir, idoxuridine, imiquimod, lamivudine, penciclovir, podophyllin, podophyllotoxin, trifluridine, tromantadine, vidarabine, intralesional and ophthalmic solutions of interferon, intravitreal injections of fomivirsen and foscarnet, and intraocular implants of ganciclovir. Patch testing in these cases only rarely caused positive reactions to the antiviral drug. • In a 44-year-old woman who used topical aciclovir for genital herpes, aciclovir contact allergy was associated with a systemic contact allergic reaction with an erythematous vesiculobullous eruption in the labial and perioral skin and a rash on the upper trunk and extremities (32A ). Patch tests were positive to aciclovir, valaciclovir, and ganciclovir, but not to famciclovir.

have replaced castor oil and lanolin as major components of lipsticks. These fatty acid esters have low allergenic potential. Recently, another case of contact allergy to di-isostearyl malate (patch tested in 7.7% in petrolatum) has been reported (33A ). In another case, a 23-year-old woman, who had cheilitis from her lipstick, showed contact allergy to glyceryl monoisostearate monomyristate; according to the authors, contact allergy to this compound has not previously been reported (34A ).

Cocamidopropyl betaine Cocamidopropyl betaine is the most commonly used amphoteric surfactant in shampoos, bath products, and other cosmetic products. It is popular because of its relatively low irritation potential. Contact allergic reactions are infrequent and have been attributed to sensitizing intermediates rather than cocamidopropyl betaine itself. Of 30 patients who were allergic to cocamidopropyl betaine, all reacted to 3-dimethylaminopropylamine (35c ). More recently, two studies have shown that cocamidopropylamine is the more relevant impurity (36c , 37c ).

Colophonium and gum resins Branched-chain fatty acid esters Branched-chain fatty acid esters, such as glyceryl di-isostearate and di-isostearyl malate, © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

168

Colophonium, a natural unmodified gum resin used in cosmetics such as mascara, lipsticks, creams, and hair removal products, is a known contact allergen. Modifications have been made to colophonium, resulting in a variety of ester gums. In a retrospective study, 1270 patients with leg ulcers were tested for contact allergy with colophonium and the modified ester gum:

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Chapter 14

Table 1. Contact allergy to ingredients of topical drugs and cosmetics Ingredient

Use

Test conc. & vehicle

Number studied

Comments

Reference

Alkylammonium amidobenzoate (Osmaron B)

Biocide in milking cream

Not stated

3135

63 positive of 3135 patients tested; alkylammonium amidobenzoate allergy may increase, owing to the use of milking cream as “natural” skin remedy

(1c )

Aminoethanolamine

Surfactant, mild foaming and cleansing agent in cosmetics

0.005, 0.1, and 0.5% in aqua

4

Rare synthesizer

(2A )

Basic Red 22

Synthetic dye used in cosmetics and textiles

1% aqua

1

Contact allergy in a patient who had used a paraphenylenediaminefree hair-colouring mousse

(3A )

Black iron oxide

Mascara

5% petrolatum

1

Eyelid dermatitis; rare

(4A )

Butylhydroxyanisole

Antioxidant in pharmaceutical products, cosmetics, and food

2% petrolatum

2

Positive reaction to pharmaceutical grade but not to analytical grade

(5A )

Chlorhexidine digluconate

Widely used topical disinfectant and preservative in topical skin products

1% alcohol

1

Both type I and type IV positive reactions on skin testing

(6A )

Chlorhexidine digluconate

Widely used topical disinfectant and preservative in topical skin products

0.5% alcohol

1

Acute pruritic balanitis 24 hours after sexual contact with his wife, who used a lubricant gel containing chlorhexidine digluconate

(7A )

Chlorquinaldol

Colposeptina vaginal ovule

5% petrolatum

1

Cross-reactivity to clioquinol

(8A )

2-Chloro-paraphenylenediamine

Hair-coloring

1% petrolatum

2

Both patients were also positive with paraphenylenediamine

(9A )

Chloroxylenol

Antiseptic

1% petrolatum

1

Contact hypersensitivity followed by leukoderma

(10A )

Cicloproxolamine

Topical antimycotic

1% petrolatum

1

Imidazoles may be a safe alternative because of the lack of cross-reactivity between the two classes of drugs

(11A )

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W.M.C. Mulder and M.M.H.M. Meinardi

Table 1. (Continued) Ingredient

Use

Test conc. & vehicle

Number studied

Comments

Reference

Doxepin

Tricyclic antidepressant, used topically as an antipruritic agent

0.5 and 1% petrolatum

1

(12A )

Enoxolone (18-glycyrrhetinic acid)

Topical anti-inflammatory agent

10% petrolatum

1

(13A )

Hydroquinone

Topical bleaching cream

3-Iodo-2-propynylbutylcarbamate

Preservative in wood, cutting oils, and cosmetics

Lanoconazole

1

Weak sensitizer, in contrast to the monobenzyl ester of hydroquinone

(14A )

0.1% petrolatum

3168

7 positive of 3168 patients tested; contact allergy from use in cosmetics is rare

(15c )

Topical antifungal

0.1, 1, and 10% petrolatum

1

This patient was also positive to neticonazole 0.1, 0.3, and 1% in petrolatum, and to diethyl sebacate 1.7 and 5% in petrolatum

(16A )

Methoxy polyethylene glycol/17-dodecyl glycol copolymer (Elfacos OW100)

Emulsion stabilizer, skin-conditioning and viscosity-increasing agent in cosmetics

10% petrolatum

1

Methyldibromoglutaronitrile

Ultrasonic gel; frequently used preservative in cosmetics, coating systems, cutting fluids, adhesives, wood preservatives, color photographic processing solutions, seed disinfectants

0.3% petrolatum

1

Methyl glucose dioleate

Emollient, emulsifier

5% petrolatum

1

Metronidazole

Oral antibiotic

50% petrolatum

1

Noxurol (Clostridiopeptidase A)

Enzymatic wound debridement

As is

1

Spearmint (Mentha spicata)

Compress

2%

1

(17A )

Dermatitis 24 hours after contact with ultrasonic gel; negative reaction to phenoxyethanol; sensitization to methyldibromoglutaronitrile is slowly increasing in frequency

(18A )

(19A ) Fixed-drug eruption; positive patch on residual skin lesion

(20A )

(21A ) Essential oil extracted from the leaves is used widely in food, pharmaceutical, and cosmetics industries

(22A )

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171

Chapter 14 Table 1. (Continued)

Ingredient

Use

Test conc. & vehicle

Number studied

Comments

Reference

Sodium dihydroxycetyl phosphate

Surfactant, wetting agent and emulsifier in cosmetics

5% petrolatum

1

Another report showed contact allergy to related chemicals

(23A )

Soybean extract

Cosmetics

1, 10, and 20% petrolatum

1

First report of delayed type allergy; did not have type I allergy to soybean extract and had not had symptoms of food allergy

(24A )

Stearyl alcohol in Efudix cream

Excipient in topical medication and cosmetics

Tea tree oil

Natural remedies and cosmetics

As is

1

Further case of erythema multiforme (SEDA-18, 170; SEDA-23, 165; SEDA-24, 177)

(26A )

Triclosan

Antiseptic in detergents, soaps, and cosmetics

2% petrolatum

1

(27A )

Triethanolamine

Emulsifier in cosmetics and topical medicaments

1 and 5% petrolatum

1

To date, the frequency of triclosan hypersensitivity is low Contact allergy from emusifiers is rare, triethanolamine being the more frequent cause

Trimebutine

Antispasmodic, oral or topical use

0.15 to 4.8 mg/ml aqua

1

Zinc ricinoleate

Cosmetics, adhesives, corrosion inhibitors, greases, varnishes, print pigments, deodorizer

(25A )

3

31 patients were positive to colophonium alone, 41 to the ester gum alone, and 33 to both colophonium and the ester gum (38c ). The authors recommended that the patch test tray for patients with leg ulcers should include both colophonium and the ester gum resin. Two other patients with cheilitis due to contact allergy to a lipstick reacted positively to glyceryl hydrogenated rosinate, an ester gum,

1

First report of contact dermatitis following 5 days of use of Proctolog, a cream for hemorrhoids and anal fissures Contact dermatitis in both axillae due to deodorant; also allergic to glyceryl ricinoleate in lipstick

(28A )

(29A )

(30A )

and the main component of the rosinate, glyceryl abietate (both patch-tested at 20% in petrolatum) (39A ).

Compositae There are over 20 000 species in the family of Compositae, including arnica, chamomile,

172 chrysanthemum, dandelion, gerbera, and marigold. Arnica, chamomile, and marigold are used in cosmetics and topical therapeutics. Delayed hypersensitivity reactions to the Compositae can arise from sesquiterpene lactones. To detect contact allergy to sesquiterpene lactones, a mixture of lactones (alantolactone, costunolide, and dehydrocostus lactone) is used. However, Compositae contain other sensitizers, such as polyacetylenes and thiophenes. In a prospective study, the lactone mixture was complemented with a mixture of Compositae (containing ether extracts of arnica, German chamomile, yarrow, tansy, and feverfew) to detect contact allergy to Compositae (40c ). Of 346 patients tested, 15 (4.3%) reacted to the mixture of Compositae, compared with eight of 1076 patients (0.7%) who gave positive results with the lactone mixture, indicating the importance of the addition of Compositae allergens to the lactone mixture. However, the authors warned that patch testing with these mixtures can cause active sensitization. An Austrian study has re-confirmed the importance of testing with not only a mixture of Compositae and a mixture of sesquiterpene lactones, but also with additional plant extracts when there is continuing clinical suspicion of allergy to one of the Compositae (41c ). By using additional short ether extracts, the authors found two of five patients who had otherwise been overlooked.

Immunomodulators Pimecrolimus is a non-steroidal ascomycin derivative with topical anti-inflammatory activity. In a 1% cream it is effective and safe in atopic dermatitis in infants, children, and adults (42C ). Tacrolimus ointment, another calcineurin inhibitor, has similar efficacy in atopic dermatitis. The main adverse effect of both drugs is local skin irritation with a stinging or burning sensation, which occurs in 30% of patients who use pimecrolimus and 50% of patients who use tacrolimus. Typically, children have less skin irritation than adults. Adverse effects such as local immunosuppression and an increased risk of local bacterial and viral infections (notably eczema herpeticum) are less common than with topical corticosteroids

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(43C ). In addition, there is a lack of skin atrophy (44R , 45C ). However, topical corticosteroids have the advantage of better skin penetration than both pimecrolimus and tacrolimus and will therefore continue to be used for more heavily keratinized skin such as in psoriasis (46r ).

Ketoprofen Topical NSAIDs can cause allergic contact dermatitis (including erythema multiforme-like reactions), as well as phototoxicity, photoallergic contact dermatitis, immediate contact reactions (contact urticaria), and contact vasculitis (SEDA-18, 163; SEDA-22, 170). A case of contact pemphigus has now been reported. • A 65-year-old Caucasian woman developed a localized skin eruption within hours of using ketoprofen gel on her knees to relieve arthralgia (47A ). The lesions were pruritic, well-demarcated, and erythematous, and later became studded with vesicles and small bullae. Histology and immunopathology suggested autoimmune pemphigus.

Local anesthetics When injected into the skin, local anesthetics often cause pseudo-allergic reactions, with similar symptoms to immediate type allergy (48c ). However, true immediate hypersensitivity to local anesthetics is extremely rare. More frequently, local anesthetics cause delayed hypersensitivity reactions, mainly after topical application. • A 50-year-old man had local infiltrations a few days after an injection of lidocaine and dexamethasone (49A ). Prick and intradermal tests were negative after 20 minutes. However, lidocaine produced a positive patch test after 2 days, with erythema and papules. • A 58-year-old man with a urological stoma used a catheter lubricated with Braum Monodose ointment (50A ). After almost 2 years he developed severe pruritus and squamous erythematous plaques in the peristomal skin. Patch tests were positive with the lubricant ointment and one of its constituents, tetracaine. • A 79-year-old man developed a weeping dermatitis of the perianal skin, buttocks, and proximal thighs (51A ). In the previous 3 weeks he had

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Chapter 14

Table 2. Contact urticaria to relatively rare antigens in cosmetic products and drugs Allergen

Allergen containing product

Patch tests

Skin prick tests

Remarks

Reference

Phenoxyethanol

Body lotion

Not done

Body lotion + + + Euxyl K 400 ++ Phenoxyethanol 1% + 5% + 10% ++

First report of immediate hypersensitvity

(55A )

Benzyl alcohol

Bacteriostatic saline

10 cm wheal after 24 hours

Not done

Immediate hypersensitivity rare

(56A )

Potassium persulfate

Hair dye

Nickel sulfate

Potassium persulfate (dilution not stated) 5 mm wheal

used Proctosedyl cream, which contains dibucaine (cinchocaine). Patch tests were positive with Proctosedyl cream and 5% dibucaine in petrolatum, while benzocaine, lidocaine, and clioquinol were negative. • A 62-year-old woman had a systemic contact dermatitis several days after topical administration of DoloPosterine ointment for hemorrhoids (52A ). She had erythematous vesicular lesions on her perianal area and an edematous erythematous rash on her upper thighs, elbow flexures, axillae, and face. Patch tests with the ointment and its constituents were positive with DoloPosterine and dibucaine 5% in petrolatum; patch tests with benzocaine and other local anesthetics were negative. • A 71-year-old Japanese man developed an itchy erythematous papular eruption after using an over-the-counter medicament for skin wounds (Makiron) for 1 month (53A ). Patch tests with the constituents showed positive reactions to dl-chlorpheniramine maleate and dibucaine hydrochloride (both 1% in petrolatum). Patch tests with lidocaine hydrochloride and mepivacaine hydrochloride showed no cross-sensitization.

Para-phenylenediamine

(SEDA-25,

177) Para-phenylenediamine, which is added to temporary henna tattoos to enhance their color, can cause contact allergic reactions as well as persistent contact leukoderma, as illustrated in five patients with paint-on henna tattoos (54A ). All were positive on patch testing with paraphenylenediamine. One developed erythema multiforme 4 weeks after the last application. The authors found no other causes of erythema multiforme.

(57A )

CONTACT URTICARIA AND IMMEDIATE REACTIONS Reports of contact urticaria to relatively rare antigens in both cosmetic products and drugs are shown in Table 2.

Methoxypsoralens The methoxypsoralens (5-methoxypsoralen and 8-methoxypsoralen) are furocoumarins used in oral photochemotherapy in the treatment of psoriasis. The first case of anaphylaxis to 5-methoxypsoralen has recently been reported (58A ). • A 36-year-old woman had been treated for a polymorphic light eruption with two annual courses of PUVA, three times weekly for 6 weeks, plus oral 5-methoxypsoralen 60 mg, without any adverse effects. However during the fourth course, 30 minutes after taking 5-methoxypsoralen 60 mg, she developed intense pruritus of the palms, spreading to the body. This was followed by erythema of the palms and symmetrical erythematous patches and urticarial lesions on the trunk. She had dizziness and slight difficulty in breathing. Her symptoms cleared within an hour after intravenous administration of an antihistamine and cortisone. Two months later skin prick tests with 5-methoxypsoralen were negative, but placebo-controlled oral provocation with 5-methoxypsoralen 20 mg resulted in symptoms similar to those she had experienced during PUVA.

174

Oxybenzone Oxybenzone is the most frequently used benzophenone in sunscreens, estimated to be present in 20–30% of commercial products. Phototoxicity and allergic contact dermatitis have been described, but reports of immediate type hypersensitivity are scarce. • A 22-year-old woman with a history of atopy had anaphylaxis 10 minutes after widespread application of a oxybenzone-containing sunscreen (59A ). Blinded patch tests with the sunscreen and its ingredients yielded wheal and flare reactions after 15 minutes to the sunscreen and to oxybenzone. Some days before skin testing the woman had had contact urticaria on the face after kissing a friend who had applied the same sunscreen.

PHOTOSENSITIVITY Felodipine

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W.M.C. Mulder and M.M.H.M. Meinardi

5%, diclofenac 1, 5, and 10%, fepradinol 1%, ibuprofen 5%, indomethacin 1, 5, and 10%, ketoprofen 1%, naproxen 5%, paracetamol 1, 5, and 10%, phenylbutazone 1%, piroxicam 1%, salicylic acid 1 and 5%, and thiosalicylic acid 0.1%, all in petrolatum).

Oral contraceptives Diffuse prickly erythema has been attributed to ethinylestradiol in oral contraceptives (62A ). • A woman taking an oral contraceptive (Marvelon® , ethinylestradiol 30 micrograms plus desogestrel 150 micrograms) developed diffuse prickly erythema in an exposed site less than 20 minutes after sun exposure. Phototesting showed photosensitivity in the UVB and UVA ranges, but routine patch and photopatch tests with Marvelon were negative. All abnormal findings were reversed 4 months after withdrawal of the oral contraceptive, but reappeared when she started using another oral contraceptive (Microgynon 30® , ethinylestradiol 30 micrograms plus levonorgestrel 150 micrograms). Repeat phototesting was again abnormal. Her symptoms disappeared after withdrawal of the oral contraceptive. Porphyrin production was normal.

Telangiectases have been described as an adverse effect of calcium channel blockers and are sometimes photodistributed. Photodistributed telangiectases, made worse by solar radiation have been reported in a 67-year-old man taking felodipine 5 mg/day (68A ). Rosacea was also present. Felodipine was withdrawn and the telangiectases improved. Rechallenge was not performed.

Although the estrogen and progestagen were not tested separately in this patient, the photosensitivity was most probably due to the estrogen, because the oral contraceptives that she used contained ethinylestradiol 30 micrograms with different progestogens, and photosensitivity has been described with estrogens (63A ).

NSAIDs

Sunscreens

The arylpropionic acid derivatives often cause allergic and photoallergic contact dermatitis, and photoallergic dermatitis to ketoprofen, with cross-photosensitivity to benzophenone and tiaprofenic acid, has been reported (60A ). Photopatch tests to these substances were positive but patch tests were negative. A case of photoallergic contact dermatitis from aceclofenac has recently been reported (61A ). Photopatch tests were positive with aceclofenac 10% in petrolatum, but not with either aceclofenac 1% or 5% in petrolatum or with a series of NSAIDs and other analgesics (benzydamine hydrochloride 3 and 5%, bufexamac

In 19 patients with positive photopatch tests to sunscreens among all the patients that were photopatch tested between 1992 and 1999 (total not stated) there were 21 positive photopatch tests to sunscreen agents (64c ). Nine patients reacted to oxybenzone, eight to butylmethoxydibenzoylmethane, three to methoxycinnamate, and one to benzophenone. There were no reactions to para-aminobenzoic acid (PABA), reflecting the increased use of PABA-free sunscreens. Six patients also had a positive patch tests to components of the sunscreen base, such as fragrances, which can complicate the diagnosis.

Dermatological drugs and topical agents

Chapter 14

PHOTOTHERAPY Carcinogenicity The PUVA Follow up Study has prospectively evaluated 1380 patients who started using PUVA for psoriasis in 1975 and 1976. They recently reported an increased risk of melanoma in PUVA-treated patients (n = 822), beginning 15 years after first exposure (65C ). Incidence rates during 1996–9 were 10-fold higher than those expected from incidence data in the general population (data available only for 1992–6). There was an nonsignificant trend towards a higher incidence of melanoma in patients who had received more courses of PUVA (over 200). This risk should be weighed against the substantial efficacy of PUVA therapy in severe psoriasis.

PSEUDOPORPHYRIA Pseudoporphyria is a photodistributed bullous disorder with clinical and histological features similar to those of porphyria cutanea tarda, but without accompanying abnormalities of porphyrin metabolism. Drugs, in particular NSAIDs and sulfur-containing diuretics, often cause pseudoporphyria and have recently been reviewed (66R ). Another case of pseudoporphyria associated with naproxen (15 mg/kg/day) has been reported in a child (67A ).

RETINOIDS

(SED-14, 449; SEDA-25, 179; see also Chapter 38)

Acitretin Nervous system The possible negative effects of short-term oral acitretin 1 mg/kg/day on peripheral nerve function have been assessed in a small prospective study in 13 patients (69c ). Patients with conditions related to peripheral neuropathy were excluded. There was a fall in the mean amplitude of the sensory action potential of the superficial peroneal nerve after 1 and 3 months of therapy. There was a significant change in one or more neurophysiological parameters in three of 13 patients after 1 month

175

and in nine of 13 patients after 3 months. None of the patients had detectable neurological abnormalities at any time during therapy. Acitretin was withdrawn, and after 6 months three patients gradually improved. Further studies are needed to determine whether neurophysiological evaluation should be routine during treatment with oral retinoids.

Isotretinoin Respiratory Immunomodulatory effects of isotretinoin in the treatment of facial acne (40 mg/day for 4 weeks) were held responsible for the recurrence of pulmonary alveolar proteinosis in a 16-year-old girl, in whom it had been in spontaneous remission for 2 years (70A ). Although the time course of this effect was suggestive, it should be born in mind that about 25% of patients with this disease have exacerbations without a clear cause. Psychiatric In 1998 depression, psychosis, and suicidal ideation, suicide attempts, and suicide were added to the product label of isotretinoin. Since then the FDA has received increasing number of reports of these problems (71c ). From the time that isotretinoin was marketed in 1982 up to May 2000 the FDA received 37 reports of patients taking isotretinoin who committed suicide, 110 reports of patients who were hospitalized for depression, suicidal ideation, or suicide attempts, and 284 reports of patients with depression who did not need hospitalization (72r ). In 62% of the suicide cases a psychiatric history or possible contributing factors were identified, and 69% of patients hospitalized for depression had either a previous psychiatric history or possible contributing factors. Drug withdrawal led to improvement in about one-third of the patients, while in 29% depression persisted after withdrawal. In 24 cases dechallenge and rechallenge were positive. However, since this was a series of spontaneous reports, and since there are no good data on the incidence of depression and suicide among adolescents with acne, a causal relation cannot be concluded. A change in dreaming pattern has been reported in two patients, occurring within 2–3 weeks after the start of treatment with

176 isotretinoin 40 mg/day for cystic acne (73A ). One patient also reported increased irritability and bouts of depression. In both patients all the symptoms abated after 4–5 weeks without a change in isotretinoin dosage. Metabolism The incidence of raised serum lipids during therapy with oral isotretinoin 1 mg/kg/day for acne has been reviewed retrospectively in 876 patients, of whom 54 had raised serum cholesterol concentrations (over 5.2 mmol/l) and 45 had triglyceride concentrations above 2.26 mmol/l (74c ). Hematologic Transient polycythemia has been reported during treatment with isotretinoin for severe nodular acne (75A ). • A 53-year-old man’s hematocrit increased from 46% to 51% after he had taken isotretinoin for 11 months (180 mg/day for 3 months, 80 mg/day for 6 months, then 20 mg/day). No secondary causes of polycythemia were found and the hematocrit fell to 48% 3 months after withdrawal of isotretinoin.

The reference range for hematocrit in men is 41–49%, and so the clinical relevance of this observation is unclear. Gastrointestinal Another case of ulcerative colitis has been reported in a 17-year-old boy shortly after he had completed a 5-month course of isotretinoin (dose not stated) for acne (76A ). There was no family history of inflammatory bowel disease. Although three other cases of inflammatory bowel disease during isotretinoin therapy have been reported (77A – 79A ), there have also been reports of the safe use isotretinoin in patents with a history of

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inflammatory bowel disease (i.e. without exacerbation of the inflammatory bowel disease) (77A , 80A , 81A ). Since retinoids are being increasingly used to treat moderately severe acne, larger studies are needed to elucidate the relation between retinoid use and inflammatory bowel disease. Liver The incidence of raised liver enzymes during therapy with oral isotretinoin 1 mg/kg/day for acne has been retrospectively reviewed in 876 patients (74c ). Liver enzymes (AsT, AlT, γ GT) were transiently raised in a minority of patients (number not stated).

MISCELLANEOUS DRUGS Griseofulvin A 40-year-old woman had a burning sensation and erythema of the lips, buccal mucosa, palate, and vulva, which recurred within 4 hours of oral rechallenge with griseofulvin 125 mg (82A ).

Thalidomide

(SEDA-24, 171)

Three new cases of thrombosis in patient taking thalidomide (25–100 mg/day) have been reported after 2 months and 2 years therapy (83A ). However, all three patients had other risk factors (heterozygous protein C resistance in one and surgical intervention or trauma in the others), so a causal role of thalidomide was debatable.

REFERENCES 1. Schnuch A. Osmaron B is a rare occupational, but a frequent cosmetic, allergen. Contact Dermatitis 2001; 44: 133. 2. Foti C, Bonamonte D, Mascolo G, Tiravanti G, Rigano L, Angelini G. Aminoethylethanolamine: a new allergen in cosmetics? Contact Dermatitis 2001; 45: 129–33. 3. Salim A, Orton D, Shaw S. Allergic contact dermatitis from Basic Red 22 in a hair-colouring mousse. Contact Dermatitis 2001; 45: 123.

4. Saxena M, Warshaw E, Ahmed DDF. Eyelid allergic contact dermatitis to black iron oxide. Am J Contact Dermatitis 2001; 12: 38–9. 5. Orton DI, Shaw S. Allergic contact dermatitis from pharmaceutical grade BHA in timodene, with no patch test reaction to analytical grade BHA. Contact Dermatitis 2001; 44: 191–2. 6. Lauerma AI. Simultaneous immediate and delayed hypersensitivity to chlorhexidine digluconate. Contact Dermatitis 2001; 44: 59.

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7. Barraza V. Connubial allergic contact balanitis due to chlorhexidine digluconate. Contact Dermatitis 2001; 45: 42. 8. Rodríguez A, Cabrerizo S, Barranco R, De Frutos C, De Barrio M. Contact cross-sensitization among quinolines. Allergy Eur J Allergy Clin Immunol 2001; 56: 795. 9. Hansson C, Thornbey-Andersson K. Allergic contact dermatitis from 2-chloro-p-phenylenediamine in a cream dye for eyelashes and eyebrows. Contact Dermatitis 2001; 45: 235–6. 10. Malakar S, Panda S. Post-inflammatory depigmentation following allergic contact dermatitis to chloroxylenol. Br J Dermatol 2001; 144: 1262–3. 11. Foti C, Diaferio A, Bonamonte D. Allergic contact dermatitis from ciclopirox olamine. Australas J Dermatol 2001; 42: 145. 12. Horn, HM, Tidman MJ, Aldridge RD. Allergic contact dermatitis due to doxepin cream in a patient with dystrophic epidermolysis bullosa. Contact Dermatitis 2001; 45: 115. 13. Tanaka S, Otsuki T, Matsumoto Y, Hayakawa R, Sugiura M. Allergic contact dermatitis from enoxolone. Contact Dermatitis 2001; 44: 192. 14. Barrientos N, Ortiz-Frutos J, Gómez E, Iglesias L. Allergic contact dermatitis from bleaching cream. Am J Contact Dermatitis 2001; 12: 33–4. 15. Bryld LE, Agner T, Menné T. Allergic contact dermatitis from 2-iodo-propynyl-butylcarbamate (IBBC)—an update. Contact Dermatitis 2001; 44: 226–8. 16. Le Coz C-J, Heid E. Allergic contact dermatitis from methoxy PEG-17/dodecyl glycol copolymer (Elfacos OW100). Contact Dermatitis 2001; 44: 308–9. 17. Umebayashi Y, Ito S. Allergic contact dermatitis due to both lanoconazole and neticonazole ointments. Contact Dermatitis 2001; 44: 48–9. 18. Erdmann SM, Merk HF. Allergic contact dermatitis due to methyldibromoglutaronitrile in Euxyl K400 in an ultrasonic gel. Contact Dermatitis 2001; 44: 39–40. 19. Corazza M, Levratti A, Virgili A. Allergic contact dermatitis due to methyl glucose dioleate. Contact Dermatitis 2001; 45: 308. 20. Gastaminza G, Anda M, Audicana T, Fernandez E, Muñoz D. Fixed-drug eruption due to metronidazole with positive topical provocation. Contact Dermatitis 2001; 44: 36. 21. Bonamonte D, Mundo L, Daddabbo M, Foti C. Allergic contact dermatitis from Mentha spicata (spearmint). Contact Dermatitis 2001; 45: 298. 22. Lisi P, Brunelli L. Extensive allergic contact dermatitis from a topical enzymatic preparation (Noruxol). Contact Dermatitis 2001; 45: 186–7. 23. Lomholt H, Rastogi SC, Andersen KE. Allergic contact dermatitis from sodium dihydroxyacetyl phosphate, a new cosmetic allergen? Contact Dermatitis 2001; 45: 143–5. 24. Shaffrali FCG, Gawkrodger DJ. Contact Dermatitis from soybean extract in a cosmetic cream. Contact Dermatitis 2001; 44: 51–2. 25. Yesudian PD, King CM. Allergic contact dermatitis from stearyl alcohol in Efudix cream. Contact Dermatitis 2001; 45: 313–14.

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26. Khanna M, Qasem K, Sasseville D. Allergic contact dermatitis to tea tree oil with erythema multiforme-like id reaction. Am J Contact Dermatitis 2000; 11: 238–42. 27. Wong CSM, Beck MH. Allergic contact dermatitis from triclosan in antibacterial handwashes. Contact Dermatitis 2001; 45: 307. 28. Chu C-Y, Sun C-C. Allergic contact dermatitis from triethanolamine in a sunscreen. Contact Dermatitis 2001; 44: 41–2. 29. Reyes JJ, Fariña MC. Allergic contact dermatitis due to trimebutine. Contact Dermatitis 2001; 45: 164. 30. Magerl A, Heiss R, Frosch PJ. Allergic contact dermatitis from zinc ricinoleate in a deodorant and glyceryl ricinoleate in a lipstick. Contact Dermatitis 2001; 44: 119–20. 31. Holdiness MR. Contact dermatitis from topical antiviral drugs. Contact Dermatitis 2001; 44: 265–9. 32. Lammintausta K, Mäkelä, L, Kalimo K. Rapid systemic valciclovir reaction subsequent to aciclovir contact allergy. Contact Dermatitis 2001; 45: 181. 33. Guin J. Allergic contact dermatitis from diisostearyl malate in lipstick. Contact Dermatitis 2001; 44: 375. 34. Asai M, Kawada A, Aragane Y, Tezuka T. Allergic contact cheilitis due to glyceryl monoisostearate monomyristate in a lipstick. Contact Dermatitis 2001; 45: 173. 35. Angelini G, Foti C, Rigano L, Vena GA. 3-dimethylaminopropylamine: a key substance in contact allergy to cocamidopropyl betaine? Contact Dermatitis 1995; 32: 96–9. 36. Fowler JF, Fowler LM, Hunter JE. Allergy to cocamidopropyl betaine may be due to amidoamine: a patch test and product use test study. Contact Dermatitis 1997; 37: 276–81. 37. McFadden JP, Ross JS, White IR, Basketter DA. Clinical allergy to cocamidopropyl betaine: reactivity to cocamidopropylamine and lack of reactivity to 3-dimethylaminopropylamine. Contact Dermatitis 2001; 45: 72–4. 38. Salim A, Shaw S. Recommendation to include ester gum resin when patch testing patients with leg ulcers. Contact Dermatitis 2001; 44: 34. 39. Bonamonte D, Foti C, Angelini G. Contact allergy to ester gums in cosmetics. Contact Dermatitis 2001; 45: 110–11. 40. Kanerva L, Estlander T, Alanko K, Jolanki R. Patch test sensitization to compositae mix, sesquiterpene lactone mix, compositae extracts, laurel leaf, chlorophorin, mansonone A, and dimethoxydalbergione. Am J Contact Dermatitis 2001; 12: 18–24. 41. Reider N, Komericki P, Hausen BM, Fritsch P, Aberer W. The seamy side of natural medicines: contact sensitization to arnica (Arnica montana L.) and marigold (Calendula officinalis L.) Contact Dermatitis 2001; 45: 269–72. 42. Van Leent EJM, Gräber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the top-

178 ical treatment of atopic dermatitis. Arch Dermatol 1998; 134: 805–9. 43. Lübbe J, Pournaras CC, Saurat J-H. Eczema herpeticum during treatment of atopic dermatitis with 0.1% tacrolimus ointment. Dermatology 2000; 201: 249–51. 44. Soter NA, Fleischer AB, Webster GF. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients. Part II, Safety. J Am Acad Dermatol 2002; 44: S39–46. 45. Reitamo S, Wollenberg A, Schopf E. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol 2000; 136: 999–1006. 46. Nghiem P. “Topical immunomodulators?”: introducing old friends and a new ally, tacrolimus. J Am Acad Dermatol 2001; 44: 111–13. 47. Kanitakis J, Souillet A-L, Faure M, Claudy A. Ketoprofen-induced pemphigus-like dermatosis: localized contact pemphigus? Acta Dermatol Venereol 2001; 81: 304–5. 48. Gall H. Kaufmann R, Kalveram CM. Adverse reactions to local anaesthetics: analysis of 197 cases. J Allergy Clin Immunol 1996; 97: 933–7. 49. Breit S, Ruëff F, Przybilla B. “Deep impact” contact allergy after subcutaneous injection of local anesthetics. Contact Dermatitis 2001; 45: 296–7. 50. Fernández-Redondo V, León A, Santiago T, Toribio J. Allergic contact dermatitis from local anaesthetic on peristomal skin. Contact Dermatitis 2001; 45: 358. 51. Kearney CR, Fewings J. Allergic contact dermatitis to cinchocaine. Australas J Dermatol 2001; 42: 118–19. 52. Erdmann SM, Sachs B, Merk HF. Systemic contact dermatitis from cinchocaine. Contact Dermatitis 2001; 44: 260–1. 53. Hayashi K, Kawachi S, Saida T. Allergic contact dermatitis due to both chlorpheniramine maleate and dibucaine hydrochloride in an overthe-counter medicament. Contact Dermatitis 2001; 44: 38–9. 54. Jappe U, Hausen BM, Petzoldt D. Erythemamultiforme-like eruption and depigmentation following allergic contact dermatitis from a paint-on henna tattoo, due to para-phenylenediamine contact hypersensitivity. Contact Dermatitis 2001; 45: 249– 50. 55. Bohn S, Bircher AJ. Phenoxyethanol-induced urticaria. Allergy 2001; 56: 922–3. 56. Guin JD, Goodman J. Contact urticaria from benzyl alcohol presenting as intolerance to saline soaks. Contact Dermatitis 2001; 45: 182–3. 57. Estrada Rodríguez JL, Gozalo Reques F, Cechini Fernandez C, Rodríguez Prieto MA. Contact urticaria due to potassium persulfate. Contact Dermatitis 2001; 45: 177. 58. Legat FJ, Wolf P, Kränke B. Anaphylaxis to 5-methoxypsoralen during photochemotherapy. Br J Dermatol 2001; 145: 821–2. 59. Emonet S, Pasche-Koo F, Perin-Minisini M-J, Hauser C. Anaphylaxis to oxybenzone, a frequent constituent of sunscreens. J Allergy Clin Immunol 2001; 107: 556–7.

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60. Kawada A, Aragane Y, Asai M, Tezuka T. Simultaneous photocontact sensitivity to ketoprofen and oxybenzone. Contact Dermatitis 2001; 44: 370. 61. Goday Buján JJ, García Alvarez-Eire GM, Martinez W, Del Pozo J, Fonseca E. Photoallergic contact dermatitis from aceclofenac. Contact Dermatitis 2001; 45: 170. 62. Cooper SM, George S. Photosensitivity reaction associated with use of the combined oral contraceptive. Br J Dermatol 2001; 144: 641–2. 63. Horkay I, Tamasi P, Prekopa A, Dalmy L. Photodermatoses induced by oral contraceptives. Arch Dermatol Res 197; 253: 53–61. 64. Cook N, Freeman S. Report of 19 cases of photoallergic contact dermatitis to sunscreens seen at the Skin and Cancer Foundation. Australas J Dermatol 2001; 42: 257–9. 65. Stern RS, for the PUVA Follow up Study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001; 44: 755–61. 66. Green JJ, Manders SM. Pseudoporphyria. J Am Acad Dermatol 2001; 44: 100–8. 67. Maerker JM, Harm A, Foeldvari I, Höger PH. Naproxeninduzierte pseudoporphyrie. Hautarzt 2001; 52: 1026–9. 68. Silvestre JF, Albares MP, Carnero L, Botella R. Photodistributed felodipine-induced facial telangiectasia. J Am Acad Dermatol 2001; 45: 323–4. 69. Chroni E, Georgiou S, Monastirly A, Paschalis C, Tsambas D. Effects of short-term oral actretin therapy on peripheral nerve function: a prospective neurological and neurophysiological study. Acta Dermatol Venereol 2001; 81: 423–5. 70. Khurshid I, Seymour JF, Nakata K, Downie GH. Recurrent manifestations of idiopathic pulmonary alveolar proteinosis after isotretinoin (Accutane® ) treatment. Chest 2001; 120 Suppl: 335. 71. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001; 45: 515–19. 72. Wysowski DK, Pitts M, Beitz J. Depression and suicide in patients treated with isotretinoin. New Engl J Med 2001; 344: 460. 73. Gupta MA, Gupta AK. Isotretinoin use and reports of sustained dreaming. Br J Dermatol 2001; 144: 919–20. 74. Alcalay J, Landau M, Zucker A. Analysis of laboratory data in acne patients treated with isotretinoin: is there really a need to perform routine laboratory tests? J Dermatol Treat 2001; 12: 9–12. 75. Çakmakci A, Yilmaz AS, Akbulut S, Güll Ü, Özyilkan E. Polycythemia in a patient treated with isotretinoin. Ann Pharmacother 2001; 35: 964–5. 76. Reniers DE, Howard JM. Isotretinoin-induced inflammatory bowel disease in an adolescent. Ann Pharmacother 2001; 35: 1214–16. 77. Godfrey KM, James MP. Treatment of severe acne with isotretinoin in patients with inflammatory bowel disease. Br J Dermatol 1990; 123: 653–5. 78. Martin P, Manley PN, Depew WT, Blakeman JM. Isotretinoin-associated proctosigmoiditis. Gastroenterology 1987; 93: 606–9.

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79. Brodin MD. Inflammatory bowel disease and isotretinoin. J Am Acad Dermatol 1986; 14: 843. 80. Schleicher SM. Oral isotretinoin and inflammatory bowel disease. J Am Acad Dermatol 1985; 13: 834–5. 81. Rosen T, Unkefer RP. Treatment of pyoderma faciale with isotretinoin in a patient with ulcerative colitis. Cutis 1999; 64: 107–9.

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82. Thami GP, Kaur S, Kanwar AJ. Erythema multiforme due to griseofulvin with positive reexposure test. Dermatology 2001; 203: 84–5. 83. Pouaha J, Martin S, Trechot P, Truchetet F, Barbaud A, Schmutz J-L. Thalidomide et thromboses: trois observations. Presse Med 2001; 30: 1008–9.

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15

Antihistamines (H1 receptor antagonists)

Histamine release from mast cells and basophils makes a major contribution to the allergic response, and antihistamines are widely used in the treatment of certain symptoms of allergic disease. However, histamine also functions as a neurotransmitter in the central nervous system, being particularly important in maintaining a state of arousal or awareness (1R ). First-generation H1 receptor antagonists easily cross the blood–brain barrier, and their consequent well-documented sedative and anticholinergic effects, together with short halflives, greatly limit their use in the treatment of allergic symptoms. However, despite these deficiencies it must be remembered that firstgeneration drugs are still widely used, mainly as over-the-counter products, often in combination with other drugs. Second-generation H1 receptor antagonists have major advantages over the earlier drugs; most notably they lack significant CNS and anticholinergic adverse effects. They have proved to be important therapeutic tools in the treatment of atopic disease, including both seasonal and perennial allergic rhinitis, urticaria, and atopic dermatitis (2R ). More recently, several studies have shown that the use of second-generation antihistamines as adjunctive therapy can benefit patients whose allergic asthma co-exists with allergic rhinitis (3R ). Recently, several novel antihistamines have been developed, which are either metabolites of existing drugs or enantiomers. The aim was to develop antihistamines with improved potency, duration and onset of action, and greater predictability and safety. Drugs that to date have received regulatory approval and are effective in several allergic conditions include desloratadine, fexofenadine, and levocetirizine. These have been developed in response to widespread © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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concerns about the potential for cardiotoxicity and the impact of drug–drug interactions associated with some second-generation H1 receptor antagonists. Furthermore, the potential for sedation by some of the newer antihistamines still remains an issue for many. This is important, as many patients using antihistamines want to remain alert and active and may also use other medications. Consequently, progress with this class of drugs should involve not only increased efficacy but also improved safety and specificity.

The cardiotoxic effects of antihistamines Several antihistamines can cause ventricular dysrhythmias of the torsade de pointes type (4R ), first reported with astemizole (5r ) and later with terfenadine (6r ). With a few exceptions, antihistamines are rapidly and completely absorbed after oral administration; peak plasma concentrations are reached after 1–4 hours and are highly variable, owing to differences in metabolism and tissue distribution (2R ). Many of the second-generation antihistamines (e.g. astemizole, ebastine, loratadine, and terfenadine) undergo extensive firstpass metabolism to pharmacologically active metabolites; as a common feature, the reaction is primarily supported by CYP3A4. Under normal circumstances this extensive metabolism leads to low or undetectable plasma concentrations of the parent drug. However, sometimes metabolism of the parent compound can be compromised. Accumulation of unmetabolized astemizole or terfenadine can result in blockade of cardiac potassium channels in the ventricular myocytes that regulate the duration of the action potential; consequent prolongation

Antihistamines (H1 receptor antagonists)

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of the QT interval can result in potentially life-threatening ventricular tachycardia (7R ). Predisposing factors to the induction of cardiac dysrhythmias by antihistamines include: liver disease; concomitant prescribing of drugs such as macrolide antibiotics; overdose; congenital QT prolongation; ischemic heart disease; congestive cardiac failure; and electrolyte imbalance. Studies in which the cardiac safety of the newer antihistamines has been assessed are therefore of great importance. Desloratadine Desloratadine is the primary metabolite of loratadine, with proven efficacy in allergic diseases; it binds to H1 receptors with higher affinity than loratadine and is a more potent antihistamine (8R ). In a large multicenter, double-blind, placebocontrolled, parallel-group study of the efficacy and tolerability of desloratadine in 346 patients with seasonal allergic rhinitis, the symptoms improved significantly and there was no significant effect on the QTc interval (9C ). In another study in 190 patients desloratadine improved the symptoms of chronic urticaria with no adverse electrocardiographic effects (10C ). The effect of co-administration of azithromycin on plasma concentrations of desloratadine has been examined in a randomized third-partyblind, placebo-controlled, parallel-group study in 90 healthy volunteers (11C ). An initial loading dose of azithromycin (500 mg) was given on day 3, followed by 250 mg od for 4 days. Concomitant azithromycin had little effect (<15%) on either the Cmax or AUC of desloratadine and there were no statistically significant increases in the PR, QT, QTc interval, QRS complex duration, or ventricular rate after administration of desloratadine with or without azithromycin. In two similar studies there were no clinically relevant interactions between desloratadine and erythromycin (12C ) or ketoconazole (13C ). In a unblinded, randomized, single-dose, crossover study in 24 healthy adults, grapefruit juice had no effect on the systemic availability of oral desloratadine (14C ). There were no clinically significant electrocardiographic changes after co-administration of grapefruit juice with desloratadine compared with desloratadine alone.

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Ebastine Ebastine in doses up to five times the recommended therapeutic dose did not cause clinically relevant changes in QTc interval in healthy subjects (15C ). Emedastine Emedastine is a potent antihistamine with proven efficacy in allergic conjunctivitis (16C ). In a study of the interaction of emedastine difumarate 4 mg bd with ketoconazole 200 mg bd in 12 subjects there was a moderate but statistically significant interaction; however, there was no increase in the QTc interval during concomitant therapy (17C ). The authors concluded that these findings are consistent with the multiple metabolic pathways that supplement the metabolism of emedastine by different enzymatic isoforms of CYP450, and that concomitant treatment with emedastine and ketoconazole in people with normal QT intervals can be undertaken without special precautions. However, it is difficult to determine the precise cardiac risk, if any, posed by the administration of emedastine eye-drops (18r ). Fexofenadine Fexofenadine is the active metabolite of terfenadine and is effective in seasonal allergic rhinitis and chronic idiopathic urticaria (19R ). The effect of co-administration of azithromycin on plasma concentrations of fexofenadine 60 mg bd has been examined in a randomized third-party-blind, placebocontrolled, parallel-group study in 98 healthy volunteers (11C ). An initial loading dose of azithromycin (500 mg) was given on day 3, followed by 250 mg od for 4 days. Concomitant azithromycin caused substantial increases in the Cmax and AUC of fexofenadine (69% and 67% respectively). However, there were no statistically significant increases in the PR, QT, QTc interval, QRS complex duration, or ventricular rate after administration of fexofenadine with or without azithromycin. The safety of fexofenadine in children aged 6–11 years with seasonal allergic rhinitis has been assessed in a large double-blind, randomized, placebo-controlled, parallel study (20C ). There were no statistically significant electrocardiographic effects, suggesting that fexofenadine is both efficacious and well tolerated in children with allergic disease. In a unblinded, randomized, single-dose, crossover study in 24 healthy adults, grapefruit juice reduced the rate of absorption and

182 the systemic availability of oral fexofenadine by 30% (14C ). However, there were no clinically significant electrocardiographic changes after co-administration of grapefruit juice with fexofenadine compared with fexofenadine alone. The authors concluded that the systemic availability of drugs that do not undergo significant intestinal or hepatic metabolism, such as fexofenadine, may nevertheless be altered when they are given with agents that affect drug transport mechanisms. Levocetirizine Levocetirizine is the R enantiomer of cetirizine dihydrochloride; it has twice the affinity for H1 histamine receptors and, like cetirizine, undergoes minimal hepatic metabolism (21E ). It is effective and well tolerated in patients with seasonal allergic rhinitis (22C ). To date, there have been no studies of any potential cardiotoxic effects of levocetirizine. However, since cetirizine is free of such adverse effects (2R ), it is likely that levocetirizine is too. Loratadine Nefazodone is a phenylpiperazine antidepressant that is predominantly metabolized by CYP3A. In a randomized, doubleblind, double-dummy, parallel-group, multipledose study in healthy men and women who were given terfenadine 60 mg every 12 hours, loratadine 20 mg od, or nefazodone 300 mg every 12 hours, the plasma concentrations of both terfenadine and loratadine were significantly increased by co-administration of nefazodone. The mean QTc interval was unchanged by terfenadine or loratadine alone, but was markedly prolonged with co-administration of nefazodone, and the extent of prolongation correlated with the plasma concentrations of the antihistamines. Terfenadine is no longer marketed, but the main conclusion from this study was that in the context of higher than clinically recommended doses of loratadine (20 mg/day) concomitant administration with a metabolic inhibitor, such as nefazodone, can result in QTc prolongation (23C ). Mizolastine The effectiveness of mizolastine as an antihistamine has been demonstrated by inhibition of histamine-induced wheal and flare and in clinical trials with patients with rhinitis or urticaria (24R ). However, erythromycin and ketaconazole both increase mizolastine plasma concentrations and patients with hepatic or renal impairment have altered pharmacokinetics

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of mizolastine, indicating the need for caution in its use in such individuals (25C ).

CNS effects of second-generation antihistamines There is a widespread tendency to consider the second-generation antihistamines as nonsedating drugs. Indeed, when they are used in their recommended dosages in objective studies in healthy volunteers, the CNS depressant effects of fexofenadine (26C , 27C ), loratadine (28R ), and mizolastine (29R ) appear to be no greater than those seen with placebo. However, the issue is further complicated by evidence that sedation in allergic disease (and subsequent impairment in performance and learning) may be a consequence of the condition itself, as opposed to being wholly due to antihistamines (2R ). This raises concerns about the purported risk-free sedation profiles of certain antihistamines, given that they are often based on objective studies in healthy volunteers (30R ). Another issue is the tendency of patients with allergies to self-medicate, titrating their antihistamine dosage upwards to achieve relief of symptoms; neurological impairment does in fact occur if the dose of cetirizine, loratadine, or mizolastine is increased sufficiently (2R ). Thus, it is more correct to describe the second-generation antihistamines as having minimal sedative effects when taken in recommended doses. Desloratadine Desloratadine appears to be minimally sedative, given that several studies (so far published only as abstracts) have shown no impairment in terms of wakefulness or psychomotor performance (31c –33c ). Moreover, in a study in which desloratadine was effective and well tolerated in patients with seasonal allergic rhinitis there were no clinically significant sedative effects (34C ). Similarly, in a multicenter, randomized, doubleblind, placebo-controlled study desloratadine was effective in the treatment of moderate to severe chronic idiopathic urticaria, and there were no significant adverse effects (10C ).

Antihistamines (H1 receptor antagonists)

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Fexofenadine Even in a high dose (360 mg bd vs the recommended dose of 60 mg bd) fexofenadine had no disruptive effects on psychomotor performance and cognitive function in healthy volunteers (35C ). Levocetirizine The effects of levocetirizine on cognitive function have been assessed in two recent comprehensive and well-controlled studies. The first analysed the effects of single and multiple doses of levocetirizine on measures of CNS activity, using integrated measures of cognitive and psychometric performance. In a three-way crossover design, 19 healthy men took either levocetirizine 5 mg, diphenhydramine 50 mg (positive control), or placebo once daily on 5 consecutive days. Critical flicker fusion tests were performed on days 1 and 5 at baseline and up to 24 hours after drug administration. The primary outcome was that, in contrast to diphenhydramine, levocetirizine did not have any deleterious effect on any cognitive or psychometric function compared with placebo (36C ). In a double-blind, crossover study levocetirizine 5 mg once daily for 4 days was compared with cetirizine 10 mg, loratadine 10 mg, promethazine 30 mg, and placebo in terms of CNS inhibitory effects in 20 healthy volunteers (37C ). With the exception of promethazine none of the drugs had disruptive or sedative effects on objective measurements in a comprehensive battery of psychomotor and cognitive tests. These studies suggest that levocetirizine has minimal sedative effects in healthy individuals when given in its recommended dose. Sensory systems There have been several reports of a bitter taste associated with azelastine nasal spray for the treatment of allergic and non-allergic rhinitis compared with placebo in

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adults and children (38C , 39C , 40R ). For example, in one study in 19% of those using azelastine experienced a bitter taste compared with 2% of controls (39C ). The first-generation antihistamine chlorpheniramine caused impaired selective auditory attention in the absence of subjective awareness of this impairment in healthy volunteers (41C ). Glaucoma has been attributed to promethazine (42A ). • A 48-year-old man presented to an ophthalmic casualty department with a three-day history of pain, redness and blurred vision in the right eye. He had had pain in the affected eye several times over the previous 2 months when he had been watching television, but had no known eye disease. Visual acuity was reduced to perception of hand movements in the right eye but was 6/6 in the left eye. The intraocular pressure was 42 mmHg in the right eye and 14 mmHg in the left: the anterior chambers were shallow. He responded to systemic and local treatments followed by peripheral laser iridectomy. For 2 days before the onset of symptoms he had been taking proprietary cold formulations (“Day Nurse” and “Night Nurse”), which included promethazine.

The authors concluded that promethazine, through its anticholinergic action, precipitated or aggravated acute angle closure glaucoma. Liver In a 23-year-old man cetirizine taken for atopic dermatitis was associated with lifethreatening hepatitis (43A ). Skin Eight episodes of a fixed drug eruption occurred in a 45-year-old man who was taking fexofenadine for seasonal allergies; after withdrawal of fexofenadine the rash did not recur (44A ). Acute generalized urticaria occurred in a 42year-old woman taking cetirizine for seasonal allergic rhinitis and conjunctivitis, which had previously been treated with loratadine (45A ).

REFERENCES 1. Nicholson AN, Pascoe PA, Stone BM. Histaminergic systems and sleep-studies in man with H1 and H2 antagonists. Neuropharmacology 1985; 24: 245–50. 2. Walsh GM, Annunziato L, Frossard N, Knol K, Levander S, Nicolas J-M, Taglialatela M, Tharp

MD, Tillement JP, Timmerman H. New insights into the second generation antihistamines. Drugs 2001; 61: 207–36. 3. Walsh GM. Second-generation antihistamines in asthma therapy—is there a protective effect? Am J Respir Med 2002; 1: 27–34.

184 4. Honig P, Baraniuk JN. Adverse effects of H1 receptor antagonists in the cardiovascular system. In: Simons FER, editor. Histamine and H1 -receptor antagonists in allergic disease. New York: Marcel Dekker Inc, 1996: 383–412. 5. Simons FER, Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-induced torsade de pointes. Lancet 1988; 2: 624. 6. Davies AJ, Harinda V, McEwan A, Ghose RR. Cardiotoxic effect with convulsions in terfenadine overdose. Br Med J 1989; 298: 325. 7. Woolsey RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996; 36: 233–52. 8. McCellan K, Jarvis B. Desloratadine. Drugs 2001; 61: 789–96. 9. Meltzer EO, Prenner BM, Nayak A, and the Desloratadine Study Group. Efficacy and tolerability of once-daily 5 mg desloratadine, an H1 receptor antagonist, in patients with seasonal allergic rhinitis. Clin Drug Invest 2001; 21: 25–32. 10. Ring J, Hein R, Gauger A, Bronsky E, Miller B, Breneman D, Conneley M, Corren J, Ceuppens J, Fierlbeck G, Friday G, Goldberg P, Graft D, Holst T, Honsinger R, Hornmark A-M, Kaiser H, Kaplan R, Kempers S, Lockey R, Miller SD, Nayak A, Nayak N, Pariser D, Prenner B, Ruzicka T, Stewart GE II, Thompson M, Wein M. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study. Int J Dermatol 2001; 40: 72–6. 11. Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo controlled, parallel-group study. Clin Ther 2001; 23: 451–66. 12. Banfield C, Hunt T, Renderman L, Statkevich P, Padhi D, Affrime M. Lack of clinically relevant interaction between desloratadine and erythromycin. Clin Pharmacokinet 2002; 41 Suppl 1: 29–35. 13. Banfield C, Herron J, Keung A, Padhi D, Affrime M. Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole. Clin Pharmacokinet 2002; 41 Suppl 1: 37–44. 14. Banfield C, Gupta S, Marino M, Lim J, Affrime M. Grapefruit juice reduces the oral bioavailability of fexofenadine but not desloratadine. Clin Pharmacokinet 2002; 41: 311–18. 15. Gillen MS, Miller B, Chaikin P, Morganroth J. Effects of supratherapeutic doses of ebastine and terfenadine on the QT interval. Br J Clin Pharmacol 2001; 52: 201–4. 16. Verin Ph, Easty DL, Secchi A, Ciprandi G, Partouche P, Nemeth-Wasmer G, Brancato R, Harrisberg CJ, Estivin-Ebrardt C, Coster DJ, Apel AJG, Coroneo MT, Knorr M, Carmichael TR, KentSmith BT, Abrantes P, Leonardi A, Cerqueti PM, Modorati G, Martinez M. Clinical evaluation of twice-daily emedastine 0.05% eye drops (Emadine eye drops) versus levocabastine 0.05% eye drops in patients with allergic conjunctivitis. Am J Ophthalmol 2001; 131: 691–8.

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17. Herranz U, Rusca A, Assandri A. Emedastine– ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers. Int J Clin Pharmacol Ther 2001; 39: 102–9. 18. Anonymous. Emedastine and allergic conjunctivitis. Prescrire Int 2001; 10: 39–40. 19. Sympson K, Jarvis B. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 2000; 59: 301–21. 20. Graft DF, Bernstein DI, Goldsobel A, Meltzer EO, Portnoy J, Long J. Safety of fexofenadine in children treated for seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2001; 87: 22–6. 21. Gillard M, Van der Perren C, Moguilevsky N, Massingham R, Chatelain P Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: contribution of Lys191 and Thr194 . Mol Pharmacol 2002; 61: 391–9. 22. Leynadier F, Mees K, Arendt C, Pinelli ME. Efficacy and safety of levocetirizine in seasonal allergic rhinitis. Acta Otorhinolaryngol Belg 2001; 55: 305–12. 23. Abernethy DR, Barbey JT, Franc J, Brown KS, Feirrera I, Ford N, Salazar DE. Loratadine and terfenadine interaction with nefazodone: both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001; 69: 96–103. 24. Salmun LM. Antihistamines in late-phase clinical development for allergic disease. Expert Opin Invest Drugs 2002; 11: 259–73. 25. Lebrun-Vignes B, Diquet B, Chosidow O. Clinical pharmacokinetics of mizolastine. Clin Pharmacokinet 2001; 40: 501–7. 26. Hindmarch I, Shamsi Z, Stanley N, Fairweather DB. A double-blind, placebo controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function. Br J Clin Pharmacol 1999; 48: 200–6. 27. Nicholson AN, Stone BM, Turner C, Mills SL. Antihistamines and aircrew: usefulness of fexofenadine. Aviat Space Environ Med 2000; 71: 2–6. 28. Kay GG, Harris AG. Loratadine, a non-sedating antihistamine. Clin Exp Allergy 1999; 29 Suppl 3: 147–50. 29. Rosenzweig P, Patat A. Lack of behavioural toxicity of mizolastine: a review of the clinical pharmacology studies. Clin Exp Allergy 1999; 29 Suppl 3: 156–62. 30. Meltzer EIO, Welch MJ. Adverse effects of H1 receptor antagonists in the central nervous system. In: Simons FER, editor. Histamine and H1 -receptor antagonists in allergic disease. Clin Allergy Immunol Series. New York: Marcel Dekker Inc, 1996: 357–81. 31. Scharf MB, Kay GC, Rikken G, Danzig MR, Staudinger H. Desloratadine has no effect on wakefulness or psychomotor performance. Allergy 2000; 55 Suppl 63: Abstract 280. 32. Vuurman E, Ramaekers JG, Rikken G, De Halleux F. Desloratadine does not impair actual driving performance: a three way crossover comparison with diphenhydramine and placebo. Allergy 2000; 55 Suppl 63: Abstract 263.

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33. Valk PJL, Van Roon DB, Simons M, Rikken G, Lether IC, Staudinger H. No impairment of flying ability with desloratadine use in healthy volunteers under conditions of simulated cabin pressure. Allergy 2001; 56 Suppl 68: Abstract 229. 34. Meltzer EO, Prenner BM, Nayak A. Efficacy and tolerability of once-daily 5 mg desloratadine, an H1 -receptor antagonist, in patients with seasonal allergic rhinitis: assessment during the spring and fall allergy seasons. Clin Drug Invest 2001; 21: 25– 32. 35. Hindmarch I, Shamsi Z, Kimber S. An evaluation of the effects of high dose fexofenadine on the central nervous system: a double-blind, placebo controlled study in healthy volunteers. Clin Exp Allergy 2002; 32: 133–9. 36. Gandon JM, Allain H. Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers. Br J Clin Pharmacol 2002; 54: 51–8. 37. Hindmarch I, Johnson S, Meadows R, Kirkpatrick T, Shamsi Z. The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance and weal and flare. Curr Med Res Opin 2001; 17: 241–55. 38. Duarte C, Baehre M, Gharakhanian S, Leynadier F. Treatment of severe seasonal rhinocon-

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junctivitis by a combination of azelastine nasal spray and eye drops: a double-blind, doubleplacebo study. J Invest Allergol Clin Immunol 2001; 11: 34–40. 39. Banov CH, Lieberman P. Efficacy of azelastine nasal spray in the treatment of vasomotor perennial nonallergic rhinitis. Ann Allergy Asthma Immunol 2001; 86: 28–35. 40. Fineman SM. Clinical experience with azelastine nasal spray in children: physician survey of case reports. Pediatr Asthma Allergy Immunol 2001; 15: 49–54. 41. Serra-Grabulosa JM, Grau C, Escera C, Sanchez-Turet M. The H1 -receptor antagonist dextro-chlorpheniramine impairs selective auditory attention in the absence of subjective awareness of this impairment. J Clin Psychopharmacol 2001; 21: 599–602. 42. Barrett V, Jordan T. Angle closure risk from proprietary medicines. Eye 2001; 15: 248–9. 43. Wantanabe M, Kohge N, Kaji T. Severe hepatitis in a patient taking cetirizine. Ann Intern Med 2001; 135: 142–3. 44. Anonymous. Reaction to fexofenadine. Consultant 2001; 41: 154. 45. Calista D, Schianchi S, Morri M. Urticaria induced by cetirizine. Br J Dermatol 2001; 144: 96.

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INHALED CORTICOSTEROIDS (SED-14, 508; SEDA-23, 175; SEDA-24, 185; SEDA-25, 194)

Inhaled corticosteroids and growth inhibition in children (SED-14, 512; SEDA-23, 178) Debate continues about the effects of inhaled corticosteroids on growth patterns in children. Uninterrupted administration of moderate-dose inhaled corticosteroids (e.g. 400 μg budesonide equivalents per day) has been associated with a suppressed growth rate in some children with asthma. Budesonide reduced growth by 1 cm and 1.4 cm over 7 months and 12 months respectively (1R ). Consequently, in the USA a class label warning for inhaled corticosteroids about growth retardation in children was introduced. However, results from trials in asthmatic children can be flawed by confounding variables. Severe asthma may itself have a negative effect on growth and adversely affect adult height, as with any chronic disease. Even in well-controlled asthma, children typically show a retardation in pubertal growth spurt and attain normal adult height later. As growth in children is non-linear over time, trials over short periods are likely to capture short-term effects of inhaled corticosteroids rather than the long-term outcome. Furthermore, the growthretarding effect of inhaled corticosteroids is more pronounced at the start of treatment. Long-term studies suggest that a temporary short- or medium-term reduction in growth velocity is normally compensated for later on, and individuals attain normal adult height © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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(2C , 3C ). The effects of inhaled corticosteroids on growth rate over weeks and months are dose-dependent, and dose-response curves of pulmonary and adverse systemic effects differ widely, so that individual titration of the inhaled corticosteroid dose according to the severity of the disease is strongly recommended, and the lowest dose of inhaled corticosteroids that controls the disease should always be preferred. In conclusion, accumulating evidence shows that asthmatic children, even when treated with inhaled corticosteroids for years, attain normal adult height. However, close growth monitoring during inhaled corticosteroid therapy is recommended, as idiosyncratic responses can occur, probably owing to individual glucocorticoid receptor polymorphism (4R ). Lumbar spine bone mineral density has been assessed in 76 prepubertal asthmatics (mean age 7.7 years, 26 girls) using corticosteroids (5c ). After stratification for dose and route of administration, the children who used over 800 μg/day of inhaled corticosteroids, with or without intermittent oral corticosteroids, had a significant lower weight-adjusted bone density than children who used 400–800 μg/day of inhaled corticosteroids (mean difference −0.05 g/cm2 ; 95% CI = −0.02, −0.09). Bone mass was similar in children who did not use inhaled corticosteroids and those who used 400–800 μg/day. The authors of a recent review concluded, from short- and intermediate-term growth studies, that there are no clinically significant adverse effects on growth with inhaled corticosteroids at normal pediatric doses (100–200 μg budesonide equivalents per day), but that growth retardation can occur with all inhaled corticosteroids at higher doses. Individual idiosyncratic adverse reactions are rare. Long-term studies and studies that have examined the effect on final adult height have been consistent

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in showing significantly reduced growth rates during the first months and up to 2 years of treatment with inhaled corticosteroids. However, children treated with inhaled corticosteroids attain their predicted adult height to the same extent as their healthy peers. It is important to note that changes in growth rate during the first year of inhaled corticosteroid treatment cannot be used to predict final adult height (6R ).

asthmatic subjects (8C ). Urinary total cortisol metabolite concentrations represented the most sensitive marker of the systemic effects of inhaled corticosteroids, and were lower in healthy subjects treated with fluticasone than in asthmatic patients, suggesting greater systemic availability of fluticasone in healthy subjects. A similar correlation was not found for budesonide. Fluticasone impaired the hypothalamic– pituitary–adrenal axis more than budesonide, while budesonide significantly lowered serum osteocalcin concentrations, which reflect osteoblastic activity. The authors suggested that different inhaled corticosteroids have different effects on the hypothalamic–pituitary–adrenal axis and bone metabolism. This study also had its limitations, given that the fluticasone and budesonide doses were not equipotent (9C ). The safety and efficacy of fluticasone, beclomethasone dipropionate, and budesonide have been compared in a randomized trial in 133 patients with chronic severe asthma who required at least 1750 μg/day of beclomethasone/budesonide (10C ). The patients were randomized to their regular beclomethasone/budesonide or to fluticasone at about half the dose for 6 months. The patients who used fluticasone had a better safety profile, especially with regard to adrenocortical function and bone turnover, while maintaining asthma control. There were significant increases in morning serum cortisol concentrations, the urine cortisol:creatinine ratio, serum osteocalcin, and the serum (deoxy)-pyridinoline:creatinine ratio only with fluticasone, suggesting less suppression of the hypothalamic–pituitary–adrenal axis. The 2 : 1 potency ratio for clinical efficacy of fluticasone and budesonide/beclomethasone seems to be maintained even at doses of 2000 μg/day or higher.

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Systemic availability of inhaled corticosteroids (SEDA-23, 175, SEDA-24, 185) Plasma concentrations have been measured in 13 healthy subjects and eight patients with mild asthma using inhaled fluticasone propionate 1000 μg twice daily via Diskus® or pressurized metered-dose inhaler and of budesonide 1000 μg twice daily via Turbuhaler® for 7 days. 24-hour plasma cortisol concentrations were determined to assess the systemic activity of fluticasone propionate and budesonide. At steady state, the systemic availability of budesonide via Turbuhaler (39%) was significantly higher than that of fluticasone propionate via Diskus (13%) or inhaler (21%). Fluticasone propionate had a larger distribution volume and slower rates of absorption and clearance. Despite a significantly higher pulmonary availability of budesonide via Turbuhaler, plasma cortisol suppression was less than that of fluticasone propionate via inhaler and similar to that of fluticasone propionate via Diskus. There were no differences between healthy subjects and patients with mild asthma in subgroup analyses. However, this study had some limitations, as the doses of fluticasone propionate and budesonide were not equipotent, fluticasone being twice as potent as budesonide (7C ). There have been inconsistent results in studies of the systemic availability of fluticasone propionate and budesonide in healthy and asthmatic subjects. Therefore, the effect of fluticasone 1500 μg/day and budesonide 1600 μg/day, both by dry powder inhalation, on three systemic markers (urinary concentrations of total cortisol metabolites, morning serum cortisol, and osteocalcin concentrations) have been investigated in 46 healthy and 31

The local adverse effects of inhaled corticosteroids have been studied in a prospective, cross-sectional, cohort study in 639 asthmatic children using beclomethasone (721 µg/day) or budesonide (835 µg/day) for at least 1 month (11C ). The local adverse effects included cough (40%), thirst (22%), hoarseness (14%), dysphonia (11%), oral candidiasis (11%), perioral dermatitis (2.9%), and tongue hypertrophy (0.1%). A spacer doubled the incidence of coughing.

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Sensory systems In a nested case-control analysis based on a retrospective observational cohort study, 103 289 asthmatic patients using inhaled corticosteroids were identified from the UK General Practice Database and were compared with 98 527 asthmatic patients with no history of corticosteroid use (12C ). There was a slightly increased risk of cataract in those who used inhaled corticosteroids (RR = 1.3, 95% CI = 1.1, 1.5). The relative risk of cataract was 2.0 in oral steroid users relative to steroid non-users (95% CI = 1.5, 2.2). The risk ratio increased with extensive use of inhaled corticosteroids, but not moderate use. The association of extensive use with cataract was most pronounced in those aged 70 years and over, and there was no effect in those aged under 40. The increased risk of cataract in patients aged 70 years and over persisted after controlling for cataract risk factors, such as smoking, diabetes mellitus, hypertension, and sex. Endocrine Hypothalamic–pituitary–adrenal axis function provides one of the most sensitive markers of the systemic activity of inhaled corticosteroids (13r ), and suppression can be used as a surrogate marker for adverse effects of inhaled corticosteroids in other tissues. In a randomized, placebo-controlled study the activity of the hypothalamic–pituitary– adrenal axis was assessed at baseline and after 21 days by determining 22-hour time-integrated serum cortisol concentrations, 24-hour urinary cortisol (corrected for creatinine), and morning salivary cortisol concentrations in 153 patients with mild to moderate asthma, randomly assigned to either inhaled flunisolide (500 or 1000 µg bd), inhaled fluticasone (110, 220, 330, or 440 µg bd), oral prednisone (7.5 mg/day), or placebo (14C ). Flunisolide and fluticasone caused dose-dependent suppression of the hypothalamic–pituitary–adrenal axis, and fluticasone was significantly more potent. However, the lowest fluticasone dose (110 µg/day) had no effect. These findings are consistent with those of a previous meta-analysis, which showed that fluticasone caused a greater dose-related suppression of the hypothalamic–pituitary–adrenal axis than other inhaled corticosteroids (15M ). Fluticasone is more lipophilic than flunisolide and therefore has a larger volume of distribution and a longer half-life (13r ), but it is not clear how this might be associated with the larger effect described here.

Max Kuhn, Markus Joerger, and Katharina Hartmann

A series of cases has illustrated the unexpected occurrence of symptomatic adrenal insufficiency in eight asthmatic children using inhaled corticosteroids (16A ). The authors concluded that therapeutic doses of inhaled corticosteroids can provoke paradoxical symptoms of adrenal insufficiency. Very high doses (calculated according to body surface area) may partly explain marked suppression of the hypothalamic–pituitary–adrenal axis. The need to taper inhaled corticosteroid doses and to recognize the possibility of life-threatening acute adrenal insufficiency is of the utmost importance. Skin Nasal corticosteroids and inhaled corticosteroids can have adverse effects on the nose and mouth, including pruritus, burning, dryness, erythema, edema, dry cough, and odynophagia; less commonly, they can cause eczema and urticaria, particularly on the face. Contact dermatitis to corticosteroids can be facilitated by impaired epithelial barriers, and has been found in 4.7% of patients receiving topical hydrocortisone (17c ). Inhaled corticosteroids can cause hypersensitivity reactions, especially in patients with chronic eczema who have been sensitized to local corticosteroids. Tixocortol pivalate is a marker for corticosteroid contact allergy, as a positive patch test suggests established contact allergy to hydrocortisone, prednisolone, and their derivatives (18R ). A literature search via Medline from 1966 to May 2000 revealed only one patient hypersensitive to tixocortol pivalate and budesonide in a pilot study in 34 patients (10 with asthma, 13 with rhinitis, 11 with both) (19M ). From case reports the prevalence of corticosteroid-induced contact allergy has been estimated at 2.9–5%. Based on these observations it has been concluded that patients who use inhaled corticosteroids and develop unprecedented skin reactions during therapy should be tested for corticosteroid-related contact allergy (20R ). Switching from one of the four main corticosteroid groups to another might prove successful in these cases. Musculoskeletal Inhaled corticosteroids and bone mineral density (SED-14, 511; SEDA-23, 178; SEDA-24, 186) Bone mineral density has been measured in a 3-year prospective study

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in 109 premenopausal asthmatic women, aged 18–45 years, all of whom used inhaled triamcinolone acetonide (21C ). They were grouped according to their inhaled corticosteroid use at base line (no corticosteroids and triamcinolone less than 800 µg/day or more than 800 µg/day). Therapy with triamcinolone was associated with a dose-related fall in bone mineral density at the hip overall and the trochanter. There was no effect at the femoral neck or the spine. None of the measured serum or urinary markers of bone turnover predicted the degree of bone loss. The dose-related loss of bone mineral density was suggested to be clinically related to prolonged treatment with inhaled corticosteroids, and periodic bone mineral density assessment in patients taking high-dose inhaled corticosteroids was proposed. The effect of beclomethasone on bone mineral density has been examined over 1 year in pre- and early postmenopausal asthmatic women: 36 asthmatic women who were using inhaled corticosteroids (beclomethasone at a mean dose of 542 µg/day) compared with 45 healthy matched controls (22C ). In early postmenopausal asthmatic women using beclomethasone bone mineral density was significantly lower than in the controls, but not in premenopausal asthmatic women using inhaled beclomethasone. Serum osteocalcin concentrations were lower in the early postmenopausal asthmatic women using inhaled corticosteroids than in the healthy controls, suggesting reduced bone formation, which leads to more pronounced bone loss. Ovarian hormones were suggested to offset the bonedepleting effects of inhaled beclomethasone in premenopausal women by maintaining or stimulating osteoblastic function. There were significant reductions in bone mineral density in the lumbar spine and femur in 32 asthmatic women taking long-term inhaled beclomethasone (750–1500 µg/day) compared with 26 healthy controls (23C ). Control subjects and asthmatic patients were matched for age, sex, menopausal status, bodymass index, calcium intake, and physical activity. Loss of bone mass was more pronounced in the postmenopausal women. The authors identified several risk factors for accelerated bone loss in the lumbar spine, including postmenopausal status, low body-mass index, long

duration of disease, long-term inhaled corticosteroid therapy, and higher average daily and cumulative inhaled corticosteroid doses. The effects of inhaled budesonide 800 µg/day and fluticasone 400 µg/day on bone metabolism, morning cortisol concentrations, and clinical parameters have been studied in eight asthmatic patients (24c ). There were no changes in serum and bone alkaline phosphatase, osteocalcin, carboxyterminal propeptide of type 1 procollagen, and urinary calcium and deoxypyridinoline concentrations over 6 months. The authors concluded that fluticasone is as effective as twice the dose of budesonide in controlling asthmatic symptoms, without adverse effects on bone metabolism. In a small cross-sectional study bone mineral density was studied in 20 prepubertal asthmatic patients treated with moderate to high doses of inhaled corticosteroids (under 400 µg/day beclomethasone or budesonide or over 200 µg/day fluticasone) (25r ). Volumetric trabecular bone mineral density of the lumbar spine and distal radius were measured using dual energy X-ray absorptiometry and were within the reference ranges. A group of 374 subjects (mean age 35 years, 55% women) with mild asthma taking betaadrenoceptor agonists only, were randomized to inhaled corticosteroids (budesonide or beclomethasone) or non-corticosteroid treatment for 2 years (26C ). Bone mineral density was measured blind after 6, 12, and 24 months. Mean doses of budesonide and beclomethasone were 389 µg/day and 499 µg/day respectively. At the end of follow-up, the subjects who had used corticosteroids had better asthma control. The mean changes in bone density over 2 years in the budesonide, beclomethasone, and control groups were 0.1%, −0.4%, and 0.4% for the lumbar spine and −0.9%, −0.9%, and −0.4% for the neck of the femur. The daily dose of inhaled corticosteroid was related to the reduction in bone mineral density only at the lumbar spine. Low to moderate doses of inhaled corticosteroids caused little change in bone mineral density over 2 years and provided better asthma control. In a retrospective cohort comparison of patients using inhaled corticosteroids or bronchodilators with controls, there was an increased risk of fractures, particularly at the hip and spine, in those using inhaled corticosteroids. There were no differences in relative

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fracture risks with different drugs, e.g. fluticasone, budesonide, beclomethasone (27c ). In an earlier retrospective study, there was a dosedependent increase in bone fracture risk with oral corticosteroids (28c ). Immunologic As cross-reactivity within corticosteroid groups may be clinically relevant, skin patch testing has been proposed in cases of suspected corticosteroid allergy, to identify the substances that can be safely administered (29A ). The prevalence of corticosteroid allergy has been studied by skin patch testing in 30 patients using inhaled or intranasal corticosteroids (30c ). Four patients had a positive patch test (three allergic reactions and one irritant reaction). Eight different corticosteroids were used, but allergic reactions occurred only with budesonide. The authors therefore suggested that budesonide is more likely to cause contact hypersensitivity, but also referred to the possible relevance of allergic or irritant reactions to preservatives. Infection risk Inhaled or topical immunosuppressive and anti-inflammatory corticosteroids increase the risk of oral candidiasis (31R ). Patients who harbor oral Candida before they use inhaled corticosteroids may have an increased risk. The location and degree of oral candidiasis seems to be related to dosage, administration frequency, and inhalation technique. Preventive measures include using a spacer, lowering the dosage, and rinsing the mouth after use.

BETA-ADRENOCEPTOR AGONISTS (SED-14, 500; SEDA-23, 181; SEDA-24, 187; SEDA-25, 192) Cardiovascular A sharp rise in asthma mortality in 1977 in New Zealand provoked debate about the safety of b2 -adrenoceptor agonists, especially the short-acting compound fenoterol. This led to the withdrawal of fenoterol in New Zealand and amendment of the American Asthma Guidelines, suggesting caution in the regular use of b2 -agonists (32S ). Although there is evidence linking fenoterol to increased morbidity and mortality in asthma (33R ), the

Max Kuhn, Markus Joerger, and Katharina Hartmann

underlying mechanisms were not known. It was suggested that the increase in mortality might be linked to fatal cardiac dysrhythmias, developing under conditions of asthma-induced hypoxia and high doses of b2 -adrenoceptor agonists (34c ). Eight men with mild asthma underwent measurement of forearm blood flow, a surrogate marker for peripheral vasodilatation (35c ). All received in sequential order the following: normoxia plus placebo, normoxia plus inhaled salbutamol 800 µg, hypoxia (Spo2 82%) plus placebo, and hypoxia plus inhaled salbutamol 800 µg. The period of mask breathing was 60 minutes and inhalation of salbutamol/placebo started after 30 minutes. While there were non-significant differences in blood pressure and potassium concentrations between the different treatments, forearm blood flow increased significantly by 45% in hypoxic patients inhaling salbutamol versus normoxic patients inhaling placebo. The authors concluded that the combination of hypoxia and inhalation of b2 -agonists has serious systemic vascular adverse effects, potentially leading to pulmonary shunting and reduced venous return, which may be associated with sudden death. Furthermore, asthmatic patients in respiratory distress should be given b2 -agonists and oxygen concomitantly whenever possible. Intravenous and intracoronary salbutamol (10–30 µg/min and 1–10 µg/min respectively), and intravenous isoprenaline (1–5 µg/min), a mixed b1 /b2 -adrenoceptor agonist, were infused in 85 patients with coronary artery disease and 22 healthy controls during fixed atrial pacing (36C ). Both salbutamol and isoprenaline produced large increases in QT dispersion (QTonset , QTpeak , and QTend ), more pronouncedly in patients with coronary artery disease. Dispersion of the QT interval is thought to be a surrogate marker for cardiac dysrhythmia (37C ). The authors concluded that b2 -adrenoceptors mediate important electrophysiological effects in human ventricular myocardium and can trigger dysrhythmias in susceptible patients. In a blind, randomized study 29 children aged under 2 years, with moderate to severe acute exacerbations of hyper-reactive airways disease, were treated with either a standard dose of nebulized salbutamol (0.15 mg/kg) or a low dose of nebulized salbutamol (0.075 mg/kg)

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plus nebulized ipratropium bromide 250 µg (38c ). Standard and low-dose nebulized salbutamol was given three times at intervals of 20 minutes and nebulized ipratropium bromide was given once. Clinical improvement, measured as O2 saturation and respiratory distress, was similar in both groups. QT dispersion was measured at baseline and after treatment and was significantly increased only by the standard dose of nebulized salbutamol.

Clenbuterol Cardiovascular The induction of physiological cardiac hypertrophy has important implications in various clinical settings, particularly in training of the left ventricle in operations for certain types of congenital heart disease. As positive effects of b2 -adrenoceptor overexpression on cardiac function have been shown in experiments in mice (39E ), the hypothesis that clenbuterol improves right ventricular systolic function in large mammalian species when given at the time of induction of pressureoverload cardiac hypertrophy has been tested in 15 open-chest operated sheep before and after 6 weeks of pulmonary artery banding (40E ). The animals were randomly assigned to either saline solution or clenbuterol. There was a highly significant improvement in the slope of the end-systolic pressure-volume loops in the clenbuterol-treated animals, without detrimental hemodynamic effects. No predictions can be made as to the lasting effects of clenbuterol’s ability to augment systolic function in a chronically pressure-overloaded, thin-walled ventricle beyond 6 weeks, or the potential for tachyphylaxis. Drug overdose The effects of overdose with clenbuterol have been described (41A ). • A 28-year-old woman developed a sustained sinus tachycardia (140/min), hypokalemia (2.4 mmol/l), hypophosphatemia (0.29 mmol/l) and hypomagnesemia (0.76 mmol/l) after accidentally ingesting a reportedly small quantity of clenbuterol. She was given metoprolol and potassium. Her serum clenbuterol concentration was 2.93 µg/l 3 hours after ingestion, well above the maximal peak serum concentration of 0.087 µg/l 2.4 hours after administration of a therapeutic dose of 20 µg of clenbuterol (42S ).

Formoterol

(SED-14, 506; SEDA-23, 182; SEDA-25, 194) High-dose formoterol (Oxis Turbuhaler® ) and terbutaline (Bricanyl Turbuhaler® ) have been compared in a randomized, double-blind trial in 48 patients with obstructive airways disease (mean FEV1 0.98 l or 33% predicted) (43C ). Patients with acute bronchoconstriction received either a cumulative dose of 90 µg inhaled formoterol or 10 mg inhaled terbutaline (corresponding to 20 puffs each) within the first 3 hours of admission. Treatment included intravenous prednisolone 40 mg after 1.5 hours and oxygen during the first 3 hours. FEV1 improved similarly in both treatment groups, serum potassium concentration fell in both groups but to the same extent, and the mean 12-hour pulse rate was significantly higher with terbutaline. The authors concluded that formoterol is at least as safe and equally well tolerated as terbutaline.

Levosalbutamol (levalbuterol) Levosalbutamol is the (R)-enantiomer of the b2 -agonist salbutamol (albuterol). It has been suggested to have a better therapeutic index than racemic salbutamol. As levosalbutamol has a much higher receptor affinity than the (S)enantiomer, the therapeutic effects of racemic salbutamol are assumed to be mediated by levosalbutamol. However, toxicity of levosalbutamol is unrelated to b2 -receptor binding, and so the (S)-enantiomer may significantly contribute to the toxicity of racemic salbutamol. The effects of two doses of inhaled levosalbutamol (0.63 mg and 1.25 mg) and racemic salbutamol (1.25 mg and 2.50 mg) on FEV1 have been studied in a randomized, doubleblind trial in 362 asthmatic patients over 4 weeks (44C ). The average peak FEV1 for levosalbutamol was significantly greater than that for racemic salbutamol after the first dose but not at week 4. The possible superior bronchodilatation achieved with lower doses of levosalbutamol may be more cost effective (45R ). The issue of enantioselective efficacy and safety of salbutamol has been reviewed (46R ). Interest in “chiral switch”, i.e. the replacement

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of the racemic formulation by the pharmacologically active (R)-enantiomer levosalbutamol, may be hampered by enantiomeric interconversion in vivo and marked interindividual variation in salbutamol pharmacokinetics and pharmacodynamics, owing to complex interactions between genetic and environmental effects. The authors concluded that the advantage of levosalbutamol over the racemic formulation appears to be small with respect to efficacy and controversial with respect to safety. Two large crossover studies with multiple inhaled doses of (S)-salbutamol in asthmatic patients showed no evidence of adverse effects on FEV1 (47c , 48C ).

Ritodrine

(SED-14, 507)

Fetotoxicity Magnetocardiography has been used to detect fetal cardiac dysrhythmias in 84 pregnant women with normal pregnancies and in 68 women receiving ritodrine for preterm labor (49C ). There were dysrhythmias in 3.5% of the fetuses in the normal pregnancy group and in 16% in the ritodrine-treated group. The hemodynamic effects of ritodrine have been assessed in 12 fetuses by cardiac and extracardiac Doppler sonography (50c ). Ritodrine significantly increased maternal and fetal heart rates, left cardiac stroke volume, and cardiac output. There was also an increase in the pulsatility index of the middle cerebral artery and a fall in the pulsatility index of the umbilical artery during ritodrine infusion. The authors suggested that ritodrine vasodilates fetal vessels in the placenta.

Salmeterol

(SED-14, 506; SEDA-23, 185; SEDA-25, 194) There has been a systematic review of the literature and of unpublished trials with single and chronic doses of inhaled salmeterol 100 µg from the GlaxoSmithKline databases (51M ). The analysis covered data available until early 1999. Of 44 trials that included a salmeterol 100 µg treatment arm, data on systemic effects were available from 19 trials that were subsequently included in a pooled weighted analysis. In the chronic dose studies in 1504 patients who

Max Kuhn, Markus Joerger, and Katharina Hartmann

took salmeterol for more than 7 days, tremor was reported in 5.6%, palpitation in 1.7%, reduced serum potassium in 0.9%, cardiographic events in 0.6%, and increased serum glucose in 0.3%. The smaller systemic effects after chronic administration compared with single salmeterol dosing possibly reflected tachyphylaxis to the systemic cardiovascular and metabolic effects of the drug. The mean systemic effects of salmeterol 100 µg are small and of doubtful clinical relevance; unintended use of twice the dose of salmeterol is unlikely to affect patients adversely. Salmeterol 42 µg bd has been compared with inhaled ipratropium bromide 36 µg/day and inhaled placebo in a randomized, doubleblind study for 12 weeks in 405 patients with chronic obstructive pulmonary disease (52C ). Both salmeterol and ipratropium bromide significantly increased the peak expiratory flow rate compared with placebo. Non-specific ear, nose, and throat symptoms (e.g. sore throat and upper respiratory tract infections) were more common with salmeterol and ipratropium than placebo. There were no significant differences between the groups in the total number of ventricular and supraventricular extra beats. There was no tolerance to the bronchodilating effects of salmeterol. In a randomized, double-blind study, 943 patients with chronic obstructive pulmonary disease were treated over 12 weeks with either inhaled salmeterol 42 µg bd via a metered-dose inhaler, or oral modified-release theophylline bd, titrated to serum concentrations of 10–20 µg/ml, or with a combination of the two drugs (53C ). Adverse events potentially related to the study drug were significantly more common in those who took theophylline compared with salmeterol alone. This was most evident for adverse gastrointestinal events (nausea, gastric upset, vomiting, diarrhea). Adverse cardiovascular events occurred in 1–4% and were comparable among the groups. Theophylline-related toxicity was considerable, as nearly 16% of the patients withdrew during the theophylline titration period owing to adverse events. In a randomized, double-blind, parallelgroup study, 911 asthmatic patients in primary care were randomly assigned to inhaled salmeterol 50 µg bd or placebo bd for 24 weeks (54C ). They continued to use their anti-inflammatory maintenance therapy throughout. Salmeterol produced a significant

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improvement in peak expiratory flow rate and a reduction in the use of short-acting b2 -agonists. Salmeterol did not increase the number of severe exacerbations of asthma.

• A 62-year-old woman with severe asthma taking pranlukast 450 mg/day was given oral prednisolone 80 mg/day for a severe asthmatic attack. After oral prednisolone was tapered and subsequently withdrawn by day 35, she was maintained on pranlukast only and 5 days later had fever, deteriorating pulmonary symptoms, hypoxemia, and bibasal reticulonodular pulmonary infiltrates on chest CT. A transbronchial biopsy was consistent with drug-related interstitial pneumonitis. A lymphocyte stimulation test was positive for pranlukast. Her fever abated and her pulmonary symptoms markedly improved 3 days after withdrawal of pranlukast, and 5 months later the pulmonary infiltrates had completely resolved.

Drugs acting on the respiratory tract

LEUKOTRIENE RECEPTOR ANTAGONISTS (SEDA-24, 184; SEDA-25, 197)

Montelukast

(SEDA-24, 184)

The safety and tolerability of montelukast in patients aged 6 years or more have been evaluated in a meta-analysis of pooled data from 11 multicenter, randomized studies and five longterm extension studies (55M ). In 3386 adults (aged 15–85 years) and 336 children (aged 6–14 years), the overall incidence of clinical and laboratory adverse events was similar among patients taking montelukast and placebo. There were no clinically important differences in individual adverse events between the two treatment groups. There were no dose-related adverse effects of montelukast up to dosages 20 times the recommended daily dose of 10 mg. The efficacy and safety of montelukast in 689 asthmatic children under 5 years have been studied in an international, multicenter, randomized study (56C ). The patients were randomly assigned to 12 weeks of treatment with placebo (n = 228) or montelukast 4 mg as a chewable tablet (n = 461). There were no clinically relevant differences between the groups in the overall frequencies of adverse effects, individual adverse effects, or the frequency of laboratory adverse effects, especially raised serum transaminase activities. Asthma was more frequent in the placebo group. The withdrawal frequency was similar in the two groups. Accidental ingestion of montelukast up to dosages 18 times the recommended daily dose of 4 mg was generally well tolerated. The authors concluded that montelukast is well tolerated in this specific group of preschool children.

Pranlukast

(SEDA-24, 184)

Respiratory Lung injury with interstitial pneumonitis has been attributed to pranlukast (57A ).

Immunologic The association of cysteinyl leukotriene receptor antagonists with eosinophilic conditions, especially Churg–Strauss syndrome, has generated widespread interest over the last 4 years. However, evaluation of the few data is hampered by poor understanding of the underlying pathophysiology of the syndrome as well as by the limited knowledge of the effect that cysteinyl leukotriene has on the immune response and the possibility of interacting genetic polymorphisms (58S ). • A 26-year-old asthmatic woman had severe acute necrotizing eosinophilic endomyocarditis while taking pranlukast, inhaled beclomethasone, and oral theophylline (59A ). Oral prednisolone had been replaced by pranlukast 9 months before the event. Cardiac injury was accompanied by peripheral eosinophilia, cardiogenic shock, and pulmonary infiltrates, suggesting atypical Churg– Strauss syndrome. She recovered after intensive treatment, steroid pulse therapy, and withdrawal of pranlukast. • A 53-year-old asthmatic woman developed pANCA-positive vasculitis while taking pranlukast 450 mg/day (60A ). Inhaled beclomethasone dipropionate had previously been tapered from 1200 µg/day to 800 µg/day over the previous 17 months. She had a mononeuritis multiplex, eosinophilia, and sinusitis. A lymphocyte stimulation test was negative for pranlukast.

In the second case, because p-ANCA had been positive before the patient started to take pranlukast, the authors suggested that her Churg–Strauss syndrome had occurred either through unmasking of a previously unrecognized forme fruste, through tapering the inhaled corticosteroid, or had been coincidental with the natural course of a pre-existing progressive Churg–Strauss syndrome. In an NIH workshop summary report on the relation between asthma therapy and Churg– Strauss syndrome, the authors concluded that

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no one compound or class of antiasthmatic agents was solely implicated. An association was found for pranlukast, montelukast, zafirlukast, the 5-lipoxygenase inhibitor zileuton, inhaled corticosteroids, and salmeterol. As corticosteroids constitute the principal therapy of Churg–Strauss syndrome, tapering of these agents may allow incipient Churg–Strauss syndrome to become manifest. In patients who develop Churg–Strauss syndrome and do not receive corticosteroids (61r , 62A , 63A ), these various antiasthmatic medications might be used to treat asthmatic symptoms but not the underlying Churg–Strauss syndrome (58S ).

Zafirlukast Liver Sporadic cases of severe hepatotoxicity (64A , 65r , 66r ) requiring orthotopic liver transplantation for subacute liver failure in two cases (67r ) prompted a revision of the “Adverse Events” section in the Physicians’ Desk Reference (68S ). Hepatitis has been attributed to zafirlukast in two cases. • A 54-year-old asthmatic man developed subacute hepatitis and hepatic encephalopathy while taking zafirlukast 20 mg bd for 8 months and co-amoxiclav 2 g/day for a few days (65A ). He also took antihistamines, inhaled corticosteroids, and beta-blockers (not specified). A percutaneous liver biopsy showed severe hepatocellular necrosis and eosinophilic infiltrates without prominent cholestasis. Raised transaminases and total serum bilirubin normalized within 3 months after withdrawal of zafirlukast and co-amoxiclav and the use of intermittent, high-dose, parenteral corticosteroids, followed by oral tapering. • A 55-year-old asthmatic woman had subacute liver injury with severe hepatic necrosis and eosinophilic infiltrates while taking zafirlukast 20 mg bd and salbutamol sulfate nasal spray for 5 months (66r ). There was no evidence of viral, metabolic, alcohol-related, or autoimmune hepatitis. Zafirlukast was withdrawn and liver function normalized within 2 months.

The authors concluded that subacute hepatitis in the second patient had been related to zafirlukast, but suggested that co-amoxiclav might also have been a precipitating factor. The long latency between the start of zafirlukast treatment and the onset of hepatotoxicity and

Max Kuhn, Markus Joerger, and Katharina Hartmann

the slow response to drug withdrawal and corticosteroid treatment are reminiscent of previous cases of zafirlukast-related hepatotoxicity.

EXPECTORANT AND MUCOLYTIC DRUGS Iodine

(SED-14; 513)

Fetotoxicity Large quantities of iodine reduce the coupling of iodotyrosine to form T3 and T4 (the Wolff–Chaikoff effect). Neonatal goiter caused by the use of potassium iodine as an expectorant during pregnancy has been reported (69A ). The neonate, a girl, had acute hypothyroidism, with myxedema and respiratory distress. She was given levothyroxine for 6 months, with complete normalization of thyroid function.

ANTICHOLINERGIC DRUGS (SED-14, 499; SEDA-24, 192) The removal of chlorofluorocarbons from industrial and household products underlies the 1987 “Montreal Protocol on Substances that Deplete the Ozone Layer”. A reformulation of ipratropium bromide using an alternative, non-chlorofluorocarbon propellant, hydrofluoroalkane, 134a (1,1,1,2-tetrafluoroethane), has been compared with the marketed, chlorofluorocarbon-containing ipratropium bromide aerosol in a randomized, double-blind, placebo-controlled trial in 507 patients with moderate to severe obstructive airways disease (70C ). The patients were given hydrofluoroalkane/ipratropium bromide 42 µg, hydrofluoroalkane/ipratropium bromide 84 µg, hydrofluoroalkane/placebo, chlorofluorocarbon/ipratropium bromide 42 µg, or chlorofluorocarbon/placebo. The incidences of adverse clinical and laboratory events and significant cardiographic effects were not different across the groups.

Drugs acting on the respiratory tract

DESENSITIZATION

Chapter 16

(SED-14, 496;

SEDA-23, 188) The efficacy of desensitization using subcutaneous maintenance venom immunotherapy is well established and is usually considered in patients with severe systemic allergic reactions to both yellow jacket and bee venom (grade III or IV according to Mueller). Among 160 patients who were mostly allergic to bee venom and who were assessed for systemic allergic reactions to sting challenges while increasing the intervals of maintenance venom immunotherapy from 4–6 weeks to 3 months there were no serious adverse events (71c ). Two of 44 patients, who were deliberately stung during the 3-monthly maintenance therapy, had a mild systemic reaction. After withdrawal of venom immunotherapy, 22 patients allergic to bee venom were sting

195 challenged; one had a mild systemic reaction. In conclusion, the conventional 4–6 week maintenance interval can be safely extended to 3 months in most patients without any adverse events. In 36 patients with a history of systemic reactions (grade III or IV according to Mueller) after exposure to a wasp sting, who were given immunotherapy with aluminium hydroxideadsorbed wasp venom extract in an open retrospective study, a maintenance monthly depot of 50 000 SQU (50 µg) of venom was used (72c ). After the first year, the dose was injected every other month. Desensitization therapy was well tolerated. There were few mild local adverse events. Thirteen patients were exposed to stings during maintenance immunotherapy and four after withdrawal at the end of the 5-year treatment period. Field stings only provoked local skin reactions.

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48. Ramsay CM, Cowan J, Flannery E, McLachlan C, Taylor DR. Bronchoprotective and bronchodilator effects of single doses of S-salbutamol, R-salbutamol and racemic salbutamol in patients with bronchial asthma. Eur J Clin Pharmacol 1999; 55: 353–9. 49. Anastasiadis PG, Anninos P, Assimakopoulos E, Koutlaki N, Kotini A, Galazios G. Fetal heart rate patterns in normal and ritodrine-treated pregnancies, detected by magnetocardiography. J Matern Fetal Med 2001; 10: 350–4. 50. Gokay Z, Ozcan T, Copel JA. Changes in fetal hemodynamics with ritodrine tocolysis. Ultrasound Obstet Gynecol 2001; 18: 44–6. 51. Shrewsbury S, Hallett C. Salmeterol 100 microg: an analysis of its tolerability in single- and chronic-dose studies. Ann Allergy Asthma Immunol 2001; 87: 465–73. 52. Rennard SI, Anderson W, ZuWallack R, Broughton J, Bailey W, Friedman M, Wisniewski M, Rickard K. Use of long-acting inhaled b2 -adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1087–92. 53. ZuWallack RL, Mahler DA, Reilly D, Church N, Emmett A, Rickard K, Knobil K. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001; 119: 1661–70. 54. D’Urzo AD, Chapman KR, Cartier A, Hargreave FE, Fitzgerald M, Tesarowski D. Effectiveness and safety of salmeterol in nonspecialist practice settings. Chest 2001; 119: 714–19. 55. Storms W, Michele TM, Knorr B, Noonan G, Shapiro G, Zhang J, Shingo S, Reiss TF. Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged > 6 years. Clin Exp Allergy 2001; 31: 77–87. 56. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, Reiss TF, Nguyen HH, Bratton DL. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001; 108: E48. 57. Takahashi N, Iwanaga T, Aizawa H, Koto H, Watanabe K, Kishikawa R, Ikeda T, Shoji S, Nishima S, Hara N. Acute interstitial pneumonia induced by ONO-1078 (pranlukast), a leukotriene receptor antagonist. Intern Med 2001; 40: 791–4. 58. Weller PF, Plaut M, Taggart V, Trontell A. The relationship of asthma therapy and Churg–Strauss syndrome: NIH workshop summary report. Allergy Clin Immunol 2001; 108: 175–83.

59. Hayashi S, Furuya S, Imamura H. Fulminant eosinophilic endomyocarditis in an asthmatic patient treated with pranlukast after corticosteroid withdrawal. Heart 2001; 86: E7. 60. Hashimoto M, Fujishima T, Tanaka H, Kon H, Saikai T, Suzuki A, Nakatsugawa M, Abe S. Churg–Strauss syndrome after reduction of inhaled corticosteroid in a patient treated with pranlukast for asthma. Int Med 2001; 40: 432–4. 61. Katz RS, Papernik M. Zafirlukast and Churg– Strauss syndrome. J Am Med Assoc 1998; 279: 1949. 62. Green RL, Vayonis AG. Churg–Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment. Lancet 1999; 353: 725–6. 63. Tuggey JM, Hosker HS. Churg–Strauss syndrome associated with montelukast therapy. Thorax 2000; 55: 805–6. 64. Reinus JF, Persky S, Burkiewicz JS, Quan D, Bass NM, Davern TJ. Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med 2000; 133: 964–8. 65. Actis GC, Morgando A, Lagget M, David E, Rizzetto M. Zafirlukast-related hepatitis: report of a further case. J Hepatol 2001; 35: 539–45. 66. Danese S, DeVitis I, Gasbarrini A. Severe liver injury associated with zafirlukast. Ann Intern Med 2001; 135: 930. 67. Torres M, Reddy KR. Severe liver injury. Ann Intern Med 2001; 135: 550. 68. Physician’s Desk Reference. Montvale, NJ: Medical Economics; 2001: 611–13. 69. Bostanci I, Sarioglu A, Ergin H, Aksit A, Cinbis M, Akalin N. Neonatal goiter caused by expectorant usage. J Pediatr Endocrinol Metab 2001; 14: 1161–2. 70. Taylor J, Kotch A, Rice K, Ghafouri M, Kurland CL, Fagan NM, Witek TJ. Ipratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPD. Chest 2001; 120: 1253–61. 71. Goldberg A, Confino-Cohen R. Maintenance venom immunotherapy administered at 3-month intervals is both safe and efficacious. J Allergy Clin Immunol 2001; 107: 902–6. 72. Poli F, Longo G, Parmiani S. The safety and efficacy of immunotherapy with aluminum hydroxide-adsorbed venom extract of Vespula spp. An open, retrospective study. Allergol Immunopathol 2001; 29: 191–6.

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J.K. Aronson

17

Positive inotropic drugs and drugs used in dysrhythmias

CARDIAC GLYCOSIDES

(SED-14, 523; SEDA-23, 193; SEDA-24, 197; SEDA-25, 205) Cardiovascular Digoxin has previously been reported to cause ventricular fibrillation in children with Wolff–Parkinson–White syndrome (1A , 2A ). There has now been another report (3A ). • A male infant, whose narrow-complex tachycardia at birth had responded to adenosine, was treated with digoxin and 1 week later, during transesophageal electrophysiology, developed coarse ventricular fibrillation after the induction of a supraventricular tachycardia. The serum digoxin concentration was not measured. Isoprenaline was withdrawn and the dysrhythmia resolved spontaneously at 160 seconds.

The effects of digoxin, isoprenaline, and transesophageal stimulation may have combined in this case to cause ventricular fibrillation. Paroxysmal atrial tachycardia with Wenckebach (Mobitz type I) atrioventricular block has been reported in a patient with a serum digoxin concentration of 3.2 ng/ml (4A ). The electrocardiographic effects of cardiac glycoside toxicity in 688 patients have been reviewed in the context of three cases of digoxin toxicity (5Ar ). The three cases featured bidirectional tachycardia in a 50-year-old man with a plasma digoxin concentration of 3.7 ng/ml, junctional tachycardia in a 59-year-old man with a plasma digoxin concentration of 4.3 ng/ml, and complete heart block in a 90-yearold woman whose post-mortem digoxin concentration was 5.0 ng/ml. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

198

Psychiatric Acute delirium is a well-known effect of digitalis intoxication, and another case has been described in a 61-year-old man whose serum digitoxin concentration was 44 ng/ml (6A ). Digitalis toxicity can occasionally cause depression (7A ), and another case has been reported (8A ). • A 77-year-old woman developed extreme fatigue, anorexia, psychomotor retardation, and social withdrawal 1 month after starting to take digoxin 0.5 mg/day for congestive heart failure. She did not respond to intravenous clomipramine 25 mg/day for 7 months. Her serum digoxin concentration was 3.2 ng/ml. Digoxin was discontinued, and 12 days later, when her serum digoxin concentration was 0.5 ng/ml, she had improved, but was left with a memory disturbance, which was attributed to background dementia.

Endocrine Early studies suggested that when breast tumors occurred in women with congestive heart failure taking cardiac glycosides, tumor size was significantly smaller and the tumor cells more homogeneous (SEDA-7, 194). It was originally thought that this action was due to an estrogen-like effect of cardiac glycosides, but more recent evidence suggests that it occurs because inhibition of the Na/K pump is involved in inhibiting proliferation and inducing apoptosis in various cell lines (9E –12E ). In a recent study it was shown that different cardiac glycosides have different potencies in their effects on cell lines such as those of ovarian carcinoma and breast carcinoma (13E ). The order of potency was proscillaridin A > digitoxin > digoxin > ouabain > lanatoside C. Metabolism It has previously been reported that withdrawal of digoxin in three patients with diabetes mellitus led to improved glucose control, implying that digoxin had caused impaired glucose tolerance (SEDA-24, 200). This possibility has again been raised in the context of 14

Positive inotropic drugs and drugs used in dysrhythmias

patients with morbid obesity, who were being given digoxin in the hope that reduced production of cerebrospinal fluid, with the consequent reduction in pressure, might be associated with weight reduction (14c ). The dosage of digoxin (Lanacrist 0.13 mg, equivalent to 0.065 mg of digoxin) was titrated to produce a minimum serum digoxin concentration of 1.0 nmol/l. One patient was already diabetic, and five developed fasting blood glucose concentrations greater than 5.0 mmol/l on three consecutive occasions, with accompanying glycosuria. Another had fasting blood glucose concentrations of 6.0– 8.5 mmol/l. There was a significant relation between the dose of digoxin and the risk of impaired glucose tolerance. However, the diabetes mellitus did not abate after digoxin withdrawal, and since all these patients were obese, the occurrence of diabetes was probably coincidental. Reproductive system Digoxin has been used to cause fetal death before termination of pregnancy (15C ). However, in a double-blind study in 126 women who had terminations by dilatation and evacuation at 20–23 weeks gestation intra-amniotic injection of digoxin 1 mg did not alter blood loss or pain; nor did it reduce difficulties with or the complications of the procedure (16C ). Significantly more women vomited after intra-amniotic digoxin. Digoxin given by this route is slowly absorbed into the systemic circulation, with a peak plasma concentration of 0.8 ng/ml at 11 hours (17c ). Risk factors A retrospective Bayesian analysis in 60 patients has confirmed that age and renal impairment are major factors in digoxin toxicity (18c ). However, an analysis of the data from the Digitalis Investigation Group (DIG) study (SEDA-20, 173) has shown that while mortality in heart failure increases with age, the actions of digoxin are independent of age (19C ). A population pharmacokinetic study in 172 neonates and infants has shown that the clearance of digoxin is affected significantly by total body weight, age, renal function, and congestive heart failure (20C ). Drug contamination Contamination with digitalis-like substances has been suspected in a herbal dietary supplement (21A ).

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• A 26-year-old woman developed chest pain lasting 7 hours after taking a herbal supplement that contained Scutellaria lateriflora, Pedicularis canadensis, Cimifuga racemosa, Humulus lupulus, Valeriana officinalis, and Capsicum annuum. Her medical history was otherwise unremarkable. Examination of her heart showed no abnormality, but during monitoring her heart rate fell to 39 beats/min and her blood pressure to 59/36 mmHg. Her serum digoxin concentration was 0.9 ng/ml.

The authors concluded that the herbal remedy contained digoxin-like factors that had caused digitalis toxicity. Drug interactions Drug interactions with digitoxin have been briefly reviewed in the context of its use in the treatment of congestive heart failure (22r ). In three large studies using either population pharmacokinetic analysis or Bayesian techniques, drugs that inhibit the transport of digoxin by inhibiting P glycoprotein significantly increased the serum digoxin concentration (20C , 23C , 24C ). These drugs included quinidine, spironolactone, and the calcium channel blockers diltiazem, nicardipine, nifedipine, and verapamil. The effects varied from about 22% to about 36%. There have been contradictory results in studies of the effects of captopril on digoxin pharmacokinetics. In some cases, captopril increased steady-state plasma digoxin concentrations (25C ), while in others there was no evidence of an interaction (26C –29C ). In a recent study of eight patients with NHYA Class IV congestive heart failure, captopril 12.5 mg tds for 1 week increased the peak digoxin concentration, reduced the time to peak, and increased the AUC during a single dosage interval at steady state; trough digoxin concentrations did not change (30C ). There are two possible explanations for these findings: that captopril reduced the clearance of digoxin or that it increased both the rate and extent of absorption of digoxin; unfortunately, the authors did not measure either the mean steady-state concentration or the half-life, which would have clarified this. On the whole, however, it is unlikely that this interaction is of any clinical significance, since in no study has there been evidence of digoxin toxicity during concomitant captopril therapy, and in one formal study (29C ) there was evidence of no pharmacodynamic interaction.

200 In 12 healthy young adults the phosphodiesterase inhibitor cilomilast 15 mg bd for 5 days had no effect on the steady-state pharmacokinetics of digoxin, apart from a small reduction in the maximal concentration and a small increase in the time to peak (31C ). This was consistent with a small effect on the rate of digoxin absorption, which is unlikely to be of clinical significance. Digoxin had no effect on the disposition of cilomilast. In a 90-year-old woman the addition of cisapride 5 mg bd reduced the mean steady-state digoxin concentration from 0.9 ng/ml to 0.6 ng/ml and 5 mg tds reduced it to 0.4 ng/ml, with recurrence of her severe biventricular failure (32A ). When the doses of digoxin and cisapride were separated, the serum digoxin concentration rose again. The mechanism of this effect is thought to be increased gastrointestinal motility, although in this case the effect of separating the doses suggests that there might be a direct chemical interaction between the two drugs. In 11 healthy adults citalopram 40 mg/day had no effect on the pharmacokinetics of a single oral dose of digoxin 1 mg (33C ). Digoxin did not affect citalopram pharmacokinetics. In 14 healthy men dofetilide 250 micrograms bd for 5 days had no effect on the pharmacokinetics of digoxin at a steady-state trough concentration of 1.0 ng/ml (34C ). However, in a placebo-controlled study in patients with atrial fibrillation or atrial flutter, conversion to sinus rhythm in patients given dofetilide was more likely if they were also given digoxin (35C ), so there may be a pharmacodynamic interaction. Macrolide antibiotics increase the systemic availability of digoxin by at least two mechanisms: by reducing its metabolism in the gut before absorption (by inhibiting the growth of the bacterium Eubacterium glenum) and by inhibiting P glycoprotein (SEDA-25, 173). Another case of digoxin toxicity has now been reported in a neonate who was also given erythromycin (36A ). She had bradycardia and coupled extra beats. Digoxin and erythromycin were withdrawn and she was given antidigoxin antibodies. Her plasma digoxin concentration, which had previously been 1.8 ng/ml, had risen to 8.0 ng/ml. The potential of itraconazole to increase digoxin concentrations has been well documented (SEDA-25, 206). The importance of this interaction has been emphasized by a report

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of two renal transplant patients who developed digoxin toxicity when they also took itraconazole (37A ). In 11 healthy adults in a double-blind, placebo-controlled study levetiracetam had no effect on the steady-state pharmacokinetics of digoxin or the actions of digoxin on the electrocardiogram (38C ). Sevelamer, a non-absorbed phosphatebinding polymer, in a dose of 2.4 g, had no effect on the pharmacokinetics of single doses of digoxin in 19 healthy volunteers (39C ). In 12 healthy subjects the 5HT4 receptor partial agonist tegaserod 6 mg bd for 3 days had a small effect on the pharmacokinetics of a single oral dose of digoxin 1 mg, reducing the mean AUC by 12% and the Cmax by 15% (40C ). There was a small delay in the time to peak, which was not significant. These results suggest that tegaserod slightly reduces the systemic availability of digoxin, perhaps because it increases gastrointestinal motility, but that the effect is of no clinical significance. It has been claimed that digoxin potentiated the effects of warfarin in a 66-year-old man (41A ). However, the discussion of the possible mechanisms of this observation was flawed, and there is no reason to expect such an interaction, which probably does not occur (42r ). Management of toxicity There has been another report of overdose of digoxin in a neonate (43A ). Complete atrioventricular block and cardiogenic shock were completely reversed within 4 hours after administration of the first dose of antidigoxin antibody; a second dose was given 48 hours later, when first-degree atrioventricular block occurred. A new formulation of antidigoxin antibody has recently been marketed. The traditional formulation (Digibind) is an ovine antibody to digoxin, whose production is stimulated by the administration of digoxin conjugated to human albumin. In contrast, the new formulation (DigiFab), also ovine, is stimulated by injected a conjugate of digoxin to keyhole-limpet hemocyanin (44r ). In 15 adults with digoxin toxicity who were given DigiFab, electrocardiographic abnormalities resolved within 4 hours in 10 patients and the signs of toxicity completely resolved within 4 hours in seven patients and within 20 hours in 14 patients. In one patient loss of the effect of digoxin resulted in

Positive inotropic drugs and drugs used in dysrhythmias

pulmonary edema, pleural effusions, and renal insufficiency. The half-life of DigiFab is slightly shorter than that of Digibind (15 versus 23 hours), but their pharmacodynamic properties are similar. It is said that DigiFab may be preferred in patients who are allergic to sheep proteins, papain, chymopapain, or bromelains. Despite the fact that hemoperfusion techniques, for example with charcoal, remove very little digoxin from the body (SEDA-12, 148), hemoperfusion continues to be reported as an effective method for treating digoxin toxicity. • In an 88-year-old woman whose serum digoxin concentration was 6.4 ng/ml, hemoperfusion with an adsorption column containing beta2 microglobulin caused a fall in serum concentration from 6 ng/ml to 2.3 ng/ml, with improvement in gastrointestinal symptoms (45A ). The serum digoxin concentration then rose again to 3.5 ng/ml over the next 3 days, and a further hemoperfusion treatment reduced it to 1.7 ng/ml, after which the serum concentration gradually fell and the patient improved. Because of chronic renal insufficiency, she also had repeated hemodialyses on alternate days, which also contributed to the reduction in serum digoxin concentrations.

In another study, the clearance of digoxin was measured in eight patients receiving hemodialysis during the use of a beta2 -microglobulin column (46C ). After 240 minutes of hemoperfusion the serum digoxin concentration fell from 1.11 to 0. 57 ng/ml and digoxin clearance was about 145 ml/min. However, this clearance rate cannot have been the true total body clearance, since it merely reflected the change in plasma concentration during hemoperfusion, which would have been almost entirely due to removal of digoxin from the plasma only and not from the tissues. This method cannot be recommended as a substitute for the use of antidigoxin antibodies in the treatment of digitalis toxicity.

OTHER POSITIVE INOTROPIC DRUGS (SED-14, 532; SEDA-23, 195; SEDA-24, 204; SEDA-25, 208) The under-reporting of the results of clinical trials in patients with heart failure has been reviewed (47R ). Some trials that have been unpublished or published only in abstract or

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preliminary form have involved drugs with positive inotropic effects, such as flosequinan, ibopamine, vesnarinone (SEDA-23, 195), and xamoterol.

Enoximone Musculoskeletal Enoximone has previously been reported to cause increased contraction in skeletal muscle in vitro in patients with a predisposition to malignant hyperthermia (48E , 49E ). Vastus lateralis muscle from a 48-year-old man with rhabdomyolysis had an increased in vitro response to increasing concentrations of enoximone above 0.6 mmol/l (50AE ). He also had a heterozygous mutation in his ryanodine receptor gene, with substitution of arginine for glycine in position 2433, a mutation that is associated with malignant hyperthermia. Phosphodiesterase inhibitors, such as enoximone, increase the release of calcium from the sarcoplasmic reticulum by activating ryanodine receptors, and the authors suggested that this may have been the mechanism whereby enoximone precipitated rhabdomyolysis in this case.

Milrinone In a randomized, open-label, parallel-group study of the hemodynamic effects of milrinone and glyceryl trinitrate in 119 patients with advanced decompensated heart failure, milrinone was significantly more effective than glyceryl trinitrate (51C ). Adverse effects caused the withdrawal of milrinone in three of the 58 patients who took it; one had ventricular extra beats, one had renal insufficiency, and one had hypokalemia. Headache was the most common adverse effect in both groups, but was less common in those who took milrinone (12% versus 29%). In a randomized, open study of milrinone and dobutamine in 120 patients with low cardiac output after cardiac surgery, the two drugs were roughly comparable in efficacy (52C ). Adverse events were more frequent with dobutamine (77%) than with milrinone (58%). With milrinone cardiovascular adverse events were the most common, including hypertension

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(13%), hypotension (20%), bradycardia (13%), new atrial fibrillation (5%), and tachycardia (8%). Other adverse events included hemorrhage and oliguria. Adverse events required withdrawal from the study in 20 patients who took milrinone. Inhaled milrinone has been used to treat patients with pulmonary hypertension after cardiac surgery (53C ). Milrinone produced a significant dose-related reduction in pulmonary vascular resistance in nine patients. There were no systemic adverse effects.

DRUGS USED IN DYSRHYTHMIAS The efficacy of a large range of antidysrhythmic drugs in converting atrial fibrillation to sinus rhythm acutely and in maintaining it during long-term treatment has been the subject of a systematic review (54M ). Adverse effects were too sporadically reported to be suitable for proper review. The results are summarized in Table 1. Cardiovascular The prodysrhythmic risks of using antidysrhythmic drugs have been mentioned in the context of a set of guidelines on the management of patients with atrial fibrillation (55Sr , 56Sr ). The recommended drugs for maintaining sinus rhythm after cardioversion vary

J.K. Aronson

depending on the presence of different risk factors for dysrhythmias: • heart failure: amiodarone and dofetilide; • coronary artery disease: sotalol and amiodarone; • hypertensive heart disease: propafenone and flecainide. The prodysrhythmic effects of antidysrhythmic drugs have also been reviewed in discussions of the pharmacological conversion of atrial fibrillation (57r ) and the relative benefits of rate control in atrial fibrillation or maintaining sinus rhythm after cardioversion (58r ). Factors that predict atrial flutter with 1 : 1 conduction as a prodysrhythmic effect of Class I antidysrhythmic drugs (cibenzoline, disopyramide, flecainide, propafenone, and quinidine) have been studied in 24 patients (aged 46–78 years) with 1 : 1 atrial flutter and in 100 controls (59C ). Underlying heart disease was present in nine patients. There was a short PR interval (PR < 0.13 msec) with normal P wave duration in leads V5 and V6 in nine of the 26 patients and only seven of the 100 controls. Signal-averaged electrocardiography showed pseudofusion between the P wave and QRS complex in 19 of the 26 patients and only 11 of the 100 controls. There was rapid atrioventricular nodal conduction (a short AH interval or second-degree atrioventricular block at atrial pacing over 200 beats/mm) in 19 of

Table 1. The results of a systematic review of the efficacy of antidysrhythmic drugs in converting atrial fibrillation to sinus rhythm and maintaining it (54M ) Drug

Amiodarone Disopyramide Dofetilide/ Ibutilide Flecainide Propafenone Quinidine Sotalol

Number of subjects

Efficacy in converting AF (OR compared with control1 )

Efficacy in maintaining sinus rhythm (OR versus control1 )

Ventricular dysrhythmias2 (%)

Other dysrhythmias3 (%)

Drug withdrawal or dosage reduction (%)

108 30 530

5.7 7.0 29

3.4

0–15 0 3–9

0–9 0

0–55

169 1168 200 34

25 4.6 2.9 0.4

3.1 3.7 4.1 7.1

0–2 0–3 0–12 0–1

0–12 0–17 0–28 2–44

0–20 0–55 0–58 4–44

1 Digoxin, diltiazem, or verapamil. 2 Ventricular fibrillation, polymorphic ventricular tachycardia, torsade de pointes. 3 Symptomatic bradycardia, junctional rhythm, non-sustained and/or monomorphic ventricular tachycardia.

Positive inotropic drugs and drugs used in dysrhythmias

the 23 patients. Pseudofusion of the P wave and QRS complex had a sensitivity of 100% and a specificity of 89% for the prediction of an atrial prodysrhythmic effect of Class I antidysrhythmic drugs. Drug overdose The use of techniques of circulatory support (extracorporeal oxygenation and intra-aortic balloon pump) in seven cases of overdose with antidysrhythmic drugs (disopyramide, flecainide, prajmaline, and quinidine) has been reviewed (60R ).

Adenosine

(SED-14, 536; SEDA-23, 197; SEDA-24, 205; SEDA-25, 210) The standard regimen for stress testing with intravenous adenosine is 140 micrograms/kg/min for 6 minutes. However, in 599 patients a 3minute infusion was associated with a lower frequency of some adverse effects (specifically flushing, headache, neck pain, and atrioventricular block) and had similar sensitivity in the diagnosis of coronary artery disease (61C ). Cardiovascular Adenosine can occasionally cause serious cardiac dysrhythmias (SEDA-20, 175), and more cases have been reported. • In a 60-year-old woman with atrial flutter with 2 : 1 block and a ventricular rate of 130/minute, the ventricular rate increased paradoxically to 260/minute with 1 : 1 conduction after intravenous administration of adenosine 6 mg; it responded to intravenous amiodarone 300 mg (62A ). • A 52-year-old woman with a wide-complex tachycardia was given adenosine 6, 12, and another 12 mg as intravenous bolus doses; immediately after the third dose she developed ventricular fibrillation (63A ). She recovered with cardioversion.

In the second case the authors did not discuss the possibility that the presence of digoxin (serum concentration 1.8 ng/ml) may have contributed; the risk of cardiac dysrhythmias after electrical cardioversion is increased in the presence of digoxin (SEDA-8, 174), and the same might be true of chemical cardioversion. In a prospective study of 187 episodes of tachycardia in 127 unselected patients adenosine was given in an average dose of 9.7 mg (64C ). In 108 cases, adenosine induced transient

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ventricular extra beats or non-sustained ventricular tachycardia after successful termination of supraventricular tachycardia; more than half had a right bundle branch block morphology that suggested that the dysrhythmias had originated from the inferior left ventricular septum. The frequency of atrioventricular block has been studied in 600 patients who underwent stress testing with intravenous adenosine 140 micrograms/kg/min for 6 minutes (65C ). The patients were young (under 49 years old; n = 75), middle-aged (50–65 years; n = 214), old (66–75 years; n = 195), or very old (over 75 years; n = 116). The respective frequencies of first-degree atrioventricular block were 15%, 9.3%, 14%, and 17% (overall average 13%), of second-degree block 15%, 7.0%, 8.7%, and 16% (overall average 10%), and of third-degree block 2.7%, 2.3%, 1.0%, and 2.6% (overall average 2.0%). The differences with age were not statistically significant. All types of atrioventricular block were of short duration, were well tolerated, and did not require withdrawal of adenosine or specific treatment. Respiratory A previous study in a few patients with chronic obstructive airways disease showed a dissociation between adenosineinduced breathlessness and bronchospasm (SEDA-24, 205). In another study, 63 of 122 patients had breathlessness during cardiac stress testing with adenosine but none had associated bronchospasm (66C ). Pre-test lung function did not predict the risk of breathlessness and neither chronic obstructive airways disease nor smoking increased the risk. The authors concluded that breathlessness during adenosine stress testing is not due to bronchospasm. Death Two cases of sudden death have been reported soon after the administration of adenosine for presumed supraventricular tachycardia, which turned out to be atrial fibrillation (67A ). The authors thought that both patients may have been unable to cope with the sudden momentary loss of cardiac function that would have occurred immediately after the administration of adenosine; in one case, a patient with chronic lung disease, bronchospasm may have contributed. Management of adverse drug reactions In 34 patients given midazolam or placebo in a

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double-blind study, midazolam significantly reduced patients’ experiences of palpitation and chest pain but had no effects on other adverse events (68C ). These effects were probably due to amnesia rather than a true reduction in the incidence of adverse events, and it is uncertain that the benefit to harm ratio is worth while. However, the authors suggested that midazolam might be useful in patients who have previously had unpleasant adverse reactions to adenosine.

Ajmaline and derivatives

(SED-14,

537; SEDA-24, 206; SEDA-25, 211) Cardiovascular Ajmaline occasionally causes cardiac dysrhythmias (SEDA-25, 211), and two cases of torsade de pointes have been reported in association with prolongation of the QT interval (69A ). Polymorphous ventricular tachycardia has been reported in three previous cases (70A –72A ).

Amiodarone

(SED-14, 537; SEDA-23, 198; SEDA-24, 206; SEDA-25, 211) The efficacy, adverse effects, and drug interactions of amiodarone have again been reviewed (73R , 74R ).

Cardiovascular Torsade de pointes occurs less commonly with amiodarone than with Class I drugs, but cases continue to be reported sporadically, as illustrated by another recent report in a 79-year-old woman who had taken 4800 mg over 6 days; the associated precipitating factors were a prolonged QT interval and hypokalemia (75A ). In another case, a 71-year-old Japanese man with bouts of sustained monomorphic ventricular tachycardia in whom non-sustained polymorphic ventricular tachycardia was induced by rapid pacing during electrophysiological studies, amiodarone therapy resulted in the appearance of three different types of sustained monomorphic ventricular tachycardia, with slightly different cycle lengths, induced and terminated by rapid pacing (76A ). The authors proposed that amiodarone had modulated

J.K. Aronson

the threshold of induction and/or termination of ventricular tachycardia. Prolongation of the QT interval and hypokalemia are well-known risk factors for torsade de pointes. In a recent study in 189 patients, five had torsade de pointes and all five had prolonged QT intervals (77C ). Two of the five, all women, also had raised blood glucose concentrations, and the authors suggested that hyperglycemia is a risk factor for torsade de pointes. However, the number of cases reported in this series was too small to justify such a conclusion. It has previously been suggested that women are more likely to develop torsade de pointes than men in response to antidysrhythmic drugs (78C ), and this has been confirmed in the case of amiodarone in a study of 189 patients given intravenous amiodarone (77C ). This is also reminiscent of the finding that prolongation of the QT interval due to quinidine is greater in women than in men at equivalent serum concentrations (79c ). In a 62-year-old man with dilated cardiomyopathy and an implantable cardioverter defibrillator for ventricular tachycardia, microvolt T wave alternans differed when amiodarone was added (80A ). The onset heart rate with T wave alternans was lower and the alternans voltage higher with amiodarone than without it. The effects of amiodarone appeared to be related to exacerbations of ventricular tachycardia and an increased defibrillation threshold. Respiratory Lung damage due to amiodarone usually presents slowly, but it can occasionally have a rapid onset, particularly in patients who are given high concentrations of inspired oxygen, and there is experimental evidence that amiodarone enhances the toxic effects of oxygen on the lungs (81E ). However, in a recent case adult respiratory distress syndrome occurred very rapidly in a 66-yearold man who took amiodarone 200 mg/day for a few weeks only (82A ). In another case pulmonary infiltrates occurred in a 72-year-old man after treatment with amiodarone (total dose 6800 mg) for only 7 days (83A ). The sialylated carbohydrate antigen KL-6 has been reported to be a serum marker of the activity of interstitial pneumonitis, and in differentiating patients with amiodarone-induced

Positive inotropic drugs and drugs used in dysrhythmias

pneumonitis from patients with similar features not associated with amiodarone (SEDA25, 181). This has been confirmed in a study of 25 patients, three of whom had proven interstitial pneumonitis and KL-6 serum concentrations of 414, 848, and 1217 U/ml; in contrast, all of the other 22 patients had normal CT scans and normal KL-6 concentrations (under 500 U/ml) (84c ). In the same study the limitations of carbon monoxide diffusing capacity in the diagnosis of amiodarone-induced lung disease (SEDA-15, 168) were again demonstrated. CT scanning can detect damage due to amiodarone, but it has also been suggested that high-resolution CT scanning may be able to detect iodine deposition from the drug (85c ). Of 16 patients taking long-term amiodarone, eight had severe respiratory and other symptoms and eight either had no symptoms or had only mild or chronic respiratory symptoms. All eight controls had negative high-resolution CT scans with no areas of high attenuation, while all eight cases had a least one high-attenuation lesion. Amiodarone can occasionally cause isolated lung masses (SEDA-15, 168) and two more cases have been reported. The first was associated with a vasculitis; the lesions resolved completely 4 months after amiodarone withdrawal (86A ). In the second an isolated mass was associated with multiple small nodules in both lungs; the lesions resolved completely 6 months after amiodarone withdrawal (87A ). Special senses Verticillate epithelial keratopathy due to amiodarone, in which there is whorl-shaped pigmentation of the cornea, has previously been proposed to be worsened by soft contact lenses (SEDA-15, 171). Two patients with hard contact lenses and amiodarone-associated keratopathy both complained of increased sensitivity to sunlight and were fitted with ultraviolet light-blocking lenses instead, as a precaution against further corneal damage; however, the authors did not think that the contact lenses had contributed to the damage (88A ). The eyes of 11 patients (eight men and three women) taking amiodarone have been compared with those of 10 healthy sex- and age-matched controls by confocal microscopy (89c ). All those taking amiodarone had bright, highly reflective intracellular inclusions in the

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epithelial layers, particularly in the basal cell layers. In eyes with advanced keratopathy there were bright microdots in the anterior and posterior stroma and on the endothelial cell layer. Keratocyte density in the anterior stroma was lower in the treated subjects than in the controls, and there was marked irregularity of the stromal nerve fibers. The authors concluded that in some patients taking long-term amiodarone corneal damage may penetrate deeper than has previously been suspected. Endocrine Amiodarone-induced thyroid disease has been reviewed in the light of a case in a 71-year-old man who was treated for hyperthyroidism with total thyroidectomy (90AR ), a 69-year-old man whose hyperthyroidism responded to carbimazole and prednisolone (91AR ), and a 74-year-old woman with hypothyroidism (91AR ). The frequency of thyroid disease in patients taking amiodarone has been retrospectively studied in 90 patients taking amiodarone 200 mg/day for a mean duration of 33 months (92c ). Hypothyroidism occurred in five patients and hyperthyroidism in 11. Hyperthyroidism became more frequent with time and was associated with recurrent supraventricular dysrhythmias in four of the 11 patients. The type of amiodarone-induced thyroid disease that occurs is said to depend on dietary iodine intake; in 229 patients taking long-term amiodarone hyperthyroidism was more common (9.6% vs. 2%) in West Tuscany, where dietary iodine intake is low, and hypothyroidism more common (22% vs. 5%) in Massachusetts, where iodine intake is adequate (SEDA-10, 148). However, other factors may play a part. In a retrospective inter-regional study in France there was a greater incidence of amiodaroneinduced hyperthyroidism in the maritime areas Aquitaine and Languedoc-Roussillon, and a greater incidence of amiodarone-induced hypothyroidism in Midi-Pyrenees, a non-maritime area, in which iodine intake is lower than in Languedoc-Roussillon (93c ). The treatment of amiodarone-induced hyperthyroidism can be problematic (SEDA-23, 199). It may not respond to thionamides (carbimazole, methimazole, or propylthiouracil); in that case corticosteroids can be added or alternatively potassium perchlorate can be used. It has been suggested that potassium perchlorate should be used in the treatment of type 1

206 hyperthyroidism (due to excess iodine and associated with normal or increased iodine uptake by the gland) and corticosteroids in the treatment of type 2 hyperthyroidism (due to a direct effect of the drug and associated with reduced iodine uptake by the gland). When five patients with type 2 amiodarone-induced hyperthyroidism were treated with a combination of an oral cholecystographic agent (sodium ipodate or sodium iopanoate) plus a thionamide (propylthiouracil or methimazole) after amiodarone withdrawal, all improved substantially within a few days and became euthyroid or hypothyroid in 15–31 weeks (94c ). Four of the five became hypothyroid and required longterm treatment with levothyroxine. In another patient taking amiodarone, with repeated episodes of ventricular fibrillation associated with hyperthyroidism, propylthiouracil plus prednisone was ineffective and subtotal thyroidectomy had to be performed (95A ). Thyroidectomy has been previously reported to be successful in some drug-resistant cases (SEDA115, 170; SEDA-17, 220). Skin Grey-blue discoloration of the skin during amiodarone therapy has been presumed to be due to lipofucsin deposition. However, it has also been suggested that amiodarone may block the maturation of melanosomes, in view of a case of discoloration associated with a reduced number of mature melanosomes and an increased number of premelanosomes in sunexposed areas of the skin, but normal numbers in non-exposed areas (96A ). Both amiodarone and minocycline can cause skin pigmentation, and this has been reported in a 70-year-old man who developed greyblue pigmentation on sun-exposed areas of his skin after taking amiodarone for 10 years and minocycline for 4 years (97A ). It has been suggested that the skin and mucosal toxicity of amiodarone may be enhanced by radiotherapy (SEDA-16, 178; SEDA-17, 221). However, in a retrospective review of 10 patients who took amiodarone when having external beam radiation therapy there were no unexpected acute sequelae (98c ). Fetotoxicity Fetal hypothyroidism can occur when a mother is given amiodarone during pregnancy (SEDA-17, 221). There has now been a report of two cases of hypothyroidism in

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neonates who had been given intravenous amiodarone as fetuses at 26 and 29 weeks and whose mothers had also taken it orally (99A ). The authors suggested that low dietary iodine intake by the mothers may have contributed, by enhancing the Wolff–Chaikoff effect. Risk factors Infancy The safety and efficacy of amiodarone for supraventricular tachycardia have been studied in 50 infants (mean age 1.0 month, 35 boys) (100C ). They had congenital heart disease (24%), congestive heart failure (36%), or ventricular dysfunction (44%). Six, who were critically ill, received a loading dose of intravenous amiodarone 5 mg/kg over 1 hour, and all took 20 mg/kg/day orally for 7–10 days, followed by 100 mg/day; if this failed to control the dysrhythmia, oral propranolol (2 mg/kg/day) was added. Follow-up was for an average of 16 months. Rhythm control was achieved in all patients. Growth and development were normal. The higher dose of amiodarone was associated with an increase in the QTc interval to over 0.44 seconds, but there were no dysrhythmias. Two infants had hypotension during intravenous loading, as has previously been reported in infants (SEDA-19, 194). AsT and AlT activities and TSH concentrations all increased, but remained within their reference ranges. There were no adverse effects that necessitated drug withdrawal. Anesthesia It has been reported that there is an increased risk of adverse reactions to amiodarone in patients undergoing anesthesia (SEDA-15, 171). However, in a retrospective survey of 12 patients who underwent anesthesia for urgent thyroidectomy due to amiodarone there were no anesthetic complications or deaths (101c ). Drug administration route The therapeutic effect of amiodarone occurs more quickly after intravenous than after oral administration, perhaps because of an effect of the diluent, polysorbate 80, that is used in the intravenous formulation (SED-14, 540). Amiodarone certainly has different electrophysiological effects when it is given intravenously. For example, intravenous amiodarone prolongs the AH interval, while oral amiodarone prolongs atrial and ventricular refractory periods and the HV interval (102C ). Furthermore, the blocking effects

Positive inotropic drugs and drugs used in dysrhythmias

of amiodarone on sodium and calcium channels and its beta-adrenoceptor blocking action occur earlier than its Class III action (103R ). Now an anecdotal report of torsade de pointes after both intravenous and oral administration of amiodarone on different occasions has underlined this difference (104A ). • A 70-year-old woman with dilated cardiomyopathy, ventricular tachydysrhythmia, and a QTc interval of 0.49 seconds was given intravenous amiodarone 240 mg over 15 minutes and 30 minutes later developed a junctional escape rhythm (48 beats/min) with QTc prolongation to 0.68 seconds; 8 hours later she developed torsade de pointes. A few years later she was given oral amiodarone 100 mg/day and 7 weeks later presented with congestive heart failure. Her QTc interval was prolonged (0.50 seconds) and increased further to 0.64 seconds after the addition of dopamine 3 micrograms/kg/min; torsade de pointes again developed. Amiodarone was withdrawn and the QTc interval shortened, but she continued to have recurrent episodes of sustained ventricular tachycardia.

The authors suggested that torsade de pointes induced by intravenous amiodarone depended on heart rate during a bout of bradycardia, while that after oral amiodarone depended on increased sympathetic nervous system activity, and that therefore different electrophysiological mechanisms had been at play. However, it is by no means clear from their description of this case that that was so. They did not report plasma concentrations of amiodarone or desethylamiodarone, its active metabolite. Drug overdose The features of amiodarone overdose and its management have been reviewed (105R ). Drug interactions Both amiodarone and cyclophosphamide can cause lung damage. Interstitial pneumonitis has been reported in a 59-year-old man, who had taken amiodarone for 18 months, 18 days after a single dose of cyclophosphamide; 1 year before he had also received six cycles of chemotherapy containing cyclophosphamide, vincristine, and prednisone, followed by four cycles of cisplatin, cytarabine, and dexamethasone (106A ). The authors suggested that the lung damage had been due to the cyclophosphamide, enhanced by the presence of amiodarone, but in view of the fact that previous similar exposure on six occasions had not resulted in the same effect, it is perhaps more

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likely that this was a long-term adverse effect of amiodarone alone. The presence of foamy histiocytes in the lung biopsy was consistent with this interpretation (SEDA-15, 168). It is true, however, that lung damage due to amiodarone is usually of a more insidious onset than was reported in this case, although a more rapid onset can occur in patients who are given high concentrations of inspired oxygen. On the other hand, lung damage has occasionally been reported to occur rapidly (82A ).

Aprindine

(SED-14, 541; SEDA-24, 210)

In a comparison of oral aprindine and propafenone in 32 patients (25 men and 7 women, aged 43–82) with paroxysmal or persistent atrial fibrillation, aprindine was effective in five of 29 and propafenone in six of 28; adverse effects were not reported (107c ).

Cibenzoline

(SED-14, 541; SEDA-23, 200; SEDA-24, 210; SEDA-25, 217)

Cardiovascular Cibenzoline is an antidysrhythmic drug of Class Ia, with some additional properties of drugs of Class III and Class IV. It can therefore cause cardiac dysrhythmias, as has been reported in a 60-year-old man with hypertrophic cardiomyopathy (108A ). In a 72-year-old woman cibenzoline was associated with left bundle branch block and heart failure (109A ). Excess cibenzoline accumulation was suspected, because of reduced renal function, but plasma cibenzoline concentrations were not reported. Metabolism Cibenzoline can cause hypoglycemia (SEDA-18, 204) and this has again been reported (110A ). The patient, a 65-yearold woman, was also taking alacepril, and the authors suggested that the hypoglycemia was associated with combined use of cibenzoline with an ACE inhibitor, since ACE inhibitors may increase insulin sensitivity (SED-14, 640). Drug overdose Fatal intoxication with cibenzoline has been reported in an 83-year-old man (111A ).

208

Disopyramide

(SED-14, 543; SEDA-23, 200; SEDA-24, 211; SEDA-25, 217)

Respiratory Pneumonitis has been attributed to disopyramide in a 72-year-old man; the symptoms began soon after the first dose (112A ). Bronchoalveolar lavage fluid contained a high percentage of lymphocytes (65%) and a high CD4 : CD8 ratio (69 : 1). The results of a lymphocyte stimulation test suggested that disopyramide had been responsible. Metabolism Hypoglycemia has again been reported in a patient taking disopyramide (113A ). Unusually, the patient, a 70-year-old woman, had type 2 diabetes mellitus, although this has been reported before (SEDA-6, 180).

Dofetilide Dofetilide is a pure Class III antidysrhythmic drug, without actions of any other class. It was developed following the observation that bis(arylalkyl)amines with methanesulfonamido moieties on both aryl groups prolong the cardiac action potential without significantly altering the maximum rate of depolarization (114ER ). The pharmacology, clinical pharmacology, uses, adverse effects, and interactions of dofetilide have been reviewed (115R –121R ). Pharmacology Dofetilide is a highly selective blocker of the rapidly activating component of the inward rectifier potassium channel, IKr (122E –128E ). It therefore delays ventricular repolarization, which becomes less heterogeneous (129E ), and prolongs the action potential duration and effective refractory period (126C , 130C , 131c ); it has the same effects in ventricular muscle in dilated cardiomyopathy and chronic ischemic cardiomyopathy (122E ). It has greater affinity for atrial than ventricular tissues in animals (132E ), but probably not in man (126C , 130C ). It preferentially blocks open channels and has Group 3 actions (SEDA-25, 209), with slow-onset kinetics (133E ) and an increased likelihood of being prodysrhythmic at slower heart rates (134E ). Dofetilide causes a dose-related and plasma concentration-related prolongation of the QTc

Chapter 17

J.K. Aronson

interval (126C , 130C , 131C , 135C –138C , 139c ), and either reduces QTc dispersion (138C ) or has no effect on it (140C , 141C ). The effects on the QTc interval are rate-dependent, being greater at slower heart rates (142C ). Dofetilide does not usually broaden the QRS complex, but this was reported (and published twice) in a single patient with atrial fibrillation, in whom it was attributed to aberrant conduction (143A , 144A ). During repeated oral administration of dofetilide 1.0–2.5 mg/day for 5 days the effect on the QT interval was slightly greater on day 1 than on day 5 at a range of plasma concentrations of about 1–4 ng/ml; this observation suggests the occurrence of tolerance, but in that case one would have expected a clockwise hysteresis loop in the effect concentration curve, and no hysteresis was seen either after a single dose or at steady state (137C ). Dofetilide has a small positive inotropic effect in animal hearts (145E , 146E ). In a doubleblind placebo-controlled study of oral dofetilide 125, 250, or 500 mg bd for the maintenance of sinus rhythm after cardioversion of sustained atrial fibrillation or flutter in 201 patients there were small changes in echocardiographic measures of atrial contractility, but no changes in stroke volume or cardiac output (147C ). Clinical pharmacology The pharmacokinetics of dofetilide are linear after single oral doses of 2–10 micrograms/kg (148C , 149C ) and repeated doses of 1.0–2.5 mg/day (137C ). Dofetilide is well absorbed (about 90%) after oral administration (136C , 148C –150C ). Its absorption is relatively slow and peak concentrations are not reached for 1–2.5 hours; absorption is slower after food. It is a low clearance drug, with a clearance rate of about 6 ml/min/kg, and has a volume of distribution of about 3 l/kg (135C , 150C ). It is mostly excreted unchanged by the kidneys, with a half-life of about 8 hours. Its clearance is therefore roughly proportional to creatinine clearance, particularly at high rates of clearance. A small proportion is metabolized in the liver by CYP3A4 to inactive metabolites (151C ). In a pharmacokinetic–pharmacodynamic study in 10 healthy volunteers intravenous dofetilide 0.5 mg caused a mean maximum prolongation of the QTc interval of 121 msec and the mean plasma concentration associated with half-maximal effect was 2.2 ng/ml (150C ).

Positive inotropic drugs and drugs used in dysrhythmias

Uses Dofetilide has been used to convert atrial fibrillation and atrial flutter to sinus rhythm, in maintaining sinus rhythm thereafter, in suppressing paroxysmal supraventricular tachycardia, inducible atrioventricular nodal re-entry tachycardia, and inducible sustained ventricular tachycardia, in suppressing the dysrhythmias of the Wolff–Parkinson–White syndrome, and in facilitating conversion of ventricular fibrillation. Open clinical studies In 19 patients with atrial fibrillation and five with atrial flutter, dofetilide 2.5–8.0 micrograms/kg caused conversion to sinus rhythm in 14 (10 with atrial fibrillation and four with atrial flutter) (152c ). In patients with sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation, who had previously been unsuccessfully treated with 0–7 other drugs, intravenous dofetilide 3–15 micrograms/kg suppressed or slowed inducible ventricular tachycardia in 17 of 41 patients, compared with none of nine patients who received only 1.5 micrograms/kg (131c ). Intravenous dofetilide 2.5–5.0 micrograms/kg produced sinus rhythm in seven patients with paroxysmal atrial fibrillation of recent onset (under 7 days) and terminated paroxysmal supraventricular tachycardia in four of six patients (153c ). In patients with electrically inducible atrioventricular re-entrant tachycardia intravenous dofetilide 1.5–15 micrograms/kg had no effect on tachycardia inducibility at the two lower doses but prevented the reinduction of tachycardia at the three higher doses in 11 of 31 patients (154c ). Placebo-controlled studies Conversion of atrial fibrillation and flutter In a crossover placebo-controlled study in 16 patients with recent onset atrial fibrillation, cardioversion was achieved in two of six patients who received dofetilide 8 micrograms/kg and in two of nine who received 12 micrograms/kg (155C ). None cardioverted with placebo. However, the average duration of atrial fibrillation was 35 days in those who cardioverted with dofetilide and 83 days in those who did not. The authors concluded that dofetilide had only limited effect in cardioverting atrial fibrillation of moderate duration.

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In a double-blind, placebo-controlled study 98 patients, who developed atrial fibrillation/flutter within 1–6 days after coronary artery bypass graft surgery, were given dofetilide 4 or 8 micrograms/kg intravenously over 15 min (156C ). Eight of 33 patients converted to sinus rhythm after placebo, 12 of 33 after dofetilide 4 micrograms/kg, and 14 of 32 after dofetilide 8 micrograms/kg. In a double-blind, placebo-controlled study in patients with sustained atrial fibrillation (n = 75) or atrial flutter (n = 16), dofetilide 8 micrograms/kg terminated the dysrhythmia in nine of 29 patients, compared with only four of 32 who received 4 micrograms/kg and none of 30 who received placebo (157C ). Patients with atrial flutter had a greater response to dofetilide (six of 11) than those with atrial fibrillation (five of 49). In a placebo-controlled study in patients with atrial fibrillation or atrial flutter with a median dysrhythmia duration of 62 (range 1– 180) days, there was conversion to sinus rhythm in 20 of 66 patients given dofetilide, compared with one of 30 patients given placebo (36C ). The conversion rate was higher in atrial flutter (7 of 11 patients) than in atrial fibrillation (13 of 55). In a double-blind placebo-controlled study in 325 patients with atrial fibrillation or flutter cardioversion rates for dofetilide 125, 250, and 500 micrograms bd were 6.1%, 9.8%, and 30% respectively, compared with 1.2% with placebo (158C ). The probabilities of remaining in sinus rhythm at 1 year with dofetilide 125, 250, and 500 micrograms bd were 0.40, 0.37, and 0.58 respectively, and 0.25 for placebo. In a double-blind, placebo-controlled study in 69 patients with atrial fibrillation or flutter, intravenous dofetilide 2–8 micrograms/kg caused conversion to sinus rhythm in 16 of 51 patients, compared with one of 18 who were given placebo; conversion of atrial flutter occurred in five of seven who were given dofetilide compared with none of three who were given placebo (159CA ). In a randomized, placebo-controlled, crossover study in 15 men, mean age 34 (range 18–63) years, with Wolff–Parkinson–White syndrome and atrial fibrillation or atrioventricular re-entrant tachycardia induced electrophysiologically, six of ten patients who were given dofetilide converted to sinus rhythm, compared with one of five who were given placebo (160C ). There were no dysrhythmias.

210 Ventricular tachydysrhythmias In a placebo-controlled study, sustained ventricular tachycardia or fibrillation, reproducibly inducible electrophysiologically, was no longer inducible in eight of 18 patients who were given intravenous dofetilide 0.1–8.0 ng/ml, compared with one of six patients who received placebo (161C ). In a randomized, double-blind, placebocontrolled study in 32 patients with ventricular extra beats (more than 30/hour on two consecutive 24-hour Holter recordings while drug free and more than 50/hour during 2-hour telemetric electrocardiography), dofetilide 7.5 micrograms/kg produced an 83% and placebo a 2.9% median reduction in ventricular extra beats (162C ). Sudden death The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) study comprised two studies in patients at high risk of sudden death: one in patients with congestive heart failure and one in patients with acute myocardial infarction within the previous 7 days (163S ). In the congestive heart failure study, 1518 patients with symptomatic congestive heart failure and severe left ventricular dysfunction were recruited at 34 Danish hospitals; 762 were randomized double-blind to dofetilide and 756 to placebo (164C ). After 1 month, 22 of 190 patients with atrial fibrillation at baseline had sinus rhythm restored by dofetilide, compared with only three of 201 who took placebo. Dofetilide was also significantly more effective than placebo in maintaining sinus rhythm (hazard ratio for the recurrence of atrial fibrillation = 0.35; CI = 0.22, 0.57). Dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio = 0.75; CI = 0.63, 0.89). During a median follow-up of 18 months, 311 patients taking dofetilide and 317 patients taking placebo died (hazard ratio = 0.95; CI = 0.81, 1.11). In the myocardial infarction study, 1510 patients with severe left ventricular dysfunction after myocardial infarction were recruited in 37 Danish coronary-care units; 749 were randomized double-blind to dofetilide and 761 to placebo (165C ). There were no significant differences between dofetilide and placebo in allcause mortality or total dysrhythmic deaths. Dofetilide was significantly better than placebo at restoring sinus rhythm in patients with atrial fibrillation or flutter.

Chapter 17

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Comparison studies with other antidysrhythmic drugs Amiodarone In a comparison of intravenous dofetilide (8 micrograms/kg; n = 48), amiodarone (5 mg/kg; n = 50), or placebo (n = 52) in converting atrial fibrillation or flutter to sinus rhythm in 150 patients, sinus rhythm was restored in 35%, 4%, and 4% respectively (166C ). Flecainide In a non-randomized comparison of flecainide (2 mg/kg; n = 11) and dofetilide (8 micrograms/kg; n = 10) in patients with atrial flutter, only one patient given flecainide converted to sinus rhythm compared with seven of the 10 patients given dofetilide (167c ). Propafenone In a randomized, placebocontrolled, parallel-group comparison of oral dofetilide 500 micrograms bd, propafenone 150 mg tds, or placebo in preventing the recurrence of paroxysmal supraventricular tachycardia in 122 symptomatic patients, the respective probabilities of remaining free of episodes of paroxysmal supraventricular tachycardia were 50%, 54%, and 6%; both dofetilide and propafenone also reduced the frequency of episodes (median numbers 1, 0.5, and 5 respectively) (168C ). Sotalol In a double-blind, randomized, crossover comparison of oral dofetilide 500 micrograms bd with sotalol 160 mg bd in 128 patients with ischemic heart disease and inducible sustained ventricular tachycardia, 46 patients responded to dofetilide and 43 to sotalol; however, only 23 patients responded to both dofetilide and sotalol (169C ). Adverse effects Cardiovascular adverse effects of dofetilide are the most troublesome. Other common effects have included mild headache, dizziness, dyspepsia, nausea, and vomiting (169C ). Cardiovascular Because dofetilide prolongs the QTc interval, there is a risk of ventricular tachydysrhythmias, which have often been reported, after both intravenous and oral administration. In 154 patients with implantable cardioverter–defibrillators randomly assigned to dofetilide or placebo, there were pause-dependent runs of polymorphic ventricular tachycardia in 15 of the 87 patients who received dofetilide and in only five of the 87 who received placebo (170C ). There were five early events (at less than 3 days of therapy), all torsade de pointes

Positive inotropic drugs and drugs used in dysrhythmias

in patients taking dofetilide. There were 15 late events, 10 with dofetilide and five with placebo. The median time to a late event was 22 (range 6–107) days for dofetilide and 99 (34–207) days for placebo. In the DIAMOND study in congestive heart failure there were 25 cases of torsade de pointes in the dofetilide group (3.3%) compared with none in the placebo group (164C ). In the DIAMOND myocardial infarction study there were seven cases of torsade de pointes (0.93%), all in those who were given dofetilide (165C ). In a double-blind, placebo-controlled study in 325 patients with atrial fibrillation or atrial flutter randomized to dofetilide 125, 250, or 500 micrograms bd or placebo there were two cases of torsade de pointes, 1 on day 2 and the other on day 3 (0.8% of all patients given the active drug); there was one sudden cardiac death, classified as prodysrhythmic, on day 8 (0.4% of all patients given the active drug). The authors recommended that dosage adjustment based on QTc interval and renal function would minimize the small but not negligible prodysrhythmic risk of dofetilide. In 128 patients who received dofetilide and sotalol in a crossover study, there were treatment-related adverse events in 2.3% of the patients who received dofetilide and 8.6% of those who received sotalol (169C ). Three patients who took dofetilide had torsade de pointes. In a comparison of intravenous dofetilide (8 micrograms/kg; n = 48), amiodarone (5 mg/kg; n = 50), or placebo (n = 52) in converting atrial fibrillation or flutter to sinus rhythm in 150 patients, two patients given dofetilide had non-sustained ventricular tachycardias; four had torsade de pointes, in one case requiring electrical cardioversion (166C ). • In one of 10 healthy men given intravenous dofetilide 0.5 micrograms/kg there was prolongation of the QTc interval from 451 to 808 msec 5 minutes after the end of the infusion; this was associated with five beats of polymorphic ventricular tachycardia, several multifocal ventricular extra beats, and ventricular couplets and triplets, all within 10 minutes after the end of the infusion (149cA ). • In a 37-year-old woman with atrial flutter with 1 : 1 conduction and partial right bundle branch block, intravenous dofetilide 5 micrograms/kg given over 5 minutes suppressed the atrioventricular nodal block to 2 : 1 or 3 : 1 but also caused complete right bundle branch block and QT interval prolongation (171A ).

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• Self-limiting torsade de pointes developed in a 67year-old man who was given 12.8 micrograms/kg (plasma concentration 7.1 ng/ml) in an open study; the QTc interval was prolonged to over 600 msec (131cA ). This patient had stopped taking amiodarone 1 month before the administration of dofetilide, and that may have contributed to the prolongation of the QTc interval. • A woman with atrial fibrillation developed torsade de pointes after receiving intravenous dofetilide 6 micrograms/kg (plasma concentration 26 ng/ml) (155C ). • A patient with atrial fibrillation received intravenous dofetilide 8 micrograms/kg and developed torsade de pointes before reverting to sinus rhythm (155C ). • One of 18 patients with sustained ventricular tachycardia or fibrillation, reproducibly inducible electrophysiologically, developed torsade de pointes after receiving intravenous dofetilide 8 micrograms/kg (plasma concentration 5.3 ng/ml) (161C ). • Short episodes of aberrant ventricular conduction and ventricular tachycardia occurred in three of 32 patients with atrial fibrillation who were given dofetilide 8 micrograms/kg (156C ). • Torsade de pointes occurred in two of 62 patients with atrial tachydysrhythmias who received dofetilide 4 or 8 micrograms/kg; two other patients had ventricular extra beats associated with prolongation of the QTc interval (157C ). • In a placebo-controlled study of the effect of dofetilide 8 micrograms/kg in converting atrial fibrillation or flutter, transient torsade de pointes occurred in two men, aged 57 and 67, with prolongation of the QTc interval from 370 and 420 msec to 450 and 510 msec respectively (36CA ). • A 58-year-old woman developed torsade de pointes with prolongation of the QTc interval to 490 msec after receiving intravenous dofetilide 4.3 micrograms/kg; she responded to intravenous magnesium sulfate plus isoprenaline (159CA ).

Other cardiac dysrhythmias that have been reported have included episodes of junctional rhythm with bundle branch block, spontaneous atrioventricular re-entrant tachycardia, and sustained supraventricular tachycardia (154c ). The risk of death in patients with supraventricular dysrhythmias taking dofetilide has been studied in a systematic review of randomized controlled trials (172M ). After adjusting for the effects of dysrhythmia diagnosis, age, sex, and structural heart disease, the hazard ratio was 1.1 (CI = 0.3, 4.3). Hypotension occasionally occurs after intravenous dofetilide (154c ). Drug interactions Digoxin In 14 healthy men dofetilide 250 micrograms bd for 5 days had no effect on the pharmacokinetics of digoxin

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at a steady-state trough concentration of 1.0 ng/ml (35C ). However, in a placebo-controlled study in patients with atrial fibrillation or atrial flutter, conversion to sinus rhythm in patients given dofetilide was more likely if they were also given digoxin (36C ), suggesting that there may be a pharmacodynamic interaction. Histamine (H2 ) receptor antagonists In a randomized, placebo-controlled study of the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide 500 micrograms in 20 healthy men, ranitidine 150 mg bd did not affect the pharmacokinetics or pharmacodynamics of dofetilide, but there was a dose-dependent increase in exposure to dofetilide with cimetidine (173C ). With cimetidine 100 and 400 mg bd the AUC of dofetilide increased by 11% and 48%, the maximum plasma dofetilide concentration increased by 11% and 29%, renal clearance fell by 13% and 33%, and non-renal clearance by 5% and 21%; dofetilide-induced prolongation of the QTc interval was increased by 22% and 33%. The authors suggested that cimetidine inhibited renal tubular dofetilide secretion, an effect that is specific to cimetidine in its class. Cimetidine should be avoided in patients taking dofetilide. Verapamil Pharmacokinetic and pharmacodynamic interactions between dofetilide 0.5 mg bd and verapamil 80 mg tds have been studied in 12 healthy men (174C ). At steady state verapamil increased the peak plasma concentration of dofetilide from 2.40 to 3.43 ng/ml, without other pharmacokinetic effects. This was accompanied by a small increase in the prolongation of the QTc interval produced by dofetilide alone, from 20 to 26 msec. Although this small effect is unlikely to be of clinical significance, it would be wise to avoid verapamil in patients taking dofetilide.

Flecainide

(SED-14, 545; SEDA-24, 211;

SEDA-25, 217) Cardiovascular Cardiac dysrhythmias are less common with flecainide (Class Ic) than with other antidysrhythmic drugs of Class I. When dysrhythmias occur, prolongation of the QT interval is an important mechanism, and in a recent report syncope occurred in a

J.K. Aronson

patient whose QRS complex duration was prolonged (175A ). In another patient, a 67-year-old woman taking flecainide 150 mg bd, widening of the QRS complex occurred during exercise; the effect did not occur at rest or with a dose of 50 mg bd (176A ). Hypokalemia can increase the risk of torsade de pointes with flecainide, as with other antidysrhythmic drugs. Torsade de pointes has been attributed to mosapride (which is related to cisapride) and flecainide in a 68-year-old man with a plasma potassium concentration of 3.2 mmol/l and prolongation of the QTc interval from 0.48 to 0.56 seconds (177A ). His plasma flecainide concentration was just above the target range at 1013 ng/ml, but the mosapride concentration was not reported. The authors speculated that mosapride may have inhibited the metabolism of flecainide by CYP2D6. In a retrospective analysis of 24 patients who developed atrial flutter while taking flecainide (n = 12) or propafenone (n = 12), the electrocardiogram was classified as typical atrial flutter in 13 cases, atypical atrial flutter in eight, or coarse atrial fibrillation in three (178c ). Counterclockwise atrial flutter was the predominant dysrhythmia. The acute results of ablation suggested that the flutter circuit was located in the right atrium and that the isthmus was involved in the re-entry mechanism. There was better long-term control of recurrent atrial fibrillation in patients with typical atrial flutter (85%) compared with atypical atrial flutter (50%). The authors suggested that patients who develop coarse drug-induced atrial fibrillation may not be candidates for ablation. Antidysrhythmic drugs increase the pacing threshold, but failure to capture is a rare consequence. It has, however, been reported twice with flecainide (179A , 180A ). The Brugada syndrome is partial right bundle branch block with ST segment elevation in the right precordial leads of the electrocardiogram; it is due to an abnormality of sodium channels and occurs in 0.05–0.1% of the population; some cases are inherited (181R ). Flecainide can bring out Brugada-type changes on the electrocardiogram (182c , 183C , 184C ). Sensory systems Ocular adverse effects of flecainide have included corneal deposits in two patients, due to deposition of flecainide (185A ). In 38 patients taking flecainide 100– 300 mg/day there were brown corneal epithelial

Positive inotropic drugs and drugs used in dysrhythmias

deposits in 11 eyes, dryness in eight eyes, and slight blurring of vision on lateral gaze in four patients (186c ). Four patients had local symptoms, including tearing, itching, and burning. Color vision, contrast sensitivity, and visual fields were all unaffected. Drug overdose Death has been reported in a two patients who took flecainide (187A ). The post-mortem femoral blood flecainide concentrations were 5.4 and 1.2 mg/l (target range 0.2–1.0).

Mexiletine

(SED-14, 547; SEDA-23, 200; SEDA-24, 212; SEDA-25, 219) Sensory systems In addition to its use as an antidysrhythmic drug, mexiletine has also been used in the treatment of various types of neuropathic pain and dystonias. In two patients with neuropathic pain and pre-existing ocular disease, mexiletine caused persistent ophthalmic changes (188A ). • A 39-year-old woman took mexiletine 300 mg tds for 3 days and developed transient blindness with residual reduced visual acuity due to an acute pigmentary retinopathy. Her vision improved markedly after withdrawal of mexiletine, but when she restarted it she developed clouding of the vision, which resolved again on withdrawal. The pigmentary changes persisted. • A man with a history of glaucoma took mexiletine 300 mg tds and developed worsening visual acuity. Mexiletine was withdrawn and he took carbamazepine 200 mg/day instead. However, he started to see red and green spots. The serum carbamazepine concentration was below that usually associated with visual disturbances. No structural abnormalities were detected.

Skin Mexiletine rarely causes skin reactions, but another case of acute exanthematous pustular eruption has recently been reported in a 56-year-old man who had taken mexiletine 300 mg/day for 1 month (189A ). There was mild liver dysfunction. Patch tests with mexiletine 10 and 20% were subsequently positive, but a lymphocyte stimulation test was negative. Drug interactions Mexiletine is metabolized by CYP2D6, CYP1A2, and CYP3A4; fluvoxamine inhibits CYP1A2. It is not surprising therefore that fluvoxamine 50 mg bd for 7

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days increased the Cmax and AUC of a single oral dose of mexiletine 200 mg in six healthy Japanese men (190C ).

Moricizine (moracizine, ethmozine) (SED-14, 548; SEDA-21, 202) In a retrospective study of 85 patients with recurrent atrial fibrillation (mean left atrial size 46 mm, mean left ventricular ejection fraction 0.51), 69 of whom had structural heart disease, moricizine (mean dose 609 mg/day) was withdrawn because of unacceptable adverse effects in 6 patients: frequent ventricular extra beats and short runs of non-sustained ventricular tachycardia (n = 2); significant widening of the QRS complex (n = 1); first-degree heart block (n = 1); a significant rise in liver enzymes (n = 1); and a severe rash (n = 1) (191c ). Six patients developed transient adverse effects that resolved spontaneously without withdrawal: brief self-limiting episodes of atrial flutter (n = 2); a small increase in blood pressure (n = 1); generalized weakness and tremor (n = 2); and reduced appetite (n = 1).

Procainamide

(SED-14, 548; SEDA-23,

201; SEDA-24, 213) Immunologic Thymus function in 10 patients with symptomatic procainamide-induced lupus has been compared with that in 13 asymptomatic patients who only developed druginduced autoantibodies (192c ). Newly generated T cells were detected in all the subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, there was a correlation between the level of T cell receptor rearrangement excision circles in peripheral lymphocytes and serum IgG antichromatin antibody activity in patients with drug-induced lupus. These results support the hypothesis that the thymus is important in the genesis of drug-induced lupus-like syndrome and that the production of autoreactive T cells starts in the thymus when procainamide hydroxylamine alters T cell tolerance.

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Propafenone

(SED-14, 551; SEDA-23, 202; SEDA-24, 214; SEDA-25, 220) In a randomized double-blind, placebo-controlled comparison of propafenone (mean dose 13 mg/kg/day; n = 102) and sotalol (mean dose 3 mg/kg/day; n = 106) in maintaining sinus rhythm after conversion of recurrent symptomatic atrial fibrillation in 300 patients, efficacy was comparable (193C ). Tolerable adverse effects in those who took propafenone were gastrointestinal discomfort (n = 15), neurological disturbances (n = 9), a metallic taste (n = 4), and generalized weakness (n = 1); nine patients withdrew owing to adverse effects, four with gastrointestinal disorders, three with dizziness, and two with headache; there were no prodysrhythmias. Cardiovascular The adverse effects of a single oral dose of propafenone for cardioversion of recent-onset atrial fibrillation have been evaluated in a systematic review (194M ). The adverse effects were transient dysrhythmias (atrial flutter, bradycardia, pauses, and junctional rhythm), reversible widening of the QRS complex, transient hypotension, and mild non-cardiac effects (nausea, headache, gastrointestinal disturbances, dizziness, and paresthesia). Risk factors Poor and extensive oxidation phenotypes for CYP2D6, which metabolizes propafenone, have been studied in 42 patients, aged 36–75 years, with paroxysmal atrial fibrillation (195C ). Efficacy was 100% in poor metabolizers, 61% in extensive metabolizers, and 0% in very extensive metabolizers. There was a significant correlation between oxidation phenotype and the ability to maintain sinus rhythm. Drug overdose The mortality from propafenone overdose is 23%, according to a retrospective series of 120 patients in Germany over 14 years (196R ). Severity was related to cardiac conduction disorders and cardiac hyperexcitability. Seizures have been reported in a case of overdose (197A ). • A 22-year-old woman took an overdose of propafenone (amount unknown) and developed tetany and then generalized convulsions requiring intra-

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venous clonazepam. She had a low blood pressure and first-degree atrioventricular block associated with prolonged intraventricular conduction. She was intubated and given intravenous fluids, equimolar sodium lactate, dopamine, and adrenaline. Her cardiac conduction returned to normal.

About 60 cases of propafenone poisoning have been reported. Even low doses can lead to serious poisoning. Some symptoms, such as gastrointestinal or neurological symptoms, are misleading. Cardiovascular abnormalities include bradycardia, atrioventricular block, abnormal intraventricular conduction, shock, and electromechanical dissociation. The simultaneous presence of neurological symptoms (especially seizures) and abnormal cardiac conduction suggests serious poisoning. Treatment is symptomatic. Lactate may be required for abnormal intraventricular conduction. Plasma exchange has been successfully used to treat propafenone overdose (198A ). • An 18-year-old woman took 35 tablets of propafenone, 300 mg each. She had dilated, non-reactive pupils and greatly increased activity of neuronspecific enolase. She had atrioventricular and intraventricular conduction disorders, and repeated resuscitation was necessary. Propafenone was eliminated by plasma exchange, and the conduction disturbances disappeared rapidly during treatment.

Quinidine

(SED-14, 552; SEDA-23, 202; SEDA-24, 214; SEDA-25, 221) Skin In a review of drug-induced skin disorders, from a list of 26 drugs or groups of drugs, only quinidine was mentioned of all antidysrhythmic drugs (199R ). The reaction rate was quoted as 12 per 1000 recipients. Drug interactions Stimulation of CYP3A4 by quinidine increased the 4′ -hydroxylation of S-warfarin and the 10-hydroxylation of Rwarfarin in human liver microsomes and intact hepatocytes (200E ). The increases were concentration-dependent and respectively maximized at about three and five times control values. In contrast, warfarin did not affect the 3-hydroxylation of quinidine. These results are consistent with previous findings suggesting that there is more than one binding site on CYP3A4 through which interactions can occur.

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effects of the new class III antiarrhythmic agents d-sotalol and dofetilide. J Cardiovasc Pharmacol 1996; 27: 571–7. 129. Gwilt M, King RC, Milne AA, Solca AM. Dofetilide, a new class III antiarrhythmic agent, reduces pacing induced heterogeneity of repolarisation in vivo. Cardiovasc Res 1992; 26: 1102–8. 130. Sedgwick ML, Dalrymple I, Rae AP, Cobbe SM. Effects of the new class III antiarrhythmic drug dofetilide on the atrial and ventricular intracardiac monophasic action potential in patients with angina pectoris. Eur Heart J 1995; 16: 1641–6. 131. Yuan S, Wohlfart B, Rasmussen HS, Olsson S, Blomström-Lundqvist C. Effect of dofetilide on cardiac repolarization in patients with ventricular tachycardia. A study using simultaneous monophasic action potential recordings from two sites in the right ventricle. Eur Heart J 1994; 15: 514–22. 132. Baskin EP, Lynch JJ. Differential atrial versus ventricular activities of class III potassium channel blockers. J Pharmacol Exp Ther 1998; 285: 135–42. 133. Snyders DJ, Chaudhary A. High affinity open channel block by dofetilide of HERG expressed in a human cell line. Mol Pharmacol 1996; 49: 949–55. 134. Sager PT. Frequency-dependent electrophysiologic effects of dofetilide in humans. Circulation 1995; 92: 1774. 135. Sedgwick M, Rasmussen HS, Walker D, Cobbe SM. Pharmacokinetic and pharmacodynamic effects of UK-68,798, a new potential class III antiarrhythmic drug. Br J Clin Pharmacol 1991; 31: 515–19. 136. Tham TC, MacLennan BA, Burke MT, Harron DW. Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK68,798) in humans. J Cardiovasc Pharmacol 1993; 21: 507–12. 137. Allen MJ, Nichols DJ, Oliver SD. The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing. Br J Clin Pharmacol 2000; 50: 247–53. 138. Boriani G, Biffi M, De Simone N, Bacchi L, Martignani C, Bitonti F, Zannoli R, Butrous G, Branzi A. Repolarization changes in a double-blind crossover study of dofetilide versus sotalol in the treatment of ventricular tachycardia. PACE Pacing Clin Electrophysiol 2000; 23: 1935–8. 139. Bashir Y, Thomsen PE, Kingma JH, Møller M, Wong C, Cobbe SM, Jordaens L, Campbell RW, Rasmussen HS, Camm AJ, for the Dofetilide Arrhythmia Study Group. Electrophysiologic profile and efficacy of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with sustained monomorphic ventricular tachycardia. Am J Cardiol 1995; 76: 1040–4. 140. Sedgwick ML, Rasmussen HS, Cobbe SM. Effects of the class III antiarrhythmic drug dofetilide on ventricular monophasic action potential duration and QT interval dispersion in stable angina. pectoris. Am J Cardiol 1992; 70: 1432–7. 141. Demolis JL, Funck-Brentano C, Ropers J, Ghadanfar M, Nichols DJ, Jaillon P. Influence of dofetilide on QT-interval duration and dispersion at various heart rates during exercise in humans. Circulation 1996; 94: 1592–9.

220 142. Lande G, Maison-Blanche P, Fayn J, Ghadanfar M, Coumel P, Funck-Brentano C. Dynamic analysis of dofetilide-induced changes in ventricular repolarization. Clin Pharmacol Ther 1998; 64: 312–21. 143. Crijns HJ, Kingma JH, Gosselink AT, Lie K. Comparison in the same patient of aberrant conduction and bundle branch reentry after dofetilide, a new selective class III antiarrhythmic agent. PACE Pacing Clin Electrophysiol 1993; 16: 1006–16. 144. Crijns HJ, Kingma JH, Gosselink AT, Dalrymple HW, De Langen CD, Lie K. Sequential bilateral bundle branch block during dofetilide, a new class III antiarrhythmic agent, in a patient with atrial fibrillation. J Cardiovasc Electrophysiol 1993; 4: 459–66. 145. Abrahamsson C, Duker G, Lundberg C, Carlsson L. Electrophysiological and inotropic effects of H 234/09 (almokalant) in vitro: a comparison with two other novel IK blocking drugs, UK-68,798 (dofetilide) and E-4031. Cardiovasc Res 1993; 27: 861–7. 146. Doggrell SA, Nand V. Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats. J Pharm Pharmacol 2002; 54: 707–15. 147. DeCara JM, Pollak A, Dubrey S, Falk RH. Positive atrial inotropic effect of dofetilide after cardioversion of atrial fibrillation or flutter. Am J Cardiol 2000; 86: 685–8. 148. Gemmill JD, Howie CA, Meredith PA, Kelman AW, Rasmussen HS, Hillis WS, Elliott HL. A dose-ranging study of UK-68,798, a novel class III anti-arrhythmic agent, in normal volunteers. Br J Clin Pharmacol 1991; 32: 429–32. 149. Tham TC, MacLennan BA, Burke MT, Harron DW. Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK68,798) in humans. J Cardiovasc Pharmacol 1993; 21: 507–12. 150. Le-Coz F, Funck-Brentano C, Morell T, Ghadanfar MM, Jaillon P. Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization. Clin Pharmacol Ther 1995; 57: 533–42. 151. Walker DK, Alabaster CT, Congrave GS, Hargreaves MB, Hyland R, Jones BC, Reed LJ, Smith DA. Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data. Drug Metab Dispos 1996; 24: 447–55. 152. Suttorp MJ, Polak PE, Van’t Hof A, Rasmussen HS, Dunselman PH, Kingma JH. Efficacy and safety of a new selective class III antiarrhythmic agent dofetilide in paroxysmal atrial fibrillation or atrial flutter. Am J Cardiol 1992; 69: 417–19. 153. Kobayashi Y, Atarashi H, Ino T, Kuruma A, Nomura A, Saitoh H, Hayakawa H. Clinical and electrophysiologic effects of dofetilide in patients with supraventricular tachyarrhythmias. J Cardiovasc Pharmacol 1997; 30: 367–73. 154. Cobbe SM, Campbell RW, Camm AJ, Nathan AW, Rowland E, Bloch-Thomsen PE, Moller M, Jordaens L. Effects of intravenous dofetilide on in-

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duction of atrioventricular re-entrant tachycardia. Heart 2001; 86: 522–6. 155. Sedgwick ML, Lip G, Rae AP, Cobbe SM. Chemical cardioversion of atrial fibrillation with intravenous dofetilide. Int J Cardiol 1995; 49: 159– 66. 156. Frost L, Mortensen PE, Tingleff J, Platou ES, Christiansen EH, Christiansen N, Dofetilide Post-CABG Study Group. Efficacy and safety of dofetilide, a new class III antiarrhythmic agent, in acute termination of atrial fibrillation or flutter after coronary artery bypass surgery. Dofetilide Post-CABG Study Group. Int J Cardiol 1997; 58: 135–40. 157. Falk RH, Pollak A, Singh SN, Friedrich T. Intravenous dofetilide, a class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. Intravenous Dofetilide Investigators. J Am Coll Cardiol 1997; 29: 385–90. 158. Singh S, Zoble RG, Yellen L, Brodsky MA, Feld GK, Berk M, Billing CB Jr. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRED) study. Circulation 2000; 102: 2385–90. 159. Lindeboom JE, Kingma JH, Crijns HJ, Dunselman PH. Efficacy and safety of intravenous dofetilide for rapid termination of atrial fibrillation and atrial flutter. Am J Cardiol 2000; 85: 1031–3. 160. Krahn AD, Klein GJ, Yee R. A randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of intravenously administered dofetilide in patients with Wolff–Parkinson–White syndrome. PACE Pacing Clin Electrophysiol 2001; 24: 1258–60. 161. Echt DS, Lee JT, Murray KT, Vorperian V, Borganelli SM, Crawford DM, Friedrich T, Roden DM. A randomized, double-blind, placebocontrolled, dose-ranging study of dofetilide in patients with inducible sustained ventricular tachyarrhythmias. J Cardiovasc Electrophysiol 1995; 6: 687–99. 162. Pool PE, Singh SN, Friedrich T. Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: a clinical trial. Clin Cardiol 2000; 23: 415–16. 163. The DIAMOND Study Group. Dofetilide in patients with left ventricular dysfunction and either heart failure or acute myocardial infarction: rationale, design, and patient characteristics of the DIAMOND studies. Clin Cardiol 1997; 20: 704– 10. 164. Torp-Pedersen C, Møller M, Bloch-Thomsen PE, Køber L, Sandøe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ, for the Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. New Engl J Med 1999 16; 341: 857–65. 165. Køber L, Bloch-Thomsen PE, Møller M, TorpPedersen C, Carlsen J, Sandøe E, Egstrup K, Agner E, Videbaek J, Marchant B, Camm AJ, on behalf of the Danish Investigations of Arrhythmia and

Positive inotropic drugs and drugs used in dysrhythmias Mortality on Dofetilide (DIAMOND) Study Group. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet 2000; 356: 2052–8. 166. Bianconi L, Castro A, Dinelli M, Alboni P, Pappalardo A, Richiardi E, Santini M. Comparison of intravenously administered dofetilide versus amiodarone in the acute termination of atrial fibrillation and flutter. A multicentre, randomized, double-blind, placebo-controlled study. Eur Heart J 2000; 21: 1265–73. 167. Crijns HJ, Van Gelder IC, Kingma JH, Dunselman PH, Gosselink AT, Lie KI. Atrial flutter can be terminated by a class III antiarrhythmic drug but not by a class IC drug. Eur Heart J 1994; 15: 1403– 8. 168. Tendera M, Wnuk-Wojnar AM, Kulakowski P, Malolepszy J, Kozlowski JW, Krzeminska-Pakula M, Szechinski J, Droszcz W, Kawecka-Jaszcz K, Swiatecka G, Ruzyllo W, Graff O. Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo. Am Heart J 2001; 142: 93–8. 169. Boriani G, Lubinski A, Capucci A, Niederle R, Kornacewicz-Jack Z, Wnuk-Wojnar AM, Borggrefe M, Brachmann J, Biffi M, Butrous GS, on behalf of the Ventricular Arrhythmias Dofetilide Investigators. A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease. Eur Heart J 2001; 22: 2180–91. 170. Mazur A, Anderson ME, Bonney S, Roden DM. Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide: a placebo-controlled, implantable cardioverter–defibrillator-based evaluation. J Am Coll Cardiol 2001; 37: 1100–5. 171. Kuruma A, Atarashi H, Ino T, Yashima M, Nomura A, Hayakawa H. Use of intravenous dofetilide in atrial flutter with hemodynamic instability. Jpn Circ J 1996; 60: 67–9. 172. Pritchett EL, Wilkinson WE. Effect of dofetilide on survival in patients with supraventricular arrhythmias. Am Heart J 1999; 138: 994–7. 173. Abel S, Nichols DJ, Brearley CJ, Eve MD. Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Br J Clin Pharmacol 2000; 49: 64–71. 174. Johnson BF, Cheng SL, Venitz J. Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic. J Clin Pharmacol 2001; 41: 1248–56. 175. Kawabata M, Hirao K, Horikawa T, Suzuki K, Motokawa K, Suzuki F, Azegami K, Hiejima K. Syncope in patients with atrial flutter during treatment with class Ic antiarrhythmic drugs. J Electrocardiol 2001; 34: 65–72. 176. Turner N, Thwaites BC. Exercise induced widening of the QRS complex in a patient on flecainide. Heart 2001; 85: 423.

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177. Ohki R, Takahashi M, Mizuno O, Fujikawa H, Mitsuhashi T, Katsuki T, Ikeda U, Shimada K. Torsades de pointes ventricular tachycardia induced by mosapride and flecainide in the presence of hypokalemia. PACE Pacing Clin Electrophysiol 2001; 24: 119–21. 178. Nabar A, Rodriguez LM, Timmermans C, Van Mechelen R, Wellens HJJ. Class IC antiarrhythmic drug induced atrial flutter: electrocardiographic and electrophysiological findings and their importance for long term outcome after right atrial isthmus ablation. Heart 2001; 85: 424–9. 179. Walker PR, Papouchado M, James AMA, Clarke LM. Pacing failure due to flecainide acetate. PACE Pacing Clin Electrophysiol 1985; 8: 900–2. 180. Antonelli D, Freedberg NA, Rosenfeld T. Acute loss of capture due to flecainide acetate. PACE Pacing Clin Electrophysiol 2001; 24: 1170. 181. Chandrasekaran B, Kurbaan AS. Brugada syndrome: a review. Br J Cardiol 2002; 9: 406–10. 182. Priori SG, Napolitano C, Terrence L, et al. Incomplete penetrance and variable response to sodium channel blockade in Brugada’s syndrome. Eur Heart J 1999 20 Suppl: 465A. 183. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, Brugada P. Sodium channel blockers identify risk for sudden death in patients with ST segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000; 101: 510–15. 184. Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E. The elusive link between LQT3 and Brugada syndrome. The role of flecainide challenge. Circulation 2000; 102: 945–7. 185. Møller HU, Thygesen K, Kruit PJ. Corneal deposits associated with flecainide. Br Med J 1991; 302: 506–7. 186. Ikaheimo K, Kettunen R, Mantyjarvi M. Adverse ocular effects of flecainide. Acta Ophthalmol Scand 2001; 79: 175–6. 187. Lynch MJ, Gerostamoulos J. Flecainide toxicity: cause and contribution to death. Legal Med 2001; 3: 233–6. 188. Leong MS, Isolani F, Gaeta RR. Mexiletine and persistent ophthalmic changes. Pain Med 2001; 2: 228–9. 189. Sasaki M, Maeda A, Fujimura A. Influence of diltiazem on the pharmacokinetics of amlodipine in elderly hypertensive patients. Eur J Clin Pharmacol 2001; 57: 85–6. 190. Kusumoto M, Ueno K, Oda A, Takeda K, Mashimo K, Takaya K, Fujimura Y, Nishihori T, Tanaka K. Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men. Clin Pharmacol Ther 2001; 69: 104–7. 191. Geller JC, Geller M, Carlson MD, Waldo AL. Efficacy and safety of moricizine in the maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Am J Cardiol 2001; 87: 172–7. 192. Rubin RL, Salomon DR, Guerrero RS. Thymus function in drug-induced lupus. Lupus 2001; 10: 795–801. 193. Bellandi F, Simonetti I, Leoncini M, Frascarelli F, Giovannini T, Maioli M, Dabizzi RP. Long-term efficacy and safety of propafenone and

222 sotalol for the maintenance of sinus rhythm after conversion of recurrent symptomatic atrial fibrillation. Am J Cardiol 2001; 88: 640–5. 194. Khan IA. Single oral loading dose of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation. J Am Coll Cardiol 2001; 37: 542–7. 195. Jazwinska-Tarnawska E, Orzechowska-Juzwenko K, Niewinski P, Rzemislawska Z, LobozGrudzien K, Dmochowska-Perz M, Slawin J. The influence of CYP2D6 polymorphism on the antiarrhythmic efficacy of propafenone in patients with paroxysmal atrial fibrillation during 3 months propafenone prophylactic treatment. Int J Clin Pharmacol Ther 2001; 39: 288–92. 196. Koppel C, Oberdisse U, Heinemeyer G. Clinical course and outcome in class Ic antiarrhythmic overdose. J Toxicol Clin Toxicol 1990; 28: 433–44.

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197. Genty A, De Brabant F, Pibarot N, Busseuil C, Dubien PY, Ducluze R. Seizure disclosing acute propafenone poisoning. Jeur 2001; 14: 248–54. 198. Schwenger V. Plasma separation in severe propafenone intoxication. Intensivmed Notf Med 2001; 38: 124–7. 199. Duncan KO. Severe cutaneous adverse reactions to medications. Prim Care Case Rev 2001; 4: 171–85. 200. Ngui JS, Chen Q, Shou M, Wang RW, Stearns RA, Baillie TA, Tang W. In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4′ - and 10-hydroxywarfarin. Drug Metab Dispos 2001; 29: 877–86.

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18

Beta-adrenoceptor antagonists and antianginal drugs

BETA-ADRENOCEPTOR ANTAGONISTS (SED-13, 488; SEDA-23, 206; SEDA-24, 220; SEDA-25, 227)

INDIVIDUAL BETA-ADRENOCEPTOR ANTAGONISTS Carvedilol

ORGANS AND SYSTEMS Metabolism That beta-blockers have unfavorable effects on lipids or insulin sensitivity is the main argument against their primary use in patients with hypertension. Another potential drawback is their propensity to cause weight gain in some patients. A systematic analysis of eight prospective randomized trials in 7048 patients with hypertension (3205 of whom were taking beta-blockers) confirmed that body weight was higher in those taking beta-blockers than in controls at the end of the studies (1M ). The median difference in body weight was 1.2 kg (range −0.4 to 3.5 kg). There was no relation between demographic characteristics and changes in body weight. The weight gain was observed in the first few months of treatment and thereafter there was no further weight gain compared with controls. The possible mechanisms of this weight gain include reduction in resting energy expenditure, reduction in exercise tolerance, inhibition of lipolysis, and exacerbation of insulin resistance. This observation suggests that first-line use of beta-blockers in obese patients with hypertension should be considered with caution.

© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Sexual function In a comparison of carvedilol with valsartan in 160 patients with hypertension (mean age 46 years) each treatment was continued for 16 weeks, with crossover after 4 weeks of placebo (2C ). Blood pressure was significantly lowered by both drugs (48% normalization with valsartan and 45% with carvedilol). In the first month of treatment, sexual activity (assessed as the number of episodes of sexual intercourse per month) fell with both treatments compared with baseline, although the change was statistically significant only with carvedilol. After the first month of treatment, sexual activity further worsened with carvedilol, but it improved or recovered fully with valsartan. The results were confirmed by the crossover. This confirms that beta-blockers can cause chronic worsening of sexual function.

Labetalol Life-threatening hyperkalemia has been reported after intravenous labetalol (3A ). • A 28-year-old man with severe hypertension and end-stage renal disease was given two intravenous doses of labetalol 20 mg 1 hour apart for malignant hypertension. The serum potassium concentration before treatment was 6.2 mmol/l but 8 hours after labetalol it rose to 9.9 mmol/l and the patient developed left bundle branch block, ventricular tachycardia, and hypotension. He was given intravenous calcium gluconate, sodium bicarbonate, and lidocaine and reverted to sinus rhythm. The potassium concentration after 2 hours was 8.0 mmol/l. After hemodialysis the potassium concentration fell to 6.1 mmol/l.

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Patients with end-stage renal disease on dialysis can have an enhanced hyperkalemic response to labetalol, which can be partly attributed to electrochemical disturbances in the cells, characterized by an increase in intracellular sodium and chloride and a decrease in intracellular potassium.

Sotalol Cardiovascular Several publications involving 962 patients treated with an intravenous infusion of racemic sotalol have been reviewed, with the aim of describing the risk of torsade de pointes (4M ). Torsade de pointes occurred in only one case (0.1%; 95% CI = 0.003, 0.6), which is less often than with oral sotalol (2– 4%). This difference can be explained by the shorter duration of treatment. The other reported complications were hypotension (0.3%), severe bradycardia (0.2%), and atrioventricular block necessitating drug withdrawal (0.03%). Risk factors Some patients with thyrotoxicosis have occult cardiac dysfunction. However, the use of beta-blockers in the treatment of thyrotoxicosis can have severe consequences in terms of severe cardiac dysfunction (5A ). • A 52-year-old woman developed atrial fibrillation with a ventricular rate of 220/minute. She had had thyrotoxicosis 20 years before, but was taking no medications. She had an 8-month history of weight loss with a normal appetite. During the previous month she had had excessive sweating, palpitation, and exercise intolerance. The diagnosis was thyroid storm. She was given intravenous sotalol 1 mg/kg over 15 minutes and within 5 minutes sinus rhythm was restored, with improvement of symptoms. However, immediately after the infusion she had an episode of ventricular tachycardia followed by sinus bradycardia, with a resultant fall in blood pressure, followed by an asystolic cardiac arrest. She underwent endotracheal intubation and was treated with inotropes. Right heart catheterization showed severe cardiac dysfunction (cardiac index 1.2 l/min). She made an uneventful recovery.

Patients with severe hyperthyroidism can have an occult cardiomyopathy that makes them extremely sensitive to beta-blockers. The long duration of action of sotalol in this case necessitated prolonged inotropic and vasopressor support. A shorter acting beta-blocker, such as esmolol, could theoretically be safer in such cases.

A.P. Maggioni, M.G. Franzosi, and R. Latini

NITRATE DERIVATIVES

(SED-14, 594; 218; SEDA-23, 207; SEDA-24, 222; SEDA-25, 228)

Glyceryl trinitrate (nitroglycerin) Drug withdrawal Adverse reactions to industrial exposure to glyceryl trinitrate were first reported in 1914 (6r ), and subsequently there have been several reports of symptoms during the weekend resulting from withdrawal of the sustained vasodilator response of nitrates. Vasoconstriction ensues and can cause Raynaud’s phenomenon, angina pectoris, or myocardial infarction, as has recently been reported again (7A ). • A 41-year-old man employed in a munitions factory was admitted with crushing chest pain on a Sunday morning. There was evidence of an acute inferior myocardial infarction, and cardiac catheterization showed 80% narrowing of the proximal right coronary artery, which was reduced to 10% by intracoronary administration of glyceryl trinitrate. The electrocardiogram became normal.

Despite continuing reports of adverse reactions to withdrawal from chronic occupational exposure to nitrates, there is no clear evidence of similar events in patients taking chronic nitrate therapy. However, since this risk cannot be excluded, patients taking chronic nitrates should be carefully advised and monitored. Gene toxicity In view of the hypothesis that nitric oxide can have mutagenic or carcinogenic effects, chromosomal alterations have been sought in blood lymphocytes from patients taking chronic nitrates and after in vitro exposure to a nitric oxide donor (8E ). No structural alterations were found in vivo or in vitro, only an increased frequency of micronucleus formation, a nuclear morphological change that has been suggested to be associated with a risk of cancer. However, this first report of a genotoxic effect of nitrates probably has no clinical relevance. Pregnancy An authoritative overview of the published evidence on the use of glyceryl trinitrate to induce uterine relaxation in obstetric emergencies has shown that it is safe for fetus and mother (9R ). However, the evidence of benefit is still to be proven by larger well-designed controlled trials.

Beta-adrenoceptor antagonists and antianginal drugs

Chapter 18

Drug interactions An elderly patient with anginal pain died after treatment with glyceryl trinitrate (10A ). The family physician discovered that the patient had also taken sildenafil, and he suggested suicidal intent, since he claimed that the patient was aware of the adverse cardiac events of the association of these two drugs.

Diltiazem

CALCIUM CHANNEL BLOCKERS (SED-14, 578; SEDA-23, 208; SEDA-24, 222; SEDA-25, 229)

Amlodipine Skin Calcium antagonists can cause lichen planus, as has again been described (11A ). • A 56-year-old Nigerian woman, with a previous history of sickle cell trait, osteoarthritis, and noninsulin-dependent diabetes mellitus, took amlodipine 5 mg/day for hypertension for 2 weeks and developed a lichenoid eruption. Histological examination confirmed the diagnosis of lichen planus. Amlodipine was withdrawn and there was rapid symptomatic and clinical improvement after treatment with corticosteroids and antihistamines.

Drug overdose A case of amlodipine overdose has been reported (12A ). • A 23-year-old woman took 60 tablets of amlodipine intentionally and developed tachycardia and severe hypotension. She did not improve with intensive therapy and developed left ventricular failure and oliguria and underwent hemodiafiltration. Her condition slowly improved over 4 days.

Barnidipine Barnidipine is a new dihydropyridine with antihypertensive activity and tolerability similar to that of other calcium antagonists of the same class. The most frequent adverse events are edema, headache, and flushing, but it does not cause reflex tachycardia (13R ).

225

Nervous system Parkinsonism associated with diltiazem has been reported (14A ). • A 53-year-old man with hypertension took diltiazem 60–120 mg/day for 5 years and then developed Parkinsonism. His neurological symptoms were treated without success and only after the substitution of diltiazem with an ACE inhibitor did his Parkinsonian symptoms began to regress, with eventual complete recovery.

Skin Four cases of photodistributed hyperpigmentation associated with long-term administration of a modified-release formulation of diltiazem hydrochloride have been reported (15A ). All the patients were African– American women, mean age 62 (range 49–72) years. The duration of diltiazem administration before the development of hyperpigmentation was 6–11 months. The hyperpigmentation was slate-gray and reticulated. Phototesting during diltiazem therapy showed a reduced minimal erythema dose to UV-A in one patient. Histological examination showed lichenoid dermatitis with prominent pigmentary incontinence. Electron microscopy showed multiple melanosome complexes. Withdrawal of diltiazem resulted in gradual resolution of the hyperpigmentation. Lichenoid purpura of 6 months’ duration occurred in a 65-year-old man with hypertension who had taken diltiazem for 1 month; topical therapy with a very potent glucocorticoid was not effective and the eruption began to regress only after diltiazem withdrawal and disappeared 3 weeks later (16A ). Drug overdose The optimum treatment of overdose with calcium antagonists has yet to be defined and has included several approaches, including gastric lavage, repeated oral doses of activated charcoal, intravenous calcium, atropine, sympathomimetic amines, digoxin, glucagon, glucose combined with insulin, ventricular pacing, charcoal hemoperfusion, and plasma exchange. Three more cases of diltiazem overdose have been reported, each treated differently (see also amlodipine above). • A 15-year-old woman intentionally took 10 modified-release tablets of diltiazem 200 mg. She developed hypertension, oliguria, pulmonary edema, and respiratory distress syndrome, and required

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mechanical ventilation for 3 days, besides intravenous calcium, dopamine, and noradrenaline. After 5 days in an intensive care unit, she was transferred to a psychiatric hospital in good physical condition (17A ). • A 50-year-old man who had taken 28 modifiedrelease tablets of diltiazem 240 mg and 28 tablets of hydrochlorothiazide presented 12–14 hours later lethargic but oriented and complaining of nausea and dizziness; he had bradypnea, hypotension, and second-degree heart block with bradycardia (18A ). He was given activated charcoal, oxygen, atropine, glucagon, and calcium gluconate by prolonged infusion. His heart rate, blood pressure, and electrocardiogram recovered to baseline over the next 24 hours, with no further episodes of dysrhythmias or hypotension. • A 38-year-old white man with a history of coronary artery disease, myocardial infarction, coronary artery by-pass, alcoholism, and depression took a combined massive overdose of diltiazem and atenolol (19A ). He underwent cardiopulmonary resuscitation because of cardiac arrest; bradycardia, hypotension, and oliguria followed and were resistant to intravenous pacing and multiple pharmacological interventions, including intravenous fluids, calcium, dopamine, dobutamine, adrenaline, prenalterol, and glucagon. Adequate mean arterial pressure and urine output were restored only after the addition of phenylephrine and transvenous pacing. He survived despite myocardial infarction and pneumonia.

Drug interactions Simvastatin is metabolized by CYP3A4, which is inhibited by diltiazem. A case of rhabdomyolysis due to an interaction of simvastatin with diltiazem has been reported (20A ). • A 75-year-old-man taking simvastatin 80 mg/day and diltiazem 240 mg/day developed extreme weakness and diffuse muscle pain. All drugs were withdrawn and he underwent hemodialysis. Within 3 weeks his muscle pain disappeared and he regained function in his legs. The activities of creatine kinase and transaminases gradually returned to normal, but he continued to need hemodialysis.

Preliminary results from two clinical studies of the interaction of diltiazem with simvastatin have shown that diltiazem increased the Cmax of simvastatin (21c ) and enhanced its cholesterolreducing effect (22c ). In 10 healthy volunteers taking oral simvastatin 20 mg/day diltiazem 120 mg bd for 2 weeks significantly increased the simvastatin Cmax 3.6-fold, the AUC 5-fold, and the half-life 2.3-fold (21c ). There were no changes in the tmax of simvastatin or simvastatin acid. Of 135 patients attending a hypertension clinic who were taking simvastatin for primary

A.P. Maggioni, M.G. Franzosi, and R. Latini

or secondary prevention of coronary heart disease, 19 were also taking diltiazem (22c ). The cholesterol reduction in the 19 patients taking diltiazem was significantly higher than in the other 116 (33% vs 25%), with less interindividual variability. Concurrent diltiazem therapy, age, and the starting dose of simvastatin were significant independent predictors of the percentage cholesterol response. The pharmacokinetic interaction of a single oral dose of diltiazem 120 mg with a single oral dose of sirolimus 10 mg has been studied in 18 healthy subjects, 12 men and 6 women, 20–43 years old, in an open, three-period, randomized, crossover study (23C ). The wholeblood sirolimus AUC increased by 60% and the Cmax by 43% with diltiazem co-administration; the apparent oral clearance and volume of distribution of sirolimus fell by 38% and 45% respectively, consistent with the change in halflife from 79 to 67 hours. Sirolimus had no effect on the pharmacokinetics of diltiazem or on the effects of diltiazem on either diastolic or systolic blood pressures or the electrocardiogram. Single-dose diltiazem co-administration leads to higher sirolimus exposure, presumably by inhibition of first-pass metabolism. Because of pronounced intersubject variability in this interaction, whole-blood sirolimus concentrations should be monitored closely in patients taking the two drugs.

Felodipine Facial telangiectasia, already attributed to other calcium channel blockers, has been attributed to felodipine (24A ). • A 67-year-old man who had taken felodipine 5 mg/day for 4 years developed facial telangiectatic lesions that worsened with solar exposure for 9 months before felodipine was withdrawn; 2 months later the lesions had markedly diminished.

Manidipine Manidipine is a new dihydropyridine calcium channel blocker that can be given once a day for hypertension. In a comparison of manidipine 10 mg/day and amlodipine 5 mg/day in a multicenter, randomized, double-blind study

Beta-adrenoceptor antagonists and antianginal drugs

in 530 patients with mild-to-moderate hypertension the two drugs had comparable antihypertensive effects, but manidipine was associated with a significantly lower incidence of ankle edema (25C ). Nevertheless, adverse events caused withdrawal from treatment in a similar number of patients, 23 with manidipine and 26 with amlodipine.

Nicardipine Hypertensive emergencies in children require intravenous infusion of antihypertensive drugs. Intravenous nicardipine reduced systolic (16%) and diastolic (23%) blood pressures in a retrospective uncontrolled series of 29 children aged 2 days to 18 years (26c ). Tachycardia was recorded in four patients, palpitation in one, and flushing in one.

Nifedipine Mouth and teeth Nifedipine and ciclosporin can cause gingival hyperplasia, which is associated with gingival inflammation and can be mitigated by careful oral hygiene, although this has not been clearly shown. In gingival biopsies from nine nifedipine-treated cardiac out-patients, 13 immunosuppressant-treated renal transplant recipients, nine of whom were also taking nifedipine, and 30 healthy individuals there were significant differences in macrophage and lymphocyte subpopulations in gingival connective tissue from patients with nifedipine-associated gingival lesions compared with healthy individuals (27c ). For example, the proportion of CD8-labelled cells was significantly higher and the CD4/CD8 ratio significantly lower in connective tissue beneath the sulcular epithelium in those taking nifedipine. The authors suggested that the immune response may be altered in drug-induced gingival overgrowth. In another study gingival samples were collected from 19 healthy individuals, 12 nifedipine-treated cardiac patients, and 22 immunosuppressant-treated organ transplant recipients, 11 of whom were also taking nifedipine (28c ). Mitotic activity was measured in the basal cell layer, and the results suggested that the increased epithelial thickness observed

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in nifedipine- and ciclosporin-induced gingival overgrowth is associated with increased mitotic activity. The true prevalence of gingival overgrowth induced by chronic treatment with calcium channel blockers is still uncertain, since most studies have been small. In a cross-sectional study in 65 patients taking nifedipine and 147 controls in a primary-care center in Barcelona there was a higher prevalence of gingival overgrowth in patients taking nifedipine (34% vs 4.1%) (29c ). Pregnancy Beta-adrenoceptor agonists reduce the incidence of preterm birth, but this has not led to a lower incidence of neonatal morbidity and mortality. The calcium channel blocker nifedipine has been used for the same indication. In a review of almost 800 patients randomized to beta-adrenoceptor agonists or nifedipine the latter was associated with more frequent prolongation of pregnancy, a lower incidence of respiratory distress syndrome, and lower incidences of maternal and fetal adverse effects (30R ).

Nimodipine In the absence of effective neuroprotective treatment for ischemic stroke, a double-blind, randomized, placebo-controlled trial has been performed in 454 patients in primary care (31c ). Nimodipine 30 mg/day or placebo was started within 6 hours after the onset of the stroke and continued for 10 days. Nimodipine had no effect on all-cause mortality or dependency in daily life. In patients with ischemic stroke documented by CT scan nimodipine had a borderline significant adverse effect on outcome. Nimodipine was tolerated as well as placebo (7 vs 8 treatment withdrawals respectively), but the lack of benefit does not support the use of any voltage-sensitive calcium antagonist in ischemic stroke.

Verapamil Cardiovascular Another case of cardiogenic shock after the ingestion of verapamil has been reported, but on this occasion with a small dose (32A ).

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• A 78-year-old woman with a history of biventricular heart failure had cardiogenic shock after she took a single tablet of verapamil 80 mg. She was resuscitated with artificial ventilation, dobutamine, noradrenaline, and calcium gluconate. Toxicological analysis showed an unexpectedly high plasma verapamil concentration, which was attributed to liver failure.

In patients with advanced heart failure a single oral therapeutic dose of verapamil may have a severe toxic effect. Nervous system Myoclonic seizures have been attributed to verapamil (33A ). • An 18-month-old girl with supraventricular tachycardia was given intravenous verapamil 0.2 mg/kg, which was discontinued after half the dose had been given, because she developed irregular, repetitive, jerky movements in both upper and lower limbs which lasted for 2 minutes. As the supraventricular tachycardia had not responded, second and third doses of 0.2 mg/kg were given intravenously under diazepam cover, but similar myoclonic seizures occurred again. There were no predisposing factors.

Musculoskeletal Arthralgia has been associated with verapamil (34A ). • A 28-year-old man with migraine and vascular pain of the face was given verapamil 480 mg/day when sumatriptan did not control the pain. Verapamil was withdrawn after 1 month and reintroduced in a dosage of 960 mg/day after a new episode of pain. He then developed arthralgia in the right hand and arm, which disappeared after withdrawal and recurred after rechallenge.

A.P. Maggioni, M.G. Franzosi, and R. Latini

Drug interactions By increasing its rate of absorption, verapamil produced transient rises in peak plasma concentrations of dofetilide in 12 young healthy male volunteers (35c ). During combination treatment at steady state there was a significant, albeit modest, increase in the mean Cmax and AUC of dofetilide. These changes were associated with corresponding short-lived increases in its pharmacodynamic effect, as measured by changes in the QTc interval. These two drugs should not be administered concurrently. An interaction of high-dose verapamil with erythromycin reportedly resulted in a lifethreatening dysrhythmia (36A ). • A 79-year-old white woman developed extreme fatigue and dizziness. Her heart rate was 40/minute and her blood pressure 80/40 mmHg. An electrocardiogram showed complete atrioventricular block, an escape rhythm at 50/minute, and QTc interval prolongation to 583 msec. This event was attributed to concomitant treatment with verapamil 480 mg/day and erythromycin 2000 mg/day, which had been prescribed 1 week before admission.

This is the first report of complete AV block and prolongation of the QTc interval after coadministration of erythromycin and verapamil, both of which are principally metabolized by CYP3A4. Both drugs are potent inhibitors of CYP3A4 and P glycoprotein, which may be the basis of this interaction.

REFERENCES 1. Sharma AM, Pischon T, Hardt S, Kunz I, Luft FC. Hypothesis. Beta-adrenergic receptor blockers and weight gain: a systematic analysis. Hypertension 2001; 37: 250–4. 2. Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L. Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am J Hypertens 2001; 14: 27–31. 3. Hamad A, Salameh M, Zihlif M, Feinfeld DA, Carvounis CP. Life-threatening hyperkalemia after intravenous labetolol injection for hypertensive emergency in a hemodialysis patient. Am J Nephrol 2001; 21: 241–4. 4. Marill KA, Runge T. Meta-analysis of the risk of torsades de pointes in patients treated with intra-

venous racemic sotalol. Acad Emerg Med 2001; 8: 117–24. 5. Fraser T, Green D. Weathering the storm: betablockade and the potential for disaster in severe hyperthyroidism. Emerg Med 2001; 13: 376–80. 6. Ebright GE. The effects of nitroglycerin on those engaged in its manufacture. J Am Med Assoc 1914; 62: 201. 7. RuDusky BM. Acute myocardial infarction secondary to coronary vasospasm during withdrawal from industrial nitroglycerin exposure. A case report. Angiology 2001; 52: 143–4. 8. Andreassi MG, Picano E, Del Ry S, Botto N, Colombo MG, Giannessi D, Lubrano V, Vassalle C, Biagini A. Chronic long-term nitrate therapy:

Beta-adrenoceptor antagonists and antianginal drugs possible cytogenetic effect in humans? Mutagenesis 2001; 16: 517–21. 9. Caponas G. Glyceryl trinitrate and acute uterine relaxation: a literature review. Anaesth Intensive Care 2001: 29: 163–77. 10. Bhalerao S. A new suicide. J Fam Pract 2001; 50: 551. 11. Swale VJ, McGregor JM. Amlodipine-associated lichen planus. Br J Dermatol 2001; 144: 920–1. 12. Feldman R, Glinska-Serwin M. Deep hypotension with transient oliguria and severe heart failure in of acute intentional poisoning with amlodipine. Pol Arch Med Wewn 2001; 105: 495–9. 13. Malhotra HS, Plosker GL. Barnidipine. Drugs 2001; 61: 989–96. 14. Remblier C, Kassir A, Richard D, Pérault MC, Guibert S. Syndrome parkinsonien sous diltiazem. Thérapie 2001; 56: 57–9. 15. Scherschun L, Lee MW, Lim HW. Diltiazemassociated photodistributed hyperpigmentation. A review of 4 cases. Arch Dermatol 2001; 137: 179– 82. 16. Inui S, Itami S, Yoshikawa K. A case of lichenoid purpura possibly caused by diltiazem hydrochloride. J Dermatol 2001; 28: 100–2. 17. Quispel R, Baur HJCM. Tentamen suicidii door diltiazem met gereguleerde afgifte. Ned Tijdschr Geneeskd 2001; 145: 918–22. 18. Shah SJ, Quartin AA, Schein RMH. Diltiazem overdose—a case report. JK Pract 2001; 8: 40–2. 19. Snook CP, Sigvaldason K, Kristinsson J. Severe atenolol and diltiazem overdose. J Toxicol Clin Toxicol 2000; 38: 661–5. 20. Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem. Nephron 2001; 89: 117–18. 21. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267–74. 22. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients. Br J Clin Pharmacol 1999; 48: 610–15. 23. Bottiger Y, Sawe J, Brattstrom C, Tollemar J, Burke JT, Zimmerman JJ. Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers. Clin Pharmacol Ther 2001; 69: 32–40. 24. Silvestre JF, Albares MP, Carnero L, Botella R. Photodistributed felodipine-induced facial telangiectasia. J Am Acad Dermatol 2001; 45: 323–4.

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25. Zanchetti A, Omboni S, La Commare P, De Cesaris R, Palatini P. Efficacy, tolerability, and impact on quality of life of long-term treatment with manidipine or amlodipine in patients with essential hypertension. J Cardiovasc Pharmacol 2001; 38: 642– 50. 26. Flynn JT, Mottes TA, Brophy PD, Kershaw DB, Smoyer WE, Bunchman T. Intravenous nicardipine for treatment of severe hypertension in children. J Pediatr 2001; 139: 38–43. 27. Pernu HE, Knuuttila MLE. Macrophages and lymphocyte subpopulations in nifedipine- and cyclosporin A-associated human gingival overgrowth. J Periodontol 2001; 72: 160–6. 28. Nurmenniemi PK, Pernu HE, Knuuttila MLE. Mitotic activity of keratinocytes in nifedipineand immunosuppressive medication-induced gingival overgrowth. J Periodontol 2001; 72: 167–73. 29. Miranda J, Brunet L, Roset P, Berini L, Farré M, Mendieta C. Prevalence and risk of gingival enlargement in patients treated with nifedipine. J Periodontol 2001; 72: 605–11. 30. Papatsonis DNM, Lok CAR, Bos JM, Geijn HP, Dekker GA. Calcium channel blockers in the management of preterm labor and hypertension in pregnancy. Eur J Obstet Gynecol Reprod Biol 2001; 97: 122–40. 31. Horn J, de Haan RJ, Vermeulen M, Limburg M. Very early nimodipine use in stroke (VENUS). A randomized, double-blind, placebo-controlled trial. Stroke 2001; 32: 461–5. 32. Stajer D, Bervar M, Horvat M. Cardiogenic shock following a single therapeutic oral dose of verapamil. Int J Clin Pract 2001; 55: 69–70. 33. Maiteh M, Daoud AS. Myoclonic seizure following intravenous verapamil injection: case report and review of the literature. Ann Trop Paediatr 2001; 21: 271–3. 34. Nicolas X, Bellard S, Zagnoli F. Arthralgies induites par de fortes doses de vérapamil. Presse Med 2001; 30: 1256–7. 35. Johnson BF, Cheng S-L, Venitz J. Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic. J Clin Pharmacol 2001; 41: 1248–56. 36. Goldschmidt N, Azaz-Livshits T, Gotsman I, Nir-Paz R, Ben-Yehuda A, Muszkat M. Compound cardiac toxicity of oral erythromycin and verapamil. Ann Pharmacother 2001; 35: 1396–9.

R. Verhaeghe

19

Drugs acting on the cerebral and peripheral circulations

DRUGS USED IN THE TREATMENT OF ARTERIAL DISORDERS OF THE BRAIN AND LIMBS Cilostazol

developed sudden chest pain, with inferior ST segment elevation. Emergency coronary angiography showed an occlusion of the circumflex coronary artery, for which a stent was inserted. At angiography 3 years earlier his coronary arteries had been normal. He died 5 months later from cardiogenic pulmonary edema.

(SED-14, 630; SEDA-24, 229;

SEDA-25, 236) Safety data relating to the use of cilostazol in 2702 patients who participated in eight USA– UK placebo-controlled trials have been reanalysed (1R ). The most frequently recorded adverse events were headache (32%), diarrhea (17%), and abnormal stools (14%). Palpitation, tachycardia, and dizziness were additional events that occurred more often in cilostazoltreated patients and were considered to be probably related to treatment. Headache led to withdrawal of cilostazol in 3.5% of patients and palpitation and diarrhea led to withdrawal in another 1%. All adverse events quickly resolved after withdrawal. Cardiovascular and allcause mortality were similar with cilostazol and placebo. Cardiovascular Myocardial ischemia is unusual during infusion of iloprost. It mainly occurs in patients with pre-existing coronary disease, when it is ascribed to a steal phenomenon detrimental to the subendocardial tissue. As a rule it is transient and exceptionally proceeds to infarction. However, such an event has now been reported in a patient with systemic sclerosis (2A ). • A 57-year-old man with a 1-year history of systemic sclerosis and ischemia of several digits received a first infusion of iloprost using the recommended stepwise increasing dosage scheme and © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

230

DRUGS USED IN THE TREATMENT OF MIGRAINE Triptans

(SED-14, 635; SEDA-23, 215; SEDA-24, 229; SEDA-25, 237) Seven triptans have been compared and rated as generally very well-tolerated (3R ). Naratriptan, almotriptan, and frovatriptan were considered to have the best safety profiles, although the differences are minor. Coronary vasoconstriction is a potential risk of the entire class, but the risk is minimal in the absence of coronary artery disease or uncontrolled hypertension; significant vascular disease is therefore a hazard of using any of the triptans. Patient preference, however, appears to be more closely related to efficacy than to tolerance. Teratogenicity The safety of drugs for migraine during pregnancy is not well established. There are now data from the Swedish Medical Birth Registry relating to 912 infants, whose mothers, at their first antenatal visit, had reported using migraine therapies, in most cases (658) sumatriptan (4R ). There was no increase in the rate of congenital malformations; slightly more infants than expected were preterm and had a birth weight lower than 2500 g, but none of the differences was statistically significant. These data suggest that sumatriptan is not teratogenic.

Drugs acting on the cerebral and peripheral circulations

OTHER PERIPHERAL VASODILATORS Sildenafil (SED-14, 636; SEDA-23, 215; SEDA-24, 231; SEDA-25, 238) The adverse effects of a single dose of sildenafil 50 mg have been evaluated in a placebocontrolled study in 40 young healthy volunteers (5c ). The most commonly reported adverse effects with sildenafil and placebo respectively were flushing (75 and 0%), headache (50 and 5%), and dyspepsia (15 and 5%). This adverse effects profile was similar to that observed in clinical trials. Heart rate changed significantly, but blood pressure did not. Nervous system Clinical trials of sildenafil have not shown increased risks of stroke or myocardial infarction. However, postmarketing drug surveillance programs have mentioned strokes associated with sildenafil, and the first case reports have now been published. • A 50-year-old man took sildenafil 50 mg, and 2 hours later developed a right-sided hemiparesis and altered hemibody sensation, a right facial paresis, and slurred speech (6A ). The symptoms gradually disappeared 4 hours later, but recurred the next week when he took sildenafil 100 mg. On the second occasion the symptoms did not resolve, and an MRI scan showed a recent infarct in the left internal capsule and lateral thalamus. No other cause of the stroke was found by evaluation of the heart and extracranial vessels. The symptoms gradually improved over 6 months. • A 44-year-old man developed a severe headache and vomiting after taking four tablets of sildenafil (of unknown strength) followed by sexual intercourse (7A ). A CT scan showed a left-sided temporal intracranial hemorrhage. He died of cerebral edema and pneumonia a few days later. Autopsy showed no vascular abnormality. • A 67-year-old man took two 25 mg tablets of sildenafil 1 hour apart (8A ). He complained of headache, confusion, and nervousness after the

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first tablet, and his symptoms increased and he developed language difficulty after the second tablet. He did not have sexual intercourse. A few days later an MRI scan showed a large left temporal subcortical hemorrhage. The symptoms resolved partially over a few days.

Whereas the suspected mechanism for ischemic stroke is analogous to that leading to myocardial infarction (hypoperfusion distal to a critical lesion), intracerebral bleeding (7A , 8A ) may be more difficult to explain. The authors considered the likelihood of sildenafilinduced spontaneous intracerebral hemorrhage due to the vasodilatory effects of the drug on the cerebral vasculature (as evidenced by headache, flushing, and nasal congestion). Sensory systems Anterior ischemic optic neuropathy is a disorder whose pathophysiology is poorly understood. The difference between the intraocular pressure and the perfusion pressure in the posterior ciliary arteries determines the circulation in the optic disc, and a reduction in this difference may contribute to ischemia. • A 42-year-old man presented with anterior ischemic optic neuropathy, leading to a visual field defect in that eye (9A ). Because the symptoms occurred within 24 hours of sildenafil, an association with the drug was suspected.

Drug interactions The effects of sildenafil can be potentiated by drugs that are metabolized by CYP3A4. Tacrolimus is an example. When sildenafil was given to patients with kidney transplants taking regular tacrolimus, peak concentrations were much higher and the halflife much longer than expected from data in healthy volunteers (10c ). However, an effect of the underlying disease and other concomitant drugs obviously could not be excluded.

REFERENCES 1. Cariski AT. Cilostazol: a novel treatment option in intermittent claudication. Int J Clin Pract 2001; Suppl 119: 11–18. 2. Marroun I, Fialip J, Deleveaux I, André M, Lamaison D, Cabane J, Piette JC, Eschalier A, Aumaitre O. Infarctus du myocarde sous iloprost chez

un patient atteint de sclérodermie. Thérapie 2001; 56: 627–33. 3. Rapoport AM, Tepper SJ. All triptans are not the same. J Headache Pain 2001; 2: S87–92. 4. Källén B, Lygner PE. Delivery outcome in women who used drugs for migraine during

232 pregnancy with special reference to sumatriptan. Headache 2001; 41: 351–6. 5. Dundar M, Kocak I, Dundar SO, Erol H. Evaluation of side effects of sildenafil in group of young healthy volunteers. Int Urol Nephrol 2001; 32: 705– 8. 6. Morgan JC, Alhatou M, Oberlies J, Johnston KC. Transient ischemic attack and stroke associated with sildenafil (Viagra) use. Neurology 2001; 57: 1730–1. 7. Buxton N, Flannery T, Wild D, Bassi S. Sildenafil (Viagra)-induced spontaneous intracerebral haemorrhage. Br J Neurosurg 2001, 15: 347–9.

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8. Monastero R, Pipia C, Camarda LKC, Camarda R. Intracerebral haemorrhage associated with sildenafil citrate. J Neurol 2001; 248: 141–2. 9. Cunningham AV, Smith KH. Anterior ischemic optic neuropathy associated with Viagra. J NeuroOphthalmol 2001; 21: 22–5. 10. Christ B, Brockmeier D, Hauck EW, Friemann S. Interactions of sildenafil and tacrolimus in men with erectile dysfunction after kidney transplantation. Urology 2001; 58: 589–93.

Pieter Joubert

20

Antihypertensive drugs

The role of endothelin receptor antagonists in hypertension It is disappointing that mechanistically novel antihypertensive drugs have not emerged during the last decade or two. The only real novelty of the last decade was the addition of angiotensin II receptor antagonists as a refinement of the approach introduced with ACE inhibitors. The expectations for direct renin antagonists have not been realized. Some of the cornerstone classes of antihypertensive drugs, such as the diuretics, beta-adrenoceptor antagonists, calcium channel blockers, and direct vasodilators, have been around for several decades. Advances have predominantly been made in the pharmacokinetic properties and pharmacodynamic specificities of compounds in existing antihypertensive drug classes. With the emergence of knowledge about endothelial factors such as nitric oxide and endothelin, there was much expectation that endothelin antagonists would become useful in the management of hypertension. Endothelin was discovered in 1988 (1R ) and is the most potent vasoconstrictor known. In terms of pathophysiology, endothelin receptor antagonists could play a role in a variety of diseases associated with vasoconstriction, such as hypertension, renal disease, occlusive vascular disease, pulmonary hypertension, and congestive heart failure (2R ). Apart from vasoconstriction, endothelin is also involved in the structural changes associated with these diseases, and it is now recognized that there is a wider target in hypertension treatment than lowering blood pressure. Vascular and myocardial remodeling may be key issues in determining long-term outcome (3R ) and effects on myocardial fibrosis and vascular compliance may be as important as lowering blood pressure. ACE inhibitor © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

treatment can produce regression of hypertensive myocardial fibrosis in animal models (4E ) and in hypertensive patients (5C ). Bosentan, an endothelinA and endothelinB receptor antagonist, is effective in pulmonary arterial hypertension (6C , 7C ) and is being marketed for this indication. The studies showed an improvement in exercise capacity and dyspnea and an increased time to clinical worsening. Efficacy in pulmonary hypertension has also been reported in an open study with a selective endothelinA receptor antagonist (8C ). As far as hypertension is concerned, there is a substantial body of preclinical evidence of the potential efficacy of endothelin antagonists in hypertension, and this has been extensively reviewed (9R ). Circulating endothelin concentrations are not increased in hypertension, but it is postulated that there is an imbalance between the vasodilatory effects of nitric oxide and the vasoconstrictor effects of endothelin at a local vascular level, resulting in increased endothelin vasoconstrictor tone and endothelinmediated end-organ damage (10R , 11R ). In a dose-finding study with bosentan (100, 500, 1000, and 2000 mg/day) in 293 hypertensive patients (12C ) there were statistically significant falls in diastolic blood pressure with the 500 and 2000 mg/day doses. The effects were similar to that of enalapril 20 mg/day. The lowering of blood pressure was not associated with any changes in heart rate, plasma noradrenaline concentrations, plasma renin activity, or angiotensin II concentrations. If endothelin antagonists do become one of the therapeutic options in hypertension, they may also bring a new adverse effects profile. The major safety issue that has emerged with bosentan, the endothelin receptor antagonist that has been most extensively studied in man, has been dose-dependent reversible impairment of hepatic function (3% with 125 mg, 7% with 250 mg), manifesting as raised transaminases (7C ). The effect of bosentan on hepatocanalicular bile salt transport has been studied in rats in

233

234 conjunction with a re-examination of the safety database from two clinical trials (in hypertension and congestive cardiac failure) and measurement of bile salt concentrations in stored blood samples from these trials (13E ). Hepatic injury was defined as a three-fold increase in ALT activity. In the hypertension trial there were no cases of hepatic injury with placebo or enalapril. With bosentan, the frequencies were 2%, 4%, 11%, and 8% at dosages of 100, 500, 1000, and 2000 mg/day respectively. There was a dose-dependent increase in bile salt concentrations. In the study in patients with heart failure (New York Heart Association classes III/IV), liver injury occurred in 4% of 126 patients taking placebo and 18% of 244 patients taking bosentan 500 mg bd. A subgroup analysis showed a higher incidence of hepatic injury in patients taking concomitant bosentan and glibenclamide. Patients with hepatic injury had raised bile salt concentrations. In rats, intravenous bosentan produced a dose-dependent increase in plasma bile salts. The effect was potentiated when glibenclamide was co-administered. In vitro studies in rat canalicular liver plasma membranes confirmed inhibition of bile-salt transport. Three bosentan metabolites were also investigated. The M2 metabolite was more potent than bosentan, whereas the M1 and M3 metabolites produced less inhibition of bile acid transport than bosentan. These data suggest that bosentan causes cholestatic liver injury due to inhibition of bile salt efflux and damage due to intracellular accumulation of bile salts.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS (SED-14, 638; SEDA-23, 217; SEDA-24, 233; SEDA-25, 240) Respiratory The genetic basis of ACE inhibitor-induced cough and its relation to bradykinin have been further explored in a study of the effect of cilazapril in two groups of healthy volunteers genotyped for ACE insertion/deletion (I/D) polymorphism (14C ). The cough threshold to inhaled capsaicin was significantly lower in the genotype II group than in the DD group.

Chapter 20

Pieter Joubert

Skin responses to intradermal bradykinin were significantly enhanced in the II group. There was no difference in responsiveness to intradermal substance P. The authors suggested that these findings provide further evidence of the link between ACE inhibitor-induced cough and I/D polymorphism of the ACE gene, and that this supports the hypothesis that ACE inhibitors cause cough by modulating tissue concentrations of bradykinin. Hematologic ACE inhibitors are used to treat erythrocytosis, for example after transplantation (15C ). Efficacy in treating erythrocytosis in chronic obstructive pulmonary disease has also been described with the angiotensin II receptor antagonist losartan (16C ). ACE inhibitors can also lower normal erythrocyte counts and cause anemia (17C ). This effect has been assessed in a retrospective study of 92 patients after transplantation with and without erythrocytosis, comparing patients taking the same anti-rejection therapy (steroids and ciclosporin or steroids, ciclosporin, and azathioprine) taking ACE inhibitors with those not taking ACE inhibitors (18c ). There were significantly lower hemoglobin and erythropoietin concentrations in patients taking ACE inhibitors. When enalapril was given to those who had not previously taken an ACE inhibitor, the hemoglobin concentration fell by around 10% and erythropoietin by around 40%. These effects were not affected by the presence or absence of azathioprine. Although the hemoglobin-lowering effect of ACE inhibition is not a new finding, the lack of an influence of azathioprine adds some further understanding to the effect.

Captopril

(SED-14, 642; SEDA-24, 237;

SEDA-25, 242) Pancreas Two new cases of pancreatitis with captopril have been reported (19A , 20A ). It has been suggested that early detection of raised serum amylase and lipase activities can prevent the development of full-blown pancreatitis (20A ).

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Enalapril

(SED-14, 643; SEDA-23, 219; SEDA-24, 237; SEDA-25, 242) Neuromuscular function Muscular weakness, believed to be the first case, has been reported in a patient with mild renal impairment taking enalapril (21A ).

• A 78-year-old man, taking enalapril (10 mg/day), furosemide, and digoxin for cardiac failure due to ischemic heart disease, suddenly developed generalized muscle weakness. He had grade 3/5 weakness of all four limbs, his cranial nerves were intact, and there was no sensory impairment. His tendon reflexes were reduced and he had flexor plantar reflexes. The initial diagnosis was Guillain–Barré syndrome. Further investigation showed peaked T waves on his electrocardiogram, with a serum potassium of 9.4 mmol/l and a creatinine of 266 µmol/l. He was treated with glucose plus insulin, calcium gluconate, and sodium bicarbonate. Enalapril was withdrawn. His potassium concentration normalized.

Hyperkalemic muscle paralysis has been reported in renal insufficiency and trauma and in patients taking spironolactone and amiloride plus hydrochlorothiazide (co-amilozide). ACE inhibitors inhibit the release of aldosterone, reducing renal potassium loss, which can be enhanced by potassium-sparing diuretics or preexisting renal insufficiency. Hematologic An equivocal case of neutropenia has been ascribed to enalapril (22A ). • A 52-year-old male renal transplant recipient on stable therapy (4.5 months) with ciclosporin, mycophenolate mofetil, and co-trimoxazole developed erythrocytosis and hypertension. His leukocyte count fell 19 days after he started to take enalapril. Enalapril was withdrawn, the dose of co-trimoxazole was halved, and the dose of mycophenolate was first reduced and then withdrawn on day 25. On day 28 the leukocyte and neutrophil counts were so low that granulocyte-stimulating factor had to be used. The leukocyte count normalized during continued treatment with ciclosporin and co-trimoxazole. CMV tests were negative.

The authors suggested a synergistic effect between enalapril and mycophenolate. As leukopenia is the commonest clinically significant adverse effect of mycophenolate, the evidence in this case is inadequate to support this hypothesis, particularly in the absence of information on mycophenolate blood concentrations.

Skin As pemphigus vulgaris has been attributed to ACE inhibitors, it is not surprising that giving an ACE inhibitor to a patient with pemphigus could worsen the disease. Recently aggravation of pre-existing childhood pemphigus by enalapril has been reported (23A ). • A 12-year-old boy with pemphigus vulgaris was treated with intravenous dexamethasone and prednisolone. He developed severe hypertension, which was unresponsive to atenolol, and he was given enalapril 2.5 mg bd. Although the blood pressure responded, the pemphigus deteriorated markedly over the next 2 weeks. Additional dexamethasone did not produce improvement. Enalapril was replaced by amlodipine, and the disease resolved over 3 weeks.

The evidence to date suggests that ACE inhibitors should be avoided in patients with preexisting pemphigus. Immunologic A case of eosinophilic gastroenteritis after enalapril has been described (24Ar ). The authors briefly reviewed this rare condition, which is diagnosed on the basis of the presence of gastrointestinal symptoms, eosinophilic infiltration of the gastrointestinal tract, and the absence of parasitic or extraintestinal disease. It has also been reported after clofazimine and naproxen. • A 63-year-old hypertensive woman, who had a carcinoma of the distal esophagus resected 19 months earlier, developed chronic diarrhea. Clostridium difficile toxin was identified in her stools and the diarrhea resolved after treatment with metronidazole. Enalapril was added to her antihypertensive treatment, and 3 months later the diarrhea recurred. Stool examination was negative and there was no Clostridium difficile toxin. Her condition worsened and she lost 5 kg. She had marked eosinophilia (2.4 × 109 /l), and a small bowel biopsy showed mild chronic inflammation and edema, partial villous atrophy, and large clusters of eosinophils in the lamina propria with some focal infiltration of the epithelium. She stopped taking enalapril and her diarrhea promptly abated and the eosinophil count fell to 0.5 × 109 /l at 3 weeks and 0.1 × 109 /l at 2 months.

Fosinopril Liver Hepatic injury has been described from time to time with ACE inhibitors. The first case of severe, prolonged cholestatic jaundice has

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been reported with fosinopril, a phosphoruscontaining ester prodrug of the ACE inhibitor fosinoprilat (25A ). The evidence of a link to fosinopril was convincing.

Urinary tract A further convincing case of ACE inhibitor-related renal insufficiency has been described with irbesartan and losartan (27A ).

• A 61-year-old man developed weakness, severe jaundice and pruritus, and weight loss over 2 weeks. He had started to take metoprolol, fosinopril and diazepam for hypertension 5 weeks before. He had raised hepatic transaminases and bilirubin. A liver biopsy showed cholestasis in a normal cellular architecture. A lymphocyte transformation assay showed reactivity to fosinopril but not diazepam or metoprolol. Bilirubin concentrations took 4 months to normalize and pruritus persisted for 6 months.

• A 67-year-old woman with congestive heart failure developed oliguric renal insufficiency 2 days after the introduction of irbesartan. She rapidly recovered after withdrawal, and was then given losartan. The condition recurred shortly afterwards and subsided when losartan was stopped.

Lisinopril

Urinary tract A further case of convincing anuric renal insufficiency (see also the case above under irbesartan) after losartan has been described in a 70-year-old man with a solitary kidney (28A ). An interesting feature was that the patient’s blood pressure could be controlled with captopril without the development of anuria. This is in line with a study in dogs, in which there was a greater deterioration in glomerular filtration with angiotensin II receptor inhibition than with ACE inhibition, for the same effect on blood pressure (29E ).

(SEDA-23, 220; SEDA-24, 238; SEDA-25, 242) Drug interactions Raised clozapine blood concentrations have been reported after the introduction of lisinopril (26A ). • A 39-year-old man with schizophrenia and diabetes, who had taken clozapine 300 mg/day and glipizide 10 mg/day for a year, took lisinopril 5 mg/day for newly diagnosed hypertension. On several occasions afterwards he had roughly a doubling of his blood concentrations of clozapine and norclozapine. He had typical effects of clozapine toxicity. After replacement of lisinopril by diltiazem, the blood concentrations of clozapine and norclozapine returned to the values that were present before lisinopril was introduced.

The information given here was sketchy and there was no information on the timing of blood samples relative to the dose of clozapine. Clozapine is metabolized by CYP1A2 and CYP3A4, but there is no evidence that lisinopril affects these pathways.

ANGIOTENSIN II RECEPTOR ANTAGONISTS (SED-14, 644; SEDA-23, 220; SEDA-24, 23; SEDA-25, 243)

Irbesartan

(SEDA-24, 240, SEDA-25,

Losartan

(SED-14, 645; SEDA-23, 221; SEDA-24, 240; SEDA-25, 245)

Drug interactions Administration of grapefruit juice (which inhibits both cytochrome P450 and P glycoprotein) to healthy volunteers resulted in an increased serum concentration ratio of losartan to its active metabolite E3174 (30c ). As both losartan and its metabolite contribute to the therapeutic effects, the absence of pharmacodynamic measurements in this study obviated conclusions about the clinical implications of this interaction. Teratogenicity A woman who took losartan from 17 to 31 weeks of gestation developed oligohydramnios and delivered a stillborn fetus with deformities of the extremities and face (31A ).

244) REFERENCES 1. Yanagisawa M, Kurihara H, Kimura S. A novel potent vasoconstrictor peptide produced by vascu-

lar endothelial cells. Nature 1988; 332: 411–15. 2. Lüscher TF, Barton M. Endothelins and endothe-

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lin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 2000; 102: 2434–40. 3. Weber KT. Cardioreparation in hypertensive heart disease. Hypertension 2001; 38: 588–91. 4. Brilla CG, Matsubara L, Weber KT. Advanced hypertensive disease in spontaneously hypertensive rats: lisinopril-mediated regression of myocardial fibrosis. Hypertension 1996; 28: 269–75. 5. Brilla CG, Funk RC, Rupp H. Lisinoprilmediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 2000; 102: 1388–93. 6. Channick RN, Simmoneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch BD, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358; 1119– 23. 7. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simmoneau G. Bosentan therapy for pulmonary arterial hypertension. New Engl J Med 2002; 346: 896–903. 8. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension. Chest 2002; 121: 1860–8. 9. Moreau P. Endothelin in hypertension: a role for receptor antagonists? Cardiovasc Res 1998; 39: 534–42. 10. Taddei S, Virdis A, Ghiadoni L, Sudano I, Magagna A, Salvetti A. Role of endothelin in the control of peripheral vascular tone in human hypertension. Heart Failure Rev 2001; 6: 277–85. 11. Donckier JE. Therapeutic role for bosentan in hypertension: lessons from the model of perinephric hypertension. Heart Failure Rev 2001; 6: 253–64. 12. Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V. The effect of an endothelin antagonist, bosentan, on blood pressure in patients with essential hypertension. New Engl J Med 1998; 338: 784–90. 13. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier P. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001; 69: 223–31. 14. Takahashi T, Yamaguchi K, Furuya K, Kawakami Y. The ACE gene polymorphism and cough threshold for capsaicin after cilazapril usage. Respir Med 2001; 95: 130–5. 15. Mazalli M, Filho GA. Use of aminophylline and enalapril in posttransplant polycythemia. Transplantation 1998; 65 1461–3. 16. Ölger AF, Özlem ÖK, Özgur K, Peri A, Doganay A. Effects of losartan on the renin– angiotensin–aldosterone system and erythrocytosis in patients with chronic obstructive pulmonary dis-

237 eases and systemic hypertension. Clin Drug Invest 2001; 21: 337–43. 17. Gossmann J, Kachel HG, Schoepe W. Enalapril associated anemia in renal transplant recipients treated for hypertension. Transplantation 1993; 56: 585–9. 18. Montanaro D, Gropuzzo P, Tulissi G, Boscutti A, Risaliti U, Baccarani U, Mioni G. Angiotensinconverting enzyme inhibitors reduce hemoglobin concentrations, hematocrit and serum erythropoietin levels in renal transplant recipients without posttransplantation erythrocytosis. Transpl Proc 2001; 33: 2038–40. 19. Iliopoulo A, Giannakopoulos G, Pagoy H, Toubanakis C, Spiropoulos T. Acute pancreatitis due to captopril treatment. Dig Dis Sci 2001; 46: 1882–3. 20. Borgia MC, Celestini A, Caravella P, Catalano C. Angiotensin-converting-enzyme inhibitor administration must be monitored for serum amylases and lipase in order to prevent an acute pancreatitis. Angiology 2001; 52: 645–7. 21. Dutta D, Fischer M, McClung A. Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis. Postgrad Med J 2001; 77: 114–15. 22. Donadio C, Lucchesi A. Neutropenia after treatment of posttransplantation erythrocytosis with enalapril. Transplantation 2001; 15: 553–4. 23. Thami GP. Severe childhood pemphigus vulgaris aggravated by enalapril. Dermatology 2001; 202: 341. 24. Barak N, Hart J, Sitrin MD. Enalapril-induced eosinophilic gastroenteritis. J Clin Gastroenterol 2001; 33: 157–8. 25. Nunes ACR, Amaro P, Maç_as F, Cipriano A, Martins I, Rosa A, Pimenta I, Donato A, Freitas D. Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report. Eur J Gastroenterol Hepatol 2001;13: 279–82. 26. Abraham G, Grunberg B, Gratz S. Possible interaction of clozapine and lisinopril. Am J Psychiatry 2001; 15: 969. 27. Lee H, Kim C, Acute oliguric renal failure associated with angiotensin II receptor antagonists. Am J Med 2001; 111: 162–3. 28. Maillard J, Descombes E, Fellay G, Regamey C. Repeated transient anuria following losartan administration in a patient with a solitary kidney. Renal Fail 2001; 23: 143–7. 29. Brooks DP, De Palma PD, Ruffolo RR. Effect of captopril and the nonpeptide angiotensin II antagonists, SKF 108566 and EXP3174, on renal function in dogs with a renal artery stenosis. J Pharmacol Exp Ther 1992; 263: 422–7. 30. Zaidenstein R, Soback S, Gips M, Avni B, Dishi V, Weissgarten Y, Golik A, Scapa E. Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Ther Drug Monit 2001; 23: 369–73. 31. Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects. Lancet 2001; 357: 363.

Domenic A. Sica

21 GENERAL Sexual function Diuretics remain important in the pharmacotherapy of hypertension. Highdose diuretic therapy was the therapeutic norm in the 1980s, but in the 1990s a low-dose stratagem was instituted. With this change the incidence of diuretic-related electrolyte and metabolic adverse effects has fallen. Now the adverse effect of diuretics that is a major obstacle to their use is sexual dysfunction. The exact incidence is poorly documented, perhaps because of the personal nature of the problem and the reluctance of patients and/or physicians to discuss it. The adverse effects of thiazide and thiazide-like diuretics on male sexual function include reduced libido, erectile dysfunction, and difficulty in ejaculating. These abnormalities have been reported with incidence rates of 3–32%. The true incidence of sexual dysfunction probably lies closer to the lower end of this range (1R ). In a meta-analysis of 13 randomized placebo-controlled trials conducted over a mean of 4 years the NNH (number needed to harm) for erectile impotence with thiazide diuretics in hypertension was 20 and the relative risk was 5.0 (2M ). The mechanisms by which thiazides affect erectile dysfunction or libido are unclear, but it has been suggested that they have a direct effect on vascular smooth muscle cells or reduce the response to catecholamines. Sexual dysfunction does not appear to be mediated by either a low serum potassium concentration or a low blood pressure. The incidence of diuretic-related impotence is much lower when weight loss occurs. Since sexual dysfunction can adversely affect the quality of life of hypertensive patients, physicians or health-care providers should take an accurate baseline sexual history and monitor sexual status for changes during therapy. If © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

238

Diuretics there are significant changes in sexual function diuretic therapy can be withdrawn and an alternative drug class substituted. However, not uncommonly sexual dysfunction will persist despite withdrawal of the diuretic, suggesting that elements of the hypertensive state itself contribute to the process.

CARBONIC ANHYDRASE INHIBITORS (SED-14, 669; SEDA-23, 229; SEDA-24, 249; SEDA-25, 249)

Acetazolamide Electrolyte balance Acetazolamide, a noncompetitive carbonic anhydrase inhibitor, can produce severe lactic acidosis, with an increased lactate:pyruvate ratio, ketosis with a low beta-hydroxybutyrate:acetoacetate ratio, and a urinary organic acid profile consistent with pyruvate carboxylase deficiency. The acquired enzymatic injury that results from inhibition of mitochondrial carbonic anhydrase V, which provides bicarbonate to pyruvate carboxylase, can damage the tricarboxylic acid cycle. Four preterm neonates with posthemorrhagic ventricular dilatation developed severe metabolic acidosis after being given acetazolamide (3c ). The acidosis suddenly disappeared after a transfusion of packed erythrocytes, which was attributed to the citrate contained in the blood. Urinary tract Renal tubular acidosis occurred in a preterm boy shortly after birth (4A ). His mother had taken oral acetazolamide during pregnancy for glaucoma. When renal tubular acidosis developed, acetazolamide was detected in his serum, demonstrating transplacental passage of acetazolamide. Acetazolamide therapy is ill-advised in pregnancy.

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239

Immunologic A case of non-fatal anaphylactic shock with acute pulmonary edema has been reported in a 79-year-old woman after a first dose of acetazolamide (5A ). There was no history of sulfonamide allergy and she had been taking hydrochlorothiazide for some time. Anaphylactic shock with acetazolamide should be recognized to occur as a first-dose phenomenon with no prior demonstrable sulfonamide allergy.

Electrolyte balance In a hospital-based survey of hypertensive patients with hyponatremia (serum sodium concentration below 135 mmol/l) the odds ratio for hyponatremia was three times higher in women. In those over 65 years there was a ten-fold higher risk. In many instances hyponatremia was insidious in its presentation and did not occur until several months after therapy had begun (10c ). However, hyponatremia can develop rapidly.

Drug overdose Acetazolamide overdose and its sequelae have not been previously reported in children.

• A 69-year-old woman with uncontrolled hypertension took two doses of hydrochlorothiazide 25 mg and her serum sodium fell to 115 mmol/l within 24 hours, with accompanying neurological symptoms (11A ). She recovered fully with the administration of 3% saline.

• A 12-month-old girl, weighing 10 kg, developed metabolic acidosis after taking 500–1250 mg of acetazolamide (6A ). The maximum base deficit recorded was 11.6. She was treated with sodium bicarbonate and recovered completely.

Accidental poisoning with acetazolamide should be included in the differential diagnosis of metabolic acidosis.

Dorzolamide Skin Topical dorzolamide caused severe periorbital dermatitis after an average exposure time of 20 weeks in 14 patients (7c ). Although the dermatitis may resolve when dorzolamide is withdrawn, this does not always occur, and in some patients all topical medications containing benzalkonium chloride must be withdrawn. Allergic contact blepharoconjunctivitis has also been reported with dorzolamide in a 72year-old man (8A ).

THIAZIDE AND LOOP DIURETICS (SED-14, 656; SEDA-23, 228; SEDA-24, 250; SEDA-25, 252) Cardiovascular A 72-year-old woman had repeated episodes of sudden-onset pulmonary edema, each occurring immediately after the ingestion of hydrochlorothiazide 12.5 mg (9A ). The close temporal relation between the ingestion of hydrochlorothiazide and the onset of symptoms, together with rapid and full clinical recovery after withdrawal of therapy, suggested drug-induced pulmonary edema and possible anaphylactoid hypotension.

Urinary tract Although it is often described in children, medullary nephrocalcinosis with furosemide has been rarely described in adults, but has now been reported in a 40-year-old woman who had taken furosemide (40–160 mg/day) for 15 years (12A ). Urinary tract A 25-year-old woman developed biopsy-proven chronic tubulointerstitial nephritis with accompanying distal renal tubular acidosis in association with furosemide abuse (up to 1.2 g/day for several months) (13A ). Chronic tubulointerstitial nephritis has not previously been reported with furosemide. Skin The first case of pemphigus foliaceus in relation to indapamide has been described (14A ). Carcinogenicity Recent studies have suggested that long-term diuretic therapy may be associated with an increased risk of renal cell carcinoma. Other cancer types have now been evaluated for their association with diuretic therapy. The development of colon cancer has been studied in 14 166 patients aged 45–74 years with a previous myocardial infarction and/or stable anginal, screened for participation in the Bezafibrate Infarction Prevention Study (15C ). Of these, 2153 used diuretics and 12 013 did not. Multivariate analysis identified diuretics as an independent predictor of an increased incidence of colon cancer (hazard ratio 2.0) and colon cancer mortality (hazard ratio 3.7). However, the association between diuretic therapy and a higher incidence of colon cancer was observed only among non-users of aspirin. There

240 was a relatively lower incidence of colon cancer in furosemide users and a higher incidence in the small combined subgroup of those who took amiloride and or hydrochlorothiazide. Further studies to test the association between diuretics and colon cancer, as well as the potential protective effects of aspirin, are needed. Until these data become available, physicians should be aware of the potential effects of diuretics, especially when choosing long-term treatment for young patients with mild hypertension. Drug interactions Intravenous furosemide is commonly given to patients with acute heart failure to relieve pulmonary congestion. Symptomatic relief occurs before the onset of diuresis, and the beneficial effect is believed to result from a venodilator action of furosemide, which precedes its diuretic effect. This venodilator response is inhibited by the cyclo-oxygenase inhibitor indomethacin, suggesting that it occurs through local prostaglandin release. Aspirin 75 mg/day and 300 mg/day has now also been shown to inhibit the venodilator effect of furosemide (16C ). These data raise the issue of whether aspirin should be routinely used in patients with congestive heart failure using furosemide.

ALDOSTERONE RECEPTOR ANTAGONISTS (SED-14, 674; SEDA-23, 239; SEDA-24, 251; SEDA-25, 254)

Spironolactone Liver A 50-year-old woman taking spironolactone for androgenic alopecia developed hepatitis with minimal cholestasis 6 weeks after starting therapy (17A ). After withdrawal of spironolactone, her symptoms resolved and liver function tests improved. She was not rechallenged. Skin A 76-year-old patient developed eczemalike lesions and severe pruritus; histological and immunological investigations showed pemphigoid (18A ). The skin lesions regressed spontaneously within 15 days of spironolactone withdrawal and no relapse was noted over the next 30 months.

Chapter 21

Domenic A. Sica

POTASSIUM-SPARING DIURETICS (SED-14, 674; SEDA-23, 239; SEDA-24, 251)

Amiloride Electrolyte balance Amiloride is a therapeutic option in reducing potassium losses in patients receiving amphotericin. When it was given to 19 oncology patients with marked amphotericin-induced potassium depletion mean serum potassium concentrations increased in the 5 days before and after administration (from 3.4 to 3.9 mmol/l) (19c ). There was also a trend towards reduced potassium supplementation (48 versus 29 mmol/day). Adverse reactions were limited to hyperkalemia in two patients who took amiloride 20 mg/day and a high potassium intake.

Triamterene Urinary tract Triamterene can cause nephrolithiasis. The frequency with which this occurs is unknown, but a recent survey from France has shed some light (20E ). In an analysis of 22 510 urinary calculi performed by infrared spectroscopy, drug-induced urolithiasis was divided into two categories: first, stones with drugs physically embedded (n = 238; 1.0%), notably indinavir monohydrate (n = 126; 53%), followed by triamterene (n = 43; 18%), sulfonamides (n = 29; 12%), and amorphous silica (n = 24; 10%); secondly, metabolic nephrolithiasis induced by drugs (n = 140; 0.6%), involving mainly calcium/vitamin D supplementation (n = 56; 40%) and carbonic anhydrase inhibitors (n = 33; 24%). Druginduced stones are responsible for about 1.6% of all calculi in France. Physical analysis and a thorough drug history are important elements in the diagnosis. The frequency with which triamterene stones occur will relate to the regional patterns of its use. Teratogenicity Neural tube defects, characterized by a failure of the neural tube to close properly after conception, affect about one in 1000 live births in the USA. Periconceptional folic acid supplementation reduces the

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risk. To determine whether periconceptional exposure to folic acid antagonists might therefore increase the risk of neural tube defects, data from a case-control study of birth defects (1979–1998) in the USA and Canada have been examined (21C ). Data on 1242 infants with neural tube defects (spina bifida, anencephaly, and encephalocele) were compared with data from a control group of 6660 infants with malformations not related to vitamin supplementation. Triamterene is a folic acid antagonist and in this series was associated with the development of neural tube defects, but there were too few cases to estimate an odds ratio. Triamterene should be avoided in pregnancy. Risk factors Age Diuretics often cause adverse effects in elderly people, often as a consequence of drug–drug interactions. In addition, multiple chronic diseases, age-dependent pharmacokinetic and pharmacodynamic changes, and impaired homeostasis complicate diuretic therapy in the elderly. Triamterene is often

241 given in combination with the thiazide diuretic bemetizide. The pharmacokinetics and the pharmacodynamics of a fixed combination of bemetizide 25 mg and triamterene 50 mg have been evaluated in 15 elderly patients (aged 70–84 years) and 10 young volunteers (aged 18–30 years) after single doses (on day 1) and multiple doses (at steady state on day 8) (22C ). Mean plasma concentrations of bemetizide, triamterene, and the active metabolite of triamterene, hydroxytriamterene, were significantly higher in the elderly subjects after single and multiple doses and urine flow and sodium excretion rates fell in tandem with the accumulation of these drugs. The glomerular filtration rate, known to be reduced in elderly people, was further reduced at higher concentrations of bemetizide and triamterene, which may explain why there were limited diuretic and saluretic effects after multiple doses. This study clearly points to a modulating effect of the degree of renal function on the diuretic actions of these compounds in the elderly.

REFERENCES 1. Fogari R, Zoppi A. Effects of antihypertensive therapy on sexual activity in hypertensive men. Curr Hypertens Rep 2002; 4: 202–10. 2. Loke Y. Hypertension 1999; 34: 710. 3. Filippi L, Bagnoli F, Margollicci M, Zammarchi E, Tronchin M, Rubaltelli FF. Pathogenic mechanism, prophylaxis, and therapy of symptomatic acidosis induced by acetazolamide. J Invest Med 2002; 50: 125–32. 4. Ozawa H, Azuma E, Shindo K, Higashigawa M, Mukouhara R, Komada Y. Transient renal tubular acidosis in a neonate following transplacental acetazolamide. Eur J Pediatr 2001; 160: 321–2. 5. Gallerani M, Manzoli N, Fellin R, Simonato M, Orzincolo C. Anaphylactic shock and acute pulmonary edema after a single oral dose of acetazolamide. Am J Emerg Med 2002; 20: 371–2. 6. Baer E, Reith DM. Acetazolamide poisoning in a toddler. J Paediatr Child Health 2001; 37: 411–12. 7. Delaney YM, Salmon JF, Mossa F, Gee B, Beehne K, Powell S. Periorbital dermatitis as a side effect of topical dorzolamide. Br J Ophthalmol 2002; 86: 378–80. 8. Mancuso G, Berdondini RM. Allergic contact blepharoconjunctivitis from dorzolamide. Contact Dermatitis 2001; 45: 243. 9. D’Aloia A, Fiorina C, Vizzardi E, Faggiano P, Cas LD. Episodi ricorrenti di edema polmonare acuto non cardiogeno indotti dall’assunzione di idroclorotiazide. Ital Heart J Suppl 2001; 2: 904–7.

10. Sharabi Y, Illan R, Kamari Y, Cohen H, Nadler M, Messerli FH, Grossman E. Diuretic induced hyponatremia in elderly hypertensive women. J Hum Hypertens 2002; 16: 631–5. 11. Al-Salman J, Pursell R. Hyponatremic encephalopathy induced by thiazides. West J Med 2001; 175: 87. 12. Simoes A, Domingos F, Prata MM. Nephrocalcinosis induced by furosemide in an adult patient with incomplete renal tubular acidosis. Nephrol Dial Transplant 2001; 16: 1073–4. 13. Park CW, You HY, Kim YK, Chang YS, Shin YS, Hong CK, Kim YC, Bang BK. Chronic tubulointerstitial nephritis and distal renal tubular acidosis in a patient with frusemide abuse. Nephrol Dial Transplant 2001; 16: 867–9. 14. Bayramgurler D, Ercin C, Apaydin R, Unal G. Indapamide-induced pemphigus foliaceus. J Dermatol Treat 2001; 12: 175–7. 15. Tenenbaum A, Grossman E, Fisman EZ, Adler Y, Boyko V, Jonas M, Behar S, Motro M, ReicherReiss H. Long-term diuretic therapy in patients with coronary disease: increased colon cancer-related mortality over a 5-year follow-up. J Hum Hypertens 2001; 15: 373–9. 16. Jhund PS, Davie AP, McMurray JJ. Aspirin inhibits the acute venodilator response to furosemide in patients with chronic heart failure. J Am Coll Cardiol 2001; 37: 1234–8.

242 17. Thai KE, Sinclair RD. Spironolactone-induced hepatitis. Australas J Dermatol 2001; 42: 180–2. 18. Modeste A-B, Cordel N, Courville Ph, Gilbert D, Lauret Ph, Jolly P. Pemphigoide regressive apres arret d’un diuretique contenant de l’aldactone. Ann Dermatol Venereol 2002; 129: 56–8. 19. Bearden DT, Muncey LA. The effect of amiloride on amphotericin B-induced hypokalaemia. J Antimicrob Chemother 2001; 48: 109–11. 20. Cohen-Solal F, Abdelmoula J, Hoarau MP, Jungers P, Lacour B, Daudon M. Les lithiases uri-

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naires d’origine medicamenteuse. Thérapie 2001; 56: 743–50. 21. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001; 153: 961–8. 22. Muhlberg W, Mutschler E, Hofner A, SpahnLanguth H, Arnold O. The influence of age on the pharmacokinetics and pharmacodynamics of bemetizide and triamterene: a single and multiple dose study. Arch Gerontol Geriatr 2001; 32: 265–73.

Gijsbert B. van der Voet and Frederik A. de Wolff

22 Aluminium

(SED-14, 683; SEDA-23, 231; SEDA-24, 253; SEDA-25, 257) Aluminium is toxic in patients on chronic hemodialysis and peritoneal dialysis and in those taking oral aluminium-containing medications. Aspects of aluminium safety (1R ) and metabolism (2R ) have been reviewed. The association between aluminium in drinking water and Alzheimer’s disease continues to be discussed and remains controversial (3R ). Nervous system Recently, acute neurotoxic adverse effects of aluminium have been reported, caused by the use of aluminiumcontaining surgical cement. • A 52-year-old woman had a resection of an acoustic neuroma (4A ). Bone reconstruction was performed with an aluminium-containing cement and 6 weeks later she had loss of consciousness, myoclonic jerks, and persistent tonic–clonic seizures, effects resembling those of dialysis encephalopathy. She died 6 months later with septic complications. Light microscopy and electron microscopy of the brain showed pathognomonic aluminium-containing intracytoplasmic argyrophylic inclusions in the choroid plexus epithelia, neurons, and cortical glia. These changes are characteristic of dialysis-associated encephalopathy. Atomic absorption spectrometry showed an increase in the mean aluminium concentration in the cortex and subcortex, up to 9.3 µg/g (reference range under 2 µg/g); a laser microprobe showed increased aluminium in subcellular structures.

This case shows again the extraordinary neurotoxic potency of aluminium, which was initiated by about 30 mg and apparently caused by direct access of aluminium to the brain parenchyma via cerebrospinal fluid leakage. Skin Persistent skin lesions occurred in three patients after the administration of aluminium hydroxide-containing vaccines. The mechanism of these persistent lesions is controversial. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Metals • A 19-year-old woman presented with multiple itchy nodules on the outer aspects of the upper arms at the sites of previous vaccine injections (5A ). There were several nodules, ranging from a few millimeters to 1 cm in diameter, some with overlying hyperpigmented skin. She had been receiving hyposensitization vaccines to treat recurrent extrinsic asthma and rhinitis for the previous 4 years. A skin biopsy showed a normal epidermis and upper dermis. There were multifocal unencapsulated granulomatous infiltrates in the deep dermis and subcutaneous tissues, disrupting the normal architecture of the latter. The infiltrate was predominantly composed of histiocytes with foreign body giant cells. There were also fibroblasts, fibrosis, and perivascular lymphocytes and plasma cells, with a few eosinophils. There was a granular basophilic material within the cytoplasm of some histiocytes. However, patch tests with aluminium chloride, nickel sulfate, and potassium dichromate were all negative. She was treated with potent topical corticosteroids and oral antihistamines, with some relief, but the nodules persisted 2 years later. • A 37-year-old woman with a 5-year history of multiple itchy nodules on the outer aspects of the upper parts of the arms at sites of previous vaccine injections had been receiving hyposensitization vaccines to treat recurrent extrinsic asthma and rhinitis for 10 years (5A ). Physical examination and a biopsy of one of the nodules were identical to those of the previous case. Patch tests with aluminium chloride were negative. Symptomatic relief was obtained with topical corticosteroids and oral antihistamines. The nodules persisted for at least 3 years. • A 52-year-old woman, allergic to wasp venom, was hyposensitized with a vaccine containing wasp venom precipitated on aluminium hydroxide (6A ). Each subcutaneous injection of the extract was followed by cooling of the acute local reaction at the injection site for about 1 hour. As soon as 24 hours after the second maintenance dose, she developed tender, erythematous, ill-demarcated, indurated plaques at the injection sites on both lateral thighs. The lesions resolved spontaneously after several weeks, leaving residual hyperpigmentation and subcutaneous atrophy. They reappeared with each treatment, even after the vaccine was changed to a lyophilized, aluminium-free extract. No further lesions occurred when the injection sites were not cooled, even though the aluminium hydroxide vaccine was continued. Patch tests with the vaccine, aluminium hydroxide, human albumin, phenol, and aluminium chloride hexahydrate were all negative. A biopsy of the skin lesions

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showed lobular panniculitis, with lipocyte necrosis and a mixed cellular infiltrate of neutrophils, lymphocytes, and histiocytes. Ultrasound examination of the atrophic areas showed significantly thinner subcutaneous tissue than in the normal contralateral skin. Rechallenge with an ice pack alone on the upper arm caused a similar skin lesion to appear within 24 hours.

Various mechanisms were postulated to explain these persistent lesions, such as a non-allergic direct toxic effect of aluminium and a delayed hypersensitivity reaction to aluminium.

Antimony

(SED-14, 683; SEDA-24, 254;

SEDA-25, 258) Pancreas Acute pancreatitis, rarely reported, developed during treatment with meglumine antimoniate for visceral leishmaniasis in a young boy (7A ). • A 2-year-old boy with a history of intermittent high-grade fever, sweating, and abdominal distension, developed visceral leishmaniasis. He was given meglumine antimoniate (Glucantime® , Rhone Poulenc, France) 5 mg/kg/day, and the dosage was doubled every other day to reach 20 mg/kg/day. Two days after he had reached the full dose, his temperature returned to normal, his general condition improved, and his liver and spleen began to shrink. However, the serum amylase increased to 254 units/l. Because he was asymptomatic, treatment with meglumine antimoniate was continued. However, on day 10 he complained of vomiting and abdominal pain with rebound tenderness. Acute pancreatitis was confirmed by serum amylase and lipase values up to 1557 and 320 units/l respectively and by ultrasound findings of dilatation and edema of the pancreatic ducts. Meglumine antimoniate was withdrawn and the pancreatitis was managed conservatively. Two days later his fever increased and the spleen and liver began to enlarge. He was given allopurinol (20 mg/kg/day) and ketoconazole (5 mg/kg/day) and became afebrile; the spleen and liver began to shrink, his pancytopenia improved, and the albumin : globulin ratio and serum amylase and lipase activities returned to normal. The acute pancreatitis recovered uneventfully.

Arsenic

(SED-14, 686; SEDA-23, 232; SEDA-24, 254; SEDA-25, 258) Arsenic trioxide is used to treat acute promyelocytic leukemia (8R ) and is emerging as a

Gijsbert B. van der Voet and Frederik A. de Wolff

therapy for multiple myeloma (9R ). It is also found in ethnic medicines. Cardiovascular In 19 patients with hematological malignancies given arsenic trioxide 10–20 mg in 500 ml of 5% dextrose/isotonic saline over 3 hours daily for up to 60 days, there were three cases of torsade de pointes (10AC ). Nervous system Arsenic-induced neurotoxicity in a child was caused by the use of an Indian ethnic remedy. • A 5-year-old child who had been taking Indian ethnic remedies for congenital bilateral retinoblastoma became anorexic and restless, with nausea, fatigue, paresthesia, and progressive weakness of the legs (11A ). A year later he developed vomiting, cough, hoarseness, and a recurrent fever. Blood tests showed a severe normochromic anemia and a leukopenia with relative and absolute neutropenia. Electromyography showed a moderate distal chronic axonal polyneuropathy. The urinary arsenic concentration was not high (15 µg/g creatinine; reference range below 40), but the hair arsenic concentration was 6.6 mg/kg (reference range below 1 mg/kg). Chronic arsenic poisoning was diagnosed. Arsenic (184 mg/g) was found in one of the ethnic remedies.

Bismuth

(SED-14, 686; SEDA-23, 232; SEDA-24, 255; SEDA-25, 259) Bismuth compounds are traditionally used in gastrointestinal disorders, including the eradication of Helicobacter pylori (12R ). Bismuth is also used topically as a bacteriostatic. Adverse effects that were reported decades ago and almost forgotten are being observed again. Skin A black tongue was reportedly caused by exogenous pigment in chewable bismuth subsalicylate tablets. • A 51-year-old white woman developed a black discoloration of her tongue (13A ). The black substance was easily removed by scraping the surface of the tongue. She denied using tobacco products or alcohol. Her medications included alprazolam, montelukast, amitriptyline, hydroxychloroquine, triamcinolone acetonide, omeprazole, cisapride, and calcium carbonate. She had recently started to chew three to six bismuth subsalicylate tablets daily. She was advised to stop using bismuth subsalicylate and to brush her tongue with

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a soft bristled toothbrush. The discoloration improved within a couple of hours and eventually disappeared completely. She continued to take hydroxychloroquine, a known cause of oral mucosal pigmentation.

Immunologic Sensitization to bismuth derivatives has been reported but is rare. • A 33-year-old woman with atopic hand eczema and allergic rhinitis was given Noviform® , an eye ointment containing bibrocathol (bismuth oxide and tetrabromocathechol), for periorbital dermatitis and noticed an exacerbation of her dermatitis (14A ). A patch-tested was positive for bismuth oxide.

Chromium

(SED-14, 683; SEDA-23, 231; SEDA-24, 255; SEDA-25, 259) Chromium compounds continue to be used in oral and parenteral nutrition, as radiopharmaceuticals, and in artificial hip and knee joints. No new adverse effects have been reported, but the mechanisms of chromium toxicity, carcinogenicity, and allergenicity have been reviewed (15R ).

significant pathology of the mesenchymal tissues, including skeletal abnormalities, vascular degeneration, and bladder diverticula. The central nervous system, in contrast, showed minimal pathology of copper metabolism compared with classical Menkes’ disease. The differential sensitivity of central nervous system and mesenchymal tissues to copper histidine may be due to heterogeneity in the responses of different copper-dependent enzymes.

Urinary tract Abuse of copper sulfate can cause nephrotoxicity. • A 21-year-old pharmacist developed acute renal insufficiency (20A ). Three days before he had dissolved a small quantity of copper sulfate in 5 ml of tap water and injected it intravenously in a suicide attempt. The serum copper concentration was 1950 µg/l (31 µmol/l). He was dialysed and gradually improved over 6 weeks. His serum copper concentration a month after the incident was 500 µg/l (8 µmol/l). At 8 weeks a renal biopsy showed marked patchy tubular atrophy with interstitial fibrosis and mild focal chronic interstitial inflammation. Some tubules showed regenerating epithelial cells with multilayering and mitosis, with a predominant loss of proximal tubules. The findings were suggestive of chronic tubulointerstitial nephritis.

Gallium Copper

(SED-14, 688; SEDA-23, 233; SEDA-24, 256; SEDA-25, 259)

Copper chloride and copper sulfate are used in parenteral nutrition solutions. However, the bulk of publications deal with the metabolism of copper as an essential trace element and the role of copper in Menkes’ disease, Wilson’s disease, and Alzheimer’s disease (16R ) and recently also in prion disease (17R ). A new compound, copper histidine, is increasingly being used in Menkes’ disease and is effective. Copper-containing intrauterine devices are still in use (18R ), without new information about adverse effects. Copper histidine modifies the severity of Menkes’ disease and allows survival into adolescence (19A ). The neurological abnormalities respond better than the connective tissue abnormalities. • A male with Menkes’ disease and low plasma concentrations of copper (3.6 µmol/l) and ceruloplasmin (50 mg/l) received copper histidine and died aged 10. Post-mortem examination showed

(SED-14, 690; SEDA-23, 234; SEDA-24, 256; SEDA-25, 260) Gallium alloys are used in dental restoration materials. Gallium compounds containing 67 Ga are also used in diagnostic imaging of cancers, inflammation, and infection (21R ). Abnormal uptake of 67 Ga is reported as an adverse effect in diagnostic procedures, as in three cases: • a 72-year-old man with acute lymphocytic leukemia who had normal 67 Ga uptake in all tissues except the liver (22A ); • a 26-year-old pregnant woman with a mediastinal lymphoma that did not accumulate 67 Ga (23A ); • a 49-year-old man with fever and increased 67 Ga uptake in the lungs but no other evidence of infection or cancer (24A ).

Gold

(SED-14, 690; SEDA-23, 234; SEDA-24, 257; SEDA-25, 260) Gold compounds still form an integral part of the armamentarium of antirheumatic drug ther-

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apy (25R ). The molecular mechanisms of action of gold have recently been reviewed (26R ). Nervous system Intrathecal colloidal gold has been used as an adjunct in the treatment of childhood neoplasms, including medulloblastoma and leukemia. Long-term follow-up of patients treated with intrathecal colloidal gold has been described and the high incidence of delayed cerebrovascular complications and their management has been emphasized (27C ). Between 1967 and 1970, 14 children with a posterior fossa medulloblastoma underwent treatment consisting of surgical resection, external beam radiotherapy, and intrathecal colloidal gold. All had persistent or recurrent disease and six died within 2 years of treatment. The eight surviving patients developed significant neurovascular complications 5–20 years after treatment. Three patients died as a result of aneurysmal subarachnoid hemorrhage, and five developed cerebral ischemic symptoms from a severe vasculopathy that resembled moyamoya disease. Although therapy with colloidal gold results in long-term survival in a number of cases of childhood medulloblastoma, this study suggests that its severe cerebrovascular adverse effects fail to justify its use. The authors recommended routine screening of any long-term survivors after colloidal gold therapy to exclude the presence of an intracranial aneurysm and to document the possibility of moyamoya disease. Respiratory Pneumonitis associated with gold has been reported in a woman with rheumatoid arthritis. • A 77-year-old woman with rheumatoid arthritis was given sodium aurothiomalate 50 mg intramuscularly weekly, following a test dose of 10 mg (28A ). Her rheumatoid arthritis responded well, but after a cumulative dose of 560 mg of gold she became progressively short of breath on exertion and generally felt unwell. She had bilateral basal inspiratory crackles and widespread ill-defined shadowing on the chest X-ray, predominantly in the middle and lower zones of both lungs. A highresolution CT scan showed ground glass opacities, particularly in the upper zones, and thickening of the peribronchovascular interstitium and interlobular septa in the middle and lower zones. Pulmonary function tests showed a restrictive lung defect.The gold injections were discontinued and she responded well to methylprednisolone. A CT scan 10 months later showed almost complete resolution, with some heterogeneity of lung density posteriorly in the lower lobes.

Gijsbert B. van der Voet and Frederik A. de Wolff

Sensory systems Gold keratopathy has been reported in a woman with rheumatoid arthritis (29A ). • A-60-year-old woman with rheumatoid arthritis who was taking prednisone, azathioprine, sulindac, plaquenil, and intramuscular injections of gold sodium thiomalate (50 mg once weekly) developed intense, bilateral ocular irritation and photophobia. She had received a total of 7.4 g of gold over the past 3 years. Her conjunctivae were mildly injected, with bilateral perilimbal chemosis. The peripheral corneae showed 360◦ stromal edema. Mid-stromal vessels were seen entering the edematous stroma from the limbus. She was given topical prednisolone acetate hourly for rheumatoid marginal keratitis. Over the next 2 months her symptoms gradually resolved, but granular, golden-brown, pigmented deposits appeared in the corneal stroma in the same peripheral ring-like distribution as the resolved stromal keratitis. Gold was discontinued. Over the next 6 months, the stromal deposits partially cleared. She then had a milder episode of photophobia and irritation, with stromal edema in the same distribution. This was controlled by topical prednisolone. One year later, she continued to use topical prednisolone once a day and was asymptomatic, with no stromal inflammation, but persistent fine golden granules.

Hematologic Lymphadenopathy is a rare complication of gold injections. • A 34-year-old woman was given intramuscular sodium aurothiomalate for rheumatoid arthritis after little response to anti-inflammatory drugs (30A ). After the sixth injection she developed enlarged neck and axillary lymph nodes. Biopsy showed subtotal infarction of a reactive node, confirmed by histochemical, immunohistochemical, and molecular techniques. Gold was discontinued and the lymphadenopathy gradually resolved over the next 2 months. She continued to suffer from rheumatoid arthritis with no evidence of malignant lymphoma after 3 years.

This case provides strong evidence that gold salts can cause malignant lymphoma. Nails Gold has been reported to cause yellow thickening of the nails and onycholysis (31A ). • A 34-year-old woman with severe rheumatoid arthritis developed yellow thickening of all 20 nails 2 years after starting gold therapy. She had received 50 mg of gold salts intramuscularly at intervals of 2–4 weeks after an initial course of weekly injections (total cumulative dose 90 mg/kg) over 4 years. There was associated thickening of the nail plate, increased transverse curvature, and mild subungual hyperkeratosis. There was onycholysis of both thumbnails and the right little fingernail. There was no associated chrysiasis. Gold

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was withdrawn. The yellow discoloration began to grow out and fingernail growth increased in the next 3 months. Six months later there was further improvement, although light yellow discoloration of all nails persisted and there was markedly increased longitudinal growth. Both thumbnails showed transverse depressions of the nail plate (Beau’s lines) where the change in growth rate had presumably occurred.

Iron

(SED-14, 697; SEDA-23, 235; SEDA-24, 257; SEDA-25, 260) A flow of articles continues to be published regarding the efficacy of iron compounds (such as iron dextran, iron sucrose, iron gluconate) in the parenteral treatment of anemia in conditions such as pregnancy and renal insufficiency. The adverse effects of the available formulations have resulted in trials to optimize dose regimens. New oral formulations with improved intestinal iron absorption are being marketed and their efficacy and toxicity are being studied (32R ). Despite the use of recombinant erythropoietin, anemia remains a significant problem for patients with end-stage renal disease (33C ). Because oral iron formulations are relatively ineffective and poorly tolerated, intravenous iron dextran has been widely used, despite the risk of adverse effects. A large database of clinical variance reports from Fresenius Medical Care North America (FMCNA) has been analysed to determine the incidence of suspected adverse drug reactions of iron dextran and the associated patient characteristics, dialysis practice patterns, and outcomes (33C ). A case–cohort design was used, comparing individuals who had suspected adverse drug reactions with the overall population. Out of 841 252 intravenous iron dextran administrations over 6 months, there were 165 reported suspected adverse drug reactions, corresponding to an overall rate of 0.000196%, or about 20 per 100 000 doses. Hospital evaluation was required in 43 patients (26%), 18 (11%) required hospitalization, and one (0.6%) died. Dyspnea (43%), nausea (34%), vomiting (23%), flushing (27%), pruritus (25%), hypotension (23%), and neurological symptoms (23%) were the most common adverse reactions. Serious adverse reactions to intravenous

247 iron dextran are rare and difficult to predict; the risk appears to depend on the specific formulation of intravenous iron dextran. Large doses of intravenous iron dextran and iron saccharate have been compared in a retrospective study of 379 patients who had attended peritoneal dialysis clinics in the past 5 years (34C ). Of these, 62 were selected to receive intravenous iron based on ferrokinetic markers of iron deficiency, non-compliance with or ineffectiveness of oral iron, or increased erythropoietin requirements. Intravenous iron was given as two injections of 500 mg each 1 week apart in 61 patients, 33 of whom received iron dextran, 23 iron saccharate, and five both iron dextran and iron saccharate. One patient developed anaphylaxis to a test dose of iron dextran and was excluded from further therapy. Blood samples were collected before and 3 and 6 months after iron infusions. Five of the 34 patients who received iron dextran developed minor adverse effects and one had anaphylaxis to the test dose. Of the 23 patients who received iron saccharate, one had an anaphylactic reaction and two had transient chest pain, which subsided without therapy. There were more adverse effects with iron dextran (7.4% of injections) compared with iron saccharate (4.3% of injections), but this difference was not statistically significant. The number of episodes of peritonitis also increased during the 6 months after intravenous iron infusion, especially with iron dextran, compared with the number of episodes during the 6 months before iron infusions, although the difference was not statistically significant. Cardiovascular Non-transferrin-bound iron, which increases after intravenous ferric saccharate, has been suggested to act as a catalytic agent in oxygen radical formation in vitro, and may therefore contribute to endothelial impairment in vivo (35C ). The effect of 10 mg ferric saccharate infusion has been investigated in 20 healthy volunteers. Ferric saccharate caused a greater than four-fold increase in non-transferrin-bound iron and transient significant reduction in flow-mediated dilatation 10 minutes after infusion of ferric saccharate. The generation of superoxide in whole blood increased significantly 10 and 240 minutes after infusion of ferric saccharate by 70% and 53% respectively. Thus, infusion of iron leads to increased oxygen radical stress and acute endothelial dysfunction.

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Lead

(SED-14, 701; SEDA-24, 258; SEDA-25, 261) Lead poisoning from occupational and environmental sources continues to be reported. The biological chemistry of lead has recently been reviewed (36R ). Lead compounds have no medical uses, but they are found in some Asian herbal medicines and can cause lead poisoning. • A 23-year-old Asian butcher developed diffuse abdominal pain, vomiting, and diarrhea, followed by constipation (37A ). He had a sinus tachycardia and generalized abdominal tenderness without peritonism. His serum bilirubin concentration and alanine transaminase activity were raised, but alkaline phosphatase activity, albumin concentration, and prothrombin time were normal. He had a blood lead concentration of 3.7 µmol/l and a raised zinc protoporphyrin concentration, diagnostic of lead poisoning. He had taken a herbal medicine, purchased in India, for vague ailments. He stopped taking it, and was asymptomatic 3 months later, with normal liver function tests and marked falls in blood lead (1.9 µmol/l) and zinc protoporphyrin.

Manganese

(SED-14, 702; SEDA-23, 235; SEDA-24, 259; SEDA-25, 261) Trace elements are required in patients receiving long-term parenteral nutrition (38A ) and the use of manganese has recently been reviewed (39R ). Adverse effects continue to be reported. Two cases of manganese intoxication during intermittent parenteral nutrition have been reported. In one case manganese had been given once or twice a week for 4 years and in the other case twice a month for 5 years. Both patients had mild headache and dizziness. One had mild hepatic dysfunction. After withdrawal of manganese the symptoms all disappeared. Patients should be carefully monitored when receiving long-term parenteral nutrition including manganese, even when the manganese dose is small and administration infrequent.

Mercury

(SED-14, 702; SEDA-23, 235; SEDA-24, 260; SEDA-25, 262) Controversy about mercury toxicity from dental amalgam continues. A recent meta-analysis

Gijsbert B. van der Voet and Frederik A. de Wolff

has shown numerous logical and methodological errors in the anti-amalgam literature (40M ). The author concluded that the evidence supporting the safety of amalgam is compelling. Mercury compounds, including thiomersal, are used as preservatives in eye drops and injection solutions. Ethylmercury toxicity and sensitization from thiomersal-containing vaccines have been indecisively discussed (41R , 42R ). The toxicity of ethylmercury has also been discussed (43R ). The use of homeopathic medicines can cause mercury allergy (baboon syndrome). • A 5-year-old girl developed an itchy erythematous macular rash, symmetrically distributed in the anogenital area and thighs (44A ). The lesions developed into a widespread maculopapular vesicular rash in 48 hours, sparing the face, palms, and soles. The eruption cleared after systemic corticosteroids and antihistamines, with scaling and post-inflammatory hypopigmentation. She had developed neonatal periumbilical dermatitis associated with the application of merbromin to the cord, and 24 hours before the onset of the rash had taken a single homeopathic tablet (Mercurius Heel® ), which contained soluble mercury. Allergy tests to a standard series of foods and respiratory allergens were negative and total IgE was normal. Patch testing to allergens showed positive reactions to thiomersal and metallic mercury.

Nickel (SED-14, 704; SEDA-23, 235; SEDA-24, 260; SEDA-25, 262) Nickel allergy is not new and continues to be an adverse effect of the use of nickel-containing medical appliances, such as orthopedic metal alloys, dental materials, and implants (45R ). Immunologic No new adverse effects have been reported, but cases of nickel allergy continue to appear in relation to medical appliances. • A 35-year-old non-atopic diver with no previous history of metal allergy slipped on a wet pier and sustained a multiple compound trimalleolar fracture of the right ankle (46A ). The tibia and fibula were immediately surgically realigned and retained by metal plates and screws, and the ankle was immobilized in plaster for 5 weeks. One month later he developed itching, scaling, vesiculopapular dermatitis on several fingers of both

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hands, which worsened over the next few months. Patch testing was positive to nickel sulfate, chromate, and cobalt.

The author concluded that the patient had become sensitized to nickel and chromate in the orthopedic metals. It was also apparent that sensitization to cobalt had occurred, even though no cobalt could be shown on analysis. The hand dermatitis improved after removal of the metal from the ankle, but nevertheless continued to relapse.

Selenium

(SED-14, 704; SEDA-23, 236; SEDA-24, 260; SEDA-25, 263) Selenium sulfide continues to be used as an antimycotic in shampoos, and selenite in mineral supplements and parenteral nutrition. The protective effects of selenium against cancer have recently been reviewed (47R ).

fective in boosting immunity. The serum silver concentration was 3.4 µmol/l (reference range under 0.02 µmol/l). Silver was withdrawn and her serum silver concentrations normalized some months later.

Reproductive system Vaginal argyrosis has been attributed to a combination of silver sulfadiazine and Aci-Jel (a buffered acid jelly containing acetic acid) (50A ). • A 67-year-old woman with a sore vulva applied flamazine cream (containing 1% silver sulfadiazine) topically for nearly 10 years and then AciJel. She developed widespread black deposits in the vagina consistent with argyrosis. There were dark pigmented areas around the urethral meatus, Skene’s ducts, and hymeneal remnants, and a circumferential deposit around the upper third of the vagina. Biopsies showed mild acanthosis and a mild chronic inflammatory infiltrate in the upper dermis, with black pigment granules 0.5–2 µm in size in the superficial dermis. Electron probe analysis confirmed the presence of silver. The creams were withdrawn and 6 months later the vagina showed no signs of argyrosis.

(SED-14, 705; SEDA-23, 236; SEDA-24, 261; SEDA-25, 263)

It is likely that reducing agents in the gel base of Aci-Jel interacted with the silver sulfadiazine, causing deposition of silver and discoloration of the vagina.

Cardiovascular A chronic inflammatory reaction in a prosthetic valve has been attributed to silver (48A ).

Titanium

Silver

• A prosthetic mitral valve (St Jude Medical Silzone) was implanted in a 72-year-old woman, and 4 months later she had acute cardiac failure due to partial detachment of the prosthetic valve. The mitral annulus was ulcerated and there were multiple erosions in the tissues in contact with the valve. Histology showed chronic inflammation with hemosiderin deposits and giant cells. She was not allergic to silver.

The silver-coated sewing cuff had caused a chronic inflammatory reaction due to a toxic reaction to silver. The Silzone valve was withdrawn from the market in January 2000. Nutrition Failure to thrive in a child has been attributed to silver toxicity (49A ). • A 12-month-old girl with failure to thrive had been treated with various supplements and alternative therapies (including a blend of kelp, Lactobacillus acidophilus, wheat, rye, and barley) or with colloidal silver. The silver was given in the form of a suspension and was thought to be ef-

(SED-14, 706; SEDA-23, 237; SEDA-24, 261; SEDA-25, 263) Titanium is used in a large number of medical devices, including dental material (51R ) and prostheses. A cohort of 120 consecutive patients (66 women, 54 men; mean age 66 years) with 126 prostheses inserted between March and December 1989 were followed prospectively both clinically and radiologically for a mean of 9.1 years (52C ). Forty patients (41 hips) died, 9 patients (9 hips) were interviewed by telephone, and 71 (76 hips) were available for follow up. Four hips had been revised: two of them because of aseptic loosening of the femoral component, one because of a late infection—all after 9 years— and one because of a periprosthetic fracture after 6 years. The 9-year survival was 97% and for aseptic loosening of the stem 98%. None of the cups had to be revised for aseptic loosening. The result was excellent or good in 88%,

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moderate in 8%, and poor in 4%. Radiological analysis showed no osteolysis or radiolucent lines in 59 prostheses (78%). Nine stems (12%) showed a radiolucent line. Focal osteolysis was detected in eight cases (10%) in one or more Gruen zones. The distribution of the osteolytic areas showed that zones VII, VI, V, and II were predominantly affected in decreasing frequency. There was no osteolysis on the acetabular side. These results do not confirm the high rate of osteolysis and revisions with the Muller titanium alloy Straight Stem used in some other institutions. Skin Exacerbation of atopic dermatitis has been attributed to titanium clips (53A ). • A 28-year-old woman with breast cancer underwent breast conservation, and three titanium clips were placed at the margin of the excision cavity, followed 2 months later by rapid exacerbation of her atopic dermatitis. The skin lesions developed progressively and involved the whole body. Patch tests and lymphocyte stimulation tests could not be performed, owing to the severity of the skin lesions. Various drugs were suspected, but the results of a bidigital O-ring test suggested an allergic reaction to titanium clips. She underwent a second operation to remove the titanium clips under local anesthesia. By 12 months after surgery, the atopic dermatitis had not completely resolved.

Zinc

(SED-14, 706; SEDA-23, 237; SEDA-24, 261; SEDA-25, 264) Zinc compounds are used as minerals, adjuvants, and adstringents. They are usually very

Gijsbert B. van der Voet and Frederik A. de Wolff

safe. The use of zinc acetate in Wilson’s disease has recently been reviewed and recommended rather than copper chelation, because of limited adverse effects. Zinc acetate (Galzin® , Gate Pharmaceutical Co), developed for the treatment of Wilson’s disease (54R ), has been approved (by the US FDA) for maintenance therapy of adult and pediatric disease, but it also has efficacy in the treatment of pregnant women and presymptomatic patients from the start. It also has value as adjunctive therapy for the initial treatment of symptomatic patients. Its mechanism of action involves induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract. Negative copper balance is caused by blockade not only of absorption of food copper but by blockade of reabsorption of the considerable amount of endogenously secreted copper in saliva, gastric juice, and intestinal secretions. It is therefore effective in controlling copper concentrations and toxicity in Wilson’s disease. Zinc’s main advantage over other anticopper agents is its extremely low toxicity. The only adverse effect is some degree of initial gastric irritation in about 10% of patients, which usually abates and becomes insignificant over time. As with all long-term therapies, compliance is a problem in some patients and dictates regular monitoring by measurement of 24-hour urine copper and zinc. As with all anticopper therapies, overtreatment can cause copper deficiency over a long period of time. This is to be avoided, particularly in children, because copper is required for growth.

REFERENCES 1. Hemstreet BA. Use of sucralfate in renal failure. Ann Pharmacother 2001; 35: 360–4. 2. Yokel RA, McNamara PJ. Aluminium toxicokinetics: an updated minireview. Pharmacol Toxicol 2001; 88: 159–67. 3. Flaten TP. Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water. Brain Res Bull 2001; 55: 187–96. 4. Reusche E, Pilz P, Oberascher G, Lindner B, Egensperger R, Gloeckner K, Trinka E, Iglseder B. Subacute fatal aluminum encephalopathy after reconstructive otoneurosurgery: a case report. Hum Pathol 2001; 32: 1136–40.

5. Nagore E, Martinez-Escribano JA, Tato A, Sabater V, Vilata JJ. Subcutaneous nodules following treatment with aluminium-containing allergen extracts. Eur J Dermatol 2001; 11: 138–40. 6. Mooser G, Gall H, Weber L, Peter RU. Cold panniculitis—an unusual differential diagnosis from aluminium allergy in a patient hyposensitized with aluminium-precipitated antigen extract. Contact Dermatitis 2001; 44: 368. 7. Kuyucu N, Kara C, Bakirtaç A, Teziç T. Successful treatment of visceral leishmaniasis with allopurinol plus ketoconazole in an infant who developed pancreatitis caused by meglumine antimoniate. Pediatr Infect Dis J 2001; 20: 455–7.

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8. Zhang T-D, Chen G-Q, Wang Z-G, Wang Z-Y, Chen S-J, Chen Z. Arsenic trioxide, a therapeutic agent for APL. Oncogene 2001; 20: 7146–53. 9. Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. Oncologist 2001; 6: 17–21. 10. Unnikrishnan D, Dutcher JP, Varhneya N, Lucariello R, Api M, Garl S, Wiernik PH, Chiaramida S. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001; 97: 1514–16. 11. Muzi G, Dell’Omo, M, Madeo G, Abbritti G, Caroli S. Arsenic poisoning caused by Indian ethnic remedies. J Pediatr 2001; 139: 169. 12. Trust TJ, Alm RA, Pappo J. Helicobacter pylori: today’s treatment and possible future treatment. Eur J Surg Suppl 2001; 586: 82–8. 13. Ioffreda MD, Gordon CA, Adams DR, Naides SJ, Miller JJ. Black tongue. Arch Dermatol 2001; 137: 968–9. 14. Wictorin Å, Hansson C. Allergic contact dermatitis from a bismuth compound in an eye ointment. Contact Dermatitis 2001; 45: 318. 15. Dayan AD, Paine AJ. Mechanisms of chromium toxicity, carcinogenicity and allergenicity: review of the literature from 1985 to 2000. Hum Exp Toxicol 2001; 20: 439–51. 16. Strausak D, Mercer JF, Dieter HH, Stremmel W, Multhaup G. Copper in disorders with neurological symptoms: Alzheimer’s, Menkes and Wilson diseases. Brain Res Bull 2001; 55: 175–85. 17. Brown DR. Copper and prion disease. Brain Res Bull 2001; 55: 165–73. 18. Thonneau P, Goulard H, Goyaux N. Risk factors for intrauterine device failure: a review. Contraception 2001; 64: 33–7. 19. George DH, Casey RE. Menkes disease after copper histidine replacement therapy: case report. Pediatr Dev Pathol 2001; 4: 281–8. 20. Bhowmik D, Mathur R, Bhargava Y, Dinda AK, Agarwal SK, Tiwari SC, Dash SC. Chronic interstitial nephritis following parenteral copper sulfate poisoning. Renal Fail 2001; 23: 731–5. 21. Boerman OC, Rennen H, Oyen WJ, Corstens FH. Radiopharmaceuticals to image infection and inflammation. Semin Nucl Med 2001; 31: 286–95. 22. Nakahara T, Fujii H, Nakamura K, Hashimoto J, Kubo A. Inexplicable suppression of hepatic uptake of gallium-67, a case report. Ann Nucl Med 2001; 15: 377–9. 23. Kurosaki H, Saito Y, Kawashima M, Ebara T, Yamakawa M, Mitsuhashi N. Accumulation of 67 Ga citrate in early pregnancy. Ann Nucl Med 2001; 15: 289–91. 24. Bernstine H, Bar-Sever Z, Cohen M, Hardoff R. Misleading thoracic Ga-67 uptake caused by splenic displacement. Clin Nucl Med 2001; 26: 147–8. 25. Gabriel SE, Coyle D, Moreland LW. A clinical and economic review of disease-modifying antirheumatic drugs. Pharmacoeconomics 2001; 19: 715–28. 26. Burmester GR. Molekulare wirkungsmechanismen von gold bei der behandlung der rheuma-

251 toiden arthritis–ein update. Z Rheumatol 2001; 60: 167–73. 27. Nussbaum ES, Sebring LA, Neglia JP, Chu R, Mattsen ND, Erickson DL. Delayed cerebrovascular complications of intrathecal colloidal gold. Neurosurgery 2001; 49: 1308–12. 28. Sinha A, Silverstone EJ, O’Sullivan MM. Goldinduced pneumonitis: computed tomography findings in a patient with rheumatoid arthritis. Rheumatology 2001; 40: 712–14. 29. Zamir E, Read RW, Affeldt JC, Ramaswamy D, Rao NA. Gold induced interstitial keratitis. Br J Ophthalmol 2001; 85: 1386–7. 30. Roberts C, Batstone PJ, Goodlad JR. Lymphadenopathy and lymph node infarction as a result of gold injections. J Clin Pathol 2001; 54: 562–4. 31. Roest MAB, Ratnavel R. Yellow nails associated with gold therapy for rheumatoid arthritis. Br J Dermatol 2001; 145: 855–6. 32. Jeppsen RB. Toxicology and safety of Ferrochel and other iron amino acid chelates. Arch Latinoam Nutr 2001; 51: 26–34. 33. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis 2001; 37: 743–9. 34. Prakash S, Walele A, Dimkovic N, Bargmans J, Vas S, Oreopoulos D. Experience with a large dose (500 mg) of intravenous iron dextran and iron saccharate in peritoneal dialysis patients. Peritoneal Dial Int 2001; 21: 290–5. 35. Rooyakkers TM, Stroes ES, Kooistra MP, Van Faassen EE, Hider R, Rabelink TJ, Marx JJ. Ferric saccharate induces radical stress and endothelial dysfunction in vivo. Eur J Clin Invest 2002; 32: 9–16. 36. Godwin HA. The biological chemistry of lead. Curr Opin Chem Biol 2001; 5: 223–7. 37. Anderson NR, Gama R, Kapadia S. Herbal remedy poisoning presenting with acute abdomen and raised urine porphyrins. Ann Clin Biochem 2001; 38: 408–10. 38. Masumoto K, Suita S, Taguchi T, Yamanouchi T, Nagano M, Ogita K, Nakamura M, Mihara F. Manganese intoxication during intermittent parenteral nutrition: report of two cases. J Parenter Enter Nutr 2001; 25: 95–9. 39. Dickerson RN. Manganese intoxication and parenteral nutrition. Nutrition 2001; 17: 689–93. 40. Dodes JE. The amalgam controversy. An evidence-based analysis. J Am Dent Assoc 2001; 132: 348–56. 41. Clements CJ, Ball LK, Ball R, Pratt RD. Thiomersal in vaccines: is removal warranted? Drug Saf 2001; 24: 567–74. 42. Van‘t Veen AJ. Vaccines without thiomersal: why so necessary, why so long coming? Drugs 2001; 61: 565–72. 43. Magos L. Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products. J Appl Toxicol 2001; 21: 1–5. 44. Audicana M, Bernedo N, Gonzalez I, Munoz D, Fernandez E, Gastaminza G. An unusual case

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of baboon syndrome due to mercury present in a homeopathic medicine. Contact Dermatitis 2001; 45: 185. 45. Grimaudo NJ. Biocompatibility of nickel and cobalt dental alloys. Gen Dent 2001; 49: 498–503. 46. Kanerva L, Förström L. Allergic nickel and chromate hand dermatitis induced by orthopaedic metal implant. Contact Dermatitis 2001; 44: 103–4. 47. Combs GF Jr, Clark LC, Turnbull BW. An analysis of cancer prevention by selenium. BioFactors 2001; 14: 153–9. 48. Tozzi P, Al-Darweesh A, Vogt P, Stumpe F. Silver-coated prosthetic heart valve: a doublebladed weapon. Eur J Cardio-Thorac Surg 2001; 19: 729–31. 49. McIntyre E, Wilcox J, McGill J, Lewindon PJ. Silver toxicity in an infant of strict vegan parents. J Pediatr Gastroenterol Nutr 2001; 33: 501–2.

Gijsbert B. van der Voet and Frederik A. de Wolff 50. Thomas K, Sproston ARM, Kingsland CR. A case of vaginal argyrosis: all that glistens isn’t gold. Br J Obstet Gynaecol 2001; 108: 890–1. 51. Kononen M, Kivilahti J. Fusing of dental ceramics to titanium. J Dent Res 2001; 80: 848–54. 52. Acklin YP, Berli BJ, Frick W, Elke R, Morscher EW. Nine-year results of Muller cemented titanium straight stems in total hip replacement. Arch Orthop Trauma Surg 2001; 121: 391–8. 53. Tamai K, Mitsumori M, Fujishiro S, Kokubo M, Ooya N, Nagata Y, Sasai K, Hiraoka M, Inamoto T. A case of allergic reaction to surgical metal clips inserted for postoperative boost irradiation in a patient undergoing breast conserving therapy. Breast Cancer 2001; 8: 90–2. 54. Brewer GJ. Zinc acetate for the treatment of Wilson’s disease. Expert Opin Pharmacother 2001; 2: 1473–7.

R.H.B. Meyboom

23 Calcitetracemate The use of calcitetracemate in the treatment of lead poisoning has been described (1cr ). A total of 58 courses were given to 16 patients, as calcitetracemate infusions 500 mg bd for 5 days. No adverse events were observed in any of these patients.

Metal antagonists tions, improve compliance, and facilitate individualization of therapy. Increasing understanding of the kinetics of iron metabolism, iron overload, and the complexity of chelation should further improve therapeutic strategies.

Deferiprone

(SED-14, 719; SEDA-23, 240; SEDA-24, 265; SEDA-25, 268)

IRON CHELATORS Iron chelation treatment has dramatically improved the prognosis of patients with betathalassemia (2R ). Parenteral deferoxamine reduces tissue iron stores, prevents iron-induced organ damage, and reduces morbidity and mortality. However, the burden of prolonged subcutaneous portable pump infusions, adverse reactions, patient non-compliance, and high cost are limiting factors, which have stimulated the development of orally active compounds. Combinations of chemically different types of chelators, which have different iron-carrying capacities and access different iron compartments, may work synergistically and result in increased efficacy, whereas lower doses of individual drugs may be less toxic (3R ). Examples are parenteral deferoxamine, oral deferiprone or 2,3-dihydroxybenzoic acid (2,3DHB), or oral deferiprone with oral N,N′ -bis(2hydroxybenzyl)ethylenediamine-N,N′ -diacetic acid (HDEB). Iron bound to a “shuttle”, an oral agent that mobilizes tissue iron, is exchanged in the blood stream with a “sink”, such as parenteral deferoxamine, and excreted via the kidneys, while the shuttle is reused. Combinations of different iron chelators can enhance iron excretion, target specific iron compartments, minimize adverse effects, increase treatment op© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Deferiprone and deferoxamine have been compared in Lebanese patients, mainly with thalassemia major, of whom 17 used oral deferiprone, 75 mg/kg/day, and 40 received subcutaneous deferoxamine, 20–50 mg/kg/day on 5 days a week; the patients were followed for 2 years (4cr ). All those who took deferiprone did so because deferoxamine had not been suitable, because of either non-compliance or adverse reactions. One of those taking deferiprone withdrew for unknown reasons (and was excluded from the study). Deferiprone was commonly associated with orange discoloration of the urine. Six patients complained of joint pains, mainly in large joints (moderate to severe in two and mild in four), not requiring drug withdrawal. Seven patients reported nausea, four had headaches, two rashes, and two fatigue. Abdominal discomfort, mouth ulcers, and sore throat each occurred in one patient. Although two patients had transient falls in neutrophil count (to 1.3 and 1.44 × 109 /l), presumably secondary to a viral infection, there were no cases of agranulocytosis.

Deferoxamine (SED-14, 714; SEDA-23, 240; SEDA-24, 265; SEDA-25, 267) Deferiprone and deferoxamine have been compared in Lebanese patients, mainly with thalassemia major, of whom 17 used oral deferiprone, 75 mg/kg/day for 2 years, and 40

253

254 received subcutaneous deferoxamine, 20–50 mg/kg/day on 5 days a week (4cr ). Those who received deferoxamine had done so for 4–24 years and were followed for 2 years. Infusion site reactions occurred in 34 patients, including pain, tenderness, itching, burning, erythema, swelling, induration, and lipodystrophy. Five patients had disturbances of vision and hearing, three had growth retardation. Six patients had increased heart rates, four had dizziness, and one had leg cramps. The use of sonography as a cheap and easy tool in the assessment of deferoxamineinduced bone dysplasia of the knee has been studied in 32 patients with thalassemia major (5CR ). Characteristic lesions were notching at the metaphyseal corner, a blurred or irregular peripheral juxtaphyseal metaphyseal contour, and widening of the peripheral juxtaphyseal metaphyseal echogenic interface. There were 14 true-positive results, 10 true-negative, 7 false-negative, and 1 false-positive. Thus, sonography is specific but not sensitive in the diagnosis of deferoxamine-induced dysplasia. Because of its high specificity, low cost, and non-invasiveness sonography may have a role in the longitudinal monitoring of deferoxamineinduced bone dysplasia. Nervous system Optic neuropathy and sensorineural hearing loss have been attributed to deferoxamine (6CR ). • A 25-year-old woman with beta-thalassemia, who had received subcutaneous deferoxamine 2 g/day (50 mg/kg) for 7 days a week for 3 years, developed visual loss. Her best-corrected visual acuity was 20/60 bilaterally. Automated perimetry showed bilateral central scotomata, and a Farnsworth Panel D-15 test showed an irregular pattern of errors. There were no lens opacities, and fundoscopy and fluorescein angiography were normal. Audiometry showed a bilateral high-frequency sensorineural deficit. Two days after withdrawal of deferoxamine and oral administration of zinc sulfate 20 mg/day the central scotomata disappeared and her color vision and audiographic abnormalities reversed completely. The serum ferritin concentration was 656 ng/l.

Since the serum ferritin concentration was relatively low, the original dose of deferoxamine may have been too high. Although zinc concentrations were not measured before treatment, the rapid and complete improvement in 48 hours after starting zinc sulfate suggested that deferoxamine-induced zinc deficiency may also have played a role.

Chapter 23

R.H.B. Meyboom

Edetate

(SED-14, 721; SEDA-23, 242; SEDA-25, 268) Despite controversy for more than a quarter of a century, chelation therapy for atherosclerotic cardiovascular disease is still widely used and accounts for about 800 000 patient visits in the USA each year. However, there is still no proof of efficacy, while the dangers are obvious (SED-14, 722; 7R ).

PENICILLAMINE AND RELATED DRUGS Bucillamine

(SED-14, 736)

Skin Bucillamine is a DMARD, particularly used in Japan, with similar autoimmunogenic properties to penicillamine. A patient taking bucillamine developed a skin eruption that simultaneously had features of pemphigus foliaceus and pemphigus vulgaris and was associated with glomerulonephritis (8CR ). • A 62-year-old man with rheumatoid arthritis developed a rash on the neck, chest, and legs after taking oral bucillamine (dose not specified) for 6 months. The lesions were of two different types: small pigmented, vesicular, erythematous macules, similar to pemphigus foliaceus, and skin erosions as seen in pemphigus vulgaris. There was no mucosal involvement. Serology was positive for antinuclear antibodies (1 : 320, nucleolar type). A biopsy showed acantholysis in the granular, spinous, and suprabasal layers. Direct immunofluorescence showed intercellular deposits of IgG and C3 throughout the epidermis, but not in the basement membrane. Indirect immunofluorescence of donor skin showed IgG reactivity in the nuclei of keratinocytes. An enzyme-linked immunoadsorbent assay (ELISA), using baculovirus-expressed recombinant desmogleins as antigen, was positive and indifferent to circulating anti-Dsg1 and antiDsg3 antibodies.

This patient also had the nephrotic syndrome (proteinuria 8.7 g/day, total serum protein 59 g/l, serum total cholesterol 10.2 mmol/l), probably also due to bucillamine. A renal biopsy was consistent with membranous glomerulonephritis. The skin lesions improved within 1 month of bucillamine withdrawal, but full recovery of both cutaneous and renal injury was achieved only after the use of prednisone, 40 mg/day for 2 weeks.

Metal antagonists

Chapter 23

Penicillamine

(SED-14, 723; SEDA-23, 242; SEDA-24, 266; SEDA-25, 269)

Although penicillamine and gold compounds were both originally used on the basis of erroneous pharmacological hypotheses, they have been strongholds in the treatment of debilitating rheumatoid arthritis for more than a quarter of a century (9R ). Whereas they do not have much effect on the progression of joint damage, they have unexpectedly been found to be associated with a remarkable diversity of serious adverse reactions. In hindsight, they have played central roles in improvements in the understanding of the pathology of rheumatoid arthritis and of the methods of studying the benefits and harms of therapeutic strategies in rheumatoid arthritis and other chronic progressive diseases. The recent advent of novel drugs with different mechanisms of action, such as cytokine antagonists, has empowered rheumatologists with effective new instruments (10R –12R ). The effect of a patient education program, taught by rheumatology nurse practitioners, on adherence of patients to treatment with penicillamine has been studied (13CR ). The program significantly and persistently increased adherence over a period of 6 months in 51 patients compared with 49 controls (who used penicillamine without the educational program). Most of the patients (in both groups) had adverse effects, including thrombocytopenia in two and myasthenia gravis in one. The number of patients who asked to have penicillamine withdrawn was far higher in the control group (n = 12) compared with the patient education group (n = 2). Taste disturbances, for example, led to self-withdrawal in four patients, all in the control group. On the other hand, the patients in the patient education group were much more reluctant to withdraw, even in the event of serious adverse effects. A diagnostic and monitoring database program called DIAMOND runs across a network of personal computers throughout the Staffordshire Rheumatology Centre (14CR ). For about 10 years drug histories, blood test results, and clinical correspondence files for about 2000 patients have been accessible, and the system is linked to the main hospital pathology database. The DIAMOND system has been used to study adverse reactions and durations of treatment for commonly prescribed DMARDs, including penicillamine (combination treatments

255 excluded). With a median survival time of 34 months, penicillamine held an intermediate position, between methotrexate (>96) and azathioprine (13) at the extremes; 38% of the patients continued to take penicillamine after 5 years. There were strong associations between penicillamine and both proteinuria and thrombocytopenia (both well established adverse effects of penicillamine; SED-14, 727-8). Myasthenia gravis occurred in eight of 582 penicillamine users (1.4%) and not in patients using other DMARDs. Endocrine Excessive enlargement of the breasts has again been attributed to penicillamine (SED-14, 733). There has now been a report of a case in which breast enlargement was accompanied by systemic lupus erythematosus (15CR ). • A 37-year-old woman had a 7-year history of rheumatoid arthritis for which she had taken penicillamine for about 1–2 years (dose not specified). When she presented at the Cambridge Breast Unit she had had rapidly increasing painful enlargement of the breasts for 7 months. The breasts were symmetrically enlarged (from an A cup to DD) and had thickened and erythematous skin. There were several palpable masses; mammography showed no evidence of malignancy and an ultrasound scan showed large hypo-echoic nodules with engorged vessels. Histology of a large lump in the left breast showed a fibroadenoma. Immunohistochemistry for estrogen receptors showed 50% nuclear staining. She had stopped taking penicillamine 2 months before because of a lupus-like syndrome with thrombocytopenia, lymphopenia, and positive ANA and DNA antibodies (whether single-stranded or double-stranded was not stated).

Although breast gigantism is a rare manifestation of idiopathic SLE, autoimmune substances could have stimulated mammary duct proliferation or mimicked estrogen or other growth factors in the breast. Liver Copper and iron are both capable of electron exchange and play a complex role in oxygen utilization. Copper proteins are critical in the transfer and transport of iron (16R ). In four patients with Wilson’s disease the fall in serum ceruloplasmin concentrations after treatment with penicillamine was associated with increased hepatic iron content; in two of these patients serum ferritin was increased (17CR ). In another patient a liver biopsy taken after 15 years of treatment

256 with penicillamine (600 mg/day) and zinc sulfate (400 mg/day) showed iron-laden hepatocytes, whereas histochemically detectable iron had been absent from an initial biopsy (18C ). The copper-containing proteins ceruloplasmin and its membrane-bound homologue hephaestin are pivotal in iron metabolism. In addition there are intracellular transfer proteins (“chaperone”) that deliver copper to ferroxidase proteins. Intracellular ferroxidase proteins accelerate the efflux of iron through stimulating the conversion of Fe2+ to Fe3+ and subsequent binding to transferrin. Presumably excess loss of copper due to penicillamine or penicillamine plus zinc, can reduce ferroxidase activity and cause intracellular iron deposition and paradoxical deterioration in liver function. Therefore, during treatment of Wilson’s disease when the non-ceruloplasmin-bound copper falls to within the reference range (<150 µg/l), the maintenance dose of penicillamine should be reduced to the minimum needed; temporary withdrawal of penicillamine may even be indicated (16R ). Urinary tract In a prospective study of renal disease in 235 patients with early rheumatoid arthritis, persistent proteinuria and a raised serum creatinine concentration were predominantly related to drugs, including penicillamine and other DMARDs, whereas isolated hematuria was more directly associated with the activity of the disease process (19CR ). Risk factors for drug-induced proteinuria were raised C reactive protein, raised erythrocyte sedimentation rate, and age over 50 years. On the basis of experience in one patient and 10 published case histories, the “scleroderma– pulmonary–renal syndrome”, a rare and usually fatal complication of systemic sclerosis, characterized by fulminant alveolar hemorrhage and rapidly progressive renal failure, has been reviewed (20Ar ). In this patient penicillamine was continued, and the disease progressed. The authors recognized that penicillamine is an established cause of a similar disorder, i.e. Goodpasture’s syndrome (SED-14, 729). However, they did not comment on the fact that five of the 11 patients in their review had been using penicillamine. Skin An 84-year-old woman, who had been taking penicillamine 1.2 g/day for 50 years

Chapter 23

R.H.B. Meyboom

for Wilson’s disease, developed generalized, rapidly progressive, acquired cutis laxa (21Cr ). Faulty production of collagen and elastin fibers lead to gross folding of the skin, giving it an appearance reminiscent of the folds of the cerebral cortex. In a 31-year-old Korean woman with Wilson’s disease, high doses (1–2 g/day) of penicillamine led to the development of a dermopathy, with mildly itchy, matchhead-sized, creamcolored papules on top of dark reddish plaques on both knees and elbows (22c ). Pregnancy The treatment of rheumatoid arthritis during pregnancy has been reviewed (23R ). The author came to a similar conclusion as expressed in SED-14 (p. 734), that penicillamine can be used in women with Wilson’s disease but is better avoided in patients with rheumatoid arthritis, because of a risk of faulty connective tissue and cutis laxa. It should be added, however, that in Wilson’s disease it is also worth considering if it is possible to control copper metabolism with less penicillamine or without it altogether.

POLYSTYRENE SULFONATES (SEDA-25, 271)

Sodium polystyrene sulfonate Gastrointestinal Acute colonic necrosis associated with sodium polystyrene sulfonate (Kayexalate) enemas continues to be reported (24A ) and critically ill and uremic patients are at particular risk. Upper gastrointestinal damage associated with Kayexalate in sorbitol is reported far less often. However, the clinical, endoscopic, and histological features have been reported in 11 patients with markedly abnormal endoscopic appearances, in some cases closely mimicking other diagnoses, including esophageal carcinoma, Candida esophagitis, and gastric bezoar. There were Kayexalate crystals in biopsies from the esophagus (n = 7), stomach (n = 6), and duodenum (n = 2) (25c ). There was histological and/or endoscopic evidence of mucosal injury in the form of an ulcer or erosion in nine patients. The authors proposed that recognition of Kayexalate crys-

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Chapter 23

tals in histological sections, as a marker of sorbitol-induced mucosal damage, may help in

257 establishing the correct diagnosis in ambiguous cases.

REFERENCES 1. De Haro L, Prost N, Gambini D, Bourdon J-H, Hayek-Lanthois M, Valli M, Jouglard J, Arditti J. Le saturnisme des adultes: experience du Centre antipoison de Marseille de 1993 à 2000. Presse Med 2001; 30: 1817–20. 2. Kontoghiorghes GJ. Clinical use, therapeutic aspects and future potential of deferiprone in thalassemia and other conditions of iron and other metal toxicity. Drugs Today 2001; 37: 23–35. 3. Giardina PJ, Grady RW. Chelation therapy in beta-thalassemia: an optimistic update. Semin Hematol 2001; 38: 360–6. 4. Taher A, Sheikh-Taha M, Koussa S, Inati A, Neeman R, Mourad F. Comparison between deferoxamine and deferiprone (L1) in iron-loaded thalassemia patients. Eur J Haematol 2001; 67: 30–4. 5. Chan Y-L, Chu C-WW, Chik K-W, Pang L-M, Shing M-K, Li C-K. Deferoxamine-induced dysplasia of the knee: sonographic features and diagnostic performance compared with magnetic resonance imaging. J Ultrasound Med 2001; 20: 723–8. 6. Pinna A, Corda L, Carta F. Rapid recovery with oral zinc sulphate in deferoxamine-induced presumed optic neuropathy and hearing loss. J NeuroOphthalmol 2001; 21: 32–3. 7. Frishman WH. Chelation therapy for coronary artery disease: panacea or quackery? Am J Med 2001; 111: 729–30. 8. Ogata K, Nakajima H, Ikeda M, Yamamoto Y, Amagai M, Hashimoto T, Kodama H. Druginduced pemphigus foliaceus with features of pemphigus vulgaris. Br J Dermatol 2001; 144: 421–2. 9. Moreland LW, Russell AS, Paulus HE. Management of rheumatoid arthritis: the historical context. J Rheumatol 2001; 28: 1431–52. 10. Blumberg SN, Fox DA. Rheumatoid arthritis: guidelines for emerging therapies. Am J Managed Care 2001; 7: 617–26. 11. Menninger H. Combination therapy for rheumatoid arthritis: update 2001. Aktuel Rheumatol 2001; 26: 146–58. 12. Russell A, Haraoui B, Keystone E, Klinkhoff A. Current and emerging therapies for rheumatoid arthritis, with a focus on infliximab: clinical impact on joint damage and cost of care in Canada. Clin Ther 2001; 23: 1824–38. 13. Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug treatment for rheuma-

toid arthritis: a randomised controlled trial. Ann Rheum Dis 2001; 60: 869–75. 14. Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to disease-modifying antirheumatic drugs in clinical practice. Q J Med 2001; 94: 309–19. 15. Upponi SS, Jadav AM, Bobrow L, Purushotham AD. Breast hypertrophy related to Dpenicillamine? Breast 2001; 10: 349–50. 16. Schilsky ML. The irony of treating Wilson’s disease. Am J Gastroenterol 2001; 96: 3055–7. 17. Shiono Y, Wakusawa S, Hayashi H, Takikawa T, Yano M, Okada T, Mabuchi H, Kono S, Miyajima H. Iron accumulation in the liver of male patients with Wilson’s disease. Am J Gastroenterol 2001;96: 3147–51. 18. Luca P, Demelia L, Lecca S, Ambu R, Faa G. Massive hepatic haemosiderosis in Wilson’s disease. Histopathology 2000; 37: 187–9. 19. Koseki Y, Terai C, Moriguchi M, Uesato M, Kamatani N. A prospective study of renal disease in patients with early rheumatoid arthritis. Ann Rheum Dis 2001; 60: 327–31. 20. Bar J, Ehrenfeld M, Rozenman J, Perelman M, Sidi Y, Gur H. Pulmonary-renal syndrome in systemic sclerosis. Semin Arthritis Rheum 2001; 30: 403–10. 21. Fraysse T, De Wazieres B. Maladie de Wilson et “vieille peau”. Pract Med Ther 2001; 15: 38–9. 22. Pyo JY, Lee WJ, Koo DW. A case of penicillamine dermatopathy. Korean J Dermatol 2001; 39: 341–3. 23. Østensen TI. Rheumatological disorders. Baillière’s Best Pract Res Clin Obstet Gynaecol 2001; 15: 953–69. 24. Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Am J Surg Pathol 2001; 25: 637–44. 25. Rogers FB, Li SC. Acute colonic necrosis associated with sodium polystyrene sulfonate (Kayexalate) enemas in a critically ill patient: case report and review of the literature. J Trauma 2001; 51: 395–7.

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24

Antiseptic drugs and disinfectants

BISBIGUANIDES Chlorhexidine

(SED-14, 764; SEDA-23, 247; SEDA-24, 270; SEDA-25, 276)

Immunologic Chlorhexidine allergy has been well described for over 30 years. Hypersensitivity reactions have been considered to be rare, as chlorhexidine is the standard skin disinfectant used before surgery or invasive procedures and is used in the general population in mouthwashes or for disinfection of minor wounds. Anaphylactic reactions have been reported in surgical patients (SED-14, 764; SEDA-23, 247). Anaphylaxis has been described in four surgical patients after the use of chlorhexidine as a skin disinfectant. All four had a history of minor symptoms, such as rashes or faints, in connection with previous surgery or invasive procedures (1A ). Chlorhexidine allergy has been well described as a result of application to mucous membranes before instrumentation, (SED-14, 764, SEDA-23, 247; SEDA-24, 270). Severe anaphylactic shock after transurethrally applied chlorhexidine gel continues to be reported (2A ). The risk of hypersensitivity with chlorhexidine-impregnated central venous catheters has not been fully defined. Randomized studies have failed to show an association (SED-24, 270; SEDA-25, 276); however, there have been reports of anaphylaxis after insertion of these catheters (SEDA-22, 262; SEDA-23, 248) and two life-threatening episodes of anaphylaxis in the same patient were attributed to a central venous catheter that had been impregnated with chlorhexidine and sulfadiazine (3A ). © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

258

Local hypersensitivity reactions to chlorhexidine-impregnated patches in neonates are known to occur (SEDA-23, 248). A randomized comparison of povidone–iodine and a chlorhexidine gluconate impregnated dressing for the prevention of central venous catheter infections in neonates showed that the risk of local contact dermatitis limited the use of the chlorhexidine dressing (4c ).

Ethylene oxide

(SED-14, 761; SEDA-23, 248; SEDA-24, 271; SEDA-25, 277) Mutagenicity There is limited epidemiological evidence for an increased risk of cancer among workers exposed to ethylene oxide and it is classified as a human carcinogen based on supporting mechanistic data (SEDA24, 271). Ethylene oxide is a genotoxic carcinogen, so the genotype of an individual could determine susceptibility to its mutagenic effects. The effects of glutathione-S-transferase T1 and M1 genotypes on hemoglobin adducts in erythrocytes and sister chromatid exchange in lymphocytes have been examined in 58 hospital operators of sterilizers that used ethylene oxide and non-exposed workers (5E ). The results suggested that the glutathione-S-transferase T1 null genotype was associated with increased formation of ethylene oxide–hemoglobin adducts in relation to occupational exposure. This suggests that individuals with the glutathione-Stransferase T1 null genotype may be more susceptible to the genotoxic effects of ethylene oxide.

Antiseptic drugs and disinfectants

DYES Triphenylmethane dyes

259

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HALOGENS (SED-14,

761) Gentian violet is a triphenylmethane dye that is used as a topical antifungal and antiseptic. It was also used in the treatment of oral candidiasis for more than 70 years, until concerns arose over its mutagenic and carcinogenic effects in animal studies. In the UK its licence is restricted to topical application on unbroken skin and it is no longer recommended for application to mucous membranes or open wounds. In the USA gentian violet is still used as a topical therapy for thrush, particularly in cases in which nystatin has failed. Respiratory Mucosal ulceration and airways obstruction can occur with application of gentian violet, and occlusive laryngotracheitis requiring orotracheal intubation has been reported (6A ). • Mucosal lesions consistent with oral candidiasis developed in a previously healthy, full-term, exclusively breast-fed, 2-week-old girl. She was treated with oral nystatin, resulting in an initial reduction in the severity of the lesions. After a few days, the thrush became more prominent. At 4 weeks of age, 1% aqueous gentian violet was prescribed and the day after she developed a cough and difficulty in feeding. There was no nasal congestion, fever, or rhinorrhea. Over the next 7 days her cough and feeding difficulties became progressively worse, and she developed a hoarse cry and stridor. Nasal washings for respiratory syncytial virus were negative. Intravenous fluconazole and ceftriaxone were given for presumed sepsis and fungal tracheitis. Lateral neck radiographs showed an absence of air in the cervical trachea. She was intubated with a 3.5 mm oral endotracheal tube for airway management, and was then taken for direct laryngoscopy under general anesthesia. The supraglottic, glottic, and subglottic structures were very edematous, but the vocal cords were mobile. Blood cultures on the day of admission failed to grow bacteria or fungi. There were no fungi in the supraglottic exudate. Nasopharyngeal samples obtained for viral culture were negative.

The obstructive chemical laryngotracheitis was believed to be secondary to the gentian violet application.

Hypochlorite

(SED-14, 767)

Respiratory Hypochlorite is widely used as a cleaning agent and to deal with blood spillages. Chlorine gas, which is released during the use of hypochlorite, can cause mucous membrane irritation, bronchospasm, pneumonia, and pulmonary edema. It is believed that the low concentrations of hypochlorite that are used as a cleaning substance do not cause respiratory damage. In a comparison of pulmonary function tests in 23 cleaning workers with those of 14 technical personnel, as a control group, even low concentrations of hypochlorite affected pulmonary function, causing irritation in the airways (7c ).

ORGANIC MERCURY COMPOUNDS (SED-14, 771; SEDA-23, 248; SEDA-25, 278)

Thiomersal In July 1999 the American Academy of Pediatrics and the US Public Health Service issued a joint statement calling for the removal of thiomersal, a mercury-containing preservative, from vaccines. This action was prompted partly by a risk assessment from the FDA (8M ). The risk assessment consisted of hazard identification, dose-response assessment, exposure assessment, and risk characterization. The review showed no evidence of harm caused by the doses of thiomersal in vaccines, except for local hypersensitivity reactions. However, it was noted that some infants may be exposed to cumulative doses of mercury during the first 6 months of life that exceed the Environmental Protection Agency recommendations. In the UK the CSM and Department of Health have reviewed the available data relating to thiomersal in vaccines and possible neurodevelopmental disorders, including autism, an issue that has gained media attention (9S ). There was no evidence of neurodevelopmental harm, a known effect of acute intoxication with mercury, caused by does of thiomersal in vaccines.

260 The amounts of thiomersal in the UK schedule of childhood vaccination is lower than those in the USA. No specific action has been recommended in the vaccination program. European and American regulatory authorities have recommended that vaccine manufacturers should phase out their use of thiomersal whenever possible as a precaution (SEDA-25, 278).

PHENOLIC COMPOUNDS (SED-14, 773; SEDA-23, 248; SEDA-24, 271) Phenol is a benzyl alcohol and a major oxidized metabolite of benzene. Although it can be prepared in an aqueous solution or in glycerin, it appears to be more effective when mixed in aqueous compounds. At a concentration of 0.2% it is bacteriostatic and at over 1% bacteriocidal (10R ). In addition to its uses as an antiseptic and disinfectant, phenol is also used as a sclerosant, as a local anesthetic on the skin, and as an analgesic, by injection into nerves or spinally. Initial reports suggested that phenol caused selective damage to small sensory nerve fibers (11R ). Later studies showed that in concentrations of 1–7% it caused indiscriminate damage to efferent and afferent nerve fibers (12A ). At concentrations under 1%, phenol appears to have a local anesthetic affect, which is fully reversible (13C ). However, at higher concentrations it causes both Wallerian degeneration and axonal demyelination, leading to muscle denervation. After injection of 2% aqueous phenol there can be damage to the microcirculation around nerves, leading to occlusion of small blood vessels and fibrosis in the injected area (14A ). Phenol can be applied percutaneously by the use of a monopolar needle electrode or by open injection when the nerve is exposed surgically. In addition, main nerve trunks or motor

Chapter 24

Pam Magee

branches can be injected, depending on the clinical indication. Nervous system The most common adverse effect of phenol injection is pain during injection, often described as a burning or stinging sensation. It can be associated with edema several hours after injection. The application of ice and the use of non-steroidal anti-inflammatory drugs often help to minimize the discomfort. In some studies lidocaine mixed with phenol has been used to help diminish the local pain response associated with injection (15R ). The most concerning adverse effect related to phenol injection is dysesthesia, caused by involvement of sensory nerve axons when perineural injection is attempted. Dysesthesia has been reported from a few days to about 2 weeks after injection; most patients describe a neuropathic component, including a burning pain with light tactile stimulation and involvement of only a small portion of the sensory distribution of the nerve that was blocked. Skin Phenol-related contact pemphigus has been described (16C ). • A 32-year-old otherwise healthy woman developed oral erosive lesions of 6 weeks duration and a bullous eruption on her lower limb, back, and chest of 2 weeks duration. She had bullae and erosions on the left thigh and bullae on the legs, back, abdomen, and chest. There was no family history of pemphigus. Pemphigus vulgaris was diagnosed, and she was given prednisone 100 mg/day. She went home for weekends during hospitalization, and returned to hospital each time with worse lesions. She reported working with a cleaning agent that she had begun using before the onset of the disease. The cleaning agent contained nonyl phenol, and she challenged herself at her next visit home by putting the same agent on her hands for a full day. As a result, new bullae appeared in the mouth. She was advised to stop using the product and was discharged a few days later taking prednisone 80 mg/day, which was tapered as the disease subsided. No new lesions appeared after 1 year of follow-up.

REFERENCES 1. Garvey LH, Roed-Peterson J, Husum B. Anaphylactic reactions in anaesthetised patients – four cases of chlorhexidine allergy. Acta Anaesthesiol Scand 2001; 45; 1290–4.

2. Leuer J, Mayser P, Schill W-B. Anaphylaktischer schock durch intraoperative Anwendung von Chlorhexidin. HGZ Hautkr 2001; 76: 160–3.

Antiseptic drugs and disinfectants

Chapter 24

3. Stephens R, Myhten M, Kallids P, Davies DWL, Egner W, Rickards A. Two episodes of life threatening anaphylaxis in the same patient to a chlorhexidine-sulphadiazine-coated central venous catheter. Br J Anaesth 2001; 87: 306–8. 4. Garland JS, Alex CP, Mueller CD, Otten D, Shivpuri C, Harris MC. A randomised trial comparing povidone-iodine to a chlorhexidine gluconateimpregnated dressing for prevention of central venous catheter infections in neonates. Pediatrics 2001; 107: 1431–7. 5. Yong LC, Schulte PA, Weincke JK, Boeniger MF, Connally LB, Walker JT, Whelan EA, Ward EW. Hemoglobin adducts and sister chromatid exchanges in hospital workers exposed to ethylene oxide: effects of glutathione S-transferase T1 and M1 genotypes. Cancer Epidemiol Biomarkers Prev 2001; 10: 539–50. 6. Baca DJ, Drexler C, Cullen E. Obstructive laryngotracheitis secondary to gentian violet exposure. Clin Pediatr 2001; 40: 233–5. 7. Demiralay R. Effects of the use of hypochlorite as a cleaning substance on pulmonary functions. Turk J Med Sci 2001; 31: 51–7. 8. Ball LK, Ball R, Pratt RD. An assessment of thiomersal use in childhood vaccines. Pediatrics 2001; 107: 1147–54.

261 9. Current Vaccine and Immunisation Issues. London: Department of Health, 15 Oct 2001. PL/CMO/2001/5. 10. Felsenthal G. Pharmacology of phenol in peripheral nerve blocks: a review. Arch Phys Med Rehabil 1974; 55: 13–16. 11. Möller J, Helweg-Larsen J, Jacobsen E. Histopathological lesions in the sciatic nerve of the rat following perineural application of phenol and alcohol solutions. Dan Med Bull 1969; 16: 116–19. 12. Bodine-Fowler S, Allsing S, Botte M. Time course of muscle atrophy and recovery following a phenol-induced nerve block. Muscle Nerve 1996; 19: 497–504. 13. Burkel W, McPhee M. Effect of phenol injection into the peripheral nerve of the rat: electron microscope studies. Arch Phys Med Rehabil 1970; 51: 391–7. 14. Glenn MB. Nerve blocks. In: Glenn M, Whyte J, editors. The Practical Management of Spasticity in Children and Adults. Philadelphia: Lea & Febiger, 1990: 227–58. 15. Petrillo CR, Knoplock S. Phenol block of the tibial nerve for spasticity: a long-term follow-up study. Int Disabil Stud 1988; 10: 97–103. 16. Goldberg I, Sasson O, Brenner S. A case of phenol-induced contact pemphigus. Dermatology 2001; 203: 355–6.

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25

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

PENICILLINS

(SED-14, 810; SEDA-23, 252; SEDA-24, 276; SEDA-25, 282) Liver Hepatotoxicity in patients taking coamoxiclav or flucloxacillin has previously been reported (SEDA-24, 276, SEDA-25, 282). Now benzylpenicillin, and piperacillin and/or imipenem/cilastatin can be added to the list.

• A 28-year-old woman developed upper abdominal pain, weakness, and dark urine 5 days after a single injection of benzylpenicillin 2 million units for suspected streptococcal pharyngitis (1A ). Liver dysfunction persisted for up to 18 months.

The authors rated the likelihood that benzylpenicillin had caused cholestasis as probable and referred to three previous reports in which penicillin was claimed to cause hepatotoxicity. • A 20-year-old man with abdominal trauma received a single dose of piperacillin (1 g) followed by nine doses of imipenem/cilastatin (500 mg tds for 3 days) and 2 weeks later developed jaundice, fatigue, and pruritus (2A ). A liver biopsy showed centrilobular cholestasis, portal infiltration with eosinophils, and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism. The patient made a full clinical and biochemical recovery after 3 months.

The authors concluded that short-term therapy with piperacillin, imipenem/cilastatin, or the combination could cause the same type of liver damage as described for co-amoxiclav or antistaphylococcal penicillins. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

262

Penicillin-induced hepatotoxicity may not be as uncommon as is thought. There have been three recent reviews. The first was a comparison of the assessment of drug-induced liver injury obtained by two different methods, the Council for International Organizations of Medical Sciences (CIOMS) scale and the Maria & Victorino (M&V) clinical scale (3R ). Three independent experts evaluated 215 cases of hepatotoxicity reported using a structured reporting form. There was absolute agreement between the two scales in 18% of cases, but there was no agreement in cases of fulminant hepatitis or death. The authors concluded that the CIOMS instrument is more likely to lead to a conclusion compatible with the specialist’s empirical approach. However, one major question remains: do we have good enough recording systems for measuring drug-induced hepatotoxicity? In the second review article some syndromes of drug-induced cholestasis were outlined with lists of typical examples of which drugs cause what (4R ). The authors stated that the treatment of drug-induced cholestasis is largely supportive and that the offending drug should be withdrawn immediately. In the third review the authors intention was to give “new insight into basic mechanism of bile secretion and cholestasis” (5R ). Some druginduced forms of cholestasis appear to be associated with certain HLA class II haplotypes in patients taking co-amoxiclav (SEDA-24; 276). Whether or not this holds true for hepatotoxicity following the use of other beta-lactam antibiotics is not known. Immunologic Penicillin allergy Fearing penicillin anaphylaxis, many clinicians overdiagnose penicillin allergy in patients who have not had a true allergic reaction. Consequently,

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

penicillins are withheld from many patients who could safely receive them. This was the background to a recent study, the objectives of which were to determine the likelihood of true penicillin allergy, taking into consideration the clinical history, and to evaluate the diagnostic value added by appropriate skin testing (6M ). The authors searched MEDLINE for relevant English-language articles dated 1966 to October 2000. Bibliographies were searched to identify additional articles. Original articles describing the precision of skin tests in the diagnosis of penicillin allergy were included, and studies that did not use both minor and major determinants were excluded; 14 studies met the inclusion criteria. At least three authors independently reviewed and abstracted the data from all the articles and reached a consensus about any discrepancies. Some of their conclusions are worth remembering. • 80–90% of all patients who report penicillin allergy have negative skin tests, suggesting that penicillins are withheld from many patients who could safely receive them; • patients who developed a rash while taking penicillins should not be automatically labelled as allergic without considering other possibilities, including rashes due to ampicillin distinct form allergic rashes, and rashes caused by the infection being treated or by other drugs; • for patients with a history of immediate (type I) penicillin allergy who have a compelling need for penicillin, skin testing should be performed; • at least 98% of patients with positive histories of penicillin allergy and negative skin test results can tolerate penicillin without any sequelae. Serum sickness Serum sickness was first described by von Pirquet and Schick in 1905 and was regarded as a syndrome resulting from the administration of heterologous serum or other foreign proteins. The immunopathology of classic serum sickness results from antigen– antibody complex formation with a foreign protein as the antigen. Characteristic symptoms include fever, cutaneous eruptions, edema, arthralgias, and lymphadenopathy. The incidence of classical serum sickness has fallen secondary to the refinement of foreign proteins.

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However, a serum sickness-like reaction that is clinically similar to classical serum sickness can result from the administration of a number of non-protein drugs, such as tetracyclines, penicillins, cephalosporins (7A ). The reaction typically occurs within 1 month of the start of therapy and resolves after withdrawal. Serum sickness has been associated with penicillins (8A ). • A 39-year-old woman developed the characteristic symptoms for serum sickness, having completed a 5-day course of amoxicillin for a perilingual infection 1 week before. She was treated with prednisone 60 mg/day and diphenhydramine 25– 50 mg tds. Her symptoms gradually resolved and the prednisolone dose was tapered over 2 weeks. • A 29-year-old woman complained of fever, rash, throat and facial swelling, abdominal pain, and increasing joint pain, leaving her wheelchair-bound. Her symptoms started a week after she had completed a 10-day course of penicillin V for a dental abscess. She was given oral methylprednisolone, 40 mg every 6 hours, and over the next few days her symptoms gradually resolved. • A 29-year-old woman developed symptoms of serum-sickness 2 weeks after completing a 21day course of co-amoxiclav for sinusitis. She responded to prednisone 40 mg/day.

The authors suggested that serum sickness may be more common than has previously been described and that the reaction may be underreported or unrecognized.

Amoxicillin Skin Contact urticaria due to amoxicillin has previously been described (9A ), but not consort urticaria (10A ). • A 22-year-old woman had labial urticaria with oropharyngeal edema some minutes after kissing her boyfriend, who had taken amoxicillin some minutes before kissing her. A few months before, she had had generalized urticaria several minutes after taking amoxicillin. A prick test with amoxicillin was positive and a similar test with penicillin G was negative. Total serum IgE was 90 kU/l and a RAST test for amoxicillin was positive (4.74 kU/l).

Piperacillin Hematologic Disseminated intravascular coagulation has been reported during long-term administration of piperacillin (11A ).

264 • A 51-year-old man was given piperacillin 2 g bd for osteomyelitis. After close to 4 weeks he developed acute renal insufficiency and superior mesenteric venous thrombosis. His coagulation profile showed disseminated intravascular coagulation. Withdrawal of piperacillin and anticoagulation therapy resulted in clinical improvement and normalization of the laboratory data.

CEPHALOSPORINS

(SED-14, 821; SEDA-23, 254; SEDA-24, 276; SEDA-25, 283)

Cefaclor Immunologic Serum sickness Serum sickness was first described by von Pirquet and Schick in 1905 and was regarded as a syndrome resulting from the administration of heterologous serum or other foreign proteins. The immunopathology of classic serum sickness results from antigen–antibody complex formation with a foreign protein as the antigen. Characteristic symptoms include fever, cutaneous eruptions, edema, arthralgias, and lymphadenopathy. The incidence of classical serum sickness has fallen secondary to the refinement of foreign proteins. However, a serum sickness-like reaction that is clinically similar to classical serum sickness can result from the administration of a number of non-protein drugs, such as tetracyclines, penicillins, cephalosporins (7A ). The reaction typically occurs within 1 month of the start of therapy and resolves after withdrawal. Serum sickness has been attributed to cefaclor (12A ).

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• A 70-year-old white woman with a history of penicillin allergy underwent an uncomplicated eye operation, at the end of which she received a subconjunctival injection of cefazolin 50 mg (13A ). About 90 minutes postoperatively she developed acute respiratory distress and a macular erythematous rash over the face, neck, chest, forearms, and lateral thighs. The rash became urticarial without pruritus. She was given bronchodilators and intravenous steroids with little improvement, but repeated subcutaneous injections of adrenaline gave some improvement in breathing. However, she had to be intubated, and was weaned from the ventilator only after some hours.

The main lesson from this case is that a small amount of a beta-lactam antibiotic anywhere in the body can cause life-threatening anaphylaxis.

Cefdinir Urinary tract Drug-induced acute tubulointerstitial nephritis is a rare cause of potentially reversible acute renal insufficiency. In a recent report of acute tubulointerstitial nephritis in a patient receiving cefdinir, it was stated that among 41 kinds of cephalosporins available in Japan, this complication has been reported with 12 (14Ar ). • A 58-year-old woman developed acute renal insufficiency soon after a 7-day course of cefdinir 300 mg/day for acute bronchitis. Renal histology showed tubular atrophy and interstitial fibrosis accompanied by moderate lymphocyte infiltration. A lymphocyte stimulation test with cefdinir was positive. Serum creatinine concentrations continued to rise even after withdrawal of cefdinir, but steroid therapy normalized renal function.

• A 2-year-old girl was given cefaclor for an infection, having been given it on one previous occasion without any adverse effects. However, on this occasion, after 6 days she developed a rash, edema, and joint swelling. Her symptoms were thought to be due to serum sickness caused by cefaclor, which was withdrawn. The rash resolved within 2 days and the arthralgia settled within 1 week.

The outcome of drug-induced acute tubulointerstitial nephritis can be life-long dialysis or renal transplantation if it is not adequately treated in time. The authors therefore concluded that it is important to look out for this complication when using any cephalosporin.

Cefazolin

Cefepime

Immunologic An anaphylactic reaction to a subconjunctival injection of cefazolin has been described.

Neuropsychiatric It has long been known that intramuscular procaine penicillin can cause some peculiar psychological adverse reactions,

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

and that other penicillin derivatives, such as amoxicillin, can cause psychiatric reactions, such as hallucinations (SEDA-21, 259). In a recent report from the Netherlands neuropsychiatric symptoms occurred in six patients who received cefepime for febrile neutropenia (15c ). The patients, two men and four women, aged 32–75 years, received 6 g/day (n = 5) or 3 g/day (n = 1). The symptoms started 1–5 days after the first dose and varied from nightmares, anxiety, agitation, visual and auditory hallucinations, to coma and seizures. After withdrawal of cefepime, they recovered within 1–5 days. The causality between their neuropsychiatric symptoms and cefepime was considered as probable (WHO criteria) because of the temporal relation, lack of other causal neurological explanations, and positive re-challenge in five patients. The mechanisms of these adverse effects are unknown, although it might be of value to take a closer look at the theory that drug-induced limbic kindling may be the principal pathogenic factor (SEDA-21, 259).

CARBAPENEMS Meropenem Meropenem can now be added to the list of drugs that can cause occupational allergic contact dermatitis (16A ). • A 45-year-old nurse presented with a 6-month history of recurrent periorbital erythema with itching and runny eyes. Each episode lasted about 5–6 days and settled on withdrawal from her place at work, where she handled a large number of drugs, including meropenem. She was patch tested with the European standard series, and was negative to all except meropenem. She had complete remission after quitting her workplace.

The authors assumed that the localization to the periorbital region was due to involuntary contact with her hands or airborne contact.

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265

TETRACYCLINES

(SEDA-14, 906; SEDA-23, 255; SEDA-24, 278; SEDA-25, 284)

Doxycycline Urinary tract A case of renal small-vessel vasculitis related to doxycycline has been reported (17A ). Drug interactions There has been a further report of bleeding and prolonged international normalized ratio in a 69-year-old man given warfarin and doxycycline (18A ).

Minocycline Immunologic Serum sickness Serum sickness was first described by von Pirquet and Schick in 1905 and was regarded as a syndrome resulting from the administration of heterologous serum or other foreign proteins. The immunopathology of classic serum sickness results from antigen–antibody complex formation with a foreign protein as the antigen. Characteristic symptoms include fever, cutaneous eruptions, edema, arthralgias, and lymphadenopathy. The incidence of classical serum sickness has fallen secondary to the refinement of foreign proteins. However, a serum sickness-like reaction that is clinically similar to classical serum sickness can result from the administration of a number of non-protein drugs, such as tetracyclines, penicillins, cephalosporins (7A ). The reaction typically occurs within 1 month of the start of therapy and resolves after withdrawal. Minocycline has been reported to cause serum sickness (19A ). • A 16-year-old girl taking minocycline for acne developed typical symptoms of serum sickness after 14 days. Minocycline was withdrawn and her symptoms resolved after a short course of systemic steroids for 5 days. • An 18-year-old woman developed typical symptoms of serum sickness after taking minocycline 50 mg/day for 10 days for acne. Her symptoms resolved gradually after minocycline was withdrawn.

The authors reviewed some other cases of serum sickness after the use of minocycline. They suggested that the syndrome is underreported, either because of unawareness that it can be an adverse effect or lack of willingness of physicians to document the event.

266 Drug-induced lupus Drug-induced lupus is a well-known phenomenon, although the mechanisms are unclear. The diagnostic features should include no prior history of systemic lupus erythematosus (SLE) before the start of treatment, at least one clinical feature of SLE, a positive antinuclear antibody during sustained drug therapy, and dramatic symptomatic improvement after drug withdrawal. Since 1970, at least 49 drugs have been reported to be associated with drug-related lupus (20R ), of which hydralazine and procainamide have been claimed to the most commonly implicated. However, new reports on minocycline-induced lupus continue to appear (21A –23A ) and it is possible that minocycline is now the most common cause. In a retrospective nested casecontrol study in 27 688 patients with acne, 7136 had used minocycline, of whom 29 had the lupus-like syndrome (24c ). Minocycline was associated with an 8.5-fold risk of the lupuslike syndrome. Minocycline-induced lupus usually occurs some months, or even years, after the start of therapy and it usually resolve when the drug is withdrawn. The diagnosis can easily be overlooked, especially in patients with rheumatoid arthritis (25A ). It would always be wise to follow the recommendation that a patient’s antinuclear antibody be checked before starting minocycline and when drug-induced lupus is suspected. Vasculitis Two cases of biopsy-proven cutaneous polyarteritis nodosa with positive perinuclear antineutrophilic cytoplasmic antibodies have been reported with long-term use of minocycline for acne vulgaris (50–100 mg/day for 44 months and 100 mg/day for 65 months) (26A ). In one of the cases involvement was not restricted to medium-size vessels alone. In both cases the vasculitis disappeared after a short course of prednisone (40 mg/day) and withdrawal of minocycline. Rechallenge was not performed. P-ANCA is usually found in microscopic polyangiitis, a vasculitis of smaller arteries, and its significance in polyarteritis nodosa is not clear.

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CHEMICALLY MODIFIED TETRACYCLINES Tetracyclines and metalloproteinases Tetracyclines have many effects on inflammatory processes (SEDA-24, 278). They have been tried—and claimed to be of some value—in the treatment of rheumatoid arthritis, periodontal disease, myocardial infections, gastric disorders, and experimentally in the treatment of cancer. In all of these disorders, the proposed mechanisms for effects are on the host rather than the microbial side. The hottest target is claimed to be inhibition of metalloproteinases. The following is a brief summary of what is known about tetracyclines and metalloproteinases, followed by some comments of possible adverse effects. Metalloproteinases The matrix metalloproteinases (MMPs) are a family of calciumand/or zinc-dependent endopeptidases involved in degradation of extracellular matrix and tissue remodeling (27Ar ). At least 21 mammalian MMPs have been described. They participate in various biological processes, such as embryonic development, ovulation, angiogenesis, apoptosis, wound healing, and nerve growth. Under normal conditions, the activity of MMPs is very low and is strongly regulated by natural tissue inhibitors (TIMPs). The TIMPS are a family of four structurally related proteins (TIMP-1, 2, 3, and 4), exerting dual control of the MMPs by inhibiting both their active forms and their activation. In additional, the proteolytic activity of MMPs is inhibited by nonspecific protease inhibitors, such as alpha2 macroglobulin and alpha1 -antiprotease. In the presence of specific stimuli, exemplified by cytokines and growth factors, MMPs can be up-regulated. Chronic activation of MMPs, due to an imbalance between the activity of MMPs and TIMPs, can result in excessive degradation of the extracellular matrix and is believed to contribute to the pathogenesis of several diseases, such as rheumatoid arthritis, osteoarthritis, periodontal disease, emphysema, atherosclerosis, skin ulceration, and cancer. The physiological and pathophysiological roles of MMPs and TIMPs have been extensively studied in knockout mice (27Ar ). For most

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

of the MMPs and TIMPs there seem to be significant overlaps in functions, and a deficiency of one enzyme can be compensated for by the presence of others (27Ar , 28A ). Each MMP is encoded by a distinct gene, and about half of the human MMP genes so far discovered are on chromosome 11 (27Ar ). The mere fact that MMPs might be involved in the pathogenesis of several chronic disorders has made this field attractive to numerous pharmaceutical companies. One major approach for controlling abnormal MMP activity has been the use of small molecular weight inhibitors, and several excellent reviews of the design of such inhibitors have already been published (references to around 20 review articles are given in reference 27Ar ). Here I shall focus on the possibility of using tetracyclines in one chronic condition (rheumatoid arthritis) and one acute condition (adult respiratory distress syndrome). As early as the 1960s it was recognized that tetracyclines might inhibit bone growth, supposedly by interference with calcium metabolism. It was not until collagenase was discovered in 1983 (29c ) that intensive interest in the non-antimicrobial properties of tetracycline-based antibiotics developed. Most of the initial studies were done with doxycycline and minocycline, i.e. semi-synthetic tetracyclines with widespread medical and dental uses. However, in 1987 a non-antibacterial chemically modified tetracycline (CMT) that inhibited mammalian collagenase activity was described (30E ). At present, the CMTs (also known as COLs, from their having been introduced by CollaGenes Pharmaceuticals Inc, Newton, PA, USA) comprise a group of at least 10 analogous compounds (CMT-1 to CMT-10) that differ in their specificity and potency in inhibiting MMP. Comparative pharmacokinetic data, obtained from animals, have recently been published, as has a bibliography covering more than 75 papers and abstracts related to the basic biological properties of these compounds (31R ). Rheumatoid arthritis In double-blind placebo-controlled studies minocycline relieved clinical symptoms and reduced some laboratory measures of disease activity in patients with rheumatoid arthritis (32C –34C ). However, the progression of radiographic damage was not significantly reduced and minocycline caused

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several adverse effects. This led to investigations of the therapeutic effects of doxycycline in patients with rheumatoid arthritis. In 13 patients with moderate rheumatoid arthritis low-dose doxycycline 20 mg bd reduced the urinary excretion of pyridinoline (35C ). Pyridinolines are collagen cross-links that are released from joints during cartilage and bone resorption and correlate with the severity of joint destruction (36c ). In a more recent study, doxycycline produced a significant reduction in the number of tender joints and a significant improvement of disability and behavior in 12 patients with rheumatoid arthritis (37c ). However, these studies were not placebocontrolled, and it was possible that the observed effects were due to factors other than doxycycline. Now the results of two double-blind, placebo-controlled trials have been published (38C , 39C ). In a cross-over study, 66 patients took 50 mg doxycycline or placebo twice a day for 12, 24, or 36 weeks (38C ). Patients’ assessments, swollen and tender joint counts, duration of morning stiffness, erythrocyte sedimentation rate, and the so-called modified disease activity score (40C ) were used as measures of disease activity. The results were straightforward: “the change of clinical or laboratory disease activity measures, pyridinoline excretion, or progression of radiographic joint damages during doxycycline or placebo treatment did not differ significantly”. Furthermore, there were adverse effects during treatment with doxycycline and not during treatment with the placebo. The authors concluded that doxycycline 50 mg bd provided no therapeutic benefit for patients with rheumatoid arthritis. In the other study, a 16-week, randomized, double-blind, placebo-controlled trial, eligible subjects with active seropositive or erosive rheumatoid arthritis were randomly allocated into three treatment groups: doxycycline 200 mg intravenously, azithromycin 250 mg orally, or placebo (39C ). The primary endpoints were the change between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline. The trial was stopped prematurely after 31 patients had been enrolled. Three subjects were withdrawn because of worsening arthritis. There were no significant differences across the groups in any of the three primary

268 clinical end-points. The authors concluded that doxycycline did not reduce disease activity or collagen cross-link production. Ten CMTs, minocycline, and doxycycline have been tested for their capacity to inhibit cartilage degradation in vitro (41E ). CMT-8 was the most active. The authors concluded that by carefully selecting a tetracycline-based MMP inhibitor and controlling dosages it should be possible to inhibit pathologically excessive MMP-8 and/or MMP-13 activity, especially that which causes bone erosion, without affecting the constitutive activity of MMP-1 needed for tissue remodelling and normal host function. They thought that of the CMTs, CMT-8 and to a lesser extent CMT-3 and CMT-7 were the most effective. However, to the best of my knowledge, these CMTs have not been tried in a full-scale trial in rheumatoid arthritis. Adult respiratory distress syndrome (ARDS) ARDS has many causes, is associated with severe lung damage, and is characterized by pulmonary edema and hypoxemia. It has a high mortality. The current method of treatment is supportive and there is no specific therapy. This was the background to a thorough review of the anti-inflammatory properties of tetracyclines in the prevention of acute lung injury (42R ). The authors ended with an optimistic forecast, that targeting the proteases that cause ARDS with CMTs may be useful in prevention and treatment. They ended by suggesting that strategies to prevent ARDS should focus on targets downstream from the initial inflammatory signals that provoke the cascade of events.

Adverse effects of the chemically modified tetracyclines (CMTs) The adverse effects profile of the classical tetracyclines, such as doxycycline and minocycline, is well established. However, the adverse effects profile of the CMTs has not been elucidated. What can be expected? Recent reviews form a good starting point (31R , 43E ). In brief, CMTs are more active in interfering with mammalian processes than the classical tetracyclines, which is the main justification for their use in non-infective problems.

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From a qualitative point of view, it might be reasonable to assume similar host-related adverse effects as the classical tetracyclines, while from a quantitative point of view, dosages, duration of therapy, etc. will influence the number of adverse effects. However, the risks might be quite high, exemplified as follows. Hematologic Sideroblastic anemia is characterized by the accumulation of iron in the mitochondria of erythroblasts. In a Phase I study in 35 patients with refractory tumors, eight taking CMT-3 developed anemia without leukopenia or thrombocytopenia (44c ). Three of these patients underwent bone-marrow examination and each had ringed sideroblasts. The authors referred to several cases of aplastic anemia, megaloblastic anemia, and hemolytic anemia in which members of the tetracycline family have been implicated. However, they stated that there have been no previous reports of sideroblastic anemia associated with any tetracycline derivative and that the molecular mechanisms by which CMT-3 might cause sideroblastic anemia are unclear. Immunologic Several drugs have been reported to cause a lupus-like syndrome. In a recent review of relevant American and European literature, hepatitis and drug-induced lupus were reported in 66 cases after minocycline therapy, mostly after long-term treatment for acne (45R ). It should be recognized that in many countries long-term minocycline is a very common therapy for acne. Based on the strategy that inhibition of angiogenesis is of importance in anticancer therapy, CMT-3 (COL-3) was recently used in a phase 1 study in 35 patients at the National Institutes of Health in the USA in patients with refractory metastatic cancer (46C ). The patients received a test dose of CMT-3, followed by pharmacokinetic testing during daily dosing for 7 days. After a few doses, three patients developed symptoms of drug-induced lupus, and the diagnoses were verified after a few days or weeks. CMT-3 was withdrawn and there was improvement. In a retrospective review of drug safety databases, minocycline was the only tetracycline derivative that caused drug-induced lupus (SEDA-22, 268; 47R ). The authors proposed that the propensity of minocycline to cause

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

drug-induced lupus may be due to the presence of a functional group that is easily oxidized to a reactive metabolite. However, CMT-3 lacks this group, so a new theory is needed. Drug tolerance (bacterial resistance) Prolonged treatment with the classical antibacterial tetracyclines results in bacterial resistance and/or opportunistic fungal infections. It has therefore been forecast, but not so far proven, that CMTs without antibacterial activity may not cause microbial resistance. How-

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ever, I am not sure that will be the case. Accepting that the major mechanism by which bacteria get rid of tetracyclines intracellularly is by increasing their efflux via P glycoprotein, the CMTs might also trigger that mechanism, thereby causing reduced sensitivity of the exposed bacterial population to all types of tetracyclines. Before this possibility has been ruled out, the new CMTs should be introduced with great care.

REFERENCES 1. Andrade RJ, Guilarte J, Salmeron FI, Lucenn MI, Bellot V. Benzylpenicillin-induced prolonged cholestasis. Ann Pharmacother 2001; 35: 783–4. 2. Quattropani C, Schneider M, Helbling A, Zimmermann A, Krähenbühl S. Cholangiopathy after short-term administration of piperacillin and imipenem/cilastatin. Liver 2001; 21: 213–16. 3. Lucena MA, Camargo R, Andrade RJ, PerezSanchez CJ, De La Costa FS. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33: 123–30. 4. Chitturi S, Farrell GC. Drug-induced cholestasis. Semin Gastrointest Dis 2001; 12: 113–24. 5. Trauner M, Boyer JL. Cholestatic syndromes. Curr Opin Gastroenterol 2001; 17: 242–56. 6. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. J Am Med Assoc 2001; 285: 2498–505. 7. Mannik M. Serum sickness and pathophysiology of immune complexes. In: Rich RR, Fleisher TA, Schwartz BD (editors). Clinical Immunology, Principles and Practice. St Louis: Mosby Year Book Inc, 1996: 1062–71. 8. Tatum AJ, Ditto AM, Patterson R. Severe serum sickness-like reactions to oral penicillin drugs: three case reports. Ann Allergy Asthma Immunol 2001: 86: 330–4. 9. Gambos P, Jauregui I, Urrutia I. Occupational sensitization to aminopenicillins with oral tolerance to penicillin V. Contact Dermatitis 1995; 32: 48. 10. Petavy-Catala C, Machet L, Vaillant L. Consort contact urticaria to amoxicillin. Contact Dermatitis 2001; 44: 251. 11. Miyaksaki H, Yanagitani S, Matsumoto T, Yoshida K, Amoh Y. Watanabe T, Yoshitigu K, Inoue K. Hypercoagulopathy with piperacillin administration in osteomyelitis. Int Med 2000; 39: 424–7. 12. Isaacs D. Serum sickness-like reactions to cefaclor. J Paediatr Child Health 2001; 37: 298–9. 13. Berrocal AM, Shuman JS. Subconjunctival cephalosporin anaphylaxis. Ophthalmic Surg Lasers 2001; 32: 79–80.

14. Diemont W, MacKenzie M, Schaap N, Goverde G, Van Heereveld H, Hekster Y, Van Grootheest K. Neuropsychiatric symptoms during cefepime treatment. Pharm World Sci 2001; 23: 36. 15. Kimura Y, Kawamura M, Owada M, Fujiwara T, Maesawa C, Hiramori K. Successful steroid therapy for cefdinir-induced acute tubulointerstitial nephritis with progressive renal failure. Int Med 2001; 40: 114–17. 16. Yesudian PD, King CM. Occupational allergic contact dermatitis from meropenem. Contact Dermatitis 2001; 45: 53. 17. Goland S, Kazarsky R, Kagan A, Huszar M, Abend I, Malnick SDH. Renal vasculitis associated with doxycycline. J Pharm Technol 2001; 17: 220– 2. 18. Baciewicz AM, Bal BS. Bleeding associated with doxycycline and warfarin treatment. Arch Intern Med 2001; 161: 1231. 19. Malahar S, Dhar S. Is serum sickness an uncommon adverse effect of minocycline treatment? Acta Dermatol 2001; 137: 100–1. 20. Hess E. Drug related lupus. New Engl J Med 1988; 318: 1460–2. 21. Gordon MM, Porter D. Minocycline induced lupus: case series in the West of Scotland. J Rheumatol 2001; 28: 1004–6. 22. Lawson TM, Amos N, Bulgen D, Williams BD. Minocycline-induced lupus: clinical features and response to rechallenge. Rheumatology 2001; 40: 329–35. 23. Graham LE, Bell AL. Minocycline-associated lupus-like syndrome with ulnar neuropathy and antiphospolipid antibody. Clin Rheumatol 2001; 20: 67–9. 24. Sturkenboom MC, Meier CR, Jick H, Stricker BHC. Minocycline and lupus-like syndrome in acne patients. Arch Intern Med 1999; 159: 493–7. 25. Marzo-Ortega H. Misbah S, Emery P. Minocycline induced autoimmune disease in rheumatoid arthritis: a missed diagnosis? J Rheumatol 2001; 28: 377–8. 26. Schaffer JV, Davindson DM, McNiff JM, Bolognia JL. Perinuclear antineutrophilic cytoplas-

270 mic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris. J Am Acad Dermatol 2001; 44: 198–206. 27. Skiles JW, Gonnella NC, Jeng AY. The design, structure and therapeutic application of metalloprotease inhibitors. Curr Med Chem 2001; 8: 425–74. 28. Hidalgo M, Eckhardt SG. Development of matrix metalloprotease inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93: 178–93. 29. Golub L, Lee HM, Lehrer G, Memiroff A, McNamara TF, Kaplan R, Ramomurthy NS. Minocycline reduces gingival collagenolytic activity during diabetes. J Periodontal Res 1983; 18: 516–24. 30. Golub LM, Macnamara TF, D’Angelo G, Greenwall RA, Ramamurthy NS. A nonantibacterial chemically modified tetracycline inhibits mammalian collagenase activity. J Dent Res 1987; 66: 1310–14. 31. Greenwald RA, Golub LM. Biologic properties on non-antibiotic, chemically modified tetracyclines (CMTs): a structured, annotated bibliography. Curr Med Chem 2001; 8: 237–42. 32. Kloppenburg M, Breedveld FC, Terwiel JP, Malle C, Dijkmans BAC. Minocycline in active rheumatoid arthritis. A placebo-controlled trial. Arthritis Rheum 1994; 37: 629–36. 33. O’Dell JR, Haire CE, Palmer W. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1997; 40: 842–8. 34. Tilley BC, Alarcon GS, Heyse SP. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. Ann Intern Med 1995; 122: 81–9. 35. Greenwald RA, Mosak SA, Golub LM. Low dose doxycycline inhibits pyridinoline excretion in selected patients with rheumatoid arthritis. Ann NY Acad Sci 1994; 732: 419–21. 36. Astbury C, Bird HA, McLaren AM, Robins SP. Urinary excretion of pyridinium crosslinks of collagen correlated with joint damage in arthritis. Br J Rheumatol 1994; 33: 11–15. 37. Nordstrom D, Lindy O, Lauchio A, Sorsa T, Santavirta S, Kontinen YT. Anticollagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis. Rheumatol Int 1998 17: 175– 80.

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38. Van der Laan W, Molenaar E, Ronday K, Verheijen J, Breedveld F, Greenwald R, Dickman B, Koppele JT. Lack of effect of doxycycline on disease activity and joint damage in patients with rheumatoid arthritis. A double blind, placebo controlled trial. J Rheumatol 2001; 28: 1967–74. 39. St Clair EW, Wilkinson WE, Pisetsky DS, Sexton DJ, Drew R, Kraus VB, Greenwald RA. The effects of intravenous doxycycline therapy for rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2001; 44: 1043–7. 40. Prevoo ML, Van’t Hof MA, Kuper HH, Van Leeuwen MA, Van den Putte LBA, Van Riel PLCM. Modified disease activity scores that include twenty-eight joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 44–8. 41. Greenwald RA, Golub LM, Ramamurthy NS, Chowdhury M, Moar SA, Sorsa T. In vitro sensitivity of the three mammalian collagenases to tetracycline inhibition: relationship to bone and cartilage degradation. Bone 1998; 22: 33–8. 42. Nieman GF, Zerler BR. A role for the antiinflammatory properties of tetracyclines in the prevention of acute lung injury. Curr Med Chem 2001; 8: 317–25. 43. Liu Y, Ramamurthy NS, Marecek J, Lee HM, Chen JL, Ryan ME, Rifkin BR, Golub LM. The lipophilicity, pharmacokinetics, and cellular uptake of different chemically-modified tetracyclines (CMTs). Curr Med Chem 2001; 8: 243–52. 44. Rudek MA, Horne M, Figg WD, Dahut W, Dyer V, Plutda JM, Reed E. Reversible sideroblastic anemia associated with the tetracycline analogue COL-3. Am J Hematol 2001; 67: 51–3. 45. Elkayam O, Yaron M, Caspi D. Minocyclineinduced autoimmune syndrome: an overview. Semin Arthritis Rheum 1999; 28: 392–7. 46. Ghate JV, Turner ML, Rudek MA, Figg, WD, Dahut W, Dyer V, Pluda JM, Reed E. Drug-induced lupus associated with COL-3; report of 3 cases. Arch Dermatol 2001; 137: 471–4. 47. Shapiro LE, Knowles SR, Shear NH. Comparative safety of tetracycline, minocycline, and doxycycline. Arch Dermatol 1997; 133: 1224–30.

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Miscellaneous antibacterial drugs

AMINOGLYCOSIDES

(SED-14, 837; SEDA-23, 264; SEDA-24. 283; SEDA-25, 287)

other had mild ototoxicity that required no action and resolved spontaneously.

Sensory systems Hearing loss was attributed to repeated exposure to aminoglycosides in 12 of 70 patients with cystic fibrosis (one child) (1C ). There was a non-linear relation between the number of courses of therapy and the incidence of hearing loss. The severity of loss was not related to the number of courses. Assuming that the risk of hearing loss was independent of each course, the preliminary estimate of the risk was less than 2 per 100 courses.

Urinary tract Nephrotoxicity occurred in five of 195 patients who received amikacin (15 mg/kg/od) with either cefepime (2 g bd) or ceftazidime (2 g tds) (3C ). In two patients the deterioration in renal function was mild and resolved without withdrawal of amikacin. In the three other patients, renal insufficiency necessitated drug withdrawal; two of these patients recovered, but one died with sepsis, and renal function was still abnormal at the time of death.

Drug monitoring In a retrospective casecontrol study, 2405 patients received aminoglycosides in doses that were decided either by individualized pharmacokinetic monitoring or by the physician (2C ). Those who received individualized pharmacokinetic monitoring were significantly less likely to develop aminoglycoside-associated nephrotoxicity. Women were also less likely to develop nephrotoxicity. Age 50 years and above, high initial aminoglycoside trough concentration, long duration of therapy, and concurrent therapy with piperacillin, clindamycin, or vancomycin increased the risk.

Amikacin Sensory systems Ototoxicity was observed in three of 195 patients who received amikacin (15 mg/kg/od) with either cefepime (2 g bd) or ceftazidime (2 g tds) (3C ). Two patients had severe loss of hearing, which persisted after drug withdrawal and resulted in permanent disability. The © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Gentamicin Nervous system Intraventricular gentamicin can cause aseptic meningitis (4A ). Sensory systems In 17 patients with suspected postoperative endophthalmitis treated with 0.2 mg vancomycin and 0.05 mg gentamicin intravitreally there were adequate intravitreal vancomycin and gentamicin concentrations for over a week; there were no adverse effects (5c ). The frequency of aminoglycoside-associated hearing loss is 2–45%. Intratympanic gentamicin therapy has gained some popularity in the treatment of vertigo associated with Menière’s disease, as it offers some advantages over traditional surgical treatment. In a 2-year followup of 15 patients with Menière’s disease, gentamicin solution 0.5 ml (20 mg/ml) injected intratympanically once a week minimized the risk of hearing loss in the treated ear, allowing complete control of vertigo in eight patients after two doses and in 14 patients after four doses (6c ).

271

272 In two animal studies methylcobalamin or dimethylsulfoxide inhibited the ototoxic adverse effects of gentamicin (7E , 8E ). Urinary tract A full course of gentamicin therapy causes nephrotoxicity in 1–55% of patients. In 45 neonates (9C ) and 123 older children (10C ) gentamicin 4–5 mg/kg once a day produced peak concentrations associated with greater efficacy and trough concentrations associated with less toxicity than 2.0–2.5 mg/kg bd. In another open, randomized, controlled trial, once-daily and thrice-daily gentamicin were compared in 173 children aged 1 month to 12 years; there was no nephrotoxicity or ototoxicity (11C ). Daily doses of gentamicin in both groups were 7.5 mg/kg (under 5 years old), 6.0 mg/kg (5–10 years old), and 4.5 mg/kg (over 10 years old). Nephrocalcinosis occurred in 16 of 101 babies born at less than 32 weeks gestation (12C ). Multivariate analysis showed that the strongest predictors of nephrocalcinosis were duration of ventilation, toxic gentamicin/vancomycin concentrations, low fluid intake, and male sex. Immunologic Allergic contact dermatitis due to gentamicin is rare in patients with eyelid dermatitis, but it can occur. • A 55-year-old housewife developed pruritic, erythematous, scaly plaques on the eyelids, spreading in a few days periorbitally after treatment with gentamicin eye-drops (Colircusi Gentamicina® ) (13A ). A positive patch test reaction to kanamycin, to which the patient had not been previously exposed, suggested cross-reactivity.

Drug interactions Aminoglycosides used in combination with non-steroidal anti-inflammatory drugs can be associated with renal insufficiency. • An adolescent with cystic fibrosis developed renal insufficiency and severe vestibular toxicity after treatment with gentamicin and standard-dose ibuprofen (14A ). A low intravascular volume was a possible contributing factor.

Drug dosage regimens Once-daily regimens are appealing for cost saving and may have a therapeutic advantage and reduced toxicity. A prolonged distribution time has been noted with high-dose gentamicin (7 mg/kg). Higher

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doses are used for extended-interval aminoglycoside therapy. In 12 healthy volunteers receiving extended-interval high-dose gentamicin, sampling within 90 minutes after the start of the infusion provided information that led to overestimation of peak serum concentration/minimum inhibitory concentration and inaccurate pharmacokinetic calculations (15C ). In 18 patients receiving empirical therapy for CAPD-related peritonitis, once-daily intraperitoneal gentamicin (0.6 mg/kg) had less therapeutic benefit and peak serum gentamicin concentrations were lower than the suggested value of 4 µg/ml, whereas trough serum gentamicin concentrations were higher than the minimum toxic concentration; dialysate gentamicin concentrations were higher than therapeutic concentrations for only 4.75 hours of each day (16c ). Increased penetration of gentamicin through a thin sclera can lead to toxic concentrations of the drug in a localized area adjacent to the site of injection, as has been shown in rabbits (17E ). These toxic effects are also influenced by the degree of pigmentation and acute inflammation.

Isepamicin Isepamicin is an aminoglycoside with properties similar to those of amikacin but better activity against strains that produce type I 6′ acetyltransferase. It can cause nephrotoxicity, vestibulotoxicity, and ototoxicity. Drug dosage regimens Isepamicin is given intravenously or intramuscularly in a dosage of 15 mg/kg od or 7.5 mg/kg bd. It is not bound to plasma proteins and it distributes in extracellular fluids and enters some cells (the outer hair cells and renal cortex) by active transport. In a randomized multicenter study 236 patients were randomly assigned to isepamicin in a calculated dose or a loading dose of 25 mg/kg (18C ). The calculated dose was estimated using a specific population model with a Bayesian method, including information about age, weight, height, sex, and serum creatinine. The Bayesian method was significantly more accurate and performed particularly well in ventilated patients and severely ill patients, compare with a loading dose of 25 mg/kg in obtaining a first isepamicin peak concentration of 80 µg/ml in patients in an intensive care unit.

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Neomycin

Tobramycin

Immunologic Thimerosal, a mercury derivative of thiosalicylic acid, is a preservative used in several types of consumer products, including cosmetics, ophthalmic and otolaryngological medications, and vaccines. In a retrospective study in 574 patients people who were allergic to thimerosal were more likely to be allergic to neomycin, bacitracin, and tixocortol pivalate (19c ).

Sensory systems Histological examination of the temporal bones from two individuals with ototoxicity due to tobramycin showed reductions in the numbers of both ganglion cells and hair cells (24c ). Spiral ganglion cell loss was not necessarily subadjacent to areas of hair cell loss in cases of aminoglycoside ototoxicity. Instead, there may be a reduction in the number of ganglion cells in segments of the cochlea with normal-appearing hair cells.

Netilmicin Sensory systems In patients with acute bacterial conjunctivitis there were adverse drug reactions in two of 106 patients treated with netilmicin (1.9%) and four of 103 treated with gentamicin (3.9%) (20C ). The adverse effects in the eyes included redness, itching, and burning, and none was serious. There was complete recovery in all cases.

Paromomycin If absorbed systemically paromomycin can cause ototoxicity and nephrotoxicity. However, it may be less ototoxic than other aminoglycosides and since it has limited systemic availability, toxicity should not be a concern in people with normal kidneys (21R ).

Respiratory Nebulized antipseudomonal antibiotics improve lung function and reduce the frequency of exacerbations of infections in patients with cystic fibrosis and Wegener’s granulomatosis (25c , 26c ). In two placebo-controlled, randomized studies inhaled tobramycin significantly reduced sputum density of Pseudomonas aeruginosa; however, more patients in the treatment group reported increased dyspnea and wheezing, although the symptoms did not limit therapy (27c , 28c ). Skin Ultraviolet recall has been reported after piperacillin, tobramycin, and ciprofloxacin therapy, with a reaction pattern different from that of chemotherapy-induced reactions. • A 31-year-old woman with a Pseudomonas pneumonia was given intravenous ciprofloxacin 400 mg 12-hourly, tobramycin 400 mg/day, and piperacillin 4 g 6-hourly (29A ). Three days after the initial administration of the intravenous antibiotics, she developed a morbilliform eruption on the sunexposed areas of her chest, back, and arms, corresponding to sites of intense sunburn that had occurred a month before.

Streptomycin Sensory systems Analysis of families with two or more members with streptomycininduced hearing loss has shown that increased susceptibility of the cochlea to streptomycin is transmitted primarily through women, by autosomal dominant inheritance, although transmission was not explained by the Mendelian inheritance rule (22M ). Fetotoxicity Streptomycin should not be used in pregnancy, as perhaps one in six babies will have problems with hearing and/or balance (23R ).

CHLORAMPHENICOL AND RELATED DRUGS (SED-14, 848; SEDA-23, 268; SEDA-24, 287; SEDA-25, 292)

Chloramphenicol Hematologic Chloramphenicol has adverse effects on the bone-marrow, the most serious of which is aplastic anemia. It has been confirmed that chloramphenicol can cause apoptosis in purified human bone-marrow CD34+ cells (30E ).

274 Gastrointestinal In 51 children with Mediterranean spotted fever randomized for 7 days to either clarithromycin, 15 mg/kg/day orally in two divided doses, or chloramphenicol, 50 mg/kg/day orally in four divided doses, the two drugs were equally well tolerated and there were no major adverse effects; there was vomiting in two patients treated with clarithromycin and in one treated with chloramphenicol (31C ). None of the patients required drug withdrawal.

FLUOROQUINOLONES

(SED-14, 852; SEDA-23, 277; SEDA-25, 293) Owing to adverse effects (including severe anaphylaxis, QT interval prolongation, and potential cardiotoxicity), several fluoroquinolones have had to be withdrawn (e.g. temafloxacin and grepafloxacin) or strictly limited in their uses (e.g. trovafloxacin) after marketing. A serious idiosyncratic reaction profile is possibly related to the immunologically reactive 1-difluorophenyl substituent that characterizes temafloxacin, tosufloxacin, and trovafloxacin (32R ).

Cardiovascular There are differences in potency among fluoroquinolones in prolongation of the QT interval. In guinea-pig ventricular myocardium sparfloxacin prolonged the action potential duration by about 8% at 10 µmol/l and 41% at 100 µmol/l (33E ). Gatifloxacin, grepafloxacin, and moxifloxacin were less potent, but prolonged the action potential duration at 100 µmol/l by about 13%, 24%, and 25% respectively. In contrast, ciprofloxacin, gemifloxacin, levofloxacin, sitafloxacin, tosufloxacin, and trovafloxacin had little or no effect on the action potential at concentrations as high as 100 µmol/l. In patients taking quinolones (ciprofloxacin 11 477; enoxacin 2790; ofloxacin 11 033, and norfloxacin 11 110; mean ages 49–57 years) there was no evidence of drug-induced dysrhythmias associated with enoxacin within 42 days of drug administration (34C ). Of the other quinolones, atrial fibrillation was reported most often within 42 days of ciprofloxacin administration, with no change in event rate over that time. The crude rate of palpitation did not

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change significantly with ciprofloxacin, norfloxacin, or ofloxacin. Syncope and tachycardia were also reported with ciprofloxacin and ofloxacin. There was no evidence of druginduced hepatic dysfunction within 42 days of drug administration with any of the quinolones used. In a retrospective database analysis 25 cases of torsade de pointes associated with ciprofloxacin (n = 2), ofloxacin (n = 2), levofloxacin (n = 13), and gatifloxacin (n = 8) were identified in the USA (35M ). Ciprofloxacin was associated with a significantly lower rate of torsade de pointes (0.3 cases/10 million prescriptions) than levofloxacin (5.4/10 million) or gatifloxacin (27/10 million). When the analysis was limited to the first 16 months after initial approval of the drug, the rates for levofloxacin (16/10 million) and gatifloxacin (27/10 million) were similar. Nervous system The main central nervous system adverse effects of the fluoroquinolones include dizziness, convulsions, psychosis, and insomnia; levofloxacin, moxifloxacin, and ofloxacin are reportedly least likely to cause these effects, based on a study of European and international data from about 130 million prescriptions (36R ). Peripheral nervous system effects can be associated with fluoroquinolones. In contrast to previous reports, a recent review has suggested that fluoroquinolone-associated peripheral nervous system events are mild and short-term (37R ). Among 53 courses of quinolones in 45 patients (levofloxacin 33 courses, ciprofloxacin 11 courses, ofloxacin 6 courses, lomefloxacin 1 course, trovafloxacin 1 course) there were 36 severe events that typically involved multiple organ systems. The symptoms lasted more than 3 months in 71% of cases and more than 1 year in 58%. The onset of adverse events was usually rapid: 15 events began within 24 hours of the start of treatment, 26 within 72 hours, and 38 within 1 week. Quinolone antibiotics vary in their ability to cause seizures. Trovafloxacin has the greatest potential and levofloxacin possibly the least. Recently there has been a report of two cases of seizures after levofloxacin and ciprofloxacin (38A ). • A 75-year-old white woman was given oral levofloxacin (500 mg on day 1 followed by 250

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mg/day) for ischemic toes. After three doses she had a seizure. One month later, she was challenged with ciprofloxacin 400 mg intravenously every 12 hours and again had a seizure. • A 74-year-old white woman was given oral levofloxacin 500 mg/day for bacterial pneumonia and had a seizure after five doses.

Skin In a mouse model pefloxacin and ciprofloxacin augmented the effect of ultraviolet A by increasing sunburn and apoptosis, depleting Langerhans cells, and suppressing local immune responses (39E ). Musculoskeletal Of 42 patients with fluoroquinolone-associated tendon disorders, 32 had tendinitis and 10 had a tendon rupture (40c ). Most of the reports concerned the Achilles tendon, and 24 patients had bilateral tendinitis. Ofloxacin was implicated in 16 cases, ciprofloxacin in 13, norfloxacin in 8, and pefloxacin in 5. The median age was 68 years and there was a male preponderance. The latency between the start of treatment and the appearance of the first symptoms was 1–510 (median 6) days. Most patients recovered within 2 months after withdrawal, but 26% had not yet recovered at follow-up. In a Russian study in children with cystic fibrosis five were withdrawn (four taking ciprofloxacin and one taking pefloxacin) (41c ). Two had an arthropathy that was drug- and agedependent. Quinolone-induced arthropathy was more common with pefloxacin and occurred only in children over 10 years old with a history of joint problems. The arthropathy fully recovered within 7 days to 3 months and there was no cartilage damage. Infection risk Ciprofloxacin, norfloxacin, and ofloxacin increased gastrointestinal colonization by Candida albicans in 17 patients (42c ). Ciprofloxacin caused the largest increase, but the difference was not statistically significant. Risk factors The penetration of routinely used fluoroquinolones into ascitic fluid after intravenous administration has been studied in patients with uncompensated hepatic cirrhosis (43c ). Three patients received three doses of ciprofloxacin 200 mg, six received three doses of ciprofloxacin 300 mg, seven received three doses of pefloxacin 400 mg, and six received

275 three doses of ofloxacin 400 mg. Pefloxacin and ofloxacin produced serum and ascitic fluid concentrations above the MICs of the common pathogens that cause spontaneous bacterial peritonitis, and the authors concluded that they could be given to cirrhotic patients in dosage regimens similar to those in patients with normal hepatic function. Based on their predominant renal elimination, dosage adjustment is necessary in the presence of renal disease for ciprofloxacin, gatifloxacin, levofloxacin, and sitafloxacin (44C ). Drug interactions All of the fluoroquinolones interact with polyvalent cations, and their systematic availability is reduced by 50% when they are co-administered with iron compounds; ciprofloxacin and moxifloxacin are more affected than gemifloxacin or levofloxacin (45R ). The interaction between theophylline and fluoroquinolones is most marked with ciprofloxacin, enoxacin, and pefloxacin; no interaction has been reported with levofloxacin (45R ). Interference with diagnostic tests The reactivity of 13 quinolones (ciprofloxacin, clinafloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, sparfloxacin, and trovafloxacin) with five commercial opiate immunoassays has been tested in vitro and in three healthy volunteers (46Ec ). In vitro, levofloxacin and ofloxacin (using Abbott AxSYM, CEDIA, EMIT II, and Roche OnLine assays), pefloxacin (using CEDIA, EMIT II, and Roche OnLine assays), enoxacin (using CEDIA and EMIT II assays), gatifloxacin (using EMIT II assay), and ciprofloxacin, lomefloxacin, moxifloxacin, and norfloxacin (using Roche OnLine assay) cross-reacted and cause a positive test result for opiates. Clinafloxacin, nalidixic acid, sparfloxacin, and trovafloxacin did not crossreact in any of the assays. A single dose of levofloxacin 500 mg caused a false-positive test result using the EMIT II assay within 2 hours for as long as 22 hours in all three volunteers. Ofloxacin (a single dose of 400 mg) produced a similar pattern. Detectable opiate activity in the urine was seen for more than 30 hours with both levofloxacin and ofloxacin.

276

Alatrofloxacin and trovafloxacin Alatrofloxacin is a fluoronaphthyridone that is hydrolysed to the active moiety, trovafloxacin, after intravenous administration. This fourthgeneration broad-spectrum fluoroquinolone has activity against Gram-positive, Gram-negative, anerobic, and atypical respiratory pathogens. Because it has significant hepatotoxicity, the list of appropriate indications for trovafloxacin has been restricted. Hematologic Alatrofloxacin has been associated with severe leukopenia (47A ). • A 79-year-old white man was treated with intravenous alatrofloxacin mesylate 200 mg bd for 5 days. His leukocyte count fell from 10.9 × 109 /l to 2.2×109 /l; the hemoglobin did not change. Alatrofloxacin was withdrawn, and 3 days later the leukocyte count had increased to 11.5 × 109 /l.

The mechanism of trovafloxacin-induced leukopenia is unknown. Nevertheless, since quinolones exert their antibacterial effect by inhibiting bacterial DNA gyrase and since similar topoisomerases are involved in the organization and function of mammalian DNA, it is possible that trovafloxacin acts by modulating bonemarrow stem-cell DNA production. Liver More than 100 cases of hepatotoxicity associated with trovafloxacin have been reported to the FDA. • A 19-year-old woman developed severe acute hepatitis and peripheral eosinophilia during oral trovafloxacin therapy for recurrent sinusitis (48A ). Liver biopsy showed extensive centrilobular hepatocyte necrosis, probably causing veno-occlusive disease. Clinical and laboratory abnormalities resolved completely after prolonged treatment with steroids.

Ciprofloxacin Antimicrobial prophylaxis to prevent inhalational anthrax has been recommended for people potentially exposed to Bacillus anthracis as a result of recent bioterrorist attacks. Of 3428 people taking ciprofloxacin, 666 (19%) reported severe nausea, vomiting, diarrhea, or abdominal pain; 484 (14%) reported fainting,

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light-headedness, or dizziness; 250 (7%) reported heartburn or acid reflux; and 216 (6%) reported rashes, urticaria, or an itchy skin. Of those taking ciprofloxacin, 287 (8%) stopped taking it, 116 (3%) because of adverse events, 27 (1%) because of fear of possible adverse events, and 28 (1%) because they “did not think it was needed” (49S , 50S , 51r , 52r ). Sensory systems In four corneal transplantation patients treated preoperatively with ciprofloxacin 0.3% ophthalmic drops, there were corneal microprecipitates associated with damaged corneal epithelium in two patients; another developed a macroprecipitate in a corneal ulcer (53c ). The crystalline precipitates were pure ciprofloxacin. Nervous system Ciprofloxacin has been associated with facial dyskinesia (54A ). Psychiatric Ciprofloxacin has been associated with hypoactive delirium (55R , 56A ). Gastrointestinal Ciprofloxacin may be associated with diarrhea due to Clostridium difficile. In 27 patients the only significant risk factor for nosocomial Clostridium difficileassociated diarrhea was the use of ciprofloxacin (57c ). Liver Ciprofloxacin causes a mild reversible rise in liver enzymes in 2–3% of patients. Acute hepatitis is rare but has been reported recently in a 32-year-old man (58A ). Urinary system Acute renal insufficiency is a rare adverse effect of ciprofloxacin in young patients. An 18-year-old woman with cystic fibrosis had pronounced impairment of renal function after taking oral ciprofloxacin 750 mg tds (30 mg/kg/day) for 3 weeks; withdrawal led to normalization of renal function within 10 days (59A ). Skin Ciprofloxacin can cause ultraviolet recall-like phenomenon (26A ), fixed drug eruption (60A ), and cutaneous vasculitis (61A ). Musculoskeletal Ciprofloxacin can be associated with partial or complete tendinitis. In 12 children with sickle cell disease treated successfully for acute osteomyelitis with oral

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ciprofloxacin transient bilateral Achilles tendon tendinitis occurred in one 5-year-old (62c ). Another case was reported in a hemodialysis patient with a ciprofloxacin-associated Achilles tendon rupture (63A ). The available data suggest that the incidence of arthropathy in children taking ciprofloxacin is the same as in adults; the use of other fluoroquinolones is too rare to obtain clear information about the risks in children (64A ). Risk factors Ten patients with peripheral arterial occlusive disease were scheduled to undergo elective percutaneous transluminal angioplasty after a single dose of ciprofloxacin 400 mg (65c ). Antibiotic concentrations were significantly reduced in ischemic lesions compared with healthy adipose tissue. However, improvement of arterial blood flow in the affected limb was associated with increased cure rates of soft tissue infections. The pharmacokinetics of intravenous ciprofloxacin have been studied in intensive care unit patients during continuous venovenous hemofiltration (n = 5) or hemodiafiltration (n = 5) (66c ). Ciprofloxacin clearance was not altered. A dosage of 400 mg/day was sufficient to maintain effective drug plasma concentrations in patients undergoing continuous renal replacement therapy. Drug interactions Methotrexate elimination can be delayed by ciprofloxacin. Two adolescents with malignant diseases had reduced elimination of methotrexate (12 g/m2 4-hourly) when they took ciprofloxacin 500 mg bd (67A ).

Fleroxacin Risk factors In patients with leg ischemia fleroxacin diffused into both ischemic and nonischemic tissues (bone, subcutaneous fat, muscle, and tendons) after a 400 mg intravenous dose (68c ). Since the maximum antibiotic concentrations were lower than the MICs of various relevant pathogens, the dose used for perioperative prophylaxis in these patients should be increased to 800 mg.

Gatifloxacin Further reviews of gatifloxacin have appeared (69R , 70c , 71c ). Cardiovascular Gatifloxacin has little effect on the QT interval of the electrocardiogram (72R ). Neurological Gatifloxacin can cause myoclonus and generalized seizures (73r ). Liver

Gatifloxacin can cause hepatitis.

• A 44-year-old woman developed acute hepatitis while taking gatifloxacin for chronic sinusitis (74A ). After 5 days she developed nausea, lethargy, and abdominal pain, all of which progressed over the next few days. Liver function tests were abnormal, and the bilirubin peaked at 161 µmol/l. A percutaneous liver biopsy showed acute hepatitis with eosinophilic infiltrates, consistent with druginduced hepatitis.

Gemifloxacin In phase II trials oral gemifloxacin 320 mg/day produced bacteriological responses of 91% in patients with acute exacerbations of chronic bronchitis (75R , 76C ). The pharmacokinetics of oral gemifloxacin have been characterized in healthy male volunteers. About 20–30% of the dose was excreted unchanged in the urine. The renal clearance was 160 ml/min on average after single and multiple doses, which was slightly greater than the accepted glomerular filtration rate (77C ). There were no adverse effects. In a crossover, randomized study, 16 fasted volunteers (8 men, 8 women) took single oral doses of gemifloxacin 320 mg and ofloxacin 400 mg on two separate occasions, in order to assess urinary excretion (78c ). Urine concentrations of ofloxacin were higher than those of gemifloxacin. There were no adverse effects. Liver Gemifloxacin was generally well tolerated in a pharmacokinetic study, although one subject was withdrawn after 6 days at 640 mg because of mild, transient rises in AlT and AsT not associated with signs or symptoms (77c ). Gemifloxacin 320 mg od and trovafloxacin 200 mg od have been compared in 571 patients

278 with community-acquired pneumonia in a multicenter, double-blind, parallel-group, randomized study (79C ). Gemifloxacin was slightly more effective (88%) than trovafloxacin (81%). Gemifloxacin was well tolerated and the incidence of transient liver function abnormalities was very low. Infection risk The effect of oral gemifloxacin 320 mg for 7 days on the human intestinal microflora has been investigated in 10 healthy subjects (80c ). The numbers of enterobacteria, enterococci, and streptococci were reduced. No other aerobic micro-organisms were affected. The numbers of anerobic cocci and lactobacilli were reduced. The microflora normalized 49 days after withdrawal. There was no selection or overgrowth of resistant bacterial strains or yeasts.

Grepafloxacin Grepafloxacin is a synthetic quinolone that has extensive tissue distribution and strong antibacterial activity in vivo. However, it was withdrawn in 1999 because of its adverse cardiovascular events, including torsade de pointes (36R ).

Levofloxacin Levofloxacin, the (−)-(S)-enantiomer of racemic ofloxacin, is an oral and parenteral fluoroquinolone that has bactericidal activity against a broad spectrum of both Gram-negative and Gram-positive bacilli (including Streptococcus pneumoniae), as well as atypical respiratory pathogens. The adverse effects rates are 1.3% for nausea, 0.1% for anxiety, 0.3% for insomnia, and 0.1% for headache. No levofloxacinrelated adverse events were reported at a rate higher than 1.3%, and most were less common. High-dose levofloxacin (750 mg) was also well tolerated. Surveillance data reported low adverse event rates: nausea 0.8%, rash 0.5%, abdominal pain 0.4%, and diarrhea, dizziness, and vomiting 0.3%. The adverse drug reactions rate for levofloxacin is still one of the lowest of any fluoroquinolone, at 2% compared with

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2–10% for other fluoroquinolones (36R , 81R , 82C , 83R ). In patients with meningitis, levofloxacin penetration in cerebrospinal fluid and the liquor-to-plasma ratio was assessed at 2 hours after dosing in five patients with spontaneous acute bacterial meningitis. Cerebrospinal fluid levofloxacin concentration at 2 hours after dosing was 2.0 µg/ml, and the liquor-to-plasma ratio at 2 hours after dosing was 0.35 (84c ). Cardiovascular There were cardiovascular problems in 1 in 15 million prescriptions compared with 1–3% of patients taking sparfloxacin, who had QTc prolongation to over 500 msec. Polymorphous ventricular tachycardia with a normal QT interval has been associated with oral levofloxacin in the absence of other causes (36R , 83R , 85R , 86R ). Among 23 patients who took levofloxacin 500 mg/day there was prolongation of the QTc interval by more than 30 ms in four patients and 60 ms in two patients (87c ). There was absolute QT interval prolongation to over 500 ms in four patients, one of whom developed torsade de pointes. Nervous system In one study convulsions occurred in two per million prescriptions (83R ). Sensory systems Compared with aminoglycosides, which caused significant loss of hair cells in the basal turn of the cochlea, ofloxacin caused no loss of hair cells in rats, even at concentrations higher than are achieved clinically (88Ec ). Moreover, auditory brainstem testing showed no change in auditory thresholds in the ofloxacin-treated animals, whereas neomycintreated animals showed substantial threshold shifts. In human studies, topical ofloxacin 0.3% had no demonstrable adverse effects on middle ear or cochlear function and was not associated with any changes in hearing. Taste disturbance occurred in less than three per million prescriptions (83R ). Liver In a study based on European and international data from about 130 million prescriptions, the adverse effects profile of levofloxacin was compared with that of other fluoroquinolones; there was a low rate of hepatic abnormalities (1/650 000) (36R ). However, two cases of severe acute liver toxicity were reported in patients who had received intravenous levofloxacin (89A , 90A ).

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Pancreas Two case reports have suggested that levofloxacin can cause pancreatitis (91A ). Skin Levofloxacin has a very low potential for causing phototoxicity, confirmed by pre-clinical animal studies and post-marketing surveillance (92R ). In preclinical studies levofloxacin was 20 times less phototoxic than sparfloxacin. Phototoxicity occurs in only 1 in 1.8 million cases. Musculoskeletal Tendinopathy is a classrelated adverse effect of the fluoroquinolones, and old age, renal dysfunction, and concomitant corticosteroid therapy are predisposing factors; tendon rupture occurred in less than four per million prescriptions (83R ). Risk factors The pharmacokinetics of intravenous levofloxacin have been studied in intensive care unit patients during continuous venovenous hemofiltration or hemodiafiltration (66c , 93c ). Levofloxacin clearance was substantially increased during both types of continuous renal replacement therapy. Levofloxacin 250 mg/day maintained effective plasma drug concentrations in these patients. Drug interactions Numerous reports have documented enhanced hypoprothrombinemia when fluoroquinolones (most notably ciprofloxacin) are given with warfarin. Two patients had a raised international normalized ratio after taking levofloxacin with warfarin sodium (94A , 95A ). Theophylline clearance was reduced by levofloxacin plus clarithromycin in a 59-year-old Japanese man, who had stimulation, insomnia, and tachycardia due to theophylline toxicity (96A ). The mechanism was probably inhibition of theophylline metabolism by CYP1A2 and CYP3A4. Levofloxacin pharmacokinetics in HIVpositive patients were not altered by steadystate treatment with nelfinavir or efavirenz (97c ).

Moxifloxacin In a multicenter, prospective, double-blind, randomized trial in 455 patients with communityacquired pneumonia oral moxifloxacin 200

279 mg/day or 400 mg/day for 10 days resulted in a bacteriological response of 91% (98C ). Most adverse events, possibly or probably related to moxifloxacin, were generally mild or moderate and were mostly related to the digestive system: diarrhea, nausea, and abdominal pain with 200 mg/day; diarrhea, liver function abnormalities, and nausea with 400 mg/day. The drugs were withdrawn because of adverse events in 7 of 229 patients taking 200 mg/day, and 11 of 224 taking 400 mg/day. Cardiovascular Moxifloxacin blocks the rapid-component delayed-rectifier potassium channel in the heart, and thus prolongs the QTc interval by 6 ms after oral administration and 12 ms after intravenous administration (99E ). Moxifloxacin should be used with caution in patients with prodysrhythmic conditions and avoided in patients taking antidysrhythmic drugs, such as quinidine, procainamide, amiodarone, and sotalol (100R ). A man developed a hypertensive crisis and transient left bundle branch block with QT interval prolongation after taking moxifloxacin (101A ). Recently, the first case of sinus tachycardia (120/minute) associated with moxifloxacin has been reported in a 49-year-old man about 45 minutes after a single 400 mg dose of moxifloxacin (102A ). The underlying mechanism may have been vasodilatation, either directly or indirectly, owing to release of histamine, with reflex tachycardia. These effects have been described for other fluoroquinolones. Skin Moxifloxacin has a low propensity for causing phototoxic reactions compared with other fluoroquinolones (100R ). Drug interactions Drug interactions with moxifloxacin have been reviewed (100R , 103R , 104R ). Drugs that contain sucralfate or polyvalent cations (e.g. Mg2+ , Al3+ , and iron supplements, but not Ca2+ ) impair the absorption of moxifloxacin (105R ). An interval of 2 hours before or 4 hours after taking antacids ensures that the effect of the interaction is not clinically relevant. There was no clinically relevant effect of moxifloxacin on the pharmacokinetics of digoxin in combination steady-state conditions.

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Concomitant administration of probenecid did not affect the elimination of moxifloxacin. The systemic availability of moxifloxacin was not affected by concurrent administration of ranitidine. Moxifloxacin did not affect the pharmacokinetics of theophylline or vice versa (106R ). The effect of food on the pharmacokinetics of moxifloxacin was not clinically important (107c ). In another study dairy products had no effect on moxifloxacin kinetics (108R ).

Nalidixic acid Teratogenicity In a case-control surveillance of congenital abnormalities in 22 865 women who had neonates or fetuses with congenital abnormalities, and 38 151 pregnant women who had neonates without any defects, treatment with nalidixic acid during pregnancy was associated with an increased risk of pyloric stenosis (109c ).

Norfloxacin In a double-blind, multicenter study 171 patients who had acute pyelonephritis were given intravenous cefuroxime for 2–3 days, followed by ceftibuten 200 mg bd or norfloxacin 400 mg bd for 10 days (110C ). There were fewer bacterial relapses after oral norfloxacin than ceftibuten. Adverse events were reported by 47% of the patients taking ceftibuten and by 38% of those taking norfloxacin. This difference was not significant, but diarrhea or loose stools occurred more often with ceftibuten. Musculoskeletal myalgia.

Fluoroquinolones can cause

• A 33-year-old man developed myalgia and rhabdomyolysis while taking norfloxacin for cystitis (111A ). He complained of general muscle fatigue, tendon disorders, and articular pain. When norfloxacin was withdrawn, his symptoms abated, with persistence of slight myalgia for 10 days.

Drug interactions Norfloxacin inhibits CYP1A2 and can therefore enhance the effects of other drugs by reducing their clearance (112r ).

Alexander Imhof

Ofloxacin Endocrine Ofloxacin 200 mg bd caused diabetes insipidus in a 25-year-old man (113A ). Salivary glands Ofloxacin can cause impaired salivary gland function. In rat parotid and submandibular glands intraperitoneal ofloxacin (20, 40, and 80 mg/kg) reduced flow rate, amylase activity, total protein, and calcium concentrations. In parotid saliva, sodium and potassium were increased (114E ). Sodium and potassium concentrations were also increased by a dose of 80 mg/kg in submandibular saliva. Fluoroquinolones alter intracellular cAMP and calcium concentrations and suppress DNA, RNA, and protein synthesis in acinar cells, which are possible mechanisms. Skin Fluoroquinolones have rarely been implicated in cases of toxic epidermal necrolysis. • A 75-year-old white man took 24 g of ofloxacin over 51 days for epididymitis (115A ). He had a severe skin reaction, diagnosed as toxic epidermal necrolysis, and died from complications.

Drug formulations Chitosan, a positively charged polysaccharide, increases the precorneal residence time of ophthalmic formulations that contain active compounds. Two chitosan products of high molecular weights (1350 and 1930 kDa) and low degrees of deacetylation (50%) significantly increased antibiotic availability compared with controls (116E ). The duration of efficacy of ofloxacin was significantly increased from about 25 minutes to 46 minutes by the chitosan of higher molecular weight. Drug interactions The antibacterial activity of polymorphonuclear leukocytes is based on the production of superoxide anions and H2 O2 in the respiratory burst. Combinations of an antibacterial agent and an anti-inflammatory drug are commonly used in immunosuppressed patients whose respiratory burst of polymorphonuclear leukocytes is impaired. An in vitro study has shown that the combination of an antiinflammatory drug (dexamethasone, methylprednisolone, betamethasone, hydrocortisone, phenylbutazone, or acetylsalicylic acid) with ofloxacin 10 mg/ml neutralizes the inhibitory effect of the former on the respiratory burst (117E ).

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Pefloxacin Immunologic Pefloxacin in suprabactericidal concentrations (2.0 mg/ml and 0.4 mg/ml) markedly suppressed T lymphocyte proliferation in blast transformation; 0.08 mg/ml did not (118E ). Pefloxacin in a maximal effective dose (200 mg/kg) suppressed delayed hypersensitivity skin reactions in mice. Risk factors In moderate impairment of renal function, prolongation of the dosage interval of pefloxacin should be considered; pefloxacin should be avoided in severe renal impairment (119c ).

floxacin more commonly causes photosensitivity than ciprofloxacin, levofloxacin, or ofloxacin, which are also effective antituberculous drugs (124R , 125c ). In 25 patients taking sparfloxacin for multiresistant tuberculosis, there were five mild phototoxic reactions (122c ). Risk factors In an in vivo study in rats, endotoxin reduced the biliary excretion of sparfloxacin and its glucuronide, probably owing to impairment of hepatobiliary transport systems and renal handling (126E ).

Tosufloxacin Sitafloxacin Liver In a phase II, open, multicenter, randomized study sitafloxacin 400 mg/day caused mild transient increases in AlT and alkaline phosphatase in 69 patients but no effects on other enzymes (120C ). Drug formulations After oral administration sitafloxacin 500 mg is rapidly absorbed, with a systemic availability of 89% (121c ). By 48 hours, about 61% is excreted unchanged in the urine after oral administration and about 75% after intravenous administration. For both routes, the high renal clearance of sitafloxacin implies active tubular secretion.

Sparfloxacin Cardiovascular In an in vitro comparison of sparfloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, tosufloxacin, and trovafloxacin, sparfloxacin caused the largest increase in QT interval (33E ). In 25 patients taking sparfloxacin for multiresistant tuberculosis, there were six cases of moderate prolongation of the electrocardiographic QT interval (30–40 ms compared to baseline) without clinical symptoms (122c ). Skin Four of nine patients taking sparfloxacin, in combination with kanamycin (for the first 3–4 months) and ethionamide for multidrugresistant pulmonary tuberculosis, developed mild to moderate phototoxicity (123c ). Spar-

Respiratory A syndrome of pulmonary infiltration with eosinophilia occurred in an 83year-old man who was given piperacillin plus tosufloxacin (127A ). In vitro blastogenesis of his peripheral blood lymphocytes was strongly enhanced by piperacillin and tosufloxacin, and they generated a large amount of interleukin-5.

FUSIDIC ACID

(SED-14, 912; SEDA-24, 288; SEDA-25, 303)

Skin Acanthosis nigricans has been associated with fusidic acid (128A ). Drug tolerance (antibacterial resistance) In an in vitro susceptibility study of 170 clinical isolates of Mycobacterium tuberculosis to fusidic acid, 19 isolates were resistant to at least one first-line antituberculous drug (129E ). A total of 1.8% of the isolates were resistant to fusidic acid. Fusidic acid can be a potential supplementary drug for the treatment of infections due to multidrug-resistant strains of M. tuberculosis.

GLYCOPEPTIDES

(SED-14, 858; SEDA-23, 269; SEDA-24, 288; SEDA-25, 303) Urinary tract The effect of co-administration of fosfomycin on glycopeptide antibioticinduced nephrotoxicity for 3 days has been

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investigated in rats (130E ). Fosfomycin reduced glycopeptide antibiotic-induced nephrotoxicity, as shown by reduced urinary excretion of N-acetyl-beta-D-glucosaminidase and fewer histological signs of nephrotoxicity in those treated with a combination of glycopeptide and fosfomycin compared with a glycopeptide alone. In addition, the higher the dose of fosfomycin, the more it reduced urinary N-acetyl-beta-D-glucosaminidase activity, suggesting that the role of fosfomycin in alleviating nephrotoxicity is dose dependent. There was significantly less accumulation of teicoplanin and vancomycin in the renal cortex of rats treated with glycopeptide antibiotics plus fosfomycin compared with the glycopeptide antibiotics alone.

Vancomycin

Drug tolerance (antibacterial resistance) In a prospective, randomized trial in 34 drug abusers a short course of a combination of a glycopeptide (vancomycin or teicoplanin) with gentamicin was significantly less effective in right-sided endocarditis caused by Staphylococcus aureus than a combination of cloxacillin and gentamicin (131C ).

Hematologic Patients undergoing allogeneic hemopoietic stem cell transplantation always require platelet transfusions, but the increase in platelet count is often less than expected. The factors responsible for poor responses to platelet transfusions in this clinical setting are largely unknown. In a prospective study in 87 consecutive transplanted children univariate analysis showed that concomitant therapy with vancomycin is significantly associated with a lower post-transfusion corrected increment in platelet count (136c ).

In a prospective study to determine if standardized vancomycin doses could produce adequate serum concentrations in 25 full-term neonates with sepsis, 13 had adequate peak vancomycin serum concentrations (20–40 mg/ml) and one had a peak concentration with a risk of ototoxicity (over 40 µg/ml) (134c ). Only 12 had adequate trough concentrations (5–10 mg/ml) and seven had a risk of nephrotoxicity (over 10 µg/ml). There was no significant difference between peak or trough concentrations and good or bad clinical outcomes. Metabolism Lactic acidosis occurred in a 56year-old woman who was given intravenous vancomycin 1 g bd for 10 days (135A ).

Teicoplanin Hematologic The incidence of teicoplanininduced leukopenia is low (0.33%) and the leukopenia is usually reversible. • A 10-year-old Malay boy with G6PD deficiency received teicoplanin (300 mg/day) for an epidural abscess and 14 days later developed an erythematous, maculopapular, non-pruritic rash over his trunk and upper limbs and a mild fever with chills (132A ). He had a leukocyte count of 2 × 109 /l. Teicoplanin was withdrawn and by 3 days the rash had almost completely subsided. After rechallenge with a single intravenous dose of teicoplanin 300 mg, he developed a fever (39.3◦ C), chills, and worsening of the rash on his arms. Teicoplanin was again withdrawn. His fever resolved after 4 days and his leukocyte count normalized by 7 days.

Skin Teicoplanin can cause an acute generalized rash and exanthematous pustulosis (132A , 133A ).

Skin Linear immunoglobulin A bullous disease has been reported in a 69-year-old white woman treated with vancomycin and ciprofloxacin, in a 53-year-old white man with septic shock, and in other cases in which both vancomycin and Varicella zoster infection were present as triggers (137A –140A ). Immunologic Hypersensitivity reactions to vancomycin occur via two different mechanisms, resulting in the red man syndrome and anaphylaxis. While both reactions involve mast cell activation, vancomycin-induced anaphylactic reactions are mediated by IgE, while the red man syndrome is not. However, in some patients the clinical presentation is identical. Vancomycin desensitization should therefore be considered for severe red man syndrome reactions that do not respond to premedication and a slower rate of infusion, and in anaphylactic reactions to vancomycin when substitution of

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another antibiotic is not feasible. Rapid desensitization is preferred, as it is effective in the majority of patients and enables administration of vancomycin within 24 hours. In patients who fail rapid desensitization, a slow desensitization protocol may be tried (141R ). Drug tolerance (antibacterial resistance) In 155 methicillin-resistant strains of Staphylococcus aureus isolated from patients in Thailand, one-point population analysis identified three methicillin-resistant strains, which contained subpopulations of cells with reduced susceptibility to vancomycin (142E ). Drug administration route In a multicenter, prospective, randomized comparison of continuous infusion of vancomycin (targeted serum plateau concentrations of 20–25 µg/ml) and intermittent infusions of vancomycin (targeted serum trough concentrations of 10–15 µg/ml) in 119 critically ill patients, microbiological and clinical outcomes and safety were similar (143C ). Continuous infusion of vancomycin produced the target concentration faster and fewer samples were required for monitoring. Serum creatinine concentrations and creatinine clearance increased non-significantly from baseline to the end of treatment in the two groups. There was nephrotoxicity in 21 patients (10 of whom received the continuous infusion). Vancomycin given concomitantly with other antibiotics was associated with a significant increase in the serum creatinine concentration, but not when it was given alone. Dialysis was required for three of those who were given intermittent infusions and six of those who were given continuous infusions. Red man syndrome was reported in one patient who was given an intermittent infusion, and phlebitis and fever in two patients who were given continuous infusions. Drug formulations Vancomycin underwent spontaneous chemical modification when kept at room temperature at neutral pH in aqueous solutions containing traces of formaldehyde or acetaldehyde (144E ). In vitro studies on two different strains of bacteria showed that the resulting compounds had reduced antibacterial activity.

Management of adverse drug reactions Vancomycin clearance is minimally altered by hemodialysis using standard cuprophane membranes. However, it is significantly increased using a high-flux polysulfone membrane. • A 17-year-old anuric woman with end-stage renal insufficiency received a massive overdose of vancomycin (40 mg/kg/day for 8 days) and was treated three times with high-flux hemodiafiltration with a polysulfone membrane (145A ). The vancomycin concentration fell from 101 to 17 mg/l at the end of the procedure. There were no adverse effects of either vancomycin or hemodiafiltration.

In a 46-year-old African-American woman with sickle-cell disease there was clinically significant removal of vancomycin during a plasma exchange transfusion (146A ).

KETOLIDES

(SEDA-24, 294; SEDA-25,

305) Telithromycin is the first member of a new family of the macrolide–lincosamide–streptogramin-B class of antimicrobials, the ketolides. It has a good spectrum of activity against respiratory pathogens, including penicillin-resistant and erythromycin-resistant pneumococci and intracellular and atypical bacteria. It penetrates rapidly into bronchopulmonary, tonsillar, sinus, and middle ear tissues/fluids, achieves high concentrations at sites of infection, and concentrates within polymorphonuclear neutrophil leukocytes. In a dosage of 800 mg/day it is well tolerated across all patient populations; adverse events, most commonly diarrhea, nausea, dizziness, and vomiting, were generally mild to moderate and seldom led to withdrawal (147R , 148R ).

LINCOSAMIDES

(SED-14, 871; SEDA-23, 273; SEDA-24, 293; SEDA-25, 306)

Clindamycin Sensory systems In a prospective study subconjunctival injections of clindamycin did not produce any general adverse effects (149c ).

284 However conjunctival inflammation and keratitis occurred in one of 13 cases, caused by an error in the administered concentration of clindamycin, which was too high. Gastrointestinal In a prospective study patients treated with antibiotics, including clindamycin, for 3 days had a significantly lower frequency of antibiotic-associated diarrhea than those treated for longer periods (150C ). Skin In a 10-week, multicenter, double-blind study 480 patients with moderate to moderately severe acne were randomized to receive twicedaily 5% benzoyl peroxide, 1% clindamycin, 5% benzoyl peroxide plus 1% clindamycin, or vehicle, all topically (151C ). There were significantly greater reductions in the numbers of inflammatory and total lesions in patients who used combination therapy compared with those who used any of its three individual components. The most frequent adverse effect, dry skin, occurred to a similar extent with the combination and with benzoyl peroxide alone. Pregnancy In pregnant women with bacterial vaginosis, a 7-day regimen of 2% vaginal clindamycin cream was effective and did not alter the rates of preterm deliveries or peripartum infections (152c , 153c ).

Lincomycin Skin Precautions are necessary to avoid ultraviolet radiation after taking photoreactive drugs (154E ). Metabolism of lincomycin can lead to the formation of reactive oxygen species and cause tissue injury and damage to various cellular macromolecules, which can result in phototoxicity.

MACROLIDES

(SED-14, 873; SEDA-23, 273; SEDA-24, 295; SEDA-25, 306) The basic structure of macrolides is characterized by a lactonic cycle with two osidic chains, and they are classified according to the number of carbon atoms in the cycle: 14-membered

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macrolides (e.g. clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin), 15-membered macrolides (e.g. azithromycin), and 16-membered macrolides (e.g. josamycin, midecamycin, spiramycin). In a prospective, single-blind, randomized study of a 7-day course of clarithromycin (7.5 mg/kg bd) and a 14-day course of erythromycin (13.3 mg/kg tds) in 153 children with pertussis, the incidence of treatment-emergent drugrelated adverse events was significantly higher with erythromycin than with clarithromycin (62% vs. 45%) (155c ). Three subjects given erythromycin withdrew prematurely because of adverse events: one because of a rash; one with vomiting and diarrhea; and one with vomiting, abdominal pain, and rash. Sensory systems The cochlear toxicity of systemic macrolides, azithromycin, clarithromycin, and erythromycin, has been investigated in guinea-pigs by measuring transiently evoked otoacoustic emissions (156E ). A single intravenous dose of erythromycin 125 mg/kg caused no change in evoked otoacoustic emissions, whereas oral azithromycin 45 mg/kg and intravenous clarithromycin 75 mg/kg reversibly reduced the emission response. This could have been caused by transient dysfunction of the outer hair cells. Drug interactions Pharmacokinetic interactions with clarithromycin, erythromycin, and troleandomycin have been reviewed (157R ). They often result from inhibition of drug metabolism by CYP3A4. Resulting interactions include rhabdomyolysis (associated with the co-administration of some statins, e.g. lovastatin or simvastatin), hypoprothrombinemia (associated with warfarin), excessive sedation (associated with certain benzodiazepines, e.g. alprazolam, diazepam, midazolam, or triazolam), ataxia (associated with carbamazepine), and ergotism (associated with ergotamine). Beneficial drug interactions can also occur; for example, co-administration of macrolides with ciclosporin may allow reduction of the dosage of the latter.

Azithromycin Of 42 adult HIV-positive patients with confirmed or presumed acute toxoplasmic en-

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cephalitis who received azithromycin 900, 1200, or 1500 mg/day plus pyrimethamine, 28 responded to therapy during the induction period (158C ). Six patients withdrew during the induction period because of reversible toxic effects (three with raised liver enzymes, two with hearing loss, one with neutropenia). Treatmentterminating adverse events occurred most often among the patients who took 1500 mg/day. In an open, prospective trial gingival hyperplasia due to ciclosporin was successfully treated with azithromycin 250 mg/day for 5 days in 30 of 35 patients, who reported esthetic satisfaction and disappearance of bleeding and pain (159c ). There was no change in ciclosporin concentration or renal function after azithromycin. Tolerability of azithromycin oral suspension, 10 mg/kg od for 3 days, has been assessed in children in a review of 16 multicenter studies (160M ). Of 2425 patients, 1213 received azithromycin and 1212 received other drugs. The incidence of treatment-related adverse events was significantly lower in those who took azithromycin, while withdrawal rates were similar. There were significantly fewer gastrointestinal events with azithromycin and their duration was significantly shorter. In a meta-analysis of randomized controlled trials of 3–5 days of azithromycin or other antibiotics that are typically given in longer courses for upper respiratory tract infections, there were no significant differences in bacteriological outcomes (161M ). Azithromycin was withdrawn because of adverse events in only 37 (0.8%) of 4870 patients. Cardiovascular Some macrolides can cause prolongation of the QTc interval, and torsade de pointes has been reported in patients given intravenous erythromycin. Torsade de pointes and cardiorespiratory arrest has been reported in a patient with congenital long QT syndrome who took azithromycin (162A ). Sensory systems Azithromycin rarely causes ototoxicity, mostly after prolonged high-dose therapy in patients with AIDS, and it results in a reversible sensorineural hearing loss. However, low-dose exposure to azithromycin has also been associated with irreversible sensorineural hearing loss in otherwise healthy subjects (163A ).

285 Hematologic The effects of combining azithromycin and rifabutin have been studied in 50 subjects with or without HIV infection, of whom 19 took azithromycin 1200 mg/day and rifabutin 600 mg/day, and 31 took azithromycin 600 mg/day and rifabutin 300 mg/day (164c ). Neutropenia was the most common adverse event, in 33 of 50 subjects. Low-grade nausea, diarrhea, fatigue, and headache were also common, and most subjects had more than one type of event. There was no significant pharmacokinetic interaction between the two drugs. Immunologic Occupational allergic contact dermatitis has been attributed to azithromycin (165A ). • A 32-year-old pharmaceutical worker had been loading reactors at three different stages of azithromycin synthesis for the past 3 years and had been exposed to airborne powders. He wore overalls and latex gloves. His symptoms had persisted for 1 year in the form of pruritus, erythema, vesicles, and scaling of the face and forearms. A positive patch test and a positive workplace challenge were considered reliable in the diagnosis of occupational allergic contact dermatitis induced by azithromycin. After transfer to another work station that excluded exposure to azithromycin, he had no further work-related symptoms.

Hypersensitivity to azithromycin has been reported (166A ). • A 79-year-old man developed fever, mental changes, a rash, acute renal insufficiency, and hepatitis after he had completed a 5-day course of oral azithromycin (500 mg initially then 250 mg/day). With intravenous hydration only, his fever abated and his urinary output and renal and hepatic function returned to normal over the next 4 days. His mental status improved significantly. The skin rash was followed by extensive desquamation.

Pregnancy In two randomized trials in pregnant women with cervical Chlamydia trachomatis infection, women were randomized to oral amoxicillin, 500 mg tds for 7 days or oral azithromycin 1 g in a single dose (167c , 168c ). The two drugs had was similar efficacy. Adverse effects were common in both groups: 40% of those who took azithromycin reported moderate to severe gastrointestinal adverse effects compared with 17% of those who took amoxicillin.

286 Risk factors In eight patients a single 500 mg oral dose of azithromycin was not substantially removed by continuous ambulatory peritoneal dialysis in the absence of peritonitis. Azithromycin cannot be recommended for widespread use in CAPD at present. However, the successful use of azithromycin in treating peritonitis, perhaps because of an intracellular drug transport mechanism, has been reported (169c ). Drug interactions In 66 patients undergoing oral surgery, treatment with azithromycin impaired the periodontal disposition of piroxicam (170c ). The effects of azithromycin 250 mg/day on the pharmacokinetics of desloratadine 5 mg/day and fexofenadine 60 mg bd have been studied in a parallel-group, third-party-blind, multiple-dose, randomized, placebo-controlled study (171c ). There were small increases (under 15%) in the mean plasma concentrations of desloratadine. In contrast, peak fexofenadine concentrations were increased by 69% and the AUC by 67%. There were no changes in the electrocardiogram.

Clarithromycin In a multicenter, double-blind, randomized comparison of cefprozil, 500 mg bd for 5 days and clarithromycin 500 mg bd for 10 days in 295 subjects with an acute exacerbation of chronic bronchitis, the most common adverse effects of clarithromycin were nausea (8%), diarrhea (12%), taste disturbance (8%), and dry mouth (5%) (172C ). Cardiovascular In a prospective, non-randomized study, phlebitis occurred in 15 of 19 patients treated with intravenous erythromycin (incidence rate of 0.40 episodes/patient-day) and in 19 of 25 patients treated with intravenous clarithromycin (0.35 episodes/patientday) (173C ). Psychiatric Two patients, a man aged 74 and a woman aged 56 years, developed delirium after taking clarithromycin (174A ).

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Skin Only a few cases of adverse skin reactions to clarithromycin have been reported. Recently a clarithromycin-induced fixed drug eruption was reproduced by oral provocation, whereas patch tests on both unaffected and residual pigmented skin were negative (175A ). Immunologic Bronchospasm with clarithromycin occurred in a 44-year-old woman who had no history of respiratory allergies but had had adverse drug reactions to general and regional anesthetics and to ceftriaxone (176A ). After the administration of a quarter of the therapeutic dose the patient had dyspnea, cough and bronchospasm throughout the lung. Drug interactions Clarithromycin can increase the steady-state concentrations of drugs that depend primarily on CYP3A metabolism, including astemizole, cisapride, pimozide, midazolam, and triazolam. This can be clinically significant for drugs that have a narrow therapeutic index, such as carbamazepine, ciclosporin, theophylline, and warfarin. The following drug interactions of clarithromycin have recently been reviewed: • reduced absorption of clarithromycin by cimetidine; • inhibition of clarithromycin metabolism (e.g. by omeprazole and ritonavir); • induction of clarithromycin metabolism (e.g. by rifampicin and rifabutin); • carbamazepine toxicity due to clarithromycin; • potentiation of the cardiovascular action of pimozide by clarithromycin; • inhibition of rifabutin metabolism by clarithromycin. Colchicine Fatal colchicine intoxication occurred in a 67-year-old man who had taken clarithromycin 500 mg bd for 4 days (177A ). Clarithromycin may have inhibited colchicine metabolism and caused a rise in colchicine concentration. Digoxin Clarithromycin can cause digoxin toxicity by two different mechanisms, inhibition of the renal excretion of digoxin and alteration of intestinal flora, which reduces the presystemic hydrolysis of digoxin.

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• A 70-year-old woman taking digoxin for atrial fibrillation developed nausea, vomiting, and dizziness 2 days after starting to take clarithromycin (178A ). Her serum digoxin concentration was 3.9 ng/ml (target range 0.5–2.0).

Disopyramide Severe cardiac dysrhythmias and major hypoglycemia have occurred in patients taking disopyramide with some macrolide antibiotics, especially erythromycin and clarithromycin (179A ). Ergotamine In patients with ergotamine toxicity, vasoconstriction can lead to frank ischemia. Clarithromycin interferes with ergotamine metabolism. • A 41-year-old woman developed worsening lower leg pain, pallor, and a sensation of coolness aggravated by exertion; there was severe vasospasm in the legs (180A ). She had taken a caffeine + ergotamine formulation for migraine for many years and had recently been given clarithromycin 500 mg bd for flu-like symptoms.

Statins The HMG-CoA reductase inhibitors (statins) have varying potentials for drug interactions, probably because of their different pharmacokinetic characteristics. Macrolide antibiotics inhibit the metabolism of statins that are metabolized by CYP3A4 (atorvastatin, cerivastatin, lovastatin, simvastatin). This interaction can cause myopathy and rhabdomyolysis, particularly in patients with renal insufficiency or in those who are concurrently taking medications associated with myopathy. A 64-year-old African-American man developed rhabdomyolysis resulting from concomitant use of clarithromycin and simvastatin (181A ). Warfarin Increases in International Normalized Ratio (INR) have been detected in patients who have previously been stabilized on warfarin when they were simultaneously given clarithromycin. In one case this caused a suprachoroidal hemorrhage (182A ).

Erythromycin Cardiovascular Torsade de pointes has been reported in patients receiving intravenous erythromycin. Erythromycin has electrophysiological effects on the cardiac conducting system

similar to those of class IA antidysrhythmic drugs. This is only likely to be a problem in patients with heart disease or in those who are receiving drugs that delay ventricular repolarization (157R ). Drug interactions When erythromycin was co-administered with atorvastatin, the mean maximum blood concentration of atorvastatin and the AUC increased by more than 30% (157R ). It has recently been proposed that the risk of myotoxicity increases when statins are prescribed concurrently with erythromycin (183R ). Studies in dogs have shown that some statins are associated with cataract when given in excessive doses (184E ). A case– control analysis of 7405 cases and 28 327 controls suggested that concomitant use of simvastatin and erythromycin is associated with an increased risk of cataract (185C ). The interaction of erythromycin with ergotamine or dihydroergotamine can cause ergotism, sometimes leading to gangrene, by inhibition of the metabolism of the ergopeptides (186r ).

Josamycin Gastrointestinal In a randomized open study, 325 children aged 2–15 years with acute tonsillitis and a positive test for Streptococcus pyogenes antigen were treated with josamycin 25 mg/kg bd for 5 days, or penicillin 50 000– 100 000 IU/day for 10 days. In five patients treated with josamycin treatment was withdrawn because of gastrointestinal adverse events (nausea/vomiting) (187c ).

Miocamycin Drug interactions CYP3A4 is mainly responsible for catalysing the hydroxylation of miocamycin metabolites. Some macrolide antibiotics cause drug interactions that result in altered metabolism of concomitantly administered drugs by the formation of a metabolic intermediate complex with CYP450 or competitive inhibition of the CYP450 (157R ). The resulting interactions can cause rhabdomyolysis (associated with the co-administration of

288 some statins, e.g. lovastatin or simvastatin), hypoprothrombinemia (associated with warfarin), excessive sedation (associated with certain benzodiazepines, e.g. alprazolam, diazepam, midazolam, or triazolam), ataxia (associated with carbamazepine), and ergotism (associated with ergotamine).

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strains from poultry, but also in some strains from pork. Among strains of Enterococcus fecium and Enterococcus fecalis isolated from pigs and poultry in Denmark, resistance to tylosin was often observed among isolates from places in which these antimicrobials had been widely used, but rarely among isolates from places in which they use had been limited (192E ).

Roxithromycin Gastrointestinal During long-term use of roxithromycin 300 mg/day for 2–66 months in nine patients with chronic diffuse sclerosing osteomyelitis of the mandible, diarrhea and stomach discomfort occurred in one case and liver dysfunction in another (188c ). Liver Hepatic failure occurred in a previously healthy 5-year-old boy after he was given roxithromycin 50 mg bd for 5 days (189A ). He developed a non-pruritic, non-urticarial, erythematous, maculopapular, generalized rash and occasional vomiting. Three days later he became jaundiced, and after 8 days underwent liver transplantation. Immunologic Roxithromycin had an immunomodulatory action on peripheral blood mononuclear cells in patients with psoriasis (190E ). The anti-inflammatory activity of roxithromycin is due to reduced production of proinflammatory mediators, cytokines, and costimulatory molecules, as has been shown in animal studies (191E ).

NITROFURANTOIN

(SED-14, 884;

SEDA-25, 310) Respiratory In a patient with nitrofurantoininduced pulmonary toxicity, in whom high resolution CT scans initially showed a widespread reticular pattern and associated distortion of the lung parenchyma, thought to represent established and irreversible fibrosis, follow-up CT scans after withdrawal of the drug showed resolution of the pulmonary changes. • An 82-year-old woman developed a productive cough after having taken nitrofurantoin 50 mg/day for 4 years (193A ). She had impaired lung function and abnormal CT scans, and lung biopsies showed features compatible with bronchiolitis obliterans organizing pneumonia. The condition improved when nitrofurantoin was withdrawn and she was given a corticosteroid.

Liver Nitrofurantoin has been associated with fatal liver necrosis (194A ). Teratogenicity No teratogenic effects have been associated with nitrofurantoin in a Hungarian case-control survey (195c ).

Drug interactions The interaction of troleandomycin with ergotamine and dihydroergotamine can produce ergotism, sometimes leading to gangrene, by inhibition of the metabolism of the ergopeptides (112r , 186r ).

Lactation Nitrofurantoin is actively transported into human milk, achieving concentrations greatly exceeding those in serum. Concern is warranted for suckling infants under 1 month old or for infants with a high frequency of glucose-6-phosphate dehydrogenase deficiency or sensitivity to nitrofurantoin (196c ).

Tylosin

OXAZOLIDINONES

Drug tolerance (antibacterial resistance) Among strains of Enterococcus fecium, resistance against tylosin was mainly detected in

The oxazolidinones represent the first truly new class of antibacterial agents to reach the marketplace in several decades. They have a unique

Troleandomycin

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mechanism of action, involving inhibition of the first step in protein synthesis. The first marketed member of the class, linezolid, has inhibitory activity against a broad range of Grampositive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptideintermediate S. aureus (GISA), vancomycinresistant enterococci (VRE), and penicillinresistant Streptococcus pneumoniae. It also has activity against certain anerobes, including Clostridium perfringens, C. difficile, Peptostreptococcus spp., and Bacteroides fragilis. In controlled phase III studies, linezolid was as effective as vancomycin in patients with infections caused by MRSA and VRE. It is effective both intravenously and orally. Although technically classified as bacteriostatic against a number of pathogens in vitro, linezolid behaves in vivo like a bactericidal antibiotic. The pharmacokinetics of linezolid in adults are not altered by hepatic or renal function, age, or sex to an extent that requires dose adjustment. Linezolid is metabolized via morpholine ring oxidation, which is independent of CYP450; linezolid is therefore unlikely to interact with medications that induce or inhibit CYP450 enzymes. The mean peak plasma concentration of linezolid was 18.3 µg/ml in six healthy men who took 600 mg orally every 12 h for five doses. There was good penetration into inflammatory fluid (197c , 198R ). Linezolid is generally well tolerated (199R – 201R ). The most frequently reported adverse events were diarrhea, headache, nausea and vomiting, insomnia, constipation, rash, and dizziness. Thrombocytopenia was also documented in few patients (about 2%). In a Phase II, open, multicenter study of intravenous linezolid followed by oral linezolid suspension, both in a dose of 10 mg/kg every 12 h in 66 children, the most common adverse effects were diarrhea (10%), neutropenia (6.4%), and raised AlT activity (6.4%) (202C ). Hematologic Myelosuppression with red cell hypoplasia has been reported in three patients taking linezolid 600 mg bd. The bone-marrow changes were similar to those seen in reversible chloramphenicol toxicity. Another patient had sideroblastic anemia after taking linezolid for 2 months (203r , 204r ).

Drug interactions The serotonin syndrome was reported in 45-year-old white man who received intravenous linezolid (600 mg 12 hourly) and sertraline (205A ).

POLYMYXINS

(SED-14, 887; SEDA-24, 300; SEDA-25, 311) Respiratory In 58 children with bronchoconstriction in response to nebulized colistin, FEV1 was significantly reduced for 15 minutes (206c ). In 20 children the reduction was greater than 10% from baseline FEV1 and was still at that level in five children after 30 minutes. Subjective assessment, baseline FEV1 , and serum IgE did not distinguish susceptible children. Nervous system Of 31 patients with cystic fibrosis 21 had one or more adverse effects attributed to colistin (207c ). The most common reactions involved reversible neurological effects, including oral and perioral paresthesia (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these effects, although bothersome, were benign and reversible. There was no relation between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetics. Urinary tract Intermittent proteinuria was observed on urinalysis in 14 of 31 patients with cystic fibrosis, and one patient developed reversible, colistin-induced nephrotoxicity (207c ). There was no relation between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetics. Drug interactions There may be difficulty in reversing neuromuscular blockade if polymyxin is given in combination with neuromuscular blocking drugs (208R ).

STREPTOGRAMINS

(SEDA-24, 300;

SEDA-25, 311)

Pristinamycin Gastrointestinal Pristinamycin can cause pseudomembranous colitis.

290 • An 85-year-old woman developed a severe illness (severe diarrhea and vomiting, abdominal tenderness, peritoneal irritation, and systemic toxicity) 8 days after receiving pristinamycin 3 g/day for 10 days (209A ). An assay for Clostridium difficile was positive. She was treated with metronidazole and her symptoms resolved after 72 h.

Quinupristin/dalfopristin The adverse events of quinupristin/dalfopristin include arthralgia, myalgias, reversible rises in serum alkaline phosphatase, itching, diarrhea, vomiting, and pain at the infusion site; adverse effects occurred in 2.5–4.6% of patients (210C – 213C , 214R , 215R ). Liver In 25 liver transplant recipients who received intravenous quinupristin/dalfopristin 7.5 mg/kg 8-hourly for vancomycin-resistant Enterococcus fecium infection, hyperbilirubinemia developed, but there was no evidence of drugspecific histological injury (216c ). Musculoskeletal Of 32 patients who received quinupristin/dalfopristin, at least 15 developed arthralgias and/or myalgias (217c ). Drug interactions Quinupristin/dalfopristin can inhibit the metabolism of drugs that are metabolized by CYP3A4 (218R ). Drug tolerance (antibacterial resistance) The use of virginiamycin, a growth-promoting streptogramin, has been associated with a high rate of resistance to quinupristin/dalfopristin (219E ).

SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE (SED-14, 896; SEDA-22, 279; SEDA-23, 280; SEDA-25, 312)

Sulfonamides Skin In a open prospective study in 95 HIV-infected patients with successfully treated Pneumocystis carinii pneumonia, pyrimethamine + sulfadoxine (25/500 mg) was given

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twice weekly to prevent relapse (220C ). There were allergic skin reactions in 16 patients, resulting in permanent withdrawal in six. Two patients developed serious adverse reactions (Stevens–Johnson syndrome), both of whom had continued to take prophylaxis despite progressive hypersensitivity reactions. Immunologic About 3% of the general population and 60% of patients with HIV infection have adverse reactions to sulfonamide antimicrobials. The most common clinical manifestations of sulfonamide hypersensitivity are fever and a maculopapular rash 7–14 days after the start of therapy, although a variety of more severe manifestations can occur. The sulfonamide structure is also present in many medications that are not antimicrobials, but hypersensitivity reactions to these medications are less common. The immunogenicity of sulfonamide antimicrobials may be due to the presence of an arylamine group at the N4 position of the sulfonamide molecule. No diagnostic tests are available to confirm sulfonamide hypersensitivity, and while avoidance of the drug is generally appropriate when a previous hypersensitivity reaction is suspected, desensitization protocols are available for use in HIV patients in whom Pneumocystis carinii pneumonia prophylaxis or treatment is indicated (221R ). Anaphylaxis to a central venous catheter (ARROWg+ ard Blue® Catheter) coated with chlorhexidine and sulfadiazine has been reported in a 50-year-old man (222A ). Teratogenicity Malaria during pregnancy is associated with an increased risk of severe anemia and babies of low birth weight. Effective intermittent therapy with pyrimethamine + sulfadoxine reduces parasitemia and severe anemia and improves birth weight in areas in which Plasmodium falciparum is sensitive to this combination. In an open, prospective trial in 287 pregnant women in the Gambia who were exposed to a single dose of a combination of artesunate and pyrimethamine + sulfadoxine there was no evidence of a teratogenic or otherwise harmful effect (223c ). Drug interactions The inhibitory effect of sulfonamides on tolbutamide metabolism is mediated by CYP2C9. Attention is also warranted when certain sulfonamides (e.g. sulfaphenazole, sulfadiazine, sulfamethizole, and

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291

sulfisoxazole) are co-administered with CYP2C9 substrates with narrow therapeutic ranges, such as phenytoin and warfarin. Combination of gliclazide, fluconazole, and sulfamethoxazole can cause severe hypoglycemia (224r ).

events, but not to previous co-trimoxazole withdrawal for reasons other than adverse events, compared with patients who did not stop taking co-trimoxazole. The survival rate was significantly shorter among patients who stopped taking co-trimoxazole for adverse events and for other reasons, compared with patients who continued to take it.

Trimethoprim

Respiratory Hypersensitivity lung disease has been attributed to co-trimoxazole (227A ).

Electrolyte balance Hyperkalemia is a relatively common complication of trimethoprim therapy and occurs at both high and standard dosages. Withdrawal of trimethoprim is often required. Trimethoprim reduces renal potassium excretion by competitively inhibiting epithelial sodium channels in the distal nephron like triamterene. Higher dosages and preexisting renal dysfunction are associated with an increased risk of hyperkalemia, as are probably other disturbances in potassium homeostasis, such as hypoaldosteronism and treatment with drugs that impair renal potassium excretion. Conversely, alkalinization of the urine and induction of high urinary flow rates block the antikaliuretic effect of trimethoprim on distal nephron cells. See also co-trimoxazole below. Drug interactions The addition of trimethoprim caused severe lithium toxicity in a 40-yearold woman with a schizoaffective disorder; following rehydration, she made a good recovery (225A ). Trimethoprim has the same effect on the kidney as amiloride, combined use of which with lithium can cause a raised serum lithium concentration.

Co-trimoxazole The relation between the onset of adverse reactions to co-trimoxazole in HIV-infected patients and the subsequent development of toxoplasmosis, other AIDS-defining events, and survival has been studied in 592 French patients (226C ). A low CD4 cell count when co-trimoxazole was introduced was the only factor associated with the onset of adverse reactions. The occurrence of toxoplasmosis and first AIDS-defining events was significantly and independently linked to a low CD4 cell count when co-trimoxazole was introduced and to previous co-trimoxazole withdrawal for adverse

• A 33-year-old man taking co-trimoxazole developed bilateral pulmonary infiltrates and a fever of 39◦ C after 2 weeks. Co-trimoxazole was withdrawn. The fever resolved 6 days later. A lung biopsy showed non-specific interstitial pneumonia. A lymphocyte stimulation test for co-trimoxazole was positive.

Nervous system Aseptic meningitis is a rare adverse effect of co-trimoxazole. The pathogenic mechanism is still uncertain. Immune complex deposition, immediate hypersensitivity, direct drug toxicity, and induction of antitissue antibodies have all been suggested. Recent case reports have again illustrated this adverse effect of co-trimoxazole. Interleukin-6 may be an important mediator of trimethopriminduced aseptic meningitis in some patients (228A , 229r ). Electrolyte balance Trimethoprim-induced hyperkalemia has been increasingly recognized in recent years, especially in patients with AIDS. Renal tubular acidosis, renal insufficiency, aldosterone deficiency, old age with reduced renal mass and function, and angiotensin converting enzyme (ACE) inhibitors can contribute. • Hyperkalemia due to high doses of co-trimoxazole (14 mg/kg/day trimethoprim and 70 mg/kg/day sulfamethoxazole) occurred in an HIV-positive patient with Pneumocystis carinii pneumonia (230A ). • Life-threatening hyperkalemia secondary to the use of standard oral doses of co-trimoxazole (trimethoprim 320 mg/day and sulfamethoxazole 1600 mg/day) occurred in a 77-year-old man with moderate chronic renal insufficiency from diabetic nephropathy (231A ). In addition to hyperkalemia, he developed severe metabolic acidosis; both resolved on appropriate medical intervention and withdrawal of co-trimoxazole.

Trimethoprim uncommonly causes hyponatremia.

292 • A 78-year-old woman developed severe symptomatic hyponatremia after treatment with anhydrous theophylline and 6 months later developed hyponatremia after treatment with co-trimoxazole for a presumptive urinary tract infection (232A ).

Hematologic Mild hemopoietic suppression due to co-trimoxazole in an immunocompromised host is common, even with low-dose regimens. This effect is notable in combination with other marrow-suppressive agents (e.g. azathioprine, ganciclovir, cyclophosphamide, and allopurinol), malnutrition, or infection (CMV and hepatitis C virus) (233R ). Skin Previous reports have suggested a significant association between fixed drug eruption and HLA class I antigens. In 42 of 67 patients with fixed drug eruptions caused by co-trimoxazole there were significantly higher frequencies of the A30 antigen and A30 B13 Cw6 haplotype than in 2378 control subjects (234C ). HLA-B55 (split of B22) was present exclusively in co-trimoxazole fixed drug eruption, and in a higher frequency than in control subjects. A 34-year-old Asian woman developed toxic epidermal necrolysis associated with cotrimoxazole (160/800 mg bd) (235A ). She recovered completely without serious sequelae. Immunologic A rare sepsis-like hypersensitivity reaction occurred in a 38-year-old HIVpositive Hispanic man after a 14-day course of co-trimoxazole (236A ). This reaction most often occurs on rechallenge and is manifested by a syndrome that resembles bacterial sepsis. The mechanism of this unusual reaction is unclear. A case of toxic epidermal necrolysis, associated with treatment with co-trimoxazole (480/2400 mg/day) for sepsis in a 66-yearold Caucasian man, was successfully treated with intravenous immunoglobulin (0.75 g/kg for 5 days) (237A ). Drug tolerance The use of co-trimoxazole in HIV-positive patients has been associated with a high frequency (40–80%) of hypersensitivity reactions. In a randomized, double-blind study in HIV patients, gradual introduction of cotrimoxazole was associated with significantly fewer adverse drug reactions compared to standard initiation of therapy (238C ).

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Drug interactions Co-trimoxazole greatly increased the risk of overanticoagulation in patients taking coumarin anticoagulants, especially acenocoumarol (239A ). In 10 HIV-positive patients who had been taking one double-strength tablet of co-trimoxazole daily for more than 1 month the concentrations of trimethoprim and sulfamethoxazole in serum were significantly reduced after the administration of rifampicin (240c ).

OTHER ANTIMICROBIAL DRUGS Bacitracin

(SED-14, 911; SEDA-23, 268; SEDA-24, 301; SEDA-25, 316) Immunologic Thimerosal, a mercuric derivative of thiosalicylic acid, is a preservative used in several types of consumer products, including cosmetics, ophthalmic and otolaryngologic medications, and vaccines. Of 574 patients those who were allergic to thimerosal were more likely to be allergic to bacitracin (19C ).

Daptomycin

(SEDA-25, 317)

Daptomycin is a novel lipopeptide antibiotic, an inhibitor of lipoteichoic acid synthesis, with potent bactericidal activity against most clinically important Gram-positive bacteria, including resistant strains (241r ).

Fosfomycin

(SED-14, 911; SEDA-24, 302; SEDA-25, 317) Hematologic The effects of fosfomycin on several indices of neutrophil function have been studied in vitro (242E ). Phagocytosis was unaffected but there was enhanced bactericidal ability, increased intracellular calcium concentrations, raised extracellular reactive oxygen intermediate production, and reduced chemotaxis; fosfomycin did not affect intracellular oxygen intermediate production or chemokinesis.

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Liver Fosfomycin-induced recurrent liver toxicity occurred in a patient with cystic fibrosis (243A ).

Virginiamycin

(SEDA-24, 302)

Drug tolerance (antibacterial resistance) Streptogramin resistance associated with the resistance genes vatA and vatG has been found in Enterococcus fecium of both ani-

293 mals and man (219E ). The use of virginiamycin has been linked with selection of quinupristin/dalfopristin-resistant E. fecium. Because virginiamycin has been used in animals and streptogramins have been used infrequently in man, an animal origin of resistance has been suggested, and spread of resistance via the food chain to humans is probable. Among E. fecium and E. fecalis strains from poultry, high resistance against virginiamycin was found in Belgium (244E ).

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296 normal human intestinal microflora. J Chemother 2001; 13: 47–51. 81. Rossi C, Sternon J. Les fluoroquinolones de troisieme et quatrieme generations. Rev Med Brux 2001; 22: 443–56. 82. Chow AT, Fowler C, Williams RR, Morgan N, Kaminski S, Natarajan J. Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers. Antimicrob Agents Chemother 2001; 45: 2122–5. 83. Kahn JB. Latest industry information on the safety profile of levofloxacin in the US. Chemotherapy 2001; 47 Suppl 3: 32-7, discussion 44–8. 84. Scotton PG, Pea F, Giobbia M, Baraldo M, Vaglia A, Furlanut M. Cerebrospinal fluid penetration of levofloxacin in patients with spontaneous acute bacterial meningitis. Clin Infect Dis 2001; 33: e109–11. 85. Paltoo B, O’Donoghue S, Mousavi MS. Levofloxacin induced polymorphic ventricular tachycardia with normal QT interval. Pacing Clin Electrophysiol 2001; 24: 895–7. 86. Carbon C. Tolerance de la levofloxacine, dossier clinique et données de pharmacovigilance. Thérapie 2001; 56: 35–40. 87. Marinucci P. Risk of torsades de pointes with non-cardiac drugs. Br Med J 2001; 322: 47. 88. Gates GA. Safety of ofloxacin otic and other ototopical treatments in animal models and in humans. Pediatr Infect Dis J 2001; 20: 104-7, discussion 120-2. 89. Karim A, Ahmed S, Rossoff LJ, Siddiqui RK, Steinberg HN. Possible levofloxacin-induced acute hepatocellular injury in a patient with chronic obstructive lung disease. Clin Infect Dis 2001; 33: 2088–90. 90. Spahr L, Rubbia-Brandt L, Marinescu O, Armenian B, Hadengue A. Acute fatal hepatitis related to levofloxacin. J Hepatol 2001; 35: 308–9. 91. Mennecier D, Thiolet C, Bredin C, Potier V, Vergeau B, Farret O. Pancreatite aïgue survenant après la prise de levofloxacine et de methylprednisolone. Gastroenterol Clin Biol 2001; 25: 921–2. 92. Yagawa K. Latest industry information on the safety profile of levofloxacin in Japan. Chemotherapy 2001; 47 Suppl 3: 38–43, discussion 44–8. 93. Hansen E, Bucher M, Jakob W, Lemberger P, Kees F. Pharmacokinetics of levofloxacin during continuous veno-venous hemofiltration. Intensive Care Med 2001; 27: 371–5. 94. Ravnan SL, Locke C. Levofloxacin and warfarin interaction. Pharmacotherapy 2001; 21: 884–5. 95. Gheno G, Cinetto L. Levofloxacin–warfarin interaction. Eur J Clin Pharmacol 2001; 57: 427. 96. Nakamura H, Ohtsuka T, Enomoto H, Hasegawa A, Kawana H, Kuriyama T, Ohmori S, Kitad M. Effect of levofloxacin on theophylline clearance during theophylline and clarithromycin combination therapy. Ann Pharmacother 2001; 35: 691–3. 97. Villani P, Viale P, Signorini L, Cadeo B, Marchetti F, Villani A, Fiocchi C, Regazzi MB, Carosi G. Pharmacokinetic evaluation of oral

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levofloxacin in human immunodeficiency virusinfected subjects receiving concomitant antiretroviral therapy. Antimicrob Agents Chemother 2001; 45: 2160–2. 98. Hoeffken G, Meyer HP, Winter J, Verhoef L. The efficacy and safety of two oral moxifloxacin regimens compared to oral clarithromycin in the treatment of community-acquired pneumonia. Respir Med 2001; 95: 553–64. 99. White CM, Grant EM, Quintiliani R. Moxifloxacin does increase the corrected QT interval. Clin Infect Dis 2001; 33: 1441–4. 100. Culley CM, Lacy MK, Klutman N, Edwards B. Moxifloxacin: clinical efficacy and safety. Am J Health-Syst Pharm 2001; 58: 379–88. 101. Garcia Morillo JS, Stiefel Garcia-Junco P, Vallejo Maroto I, Carneado de la Fuente J. Crisis hipertensiva y bloqueo transitorio de rama izquierda con prolongacion del intervalo qt asociados a moxifloxacino. Med Clin (Barc) 2001; 117: 198–9. 102. Siepmann M, Kirch W. Drug points: tachycardia associated with moxifloxacin. Br Med J 2001; 322: 23. 103. Stass H, Kubitza D. Profile of moxifloxacin drug interactions. Clin Infect Dis 2001; 32 Suppl 1: S47–50. 104. Stass H, Kubitza D, Schuhly U. Pharmacokinetics, safety and tolerability of moxifloxacin, a novel 8-methoxyfluoroquinolone, after repeated oral administration. Clin Pharmacokinet 2001; 40 Suppl 1: 1–9. 105. Stass H, Kubitza D. Effects of iron supplements on the oral bioavailability of moxifloxacin, a novel 8-methoxyfluoroquinolone, in humans. Clin Pharmacokinet 2001; 40 Suppl 1: 57–62. 106. Stass H, Kubitza D. Lack of pharmacokinetic interaction between moxifloxacin, a novel 8-methoxyfluoroquinolone, and theophylline. Clin Pharmacokinet 2001; 40 Suppl 1: 63–70. 107. Lettieri J, Vargas R, Agarwal V, Liu P. Effect of food on the pharmacokinetics of a single oral dose of moxifloxacin 400 mg in healthy male volunteers. Clin Pharmacokinet 2001; 40 Suppl 1: 19– 25. 108. Stass H, Kubitza D. Effects of dairy products on the oral bioavailability of moxifloxacin, a novel 8-methoxyfluoroquinolone, in healthy volunteers. Clin Pharmacokinet 2001; 40 Suppl 1: 33–8. 109. Czeizel AE, Sorensen HT, Rockenbauer M, Olsen J. A population-based case-control teratologic study of nalidixic acid. Int J Gynaecol Obstet 2001; 73: 221–8. 110. Cronberg S, Banke S, Bergman B, Boman H, Eilard T, Elbel E, Hugo-Persson M, Johansson E, Kuylenstierna N, Lanbeck P, et al. Fewer bacterial relapses after oral treatment with norfloxacin than with ceftibuten in acute pyelonephritis initially treated with intravenous cefuroxime. Scand J Infect Dis 2001; 33: 339–43. 111. Guis S, Jouglard J, Kozak-Ribbens G, Figarella-Branger D, Vanuxem D, Pellissier JF, Cozzone PJ. Malignant hyperthermia susceptibility revealed by myalgia and rhabdomyolysis during

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fluoroquinolone treatment. J Rheumatol 2001; 28: 1405–6. 112. Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions. Clin Pharmacokinet 2001; 40: 833–68. 113. Bharani A, Kumar H. Drug points: Diabetes insipidus induced by ofloxacin. Br Med J 2001; 323: 547. 114. Abdollahi M, Isazadeh Z. Inhibition of rat parotid and submandibular gland functions by ofloxacin, a fluoroquinolone antibiotic. Fundam Clin Pharmacol 2001; 15: 307–11. 115. Melde SL. Ofloxacin: a probable cause of toxic epidermal necrolysis. Ann Pharmacother 2001; 35: 1388–90. 116. Felt O, Baeyens V, Buri P, Gurny R. Delivery of antibiotics to the eye using a positively charged polysaccharide as vehicle. AAPS PharmSci 2001; 3: E34. 117. Cabrera E, Velert MM, Orero A, Martinez P, Canton E. Efecto de los antiinflamatorios, solos y asociados con ofloxacino, en la explosion respiratoria de los leucocitos polimorfonucleares humanos. Rev Esp Quimioter 2001; 14: 165–71. 118. Artsimovich NG, Nastoiashchaia NN, Navashin PS. Vliianie perfloksatsina na immunnyi otvet. Antibiot Khimioter 2001; 46: 11–12. 119. Ma L, Sun C, Wu J. Study of pefloxacin concentration in blood and sputum in the aged pneumonia patients with impairment of renal function [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi 2001; 24: 596–8. 120. Feldman C, White H, O’Grady J, Flitcroft A, Briggs A, Richards G. An open, randomised, multi-centre study comparing the safety and efficacy of sitafloxacin and imipenem/cilastatin in the intravenous treatment of hospitalised patients with pneumonia. Int J Antimicrob Agents 2001; 17: 177–88. 121. O’Grady J, Briggs A, Atarashi S, Kobayashi H, Smith RL, Ward J, Ward C, Milatovic D. Pharmacokinetics and absolute bioavailability of sitafloxacin, a new fluoroquinolone antibiotic, in healthy male and female caucasian subjects. Xenobiotica 2001; 31: 811–22. 122. Lubasch A, Erbes R, Mauch H, Lode H. Sparfloxacin in the treatment of drug resistant tuberculosis or intolerance of first line therapy. Eur Respir J 2001; 17: 641–6. 123. Singla R, Gupta S, Gupta R, Arora VK. Efficacy and safety of sparfloxacin in combination with kanamycin and ethionamide in multidrug-resistant pulmonary tuberculosis patients: preliminary results. Int J Tuberc Lung Dis 2001; 5: 559–63. 124. Stahlmann R, Lode H. Toxicity of quinolones. Drugs 1999; 58 Suppl 2: 37–42. 125. Pierfitte C, Royer RJ, Moore N, Begaud B. The link between sunshine and phototoxicity of sparfloxacin. Br J Clin Pharmacol 2000; 49: 609– 12. 126. Nadai M, Lan Zhao Y, Wang L, Nishio Y, Takagi K, Kitaichi K, Tagaki K, Yoshizumi H, Hasegawa T. Endotoxin impairs biliary transport of

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298 Hiramatsu K. First report of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin in Thailand. J Clin Microbiol 2001; 39: 591–5. 143. Wysocki M, Delatour F, Faurisson F, Rauss A, Pean Y, Misset B, Thomas F, Timsit J-F, Similowski T, Mentec H, et al. Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother 2001; 45: 2460–7. 144. Heck AJ, Bonnici PJ, Breukink E, Morris D, Wills M. Modification and inhibition of vancomycin group antibiotics by formaldehyde and acetaldehyde. Chemistry 2001; 7: 910–16. 145. Akil IO, Mir S. Hemodiafiltration for vancomycin overdose in a patient with end-stage renal failure. Pediatr Nephrol 2001; 16: 1019–21. 146. Foral MA, Heineman SM. Vancomycin removal during a plasma exchange transfusion. Ann Pharmacother 2001; 35: 1400–2. 147. Balfour JA, Figgitt DP. Telithromycin. Drugs 2001; 61: 815–29, discussion 830–1. 148. Bearden DT, Neuhauser MM, Garey KW. Telithromycin: an oral ketolide for respiratory infections. Pharmacotherapy 2001; 21: 1204–22. 149. Ben Zina Z, Abid D, Kharrat W, Chaker N, Aloulou K, Chaabouni M. Interêt du traitement par clindamycine en sous conjonctivale dans les retinochoroïdites toxoplasmiques. Tunis Med 2001; 79: 157–60. 150. Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granstrom G, Lagergren L, Englund G, Nord CE, Svenungsson B. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001; 47: 43–50. 151. Leyden JJ, Berger RS, Dunlap FE, Ellis CN, Connolly MA, Levy SF. Comparison of the efficacy and safety of a combination topical gel formulation of benzoyl peroxide and clindamycin with benzoyl peroxide, clindamycin and vehicle gel in the treatments of acne vulgaris. Am J Clin Dermatol 2001; 2: 33–9. 152. Kekki M, Kurki T, Pelkonen J, Kurkinen-Raty M, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstet Gynecol 2001; 97: 643–8. 153. Vermeulen GM, Van Zwet AA, Bruinse HW. Changes in the vaginal flora after two percent clindamycin vaginal cream in women at high risk of spontaneous preterm birth. Br J Obstet Gynaecol 2001; 108: 697–700. 154. Ray RS, Mehrotra S, Shankar U, Babu GS, Joshi PC, Hans RK. Evaluation of UV-induced superoxide radical generation potential of some common antibiotics. Drug Chem Toxicol 2001; 24: 191–200. 155. Lebel MH, Mehra S. Efficacy and safety of clarithromycin versus erythromycin for the treatment of pertussis: a prospective, randomized, single blind trial. Pediatr Infect Dis J 2001; 20: 1149–54.

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156. Uzun C, Koten M, Adali MK, Yorulmaz F, Yagiz R, Karasalihoglu AR. Reversible ototoxic effect of azithromycin and clarithromycin on transiently evoked otoacoustic emissions in guinea pigs. J Laryngol Otol 2001; 115: 622–8. 157. Rubinstein E. Comparative safety of the different macrolides. Int J Antimicrob Agents 2001; 18 Suppl 1: S71–6. 158. Jacobson JM, Hafner R, Remington J, Farthing C, Holden-Wiltse J, Bosler EM, Harris C, Jayaweerag DT, Roque C, Luft BJ, et al. Doseescalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 2001; 15: 583–9. 159. Citterio F, Di Pinto A, Borzi MT, Scata MC, Foco M, Pozzetto U, Castagneto M. Azithromycin treatment of gingival hyperplasia in kidney transplant recipients is effective and safe. Transplant Proc 2001; 33: 2134–5. 160. Treadway G, Reisman A. Tolerability of 3-day, once-daily azithromycin suspension versus standard treatments for community-acquired paediatric infectious diseases. Int J Antimicrob Agents 2001; 18: 427–31. 161. Ioannidis JPA, Contopoulos-Ioannidis DG, Chew P, Lau J. Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for upper respiratory tract infections. J Antimicrob Chemother 2001; 48: 677–89. 162. Arellano-Rodrigo E, Garcia A, Mont L, Roque M. Torsade de pointes y parada cardiorrespiratoria inducida pot azitromicina en una paciente con sindrome de qt largo congenito. Med Clin (Barc) 2001; 117: 118–19. 163. Mamikoglu B, Mamikoglu O. Irreversible sensorineural hearing loss as a result of azithromycin ototoxicity. A case report. Ann Otol Rhinol Laryngol 2001; 110: 102. 164. Hafner R, Bethel J, Standiford HC, Follansbee S, Cohn DL, Polk RE, Mole L, Raasch R, Kumar P, Mushatt D, Drusano G. Tolerance and pharmacokinetic interactions of rifabutin and azithromycin. Antimicrob Agents Chemother 2001; 45: 1572–7. 165. Milkovic-Kraus S, Kanceljak-Macan B. Occupational airborne allergic contact dermatitis from azithromycin. Contact Dermatitis 2001; 45: 184. 166. Cascaval RI, Lancaster DJ. Hypersensitivity syndrome associated with azithromycin. Am J Med 2001; 110: 330–1. 167. Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized trial of azithromycin versus amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol 2001; 9: 197–202. 168. Jacobson GF, Autry AM, Kirby RS, Liverman EM, Motley RU. A randomized controlled trial comparing amoxicillin and azithromycin for the treatment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol 2001; 184: 1352–4, discussion 1354–6. 169. Kent JR, Almond MK, Dhillon S. Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD. Peritoneal Dial Int 2001; 21: 372–7.

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170. Malizia T, Batoni G, Ghelardi E, Baschiera F, Graziani F, Blandizzi C, Gabriele M, Campa M, Del Tacca M, Sensi S. Interaction between piroxicam and azithromycin during distribution to human periodontal tissues. J Periodontol 2001; 72: 1151–6. 171. Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study. Clin Ther 2001; 23: 451–66. 172. McCarty JM, Pierce PF. Five days of cefprozil versus 10 days of clarithromycin in the treatment of an acute exacerbation of chronic bronchitis. Ann Allergy Asthma Immunol 2001; 87: 327–34. 173. De Dios Garcia-Diaz JD, Santolaya Perrin R, Paz Martinez Ortega M, Moreno-Vazquez M. Flebitis relacionada con la administracion intravenosa de antibioticos macrolidos. Estudio comparativo de eritromicina y claritromicina. Med Clin (Barc) 2001; 116: 133–5. 174. Pijlman AH, Kuck EM, Van Puijenbroek EP, Hoekstra JB. Acuut delier, waarschijnlijk uitgelokt door claritromycine. Ned Tijdschr Geneeskd 2001; 145: 225–8. 175. Hamamoto Y, Ohmura A, Kinoshita E, Muto M. Fixed drug eruption due to clarithromycin. Clin Exp Dermatol 2001; 26: 48–9. 176. Gangemi S, Ricciardi L, Fedele R, Isola S, Purello-D’Ambrosio F. Immediate reaction to clarithromycin. Allergol Immunopathol (Madr) 2001; 29: 31–2. 177. Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C. Acute fatal colchicine intoxication in a patient on continuous ambulatory peritoneal dialysis (CAPD). Possible role of clarithromycin administration. Clin Nephrol 2001; 55: 181–2. 178. Xu H, Rashkow A. Clarithromycin-induced digoxin toxicity: a case report and a review of the literature. Conn Med 2001; 65: 527–9. 179. Anonymous. Disopyramide: interactions with macrolide antibiotics. Prescrire Int 2001; 10: 151. 180. Ausband SC, Goodman PE. An unusual case of clarithromycin associated ergotism. J Emerg Med 2001; 21: 411–13. 181. Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother 2001; 35: 26–31. 182. Dandekar SS, Laidlaw DA. Suprachoroidal haemorrhage after addition of clarithromycin to warfarin. J R Soc Med 2001; 94: 583–4. 183. Prieto JC. El perfil de seguridad de las estatinas. Rev Med Chil 2001; 129: 1237–40. 184. Bernini F, Poli A, Paoletti R. Safety of HMGCoA reductase inhibitors: focus on atorvastatin. Cardiovasc Drugs Ther 2001; 15: 211–18. 185. Schlienger RG, Haefeli WE, Jick H, Meier CR. Risk of cataract in patients treated with statins. Arch Intern Med 2001; 161: 2021–6. 186. Eadie MJ. Clinically significant drug interactions with agents specific for migraine attacks. CNS Drugs 2001; 15: 105–18.

299 187. Portier H, Bourrillon A, Lucht F, Choutet P, Gehanno P, Meziane L, Bingen E. Traitement des angines aigues a streptocoque beta-hemolytique du groupe A chez l’enfant par la josamycine pendant cinq jours. Arch Pediatr 2001; 8: 700–6. 188. Yoshii T, Nishimura H, Yoshikawa T, Furudoi S, Yoshioka A, Takenono I, Ohtsuka Y, Komori T. Therapeutic possibilities of long-term roxithromycin treatment for chronic diffuse sclerosing osteomyelitis of the mandible. J Antimicrob Chemother 2001; 47: 631–7. 189. Easton-Carter KL, Hardikar W, Smith AL. Possible roxithromycin-induced fulminant hepatic failure in a child. Pharmacotherapy 2001; 21: 867– 70. 190. Ohshima A, Takigawa M, Tokura Y. CD8+ cell changes in psoriasis associated with roxithromycininduced clinical improvement. Eur J Dermatol 2001; 11: 410–15. 191. Shimane T, Asano K, Suzuki M, Hisamitsu T, Suzaki H. Influence of a macrolide antibiotic, roxithromycin, on mast cell growth and activation in vitro. Mediators Inflamm 2001; 10: 323–32. 192. Aarestrup FM, Seyfarth AM, Emborg HD, Pedersen K, Hendriksen RS, Bager F. Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark. Antimicrob Agents Chemother 2001; 45: 2054–9. 193. Fawcett IW, Ibrahim NB. BOOP associated with nitrofurantoin. Thorax 2001; 56: 161. 194. Edoute Y, Karmon Y, Roguin A, Ben-Ami H. Fatal liver necrosis associated with the use of nitrofurantoin. Isr Med Assoc J 2001; 3: 382–3. 195. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Nitrofurantoin and congenital abnormalities. Eur J Obstet Gynecol Reprod Biol 2001; 95: 119–26. 196. Gerk PM, Kuhn RJ, Desai NS, McNamara PJ. Active transport of nitrofurantoin into human milk. Pharmacotherapy 2001; 21: 669–75. 197. Gee T, Ellis R, Marshall G, Andrews J, Ashby J, Wise R. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother 2001; 45: 1843–6. 198. Perry CM, Jarvis B. Linezolid: a review of its use in the management of serious gram-positive infections. Drugs 2001; 61: 525–51. 199. Marchese A, Schito GC. The oxazolidinones as a new family of antimicrobial agent. Clin Microbiol Infect 2001; 7 Suppl 4: 66–74. 200. Diekema DJ, Jones RN. Oxazolidinone antibiotics. Lancet 2001; 358: 1975–82. 201. Zurenko GE, Gibson JK, Shinabarger DL, Aristoff PA, Ford CW, Tarpley WG. Oxazolidinones: a new class of antibacterials. Curr Opin Pharmacol 2001; 1: 470–6. 202. Kaplan SL, Patterson L, Edwards KM, Azimi PH, Bradley JS, Blumer JL, Tan TQ, Lobeck FG, Anderson DC.. Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Linezolid Pediatric Pneumonia Study Group. Pediatr Infect Dis J 2001; 20: 488–94.

300 203. Lawyer MC, Lawyer EZ. Linezolid and reversible myelosuppression. J Am Med Assoc 2001; 286: 1974. 204. Green SL, Maddox JC, Huttenbach ED. Linezolid and reversible myelosuppression. J Am Med Assoc 2001; 285: 1291. 205. Lavery S, Ravi H, McDaniel WW, Pushkin YR. Linezolid and serotonin syndrome. Psychosomatics 2001; 42: 432–4. 206. Cunningham S, Prasad A, Collyer L, Carr S, Lynn IB, Wallis C. Bronchoconstriction following nebulised colistin in cystic fibrosis. Arch Dis Child 2001; 84: 432–3. 207. Reed MD, Stern RC, O’Riordan MA, Blumer JL. The pharmacokinetics of colistin in patients with cystic fibrosis. J Clin Pharmacol 2001; 41: 645–54. 208. Cammu G. Interactions of neuromuscular blocking drugs. Acta Anaesthesiol Belg 2001; 52: 357–63. 209. Gavazzi G, Barnoud R, Lamloum M, Coume M, Fillipi M, Debray M, Couturier P, Franco A. Colite pseudomembraneuse apres pristinamycine. Rev Med Interne 2001; 22: 672–3. 210. Raad I, Hachem R, Hanna H, Girgawy E, Rolston K, Whimbey E, Husni R, Bodey G. Treatment of vancomycin-resistant enterococcal infections in the immunocompromised host: quinupristindalfopristin in combination with minocycline. Antimicrob Agents Chemother 2001; 45: 3202–4. 211. Rehm SJ, Graham DR, Srinath L, Prokocimer P, Richard MP, Talbot GH. Successful administration of quinupristin/dalfopristin in the outpatient setting. J Antimicrob Chemother 2001; 47: 639–45. 212. Linden PK, Moellering RC, Jr., Wood CA, Rehm SJ, Flaherty J, Bompart F, Talbot GH. Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin. Clin Infect Dis 2001; 33: 1816–23. 213. Verma A, Dhawan A, Philpott-Howard J, Rela M, Heaton N, Vergani GM, Wade J. Glycopeptideresistant Enterococcus faecium infections in paediatric liver transplant recipients: safety and clinical efficacy of quinupristin/dalfopristin. J Antimicrob Chemother 2001; 47: 105–8. 214. Allington DR, Rivey MP. Quinupristin/ dalfopristin: a therapeutic review. Clin Ther 2001; 23: 24–44. 215. Bonfiglio G, Furneri PM. Novel streptogramin antibiotics. Expert Opin Investig Drugs 2001; 10: 185–98. 216. Linden PK, Bompart F, Gray S, Talbot GH. Hyperbilirubinemia during quinupristindalfopristin therapy in liver transplant recipients: correlation with available liver biopsy results. Pharmacotherapy 2001; 21: 661–8. 217. Olsen KM, Rebuck JA, Rupp ME. Arthralgias and myalgias related to quinupristin-dalfopristin administration. Clin Infect Dis 2001; 32: e83–6. 218. Manzella JP. Quinupristin-dalfopristin: a new antibiotic for severe gram-positive infections. Am Fam Phys 2001; 64: 1863–6. 219. Hayes JR, McIntosh AC, Qaiyumi S, Johnson JA, English LL, Carr LE, Wagner DD, Joseph

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SW. High-frequency recovery of quinupristindalfopristin-resistant Enterococcus faecium isolates from the poultry production environment. J Clin Microbiol 2001; 39: 2298–9. 220. Schurmann D, Bergmann F, Albrecht H, Padberg J, Grunewald T, Behnsch M, Grobusch M, Vallee M, Wunsche T, Ruf B, Suttorp N. Twiceweekly pyrimethamine-sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS. J Infect 2001; 42: 8–15. 221. Tilles SA. Practical issues in the management of hypersensitivity reactions: sulfonamides. South Med J 2001; 94: 817–24. 222. Stephens R, Mythen M, Kallis P, Davies DW, Egner W, Rickards A. Two episodes of lifethreatening anaphylaxis in the same patient to a chlorhexidine-sulphadiazine-coated central venous catheter. Br J Anaesth 2001; 87: 306–8. 223. Deen JL, von Seidlein L, Pinder M, Walraven GE, Greenwood BM. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy. Trans R Soc Trop Med Hyg 2001; 95: 424–8. 224. Abad S, Moachon L, Blanche P, Bavoux F, Sicard D, Salmon-Ceron D. Possible interaction between gliclazide, fluconazole and sulfamethoxazole resulting in severe hypoglycaemia. Br J Clin Pharmacol 2001; 52: 456–7. 225. De Vries PL. Lithiumintoxicatie bij gelijktijdig gebruik van trimethoprim. Ned Tijdschr Geneeskd 2001; 145: 539–40. 226. Rabaud C, Charreau I, Izard S, Raffi F, Meiffredy V, Leport C, Guillemin F, Yeni P, Aboulker J-P. Adverse reactions to cotrimoxazole in HIV-infected patients: predictive factors and subsequent HIV disease progression. Scand J Infect Dis 2001; 33: 759–64. 227. Hashizume T, Numata H, Matsushita K. Druginduced pneumonitis caused by sulfamethoxazole– trimethoprim [in Japanese]. Nihon Kokyuki Gakkai Zasshi 2001; 39: 664–7. 228. Muller MP, Richardson DC, Walmsley SL. Trimethoprim–sulfamethoxazole induced aseptic meningitis in a renal transplant patient. Clin Nephrol 2001; 55: 80–4. 229. Antonen JA, Saha HH, Hurme M, Pasternack AI. IL-6 may be the key mediator in trimethopriminduced systemic adverse reaction and aseptic meningitis: a reply to Muller et al. Clin Nephrol 2001; 55: 489–90. 230. Brazille P, Benveniste O, Herson S, Cherin P. Une cause meconnue d’hyperkaliemie: le trimethoprime–sulfamethoxazole. Rev Med Interne 2001; 22: 82–3. 231. Margassery S, Bastani B. Life threatening hyperkalemia and acidosis secondary to trimethoprim–sulfamethoxazole treatment. J Nephrol 2001; 14: 410–14. 232. Dreiher J, Porath A. Severe hyponatremia induced by theophylline and trimethoprim. Arch Intern Med 2001; 161: 291–2. 233. Fishman JA. Prevention of infection caused by Pneumocystis carinii in transplant recipients. Clin Infect Dis 2001; 33: 1397–405.

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234. Ozkaya-Bayazit E, Akar U. Fixed drug eruption induced by trimethoprim–sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. J Am Acad Dermatol 2001; 45: 712–17. 235. See S, Mumford JM. Trimethoprim/sulfamethoxazole-induced toxic epidermal necrolysis. Ann Pharmacother 2001; 35: 694–7. 236. Moran KA, Ales NC, Hemmer PA. Newly diagnosed human immunodeficiency virus after sepsis-like reaction of trimethoprim-sulfamethoxazole. South Med J 2001; 94: 350–2. 237. Paquet P, Jacob E, Damas P, Pierard GE. Treatment of drug-induced toxic epidermal necrolysis (Lyell’s syndrome) with intravenous human immunoglobulins. Burns 2001; 27: 652–5. 238. Leoung GS, Stanford JF, Giordano MF, Stein A, Torres RA, Giffen CA, Wesley M, Sarracco T, Cooper EC, Dratter V, et al. Trimethoprimsulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis 2001; 184: 992–7. 239. Penning van Beest FJ, Van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a

301 cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs. Clin Pharmacol Ther 2001; 69: 451–7. 240. Ribera E, Pou L, Fernandez-Sola A, Campos F, Lopez RM, Ocana I, Ruiz I, Pahissa A. Rifampin reduces concentrations of trimethoprim and sulfamethoxazole in serum in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2001; 45: 3238–41. 241. Stephenson J. Researchers describe latest strategies to combat antibiotic-resistant microbes. J Am Med Assoc 2001; 285: 2317–18. 242. Krause R, Patruta S, Daxbock F, Fladerer P, Wenisch C. The effect of fosfomycin on neutrophil function. J Antimicrob Chemother 2001; 47: 141–6. 243. Durupt S, Josserand RN, Sibille M, Durieu I. Acute, recurrent fosfomycin-induced liver toxicity in an adult patient with cystic fibrosis. Scand J Infect Dis 2001; 33: 391–2. 244. Butaye P, Devriese LA, Haesebrouck F. Differences in antibiotic resistance patterns of Enterococcus faecalis and Enterococcus faecium strains isolated from farm and pet animals. Antimicrob Agents Chemother 2001; 45: 1374–8.

Andreas H. Groll and Thomas J. Walsh

27 AMPHOTERICIN B

(SED-14, 922; SEDA-23, 289; SEDA-24, 315; SEDA-25, 331) Amphotericin remains one of the most important agents for the management of invasive mycoses. Compared with conventional amphotericin B deoxycholate, lipid-based formulations (amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B) are less nephrotoxic. Data on their safety and tolerance continue to accrue.

Amphotericin B deoxycholate (DAMB) Urinary tract The epidemiology of the nephrotoxicity of conventional amphotericin B has been investigated in a retrospective study in 494 adult in-patients who received two or more doses (1c ). Nephrotoxicity was defined as a 50–100% increase in the baseline creatinine concentration. The median cumulative dose was 240 mg and most of the patients received it for empirical therapy. Overall, 139 patients (28%) had renal toxicity, including 58 (12%) with moderate to severe nephrotoxicity. For each 10 mg increase in the mean daily dose, the adjusted rate of renal toxicity increased by a factor of 1.13. Five risk factors were defined: a mean daily dose of 35 mg or more, male sex, weight 90 kg or more, chronic renal disease, and concurrent use of amikacin or ciclosporin. The incidence of moderate to severe nephrotoxicity was 4% in patients with none of these risk factors, 8% in those with one, 18% in those with two, and 29% in those with three or more. Nephrotoxicity rarely led © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

302

Antifungal drugs to hemodialysis (n = 3). However, at the time of discharge or death, 70% of the patients with moderate to severe nephrotoxicity had a serum creatinine that was at least 44 µmol/l above baseline. This study shows dose-dependency of nephrotoxicity related to amphotericin B deoxycholate, accentuated by other nephrotoxic drugs and patient risk factors. The authors suggested that in patients with more than two risk factors alternative antifungal drugs should be considered.

Amphotericin B Colloidal Dispersion (ABCD) Mucormycosis has an exceedingly high mortality rate in immunocompromised patients. In five phase I and phase II studies of ABCD, 21 patients were given ABCD (mean dose 4.8 mg/kg per infusion for a mean duration of 37 days) on the basis of pre-existing renal insufficiency, nephrotoxicity during amphotericin B therapy, or refractory infections (2c ). Of 20 evaluable patients, 12 responded to ABCD, and there was no renal or hepatic toxicity. However, a previous randomized comparative trial showed an at least similar if not increased frequency and severity of infusion-related reactions compared with conventional amphotericin B (3C ).

Amphotericin B Lipid Complex (ABLC) The safety and efficacy of low dose ABLC (1 mg/kg/day) for empirical treatment of fever and neutropenia has been studied in 69 episodes in 61 patients with hematological malignancies (4C ). The median duration of therapy was 8 (range 2–19) days and 13 patients had mild to moderate infusion–related adverse events.

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Creatinine concentrations remained stable in 42 cases, improved in nine, and deteriorated in 18. There were no other toxic effects. The response rate (resolution of fever during neutropenia and absence of invasive fungal infection) was 67%. Fungal infection remains an important cause of morbidity and mortality in lung transplant patients. In a prospective non-comparative evaluation in lung- or heart-lung transplant recipients, ventilated patients received undiluted aerosolized ABLC 100 mg, and extubated patients received 50 mg; in all, 381 treatments (98 in ventilated patients and 283 in extubated patients) were given (5c ). The treatment was administered by face mask jet nebulizer with compressed oxygen at a flow rate of 7–8 l/min and inhaled over 15–30 minutes. Treatments were delivered once every day for four consecutive days, then once a week for 2 months. In all, 381 treatments were given to 51 patients, and ABLC was subjectively well tolerated in 98%. Pulmonary function worsened by 20% or more in under 5% of all treatments. There were no significant adverse events. Risk factors Children The safety and efficacy of ABLC in 11 neonates with systemic Candida infections have been reported (6c ). The infants were aged 3–14 (median 7) weeks and weighed 0.7–5 (median 1.4) kg. The median duration of ABLC treatment was 23 (range 4–41) days at an average dose of 4.9 (range 3.2–6.5) mg/kg/day. Nine of the 11 patients improved clinically, and eight of nine evaluable patients had a mycological cure. No infant discontinued treatment because of adverse drug reactions, and none had appreciable hepatic or hematological toxicity. Renal function improved or did not change in eight of the 11. The median pretreatment serum creatinine concentration was 80 (range 35–522) µmol/l and the median creatinine concentration at the end of treatment was 44 (range 18–628) µmol/l.

Liposomal Amphotericin B (L-AmB) In order to determine the maximum tolerated dosage of liposomal amphotericin B, a phase

303 I/II study was conducted in 44 adult patients with proven (n = 21) or probable (n = 23) infections due to Aspergillus spp. and other filamentous fungi (7C ). The dosages were 7.5, 10, 12.5, and 15 mg/kg/day. The number of infusions was 1–83 with a median duration of 11 days. The maximum tolerated dosage was at least 15 mg/kg. Infusion-related reactions included fever in eight and chills and rigors in five of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above base line in 32% of patients, but this increase was not dose-related. Hepatotoxicity developed in one patient. Altogether, the most common adverse events included fever (48%), increased creatinine concentration (46%), hypokalemia (39%), chills (32%), and abdominal pain (25%), with no obvious dose-dependency. Nine patients (20%) stopped taking the drug because of an adverse event. The reasons included raised serum creatinine, renal insufficiency, pancreatitis, hyperbilirubinemia, hypotension associated with the infusion, cardiorespiratory failure, multiorgan failure, and relapse of the primary malignancy. The last three events were attributed to the underlying disease process. Discontinuation was unrelated to dosage. Pharmacokinetic analysis showed dose-related nonlinear kinetics at dosages of 7.5 mg/kg/day and over. LAMB and amphotericin B lipid complex (ABLC) have been compared in an open randomized study in 75 adults with leukemia and 82 episodes of suspected or documented mycosis (8c ). The median durations of treatment and dosages were 15 days at 4 mg/kg/day for LAMB and 10 days at 3 mg/kg/day for ABLC. Acute but not dose-limiting infusion-related adverse events occurred in 36 vs. 70%. Bilirubin increased to over 1.5 times baseline in 59 vs. 38%. There was no difference in the effects of either agent on renal function and drug-related withdrawals. The overall response rate to therapy in documented fungal infections (29 and 30% respectively) was not different between the two drugs.

304

AZOLE DERIVATIVES

(SED-14, 928; SEDA-23, 295; SEDA-24, 318; SEDA-25, 333)

Ketoconazole Respiratory Patients undergoing esophagectomy are at increased risk of acute lung injury, perhaps related to increased concentrations of thromboxane in the postpulmonary circulation. In 38 consecutive patients undergoing esophagectomy perioperative ketoconazole, which inhibits thromboxane synthesis, reduced the incidence of acute lung injury (9c ). Hematologic Fatal aplastic anemia has been reported during ketoconazole therapy (10A ). Liver A girl developed fatal liver failure while taking ketoconazole for Cushing’s syndrome (11A ). The authors proposed using metapyrone when temporary control of hypercortisolism is required in childhood and adolescence. Drug interactions Ciclosporin The effect of ketoconazole in ciclosporin-treated kidney transplant recipients has been the subject of a prospective randomized study (12C ). In 51 ketoconazole-treated patients and 49 controls there was a similar frequency of acute rejection episodes. However, in the control group rejection episodes were more recurrent, with a poorer response to treatment. Acute ciclosporin nephrotoxicity was more common in the ketoconazole group, but this was encountered more at induction and rapidly reversed on further reduction of the dose of ciclosporin. Chronic graft dysfunction was significantly less in the ketoconazole group during the first year, but by the end of the study the difference was not statistically significant. Hepatotoxicity was similar in the two groups. Serum concentrations of cholesterol, low-density lipoprotein, and triglyceride were lower in the ketoconazole group. The authors concluded that long-term low-dose ketoconazole in ciclosporin-treated kidney transplant recipients is safe and costsaving.

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Citalopram The effect of ketoconazole on the pharmacokinetics of citalopram has been studied in a double-blind, three-way, crossover trial in 18 men and women (13C ). The subjects received three treatments with a 14-day washout period: a single dose of ketoconazole 200 mg plus placebo, a single dose of citalopram 40 mg plus placebo, and a single dose of ketoconazole 200 mg plus a single dose of citalopram 40 mg. There were no changes in the pharmacokinetics of citalopram after co-administration of ketoconazole, suggesting that ketoconazole and other CYP3A4 inhibitors may be safely coadministered with citalopram. Clozapine The interaction of ketoconazole (400 mg/day for 7 days) and clozapine has been evaluated in five patients with schizophrenia given a single dose of clozapine 50 mg at the end of ketoconazole therapy (14c ). Ketoconazole did not significantly change the disposition of clozapine or its metabolism to its principal metabolites, desmethylclozapine and clozapine-N-oxide. Emedastine difumarate The pharmacokinetic and pharmacodynamic interactions of the antihistamine emedastine difumarate and ketoconazole have been investigated in 12 healthy volunteers (15c ). Emedastine difumarate 4 mg was given orally for 10 consecutive days, and on days 6–10 ketoconazole 200 mg bd was co-administered. Emedastine steady-state pharmacokinetics were slightly altered by ketoconazole: the AUC rose by about 33% and total clearance fell by about 30%, with no change in the half-life, suggesting that the volume of distribution also changed; this pattern could have arisen from protein binding displacement. However, there was no change in the QTc interval after 5 days of co-treatment. The authors concluded that concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals could therefore be undertaken without special precautions. Ifosfamide The effect of ketoconazole on the CYP-mediated metabolism of ifosfamide to 4-hydroxyifosfamide and the ultimate cytotoxic ifosforamide mustard and its deactivation to 2- and 3-dechloroethylifosfamide has been studied in a randomized crossover study in

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16 patients, who received intravenous ifosfamide 3 g/m2 /day, either alone or in combination with ketoconazole 200 mg bd, 1 day before treatment and 3 days of concomitant administration (16C ). Ketoconazole did not affect the fraction metabolized or exposure to the dechloroethylated metabolites and thus did not alter the pharmacokinetics of ifosfamide or its metabolism.

Fluconazole The prophylactic use of oral fluconazole to prevent invasive candidal infections in 260 critically ill surgical patients has been investigated in a prospective, randomized, placebocontrolled trial in a single-center, tertiary-care surgical intensive care unit (17C ). The patients were randomly assigned to receive either oral fluconazole 400 mg/day or placebo. The risk of presumed and proven candidal infections in the patients who received fluconazole was significantly less than the risk in those who received placebo. After adjusting for several potentially confounding effects, fluconazole reduced the risk of presumed and proven fungal infection by 55%. There was no difference in death rate between fluconazole and placebo. The authors concluded that enteral fluconazole safely decreased the incidence of fungal infections in this high-risk population. Cardiovascular Prolongation of the QT interval is a class effect of the antifungal azoles and has occasionally been reported with fluconazole, with a risk of torsade de pointes (18A ). • A 68-year-old woman with Candida glabrata isolated from a presacral abscess developed torsade de pointes after 8 days treatment with oral fluconazole 150 mg/day. She had no other risk factors for torsade de pointes, including coronary artery disease, cardiomyopathy, congestive heart failure, or electrolyte abnormalities. The dysrhythmia resolved when fluconazole was withdrawn, but she continued to have ventricular extra beats and nonsustained ventricular tachycardia for 6 days.

Metabolic Whereas ketoconazole interferes with steroidogenesis and can cause adrenal insufficiency, fluconazole in standard doses is believed not to. However, two critically ill

305 patients, a 77-year-old man with esophageal cancer and a 66-year-old woman with multiple organ failure, developed reversible adrenal insufficiency temporally related to the use of high-dose fluconazole (800 mg loading dose followed by 400 mg/day), as assessed by short stimulation tests with cosyntropin (ACTH) (19A ). Although anecdotal, these data suggest that the possibility that high-dose fluconazole can cause adrenal insufficiency in already compromised critically ill patients needs to be investigated further. Another report has supported the notion that fluconazole can cause adrenal insufficiency (20A ). • A 63-year-old man received high-dose cyclophosphamide for peripheral blood stem-cell harvesting, having been taking fluconazole 200 mg/day. On day 3 he developed atrial fibrillation and his blood pressure fell to 78 mmHg. A rapid ACTH stimulation test showed a blunted adrenal response. He was suspected of having adrenal failure, and fluconazole was withdrawn. A rapid ACTH test was normal on day 14. To clarify the association between adrenal failure and fluconazole, he was rechallenged with fluconazole 400 mg/day from day 16 and a rapid ACTH test was performed on day 21; it showed a blunted adrenal response.

Teratogenicity The teratogenic activity of triazole and two triazole derivatives, flusilazole (an agricultural triazole monoderivative fungicide) and fluconazole, has been studied in vitro (21E ). Rat embryos 9.5 days old (1–3 somites) were exposed in vitro to triazole 500–5000 µmol/l, flusilazole 3.125–250 µmol/l, or fluconazole 62.5–500 µmol/l and examined after 48 hours in culture. There were similar teratogenic effects (abnormalities at the branchial apparatus level and cell death at the level of the branchial mesenchyme) at 6.25 µmol/l and higher for flusilazole and 125 µmol/l and higher for fluconazole. In contrast, there was little effect at the highest concentrations of triazole, suggesting no teratogenic activity. These investigations have confirmed the embryotoxic potential of antifungal triazole derivatives, specificity on the branchial apparatus. The risk of malformations and other outcomes in children exposed to fluconazole in utero has been examined in 165 women who had taken fluconazole just before or during pregnancy, mostly as a single dose of 150 mg to treat vaginal candidiasis (22C ). Birth outcomes

306 (malformations, low birth weights, and preterm delivery) were compared with the outcomes in 13 327 women who did not receive any prescriptions during their pregnancies. The prevalence of malformations was 3.3% (four cases) among the 121 women who had used fluconazole in the first trimester, and 5.2% (697 cases) in the offspring of controls (OR = 0.65; 95% CI = 0.24, 1.77). The risk of preterm delivery (OR = 1.17; 95% CI = 0.63, 2.17) and low birth weight (OR = 1.19; 95% CI = 0.37, 3.79) was not significantly increased by fluconazole. Thus, this study showed no increased risk of congenital malformations, low birth weights, or preterm birth in the offspring of women who took a single dose of fluconazole before conception or during pregnancy. Drug interactions Calcineurin inhibitors The interaction of calcineurin inhibitors (tacrolimus and ciclosporin) with fluconazole has been retrospectively evaluated in 19 kidney and pancreas/kidney transplant recipients (23c ). Both intravenous and oral fluconazole altered the blood concentrations of the calcineurin inhibitors. Five subjects did not have a significant interaction and 15 did. Tacrolimus concentrations were significantly more affected than ciclosporin concentrations. No patient had nephrotoxicity or transplant rejection related to antifungal therapy. Oral contraceptives The potential pharmacokinetic interaction between fluconazole 300 mg once weekly and an oral contraceptive containing ethinylestradiol and norethindrone (Ortho Novum 7/7/7; Ortho-McNeil Pharmaceutical Inc, Raritan, NJ) has been studied in a placebo-controlled, double-blind, randomized, two-way, crossover study in 26 healthy women aged 18–36 years (24C ). During the first cycle they took the oral contraceptive only. During the second cycle they were assigned randomly to oral contraceptive + fluconazole or oral contraceptive + placebo. In the third cycle they were given the other treatment. Fluconazole caused small but statistically significant increases in the AUC0-24 of both ethinylestradiol and norethindrone. There were no adverse events related to treatment in those given fluconazole. It therefore appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.

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Protease inhibitors The effect of fluconazole on the steady-state pharmacokinetics of the protease inhibitors ritonavir and saquinavir has been studied in patients infected with HIV-1 (25c ). They received the protease inhibitor (saquinavir 1200 mg tds, n = 5, or ritonavir 600 mg bd, n = 3) alone on day 1 and then with fluconazole 400 mg on day 2 and 200 mg on days 3–8. The median increase in saquinavir AUC was 50%, and the median increase in Cmax was 56%. In contrast, fluconazole had no effect on the disposition of ritonavir. Sulfonylureas A 56-year-old HIV-positive patient with diabetes mellitus taking gliclazide 160 mg/day developed severe hypoglycemia when treated with co-trimoxazole 480 mg/day and fluconazole 200 mg/day (26A ). The authors speculated that fluconazole might have inhibited gliclazide metabolism by inhibiting CYP2C9. The effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride have been studied in a randomized, double-blind, crossover study in 12 healthy volunteers who took fluconazole 200 mg/day (400 mg on day 1), fluvoxamine 100 mg/day, or placebo once daily for 4 days (27C ). On day 4 they took a single oral dose of glimepiride 0.5 mg. Fluconazole increased the mean total AUC of glimepiride to 238% and the peak plasma concentration to 151% of control values, and the half-life of glimepiride was prolonged from 2.0 to 3.3 hours. This was probably due to inhibition of CYP2C9-mediated biotransformation of glimepiride by fluconazole. However, fluconazole did not cause statistically significant changes in the effects of glimepiride on blood glucose concentrations.

Itraconazole Data on the safety of itraconazole have been collected in an open randomized multicenter study in 277 adults with cancer and neutropenia (28c ). Itraconazole oral solution (100 mg bd, n = 144) was compared with a combination of amphotericin capsules and nystatin oral suspension (n = 133). Adverse events were reported in about 45% of patients in each group. The most frequent were vomiting (14 vs. 12 patients), diarrhea (12 vs. 9), nausea (5 vs. 12), and rash

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(2 vs. 13 patients). There were no differences in liver function test abnormalities. Treatment had to be withdrawn because of adverse events (including death) in 34 patients who took itraconazole and 33 of those who took amphotericin plus nystatin; there were 17 deaths in each group and death was recorded as adverse event in 13 and 9 patients respectively. The pharmacokinetics, safety, and antifungal efficacy of intravenous itraconazole (400 mg for 2 days then 200 mg for 12 days), followed by 12 weeks of oral capsules (400 mg/day) have been investigated in 31 immunocompromised patients with invasive pulmonary aspergillosis (29c ). All received intravenous itraconazole and 26 then took oral itraconazole for a median of 79 days. Potentially therapeutic trough plasma itraconazole concentrations of 0.5 µg/ml or more were achieved in 64% of the patients by day 2 and were generally maintained after switching to oral therapy. There was a complete or partial response in 15 patients. There were adverse events during intravenous therapy in 28 patients, and 13 had adverse events that were possibly related to the drug. The main events (at least 10% incidence) were fever, diarrhea, increased blood urea nitrogen, and nausea. Two of these 13 patients had intravenous therapy withdrawn. There were no consistent clinically relevant changes in laboratory parameters. During oral therapy, nine patients had similar adverse events that were possibly related to itraconazole. Treatment was withdrawn in seven patients because of adverse events during this phase. There were no deaths related to itraconazole. The pharmacokinetics and safety of intravenous itraconazole for 7 days (200 mg bd for 2 days then 200 mg od for 5 days), followed by itraconazole oral solution 200 mg od or bd for 14 days, have been assessed in 17 patients with hematological malignancies requiring antifungal prophylaxis (30c ). The mean trough plasma concentration at the end of the intravenous period was 0.54 µg/ml. This concentration was not maintained during once-daily oral treatment but increased further during twice-daily treatment, with a trough itraconazole concentration of 1.12 µg/ml at the end of oral treatment. All patients had some adverse events, mainly gastrointestinal. The two patients who were withdrawn from the study during intravenous treatment both reported fever; one also had

307 pneumonitis and died from pneumonia 2 weeks after withdrawal, but this was unrelated to the drug. Patients were withdrawn during oral treatment because of fever (n = 3), pneumonitis (n = 2), colitis (n = 1), and abdominal pain and diarrhea (n = 1). Biochemical and hematological abnormalities were frequent, but there were no consistent changes. Itraconazole (400 mg intravenously for 2 days, 200 mg intravenously for up to 12 days, then 400 mg/day orally) and intravenous amphotericin deoxycholate (0.7–1.0 mg/kg) have been compared in 384 granulocytopenic patients with persistent fever in a randomized, multicenter trial (31C ). The median duration of therapy was 8.5 days. The incidence of drug related adverse events (5 vs. 54%) and the rate of withdrawal due to toxicity (19 vs. 38%) were significantly lower with itraconazole. The most frequent reasons for withdrawal in patients taking itraconazole were nausea and vomiting (5%), rash (3%), and abnormal liver function tests (3%). Significantly fewer of the patients who received itraconazole had nephrotoxicity (5 vs. 24%); however, more had hyperbilirubinemia (10 vs. 5%). There was no difference in gastrointestinal adverse events between the two groups. Cardiovascular Unpublished studies in dogs and healthy human volunteers have suggested that itraconazole has a negative inotropic effect; the mechanism is unknown. A systematic analysis of data from the FDA’s Adverse Event Reporting System (AERS) identified 58 cases suggestive of congestive heart failure in patients taking itraconazole (32c ). A simultaneous search did not identify any cases of congestive heart failure in patients taking fluconazole and ketoconazole, ruling out the possibility of a class effect. In consequence, the labelling of itraconazole has been revised. Itraconazole is now contraindicated for the treatment of onychomycosis in patients with evidence of ventricular dysfunction. For systemic fungal infections, the risks and benefits of itraconazole should be reassessed if signs or symptoms of congestive heart failure develop. Liver Focal nodular hyperplasia of the liver has been reported in a 38-year-old woman who had taken itraconazole 200 mg/day for 4 months for a fungal infection of the fingernails (33A ). She had taken no other drugs in the year during which focal nodular hyperplasia developed.

308 Skin A 70-year-old woman taking itraconazole developed erythema, edema, and vesicles on sun-exposed areas after taking itraconazole for 5 days for oral candidiasis (34A ). Photosensitivity from azoles is uncommon; only three other cases have been described, two attributed to ketoconazole and one to itraconazole. Drug interactions Digoxin The potential of itraconazole to increase digoxin concentrations has been well documented. The importance of this interaction has been emphasized by a report of two renal transplant patients who had digoxin toxicity when they took itraconazole concurrently (35A ). Methylprednisolone The effects of oral itraconazole (400 mg on the first day then 200 mg/day for 3 days) on the pharmacokinetics of a single oral dose of prednisolone 60 mg or methylprednisolone 48 mg have been studied in 14 healthy men in a two-period, crossover study (36c ). Plasma cortisol concentrations were determined as a pharmacodynamic index. Itraconazole significantly increased the mean AUC of methylprednisolone from 2773 to 7011 h.ng/ml and the half-life from 3.2 to 5.5 h. The disposition of prednisolone was unchanged. Cortisol concentrations at 24 hours were significantly lower after the administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 vs. 109 ng/ml). The interaction of methylprednisolone with itraconazole is probably due to inhibition of hepatic CYP3A4 by itraconazole. Ropivacaine The effects of clarithromycin (250 mg bd) and itraconazole (200 mg od) for 4 days on the pharmacokinetics of ropivacaine (given intravenously as a single dose of 0.6 mg/kg on day 4) have been studied in a double-blind, three-way, crossover study in eight healthy volunteers (37C ). There were no significant changes in the pharmacokinetics of ropivacaine after clarithromycin or itraconazole. Although clarithromycin and itraconazole inhibited formation of the (S)-2′ ,6′ pipelodoxylidide metabolite of ropivacaine, there were no significant changes in the pharmacokinetics of ropivacaine itself. Selegiline The effects of itraconazole (200 mg/day for 4 days) on the pharmacokinetics

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Andreas H. Groll and Thomas J. Walsh

of selegiline (10 mg on day 4) have been investigated in a randomized, placebo-controlled, crossover study (38CE ). Itraconazole did not alter the pharmacokinetics of selegiline and its primary metabolites, desmethylselegiline and 1-methamphetamine. In human liver microsomes, itraconazole did not inhibit the formation of either metabolite. These findings suggest that selegiline is not susceptible to interactions with CYP3A4 inhibitors. Tacrolimus The interaction of itraconazole (100 mg bd) with tacrolimus has been studied in 28 heart or lung transplant recipients (39c ). Tacrolimus blood concentrations were monitored on alternate days for up to 21 days after the start of itraconazole therapy (n = 18) or withdrawal (n = 10). The dose of tacrolimus was adjusted with the aim of keeping the 12-hour trough blood concentration at 7–12 µg/ml. The mean dose of tacrolimus during itraconazole therapy fell significantly from 8.4 to 2.9 mg/day. There was no significant change in serum creatinine or liver function tests. In patients in whom itraconazole was withdrawn, the mean dose of tacrolimus required increased significantly from 4.7 to 8.8 mg/day. Thus, substantial changes in the dose of tacrolimus were required both when itraconazole was begun and when it was withdrawn, and it was difficult to maintain tacrolimus blood concentrations within the target range during the first 2 weeks. However, major toxicity or rejection did not occur. Co-administration of itraconazole may reduce the cost of post-transplant immunosuppression. This interaction is probably due to inhibition of CYP3A4 by itraconazole. Vinca alkaloids Enhanced and potentially life-threatening neurotoxicity of vinca alkaloids through concomitant therapy with itraconazole has been the subject of several compelling reports (40A –42A , 43Ar ). This interaction appears to be dose-dependent and reversible; readministration of vinca alkaloids may be safe after a prolonged washout (40A ). The mechanism of this interaction has not been formally elucidated, but may be either competition for oxidative metabolism, leading to increased systemic exposure (44E ), or inhibition of the transmembrane P-glycoprotein efflux pump, leading to increased intracellular concentrations of vinca alkaloids (45E ). The concomitant use of itraconazole and vinca alkaloids is therefore contraindicated.

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Voriconazole Voriconazole is a novel synthetic, intravenous and oral antifungal triazole that is structurally related to fluconazole. It is active against a wide spectrum of clinically important fungi, including Candida spp., Trichosporon beigelii, Cryptococcus neoformans, Aspergillus spp., Fusarium spp., and other hyaline molds, as well as dematiaceous and dimorphic molds. It has demonstrated efficacy in various animal models of invasive fungal infections (46RE , 47RE ). In humans, voriconazole has a half-life of about 6 hours. There is some non-linearity in its disposition, it undergoes complex hepatic metabolism, and it has the potential for drug–drug interactions through its affinity for CYP450 isozymes, in particular CYP3A4, CYP2C9, and CYP2C19. Voriconazole has demonstrated excellent clinical efficacy in a non-comparative phase I/II studies in patients with oropharyngeal and esophageal candidiasis and acute and chronic invasive aspergillosis (48R ). In a randomized, open, multicenter trial for first-line therapy of invasive aspergillosis it gave comparable composite success rates to conventional amphotericin B, but breakthrough infections, infusionrelated toxicity, and nephrotoxicity were possible risks. Patients who received voriconazole had significantly more frequent episodes of transient visual disturbances and hallucinations. The efficacy, safety, and tolerability of voriconazole and fluconazole have been compared in 391 immunocompromised adults with esophageal candidiasis in a randomized, double-blind, multicenter trial (49C ). Most of the patients (94%) had AIDS. Following randomization, they took either voriconazole (200 mg bd) or fluconazole (400 mg on day 1 followed by 200 mg od) for a median of 14 or 15 days respectively. Treatment was continued for 7 days after the resolution of all signs and symptoms but was not allowed to exceed 42 days. The two drugs achieved comparable success rates (98% voriconazole, 95% fluconazole), as assessed by esophagoscopy in the primary efficacy analysis in 256 patients. More patients discontinued voriconazole because of laboratory test abnormalities (3.5 vs. 1%) or treatment-related adverse events (2.5 vs. 0.5%). The most frequent adverse event

with voriconazole was transient visual disturbances (23 vs. 8%); other clinical adverse events were similar in frequency. Increases of over three times the upper limit of the reference range in AsT (20 vs. 8%), AlT (11 vs. 7%), and alkaline phosphatase (10 vs. 8%) were more frequent with voriconazole. Mild, transient, reversible visual adverse events, in particular enhanced brightness of light, have been reported previously with voriconazole, but comprehensive ophthalmological investigations have not shown any morphological correlates or longterm visual sequelae. The higher incidence of liver function test abnormalities in patients taking voriconazole is not unexpected for an azole and can be explained by the extensive hepatic metabolic clearance of voriconazole.

ALLYLAMINES

(SED-14, 937; SEDA-23, 298; SEDA-24, 314; SEDA-25, 331)

Terbinafine Hematologic With increasing use of terbinafine world-wide, anecdotal cases of hematological toxicity are being reported. The projected rate of all blood dyscrasias associated with terbinafine has been estimated to be 32 per million patient-years (50A ). • Agranulocytosis occurred in a 15-year-old who took terbinafine 250 mg/day for toenail onychomycosis and tinea pedis (51A ). This effect was noted 4 weeks after starting terbinafine and resolved within 1 week after its withdrawal.

As the incidence of severe adverse effects is not completely clear in children, this case argues for careful evaluation of the indication for treatment with terbinafine and continued blood surveillance during therapy. Liver Several cases of symptomatic hepatobiliary reactions have been reported in association with terbinafine, including at least two cases of fatal liver failure. • A 41-year-old man developed severe hepatic dysfunction following a 3.5-week course of terbinafine (250 mg/day) (52A ). He had marked pruritus, jaundice, malaise, anorexia, and loin pain. His serum bilirubin rose to a peak of 718 µmol/l

310 with alkaline phosphatase 569 U/l, AlT 90 U/l, AsT 63 U/l, and a prolonged prothrombin time of 21 s, unresponsive to vitamin K. Liver biopsy showed canalicular cholestasis consistent with a drug reaction. His symptoms resolved 11 months after drug withdrawal, and his liver function tests normalized after 15 months. • A previously healthy 46-year-old man developed acute fulminant hepatitis following treatment with rabeprazole, citalopram hydrobromide, terbinafine, and a multivitamin formulation (53A ). Liver biopsy showed submassive centrilobular necrosis and intrahepatic cholestasis with florid bile duct proliferation.

Because of the similarity of the clinical, laboratory, and histological effects of omeprazole and lansoprazole, as previously reported, the authors concluded that the reaction in the second patient might have been caused by the proton pump inhibitor rather than terbinafine. Because of the rare and unpredictable nature of hepatobiliary reactions to terbinafine, the mechanism of hepatotoxicity has been hypothesized to be either an immunological or metabolically mediated. A potentially toxic reactive metabolite of terbinafine, 7,7-dimethylhept-2ene-4-ynal (TBF-A), the N-dealkylation product of terbinafine, has been identified in vitro (54E ). The authors speculated that this allylic aldehyde metabolite, formed by liver enzymes and conjugated with GSH, would be transported across the canalicular membrane of hepatocytes and concentrated in the bile. The reactive monoglutathione conjugate could bind to hepatobiliary proteins and cause direct toxicity. Alternatively, it could modify canalicular proteins and lead to an immune-mediated reaction, causing cholestatic dysfunction. Skin Acute generalized exanthematous pustulosis has again been attributed to terbinafine (250 mg/day) (55A ). Epicutaneous and intracutaneous skin tests were negative, and there was no evidence of viral infection. A fixed drug eruption with the distribution of the baboon-syndrome has been reported in a patient taking terbinafine (250 mg/day) (56A ). Epicutaneous and intracutaneous allergy testing was negative, but the symptoms reappeared 20 hours after oral provocation with terbinafine 250 mg. Hair Hair loss has been attributed to terbinafine (57A ).

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• A 69-year-old woman took terbinafine 250 mg/day for 112 days for subungual hyperkeratosis and developed hair loss after 3 months. She was also taking hydrochlorothiazide, amiloride hydrochloride, and amlodipine besilate, all in the same dosage for more than 5 years. Clinical and laboratory investigations showed no other obvious causes, and hair loss completely reversed on withdrawal of terbinafine.

Musculoskeletal Since its introduction, the Netherlands Pharmacovigilance Foundation Lareb has received eight reports of arthralgia in patients taking terbinafine (58A ). In four cases skin reactions were also present, in two cases urticaria. Two patients who reported arthralgia also had a fever. Logistic regression modelling showed that both urticaria and arthralgia were statistically significantly associated with reports on terbinafine compared with all other reports in the database. These findings may point towards a clustering of these symptoms in patients using terbinafine, suggesting a shared immunological reaction. Immunologic Induction of subacute cutaneous lupus erythematosus and exacerbation of systemic lupus erythematosus by terbinafine have been previously reported (SEDA-23, 299). A further five patients who had either exacerbated or new subacute cutaneous lupus erythematosus while taking terbinafine for presumed onychomycosis have been reported from a single academic center in the USA (59A ). Of 21 consecutive patients with subacute cutaneous lupus erythematosus who attended an out-patient dermatology department in Germany during 1 year, four had terbinafineassociated disease (60c ). In addition to high titers of antinuclear antibodies with a homogeneous pattern, anti-Ro(SS-A) antibodies were present; in three of the four women, anti-La(SSB) antibodies were also found. All the patients had antihistone antibodies, as in drug-induced lupus, and showed the characteristic genetic association with the HLA-B8,DR3 haplotype; moreover, in two cases HLA-DR2 was also present. After withdrawal of terbinafine, antinuclear antibody titers fell and antihistone antibodies became undetectable within 4.5 months in three patients. Risk factors Children In 14 children, aged 1–15 years, with Microsporum canis tinea capitis given oral terbinafine for 4 weeks the recommended daily dose produced no response by

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week 4; the dose was doubled (to 250 mg/day) for an additional 4–8 weeks in six patients and continued at the original dose in six patients (61c ). Two patients withdrew from the study. Four patients were cured after 8–12 weeks of treatment, and all had taken the doubled dose of terbinafine, except for one who had taken the usual adult dose of 250 mg/day from the start. Oral terbinafine was well tolerated by all but one patient, who had gastrointestinal disturbance and slightly raised transaminase activities during the first 4 weeks of treatment.

The efficacy of anidulafungin, caspofungin, and micafungin against Candida spp. has been documented in phase II and phase III studies in immunocompromised patients with esophageal candidiasis. All achieved therapeutic efficacy at least comparable with standard agents. The results of phase III efficacy studies in invasive candidiasis and empirical antifungal therapy in persistently febrile neutropenic patients are awaited. Caspofungin is approved in the USA and the EC for second-line therapy of definite or probable invasive aspergillosis (48R , 63R ).

Drug interactions A 51-year-old patient developed imipramine toxicity and increased plasma concentrations associated with the introduction of terbinafine, possibly due to inhibition of CYP2D6 (62A ).

Caspofungin

ECHINOCANDINS

(SEDA-25, 338)

The echinocandins are a novel class of intravenous semisynthetic antifungal lipopeptides that act by non-competitive inhibition of 1,3beta-D-glucan, a homopolysaccharide that is a major constituent of the cell wall of many pathogenic fungi and plays a key role in cell division and cell growth. The currently available echinocandins (anidulafungin, Versicor Inc, Freemont, CA; caspofungin, Merck & Co Inc, Rahway, NJ; micafungin, Fujisawa Inc, Deerfield, IL) have potent and broadspectrum antifungal activity against Candida and Aspergillus spp. without cross-resistance to existing agents. Their efficacy against these organisms in vivo has been demonstrated in various animal models. The echinocandins have dose-independent pharmacokinetics and a half-life of 10–15 hours. They are highly protein bound (over 95%) and distribute into all major tissues, including the brain; however, concentrations in non-inflammatory CSF are low. They are metabolized in the liver and are slowly excreted as inactive metabolites into the urine and feces; only small amounts are excreted into the urine unchanged. They lack significant potential for drug interactions mediated by CYP450 isozymes and are generally well tolerated.

Caspofungin has been compared with amphotericin in a multicenter, double-blind, randomized trial in 128 adults with endoscopically documented symptomatic Candida esophagitis (64C ). There was endoscopically verified clinical success in 74 and 89% of the patients who received caspofungin 50 and 70 mg/day respectively, and in 63% of patients given amphotericin B deoxycholate 0.5 mg/kg/day. Therapy was withdrawn because of drugrelated adverse events in 24% of the patients who were given amphotericin and in 4 and 7% of those who were given caspofungin 50 and 70 mg/day respectively. The most frequent adverse events with caspofungin were fever, phlebitis, headache, and rash. Fewer patients who received caspofungin had drug related fever, chills, or nausea than those who received amphotericin. More patients who received amphotericin (91%) than caspofungin (61 and 32%) developed drug-related laboratory abnormalities, the most common in the caspofungin groups being hypoalbuminemia and increased serum activities of alkaline phosphatase and aminotransferases. There were drug-related increases in blood urea nitrogen concentrations in 15% of the patients who received amphotericin but none of those who received caspofungin. Likewise, serum creatinine concentrations increased in 16 patients who received amphotericin but in only one who received caspofungin. In summary, caspofungin was as effective as amphotericin but better tolerated in the treatment of esophageal candidiasis.

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REFERENCES 1. Harbarth S, Pestotnik SL, Lloyd JF, Burke JP, Samore MH. The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy. Am J Med 2001 111: 528–34. 2. Herbrecht R, Letscher-Bru V, Bowden RA, Kusne S, Anaissie EJ, Graybill JR, Noskin GA, Oppenheim, Andres E, Pietrelli LA. Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion. Eur J Clin Microbiol Infect Dis 2001; 20: 460–6. 3. White MH, Bowden RA, Sandler ES, Graham ML, Noskin GA, Wingard JR, Goldman M, Van Burik JA, McCabe A, Lin JS, Gurwith M, Miller CB. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998; 27: 296–302. 4. Subira M, Martino R, Sureda A, Altes A, Briones J, Brunet S, Sierra J. Safety and efficacy of lowdose amphotericin B lipid complex for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies. Methods Find Exp Clin Pharmacol 2001; 23: 505–10. 5. Palmer SM, Drew RH, Whitehouse JD, Tapson VF, Davis RD, McConnell RR, Kanj SS, Perfect JR. Safety of aerosolized amphotericin B lipid complex in lung transplant recipients. Transplantation 2001; 72: 545–8. 6. Adler-Shohet F, Waskin H, Lieberman JM. Amphotericin B lipid complex for neonatal invasive candidiasis. Arch Dis Child Fetal Neonatal Ed 2001; 84: F131–3. 7. Walsh TJ, Goodman JL, Pappas P, Bekersky I, Buell DN, Roden M, Barrett J, Anaissie EJ. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother 2001; 45: 3487–96. 8. Fleming RV, Kantarjian HM, Husni R, Rolston K, Lim J, Raad I, Pierce S, Cortes J, Estey E. Comparison of amphotericin B lipid complex (ABLC) vs. AmBisome in the treatment of suspected or documented fungal infections in patients with leukemia. Leuk Lymphoma 2001; 40: 511–20. 9. Schilling MK, Eichenberger M, Maurer CA, Sigurdsson G, Buchler MW. Ketoconazole and pulmonary failure after esophagectomy: a prospective clinical trial. Dis Esophagus 2001; 14: 37–40. 10. Duman D, Turhal NS, Duman DG. Fatal aplastic anemia during treatment with ketoconazole. Am J Med 2001; 111: 737. 11. Zollner E, Delport S, Bonnici F. Fatal liver failure due to ketoconazole treatment of a girl with Cushing’s syndrome. J Pediatr Endocrinol Metab 2001; 14: 335–8. 12. Sobh MA, Hamdy AF, El Agroudy AE, El Sayed K, El-Diasty T, Bakr MA, Ghoneim MA. Coadministration of ketoconazole and cyclosporine for kidney transplant recipients: long-term follow-

up and study of metabolic consequences. Am J Kidney Dis 2001; 37: 510–17. 13. Gutierrez M, Abramowitz W. Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram. Pharmacotherapy 2001; 21: 163–8. 14. Lane HY, Chiu CC, Kazmi Y, Desai H, Lam YW, Jann MW, Chang WH. Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo. Drug Metab Drug Interact 2001; 18: 263–78. 15. Herranz U, Rusca A, Assandri A. Emedastine– ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers. Int J Clin Pharmacol Ther 2001; 39: 102–9. 16. Kerbusch T, Jansen RL, Mathot RA, Huitema AD, Jansen M, Van Rijswijk RE, Beijnen JH. Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin. Clin Pharmacol Ther 2001; 70: 132–41. 17. Pelz RK, Hendrix CW, Swoboda SM, DienerWest M, Merz WG, Hammond J, Lipsett PA. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg 2001; 233: 542–8. 18. Tholakanahalli VN, Potti A, Hanley JF, Merliss AD. Fluconazole-induced torsade de pointes. Ann Pharmacother 2001; 35: 432–4. 19. Albert SG, DeLeon MJ, Silverberg AB. Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients. Crit Care Med 2001; 29: 668–70. 20. Shibata S, Kami M, Kanda Y, Machida U, Iwata H, Kishi Y, Takeshita A, Miyakoshi S, Ueyama J, Morinaga S, Mutou Y. Acute adrenal failure associated with fluconazole after administration of high-dose cyclophosphamide. Am J Hematol 2001; 66: 303–5. 21. Menegola E, Broccia ML, Di Renzo F, Giavini E. Antifungal triazoles induce malformations in vitro. Reprod Toxicol 2001; 15: 421–7. 22. Sorensen HT, Nielsen GL, Olesen C, Larsen H, Steffensen FH, Schonheyder HC, Olsen J, Czeizel AE. Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol 1999; 48: 234–8. 23. Mathis AS, DiRenzo T, Friedman GS, Kaplan B, Adamson R. Sex and ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors. Transplantation 2001; 71: 1069–75. 24. Hilbert J, Messig M, Kuye O, Friedman H. Evaluation of interaction between fluconazole and an oral contraceptive in healthy women. Obstet Gynecol 2001; 98: 218–23. 25. Koks CH, Crommentuyn KM, Hoetelmans RM, Burger DM, Koopmans PP, Mathot RA, Mulder JW, Meenhorst PL, Beijnen JH. The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals. Br J Clin Pharmacol 2001; 51: 631–5.

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26. Abad S, Moachon L, Blanche P, Bavoux F, Sicard D, Salmon-Ceron D. Possible interaction between gliclazide, fluconazole and sulfamethoxazole resulting in severe hypoglycaemia. Br J Clin Pharmacol 2001; 52: 456–7. 27. Niemi M, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ, Kivisto KT. Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 2001; 69: 194–200. 28. Boogaerts M, Maertens J, Van Hoof A, de Bock R, Fillet G, Peetermans M, Selleslag D, Vandercam B, Vandewoude K, Zachee P, De Beule K. Itraconazole versus amphotericin B plus nystatin in the prophylaxis of fungal infections in neutropenic cancer patients. J Antimicrob Chemother 2001; 48: 97–103. 29. Caillot D, Bassaris H, McGeer A, Arthur C, Prentice HG, Seifert W, De Beule K. Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS. Clin Infect Dis 2001; 33: e83–90. 30. Boogaerts MA, Maertens J, Van der Geest R, Bosly A, Michaux JM, Van Hoof A, Cleeren M, Wostenborghs R, De Beule K. Pharmacokinetics and safety of a 7-day administration of intravenous itraconazole followed by a 14-day administration of itraconazole oral solution in patients with hematologic malignancy. Antimicrob Agents Chemother 2001; 45: 981–5. 31. Boogaerts M, Winston DJ, Bow EJ, Garber G, Reboli AC, Schwarer AP, Novitzky N, Boehme A, Chwetzoff E, De Beule K, for the Itraconazole Neutropenia Study Group. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med 2001; 135: 412–22. 32. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with itraconazole. Lancet 2001; 357: 1766–7. 33. Wolf R, Wolf D, Kuperman S. Focal nodular hyperplasia of the liver after itraconazole treatment. J Clin Gastroenterol 2001; 33: 418–20. 34. Alvarez-Fernandez JG, Castano-Suarez E, Cornejo-Navarro P, De la Fuente EG, Ortiz de Frutos FJ, Iglesias-Diez L. Photosensitivity induced by oral itraconazole. J Eur Acad Dermatol Venereol 2000; 14: 501–3. 35. Mathis AS, Friedman GS. Coadministration of digoxin with itraconazole in renal transplant recipients. Am J Kidney Dis 2001; 37: E18. 36. Lebrun-Vignes B, Archer VC, Diquet B, Levron JC, Chosidow O, Puech AJ, Warot D. Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects. Br J Clin Pharmacol 2001; 51: 443–50. 37. Jokinen MJ, Ahonen J, Neuvonen PJ, Olkkola KT. Effect of clarithromycin and itraconazole on

313 the pharmacokinetics of ropivacaine. Pharmacol Toxicol 2001; 88: 187–91. 38. Kivisto KT, Wang JS, Backman JT, Nyman L, Taavitsainen P, Anttila M, Neuvonen PJ. Selegiline pharmacokinetics are unaffected by the CYP3A4 inhibitor itraconazole. Eur J Clin Pharmacol 2001; 57: 37–42. 39. Banerjee R, Leaver N, Lyster H, Banner NR. Coadministration of itraconazole and tacrolimus after thoracic organ transplantation. Transplant Proc 2001; 33: 1600–2. 40. Jeng MR, Feusner J. Itraconazole-enhanced vincristine neurotoxicity in a child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2001; 18: 137–42. 41. Bosque E. Possible drug interaction between itraconazole and vinorelbine tartrate leading to death after one dose of chemotherapy. Ann Intern Med 2001; 134: 427. 42. Kamaluddin M, McNally P, Breatnach F, O’Marcaigh A, Webb D, O’Dell E, Scanlon P, Butler K, O’Meara A. Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies. Acta Paediatr 2001; 90: 1204–7. 43. Sathiapalan RK, El-Solh H. Enhanced vincristine neurotoxicity from drug interactions: case report and review of literature. Pediatr Hematol Oncol 2001; 18: 543–6. 44. Zhou-Pan X-R, Seree E, Zhou X-J, Placidi M, Maurel P, Barra Y, Rahmani R. Involvement of human liver cytochrome P4503A in vinblastine metabolism: drug interactions. Cancer Res 1993; 53: 5121–6. 45. Gupta S, Kim J, Gollapudi S. Reversal of daunorubicin resistance in P388/ADR cells by itraconazole. J Clin Invest 1991; 87: 1467–9. 46. Hoffman HL, Ernst EJ, Klepser ME: Novel triazole antifungal agents. Expert Opin Invest Drugs 2000; 9: 593–605. 47. Chiou, C, Groll AH, Walsh TJ. New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. Oncologist 2000; 5: 120–35. 48. Groll AH, Walsh TJ. Antifungal chemotherapy: recent advances and current perspectives. Swiss Medical Weekly 2002; 132: 303–11. 49. Ally R, Schurmann D, Kreisel W, Carosi G, Aguirrebengoa K, Dupont B, Hodges M, Troke P, Romero AJ, for the Esophageal Candidiasis Study Group. A randomized, double-blind, doubledummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis 2001; 33: 1447–54. 50. Gupta AK, Soori GS, Del Rosso JQ, Bartos PB, Shear NH. Severe neutropenia associated with oral terbinafine therapy. J Am Acad Dermatol 1998; 38: 765–7. 51. Aguilar C, Mueller KK. Reversible agranulocytosis associated with oral terbinafine in a pediatric patient. J Am Acad Dermatol 2001; 45: 632–4. 52. Chambers WM, Millar A, Jain S, Burroughs AK. Terbinafine-induced hepatic dysfunction. Eur J Gastroenterol Hepatol 2001; 13: 1115–18.

314 53. Johnstone D, Berger C, Fleckman P. Acute fulminant hepatitis after treatment with rabeprazole and terbinafine. Arch Intern Med 2001; 161: 1677–8. 54. Iverson SL, Uetrecht JP. Identification of a reactive metabolite of terbinafine: insights into terbinafine-induced hepatotoxicity. Chem Res Toxicol 2001; 14: 175–81. 55. Rogalski C, Húrlimann A, Burg G, Wúthrich B, Kempf W. Arzneimittelreaktion auf Terbinafin unter dem bild einer akuten generalisierten exanthematischen pustulose (AGEP). Hautarzt 2001; 52: 444–8. 56. Weiss JM, Mockenhaupt M, Schöpf E, Simon JC. Fixes arzneimittelexanthem auf Terbinafin mit charakteristischem verteilungsmuster eines baboon-syndroms. Hautarzt 2001; 52: 1104–6. 57. Richert B, Uhoda I, De la Brassinne M. Hair loss after terbinafine treatment. Br J Dermatol 2001; 145: 842. 58. Van Puijenbroek EP, Egberts AC, Meyboom RH, Leufkens HG. Association between terbinafine and arthralgia, fever and urticaria: symptoms or syndrome? Pharmacoepidemiol Drug Saf 2001; 10: 135–42.

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59. Callen JP, Hughes AP, Kulp-Shorten C. Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine: a report of 5 cases. Arch Dermatol 2001; 137: 1196–8. 60. Bonsmann G, Schiller M, Luger TA, Stander S. Terbinafine-induced subacute cutaneous lupus erythematosus. J Am Acad Dermatol 2001; 44: 925–31. 61. Koumantaki E, Kakourou T, Rallis E, Riga P, Georgalla S. Doubled dose of oral terbinafine is required for Microsporum canis tinea capitis. Pediatr Dermatol 2001; 18: 339–42. 62. Teitelbaum ML, Pearson VE. Imipramine toxicity and terbinafine. Am J Psychiatry 2001; 158: 2086. 63. Groll AH, Walsh TJ. Caspofungin: pharmacology, safety, and therapeutic potential in superficial and invasive fungal infections. Expert Opin Invest Drugs 2001; 10: 1545–58. 64. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001; 33: 1529–35.

Tihana Bicanic, Tim Planche, and Sanjeev Krishna

28

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ANTIMALARIAL DRUGS 4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) (SED-14, 950; SEDA-23, 305; SEDA-24, 331; SEDA-25, 343)

Amodiaquine Amodiaquine is a Mannich base derivative related to chloroquine. It may be an alternative first-line drug in the treatment of falciparum malaria in chloroquine-resistant areas. Cardiovascular Prolongation of the QTc interval is a recognized effect of 4-aminoquinolines. In 20 adult Cameroonian patients with non-severe falciparum malaria treated with amodiaquine (total dose 30 mg/kg or 35 mg/kg over 3 days) there was asymptomatic sinus bradycardia (n = 16) and prolongation of the PQ, QRS, and QTc intervals at the time of maximum cumulative concentration of drug (day 2 of treatment) (1C ).

Chloroquine and hydroxychloroquine Chloroquine remains effective against most non-falciparum malaria, but owing to widespread resistance has limited efficacy in the management of P. falciparum infections. Nevertheless, because of its low cost and wide availability it is still widely used in many countries. Amodiaquine and chloroquine have been compared in an open randomized trial in uncomplicated falciparum malaria in Nigerian © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

children (2C ). The doses were amodiaquine (n = 104) 10 mg/kg/day for 3 days and chloroquine (n = 106) 10 mg/kg/day for 3 days. After 28 days the cure rate was significantly higher with amodiaquine than chloroquine (95% vs. 58%). The rates of adverse events, most commonly pruritus (10%) and gastrointestinal disturbances (3%), were similar in the two groups. Cross-resistance between the two aminoquinolines is common, and there are concerns regarding toxicity of amodiaquine with repeated use. Cardiovascular Long-term chloroquine can cause cardiac complications, such as conduction disorders and cardiomyopathy (restrictive or hypertrophic), by structural alteration of the interventricular septum (3Ar ). Thirteen cases of cardiac toxicity associated with long-term chloroquine and hydroxychloroquine have been reported in patients with systemic autoimmune diseases. The cumulative doses were 600–2281 g for chloroquine and 292–4380 g for hydroxychloroquine. • A 64-year-old woman with systemic lupus erythematosus took chloroquine for 7 years (cumulative dose 1000 g). She developed syncope, and the electrocardiogram showed complete heart block; a permanent pacemaker was inserted. The next year she presented with biventricular cardiac failure, skin hyperpigmentation, proximal muscle weakness, and chloroquine retinopathy. Coronary angiography was normal. An echocardiogram showed a restrictive cardiomyopathy. A skeletal muscle biopsy was characteristic of chloroquine myopathy. Chloroquine was withdrawn and she improved rapidly with diuretic therapy.

Regular cardiac evaluation should be considered for those who have taken a cumulative chloroquine dose of 1000 g, particularly elderly patients. Nervous system Chloroquine can cause seizures in patients with epilepsy. The mechanism is uncertain, but it may include reductions in inhibitory neurotransmitters and pharmacokinetic

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interactions that alter anticonvulsant concentrations. There has been a further case report of chloroquine-induced seizures (4A ). • A 59-year-old woman had a generalized convulsion 24 hours after returning from a trip to Vietnam. She had a history of partial complex seizures (controlled with carbamazepine) due to a previous ruptured cerebral aneurysm. For the preceding 3 weeks she had been taking chloroquine 100 mg/day and proguanil 200 mg/day. A blood film was negative for malaria. A CT scan of the brain showed changes compatible with the previous hemorrhage. She was successfully treated with clobazam (dose not stated) until withdrawal of chemoprophylaxis.

The interaction between chloroquine and carbamazepine was not examined. Chloroquine should not be given to adults with a history of epilepsy. Sensory systems Retinopathy is a wellrecognized adverse effect of long-term chloroquine therapy. The most sensitive clinical indicator of 4-aminoquinoline-associated retinopathy is a pericentral scotoma on visual field testing. Isolated visual field defects are usually reversible on drug withdrawal, while changes in visual acuity, colour vision, and bull’s eye changes on fundoscopic examination appear late and generally signify fixed retinopathy. Retinopathy can occur after chloroquine antimalarial chemoprophylaxis for less than 10 years: the lowest reported total dose was 110 g (5A ). A further case of hydroxychloroquineinduced retinopathy in a 45-year-old woman with systemic lupus erythematosus has illustrated that maculopathy can be associated with other 4-aminoquinolines (6Ar ). Mutations in the ABCR gene (a photoreceptor-specific ATP-binding cassette transporter gene) have been associated with Stargardt disease, which has some features similar to chloroquine-induced retinopathy. In a recent case-control study of eight cases of chloroquineinduced retinopathy five of the eight cases had mis-sense mutations in the ABCR gene, two of which have been associated with Stargardt disease (7C ). It may be that polymorphisms in the ABCR gene predispose to chloroquine-induced retinopathy.

Tihana Bicanic, Tim Planche, and Sanjeev Krishna

Skin The most common dermatological adverse event associated with chloroquine is skin discomfort (often called pruritus). It is much more common in people with darker skins and has been ascribed to chloroquine binding to increased melanin concentrations in the skin. In a recent pharmacokinetic study, the ratio of AUC0-48 for chloroquine and its major metabolite desethylchloroquine was significantly higher in the plasma and urine of 18 patients with chloroquine-induced pruritus than 18 patients without (8C ). These results imply that differences in metabolism and higher chloroquine concentrations may be partly responsible for chloroquine-induced pruritus. Other less frequent chloroquine-associated skin reactions have been described, including a case of fatal toxic epidermal necrolysis associated with hydroxychloroquine (9A ). • A 39-year-old woman with rheumatoid arthritis took hydroxychloroquine 200 mg bd for painful synovitis, in addition to meloxicam, codydramol, and Gaviscon. She inadvertently took twice the prescribed dose of hydroxychloroquine, but stopped it after 2 weeks because of nausea. The next day she developed a widespread blotchy erythema and 2 weeks later was admitted to hospital with clinical and histological toxic epidermal necrolysis and deteriorated rapidly with multiorgan failure; she died 1 week later.

There have been four recent case reports of photosensitivity associated with hydroxychloroquine (10Ar ), which has an estimated incidence of about 10 per 1000 patient-years (11R ). Pregnancy An observational comparison in a rural Ghanaian hospital of 2083 pregnant women and 3084 historical controls showed no serious adverse events with chloroquine chemoprophylaxis (300 mg/week), but a high rate of pruritus (12C ). There was a decrease in anemia in pregnancy but no increase in perinatal mortality or birth weight in the chloroquine-treated mothers, although this was only in comparison with historical controls. Drug overdose Overdose with hydroxychloroquine is far less common than with chloroquine. Three of eight recently reported patients died (13Ar ). Life-threatening symptoms, such as hypotension, conduction disturbances, and hypokalemia can occur within 30 minutes of

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ingestion and are similar to those seen in chloroquine overdose. The lethal plasma concentration of hydroxychloroquine is not well established. Therapeutic drug concentrations are usually less than 1 µmol/l. Serious toxicity has been reported at plasma concentrations of 2.1–2.9 µmol/l. Management of hydroxychloroquine overdose is similar to that of chloroquine overdose, including the use of charcoal for drug adsorption, diazepam for seizures and sedation, early intubation and mechanical ventilation, and potassium replacement for severe hypokalemia. Drug formulations Chloroquine has a bitter taste, which can deter children from taking it, so a new sweet effervescent formulation of chloroquine phosphate has been compared with chloroquine tablets in a pharmacodynamic study (14C ). With sweet-tasting medications there is a risk of accidental overdose in children.

Halofantrine

(SED-14, 968; SEDA-23, 305; SEDA-24, 311; SEDA-25, 344)

Cardiovascular The popularity of halofantrine in the treatment of chloroquine-resistant falciparum malaria has dwindled, because of prolongation of the QTc interval. This complication occurred in 10 of 25 children treated with halofantrine (24 mg/kg oral suspension in three divided doses) for acute falciparum malaria (15C ). Electrocardiographic monitoring is recommended for children and adults taking halofantrine.

Mefloquine

(SED-13, 808; SEDA-23, 303; SEDA-24, 332; SEDA-25, 343) Mefloquine is a fluorinated quinolinemethanol compound effective against all malaria species. Neuropsychiatric Malaria prevention measures taken by 5626 returning North American and European travellers departing from Kenyan airports have been examined in a cross-sectional questionnaire study. Mefloquine (74%) and chloroquine and proguanil (15%)

317 were the most common drugs used (16C ). There were adverse events in 20% of the travellers who took mefloquine and 16% of those who took chloroquine and proguanil. Neuropsychological adverse events were reported by 7.8% of those taking mefloquine and 1.9% of those taking chloroquine. Despite adverse events, adherence was better in the mefloquine group (95 vs. 81%; OR = 0.25), which may have been due to a lower dosing frequency. Atovaquone + proguanil (250/100 mg/day; n = 493) and mefloquine (250 mg/week; n = 483) have been compared in non-immune subjects attending travel clinics in North America, Europe, and South Africa in a randomized, double-blind study (17C ). Adverse events were reported by an equivalent proportion of subjects who had taken either drug (71 vs. 67%). Those who took atovaquone + proguanil had significantly fewer treatment-related neuropsychiatric adverse events (14 vs. 29%), fewer adverse events of moderate or severe intensity (10 vs. 19%), and fewer adverse events that caused prophylaxis to be withdrawn (1.2 vs. 5%), compared with those who took mefloquine. Adherence was better in the atovaquone + proguanil group, which may have been due to the shorter duration of post-travel dosing (1 week vs. 4 weeks for mefloquine). There were no confirmed cases of malaria. Mefloquine (125 or 250 mg/week; n = 56) has been compared with proguanil (100 or 200 mg/day; n = 57) for short-term (6 months) malaria chemoprophylaxis in Nigerians with sickle cell anemia in a non-blinded, randomized study (18c ). Efficacy was similar (89% for mefloquine and 82% for proguanil). Adverse events were reported by 32% of those who took proguanil and 20% of those who took mefloquine. Surprisingly, only 3.6% of the mefloquine group reported neuropsychiatric adverse events. Further cases of neuropsychiatric events associated with mefloquine have been reported (19A , 20A ). • A 42-year-old man with no previous psychiatric history suddenly developed visual symptoms after the third dose (total dose 750 mg) of prophylactic mefloquine. The symptoms consisted of an impression of focussing on two different planes and of perceiving his surroundings as very far from him. They were associated with slurred speech and altered comprehension. They occurred daily, lasting up to an hour, for 6 months. He had previously

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taken a course of mefloquine for 7 weeks without any adverse events. • A 52-year-old woman with no psychiatric history developed anxiety, paranoia, visual hallucinations, confusion, and depressive symptoms after 3 doses of prophylactic mefloquine (250 mg/week). She had previously taken mefloquine prophylaxis intermittently for 4 years with no adverse events.

These case reports illustrate important neuropsychiatric adverse effects of mefloquine in individuals who had previously taken mefloquine safely and had no psychiatric history. Risk factors Children Single-dose pyrimethamine + sulfadoxine (25 mg/kg; n = 54) has been compared with mefloquine (15 mg/kg; n = 48) in the treatment of uncomplicated P. falciparum malaria in an unblinded, randomized study in 102 Malawi children (21C ). Immediate vomiting was more common in those who took mefloquine (eight cases) than in those who took pyrimethamine + sulfadoxine (one case), with comparable parasite failure rates at 14 days (20 and 22% respectively).

QUININE AND CONGENERS (SED-14, 962; SEDA-23, 307; SEDA-24, 333) Quinine remains effective against all Plasmodium species, and is the drug of choice for the management of severe malaria in most areas of the world, either alone or with other antimalarial drugs. Well-known adverse effects include nausea, tinnitus, dizziness, and hypoglycemia. Cheaper and more convenient alternatives to intravenous quinine are being explored in resource-poor settings. A population pharmacokinetic study of intramuscular quinine (loading dose 20 mg/kg salt diluted 1 : 1 in water) in 120 Ghanaian children with severe malaria showed predictable profiles, which were within the target range for quinine (15–20 mg/l) and independent of clinical and laboratory variables (22C ). Adverse events included skin induration or abscesses at the injection site (12%), all of which resolved without surgical intervention, and hypoglycemia (10%), an especial risk in children who were hypoglycemic at presentation. A double-blind, placebo-controlled trial of a 3-day combination regimen of quinine (8 mg/kg

Tihana Bicanic, Tim Planche, and Sanjeev Krishna

tds) and clindamycin (5 mg/kg tds) (n = 53) vs. 7-day quinine (8 mg/kg tds intravenously for 3 days, then orally; n = 55) to treat uncomplicated imported falciparum malaria showed no significant differences in the parasite and fever clearance times or the 28-day cure rate (100 vs. 96%) (23C ). The frequencies of mild adverse events (tinnitus and nausea) were similar in the two groups. There were two serious adverse events that necessitated treatment withdrawal: one patient taking quinine alone had a hemolytic episode and another a “severe toxic rash”. Hematologic In a retrospective survey of thrombotic thrombocytopenic purpura with hemolytic uremic syndrome reported to the Oklahoma TTP/HUS Registry 17 of 225 cases were associated with quinine (doses not stated) taken long term for leg cramps (24CR ). Patients typically presented with an acute onset of fever, chills, nausea, vomiting, diarrhea, and abdominal pain within hours of quinine ingestion. Laboratory findings included thrombocytopenia, microangiopathic hemolytic anemia, and liver and renal dysfunction. This is an immune-mediated reaction associated with quinine-dependent antiplatelet antibodies and a high mortality (three of the 17 patients). It can be triggered by small amounts of quinine, such as those present in tonic water.

PRIMAQUINE AND CONGENERS (SED-14, 958; SEDA-23, 306; SEDA-24, 332; SEDA-25, 345)

Primaquine Primaquine is active against the liver stages of Plasmodium species, which allows treatment of hypnozoites in vivax and ovale malaria to prevent recurrence. It should not be used in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or during pregnancy, because of the risk of hemolysis. A randomized, placebo-controlled trial of supervised malaria prophylaxis with primaquine (30 mg/day for 20 weeks) in 97 non-immune adults with normal G6PD concentrations in Papua New Guinea showed 93% protective

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efficacy of primaquine against malaria (95% CI = 71, 98%) (25C ). The most common adverse events were headache, abdominal pain, cough, and nausea, but these were not more frequent than with placebo. Transient rises in methemoglobin concentrations (mean 3.4% on the last day of prophylaxis, resolving by day 18) were asymptomatic. Supervised treatment of P. vivax malaria with chloroquine (600 mg on day 1, 450 mg on days 2 and 3) and primaquine (15 mg/day for 14 days) has been studied in 50 patients in a non-endemic area of Brazil in a prospective open trial (26C ). G6PD status was not checked. The relapse-free cure rate at 6 months was 86%. There were “no important” adverse events. Risk factors for relapse included lower doses of primaquine. In patients over 60 kg in weight the dose of primaquine can fall short of recommendations (0.25–0.3 mg/kg/day), and this can contribute to the risk of relapse.

Proguanil plus atovaquone (SEDA-24, 333; SEDA-25, 345) Proguanil plus atovaquone (Malarone™) is a prophylactic agent for malaria that is effective against liver stages of the parasite and need only be taken for 1 week after return from malaria endemic areas. The use of proguanil plus atovaquone has been reviewed (27R ). Neuropsychiatric adverse events were more frequent with mefloquine, whereas other adverse events occurred with similar frequencies as with chloroquine plus proguanil and mefloquine. Proguanil plus atovaquone is contraindicated in severe renal insufficiency. Co-administration of proguanil plus atovaquone with rifampicin is not recommended because of reductions in plasma atovaquone concentrations.

ENDOPEROXIDES Artemisia derivatives

(SED-14, 966; SEDA-23, 305; SEDA-24, 331; SEDA-25, 346) Artemisinin is a sesquiterpene lactone peroxide obtained from sweet wormwood (Artemisia

319 annua), and is available in oral and rectal formulations. Its derivatives are artemether (oral and intramuscular formulations) and artesunate (oral, intravenous, intramuscular, and rectal formulations). This class of antimalarial drugs produces rapid symptomatic recovery from uncomplicated malaria and clearance of parasites, but monotherapy is associated with a high rate of recrudescence. In a double-blind, randomized study in Vietnam (n = 227), extending the duration of oral artemisinin monotherapy (500 mg/day) from 5 to 7 days did not reduce recrudescence rates (total 23%) (28C ). A crossover pharmacokinetic study of singledose rectal artesunate (10 or 20 mg/kg as a suppository) or intravenous artesunate (2.4 mg/kg) in moderate falciparum malaria in 34 Ghanaian children has recently been reported (29C ). The intravenous route gave much higher peak concentrations but more rapid elimination of artesunate and its active metabolite dihydroartemisinin than the rectal route. Rectal artesunate had higher systemic availability in the low-dose group than in the high-dose group (58% vs. 23%). This is lower than published estimates of the systemic availability of oral artesunate (61–85%) (30C ). Parasite clearance kinetics were comparable in the two groups. There were no adverse events attributable to the drug. The results of phase III and phase IV studies of rectal artesunate as an alternative to parenteral antimalarial drugs in African children are awaited. Artemisinin derivatives may be used in combination with other antimalarial drugs. Theoretically, this should reduce the rate of recrudescence associated with artemisinin. In Irian Jaya, a randomized controlled trial (n = 105; 88 children) of oral artesunate (4 mg/kg od for 3 days) with pyrimethamine (1.25 mg/kg) + sulfadoxine or pyrimethamine + sulfadoxine alone (same dose) showed reduced gametocyte carriage and reduced treatment failure rates (RR = 0.3; 95% CI = 0.1, 1.3) in the combination group (31C ). Self-limiting adverse events of combination treatment were mild diarrhea (2.1%), rashes (4.3%), and itching (2.1%). In a double-blind, randomized, placebocontrolled trial in Gambian children with uncomplicated falciparum malaria treated with pyrimethamine + sulfadoxine (25/500 mg; n = 600) or pyrimethamine + sulfadoxine combined with two regimens of oral artesunate

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(4 mg/kg, n = 200 or 4 mg/kg od for 3 days, n = 200), there were mild adverse events, such as headache, anorexia, nausea, vomiting, abdominal pain, and diarrhea, in a high proportion of children (56%) (32C ). Combination treatment with artesunate was associated with more rapid parasite clearance and less gametocytemia. Three-dose artesunate conferred no additional benefit over the one-dose regimen. Pregnancy Artemisinin derivatives have been studied in 461 pregnant women in a prospective cohort study in Thailand over 8 years (33C ). Oral artesunate monotherapy was associated with a treatment failure rate of 6.6%. Artesunate and artemether were well tolerated. The rates of abortions (including 44 first-trimester exposures), stillbirths, or congenital abnormalities were 4.8%, 1.58%, and 0.8% respectively, and were not significantly different from pregnant controls. These results are reassuring, but further information is needed before the safety of artesunate in pregnancy can be confirmed.

Pyrimethamine plus sulfadoxine (SED-13, 811; SEDA-21, 296; see also Drugs used for Pneumocystis carinii pneumonia below) In a study of chemoprophylaxis for malaria, 701 Tanzanian infants were assigned to intermittent pyrimethamine + sulfadoxine (under 5 kg, a quarter of a tablet; 5–10 kg, half a tablet; over 10 kg, 1 tablet; each tablet contains pyrimethamine 25 mg and sulfadoxine 500 mg) or placebo alongside routine childhood immunizations and iron supplementation at 2, 3, and 9 months of age (34C ). Pyrimethamine + sulfadoxine was well tolerated, with no reported adverse events. Episodes of clinical malaria fell by 59% (95% CI = 41, 72) and the incidence of severe anemia by 50% (95% CI = 8, 73%) in the first year of life. Contrary to previous studies involving continuous prophylaxis in infants, there was no increase in the frequency of rebound episodes of malaria up to 18 months of age, suggesting that the development of malaria-specific immunity was unimpaired. Responses to vaccines were unaffected.

Tihana Bicanic, Tim Planche, and Sanjeev Krishna

DRUGS USED FOR PNEUMOCYSTIS CARINII PNEUMONIA (SED-14, 970; SEDA-23, 307; SEDA-24, 334; SEDA-25, 347)

Atovaquone Atovaquone is effective and well tolerated for prophylaxis and treatment of mild or moderate Pneumocystis carinii pneumonia in patients who cannot tolerate co-trimoxazole. Atovaquone suspension (750 mg bd; n = 34) or tablets (750 mg tds; n = 20) have been retrospectively compared in the treatment of Pneumocystis carinii pneumonia in HIV-positive individuals (35C ). Efficacy was similar (74 and 70% successfully treated). Atovaquone suspension was associated with nausea in one patient and a rash in another. In a prospective efficacy trial of atovaquone suspension (750 mg od or 250 mg tds for 1 year) in Pneumocystis carinii prophylaxis in 28 liver transplant recipients intolerant of co-trimoxazole, the adverse events reported included diarrhea (n = 7) and bloating or abdominal pain (n = 3) (36C ). No patients had developed Pneumocystis carinii pneumonia by 37 months. This is a smaller dose than approved for Pneumocystis prophylaxis in HIV infection (1500 mg/day). Further studies in recipients of solid organ transplants are needed to confirm the efficacy of this prophylactic dose.

Co-trimoxazole (trimethoprim plus sulfamethoxazole) Co-trimoxazole remains the first-line agent in the therapy and prophylaxis of Pneumocystis carinii pneumonia. HIV-infected patients are susceptible to adverse events, particularly fever or rash. The US Centre for Disease Control (CDC) recommends a dose of co-trimoxazole containing trimethoprim 150 mg/m2 /day and sulfamethoxazole 750 mg/m2 /day for Pneumocystis carinii prophylaxis in HIV-infected children. In a retrospective study of the records of 49 HIV-infected children who met CDC criteria for Pneumocystis prophylaxis there were no cases of proven or suspected Pneumocystis carinii

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pneumonia, despite the fact that 67% of them received less than two-thirds of the dose recommended by the CDC (37C ). Co-trimoxazole was well tolerated and only three children withdrew because of adverse effects (a rash in one and neutropenia in two). This study was too small to prompt reconsideration of the recommended prophylactic dose in children. Nervous system There have been 27 documented cases of aseptic meningitis associated with sulfonamides and trimethoprim (38AR ). Symptoms of meningitis (associated with CSF polymorphonuclear pleocytosis) typically begin within hours of ingestion, tend to increase in severity with subsequent exposure, and resolve completely within 48–72 hours of withdrawal. In some cases co-trimoxazole-induced aseptic meningitis was associated with systemic features of hypersensitivity, such as rash, pruritus, conjunctival injection, and facial swelling. The reactions occurred most commonly in the context of HIV infection (four cases) and connective tissue diseases (seven cases), which may relate to an underlying immune predisposition to co-trimoxazole-induced hypersensitivity or may simply reflect increased drug exposure in this population. Skin Toxic-epidermal necrolysis due to cotrimoxazole has recently been reviewed (39R ). Almost a third of cases are associated with sulfonamides and occur in patients who are slow acetylators and unable to detoxify a reactive metabolite that binds to epidermal cells, inducing an immune response. The onset usually occurs within 2 weeks of initial treatment with co-trimoxazole. It is not dose-related and can occur in individuals with no previous adverse reactions to co-trimoxazole. Management is supportive; systemic corticosteroids are not recommended. In 42 subjects there was a highly significant association between fixed drug eruption due to co-trimoxazole and the HLA A30 antigen and the A30 B13 Cw6 haplotype compared with 2378 control subjects (RR = 6.2) (40C ). Electrolyte balance Hyperkalemia occurs in 20–50% of patients taking co-trimoxazole, due to the amiloride-like effect of trimethoprim on the collecting duct. There have been few reports of metabolic acidosis associated with cotrimoxazole, which has been attributed to the

321 acetazolamide-like action of sulfamethoxazole on the proximal tubules. A recent report has implicated co-trimoxazole in hyperkalemia and acidosis (41A ). Metabolism Hypoglycemia associated with co-trimoxazole may be due to hyperinsulinemia, sulfamethoxazole being structurally similar to the sulfonylureas. Hypoglycemia is more common in elderly people and in those with renal impairment. Two cases of co-trimoxazoleinduced hypoglycemia have been reported in men with HIV infection (42A , 43A ). • A 41-year-old HIV-positive man developed hypoglycemia after 10 days of treatment with cotrimoxazole (160/800 mg qds po) for Pneumocystis carinii pneumonia. Despite withdrawal of co-trimoxazole and intravenous administration of dextrose, blood glucose concentrations remained low for 36 hours, with raised insulin and C-peptide concentrations.

The high insulin and C peptide concentrations in this case are consistent with hyperinsulinemic hypoglycemia due to co-trimoxazole. • A 56-year-old HIV-positive man who had taken gliclazide 160 mg od for 2 years for diabetes mellitus and co-trimoxazole (80/400 mg) for Pneumocystis prophylaxis for 2 months became weak and confused 2 days after starting fluconazole 200 mg od for oral candidiasis. His blood glucose concentration was 2.2 mmol/l. Insulin concentrations were not measured. Gliclazide was withdrawn. He had one further episode of loss of consciousness 2 days later and was well thereafter.

Fluconazole and sulfamethoxazole both inhibit CYP2C9, which metabolizes gliclazide. Co-administration of these three drugs resulted in severe hypoglycemia. This adverse event may become more common as more HIVpositive patients taking protease inhibitors develop diabetes requiring sulfonylurea therapy. Recent studies in healthy volunteers have shown that trimethoprim can cause increased serum homocysteine concentrations. However, this was not confirmed in 34 HIV-positive patients taking co-trimoxazole (80/400 mg/day) (44c ). Reproductive system Two cases of balanitis and genital ulceration associated with cotrimoxazole have been reported (45A ).

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Risk factors In a French study of 592 HIV-positive patients given co-trimoxazole a low CD4+ cell count at the time that cotrimoxazole therapy was begun was associated with an increased risk of adverse events (46C ). Toxoplasmosis was associated with a low CD4+ cell count at the start or end of cotrimoxazole therapy, supporting the idea that co-trimoxazole provides prophylaxis against toxoplasmosis. Drug interactions In 10 adult HIV-infected patients taking co-trimoxazole prophylaxis against Pneumocystis carinii (160/800 mg/day for over 1 month), tuberculosis therapy reduced trimethoprim and sulfamethoxazole mean AUC0-24 by 47% and 23% respectively (47C ). This effect was attributed to rifampicin, a potent inducer of hepatic enzymes. There have been no studies of the effect of rifampicin on co-trimoxazole efficacy in Pneumocystis prophylaxis. This interaction may have greater clinical implications when lower prophylactic doses of co-trimoxazole are used. Drug dosage regimens A 6-day dose escalation regimen of co-trimoxazole has been compared with direct re-challenge for Pneumocystis prophylaxis in 191 HIV-infected adults with previous rashes or fever while taking cotrimoxazole (48C ). The primary end-point, the ability to take single-strength co-trimoxazole daily at six months (half the dose recommended in the USA), was reached by 75% of the dose escalation group and 57% of the direct rechallenge group. Treatment was withdrawn in 14% of the dose escalation group and 31% of the direct rechallenge group because of adverse events, most commonly rashes and fever, none of which was life-threatening. Previous studies have also shown that dose escalation is associated with fewer adverse events than direct rechallenge.

Pyrimethamine plus sulfadoxine (SED-13, 811; SEDA-21, 296) Pyrimethamine + sulfadoxine (Fansidar™) prevents Pneumocystis carinii pneumonia and toxoplasmosis. In a single-arm, open, prospective study between 1990 and 1995 (before

Tihana Bicanic, Tim Planche, and Sanjeev Krishna

HAART) the prophylactic efficacy of Fansidar was evaluated in 95 HIV-infected patients with successfully treated Pneumocystis carinii pneumonia and no history of toxoplasma encephalitis (49C ). Patients took Fansidar (25–500 mg) with folinic acid (15 mg) twice weekly and were followed for a median of 19 (range 1–72) months. Five patients had a Pneumocystis relapse, but three had not taken their therapy. Of the 69 patients positive for anti-toxoplasma IgG antibodies only one developed toxoplasma encephalitis after 50 months. A rash developed in 16 patients after a median of 3 weeks, and required withdrawal in six. Two developed Stevens–Johnson syndrome after three or four doses. There was no significantly increased risk of adverse reactions to Fansidar in patients with previous hypersensitivity reactions to cotrimoxazole. The results of this study are of particular relevance to areas in which HAART is unavailable and where the antimalarial activity of Fansidar may confer additional benefit.

DRUGS USED FOR TOXOPLASMOSIS Pyrimethamine plus azithromycin Azithromycin is efficacious in animal models of toxoplasmic encephalitis. In a Phase I/II doseescalation study of pyrimethamine (50 mg od) plus azithromycin (900, 1200, or 1500 mg/day) for induction and maintenance treatment in 30 patients with AIDS and definite or suspected toxoplasma encephalitis, the overall response rate was 67% after 6 weeks of induction therapy (50C ). However, maintenance therapy for 24 weeks with this combination was associated with a high relapse rate (47%); only six patients successfully completed induction and maintenance therapy. Adverse events were common (particularly in those taking azithromycin 1500 mg) and included hepatotoxicity, bonemarrow suppression, ototoxicity, and gastrointestinal disturbances, which led 20% of patients to withdraw. All adverse events resolved on withdrawal. Pyrimethamine (50 mg/day) plus azithromycin (900 or 1200 mg/day) may be a useful

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alternative for those who cannot tolerate standard therapy that includes a sulfonamide or clindamycin. Further studies are warranted.

Sulfadiazine Urinary tract Sulfadiazine-related nephrolithiasis was common in the 1940s and has re-emerged in the context of HIV-related infections. There has been a further case report of crystalluria occurring within 24 hours of sulfadiazine treatment (1 g qds) in a 22-year-old HIV-negative woman with ocular toxoplasmosis (51A ). This was successfully treated by drug withdrawal, intravenous fluids, and the insertion of a stent to relieve vesicoureteric obstruction.

DRUGS USED FOR HUMAN AFRICAN TRYPANOSOMIASIS There has been a large rise in the number of cases of human African trypanosomiasis in the last 10 years. Drugs for human African trypanosomiasis, such as pentamidine, suramin, and melarsoprol, were developed decades ago. There has been a recent welcome initiative to manufacture and distribute antitrypanosomal drugs free of charge. However, increasing drug resistance and frequent serious drugrelated toxicity underline the urgent need for new medicines.

Melarsoprol DRUGS USED FOR LEISHMANIASIS Pentavalent antimonials remain the mainstay of treatment for leishmaniasis. These compounds are expensive and difficult to procure, they need to be administered parenterally, and they have significant adverse effects. There is an urgent need for alternative therapeutic agents.

Pentamidine

(SED-13, 823; SEDA-21,

299) When given parenterally for the treatment of Pneumocystis carinii pneumonia, pentamidine has a high rate of adverse events, including hypotension, pancreatitis, electrolyte disturbances, hypoglycemia or hyperglycemia, and renal impairment. In an uncontrolled study in French Guiana intramuscular pentamidine isethionate (two 4 mg/kg injections 48 hours apart) in 198 patients with cutaneous leishmaniasis produced a cure rate of 87%; 80% of treatment failures responded to an identical second course (52C ). Compared with published studies, adverse events were relatively mild: pain on injection (54%), gastrointestinal effects (53%), and hypotension (8%). There were no dysrhythmias or glucose abnormalities. This may reflect the brief course of pentamidine used.

(SED-14, 981; SEDA-23, 310; SEDA-24, 335) Nervous system Encephalopathic syndromes complicating treatment of stage II human African trypanosomiasis with melarsoprol in 588 patients have recently been reviewed (53C ). The overall rate of encephalopathy was 5.8% and presented in three ways: coma, convulsions, and psychotic reactions. The overall death rate was 38%. Comatose patients had a death rate of 52% and were commonly co-infected with malaria (14/16). Symptoms during treatment of fever (RR = 11.5), headache (RR = 2.5), bullous eruptions (RR = 4.5), and systolic hypotension (RR = 2.6) were associated with an increased risk of encephalopathic syndromes, especially coma.

OTHER COMPOUNDS Metronidazole

(SED-14, 977; SEDA-23, 309; SEDA-25, 350; see also Chapter 26)

Metronidazole is used for the treatment of protozoal infections, including amebiasis, giardiasis, and trichomoniasis. Nausea, a metallic taste, a disulfiram-reaction with alcohol, and peripheral neuropathy are well-recognized adverse effects.

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Nervous system Encephalopathy associated with metronidazole has been reported in a patient with chronic renal insufficiency (54A ). • A 58-year-old woman with end-stage renal insufficiency secondary to diabetic nephropathy developed abdominal wall cellulitis 4 days after insertion of a peritoneal dialysis catheter. She was given vancomycin, cefepime, and metronidazole in reduced doses (doses not stated) and 2 days later developed dysarthria, an intention tremor, dysmetria, and dysdiadochokinesis. “Routine” biochemical tests were unchanged and a CT scan of the brain was unremarkable, but an MRI scan showed cerebral and cerebellar atrophy with multifocal ischemic glial lesions. Metronidazole was withdrawn and 2 days later her symptoms and signs had completely resolved.

It is difficult to ascribe encephalopathy unequivocally to metronidazole in this case. Metronidazole-associated sensory neuropathy usually presents with pain and reduced thermal and pinprick sensation, but normal strength, proprioception, and tendon reflexes. Four patients with metronidazole-associated sensory symptoms had detailed electrodiagnostic studies and nerve or muscle biopsies (55AR ). All had taken different doses of metronidazole and one (with a mitochondrial myopathy) had only used the drug topically. After withdrawal, sensory complaints persisted without progression in two patients and resolved in one. In the fourth, a lower dosage led to partial resolution. Nerve conduction studies were normal in all four cases, but quantitative sensory testing and quantitative sudomotor autonomic reflex testing showed abnormalities of small fiber function. A sural nerve biopsy from one patient confirmed some loss of small myelinated axons. Metronidazole probably caused a small-fiber neuropathy in these four cases. The authors also reviewed nerve conduction studies in 30 reported cases of metronidazole-associated neuropathy; they were sometimes normal, suggesting that sensory symptoms related to

Tihana Bicanic, Tim Planche, and Sanjeev Krishna

metronidazole may be caused by a mixture of small-fiber and large-fiber sensory dysfunction. Pregnancy In a prospective case-control study in Israel of 857 pregnant women seeking telephone advice regarding gestational exposure to prescribed drugs, 228 women who had taken metronidazole were compared with 629 controls exposed to non-teratogenic agents (56C ). The mean daily dose of metronidazole was 973 mg for a mean duration of 7.9 days; 90% had used the medication orally, 6% by suppository, and 4% intravenously. Most (86%) had been exposed to metronidazole in the first trimester of pregnancy. There was no difference in the rate of major congenital malformations between the groups (1.6 vs. 1.4%), even after accounting for terminations due to prenatally diagnosed malformations. Neonatal birth weight was reduced in the metronidazole group (3.2 kg vs 3.3 kg) and this was not explained by an earlier gestational age at delivery or a higher prematurity rate but may have been due to the underlying conditions for which metronidazole was prescribed. These findings agree with previous meta-analyses showing that the use of metronidazole in pregnancy is not associated with an increased risk of fetal abnormality, despite in vitro evidence of mutagenesis and inconsistent animal evidence of fetal abnormalities caused by metronidazole. Risk factors Children In a randomized trial in 100 Iranian children mebendazole (200 mg tds for 5 days; n = 50) was compared with metronidazole (5 mg/kg tds for 7 days; n = 50) in giardiasis (57C ). The two drugs were equally effective (over 85% cure rates). There were no adverse effects of mebendazole, whereas nausea, anorexia, and metallic taste were respectively observed in 4.9, 6, and 24% of those taking metronidazole.

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in children. Ann Trop Med Parasitol 2001; 95: 549–58. 3. Cervera A, Espinosa G, Font J, Ingelmo M. Cardiac toxicity secondary to long term treatment with chloroquine. Ann Rheum Dis 2001; 60: 301. 4. Guilloton L, Burckard E, Fresse S, Drouet A, Felten D. Crise epileptique apres chimioprophylaxie antipalustre par chloroquine. Presse Med 2001; 30: 1745. 5. Bertagnolio S, Tacconelli E, Camilli G, Tumbarello M. Case report. Retinopathy after malaria prophylaxis with chloroquine. Am J Trop Med Hyg 2001; 65: 637–8. 6. Warner AE. Early hydroxychloroquine macular toxicity. Arthritis Rheum 2001; 44: 1959–61. 7. Shroyer NF, Lewis RA, Lupski JR. Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease? Am J Ophthalmol. 2001; 131: 761–6. 8. Onyeji CO, Ogunbona FA. Pharmacokinetic aspects of chloroquine-induced pruritus: Influence of dose and evidence for varied extent of metabolism of the drug. Eur J Pharm Sci 2001; 13: 195–201. 9. Murphy M, Carmichael AJ. Fatal toxic epidermal necrolysis associated with hydroxychloroquine. Clin Exp Dermatol 2001; 26: 457–8. 10. Metayer I, Balguerie X, Courville P, Lauret P, Joly P. Toxidermies photo-induites par l’hydroxychloroquine: 4 cas. Ann Dermatol Venereol 2001; 128: 729–31. 11. Singh G, Fries JF, Williams CA, Zatarain E, Spitz P, Bloch DA. Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis. J Rheumatol 1991; 18: 188–94. 12. Geelhoed DW, Visser LE, Addae V, Asare K, Van Schagen LJH, Van Roosmalen J. Malaria prophylaxis and the reduction of anemia at childbirth. Int J Gynecol Obstet 2001; 74: 133–8. 13. Marquardt K, Albertson TE. Treatment of hydroxychloroquine overdose. Am J Emerg Med 2001; 19: 420–4. 14. Yanze MF, Duru C, Jacob M, Bastide JM, Lankeuh M. Rapid therapeutic response onset of a new pharmaceutical form of chloroquine phosphate 300 mg: effervescent tablets. Trop Med Int Health 2001; 6: 196–201. 15. Lavallee I, Marc E, Moulin F, Treluyer JM, Imbeft P, Gendrel D. Troubles du rythme et allongement de l’espace QT sous halofantrine. Arch Pediatr 2001; 8: 795–800. 16. Lobel HO, Baker MA, Gras FA, Stennies GM, Meerburg P, Hiemstra E, Parise M, Odero M, Waiyaki P. Use of malaria prevention measures by North American and European travelers to East Africa. J Travel Med 2001; 8: 167–72. 17. Overbosch D, Schilthuis H, Bienzle U, Behrens RH, Kain KC, Clarke PD, Toovey S, Knobloch J, Nothdurft HD, Shaw D, et al. Atovaquone– proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 2001; 33: 1015–21. 18. Nwokolo C, Wambebe C, Akinyanju O, Raji AA, Audu BS, Emodi IJ, Balogun MO, Chukwuani

325 CM. Mefloquine versus proguanil in short-term malaria chemoprophylaxis in sickle cell anaemia. Clin Drug Invest 2001; 21: 537–44. 19. Borruat F-X, Nater B, Robyn L, Genton B. Prolonged visual illusions induced by mefloquine (Lariam® ): a case report. J Travel Med 2001; 8: 148–9. 20. Javorsky DJ, Tremont G, Keitner GI, Parmentier AH. Cognitive and neuropsychiatric adverse effects of mefloquine. J Neuropsychiatry Clin Neurosci 2001; 13: 302. 21. MacArthur JR, Stennies GM, Macheso A, Kolczak MS, Green MD, Ali D, Barat LM, Kazembe PN, Ruebush II TK. Efficacy of mefloquine and sulfadoxine–pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998. Am J Trop Med Hyg 2001; 65: 679–84. 22. Krishna S, Nagaraja NV, Planche T, Agbenyega T, Bedo-Addo G, Ansong D, Owusu-Ofori A, Shroads AL, Henderson G, Hutson A, et al. Population pharmacokinetics of intramuscular quinine in children with severe malaria. Antimicrob Agents Chemother 2001; 45: 1803–9. 23. Parola P, Ranque S, Badiaga S, Niang M, Blin O, Charbit JJ, Delmont J, Brouqui P. Controlled trial of 3-day quinine–clindamycin treatment versus 7-day quinine treatment for adult travelers with uncomplicated falciparum malaria imported from the tropics. Antimicrob Agents Chemother 2001; 45: 932–5. 24. Kojouri K, Vesely SK, George JN. Quinineassociated thrombotic thrombocytopenic purpurahemolytic uremic syndrome: frequency, clinical features, and long-term outcomes. Ann Intern Med 2001; 135: 1047–51. 25. Baird JK, Lacy MD, Basri H, Barcus MJ, Maguire JD, Bangs MJ, Gramzinski R, Sismadi P, Krisin, Ling J, et al. Randomized, parallel placebocontrolled trial of primaquine for malaria prophylaxis in Papua, Indonesia. Clin Infect Dis 2001; 33: 1990–7. 26. Duarte EC, Pang LW, Ribeiro LC, Fernandes FCJ. Association of subtherapeutic dosages of a standard drug regimen with failures in preventing relapses of vivax malaria. Am J Trop Med Hyg 2001; 65: 471–6. 27. Anonymous. Atovaquone + proguanil for malaria prophylaxis. Drug Ther Bull 2001; 39: 73–5. 28. Phan TG, Tran QB, Kager PA, Ho PL, Nguyen VT, Nguyen VN, de Vries PJ. Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy? Am J Trop Med Hyg 2001; 65: 690–5. 29. Krishna S, Planche T, Agbenyega T, Woodrow C, Agranoff D, Bedu-Addo G, Owusu-Ofori AK, Appiah JA, Ramanathan S, Mansor SM, Navaratnam V. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrob Agents Chemother 2001; 45: 509–16. 30. Newton P, Suputtamongkol Y, Teja-Isavadharm P, Pukrittayakamee S, Navaratnam V, Bates I,

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White N. Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrob Agents Chemother 2000; 44: 972–7. 31. Tjitra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM. Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine–pyrimethamine versus sulfadoxine–pyrimethamine alone in Irian Jaya, Indonesia. Am J Trop Med Hyg 2001; 65: 309–17. 32. Von Seidlein L, Milligan P, Pinder M, Bojang K, Anyalebechi C, Gosling R, Coleman R, Ude JI, Sadiq A, Duraisingh M, et al. Efficacy of artesunate plus pyrimethamine–sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial. Lancet 2000; 355: 352–7. 33. McGready R, Cho T, Keo NK, Kyaw LT, Villegas L, Looareesuwan S, White NJ, Nosten F. Artemisinin antimalarials in pregnancy: A prospective treatment study of 539 episodes of multidrugresistant Plasmodium falciparum. Clin Infect Dis 2001; 33: 2009–16. 34. Schellenberg D, Menendez C, Kahigwa E, Aponte J, Vidal J, Tanner M, Mshinda H, Alonso P. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial. Lancet 2001; 357: 1471–7. 35. Rosenberg DM, McCarthy W, Slavinsky J, Chan CKN, Montaner J, Braun J, Dohn MN, Caldwell PT. Atovaquone suspension for treatment of Pneumocystis carinii pneumoria in HIV-infected patients. AIDS 2001; 15: 211–14. 36. Meyers B, Borrego F, Papanicolaou G. Pneumocystis carinii pneumonia prophylaxis with atovaquone in trimethoprim–sulfamethoxazoleintolerant orthotopic liver transplant patients: a preliminary study. Liver Transplant 2001; 7: 750–1. 37. Fisher RG, Nageswaran S, Valentine ME, McKinney RE. Successful prophylaxis against Pneumocystis carinii pneumonia in HIV-infected children using smaller than recommended dosages of trimethoprim–sulfamethoxazole. AIDS Patient Care STDs 2001; 15: 263–9. 38. Muller MP, Richardson DC, Walmsley SL. Trimethoprim–sulfamethoxazole induced aseptic meningitis in a renal transplant patient. Clin Nephrol 2001; 55: 80–4. 39. See S, Mumford JM. Trimethoprim/ sulfamethoxazole-induced toxic epidermal necrolysis. Ann Pharmacother 2001; 35: 694–7. 40. Ozkaya-Bayazit E, Akar U. Fixed drug eruption induced by trimethoprim–sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. J Am Acad Dermatol 2001; 45: 712–17. 41. Margassery S, Bastani B. Life threatening hyperkalemia and acidosis secondary to trimethoprim–sulfamethoxazole treatment. J Nephrol 2001; 14: 410–14. 42. Abad S, Moachon L, Blanche P, Bavoux F, Sicard D, Salmon-Ceron D. Possible interaction between gliclazide, fluconazole and sulfamethoxazole

Tihana Bicanic, Tim Planche, and Sanjeev Krishna resulting in severe hypoglycaemia. Br J Clin Pharmacol 2001; 52: 456–7. 43. Hughes CA, Chik CL, Taylor GD. Cotrimoxazole-induced hypoglycemia in an HIV-infected patient. Can J Infect Dis 2001; 12: 314–16. 44. Smulders YM, De Spoelstra MAME, Slaats EH, Weigel HM, Stehouwer CDA, Jos FPH. Trimethoprim–sulphamethoxazole as primary Pneumocystis carinii prophylaxis does not increase serum homocysteine concentrations in HIV-positive subjects. Eur J Intern Med 2001; 12: 363–5. 45. Cherian G. Co-trimoxazole and genital ulceration. Int J Clin Pract 2001; 55: 151. 46. Rabaud C, Charreau I, Izard S, Raffi F, Meiffredy V, Leport C, Guillemin F, Yeni P, Aboulker J-P. Adverse reactions to co-trimoxazole in HIV-infected patients: predictive factors an subsequent HIV disease progression. Scand J Infect Dis 2001; 33: 759–64. 47. Ribera E, Pou L, Fernandez-Sola A, Campos F, Lopez RM, Ocana I, Ruiz I, Pahissa A. Rifampin reduces concentrations of trimethoprim and sulfamethoxazole in serum in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2001; 45: 3238–41. 48. Leoung GS, Stanford JF, Giordano MF, Stein A, Torres RA, Giffen CA, Wesley M, Sarracco T, Cooper EC, Dratter V, et al. Trimethoprim– sulfamethoxazole (TMP–SMZ) dose escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP–SMZ. J Infect Dis 2001; 184: 992–7. 49. Schurmann D, Bergmann F, Albrecht H, Padberg J, Grunewald T, Behnsch M, Grobusch M, Vallee M, Wunsche T, Ruf B, Suttorp N. Twice-weekly pyrimethamine–sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS. J Infect 2001; 42: 8–15. 50. Jacobson JM, Hafner R, Remington J, Farthing C, Holden-Wiltse J, Bosler EM, Harris C, Jayaweera DT, Roque C, Luft BJ, et al. Doseescalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 2001; 15: 583–9. 51. Smith JMA, Curi ALL, Pavesio CE. Crystalluria with sulphadiazine. Br J Ophthalmol 2001; 85: 1265. 52. Nacher M, Carme B, Sainte Marie D, Couppie P, Clyti E, Guibert P, Pradinaud R. Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana. Ann Trop Med Parasitol 2001; 95: 331–6. 53. Blum J, Nkunku S, Burri C. Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis. Trop Med Int Health 2001; 6: 390–400.

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54. Arik N, Cengiz N, Bilge A. Metronidazoleinduced encephalopathy in a uremic patient: a case report. Nephron 2001; 89: 108–9. 55. Zivkovic SA, Lacomis DL, Giuliani MJ. Sensory neuropathy associated with metronidazole: report of four cases and review of the literature. J Clin Neuromuscular Dis 2001; 3: 8–12. 56. Diav-Citrin O, Shechtman S, Gotteiner T, Arnon J, Ornoy A. Pregnancy outcome after ges-

327 tational exposure to metronidazole: a prospective controlled cohort study. Teratology 2001; 63: 186– 92. 57. Sadjjadi SM, Alborzi AW, Mostovfi H. Comparative clinical trial of mebendazole and metronidazole in giardiasis of children. J Trop Pediatr 2001; 47: 176–8.

Ian R. McNicholl

29 DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS Five antiviral drugs that are active against cytomegalovirus have been approved and are available for use. Mainstays for treatment continue to be intravenous ganciclovir and foscarnet, possibly because of their established efficacy and safety. Valganciclovir, an oral prodrug that is rapidly hydrolysed by plasma esterases to ganciclovir, has recently been added. It has high systemic availability and causes adverse reactions as often as an equivalent dose of intravenous ganciclovir.

Antiviral drugs were taking it prophylactically, and there was no relation between dosage and nephrotoxicity. Toxicity occurred early in therapy, and usually within the first 3 weeks. Other adverse effects included nausea, vomiting, thrombocytopenia, and eye toxicity. Prophylactic cidofovir treatment for CMV antigenemia has been investigated in a prospective study in patients with transplants (3c ). Renal toxicity, occasionally with proteinuria, was reported, as was nausea. The renal toxicity was mild and reversible.

Fomivirsen

(SEDA-24, 341; SEDA-25,

354)

Cidofovir

(SED-14, 989; SEDA-23, 314; SEDA-24, 340; SEDA-25, 353)

Urinary tract Nephrotoxicity continues to be the main adverse effect that limits the use of cidofovir. In a rare cytomegalovirus comparison trial, a ganciclovir insert (an intraocular implant) plus oral ganciclovir was compared with intravenous cidofovir (1C ). Based on data from 61 patients (the trial was stopped early owing to low recruitment), cidofovir was associated with a raised serum creatinine concentration of 1.6 mg/dl (142 µmol/l) or greater (0.48 per person-year), 3+ or greater proteinuria (0.29 per person-year), uveitis (0.35 per person-year), and neutropenia (0.11 per personyear). Cidofovir is being used in the transplant field for prophylaxis and treatment of CMV infections, because of its dosing convenience. Renal toxicity, including severe toxicity requiring dialysis, has been noted (2c ). The risk of renal toxicity was higher in patients with established CMV infections than in those who © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

328

Sensory systems Fomivirsen is a phosphorothioate antisense oligonucleotide that must be given by injection. It has been approved for treating CMV infection. Intraocular inflammation and retinal pigment epithelial changes have been noted at doses that overlap with those used to treat CMV retinitis (4r ).

Foscarnet

(SED-14, 989; SEDA-24, 340;

SEDA-25, 354) Skin Eosinophilic folliculitis is a common skin manifestation associated with HIV infection; it is not commonly associated with medications. • A 38-year-old patient with AIDS was given intravenous foscarnet 400 mg tds. and no other medications (5A ). On the second day, a pruritic, erythematous, maculopapular, urticarial rash was noted on the limbs and trunk. The infusion was stopped and the reaction disappeared. On restarting the infusion, the reaction recurred but did not clear after withdrawal. Histology showed a pattern consistent with eosinophilic folliculitis. After UVB phototherapy for 2 months the folliculitis resolved.

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Ganciclovir

(SED-14, 990; SEDA-24, 341; SEDA-25, 354) Sensory systems For HIV-infected patients who have failed the intravenous CMV treatment options, intravitreal injections may be the last line. In one case only mild iris atrophy was noted, despite high-dose intravitreal ganciclovir (3 mg twice weekly) and high-dose intravitreal foscarnet (2.4 mg twice weekly) (6A ).

DRUGS ACTIVE AGAINST HEPATITIS C VIRUS Ribavirin (tribavirin)

those seen with 100–1200 mg/day in the treatment of hepatitis C. Anemia occurred in 37% of the ribavirin treated patients and in the same number of controls, suggesting that ribavirin was equally tolerated in the two groups. Drug interactions Co-administration of didanosine with ribavirin can lead to increased toxicity secondary to raised intracellular concentrations of phosphorylated didanosine (ddATP) (11A , 12A ).

DRUGS ACTIVE AGAINST HERPESVIRUSES

(SED-14, 992; SEDA-23, 315; SEDA-24, 341; SEDA-25, 355)

Aciclovir

Metabolism Multisystem organ dysfunction and lactic acidemia occurred in two of 15 patients with HIV and hepatitis C infections who received interferon alfa and ribavirin (7c ). They were also taking didanosine, and the evidence suggests that the combination of didanosine plus ribavirin increased the risk of lactic acidosis.

Skin Aciclovir was the first compound effective against herpesvirus to be introduced. While it is still commonly used, its usefulness is limited by the frequency of dosing, particularly in Varicella zoster infections. Although allergy is unusual, it can occur; in one case it resulted in a skin rash (13A ).

Hematologic The most common, dose-limiting adverse effect of ribavirin is anemia. A low pretreatment platelet count, the dose of interferon alfa, and the haptoglobin phenotype are risk factors, and the fall in hemoglobin is independent of dose (8c ). In five patients with chronic hepatitis C on hemodialysis who received subcutaneous interferon alfa-2b and oral ribavirin for 40 weeks, the dose of ribavirin was titrated based on hemoglobin, with bonemarrow support by erythropoietin (9c ). There was significant bone-marrow toxicity in all five. A dose of 200 mg/day produced a steadystate AUC comparable to that obtained with 1000–1200 mg/day in historical controls with normal renal function. More severe anemia was possibly due to chronic renal insufficiency in addition to the prolonged effects of ribavirin. In 140 patients with Nipah virus infection there was no difference in the incidence of adverse effects between those who elected to have ribavirin treatment and those who refused (10c ). Dosing was based on recommendations used to achieve the same approximate concentrations as

(SED-14, 990; SEDA-23, 314; SEDA-25, 353)

• A 38-year-old woman of African descent, with a history of atopy and mild asthma, developed a periumbilical, erythematous, maculopapular rash and generalized pruritus after starting aciclovir. The reaction resolved within a few days after withdrawal, recurred when famciclovir was used, and again resolved when famciclovir was withdrawn. She was successfully stabilized on suppressive therapy after a graded challenge with aciclovir four times a day for 5 days.

Cross-reactivity between aciclovir and famciclovir is unusual. Aciclovir desensitization may be a novel method of treating patients with aciclovir allergy.

Famciclovir

(SED-14, 991; SEDA-23, 315; SEDA-25, 353) Gastrointestinal Adverse effects associated with famciclovir have been collected in over 6000 patients in two post-marketing surveillance studies (14c ). Only headache, abdominal symptoms, dizziness, vomiting, and diarrhea

330 were associated with the drug. Two prospective trials have confirmed the low frequency of adverse effects, the more common ones being nausea, headache, vomiting, and diarrhea (15C , 16C ).

Valaciclovir Nervous system Adverse effects of valaciclovir, the L-valyl ester of aciclovir, can be associated with increased drug concentrations when the dose is not adjusted for reduced renal function. For example, aseptic meningitis has been associated with valaciclovir in a patient with renal insufficiency (17A ). • An 88-year-old man with renal insufficiency took valaciclovir 1000 mg tds. After the first dose, he became disoriented and incontinent. Valaciclovir was withdrawn, but the symptoms continued and progressed to drowsiness and nuchal rigidity. After an extensive work-up, aseptic meningitis was diagnosed.

Given the patient’s age and renal dysfunction, it is likely that excessive valaciclovir accumulation was responsible for this presentation. Psychiatric Ocular and auditory hallucinations have been reported in a 60-year-old woman on CAPD (18A ).

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) (SED-14, 993; SEDA-23, 319; SEDA-24, 342; SEDA-25, 356) Metabolism Lactic acidosis continues to be a significant, if uncommon, risk of nucleoside reverse transcriptase inhibitors. The mechanism is thought to be inhibition of mitochondrial DNA polymerase γ , leading to depletion of mitochondrial DNA. Diagnosis is difficult, as patients with lactic acidosis present with nonspecific complaints of nausea, vomiting, abdominal pain, and malaise, which may occur

Chapter 29

Ian R. McNicholl

months or years after the start of treatment. The incidence of lactic acidosis is unknown. However, of 349 Australian patients studied for 18 months (516 patient-years) only two had severe lactic acidosis (19C ). However, routine monitoring of lactate is still not recommended, since lactate concentrations do not correlate with symptoms and patients may have asymptomatic lactatemia. Furthermore, technical difficulties in blood collection and processing, and the lack of a standardized definition of lactic acidosis for patients taking NRTIs, prevent any routine monitoring recommendations in the absence of symptoms. In addition, it is possible that NRTIs can also cause other forms of mitochondrial dysfunction.

Abacavir

(SED-14, 995; SEDA-24, 342)

Metabolism While abacavir has been associated with hyperglycemia, there were no significant effects in clinical trials. Hyperglycemia has again been reported recently (20A , 21A ). • A 47-year-old man, with normoglycemia and no family history of diabetes mellitus, who was taking highly active antiretroviral therapy, was given abacavir for treatment intensification. He became lethargic and hyperglycemic. Despite metformin and glibenclamide, the hyperglycemia continued. Abacavir was withdrawn, and within 2 weeks his blood glucose concentration returned to baseline and the hypoglycemic drugs were withdrawn.

The patient was also taking hydrochlorothiazide, but the time-course of onset and resolution were consistent with abacavir-induced hyperglycemia. Immunologic The risk of hypersensitivity reactions to abacavir is 5–8%, although in one study it was only 3.4% (22c ). Patients typically present with non-specific complaints suggestive of an upper respiratory tract infection, and they may have abdominal symptoms, which get progressively worse with each subsequent dose. The question of the safety of restarting abacavir in patients who interrupt treatment without having had a hypersensitivity reaction often arises in practice. The results of a recent study have suggested that it is safe. Of 1201 patients treated in clinical trials, 219 interrupted abacavir therapy for reasons other than hypersensitivity; on reintroduction, there were no cases of hypersensitivity or anaphylaxis (23r ).

Antiviral drugs

Stavudine

Chapter 29

(SEDA-20, 273; SEDA-23,

319) Metabolism Lipodystrophy, a syndrome characterized by fat redistribution, hyperglycemia/ insulin resistance, and dyslipidemia, can be associated with long-term HIV infection or with highly active antiretroviral therapy (HAART). In 1035 patients, those who took stavudine were 1.35 times more likely to report lipodystrophy (24c ). However, the study was retrospective, and other factors unrelated to specific drug therapy may have had a greater effects on the adjusted odds ratio. Urinary tract Renal tubular dysfunction and hypophosphatemia occurred in a patient who was taking both stavudine and lamivudine (25r ).

Tenofovir Tenofovir is the newest member of this class, and, in contrast to the others, it only needs to be phosphorylated twice intracellularly before it is pharmacologically active. Adverse effects have been reported as flatulence, raised transaminases, raised creatine kinase, and rarely a raised serum creatinine (26c ). However, tenofovir does not currently appear to be nephrotoxic.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) (SED-14, 996; SEDA-23, 320; SEDA-24, 344; SEDA-25, 357)

Efavirenz

(SED-14, 996; SEDA-24, 344;

SEDA-25, 357) Efavirenz-induced adverse effects often begin on the first day of therapy and resolve within 14–28 (median 13) days (27C ). In this same randomized, double blind study of 327 patients, cholesterol and triglycerides were raised in patients taking efavirenz, although this did not

331 reach statistical significance. In contrast to other NNRTIs, efavirenz is not associated with a significant risk of rash. Psychiatric Most clinicians tend to avoid efavirenz in patients with a psychiatric history. However, it is important to remember that efavirenz can precipitate sudden and severe psychiatric symptoms in patients with no history. Three patients developed sudden irritability; excitability with anxiety; and insomnia, confusion, and amnesia (28A ). The psychiatric adverse effects of efavirenz correlate with its plasma concentrations. In 130 HIV-infected patients toxicity was three times more common in patients who had an efavirenz concentration over 4000 µg/l (29c ). Skin Efavirenz has been associated with UV photosensitivity, which recurred after skin challenge with efavirenz powder (30A ). Reproductive system Gynecomastia and breast hypertrophy have been reported in at least three patients. All had had indinavir replaced by efavirenz. No other medications were changed, and gynecomastia was not present before substitution (31A ). The breast enlargement was generally asymmetrical and painful. Needle biopsy was consistent with gynecomastia. Six other reports have confirmed painful breast hypertrophy in patients taking efavirenz (32A ). Immunologic In a 39-year-old man efavirenz caused a confluent maculopapular rash, and pulmonary interstitial infiltrates without lymphadenopathy (33r ). The symptoms resolved when efavirenz was withdrawn while other antiretroviral drugs were continued. The patient was rechallenged, and the rash and fever reappeared; however, recurrence of the pulmonary infiltrates was not addressed. Drug interactions Efavirenz induces CYP3A4. Since methadone is partly metabolized by CYP3A4, the interaction of efavirenz with methadone has been investigated prospectively in 11 patients taking stable methadone maintenance therapy (34C ). Efavirenz reduced the steady-state methadone AUC by 50%. However, patients generally only needed a 22% increase in their methadone dose to eliminate the symptoms of methadone withdrawal, and the full basis of the interaction is not understood.

332

Nevirapine

Chapter 29

Ian R. McNicholl

(SED-14, 997; SEDA-23, 320; SEDA-24, 345; SEDA-25, 357)

Amprenavir

Liver In four men aged 27, 41, 47, and 49 years, nevirapine was associated with a skin rash, malaise, and icteric hepatitis, 4–6 weeks after the start of therapy; resolution occurred after withdrawal of nevirapine (35A ).

The use of amprenavir has been limited to patients who are highly motivated, because of the high capsule burden (16/day). Those who take amprenavir have complained of diarrhea, nausea, headache, and fatigue (43c ). The frequency of diarrhea may be as high as 50%.

Skin Stevens–Johnson syndrome, is a wellestablished but rare adverse effect of nevirapine (36A ). The incidence of rashes is 3–20%; a 14-day lead-in period reduces the frequency of rash, and other effective interventions include antihistamines and a longer lead-in period (4 weeks) (37r ). Rash appears to be sex-specific. In 95 women and 263 men, women had a seven-fold higher risk of severe rash and were 3.5 times more likely to discontinue nevirapine than men (38C ). Drug interactions St John’s wort reduced nevirapine concentrations, because of induction of CYP3A4 (39A ). Nevirapine itself induces CYP3A4 activity. A patient taking stable warfarin therapy for severe primary pulmonary hypertension was given lamivudine, stavudine, and nevirapine; the INR fell to 1.3 and an increased dose of warfarin was required (40A ). Nevirapine can occasionally reduce plasma methadone concentrations, putting patients at risk of opioid withdrawal (41A ).

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: PROTEASE INHIBITORS

(SED-14, 998; SEDA-25,

358)

Drug interactions Amprenavir is extensively metabolized by and induces CYP3A4. Plasma methadone concentrations fell by 35% when amprenavir was used (44A ). Including amprenavir in a protease inhibitor boosted regimen can be problematic, owing to unpredictable interactions with other protease inhibitors. In an open, randomized study of amprenavir combined with indinavir, nelfinavir, and saquinavir (45c ), saquinavir lowered the amprenavir AUC by 32%; amprenavir did not alter the pharmacokinetics of saquinavir. The amprenavir AUC increased by 35% when it was combined with indinavir, and indinavir concentrations also fell, suggesting that this protease inhibitor combination should be avoided. There was no significant interaction of amprenavir with nelfinavir. In attempts to lower the amprenavir capsule burden, low-dose ritonavir has been used as a pharmacokinetic booster. When ritonavir was added to amprenavir, the amprenavir AUC increased 3–4 times (46c ), which should allow the total daily capsule burden to be reduced. Adverse effects included diarrhea, nausea, paresthesia, rash, increased cholesterol, and increased triglycerides. The frequency of adverse events correlated with the dose of ritonavir.

(SED-14, 997; SEDA-23, 316; SEDA-24, 345; SEDA-25, 358)

Indinavir

Metabolism Protease inhibitors can be associated with lipodystrophy. Of 494 patients during median follow-up of 18 months, 17% developed lipodystrophy (42c ). Study limitations included the short time of follow-up and the lack of a standardized and accepted definition of lipodystrophy.

Cardiovascular In a retrospective analysis of 198 normotensive patients in a protease inhibitor comparison study, 30% of those who took indinavir developed stage I or worse hypertension, compared with none of the patients who took nelfinavir, ritonavir, or saquinavir (47c ).

(SED-14, 998; SEDA-23, 316; SEDA-24, 346; SEDA-25, 359)

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333

Chapter 29

Metabolism Protease inhibitors are associated with hyperglycemia and possible diabetes mellitus. In a prospective study in 12 patients indinavir caused hyperglycemia and reduced insulin sensitivity (48c ). Liver Indinavir has been compared with abacavir in a randomized equivalence trial in 562 patients who were also taking lamivudine and zidovudine (49C ). The only significant difference in adverse effects was that there was hyperbilirubinemia in 8% of those taking indinavir and 2% of those taking abacavir. Urinary tract Nephrolithiasis due to indinavir is dose-dependent and can be prevented by adequate hydration. In 615 patients (18 864 person-years of follow-up) who did not have risk factors for nephrolithiasis, the incidence was 8.6 episodes per 1000 person-years (50r ). Skin In 288 patients in a retrospective cohort study, paronychia was associated with indinavir, with a hazard ratio of 4.7 (51c ).

Fluid balance Two of 16 patients taking lopinavir/ritonavir developed inflammatory edema that resolved on withdrawal and recurred after rechallenge (55A ). Gastrointestinal In a prospective, randomized trial in 100 patients, the most common adverse effects of lopinavir/ritonavir included abnormal stools, diarrhea, and nausea (56c ).

Nelfinavir

(SED-14, 998; SEDA-23, 317; SEDA-24, 347; SEDA-25, 359)

Skin Patients often develop skin rashes due to HIV infection or drug allergy. Sulfa desensitization is well documented, but desensitization to other medications is not as well studied. One patient taking nelfinavir developed a severe, pruritic rash; management included nelfinavir desensitization over 12 days (57A ).

Drug interactions Venlafaxine 50 mg 8hourly reduced the AUC of a single dose of indinavir 800 mg by 28% in nine healthy subjects (52A ). Using ritonavir as a booster may allow indinavir to be given twice daily and with food. In a cohort survey of 100 patients the combination of indinavir plus ritonavir (400 mg/400 mg or 800 mg/100 mg bd) was a safe and effective option to reduce the tablet burden and improve adherence (53c ).

Drug interactions Since HMG CoA reductase inhibitors (statins) are partially or completely metabolized by CYP3A4, protease drug interactions can be expected. When nelfinavir was combined with atorvastatin and simvastatin, their AUCs increased by 74% and 505% respectively (58c ). As myopathy and rhabdomyolysis are concentration-related, simvastatin is contraindicated with any protease inhibitor, not just nelfinavir. Based on the data, the starting dose of atorvastatin should be reduced by about 50%.

Lopinavir/ritonavir

Ritonavir

Sensory systems Ototoxicity has not previously been reported with antiretroviral drugs, but has recently been attributed to lopinavir/ritonavir (54A ). • A 46-year-old man took a regimen containing lopinavir/ritonavir, and 4 weeks later complained of reduced auditory acuity accompanied by lancinating pain. Audiology showed mild to moderate bilateral sensorineural hearing loss. On withdrawal and use of efavirenz his hearing recovered.

Based on the time-course and the effect of withdrawal, lopinavir/ritonavir appears to have been the causative agent.

(SED-14, 998; SEDA-23, 317; SEDA-24, 347; SEDA-25, 360) Drug interactions Ergot alkaloids are among the many medications that are contraindicated in patients taking ritonavir. One patient developed severe ergotism after taking ritonavir and ergotamine for 13 days (59A ). In studies of combining ritonavir with fluconazole (60A ) and ritonavir with mefloquine (61A ) there were no significant effects, and dosage adjustment is not warranted. The treatment of tuberculosis is a challenge in patients taking antiretroviral drugs, as many HIV medications and antituberculous drugs

334 induce or inhibit CYP3A4. In a pilot, nonrandomized study, HIV-infected patients with tuberculosis were treated with regimens containing rifampicin and ritonavir (62A ). Despite the effects on CYP3A4, there was no significant interaction; plasma ritonavir concentrations remained sufficiently high and rifampicin concentrations did not rise to the toxic range.

Saquinavir

(SED-14, 998; SEDA-23, 318; SEDA-24, 348) Drug interactions The combination of saquinavir with ritonavir is perhaps the most widely used of protease inhibitor combinations. Using 400 mg/400 mg and 800 mg/200 mg, the saquinavir soft gelatin capsule AUC increased by 17–23 times compared with saquinavir alone (63c ). Saquinavir had no clinically significant effect on the pharmacokinetics of ritonavir. Ritonavir as a booster allows a much higher saquinavir concentration to be obtained, allowing twice-daily dosing and a reduced capsule burden. In 11 healthy men, erythromycin 250 mg qds increased the AUC of saquinavir (given as a soft gel capsule 1200 mg tds) by 69% when both were given for 7 days (64c ). In 12 healthy men, ketoconazole 400 mg/day increased the AUC of saquinavir (given as a soft gel capsule 1200 mg tds) by 190% when both were given for 7 days (64c ). In 14 healthy men, rifampicin 600 mg/day reduced the AUC of saquinavir (given as a soft gel capsule 1200 mg tds) by 46% when both were given for 14 days; this reduction can be counteracted by the addition of ritonavir (64c ).

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: M2 ION CHANNEL INHIBITORS (SED-14,

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drugs work by blocking the M2 ion channel, which is needed to affect a pH change that helps to initiate viral uncoating.

Amantadine

(SED-14, 999)

Psychiatric Amantadine and phenylpropanolamine may have caused intense recurrent déjà vu experiences in a healthy 39-year-old within 24 hours of starting both drugs for influenza (66A ).

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS (SED-14, 999; SEDA-23, 321; SEDA-24, 348; SEDA-25, 360) Of the neuraminidase inhibitors, inhaled zanamivir has the fewest adverse effects, but there are concerns about its use in young and elderly patients, who are generally unable to achieve the inspiratory flow rate needed to ensure adequate lung deposition (67R ). Oral oseltamivir is more convenient and easier to administer, but needs to be given with food to lower the frequency of gastrointestinal adverse effects.

Oseltamivir

(SED-14, 999; SEDA-25,

360) Gastrointestinal The oral capsule of oseltamivir can be used in any patient who can swallow. However, it must be given with food, to reduce the frequency of nausea and gastrointestinal discomfort. Of 695 children aged 1–12 years, 14.3% had vomiting compared with 8.5% of those who took placebo; otherwise oseltamivir was well tolerated (68C ).

999) Rimantidine is generally tolerated better than amantadine, because it causes fewer CNS adverse effects (65R ). Unfortunately, rimantidine is more costly, which has led many institutions to develop influenza treatment guidelines. Both

Zanamivir

(SED-14, 999; SEDA-23, 321; SEDA-24, 348; SEDA-25, 360) Respiratory Zanamivir can cause temporary bronchospasm in patients with asthma

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Chapter 29

or chronic obstructive pulmonary disease who use the dry powder inhaler. The bronchospasm can be reduced in frequency by using an inhaled β2 -agonist before zanamivir. Proper drug deposition depends on flow rate and inhaler technique, so young and elderly patients may not be the best to treat in this way (67R , 69c ).

OTHER DRUGS Adefovir While adefovir has activity against both HIV and hepatitis B, only hepatitis B has been studied clinically. The dose used for treatment of hepatitis B is about one-tenth that needed to treat HIV infection, so patients with hepatitis B

335 must have co-infection with HIV ruled out before treatment is started. Liver In 35 patients co-infected with hepatitis B virus and HIV given adefovir 10 mg/day plus lamivudine 150 mg bd as part of treatment for hepatitis B and followed for 48 weeks, common adverse effects included raised transaminases, particularly alanine aminotransferase, increased serum creatinine, and increased blood glucose (70c ). Concerns about the study include the small number of patients and the lack of a comparison group. Urinary tract Adefovir can cause nephrotoxicity, and the possible mechanism has been investigated in a 39-year-old man, who had severe acute tubular degenerative changes mainly affecting the proximal tubule; the mitochondria were significantly enlarged, possibly as a result of depletion of mitochondrial DNA (71A ).

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7. Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet 2001; 357: 280–1. 8. Van Vlierberghe H, Delanghe JR, De Vos M, Leroux-Roel G. Factors influencing ribavirininduced hemolysis. J Hepatol 2001; 34: 911–16. 9. Jie K, Rensma PL, Van Veen S, Bosch FH, Valentijn RM. Safety of interferon and ribavirin therapy in haemodialysis patients with chronic hepatitis C: results of a pilot study. Nephrol Dial Transplant 2001; 16: 193–4. 10. Chong HT, Kamarulzaman A, Tan CT, Goh KJ, Thayaparan T, Kunjapan SR, Chew NK, Chua KB, Lam SK. Treatment of acute Nipah encephalitis with ribavirin. Ann Neurol 2001; 49: 810–13. 11. Kakuda TN, Brinkman K. Mitochondrial toxic effects and ribavirin. Lancet 2001; 357: 1802–3. 12. Salmon-Ceron D, Chauvelot-Moachon L, Abad S, Silbermann B, Sogni P. Mitochondrial toxic effects and ribavirin. Lancet 2001; 357: 1803–4. 13. Kawsar M, Parkin JM, Forster G. Graded challenge in an aciclovir allergic patient. Sex Transm Infect 2001; 77: 204–5. 14. Engst R, Schiewe U, Hobel W, Machka K, Meister W. Famciclovir in treatment of acute herpes zoster: results of two post-marketing surveillance studies in Germany. Acta Dermatol Venereol 2001; 81: 59–60. 15. Tyring S, Engst R, Corriveau C, Robillard N, Trottier S, Van Slycken S, Crann RA, Locke LA, Saltzman R, Palestine AG. Famciclovir for oph-

336 thalmic zoster: a randomised aciclovir controlled study. Br J Ophthalmol 2001; 85: 576–81. 16. Manns MP, Neuhaus P, Atkinson GF, Griffin KE, Barnass S, Vollmar J, Yeang Y, Young CL. Famciclovir treatment of hepatitis B infection following liver transplantation: a long-term, multicentre study. Transplant Infect Dis 2001; 3: 16–23. 17. Fobelo MJ, Corzo Delgado JE, Romero Alonso A, Gomez-Bellver MJ. Aseptic meningitis related to valacyclovir. Ann Pharmacother 2001; 35: 128–9. 18. Izzedine H, Launay-Vacher V, Aymard G, Legrand M, Deray G. Pharmacokinetics of nevirapine in haemodialysis. Nephrol Dial Transplant 2001; 16: 192–3. 19. John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, Mallal SA. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS 2001; 15: 717–23. 20. Modest GA, Fuller J, Hetherington SV, Lenhard JM, Powell GS. Abacavir and diabetes. New Engl J Med 2001; 244: 142–4. 21. Hetherington SV, Lenhard JM, Powell GS. Abacavir and diabetes. New Engl J Med 2001; 244: 142–4. 22. Henry K, Wallace RJ, Bellman PC, Norris D, Fisher RL, Ross LL, Liao Q, Shaefer MS. Twice-daily triple nucleoside intensification treatment with lamivudine–zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the TARGET study. J Infect Dis 2001; 183: 571–8. 23. Loeliger AE, Steel H, McGuirk S, Powell WS, Hetherington SV, Frissen PHJ, De Vries J, Weigel HM, Brinkman K. The abacavir hypersensitivity reaction and interruptions in therapy. AIDS 2001; 15: 1325–6. 24. Heath KV, Hogg RS, Chan KJ, Harris M, Montessori V, O’Shaughnessy MV, Montaner JSG. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a populationbased HIV/AIDS treatment database. AIDS 2001; 15: 231–9. 25. Morris AAM, Baudouin SV, Snow MH. Renal tubular acidosis and hypophosphataemia after treatment with nucleoside reverse transcriptase inhibitors. AIDS 2001; 15: 140–1. 26. Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, Miller M, Kearney BP, Coleman RL, Lamy PD, Kahn JO, McGowan I, Lietman PS. Phase I/II trial of the pharmacokinetics, safety and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2001; 45: 2733–9. 27. Haas DW, Fessel WJ, Delapenha RA, Kessler H, Seekins D, Kaplan M, Ruiz NM, Ploughman LM, Labriola DF, Manion DJ, et al. Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebocontrolled trial. J Infect Dis 2001; 183: 392–400. 28. Peyriere H, Mauboussin J-M, Rouanet I, Fabre J, Reynes J, Hillaire-Buys D. Management of sud-

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den psychiatric disorders related to efavirenz. AIDS 2001; 15: 1323–4. 29. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001; 15: 71–5. 30. Treudler R, Husak R, Raisova M, Orfanos CE, Tebbe B. Efavirenz-induced photoallergic dermatitis in HIV. AIDS 2001; 15: 1085–6. 31. Arranz Caso JA, Prieto J, Casas En Sanz J. Gynecomastia without lipodystrophy syndrome in HIV-infected men treated with efavirenz. AIDS 2001; 15: 1447–8. 32. Mercie P, Viallard J-F, Thiebaut R, Faure I, Rispal P, Leng B, Pellegrin J-L. Efavirenzassociated breast hypertrophy in HIV-infected patients. AIDS 2001; 15: 126–9. 33. Behrens GMN, Stoll M, Schmidt RE. Pulmonary hypersensitivity reaction induced by efavirenz. Lancet 2001; 357: 1503–4. 34. Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001; 51: 213–17. 35. Prakash M, Poreddy V, Tiyyagura L, Bonacini M. Jaundice and hepatocellular damage associated with nevirapine therapy. Am J Gastroenterol 2001; 96: 1571–4. 36. Metry DW, Lahart CJ, Farmer KL, Hebert AA. Stevens–Johnson syndrome caused by the antiretroviral drug nevirapine. J Am Acad Dermatol 2001; 44: 354–7. 37. Barreiro P, Soriano V, Gonzalez-Lahoz J, Colebunders R, Schrooten W, Desmet P, De Roo A, Dreezen C. Prevention of nevirapine-associated rash. Lancet 2001; 357: 392–3. 38. Bersoff-Matcha SJ, Miller WC, Aberg JA, Van der Horst C, Hamrick HJ Jr, Powderly WG, Mundy LM. Sex differences in nevirapine rash. Clin Infect Dis 2001; 32: 124–9. 39. De Maat MMR, Hoetelmans RMW, Mathot RAA, Van Gorp ECM, Meenhorst PL, Mulder JW, Beijnen JH. Drug interaction between St John’s wort and nevirapine. AIDS 2001; 15: 420–1. 40. Dionisio D, Mininni S, Bartolozzi D, Esperti F, Vivarelli A, Leoncini F. Need for increased dose of warfarin in HIV patients taking nevirapine. AIDS 2001; 15: 277–8. 41. Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis 2001; 33: 1595–7. 42. Martinez E, Mocroft A, Garcia-Viejo MA, Perez-Cuevas JB, Blanco JL, Mallolas J, Bianchi L, Conget I, Blanch J, Phillips A, Gatell JM. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet 2001; 357: 592–8. 43. Kost RG, Hurley A, Zhang L, Vesanen M, Talal A, Furlan S, Caldwell P, Johnson J, Smiley

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L, Ho D, Markowitz M. Open-label phase II trial of amprenavir, abacavir, and fixed-dose zidovudine/lamivudine in newly and chronically HIV-1infected patients. J Acquired Immune Defic Syndr 2001; 26: 332–9. 44. Bart PA, Rizzardi PG, Gallant S, Golay KP, Baumann P, Pantaleo G, Eap CB. Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir. Ther Drug Monit 2001; 23: 553–5. 45. Sadler BM, Gillotin C, Lou Y, Eron JJ, Lang W, Haubrich R, Stein DS. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001; 45: 3663–8. 46. Sadler BM, Gillotin C, Lou Y, Stein DS. Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing. Antimicrob Agents Chemother 2001: 45: 30–7. 47. Cattelan AM, Trevenzoli M, Sasset L, Rinaldi L, Balasso V, Cadrobbi P. Indinavir and systemic hypertension. AIDS 2001; 15: 805–7. 48. Dube MP, Edmondson-Melancon H, Qian D, Aqeel R, Johnson D, Buchanan TA. Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients. J Acquired Immune Defic Syndr 2001; 27: 130–4. 49. Staszewski S, Keiser P, Montaner J, Raffi F, Gathe J, Brotas V, Hicks C, Hammer SM, Cooper D, Johnson M, Tortell S, Cutrell A, Thorborn D, Isaacs R, Hetherington S, Steel H, Spreen W. Abacavir–lamivudine–zidovudine vs indinavir– lamivudine–zidovudine in antiretroviral-naïve HIVinfected adults: a randomized equivalence trial. J Am Med Assoc 2001; 285: 546–7. 50. Dworkin MS, Wan P-CT. Indinavir, zidovudine, lamivudine: 3-year follow-up. Ann Intern Med 2001; 134: 165. 51. Colson AE, Sax PE, Keller MJ, Turk BK, Pettus PT, Platt R, Choo PW. Paronychia in association with indinavir treatment. Clin Infect Dis 2001; 32: 140–3. 52. Levin GM, Nelson LA, DeVane CL, Preston SL, Eisele G, Carson SW. A pharmacokinetic drug– drug interaction study of venlafaxine and indinavir. Psychopharmacol Bull 2001; 35: 62–71. 53. Burger DM, Hugen PWH, Aarnoutse RE, Dieleman JP, Prins JM, Van der Poll T, Ten Veen JH, Mulder JW, Meenhorst PL, Blok WL, Van der Meer JTM, Reiss P, Lange JMA. A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy. J Acquired Immune Defic Syndr 2001; 26: 218–24. 54. Williams B. Ototoxicity may be associated with protease inhibitor therapy. Clin Infect Dis 2001; 33: 2100–2. 55. Lascaux A-S, Lesprit P, Bertocchi M, Levy Y. Inflammatory oedema of the legs: a new side-effect of lopinavir. AIDS 2001; 15: 819. 56. Murphy RL, Brun S, Hicks C, Eron JJ, Gulick R, King M, White AC Jr, Benson C, Thompson M, Kessler HA, Hammer S, Bertz R, Hsu A, Japour

337 A, Sun E. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naïve adults with HIV-1 infection: 48-week results. AIDS 2001; 15: F1–9. 57. Abraham PE, Sorensen SJ, Baker WH, Cushing HE. Nelfinavir desensitization. Ann Pharmacother 2001; 35: 553–6. 58. Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45: 3445–50. 59. Vila A, Mykietiuk A, Bonvehi P, Temporiti E, Uruena A, Herrera F. Clinical ergotism induced by ritonavir. Scand J Infect Dis 2001; 33: 788–9. 60. Koks CHW, Crommentuyn KML, Hoetelmans RMW, Burger DM, Koopmans PP, Mathot RAA, Mulder JW, Meenhorst PL, Beijnen JH. The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals. Br J Clin Pharmacol 2001; 51: 631–5. 61. Khaliq Y, Gallicano K, Tisdale C, Carignan G, Cooper C, McCarthy A. Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers. Br J Clin Pharmacol 2001; 51: 591–600. 62. Moreno S, Podzamczer D, Blazquez R, Iribarren JA, Ferrer E, Reparaz J, Pena JM, Cabrero E, Usan L. Treatment of tuberculosis in HIV-infected patients: Safety and antiretroviral efficacy of the concomitant use of ritonavir and rifampin. AIDS 2001; 15: 1185–7. 63. Buss N, Snell P, Bock J, Hsu A, Jorga K. Saquinavir and ritonavir pharmacokinetics following combined ritonavir and saquinavir (soft gelatin capsules) administration. Br J Clin Pharmacol 2001; 52: 255–64. 64. Grub S, Bryson H, Goggin T, Ludin E, Jorga K. The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients. Eur J Clin Pharmacol 2001; 57: 115–21. 65. Fleming DM. Managing influenza: amantadine, rimantadine and beyond. Int J Clin Pract 2001; 55: 189–95. 66. Taiminen T, Jaaskelainen SK. Intense and recurrent déja vu experiences related to amantadine and phenylpropanolamine in a healthy male. J Clin Neurosci 2001; 8: 460–2. 67. McNicholl IR, McNicholl JJ. Neuraminidase inhibitors: zanamivir and oseltamivir. Ann Pharmacother 2001; 35: 57–70. 68. Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D, Mills RG, Ward P. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20: 127–33. 69. Lalezari J, Campion K, Keene O, Silagy C. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Arch Intern Med 2001; 161: 212–17. 70. Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, Gibbs CS, Brosgart C, Fry J,

338 Namini H, Katlama C, Poynard T. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001; 358: 718–23.

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71. Tanji N, Tanji K, Kambham N, Markowitz GS, Bell A, D’Agati VD. Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol 2001; 32: 734–40.

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Drugs used in tuberculosis and leprosy

An increasing number of patients with multidrug-resistant tuberculosis are being treated with second-line drugs worldwide, often in places with poor resources. The number of drugs used is large (4–7) and treatment is prolonged (1–2 years). There is justifiable concern over patients’ tolerance of such regimens and their adverse effects, which determine adherence to treatment. Treatment has to be individualized according to the WHO guidelines for a DOTs-plus strategy. It is therefore encouraging to read a report from Lima, Peru, where 60 patients from a shanty town tolerated a median of eight antituberculous drugs fairly well for a median duration of 20 months (1c ). All received a parenteral aminoglycoside daily for 6 months, cycloserine, and a fluoroquinolone, and most also took paraaminosalicylic acid and ethionamide. Of 60 patients, 23 took clofazimine, 23 pyrazinamide, 25 isoniazid, and three rifampicin. Commonly encountered adverse effects included dermatological effects (including bronzing of the skin— many of these patients were taking clofazimine and fluoroquinolones), depression, anxiety, and peripheral neuropathy. All complained of mild gastritis. There were no cases of serious hepatic or renal toxicity. This may have been because only a few patients took rifampicin. Absence of eighth nerve toxicity was striking, and can be attributed to close monitoring of patients by physicians with experience of DOTs-plus regimens. In a similar report from Turkey adverse reactions to drugs led to discontinuation of one or more drugs in 62 of 158 patients (39%) (2C ). The outcome was favorable and cultures became negative in 95% of the patients within 2 months. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Hepatotoxicity of antituberculous agents revisited There are four issues related to the management of patients who develop hepatotoxicity during treatment with antituberculous drugs: • what the preferred treatment regimen should be for patients with significantly abnormal liver functions at baseline; • when treatment should be stopped/modified if hepatic dysfunction develops; • what antituberculous treatment, if any, should be used until liver function improves; • what a safe regimen is for re-treatment of these patients. The use of ofloxacin instead of rifampicin in antituberculous drug regimens for patients with underlying chronic liver disease has been reported to be associated with a significantly lower risk of hepatotoxicity (3c ). Similar observations have been reported among carriers of hepatitis B and liver transplant recipients by other investigators, and were reviewed in SEDA-25 (p. 363). One of the most important predictors of hepatotoxicity during antituberculous drug therapy is abnormal liver function tests at baseline. It is reasonable to avoid potentially hepatotoxic drugs in the management of patients with pre-existing liver disease. Pyrazinamide in antituberculous drug regimens has generally not been considered to contribute to an increased risk of hepatotoxicity, although certain investigators have made contrary observations. Two cases of severe and fatal hepatitis have been reported to the CDC from New York and Georgia among patients taking rifampicin and pyrazinamide for latent tuberculosis (4A ). Between February and August 2001 another 21 patients had severe hepatotoxicity following treatment with rifampicin

339

340 plus pyrazinamide for 2 months for latent tuberculosis, as reported to the CDC; five died of fulminant hepatic failure, two of whom had recovered from isoniazid-induced hepatitis (5c ). This report led to revision of previous guidelines of the American Thoracic Society. According to the revised guidelines, isoniazid for 9 months is the preferred treatment for latent tuberculosis infection in HIV-negative subjects. Rifampicin plus pyrazinamide for 2 months can be used with caution in these patients, especially if they are taking other medications that are associated with liver injury, and those who drink a lot of alcohol. This combination is not recommended for those with underlying liver disease or who have had isoniazid-associated liver damage. Liver function tests should be measured at baseline and at 2-weekly intervals thereafter for 6 weeks. There are mild to moderate increases in liver transaminases during treatment with rifampicin plus isoniazid in most patients. However, biochemical hepatitis is diagnosed when AsT and AlT activities increase to more than four times the upper limit of the reference ranges on two occasions at least 1 week apart, or more than five times on any single occasion. This calls for withdrawal of all potentially hepatotoxic drugs (rifampicin, isoniazid, and pyrazinamide) until the enzymes return to the reference ranges. During this period, streptomycin plus ethambutol, with or without cycloserine, is recommended in seriously ill patients. There is a lack of consensus on the best retreatment protocol for patients who develop hepatotoxicity during treatment with standard antituberculous agents. Investigators from Turkey have reported a high risk of recurrence of hepatitis (in six of 25 patients) on re-introduction of all drugs in full doses after recovery from hepatitis (6c ). This risk was less when rifampicin and isoniazid were re-introduced sequentially in increasing doses and when pyrazinamide was replaced by streptomycin. Slow acetylation of isoniazid by the NAT2 isozyme of N-acetyltransferase has been associated with an increased risk of hepatotoxicity after rifampicin and isoniazid combination chemotherapy for tuberculosis in some studies (SEDA-25, 363). A recent case-control study has suggested that there is also an increased risk of antituberculous drug-induced hepatotoxicity in individuals with a glutathione Stransferase M1 “null” mutation (7C ). Reduced

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glutathione transferase activity could theoretically predispose individuals to adverse effects of toxic metabolites and xenobiotics. These observations need to be confirmed.

Dapsone

(SED-14, 1021; SEDA-23, 326; SEDA-25, 365) The adverse effects of dapsone have been comprehensively reviewed (8R ). Methemoglobinemia can be a problem at doses over 200 mg/day. Hemolysis, causing a fall in hemoglobin by 2–3 g/dl from baseline, is common; patients with G6PD deficiency are likely to develop more severe hemolysis. Agranulocytosis is rare but potentially fatal. Under 0.5% of the patients taking prolonged dapsone therapy develop the “dapsone syndrome”, which is characterized by skin lesions, pruritus, photosensitivity, lymphadenopathy, hepatic dysfunction, and hepatosplenomegaly. The syndrome develops about 1 month after the start of therapy. It appears to be a hypersensitivity reaction and is managed by withdrawing the drug and giving prednisolone 30–60 mg/day. Other rare adverse effects include peripheral neuropathy, psychosis, hepatitis, nephritic syndrome, and renal papillary necrosis. Dapsone is used in many conditions besides leprosy. In France, it is available in combination with ferrous oxalate as Disulone® (Aventis), and in 1983–98, 249 adverse reactions were reported to French pharmacovigilance centers, mainly blood dyscrasias (often neutropenia and agranulocytosis, rarely hemolysis and anemia) (9c ). Five patients died; three of them had septicemia secondary to agranulocytosis. There were 29 cases of “hypersensitivity syndrome”, 39 skin reactions, 27 cases of liver damage, and 27 cases of neurological and psychiatric adverse effects. Patients taking dapsone need to be under close medical supervision for early recognition of adverse reactions.

Fluoroquinolones

(see also

Chapter 26) Skin Phototoxicity occurred in four of nine patients with multidrug-resistant tuberculosis

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treated with a combination of sparfloxacin (400 mg od), ethionamide, and kanamycin (initially for 3–4 months) (10c ). It occurred after several months of treatment and was presumably due to the sparfloxacin. Sparfloxacin more commonly causes photosensitivity than ciprofloxacin, levofloxacin, or ofloxacin, which are also effective antituberculous drugs (11R , 12c ). Skin reactions can be severe enough to require withdrawal of sparfloxacin in some patients. In view of this, other fluoroquinolones, particularly ofloxacin, are preferable to sparfloxacin in the management of multidrugresistant tuberculosis.

Isoniazid

(SED-14, 1009; SEDA-23, 324; SEDA-24, 352; SEDA-25, 364) Pancreas Acute pancreatitis has been attributed to isoniazid (13A ). • A 42-year-old Asian man developed clinical, biochemical, and imaging features of acute pancreatitis 11 days after starting to take rifampicin, isoniazid, and pyrazinamide for spinal tuberculosis. He had no history of excessive alcohol or other drug therapy. He improved after withdrawal of all drugs, but the pancreatitis recurred on reintroduction of isoniazid and resolved after withdrawal.

There have been three previous case reports of this association, and causality is difficult to establish. Pancreatitis has rarely been seen in patients who have taken an overdose of isoniazid. Rifampicin, also used in this case, is more likely to cause pancreatitis in usual doses. Musculoskeletal Rhabdomyolysis occurred in subjects with isoniazid poisoning in a retrospective analysis of 270 patients seen over a 5-year period at the Phillipine General Hospital in Manilla (14c ). Skeletal muscle creatine kinase activity was raised in 31 of the 52 evaluable subjects who had taken more than 2.4 g/day of isoniazid. Creatine kinase activity peaked on days 5–6 and fell thereafter. Two patients developed acute renal insufficiency and required dialysis. Seizures occurred in all patients, and their duration, but not their frequency, correlated with raised creatine kinase activity. However, it is likely that factors other than seizures contribute to rhabdomyolysis in patients with isoniazid poisoning.

Rifamycins (SED-14, 1014; SEDA-23, 324; SEDA-24, 353; SEDA-25, 364) Rifabutin In a multicenter study from the National Institute of Allergy and Infectious Diseases in the USA azithromycin (600 mg/day) plus rifabutin (300 mg/day) was poorly tolerated by 31 patients with or without HIV infection (15C ). Gastrointestinal symptoms and neutropenia were the major adverse effects. This combination is currently recommended for patients with AIDS and disseminated Mycobacterium avium complex infection. There were no significant pharmacokinetic interactions between the two drugs. Musculoskeletal Polyarthralgia has been described in up to one-fifth of patients taking rifabutin. A combination of rifabutin and clarithromycin has been used in patients with disseminated Mycobacterium avium complex infection, but adverse effects, including myelosuppression, arthritis, and ocular complications, limit its usefulness. Drug interactions Severe interactions have been observed when rifabutin and clarithromycin are given simultaneously (16R ). The mean concentrations of rifabutin and 25-O-desacetylrifabutin in healthy subjects who took clarithromycin and rifabutin concomitantly were respectively more than 4 times and 37 times greater than the concentrations recorded when rifabutin was administered alone. Neutropenia was detected in 14 of 18 subjects taking rifabutin. Myalgia and high fever were also common. Physicians should be aware that recommended prophylactic doses of rifabutin can be associated with severe neutropenia within 2 weeks after the start of therapy, and all patients taking rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia.

Rifampicin Urinary tract Acute interstitial nephritis has been reported after first-time daily rifampicin administration (17A ).

342 • A 61-year-old alcoholic developed non-oliguric rapidly progressive renal insufficiency 10 weeks after starting to take daily rifampicin, isoniazid, ethambutol, and pyrazinamide for pulmonary tuberculosis. There was proteinuria but a normal sediment. Renal biopsy showed acute interstitial nephritis. He improved when rifampicin was replaced by sparfloxacin.

Acute renal insufficiency is a well-recognized complication of “interrupted” or “intermittent” rifampicin therapy. It occurs as a hypersensitivity reaction mediated by rifampicindependent antibodies. Only 14 cases have been reported during continuous daily treatment. The pathology is an interstitial nephritis and rifampicin-dependent antibodies are absent. Drug interactions Rifampicin greatly increases the clearance of warfarin by inducing hepatic enzymes. Although this interaction has been recognized for a long time, difficulty in achieving an optimal INR despite an increase in the dose of warfarin has again been highlighted (18A ). A two- to three-fold increase in the dose of warfarin is recommended in the first week of rifampicin therapy and close monitoring is

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required during the initial weeks to achieve a therapeutic INR (19R ). Offset of the interaction may take as long as 4–5 weeks, during which the dose of warfarin should be reduced gradually to avoid a high INR and bleeding complications. In patients taking co-trimoxazole, rifampicin in a standard oral antituberculous regimen (600 mg/day plus isoniazid 300 mg/day and pyrazinamide 30 mg/kg for more than 12 days) reduced the steady-state AUC of trimethoprim and sulfamethoxazole by 47% and 23% respectively (20c ). The same authors had previously reported reduced efficacy of co-trimoxazole in the prevention of toxoplasmosis in HIVinfected subjects (21c ). The reduction in prophylactic efficiency was more pronounced in subjects who took a single double-strength tablet. There have been no reports on the risk of Pneumocystis carinii pneumonia in patients taking rifampicin plus co-trimoxazole prophylaxis. Until such time as more data are available, it is prudent to use double-strength co-trimoxazole tablets twice daily for prophylaxis of toxoplasmosis and Pneumocystis carinii pneumonia in patients taking concomitant rifampicin.

REFERENCES 1. Furin JJ, Mitnick CD, Shin SS, Bayona J, Becerra MC, Singler JM, Alcantara F, Castanieda C, Sanchez E, Acha J, Farmer PE, Kim JY. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001; 5: 648– 55. 2. Tahaoglu K, Torun T, Sevim T, Atac G, Kir A, Karasulu L, Ozmen I, Kapakli N. The treatment of multidrug resistant tuberculosis in Turkey. New Engl J Med 2001; 345: 170–4. 3. Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report. J Gastroenterol Hepatol 2001; 16: 1028–32. 4. Anonymous. Fatal and severe hepatitis associated with rifampicin and pyrazinamide for the treatment of latent tuberculosis infection—New York and Georgia, 2000. MMWR Morb Mortal Wkly Rep 2000; 50: 289–91. 5. Anonymous. Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations—United

States, 2001. MMWR Morb Mortal Wkly Rep 2001; 50: 733–5. 6. Tahaoglu K, Atac G, Sevim T, Torun T, Yazicioglu O, Horzum G, Gemci I, Ongel A, Kapakli, N, Aksoy E. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis 2001; 5: 65–9. 7. Roy B, Chowdhury A, Kundu S, Santra A, Dey B, Chakraborty M, Majumdar PP. Increased risk of anti-tuberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 “null” mutation. J Gastroenterol Hepatol 2001; 16: 1033– 7. 8. Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol 2001; 45: 420–34. 9. Benedetti-Bardet C, Guy C, Boudignat O, Regnier-Zerbib A, Ollagnier M. Effets indesirables de la Disulone® : resultants de l’enquete française de pharmacovigilance. Thérapie 2001; 56: 295–9. 10. Singla R, Gupta S, Gupta R, Arora VK. Efficacy and safety of sparfloxacin in combination with kanamycin and ethionamide in multidrug-resistant pulmonary tuberculosis patients: preliminary results. Int J Tuberc Lung Dis 2001; 5: 559–63.

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11. Stahlmann R, Lode H. Toxicity of quinolones. Drugs 1999; 58 Suppl 2: 37–42. 12. Pierfitte C, Royer RJ, Moore N, Begaud B. The link between sunshine and phototoxicity of sparfloxacin. Br J Clin Pharmacol 2000; 49: 609–12. 13. Stephenson I, Wiselka MJ, Qualie MJ. Acute pancreatitis induced by isoniazid in the treatment of tuberculosis. Am J Gastroenterol 2001; 96: 2271–2. 14. Panganiban LR, Makalinao IR, CortesMaramba NP. Rhabdomyolysis in isoniazid poisoning. Clin Toxicol 2001; 39: 143–51. 15. Hafner R, Bethel J, Standiford HC, Follansbee S, Cohn DL, Polk RE, Mole L, Raasch R, Kumar P, Mushatt D, Drusano G. Tolerance and pharmacokinetic interactions of rifabutin and azithromycin. Antimicrob Agents Chemother 2001; 45: 1572–7. 16. Rubinstein E. Comparative safety of the different macrolides. Int J Antimicrob Agents 2001; 18 Suppl 1: S71–6. 17. Bassilios N, Vantelon C, Baumelou A, Deray G. Continuous rifampicin administration inducing

343 acute renal failure. Nephrol Dial Transplant 2001; 16: 190–1. 18. Lee CR, Thrasher, KA. Difficulties in anticoagulation management during coadministration of warfarin and rifampicin. Pharmacotherapy 2001; 21: 1240–6. 19. Cropp JS, Bussey HI. A review of enzyme induction of warfarin metabolism with recommendations for patient management. Pharmacotherapy 1997; 17: 917–28. 20. Ribera E, Pou L, Fernandez-Sola A, Campos F, Lopez RM, Ocana I, Pahissa A. Rifampin reduces concentration of trimethoprim and sulfamethoxazole in serum in human immunodeficiency virusinfected patients. Antimicrob Agents Chemother 2001; 45: 3238–41. 21. Ribera EA, Fernandez-Sola A, Juste C, Rovira A, Romero FJ, Armadans-Gil L, Ruiz I, Ocana I, Pahissa A. Comparison of high and low doses of trimethoprim–sulfamethoxazole for primary prevention of toxoplasmic encephalitis in HIV-infected patients. Clin Infect Dis 1999; 29: 1461–6.

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Antihelminthic drugs

BENZIMIDAZOLES

(SED-14, 1030; SEDA-23, 327; SEDA-24, 356; SEDA-25, 367)

Albendazole, mebendazole, and thiabendazole Benzimidazoles and human neurocysticercosis The controversies in the management of neurocysticercosis have been described in an excellent review (1R ). Cysticercosis is caused by the larval stage of the pork tapeworm Tenia solium. Neurocysticercosis is the most severe and common clinical manifestation and probably the most frequent parasitic infection of the central nervous system. Tenia solium is endemic in Latin America, Asia, and sub-Saharan Africa. However, the management of neurological complications of cysticercosis and particularly the role of antiparasitic drugs remain issues of debate. It is commonly believed that the use of antiparasitic drugs and corticosteroids should be individualized based on the presence of active or inactive disease, location of the cysts, and the presence or absence of complications such as hydrocephalus. Albendazole is an excellent alternative to praziquantel in the treatment of cysticercal brain cysts. It is usually well absorbed and well tolerated and albendazole serum concentrations are not significantly affected by corticosteroids or anticonvulsant drugs. A fatty meal improves the absorption of albendazole. In initial studies, albendazole was given in daily doses of 15 mg/kg for 30 days. Further studies, however, showed that a treatment course could be shortened from 30 to 8 days without affecting efficacy. In direct comparative trials albendazole has been more effective in destroying parenchymal brain cysts than praziquantel. Albendazole is possibly more effective in treating © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

344

subarachnoid, ventricular, and spinal forms of cysticercosis, and frequently obviates the need for surgery. Benzimidazoles and filariasis Encephalopathy is an adverse event related to the treatment of Loa loa with diethylcarbamazine or ivermectin, and it has now also been related to albendazole (2A ). • A 55-year-old woman from Cameroon took oral albendazole 200 mg bd for a symptomatic Loa loa infection with microfilaremia of 152 microfilariae/ml and a Mansonella perstans infection of 133 microfilariae/ml. Three days after the start of therapy she developed an encephalopathy. Albendazole was withdrawn and she recovered without any specific treatment within the next 16 hours. On day 4, the Loa loa microfilarial count was 29 microfilariae/ml.

The clinical presentation, the interval after starting treatment, the evolution of the episode, and the results of cerebral spinal fluid analysis and EEG findings in this case were similar to those seen in cases of encephalopathy following Loa loa treatment with ivermectin or diethylcarbamazine. However, pre-treatment filaremia was relatively low and Loa loa microfilariae were not detectable in the cerebral spinal fluid. Thus, pre-existing conditions might increase the susceptibility to encephalopathy. Benzimidazoles and hookworms In 13 British soldiers with cutaneous larva migrans after a 2-week jungle training exercise in Belize the median incubation period was 10 (range 4– 38) days; in 12 there were skin lesions on the calves or shins, and only two had foot or ankle lesions (3A ). Ten received oral thiabendazole, one oral mebendazole, one oral albendazole, and one topical thiabendazole. All those treated with oral thiabendazole complained of unpleasant reactions, predominantly nausea, vomiting, and dizziness. The one patient treated with topical thiabendazole returned with a new lesion 12 months later. He was then treated with systemic

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albendazole, with rapid resolution of symptoms. A 45-year-old woman developed larva migrans 20 days after lying on a beach in Singapore and was treated with thiabendazole 50 mg/kg in two doses for one day; she had no adverse effects (4A ). The treatment of cutaneous larva migrans in 56 Italian patients aged 2–60 years has been retrospectively reviewed (5c ). All 13 patients treated with cryotherapy reported that it was painful, but none had recurrent disease or scarring. A further six patients were treated with oral thiabendazole 25–50 mg/kg/day for 2 days, and one had both thiabendazole and cryotherapy. In all cases there was regression of itching and skin lesions, but they had nausea, diarrhea, and dizziness while taking oral thiabendazole. No adverse effects were reported in 36 patients who were treated with albendazole 400 mg/day for 3 days (two were also treated with cryotherapy). Despite the low dose, larval migration was stopped in 1–2 days. Although a prompt and definitive cure was achieved in all 56 patients, albendazole was considered the treatment of choice given its minimal adverse effects.

carcinoembryonic antigen (CEA) and alphafetoprotein (AFP) were measured to monitor treatment efficacy. One other patient with a neuroendocrine cancer and a mesothelioma was treated on a compassionate basis and only monitored for adverse effects. Albendazole was given orally in a dose of 10 mg/kg/day in two divided doses for 28 days. Albendazole reduced CEA in two patients and in the other five patients with measurable tumor markers, serum CEA or AFP was stabilized in three. In the seven patients who completed this pilot study, albendazole was well tolerated and there were no significant changes in any hematological, kidney, or liver function tests. However, three patients were withdrawn because of severe neutropenia, which resulted in the death of one. Neutropenia was more frequent than is usually experienced in the treatment of hydatid disease. The authors speculated that this may relate to reduced metabolism in patients with liver cancer or liver metastases, leading to the passage of unmetabolized drug into the circulation.

Benzimidazoles and round worms The efficacy of albendazole plus prednisolone has been studied in five patients aged 11–72 years with ocular toxocariasis (6c ). All had uveitis and retinochoroidal granulomas. Their symptoms had persisted for a mean of 14 months (range 3 days to 24 months). The adults were treated with albendazole 800 mg bd for 2 weeks plus prednisolone starting at 1.5 mg/kg/day tapering over 3 months. The children were treated with 400 mg bd for 2 weeks plus prednisolone 1.0 mg/kg/day. All tolerated the therapy well without adverse effects. In particular, there were no significant hypersensitivity reactions to dying Toxocara larvae. The uveitis resolved in all cases and there were no relapses. After treatment, all the granulomas had disappeared, leaving heavily pigmented chorioretinal scars without loss of vision.

Diethylcarbamazine

Benzimidazoles and advanced malignancy The efficacy of albendazole has been evaluated in a few patients with either hepatocellular carcinoma (n = 1) or colorectal cancer and hepatic metastases refractory to other forms of treatment (n = 8) (7c ). Apart from hematological and biochemical indices, the tumor markers

(SED-14, 1034; SEDA-24, 357; SEDA-25, 368) Diethylcarbamazine is a microfilaricidal drug with potential macrofilaricidal properties, widely used, in particular for Loa loa infections and lymphatic filariasis. However, it can be associated with significant systemic adverse effects, such as fever, headache, and myalgia, which can compromise compliance. It is commonly believed that adverse reactions to diethylcarbamazine are the result of proinflammatory responses to antigens released from killed microfilariae, rather than through direct drug or metabolite toxicity. Diethylcarbamazine and lymphatic filariasis In 15 Indonesian patients with Brugia malayi infection, the release of Wolbachia bacteria was studied in relation to adverse events after diethylcarbamazine treatment (6 mg/kg orally for 12 days) (8c ). Three patients had severe reactions and six patients had moderate reactions. In all samples from the three patients with severe reactions and in one of the six with moderate reactions, Wolbachia PCR products were

346 detected from 4 hours after treatment, and persisted for 8–20 hours. These data suggest that release of Wolbachia bacteria into the blood may be associated with severe inflammatory reactions after diethylcarbamazine. Adverse reactions associated with increases in proinflammatory cytokines have also been reported in bancroftian filariasis and onchocerciasis, suggesting that similar events can also occur in these filarial infections.

Ivermectin

(SED-14, 1035; SEDA-23, 328; SEDA-24, 357; SEDA-25, 370) Ivermectin, a dihydroavermectin B1, is an effective microfilaricide used in the treatment of strongyloides, scabies, and all types of filariasis except Dipalonema perstans infections. Its mode of action, recently reviewed (SEDA25, 370), has tentatively been identified as an agonist action at GABA receptors, inhibiting channels that control specific nerve cell connections. The functioning of chloride ion channels should thus be altered in most organisms, leading to paralysis and death of parasites. Another mechanism of action involves the binding of ivermectin to P glycoprotein. Ivermectin and scabies In a randomized trial a single oral dose of ivermectin (200 µg/kg) has been compared with 1% lindane lotion for topical application overnight in 200 patients with scabies (9C ). The patients were assessed after 48 hours, 2 weeks, and 4 weeks. After 4 weeks, 83% showed marked improvement with ivermectin, compared with 44.4% of those treated with lindane. There were no adverse events reported with lindane. Headache was reported only once with ivermectin. Ivermectin and lymphatic filariasis Earlystage elephantiasis caused by bancroftian filariasis in a 27-year-old traveller was treated with a single-dose oral combination of ivermectin 24 mg plus 400 albendazole mg, followed by albendazole 800 mg for 21 days (10A ). To avoid a severe Mazotti-like reaction, he was given oral steroids and antihistamines for 3 days. He had a transient rash, pruritus, and mild hypotension on the days after the initial treatment, but

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otherwise remained well and the swelling subsided. Within 1 month he was free of symptoms. At the last follow-up examination, 3 years after treatment, there no clinical or laboratory evidence of relapse. The authors thought that this type of treatment should be evaluated on a wider scale, given the minimal adverse events and apparent therapeutic efficacy. The efficacy of annual mass chemotherapy with a combination of diethylcarbamazine and ivermectin on bancroftian filariasis in rural southern India has been studied, as has the supplementary role of controlling the vector mosquito Culex quinquefasciatus (11C ). Nine villages, topographically and ecologically similar but reasonably isolated from each other, were selected and split into three comparable groups of three villages each. Group A received chemotherapy with diethylcarbamazine at about 6 mg/kg and ivermectin at 400 µg/kg. Group B received chemotherapy and vector control. The most important vector-breeding sites were soakage pits, which were treated with expanded polystyrene beads. Minor vectorbreeding sources, such as domestic or irrigation wells, were treated by adding larvae-eating Tilapia fish or a commercial insecticide based on Bacillus sphaericus. Group C received no intervention. After the first round of treatment, combination chemotherapy alone caused a 60% drop in the annual filarial transmission potential, whereas the combined strategy reduced the transmission potential by 96%. After two rounds of treatment, the reduction in transmission potential was similar with the two strategies (about 91–96% reduction), whereas the prevalence of microfilaremia was reduced by 88–92%. Adverse events after combination therapy were reported in 20% of those who had taken diethylcarbamazine and ivermectin for the first time. The patients with adverse events had increased microfilarial counts. The most common adverse effects were headache (72% of adverse events), giddiness (67%), fever, and weakness. The incidence of adverse events among those taking combination therapy for a second time was relatively low (5.5%). The adverse events were also less severe in the second round than in the first. When antifilarial treatment was withdrawn in the third and final year of the study, transmission was resumed in the absence of vector control, whereas no infective female mosquitoes were detected in

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villages with vector control. Vector control, although obviously not cost-effective in the short term, could therefore play an important supplementary role in an integrated program, by preventing re-establishment of transmission after chemotherapy has been completed.

Levamisole

(SED-14, 1037; SEDA-23, 330; SEDA-24, 358; SEDA-25, 372) Levamisole was originally developed as an antihelminthic drug, but is nowadays mainly used as an immunomodulating drug in adjuvant therapy for colon cancer, usually in combination with 5-fluorouracil. It is also used in other conditions, including nephrotic syndrome, and in some infections, such as pediculosis. Nervous system A 3-year-old girl who took levamisole 100 mg bd for 3 days for anorexia suddenly developed hyperkinesia, paresthesia, fidgetiness, an unstable gait, and frequent falling (12A ). An MRI scan of the brain did not show any demyelinating changes. She recovered fully within 48 hours without any specific intervention. The authors suggested that levamisole overdose had contributed to the profound encephalitis-like effects. Levamisole and pediculosis In 28 patients with pediculosis capitis (aged 7–12 years) levamisole was given in a dose of 3.5 mg/kg for 10 days (13c ). On the 11th day meticulous hair examination showed that 23 patients had responded to treatment, and 18 had complete responses. There were no adverse reactions. Levamisole and warts In 44 patients with multiple recalcitrant warts randomized to either oral cimetidine 30 mg/kg/day in three doses for 12 weeks or 30 mg/kg/day for 12 weeks plus levamisole 2.5 mg/kg on 2 days per week, cimetidine plus levamisole produced significant improvement (14c ). Complete clearance was obtained in 32% of patients who took cimetidine and 65% of those who took cimetidine plus levamisole. Adverse effects of levamisole were infrequent, except for a metallic taste in one patient and nausea in two. In one patient the nausea was severe enough to necessitate withdrawal. There were no significant changes in leukocyte count or differential counts.

347 Levamisole and colorectal cancer The efficacy of levamisole has been studied in several studies of patients with colorectal carcinoma (15C –17C ). In a phase III trial 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation have been compared in patients with residual, nonmeasurable, intra-abdominal metastases after resection of colorectal carcinoma (15C ). Overall, 229 patients with no hepatic metastases (group A) were randomized to receive 5fluorouracil (n = 116) or 5-fluorouracil with levamisole (n = 113). In addition, 168 patients with hepatic metastases (group B) received 5fluorouracil alone (n = 60), 5-fluorouracil with levamisole (n = 54), or 5-fluorouracil and hepatic irradiation (n = 54). In group A median survival was virtually similar in both treatment arms at about 15 months. In group B the median survival rates in the three treatment arms were similar at 14–17 months. The adverse effects were as expected with each regimen, and there were no differences between any of the treatments. The main adverse effects were hematological and gastrointestinal. However, analysis of life-threatening adverse effects showed some slight differences: there were fewer than expected in the 5-fluorouracil alone group, and more than expected in the 5-fluorouracil plus hepatic irradiation group. There was no treatment advantage for any of the combinations over 5-fluorouracil alone. QUASAR was a study of the effects of a higher dose of leucovorin or the addition of levamisole to 5-fluorouracil and leucovorin on survival in 4927 patients with colorectal cancer with no evidence of residual disease after resection (16C ). High-dose leucovorin was not associated with a survival or recurrence benefit compared with low-dose leucovorin. The addition of levamisole had no apparent survival benefit compared with placebo, with slightly more deaths in patients assigned to levamisole than placebo. Tumor recurrences were also higher in those who took levamisole. Dermatological adverse effects were significantly more frequent in those who took levamisole compared with placebo. In 680 patients with curatively resected stage III colon cancer, adjuvant treatment with 5-fluorouracil plus leucovorin was significantly more effective than 5-fluorouracil plus levamisole in reducing tumor relapse and

348 improving survival (17C ). There were fewer adverse effects in those given 5-fluorouracil plus levamisole compared with 5-fluorouracil plus leucovorin (820 vs. 1190); the difference was mainly due to gastrointestinal toxicity. Only a few patients developed grade 3 or grade 4 adverse effects. There were no treatment-related deaths in either group. Levamisole and head and neck carcinoma In 63 patients with stage III and stage IV squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx, with no distant metastases, randomized to either adjuvant oral chemotherapy with futraful, uracil, and levamisole (n = 29) or no treatment (n = 34), oral chemotherapy showed a trend of better control of distant tumor recurrence (18c ). However, there was no statistically significant improvement in overall long-term survival. Of the 29 patients who received adjuvant oral chemotherapy, 17 finished the 1-year course without withdrawing. In nine patients futraful, uracil, and levamisole was withdrawn because of local, regional, or distant metastases. Three patients withdrew after 4 months because of vomiting and mucositis. One developed a mild gastric upset and completed the course. There were no major hematological or nephrotoxic adverse effects. Levamisole and the nephrotic syndrome Levamisole is also used in the treatment of rheumatic disease and in nephrotic syndrome in children as a steroid-sparing drug. In a retrospective analysis in 51 children with steroiddependent nephrotic syndrome, the ability of levamisole to reduce the relapse rate and to spare prednisone therapy was compared with that of cyclophosphamide (19c ). There were no significant differences in efficacy between levamisole and cyclophosphamide: in the levamisole group the mean relapse rate was lowered by 0.28 relapses/patient/month and the mean cumulative dose of prednisone was reduced by 336 mg/m2 /month compared with 0.32 relapses/patient/month and 387mg/m2 / month in the cyclophosphamide group. Apart from one patient who had a spontaneously resolving skin rash with levamisole and three patients who had transient neutropenia with cyclophosphamide, there were no other clinically significant adverse effects.

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Levamisole and aphthous ulcers The value of levamisole in the treatment of recurrent oral aphthous ulcers has been reviewed (20R ). In four of seven placebo-controlled studies there was a reduction in the frequency and duration of aphthous ulcers during levamisole treatment. Efficacy did not differ whether levamisole was given routinely or started at the first sign of ulcers. In most patients levamisole was well tolerated. Of 128 patients who took levamisole, two withdrew as result of adverse effects (nausea and flu-like symptoms). The most frequent adverse effects were dysgeusia (21%) and nausea (16%). The other adverse effects occurred in less than 10% of the patients and included dysosmia, headaches, diarrhea, flu-like symptoms, and rash, but not all may have been due to levamisole.

Myrrh Myrrh is an oleo gum resin obtained from the stem of Commiphora molmol, a tree that grows in north-east Africa and the Arabian Peninsula. In mice, myrrh showed no mutagenic effects and was a potent cytotoxic drug against solid tumor cells (21E ). The antitumor potential of C. molmol was comparable with that of cyclophosphamide. Studies in hamsters suggested an anti-schistosomal activity of myrrh (22c ). Myrrh and schistosomiasis The efficacy and adverse effects of myrrh and the most effective dosage schedule have been studied in 204 (169 men and 35 women) patients with schistosomiasis aged 12–68 years and 20 healthy noninfected age- and sex-matched volunteers (22c ). The patients were divided into two groups: 86 patients with schistosomal colitis and 118 with hepatosplenic schistosomiasis, further divided into two subgroups—77 patients with compensated disease and 41 with decompensated disease. All but 12 had received one or more courses of praziquantel. The dosage of myrrh was 10 mg/kg/day for 3 days on an empty stomach 1 hour before breakfast. A second course of 10 mg/kg/day for 6 days was given to patients who still had living ova in rectal or colonic biopsy specimens. The response rate to a single course of myrrh was 92% in 187 patients. The cure rates were 91%, 94%,

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and 90% in patients with schistosomal colitis, compensated hepatosplenic schistosomiasis and decompensated hepatosplenic schistosomiasis respectively. The cure rate was less in patients who had previously taken praziquantel and in patients with impaired liver function. S. hematobium infection was the most responsive (n = 4, cure rate 100%), followed by mixed infections (n = 29, cure rate 93%). Those infected with S. mansoni had the lowest cure rate (n = 171, cure rate 91%). There was no impairment of liver function after treatment with myrrh. In contrast, liver function tests significantly improved in patients with impaired liver function. There were no significant effects of myrrh on the electrocardiogram. Adverse effects of myrrh were reported in 24 of the 204 patients. Giddiness, somnolence, or mild fatigue were the most common (2.5%), and all other adverse effects were minor and less frequent. None of the healthy volunteers reported any adverse effects, nor were there any significant changes in liver or kidney function. A second course of myrrh resulted in a cure in 13 of the 17 patients who did not respond to a single course. Myrrh and fascioliasis The efficacy of myrrh has been studied in seven patients aged 10–41 years (five men, two women) with fascioliasis and 10 age- and sex-matched healthy volunteers (23c ). Myrrh was given orally in the morning on an empty stomach in a dosage of 12 mg/kg/day for 6 days. All the patients were passing Fasciola eggs in their stools (mean 36 eggs per gram of stool). The symptoms and signs of fascioliasis resolved during treatment with myrrh, and Fasciola eggs could not be demonstrated in the stools 3 weeks and 3 months after treatment. Anti-fasciola antibody titers became negative in six of the seven patients. There were no adverse effects.

Praziquantel

(SED-14, 1041; SEDA-24, 360; SEDA-25, 372) Drug interactions Praziquantel is well absorbed after oral administration and undergoes extensive first-pass metabolism, especially when it is given simultaneously with corticosteroids and anticonvulsants (1R ). Cimetidine

349 (20 mg/kg/day in three doses) significantly increases praziquantel serum concentrations by inhibiting its first-pass metabolism. Serum praziquantel concentrations increase when a carbohydrate-rich diet is administered (1R ). Praziquantel and neurocysticercosis Recently, the management of neurocysticercosis has been reviewed in detail (1R ). Praziquantel is effective in human cysticercosis in doses of 10–100 mg/kg for 3–21 days. Initially, longer courses of praziquantel were advocated, but even shorter treatment regimens are equally effective: a complete course can be administered in a single day with comparable efficacy as conventional therapy of 15 days. The most common adverse events of praziquantel result from the host’s inflammatory response to dying cysticerci. Fever, headache, meningism, and exacerbation of neurological symptoms have all been noted. The simultaneous use of corticosteroids with cysticidal drugs is an important aspect of drug treatment in neurocysticercosis, recommended to avoid the secondary effects of treatment due to destruction of parasites within the brain parenchyma. However, these reactions are usually mild and transient and can be ameliorated with analgesics or antiemetics, thus questioning the need for corticosteroids in every case. The use of corticosteroids is currently indicated for patients who develop intracranial hypertension during treatment with cysticidal drugs. This may be anticipated in patients with a massive parasitic load. Both albendazole and praziquantel can exacerbate the syndrome of intracranial hypertension observed in patients with cysticercotic encephalitis, and are contraindicated during the acute phase of the disease (1R ). In patients with mixed forms of neurocysticercosis, including hydrocephalus and parenchymal brain cysts, cysticidal drugs can only be used after prior ventricular shunt placement to avoid a further increase in intracranial pressure after treatment. Failure of one-day praziquantel treatment in patients with multiple neurocysticercosis lesions has recently been described (24c ). Praziquantel was given in three doses of 25 mg/kg at 2-hour intervals in eight patients (two men, six women, aged 22–53 years). Of five patients with a single brain cyst, three had complete resolution of the lesion on CT scan. The other

350 two had partial resolution, leaving enhancing lesions. Conversely, no cyst disappeared in patients with multiple brain cysts. Two other patients with multiple cysts were treated with praziquantel for 1 day but had to be excluded from the analysis because of an already degenerating lesion on the pre-treatment CT scan. Praziquantel was associated with adverse effects in five patients (mild headache in five, dizziness in two, nausea in two, and vomiting in one). All adverse effects remitted with analgesics or dexamethasone 0.2 mg/kg/day and continued for 2 days. Praziquantel and paragonimiasis Paragonimiasis is a food-borne parasitic disease common in Southeast Asia, especially in Japan, Korea, The Philippines, Taiwan, and parts of China. In Japan, paragonimiasis is caused by either Paragonimus westermani or Paragonimus miyazakii. In a recent study the radiological features and treatment of paragonimiasis were described in 13 patients (10 men, three women, aged 25–77 years) (25c ). All were treated with praziquantel 75 mg/kg/day for 2–3 days. One patient with empyema was also given bithionol. There was mild urticaria in two patients and no serious adverse effects.

Suramin (SED-14, 1042; SEDA-23, 332; SEDA-24, 361; SEDA-25, 373) Suramin and hormone-refractory metastatic prostate cancer Because of serious toxicity suramin is rarely used nowadays as a macrofilaricidal drug for the treatment of onchocerciasis or for the treatment of African trypanosomiasis. However, its potential anti-tumor effects have renewed interest in suramin, in particular in the treatment of hormone-refractory prostate cancer. The treatment of hormone refractory prostate cancer has been discussed in an excellent review (26R ). There are differences of opinion about the relative merits of suramin. In initial studies it had some activity against hormone-refractory prostate cancer. However, these studies may have overestimated its antitumor activity, since it inhibits the release of prostate-specific antigen, despite disease progression. It also suppresses adrenocortical function and is there-

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fore usually given in conjunction with corticosteroids. The concomitant use of corticosteroids and anti-androgen withdrawal usually make it difficult to establish the true response to suramin. Suramin had only minimal activity in patients with measurable disease who received it only after documented progression following withdrawal of anti-androgens and corticosteroids. At best, treatment with suramin may provide modest pain palliation, but with no overall impact on the quality of life. In contrast, it has an impressive range of adverse effects, including a Guillain–Barré type of sensory–motor polyneuropathy. In most patients suramin had to be withdrawn because of dose-limiting toxicity, primarily a syndrome of fatigue, malaise, and lethargy. In 50 patients with hormone-refractory prostate cancer, fixed-dose suramin plus hydrocortisone had a better tolerance profile (27c ). Suramin was initially given as a 30-minute test infusion of 200 mg. In the absence of hypersensitivity reactions, additional 24-hour intravenous infusions of 500 mg/m2 were given daily for the next 5 days. Thereafter, 2-hour intravenous infusions (350 mg/m2 ) were given weekly on a out-patient basis for 12 weeks or until disease progression. The median duration of response was 16 weeks and the median time to disease progression 13 weeks. Fatigue and lymphopenia were the most commonly reported adverse effects, in 27 patients (54%) and 39 patients (78%) respectively. Skin rash occurred in 12 patients (24%). Suramin was withdrawn in three patients because of acute renal insufficiency (two patients) and Stevens–Johnson syndrome (one patient). In 13 men with advanced hormone-refractory prostate cancer the interaction between suramin and warfarin was studied because of potential worries that suramin may affect blood coagulation (28c ). After initial stabilization to an International Normalized Ratio (INR) of about 2.0 suramin plus hydrocortisone was started, after which warfarin requirements fell by 0.50– 0.78 mg/day. The difference did not reach statistical significance. There were no bleeding problems. These results suggest that suramin and warfarin can be safely co-administered, provided that coagulation status is monitored. Suramin and recurrent high-grade glioma The efficacy, toxicity, and pharmacology of

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suramin have been studied in 12 patients with recurrent or progressive recurrent high-grade gliomas aged 26–67 years (29c ). Suramin was given in doses similar to those used in patients with hormone-refractory prostate cancer. Treatment-related adverse effects were usually mild and reversible. Three patients developed transient grade 3–4 toxicity (leukopenia, a rise in serum creatinine, and diarrhea). There was no coagulopathy or central nervous system bleeding. All patients reached target suramin concentrations. The pharmacology of suramin was not affected by anticonvulsant therapy. Median time to progression was 55 days (range 17–242) and median survival was 191 days (range 42–811). There were no partial or complete remissions at 12 weeks. However, the clinical outcome in three patients suggested that effect of suramin may be delayed. One patient who progressed after 12 weeks had a subsequent marked reduction in tumor size and maintained an excellent partial response for over 2 years without other therapy. The two others

351 had disease stabilization and lived for 16 and 27 months respectively. Based on these observations, suramin and radiotherapy are now being used concurrently in patients with newly diagnosed glioblastoma multiforme to study survival as the primary outcome. Suramin and advanced renal cell carcinoma In a phase II study suramin was given in a fixed dose plus hydrocortisone to 22 patients (19 men, 3 women, aged 30–74 years) with advanced renal cell carcinoma (30c ). There were no treatment responses. The median survival time was 10 months. Three patients had grade 4 toxicity (hypersensitivity, urethral obstruction, hypotension, and neutropenic sepsis). Eleven developed grade 3 toxicity, mainly abdominal pain, anemia, diarrhea, erythema, dyspnea, fatigue, and fever. The authors concluded that suramin has no significant activity in advanced renal cell carcinoma.

REFERENCES 1. Garg RK. Medical management of neurocysticercosis. Neurol India 2001; 49: 329–37. 2. Blum J, Wiestner A, Fuhr P, Hatz C. Encephalopathy following Loa Loa treatment with albendazole. Acta Trop 2001; 78: 63–5. 3. Green AD, Mason C, Spragg PM. Outbreak of cutaneous larva migrans among British military personnel in Belize. J Travel Med 2001; 8: 267–9. 4. Gourgiotou K, Nicalaidou E, Panagiotopoulos A, Hatziolou E, Katsambas AD. Treatment of widespread cutaneous larva migrans with thiabendazole. J Eur Acad Dermatol Venereol 2001; 15: 578–80. 5. Albanese G, Venturi C, Galbiati G. Treatment of larva migrans cutanea (creeping eruption): a comparison between albendazole and traditional therapy. Int J Dermatol 2001; 40: 67–71. 6. Barisani-Asenbauer T, Maca SM, Hauff W, Kaminski SL, Domanovits H, Theyer I, Auer H. Treatment of ocular toxocariasis with albendazole. J Ocul Pharmacol Ther 2001; 17: 287–94. 7. Morris DL, Jourdan JL, Pourgholami MH. Pilot study of albendazole in patients with advanced malignancy. Oncology 2001; 61: 42–6. 8. Cross HF, Haarbrink M, Egerton G, Yazdanbaksh M, Taylor MJ. Severe reactions to filarial chemotherapy and release of Wolbachia endosymbionts into blood. Lancet 2001; 358: 1873–5. 9. Madan V, Jaskiran K, Gupta U, Gupta DK. Oral ivermectin in scabies patients: a comparison with

1% topical lindane lotion. J Dermatol 2001; 28: 481–4. 10. Grobusch MP, Goebels K, Teichmann D, Bergmann F, Suttorp N. Early-stage elephantiasis in bancroftian filariasis. Eur J Clin Microbiol Infect Dis 2001; 20: 835–6. 11. Reuben R, Rajendran R, Sunish IP, Mani TR, Tewari SC, Hiriyan J, Gajanana A. Annual singledose diethylcarbamazine plus ivermectin for control of bancroftian filariasis: comparative efficacy with and without vector control. Ann Trop Med Parasitol 2001; 95: 361–78. 12. Dubey AK, Gupta RK, Sharma RK. Levamisole induced ataxia. Indian Pediatr 2001; 38: 417–19. 13. Namazi MR. Levamisole: a safe and economical weapon against pediculosis. Int J Dermatol 2001; 40: 292–4. 14. Parsad D, Pandhi R, Juneja A, Negi KS. Cimetidine and levamisole versus cimetidine alone for recalcitrant warts in children. Pediatr Dermatol 2001; 18: 349–52. 15. Witte RS, Cnaan A, Mansour EG, Barylak E, Harris JE, Schutt AJ. Comparison of 5fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma. Cancer 2001; 91: 1020–8.

352 16. Kerr DJ. A United Kingdom Coordinating Committee on Cancer Research study of adjuvant chemotherapy for colorectal cancer: preliminary results. Semin Oncol 2001; 28: 31–4. 17. Porschen R, Bermann A, Loffler T, Haack G, Rettig K, Anger Y, Strohmeyer G, for the Arbeitsgemeinschaft Gastrointestinale Onkologie. Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: Results of the trial adjCCA-01. J Clin Oncol 2001; 19: 1787–94. 18. Lam P, Yuen APW, Ho CM, Ho WK, Wei WI. Prospective randomized study of post-operative chemotherapy with levamisole and UFT for head and neck carcinoma. Eur J Surg Oncol 2001; 27: 750–3. 19. Alsaran K, Grisaru S, Stephens D, Arbus G. Levamisole vs. cyclophosphamide for frequentlyrelapsing steroid-dependent nephritic syndrome. Clin Nephrol 2001; 56: 289–94. 20. Barrons RW. Treatment strategies for recurrent oral aphthous ulcers. Am J Health-Syst Pharm 2001; 58: 41–53. 21. Al Harbi MM, Qureshi S, Ahmed MM, Rafatulla S, Shah AH. Effect of Commiphora molmol (oleogum-resin) on the cytological and biochemical changes induced by cyclophosphamide in mice. Am J Chin Med 1994; 22: 77–82. 22. Sheir Z, Nasr AA, Massoud A, Salama O, Badra GA, El Shennawy H, Hassan N, Hammad SM. A safe, effective, herbal antischistosomal therapy derived from myrrh. Am J Trop Med Hyg 2001; 65: 700–4. 23. Massoud A, El Sisi S, Salama O, Massoud A. Preliminary study of therapeutic efficacy of a new

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fasciolicidal drug derived from Commiphora molmol (myrrh). Am J Trop Med Hyg 2001; 65: 96–9. 24. Pretell EJ, Garcia HH, Gilman RH, Saavedra H, Martinez M, for the Cysticercosis Working Group in Peru. Failure of one-day praziquantel treatment in patients with multiple neurocysticercosis lesions. Clin Neurol Neurosurg 2001; 103: 175–7. 25. Mukae H, Taniguchi H, Matsumoto N, Iiboshi H, Ashitani JI, Matsukura S, Nawa Y. Clinicoradiologic features of pleuropulmonary Paragonimus westermani on Kyusyu Island, Japan. Chest 2001; 120: 514–20. 26. Knox JJ, Moore MJ. Treatment of hormone refractory prostate cancer. Semin Urol Oncol 2001; 19: 202–11. 27. Calvo E, Cortes J, Rodriguez J, Sureda M, Beltran C, Rebollo J, Martinez-Monge R, Berian JM, De Irala J, Brugaroles A. Fixed higher dose schedule of suramin plus hydrocortisone in patients with hormone refractory prostate carcinoma. Cancer 2001; 92: 2435–43. 28. Meyer M, Jeong E, Bolinger B, Chen L, Lenehan P, Slichenmyer W, Natale RB. Phase I drug interaction study of suramin and warfarin in patients with prostate cancer. Am J Clin Oncol 2001; 24: 167–71. 29. Grossman SA, Phuphanich S, Lesser G, Rozental J, Grachow LB, Fisher J, Piantadosi S. Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas. J Clin Oncol 2001; 19: 3260–6. 30. Schroder LE, Lew D, Flanigan RC, Eisenberger MA, Seay TE, Hammond N, Needles BM, Crawford ED. Phase II evaluation of suramin in advanced renal cell carcinoma. A Southwest Oncology Group study. Urol Oncol 2001; 145–8.

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Vaccines

Editor’s note: Abbreviations used in this chapter include: • • • • • • • • • • • • • •

BCG: Bacillus Calmette–Guérin DT: Diphtheria + tetanus toxoids (childhood formulation) DTaP: Diphtheria + tetanus toxoids + acellular pertussis DTP: Diphtheria + tetanus toxoids + pertussis DTP-Hib: Diphtheria + tetanus toxoids + whole cell pertussis + Hemophilus influenzae type b DTP-IPV: Diphtheria + tetanus toxoids + whole cell pertussis + inactivated poliovaccine DTwP: Diphtheria + tetanus toxoids + whole cell pertussis HB: Hepatitis B Hib: Hemophilus influenzae type b IPV: inactivated poliovaccine MMR: measles + mumps + rubella OspA: Borrelia burgdorferi outer surface protein A RRV-TV: tetravalent rhesus-based rotavirus vaccine, Rotashield Td: Diphtheria + tetanus toxoids (adult formulation)

Surveillance of adverse events following immunization (AEFI) Perspectives on pre-licensure trials The recent withdrawal of tetravalent rhesus-based rotavirus vaccine from the market illustrates an important problem regarding pre-licensure testing and its ability to identify rare vaccinerelated adverse events. A sample size of 10 000 volunteers may provide excellent estimates of reactogenicity (local and systemic reactions) and efficacy but be inadequate as a denominator for ruling out rare adverse events. Table 1 shows how trial size determines the ability to detect frequent and rare events. Plans for future large pre-licensure trials, e.g. for newly developed rotavirus vaccines, therefore include 10 000–60 000 volunteers. These large trials can be seen as a bridge between prelicensure and improved post-licensure surveillance (1R , 2R ). © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Table 1. Sample size necessary to have 80% power to detect an increase in the risk of a rare event Background rate

Detectable relative risk

Total study population required (1 : 1 randomization)

1 : 100 1 : 100 1 : 1000 1 : 1000 1 : 10 000 1 : 10 000

5.0 2.0 5.0 2.0 5.0 2.0

1443 5916 14 428 59 160 144 280 591 600

Improving monitoring of vaccine safety through post-licensure studies Gaps in current vaccine safety monitoring methods have been analysed and the needs for improvements outlined (3R , 4R ). The well-known limitations associated with pre-licensure trials have led to the expectation that post-licensure studies would address safety issues better. To meet this expectation, steps that should be taken include bar-code labelling of vaccines to improve the accuracy and completeness of information about administered vaccines, establishing immunization registers to provide numerator data,

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developing generally agreed case definitions for adverse events following immunization (AEFI), to allow comparability between studies, to facilitate long-term follow-up, and to do linked database studies. Only by investing in vaccine safety infrastructure will the high expectations of post-licensure studies be met. Improved case definitions The so-called Brighton Collaboration, which was initiated in 1999 during a vaccine meeting in Brighton, UK, took into consideration the fact that there is a general lack of widely accepted and implemented case definitions in order to allow comparability between studies. Based on a network of more than 300 participants from 34 countries and collaborating with many national and international organizations, institutions, and manufacturers (e.g. WHO, FDA, CDC, GlaxoSmithKline), case definitions and guidelines have been developed for intussusception, fever, prolonged crying, seizure, hypotonic– hyporesponsive episodes, and local reactions, such as nodules, swelling, cellulitis, and abscesses. A “Brighton” Internet site has been created (5R ). Passive surveillance and reported fatalities The fatalities reported to the federally administered (US) Vaccine Adverse Event Reporting System (VAERS, described in SED-14, 1049) have been examined (6C ). A total of 1266 deaths were reported to VAERS between July 1990 and June 1997. Table 2 shows the numbers of deaths by age, and Table 3 shows the causes of death. Nearly half of the deaths were attributed to sudden infant death syndrome (SIDS). Since 1992/3, the trend of decreasing numbers of reported deaths follows that observed for SIDS overall in the US general population following Table 2. Deaths related in time to immunization reported to VAERS 1990–1997, by age Age (years)

N (%)

Overall <1 1–4 5–9 10–17 18–45 46–64 ≥ 65

1199 (100) 808 (67.4) 117 (9.8) 18 (1.5) 17 (1.4) 43 (3.6) 55 (4.6) 141 (11.7)

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Table 3. Causes of death related in time to immunization reported to VAERS 1990–1997 Causes of death

N (%)

Overall SIDS Congenital Infectious Neoplastic Other∗ Unknown

1244 (100) 592 (47.6) 38 (3.1) 164 (13.2) 15 (1.2) 261 (21.0) 174 (14.0)

∗ The category “other” contained cases such as heart failure, Guillain–Barré syndrome, dehydration, asphyxia, asthma, diabetes, stroke, hyperthermia, intussusception, aspiration, and trauma.

implementation of the “Back to Sleep” program. Therefore, the VAERS data support the findings of controlled studies that show that the association between infant immunization and SIDS is coincidental and not causal.

Bioterrorism and prevention through immunization Anthrax vaccine (SEDA-23, 336; SEDA-25, 378) Anthrax continues to be a significant threat as a biological weapon for use in both military and domestic acts of bioterrorism. Currently, three human vaccines against anthrax are available, produced in Russia (a live attenuated spore vaccine) and in the UK and USA (vaccines using filtrates of attenuated strains of anthrax bacillus). In 1970, an anthrax vaccine, derived from a sterile filtrate of an avirulent non-encapsulated strain of Bacillus anthracis and adsorbed on to aluminium hydroxide, was licensed by the Food and Drug Administration (FDA) to protect people who might be exposed to anthrax. The Advisory Committee on Immunization Practices (ACIP) has recommended immunization with this vaccine for people working with B. anthracis in the laboratory, those working with imported animal hides or furs in conditions that are inadequate to prevent exposure to anthrax spores, and military personnel deployed to areas with high risk for exposure. The vaccine was used to protect military personnel during the Gulf War. Although it has a safety record based on clinical trials carried out in the 1950s and 1960s and on the

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experience of over 30 years of use by thousands of military personnel, woolworkers, and veterinarians (7C , 8C ), the debate over its safety has come to the forefront in recent years, including the hypothesis of an alleged link between anthrax vaccine and disease reported by military personnel after the Gulf War. As a result of this concern, Congress ordered an in-depth investigation into the safety of the anthrax vaccine. The Institute of Medicine was asked to initiate a comprehensive study and to report on the safety and efficacy of the vaccine in an effort to answer the questions raised by Congress, the Department of Defense, and the public. The study will require about 24 months to complete. Because of immediate concerns over anthrax vaccine safety issues, the Institute of Medicine provided on 30 March 2000 a letter report to the Department of Defense, summarizing the Institute’s literature review on the safety of anthrax vaccine, prepared by its Committee on Health Effects Associated with Exposures during the Gulf War (9C ). The committee evaluated primary peer-reviewed literature and did not draw conclusions from secondary literature. It considered that there have been only a few published peer-reviewed studies of the safety of the anthrax vaccine in humans, and only one published series of studies discussed the long-term follow-up of individuals who received multiple vaccines including the anthrax vaccine. The committee concluded that (a) published studies have reported no significant adverse effects of the vaccine, but the literature is limited to a few short-term studies, and (b) in peer-reviewed publications there is inadequate/insufficient evidence to determine whether there is or is not an association between anthrax immunization and long-term adverse health outcomes. The committee considered the findings and conclusions as an early step in the complex process of understanding the vaccine’s safety, which began with its licensure in 1970 and includes the 1985 FDA advisory panel’s finding that categorized the anthrax vaccine as safe and effective. The committee included in its evaluation the results of the Vaccine Adverse Event Reporting System (VAERS), and considered the VAERS data as being useful as a sentinel for adverse events but of limited value for assessing the rate of causality of adverse events. The VAERS data are as follows:

• from 1 January 1990 to 31 August 2000, 1544 adverse events after anthrax immunization (nearly 2 million doses administered) have been reported to VAERS; • the most frequently reported adverse events were local reactions (864 reports); • other reports included headache (239 reports), arthralgia (232 reports), weakness (215 reports), pruritus (212 reports), and a few other systemic reactions; • there were 76 (5%) serious adverse events (death or life-threatening disease, hospitalization, permanent disability); based on autopsy results, one of two reported deaths was due to aplastic anemia and the other was due to coronary arteritis (10C ). • A 34-year-old man reported mild tenderness at the injection site after the first dose of anthrax vaccine; after the second dose he felt sweaty and weak and was pale; 20 hours after the third dose he had a life-threatening anaphylactic reaction (dyspnea, sweating, pallor, and urticarial wheals on the face, arms, and torso). After intensive care measures all his symptoms and signs resolved (11A ).

Immunologic The questions of whether early childhood immunization affects the development of atopy and whether it causes allergic reactions have been reviewed (12R ). The authors concluded that immunization programs do not explain the increasing incidence of allergic diseases, but that individual children may uncommonly develop an allergic reaction to a vaccine.

BACTERIAL VACCINES Bacille Calmette-Guérin (BCG) vaccine (SED-14, 1056; SEDA-23, 337; SEDA-25, 380) Skin Lupus vulgaris has been reported after BCG immunization (13A ). • Six months after BCG vaccination, an 18-year-old boy developed lupus vulgaris on his right shoulder. He was successfully treated with rifampicin, isoniazid, and ethambutol. He had had lupus vulgaris after BCG vaccination on his left shoulder 8 years before.

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Drug administration route Following intravesical instillation of BCG as immunotherapy in the treatment of transitional cell carcinoma of the bladder, local reactions are frequent and well known, whereas systemic reactions are less frequent. There have been two reports of micronodular pulmonary infiltrates (BCG pneumonitis) associated with fever, chills, and night sweats following multiple instillations of intravesical BCG (14A ). Both patients were 71 years old. The reactions, including radiographic infiltrates, resolved spontaneously or after steroid therapy.

• A six-year-old child had anaphylaxis 30 minutes after a fifth dose of DT vaccine (16A ). Skin tests, in vitro determination of specific IgE antibodies, and immunoblotting assays showed that the IgE response was directed against tetanus and diphtheria toxoids. Cross-reactivity between the two toxoids was not demonstrated, indicating the presence of co-existing but non-cross-reacting IgE and IgG antibodies.

Diphtheria-tetanus vaccine

(SED-14, 1086; SEDA-23, 341; SEDA-24, 371; SEDA-25, 382)

(SED-14, 1064; SEDA-21, 328) To avoid increasing reactogenicity of booster doses, diphtheria–tetanus vaccines or other combination vaccines that include the diphtheria component, used either for primary immunization in young children or for booster immunization in school-children, adolescents, and adults, contain different amounts of diphtheria toxoid. The formulations used in most countries are a childhood formulation containing 25–30 Lf (flocculating units) of diphtheria toxoid (D) and an adult formulation containing 2 Lf of diphtheria toxoid (d). In a prospective cohort study in Italy, 380 children aged 6 years were randomly assigned to receive either the DT or the Td vaccine as a booster dose in order to determine whether a booster dose of Td (diphtheria– tetanus vaccine with a reduced amount of diphtheria toxoid, adult formulation) would produce comparable diphtheria antibody titers but lower reactogenicity than DT (childhood formulation). The frequencies of symptoms within 3 days of vaccine administration were similar in the two groups, except for local redness and swelling, which were significantly more common in the children who received DT vaccine: redness 31% vs 16%, and swelling 36% vs 26%. The mean duration of local symptoms was 3.3 days in the DT group and 2.6 days in the Td group. After booster immunization, 97% of children in the DT group and 91% of those in the Td group had antibody concentrations of at least 1 IU/ml (“long-term” protection titer) (15C ).

Diphtheria/tetanus or diphtheria/ tetanus/pertussis vaccines in combination with other vaccines

DTaP or DTwP vaccine can be combined with other antigens, such as Hemophilus influenzae type b (Hib), inactivated poliovirus (IPV), and hepatitis B vaccine. In children DTaP or DTwP vaccines are the basis for such combinations, while in adults it is mostly Td vaccine, Current safety concerns regarding combination vaccines have been defined and reviewed (17R ). The author concluded that there is no evidence that adding vaccines to combination products increases the burden on the immune system, which can respond to many millions of antigens. Combining antigens usually does not increase adverse effects, but it can lead to an overall reduction in adverse events. Before licensure, combination vaccines undergo extensive testing to assure that the new products are safe and effective. The frequency, severity, and types of adverse reactions after DTP-Hib immunization in very pre-term babies have been studied (18C ). Adverse reactions were noted in 17 of 45 babies: nine had major events (apnea, bradycardia, or desaturation) and eight had minor reactions (increased oxygen requirements, temperature instability, poor handling, and feeding intolerance). Babies who had major adverse reactions were significantly younger at the time of immunization than the babies who did not have major reactions. Of 27 babies immunized at 70 days or less, nine developed major reactions compared with none of those who were immunized at over 70 days.

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Cardiovascular Myopericarditis has been attributed to Td-IPV vaccine (19A ). • A 31-year-old man developed arthralgia and chest pain 2 days after Td-IPV immunization and had an acute myopericarditis. He recovered within a few days with high-dose aspirin.

The authors discussed two possible causal mechanisms, natural infection or an immune complex-mediated mechanism. Infection was excluded by negative bacterial and viral serology and the favorable outcome within a few days without antimicrobial treatment. Sensory systems Optic neuritis has been attributed to Td-IPV vaccine (20A ). • Ten days after receiving Td-IPV vaccine a 56-yearold woman developed acute unilateral optic neuritis. Complete remission occurred within 6 weeks of prednisolone treatment. No other causes were found.

Skin Bullous pemphigoid has been attributed to DTP-IPV vaccine (21A ). • A previous healthy 3.5-month-old infant developed bullous pemphigoid 3 days after receiving a first dose of DTP-IPV vaccine. Staphylococcus aureus was isolated from purulent bullae. The lesions resolved rapidly after treatment with antibiotics and methylprednisolone.

The authors mentioned 12 other cases of bullous pemphigoid, reported during the last 5 years, that had possibly been triggered by vaccines (influenza, tetanus toxoid booster, and DTP-IPV vaccine).

Lyme disease vaccine

(SEDA-23, 338;

SEDA-24, 366; SEDA-25, 380) Because of poor sales, the first Lyme disease vaccine (LYMErix® ) was withdrawn from the market by the manufacturer (SEDA-25, 380). Dr Neal Halsey, head of the Institute for Vaccine Safety at Johns Hopkins University, has explained that the poor sales had resulted from “public misperception and the promotion of false concerns” (22r ). Lyme disease researchers consider the Lyme vaccine story in the USA to have been a setback in Lyme disease prevention. Four cases of arthritis associated with the administration of Lyme vaccine have been reported (23A ):

• 15 weeks after a third dose of Lyme vaccine a 9-year-old boy developed arthritis, including both knees, the right elbow, the left hip, the right ankle, and the right thumb; he was probably in an asymptomatic phase of natural Lyme infection; • about 3 months after a third dose of Lyme vaccine a 16-year-old boy developed arthritis of both knees; • 24 hours after a second dose of Lyme vaccine a 53-year-old man developed flu-like symptoms and arthralgia; he later developed swelling of the finger joints and toe joints; • 24 hours after a second dose of Lyme vaccine a 43-year-old man developed multiple synovitis.

In all cases the disease was self-limiting and to the knowledge of the authors inconsequential in the long term. They considered that the findings supported post-infectious and mimicry models, by showing that OspA, an outer surface protein of the causative organism of Lyme disease, Borrelia burgdorferi, could cause acute arthritis, the possibility that it was associated with a more protracted form of arthritis, and that it perhaps had a modulating effect in individuals with concurrent Lyme infection.

VIRAL VACCINES Hepatitis B vaccine

(SED-14, 1067; SEDA-23, 345; SEDA-24, 374) Nervous system Two episodes of leukoencephalitis occurred in a previously healthy patient after a second dose of HB vaccine and re-challenge with a third dose (24A ). • A 39-year-old woman developed a complete right homonymous hemianopia and severe dyslexia 4 weeks after receiving a second dose of HB vaccine. Brain MRI showed a large lesion that occupied most of the left occipital lobe and extended into the splenium of the corpus callosum. Histological examination with immunoperoxidase staining, although not pathognomonic, was consistent with demyelinating disease. She underwent surgery and 1 week later there was marked improvement in her condition. Three months later (4.5 months after the second dose), she received a third dose of HB vaccine and 11 days later developed a left hemiparesis and acute progressive deterioration in vision. Brain MRI showed a new large lesion in the right parietooccipital region, with the characteristics associated with the previous lesion. In comparison with previous findings, there was significant improvement in the left occipital lobe, in which there remained a proencephalic cyst. She was treated with dexamethasone and markedly improved. At 1 year and

358 2.5 years after the first episode she had residual dyslexia and a complete right homonymous hemianopia. An MRI scan showed almost complete resolution of the previous findings, with the exception of the proencephalic cyst.

The authors considered that acute leukoencephalitis is a rare but possible complication of HB vaccine. Fatal inflammatory polyradiculoneuropathy has been reported in temporal relation to hepatitis B administration (25A ). Sensory systems Acute tinnitus with permanent audiovestibular damage has been reported in temporal relation to hepatitis B administration (26A ). Hematologic Pancytopenia has been reported in temporal relation to hepatitis B administration (27A ). Mouth Oral lichenoid lesions have been reported in temporal relation to hepatitis B administration (28A ). Immunologic Large artery vasculitis (two cases) (29A ) and polyarteritis nodosa (30A ) have been reported in temporal relation to hepatitis B administration.

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countries, and is particularly dangerous in pregnant women. Through recombinant technology a hepatitis E vaccine has been developed; in its first clinical trials the vaccine was found to be safe and immunogenic (32R ).

Human papilloma virus vaccine Cervical cancer is the second most common cause of cancer deaths in women world-wide. It is almost invariably associated with human papilloma virus (HPV) infection. HPV type 16 is found in about 50% of cervical cancers, and types 18, 31, and 45 account for a further 25–30% of HPV-positive tumors. The development of a safe and effective HPV vaccine could prevent premalignant and malignant disease associated with HPV infection. There has been a trial of a papilloma virus (HPV16) virus-like particle vaccine in 72 healthy volunteers, aged 18–27 years (33C ). The vaccine was well tolerated and highly immunogenic. Clinical studies with a recombinant vaccine (using vaccinia virus expressing HPV 16, 18 E6 and E7 proteins) in patients with pre-invasive and invasive cancer have been reviewed (34R ).

Influenza vaccine Combination vaccine against Hepatitis A and B Sensory systems Optic neuritis has been attributed to immunization with hepatitis A and B (31A ). • A 21-year-old women developed acute irreversible loss of vision to 0.05 and a nasal visual field defect in the left eye 2 weeks after immunization with hepatitis A and B and yellow fever vaccine. An MRI scan showed hyperintense thickening of the optic nerve, and a diagnosis of optic neuritis was made. Vision acuity did not recover but the scotoma disappeared within 6 weeks.

Hepatitis E vaccine Hepatitis E is an important cause of morbidity and mortality in young adults in developing

(SED-14, 1072; SEDA-23, 347; SEDA-24, 375) In addition to reports on the immunogenicity and safety of inactivated intranasal influenza vaccine (SEDA-25, 386), this subject has been reviewed (35R ). The author concluded that the vaccine is highly immunogenic and well tolerated by most vaccinees, in terms of both local nasal symptoms and possible vaccine-mediated systemic symptoms. The symptoms were primarily mild, occasionally moderate, and in a few cases more severe; in most cases they lasted for only 1–2 days. In 1997, an avian influenza A/Hongkong/97 (H5N1) virus emerged as a pandemic threat. A non-pathogenic variant, influenza A/duck/ Singapore/97 (H5N3) was identified as a leading vaccine candidate, but the non-adjuvanted antibody response was poor; however, the addition of the adjuvant MF59 (oil-in-water suspension) boosted the antibody responses to protective levels. In 65 volunteers who received either

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the non-adjuvanted or the adjuvanted vaccine, both vaccines were well tolerated and did not differ significantly. There was pain at the injection site of varying intensity in nine of the 32 volunteers who received the adjuvanted vaccine, and in none of the volunteers who received the non-adjuvanted vaccine (36C ). Skin A 90-year-old woman developed a generalized bullous eruption resembling bullous pemphigoid 12 hours after influenza immunization (37A ). Immunologic Responding to a report of giant cell arteritis (SEDA-25, 386), other authors have described a 70-year-old man, previously healthy, who developed giant cell arteritis 5 days after influenza immunization (38A ). The authors mentioned another case reported in 1976.

Japanese encephalitis vaccine (SED-14, 1075; SEDA-23, 347) Immunologic Allergic reactions to Japanese encephalitis vaccine have been reported. In Japan, children who had immediate-type allergic reactions to Japanese encephalitis vaccine had antigelatin IgE in their sera. However, the immunological mechanism of non-immediatetype allergic reactions that consist of cutaneous signs developing several hours or more after Japanese encephalitis immunization is not yet clear. Serum samples taken from 28 children who had non-immediate-type allergic skin reactions have been compared with serum samples taken from 10 children who had immediatetype reactions (39C ). All the children who had had immediate-type reactions had antigelatin IgE and IgG. Of 28 children who had had nonimmediate-type reactions, one had antigelatin IgE and nine had antigelatin IgG. These results suggest that some children who develop non-immediate-type allergic reactions have also been sensitized to gelatin.

1 month after measles immunization (40A ). The hypertrichosis and induration persisted during the follow-up period of 3 months.

Measles–mumps–rubella (MMR) vaccine (SED-14, 1078; SEDA-23, 351; SEDA-24, 377; SEDA-25, 387) Nervous system To test the hypothesis that MMR vaccine can cause Guillain–Barré syndrome, a retrospective study has been carried out in Finland, based on linkage of individual immunization records with nation-wide hospital discharge registers (41C ). MMR vaccine did not cause any increase in the incidence of Guillain–Barré syndrome over background and there was no clustering of cases at any time after the administration of the vaccine. The authors concluded that there is no causal association between MMR immunization and Guillain–Barré syndrome. A cranial nerve palsy has been attributed to MMR (42A ). • A 13-month-old girl developed a recurrent sixth nerve palsy 1 week after MMR immunization. This resolved completely over 8 weeks and recurred 15 weeks after initial onset. Other causes for the sixth nerve palsy were excluded.

Measles vaccine

Psychiatric The hypothesis that MMR vaccine can cause autism and Crohn’s disease, mainly suggested by Wakefield, has previously been discussed at length (SED-14, 1079; SEDA-23, 350; SEDA-24, 377; SEDA-25, 387). Data from an earlier study have been reanalysed to test the hypothesis that MMR vaccine might cause autism but that the induction interval needs to be short (43M ). Evidence for an increased incidence was sought using the case-series method. The study used data on all MMR vaccines, including booster doses. The results of this study, combined with results obtained earlier by the same authors, provided powerful evidence against the hypothesis that MMR vaccine causes autism at any time after immunization.

Skin An 11-month-old boy developed hypertrichosis at the injection site (2.5 × 3 cm)

Hematologic A causal relation between MMR vaccine and idiopathic thrombocytopenic purpura has been confirmed using linkage of

(SED-14, 1076; SEDA-23, 348; SEDA-24, 377)

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Table 4. Rubella immunization and arthritic reactions reported to the VAERS database Arthritis reaction type

Reports

Women

Men

Mean onset days

Mean age (years)

Incidence per million immunizations

Arthralgia Arthrosis Arthritis Joint disease

191 58 46 13

170 51 41 13

17 4 2 0

11 12 11 12

40 43 38 39

78 24 19 5

immunization records and hospital admission records; the absolute risk within 6 weeks of immunization was 1 per 22 300 doses (44C ).

vaccine, these reactions occurred primarily in the adult women. The incidence of arthritic reactions was 126 per million rubella immunizations, whereas the hepatitis A vaccine adult control group had an incidence rate of 3.2 per million immunizations.

Rotavirus vaccine

(SED-14, 1091; SEDA-23, 354; SEDA-24, 379; SEDA-25, 390) Gastrointestinal Further studies have confirmed that there is an increased risk of intussusception associated with the use of rhesus rotavirus tetravalent vaccine (RRV-TV). The association has been assessed in infants in 19 states of the USA (45C ). Each infant hospitalized with intussusception between 1 November 1998 and 30 June 1999 was matched according to age with four healthy controls who had been born at the same hospital. The authors estimated that one case of intussusception would occur for every 4670–9474 infants immunized. In a retrospective cohort study in 10 managed car organizations there was an increased risk of intussusception in immunized children (46C ). The risk was greatest at 3–7 days after the first dose of RRV-TV.

Rubella vaccine

(SED-14, 1092; SEDA-24, 379; SEDA-25, 390) Data from the VAERS (Vaccine Adverse Events Reporting System) on arthritic reactions (arthralgia, arthrosis, arthritis, and joint disease) after rubella immunization during 1991–8 have been analysed (Table 4) (47C ). Hepatitis A vaccine-associated arthritic reactions reported to VAERS during 1997–8 were used as controls. The analysis confirmed that rubella vaccine is associated with a large number of arthritic reactions. Among the female subjects given rubella

Varicella vaccine

(SED-14, 1096, SEDA-23, 355; SEDA-24, 380) The safety and efficacy of Varicella vaccine have been critically reviewed (48R ). Risk factors Immunocompromised individuals To determine the safety and immunogenicity of Varicella immunization in HIVinfected children, 41 children (aged 1–8 years) who were asymptomatic or mildly affected (according to CDC stages) received two doses of live attenuated Varicella vaccine 12 weeks apart (49C ). Two months after the second dose, 60% of the recipients had anti-Varicella antibody in their serum. A minority of recipients developed mild local or systemic reactions. The immunization had no effect on the clinical stage of HIV infection or the HIV RNA plasma load. Children In 29 children aged 1–12 years with chronic liver disease who received one dose of Varicella vaccine, seroconversion rates at 8 weeks after immunization were 100% (450C ). The geometric mean titers tended to relate to the severity of liver disease. Local and systemic reactions did not differ from reactions reported in healthy children. • A 5-year-old boy developed zoster-like vesicular lesions 4 years after Varicella immunization. Virological examination showed Herpes simplex virus type 1, and so the vesicular lesions could not be attributed to the Varicella zoster virus vaccine strain, demonstrating the difficulty in confirming causality between time-related events (51C ).

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REFERENCES 1. Black S. Perspectives on the design and analysis of pre-licensure trials: bridging the gap to postlicensure studies. Clin Infect Dis 2001; 33 Suppl 4: S323–6. 2. Jacobson RM, Adegbenro A, Pankratz VS, Poland GA. Adverse events and vaccination— the lack of power and predictability of infrequent events in pre-licensure study. Vaccine 2001; 19: 2428–33. 3. Heijbel H, Jefferson T. Vaccine safety— improving monitoring. Vaccine 2001; 19: 2457–60. 4. Chen RT, Pool V, Takahashi H, Weniger BG, Patel B. Combination vaccines: post-licensure safety evaluation. Clin Infect Dis 2001; 33 Suppl 4: S327– 33. 5. http://Brightoncollaboration.org/ (accessed 22 October 2002). 6. Silvers LE, Ellenberg SS, Wise RP, Varricchio FE, Mootrey GT, Salive ME. The epidemiology of fatalities reported to the Vaccine Adverse Event Reporting System 1990–1997. Pharmacoepidemiol Drug Saf 2001; 10: 279–85. 7. Snyder JW. The anthrax vaccine: a question of safety. Clin Microbiol Newslett 2001; 23: 51–4. 8. Pittman PR, Gibbs PH, Cannon TL, Friedlander AM. Anthrax vaccine: short-term safety experience in humans. Vaccine 2001; 20: 972–8. 9. Committee on Health Effects Associated with Exposures during the Gulf War. An assessment of the safety of the anthrax vaccine. A letter report. Washington, DC: Institute of Medicine, 30 March 2000. http://www.nap.edu/html/anthrax_vaccine/ (accessed 27 October 2002). 10. Centers for Disease Control and Prevention. Use of anthrax vaccine in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep 2000; 49: 1–17. 11. Swanson-Biearman B, Krenzelok EP. Delayed life-threatening reaction to anthrax vaccine. Clin Toxicol 2001; 39: 81–4. 12. Grüber C, Nilsson L, Bjorksten B. Do early childhood immunizations influence the development of atopy and do they cause allergic reactions? Pediatr Allergy Immunol 2001; 12: 296–311. 13. Sasmaz R, Altinyazar HC, Tatlican S, Eskioglu F, Yurtsever P. Recurrent lupus vulgaris following repeated BCG (Bacillus Calmette Guerin) vaccination. J Dermatol 2001; 28: 762–4. 14. Namen AM, Grosvenor AR, Chin R, Daybell D, Adair N, Woodruff RD, Kavanagh PV, Haponik EF. Pulmonary infiltrates after intravesical Bacille Calmette-Guerin: two cases and review of the literature. Clin Pulm Med 2001; 8: 177–9. 15. Ciofi degli Atti ML, Salmaso S, Cotter B, Gallo G, Alfarone G, Pinto A, Bella A, Von Hunolstein C. Reactogenicity and immunogenicity of adult versus paediatric diphtheria and tetanus booster dose at 6 years of age. Vaccine 2001; 20: 74–9.

16. Martin-Muñoz MF, Pereira MJ, Posads S, Sánchez-Sabaté E, Blanca M, Álvarez J. Anaphylactic reaction to diphtheria–tetanus vaccine in a child: specific IgE/IgG determination and cross reactivity studies. Vaccine 2002; 20: 3409–12. 17. Halsey NA. Combination vaccines: defining and addressing current safety concerns. Clin Infect Dis 2001; 33 Suppl 4 S312–18. 18. Sen S, Cloete Y, Hassan K, Buss P. Adverse events following vaccination in premature infants. Acta Paediatr 2001; 90: 916–20. 19. Boccara F, Benhaiem-Sigaux N, Cohen A. Acute myopericarditis after diphtheria, tetanus, and polio vaccination. Chest 2001; 120: 671–2. 20. Burkhard C, Choi M, Wilhelm H. Optikusneuritis als Komplikaton einer Tetanus–Diphtherie– Poliomyelitis–Schutzimpfung: ein Fallbericht. Klin Monatsbl Augenheilkd 2001; 218: 51–4. 21. Baykal C, Okan G, Sarica R. Childhood bullous pemphigoid developed after the first vaccination. J Am Acad Dermatol 2001; 44 Suppl 348–50. 22. Immunization News for April 26, 2002. http:// www.immunizationinfo.org/ (accessed 27 April 2002). 23. Rose CD, Fawcett PT, Gibney KM. Arthritis following recombinant outer surface protein A vaccination for Lyme disease. J Rheumatol 2001; 28: 2555–7. 24. Konstantinou D, Paschalis C, Maraziotis T, Dimopoulos P, Bassaris H, Skoutelis A. Two episodes of leukoencephalitis associated with recombinant hepatitis B vaccination in a single patient. Clin Infect Dis 2001; 33: 1772–3. 25. Sindern E, Schroder JM, Krismann M, Malin JP. Inflammatory polyradiculo-neuropathy with spinal cord involvement and lethal outcome after hepatitis B vaccination. J Neurol Sci 2001; 186: 81–5. 26. DeJonckere PH, De Surgeres GDG. Acute tinnitus and permanent audiovestibular damage after hepatitis B vaccination. Int Tinnitus J 2001; 7: 59–61. 27. Ashok Shenoy K, Prabha Adhikari MR, Chakrapani M, Shenoy D, Pillai A. Pancytopenia after recombinant hepatitis B vaccine—an Indian case report. Br J Haematol 2001; 114: 955. 28. Anonymous. Cutaneous drug reaction case reports: from the world literature. Am J Clin Dermatol 2001; 2: 49–56. 29. Zaas A, Scheel P, Venbrux A, Hellmann DB. Large artery vasculitis following recombinant hepatitis B vaccination: 2 cases. J Rheumatol 2001; 28: 1116–20. 30. Saadoun D, Cacoub P, Mahoux D, Sbai A, Piette JC. Vascularites postvaccinales: à propos de trois observations. Rev Med Interne 2001; 22: 172–6. 31. Voigt U, Baum U, Behrendt W, Hegemann S, Terborg C, Strobel J. Optikusneuritis nach Impfung gegen Hepatitis A, B und Gelbfieber mit

362 irreversiblem Visusverlust. Klin Monatsbl Augenheilkd 2001; 218: 688–90. 32. Safary A. Perspectives of vaccination against hepatitis E. Intervirology 2001; 44: 162–6. 33. Harro CD, Pang Y-YS, Roden RBS, Hildesheim A, Wang Z, Reynolds MJ, Mast TC, Robinson R, Murphy BR, Karron RA, Dillner J, Schiller JT, Lowy DR. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 viruslike particle vaccine. J Natl Cancer Inst 2001; 93: 284–92. 34. Adams M, Borysiewicz L, Fiander A, Man S, Jasani B, Navabi H, Lipetz C, Evans AS, Mason M. Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer. Vaccine 2001; 19: 2549–56. 35. Glueck R. Review of intranasal influenza vaccine. Adv Drug Deliv Rev 2001; 51: 203–11. 36. Nicholson KG, Colegate AE, Podda A, Stephenson I, Wood J, Ypma E, Zambon MC. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001; 357: 1937–43. 37. Garcia-Doval I, Roson E, Feal C, De la Torre C, Rodriguez T, Cruces MJ. Generalized bullous fixed drug eruption after influenza vaccination, simulating bullous pemphigoid. Acta Derm Venereol 2001; 81: 450–1. 38. Finsterer J, Artner C, Kladosek A, Kalchmayr R, Redtenbacher S. Cavernous sinus syndrome due to vaccination-induced giant cell arteritis. Arch Intern Med 2001; 161: 1008–9. 39. Sakaguchi M, Miyazawa H, Inouye S. Specific IgE and IgG to gelatin in children with systemic cutaneous reactions to Japanese encephalitis vaccines. Allergy Eur J Allergy Clin Immunol 2001; 56: 536–9. 40. Ozkan H, Dudar ON, Ozkan S, Kumral A, Duma N, Gulcan H. Hypertrichosis following measles immunization. Pediatr Dermatol 2001; 18: 457–8. 41. Patja A, Paunio M, Kinnunen E, Junttilla O, Hovi T, Peltola H. Risk of Guillain–Barré syndrome

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after measles–mumps–rubella vaccination. J Pediatr 2001; 138: 250–4. 42. McCormick A, Dinakaran S, Bhola R, Rennie IG. Recurrent sixth nerve palsy following measles mumps rubella vaccination. Eye 2001; 15: 356–7. 43. Farrington CP, Miller E, Taylor B. MMR and autism: further evidence against a causal association. Vaccine 2001; 19: 3632–5. 44. Miller E, Waight P, Farrington P, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine. Arch Dis Child 2001; 84: 227–9. 45. Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, Zanardi LR, Setia S, Fair E, LeBaron CW, Wharton M, Livingood JR. Intussusception among infants given an oral rotavirus vaccine. New Engl J Med 2001; 344: 564–72. 46. Kramarz P, France EK, Destefano F, Black SB, Shinefield H, Ward JI, Chang EJ, Chen RT, Shatin D, Hill J, Lieu T, Ogren JM. Population-based study of rotavirus vaccination and intussusception. Pediatr Infect Dis J 2001; 20: 410–16. 47. Geier DA, Geier MR. Rubella vaccine and arthritic adverse reactions: an analysis of the Vaccine Adverse Events Reporting System (VAERS) database from 1991 through 1998. Clin Exp Rheumatol 2001; 19: 724–6. 48. Skull SA, Wang EEL. Varicella vaccination— a critical review of the evidence. Arch Dis Child 2001; 85: 83–90. 49. Levin MJ, Gershon AA, Weinberg A, Blanchard S, Nowak B, Palumbo P, Chan CY. Immunization of HIV-infected children with varicella vaccine. J Pediatr 2001; 139: 305–10. 50. Nithichaiyo C, Chongsrisawat V, Hutagalung Y, Bock HL, Poovorawan Y. Immunogenicity and adverse effects of live attenuated varicella vaccine (Oka-strain) in children with chronic liver disease. Asian Pac J Allergy Immunol 2001; 19: 101–5. 51. Takayama N, Takayama M, Takita J. Herpes simplex mimicking Herpes zoster in a child immunized with varicella vaccine. Pediatr Infect Dis J 2001; 20: 226–8.

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33

Blood, blood components, plasma, and plasma products

ALBUMIN

(SED-14, 1123; SEDA-23, 359; SEDA-24, 383; SEDA-25, 396) Albumin has been used to prevent the ovarian hyperstimulation syndrome (OHSS) associated with ovulation stimulation. In 98 women albumin had no positive effect on OHSS (1C ). Because of adverse effects, such as exacerbation of ascites in OHSS, nausea, vomiting, febrile reactions, allergic reactions, anaphylactic shock, and the risk of pathogen transmission, albumin should not be used to prevent OHSS. Hypovolemic shock due to acute blood loss during delivery is one of the major causes of maternal mortality. It has been suggested that albumin may increase the risk of death, and crystalloids have been suggested to be the volume expanders of choice (2R ). Drug interactions In children with the nephrotic syndrome, albumin in combination with furosemide carries a risk of thrombotic complications. In 12 children although antithrombin and alpha2 macroglobulin fell, which is in accordance with a thrombotic tendency, there were no thrombotic complications (3c ). Furthermore, there was a fall in fibrinogen concentration, which is not consistent with a thrombotic tendency.

ANTICOAGULANT PROTEINS Severe sepsis and septic shock are associated with activation of the coagulation system and depletion of endogenous anticoagulants. Anticoagulant proteins may prevent microthrombus © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

formation, thereby reducing the risk of multiorgan failure. High dose of antithrombin III, given to patients with severe sepsis, increased the risk of hemorrhage notably when given concomitantly with heparin, while there was no treatment benefit (4C ). Recombinant human activated protein C also increased the risk of bleeding in patients with severe sepsis (5C ).

BLOOD SUBSTITUTES

(SED-14, 1703; SEDA-23, 359; SEDA-24, 383; SEDA-25, 396) Several oxygen carriers, which can act as alternatives for allogenic erythrocyte transfusions, are currently being tested clinically. These substances can be divided into two classes: hemoglobin-based oxygen carriers, prepared from hemoglobin of human or bovine origin, and synthetic perfluorocarbons.

Hemoglobin-based oxygen carriers Hemoglobin-based oxygen carriers have benefits, such as the lack of pathogen transmission, no need for cross-matching, and increased stability and storage time. However, they bind endogenous nitric oxide, thereby causing transient hypertension, esophageal dysfunction, and abdominal discomfort. Compared with erythrocyte transfusions, these products have a short half-life. In a phase II study using O-raffinose cross-linked hemoglobin (Hemolink™) in patients undergoing coronary artery bypass grafting surgery raised blood pressure, probably caused by binding of O-raffinose cross-linked hemoglobin to nitric oxide, and jaundice were

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observed (6R ). Jaundice was expected, owing to metabolism of cell-free hemoglobin.

licensed for a limited number of indications, such as immunodeficiency diseases, idiopathic thrombocytopenic purpura, bone-marrow transplantation, and Kawasaki disease (12C , 13AR , 14CR ). Intravenous immunoglobulin administered to allogeneic bone-marrow transplant recipients modifies graft-versus-host disease and prevents interstitial pneumonia and infections (14CR ). Intravenous immunoglobulin has also been successfully used in a variety of other conditions, mainly autoimmune diseases. Several randomized clinical trials have demonstrated the efficacy of high doses of intravenous immunoglobulin in Guillain–Barré syndrome (15C ). In addition, high-dose intravenous immunoglobulin has been beneficial in myasthenia gravis, multiple sclerosis, and multifocal motor neuropathy (16c , 17c ). Recent studies have shown that immunoglobulin therapy appears to be effective in patients with pemphigus vulgaris and bullous pemphigoid nonresponsive to conventional immunosuppressive drugs (18C , 19C ). In patients with congenital and acquired immunodeficiencies, intravenous immunoglobulin is used to substitute IgG deficiency. In contrast, the effect of high-dose immunoglobulin in autoimmune diseases has been attributed to a variety of effects on the immune system, including inhibition of Fc receptors on neutrophils and macrophages, inhibition of complement activation, cytokine modification, and neutralization of superantigens (20R ). Adverse effects after intravenous immunoglobulin administration are infrequent and usually mild (20R ). In about 10% of cases reactions, such as flushing, myalgia, headache, fever, chills, low backache, nausea and vomiting, chest tightness, wheezing, changes in blood pressure, and tachycardia, occur at 30–60 minutes after the start of treatment (SEDA-25, 398). Of 56 patients with autoimmune diseases who received high dosages of intravenous immunoglobulin, 20 had at least one adverse effect after one or more courses of treatment (12C ). The most frequently reported adverse effects were low-grade fever, headache, and chills. The authors concluded that the occurrence of adverse effects with intravenous immunoglobulin was not related to the clinical response to treatment. However, patients who developed

Perfluorocarbons Perfluorocarbons have gained wide acceptance in the surgical management of complicated retinal detachment (7R ). These heavy low-viscosity liquids are inert, are optically clear, and have a high specific gravity and good surface tension. Their chemical and physical properties make them a suitable temporary intraoperative tool to flatten the retina during surgery. Although the high surface tension allows closure of retinal breaks and prevents the perfluorocarbons from flowing into the subretinal space, particularly during intraocular manipulation, these liquids can gain entry into the subretinal space, resulting in residues in the eye (8A , 9A ). The removal of perfluorocarbons is recommended at the end of surgery, but they can be left in the eye for limited periods of time (10R ). • A 29-year-old man with high myopia developed a rhegmatogenous retinal detachment due to a giant retinal tear following blunt trauma (11c ). After surgical treatment perfluorodecalin was left in the eye as a tamponade; 2 weeks later it was removed and 20% sulfahexafluoride was injected. On the following day the retina was flat and residual perfluorodecalin was not detected in the vitreous cavity. A week later he developed severe pain in the operated eye and his vision worsened. There was a marked cellular response in the vitreous cavity and total retinal detachment. Examination with retroillumination showed that there was residual perfluorocarbon trapped in the retrolental space. There also appeared to be a precipitate of pigmented cells adherent to the vitreous surface of the posterior lens capsule, as seen on slit lamp biomicroscopy. Posterior capsulotomy removed the obstruction caused by the deposits, confirming the suspicion of the site of the pigmentary infiltration. A small amount of heavy liquid was found subretinally and removed. Although retinal reattachment was not possible due to very severe proliferative vitreoretinopathy, the intravitreal inflammation resolved.

INTRAVENOUS IMMUNOGLOBULIN

(SED-14, 1123; SEDA-23, 360; SEDA-24, 385; SEDA-25, 398) Intravenous immunoglobulin, highly purified IgG prepared from pooled human plasma, is

Blood, blood components, plasma, and plasma products

adverse effects during the first course of treatment were more at risk of adverse effects during subsequent courses. The rate of adverse effects associated with intravenous immunoglobulin varies among different studies, which has been attributed to factors such as the indication, the dosage, the infusion rate, and the patient’s age (12C ). In one study, the adverse effects headache and chills were related to a higher dosage (14CR ). Infusion of intravenous immunoglobulin 0.14 g/kg in 17 patients with autoimmune diseases in whom circulating immunoglobulins had been depleted, was associated with a high incidence of serious adverse effects (21C ). Treatment was terminated in four patients because of adverse effects, including urticaria, severe hypotension, arthralgia, and chest discomfort. Cardiovascular So far, 13 cases of thrombosis subsequent to intravenous immunoglobulin have been reported, including myocardial infarction in five patients, stroke in four cases, and spinal cord ischemia in one (22c ). It has been postulated that these events are induced by platelet activation and increased plasma viscosity (12C ). It has been recommended that patients with cardiac diseases should be monitored during intravenous immunoglobulin therapy, because hypertension and cardiac failure have occurred, presumably as a result of fluid overload or electrolyte shifts (23R ). Respiratory In a patient with Guillain– Barré syndrome treated with intravenous immunoglobulin 400 mg/kg for 5 consecutive days, severe bronchospasm and hypercapnia occurred after a dose of 12.5 g had been given (15C ). In this patient, who had a history of ischemic heart disease, the complaints disappeared after withdrawal of the intravenous immunoglobulin. Nervous system Aseptic meningitis is one of the rare adverse effects of intravenous immunoglobulin and has been especially reported in subjects with a history of migraine (20R ). Symptoms such as severe headache, photophobia, drowsiness, and nausea start within 24 hours and can last for 3–5 days. In the cerebrospinal fluid there is a raised protein concentration and an increased number of leukocytes.

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Hematologic Severe hemolytic anemia after high doses of intravenous immunoglobulin has been reported in a 23-year-old woman with polymyositis (24A ). This adverse reaction was probably due to the presence of allohemagglutinins A and B and high molecular weight IgG complexes in the formulation. Specifications in pharmacopeial monographs and product licenses require that intravenous immunoglobulin be free of significant titers of anti-A anti-B antibodies (SEDA-24, 385). In patients with anemia, high-molecularweight complexes present in intravenous immunoglobulin can mimic the effect of immune complexes, by activating complement, binding to CR1 of erythrocytes, and mediating erythrophagocytosis. Leukopenia and neutropenia have been reported after infusion of intravenous immunoglobulin. Neutropenia during intravenous immunoglobulin treatment can be transient and reversible. It has been recommended that the blood count be monitored during intravenous immunoglobulin therapy if there is evidence of mild leukopenia, neutropenia, or thrombocytopenia before the first infusion (16r ). Urinary tract Renal insufficiency is a relatively rare, but increasingly recognized adverse effect of intravenous immunoglobulin. In most cases it was reversible (mean within 2 weeks) after withdrawal of intravenous immunoglobulin. Hemodialysis was required in about 30% of the patients and some developed chronic renal insufficiency. Renal biopsies from most patients with acute renal insufficiency showed marked swelling of proximal tubular cells, with vacuolization accompanied by obstruction of tubular lumina. It has therefore been postulated that stabilizing agents, such as sucrose, may lead to osmotic renal damage (13AR ). Risk factors for the development of acute renal insufficiency are older age (65 and above), underlying renal insufficiency, and a history of diabetes mellitus (13AR , 25cr ). It has been suggested that kidney function should be monitored during intravenous immunoglobulin therapy if it is abnormal before the first infusion (16r ). In addition, these patients should be adequately hydrated during treatment with intravenous immunoglobulin (23R ).

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Skin Skin reactions, such as urticaria, erythema, pruritus, and eczematous reactions, have been reported, but are rare (21C , 23R ), (26C ).

hemophiliacs with inhibitors who received continuous infusion of recombinant factor VIIa to allow elective surgery (29c ). In 25 hemophilia patients with inhibitors, who received recombinant factor VIIa for surgical procedures or spontaneous bleeding, there was one case of thrombophlebitis in 35 continuous infusion courses (30c ). Furthermore, continuous infusion of recombinant factor IX in six hemophilia B patients undergoing surgery or suffering bleeding was complicated in two cases by thrombophlebitis (31c ). In most instances, the thrombophlebitis can be prevented by parallel infusion of saline or heparin. Among patients who had more than 2400 treatment episodes with recombinant factor VIIa, there were two cases of acute myocardial infarction (32R ). One of these patients had a history of cardiovascular disease and the other was very overweight and received massive transfusions, human factor VIII, activated prothrombin complex, and finally recombinant factor VIIa to treat severe intra-abdominal bleeding and shock.

Immunologic Severe anaphylactic reactions in patients who have severe IgA deficiency are rare. This serious adverse effect has been thought to be associated with IgE or IgG antibodies against IgA, which react with IgA in intravenous immunoglobulin (13AR , 21C , 23R ). Infection risk Following reports of transmission of hepatitis C virus after intravenous immunoglobulin infusion, additional viral safety steps, such as solvent detergent treatment, have been implemented in the production process. Of 56 patients with autoimmune diseases who received 167 infusions of intravenous immunoglobulin, none developed antibodies to human immunodeficiency virus and hepatitis C virus or hepatitis B surface antigen (12C ). A novel DNA virus, TT virus, has been implicated as a cause of post-transfusion hepatitis. A high prevalence of TT virus infection has been found in patients who received blood or blood components, such as factor VIII and IX concentrates. However, the PCR for TT virus DNA was negative in all 17 patients with immunodeficiency, who were treated prophylacticly with intravenous immunoglobulin, as well as in 15 tested immunoglobulin formulations (27c ). Drug interactions Recently, acute renal insufficiency after intravenous immunoglobulin therapy has been reported in association with the injection of iodinated radiocontrast agents (28A ). Contrast media and intravenous immunoglobulin formulations containing maltose or sucrose both have toxic effects on renal cells.

CLOTTING FACTORS

(SED-14, 1125; SEDA-23, 362; SEDA-24, 386; SEDA-25, 399) Cardiovascular Thrombophlebitis at the infusion site is a common complication of continuous infusion of various clotting factor concentrates, as observed in one of eight

Respiratory Shortness of breath was observed in a young hemophilia B patient with inhibitors after a number of attempts to induce immune tolerance with a high dose of factor IX:C (33c ). In a retrospective study of 29 treatments with porcine factor VIII:C in 18 hemophilia A patients with inhibitors, the initial bolus administration of porcine factor VIII:C before continuous infusion caused bronchospasm in one patient (34c ). Hematologic The administration of prothrombin complex concentrate to reverse anticoagulant treatment has raised concerns about the risk of thrombotic complications, such as myocardial infarction and disseminated intravascular coagulation. However, such complications have typically occurred in patients with liver failure or after repeated treatment, such as in hemophilia B patients treated with prothrombin complex concentrate (35A ). The usefulness of recombinant factor VIIa for correcting the prothrombin time has been demonstrated in three neonates with liver failure undergoing liver biopsy and central venous catheter placement (36A ). Recombinant factor VIIa has also been shown to be a reliable option for the treatment

Blood, blood components, plasma, and plasma products

of serious bleeding, including bleeding related to anticoagulant therapy or liver failure, because factor VII is the most sensitive of the vitamin Kdependent clotting factors. Recombinant factor VIIa has also been used effectively and safely to treat and prevent bleeding episodes in thrombocytopenia. A disadvantage of recombinant factor VIIa is the need for frequent administration, because of its short half-life. No causality has been demonstrated between administration of recombinant factor VIIa and thrombotic complications (37r , 38r ). During continuous infusion of porcine factor VIII:C in hemophilia A patients with inhibitors there is a smaller fall in platelet count and fewer other adverse effects than during the period after the initial bolus administration, as was shown in a retrospective study of 29 treatments with porcine factor VIII:C of 18 hemophilia A patients with inhibitors (34c ). The authors attributed these differences to the dose of factor VIII:C and the rate of administration. In 20 previously treated patients with severe or moderate hemophilia A, there was a high percentage of CD4-positive cells, and a low percentage of CD8-positive cells, leading to a raised CD4/CD8 ratio in an HIV-negative patient, which was judged to be possibly related to treatment with recombinant factor VIII formulated with sucrose (39C ). Skin A young hemophilia B patient with inhibitors developed an urticarial rash after several attempts to induce immune tolerance with a high dose of factor IX:C (33c ). Urticaria and periorbital edema after initial bolus administration of porcine factor VIII:C before continuous infusion have been observed in one of 18 hemophilia patients with inhibitors receiving a total of 29 treatments with porcine factor VIII:C (34c ). Immunologic A major complication of the treatment of hemophilia with clotting factor concentrates or recombinant factor products is the formation of antibodies (also called inhibitors) against the deficient coagulation factor. The formation of inhibitors of factor VIII is not restricted to patients with severe hemophilia. There have been two cases of hightiter factor VIII inhibitors in two children with mild hemophilia A; one occurred after only minimal exposure to factor VIII:C (40A ). In

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20 previously treated patients with severe or moderate hemophilia A treated with recombinant factor VIII formulated with sucrose, no inhibitors were found (39C ). The risk of forming inhibitors after treatment with B domaindeleted recombinant factor VIII was comparable to that seen with full-length recombinant products (41A , 42A ). Treatment options for patients with inhibitors are high dosages of clotting factor or recombinant factor VIIa for both hemophilia A and B or, in the case of hemophilia A, porcine factor VIII:C or activated prothrombin complex (43r ). Recombinant and high-purity coagulation factor products appear to have a greater tendency to induce inhibitors than human-derived concentrates of intermediate or low purity (43r ). These intermediate-purity or low-purity human-derived concentrates are probably more suitable for inducing immune tolerance in hemophilia patients with inhibitors. It has been suggested that for immune tolerance a high content of Von Willebrand factor in factor VIII concentrates is required, although direct comparisons of different products have not been made (44r ). Treatment with high dosages of clotting factors to induce immune tolerance brings a risk of allergic reactions, as has been observed in a 4-year-old child with hemophilia B (33A ). No antibodies against recombinant factor VIIa were observed in a group of 222 hemophilia A and 16 hemophilia B patients with inhibitors treated with high doses of factor VIIa (32R ). Infection risk Treatment of hemophilia with human plasma-derived coagulation factor concentrates carries the risk of transmission of blood-borne viruses, such as hepatitis B and C and human immunodeficiency virus. This risk is diminished in current blood products, which are derived from plasma of donors who are properly screened and which undergo various virus-inactivation steps during the production process. However, the risk of transmission of new-variant Creutzfeldt–Jakob disease (nvCJD) by plasma-derived coagulation concentrates is still unknown. Recombinant coagulation factor products have never been associated with viral transmission, although the risk of long-term adverse effects is unknown, as is the risk of transmission of nvCJD by cell cultures (45r ).

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Reversal of anticoagulant treatment, as required in the case of surgery or bleeding, can be achieved by fresh frozen plasma and prothrombin complex concentrate. The risk of viral transmission by fresh frozen plasma is higher than with prothrombin complex concentrate, because several virus-eliminating steps are included in the manufacturing process of the latter. Another disadvantage of fresh frozen plasma is the large volume that is required to correct the clotting factor defect.

ment of anemia due to chronic renal insufficiency. It has also been used for anemia associated with cancer chemotherapy and HIV infection. Epoetin improves the quality of life and relieves symptoms of fatigue in patients with cancer (50M , 51C ), in whom it increases hemoglobin and reduces transfusion requirements (52C ). Recently, a novel erythropoiesis-stimulating protein, NESP or darbepoetin alfa, has been developed. This long-acting form of erythropoietin, with its additional sialic acid residues, does not require such frequent administration as epoetin; its long half-life allows administration once every 1 or 2 weeks (53R ). The safety profiles of epoetin and darbepoetin are similar, and both are generally well tolerated. Adverse effects include hypertension, injection site pain (generally mild and transient) in the case of subcutaneous administration, cardiovascular events, headache, vascular disorders (vascular access thrombosis), flu-like symptoms, and skin rashes (50M , 53R , 54R ). Adverse effects such as hypertension and thrombophlebitis are observed in uremic patients requiring dialysis but not in patients with hematological malignancies (55R ). In a prospective trial in 3012 patients, the clinical benefits and adverse events profiles were similar with once-weekly epoetin compared with historical experience with thriceweekly dosing (56C ). In 194 patients a low dose of epoetin beta before elective surgery was well tolerated and reduced the need for transfusions (57C ). Epoetin combined with parenteral iron is also effective and safe for moderate and severe iron deficiency anemia during pregnancy (58c ). Iron deficiency is one of the major causes of inadequate responses to epoetin, and so iron supplementation is often required (59C ). The use of epoetin in combination with intravenous iron makes collection of larger numbers of autologous erythrocyte units feasible. However, epoetin does not synergize with G-CSF for the mobilization of peripheral blood progenitor cells in healthy donors (60c ). Epoetin has also been used in combination with G-CSF and amifostine or G-CSF and IL-3 as adjunctive treatment for cytopenias complicating myelodysplastic syndrome (61C , 62c ). Although these combinations are well tolerated, they promote hemopoiesis only in a subgroup of these patients.

Body temperature Febrile reactions occurred in two patients after the initial bolus administration of porcine factor VIII:C in a retrospective study of 29 treatments with porcine factor VIII:C in 18 hemophilia A patients with inhibitors (34A ).

Coagulation factor gene therapy Phase I trials of gene therapy in hemophilia A and B, to determine safety and efficacy, are currently under way (46R ). The hazards of current vectors include insertion mutagenesis, immunogenesis, hepatotoxicity, and carcinogenic effects. In particular, retroviral vectors have a considerable carcinogenic potential. Adenoviruses, which do not integrate into the genome and consequently have only a transient effect, are considered to be safer. Also adeno-associated viruses have a low pathogenic potential in humans, as do lentiviruses. The death of a young patient who took part in a clinical study, probably caused by an adverse reaction to the viral vector (47R , 48R ) has led to increased interest in the application of non-viral techniques for gene therapy. When factor VIII genes were introduced into autologous skin cells in culture by electroporation, and thereafter implanted in the omentum in six patients with hemophilia A, no adverse events were reported (49c ).

ERYTHROPOIETIN AND DERIVATIVES (SED-14, 1128; SEDA-23, 364; SEDA-24, 388; SEDA-25, 402) Recombinant human erythropoietin (epoetin) was registered in the late 1980s for the treat-

Blood, blood components, plasma, and plasma products

Effective epoetin treatment has been reported in a transfusion-dependent b-thalassemia major patient: there were no adverse effects (63A ). In four patients with chronic diffuse gastrointestinal bleeding that was difficult to control, epoetin was successfully used as a hemostatic agent (64c ). Cardiovascular Hypertension, the most common adverse effect, has been observed in about 20% of 1500 patients with chronic renal insufficiency treated with epoetin or darbepoetin. It also occurs in patients with cancer, although with a lower incidence. In two of 44 cancer patients treated with epoetin during cisplatincontaining chemotherapy, epoetin was withdrawn owing to hypertension (diastolic pressure over 100 mmHg) (65c ). It is therefore recommended that blood pressure be monitored during treatment. Erythropoietin-induced hypertension can easily be treated by initiating or increasing antihypertensive medication (66R ). For example, two of 26 pregnant women treated with epoetin for iron deficiency anemia had worsening of mild hypertension, which was managed effectively with methyldopa 250 mg tds (58c ). Although the specific mechanism of epoetinrelated hypertension is unknown, theories have focussed on the possible role of stimulation of endothelin by epoetin (67c ). In 10 normotensive hemodialysis patients with severe anemia treated with epoetin there was increased adrenergic activity, which may contribute to hypertension during epoetin treatment (67c ). Epoetininduced hypertension may be associated with an angiotensinogen gene polymorphism; the incidence of hypertension was increased in patients carrying a homozygous T on position 235 of the angiotensinogen gene (68C ). The authors speculated that erythropoietin causes a rise in blood pressure via the T allele, which influences components of the renin–angiotensin system, thereby stimulating production of angiotensinogen, which leads to hypertension. In a randomized study of 180 patients with anemia due to hormone-refractory prostate cancer, who were treated with epoetin beta 1000 IU or 5000 IU subcutaneously 3 times a week for 12 weeks, cardiovascular events were more frequent with the higher dosage. Four patients had deep vein thrombosis and two had myocardial

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infarctions; all were taking the higher dosage. However, only one of the patients with deep vein thrombosis had a high hemoglobin concentration (51C ). Nervous system Hypertensive encephalopathy and seizures occur rarely in patients taking epoetin (69r ). Analysis of the safety of epoetin in cancer patients is often hampered by toxicity of the concomitant chemotherapy. In a prospective open study, three of 183 anemic cancer patients who did not receive chemotherapy complained of headache, possibly or probably related to epoetin (52c ). Complaints of dizziness and headache, possible due to epoetin, occurred in two of 44 cancer patients during cisplatincontaining chemotherapy (65c ). Hematologic The increase in hemoglobin concentration produced by epoetin has raised concerns of an increased risk of thromboembolic disease. However, in 26 patients the effect of epoetin on hemostasis was minimal, with only a clinically insignificant fall in the total amount of protein S. In contrast to earlier studies, this study did not show changes in the number of platelets or platelet function (70c ). Regular epoetin treatment in 39 hemodialysis patients with anemia did not result in adversely high blood viscosity and in an overview of data from 3000 patients there was no increase in shunt or fistula occlusion (71r ). Gastrointestinal In a prospective open study in 183 anemic cancer patients who did not receive chemotherapy, seven complained of nausea, possibly or probably related to epoetin (52C ). Skin Skin rashes have rarely been observed after epoetin treatment (50M ). Of 61 patients with malignancies of the oral cavity and oropharynx who were treated with epoetin before perioperative chemoradiation, one had a mild transient skin rash related to epoetin (72C ). Hair At the start of treatment with epoetin alpha for anemia, a 60-year-old man with nephrotic syndrome developed reversible total alopecia (73A ).

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Immunologic Formation of anti-erythropoietin antibodies has occurred following the use of epoetin alfa or beta. There is so far no evidence of antibody formation to darbepoetin alfa, probably in part owing to the fact that carbohydrate chains are rarely immunogenic (54R , 74C , 75c ). An allergic reaction led to early termination of epoetin treatment in one of 26 pregnant women treated with epoetin for iron deficiency anemia (58c ).

Risk factors Children In a multicenter, randomized, double-blind trial in 21 anemic HIV-infected children, that were concomitantly treated with antiretroviral drugs, epoetin was effective and safe (76C ). Anemia in preterm infants can also be treated with epoetin. In 30 preterm infants epoetin 300 µg/kg three times a week for 4 weeks reduced transfusion requirements without problems with tolerability (77C ). High doses of epoetin in children undergoing long-term hemodialysis is associated with increased heparin requirements during hemodialysis, suggesting that careful monitoring of thrombotic events, especially in small children who need catheters for hemodialysis access, is warranted (78c ).

Body temperature Of 183 anemic cancer patients who did not receive chemotherapy in a prospective open study, four had fever, possibly or probably related to the use of epoetin (52C ).

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45. Mauser-Bunschoten EP, Roosendaal G, Van den Berg HM. Product choice and haemophilia treatment in the Netherlands. Haemophilia 2001; 7: 96–8. 46. Liras A. Gene therapy for haemophilia: the end of a ‘royal pathology’ in the third millennium? Haemophilia 2001; 7: 441–5. 47. Dettweiler U, Simon P. Points to consider for ethics committees in human gene therapy trials. Bioethics 2001; 15: 491–500. 48. Rubanyi GM. The future of human gene therapy. Mol Aspects Med 2001; 22: 113–42. 49. Stephenson J. New therapies show promise for patients with leukemia, hemophilia, and heart disease. J Am Med Assoc 2001; 285: 153–5. 50. Turner R, Anglin P, Burkes R, Couture F, Evans W, Goss G, Grimshaw R, Melosky B, Paterson A, Quirt I. Epoetin alfa in cancer patients: evidencebased guidelines. J Pain Symptom Manage 2001; 22: 954–65. 51. Johansson JE, Wersäll P, Brandberg Y, Andersson SO, Nordström L. Efficacy of epoetin beta on hemoglobin, quality of life, and transfusion needs in patients with anemia due to hormone-refractory prostate cancer. Scand J Urol Nephrol 2001; 35: 288–94. 52. Quirt I, Robeson C, Lau CY, Kovacs M, Burdette-Radoux S, Dolan S, Tang SC, McKenzie M, Couture F. Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anaemia who are receiving chemotherapy. J Clin Oncol 2001; 19: 4126–34. 53. Ibbotson T, Goa KL. Darbepoetin alfa. Drugs 2001; 61: 2097–104. 54. Locatelli F, Del Vecchio L. Darbepoetin alfa Amgen. Curr Opin Invest Drugs 2001; 2: 1097– 104. 55. Kasper C. Recombinant human erythropoietin in the treatment of anemic patients with hematological malignancies. Ann Hematol 2001; 80: 319–29. 56. Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B, Winer E, Einhorn LH. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001; 19: 2875–82. 57. Wurnig C, Schatz K, Noske H, Hemon Y, Dahlberg G, Josefsson G, Milbrink J, Hamard C. Subcutaneous low-dose epoetin beta for the avoidance of transfusion in patients scheduled for elective surgery not eligible for autologous blood donation. Eur Surg Res 2001; 33: 303–10. 58. Sifakis S, Angelakis E, Vardaki E, Koumantaki Y, Matalliotakis I, Koumantakis E. Erythropoietin in the treatment of iron deficiency anemia during pregnancy. Gynecol Obstet Invest 2001; 51: 150–6. 59. Kaufman JS, Reda DJ, Fye CL, Goldfarb DS, Henderson WG, Kleinman JG, Vaamonde CA. Diagnostic value of iron indices in hemodialysis patients receiving epoetin. Kidney Int 2001; 60: 300–8.

60. Sautois B, Baudoux E, Salmon J-P, Michaux S, Schaaf-Lafontaine N, Pereira M, Paulus J-M, Fillet G, Beguin Y. Administration of erythropoietin and granulocyte colony-stimulating factor in donor/recipient pairs to collect peripheral blood progenitor cells (PBPC) and red blood cell units for use in the recipient after allogeneic PBPC transplantation. Haematologica 2001; 86: 1209–18. 61. Musto P, Sanpaolo G, D’Arena G, Scalzulli PR, Matera R, Falcone A, Bodenizza C, Perla G, Carotenuto M. Adding growth factors or interleukin-3 to erythropoietin has limited effects on anemia of transfusion-dependent patients with myelodysplastic syndromes unresponsive to erythropoietin alone. Haematologica 2001; 86: 44–51. 62. Neumeister P, Jaeger G, Eibl M, Sormann S, Zinke W, Linkesch W. Amifostine in combination with erythropoietin and G-CSF promotes multilineage hematopoiesis in patients with myelodysplastic syndrome. Leuk Lymphoma 2001; 40: 345–9. 63. Makis AC, Chaliasos N, Hatzimichael EC, Bourantas KL. Recombinant human erythropoietin therapy in a transfusion-dependent b-thalassemia major patient. Ann Hematol 2001; 80: 492–5. 64. Zaharia-Czeizler V. Erythropoietin stops chronic diffuse transfusion-dependent gastrointestinal bleeding. Ann Intern Med 2001; 135: 933. 65. Savonije JH, Spanier BWM, Van Groeningen CJ, Giaccone G, Pinedo HM. Decrease in the need for blood transfusions in cancer patients as a result of the use of epoetin alpha during cisplatincontaining chemotherapy. Ned Tijdschr Geneeskd 2001; 145: 878–81. 66. Tong EM, Nissenson AR. Erythropoietin and anemia. Semin Nephrol 2001; 21: 190–203. 67. Ksiazek A, Zaluska WT, Ksiazek P. Effect of recombinant human erythropoietin on adrenergic activity in normotensive hemodialysis patients. Clin Nephrol 2001; 56: 104–10. 68. Kuriyama S, Tomonari H, Tokudome G, Kaguchi Y, Hayashi H, Kobayashi H, Horiguchi M, Ishikawa M, Hara Y, Hosoya T. Association of angiotensinogen gene polymorphism with erythropoietin-induced hypertension: a preliminary report. Hypertens Res 2001; 24: 501–5. 69. Anonymous. Erythropoietin (Procit; Epogen) revisited. Med Lett Drugs Ther 2001; 43: 40–1. 70. Christensson AG, Danielson BG, Lethagen SR. Normalization of haemoglobin concentration with recombinant erythropoietin has minimal effects on blood haemostasis. Nephrol Dial Transplant 2001; 16: 313–19. 71. Silberberg J. Total correction of renal anaemia does not lead to adversely high blood viscosity. Erythropoiesis New Dimens Treat Anaemia 2001; 11: 25–6. 72. Glaser CM, Millesi W, Kornek GV, Lang S, Schüll B, Watzinger F, Selzer E, Lavey RS. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001; 50: 705–15.

Blood, blood components, plasma, and plasma products 73. Reddy V, Turney JH. Epoietin-alpha-associated total alopecia. Nephrol Dial Transplant 2001; 16: 1525. 74. Smith RE Jr, Jaiyesimi IA, Meza LA, Tchekmedyian NS, Chan D, Griffith H, Brosman S, Bukowski R, Murdock M, Rarick M, et al. Novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer. Br J Cancer 2001; 84 Suppl 1: 24–30. 75. Heatherington AC, Schuller J, Mercer AJ. Pharmacokinetics of novel erythropoiesis stimulating protein (NESP) in cancer patients: preliminary report. Br J Cancer 2001; 84: 11–16. 76. Rendo P, Freigeiro D, Barboni G, Donato H, Drelichman G, González F. A multicenter, random-

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ized, double-blind trial with recombinant human erythropoietin (rhuEPO) in anemic HIV-infected children treated with antiretrovirals. Int J Pediatr Hematol Oncol 2001; 7: 235–9. 77. Bader D, Kugelman A, Maor-Rogin N, Weinger-Abend M, Hershkowitz S, Tamir A, Lanir A, Attias D, Barak M. The role of high-dose oral iron supplementation during erythropoietin therapy for anemia of prematurity. J Perinatol 2001; 21: 215–20. 78. Seeherunvong W, Rubio L, Abitbol CL, Montane B, Strauss J, Diaz R, Zilleruelo G. Identification of poor responders to erythropoietin among children undergoing hemodialysis. J Pediatr 2001; 138: 710–14.

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34

Intravenous infusions— solutions and emulsions

PLASMA SUBSTITUTES

(SED-14, 1145; SEDA-23, 368; SEDA-24, 393; SEDA-25, 406)

Dextrans Urinary tract Acute renal insufficiency is a well-documented but infrequent complication of dextran infusion. Two further cases have been reported. The first involved an insulindependent diabetic recovering from a motor accident who required additional surgery (1A ). • A 45-year-old man with insulin-dependent diabetes, associated with nephropathy, neuropathy, and retinopathy, was given dextran 40 (25 ml/h) after orthopedic surgery. His urine output fell from 2–3 liters on postoperative day 1 to 40 ml/day on day 2 and his creatinine clearance fell from 54 to 32 ml/min. There were many casts in the urine. Dextran was withdrawn, but his creatinine clearance fell to 12 ml/min on day 5. On day 6 a large hematoma in the rectus sheath was drained, followed by plasmapheresis (to remove dextran) and hemodialysis. Over the next 24 h, his urine output increased to 2.2 l/day and his creatinine clearance increased to 20 ml/min. Plasmapheresis was repeated. Nine days later, his renal function had improved.

This is another case of dextran-induced renal insufficiency in a patient with pre-existing renal insufficiency, in this case caused by insulin-dependent diabetes mellitus of more than 30 years duration. The authors recommended that dextran should not be used in patients with chronic renal insufficiency and a creatinine clearance below 40 ml/minute. If dextran-induced renal insufficiency develops, dextran should be withdrawn and if renal function does not recover plasmapheresis should be used to remove the dextran load. © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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In the second report three cases of acute renal insufficiency occurred after low molecular weight dextran infusion; two of the patients had only received standard therapeutic doses (total 450 and 650 g) (2A ). In both of these cases a contrast medium was co-administered, and the authors suggested that this could have predisposed to acute renal insufficiency.

Hydroxyethyl starch (hetastarch) Skin In a retrospective study of the dosedependency of pruritus caused by hydroxyethyl starch, 50 consecutive patients were evaluated by questionnaire about 6 months after treatment; 37 returned the questionnaires, of whom 20 reported pruritus, lasting an average of 15 weeks (3c ). There was significantly more pruritus in patients who received more than 5 l of hydroxyethyl starch compared with those who received less than 5 l. The pruritus had a delayed onset and occurred in acute bouts lasting 2–30 min. The authors concluded that hydroxyethyl starch-induced pruritus is doserelated, and that in some cases it can be prolonged and severe. Hematologic High molecular weight hydroxyethyl starch has previously been reported to cause acquired type I von Willebrand’s disease. A recent report has suggested that medium molecular weight hydroxyethyl starch may have the same adverse effect. Of nine patients with hemostatic disorders, all treated with medium molecular weight hydroxyethyl starch (Elohes® ), six developed type I von Willebrand’s disease (4c ). Before the abnormalities in coagulation were discovered, the patients had received a mean dose of pentastarch of 121 ml/kg. The abnormalities resolved each time pentastarch was withdrawn. The authors

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Chapter 34

hypothesized that accumulation of starch probably led to quantitative defects of complex factor VIII and von Willibrand factor by accelerated elimination from the circulation of complexes attached to starch molecules. Because Elohes is highly substituted, it is difficult to break down and is therefore eliminated more slowly. Accumulation of Elohes after repeated administration may explain why its adverse effects on coagulation resemble those of high molecular weight starch, while other medium molecular weight starches affect coagulation much less. The authors recommended that the dose of Elohes® should be limited to 33 ml/kg/day and the cumulative dose to 80 ml/kg. Treatment should be given over no more than 3 days and Elohes is contraindicated in patients with coagulation disorders. Hydroxyethyl starch altered hemostasis in vitro in blood taken from patients undergoing abdominal surgery; the effect was more pronounced in patients with blood group O (5E ). The authors recommended that intraoperative hydroxyethyl starch should be restricted in patients with blood group O undergoing surgical procedures with a high risk of bleeding. Urinary tract Osmotic nephrosis-like lesions have been previously reported in kidney transplant patients who have received kidneys from brain-dead donors treated with hydroxyethyl starch. Two cases have recently been reported in which similar changes have been noted, accompanied by evidence of renal insufficiency. The first case occurred after the administration of hydroxyethyl starch during surgery (6A ). • A 67-year-old woman with no history of nephritis was given hydroxyethyl starch (500 ml) and Ringer’s lactate (2.5 l) for hypotension during surgery. Postoperatively she developed acute renal insufficiency (urine output below 600 ml/day) and her serum creatinine rose to 443 µmol/l, despite fluid challenge. Ultrasound showed no urinary obstruction, no thrombosis in the renal vessels, and normal kidneys. A renal biopsy showed major osmotic nephrosis-like lesions in the proximal tubules, but no lesions suggestive of acute tubular necrosis. Renal function returned to normal within 14 days after surgery.

The authors suggested that the renal insufficiency had been due to the perioperative infusion of hydroxyethyl starch, even though she received a much smaller dose (less than

375

10 ml/kg) than kidney donors usually receive. They further suggested that nephrotoxicity can occur within a few hours after even low-dose infusion of hydroxyethyl starch. The second case concerned a patient with polymyositis and hepatic cirrhosis (7A ). • A 20-year-old man from Mali with polymyositis that had not responded to prednisolone, monthly infusions of immunoglobulin, and plasma exchanges with albumin and modified gelatin, was given ciclosporin, which led to marked improvement. When he developed hepatic cirrhosis the ciclosporin was withdrawn and corticosteroids were reintroduced in association with plasma exchanges three times a week with 6% hydroxyethyl starch and 4% albumin. After seven plasma exchanges (cumulative dose 320 g) his serum creatinine rose to 216 µmol/l without proteinuria or hematuria. Renal biopsy showed diffuse microvacuolization of the tubular epithelial cells (osmotic nephrosislike lesions). Plasma exchange was restarted with 4% albumin alone, after which his renal function improved and the polymyositis stabilized.

The authors concluded that the most likely cause of renal insufficiency was hydroxyethyl starch-induced tubulopathy, and hypothesized that even low amounts of hydroxyethyl starch as replacement fluid in plasma exchange can cause renal tubular lesions in patients predisposed for other reasons (such as drugs or renal hypoperfusion) to renal insufficiency. In this context, albumin should be combined with replacement fluids other than hydroxyethyl starch. Reproductive system Ovarian hyperstimulation syndrome has been attributed to hydroxyethyl starch (8A ). • A 32-year-old Caucasian woman underwent IVF for primary tubal sterility and hyperandrogenemia as reflected by polycystic disease. Follicle formation was stimulated with FSH. The first stimulation cycle had to be discontinued because of threatened ovarian hyperstimulation syndrome. During the second attempt the dose of FSH was reduced to 100 IU/day for 10 days then 150 IU/day for 7 days, when follicles were observed. Ovulation was induced with a reduced dose of HCG (5000 IU). She was given crystalloids, 50 ml of serum albumin 20%, and 500 ml of medium molecular weight hydroxyethyl starch 10% (HEAS® , Fresenius). This was repeated on days 5–8 and 11–15, this time with high molecular weight hydroxyethyl starch 6% (Plasmasteril® , Fresenius), together with other fluids. After 4 days she developed massive ascites, abdominal pain, dysnea, hemoconcentration, and a leukocytosis of 27 × 109 /l. Her girth increased between days 7 and 12, and continuous

376 abdominal paracentesis over 6 days was necessary. Her renal function was supported using diuretics and by a continuous infusion of dopamine. On day 17 she developed increased dyspnea and headache and a pleural effusion. Her anemia was severe (hemoglobin 7.8 g/dl) and nearly all the factors in the intrinsic coagulation cascade were greatly reduced. Disseminated intravascular coagulopathy and primary liver disease were excluded. The pleural effusion contained a high concentration of hydroxyethyl starch (74% of the plasma concentration). She gradually improved and was discharged on day 36.

The authors concluded that the most likely cause of severe ovarian hyperstimulation syndrome was overinfusion of hydroxyethyl starch.

Polygeline Immunologic Severe life-threatening anaphylaxis to polygeline (Haemaccel® ) has been reported (9c ). • A 45-year-old woman, who had used salbutamol and budesonide inhalers and oral theophylline for asthma and who had developed bronchospasm during induction of general anesthesia 6 weeks before, was readmitted for surgery under spinal anesthesia. During the procedure she developed two episodes of hypotension, which was corrected with fluids and intravenous mephentermine 6 mg. When blood loss reached 750 ml she was given an infusion of 3.5% Haemaccel, and 10 minutes later complained of respiratory difficulty and developed severe respiratory distress. Haemaccel was withdrawn and she was given 100% oxygen with halothane by facemask. The oxygen saturation fell by more than 80% and she developed severe bradycardia and ventricular fibrillation. She was resuscitated.

The authors concluded that the severe reaction had been due to Haemaccel® , despite careful preparation of the patient with corticosteroids and antihistamines. They recommended that the use of polygeline was therefore inappropriate and should be avoided in any patient with reactive airway disease. Preoperative antihistamines and corticosteroids may not prevent reactions induced by polygeline administration in such patients. There has been another example of a severe reaction to a polygeline product, which led to cardiac collapse (10c ). • A 46-year-old man with diabetes mellitus and a history of allergy to penicillin, seafood, and soap

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M.C. Allwood

had spinal anesthesia, and his systolic blood pressure fell to 90 mmHg. He was given 500 ml of gelafundin. Within minutes, he complained of pruritus along the drip site. There was no rash or uticaria, but the infusion was stopped immediately. He became restless, had copious oral secretions, complained of dyspnea, quickly lost consciousness, and was bradycardic and hypotensive, with a systolic blood pressure of 65 mmHg. He was given Hartman’s solution, Haesteril® 6%, adrenaline, and atropine. He had a markedly raised IgE concentration (16000 iu/ml). He eventually recovered.

The authors suggested that the sequence of events strongly suggested an anaphylatic reaction to gelafundin and concluded that while polygelines are useful volume substitutes they should be used carefully in atopic individuals or those with previous drug allergies. Hydroxyethyl starch is considered a safer alternative in such patients.

MANNITOL

(SED-14, 1162)

Psychiatric Acute mania has been reported in a patient who was given intravenous mannitol (11A ). • A previously well 75-year-old woman without a personal or family history of mental disorders developed severe major depression. And was given nortriptyline 50 mg/day. After 10 days a diagnosis of bilateral acute angle-closure glaucoma was made and she was given a continuous intravenous infusion of mannitol 20%, oral acetazolamide 500 mg, and topical pilocarpine 2%, timolol 0.5%, and dexamethasone 0.1% (each 1 drop every 15 minutes). She became euphoric 30 minutes later and remained overactive, overly affectionate, and talkative, telling jokes, with pressured speech and flight of ideas. Her manic state remitted 1 hour after the end of the mannitol infusion and her severe depression recurred dramatically.

Mannitol can cause both acute expansion of extracellular fluid volume and a rapid reduction of intracellular fluid volume with retention of brain electrolytes; these may have been the mechanisms in this case. Skin Extravasation is one of the common complications seen with intravenous infusion. In a case of subcutaneous extravasation of mannitol there was swelling and multiple cutaneous

Intravenous infusions—solutions and emulsions

Chapter 34

bullous eruptions in the hand and forearm during craniotomy (12A ). This case emphasizes the risk of local reactions to hypertonic substances and stresses the importance of identifying and maintaining a proper intravenous infusion site.

PARENTERAL NUTRITION (SED-14, 1150; SEDA-23, 369; SEDA-24, 395; SEDA-25, 407) Liver The link between cholestatic jaundice in infants receiving parenteral nutrition and manganese intake continues to be investigated. The most recent investigation comprised a randomized controlled study on a group of 244 infants (13C ). These were randomized into two groups, the first (n = 123) received lower concentrations of manganese (0.0182 µmol/kg/day as Peditrace® 1 ml/kg/day) while the second (n = 121) received 1 µmol/kg/day (as Pedel® 4 ml/kg/day). All other components of the parenteral nutrition regimen were standardized. Monitoring comprised whole-blood manganese and serum direct bilirubin concentrations, the indicator for the development of cholestasis being a peak bilirubin concentration over 50 µmol/l. Those who were given extra manganese had higher peak whole blood manganese concentrations and higher peak serum

377

direct bilirubin concentrations, but the differences were not significant. The two groups did not differ in terms of the occurrence of cholestasis (63/121 vs 57/123), but more infants in the high manganese group developed a more severe degree of hyperbilirubinemia. The authors concluded that the pathogenesis of cholestasis during parenteral nutrition is probably multifactorial, and that a high manganese intake is a significant contributory factor. The link between cholestasis during home parenteral nutrition and inflammatory markers has been investigated in 17 patients on longterm home parenteral nutrition and 10 agematched and sex-matched controls (14c ). Liver enzyme concentrations were used as markers of liver disease. Circulating inflammatory and immune markers were determined as measures of inflammatory activity. There were abnormal liver function tests in 14 of the patients. Alkaline phosphatase was positively correlated with markers of persistent inflammation and immune activation. Liver enzyme activities were also related to the amounts of total intravenous calories and calories originating from carbohydrates, but not lipids, in contrast to other recent data. The authors suggested that these results confirm that the number of infused calories contributes to liver toxicity in patients receiving home parenteral nutrition and strongly imply that sustained inflammation is probably a key factor in worsening the associated cholestasis.

REFERENCES 1. Brooks D, Okeefe P, Buncke HJ. Dextraninduced acute renal failure after microvascular transplantation. Plast Reconstr Surg 2001; 108: 2057–60. 2. Kato A, Yonemura K, Matsushima H, Ikegaya N, Hishida A. Complication of oliguric acute renal failure in patients treated with low-molecular weight dextran. Renal Fail 2001; 23: 679–84. 3. Kimme P, Jannsen B, Ledin T, Gupta A, Vegfors M. High incidence of pruritus after large doses of hydroxyethyl starch (HES) infusions. Acta Anaesthesiol Scand 2001; 45: 686–9. 4. Jonville-Bera A-P, Autret-Leca E, Gruel Y. Acquired type I von Willebrand’s disease associated with highly substituted hydroxyethyl starch. New Engl J Med 2001; 345: 622–3. 5. Huraux C, Ankri AA, Eyraud D, Sevin O, Menegaux F, Coriat P, Samama CM. Hemostatic changes in patients receiving hydroxyethyl starch: The in-

fluence of ABO blood group. Anesth Analg 2001; 92: 1396–401. 6. De Labarthe A, Jacobs F, Blot F. Acute renal failure secondary to hydroxyethylstarch administration in a surgical patient. Am J Med 2001; 111: 417–18. 7. Peron S, Mouthon L, Guettier C, Brechgnac S, Cohen P, Guillevin L. Hydroxyethyl starch-induced renal insufficiency after plasma exchange in a patient with polymyositis and liver cirrhosis. Clin Nephrol 2001; 55: 408–11. 8. Kissler S, Nedihardt B, Siebzehnrubl E, Schmitt H, Tschaikowsky K, Wildt L. The detrimental role of colloidal volume substitutes in severe ovarian hyperstimulation syndrome: a case report. Eur J Obst Gynecol Reproduc Biol 2001; 99: 131–4. 9. Kathirvel S, Podder S, Batra YK, Malhotra N, Mahajan R. Severe life threatening reaction to Haemaccel, in a patient with bronchial asthma. Eur J Anaesthesiol 2001; 18: 122–3.

378 10. Ong EL. A case of hypersensitivity to gelafundin. Singapore Med J 2001; 42: 176–7. 11. Navarro V, Vieta E, Gasto C. Mannitol-induced acute manic state. J Clin Psychiatry 2001; 62: 126. 12. Chang KA, Jawan B, Luk HN, Fung ST, Lee JH. Bullous eruptions caused by extravasation of mannitol—a case report. Acta Anaesthesiol Sin 2001; 39: 195–8. 13. Fok TF, Chui KKM, Cheung R, Ng PC, Cheung KL, Hjelm M. Manganese intake and cholestatic

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jaundice in neonates receiving parenteral nutrition: a randomised controlled study. Acta Paediatr Int J Paediatr 2001; 90: 1009–15. 14. Reimund J-M, Duclos B, Arondel Y, Baumann R. Persistent inflammation and immune activation contribute to cholestasis in patients receiving home parenteral nutrition. Nutrition 2001; 17: 300–4.

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35

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

COUMARIN CONGENERS (SED-14, 1184; SEDA-23, 377; SEDA-24, 398; SEDA-25, 411) Drug interactions In a case-control study in 300 previously stable out-patients taking phenprocoumon or acenocoumarol with INR values of 6 or more and 302 matched controls with INR values within the target range potentially interacting drugs were predominantly antibacterial drugs (1C ). A course of co-trimoxazole was associated with a large increase in the risk of excess anticoagulation (adjusted OR = 24; 95% CI = 2.8, 209) and co-amoxiclav was associated with a small increase in risk (OR = 2.4; 95% CI = 1.0, 5.5). Of 87 potentially interacting drugs 45 were not used during the 4-week study and only 15 drugs were used by at least 10 patients. The authors concluded that unless no therapeutic alternative is available, co-trimoxazole and coamoxiclav should be avoided in patients taking coumarins. If no therapeutic alternative is available, increased monitoring of INR values is warranted to prevent overanticoagulation and potential bleeding complications. Sevelamer, a non-absorbed phosphate-binding polymer, in a dose of 2.4 g, had no effect on the pharmacokinetics of single doses of warfarin in 19 healthy volunteers (2C ).

HEPARINS

(SED-14, 1177)

Liver During treatment with low molecular weight heparins three patients developed in© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

creased transaminases, which returned to normal after withdrawal (3A , 4A ). Skin Two renal transplant recipients developed calcinosis cutis (tender erythematous subcutaneous nodules with induration, ulceration, and necrosis), confirmed by bone scan and biopsies, at the site of subcutaneous administration of nadroparin (5A ). Both had secondary hyperparathyroidism and a raised calcium– phosphate product at the time of administration. The authors suggested that the high concentration of calcium in nadroparin (220 mmol/l) had been an important factor, since in the same patients subcutaneous injections of nicomorphine or dalteparin (a sodium salt of low molecular weight heparin) did not cause subcutaneous nodules. Three more cases were found after retrospective examination of all 51 adult patients who underwent a renal transplantation in the same hospital during 7 months, and no other cases of calcinosis cutis at the injection sites of low molecular weight heparins were observed after nadroparin was replaced by dalteparin.

HIRUDIN The effects on activated partial thromboplastin time and the incidence and clinical relevance of antihirudin antibodies in patients treated with lepirudin have been studied using data from two prospective multicenter studies, in which patients with heparin-induced thrombocytopenia received one of four intravenous lepirudin dosage regimens (6C ). Of 196 evaluable patients 87 (44%) had IgG antihirudin antibodies. The development of antihirudin antibodies depended on the duration of

379

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treatment (antibody-positive patients 18.6 days vs. antibody-negative patients 11.6 days). Antihirudin antibodies were not associated with increases in clinical endpoints (limb amputation, new thromboembolic complications, or major bleeding). In 23 of 51 evaluable patients in whom antihirudin antibodies developed during treatment with lepirudin the antibodies enhanced the anticoagulatory effect of lepirudin. During prolonged treatment with lepirudin, anticoagulatory activity should be monitored daily.

DRUGS THAT ALTER PLATELET FUNCTION Clopidogrel

(SED-14, 1194; SEDA-23, 378; SEDA-24, 399) Hematologic Fatal aplastic anemia has been reported in two patients taking clopidogrel (7A , 8A ). Aplastic anemia was diagnosed 5 months after starting clopidogrel in the first patient and after 3 months in the second. Both patients died from infection (sepsis and pneumonia). Except for allopurinol in the first case, these patients did not take any medications associated with aplastic anemia. Immunologic Severe hypersensitivity been associated with clopidogrel (9A ).

has

• A 57-year-old man took clopidogrel after a myocardial infarction and after 5 days developed a fever, rash, pruritus, and abdominal pain. Three days later he developed shock. He had thrombocytopenia, lymphopenia, aseptic leukocyturia, and raised serum aminotransferases, amylase, and gglutamyltranspeptidase activities. Blood cultures were negative. Clopidogrel was withdrawn and within 1 week he had completely recovered and all blood tests had returned to normal. One month later, the patient took clopidogrel again; 4 hours later the same symptoms reappeared, with aseptic leukocyturia and raised aminotransaminases and gglutamyltranspeptidase. Drug hypersensitivity was suspected and clopidogrel was withdrawn. All the symptoms disappeared within a few days and did not recur during the following year.

It is highly probable that this reaction was provoked by clopidogrel because of the positive rechallenge and because the patient did not take any other drug.

K. Peerlinck and J. Vermylen

Dipyridamole (SED-14, 1698; SEDA-24, 398; SEDA-25, 412) Dipyridamole has been marketed since 1959, originally as an antianginal drug on the basis of its acute coronary vasodilatory effect; the addition of atropine to dipyridamole for stress echocardiography increases the sensitivity of the test without loss of specificity and without worsening its safety profile (10R ). Cardiovascular A 43-year-old man developed an acute myocardial infarction immediately after exercise and pharmacological stress echocardiography with dipyridamole + atropine 1 month after successful stent implantation (11A ). In an assessment of the efficacy and safety of dipyridamole in the treatment of patients with chronic stable angina in a large-scale, international, randomized, placebo-controlled, parallel group study, 400 patients with chronic stable angina pectoris and a positive treadmill exercise test were randomized to receive either modified-release dipyridamole (200 mg bd orally; n = 198) or placebo (n = 202) for 24 weeks as an add-on to conventional antianginal therapy and for 4 additional weeks as monotherapy, the latter after withdrawal of standard treatment with calcium channel blockers and/or beta-blockers and/or long-acting (prophylactic) nitrates (12C ). Of the 198 patients randomized to dipyridamole, 134 completed the add-on phase but only 12 completed the monotherapy phase. Of the 202 patients randomized to placebo, 162 reached the addon phase but only 12 reached the monotherapy phase. There were serious adverse events in 15 patients who took dipyridamole and 12 who took placebo (7.6 vs. 6.0%). These included chest pain, angina pectoris, and non-cardiac adverse effects, such as diarrhea, nausea, and headache. A 59-year-old man developed unstable angina 1 month after coronary artery bypass surgery (13c ). During dipyridamole scintigraphy, 2 minutes after the beginning of dipyridamole infusion, ST segment elevation occurred in the inferior electrocardiographic leads and there were two marked anteroseptal and inferior defects on myocardial scintigraphy.

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

Ticlopidine

(SED-14, 1193; SEDA-23, 378; SEDA-24, 399; SEDA-25, 413)

A lupus-like illness (fever, rash, arthritis, renal involvement, and positive antinuclear and antihistone antibodies) developed in three patients 2–8 weeks after they started to take ticlopidine (14A ). After withdrawal there was slow but compete resolution in all patients.

ANTIFIBRINOLYTIC DRUGS

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381

• A 21-year-old man developed oliguria and uremia after 3 days of treatment with tranexamic acid 3 g/day for epistaxis. He did not recover. Renal angiography showed reduced cortical contrast enhancement, compatible with renal cortical necrosis. No other risk factors for renal cortical necrosis were present in this patient.

Renal impairment associated with acute renal cortical necrosis caused by tranexamic acid is rare. The authors found only three previously reported cases in English, of which at least one other was without any known risk factor for acute renal cortical necrosis (16A ).

(SED-14, 1192; SEDA-23, 378; SEDA-24, 309; SEDA-25, 413)

Tranexamic acid Acute renal cortical necrosis has been attributed to tranexamic acid in a patient with hemophilia A (15A ).

REFERENCES 1. Penning-Van Beest FJA, Van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs. Clin Pharmacol Ther 2001; 69: 451–7. 2. Burke S, Amin N, Incerti C, Plone M, Watson N. Sevelamer hydrochloride (Renagel), a nonabsorbed phosphate-binding polymer, does not interfere with digoxin or warfarin pharmacokinetics. J Clin Pharmacol 2001; 41: 193–8. 3. Carlson MK, Gleason PP, Sen S. Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and lowmolecular-weight heparin-induced hepatotoxicity. Pharmacotherapy 2001; 21: 108–13. 4. Hui CK, Yuen MF, Ng IO, Tsang KW, Fong GC, Lai CL. Low molecular weight heparin-induced liver toxicity. J Clin Pharmacol 2001; 41: 691–4. 5. Van Haren FMP, Ruiter DJ, Hilbrands LB. Nadroparin-induced calcinosis cutis in renal transplant recipients. Nephron 2001; 87: 279–82. 6. Eichler P, Friesen HJ, Lubenow N, Jaeger B, Greinacher A. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000; 96: 2373–8. 7. Trivier JM, Caron J, Mahieu M, Cambier N, Rose C. Fatal aplastic anaemia associated with clopidogrel. Lancet 2001; 357: 446. 8. Meyer B, Staudinger T, Lechner K. Clopidogrel and aplastic anaemia. Lancet 2001; 357: 1446–7.

9. Sarrot-Reynauld F, Bouillet L, Bourrain JL. Severe hypersensitivity associated with clopidogrel. Ann Intern Med 2001; 135: 305–6. 10. Picano E, Pingitore A, Conti U, Kozakova M, Boem A, Cabani E, Ciuti M, Distante A, L’Abbate A. Enhanced sensitivity for detection of coronary artery disease by addition of atropine to dipyridamole echocardiography. Eur Heart J 1993; 14: 1216–22. 11. Nedeljkovic MA, Ostojic M, Beleslin B, Nedeljkovic IP, Stankovic G, Stojkovic S, Saponjski J, Babic R, Vukcevic V, Vistic AD, Orlic D. Dipyridamole–atropine-induced myocardial infraction in a patient with patent epicardial coronary arteries. Herz 2001; 26: 485–8. 12. Picano E. Dipyridamole in chronic stable angina pectoris. Eur Heart J 2001; 22: 1785–93. 13. Wartski M, Caussin C, Lancelin B. Spasme coronaire plurifocal declenche par l’injection de dipyridamole. Med Nucl 2001; 25: 153–9. 14. Braun-Moscovici Y, Schapira D, BalbirGurman A, Sevilia R, Menachem Nahir A. Ticlopidine-induced lupus. J Clin Rheumatol 2001; 7: 102–5. 15. Odabas AR, Cetinkaya R, Selcuk Y, Kaya H, Coskun U. Tranexamic-acid-induced acute renal cortical necrosis in a patient with haemophilia A. Nephrol Dial Transplant 2001; 16: 189–90. 16. Koo JR, Lee YK, Kim YS, Cho WY, Kim HK, Won NH. Acute renal cortical necrosis caused by an antifibrinolytic drug (tranexamic acid). Nephrol Dial Transplant 1999; 14: 750–2.

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ANTIEMETICS Cisapride

(SED-14, 1223; SEDA-23, 380; SEDA-24, 401, SEDA-25, 416)

Cardiovascular The efficacy and tolerability of cisapride in children has been reviewed (1R ). The published data suggest that cisapride can cause prolongation of the QTc interval. However, provided that precautions for its administration are followed, the most relevant being correct dosage and the avoidance of concurrent treatment with macrolides and/or azoles, QTc prolongation is consistently without clinically important adverse effects. The effect of cisapride 0.2 mg/kg tds for 8 weeks on cardiac rhythm has been studied in a placebo-controlled, double-blind trial in 49 children aged 0.5–4 years with gastroesophageal reflux resistant to other medical therapy (2C ). None had underlying cardiac disease or electrolyte imbalance. Cisapride had no effect on cardiac electrical function. However, in a prospective study cisapride 2 mg/kg qds given for 72 h to 10 premature infants caused a significant increase in the QTc interval compared with pretreatment values (3c ). The relation between cisapride plasma concentrations, QTc interval, and cardiac rhythm has been evaluated in a controlled study in 211 infants undergoing routine 8-hour polysomnography (4C ). Cisapride was given for at least 4 days. At comparable doses of cisapride and comparable plasma concentrations, the QTc was significantly higher in infants below 3 months of age. In a postmarketing study of the safety of cisapride during 1993–9, 341 patients had cardiac effects, of whom 80 (23%) died, the deaths being directly or indirectly associated with a dysrhythmic event (5C ). The cardiac effects included QT prolongation, torsade de pointes, © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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polymorphous ventricular tachycardia, ventricular fibrillation, ventricular tachycardia, cardiac arrest, unspecified “serious” dysrhythmias, and sudden death. In most instances the dysrhythmia occurred in the presence of risk factors such as other drugs or medical conditions. Drug interactions A possible interaction between cisapride and digoxin has been reported (6A ). • A 90-year-old woman took cisapride, first in a dose of 5 mg bd and then 5 mg tds. She had been taking digoxin for a long time, but the serum digoxin concentration began to fall gradually after cisapride was given, from 1.1 nmol/l in January to 0.7 nmol/l in March and 0.5 nmol/l in August. The tablets were of reportedly high dissolution rate, with an onset of action at 30–60 minutes and a peak effect at 4–6 hours after a single dose. The onset of action of cisapride is 30–60 minutes, but the duration of its promotility effect during multiple dose therapy is not clear. The drugs were then separated by 4 hours, with the aim of reducing the promotility effect of cisapride on digoxin absorption, and there was an improvement in both clinical response and digoxin concentration.

The authors speculated that cisapride reduced digoxin absorption by accelerating bowel transit time.

5-HT3 RECEPTOR ANTAGONISTS (SED-14, 1225; SEDA-23, 381; SEDA-24, 401, SEDA-25, 417) The antiemetic effect of combined intravenous ondansetron 8 mg, oral dexamethasone 20 mg, and oral lorazepam 0.5 mg was significantly better than that of intravenous metoclopramide 10 mg, dexamethasone 20 mg, and oral lorazepam 0.5 mg in 30 patients receiving chemotherapy for ovarian cancer in a randomized trial (7c ). All the antiemetics were given

Gastrointestinal drugs

30 minutes before and 6 hours after chemotherapy. Significantly more patients given metoclopramide (40% compared with 13%) complained of adverse effects. The most frequent adverse effects with both regimens were sedation and headache. Intravenous ondansetron (4 mg at induction of anesthesia and 0.13 mg with each 1 mg bolus of morphine) has been compared with intravenous droperidol (0.5 mg at induction and 0.05 mg with each bolus of morphine) in a double-blind trial in 142 patients (8C ). The two regimens had similar efficacy in the prevention of postoperative nausea and vomiting. The most important adverse effect was sedation; significantly more patients given droperidol (15%) had excessive sedation than patients given ondansetron (5%). The efficacy of converting from intravenous ondansetron to oral granisetron in preventing chemotherapy-induced nausea and vomiting has been assessed in 608 patient interviews (9C ). There was no difference in the control of nausea and vomiting between the two treatments. Patient compliance increased from 48% to 78% after the use of oral granisetron. The costs of preventing acute chemotherapyinduced nausea and vomiting also fell, from US $107 to US $65 per treatment.

Alosetron

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(SEDA-25, 418)

Gastrointestinal Constipation is a common adverse effect of alosetron. In 30 patients (15 men, 15 women) using scintigraphy to measure bowel transit, alosetron 1 mg bd for 6 weeks caused significantly delayed small bowel and colonic transit times (10c ). This effect was significantly greater in the women. Alosetron 1 mg bd was significantly more effective than placebo in the treatment of diarrhea-predominant irritable bowel syndrome in a multicenter, double-blind, placebo-controlled study in 801 women (11C ). Constipation was the most frequently reported adverse effect. The tolerability and safety of alosetron 1 mg bd during long-term administration (48 weeks) has been studied in a multicenter, double-blind, placebo-controlled trial in 859 subjects (12C ). Alosetron was generally well tolerated. The frequencies of adverse events were similar in the

two groups, with the exception of constipation, which occurred significantly more often in the treatment group (32% compared with 5%). In most cases (72%) constipation was mild to moderate. There were two deaths in subjects with pre-existing cardiovascular risk factors in the treatment group, but neither was attributed to alosetron. A dose-ranging, randomized, placebo-controlled, multicenter trial has been performed in 320 patients to assess the benefit of alosetron in functional dyspepsia (13C ). Alosetron 0.5 mg bd and 1 mg bd showed potential benefit over placebo in symptom control. Women showed significantly greater responses than men. Constipation was the most commonly reported adverse effect of alosetron (49% compared with 13% in the placebo group). In a randomized, double-blind, placebocontrolled trial in 626 women with diarrheapredominant irritable bowel syndrome, alosetron 1 mg bd was significantly more effective than placebo in controlling symptoms (14C ). Constipation was the most common adverse effect of alosetron (25% compared with 5% in the placebo group). Ischemic colitis has been attributed to alosetron (15A ). • A 55-year-old man with irritable bowel syndrome who took alosetron 1 mg bd for 4 days developed symptoms of ischemic colitis, including rectal bleeding, and the diagnosis was confirmed macroscopically and histologically at colonoscopy. The symptoms suggestive of colitis abated on withdrawal of alosetron, but the symptoms of irritable bowel syndrome returned. Colonoscopy 2 weeks later showed a normal colon and biopsies showed normal colonic histology.

Drug interactions In an open-label, nonrandomized, crossover study in 12 healthy female and male volunteers alosetron 1 mg bd had no effect on the pharmacokinetics of fluoxetine 20 mg/day) (16c ). Co-administration of the two drugs was well tolerated by all the subjects.

Granisetron

(SEDA-25, 418)

Oral granisetron 2 mg has been studied in the prophylaxis of nausea and vomiting following fractionated upper abdominal radiotherapy in a double-blind, placebo-controlled trial in

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160 patients (17C ). Granisetron was significantly more effective than placebo. The common adverse effects attributed to granisetron were diarrhea, weakness, and constipation.

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H.J. de Silva

trial in 994 individuals with heartburn in an “at-home” setting (21C ). Nizatidine relieved heartburn significantly faster and/or more consistently than placebo. Nizatidine was well tolerated and the frequencies of adverse events were similar in the two groups.

(SEDA-25, 418)

In a randomized, double-blind, placebo-controlled study, intravenous tropisetron 2 mg and 5 mg was effective in preventing emesis in 60 patients who underwent general anesthesia (18c ). Both doses of tropisetron were equally effective. Adverse effects were not mentioned.

HISTAMINE H2 RECEPTOR ANTAGONISTS (SED-14, 1225; SEDA-23, 382; SEDA-24, 402; SEDA-25, 419) The effects of ranitidine 75 mg, famotidine 10 mg, and placebo, given 1 hour after a standard lunch, on intragastric acidity have been compared in 24 healthy volunteers (19c ). Lowdose ranitidine and famotidine reduced acidity significantly more than placebo during the daytime and night-time. The effect of ranitidine was significantly greater than famotidine during the first 2.5 h after dosing.

Cimetidine Nervous system A dystonic reaction has been attributed to cimetidine (20A ). • A 39-year-old woman developed a dystonic reaction (masseter spasm, lip smacking, oculogyric crisis, and mild neck spasm) within 5 min of intravenous administration of cimetidine 300 mg for epigastric pain. She was an epileptic who had not taken her anticonvulsant regularly. She had developed a similar dystonic reaction to prochlorperazine 1 week before. She recovered within 5 minutes of treatment with intravenous diphenhydramine and lorazepam.

Nizatidine The efficacy and safety of nizatidine 75 mg/day have been studied in a placebo-controlled

Ranitidine In a randomized, placebo-controlled, four-way, crossover study of the effects of low-dose ranitidine and an antacid on meal-induced heartburn and acidity in 26 subjects, ranitidine 75 mg significantly reduced gastric but not esophageal acidity, calcium carbonate 420 mg significantly reduced esophageal but not gastric acidity, and ranitidine plus calcium carbonate reduced both esophageal and gastric acidity (22c ). Both drugs given alone reduced heartburn severity compared with placebo. Urinary tract Acute interstitial nephritis in a cadaveric renal allograft occurred in a 44-yearold man who had taken ranitidine 150 mg bd for 2 days (23A ). Allograft function improved rapidly and returned to normal after ranitidine was withdrawn. Skin Stevens–Johnson syndrome has been reported in two patients, a 62-year-old woman and a 58-year-old man, with severe liver disease and jaundice, who had taken ranitidine 150 mg bd; both recovered on withdrawal (24A ).

PROTON PUMP INHIBITORS (SED-14, 1230; SEDA-23, 383; SEDA-24, 402, SEDA-25, 420) Esomeprazole 40 mg/day and omeprazole 20 mg/day for 8 weeks have been compared in the treatment of erosive esophagitis in a multicenter, randomized, double-blind trial in 2425 patients (25C ). Significantly more patients were healed with esomeprazole. There was no significant difference in reported adverse events between the treatment groups. The most commonly reported were headache, diarrhea, and nausea.

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Pantoprazole 20 mg/day and omeprazole 20 mg/day for 8 weeks have been compared in the treatment of grade I reflux esophagitis in a multicenter, randomized, open trial in 328 patients (26C ). Symptom relief and healing rates were similar and both treatments were well tolerated. There was no significant difference in reported adverse events between the groups. The most commonly reported were nausea, diarrhea, and headache. Lansoprazole 30 mg/day and omeprazole 20 mg/day for 8 weeks have been compared in the relief of heartburn in a multicenter, randomized, double-blind trial in 3510 patients with erosive esophagitis (27C ). Symptom control was significantly more effective and faster with lansoprazole than omeprazole. Both drugs were well tolerated. The most common adverse effect was diarrhea. Rabeprazole 10 mg bd or 20 mg/day, omeprazole 20 mg/day, and placebo for 7 days in reducing esophageal acid exposure have been compared in a multicenter, randomized, double-blind trial in 82 patients with symptomatic gastro-esophageal reflux disease (28C ). Esophageal pH was monitored for 24 hours before treatment and on day 7. Esophageal acid exposure was significantly reduced in all the treatment groups compared with placebo, with no significant difference in efficacy. Both rabeprazole and omeprazole were well tolerated. The most commonly reported adverse effects were diarrhea, abdominal pain, nausea, and headache. Cardiovascular Reversible peripheral edema has been reported in five women taking the proton pump inhibitors omeprazole, lansoprazole, or pantoprazole for 7–15 days for peptic disorders in recommended standard doses (29A ). Edema disappeared within 2–3 days of withdrawal and reappeared in all five patients after re-exposure. High-dose intravenous infusions of omeprazole and pantoprazole (8 mg/hour) caused peripheral edema in three of six young female volunteers and two of six female volunteers respectively. The edema disappeared within 24 hours of stopping the infusion. Similar high doses of omeprazole did not produce edema in male volunteers. Subsequent studies performed on 10 female volunteers to elucidate the cause of the edema did not show any changes in concentrations of serum hormones or C1 esterase inhibitor.

Esomeprazole To assess symptom control, esomeprazole 20 mg on demand has been compared with placebo on demand (maximum of one dose a day) for 6 months in a multicenter, doubleblind study in 342 endoscopy-negative patients with gastro-esophageal reflux disease (30C ). There was complete resolution of heartburn after 4 weeks of daily esomeprazole therapy. On-demand therapy with esomeprazole was significantly more effective than placebo in controlling symptoms. The frequencies of adverse effects and laboratory profiles were similar in the two groups when adjusted for the time spent in the study. To examine the pharmacokinetics and pharmacodynamics of esomeprazole, 12 healthy men took once-daily esomeprazole 5, 10, or 20 mg, or omeprazole 20 mg for 5 days in a crossover study (31c ). The pharmacokinetics of esomeprazole were time- and dose-dependent. There was greater acid inhibition with esomeprazole compared with omeprazole.

Omeprazole The use of omeprazole in the treatment of acidrelated disorders in children has been reviewed (32R ). Different formulations of the drug have been used in children aged 2 months to 18 years for the treatment of erosive esophagitis, gastric and duodenal ulcer, Helicobacter pylori infection, and related conditions in dosages of 5–80 mg/day (0.2–3.5 mg/kg/day). The initial dose most consistently reported to heal esophagitis and relieve symptoms of gastro-esophageal reflux disease appears to be 1 mg/kg/day. Omeprazole was well tolerated during both acute and chronic use. Omeprazole, in a starting dose of 0.7 mg/kg/ day, was effective in the treatment of severe esophageal reflux after failed fundoplication in 18 children (mean age at presentation 7.8 years) over a mean follow-up period of 4.4 years (33c ). It was also well tolerated. A hyperplastic polyp was noted in one child after 38 months of treatment and persisted without any dysplastic change. One to three gastric nodules were seen in three children after a mean of 45 months; histology of the nodules showed only mucosal edema.

386 To investigate the pharmacokinetics of omeprazole MUPS tablets and its encapsulated form, 38 healthy male volunteers were given a single 20 mg oral dose of each formulation in a crossover study (34c ). Encapsulation did not influence the extent and rate of absorption of the drug, demonstrating bioequivalence. Both formulations were well tolerated. The most commonly reported adverse effect with both formulations was headache. The effect on serum gastrin concentrations of omeprazole 20 mg/day and 20 mg on alternate days given long-term has been studied in 53 patients with reflux esophagitis in a controlled trial (35c ). The mean serum gastrin concentration was significantly raised in the first group. Gastrin concentrations in the alternate day treatment group were similar to controls who did not take omeprazole. Urinary tract Acute interstitial nephritis has been reported in a 36-year-old woman who had taken omeprazole 20 mg/day for 3 months (36A ). The drug was withdrawn and she made a full recovery after 4 weeks of steroid therapy. Skin Erythroderma has been reported in a 58-year-old woman with scleroderma who had taken omeprazole 20 mg/day for 6 months (37A ). She made a full recovery after omeprazole was withdrawn. She was then given pantoprazole 40 mg/day, which was well tolerated. Drug interactions The effect of acid secretion blockade by omeprazole 20 mg/day for 5 days on the systemic availability of oral furazolidone has been investigated in a randomized, crossover study in 18 healthy volunteers (38c ). Treatment with omeprazole significantly reduced the systemic availability of furazolidone. This could partially explain reports of modest Helicobacter pylori eradication rates (50%) when the two drugs are used in combination, despite the fact that furazolidone is considered to be highly effective against the bacterium, and low resistance to the drug has been reported.

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have been compared in the treatment of gastroesophageal reflux disease in a multicenter, randomized, double-blind trial in 350 patients (39C ). The addition of cisapride did not significantly improve symptom control or healing rates. The frequency of adverse effects in the two groups was similar. Compliance was worse in the pantoprazole plus cisapride group.

Rabeprazole The use of rabeprazole in acid-related disorders has been reviewed (40R ). Rabeprazole has proven efficacy in healing, symptom relief, and prevention of relapse of peptic ulcer and gastro-esophageal reflux disease and can form part of effective Helicobacter pylori eradication regimens. It was generally well tolerated in both short-term and long-term studies of up to 2 years. Headache was the most important reported adverse effect. Other commonly reported adverse effects were diarrhea, rhinitis, nausea, pharyngitis, abdominal pain, and flatulence. The changes in serum gastrin concentrations were consistent with proton pump inhibitor pharmacology, and no study has reported mean values at end-point that were outside the reference range. In controlled trials, the frequency of abnormalities of hepatic aminotransferases was similar to that of placebo. Scoring of enterochromaffin-like cells in gastric biopsies taken prospectively from patients in studies of up to 2 years have shown some hyperplastic changes, but no evidence of adenomatous, dysplastic, or neoplastic changes. Liver Acute fulminant hepatitis has been reported in a previously healthy 46-year-old man who took rabeprazole and terbinafine (41A ). His condition improved gradually after withdrawal of both drugs.

HELICOBACTER PYLORI ERADICATION REGIMENS Pantoprazole

(SEDA-23, 384; SEDA-24, 404, SEDA-25, 422)

Pantoprazole 40 mg/day and pantoprazole 40 mg/day plus cisapride 20 mg bd for 8 weeks

Many studies of Helicobacter pylori eradication therapies have been reported in the year under

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review. Regimens for Helicobacter pylori eradication usually include a proton pump inhibitor or H2 receptor antagonist, two or three antibiotics, and less commonly bismuth compounds or sucralfate. Adverse effects are related to the individual drugs used. Pseudomembranous colitis has been reported in a 86-year-old woman with non-ulcer dyspepsia a few days after she had taken triple eradication therapy (omeprazole 20 mg bd, metronidazole 400 mg tds, and clarithromycin 500 mg bd); she recovered after treatment with oral vancomycin (42A ). In a randomized, placebo-controlled trial in 60 healthy, asymptomatic subjects who screened positive for Helicobacter pylori infection, supplementation with Lactobacillus GG twice daily for 14 days significantly reduced the adverse effects (diarrhea, nausea, taste disturbance) and improved the overall tolerability of a standard 7-day eradication regimen consisting of rabeprazole 20 mg bd, clarithromycin 500 mg bd, and tinidazole 500 mg bd (43c ). Drug interactions In an open, randomized, crossover study of the effects of oral omeprazole 20 mg/day for 7 days on the distribution of co-administered clarithromycin in the gastric juice in 18 male volunteers with Helicobacter pylori, short-term omeprazole increased the amount of clarithromycin transferred to the gastric juice, confirming synergy between these two drugs (44c ).

psyllium for the treatment of constipation in a randomized, double blind, study (46c ). There was a significant increase in the weekly number of defecations with the combined formulation, which was well tolerated; no adverse effects were reported. Gastrointestinal The effects of lactulose and lactilol in daily doses of 18–36 g for 6 months have been evaluated in a prospective open study in 31 cirrhotic patients with chronic encephalopathy (47c ). Mean daily stool frequency (2.5 vs. 1.7) and frequency of reported adverse effects (59% vs. 14%) were significantly higher with lactulose. Common adverse effects were nausea, intestinal discomfort, flatulence, and diarrhea. Pneumatosis intestinalis and pneumoperitoneum have been reported in a 57-year-old cirrhotic man with colonic inertia who had been taking oral lactulose 30 ml tds (48A ). Because of constipation the dose of lactulose had been gradually increased to 60 ml qds together with lactulose enemas. Both conditions resolved 3 days after oral lactulose was withdrawn. Aphthous ulcers in the rectal mucosa have been reported in association with the use of Fleet-phospho-soda enema in preparation for colonoscopy in a 54-year-old woman (49A ).

AMINOSALICYLATES ACTIVATED CHARCOAL

(SED-14,

1241; SEDA-24, 405) Esophageal laceration with charcoal mediastinum has been reported in a 19-year-old woman who underwent multiple attempts at orogastric lavage with isotonic saline followed by 50 g of activated charcoal and sorbitol via the orogastric tube for a drug overdose (45A ). She recovered after surgical intervention.

LAXATIVES

(SED-14, 1235; SEDA-23, 384; SEDA-24, 406, SEDA-25, 423) Psyllium husk combined with microencapsulated paraffin has been compared with standard

(SED-14, 1237; SEDA-23, 386; SEDA-24, 406; SEDA-25, 423) The adverse effects of sulfasalazine 2–3 g/day and mesalazine 1.2–2.4 g/day in 685 patients have been reviewed for a median follow-up period of 7 and 5 years respectively (50c ). Adverse effects were observed overall in 20% of patients taking sulfasalazine and 6.5% of those taking mesalazine. The commonest adverse effects due to sulfasalazine (reported by more than 10% of patients) were dyspepsia, rash, and headache, while the commonest due to mesalazine were rash, diarrhea, headache, fever, abdominal pain, impaired renal function, dyspepsia, and edema. Fertility was affected in all 42 male patients taking sulfasalazine who were assessed, but improved when they changed to mesalazine.

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Mesalazine (5-aminosalicylic acid, mesalamine) In a randomized open trial in 227 patients with mild to moderate ulcerative colitis, mesalazine 4 g/day given as prolonged-release granules bd and qds was as effective as prolonged-release tablets given qds (51c ). All the treatments were well tolerated and the frequencies of adverse effects were similar in the treatment groups. The patients preferred twice-daily dosing. Daily mesalazine 4 g orally plus placebo enema and mesalazine 2 g orally plus mesalazine 2 g rectally as a liquid enema have been compared in the treatment of mild to moderate ulcerative colitis in a multicenter, randomized, double-blind trial in 130 patients (52C ). Both treatments were equally effective in inducing disease remission. Both were well tolerated, and the frequencies of adverse effects were similar in the two groups. The relapse-preventing effects and safety profiles of balsalazide 1.5 g bd, balsalazide 3 g bd, and mesalazine 0.5 g tds have been studied in a multicenter, randomized, double-blind trial in 133 patients with ulcerative colitis in remission (53C ). High-dose balsalazide was significantly more effective in maintaining remission compared with the other two treatments. All three treatments were well tolerated. Cardiovascular Acute pericarditis has been reported in a 17-year-old man with severe ulcerative colitis who had taken mesalazine 1.5 g/day for 2 weeks (54A ). The pericarditis resolved on withdrawal and recurred on re-challenge with a low dose (62.5 mg) of mesalazine 3 weeks later. Respiratory Bronchiolitis obliterans has been reported in a 18-year-old female non-smoker with ulcerative colitis, 3 months after reintroduction of mesalazine 1.6 g/day orally (55A ). She recovered after mesalazine withdrawal and treatment with corticosteroids. Interstitial pulmonary disease (lymphocytic alveolitis and mild interstitial pulmonary fibrosis) has been reported in a 70-year-old woman with ulcerative colitis who had taken mesalazine 2.4 g/day for 3 months (56A ). Halving the dose of mesalazine to 1.2 g/day led to resolution of her lung disorder without relapse of ulcerative colitis.

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Nervous system Acute headache due to benign intracranial hypertension has been reported in a 11-year-old girl with Crohn’s disease who had been taking mesalazine 3 g/day for 3 weeks (57A ). Her symptoms and papillary edema regressed after withdrawal of mesalazine. Gastrointestinal Adult fibrosing colonopathy has been reported in a 56-year-old woman with Crohn’s disease who had been taking mesalazine 2.4 g/day for 12 months (58A ). She recovered after resection of the stenotic segment. Urinary tract Interstitial nephritis has been reported in a 29-year-woman with ulcerative colitis and a 48-year-old woman with Crohn’s disease who were taking mesalazine (59A ). Two studies in 21 (60c ) and 95 (61c ) patients with ulcerative colitis and Crohn’s disease have shown that proteinuria of tubular marker proteins is common and is related to disease activity rather than to treatment with mesalazine. Thus, tubular proteins are not useful predictors of an adverse renal response to the drug. Drug interactions In a prospective, parallelgroup study in 34 patients with Crohn’s disease taking azathioprine or mercaptopurine, co-administration of mesalazine 4 g/day, sulfasalazine 4 g/day, or balsalazide 6.75 g/day for 8 weeks resulted in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leukopenia (62c ). Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6mercaptopurine are at risk of myelosuppression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors and pro-drugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia.

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Olsalazine Gastrointestinal In a randomized, doubleblind, placebo-controlled trial in 328 patients with quiescent Crohn’s disease, olsalazine 2 g/day given for 52 weeks was not superior to placebo in maintaining remission (63C ). Gastrointestinal adverse effects were significantly more frequent in the olsalazine group; diarrhea was the most commonly reported adverse effect.

Sulfasalazine Nervous system Seizures with acute encephalopathy have been reported in a woman taking sulfasalazine for polyarthritis (64A ).

did not influence symptoms, but resulted in significant improvement in liver biochemistry and a significant reduction in the progression of cholangiographic appearances and liver fibrosis, as assessed by disease staging. No significant adverse effects were reported. Ursodeoxycholic acid 250 mg tds plus ofloxacin 200 mg bd has been compared with ursodeoxycholic acid alone in the prevention of occlusion of biliary stents in a randomized trial in 52 patients with inoperable obstructive jaundice (67c ). Combination treatment was not superior to ursodeoxycholic acid alone. There was no significant difference in the frequency of adverse events between the two groups. Skin Lichenoid eruptions have been reported in a 61-year-old man with gall stones who took ursodeoxycholic acid 600 mg/day for a few weeks (68A ). The eruption improved on withdrawal, but recurred when ursodeoxycholic acid was reintroduced 3 months later.

ANTISPASMODIC AGENTS (SED-13, 1084; SEDA-22, 394; SEDA-25, 426) A meta-analysis of 23 randomized clinical trials assessing the efficacy and tolerance of smooth muscle relaxants in irritable bowel syndrome has shown that these drugs are superior to placebo (65C ). Six drugs were analysed: cimetropium bromide (five trials), hyoscine butyl bromide (three trials), mebeverine (five trials), otilium bromide (two trials), and trimebutine (four trials). There was no overall significant difference in the frequency of adverse effects compared with placebo.

CHOLELITHOLYTIC AGENTS Bile acids

(SED-14, 1240; SEDA-23, 387; SEDA-24, 408; SEDA-25, 426) High-dose ursodeoxycholic acid (20 mg/kg/day) has been compared with placebo in the treatment of primary sclerosing cholangitis in a 2-year double-blind preliminary study in 26 patients (66c ). High-dose ursodeoxycholic acid

PANCREATIC ENZYME SUPPLEMENTS (SED-14, 1242; SEDA-23, 387; SEDA-24, 408) The effect of oral pancreatic enzyme supplementation (Creon 10 000 in a dose of 1000 units of lipase per gram of ingested dietary fat) on fat malabsorption has been evaluated in an openlabel study in 24 patients with HIV infection (69c ). Pancreatic enzyme supplementation was highly effective in reducing fecal fat loss. There were no clinical adverse effects or changes in serum biochemistry attributable to the drug. The effects of pancreatic exocrine supplements (four capsules with meals, two with snacks; each capsule containing lipase 10 000 units, protease 37 500 units, amylase 33 200 units) on pancreatic endocrine dysfunction has been studied in a 2-week parallel, randomized, placebo-controlled trial in 29 patients with chronic pancreatitis who had stool fat excretion of over 10 g/day, 18 of whom were diabetic and 15 of whom were malnourished (70c ). There were major problems with blood glucose control in 28 of the 29 patients.

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of alosetron in patients with functional dyspepsia. Aliment Pharmacol Ther 2001; 15: 525–37. 14. Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE, McSorley D, Mangel AM. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001; 161: 1733–40. 15. Friedel D, Thomas R, Fisher RS. Ischemic colitis during treatment with alosetron. Gastroenterology 2001; 120: 557–60. 16. D’Souza DL, Dimmitt DC, Robbins DK, Nezamis J, Simms L, Koch M. Effect of alosetron on the pharmacokinetics of fluoxetine. J Clin Pharmacol 2001; 41: 455–8. 17. Lanciano R, Sherman DM, Michalski J, Preston AJ, Yocom K, Friedman C. The efficacy and safety of once-daily Kytril (granisetron hydrochloride) tablets in the prophylaxis of nausea and emesis following fractionate upper abdominal radiotherapy. Cancer Invest 2001; 19: 763–72. 18. Yilmazlar A, Tokat O, Kutlay O, Yilmazlar T, Turker G. Comparison of the efficacy of 2 mg versus 5 mg tropisetron in the management of postoperative nausea and vomiting. J Int Med Res 2001; 29: 385–8. 19. Hamilton MI, Sercombe J, Pounder RE. Control of intergastric acidity with over-the-counter doses of ranitidine or famotidine. Aliment Pharmacol Ther 2001; 15: 1579–83. 20. Peiris RS, Peckler BF. Cimetidine-induced dystonic reaction. J Emerg Med 2001; 21: 27–9. 21. Paul K, Redman CM, Chen M. Effectiveness and safety of nizatidine, 75 mg, for the relief of episodic heartburn. Aliment Pharmacol Ther 2001; 15: 1571–7. 22. Robinson M, Rodriguez-Stanley S, Ciociola AA, Filinto J, Zubaidi S, Miner PB Jr, Gardner JD. Synergy between low-dose ranitidine and antacid in decreasing gastric oesophageal acidity and relieving meal-induced heartburn. Aliment Pharmacol Ther 2001; 15: 1365–74. 23. Emovon OE, King JAC, Op’t Holt C, Browne BJ. Ranitidine-induced acute interstitial nephritis in a cadaveric renal allograft. Am J Kidney Dis 2001; 38: 169–72. 24. Lin C-C, Wu J-C, Huang D-F, Huang YS, Huang Y-H, Hou T-I, Chang F-Y, Lee S-D. Ranitidine-related Stevens–Johnson syndrome in patients with severe liver diseases. A report of two cases. Gastroenterol Hepatol 2001; 16: 481–3. 25. Richter JE, Kahrilas PJ, Johanson J, Maton P, Breiter JR, Hwang C, Marino V, Hamelin B, Levine JG. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis. A randomized controlled trial. Am J Gastroenterol 2001; 96: 656–65. 26. Bardhan KD, Van Rensburg C. Comparable clinical efficacy and tolerability of 20 mg pantoprazole and 20 mg omeprazole in patients with grade I

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reflux oesophagitis. Aliment Pharmacol Ther 2001; 15: 1585–91. 27. Richter JE, Kahrilas PJ, Sontag SJ, Kovacs TOG, Huang B, Pencyla JL. Comparing lansoprazole and omeprazole in onset of heartburn relief. Results of a randomized, controlled trial in erosive esophagitis patients. Am J Gastroenterol 2001; 96: 3089–98. 28. Galmiche JP, Zerbib F, Ducrotte P, Fournet J, Rampal P, Avasthy N, Humphries TJ. Decreasing oesophageal acid exposure in patients with GERD. A comparison of rabeprazole and omeprazole. Aliment Pharmacol Ther 2001; 15: 1343–50. 29. Brunner G, Athmann C, Boldt JH. Reversible peripheral edema in female patients taking proton pump inhibitors for peptic acid diseases. Dig Dis Sci 2001; 46: 993–6. 30. Talley NJ, Lauritsen K, Tunturi- Hihnala H, Lind T, Moum B, Bang C, Schulz T, Omland TM, Delle M, Junghard O. Esomeprazole 20 mg maintains symptom control in endoscopy-negative gastro-oesophageal reflux disease. A controlled trial of ‘on-demand’ therapy for 6 months. Aliment Pharmacol Ther 2001; 15: 347–54. 31. Andersson T, Rohss K, Bredberg E, HassanAlin M. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 2001; 15: 1563–9. 32. Zimmermann AE, Walters JK, Katona BG, Souney PF, Levine D. A review of omeprazole use in the treatment of acid-related disorders in children. Clin Ther 2001; 23: 660–79. 33. Pashankar D, Blair GK, Israel DM. Omeprazole maintenance therapy for gastroesophageal reflux disease after failure of fundoplication. J Pediatr Gastroenterol Nutr 2001; 32: 145–9. 34. Schaltenbrand R, Huber R, Cotoraci CA, Mascher H, Potthast H, Hole U. Bioequivalence between omeprazole MUPS 20 mg as tablet and omeprazole 20 mg as tablet encapsulated in a hard gelatine capsule. Int J Clin Pharmacol Ther 2001; 39: 453–9. 35. Ligumsky M, Lysy J, Siguencia G, Friedlander Y. Effect of long-term, continuous versus alternateday omeprazole therapy on serum gastrin in patients treated for reflux esophagitis. J Clin Gastroenterol 2001; 33: 32–5. 36. Robert P, Myers MD, McLaughlin K, Hollomby DJ. Acute interstitial nephritis due to omeprazole. Am J Gastroenterol 2001; 96: 3428–31. 37. Borras-Blasco J, Navarro-Ruiz A, NavarroBlasco F, Tovar-Beltran J, Gonzalez-Delgado M. Erythrodermia induced by omeprazole. Int J Clin Pharmacol Ther 2001; 39: 219–23. 38. Calafatti SA, Ortiz RAM, Deguer M, Martinez M, Pedrazzoli J Jr. Effect of acid secretion blockade by omeprazole on the relative bioavailability of orally administered furazolidone in healthy volunteers. Br J Clin Pharmacol 2001; 52: 205–9. 39. Van Rensburg CJ, Bardhan KD. No clinical benefit of adding cisapride to pantoprazole for treatment of gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 2001; 13: 909–14.

391 40. Carswell CI, Goa KL. Rabeprazole: An update of its use in acid-related disorders. Drugs 2001; 61: 2327–56. 41. Johnstone D, Berger C, Fleckman P. Acute fulminant hepatitis after treatment with rabeprazole and terbinafine. Arch Intern Med 2001; 161: 1677–8. 42. Harsch IA, Hahn EG, Konturek PC. Pseudomembranous colitis after eradication of Helicobacter pylori infection with a triple therapy. Med Sci Monit 2001; 7: 751–4. 43. Armuzzi A, Cremonini F, Bartolozzi F, Canducci F, Candelli M, Ojetti V, Cammarota G, Anti M, De Lorenzo A, Pola P, Gasbarrini G, Gasbarrini A. The effect of oral administration of Lactobacillus GG on antibiotic-associated gastrointestinal side-effects during Helicobacter pylori eradication therapy. Aliment Pharmacol Ther 2001; 15: 163–9. 44. Pedrazzoli J Jr, Calafatti SA, Ortiz RAM, Dias FE, Deguer M, Mendez MD, Bento AP, Pereira AA, Piovesana H, Ferraz JGP, Lerner F, De Nucci G. Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pyloriinfected individuals. Scand J Gastroenterol 2001; 36: 1248–53. 45. Caravati EM, Knight HH, Linscott MS, Stringham JC. Esophageal laceration and charcoal mediastinum complicating gastric lavage. J Emerg Med 2001; 20: 273–6. 46. Chicouri M-J. Estudo clinico do psyllium husk associado a parafina microencapsulada no tratamento da constipacao intestinal essencial. Rev Bras Med 2001; 58: 672–6. 47. Shibasaki K, Tsuboi Y, Hasegawa K, Toshima M, Soga K. Effects of long-term administration of lactitol or lactulose in cirrhotic patients with chronic hepatic encephalopathy. Ther Res 2001; 22: 899–907. 48. Goodman RA, Riley III TR. Lactulose-induced pneumatosis intestinalis and pneumoperitoneum. Dig Dis Sci 2001; 46: 2549–53. 49. Berthelet O, Rolachon A, Papillon E, Fournet J. Lesions rectales induites par la preparation colique fleet-phospho-sodar. Gastroenterol Clin Biol 2001; 25: 437–9. 50. Di Paolo MC, Paoluzi OA, Pica R, Iacopini F, Crispino P, Rivira M, Spera G, Paoluzi P. Sulphasalazine and 5-aminosalicylic acid in long-term treatment of ulcerative colitis. Report on tolerance and side-effects. Dig Liver Dis 2001; 33: 563–9. 51. Farup PG, Hinterleitner TA, Lukas M, Hebuterne X, Rachmilewitz D, Campieri M, Meier R, Keller R, Rathbone B, Oddsson E. Mesalazine 4 g daily given as prolonged-release granules twice daily and four times daily is at least as effective as prolonged-release tablets four times daily in patients with ulcerative colitis. Inflammatory Bowel Dis 2001; 7: 237–42. 52. Vecchi M, Meucci G, Gionchetti P, Beltrami M, Di Maurizio P, Beretta L, Ganio E, Usai P, Campieri M, Fornaciari G, De Franchis R. Oral versus combination mesalazine therapy in active ulcerative colitis, a double-blinded, double-dummy,

392 randomized multicentre study. Aliment Pharmacol Ther 2001; 15: 251–6. 53. Kruis W, Schreiber S, Theuer D, Brandes J-W, Schtutz E, Howaldt S, Krakamp B, Hamling J, Monnikes H, Koop I, Stolte M, Pallant D, Ewald U. Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses. Gut 2001; 49: 783–9. 54. Ishikawa N, Imamura T, Nakajima K, Yamaga J, Yuchi H, Ootsuka M, Inatsu H, Aoki T, Eto T. Acute pericarditis associated with 5-aminosalicylic acid (5-ASA) treatment for severe active ulcerative colitis. Intern Med 2001; 40: 901–4. 55. Heralambou G, Teirstein AS, Gil J, Present DH. Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesalamine. Mt Sinai J Med 2001; 68: 384–8. 56. Sossai P, Cappellato MG, Stefani S. Can a drug-induced pulmonary hypersensitivity reaction be dose-dependent? A case with mesalamine. Mt Sinai J Med 2001; 68: 389–95. 57. Rottembourg D, Labarthe F, Arsene S, JonvilleBera A-P, Maurage C, Rolland J-C. Headache during mesalamine therapy. A case report of mesalamine-induced pseudotumor cerebri. J Pediatr Gastroenterol Nutr 2001; 33: 337–8. 58. Gaia E, Sambatoro A, De Guili P, Angeli A. Adult fibrosing colonopathy associated with mesalazine treatment. Am J Gastroenterol 2001; 96: 2508–9. 59. Margetts PJ, Churchill DN, Alexopoulou I. Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine. J Clin Gastroenterol 2001; 32: 176–8. 60. Fraser JS, Muller AF, Smith DJ, Newman DJ, Lamb EJ. Renal tubular injury is present in acute inflammatory bowel disease prior to the introduction of drug therapy. Aliment Pharmacol Ther 2001; 15: 1131–7. 61. Herrlinger KR, Noftz MK, Fellermann K, Schmidt K, Steinhoff J, Stange EF. Minimal renal dysfunction in inflammatory bowel disease is related to disease activity but not to 5-ASA use. Aliment Pharmacol Ther 2001; 15: 363–9.

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62. Lowry PW, Fraklin CL, Weaver AL, Szumlanski CL, Mays DC, Loftus EV, Tremaine WJ, Lipsky JJ, Weinshilboum RM, Sandborn WJ. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut 2001; 49: 656–64. 63. Mahmud N, Kamm MA, Dupas JL, Jewell DP, O’Morain CA, Weir DG, Kelleher D. Olsalazine is not superior to placebo in maintaining remission of inactive Crohn’s colitis and ileocolitis. A double blind, parallel, randomised, multicentre study. Gut 2001; 49: 552–6. 64. Chadenat ML, Morelon S, Dupont C, Dechy H, Raffin-Sanson ML, Dorra M, Rouveix E. Neurotoxicite a la sulfasalazine. Ann Med Interne 2001; 152: 283–4. 65. Poynard T, Regimbeau C, Benhamou Y. Metaanalysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2001; 15: 355–61. 66. Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman R. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 2001; 121: 900–7. 67. Halm U, Schiefke I, Fleig WE, Mossner J, Keim V. Ofloxacin and ursodeoxycholic acid versus ursodeoxycholic acid alone to prevent occlusion of biliary stents. A prospective, randomised trial. Endoscopy 2001; 33: 491–4. 68. Horiuchi Y. Lichenoid eruptions due to ursodeoxycholic acid administration. Gastroenterology 2001; 121: 501–2. 69. Carroccio A, Guarino A, Zuin G, Verghi F, Canani RB, Fonatana M, Bruzzese E, Montalto G, Notarbartolo A. Efficacy of oral pancreatic enzyme therapy for the treatment of fat malabsorption in HIV-infected patients. Aliment Pharmacol Ther 2001; 15: 1619–25. 70. O’Keefe SJD, Cariem AK, Levy M. The exacerbation of pancreatic endocrine dysfunction by potent pancreatic exocrine supplements in patients with chronic pancreatitis. J Clin Gastroenterol 2001; 32: 319–23.

Thierry Vial, Jacques Descotes, Gavin Screaton, Matthias Behrend, and Corinna Ludwig

37

Drugs acting on the immune system

Editor’s note: Because the range of drugs that affect the immune system is so wide, this year’s chapter has been contributed by several authors. Although there was some overlap in contributions, for the most part Drs Vial and Descotes contributed the sections on cytokines, Dr Screaton the sections on monoclonal antibodies, and Drs Behrend and Ludwig the sections on immunosuppressant and immunoenhancing drugs.

INTERFERONS

(SED-14, 1246; SEDA-23, 391; SEDA-24, 411; SEDA-25, 431)

Interferon alfa In 1530 patients with chronic hepatitis C pegylated interferon alfa-2b had a similar profile of adverse effects to unmodified interferon alfa-2b, but with more frequent dose-limiting neutropenia (1C ). No particular adverse effect has emerged since the use of this new formulation. Respiratory The first case of pulmonary artery hypertension has been reported (2A ). • A 23-year-old man taking hydroxycarbamide (1.5 g/day) and interferon alfa-2b (less than 10 MU/day) for chronic lymphocytic leukemia had progressive dyspnea and a non-productive cough after about 5 months. The electrocardiogram showed right axis deviation, incomplete right bundle-branch block, and right ventricular hypertrophy. The estimated pulmonary artery pressure by echocardiography was 80 mmHg and there were signs of right heart failure. Respiratory function tests showed a restrictive defect, and the chest X-ray showed pulmonary congestion without infiltrates. The patient’s clinical status and respiratory function tests improved rapidly after withdrawal of interferon alfa while hydroxycarbamide was © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

continued, and a mean pulmonary artery pressure of 34 mmHg was measured by right heart catheterization 1 month later. At 6 months the systolic pulmonary artery pressure estimated by echocardiography had fallen to 35 mmHg and the electrocardiogram returned to normal after 1 year.

The authors mentioned that intravenous interferon alfa in sheep had caused an increase in pulmonary artery pressure. Interstitial pneumonia is a well-recognized complication of interferon, as has again been reported in a 57-year-old man (3A ). The uncommon features of bronchiolitis obliterans organizing pneumonia have been reported in three other patients who received interferon alfa together with ribavirin or cytosine arabinoside (4A , 5A ). Nervous system Chorea is a very rare manifestation of interferon alfa neurotoxicity (6A ). • A 68-year-old woman developed progressive personality changes and 2 months later permanent choreic movements of the four limbs. She had taken interferon alfa-2b (3 MU/day) and hydroxyurea (50 mg/kg/day) for chronic myeloid leukemia for 2 years and had no history of psychiatric disorders. Neuropsychological testing showed frontal subcortical dysfunction. There were no abnormalities in the Huntington disease gene. She progressively worsened over the next 6 months. The electroencephalogram was disorganized, with diffuse slow waves, and she was bedridden. Interferon alfa was withdrawn. The chorea ceased 1 month later and she completely recovered cognitive function. Electroencephalography was normal 6 and 12 months later.

393

394 The authors attributed these events to antidopaminergic effects of interferon alfa. Neuromuscular function Myasthenia gravis developed in two patients treated with interferon alfa-2b for chronic hepatitis C, one of whom also took ribavirin (7A , 8A ). Both had an increase in acetylcholine receptor antibody titers and required permanent pyridostigmine and immunosuppressant treatment. This suggested the unmasking of myasthenia gravis by interferon alfa, rather than truly drug-induced disease. Sensory systems New studies of retinal complications associated with interferon alfa continue to appear (9A , 10c , 11C ). In one study, in which prospective ophthalmic examinations were made before and at regular 2-week intervals after the beginning and end of treatment, 28 of 81 patients who received a uniform total dose of natural interferon alfa (478 MU) for chronic hepatitis C developed the typical findings of interferon-induced asymptomatic retinopathy (cotton-wool spots and/or retinal hemorrhages) (11C ). In contrast, there were no lesions in the 25 patients with chronic hepatitis C who did not receive interferon alfa or in the 20 with diabetes mellitus and/or hypertension but without chronic hepatitis C. Most of the cases were observed within 4 months of treatment, and the lesions always abated after withdrawal or even despite continuation, suggesting that treatment can be continued unless patients develop symptoms. Indeed, most patients with retinopathy associated with interferon alfa remained asymptomatic. However, complications, such as severe visual loss, are still reported in few instances (9A ). Older age, and the presence of hypertension and/or diabetes mellitus are well-known risk factors. Although this has not been yet specifically addressed, concomitant treatment with paroxetine has been suggested as a possible additional risk factor (9A ). Psychiatric The identification of patients at risk of depressive disorders during treatment with interferon alfa is being continuously investigated. Of 33 patients with chronic hepatitis C treated with interferon alfa 9 MU/week for 3–12 months prospectively evaluated using the Montgomery–Asberg Depression Rating Scale

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(MADRS) before and after 12 weeks of treatment eight developed depressive symptoms, of whom four had major depression without a previous psychiatric history (12c ). All four recovered after treatment with antidepressants. This study confirmed that a high baseline MADRS is significantly associated with the occurrence of depressive symptoms. The clinical manifestations of psychiatric complications due to interferon alfa has also included rare cases of homicidal ideation (13A ). Endocrine The detection of a wide range of autoantibodies during treatment with interferon alfa has been previously widely documented (SED-14, 1254). Of 62 initially autoantibodynegative patients treated with interferon alfa for chronic hepatitis C for a mean of 8 months, three developed antibodies to 21β-hydroxylase, a sensitive assay to detect adrenocortical autoimmunity (14C ). However, there were no cases of Addison’s disease or subclinical adrenal insufficiency. Similarly, islet cellspecific autoantibodies (i.e. antibodies to glutamic acid decarboxylase GAD65 and protein tyrosine phosphatase IA2) were found in six of 62 initially negative patients, but none developed diabetes mellitus or impaired glucose tolerance. In addition to thyroid and pancreatic islet cells, this study suggested that the adrenal cortex is another potential target organ of autoimmune effects of interferon alfa. Cases of insulin-dependent diabetes mellitus attributed to interferon alfa are repeatedly described (15A , 16A ). In three middle-aged patients, diabetes was diagnosed after 3–7 months of treatment with interferon alfa-2b and ribavirin, and two presented with severe ketoacidosis. There was a family history of diabetes in one patient and two had high titers of glutamic acid decarboxylase antibodies before treatment. One patient never had diabetes-related serum autoantibodies before or after interferon alfa therapy. All three required permanent insulin treatment despite withdrawal of interferon alfa. Although much work on thyroid autoimmunity associated with interferon alfa has accumulated, little is known about the very long-term outcome of this disorder. In 114 patients with chronic hepatitis C and no previous thyroid disease who were treated with interferon alfa-2a for 12 months, data on thyroid status were retrospectively obtained at the end of treatment,

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6 months after withdrawal, and after a median of 6.2 years (17C ). Among 36 patients who had thyroid autoantibodies at the end of treatment, the authors identified three groups according to the long-term outcome: 16 had persistent thyroiditis, 10 had remitting/relapsing thyroiditis (i.e. antibodies became negative after 6 months of therapy and were again positive thereafter), and 10 had transient thyroiditis. Therefore, 72% of these patients had chronic thyroid autoimmunity at the end of follow-up and 12 developed subclinical hypothyroidism. In contrast, only one of 78 patients negative for thyroid autoantibodies developed thyroid autoantibodies. Although none of the patients had clinical thyroid dysfunction, this study suggests that long-term surveillance of thyroid disorders is useful in patients who have high autoantibody titers at the end of treatment with interferon alfa. Hematologic Neutropenia is a dose-limiting adverse effect of interferon alfa, particularly in patients with chronic hepatitis C and cirrhosis. The dose of interferon alfa is therefore usually halved or the drug is permanently withdrawn when neutrophil counts fall below 0.75 × 109 /l or 0.5 × 109 /l respectively. This issue has recently been challenged by a retrospective analysis of 11 patients with compensated cirrhosis, four of whom had severe neutropenia (i.e. 0.4 to 0.67 × 109 /l) during the first 2 months of treatment (18c ). They remained asymptomatic and the neutropenia spontaneously reversed despite continued treatment. Interferon alfa sometimes causes autoimmune thrombocytopenia (SED-14, 1251). In a 45-year-old man treated with pegylated interferon alfa-2b for relapsing chronic hepatitis C, thrombocytopenia recovered over 2 months, despite initial treatment with steroids and immunoglobulin (19A ). The authors suggested that the prolonged half-life of this formulation of interferon alfa may have explained this slow recovery. A case of pernicious anemia with a low vitamin B12 concentration and positive intrinsic factor antibodies has been reported in a 54-yearold woman who received interferon alfa as a maintenance treatment for relapsing chronic hepatitis C (20A ). Clotting disorders due to interferon alfa have been rarely reported. Asymptomatic prolongation of the activated partial thromboplastin time

395 associated with lupus anticoagulant and a reduction in the coagulation activity of factors IX, XI, and XII occurred after 10 weeks of interferon alfa-2b and ribavirin in a 60-year-old woman with chronic hepatitis C (21A ). There were no arguments in favor of an antiphospholipid syndrome, and all the abnormalities normalized after withdrawal. Liver In 25 children with chronic hepatitis C, pretreatment positivity for liver/kidney microsomal type 1 (LKM-1) antibodies was associated with more frequent treatment-limiting increases in serum AlT activity (22c ). Withdrawal of interferon alfa-2b because of hypertransaminasemia was required in three of four LKM-1 positive children compared with two of the 21 LKM-1 negative children. Although none developed features of autoimmune hepatitis, careful surveillance of hepatic function is recommended in LKM-1 positive patients. Skin Cutaneous necrosis at injection sites has been commonly reported with interferon alfa, and has also been described with pegylated interferon alfa-2b (23A ). In the latter case, the lesions healed under local therapy and the same dose of interferon was maintained. Extensive oral pemphigus due to interferon alfa has rarely been reported (24A ). • A 28-year-old woman developed oral ulcers after a 5-month course of interferon alfa-2a for chronic hepatitis C. She had multiple erosions on both lips, the tongue, the floor of the mouth, the soft palate, the pharyngeal walls, and the laryngeal mucosa, but there were no skin or genital lesions. Raised double-stranded DNA antibody titers were found. Histology showed pemphigus vulgaris, and complete resolution was obtained by withdrawal of interferon alfa and immunosuppressive and local treatment.

This case was thought to have been due to the immunomodulatory effects of interferon alfa. Radiation recall dermatitis developed in a 29-year-old woman after high-dose intravenous interferon alfa-2b was given 5 days after the completion of radiotherapy for malignant melanoma (25A ). The authors suggested that interferon alfa can trigger an inflammatory reaction in patients whose inflammatory response threshold has been lowered by irradiation. Interferon alfa is sometimes associated with sarcoidosis. In addition to two additional cases

396 of cutaneous sarcoidosis, 27 previously published cases have been reviewed (26A ). The time to onset was 15 days to 30 months, and there were dermatological signs in 50%. Five patients had also taken ribavirin, but an enhanced T cell immune reaction from the combination of interferon alfa plus ribavirin is speculative. Musculoskeletal Acute rhabdomyolysis, which has been rarely described (SEDA-21, 372; SEDA-25, 434) occurred in a 34-year-old woman with melanoma treated with interferon alfa 20 MU/m2 /day (27A ). There was no recurrence on retreatment with a lower dose (down to 6.6 MU/m2 /day), suggesting that this was a dose-related complication. In contrast, in another case rhabdomyolysis occurred at even lower doses (28A ). • A 34-year-old man with scleromyxedema had flulike symptoms and muscle pain after the first injection of interferon alfa 6 MU. After three additional injections at 2-day intervals, his muscle symptoms worsened and were associated with mild quadriparesis, reduced deep tendon reflexes, dark urine, confusion, and agitation. Biological findings were consistent with acute rhabdomyolysis, and electromyography showed rare denervation potentials. His symptoms resolved and the laboratory findings normalized within 15 days.

Immunologic Hypersensitivity reactions to interferon alfa have not been conclusively demonstrated. Two cases have recently been reported. • A 64-year-old man with no history of allergy had progressive fatigue, loss of appetite, and facial edema after 6 months of interferon alfa-2b treatment for chronic hepatitis C (29A ). Angio-edema was diagnosed and it resolved after withdrawal of interferon alfa and a short course of prednisolone. Serum immunoglobulin E and plasma bradykinin concentrations were raised, but the C1 esterase inhibitor and serum complement concentrations were normal. • A 47-year-old man, who had previously received a 2-month course of interferon alfacon-1 for chronic hepatitis C, started interferon alfa-2b 8 months later (30A ). He developed mild generalized pruritus the day after the second injection, and dyspnea with diffuse urticaria within a few hours after the third injection. Skin tests were not performed, and IgG but not IgE antibodies to interferon alfa were found.

These cases do not formally show a causal relation with interferon alfa and at best they

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suggest that an IgE-mediated reaction is probably not the cause of hypersensitivity reactions to interferon alfa. In the first case, the mechanism may have been similar to that observed with angiotensin-converting inhibitors. Immunologic There are still uncertainties about the possible relation between interferon alfa and an increased incidence or severity of acute graft–versus–host disease after bone-marrow transplantation. Late-onset, severe, atypical chronic graft-versus-host disease (GVHD) has been attributed to interferon alfa (31A ). • A 44-year-old woman received interferon alfa 6 MU/day for relapse of chronic myeloid leukemia 7 years after successful bone-marrow transplantation. About 2 years later, interferon alfa was withdrawn because of diffuse erythematous skin lesions with discoid lupus erythematosus on skin biopsy and severe dysphagia with esophagitis and pseudomembranes at endoscopy. Fever, bilateral pulmonary infiltrates, and respiratory distress syndrome subsequently developed, and she required mechanical ventilation. An open lung biopsy showed features of chronic pulmonary GVHD. All her symptoms completely resolved with ciclosporin and corticosteroids. An infectious cause was ruled out.

In this case, the clinical presentation was compatible with typical chronic GVHD. Whether interferon alfa induced or aggravated chronic GVHD in this patient remains an open question. Teratogenicity Successful outcomes has been reported in five pregnancies during interferon alfa treatment (32A –34A ). Subsequent followup confirmed that the infants had normal growth and development. A review of 26 other exposed pregnancies provided reassuring data, suggesting that inadvertent interferon alfa exposure during pregnancy has no harmful effects on the fetus. One report mentioned transient and moderate thrombocytopenia in a neonate born to a woman who had received interferon alfa throughout pregnancy (33A ). Drug interactions Owing to its antineoplastic properties, interferon alfa is sometimes used with cytostatic drugs. In 275 patients randomized to receive radiation and carmustine either alone or with interferon alfa for high-grade glioma, there was no significant improvement

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in the overall survival and time to disease progression in those given interferon alfa, but a higher incidence of adverse effects, namely fever, chills, myalgia, lethargy, headache, and seizures (35C ). In 13 patients with metastatic renal cell carcinoma, the combination of interferon alfa-2a (27 MU/week) and thalidomide produced severe neurological toxicity in four patients, an incidence that was considered to be far greater than would be expected with either drug alone (36c ).

Interferon beta Sensory systems Retinal complications of interferon alfa in chronic viral hepatitis patients are well known, but few cases have been described with interferon beta. Bilateral retinopathy with similar features to those observed with interferon alfa has been reported in a 40-yearold woman treated with interferon beta-1b for multiple sclerosis (37A ). Skin Injection site reactions to interferon beta-1b are frequent and usually reverse with subsequent injections. However, delayed complications are still possible. A 44-year-old woman had painful cutaneous induration, secondary to panniculitis, after receiving subcutaneous interferon-beta-1b for 4 years (38A ). Intravascular papillary endothelial hyperplasia with multiple lesions on both hands has been attributed to interferon beta-1b in a 50year-old man with multiple sclerosis (39A ). Musculoskeletal Rhabdomyolysis associated with interferon beta has been reported for the first time (40C ). • A 39-year-old man developed acute generalized myalgia and weakness in all four limbs 3 months after starting interferon beta-1a (22 µg three times a week) for relapsing-remitting multiple sclerosis. Serum creatine kinase activity peaked at about 95 times the upper limit of the reference range. Infectious and metabolic causes were ruled out and there was no argument in favor of an underlying metabolic muscle disorder. He recovered fully after interferon beta withdrawal and supportive treatment.

Although rhabdomyolysis has not been previously attributed to interferon beta, this case is in keeping with those described with interferon alfa. Nervous system A 56-year-old woman developed numbness and difficulty in swallowing and closing her left eye several weeks after starting interferon beta for chronic hepatitis C (41A ). She had facial paresthesia, a left facial nerve palsy, dysphagia, and signs of radiculopathy on the left side. Serum angiotensinconverting enzyme activity was raised. She had bilateral hilar lymphadenopathy without interstitial changes and increased radiogallium uptake in hilar lymph nodes and the parotid glands. Although the cerebrospinal fluid was normal, a diagnosis of neurosarcoidosis was considered, and she recovered completely after interferon beta withdrawal and corticosteroid therapy. Teratogenicity The first data on the outcome of pregnancy after treatment with interferon beta-1a in patients with multiple sclerosis has been obtained from clinical trials (42c ). Of 29 pregnancies that occurred during or shortly after treatment withdrawal, 13 resulted in normal outcomes, two in premature births, one in fetal death, six in induced abortions, and seven in spontaneous abortions. A child whose mother had received interferon beta until 2.5 months before pregnancy had a right incomplete double renal pelvis and ureter (43A ). Although the authors discussed the possible role of interferon therapy, the timing of exposure was obviously not suggestive of a causal relation. Although the data are still very limited, it is advisable to reassure exposed patients and to withdraw interferon beta up to delivery.

INTERLEUKINS

(SED-14, 1260; SEDA-23, 398; SEDA-24, 416; SEDA-25, 436)

Interleukin-1 receptor antagonist (anakinra) Anakinra, a human recombinant form of interleukin-1 receptor antagonist (IL-1Ra), has been

398 developed for the treatment of rheumatoid arthritis (44R ). According to published trials data, moderate injection site reactions were the primary adverse effect and required treatment withdrawal in under 5% of patients. An erythematous rash was seldom observed. Although a few patients have developed antibodies to anakinra, these have not so far been associated with lack of efficacy or allergic skin reactions.

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patients with refractory immune thrombocytopenic purpura was recently halted, since all of the first seven patients had adverse effects without significant changes in the platelet count (48c ). Adverse effects consisted of conjunctival injection, diffuse aches and joint pains, marked pedal edema, petechiae, and mild anemia. In addition, one patient had a neuropathy, which resolved more than 1 month after IL-11 withdrawal.

Interleukin-2 (IL-2) High-dose IL-2 is associated with a wide range of adverse effects, and practical guidelines for their avoidance and management have been detailed (45R ). Denileukin diftitox is a recombinant fusion protein consisting of IL-2 and the cytotoxic A chain of the diphtheria toxin molecule. This product binds to the IL-2 receptor and inhibits protein synthesis, resulting in cell death. It has been approved for the treatment of persistent or recurrent cutaneous T cell lymphoma and is also being evaluated in patients with severe psoriasis. In 71 patients with cutaneous T cell lymphomas randomized to denileukin diftitox 9 or 18 µg/kg/day, flu-like and gastrointestinal symptoms were observed in 92% (46C ). About 60% had an acute hypersensitivity reaction, with dyspnea, back pain, hypotension, and chest pain or tightness within 24 hours of infusion. A vascular leak syndrome, as defined by the presence of at least two of edema, hypoalbuminemia, and hypotension, occurred in 25%. A dose-escalation study in 35 patients with psoriasis confirmed that constitutional symptoms were dose-dependent and less frequent with lower doses (below 5 micrograms/kg/day) (47c ). There was only one case of mild vascular leak syndrome. Skin reactions compatible with delayed hypersensitivity reactions were noted in three patients, including one case of exfoliative dermatitis.

Interleukin-11 (IL-11, oprelvekin) A preliminary study of the thrombopoietic effect of IL-11 (50 µg/kg/day for 21 days) in

COLONY-STIMULATING FACTORS (SED-14, 1270; SEDA-23, 399; SEDA-24, 417; SEDA-25, 437)

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) Hematologic The differential effects of GCSF and GM-CSF on several coagulation parameters have been compared in 34 patients who received the colony-stimulating factors after bone-marrow transplantation (49c ). The data suggested activation of the coagulation system in patients treated with GM-CSF, which resulted in a tendency to more frequent venoocclusive disease of the liver and a significantly higher incidence of hemorrhage. Gastrointestinal All 13 patients with glycogen storage disease type 1b and neutropenia or neutrophil dysfunction treated with G-CSF developed splenomegaly, usually after 3 months of treatment (50c ). Hypersplenism, as defined by moderate thrombocytopenia on at least two consecutive blood counts, was found in five patients, but none required specific interventions. However, splenic rupture should probably be anticipated by regular assessment of splenic size during prolonged treatment. Experimental data suggested that reseeding of hemopoietic cells from the bone marrow may account for this phenomenon (51E ).

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Urinary tract Renal dysfunction has been reported only after long-term use of G-CSF, as illustrated by the following case (52A ). • A 4-year-old girl was given filgrastim (30 µg/kg/ day) for severe congenital neutropenia diagnosed at birth. Two months later she developed microscopic hematuria and recurrent episodes of macroscopic hematuria and proteinuria. Renal ultrasonography was normal and no obvious cause was found, but filgrastim was continued. Microscopic hematuria and multiple episodes of macroscopic hematuria with mild proteinuria persisted for 4 years. At this stage, she had an acute episode of macroscopic hematuria with more severe proteinuria and an increase in serum creatinine concentration (202 µmol/l). There were features of membranoproliferative glomerulonephritis type I on renal biopsy. Her renal function improved after filgrastim withdrawal and again deteriorated after reintroduction, with a persistent increase in serum creatinine concentration (114–123 µmol/l). Hematuria and proteinuria partially responded to corticosteroids. Filgrastim was finally replaced by lenograstim when she was 13 years old, and this resulted in reduced proteinuria and improved renal function.

Although she also had hepatitis C virus infection during the course of her disease, renal dysfunction preceded this. The persistence of hematuria and proteinuria after the disappearance of hepatitis C virus RNA also argued against a role of hepatitis C infection. Skin Erythema exsudativum multiforme developed in a 40-year-old healthy donor 3 days after lenograstim was started for peripheral blood stem cell mobilization (53A ). The lesions were on the hips, apart from the site of lenograstim injection, and resolved 1 week after withdrawal. The spectrum of G-CSF-induced neutrophilic dermatoses is wide. In two children with painful erythematous lesions attributed to G-CSF, histology showed microscopic, sterile, neutrophilic abscesses in one and neutrophilic panniculitis in the other (54A ). Musculoskeletal Significant bone loss and severe osteopenia can occur in children treated with G-CSF for severe congenital neutropenia (SED-14, 1273) and has recently been reported again in a 13-year-old boy (55A ). Significant improvement in bone mineral density was obtained with pamidronate.

TUMOR NECROSIS FACTOR ANTAGONISTS (SEDA-24, 420; SEDA-25, 440)

Etanercept The clinical use and safety of etanercept have been thoroughly reviewed (56R ). Nervous system Neurological events suggestive of demyelinating disorders in patients treated with tumor necrosis factor alfa antagonists and reported to the FDA’s Adverse Events Reporting System have been reviewed (57A ). These included 17 cases temporarily associated with etanercept and two with infliximab, but complete information was lacking in a number of cases. One additional case with etanercept was more extensively detailed. The first symptoms occurred after a large range of delay after first drug administration (1 week to 15 months; mean 5 months) and mostly included paresthesia, optic neuritis, and confusion. MRI scans in 19 patients showed demyelination in various brain areas in 16. Although a causal relation is not yet proven, it is noteworthy that most patients improved after withdrawal and one patient had recurrent neurological symptoms after etanercept readministration. The various hypothetical mechanisms by which tumor necrosis factor alfa antagonists might produce demyelinating events have been discussed elsewhere (58R ). Briefly, they cause an increase in peripheral T cell autoreactivity, and their inability to cross the blood brain barrier may account for exacerbation of central demyelinating disorders. Endocrine Transient hyperthyroidism has been reported after 6 months of etanercept treatment in a 37-year-old woman with rheumatoid arthritis (59A ). However, a direct causal relation with etanercept is debatable, because there was complete resolution with propranolol and despite continuation of etanercept. Hematologic Etanercept has reportedly caused abrupt exacerbation of the macrophage activation syndrome (60A ). • A 22-year-old woman with adult-onset Still’s disease developed symptoms suggestive of the

400 macrophage activation syndrome. After initial corticosteroid treatment, she received two doses of etanercept, and within 6 days her white blood cell count fell from 6.4 × 109 /l to 2.5 × 109 /l and the neutrophil count from 0.8 × 109 /l to 0.2 × 109 /l. There was also thrombocytopenia and impaired coagulation and her liver enzymes were raised. A bone-marrow aspirate showed delayed myelopoiesis. She received multiple transfusions, intravenous immunoglobulin, and granulocyte–macrophage colony-stimulating factor. The macrophage activation syndrome was diagnosed at that time and she was successfully treated with pulse methylprednisolone and ciclosporin. Epstein–Barr virus infection was subsequently confirmed.

Because soluble TNF alfa receptors are supposedly involved in the macrophage activation syndrome, the authors speculated that the administration of additional soluble TNF alfa receptors may have been the cause of a prolonged and exacerbated syndrome. Skin Etanercept-induced injection site reactions are common. The clinical and histological characteristics of these lesions have been analysed in a retrospective review of 103 etanercept-treated patients and in three other patients assessed prospectively (61c ). Of 103 patients 21 had injection site reactions (erythema, pain, pruritus or edema) within the first 2 months of treatment, and typically within 1–2 days after the last injection. In addition, eight patients developed recall reactions while continuing to take etanercept. Skin biopsies and immunohistological analysis of reaction sites in three patients showed an inflammatory infiltrate consistent with a T cell-mediated delayed hypersensitivity reaction. Immunologic Although etanercept-treated patients commonly develop new antinuclear antibodies or anti-double-stranded DNA antibodies, no reports of cutaneous or systemic lupus erythematosus have emerged from clinical trials. Since then, at least eight cases have been reported which included five patients with a lupus-like syndrome, two with acute discoid lupus, and one with subacute cutaneous lupus erythematosus (62A –65A ). All were women and they developed their first symptoms 6 weeks to 14 months after the first injection of etanercept. Antinuclear and/or anti-DNA antibodies were positive in most of them. Etanercept was withdrawn in all patients

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with features of systemic lupus erythematosus, and the symptoms resolved within 2–8 weeks. The skin lesions also improved with local corticosteroids, despite continued etanercept treatment in two patients with discoid lupus or subacute cutaneous lupus erythematosus. This suggests that etanercept-induced autoantibodies are sometimes associated with clinical autoimmune disease. Infection risk In contrast to infliximab, etanercept is rarely associated with severe infectious complications. This has been attributed to different mechanisms of TNF alpha neutralization by the two drugs. Indeed, only nine cases of tuberculosis have previously been reported to the FDA in more than 100 000 patients treated worldwide (66A ). However, recently severe or uncommon infectious complications (severe viral pneumonia, fatal pneumococcal sepsis due to necrotizing fasciitis, osteoarticular tuberculosis) have been described in patients taking etanercept and long-term corticosteroids (67A –69A ). Risk factors In eight children with juvenile rheumatoid arthritis who had failed to respond to disease-modifying anti-rheumatic drugs high-dose etanercept was well tolerated (70c ). None withdrew because of etanerceptrelated adverse events. One child reported transient erythema at the injection site after the first injection. Three patients had mild transient upper respiratory tract infections. There were no laboratory abnormalities.

Infliximab Cardiovascular The preliminary results of a phase II trial in patients with moderate to severe congestive heart failure showed a higher incidence of worsening congestive heart failure and death in patients treated with infliximab compared with placebo (73R ). This has led to warnings from regulatory agencies and to the limited use of infliximab in patients with congestive heart failure. The possible role of infliximab in the development of hypercoagulability disorders has been discussed in the context of a case of arterial thrombosis (74A ).

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• A 72-year-old woman with refractory sarcoidosis developed venous thrombosis at a catheter site and extensive multiple thromboses in small arteries in her legs after receiving a third dose of infliximab for severe enteropathy. Anticardiolipin antibodies were detected, but antinuclear and anti-double stranded DNA antibodies were negative.

Although infliximab has been associated with autoantibody production, it is not known whether it contributed to hypercoagulability in this patient. Respiratory Allergic granulomatosis of the lung has been described in a patient with active ankylosing spondylitis after a second infusion of infliximab (75A ). The clinical and radiological symptoms resolved 8 weeks after withdrawal, but no other details were given. Nervous system Features of aseptic meningitis have been reported after multiple infliximab injections (76A ) • A 53-year-old man with severe rheumatoid arthritis and mixed type III cryoglobulinemia received his first four injections of infliximab uneventfully, but 4 hours after the fifth injection had severe muscle pain in the lower limbs, which required morphine and abated within 3 days. Similar symptoms were observed after the sixth injection. There were no signs of meningitis, the cerebrospinal fluid contained lymphocytes and increased protein and IgG concentrations. Cultures were negative and MRI scans of the brain and the spine were normal. The CSF was normal 1 month later.

The authors speculated that the most likely explanation for these observations was linked to the lack of transfer of high-molecular weight soluble receptors and IgG across the bloodbrain barrier, implying that control of brain TNF alfa cannot be obtained with monoclonal antibodies. They thought that neurological complications in diseases other than multiple sclerosis might be related to control of TNF alfa in the periphery, resulting in an enhanced contribution of brain-derived TNF alfa or other cytokines, such as IL1. Demyelinating disorders reported with infliximab are discussed elsewhere (see etanercept below).

401 Skin Cutaneous vasculitis has been previously reported with etanercept, another TNF alfa inhibitor (SEDA-25, 440). A 73-year-old woman had three separate episodes of vascular purpura (with leukocytoclastic vasculitis during the third episode) during each sequence of treatment with etanercept; she later developed similar cutaneous lesions after a third injection of infliximab (77A ). Immunologic Both acute and delayed hypersensitivity reactions to infliximab have been reported (SEDA-24, 439). Acute hypersensitivity reactions can mimic an anaphylactic reaction, but specific IgE antibodies have not so far been identified. A dose-escalation protocol has been proposed to desensitize patients who have acute systemic reactions (78A ), but this has not always been successful (79A ). Although most reported anaphylactic reactions to infliximab have been mild, a 35-year-old woman with known hypersensitivity to mesalazine had severe symptoms, namely chest pain, dyspnea, productive cough, skin rash, and hypotension, during a third infusion of infliximab, and she died 6 hours later from refractory hypotension and respiratory failure (80A ). Specific IgE or human antichimeric antibodies were not checked. Delayed hypersensitivity reactions were mostly observed in patients with Crohn’s disease who received episodic treatment. In one patient, this complication was associated with acute respiratory distress syndrome, which became evident only 10 days after retreatment (81A ). • A 33-year-old man with a 3-year history of Crohn’s disease had previously received a well-tolerated single infusion of infliximab. When, 14 months later, he received a second infusion for exacerbation of the disease he had no immediate adverse effects but complained of myalgia, arthralgia, nausea, and vomiting 7 days later and received diphenhydramine. After 3 days he had dyspnea, fever, and chills. An open lung biopsy showed features of eosinophilic pneumonia and no infections or other obvious causes were found. He subsequently worsened and required intubation and mechanical ventilation for 13 days. He was given corticosteroids and quadruple antituberculosis therapy and completely recovered within 2 months. Human antichimeric antibodies were raised (13 times normal).

Risk factors for the development of severe systemic reactions after infliximab retreatment

402 have been analysed in 52 adults and 34 children with Crohn’s disease (82C ). Acute severe systemic reactions were defined by symptoms of anaphylactic reactions that required pharmacological treatment, and delayed severe systemic reactions were defined by the occurrence of arthralgia and joint stiffness (i.e. serum sickness-like symptoms) requiring corticosteroids in the days after infliximab retreatment. According to these definitions, severe systemic reactions developed in 14% of patients (four acute and eight delayed) during retreatment. They were significantly more frequent in adults than in children (21% vs. 3%), and delayed systemic reactions were observed exclusively in adults. These reactions mostly occurred during the second infliximab infusion, and particularly when retreatment was distant from the first infusion, i.e. beyond a 20-week interval. This suggested a higher potential for delayed hypersensitivity reactions when repeated doses are given within a longer time interval, and led the authors to recommend multiple early infusions if future infliximab retreatment is anticipated. Infection risk An increased risk of tuberculosis in infliximab-treated patients has previously been discussed (SEDA-25, 439). Since then, several case reports have provided detailed information in at least seven other patients, including three who developed miliary tuberculosis and one Mycobacterium tuberculosis enteritis (83A –87A ). According to the data from the manufacturers, 130 cases of active tuberculosis have been notified as of October 2001. Many of the cases were disseminated or extrapulmonary tuberculosis, and several patients died. Other opportunistic infections, including invasive pulmonary aspergillosis, histoplasmosis, listeriosis, and pneumocystosis, have also been published or reported to the manufacturers (88A –91A ). Owing to the risk of severe infection, it is therefore currently recommended that patients should be evaluated for latent infection, particularly tuberculosis, before infliximab treatment.

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MONOCLONAL ANTIBODIES (SED-14, 1308; SEDA-23, 401; SEDA-24, 419; SEDA-25, 438)

Dacluzumab Infection risk Dacluzumab is a humanized antibody directed against the alpha chain of the IL2 receptor. Its efficacy in acute and chronic steroid-refractory graft-versus-host disease has recently been studied in 16 patients, of whom nine responded (71c ). However 14 developed infectious complications during treatment, with a high incidence of cytomegalovirus reactivation; there were three infection-related deaths.

Gemtuzumab ozogamicin Liver Gemtuzumab ozogamicin (Mylotarg) consists of a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic enediyne antibiotic calicheamicin. It has been approved for the treatment of a subset of patients with acute myeloid leukemia. Hepatic veno-occlusive disease is a relatively common and potentially severe adverse reaction. In a recent study in 119 patients (92 with acute myeloid leukemia, 25 with advanced myelodysplastic syndrome, and two with chronic myeloid leukemia), who did not receive concomitant stem cell transplantation, 14 developed venoocclusive disease (72c ). Five of these 14 patients had not received prior antileukemic therapy, and in two cases gemtuzumab ozogamicin was used as single-agent chemotherapy.

Omalizumab Omalizumab (formerly rhuMab-E25) is a humanized monoclonal antibody against IgE that blocks the interaction of IgE with mast cells. Several phase I and phase II trials have demonstrated its efficacy in patients with allergic asthma (92C , 93C , 94R , 95R ). In a placebo-controlled study of subcutaneous omalizumab (50, 150, and 300 mg before the ragweed season and every 3 or 4 weeks during the pollen season) in 536 patients with seasonal allergic rhinitis, injection site reactions

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were mild and infrequent, there were no clinically significant alterations in laboratory values, and anti-idiotypic antibodies to omalizumab were not detected; there was no evidence of immune complex-related adverse events (93C ). In another placebo-controlled trial in 525 patients with severe asthma, the adverse effects profiles were similar in the treatment and placebo groups (95C ). Skin The safety of subcutaneous omalizumab has been assessed in 334 boys and premenarchal girls aged 6–12 years with moderate to severe allergic asthma requiring inhaled corticosteroids in a randomized, placebo-controlled, double-blind trial (96C ). There were no serious treatment-related adverse events, and the frequencies of most adverse events were similar with omalizumab and placebo. However, urticaria was more frequent with omalizumab (4% vs. 0.9%). It usually resolved spontaneously or with antihistamine therapy and did not recur with subsequent treatment. Urticaria was also reported in a small number of adults (0.5%) given omalizumab for allergic rhinitis (97R ).

Palivizumab In 565 patients with respiratory syncytial virus infections injection site reactions (2.3%), fever (1.5%), and nervousness/irritability (under 1%) were the only adverse effects reported (98c ).

Rituximab Rituximab is a chimeric anti-CD20 monoclonal antibody that has become important in treating non-Hodgkin’s lymphoma and is being tried in other B cell malignancies. There has also been recent interest in its use to treat autoimmune diseases. Severe reactions are rare, but are seen in patients with bulky tumors or with leukemic involvement with high numbers of CD20 positive cells (99c , 100c ). It has been suggested that this is due to a tumor lysis syndrome and that complement activation can play a pivotal role (101E ).

Hematologic Thrombocytopenia leading to gastrointestinal bleeding has been attributed to rituximab (102c ). Infection risk Severe viral infections/reactivation that have been reported have included fulminant hepatitis B, parvovirus-induced red cell aplasia, and fatal Varicella zoster infection (103A –105A ). There was a high incidence of reactivation of cytomegalovirus and Varicella zoster virus when rituximab was combined with high-dose chemotherapy in high-risk patients with non-Hodgkin’s lymphoma (106c ).

Trastuzumab Trastuzumab (Herceptin) is a humanized monoclonal antibody to the human epidermal growth factor receptor (HER-2), which is expressed in about 25% of breast tumors. Its main use is in the treatment of metastatic breast cancer, and it is often used in combination with other chemotherapeutic agents. Relatively mild reactions at the time of infusion are common. Cardiovascular Cardiotoxicity is a major concern, particularly as it is often used in patients who are receiving or who have previously received anthracycline antibiotics (107c ). The efficacy and safety of trastuzumab have been evaluated in 235 women with metastatic breast cancer receiving standard chemotherapy (108C ). The most important adverse event was cardiac failure, which occurred in 27% of those who were given an anthracycline, cyclophosphamide, and trastuzumab, 8% of those who were given an anthracycline and cyclophosphamide alone, 13% of those who were given paclitaxel and trastuzumab, and 1% of those who were given paclitaxel alone. The incidence of cardiac failure of NYHA class III or class IV was highest among patients who had received an anthracycline, cyclophosphamide, and trastuzumab. The mechanism is unknown. In a retrospective analysis of all cases with cardiac failure by an independent review and evaluation committee, the only significant risk factor was older age. Although the cardiotoxicity was severe, and in some cases life-threatening, the symptoms improved with standard medical management.

404

IMMUNOSUPPRESSIVE DRUGS Azathioprine

(SED-14, 1280; SEDA-23, 401; SEDA-24, 422; SEDA-25, 440) Hematologic There is heterogeneity in erythrocyte thiopurine methyl transferase (TPMT) activity, and patients with negligible enzyme activity (0.3%) or low activity (11%) have an increased risk of azathioprine-induced myelosuppression (109c ). Pre-treatment measurement of erythrocyte thiopurine methyl transferase activity should identify patients who have a high risk of bone-marrow failure (110R ). Gastrointestinal In two cases azathioprine caused severe gastrointestinal symptoms that could have been easily confused with an acute exacerbation of the underlying inflammatory bowel disease (111A ). • A 32-year-old man with ulcerative colitis improved with prednisolone, mesalazine, and antibiotics. The dose of prednisolone was reduced and the disease flared up again. He was therefore given azathioprine and an increased dose of prednisolone, with rapid clinical improvement. After 3 weeks, he reported increasing abdominal pain, worse diarrhea, and weight loss of 3 kg. He stopped taking azathioprine and the pain improved. Because of progressive disease and active pancolitis at colonoscopy, he was given high-dose prednisolone, mesalazine, and ciprofloxacin, without improvement. He was therefore given intravenous azathioprine, but developed devastating diarrhea and weight loss of more than 6 kg in 24 hours, his CRP rose from 5 to 305 mg/l, and he developed hypovolemic shock. He recovered after treatment with parenteral nutrition for 7 days. • A 50-year-old woman with Crohn’s disease and active disease throughout the colon was given prednisolone, mesalazine, and azathioprine 50 mg/day. After 3 weeks the dose of azathioprine was increased to 100 mg/day, but she developed nausea, severe diarrhea, and abdominal tenderness. The symptoms subsided after azathioprine was withdrawn. She was then given mercaptopurine, without significant adverse effects.

Ciclosporin

(SED-14, 1286; SEDA-23, 402; SEDA-24, 424; SEDA-25, 441) Of 20 patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy treated with ciclosporin, six

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withdrew owing to toxicity (112c ). The target blood concentration range was identical to that aimed at in the first 3 months after kidney transplantation. The most common adverse effects were hypertension, headache, and severe myalgia. The antileukemic effect of ciclosporin has been harnessed in the treatment of cytopenias associated with chronic lymphatic leukemia. In 31 patients the most common adverse effect was a raised serum creatinine concentration of grade 2 or worse in six patients (19%); three patients developed opportunistic infections (113c ). Nervous system The incidence of central nervous system adverse effects of ciclosporin is 10%. A case of tonic–clonic seizures has been reported (114A ). • A 13-year-old boy with severe Crohn’s disease developed hematochezia, and required blood transfusion. He was given ciclosporin on day 22 because of persistent rectal bleeding and diarrhea, despite high-dose intravenous corticosteroids. After 6 days he developed multiple episodes of generalized tonic-clonic seizures with MRI findings typical but not pathognomonic of ciclosporin: prominent meningeal enhancement, bifrontal, bitemporal, biparietal, and bioccipital cortical and subcortical white matter high-signal changes, and swelling of the gyrae, which obliterated the sulci.

This case illustrates that severe ciclosporin neurotoxicity can develop in patients with predisposing factors, such as hypomagnesemia, hypocholesterolemia, hypertension, and corticosteroid therapy. Metabolism The pathology of post-transplantation hyperlipidemia is multifactorial, but it is clearly dose-dependently related to immunosuppressive therapy. This results in cardiovascular disease, which is one of the most common causes of morbidity and mortality in long-term survivors of organ transplantation (115R ). Hyperlipidemia can also cause renal atheroma, resulting in graft rejection. A combination of lipid-lowering drugs and optimization of immunosuppressive regimens compatible with long-term allograft survival is probably required to reduce post-transplantation hyperlipidemia.

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Hematologic Ciclosporin-associated thrombotic microangiopathy occurs in 3–14% of patients with a renal transplant and can cause allograft loss. Renal impairment, reflected by an increase in serum creatinine concentration, is often the only change found, and hemolysis is not always present. Plasmapheresis has been used to treat this complication (116A ). • A 47-year-old multiparous Hispanic woman received a living-unrelated kidney transplant for end-stage renal disease secondary to polycystic kidney disease. On the day of transplantation she received intravenous daclizumab 1 mg/kg plus methylprednisolone 300 mg and mycophenolate mofetil 3 g/day, and on day 3 ciclosporin emulsion 4 mg/kg/day. On day 8 she developed thrombotic microangiopathy without evidence of rejection. Ciclosporin was withdrawn. Plasmapheresis with fresh frozen plasma was started. Daclizumab on day 14 was postponed for 24 hours and plasmapheresis was stopped, to avoid clearance of daclizumab. Thereafter she was given tacrolimus, without recurrence of hemolysis.

Urinary tract The mechanisms of the nephrotoxic effects of ciclosporin are vasoconstriction of efferent and afferent glomerular arterioles and cellular hypoxia. The major effect of ciclosporin is to promote calcium accumulation in the mitochondrial matrix, which in turn reduces ATP synthesis (117c ). Among antiischemic drugs, trimetazidine might be a good choice, because it prevents the loss of ATP synthesis caused by ciclosporin in rat kidney cells. S-15176 and S-16950 are trimetazidine derivatives that antagonize the mitochondrial toxicity without changing the immunosuppressive effect of ciclosporin. Musculoskeletal Previous studies have shown that both ciclosporin and tacrolimus cause increased bone turnover and significant reductions in bone mass, more marked with tacrolimus (FK506). As most transplantation regimens include glucocorticosteroids, the individual effects of ciclosporin and tacrolimus are uncertain. As tacrolimus is the more potent immunosuppressive agent, theoretically its use after transplantation should allow reduction in the dose of glucocorticosteroids, which would be associated with higher bone mineral density. Preliminary data suggest that there is a lower rate of vertebral fractures in patients taking tacrolimus compared with those taking ciclosporin. In 18 men who underwent liver transplantation and received ciclosporin and seven

405 patients who received tacrolimus, bone mineral density in the lumbar spine and proximal femur was prospectively measured before and at 6, 12, and 24 months after transplantation (118c ). Serum concentrations of parathyroid hormone and 25-hydroxycholecalciferol were determined at the same time. Although both groups had the same pattern of rapid early bone loss, tacrolimus was associated with lower doses of corticosteroids and a trend to faster lumbar bone mass recovery. This may have a favorable effect on long-term bone mass evolution, especially in the femoral neck. Drug interactions In a study of the safety and efficacy of simvastatin in hyperlipidemia after renal transplantation in 15 patients the Cmax and AUC of simvastatin were increased seven-fold by ciclosporin (119c ). In contrast, in 17 patients tacrolimus had no effect. Although there were no complications, such as myopathy or rhabdomyolysis, creatine kinase activity must be monitored during co-administration of simvastatin and ciclosporin. Herbal medicines and dietary supplements, such as St John’s wort, represent a potential and possibly overlooked source of interactions in transplant patients; it has been estimated that about 15 million Americans take dietary/herbal supplements as well as prescription medications (120A ). • A 44-year-old black woman with a living-related renal transplant had an acute rejection within 3 months and was given OKT3 (muromonab CD3) but was from then on stable. She was later given oral ciclosporin (Neoral 2 mg/kg bd), mycophenolate mofetil 1000 mg bd, and prednisolone 7.5 mg/day. Over 6 months her ciclosporin blood concentrations were consistently below the target concentration of 200 ng/ml. It was then discovered that she had also been taking 2–3 tablets/day of St John’s wort (Your Life, Leiner Health Products, Carson CA, 300 mg standardized to 0.3% hypericin). The St John’s wort was withdrawn and her blood ciclosporin concentrations reached the target within 2 weeks. • A 29-year-old white woman with cadaveric kidney and pancreas transplants had two early rejection episodes but then stabilized on ciclosporin 100 mg bd and prednisolone 5 mg/day. Her blood ciclosporin concentration was consistently 200–350 ng/ml. She then started to take St John’s wort and over the next 30 days her blood ciclosporin concentration fell to 155 ng/ml and 3 weeks later to 97 ng/ml. Her serum creatinine rose to 1.3 mg/dl (115 µmol/l) and her serum amylase rose from

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a baseline of 60–90 to 314 u/l; this was associated with abdominal pain. Renal biopsy confirmed acute rejection, which was treated. She subsequently developed chronic rejection, confirmed by renal biopsy.

two had normal sperm counts; 10 had azoospermia and five had oligospermia (129c ). The two patients with normal sperm counts had taken the lowest doses of cyclophosphamide.

St John’s wort contains a variety of phytochemicals and it induces the activities of CYP3A4 and P glycoprotein, reducing the systemic availability of ciclosporin. In a phase I study of the pharmacokinetics of twice-daily oral paclitaxel 60–160 mg/m2 in 15 patients in combination with ciclosporin (15 mg/kg), which inhibits P glycoprotein and cytochrome P450, there was a seven-fold increase in the systemic exposure to paclitaxel; the plasma concentration increased from negligible to therapeutic concentrations (121c ).

Carcinogenicity To determine the frequency and types of malignancies that occur in children with end-stage renal insufficiency who required renal replacement therapy, data from 249 patients were analysed retrospectively (130R ). There were 22 malignancies in 21 patients; skin cancers accounted for 59% and non-Hodgkin’s lymphomas for 23%. At 25 years after first renal replacement therapy, the probability of developing a malignancy was 17%. The incidence of cancers overall was ten-fold higher than in the general population. For cancers other than melanoma and non-Hodgkin’s lymphoma, the standardized risks were 222 and 46 respectively. The use of more than 20 mg/kg cyclophosphamide was associated with an increased risk of malignancy. Six patients died as a result of their malignancy, accounting for 9.5% of overall mortality. The long-term risk of certain malignancies is significantly increased in children who have undergone renal replacement therapy, especially after treatment with cyclophosphamide.

Pregnancy In a meta-analysis of the effects of exposure to ciclosporin during pregnancy, 15 studies (total 410 patients; six studies with control groups who were not given ciclosporin) met inclusion criteria for malformations, 10 for preterm delivery, and five for low birth weight (122M ). Ciclosporin did not appear to be a major human teratogen, but was associated with increased rates of prematurity. Carcinogenicity Fibroadenomata are the most common solid breast masses in young women. Between 1997 and 2000 five women who had had transplant surgery and who were taking ciclosporin developed new breast masses, which were histologically confirmed to be fibroadenomata (123A ). Benign mammary hyperplasia occurs in 0.7% of women taking ciclosporin (124c ). The mechanism is poorly understood, but it may be related to trophic effects in the breast through ciclosporin receptors on fibroblasts (125E ), to an effect of ciclosporin on the hypothalamic– pituitary axis (126E ), or to antagonism at prolactin receptor sites on B and T (127E , 128E ).

Cyclophosphamide

(SED-14, 1283; SEDA-23, 405; SEDA-24, 427; SEDA-25, 443) Reproductive function Of 17 adult male survivors of childhood sarcomas treated before puberty with high-dose cyclophosphamide, only

Everolimus Drug interactions Both everolimus and ciclosporin are extensively biotransformed by CYP3A and are substrates for P glycoprotein. However, in a multicenter randomized doubleblind study in 101 patients, 1 year after kidney transplantation, who were randomly assigned to receive everolimus 0.5, 1, and 2 mg bd plus ciclosporin and prednisone, the pharmacokinetics of ciclosporin were similar to published values in patients not taking everolimus (131C ).

Methotrexate

(SED-14, 1297; SEDA-23, 406; SEDA-24, 427; SEDA-25, 444) Hematologic In a double-blind, placebocontrolled study of the safety and efficacy of methotrexate therapy combined with corticosteroids in patients with giant cell arteritis over

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24 months, adverse events were defined as a new diagnosis of any condition during treatment (132C ). The combination of methotrexate plus prednisolone reduced the number of relapses and improved the course of the disease. Methotrexate was withdrawn in three patients who had adverse events that were clearly drugrelated. One had leukopenia, anemia, and mucositis, one developed pancytopenia, and one oral ulcers. These patients were not taking folic acid or folinic acid supplements. Carcinogenicity A second malignancy in a patient taking methotrexate for chronic lymphatic leukemia has been described (133A ). • A 55-year-old man with chronic lymphocytic leukemia and rheumatoid arthritis took methotrexate for 4 years and developed a B cell nonHodgkin’s lymphoma in the shoulder and axillary lymph nodes; he had Epstein–Barr viral antigens in the serum. After radiation and chemotherapy had failed, complete remission was achieved with a combination of rituximab and EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin).

The development of a second malignancy in a patient taking methotrexate has not previously been described. The authors thought that the T cell deficiency induced by methotrexate, chronic lymphatic leukemia, and rheumatoid arthritis may have contributed to the development of the B cell lymphoma.

Mycophenolate mofetil

(SED-14, 1303; SEDA-23, 406; SEDA-24, 429; SEDA-25, 445) Immunologic In 11 patients with orthotopic liver transplants who had adverse effects from ciclosporin or tacrolimus, mycophenolate mofetil monotherapy for 1 year was successful. This was followed by a randomized controlled trial in 18 patients, of whom nine were given mycophenolate mofetil (134C ). Five patients completed the 3-month trial. Of these, two had an episode of acute rejection, one after 2 and one after 3 months, which did not respond to the reintroduction of tacrolimus and intravenous steroids. One had a steroid-responsive episode of severe acute rejection after 3 weeks. The

407 other two patients had normal liver function tests after 2 weeks and 2 months respectively, when the trial was stopped. Mycophenolate mofetil allows a reduction of the dose of calcineurin inhibitor, with a low risk of rejection and improvement in renal function. However, it is associated with an unacceptable risk of acute rejection. In a randomized study, 14 patients with liver transplants were given calcineurin inhibitors and 14 mycophenolate mofetil monotherapy (135C ). Those who were given mycophenolate had reversible episodes of acute graft rejection; there were no such episodes in those who were given calcineurin inhibitors. Infection risk Mycophenolate mofetil has been compared with azathioprine in combination with ciclosporin and corticosteroids in 65 children after kidney transplantation (136c ). The main adverse effects of this treatment were infections of the urinary tract and the upper respiratory tract, abdominal pain, and diarrhea. Opportunistic infections with cytomegalovirus or cytomegalovirus syndrome occurred in 20% within the first 6 months and tissue-invasive cytomegalovirus disease in 3.1%. These results were similar to those in adults. To evaluate whether mycophenolate mofetil is effective in treating moderate to severe atopic dermatitis an open pilot study was conducted in 10 patients (137c ). There were no serious adverse effects, but one patient had to discontinue treatment because he developed Herpes simplex retinitis, which resolved after treatment with aciclovir. Although there is no direct evidence that mycophenolate mofetil is a major cause of herpes retinitis, in this patient it seems likely that it was due to immunosuppression. In contrast, in vivo and in vitro mycophenolate mofetil strongly potentiates the antiherpetic effects of aciclovir, ganciclovir, and penciclovir (138E ). It is probably therefore enough to give antiviral therapy only when clinical signs of herpes infection occur. Pregnancy A 33-year-old woman was given a living related-donor kidney transplantation during the first trimester, followed by mycophenolate mofetil, tacrolimus, and prednisone (139A ). This case is the first in which mycophenolate mofetil has been given during the first trimester of pregnancy, at the time of organogenesis. The mother did well, except for mild

408 pre-eclampsia and mild renal insufficiency. The child was born prematurely during the 36th week. The only teratogenic effects detected were hypoplastic nails and a short fifth finger.

Sirolimus (rapamycin)

(SED-14, 1304; SEDA-24, 430; SEDA-25, 446) Drug interactions In 18 healthy subjects in a randomized, crossover study of the pharmacokinetics of a single oral dose of sirolimus 10 mg, a single dose of diltiazem 120 mg, and the combination, diltiazem increased exposure to sirolimus, presumably by inhibiting its firstpass metabolism (140c ).

Tacrolimus

(SED-14, 1304; SEDA-24, 431; SEDA-25, 446)

Nervous system In children one advantage of tacrolimus is that it can reduce the dose of corticosteroids required for immunosuppression. This in turn improves growth. When in one center the immunosuppression protocol was changed to tacrolimus, mycophenolate mofetil, and prednisone, two patients developed transient encephalopathy associated with tacrolimus (141A ). In both cases, the encephalopathy was managed by treating the associated hypertension and fluid overload; tacrolimus was not withdrawn. Both tacrolimus and ciclosporin are hydrophobic, and can alter the properties of the cell membrane. They bind to an intracellular peptidylprolyl-isomerase that regulates T cell activation and can interfere with cytoskeletal components that prevent IL-2 synthesis and release. Cytotoxic edema caused by acute cerebral ischemia is associated with reduced diffusion, reflecting the failure of sodium membrane pumps. Altered electrolyte or fluid balance can precede the onset of encephalopathy. This can be shown by fluid-attenuated inversion recovery and diffusion-weighted MRI images (142c ). Metabolism In animals high-dose tacrolimus causes glucose intolerance and reduced insulin release (143E ). This resolves after withdrawal.

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Diabetes mellitus after transplantation is a relatively common complication in pediatric thoracic organ recipients receiving tacrolimus (144c ). Specific risk factors have not been identified. A switch from tacrolimus to ciclosporin for other reasons in two patients did not resolve the problem. Of 834 primary adult liver transplant recipients, of whom 499 were alive and taking tacrolimus, 70% were steroid-free after 1 year; this did not change over the next 5 years (145c ). However, steroid-associated adverse effects, such as hypertension, diabetes, and hyperlipidemia, were not statistically significantly less common in patients not taking steroids. This may have been because of the diabetogenic effect of tacrolimus. Liver In children 0.1% tacrolimus ointment has been used daily without major adverse effects. One patient, a 3-year-old African– American boy with moderate atopic dermatitis, had raised AsT, AlT, and LDH activities; tacrolimus was withdrawn on day 29, but no further information was given about liver function tests (146c ). Skin In 631 adult patients with moderate to severe atopic dermatitis enrolled in a randomized, double-blind, multicenter comparison of tacrolimus (0.03% or 0.1%) with a vehicle applied twice daily for 12 weeks, the most common adverse events were skin burning, erythema, and pruritus (147C ). Others were flu-like symptoms and headache. Withdrawal was required in 50 patients because of adverse events, twice as many as in the vehicle group. There was pruritus in 30 patients, skin burning in 19, skin erythema in 12, and skin infections in two. Skin burning and pruritus have consistently been observed with tacrolimus ointment, typically during the first days of treatment, reducing in incidence within the first week; they tend to be mild or moderate. In 255 children with atopic dermatitis, tacrolimus 0.1% ointment caused transient skin burning and itching as the most common adverse events (146c ). Two patients required hospital admittance to control skin infections. A flu-like syndrome was the major non-topical adverse event.

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Infection risk In a randomized, double-blind, placebo-controlled study at 23 centers in the USA, children with moderate to severe atopic dermatitis applied the vehicle, tacrolimus ointment 0.03%, or tacrolimus ointment 0.1% for 12 weeks (148C ). Burning and pruritus were the main adverse effects. Varicella and vesiculobullous rashes on non-application areas occurred, but with a low incidence (below 5%). Since they occurred in those who used tacrolimus 0.03%, it is likely that they were random events rather than drug-related. Regardless of dose, there were some age-related differences in the incidence of individual adverse events. For example, otitis media was more common in younger children (2–6 years). Tacrolimus ointment had no age-selective effect that was not also observed with the vehicle. Each of the adverse events resolved without sequelae.

IMMUNOENHANCING DRUGS (SED-14, 1311; SEDA-23, 410; SEDA-24, 433; SEDA-25, 448)

Bryostatin 1 Bryostatin 1 is a naturally occurring macrocyclic lactone derived from the marine invertebrate Bugula neritina. It is a protein kinase C partial agonist. In preclinical and phase I clinical studies it had promising antitumor and immunomodulating effects. It amplifies expansion of myeloid and erythroid progenitor cells stimulated by the cytokines GM-CSF, M-CSF, and IL-3. Similarly, it induces the production of peripheral blood mononuclear cells with enhanced lymphokine-activated killer cell activity and proliferation in the presence of IL-2 (149c ).

In a phase II study, 17 patients with progressive indolent non-Hodgkin’s lymphoma previously treated with chemotherapy received bryostatin 1. Phlebitis was initially due to the 60% ethanol formulation used for administration, and the subsequent use of another formulation (60% polyethylene glycol, 30% ethanol, 10% Tween 80) reduced the incidence. In one patient bryostatin 1 was withdrawn because of grade 2 thrombocytopenia. The dose-limiting adverse effect was myalgia, which occurred in eight patients.

LJP 394 LJP 394 is an investigational drug under development as a selective immunomodulator for the treatment of systemic lupus erythematosus. It reduces serum dsDNA antibodies and splenic dsDNA antibody-producing cells in BXSB mice and causes improved renal function and histopathology, as well as prolonged survival (150E ). In a phase 2, partially randomized, doubleblind, placebo-controlled study of three different doses of LJP394 in 58 patients, seven did not receive all doses of LJP394 because of adverse events (151c ). Five withdrew because of adverse events related to their lupus erythematosus: non-renal exacerbations in two, hematuria and hypertension in one, worsening rash in one, and nephritis in one. One patient withdrew because of cellulitis and another because of a localized Herpes zoster infection. None of the reported adverse events was considered to be definitely related to the drug.

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is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 2001; 92: 406–13. 73. Weisman MH. What are the risks of biologic therapy in rheumatoid arthritis? An update on safety. J Rheumatol Suppl 2002; 65: 33–8. 74. Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001; 135: 27–31. 75. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sorensen H, Zeidler H, Thriene W, Sieper J. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 1187–93. 76. Marotte H, Charrin JE, Miossec P. Infliximabinduced aseptic meningitis. Lancet 2001; 358: 1784. 77. McCain ME, Quinet RJ, Davis WE. Etanercept and infliximab associated with cutaneous vasculitis. Rheumatology 2002; 41: 116–17. 78. Puchner TC, Kugathasan S, Kelly KJ, Binion DG. Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn’s disease patients with prior anaphylactic reaction. Inflammatory Bowel Dis 2001; 7: 34–7. 79. O’Connor M, Buchman A, Marshall G. Anaphylaxis-like reaction to infliximab in a patient with Crohn’s disease. Dig Dis Sci 2002; 47: 1323–5. 80. Lankarani KB. Mortality associated with infliximab. J Clin Gastroenterol 2001; 33: 255–6. 81. Riegert-Johnson DL, Godfrey JA, Myers JL, Hubmayr RD, Sandborn WJ, Loftus EV. Delayed hypersensitivity reaction and acute respiratory distress syndrome following infliximab infusion. Inflammatory Bowel Dis 2002; 8: 186–91. 82. Kugathasan S, Levy MB, Saeian K, Vasilopoulos S, Kim JP, Prajapati D, Emmons J, Martinez A, Kelly KJ, Binion DG. Infliximab retreatment in adults and children with Crohn’s disease: risk factors for the development of delayed severe systemic reaction. Am J Gastroenterol 2002; 97: 1408–14. 83. Mayordomo L, Marenco JL, Gomez-Mateos J, Rejon E. Pulmonary miliary tuberculosis in a patient with anti-TNF-alpha treatment. Scand J Rheumatol 2002; 31: 44–5. 84. Nunez Martinez O, Ripoll Noiseux C, Carneros Martin JA, Gonzalez Lara V, Gregorio Maranon HG. Reactivation tuberculosis in a patient with antiTNF-alpha treatment. Am J Gastroenterol 2001; 96: 1665–6. 85. Roth S, Delmont E, Heudier P, Kaphan R, Cua E, Castela J, Verdier JM, Chichmanian RM, Fuzibet JG. Anticorps anti-TNF alpha (infliximab) et tuberculose: à propos de 3 cas. Rev Med Interne 2002; 23: 312–16. 86. Rovere Querini P, Vecellio M, Sabbadini MG, Ciboddo G. Miliary tuberculosis after biological therapy for rheumatoid arthritis. Rheumatology 2002; 41: 231. 87. Wagner TE, Huseby ES, Huseby JS. Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn’s disease after treatment with

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a tumor necrosis factor-alpha inhibitor. Am J Med 2002; 112: 67–9. 88. Kamath BM, Mamula P, Baldassano RN, Markowitz JE. Listeria meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr 2002; 34: 410–12. 89. Nakelchik M, Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med 2002; 112: 78. 90. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. New Engl J Med 2001; 344: 1099–100. 91. Zhang Z, Correa H, Bégué RE. Tuberculosis and treatment with infliximab. New Engl J Med 2002; 246: 624. 92. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, Van As A, Gupta N. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108: 184–90. 93. Casale TB, Condemi J, LaForce C, Nayak A, Rowe M, Watrous M, McAlary M, Fowler-Taylor A, Racine A, Gupta N, Fick R, DellaCioppa G. Effect of omalizumab on symptoms of seasonal allergic rhinitis. J Am Med Assoc 2001; 286: 2956– 67. 94. Busse WW. Anti-immunoglobulin E (omalizumab) therapy in allergic asthma. Am J Respir Crit Care Med 2001; 164; S12–17. 95. Boushey HA. Experiences with monoclonal antibody therapy for allergic asthma. J Allergy Clin Immunol 2001; 108: S77–83. 96. Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, Fowler-Taylor A, Rohane P. Treatment of childhood asthma with antiimmunoglobulin E antibody (omalizumab). Pediatrics 2001; 108: E36. 97. Casale TB. Experience with monoclonal antibodies in allergic mediated disease: seasonal allergic rhinitis. J Allergy Clin Immunol 2001; 108 Suppl 2: S84–8. 98. Groothuis JR, Simpson SJ. Safety and tolerance of palivizumab administration in a large Northern hemisphere trial. Pediatr Infect Dis J 2001; 20: 628–30. 99. Byrd JC, Waselenko JK, Maneatis TJ, Murphy T, Ward FT, Monahan BP, Sipe MA, Donegan S, White CA. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999; 17: 791–5. 100. Davis TA, White CA, Grillo-Lopez AJ, Velasquez WS, Link B, Maloney DG, Dillman RO, Williams ME, Mohrbacher A, Weaver R, Dowden S, Levy R. Single-agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma: results of a phase II trial of rituximab. J Clin Oncol 1999; 17: 1851–7. 101. Van der Kolk LE, Grillo-Lopez AJ, Baars JW, Hack CE, Van Oers MH. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol 2001; 115: 807–11.

413 102. Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 2001; 115: 609–11. 103. Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab. New Engl J Med 2001; 344: 68–9. 104. Sharma VR, Fleming DR, Slone SP. Pure red cell aplasia due to parvovirus B19 in a patient treated with rituximab. Blood 2000; 96: 1184–6. 105. Bermudez A, Marco F, Conde E, Mazo E, Recio M, Zubizarreta A. Fatal visceral varicella-zoster infection following rituximab and chemotherapy treatment in a patient with follicular lymphoma. Haematologica 2000; 85: 894–5. 106. Ladetto M, Zallio F, Vallet S, Ricca I, Cuttica A, Caracciolo D, Corradini P, Astolfi M, Sametti S, Volpato F, Bondesan P, Vitolo U, Boccadoro M, Pileri A, Gianni AM, Tarella C. Concurrent administration of high-dose chemotherapy and rituximab is a feasible and effective chemo/immunotherapy for patients with high-risk non-Hodgkin’s lymphoma. Leukemia 2001; 15: 1941–9. 107. Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D’Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19: 2587–95. 108. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Engl J Med 2001; 344: 783–92. 109. Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48: 642–6. 110. Meggitt SJ, Reynolds NJ. Azathioprine for atopic dermatitis. Clin Exp Dermatol 2001; 26: 369–75. 111. Marbet U, Schmid I. Severe life-threatening diarrhea caused by azathioprine but not by 6mercaptopurine. Digestion 2001; 63: 139–42. 112. Kappers-Klunne MC, Van’t Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy. Br J Haematol 2001; 114: 121–5. 113. Cortes J, O’Brien S, Loscertales J, Kantarjian H, Giles F, Thomas D, Koller C, Keating M. Cyclosporin A for the treatment of cytopenia associated with chronic lymphocytic leukemia. Cancer 2001; 92: 2016–22. 114. Rosencrantz R, Moon A, Raynes H, Spivak W. Cyclosporine-induced neurotoxicity during treatment of Crohn’s disease: lack of correlation with previously reported risk factors. Am J Gastroenterol 2001; 96: 2778–82.

414 115. Massy ZA. Hyperlipidemia and cardiovascular disease after organ transplantation. Transplantation 2001; 72 Suppl 6: S13–15. 116. Trimarchi H, Freixas E, Rabinovich O, Schropp J, Pereyra H, Bullorsky E. Cyclosporineassociated thrombotic microangiopathy during daclizumab induction: a suggested therapeutic approach. Nephron 2001; 87: 361–4. 117. Albengres E, Le Louet H, D’Athis P, Tillement JP. S15176 and S16950 interaction with cyclosporin A antiproliferative effect on cultured human lymphocytes. Fundam Clin Pharmacol 2001; 15: 41–6. 118. Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba MJ, Rimola A, Rodes J, Munoz-Gomez J. Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A. Calcif Tissue Int 2001; 68: 83–6. 119. Ichimaru N, Takahara S, Kokado Y, Wang JD, Hatori M, Kameoka H, Inoue T, Okuyama A. Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis 2001; 158: 417–23. 120. Barone GW, Gurley BJ, Ketel BL, Abul-Ezz SR. Herbal supplements: a potential for drug interactions in transplant recipients. Transplantation 2001; 71: 239–41. 121. Malingre MM, Beijnen JH, Rosing H, Koopman FJ, Van Tellingen O, Duchin K, Ten BokkelHuinink WW, Swart M, Lieverst J, Schellens JH. A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A. Cancer Chemother Pharmacol 2001; 47: 347–54. 122. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001; 71: 1051–5. 123. Weinstein SP, Orel SG, Collazzo L, Conant EF, Lawton TJ, Czerniecki B. Cyclosporin Ainduced fibroadenomas of the breast: report of five cases. Radiology 2001; 220: 465–8. 124. Baildam AD, Higgins RM, Hurley E, Furlong A, Walls J, Venning MC, Ackrill P, Mansel RE. Cyclosporin A and multiple fibroadenomas of the breast. Br J Surg 1996; 83: 1755–7. 125. Foxwell BM, Woerly G, Husi H, Mackie A, Quesniaux VF, Hiestand PC, Wenger RM, Ryffel B. Identification of several cyclosporine binding proteins in lymphoid and non-lymphoid cells in vivo. Biochim Biophys Acta 1992; 1138: 115–21. 126. Lopez-Calderon A, Soto L, Villanua MA, Vidarte L, Martin AI. The effect of cyclosporine administration on growth hormone release and serum concentrations of insulin-like growth factor-I in male rats. Life Sci 1999; 64: 1473–83. 127. Russell DH, Kibler R, Matrisian L, Larson DF, Poulos B, Magun BE. Prolactin receptors on human T and B lymphocytes: antagonism of prolactin binding by cyclosporine. J Immunol 1985; 134: 3027–31.

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128. Larson DF. Cyclosporin. Mechanism of action: antagonism of the prolactin receptor. Prog Allergy 1986; 38: 222–38. 129. Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 2001; 91: 613–21. 130. Coutinho HM, Groothoff JW, Offringa M, Gruppen MP, Heymans HS. De novo malignancy after paediatric renal replacement therapy. Arch Dis Child 2001; 85: 478–83. 131. Kovarik JM, Kahan BD, Kaplan B, Lorber M, Winkler M, Rouilly M, Gerbeau C, Cambon N, Boger R, Rordorf C. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 2001; 69: 48–56. 132. Jover JA, Hernandez-Garcia C, Morado IC, Vargas E, Banares A, Fernandez-Gutierrez B. Combined treatment of giant-cell arteritis with methotrexate and prednisone: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 134: 106–14. 133. Stewart M, Malkovska V, Krishnan J, Lessin L, Barth W. Lymphoma in a patient with rheumatoid arthritis receiving methotrexate treatment: successful treatment with rituximab. Ann Rheum Dis 2001; 60: 892–3. 134. Stewart SF, Hudson M, Talbot D, Manas D, Day CP. Mycophenolate mofetil monotherapy in liver transplantation. Lancet 2001; 357: 609–10. 135. Schlitt HJ, Barkmann A, Boker KH, Schmidt HH, Emmanouilidis N, Rosenau J, Bahr MJ, Tusch G, Manns MP, Nashan B, Klempnauer J. Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study. Lancet 2001; 357: 587–91. 136. Staskewitz A, Kirste G, Tonshoff B, Weber LT, Boswald M, Burghard R, Helmchen U, Brandis M, Zimmerhackl LB. Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. German Pediatric Renal Transplantation Study Group. Transplantation 2001; 71: 638–44. 137. Grundmann-Kollmann M, Podda M, Ochsendorf F, Boehncke WH, Kaufmann R, Zollner TM. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 2001; 137: 870–3. 138. Neyts J, Andrei G, De Clercq E. The novel immunosuppressive agent mycophenolate mofetil markedly potentiates the antiherpesvirus activities of acyclovir, ganciclovir, and penciclovir in vitro and in vivo. Antimicrob Agents Chemother 1998; 42: 216–22. 139. Pergola PE, Kancharla A, Riley DJ. Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Transplantation 2001; 71: 994–7.

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140. Bottiger Y, Sawe J, Brattstrom C, Tollemar J, Burke JT, Hass G, Zimmerman JJ. Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers. Clin Pharmacol Ther 2001; 69: 32–40. 141. Parvex P, Pinsk M, Bell LE, O’Gorman AM, Patenaude YG, Gupta IR. Reversible encephalopathy associated with tacrolimus in pediatric renal transplants. Pediatr Nephrol 2001; 16: 537–42. 142. Furukawa M, Terae S, Chu BC, Kaneko K, Kamada H, Miyasaka K. MRI in seven cases of tacrolimus (FK-506) encephalopathy: utility of FLAIR and diffusion-weighted imaging. Neuroradiology 2001; 43: 615–21. 143. Tze WJ, Tai J, Murase N, Tzakis A, Starzl TE. Effect of FK 506 on glucose metabolism and insulin secretion in normal rats. Transplant Proc 1991; 23: 3158–60. 144. Paolillo JA, Boyle GJ, Law YM, Miller SA, Lawrence K, Wagner K, Pigula FA, Griffith BP, Webber SA. Posttransplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression. Transplantation 2001; 71: 252–6. 145. Jain A, Kashyap R, Marsh W, Rohal S, Khanna A, Fung JJ. Reasons for long-term use of steroid in primary adult liver transplantation under tacrolimus. Transplantation 2001; 71: 1102–6.

415 146. Kang S, Lucky AW, Pariser D, Lawrence I, Hanifin JM. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001; 44 Suppl 1: S58–64. 147. Soter NA, Fleischer AB Jr, Webster GF, Monroe E, Lawrence I. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients. Part II, safety. J Am Acad Dermatol 2001; 44 Suppl 1: S39–46. 148. Paller A, Eichenfield LF, Leung DY, Stewart D, Appell M. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001; 44 Suppl 1: S47–57. 149. Blackhall FH, Ranson M, Radford JA, Hancock BW, Soukop M, McGown AT, Robbins A, Halbert G, Jayson GC. A phase II trial of bryostatin 1 in patients with non-Hodgkin’s lymphoma. Br J Cancer 2001; 84: 465–9. 150. Coutts SM, Plunkett ML, Iverson GM, Barstad PA, Berner CM. Pharmacological intervention in antibody mediated disease. Lupus 1996; 5: 158–9. 151. Furie RA, Cash JM, Cronin ME, Katz RS, Weisman MH, Aranow C, Liebling MR, Hudson NP, Berner CM, Coutts S, de Haan HA. Treatment of systemic lupus erythematosus with LJP 394. J Rheumatol 2001; 28: 257–65.

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38 VITAMIN A (RETINOL)

(SED-14, 1340; SEDA-23, 418; SEDA-24, 443; SEDA-25, 458) The recommended daily allowance of vitamin A for children up to 12 years of age is 1500–4500 IU. Toxic reactions occur when retinol-binding proteins in the plasma are saturated with vitamin A. Excess vitamin A is bound to plasma lipoproteins, and in this form it causes toxic effects when it comes into contact with cells (1R ). Acute vitamin A intoxication can occur after ingestion of 500 000 IU in adults and proportionately less in children. Chronic intoxication is more common, and in children it can occur even with doses as small as 1500 IU/kg/day. The problem is underrecognized in children, and cases often present as diagnostic dilemmas. Two children with vitamin A toxicity have been reported (2A ). • A 2-year-old girl developed anorexia, lethargy, and bilateral leg pain and refused to walk. She had been unwell for the previous 3 weeks. She was lethargic and irritable and had tenderness over both tibial surfaces and an erythematous rash over her back and both elbows. She had a raised calcium concentration (3.05 mmol/l), a serum phosphate concentration in the reference range, and a raised serum vitamin A concentration (3.9 µmol/l; reference range 1.3–2.9 µmol/l). A skull X-ray showed widening of the coronal suture, and a leg Xray showed abnormal metaphyseal densities at the knees and ankles. Radionuclide bone scans showed increased uptake in both anterior tibiae, anteriorly in multiple ribs close to the costochondral junctions, in the distal right ulnar shaft, and in the distal left femoral shaft. Her parents had given her a vitamin supplement containing 9000 IU/ml vitamin A 3 ml/day for several months. On withdrawal of the vitamin supplement her symptoms resolved over 2 weeks. • A 4-year-old boy presented with a 4-day history of bilateral leg pain and refusal to walk. He had tenderness over both tibial surfaces, generalized © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

416

Vitamins skin exfoliation, and reduced visual acuity in both eyes. Symmetrical bone scan changes (increased uptake throughout each ulna and tibia and foci in the 10th and 11th ribs and 11th thoracic vertebra), together with benign intracranial pressure, suggested vitamin A toxicity. His dermatologist had prescribed oral etretinate, but his parents had withdrawn it after consulting a naturopath. He was then given numerous medications, including vitamin A, D, and E supplements, calcium, and magnesium. After withdrawal of all vitamin supplements his condition steadily improved, except for visual acuity, which was unchanged.

These two cases clearly underline the importance of a detailed drug history, including the use of complementary medicines. Mineral balance Vitamin A toxicity in an adult woman resulted in hypercalcemia with renal insufficiency (3A ). • An 86-year-old woman developed anorexia, thirst, and nocturia. During the previous 7 months her weight had fallen by 11 kg. She was taking domperidone and 1–6 vitamin tablets daily, each of which contained retinol palmitate 600 IU and cholecalciferol 200 IU. She had hypercalcaemia (serum calcium 3.34 mmol/l) and renal insufficiency (serum creatinine 333 µmol/l). Other causes of hypercalcaemia were excluded.

In chronic vitamin A ingestion, risk factors for vitamin A toxicity are age, body weight, and renal insufficiency, The hypercalcaemia caused by chronic vitamin A ingestion is explained by upregulation of osteoclasts by retinol metabolites. Drug formulations The readily available vitamin formulations have usually not been tested for either efficacy or safety in controlled trials. An aqueous dispersion of vitamin A causes higher plasma concentrations than oily formulations (4E ).

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All-trans retinoic acid A novel intravenous liposomal formulation of all-trans retinoic acid (Atragen™, Aronex Pharmaceuticals Inc, The Woodlands, TX), which provides a reliable dose for patients who are unable to swallow or absorb medications, has been evaluated in 69 patients with acute promyelocytic leukemia (5C ). Liposomal all-trans retinoic acid (90 mg/m2 ) was given every other day until complete remission or a maximum of 56 days. Treatment after complete remission was liposomal all-trans retinoic acid with or without chemotherapy. Adverse effects (grade 1–2 according to the NCI common toxicity criteria) were the retinoic acid syndrome in 18 patients (grade 3/4 in 10), leukocytosis in 36, headache in 46, dry skin in 23, hypertriglyceridemia in 23, fever in 18, nausea in 13, stomatitis in 11, vomiting in 10, chelitis in 9, exfoliative dermatitis in 9, rash in 8, myalgia in 8, liver enzyme abnormalities in 7, bone pain in 6, arthralgia in 5, raised LDH activity in 4, pseudotumor cerebri in 4 (with severe headache, papilledema, increased cerebrospinal fluid pressure, and absence of structural cranial lesions by CT or MRI scanning), hypercholesteremia in 4, chills in 4, pruritus in 3, and diarrhea in 2. Retinoic acid syndrome The retinoic acid syndrome, a generalized severe capillary leakage syndrome with leukocyte activation, which results in weight gain, pulmonary infiltrates or pleural effusions with acute respiratory distress, and fever without infection, occurs in up to 25% of patients. Until now no predictive factors have been found. Post-mortem reports of patients who have died from this syndrome have shown infiltration of maturing myeloid cells and edema in the lungs (6R ). The myeloid cells are considered to release various types of cytokines responsible for symptoms such as fever, weight gain, and heart failure. Improvement can be obtained by corticosteroid treatment, which suppresses the effects of cytokines. Chest CT provides an accurate assessment of the size, number, and distribution of pulmonary opacities associated with the syndrome, as has recently been demonstrated anecdotally (7A ). • A 69-year-old man developed dyspnea, hypoxia, and heart failure 4 days after starting to take alltrans retinoic acid 70 mg/day. His highest white

417 blood cell count was 72 × 109 /l. A plain chest X-ray showed two pulmonary opacities, increased attenuation in the left lower lobe, and bilateral pleural effusions, but a chest CT also showed multiple irregular-shaped opacities localized in the centrilobular and subpleural regions. He improved over 10 days with prednisolone (total dose 5750 mg) and daunorubicin (total dose 360 mg).

In a retrospective study 22 children taking all-trans retinoic acid (median age 9.3 years, range 1.8–16.3) for a median of 38 (6–138) days were compared with 22 taking conventional therapy (median age 12.3 years, range: 3.2–16.7) (8C ). Overall, 12 of 22 patients had symptoms associated with all-trans retinoic acid (Table 1). Three developed the retinoic acid syndrome. Cardiovascular An increased risk of thrombotic events, especially coronary thrombosis, has been reported in elderly patients (9A ). Two patients with acute promyelocytic leukemia developed thrombus in the right ventricle during induction treatment with all-trans retinoic acid plus idarubicin (10A ). • A 51-year-old man with acute promyelocytic leukemia suddenly developed hypoxemia, pulmonary infiltrates, and arterial hypotension, without fever or thoracic pain on day 11 of all-trans retinoic acid treatment. He was pancytopenic, his coagulation parameters were normal, and cardiological examination was normal. High-dose dexamethasone (10 mg bd) was started, with prompt resolution of the clinical and radiological signs. Eight days later echocardiography showed a 3 cm non-homogeneous mass in the right ventricle. He was given subcutaneous low molecular weight heparin and the thrombus started to get smaller after 17 days. Oral anticoagulant therapy was started, and there was a further reduction of the size of the thrombus over the following year. • A 32-year-old woman with acute promyelocytic leukemia developed severe retinoic acid syndrome after 3 days, with respiratory failure, fever, and bilateral lung infiltrates. Withdrawal of all-trans retinoic acid and treatment with dexamethasone and antibiotics rapidly ameliorated the syndrome, and on day 10 all-trans retinoic acid was restarted. However, routine echocardiography showed a 3 cm pedunculated mass in the right ventricle. There was consistent and stable reduction of the mass after 1 year of oral anticoagulant therapy.

Mineral balance Hypercalcemia has been reported as adverse effect of systemic all-trans retinoic acid therapy. Severe hypercalcemia has been attributed to all-trans retinoic acid in acute promyelocytic leukemia (11A ).

418

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H.D. Reuter

Table 1. All-trans retinoic acid toxicity Organ system

n

Symptoms

n

All-trans retinoic acid-related toxicity

12/22 (55%)

Retinoic acid syndrome (fever, pulmonary infiltrate/pleural effusion, weight gain, cerebral symptoms)

3/22 (14%)

Cardiovascular

5 (23%)

Pericardial effusion Weight gain Arterial hypotension

1 (5%) 5 (23%) 2 (9%)

Respiratory

3 (14%)

Adult respiratory distress syndrome Pleural effusion Pulmonary infiltrate

2 (9%) 1 (5%) 1 (5%)

Nervous system

6 (27%)

Headache Intracranial pressure

6 (27%) 1 (5%)

Liver and metabolic

12 (55%)

Raised transaminases Raised bilirubin Raised triglycerides

6 (27%) 1 (5%) 2 (9%)

Hematologic

4 (18%)

Leukocytosis

4 (18%)

Skin and musculoskeletal

4 (18%)

Dry skin Itching Joint/bone/muscle pain Osteonecrosis

1 (5%) 1 (5%) 3 (14%) 1 (5%)

• An 11-year-old boy with acute promyelocytic leukemia was given all-trans retinoic acid 47 mg/ m2 /kg. On day 10 he developed headache and nausea. The dose was reduced to 39 mg/m2 and he was given glycerol, but his symptoms of pseudotumor cerebri continued. Cranial CT showed neither space-occupying lesions nor brain edema. On day 25 hypercalcemia (3.2 mmol/l) was observed. In spite of conventional therapy the serum calcium concentration continued to rise to 4.0 mmol/l. All-trans retinoic acid was withdrawn on day 33. Within 1 week his symptoms resolved. On the second day of a second phase of all-trans retinoic acid therapy, he again developed nausea and headache and the serum calcium concentration gradually increased to 3.3 mmol/l by day 7. Raised concentrations of type 1 cross-linked N-telopeptide and deoxypyridinoline suggested increased bone resorption. A bisphosphonate (pamidronate 30 mg) was administered intravenously; the calcium normalized within 2 days and the nausea and headache resolved.

Pancreas Acute pancreatitis is a rare but serious adverse effect of all-trans retinoic acid. Three cases associated with isotretinoininduced hyperglyceridemia have previously been described and two cases associated with all-trans retinoic acid (12A , 13A ). A further case associated with all-trans retinoic acid has now been reported (14A ). • A 48-year-old man received all-trans retinoic acid (45 mg/m2 /day) followed 9 days later by combi-

nation chemotherapy for 5 days. On day 15 he developed acute epigastric and upper left quadrant pain. He had raised serum lipase (1312 IU/l; reference range 27–208), amylase (509 IU/l; 30–110), and triglycerides (7.77 mmol/l; 0.45–1.82). Abdominal CT showed mild trabeculation of the peripancreatic adipose tissue, but no lithiasis or dilatation of the biliary ducts. Acute pancreatitis caused by hypertriglyceridemia was diagnosed and he was given supportive treatment plus fenofibrate (200 mg/day), without withdrawal of all-trans retinoic acid. His lipase, amylase, and triglycerides normalized over 10 days.

Urinary tract During all-trans retinoic acid therapy some patients with retinoic acid syndrome or with a hypercoagulable state develop acute renal insufficiency, usually accompanied by dysfunction of other organs. A patient with acute promyelocytic leukemia developed renal insufficiency alone during all-trans retinoic acid treatment (15A ). • A 72-year-old Japanese man with acute promyelocytic leukemia was given all-trans retinoic acid 48 mg/m2 plus idarubicin. On day 17 oliguria occurred and all-trans retinoic acid was withdrawn on day 20 when the serum creatinine concentration rose to 619 µmol/l (7.0 mg/dl). There were no signs or symptoms of retinoic acid syndrome. A needle biopsy of the left kidney on day 38, when the serum creatinine concentration was 212 µmol/l (2.4 mg/dl) showed granulomatous tubulointerstitial nephritis. The glomeruli were mostly intact and

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419

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there were no fibrin thrombi or leukemic cell infiltration. After one course of consolidation therapy he was discharged with a normal serum creatinine concentration.

Tretinoin Skin Topical retinoids and similar drugs, including all-trans retinoic acid, adapalene, and tazaroten, are the most commonly used topical drugs for acne (16R ). Adapalene is a synthetic polyaromatic retinoid and is formulated in a water-based gel (1.0%, Galderma Labs Inc, San Antonio, TX). In a double-blind, multicenter, parallel-group, randomized study the efficacy and adverse effects of 0.1% adapalene gel and 0.1% tretinoin gel in a microphere formulation were compared over 12 weeks (17C ). The two drugs had similar effects on the resolution of acne lesions, but tretinoin was significantly more effective in reducing the number of comedones. There were no statistically significant differences between tretinoin and adapalene in the incidences of erythema, burning/stinging, or itching. Most patients had at least one sign of cutaneous irritation over the course of the study (tretinoin 95%, adapalene 91%). The most common adverse effect was erythema (tretinoin 83%, adapalene 66%), followed by peeling (80% and 66%), dryness (67% and 65%), burning/stinging (45% and 36%), and itching (37% and 35%). There were significant differences in the incidence of cutaneous effects in favor of adapalene for dryness at week 8 (tretinoin 34%, adapalene 18%) and week 10 (29% and 12%), and for peeling at week 3 (56% and 39%), week 6 (46% and 26%), week 8 (45% and 17%) and week 10 (35% and 17%). There were no serious adverse events in either group. In another comparison of the efficacy and adverse effects of adapalene gel 1% or 0.025% tretinoin gel in 150 Chinese patients, similar effects were observed (18C ). In both groups skin irritation was mild, but it was more pronounced with tretinoin. Burning was the most common unwanted effect in those who used tretinoin compared with adapalene (34% versus 11%). There was dryness of the skin in 34% of those who used tretinoin and in 22% of those who used adapalene. The respective frequencies of scaling were 26% and 15%, and of erythema 26% and 2.7%. Pruritus was the only adverse

effect experienced exclusively by those who used adapalene, and it occurred in under 4%. Overall 46% of those who used tretinoin hadsome form of irritation, compared with 32% of those who used adapalene. With topical application of all-trans retinoic acid special care should be taken when other drugs are given simultaneously. Dramatic photosensitivity has been associated with the combination of fluorouracil, prochlorperazine, and topical tretinoin (19A ). • A 52-year-old woman with a colonic cancer was treated with chemotherapy after surgical resection. She had been applying topical tretinoin (Renova; Ortho Pharmac, Raritan N) cream 0.05% nightly to her face for about 5 years. During that time she had applied a sunscreen while outdoors and had tolerated tretinoin without incident. Her daily oral multivitamin supplement contained 5000 IU of retinol equivalents. About 3 days after her last dose of chemotherapy (leucovorin, fluorouracil, prochlorperazine) she exposed her face to the sun for about 1 hour after applying her usual sunscreen. Shortly afterwards the skin on her face became erythematous and worsened over several days. Her eyes became edematous, itchy, and painful. Within a week the skin on her face had completely desquamated. She stopped using tretinoin. The reaction began to improve and she was pain free within 1 week. Her appearance returned to normal after about 10 days. During a second cycle of chemotherapy she received the same drugs as during the first, except tretinoin and reported no significant change in sun exposure or sunscreen application. She tolerated subsequent cycles without adverse skin effects. After completing her monthly chemotherapy cycles, she resumed topical tretinoin without adverse effects.

VITAMINS OF THE B GROUP (SED-14, 1344; SEDA-23, 419, SEDA-24, 446; SEDA-25, 462)

Nicotinic acid (niacin) and nicotinamide Modified-released niacin formulations are better tolerated than the immediate-release formulation, because they reduce the vasodilatory effects of the drug. However, the low frequency of flushing produced by modified-release formulations may be offset by an increased risk of

420 hepatotoxicity. Reports have suggested a threefold higher frequency of hepatic dysfunction with traditional modified-release niacin formulations compared with immediate-release products (20C , 21C ). Niaspan (Kos Pharmaceuticals Inc, Miami Lakes, FL) is a unique formulation with both immediate- and extended-release characteristics. The efficacy and adverse effects of Niaspan have been studied in 32 patients with type 2 diabetes (22C ). Of 22 patients who completed 6 months of therapy, 17 received 1000 mg/day, three 1500 mg/day, and two 2000 mg/day. Seven of 32 patients discontinued therapy. Of these, three withdrew after 2, 5, and 6 months because of flushing and itching. Three other patients withdrew within 2 months because of nausea, diarrhea, and dyspepsia. One patient withdrew after 7 days because of increased blood glucose concentrations. There were no significant increases in mean transaminase activities, which remained within the reference ranges in all patients.

Vitamin B2 (riboflavin) Immunologic Anaphylaxis has been reported in a boy who took a multivitamin tablet containing riboflavin (23A ). • A 15-year-old boy developed flushing and a generalized papular rash after taking one multivitamin tablet, followed by dizziness, dyspnea, nausea, and severe angio-edema of the face 40 minutes later. He became drowsy and developed hypotension (67/48 mmHg) and tachycardia (131 beats/min). He was given subcutaneous adrenaline, intravenous isotonic saline, and diphenhydramine and hydrocortisone injections iv, and after 30 minutes his vital signs became stable; he recovered consciousness shortly after. He had no history of atopic diseases or adverse drug reactions, but reported that he had had dizziness many times after drinking one particular yellow-colored brand of soft drink and that he had lost consciousness twice after drinking it about 5 years before. Intradermal skin tests with the vitamins and determination of in vitro histamine release showed a strong positive response to vitamin B2 . He was advised to exclude riboflavin-containing products from his diet and to carry adrenaline for self administration. During the next 13 months he had no further adverse reactions.

The multivitamin tablet that this boy took contained 100 mg of vitamins B1 , B2 , and B6 ,

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cyanocobalamin concentrate 500 µg, and vitamin C 500 mg. The soft drink contained vitamin B1 (0.6 ppm), vitamin B2 (8.9 ppm), and vitamin C 200 mg/l.

Vitamin B6 (pyridoxine) In India, pyridoxine hydrochloride, along with thiamine and cyanocobalamin, is often injected or given orally as a “neurotonic” to large numbers of people. Skin Contact hypersensitivity to pyridoxine is rare. Only three cases of allergy to pyridoxine have been reported: in hair lotion (24A ), a corticosteroid cream (25A ), and a skin cream (Iruxol) (26A ). There have also been a few reports of photosensitivity due to pyridoxine hydrochloride (27A –29A ). Occupational systemic contact dermatitis with photosensitivity has been attributed to vitamin B6 (30A ). • A 45-year-old man developed eczema over the backs of his hands, the backs and sides of his fingers (sparing the little fingers), the forearms, and the face. This lasted for 6 years, with recurrences and remissions. He was tested with allergens, supplemented with a drop each of various injectable medicaments (streptomycin, benzylpenicillin, ampicillin–cloxacillin, oxytetracycline, vitamins B1 , B2 , and B12 , gentamicin, amikacin, and analgesics). Patch tests were positive to nitrofurazane and three different B vitamins. Reactivation of lesions on the hands, face, and neck was noted during patch testing, and subsided within 1 week. After a further 6 weeks he was tested on the forearms with B1 , B6 , and B12 , each in 10% propylene glycol, resulting in a ++ reaction for B6 . Prick testing with B1 , B2 , and B6 gave negative results. Another 2 months later oral provocation with two tablets each containing B6 100 mg was performed. Before taking the second tablet he started to itch, and 18 h later he developed itching and severe erythema over the face, neck, backs of the hands, forearms, and the distal half of the upper arms (sun-exposed areas). Reactivation of previous positive patch test sites (on the back and forearms) and a negative prick test site were also observed.

Rosacea fulminans is a rare variant of rosacea conglobata and is seen almost exclusively in postadolescent women. It is characterized by the sudden appearance of abscessforming nodules and draining sinuses. The lesions are usually limited to the center of

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the face and are precipitated by marked seborrhea. The cause is unknown. Rosacea fulminans temporally associated with the ingestion of high-dose vitamin B supplements has been reported (31A ). • A 17-year-old woman with a 5-week history of a facial rash took minocyline (100 mg/d for 14 days) without effect. She had been taking vitamin B supplements (80 mg vitamin B6 – 40 times the recommended daily allowance) and vitamin B12 (20 µg – 20 times the recommended daily allowance) for 2 weeks before the onset of the eruption. She had had low-grade acne vulgaris since puberty and a tendency to facial flushing after drinking alcohol and eating spicy food. There were numerous confluent nodules and pustules on a livid erythematous background on the cheeks and chin, and a few pustules on the neck. There was seborrhea on the affected skin areas. There was an indolent lymphadenopathy in the submanibular region. Histology showed a superficial and deep inflammatory infiltrate with perifollicular distribution, from the upper dermis down to the septa of the subcutaneous fat. Routine laboratory tests showed no abnormalities. There were no pathogenic organisms in bacteriological or mycological cultures from the pustules on the face. She stopped taking the nutritional supplement and was given warm compresses and clobetysol propionate cream bd for 2 weeks, methylprenisolone 60 mg/day for 2 weeks, followed by isotretinoin 60 mg/day. Her skin changes resolved within 4 months, with no residual scarring.

VITAMIN C (ASCORBIC ACID) (SED 13, 1175; SEDA-22, 438; SEDA-23, 423; SEDA-25, 464) Skin Contact dermatitis has been attributed to vitamin C in a cosmetic anti-ageing cream (32A ). • A 47-year-old woman developed eczema of the face, consisting initially of edematous lesions on the eyelids and then spreading to the rest of the face and the folds of the neck. Patch tests to a cosmetic cream she had used before the start of the eczema (Active C dry skin® , La Roche Posay Laboratory) gave positive results (++D2 and D3). Subsequent patch tests with the ingredients showed positive results only to ascorbic acid. Oral provocation tests with ascorbic acid 50–2000 mg were negative. Withdrawal of the cream resulted in complete healing of the eczema without relapse over 6 months.

VITAMIN D (CALCIFEROL) AND ANALOGS (SED-14, 1351; SEDA-23, 423; SEDA-24, 446; SEDA-25, 464) Mineral balance Hypercalcemia Severe vitamin D intoxication with spontaneously reversible anemia and biphosphonate-responsive hypercalcemia has been reported (33A ). • A 31-year-old woman developed diffuse musculoskeletal pain. She had been taking calcium and dihydrotachysterol up to 4 mg/day for 6 months for hypoparathyroidism after subtotal thyroid resection. She had severe hypercalcaemia (4.1 mmol/l), no detectable intact parathormone, renal insufficiency (serum creatinine 486 µmol/l) and a normochromic anemia (6.6 g/dl). Rehydration and forced diuresis initially improved renal function and reduced the serum calcium concentration, but the calcium concentration after 4 weeks was still 3.0 mmol/l and it did not normalize until she was given a single intravenous dose of pamidronate 15 mg.

This case suggests that treatment with dihydrotachysterol and other vitamin D analogues should be carefully monitored, because it may result in severe hypercalcemia that can be controlled only with difficulty. Hypercalcemia has been associated with the ingestion of an over-the-counter vitamin D supplement (34A ). • A 42-year-old man who for 2 years had taken a supplement containing vitamin D2 had a serum calcium concentration of 3.75 mmol/l and a serum 25-hydroxycholecalciferol concentration of 487 ng/ml (reference range 9–47). He had normal concentrations of 1,25-dihydroxycholecalciferol, parathormone, angiotensin-converting enzyme, and thyroid hormone, and had normal bonemarrow, radiography, and CT of the chest, neck, and abdomen. Vitamin D2 was withdrawn and he was rehydrated. He was advised to wear sunscreen at all times when outdoors. Three months after discharge the results of all blood tests were in the reference ranges, including serum concentrations of calcium and 25-hydroxycholecalciferol.

Examination of three lots of the over-thecounter formulation the patient had used revealed mean vitamin D contents of 1.3, 13, and 22 mg/g of powder. The patient had taken 3 g/day, or 156 000–2 604 000 IU/day of vitamin D2 , which is about 80–1300 times the recommended safe upper limit of 2000 IU/day. In another case severe hypercalcemia in a child receiving vitamin D was associated with hyperlipidemia (35A ).

422 • An 11-month-old girl developed polyuria, polydipsia, and vomiting. She had been given vitamin D 400 IU/day for just 1 month. A misdiagnosis of rickets was made, and 1 month before admission she was given bolus vitamin D 600 000 IU in two doses 15 days apart. Her serum calcium concentration was 5.5 mmol/l; total cholesterol, high density lipoprotein cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and triglyceride concentrations were respectively: 6.37 mmol/l, 0.77 mmol/l, 1.37 mmol/l, 4.1 mmol/l, and 3.0 mmol/l. After 16 days of therapy with intravenous fluids, furosemide, corticosteroids, calcitonin, magnesium sulfate, and phosphorus, her serum calcium concentration fell below 3 mmol/l. Her hyperlipidemia resolved gradually.

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concentrations throughout the study between the groups. However, the respective percentages of subjects who had severe hyperphosphatemia (serum phosphorus over 0.84 mmol/l) after 8, 16, and 20 weeks were about 18, 16, and 14% in 19 patients treated with calcitriol and 6.8, 8.6, and 9.8% in 19 patients treated with paricalcitol. The results of this study suggest that paricalcitol reduces parathormone concentrations more rapidly than calcitriol does, with fewer episodes of hyperphosphatemia.

VITAMIN E (TOCOPHEROLS) (SED-13, 542, 1181; SEDA-21, 408)

Paricalcitol (19-nor-1a,25dihydroxycholecalciferol) Calcitriol, used for suppression of parathormone in patients with end-stage renal disease, especially in conjunction with calciumcontaining phosphate binders, greatly increases the risks of hypercalcemia and hyperphosphatemia. Efforts have therefore been made to develop therapies that do not cause an increased calcium burden. Paricalcitol has recently been introduced as an alternative to calcitriol. The efficacy of intravenous paricalcitol and calcitriol and the risks of hypercalcemia and hyperphosphatemia have been studied in an international, randomized, double-blind comparison in 38 patients in dialysis units (36C ). The end points were a reduction of at least 50% in baseline parathormone concentration and the occurrence of hypercalcemia and hyperphosphatemia. Paricalcitol therapy was started at a dose of 0.04 micrograms/kg and increased in 0.04 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.24 micrograms/kg or until there was at least a 50% fall in serum parathormone concentration. Calcitriol was started at a dose of 0.01 micrograms/kg and increased in 0.01 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.06 microgram/kg or until there was at least a 50% fall in serum parathormone concentration. Mean baseline serum parathormone, calcium, and phosphorus concentrations were similar. Reductions in parathormone occurred more rapidly with paricalcitol than with calcitriol, but there were no differences in serum calcium

Hematologic There have been two cases of coagulation disorders with the herbal drug Cucurbicin, each tablet of which contains vitamin E 10 mg (37A ). Cucurbicin is an approved herbal drug in Sweden, traditionally used for micturition difficulties. The active components are extracts from the fruit of Serenoa repens and the seed of Cucurbita pepo. • A 73-year-old man with a common cold, who had been taking Cucurbicin three tablets daily for more than 1 year, developed a coagulation disorder, with an INR (international normalized ratio) of 2.1, despite a normal albumin concentration and no anticoagulant treatment. His INR improved to 1.4 on treatment with vitamin K, but was not normalized until Cucurbicin was withdrawn 1 week later. • A 61-year-old man, who had taken warfarin and simvastatin for a long time, and had an INR of 2.4, started to take Cucurbicin five tablets daily for micturition difficulties. After 6 days his INR had increased to 3.4. After withdrawal of Cucurbicin the INR returned to the previous value within 1 week.

No anticoagulant effect has been reported with either of the major components of Cucurbicin. However, vitamin E antagonizes the effect of vitamin K and can cause an increased risk of bleeding, especially in patients taking oral anticoagulants. The amount of vitamin E in Cucurbicin that these two patients consumed was 30–50 mg/day, corresponding to the recommended dose of 40–50 mg daily for vitamin E deficiency. The two cases suggest that caution should be exercised when Cucurbicin is used concurrently with warfarin.

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Co-medication and multimedication in users of acetylsalicyclic acid and vitamin E in Germany (38M ) Although acetylsalicylic acid and its derivatives are widely used, reliable pharmacoepidemiological data about drug usage frequency in the population are sparse. Recent investigations have revealed serious adverse effects resulting from acetylsalicylic acid and other salicylates (39M , 40A –44A , 45r ). Of special interest are potential adverse effects in those who concurrently take vitamin E formulations, which is common in the population (46E , 47c ). The first pharmacoepidemiological survey was published in 1995, covering data from 1984 to 1996 (48M ). Now the populationbased data collected in Germany from 1984 to 1999 have been analysed, including data from five epidemiological surveys, concerning total drug usage, physiological, clinical chemistry and hematological data, and information about the serum concentrations of active drugs and/or their metabolites (48M ). The data were analysed with regard to the usage of salicylates and drugs with potential interactions relevant to the highly sensitive balance between hemostasis and bleeding. Special attention was paid to serum concentrations of the various tocopherols, because of their potential activity in anticoagulation processes (47c , 49M , 50M ). The data are representative of the resident population aged 25–69 years in the first four surveys and the age group 18–79 years in the last (1997–9), covering more than 20 000 study participants (see Table 2). Patient drug usage data for the 7 days before the clinical examination were recorded using a standardized questionnaire in all the surveys (48M ). Measurements of salicylic acid and tocopherols were by HPLC with fluorescence detection or GC/MS (51E ). In male users of salicylates and vitamin E the frequency of co-medication with lipid lowering drugs was 14%, with cardiovascular drugs 11%, and with analgesics 9%. Of female users of salicylates and vitamin E, 23% also took mineral products, 11% thyroid drugs, 10% estrogens, and 9% beta-blockers. In all surveys salicylate use was higher in women (14%) than men (12%). Owing to massive advertising, vitamin E consumption has

Table 2. Numbers of participants in the five surveys Survey

Total

Men

Women

1984–6 1987–9 1990–1 1997–9

4780 5335 5311 7124

2417 2649 2688 3450

2373 2686 2623 3674

risen since the first survey, and was 5.6% in women and 3.6% in men in the German population aged 18–79 years (survey 1997–9). Comedication with salicylates was observed in 17% of the vitamin E users (55% women, 45% men) and 90% of the reported concomitant use was in those over 50 years. Mean salicylate concentrations in those who used acetylsalicylic acid as an analgesic were 8.3 μmol/l in 1985, and 16.5 μmol/l in 1988, 1991, and 1998, while salicylate concentrations in subjects who used acetylsalicylic acid as an antiplatelet drug fell from 0.98 mg/dl in 1985 to 0.78 mg/dl in 1988, 0.30 mg/dl in 1991, and 0.08 mg/dl in 1998. This fall in serum salicylate concentrations reflects changes in the usual dose of acetylsalicylic acid. In contrast the mean concentrations of αtocopherol in vitamin E users increased from 28 μmol/l in 1985 to 29 μmol/l in 1988, 35 μmol/l in 1991, and 56 μmol/l in 1998. Controls not taking any medications had much lower serum concentrations of α-tocopherol (7.5, 9.8, 11.8, and 18.3 mg/l). Concentrations of β-tocopherol, γ -tocopherol, and δtocopherol in users of vitamin E were lowered by up to 50% in users of vitamin E formulations. From these data the authors concluded that there is a considerable risk in the availability of over-the-counter drugs, especially those that can affect the balance between blood clotting and hemorrhage, such as salicylates and α-tocopherol. Since women over 40 in particular tend to use so-called dietary supplements, in the belief that such products might prevent illness, and because there is unrestricted advertising in the mass media, physicians should obtain a clear medication history from their patients. The fact that blood concentrations of βtocopherol, γ -tocopherol, and δ-tocopherol are lowered by α-tocopherol (50M ) should be taken into account in future investigations on the clotting and bleeding balance and in cancer research.

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VITAMIN K (PHYTOMENADIONE)

(SED-14, 1356; SEDA-23, 423; SEDA-24, 448; SEDA-25, 465) Drug interactions An interaction of warfarin with a nutritional supplement containing vitamin K has been reported (52A ). • A 72-year-old man taking warfarin (42.5 mg/week) to prevent thromboembolism related to atrial fibrillation/flutter wanted to take an over-thecounter nutritional supplement containing vitamin K (Nature’s Life Greens® , a blend of more than 20 herbs). He was instructed to withhold two doses of warfarin. Two weeks later he had an INR of 1.68; however, he had missed three doses of warfarin within the previous 10 days because of cataract surgery. Two weeks later his INR was 3.34. The warfarin dosage was reduced from 42.5 mg/week to 40.5 mg/week and the INR was in the target range 2 weeks later.

This report underlines the need for monitoring the use of nutritional and herbal products in patients taking warfarin. The safety and efficacy of intravenously administered phytonadione have been retrospective studied in patients taking long-term oral anticoagulant therapy (53C ). Of 105 patients, 85 initially received intravenous phytonadione 0.5–1 mg, and 29 received a second dose. Only two of the 105 patients had suspected adverse reactions to phytonadione. Both were men with prior lung disease (one with an adenocarcinoma and one with chronic obstructive lung disease) and were to receive a 0.5 mg dose of phytonadione. During the phytonadione infusion both patients developed dyspnea and chest tightness, which resolved within 15 minutes of stopping the infusion; neither patient had hypotension.

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VITAMIN-LIKE SUBSTANCES Vitamin B5 , vitamin H Vitamin B5 and vitamin H (biotin) are proposed treatments for hair loss. Vitamin B5 has been used for pantothenic acid deficiency, acne, and rheumatoid arthritis. Vitamin H has been used in biotin deficiency, multiple carboxylase deficiency, brittle nails, and dermatitis. Over the past 30 years, only mild adverse reactions, such as rash and diarrhea, have been reported with vitamin B5 . Cardiorespiratory Eosinophilic pleural effusion with eosinophilic pericardial tamponade has been attributed to concomitant use of vitamin B5 and vitamin H (54A ). • A 76-year-old woman developed chest pain and difficulty in breathing. She had no history of allergy and had been taking vitamin H 10 mg/day and vitamin B5 300 mg/d for 2 months for alopecia. Chest X-rays showed pleural effusions and cardiac enlargement. Blood tests showed an inflammatory syndrome, with an erythrocyte sedimentation rate of 51 mm/h and an eosinophil count of 1200–1500 cells/ml. Pericardiotomy showed an eosinophilic infiltrate. There was no evidence of vasculitis. Serological studies were negative for antinuclear antibodies, rhemuatoid factor, viruses, bacteria, and Lyme disease. Stool examination and parasitological serologies were negative. A malignant tumor was excluded by mammography, thoracoscopy, and a CT scan. Myelography, a biopsy specimen of the iliac crest bone, and the concentrations of IgE, lysozyme, and vitamin B12 were also normal. During the week after withdrawal of vitamins B5 and H she improved dramatically and her eosinophilia resolved.

According to a MEDLINE search, this is the first report of eosinophilic pleuropericardidis related to vitamins B5 and H.

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a report of the International Vitamin A Consultative Group Washington DC: Nutrition Foundation, 1980. 5. Douer D, Estey E, Santillana S, Bennett JM,Lopez-Bernstein G, Boehm K, Williams T. Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid. Blood 2001; 97: 73–80. 6. De BottonS, Dombret H, Sanz M, San Miguel J, Caillot D, Zittoun R, Gardembas M, Stamatoulas A, Condé E, Guerci A, Gardin C, Geiser K, Cony Makhoul D, Reman R, de la Serna J, Lefrere F, Chomienne C, Chastang C, Degos L, Fenaux P, and the European APL Group. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. Blood 1998; 92: 2712–18. 7. Amano Y, Tajika K, Mizuki T, Amano M, Dan K, Kumazaki T. All-trans retinoic acid syndrome: chest CT assessment. Eur Radiol 2001; 11: 1516–17. 8. Mann G, Reinhardt D, Ritter J, Hermann J, Schmitt K, Gadner H, Creutzig U. Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. Ann Hematol 2001; 80: 417–22. 9. Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Berrnasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MCC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F. Molecular remission in PML/RAR alpha-positive acute promyeloic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-malattie Ematologiche Mligne dell’ Adulto Cooperative Groups. Blood 1997; 90: 1014–21. 10. Torromeo C, Latagliata R, Avvisati G, Petti MC, Mandelli F. Intraventricular thrombosis during all-trans retinoic acid treatment in acute promyelocytic leukemia. Leukemia 2001; 15: 1311–13. 11. Sakamoto O, Yoshinari M, Rikiishi T, Fujiwara I, Imaizumi M, Tsuchiya S, Iinuma K. Hypercalcemia due to all-trans retinoic acid therapy for acute promyelocytic leukemia: a case report of effective treatment with bisphosphonate. Pediatr Int 2001; 43: 688–90. 12. Izumo T, Hatake K, Miura Y. Acute promyelocytic leukemia. New Engl J Med 1994; 330: 141. 13. Yutzudo Y, Imoto S, Ozuru R, Kajimoto K, Itoi H, Koizumi T, Nishimura R, Nakagawa T. Acute pancreatitis after all-trans retinoic acid therapy. Ann Hematol 1997; 74: 195–6. 14. Abou Chacra L, Ghosn M, Ghayad E, Honein K. A case of pancreatitis associated with alltrans-retinoic acid therapy in acute promyelocytic leukemia. Hematol J 2001; 2: 406–7. 15. Tomita N, Kanamori H, Fujita H, Maruta A, Naltoh A, Nakamura S, Ota Y, Nozue N, Kihara M, Ishigatsubo Y. Granulomatous tubulointerstitial nephritis induced by all-trans retinoic acid. AntiCancer Drugs 2001; 12: 677–80. 16. Leyden JJ. Therapy for acne vulgaris. New Engl J Med 1997; 336: 1156–62.

425 17. Nyirady J, Grossman RM, Nighland M, Berger RS, Jorizzo JL, Kim YH, Martin AG, Pandya AG, Schulz KK, Strauss JS. A comparative trial of two retinoids commonly used in the treatment of acne vulgaris. J Dermatol Treat 2001; 12: 149–57. 18. Tu P, Li G-Q, Zhu X-J, Zheng J, Wong W-Z. A comparison of adapalene gel 0.1% vs. tretinoin gel 0.025% in the treatment of acne vulgaris in China. J Acad Dermatol Venereol 2001; 15 Suppl 3: 31–6. 19. Birner AM, Meyer LP. Photosensitivity associated with fluorouracil, prochlorperazine, and topical tretinoin. Pharmacotherapy 2001; 21: 258–60. 20. Keenan JM, Fontain PL, Wenz JB, Myers S, Huang Z, Ripsin CM. Niacin revisited: a randomized, controlled trial of wax matrix sustainedrelease niacin in hypercholesterolemia. Arch Intern Med 1991; 151: 1424–32. 21. McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. J Am Med Assoc 1994; 271: 672–7. 22. Kane MP, Hamilton RA, Addesse E, Busch RS, Bakst G. Cholesterol and glycemic effects of Niaspan in patients with type 2 diabetes. Pharmacotherapy 2001; 21: 1473–8. 23. Ou L-S, Kuo M-L, Huang J-L. Anaphylaxis to riboflavin (vitamin B2 ). Ann Allergy Asthma Immunol 2001; 87: 430–3. 24. Fujita M, Aoki T. Allergic contact dermatitis to pyridoxine ester and hinokitiol. Contact Dermatitis 1983; 9: 61–5. 25. Yoshikawa, K, Watanabe K, Mizumo N. Contact allergy to hydrocortisone 17-butyrate and pyridoxine hydrochloride. Contact Dermatitis 1985; 12: 55–6. 26. Camarasa JG, Serra-Baldrich E, Liuch M. Contact allergy to vitamin B6 . Contact Dermatitis 1990; 23: 115. 27. Baer RL, Stilman MA. Cutaneous skin changes probably due to pyridoxine abuse. J Am Acad Dermatol 1984; 10: 527–8. 28. Morimoto J, Kawada A, Hiruma M, Ishibashi A. Photosensitivity from pyridoxine hydrochloride (vitamin B6 ). J Am Acad Dermatol 1996; 35: 304– 5. 29. Murata Y, Kumano K, Ueda T, Araki N, Nakamura T, Tani M. Photosensitive dermatitis caused by pyridoxine hydrochloride. J Am Acad Dermatol 1988; 39: 314–17. 30. Bajaj AK, Rastogi S, Misra A, Misra K, Bajaj S. Occupational and systemic contact dermatitis with photosensitivity due to vitamin B6 . Contact Dermatitis 2001; 44: 184. 31. Jansen T, Romiti R, Kreuter A, Altmeyer P. Rosacea fulminans triggered by high-dose vitamins B6 and B12 . J Eur Acad Dermatol Venereol 2001; 15: 484–5. 32. Belhadjali H, Giordano-Labadie F, Bazex J. Contact dermatitis from vitamin C in a cosmetic anti-aging cream. Contact Dermatitis 2001; 45: 317.

426 33. Blind E, Fassnacht M, Korber C, Korber-Hafner N, Reiners Chr, Allolio B. Schwere VitaminD(dihydrotachysterol)-Intoxikation mit spontan reversibler Anämie und bisphosphonat-responsiver Hyperkalziämie. Dtsch Med Wochenschr 2001; 126: 334. 34. Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an over-the-counter supplement. New Engl J Med 2001; 345: 66–7. 35. Evliyaoglu O, Berberoglu M, Ocal G, Adiyaman P, Aycan Z. Severe hypercalcemia of an infant due to vitamin D toxicity associated with hypercholesterolemia. J Pediatr Endocrinol Metab 2001; 14: 915–19. 36. Sprague SM, Lerma E, McCormmick D, Abraham M, Battle D. Suppression of parathyroid hormone secretion in hemodialysis patients: comparison of paricalcitol with calcitriol. Am J Kidney Dis 2001; 38 Suppl 5: S51–6. 37. Yue Q-Y, Jansson K. Herbal drug curbicin and anticoagulant effect with and without warfarin: possibly related to the vitamin E component. J Am Geriatr Soc 2001; 49: 838. 38. Melchert H-U, Knopf H, Pabel E, BraemerHauth M, Du Y. Co- and multimedication in users of ASA and vitamin E drugs in the Federal Republic of Germany. Results of the Federal Health Surveys 1984-1999. Int J Clin Pharmacol Ther 2001; 39: 488–91. 39. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long-term use of aspirin: metaanalysis. Br Med J 2000; 321: 1183–7. 40. Jang AS. Severe reaction to lysine aspirin. Allergy Eur J Allergy Clin Immunol 2000; 55: 1092– 3. 41. Janssen T, Boege P, Oestreicher E, Arnold W. Tinnitus and 2f1–f2 distortion product otoacoustic emissions following salicylate overdose. J Acoustic Soc Am 2000; 107: 1790–2. 42. Karabulut AK, Ülger H, Pratten MK. Protection by free oxygen scavenging enzymes against salicylate-induced embryonic malformations. Toxicol Vitro 2000; 14: 297–307. 43. Manfredini R, Ricci L, Giganti M, La Caecilia O, Cuvornu H, Chierici F, Gallerani M. An uncommon case of fluid retention simulating a congestive heart failure after aspirin consumption. Am J Med Sci 2000; 320: 72–4. 44. Tramèr MR. Aspirin, like other drugs, is a poison. Br Med J 2000: 1170–1.

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45. Wong KS, Lam WWM, Kay R, Tang A, Chan YL, Woo J. Aspirin-associated intracerebral hemmorhage. Neurology 2000; 54: 2298–301. 46. Abate A, Yang G, Dennerry PA, Oberle S, Schröder H. Synergistic inhibition of cyclooxygenase-2 expression by vitamin E and aspirin. Free Radic Biol Med 2000; 29: 1135–42. 47. Liede KE, Haukka JK, Saxén LM, Heinonen OP. Increased tendency towards gingival bleeding caused by joint effect of a tocopherol supplementation and acetylsalicylic acid. Ann Med 1998; 30: 542–6. 48. Melchert H-U, Görsch B, Hoffmeister H. Nicht-stationäre Arzneimittelanwendung und subjektive Arzneimittelverträglichkeit in der bundesdeutschen Wohnbevölkerung der 25–69-Jährigen— Ergebnisse der Erhebung des ersten nationalen Untersuchungs-Surveys 1984–1986. RKI-Schrift 195, München: MMV Medizin-Verlag, 1995. 49. Melchert H-U, Pabel E. Verbrauch acetylsalicylhaltiger Präparate im ersten und zweiten Durchgang des Nationalen UntersuchungsSurveys. Tätigkeitsbericht 1991 des Bundesgesundheitsamtes. München: MMV Medizin-Verlag, 1992: 262–4. 50. Melchert H-U, Pabel E. The tocopherol pattern in human serum is markedly influenced by intake of vitamin E drugs – Results of the German National Health Surveys. J Am Oil Chem Soc 1998; 75: 213–16. 51. Melchert H-U, Pabel E. Qunatitative determination of a-, b-, g-, and d-tocopherols in human serum by high-performance liquid chromatography and gas chromatography–mass spectrometry as trimethylsilyl derivatives with a two-step sample preparation. J Chromatogr A 2000; 896: 209–15. 52. Bransgrove LL. Interaction between warfarin and a vitamin K-containing nutritional supplement: a case report. J Herbal Pharmacother 2001; 1: 85–9. 53. Shields RC, McBane RD, Kuiper JD, Li H, Heit JA. Efficacy and safety of intravenous phytonadione (vitamin K1) in patients on long-term oral anticoagulant therapy. Mayo Clin Proc 2001; 76: 260–6. 54. Debourdeau PM, Djezzar S, Estival JLF, Zammit CM, Richard RC, Castot AC. Life-threatening eosinophilic pleuropericardial effusion related to vitamins B5 and H. Ann Pharmacother 2001; 35: 424–6.

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39

Corticotrophins, corticosteroids, and prostaglandins

Editor’s note: In this chapter adverse effects arising from the oral or intravenous administration of corticosteroids are covered in the section on systemic glucocorticosteroids. Other routes of administration are dealt with in the section after that, apart from inhalation and nasal administration, which are dealt with in Chapter 16, and topical administration, which is covered in Chapter 14.

SYSTEMIC GLUCOCORTICOSTEROIDS (SED-14, 1369; SEDA-23, 427; SEDA-24, 450; SEDA-25, 465) Respiratory In a double-blind, randomized, placebo-controlled study of high-dose methylprednisolone sodium succinate in 23 patients with acute spinal injuries, pneumonia occurred in eight patients compared with one in the placebo group (1C ). Several factors, such as respiratory muscle dysfunction, positioning problems, steroid-mediated immunosuppression, and age increase the risk of this complication. Psychiatric Glucocorticoids can cause neuropsychiatric adverse effects that require a dosage reduction and sometimes withdrawal of treatment. Budesonide has been recently marketed for the treatment of Crohn’s disease by mouth, and can be useful as an alternative if neuropsychiatric adverse symptoms are caused by systemic glucocorticoids (2A ). • A 32-year-old woman developed irritability, anger, and insomnia after taking oral prednisone (60 mg/day) for a relapse of ileal Crohn’s disease. The prednisone was withdrawn and replaced by budesonide (9 mg/day), and the psychiatric adverse effects were relieved after 3 days. A good © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

clinical response was maintained, with no relapse after 2 months of budesonide therapy.

Metabolism In 91 renal transplant recipients without diabetes, a 75 g oral glucose tolerance test at 10 weeks and 1 year showed that reduction of the oral dose of prednisolone improved glucose tolerance 1 year after kidney transplantation (3c ). Skin Topical corticosteroids are well-known contact sensitizers. Immediate allergic or allergic-like reactions to systemic corticosteroids also occur, but less often. Two atopic patients developed urticaria, possibly IgE-mediated, from a hydrocortisone injection or infusion (4A ) and other reactions have been reported. • A 50-year-old woman developed contact dermatitis on her legs after she applied hydrocortisone aceponate cream (Efficort® ) to psoriatic lesions on her lower back (5A ). Similar lesions also occurred on her legs after she used topical betamethasone cream (Diprosone® ). However, no eczema developed on or around the site of application. Patch tests were negative to a range of corticosteroids, including Efficort® and Diprosone® creams. However, a repeated open application test was positive with Efficort® cream, hydrocortisone aceponate 0.127% in petroleum, and tixocortol pivalate 1% in petroleum. • A 42-year-old woman developed a non-pigmented fixed drug eruption after skin testing and an intraarticular injection of triamcinolone acetonide, which has not been previously reported (6A ).

427

428 Musculoskeletal The precise mechanism of osteoporosis due to long-term glucocorticoid therapy is not known. Osteoprotegerin (osteoclastogenesis inhibitory factor, OCIF) has been identified as a novel secreted cytokine receptor that plays an important role in the negative regulation of osteoclastic bone resorption. There are reports that suggest that glucocorticoids promote osteoclastogenesis by inhibiting osteoprotegerin production in vitro, thereby enhancing bone resorption. However, there are only a few clinical reports in which the regulatory functions of osteoprotegerin have been explored. In order to clarify the potential role of osteoprotegerin in the pathogenesis of glucocorticoid-induced osteoporosis, Japanese investigators have measured serum osteoprotegerin and other markers of bone metabolism before and after glucocorticoid therapy in patients with various renal diseases (7c ). The findings suggested that short-term administration of glucocorticoids significantly suppresses serum osteoprotegerin and osteocalcin. This might be relevant to the development of glucocorticoidinduced osteoporosis via enhancement of bone resorption and suppression of bone formation. Further long-term studies are needed to elucidate the mechanism of the glucocorticoidinduced reduction in circulating osteoprotegerin and its participation in the pathogenesis of osteoporosis. Osteoporosis and an increase in the risk of fractures has been found after the administration of corticosteroids by both the oral and inhaled routes. Bone loss induced by corticosteroids has been assessed in three different populations. A group of 374 subjects (mean age 35 years, 55% women) with mild asthma taking beta-adrenoceptor agonists only, were randomized to inhaled corticosteroids (budesonide or beclomethasone) or non-corticosteroid treatment for 2 years (8C ). Bone mineral density was measured blind after 6, 12, and 24 months. Mean doses of budesonide and beclomethasone were 389 µg/day and 499 µg/day respectively. At the end of follow-up, the subjects who had used corticosteroids had better asthma control. The mean changes in bone density over 2 years in the budesonide, beclomethasone, and control groups were 0.1%, −0.4%, and 0.4% for the lumbar spine and −0.9%, −0.9%, and −0.4% for the neck of the femur. The daily dose of inhaled corticosteroid was related to the reduction in bone mineral density only at the lumbar

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spine. Low to moderate doses of inhaled corticosteroids caused little change in bone mineral density over 2 years and provided better asthma control. Lumbar spine bone mineral density has been assessed in 76 prepubertal asthmatics (mean age 7.7 years, 26 girls) using corticosteroids (9c ). After stratification for dose and route of administration, the children who used over 800 µg/day of inhaled corticosteroids, with or without intermittent oral corticosteroids, had a significant lower weight-adjusted bone density than children who used 400–800 µg/day of inhaled corticosteroids (mean difference −0.05 g/cm2 ; 95% CI = −0.02, −0.09). Bone mass was similar in children who did not use inhaled corticosteroids and those who used 400–800 µg/day. In kidney transplant recipients, lumbar bone loss was significantly higher in 20 patients who took daily prednisone (5.9%, mean dosage 0.19 mg/kg/day) than in 27 patients who used alternate-day prednisone (1.1%, mean dosage 0.15 mg/kg/day) (10c ). A group of 367 patients with lung disease taking oral corticosteroids (177 women, mean age 68 years, 190 men, mean age 70 years) and 734 matched controls completed a questionnaire about lifestyle, fractures, and other possible adverse effects of corticosteroids (11C ). The cumulative incidence of fractures from the time of diagnosis was 23% in patients taking oral corticosteroids and 15% in the controls (OR = 1.8; 95% CI = 1.3, 2.6). Fractures of the vertebrae were more likely (OR = 10; 95% CI = 2.9, 35). The adverse effects were doserelated, with a higher risk of all fractures (OR 2.22; 95% CI = 1.04, 4.8) and vertebral fractures (OR 9.2; 95% CI = 2.4, 36) in those who took the highest compared with the lowest cumulative doses (61 g versus 5 g). There have recently been reviews of glucocorticoid-induced osteoporosis (12R ) and the prevention and treatment of glucocorticoid bone loss in dermatology patients (13R ). Bisphosphonates have good efficacy in the prevention of bone loss and fractures induced by steroids. In a 1-year extension of a previous double-blind, randomized, placebocontrolled study, two doses of alendronate (5 and 10 mg/day) were compared in 66 men and 142 women taking corticosteroids (at least 7.5 mg/day of prednisone or equivalent) (14C ).

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The extension was also double-blind, but those who had taken alendronate 2.5 mg/day in the previous study were given 10 mg/day. All the patients took supplementary calcium and vitamin D. The primary end-point was the mean percentage change in lumbar spine bone mineral density from baseline to 2 years. In those who took alendronate 5, 10, and 2.5/10 mg/day bone mineral density increased significantly by 2.8, 3.9, and 3.7% respectively, and fell by −0.8% with placebo. There were significantly fewer patients with new vertebral fractures in the alendronate group compared with placebo (0.7 vs 6.8%). Adverse events were similar across the groups. Osteonecrosis (aseptic necrosis or avascular necrosis) is a well-recognized adverse effect related to high-dose corticosteroid therapy (equivalent to more than 4000 mg of prednisone) for extended periods (3 months or longer) but can occur after short-term corticosteroid therapy. In 15 men with osteonecrosis of the femoral head after short-term therapy the mean duration of therapy was 21 (range 7–39) days and the mean dose in milligram equivalents of prednisone was 850 (range 290–3300) mg (15A ). The time from administration of steroids to hip pain was 17 (range 6–33) months. A new case of bilateral avascular necrosis of the femoral heads after highdose short-term dexamethasone therapy as an antiemetic in cancer chemotherapy has been reported (16A ).

Herpes simplex virus encephalitis after myxedema coma has been described in 81-yearold man treated with hydrocortisone (100 mg 8-hourly) and levothyroxine (18A ).

Immunologic Parenteral steroid pulse therapy can produce hypogammaglobulinemia and an increased risk of opportunistic infections (see Infection risk) (17C ). Infection risk Patients taking corticosteroids have an increased risk of infections, including those produced by opportunistic and rare pathogens. Of 111 consecutive heart transplant recipients taking oral prednisone (mean 13.8 months) 57% developed hypogammaglobulinemia (IgG below 7 g/l) (17C ). Those with severe hypogammaglobulinemia (IgG below 3.5 g/l) were at increased risk of opportunistic infections compared with those with IgG concentrations over 3.5 g/l (55% versus 5%, OR = 23). Parenteral steroid pulse therapy was associated with a significantly increased risk of severe hypogammaglobulinemia (OR = 15).

Death Mortality associated with glucocorticoid has been retrospectively studied in 556 patients with chronic obstructive pulmonary disease admitted to a rehabilitation center (19C ). Median survival was 38 months and 280 patients died during follow-up. On multivariate analysis, oral glucocorticoid use at a prednisone equivalent of 10 mg/day without inhaled glucocorticoid was associated with an increased risk of death (RR = 2.34; 95% CI = 1.24, 4.44), and 15 mg/day increased the risk further (RR = 4.03; 95% CI = 1.99, 8.15). The risk of death was not increased in those using 5 mg/day or when patients used any oral dose in combination with inhaled corticosteroids. Risk factors Premature infants The use of postnatal glucocorticosteroids in very premature infants is controversial; although dexamethasone reduces bronchopulmonary dysplasia, it has been associated with severe adverse effects (20r ). In 220 infants with a birth weight of 501–1000 g randomized to placebo or dexamethasone (0.15 mg/kg/day for 3 days and tapering over a period of 7 days) the relative risk of death or chronic lung disease compared with controls was 0.9 (95% CI = 0.8–1.1) at 36 weeks of gestational age (21C ). Infants treated with dexamethasone were less likely to need supplementary oxygen. Dexamethasone was associated with increased risks of hypertension (RR = 7.4; 95% CI = 2.7, 20.2), hyperglycemia (RR = 2.0; 95% CI = 1.1, 3.6), spontaneous gastrointestinal perforation (13% versus 4%), lower weight, and a smaller head circumference. Fetotoxicity The effect of prolonged antenatal betamethasone (three or more weekly administrations) has been studied in 414 fetuses (22C ). Multidose betamethasone was not associated with higher risks of antenatal maternal fever, chorioamnionitis, reduced birth weight, neonatal adrenal suppression, neonatal sepsis, or neonatal death. The effects of antenatal dexamethasone on birth weight have been studied in 961 infants and matched controls (23C ). Dexamethasonetreated infants had significantly lower birth

430 weights (after adjustment for week of gestation). The average differences from controls were 12 g at 24–26 weeks, 63 g at 27–29 weeks, 161 g at 30–32 weeks, and 80 g at 33–34 weeks. In the case of preterm rupture of membranes the data were not conclusive. A recent meta-analysis, including 15 controlled trials and involving more than 1400 women, has shown that antenatal corticosteroids in women with ruptured membranes may be beneficial in reducing the risks of neonatal death (RR = 0.68; 95% CI = 0.43, 1.07) and respiratory distress syndrome (RR = 0.56; CI = 0.46, 0.70), with no increase in the risk of infection in either the mother (RR = 0.88; CI = 0.61, 1.20) or baby (RR = 1.05; CI = 0.66, 1.68) (24M ).

PROSTAGLANDINS (SED-14, 1396; SEDA-23, 432; SEDA-24, 459; SEDA-25, 472) Alprostadil (prostaglandin E1 ) Hematologic Prostaglandin E1 is widely used in neonates with cyanotic congenital heart disease to maintain the patency of the ductus arteriosus. Reported adverse effects of PGE1 include fever, apnea, flushing, bradycardia, and hyperostosis. Investigators from the Department of Pediatrics in Johns Hopkins Hospital, after seeing a neonate who had marked leukocytosis temporally related to PGE1 , conducted a retrospective study of neonatal leukocytosis induced by PGE1 in 45 neonates (25C ). They concluded that PGE1 infusion is a predictable cause of leukocytosis in neonates with congenital heart disease. PGE1 -induced leukocytosis was especially prominent in three patients with splenic disorders associated with the heterotaxy syndrome. Many of the other adverse effects of PGE1 , including respiratory depression, hypotension, fever, and lethargy, were also associated with sepsis. The authors considered that it is reasonable to look for sepsis in infants receiving PGE1 , but that it is equally reasonable to withdraw empirical therapy once infection has been ruled out. Leukocytosis associated with PGE1 infusion has not been previously reported and is not listed in the alprostadil package insert.

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Bimatoprost Bimatoprost is a new ocular hypotensive agent that mimics the actions of prostamides. It can cause ocular pruritus, dryness, and burning sensations, and conjunctival hyperemia. Eyelash growth was reported in 36–48% of patients after 6 months, and there was darkening of the iris in 1.1% of patients (26C ). Similar changes have previously been described with latanoprost.

Gemeprost plus mifepristone In a double-blind, randomized, controlled trial, 896 healthy women requesting a medical abortion (57–63 days gestation, mean age 25 years) were randomized to a single oral dose of mifepristone 200 mg or 600 mg, both followed in 48 hours by gemeprost 1 mg vaginally (27C ). The complete abortion rates were similar with the lower and higher doses of mifepristone (92% versus 92%). The incidences of adverse effects were similar, with the exception of nausea at 1 week, which was less frequent in the low-dose group (3.6% versus 7.6%).

Iloprost In a randomized controlled study of cyclic iloprost or nifedipine in 46 patients with systemic sclerosis, the predictable adverse effects of iloprost (headache, nausea and vomiting, and diarrhea) were common but quickly resolved after the end of the infusion (28c ). They rarely required a temporary dose reduction. Hypotension occurred less often than with nifedipine.

Latanoprost Nervous system Three cases of headache after latanoprost have been described (29A ). • A 65-year-old man with primary open-angle glaucoma intolerant of dipivefrin and beta-blockers used latanoprost in both eyes at bedtime. He had no prior history of migraine, but he began to have headaches, the frequency and severity of

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Chapter 39

which increased until they were occurring daily. The pain was not relieved by over-the-counter or narcotic analgesics, and he was virtually incapacitated. Latanoprost was discontinued and he had almost immediate relief, with only one migraine during the following week, and he was headachefree for the next 10 months. He then agreed to rechallenge. After the second night of latanoprost therapy his headache recurred, and therapy was withdrawn 2 days later when he had incapacitating pain. Headache did not recur within 4 months of follow-up. • A 65-year-old man with primary open-angle glaucoma, using levobunolol hydrochloride 0.5%, was given a night-time dose of latanoprost. The next morning he awoke with a severe bifrontal throbbing headache, photophobia, and slight blurring of vision. The headache intensified, and 4 days later a CT scan was normal. On the sixth day he stopped using latanoprost. His headache disappeared within 24 hours and did not recur during follow-up for 1 year. • A 54-year-old woman with primary open-angle glaucoma, using betaxolol hydrochloride 0.5%, had mild progression of visual field loss in her left eye. Latanoprost was added nightly to her left eye. A few hours after the first dose she was awakened by a severe unilateral pounding headache extending from the left eye and brow to the left cranium. There were no associated neurological symptoms. The headache resolved spontaneously the next day, but recurred on three nights after instillation of latanoprost. On the fourth night the headache did not occur. She continued to use latanoprost, and the headache did not return.

(32C ). The changes included increased length, thickness, density, and color.

Sensory systems Latanoprost can cause permanent darkening of the iris, the mechanism of which is obscure. Of 17 patients requiring filtering surgery for primary open-angle glaucoma randomized to receive latanoprost (n = 8) or alternative medications (n = 9) for 3 months before surgery, all had peripheral iridectomy specimens, and there were color changes in one case (30A ). No morphological changes or cellular proliferation were found in any specimen. Skin Periocular skin color change has been reported (31A ). • A 75-year-old woman with open-angle glaucoma who had used latanoprost for 15 months reported that the skin around her eyes was much darker than on the rest of her face. The darkening had occurred gradually. Latanoprost was withdrawn; 1 month later there was a discernible lightening of the periocular skin and 2 months after withdrawal the skin was significantly lighter.

Hair Latanoprost caused changes in eyelashes in 26% of 194 patients over 12 months

Infection risk Two cases of Herpes simplex virus dermatitis of the periocular skin have been reported (33A ).

Misoprostol Misoprostol has been used to induce abortions in 150 adolescents (age range 12–17 years) at gestations of 63–84 days (34C ). They received vaginal misoprostol 800 µg/day to a maximum of three doses. Complete abortion occurred in 84%. Adverse effects were more frequent in these adolescents than in adult women, and included nausea (31%), vomiting (41%), diarrhea (48%), dizziness (19%), headache (17%), a subjective feeling of fever (26%), flushing (16%), and chills (49%). Obstetric hemorrhage is the leading cause of maternal mortality. Oxytocic drugs are widely used to reduce postpartum hemorrhage, but their use is limited in poor countries, owing to cost, transport and storage difficulties, and the need for parenteral administration. Some authors consider that misoprostol could be an alternative to oxytocic drugs because of its low price, stability at room temperature, and easy routes of administration (intravaginally, rectally, or orally). Misoprostol and oxytocin have been compared in three trials during vaginal and cesarean delivery. The first trial included 663 women (mean age 25 years, mean parity 2) with uncomplicated vaginal deliveries (35C ). They were randomized to receive two tablets of misoprostol (total dose 400 µg, dissolved in saline 5 ml and given as a micro-enema) or oxytocin (10 IU intramuscularly), with a double-dummy technique. There were no significant differences between the groups in mean hemoglobin and hematocrit, volume of blood loss, or duration of third stage labor. Shivering (38% versus 15%) and an increased mean temperature were significantly more common among those who received misoprostol. The second trial included 60 women who were randomized to oral misoprostol (400 µg) or intravenous oxytocin (10 IU) during cesarean section (36c ). Estimated blood loss was 545 ml (95% CI = 476, 614) in those given misoprostol and 533 ml (95% CI = 427, 639) in those

432 given oxytocin. The hemoglobin concentration and hematocrit were similar in the two groups. The third trial included 2058 patients (mean age 28 years, 53% nulliparous) with a singleton pregnancy, a low risk of postpartum hemorrhage, and vaginal delivery (37C ). They were randomly assigned to either intramuscular Syntometrine® 1 ml (oxytocin 5 units plus ergometrine 0.5 mg) or oral misoprostol 600 µg. There were no significant differences between the two groups in mean blood loss, the incidence of postpartum hemorrhage, or the fall in hemoglobin concentration. The need for oxytocic medication was higher with misoprostol, but manual removal of the placenta was required more often. Shivering (30% versus 9.9%) and transient pyrexia (temperature over 38◦ C, 8.5% versus 1.3%) were more common with misoprostol. Misoprostol could be an alternative to oxytocic drugs in reducing postpartum blood loss.

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J. Costa and M. Farré

Reproductive system Cervical laceration associated with misoprostol has been reported in a 33-year-old woman who received four doses of vaginal misoprostol (total dose 100 µg) for labor induction (38c ). Uterine rupture has been associated with misoprostol (200 µg vaginally) during second trimester termination of pregnancy (39c ).

Travoprost Travoprost is a derivative of fluprostenol and prostaglandin F2α and it has intraocular pressure-lowering activity. It causes changes in iris pigmentation (3.1–5.0%) and changes in eyelash characteristics, including length, thickness, density, and color (44–57%), similar to those described with latanoprost, after 12 months (32C ).

REFERENCES 1. Matsumoto T, Tamaki T, Kawakami M, Yoshida M, Ando M, Yamada H. Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury. Spine 2001; 26: 426–30. 2. Nahon S, Pisanté L, Delas N. A successful switch from prednisone to budesonide for neuropsychiatric adverse effects in a patient with ileal Crohn’s disease. Am J Gastroenterol 2001; 96: 1953–4. 3. Hjelmesaeth J, Hartmann A, Kofstad J, Egeland T, Stenstrom J, Fauchald P. Tapering off prednisolone and cyclosporin the first year after renal transplantation: the effect on glucose tolerance. Nephrol Dial Transplant 2001; 16: 829–35. 4. Rasanen L, Tarvainen K, Makinen-Kijunen S. Urticaria to hydrocortisone. Allergy Eur J Allergy Clin Immunol 2001; 56: 352–3. 5. Weber F, Barbaud A, Reichert-Penetrat S, Danchin A, Schmutz JL. Unusual clinical presentation in a case of contact dermatitis due to corticosteroids diagnosed by ROAT. Contact Dermatitis 2001; 44: 104. 6. Sener O, Çaliskaner Z, Yaziciouglu K, Karaayvaz M, Ozangüç N. Nonpigmenting solitary fixed drug eruption after skin testing and intra-articular injection of triamcinolone acetonide. Ann Allergy Asthma Immunol 2001; 86: 335–6. 7. Sasaki N, Kusano E, Ando Y, Yano K, Tsuda E, Asano Y. Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephrol Dial Transplant 2001; 16: 479–82.

8. Tattersfield AE, Town GI, Johnell O, Picado C, Aubier M, Braillon P, Karlström R. Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years. Thorax 2001; 56: 272–8. 9. Harris M, Hauser S, Nguyen TV, Kelly PJ, Rodda C, Morton J, Freezer N, Strauss BJG, Eisman JA, Walker JL. Bone mineral density in prepubertal asthmatics receiving corticosteroid treatment. J Paediatr Child Health 2001; 37: 67–71. 10. Masse M, Girardin C, Ouimet D, Dandavino R, Boucher A, Madore F, Hébert MJ, Leblanc M, Pichette V. Initial bone loss in kidney transplant recipients: a prospective study. Transplant Proc 2001; 33: 1211. 11. Walsh LJ, Wong CA, Oborne J, Cooper S, Lewis SA, Pringle M, Hubbard R, Tattersfield AE. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax 2001; 56: 279–84. 12. Lane NE. An update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am 2001; 27: 235–53. 13. Yosipovitch G, Hoon TS, Leok GC. Suggested rationale for prevention and treatment of glucocorticoid-induced bone loss in dermatologic patients. Arch Dermatol 2001; 137: 477–81. 14. Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E, Lane NE, Kaufman JM, Poubelle PEE, Hawkins F, Correa-Rotter R, Menkes CJ, Rodriguez-Portales JA, Schnitzer TJ,

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Block JA, Wing J, McIlwain HH, Westhovens R, Brown J, Melo-Gomes JA, Gruber BL, Yanover MJ, Leite MOR, Siminoski KG, Nevitt MC, Sharp JT, Malice MP, Dumortier T, Czachur M, Carofano W, Daifotis A. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, doubleblind, placebo-controlled extension trial. Arthritis Rheum 2001; 44: 202–11. 15. McKee MD, Waddell JP, Kudo PA, Schemitsch EH, Richards RR. Osteonecrosis of the femoral head in men following short-course corticosteroid therapy: a report of 15 cases. Can Med Assoc J 2001; 164: 205–6. 16. Virik K, Karapetis C, Droufakou S, Harper P. Avascular necrosis of bone: the hidden risk of glucocorticoids used as antiemetics in cancer chemotherapy. Int J Clin Pract 2001; 55: 344–5. 17. Yamani MH, Avery RK, Mawhorter SD, Young JB, Ratliff NB, Hobbs RE, McCarthy PM, Smedira NG, Goormastic M, Pelegrin D, Starling RC. Hypogammaglobulinemia following cardiac transplantation: a link between rejection and infection. J Heart Lung Transplant 2001; 20: 425–30. 18. Doherty MJ, Baxter AB, Longstreth WT Jr. Herpes simplex virus encephalitis complicating myxedema coma treated with corticosteroids. Neurology 2001; 56: 1114–15. 19. Schols AMWJ, Wesseling G, Kester ADM, De Vries G, Mostert R, Slangen J, Wouters EFM. Dose dependent increased mortality risk in COPD patients treated with oral glucocorticoids. Eur Respir J 2001; 17: 337–42. 20. Thébaud B, Lacaze-Masmonteil T, Watterberg K. Postnatal glucocorticoids in very preterm infants: “the good, the bad, and the ugly”? Pediatrics 2001; 107: 413–15. 21. Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S, Donovan EF, Oh W, Bauer CR, Saha S, Poole WK, Stoll BJ, for the National Institute of Child Health and Human Development Neonatal Research Network. Adverse effects of early dexamethasone in extremely-lowbirth-weight infants. New Engl J Med 2001; 344: 95–101. 22. Thorp JA, Jones AMH, Hunt C, Clark R. The effect of multidose antenatal betamethasone on maternal and infant outcomes. Am J Obstet Gynecol 2001; 184: 196–202. 23. Bloom SL, Sheffield JS, McIntire DD, Leveno KJ. Antenatal dexamethasone and decreased birth weight. Obstet Gynecol 2001; 97: 485–90. 24. Harding JE, Pang JM, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm rupture of membranes? Am J Obstet Gynecol 2001; 184: 131–9. 25. Arav-Boger R, Baggett HC, Spevak PJ, Willoughby RE. Leukocytosis caused by prostaglandin E1 in neonates. J Pediatr 2001; 138: 263–5. 26. Sherwood M, Brandt J. Six-month comparison of bimatoprost once-daily and twice-daily with tim-

olol twice-daily in patients with elevated intraocular pressure. Surv Ophthalmol 2001; 45 Suppl 4: S361–8. 27. World Health Organization Task Force on PostOvulatory Methods of Fertility Regulation. Medical abortion at 57 to 63 days’ gestation with a lower dose of mifepristone and gemeprost. A randomized controlled trial. Acta Obstet Gynecol Scand 2001; 80: 447–51. 28. Scorza R, Caronni M, Mascagni B, Berruti V, Bazzi S, Micalleff E, Arpaia G, Sarsina M, Origgi L, Vanoli M. Effects of long-term iloprost therapy in systemic sclerosis with Raynaud’s phenomenon. A randomised, controlled study. Clin Exp Rheumatol 2001; 19: 503–8. 29. Weston BC. Migraine headache associated with latanoprost. Arch Ophthalmol 2001; 119: 300–1. 30. Pfeiffer N, Grierson I, Goldsmith H, Hochgesand D, Winkgen-Böhres A, Appleton P. Histological effects in the iris after 3 months of latanoprost therapy: the Mainz 1 study. Arch Ophthalmol 2001; 119: 191–6. 31. Wand M, Ritch R, Isbey EK Jr, Zimmerman TJ. Latanoprost and periocular skin color changes. Arch Ophthalmol 2001; 119: 614–15. 32. Netland PA, Landry T, Sullivan EK, Andrew R, Silver L, Weiner A, Mallick S, Dickerson J, Bergamini MV, Robertson SM, Davis AA. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2001; 132: 472–84. 33. Morales J, Shihab ZM, Brown SM, Hodges MR. Herpes simplex virus dermatitis in patients using latanoprost. Am J Ophthalmol 2001; 132: 114–16. 34. Carbonell JLL, Velazco A, Varela L, Tanda R, Sánchez C, Barambio S, Chami S, Valero F, Aragón S, Marí J. Misoprostol for abortion at 9–12 weeks’ gestation in adolescents. Eur J Contracept Reprod Health Care 2001; 6: 39–45. 35. Bugalho A, Daniel A, Faúndes A, Cunha M. Misoprostol for prevention of postpartum hemorrhage. Int J Gynecol Obstet 2001; 73: 1–6. 36. Acharya G, Al-Sammarai MT, Patel N, AlHabib A, Kiserud T. A randomized, controlled trial comparing effect of oral misoprostol and intravenous syntocinon on intra-operative blood loss during cesarean section. Acta Obstet Gynecol Scand 2001; 80: 245–50. 37. Ng PS, Chan ASM, Sin WK, Tang LCH, Cheung KB, Yuen PM. A multicentre randomized controlled trial of oral misoprostol and i.m. syntometrine in the management of the third stage of labour. Hum Reprod 2001; 16: 31–5. 38. Oyelese Y, Landy HJ, Collea JV. Cervical laceration associated with misoprostol induction. Int J Gynecol Obstet 2001; 73: 161–2. 39. Al-Hussaini TK. Uterine rupture in second trimester abortion in a grand multiparous woman. A complication of misoprostol and oxytocin. Eur J Obstet Gynecol Reprod Biol 2001; 96: 218–19.

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GONADOTROPHINS AND OVULATION INDUCING DRUGS (SED-14, 1464; SEDA-23, 444: SEDA-24, 473; SEDA-25, 478) Reproductive system Ovarian hyperstimulation has been estimated to occur in some 4% of patients in whom exogenous gonadotrophins are given to induce ovulation. In an unusual case reported in detail from Saudi Arabia, a 28-year-old woman receiving gonadotrophins developed acute respiratory distress, abdominal pain, and severe hyponatremia associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (1A ). A multiple pregnancy nevertheless resulted and three fetuses went to term successfully. While it is possible that the gonadotrophins themselves induced SIADH, it seems more likely that it was a secondary complication of ovarian hyperstimulation.

Could fertility treatments cause malignant melanoma? Concern that the drug treatment of female infertility might predispose the user to malignant melanoma was first engendered by a US study published in 1995 (2C ). Among women who had used clomiphene citrate for infertility the incidence of melanoma was higher (RR = 1.8; 95% CI = 0.8, 3.5) than among American women in general. However, in a case–cohort study © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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of nearly 4000 infertile women there was a similar increase in the incidence of melanoma among those who had been treated with human chorionic gonadotrophin compared with the rest; there was no association with the use of clomiphene. Quite apart from the inherent discrepancy in these findings, several pieces of evidence have confused the debate. In the first place, the cohort of melanoma cases was small— barely a handful. In the second place, some earlier papers had suggested that infertility in women might of itself have an association with melanoma. The same impression came from various studies, in which the incidences of cancers in infertile women were examined (3M , 4C , 5C ). If that were true, it could affect the initial findings in either direction: a high spontaneous incidence might mask a real drug effect, or it might provide a predisposition to melanoma, which the drugs might then more readily trigger. In the meantime, data from Australia have shown no greater incidence of melanoma among women who had used fertility drugs and undergone in vitro fertilization than in the country’s general female population (6C ). Since then there has been one more significant paper, again from Australia, using data from a specialized fertility clinic in Queensland, relating to all women who attended the center over a decade (7 C ). Whenever possible, the women were traced and their subsequent history noted. Originally intended as a retrospective case–cohort study using a subcohort, the approach had to be amended because no cases of melanoma were found in the subcohort. The work therefore proceeded as a matched case–control study; all the data were taken and set against publicly available figures on melanoma in Queensland. After some

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necessary exclusions, 3186 women were included; care was taken to minimize recall bias. Fourteen women developed melanoma after fertility treatment, eight cases being invasive. The expected incidence in the general population would have been 15.8 cases in the same period. The incidence actually observed was therefore only 0.89 of that anticipated (95% CI = 0.54, 1.48). The numbers of women who had used clomiphene or human menopausal gonadotrophin were too small to make more differentiated calculations, but the incidence of melanoma seemed to correspond to that in the general population. On current evidence there seems no reason to discourage fertility-promoting drug treatments because of any risk of melanoma; they may even reduce it to some extent. However, this does not alter the fact that the data are deficient in various ways. Quite apart from the small numbers of melanoma cases that have been recorded, all the work to date has been performed in relatively sunny parts of the world; it is not known what would happen in other climates. Within countries there are sharp differences in melanoma figures; in the USA, where about 32 000 new cases of skin melanoma were projected for 1994 (8M ), the highest melanoma rates occur among light-skinned populations in areas of intense sunlight, e.g. Arizona; the same applies to Australia’s Queensland. In the USA as a whole there is a melanoma incidence among whites of 12.4 per 100 000 (9M ), while mortality rates vary inversely with latitude (10M ). Furthermore, in whites there has been a recent increase in the incidence of melanoma, during the precise period that this type of treatment has become popular, but probably for entirely different reasons, which may be associated with lifestyles and holiday habits; the reported incidence in whites rose by no less than 102% from 1973 to 1991 (10M ). Finally, as the Australian authors themselves have stressed, the fact that the Queensland clinic was a private institution specializing in IVF/GIFT therapy means that women with endocrineor ovulation-associated infertility may not so readily have been referred to it. All this makes it very difficult to find a baseline incidence for melanoma with which cases treated for infertility can be compared. It is to be hoped that data of this type will continue to

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arrive from other centers, so that a definitive judgement will become possible.

Recombinant human chorionic gonadotrophin (RhCG) Recombinant human chorionic gonadotrophin is now well on the way to replacing the product prepared from the urine of pregnant women, and it is necessary that sound comparisons between the two be made if the recombinant product is to be used optimally. In an open randomized trial in 297 ovulatory infertile women in 20 US infertility centers, recombinant hCG 250 µg and 500 µg was compared with urinary hCG 10 000 U USP in assisted reproduction (11C ). The women were treated for a single cycle with one or the other. The mean numbers of oocytes retrieved per treatment group were equivalent (13–14). Although the numbers of fertilized oocytes on day 1 after oocyte retrieval and of cleaved embryos on the day of embryo transfer were significantly higher with 500 µg of recombinant hCG than with 250 µg, the incidence of the anticipated adverse events also tended to be higher. More exact data on the adverse effects and relative safety of the recombinant and urinary formulations have been provided in a similar investigation in 259 women (12C ). In terms of safety, rHCG was well tolerated at a dose of up to 30 000 IU. Moderate ovarian hyperstimulation syndrome was reported in 12% of patients who received uHCG and 12% of those who received two injections of rHCG. There were no moderate or severe complications in patients who received a single dose of rHCG up to 30 000 IU. The results seem to show that a single dose of rHCG is effective in inducing final follicular maturation and early luteinization in in vitro fertilization and embryo transfer patients and is comparable with uHCG 5000 IU. The dose of rHCG that gave the highest efficacy to safety ratio was 15 000–30 000 IU. The recombinant and urinary forms of human chorionic gonadotrophin have also been compared in an international multicenter study, with similar findings (13C ), but it was notable that significantly more patients who were given

436 uHCG reported local reactions (particularly inflammation and pain), presumably because of the presence of biological impurities.

ESTROGENS

(SED-14, 1448; SEDA-23, 440; SEDA-24, 467; SEDA-25, 478)

Diethylstilbestrol (stilbestrol) Diethylstilbestrol continues to be recommended in some centers as one of the agents of last resort when prostate cancer proves refractory to steroid hormones or androgen deprivation therapy has done all it can (14cr ). In a Japanese study in which 16 patients were given a daily intravenous injection of 250 mg of diethylstilbestrol diphosphate for 28 days the shortterm response was favorable and the drug was well-tolerated (15c ). Carcinogenicity Vaginal cancer The evidence incriminating fetal exposure to diethylstilbestrol as a cause of serious complications in the second generation is by now massive, but as “DES-daughters” grow older it continues to accumulate, especially with regard to carcinogenicity and related adverse effects. Diethylstilbestrol has clearly been shown to cause primary vaginal carcinoma in the second generation, and tumors continue to occur in women who are now in middle age. One recent report concerned a diethylstilbestrol-exposed woman who at the age of 39 developed concurrent primary cancers of both the vagina and the endometrium (16A ). However, it is important to bear in mind that cases occur in which there is no history of the mother’s having taken diethylstilbestrol during pregnancy. In one such case HIV/AIDS infection was also a predisposing factor for vaginal carcinoma and this could explain a proportion of new cases that are being reported today (17Ar ). Miscellaneous cancers A further follow-up and analysis of 3879 women, taken from two earlier US studies, who had been were exposed to diethylstilbestrol during pregnancy has been presented (18Cr ). The results showed a modest association between stilbestrol exposure and the risk of breast cancer (RR = 1.27; 95% CI =

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1.07, 1.52). The increased risk was not further aggravated by a family history of breast cancer, by use of oral contraceptives, or by HRT. There was no evidence that diethylstilbestrol was associated with a raised risk of ovarian, endometrial, or other hormone-associated cancers. Immunologic In 13 women exposed to diethylstilbestrol in utero compared with similar control subjects with respect to the in vitro T cell response to the mitogens phytohemagglutinin, concanavalin A, and interleukin 2, incorporation of tritiated thymidine by T cells from stilbestrol-exposed women was increased three-fold over a range of concentrations in response to concanavalin A increased by 50% over a range of concentrations in response to phytohemagglutinin, and increased two-fold in response to the endogenous mitogen interleukin 2 (19E ). This in vitro evidence of a change in T cell-mediated immunity clearly raises questions about the clinical consequences.

Hormone replacement therapy (HRT) (SED-14, 1457; SEDA-23, 440; SEDA-24, 468; SEDA-25, 479) An extraordinarily thorough review of all significant controlled studies of estrogen replacement therapy has been published (20M ). The participants totalled 2511 and the trials lasted 0.25–3 years. The primary purpose was to confirm efficacy, but data on adverse effects were also collected. Withdrawal because of adverse events, commonly breast tenderness, edema, joint pains, and psychological symptoms, was not significantly higher with HRT than placebo (OR = 1.38; 95% CI = 0.87, 2.21). Breast tenderness and withdrawal bleeding were the only significant problems in terms of frequency. The studies did not justify the conclusion that there are serious adverse effects, such as thrombosis and malignancies. Carefully assessed data like these illustrate the delicacy of the balance in the debate regarding the benefit:harm ratio of long-term HRT; extreme statements have been made in both directions, and clearly most are not justified.

Sex hormones and related compounds, including hormonal contraceptives

A reasoned critical review, stressing how inadequate many of the data still are on both efficacy and safety issues, has been published (21R ). The dispute about the benefit : harm ratio of the various competing forms of HRT for use in the climacteric or postmenopausally is becoming increasingly intense, with a sharp division of opinion between protagonists and critics of the individual patterns of treatment. The view was often defended by earlier workers that, at least for certain classes of users, some form of combined estrogen plus progestogen treatment is likely to be more appropriate and perhaps more physiological than replacement with estrogen alone. Many variants have been used and none is likely to be ideal for all subjects. Rosenberg is one of those who argue that in the climacteric there are sound reasons for using estrogen with intermittent progestogen and that it is much underused, despite the fact that uterine bleeding and other adverse progestogenic effects are with some combined formulations (but not all) major reasons for patient noncompliance and early discontinuation (22CR ). In 438 postmenopausal women, randomly assigned to either constant 17-beta-estradiol (1 mg/day) plus intermittent norgestimate 90 µg (3 days off, 3 days on) or a fixed combination of 17-beta-estradiol (2 mg/day) with norethisterone acetate (1 mg), the two regimens had similar bleeding profiles and provided comparable relief from vasomotor symptoms (22CR ). However, breast discomfort and edema were experienced by twice as many subjects who used the fixed combination. The intermittent regimen was notably free of endometrial hyperplasia. One finding from a recent study is that, while the extent of vaginal bleeding when using both estrogens and progestogens varies somewhat with the exact formulation and dose, another determining factor is the pretreatment state of the endometrium: a thick endometrium at the start of treatment results in significantly more bleeding days than a thin endometrium (23c ). This might be a helpful predictor of the extent to which a particular woman will find this type of HRT acceptable. The addition of an androgen to a hormone replacement program for women has been studied many times, starting from the observation that (particularly after oophorectomy) there is a deficiency of both testosterone and androstenedione, and from the observation that estrogens

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alone do not relieve all menopausal symptoms. Adding androgens has sometimes been found to improve relief of vasomotor symptoms, as well as alleviating some psychosexual problems. However, evidence has also been advanced that part of the value of estrogens lies in their ability to exert a positive inotropic effect on cardiac muscle and to increase cardiac output, left ventricular mass, and end-diastolic volume. In theory, one might expect the addition of androgens to interfere with these effects. This possibility has now been examined by an Italian group using Doppler flowmetry in an open randomized study in 40 patients over 8 months. All were using transdermal E2 (50 µg/day) and cyclic medroxyprogesterone acetate (10 mg/day). Half of the trial subjects now received in addition testosterone undecanoate (40 mg/day). The investigators concluded that while the androgen improved sexual desire and satisfaction and had no effect on endometrial thickness it did in part counteract the beneficial effects of estrogens on cerebral vascular activity and lipid profiles. The most notable change was a significant increase in the pulsatility index of the middle cerebral artery. Androgen resulted in a 10% reduction in HDL cholesterol concentrations within 8 months. They therefore urged caution in using androgens, at least in the manner adopted in this study (24cr ). Cardiovascular The findings of the randomized Heart and Estrogen/progestin Replacement Study (HERS) suggested that in women with clinically recognized heart disease, HRT might be associated with early harm but late benefit in terms of coronary events. The findings of that study seem in the meantime to have been confirmed by some further US work. In one study the histories and subsequent course of 981 postmenopausal women who had survived a first myocardial infarct and had thereafter used estrogen or estrogen plus progestogen were examined (25C ). Relative to the risk in a parallel group of women not currently using hormones there was a suggestion of increased risk during the first 60 days after starting hormone therapy (RR = 2.16; CI = 0.94, 4.95) but of reduced risk with current hormone use for longer than 1 year (RR = 0.76), although the confidence intervals were wide. However, in a second study, data on 1857 women from the Coumadin Aspirin Reinfarction Study were used to assess the incidence of

438 cardiac deaths or unstable angina as related to the use of HRT. Of the population studied, 524 (28%) had used HRT at some point and 111 of the latter (21%) had started HRT after suffering a myocardial infarct (“new users”). Women who began HRT after their first myocardial infarct had a significantly higher subsequent incidence of unstable angina than women who had never used hormones (39% vs 20%); however, these new hormone users suffered death or recurrence of myocardial infarct at a much lower rate than never-users (4% vs. 15%). These differences are striking. Prior/current users had no excess risk of the composite end point after adjustment. Users of estrogen plus progestogen had a lower incidence of death, infarct, or unstable angina during follow-up than users of estrogen only (RR = 0.56) (26C ). As Grady and Hulley have commented in an editorial, current data seem to make it clear that “postmenopausal hormone therapy should not be used for the purpose of preventing coronary disease unless future data from well-designed randomized trials document such benefit” (27r ). Psaty and others in Seattle set out to examine the issue in more depth and to look for possible hematological risk indicators in these populations (28Cr ). They carried out a population-based, case–control study in 232 postmenopausal women who had had a nonfatal myocardial infarct during the previous 3 years; a stratified random sample of 723 postmenopausal women without a history of infarction acted as controls. Among hypertensive women, the presence of the prothrombin 20210 GÆA variant proved to be a significant risk factor for infarct (OR = 4.32; 95% CI = 1.52, 12) and in this group there was also a significant interaction between the use of HRT and the presence of the prothrombin variant in increasing the risk of infarction. Compared with non-users of HRT with the wild-type genotype, women who were current users and who had the prothrombin variant (n = 8) had a nearly 11fold increase in the risk of a non-fatal myocardial infarct. The interaction was absent among non-hypertensive women. No interaction with HRT was found for factor V Leiden in either hypertensive or non-hypertensive women. These findings suggest that screening for the prothrombin variant may allow a better assessment of the risks and benefits associated with HRT in individual postmenopausal women.

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Nervous system Over the years there have been reports that headache or classical migraine is either alleviated or exacerbated by HRT. This has been studied in 50 menopausal women with headaches who were randomized to either transdermal estradiol 50 µg for 7 days a month or oral conjugated estrogens 0.625 mg/day for 28 days, both regimens being supplemented with medroxyprogesterone acetate 10 mg/day during the latter half of each month (29Cr ). In patients with episodic tension headache there was no significance change in headache pattern. However, in women with migraine without aura the frequency and duration of the attacks increased significantly during HRT in the subgroup using the oral formulation; the transdermal formulation had no effect on the migraine pattern. Metabolism Changes in lipids have been observed with both HRT and oral contraceptives and have sometimes been promoted as potentially advantageous, but it is not clear how significant such changes are, at least in biochemical terms. A review and pooled analysis of 248 prospective studies available up to the year 2000 has provided data on this issue in postmenopausal women (30M ). All estrogen-only regimens raised HDL cholesterol and lowered LDL and total cholesterol. Oral estrogens raised triglycerides. Transdermal 17-beta-estradiol lowered triglycerides. Progestogens had little effect on estrogeninduced reductions in LDL and total cholesterol. Estrogen-induced increases in HDL and triglycerides were opposed according to the type of progestogen in the following order (from least to greatest effect): dydrogesterone and medrogestone, progesterone, cyproterone acetate, medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and oral norethindrone acetate. Tibolone reduced HDL cholesterol and triglyceride concentrations. Raloxifene reduced LDL cholesterol concentrations. In 41 studies of 20 different formulations, HRT generally lowered lipoprotein(a). Thus, the route of estrogen administration and the type of progestogen given determine the effects of HRT on lipid and lipoprotein concentrations. The clinical significance, if any, of these various effects has yet to be determined. The evidence could be helpful in selecting treatment for women with conditions with a metabolic

Sex hormones and related compounds, including hormonal contraceptives

component, but risk studies in such groups of women will then need to be carried out. Female sex hormones can also have effects on lipids when they are given transdermally, and this has been studied retrospectively in 159 women who used transdermal or oral replacement therapy (31C ). All used either transdermal estradiol 0.05 mg twice weekly or oral conjugated estrogen 0.625 mg/day, each combined with oral medroxyprogesterone acetate 2.5 mg/day. The mean increases in HDL cholesterol in the first year and second year averaged 10% and 31% with oral treatment, the corresponding figures for transdermal therapy being 14% and 34%. With oral therapy the mean reductions in total cholesterol in the first and second years were 2.9% and 15%, and with transdermal treatment 5.6% and 5.7%. With oral treatment, the mean falls in LDL cholesterol in the first and second years were 6.2% and 18% and with transdermal treatment 7.9% and 16% respectively. Transdermal treatment reduced triglyceride concentrations by 34%, whereas oral estrogen treatment increased them by 19% at the end of 2 years. Both treatments changed serum lipids favorably. Nevertheless, triglycerides were increased by oral estrogen but reduced by transdermal treatment at 2 years. It has been hypothetically suggested that the use of HRT could slow the progression of atherosclerosis by an effect on lipids. In a 1-year study of 321 women with increased thickness of the carotid intima media who were using either various forms of HRT or none at all, there was no slowing in the progression of subclinical atherosclerosis and no unfavorable effect on the process (32Cr ). HRT significantly reduced LDL cholesterol, fibrinogen, and FSH. Weight gain is widely believed to be a common consequence of HRT, and the desire to avoid obesity is a major reason why some women decline treatment. However, the potential effects of HRT need to be distinguished from effects that could be due to changing lifestyle or ageing. The effects of short-term hormone replacement and age on alterations in weight, body composition, and energy balance have therefore recently been studied (33c ). This prospective study, in 18 healthy women aged 45–55 years and 15 aged 70–80 years, involved measurements at baseline, repeated after 1 month of transdermal estrogen (Estraderm,

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50 µg/day), and again after a further month of transdermal estrogen with vaginal progesterone (100 mg bd) added for the final 7 days. In neither age group did estrogen treatment correlate with anthropometric changes. Resting energy expenditure and activity were positively correlated with fat-free mass, while energy intake was not. Resting energy expenditure, energy intake, and activity were lower in older women when adjusted for fat-free mass. Changes in weight during treatment were not statistically significant. In addition, there was no difference between the groups in body mass index, fat mass, fat-free mass, total body water, or waistto-hip ratio. This work has confirmed the reduction in energy expenditure that occurs with ageing, and it suggests that there is no effect of HRT on resting energy expenditure or body weight. Hematologic It has been firmly concluded, in the light of all prior evidence, that HRT increases the risk of venous thrombosis, this risk not being outweighed by any demonstrable benefit in terms of arterial cardiovascular disease (34R ). This conclusion is now being increasingly accepted, and the effects of postmenopausal HRT on blood coagulation have been intensively studied and documented over the years. However, the effects in older women, who have the highest risk of thromboembolism, are not well defined, and it is good to see that a US group has now studied the association between HRT and concentrations of natural anticoagulant proteins in this subpopulation (35Cr ). This cross-sectional study involved women of 65 years or older participating in the Cardiovascular Health Study. Protein C antigen and antithrombin were measured in HRT users (230 taking an unopposed estrogen and 60 an estrogen with a progestogen) and a comparison group of 196 non-users. Estrogen use was associated with significantly higher protein C concentrations (4.80 vs. 4.30 µg/ml); the results were similar with estrogen/progestogen. In both user groups, antithrombin was significantly lower than in non-users (109% for each treatment group vs. 115% in non-users). Adjustment for factors related to prescription of HRT and to anticoagulant protein concentrations had little impact on the results. For antithrombin, the association with HRT was larger for thinner Caucasian women and black

440 women. The authors concluded that venous thrombosis from HRT may be partly mediated by alterations in antithrombin, but not by protein C concentrations. Further studies of HRT-induced alterations in anticoagulant function in relation to the actual occurrence of thrombosis with HRT would now be helpful. Urinary tract Since microalbuminuria can be regarded as being associated with renal and cardiovascular disease, evidence that the incidence of microalbuminuria is higher during treatment with oral contraceptives or hormone replacement therapy deserves to be taken seriously. A Dutch group has performed a case– control study of baseline and dispensing data relating to 4301 women participating in a study on the prevention of renal and vascular disease; the main outcome measure was microalbuminuria (30–300 mg/day) (36C ). After adjusting for age, hypertension, diabetes, obesity, hyperlipidemia, and smoking, the odds ratio for microalbuminuria was 1.90 (CI = 1.23, 2.93) for premenopausal oral contraceptive users and 2.05 (1.12, 3.77) for postmenopausal hormone replacement therapy users. The point estimate increased dose-dependently, albeit insignificantly, according to the estrogen content of the oral contraceptives (30–50 µg) and was greater in oral contraceptives with a second-generation progestogen (OR = 2.04) than those using a third-generation progestogen (OR = 1.39; CI = 0.63, 3.06). In the case of HRT, the odds ratio increased with the duration of HRT, that in women who had used the product for more than 5 years being double that in others. Skin Transdermal administration of estrogens for HRT continues to be used in a minority of patients and is generally well tolerated. Exceptional is an instance of allergic contact dermatitis described in Korea, where the reaction was found to be due to 17-beta-estradiol itself and not to an excipient (37A ). Musculoskeletal Despite the evidence that estrogens can be of value in countering osteoporosis, some studies have suggested that women who use them are more likely to have back pain than those who do not; the possible causal link has remained unclear, and continues so despite recent confirmation of the phenomenon.

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Baseline information on estrogen replacement therapy, functional status, back pain and function, and other variables has been obtained in 7209 elderly white American women (mean age 71 years) enrolled in a study of osteoporotic fractures; X-rays were also taken at baseline and an average of 3.7 years later (38C ). A total of 1039 women were using estrogen replacement therapy at baseline, 2016 reported former use, and 4154 had never used estrogen replacement therapy. Compared with never-users, a significantly higher percentage of current estrogen users reported clinical back pain (53% vs. 43%) and back impairment (12% vs. 9.2%) at baseline and at the follow-up visit (pain 51% vs. 41%; impairment 16% vs. 12%). This occurred despite a higher prevalence of vertebral fractures in never-users of estrogen at the baseline visit. The increased likelihood of back pain and impairment of function in current and former estrogen users remained in evidence, despite statistical adjustment for possibly interfering factors. The relative risks for impaired back function in former and current users at follow-up were 1.1 (0.9, 1.3) and 1.6 (1.3, 2.0) respectively (39CR ). Reproductive system (see also “Carcinogenicity” below) It has long been recognized that periodic or irregular uterine bleeding will occur in some women using HRT. While it is simple to dismiss this merely as a reactivation of endometrial proliferation and shedding, some workers have sought to examine the precise mechanism of this unwanted complication, particularly because it might prove to be the harbinger of more serious events involving the endometrium. From recent work in the UK it has been concluded that estrogen treatment appears to alter the endometrial expression of matrix metalloprotease 9 (MMP-9) and the tissue inhibitor of MMPs (TIMP-1) as well as the local balance between these molecules (40C ). This alteration may promote breakdown of the endometrial extracellular matrix and blood vessels and hence bleeding. There could be fairly simple ways of screening for endometrial disorders in women using HRT. A study in 93 such women has confirmed the earlier finding that if a Papanicolaou smear is taken from the vagina the presence of endometrial cells in the smear gives some (nonspecific) indication that there are endometrial

Sex hormones and related compounds, including hormonal contraceptives

changes, which may range from hyperplasia or polyps to endometrial carcinoma (41c ). Carcinogenicity Many clinicians continue to withhold estrogen-based replacement therapy from women who have a history of breast cancer because they fear impairing their prognosis; the evidence is not firm, but experts continue to urge caution in the absence of firm data either way (42R ). A well-designed study from Finland in 131 such women, two-thirds of whom used HRT, showed no increase in the breast cancer recurrence rate after an average of 2.5 years (43c ). However, the limited size of the study (and the fact that various different forms of HRT were used) make it difficult to exclude the risk on the basis of these data alone. Because hyperplastic or fibrocystic changes in the breast may be pre-malignant, there has been a study of 42 women who at breast biopsy had atypical hyperplasia, 74 age-matched women with proliferative fibrocystic changes, and 74 with non-proliferative fibrocystic changes (44cr ). The patients were aged 26–77 years, and had taken predominantly HRT (usually conjugated estrogen) but sometimes oral contraceptives. There was a strong association between exogenous hormone use and the presence of atypical hyperplasia. The authors considered their results in line with the theory that there is a continuum between hyperplasia and carcinoma and considered that exogenous hormone use may influence the transition from one to the other in a (still undefined) subset of women. It is difficult to interpret a Japanese report of a woman aged 62 years who developed a benign fibrous tumor of the breast. The mass, which had been noted 1 year before, progressively enlarged. Bearing in mind that such fibrous tumors of the breast are almost always premenopausal, it may be significant that she had been taking estrogens irregularly for the previous 10 years but had taken them intensively during the last year. In addition, there was positive immunohistochemical nuclear staining for estrogen receptor antibodies in stromal cells (45A ). The link between HRT and endometrial cancer must now be considered clear, although it is not clear why the complication develops only in certain users. The risk of developing endometrial cancer during HRT seems to vary individually, perhaps because of genetic rather than

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exogenous factors. In women with endometrial cancer, women who reported ever taking HRT were more than twice as likely to develop endometrial cancer as women who had never taken it (OR = 2.24; 95% CI = 1.19, 4.23) and among these women the risk of endometrial cancer was higher for women homozygous for the CYP17 T allele (OR = 4.10; 95% CI = 1.64, 10.3), but not for women with the C allele. These preliminary findings suggest that CYP17 or other variants in estrogen biosynthesis or metabolism pathways may be markers of susceptibility to endometrial cancer among users of estrogen replacement therapy (46C ). Like a history of breast cancer, a history of cancer of the endometrium is commonly regarded as a reason to avoid HRT with estrogens. One recent study, though limited in duration, has provided encouraging evidence that such treatment at least does not adversely affect the rate of recurrence or the survival time (47Cr ). Of 249 women with surgical stage I, II, and III endometrial cancer treated between 1984 and 1998, 130 used estrogen replacement after their primary cancer treatments and half of these used progesterone in addition to estrogen. Among this cohort, 75 matched treatment– control pairs were identified. The hormone users were followed for a mean of 83 months and the non-hormone users for a mean of 69 months. There were two recurrences among the 75 HRT users compared with 11 recurrences in the 75 non-hormone users. Hormone users had a statistically significant longer disease-free interval than untreated women. Whether this is sufficient to conclude that the effect is actually positive is not clear, but no evidence of an increase in risk came to the fore. Finally, in view of the possibility that HRT can trigger malignancy in the endometrium itself, it is not surprising to find that it has also been reported to do so in endometriosis deposits elsewhere. An adenocarcinoma arose after many years of HRT in abdominal areas of endometriosis in a woman who had undergone hysterectomy and salpingo-oophorectomy 17 years before (48Ar ). It is of course known that some 1–2% of endometriosis deposits undergo malignant degeneration, and the link with HRT could therefore have been fortuitous.

442

HORMONAL CONTRACEPTIVES (SED-14, 1405; SEDA-23, 442; SEDA-24, 471; SEDA-25, 484)

Oral contraceptives The third-generation oral contraceptives: a judicial assessment and further evidence It is extraordinary to find a major epidemiological dispute regarding drug safety being handled by the High Court in England. However, that is precisely what happened in late July 2002, when the Court handed down its decision regarding thromboembolic events induced by the third-generation oral contraceptives (49R ). Essentially, a group of women who claimed to have been injured as a consequence of having using this latest version of “the pill”, based on two new progestogens, had sought to reclaim extensive damages from the manufacturers, since in their view the product did not possess the degree of safety which, in the words of European law, the user was legitimately entitled to expect. Since the safety achieved with the widely used products of the second generation was so widely regarded as acceptable, the Court had to decide whether the newer products had significantly failed to meet that standard. Faced with a long procession of expert epidemiological witnesses from both sides, and with some flat contradictions, the judge was obliged to rule on their arguments. That the issue reached an English court was not surprising, for it was in England that the Committee on Safety of Medicines had written to prescribers in 1995 stating that three unpublished studies on the safety of combined oral contraceptives in relation to venous thromboembolism had indicated about “a two-fold increase in the risk of such conditions” compared with the preceding generation of products. This issue of a “two-fold increase” became crucial to the case. “For reasons of causation”, as the Judge put it, the claimants had accepted the burden of proving that the increase in risk was indeed not less than two-fold. In fact, the English authorities, having rejected a vigorous defence of these products by the manufacturers, were by 1999 speaking more

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precisely of an increase in risk, as compared with the earlier products “of about 1.7–1.8 after adjustment”, which was “not fully explained by bias or confounding”; appropriate label warnings were therefore imposed. These new warnings, summarized, said that an increased risk associated with combined oral contraceptives generally was well established, but was smaller than that associated with pregnancy (60 cases per 100 000 pregnancies). In healthy non-pregnant women who were not taking any combined contraceptive it was about five cases per 100 000 woman years; in those taking the second-generation products it was about 15; and for third-generation products it was about 25. By September 2001, the European Union’s Committee on Proprietary Pharmaceutical Products had formed its own view, and here too it was concluded that the “best estimate of the magnitude of the increased risk is in the range of 1.5–2.0”. The individual studies on which the case turned have been familiar to readers of the literature over the last 7 years, have been reported in SEDA, and will not be presented here again. In Court to support the claimants, Professor Alexander Walker assessed the relative risk of the third-generation products at 2.2, Dame Margaret Thorogood at 2.1, and Professor Klim McPherson at about 1.9. The experts for the defendants took the view that the relative risk was well below 2, and could well be zero. As Mr Justice Mackay noted, having listened to these experts: “. . . the debate between them has been unyielding, at times almost rancorous in tone, and with a few honourable exceptions . . . devoid of willingness to countenance that there may be two sides to the question. So, science has failed to give women clear advice spoken with one voice”. There was also fundamental disagreement on confidence intervals when calculating relative risks in such matters: “The Defendants say that to establish causation in the individual, and therefore a relative risk which is greater than 2, there must be seen not just a point estimate but also a lower confidence interval which is greater than 2 in order for the result to be significantly different from 2”. The Court was faced with “a series of studies with different point estimates and largely overlapping confidence intervals. Time after time experts have had their attention drawn

Sex hormones and related compounds, including hormonal contraceptives

to point estimates from studies that appear, to the layman’s eye, to be very different. Almost invariably they have dismissed those apparent differences by reference to the overlapping confidence intervals, saying that the figures are statistically compatible and there is no significant difference”. Confronted with such material, the Court chose to set aside as inexact and theoretical much of the statistical rhetoric. Having done that, the Judge felt himself in a position to emerge “from that forest into broader more open country where the simpler concept of the balance of probabilities rules”. Constructing his judgement in that way, Mr Justice Mackay advanced in the course of 100 pages to the conclusion that the claimants had failed to demonstrate a doubling of the risk. In his view, “the most likely figure to represent the relative risk is around 1.7”. This extraordinary and wise judgement merits most careful reading by anyone anxious to understand the safety issues surrounding oral contraceptives. First, because of the insight that it demonstrates into the—not always edifying— manner in which evidence in this vital matter has been adduced, interpreted, and argued over in the course of more than a decade. Secondly, because it arrives, through a process of tight reasoning, at what is for the moment the most reliable conclusion that we have. It seems beyond all possible doubt that, as concluded in earlier volumes in this series, the third generation of oral contraceptives is primarily characterized by an increased risk of thromboembolic complications. Whether that risk is great enough to warrant financial compensation is a matter for lawyers to decide. But given the lack of any tangible benefit to the user, the risk is clearly significant in human terms, and it is hard to see that there is any valid reason at all for continuing to use these products. Meanwhile, evidence of the increased risk of thromboembolic complications with the thirdgeneration oral contraceptives compared with earlier formulations has continued to accumulate. Individual studies in recent months have not added a great deal to the evidence considered judicially. A group in The Netherlands has stressed the fact that even though the risk of venous thrombosis is small in absolute terms, oral contraceptives form the major cause of thrombotic disease in young women. The risk is higher during the first year of use (up to 1 per

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1000 per year), with third-generation progestogens, and among women with a prothrombotic predisposition (50R ). The reasons for postulating an increased risk of thromboembolism have always been distilled mainly from large-scale epidemiological experience. The critical view is in part supported, but also in part contradicted, by laboratory findings, but the relevance of the latter has been disputed. Some work that was considered to show severe acquired plasma resistance to activated protein C among users of thirdgeneration (as opposed to second-generation) products has been re-examined by a French group (51R ). In their view the technical measures used to demonstrate the effect of activated protein C introduced a bias of interpretation and hence false results; they have further argued that such a test cannot demonstrate the presence of a raised thromboembolic risk in asymptomatic women taking these contraceptives, since it is non-specific and subject to changes in the plasma concentrations of many coagulation factors that are themselves increased or decreased by estrogens and progestogens. They point, for example, to protein S (52E ), changes in which account for the differential effect of oral contraceptives on Rosing’s assay (53C ), but which are in their view irrelevant to issues of thromboembolic risk with oral contraceptives; the androgenic potential of the progestogen may further counteract the effect of estrogens in the test. More generally, in such a complex situation in which there is a “modification of the modification”, there is no hemostasis-related test that provides a risk indicator for thrombosis. This argument is sound, but it naturally remains theoretical; the question of thromboembolism with the thirdgeneration products must, as pointed out above, be resolved on the basis of epidemiological data, and certainly those data now strongly point to an increased risk. Liver Hepatic adenomatosis, which seems to have been reported only some 38 times, is a condition with a female preponderance; in earlier work it was noted that in 46% of the female patients oral contraception had been used. This means, however, that in the other 54% it had not, and it should be borne in mind that the condition can also occur in men.

444 • A 35-year-old woman, who had been fitted with Norplant 2 years before and had used oral contraceptives for some 20 years before that, developed epigastric and right upper quadrant abdominal pain (54Ar ). A liver mass was found and at surgery proved to consist of multiple adenomata; part of the liver had to be resected.

What is of potential concern is that in this case, as in a very few described before, there was also evidence of hepatocellular dysplasia, which could be a pre-malignant condition. However, with widespread use of Norplant, some reported adverse events, such as this, may be purely coincidental. Drug formulations Further work with lowdose oral contraceptives based on the older progestogens has produced no surprises: they continue to be relatively well-tolerated in the short term, better so than the products that preceded them and those that came later. Two new placebo-controlled studies with the combination of levonorgestrel 100 µg and ethinylestradiol in 704 patients over six cycles showed no differences in unwanted effects from placebo; in particular there was no evidence of weight gain (55C ). Injectable depot contraceptives Injectable depot contraceptives have long been preferred in some underprivileged or minority populations, because problems with literacy or social acceptance have impeded the use of oral products. A difficulty is that in such populations one may be dealing with subjects who face particular health problems, such as those resulting from poor nutrition, disease, or other forms of deprivation, and this can adversely affect tolerance or safety. For example, depot medroxyprogesterone acetate contraception is widely used by women of the Navajo tribe of American Indians, and they constitute a high-risk population for diabetes mellitus. However, medroxyprogesterone can cause weight gain and independently reduce sensitivity to insulin, which would be particularly undesirable in such women. Recently, contraceptive use has been studied in 284 diabetic Navajo women and 570 non-diabetic controls. Users of depot medroxyprogesterone were more likely to develop diabetes than those who had used combination estrogen– progestogen oral contraception only (OR = 3.8;

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95% CI = 1.8, 7.9). The excess risk persisted after adjustment for body mass index and it became more pronounced with longer use (56Cr ). Implantable contraceptives As in the case of injectable depot contraceptives (see above) the situation with subdermal contraceptive implants (Norplant) is that they are rather more likely to be used in developing countries, in order to overcome social and compliance problems, and that this can in principle involve risks to which underprivileged populations may be especially subject. All the same, acceptance is strikingly good. Of the many studies of Norplant in the third world, a recent one surveyed data from eight developing countries. Information was available on 7977 women starting Norplant, of whom 6625 used intrauterine devices and 1419 had been sterilized; most of the participants were followed for 5 years. All of the methods produced satisfactory degrees of contraception and, with a few exceptions, no characteristic morbidity was detected among Norplant users compared with the other groups. The two principal exceptions concerned gallbladder disease, which was 50% more common in women who used Norplant, and hypertension and borderline hypertension, the incidence of which was markedly raised in current implant users (RR = 1.81; 95% CI = 1.12, 2.92). Other unexpected findings were increased rates of respiratory disease and reduced risks of inflammatory disease of the genital tract in Norplant users compared with sterilized women and those who used an intrauterine device (57M ). A Thai study in 88 asymptomatic young HIV-1-positive women immediately after delivery has similarly confirmed the good acceptability of Norplant in a developing country, despite the high incidence of irregular bleeding and some instances of headache and hair loss (58c ). Reviewing the overall scene in Britain, Hannaford has pointed to the considerable difference in acceptance rates for Norplant in the industrialized world and developing countries and has stressed the fact that the adverse reaction incidence is, according to the best evidence, low (59R ). Intrauterine release systems See under “Progestogens” below.

Sex hormones and related compounds, including hormonal contraceptives

Transdermal contraception The various transdermal forms of hormonal contraception in their current formulations are well tolerated, and there are no specific local effects (60c ). Drug interactions Since oral contraceptive users sometimes need to be treated for vaginal candidiasis, the question arises which of the available treatments can be used without risk of impairing contraception. In a crossover placebo-controlled study fluconazole (300 mg weekly for two cycles) has been studied in 21 healthy women using Ortho-Novum 7/7/7 as a contraceptive (61c ). Fluconazole in this dose, which is twice that ordinarily recommended, produced small but statistically significant increases in the AUC0-24 for both ethinylestradiol (mean 24% increase) and norethindrone (mean 13%). The Cmax of ethinylestradiol was slightly, but just significantly, higher with fluconazole than placebo. The Cmax for norethindrone was not different between the two groups. There were no adverse events related to fluconazole. These changes are such that one should not anticipate any increased risk of contraceptive failure when fluconazole is given simultaneously.

ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SED-14, 1466; SEDA-23, 223; SEDA-24, 475; SEDA-25, 489) The word “antiestrogen” is progressively falling into the background and being supplanted by the term “selective estrogen receptor modulator” (SERM). Since most “antiestrogens” have weak hormonal activity but block the receptors from reacting to more potent substances, a more subtle term was required, especially since they do not act on the same way in every organ system. Tamoxifen, the most widely used “antiestrogen” of the last two decades, has antiestrogenic properties in the breast and estrogenic effects in tissues such as bone and the cardiovascular system. In most cases there is endometrial thickening on ultrasonography, and additional tests, such as hydrosonography or hysteroscopy, are

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required to confirm the presence of an empty atrophic uterus, as seen in most asymptomatic women taking tamoxifen. Newer compounds, such as raloxifene, have a generally similar SERM profile to tamoxifen but are neutral on the uterus. Whether other SERMs in development are better, and which of them is better for the breast, remains to be seen. Some specialized SERMs could reduce the risk of osteoporosis after the menopause without having other troublesome hormonal effects (62R ), but much more work is needed to determine whether they will fulfil this hope.

Letrozole Letrozole, an oral aromatase inhibitor, is now being advanced as an alternative to tamoxifen for first-line treatment in postmenopausal women with advanced breast cancer (63c ). In one randomized study of 970 patients given letrozole 2.5 mg/day or tamoxifen 20 mg/day the therapeutic results were at least equivalent and the time to progression was significantly longer with letrozole than tamoxifen (median 41 vs. 26 weeks). Both drugs were well tolerated, but this aspect has yet to be documented in detail.

Raloxifene Raloxifene is a non-steroidal selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium; it is also claimed by its protagonists to have cardioprotective effects, perhaps through an effect on endothelial cells and a reduction in homocysteine concentrations (64R ). However, earlier reports have pointed to a considerable increase in thromboembolism, as has some recent large-scale work (65C ), and it would be premature to draw final conclusions about the conditions in which it can safely be used. Drug interactions To assess the potential for an interaction between raloxifene and warfarin, 15 healthy postmenopausal women each received single doses of warfarin (20 mg) before

446 and during 2 weeks of dosing with raloxifene 120 mg/day (66c ). Raloxifene reduced the oral clearance of R- and S-warfarin respectively by 7.1% and 14% and the oral volume of distribution by 7.4% and 9.8%. Raloxifene reduced the maximum prothrombin time by 10% and the area under the prothrombin versus time curve from 0–120 hours by an average of 8%. The authors concluded that raloxifene may produce a small increase in systemic warfarin exposure but a reduced pharmacodynamic effect. Since the effects are slight this interaction is unlikely to have clinical consequences.

Tamoxifen One expert in the USA (PA Ganz, cited in 67r ) has publicly defended the safety of tamoxifen on the grounds that some of its supposed adverse effects may in fact have other causes. It is a difficult argument to follow, since she postulates that various of the unwanted effects referred to are in fact menopausal; however, these are largely likely to be inevitable consequences of the very changes that treatment with tamoxifen is intended to induce, i.e. suppression of estrogenic effects. Virtually the opposite belief can be derived from a Canadian study, which showed that 25 women taking tamoxifen were diffident about attributing adverse events to the drug, and therefore tended to under-report adverse effects (68cr ). Menopause-like problems with these drugs are clearly likely to persist unless or until more selective SERMs become available, e.g. substances that act exclusively on the breast tumor. Cardiovascular Both deep vein thrombosis and pulmonary embolism have been described with tamoxifen. There has been a recent report of cerebral sinus thrombosis, progressing to hemorrhagic cerebral infarction in a 52-yearold woman (69A ). Although the authors pointed to the absence of risk factors other than the drug, it must be remembered that cerebral venous thrombosis is a recognized complication of various malignancies. In this case the breast tumor had been treated with various cytostatic drugs and stem cell transplantation, and tamoxifen had been given as an adjuvant, and it was believed that the tumor had been eliminated. Nevertheless, in this complex case one should

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perhaps be hesitant in attributing the complication solely to the drug. In the light of three further cases of thrombosis, it has been suggested that there may be a particular predisposition to this complication in patients with high circulating concentrations of homocysteine, and that these should be checked for in advance of treatment (70A ). Metabolism There has been a series of reports of hypertriglyceridemia and fatty liver disease in tamoxifen users, but only recently has attention been devoted to effects on fat deposits. Steatosis and adipose tissue distribution has been evaluated using CT scanning in a crosssectional study of 32 women taking tamoxifen for breast cancer and a similar control group (71cr ). Tamoxifen users generally had more visceral adipose tissue and more liver fat than controls, and had a higher risk of diabetes. It is still unclear whether tamoxifen causes longterm metabolic abnormalities in obese patients, or whether patients with the “metabolic syndrome X of obesity” are at increased risk of the complications of tamoxifen. In view of this finding, and earlier results pointing in the same direction, it would be wise in future studies of tamoxifen to monitor metabolic changes in obese women with or without breast cancer. Hair Effects of hormonal or antihormonal products on the hair are reported sporadically. A woman taking tamoxifen for metastatic cancer (presumably from the breast) developed alopecia; she began to lose her hair within 3 months and was entirely bald after 13 months of treatment (72A ). The authors did not make it clear whether cytostatic drugs (which can cause alopecia) were also used, but it is striking that there have been several earlier reports of baldness with tamoxifen. Reproductive system Ovarian cysts can occur when tamoxifen is used in women with breast cancer. In a recent case, a complex cyst, thought to be due to ovarian hyperstimulation, resolved after monthly administration of a depot GnRH-agonist (GnRH-a) without abandoning tamoxifen (73A ). One might expect some patients to react to tamoxifen with ovarian hyperstimulation, since another non-steroidal “antiestrogen” (i.e. clomiphene) is used for ovarian stimulation and also on occasion produces cysts.

Sex hormones and related compounds, including hormonal contraceptives

Endometrial polyps are common during postmenopausal treatment with tamoxifen, and up to 3% can show malignant changes. There has been an attempt to identify risk factors for the development of these polyps, by analysing the histories of 54 women in whom they occurred, as well as the histories of a larger control group without polyps (74c ). The women who developed polyps had a later menopause, had breast cancer for a longer period, and weighed more. Carcinogenicity (see also “Toremifene” below) The risk that tamoxifen may cause endometrial cancer has been the subject of lively correspondence in the Lancet (75r ), fired by the paper published in 2000 by Bergman and her colleagues, who had concluded that the endometrial cancers seen with tamoxifen are unusually aggressive (76C ). Concern was expressed that such a conclusion could lead to even wider hesitation to use tamoxifen in breast cancer, despite the fact that it is already used very selectively, e.g. in women with positive estrogen receptors. A contradiction between Bergman’s results and those of the National Surgical Adjuvant Breast and Bowel Project P-1 were also highlighted, and doubts expressed whether Bergman’s findings justify restricting the use of tamoxifen as a preventive agent. However, a Canadian group adduced its own work to support Bergman’s findings, while French workers suggested that her unfavorable results, which were not seen in their own patients, could have been due to selection bias. It was also argued that a progestogen-releasing intrauterine contraceptive device might be used to counter the undesirable effects of tamoxifen on the endometrium. Clearly the issue raised by Bergman is still subject to debate, but it is obvious that physicians who use tamoxifen in advanced breast cancer or as a preventive agent should continue to do so selectively and that ways of protecting the endometrium during tamoxifen therapy need to be found.

Toremifene The unwanted gynecological effects of toremifene (40 mg dd), when used in breast cancer, have been compared with those of tamoxifen (20 mg/day) in 167 women (77Cr ). There were vasomotor symptoms in 35% of the women before the start of the trial, but the incidence rose

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to some 60% with both products during the first year. Vaginal dryness, present in 6% at baseline, increased with both drugs to around 26% and endometrial thickness increased from a mean of 3.9 mm to 6.8 mm. The endometrium became proliferative more often with tamoxifen (48%) than with toremifene (32%). The only really striking difference between the two regimens was in the pulsatility of the uterine artery, which was unchanged with tamoxifen but reduced by 15% with toremifene. There were no premalignant endometrial changes. The authors suggested there is no justification for close endometrial surveillance during the first 3 years of antiestrogen treatment.

PROGESTOGENS (see also “Implantable contraceptives” above) (SED-14, 1468; SEDA-23, 442) Skin Rosacea, accompanied the use of Mirena in a 36-year-old woman for 2 years and disappeared within 6 months of removal (78A ). Although, as the authors noted, skin complications (acne, alopecia, and pruritus) have been associated with Mirena, one is bound to wonder whether this was a direct reaction to levonorgestrel or a stress reaction to the absence of menstrual periods. Like many other Mirena users, this woman had amenorrhea associated with facial flushing and pustules; conditions such as urticaria, eczema, pompholyx, and erythema multiforme occur cyclically in some women in the second half of the menstrual cycle, irrespective of contraceptive use. Drug formulations Intrauterine release systems The fiber-based (“frameless”) FibroPlant delivery system for levonorgestrel has been tested in an open study in 32 women as a means of relieving menorrhagia or for contraceptive purposes (79c ). The period of exposure was 1–23 months. This system, which releases levonorgestrel 14 µg/day, appeared to be effective for both purposes, and there were no cases of infection, expulsion or perforation. An alternative intrauterine delivery system (LNG-IUS) consists of an adapted Nova-T device with a silastic reservoir attached to the vertical arm; the reservoir is impregnated with levonorgestrel and is covered with a rate-limiting

448 silastic membrane. The release rate of levonorgestrel is about 20 µg/day for at least 5 years. In a 5-year study in which 1821 women used the combined device and 937 others used the plain Nova-T device, the Pearl index (the number of unwanted pregnancies occurring in 100 couples using a given method for a period of one year) was 0.09/100 woman-years for the LNG-IUS and the ectopic pregnancy rate was 0.02/100 woman-years (80C ). There were fewer withdrawals because of bleeding problems and pelvic inflammatory disease with LNG-IUS compared with Nova-T, but there were more withdrawals because of hormonal adverse effects and absence of bleeding. One of the advantages claimed for LNG-IUS is that there will be less menstrual blood loss. However, all women who used LNG-IUS had some change in their bleeding pattern after the device had been inserted, and some had many days of spotting. Of another 30 women who used the LNG-IUS system to relieve menorrhagia and who were followed for a year, 13 reported one or more pelvic adverse event; there were six complaints of irregular bleeding, four of abdominal pain, three of breast tenderness, and occasional cases of headache, mood changes, or acne (81C ). A systematic review of Mirena, an intrauterine progestogen release system (82M ) has attracted correspondence (83r , 84r ). Like other devices, Mirena releases levonorgestrel, in this case 20 µg/day. Since it had no greater efficacy than the Copper T device and was very much more costly, the debate has turned on safety. Amenorrhea is common with this device, as with others like it, and correspondents have pointed out that this is regarded by many women as an unwelcome complication. Intravaginal administration To provide luteal support in ovarian stimulation protocols, especially when following the long procedure, progesterone can be administered by various routes. The oral route is relatively ineffective, since progesterone has a low oral systemic availability (below 10%), which may result in adverse effects such as somnolence. Intramuscular administration is painful and inconvenient. Some workers have therefore given progesterone in the form of an 8% vaginal gel, which is effective and better tolerated than alternative approaches. The gel adheres to the

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vaginal epithelium, and leakage is substantially less than when using capsules or suppositories; there are no local complications (85cr ).

Medroxyprogesterone There has been something of a revival of oral medroxyprogesterone, which is being used to stimulate the appetite in patients receiving palliative care for cancer, although little published work can be found to support this indication. To date medroxyprogesterone does not seem to have been associated with thrombosis, but an authoritative review has pointed out that this remains a possible risk (86R ).

PROGESTERONE ANTAGONISTS (SED-14, 1471; SEDA-21, 422; SEDA-25, 492)

Mifepristone (RU 486) The optimal dose of mifepristone to secure an abortion without excessive adverse effects is not known. In a study in nearly 900 women there was no appreciable difference between oral doses of 200 or 600 mg, followed after 48 hours by gemeprost 1 mg vaginally (87C ). The similarity of adverse reactions with the lower and higher doses of mifepristone has been confirmed by others (88Cr ). However, in another study mifepristone 0.5 mg, which has sometimes been recommended on supposed safety grounds, was not sufficient to induce abortion (89C ). The frequencies of various adverse effects of mifepristone in effective doses have emerged from various studies. In one study nausea, vomiting, or diarrhea in women using a standard regimen occurred in 68%, 36%, and 20% respectively (90c ); these risks are not considered to be problematic. The combination of oral mifepristone and vaginal misoprostol is also effective and safe, has few serious adverse effects, and is well accepted by women (91c ). Whatever the adverse effects of mifepristone, the risks have to be looked at realistically and compared with those of the alternatives available to a particular woman in a given

Sex hormones and related compounds, including hormonal contraceptives

situation. Particularly in rural areas in developing countries, the risks of surgical and nonprofessional abortion are high, whereas, as has been shown in a study in rural India, a regimen of mifepristone plus misoprostol can be used as effectively and safely, through family planning clinics and country hospitals, as in a European environment (92C ). Reproductive system Long-term mifepristone is primarily used as a means of treating uterine myomas, endometriosis (25–100 mg/day), and possibly inoperable meningiomas (200 mg/day) or inoperable Cushing’s syndrome (see above). While it is primarily regarded as an antiprogestogen, some of these uses reflect its antiglucocorticoid and antiproliferative effects. However, there are also data to suggest that, acting as an antiprogestogen, mifepristone can promote an unopposed estrogen milieu, and can thus have a proliferative effect on the endometrium, as a recent case shows. • An adolescent girl with Cushingoid features and osteoporosis took mifepristone 400 mg/day for its antiglucocorticoid effect in an attempt to prevent further bone loss (93A ). Her striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6-month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reverted to normal after withdrawal of mifepristone.

The authors suggested that interval pelvic imaging may be advisable in women who take long-term mifepristone. Mineral balance Severe hypokalemia has been attributed to long-term mifepristone (94A ). • An extremely ill 51-year-old man with Cushing’s syndrome, due to an ACTH-secreting pituitary macroadenoma, which had failed to respond to conventional surgical, medical, and radiotherapeutic approaches, responded dramatically in the short- and long-term to high-dose mifepristone (up to 25 mg/kg/day) for 18 months. However, he developed severe hypokalemia, attributed to excessive cortisol activation of mineralocorticoid receptors; it responded to spironolactone.

This case shows the potential need for concomitant mineralocorticoid receptor blockade when mifepristone is used to treat Cushing’s syndrome, since mineralocorticoid concentrations can rise markedly, reflecting corticotrophin disinhibition.

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ANABOLIC STEROIDS, ANDROGENS, AND RELATED COMPOUNDS (SED-14, 1471; SEDA-23, 444; SEDA-24, 476; SEDA-25, 493)

Testosterone Drug formulations Transdermal administration Transdermal testosterone, in the form of a gel, has been promoted as a convenient form of androgen replacement therapy, more acceptable than patches and avoiding the nonphysiological plasma concentrations that can result from depot injections. In a US study, 10 middle-aged or elderly men with recent diagnoses of hypogonadism were treated with increasing dosages of testosterone gel until physiological concentrations of testosterone were reached or until the 6-week study was over (95C ). Satisfactory circulating concentrations of testosterone were achieved, sexual function was generally improved, and there were no adverse effects. However, adverse effects have occasionally been reported, including hypertension. • A 65-year-old white man used topical testosterone to increase his libido and developed hypertension and an increased hematocrit. After withdrawal of the testosterone, the hematocrit and blood pressure normalized (96A ).

Clinicians should be cautious in prescribing topical formulations of testosterone for selfadministration by the patient and should be alert to the possibility of hypertension in this population, in which age increases the risk of cardiovascular complications. In this particular case it transpired that the patient had been advised to apply the gel to the scrotum; administration of any topical product to the scrotum or groin is unwise, in view of the greatly increased absorption at these sites and the possibility of transfer to the partner. Whether the amounts of testosterone reaching the systemic circulation after topical administration are sufficient to have a significant effect on blood lipids seems dubious. One recent study of the effect of transdermal testosterone on lipids was limited to men aged over 65 years with significantly low circulating concentrations of testosterone (97C ). Over 36 months, 108 men used transdermal testosterone

450 or placebo in a double-blind design. Serum total cholesterol concentrations fell in both groups, and the 3-year mean reductions were the same. Similarly, LDL cholesterol concentrations fell and lipoprotein(a) concentrations increased to similar extents in both groups. The number of cardiovascular events was small, and although it was higher in the treated group (9 versus 5) the confidence interval was too wide to justify immediate conclusions; clearly, however, this is a matter that needs further study if such products are to continue to be popular among aging men. Immunologic All steroids, even corticosteroids, can on occasion cause allergic reactions, although when they do it can be difficult to exclude the possibility that an excipient is responsible. However, what appears to be a true case of allergy to transdermal testosterone has been described in a 70-year-old man (98A ); it was readily relieved by a topical corticosteroid.

Androgenic anabolic steroids Nervous system An old indication for anabolic steroids, still followed in a few centers, is the treatment of aplastic anemia. A 40-year-old Korean woman who had taken oxymetholone for aplastic anemia (doses not stated) developed cerebral venous thrombosis accompanied by a tentorial subdural hematoma (99Ar ). Hiccups have been classified as a neurological reaction that can be triggered by many factors. There have been a few published reports of persistent hiccups associated with oral and intravenous corticosteroids and one of progesterone-induced hiccups, which were thought to be secondary to the glucocorticoidlike effects of progesterone on the brainstem. • Anabolic steroid-induced hiccups have now also been reported in a champion power lifter (100Ar ). The hiccups occurred within 12 hours of an increase in the dose of oral methandrostenolone from 50 mg to 75 mg dd, and persisted for 12 consecutive hours until medical attention was sought. The hiccups abated rapidly after the dose of methandrostenolone was reduced, but he was unwilling to abandon it completely.

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Drug abuse Although androgenic anabolic steroids have largely disappeared from routine medical practice their adverse effects continue to merit study, if only because papers still appear promoting their prolonged use in patients who are seriously ill and may therefore be particularly likely to develop adverse effects. Recently proposed indications include Duchenne’s muscular dystrophy and the severe anemia that can occur in patients on dialysis. In addition there is a persistent illegal market in these compounds, to promote physical strength. A difficulty in determining the ultimate consequences of anabolic steroid abuse for body-building or to advance sporting achievement is that individuals prone to such abuse may well have taken several different types of substance at the same time or in succession. Indeed, an analysis of the hair of seven body builders showed what the authors termed a “complete pharmacopeia” of drug residues, ranging from corticosteroids, anabolic steroids, and androgens to beta-adrenoceptor agonists, antidepressants, diuretics, and human chorionic gonadotrophin (101c ). In one case a partial empty sella syndrome occurred in an elite 39-year-old body-builder with a 17-year history of drug abuse involving growth hormone, anabolic steroids, testosterone, and thyroid hormone (102A ). The pituitary is a hormone-responsive gland, but it has not previously been shown to suffer negative feedback in response to any of these substances. Various of them could in principle have contributed to the effect, or it could have been an indirect consequence of drug abuse, by way of an increase in intracranial pressure, which is a known cause of empty sella syndrome. Apart from the physical effects of exogenous anabolics and androgens, they can also have behavioral effects, including promotion of sexual behavior (which may or may not be regarded as an unwanted effect) and perhaps enhanced aggressiveness. However, most of the evidence on the latter is derived from raised concentrations of endogenous testosterone. Men who use androgenic anabolic steroids to enhance their sporting achievements seem to be more likely to have cyclic depression, but young men who have stopped using anabolic steroids can also develop depression and fatigue as withdrawal effects (103R ).

Sex hormones and related compounds, including hormonal contraceptives

ANTIANDROGENS

(SED-14, 1475; SEDA-23, 445; SEDA-24, 479; SEDA-25, 494) In reviews of various means of treating locally advanced prostatic cancer it has been concluded that, compared with castration and other methods, monotherapy with a non-steroidal antiandrogen ensures a comparable survival rate and offers potential advantages with respect to maintenance of sexual interest and physical capacity (104R –106R ). Bicalutamide 150 mg/day maintains bone mineral density and is well tolerated; gynecomastia and breast pain, common adverse effects of antiandrogens, can be managed by prophylactic irradiation or surgery. LHRH agonists are comparable to surgical castration, but are also associated with an initial flare-up of symptoms and signs of the disease that require treatment with antiandrogens. For the treatment of the most advanced cases of prostatic cancer, antiandrogen monotherapy has not been consistently proven to be equivalent to surgical castration or complete androgen blockade, but still has the advantage that sexual function can be preserved. It is common to use a combination of treatments, but there are alternative approaches. Initial treatment with, for example, polyestradiol phosphate every 2 weeks for 8 weeks can be followed by monthly subcutaneous injections. If complete androgen ablation is unavoidable, it can be achieved by either bilateral orchidectomy or triptorelin 3.75 mg/month, which can be combined with the anti-androgen flutamide 250 mg tds. This usually causes severe deprivation symptoms (primarily hot flushes), and a Swedish group has sought to quantify these in 915 men (107C ). At 18.5 months the incidence of hot flushes was 30% in men who received polyestradiol phosphate and 74% in those who had had complete androgen ablation. In those who used polyestradiol phosphate the frequency of hot flushes and the accompanying distress were also significantly less than in the androgen ablation group. The hot flushes later disappeared in 50% of the men taking polyestradiol phosphate, but the problem was unchanged in those who had had androgen ablation. Similarly promising findings have been reported by Japanese workers who combined flutamide with other LH-releasing hormone agonists (leuprorelide or goserelin) (108c ).

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The effects of androgen deprivation on bone mineral density are of particular concern because of their physical consequences. The effects of radical androgen deprivation treatment on bone density in the hip and spine have been evaluated for up to 10 years in 36 patients in a cross-sectional study (109c ). Hip bone density was significantly lower in patients on deprivation therapy; after a number of years bone density averaged only 55% of that in controls and loss was still continuing at 10 years. The loss was more dramatic in patients who had undergone surgical castration than in those who received medical deprivation treatment, and by 6 years it was least pronounced in those patients in whom intermittent drug treatment had been used.

Finasteride Finasteride is likely to be used less intensively in benign prostatic hyperplasia than in malignancies. In one study in 3040 men with benign prostatic hyperplasia the effects of finasteride 5 mg/day for 4 years were compared in men over and under 65 years (110C ). In both groups the drug was effective and there were no significant differences in cardiovascular adverse events between placebo- and finasteridetreated patients. There were significant differences between placebo and finasteride in the incidence of typical drug-related adverse events, but there were no specific differences associated with age. The principal events were impotence (8.8%), reduced libido (6.8%), reduced volume of ejaculate (3.5%), other ejaculation disorders (1.5%), rash (0.6%), breast enlargement (0.5%), and breast tenderness (0.2%). There were no drug interactions of clinical importance with finasteride.

Flutamide Hematologic Since flutamide belongs to a class of nitro compounds, some of which cause methemoglobinemia, this should be looked for during treatment; however, in one specific study in more than 50 elderly patients there were no cases (111c ).

452 Gastrointestinal With flutamide, gastrointestinal toxicity can be problematic, but this led to drug withdrawal in only seven of 100 patients with symptomatic hormone-resistant prostate cancer taking oral flutamide 250 mg tds (112c ).

Nilutamide Data on the use of nilutamide, collected over 5 years in 725 patients attending various centers in The Netherlands, have shown good tolerance in effective doses (113Cr ). However, the data were superficial, from post-marketing surveillance in a wide range of circumstances, and more concrete analyses would be helpful.

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MISCELLANEOUS COMPOUNDS Tibolone

(SEDA-24, 480; SEDA-25, 495)

Efforts continue to define the usefulness and unwanted effects of tibolone, with its unusual mixed spectrum of estrogenic, progestogenic, and androgenic effects. There is a widespread view that it could be preferable to other compounds in countering osteoporosis in postmenopausal women, particularly regarding adverse effects (114r ). In an Italian study of 200 women taking different forms of HRT, estradiol with medroxyprogesterone acetate was compared with continuous tibolone 2.5 mg/day (115Cr ). Mastodynia sufficient to require withdrawal was less common with tibolone (4% vs. 13%), as was irregular bleeding (19% vs 42%), but there was modest weight gain; 23% of users reported a gain of at least 2 kg because of which half of them suspended treatment. Only half of the original women were still taking treatment in each group 2 years after the start of therapy.

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activated protein C: a randomised cross-over study. Lancet 1998; 354: 2036–40. 54. Suarez AA, Brunt EM, Di Bisceglie AM. A 35year-old woman with progesterone implant contraception and multiple liver masses. Semin Liver Dis 2001; 21: 453–9. 55. Coney PJ, Washenik K, Langley RGB, DiGiovanna JJ, Harrison DD. Weight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials. Contraception 2001; 63: 297–302. 56. Kim C, Seidel KW, Begier EA, Kwok YS. Diabetes and depot medroxyprogesterone contraception in Navajo women. Arch Intern Med 2001; 161: 1766–71. 57. Meirik O, Farley TMM, Sivin I. Safety and efficacy of levonorgestrel implant, intrauterine device, and sterilization. Obstet Gynecol 2001; 97: 539–47. 58. Taneepanichskul S, Tanprasertkul C. Use of Norplant implants in the immediate postpartum period among asymptomatic HIV-1-positive mothers. Contraception 2001; 64: 39–41. 59. Hannaford P. Postmarketing surveillance study of Norplant in developing countries. Lancet 2001; 357: 1815–16. 60. Abrams LS, Skee DM, Wong FA, Anderson NJ, Leese PT. Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin Pharmacol 2001; 41: 1232–7. 61. Hilbert J, Messig M, Kuye O, Friedman H. Evaluation of interaction between fluconazole and an oral contraceptive in healthy women. Obstet Gynecol 2001; 98: 218–23. 62. Albertazzi P, Purdie DW. Oestrogen and selective oestrogen receptor modulators (SERMs): current roles in the prevention and treatment of osteoporosis. Baillière’s Best Pract Res Clin Rheumatol 2001; 15: 451–68. 63. Mouridsen H, Gershanovich M, Sun Y, PerezCarrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, ChaudriRoss HA, Dugan M. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the international letrozole breast cancer group. J Clin Oncol 2001; 19: 2596–606. 64. Saitta A, Morabito N, Frisina N, Cucinotte D, Corrado F, D’Anna R, Altavilla D, Squadrito G, Minutoli L, Arcoraci V, Cancellieri F, Squadrito F. Cardiovascular effects of raloxifene hydrochloride. Cardiovasc Drug Rev 2001; 19: 57–74. 65. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, Farrerons J, Karasik A, Mellstrom D, Kong Wah Ng, Stepan JJ, Powles TJ, Morrow M, Costa A, Silfen SL, Walls EL, Schmitt H, Muchmore DB, Jordan VC. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treat 2001; 65: 125–34. 66. Miller JW, Skerjanec A, Knadler MP, Ghosh A, Allerheiligen SRB. Divergent effects of raloxifene

Sex hormones and related compounds, including hormonal contraceptives HCl on the pharmacokinetics and pharmacodynamics of warfarin. Pharm Res 2001; 18: 1024–8. 67. Jones J. Tamoxifen side effects may be attributable to other causes. J Nat Cancer Inst 2001; 93: 11–12. 68. Arnold BJ, Cumming CE, Lees AW, Handman MD, Cumming DC, Urion C. Tamoxifen in breast cancer: symptom reporting. Breast 2001; 7: 97– 100. 69. Finelli PF, Schauer PK. Cerebral sinus thrombosis with tamoxifen. Neurology 2001; 56: 1113– 14. 70. Tisman G. Thromboses after estrogen hormone replacement, progesterone or tamoxifen therapy in patients with elevated blood levels of homocysteine. Am J Hematol 2001; 68: 135. 71. Nguyen MC, Stewart RB, Banerji MA, Gordon DH, Kral JG. Relationships between tamoxifen use, liver fat and body fat distribution in women with breast cancer. Int J Obes 2001: 25: 296–8. 72. Puglisi F, Aprile G, Sobrero A. Tamoxifeninduced total alopecia. Ann Intern Med 2001; 134: 1154–5. 73. Turan C, Unal O, Dansuk R, Guzelmeric K, Cengizoglu B, Esim E. Successful management of an ovarian enlargement resembling ovarian hyperstimulation in a premenopausal breast cancer patient receiving tamoxifen with cotreatment of GnRH-agonist. Eur J Obstet Gynecol Reprod Biol 2001; 97: 105–7. 74. Cohen I, Azaria R, Bernheim J, Shapira J, Beyth Y. Risk factors of endometrial polyps resected from postmenopausal patients with breast carcinoma treated with tamoxifen. Cancer 2001; 92: 1151–5. 75. Tempfer C, Kubista E, Atkins CD, Narod SA, Pal T, Graham T, Mitchell M, Fyles A, Lasset C, Bonadona V, Mignotte H, Bremond A, Van Leeuwen FE, Bergman L, Beelen MLR, Gallee MPW, Hollema H, Dickson MJ, Pandiarajan T, Kairies P, Marsh F, Mayfield M [Seven letters]. Tamoxifen and risk of endometrial cancer. Lancet 2001; 357; 65–8. 76. Bergman L, Beelen MLR, Gallee MPW, Hollema H, Benraadt J, Van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–7. 77. Marttunen MB, Cacciatore B, Hietanen P, Pyrhonen S, Tiitinen A, Wahlstrom T, Ylikorkala O. Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women. Br J Cancer 2001; 84: 897–902. 78. Choudry K, Humphreys F, Menage J. Rosacea in association with the progesterone-releasing intrauterine contraceptive device. Clin Exp Dermatol 2001; 26: 102. 79. Wildemeersch D, Schacht E. Treatment of menorrhagia with a novel ‘frameless’ intrauterine levonorgestrel-releasing drug delivery system: a pilot study. Eur J Contracept Reprod Health Care 2001; 6: 93–101. 80. Andersson K, Guillebaud J. The levonorgestrel intrauterine system: more than a contraceptive. Eur

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J Contracept Reprod Health Care 2001; 6 Suppl 1: 15–22. 81. Istre O, Trolle B. Treatment of menorrhagia with the levonorgestrel intrauterine system versus endometrial resection. Fertil Steril 2001; 76: 304–9. 82. French RS, Cowan FM, Maansour D. Levonorgestrel-releasing (20 µg/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives. Br J Obstet Gynaecol 2000; 107: 1218–25. 83. Cohen I, Gerber B, Reimer T, Krause A, Friese K, Muller H. Levonorgestrel-releasing intrauterine devices. Lancet 2001; 357: 801. 84. Onyeka BA, French R, Mansour D, Robinson A, Guillebaud J. Levonorgestrel-releasing (20 µg/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives. Br J Obstet Gynaecol 2001; 108: 770–1. 85. Ludwig M, Diedrich K. Evaluation of an optimal luteal phase support protocol in IVF. Acta Obstet Gynecol Scand 2001; 80: 452–66. 86. Anonymous. Medroxyprogesterone and palliative care. No impact on quality of life. Prescrire Int 2001; 10: 3–4. 87. Dhall GI, Calder A, Gomez-Alzugaray M, Ho PC, Pretnar Darovec A, Chen J-K, Bygdeman M, Kovacs L, Albert S-G, Kavkasidze G, Song L-J, Van Look PFA, Von Hertzen H, Noonan E, Ali M, Peregoudov A, Laperriere N, Grimes D. Medical abortion at 57 to 63 days’ gestation with a lower dose of mifepristone and gemeprost. A randomized controlled trial. Acta Obstet Gynecol Scand 2001; 80: 447–51. 88. Creinin MD, Pymar HC, Schwartz JL. Mifepristone 100 mg in abortion regimens. Obstet Gynecol 2001; 98: 434–9. 89. Templeton A, Dhall GI, Calder A, GomezAlzugaray M, Ho PC, Pretnar-Darovec A, Sikazwe C, Jun-Kang C, Prasad RNV, Bygdeman M, Kovacs L, Kavkasidze G, Li-Juan S, Noonan E, Ali M, Peregoudov A, Laperriere N, Von Hertzen H, Grimes D, Ali MBR. Lowering the doses of mifepristone and gemeprost for early abortion: a randomised controlled trial. J Obstet Gynaecol 2001; 108: 738–42. 90. Creinin MD, Schwartz JL, Pymar HC, Fink W. Efficacy of mifepristone followed on the same day by misoprostol for early termination of pregnancy: report of a randomised trial. Br J Obstet Gynaecol 2001; 108: 469–73. 91. Knudsen UB. First trimester abortion with mifepristone and vaginal misoprostol. Contraception 2001; 63: 247–50. 92. Coyaji K, Elul B, Krishna U, Otiv S, Ambardekar S, Bopardikar A, Raote V, Ellertson C, Winikoff B. Mifepristone abortion outside the urban research hospital setting in India. Lancet 2001; 357: 120–2. 93. Newfield RS, Spitz IM, Isacson C, New MI. Long-term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia. Clin Endocrinol 2001; 54: 399–404. 94. Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, Feldman DJ. Successful longterm treatment of refractory Cushing’s disease with

456 high-dose mifepristone (RU 486). J Clin Endocrinol Metab 2001; 86: 3568–73. 95. Cutter CB. Compounded percutaneous testosterone gel: use and effects in hypogonadal men. J Am Board Fam Pract 2001: 14: 22–32. 96. Tangredi JF, Buxton ILO. Hypertension as a complication of topical testosterone therapy. Ann Pharmacother 2001; 35: 1205–7. 97. Snyder PJ, Peachey H, Berlin JA, Rader D, Usher D, Loh L, Hannoush P, Dlewati A, Holmes JH, Santanna J, Strom BL. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med 2001; 111: 255–60. 98. Shouls J, Shum KW, Gadour M, Gawkrodger DJ. Contact allergy to testosterone in an androgen patch: control of symptoms by preapplication of topical corticosteroid. Contact Dermatitis 2001; 45: 124–5. 99. Chu K, Kang D-W, Kim D-E, Roh J-K. Cerebral venous thrombosis associated with tentorial subdural hematoma during oxymetholone therapy. J Neurol Sci 2001; 185: 27–30. 100. Dickerman RD, Jaikumar S. The hiccup reflex arc and persistent hiccups with high-dose anabolic steroids: Is the brainstem the steroid-responsive locus? Clin Neuropharmacol 2001; 24: 62–4. 101. Dumestre-Toulet V, Kintz P, Cirimele V, Gromb S, Ludes BJ. Analyse des cheveux de 7 culturistes: toute une pharmacopée. J Med Leg Droit Med 2001; 44: 38–44. 102. Dickerman RD, Jaikumar S. Secondary partial empty sella syndrome in an elite bodybuilder. Neurol Res 2001; 23: 336–8. 103. Christiansen KJ. Behavioural effects of androgen in men and women. Endocrinol 2001; 170: 39–48. 104. Abrahamsson P-A. Treatment of locally advanced prostate cancer—a new role for antiandrogen monotherapy? Eur Urol 2001; 39 Suppl 1: 22–8. 105. Iversen P, Melezinek I, Schmidt A. Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function. Br J Urol Int 2001; 87: 47–56. 106. Iversen P, Abrahamsson P-A, Mulders PFA. Advanced prostate cancer. Eur Urol 2001; 39: 1– 10.

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107. Spetz A-C, Hammar M, Lindberg B, Spangberg A, Varenhorst E, Krarup T, Hvidt V, Mogensen P, Luke M, Sorensen O, et al. Prospective evaluation of hot flashes during treatment with parenteral estrogen or complete androgen ablation for metastatic carcinoma of the prostate. J Urol 2001; 166: 517–20. 108. Noguchi K, Uemura H, Harada M, Miura T, Moriyama M, Fukuoka H, Kitami K, Hosaka M. Inhibition of PSA flare in prostate cancer patients by administration of flutamide for 2 weeks before initiation of treatment with slow-releasing LH-RH agonist. Int J Clin Oncol 2001; 6: 29–33. 109. Kiratli BJ, Srinivas S, Perkash I, Terris MK. Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology 2001; 57: 127–32. 110. Kaplan SA, Holtgrewe HL, Bruskewitz R, Saltzman B, Mobley D, Narayan P, Lund RH, Weiner S, Wells G, Cook TJ, Meehan A, Waldstreicher J. Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia. Urology 2001; 57: 1073–7. 111. Schulz M, Schmoldt A, Donn F, Becker H. Lack of methemoglobinemia with flutamide. Ann Pharmacother 2001; 35: 21–5. 112. Fossa SD, Brausi SM, Horenblas S, Hall RR, Hetherington JW, Aaronson N, De Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European Organization for Research and Treatment of Cancer Genitourinary Group. J Clin Oncol 2001; 19: 62–71. 113. Schasfoort EMC, Van de Beek C, Newling DWW. Safety and efficacy of a non-steroidal antiandrogen, based on results of a post marketing surveillance of nilutamide. Prostate Cancer Prostatic Dis 2001; 4: 112–17. 114. Willis M, Ödegaard K, Persson U, Hedbrant J, Mellstrom D, Hammar M. A cost-effectiveness model of tibolone as treatment for the prevention of osteoporotic fractures in postmenopausal women in Sweden. Clin Drug Invest 2001; 21: 115–27. 115. Cavalieri AP, Pace M, Capri O, Galoppi P, D’Amelio R, Perrone G, Zichella LG. Terapia ormonale sostitutiva con regime continuativo: effetti collaterali e compliance. G Ital Ostet Ginecol 2001; 23: 29–32.

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Thyroid hormones and antithyroid drugs

THYROID HORMONES

(SED-14, 1485; SEDA-23, 451; SEDA-24, 484; SEDA-25, 503) Cardiovascular It is well recognized that worsening of angina, precipitation of acute myocardial infarction, and even death in subjects with underlying coronary artery disease can occur, albeit uncommonly, when thyroxine replacement is begun. This recognition has led to the recommendation, especially in those known to have heart disease and with severe and longstanding hypothyroidism, that thyroxine should be introduced gradually (1R ). In two cases of hypothyroidism myocardial infarction occurred at the start of thyroxine therapy in the absence of evidence of significant coronary artery disease (2A ).

Drug abuse Abuse of thyroid hormones can have adverse effects. • Partial empty sella syndrome (pituitary atrophy) has been described in an elite body builder who had abused various hormones, including testosterone, growth hormone, and tri-iodothyronine (T3 25 µg qds) for many years (3A ). He presented with infertility, and investigations showed suppression of serum TSH, a raised serum T3 , and a partially empty pituitary sella.

It is likely that in this case long-standing suppression of pituitary function secondary to negative feedback from exogenous hormone ingestion (including T3 ) resulted in pituitary atrophy.

• A 58-year-old man with a previous smoking history and a history of hypertension was severely biochemically hypothyroid (serum TSH 221 mU/l) and was given thyroxine, initially in a low dose (25 µg/day), increasing to 100 µg/day after 2 weeks. A month later he sustained a subendocardial myocardial infarction associated with only minor abnormalities on coronary angiography. • A 61-year-old woman with severe hypothyroidism (serum TSH 115 mU/l) had an acute myocardial infarction (but no demonstrable abnormality on coronary angiography) 1 month after a thyroxine dosage increase from 50 to 100 µg/day.

Drug interactions Thyroxine is one of the most frequently prescribed medications. It is more than 80% absorbed in the small intestine, peak serum concentrations being reached after 6–12 hours. Non-compliance is by far the commonest cause of persistent hypothyroidism, despite apparently adequate prescription of thyroxine, but it is recognized that severe gastrointestinal disease can rarely affect absorption and hence result in a reduced effect of thyroxine. Case reports have shown that certain drugs can also affect thyroxine absorption, including cholestyramine, aluminum hydroxide, and ferrous sulfate.

These cases serve to remind us that the increase in cardiac output associated with starting thyroxine treatment for severe hypothyroidism can precipitate cardiac ischemia, even without a preceding history of coronary artery disease or even angiographically proven disease. Cautious introduction of thyroxine, especially in elderly people and those with severe or long-standing hypothyroidism, is prudent.

• A 61-year-old woman who, as well as being hypothyroid, had celiac disease and a history of bowel resection for pancreatic cancer, was euthyroid taking thyroxine 175–188 µg/day (4A ). However, when she simultaneously took calcium carbonate (1250 mg/day) she had a raised serum thyrotropin (TSH) concentration of 41 mU/l. Delaying calcium carbonate ingestion by 4 hours returned her serum TSH concentration to high normal (5.7 mU/l) within a month.

© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

This case adds support to the view that calcium carbonate can affect thyroxine replacement, probably by reducing its absorption; this

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458 effect may be greater in patients with other gastrointestinal conditions. It is prudent to suggest that patients should separate their medications.

ANTITHYROID DRUGS

(SED-14, 1489; SEDA-23, 451; SEDA-24, 484; SEDA-25, 503) Hematologic The most feared complication of thionamide drugs is bone-marrow suppression. The reported incidence of agranulocytosis is 0.1–0.3%. Pancytopenia occurs less commonly. • A 16-year-old girl who had taken methimazole for 1 month (30 mg/day) developed a sore throat and dysphagia and had pancytopenia (5A ). Instead of the expected picture of hypoplasia, bone-marrow aspiration showed replacement with plasma cells, a finding suggestive of myeloma and representing a picture not previously described in this context. Methimazole was withdrawn and she was given antibiotics, dexamethasone, and granulocyte-colony stimulating factor (G-CSF). Her hematology and bone-marrow findings normalized within days and she was well at follow-up at 24 months.

Anecdotal use of G-CSF in cases of thionamide-induced agranulocytosis has again been reported (6A ). A retrospective review (7c ) has compared outcomes in 10 severe cases treated with G-CSF and in 10 treated without. The time to hematological recovery, the duration of antibiotic use, and the duration of hospitalization were all shorter in those treated with G-CSF, although there were no deaths in either group. These findings are in accord with the results of other non-randomized studies of the use of G-CSF in drug-induced agranulocytosis, but conflict with the results of one randomized study that showed no benefit (8C ). The latest findings must therefore be interpreted with caution, although it is notable that this study was confined to those with severe suppression of leukocyte counts and clinical evidence of infection. Further study of the role of G-CSF in this life-threatening condition is required. Liver Propylthiouracil can cause liver damage, sometimes as part of a hypersensitivity reaction associated with pruritus, rash, fever,

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and arthralgia. Fatal hepatitis and hepatic necrosis have been described, but severe liver injury is believed to be rare, with only 20 reported cases up to 1993 (9AC ). In contrast, subclinical hepatic dysfunction, characterized by a rise in hepatic enzymes, may be common and does not necessitate propylthiouracil withdrawal in the absence of symptoms (9AC ). In a retrospective review of 497 patients treated for hyperthyroidism with propylthiouracil, clinically overt hepatitis developed in six patients at 12–49 days after starting the drug (10C ). Jaundice and itching were present in five, fever in two, rash in two, and arthralgia in one. Serum bilirubin, alanine transaminase, and alkaline phosphatase were increased in five, four, and six patients respectively. The type of hepatic injury was cholestatic in three, hepatocellular in one, and mixed in two. There were no differences in age, sex, drug dose, or serum thyroid hormone concentrations at time of diagnosis in those with hepatic injury compared with those without. Liver function normalized in all patients at 16–145 days after withdrawal of propylthiouracil. In addition to these cases of overt liver injury, 14% of the cohort had mild asymptomatic liver enzyme rises at a mean of 75 days after the start of treatment. The reported incidence of liver injury in this report is higher (at 1.2%) than in previous reports, perhaps reflecting patient selection or ethnic differences in study populations. An association with propylthiouracil in the six cases described is supported by the temporal association with the start of therapy and recovery after withdrawal. This complication is likely to be idiosyncratic, given the lack of dose association, unpredictable occurrence, and an association with symptoms of hypersensitivity. The findings of this retrospective study do not indicate the need for regular monitoring of liver function tests in those taking propylthiouracil, but they do highlight the need to consider drug toxicity if overt hepatic injury develops, especially early in the course of propylthiouracil therapy. Immunologic An important group of adverse effects of the thionamides is vasculitis. Antineutrophil cytoplasmic antibody (ANCA)associated vasculitis is well described, particularly with propylthiouracil and to a lesser extent with carbimazole, and has been most often described in patients with Graves’ disease.

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A further report has been published, describing ANCA-positive microscopic polyangiitis associated with propylthiouracil, with a fatal outcome despite treatment with corticosteroids and cyclophosphamide (11A ). Another patient presented atypically with acute pericarditis 10 months after starting to take propylthiouracil 100 mg tds (12A ). Another patient developed ANCA-negative leukocytoblastic vasculitis of the skin (13A ). Teratogenicity Aplasia cutis congenita has been attributed to the administration of carbimazole, or its active metabolite methimazole, during early pregnancy, and a recent review revealed 16 cases of solitary skin defects associated with intrauterine exposure to methimazole (14AR ). Additional cases of aplasia cutis congenita in thionamide-exposed infants associated with other congenital abnormalities, such as choanal atresia, esophageal atresia, imperforate anus, and cardiovascular defects, were also reviewed. This pattern of abnormalities has previously led to the term “methimazole embryopathy” (15A ). In a prospective study in 241 women referred to a teratology service because of exposure to methimazole during pregnancy, congenital abnormalities were compared with those found in offspring of 1089 controls referred because of exposure to non-teratogenic drugs or radiography (15C ). There were no statistically significant differences between the two groups in terms of major abnormalities, gestational age at delivery, neonatal weight, or head circumference, but among the methimazole-exposed infants two had a major malformation consistent with “methimazole embryopathy”. One had choanal atresia (exposed at 4–7 gestational weeks) and the other had esophageal atresia

(exposed at 0–16 gestational weeks) (16Ac ). These are very rare malformations, and the number of cases in the cohort was insufficient to reach statistical significance, so the possibility of a chance association with methimazole exposure cannot be excluded. These cases do, however, lend support to the view that methimazole may be teratogenic, although thyrotoxicosis itself may be the associated factor. Until further data are available, treatment of thyrotoxicosis with propylthiouracil may be preferable in women who are planning a pregnancy.

IODINE AND THE IODIDES (SED-14, 1492; SEDA-23, 452; SEDA-24, 485; SEDA-25, 505) Drug overdose Acute renal insufficiency necessitating hemodialysis occurred in patient who deliberately took potassium iodide solution 50 ml and a small dose of mefenamic acid (6 capsules) as part of a suicide attempt (17A ). Iodinated radiographic contrast media can also cause acute renal insufficiency, perhaps as a result of reduced renal blood flow, an intrarenal osmotic effect, or direct tubular toxicity. In this case the authors postulated that iodide toxicity had resulted in hemolysis and hemoglobinuria, which, together with acute interstitial nephritis secondary to inhibition of prostaglandin synthesis from mefenamic acid ingestion, had resulted in acute renal insufficiency. The patient recovered normal renal function after 10 days of hemodialysis. The mechanism of hemolysis resulting from toxic doses of iodine is not clear, although it may reflect inhibition of various red cell enzymes.

REFERENCES 1. Toft AD, Boon NA. Thyroid disease and the heart. Heart 2000; 84: 455–60. 2. Kohno A, Hara Y. Severe myocardial ischemia following hormone replacement in two cases of hypothyroidism with normal coronary arteriogram. Endocr J 2001; 48: 565–72. 3. Dickerman RD, Jaikumar S. Secondary partial empty sella syndrome in an elite bodybuilder. Neurol Res 2001; 23: 336–8.

4. Csako G, McGriff NJ, Rotman-Pikielny P, Sarlis NJ, Pucino F. Exaggerated levothyroxine malabsorption due to calcium carbonate supplementation in gastrointestinal disorders. Ann Pharmacother 2001; 35: 1578–83. 5. Breier DV, Rendo P, Gonzalez J, Shilton G, Stivel M, Goldztein S. Massive plasmocytosis due to methimazole-induced bone marrow toxicity. Am J Hematol 2001; 67: 259–61.

460 6. Calabro L, Alonci A, Bellomo G, D’Angelo A, Di Giacomo V, Musolino C. Methimazole-induced agranulocytosis and quick recovery with G-CSF: case report. Hepatology 2001; 5: 479–82. 7. Andres E, Kurtz JE, Perrin AE, Dufour P, Schlienger JL, Maloisel F. Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis. Q J Med 2001; 94: 423–8. 8. Fukata S, Kuma K, Sugawara M. Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroid 1999; 9: 29–31. 9. Liaw YF, Huang MJ, Fan KD, Li KL, Wu SS, Chen TJ. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study. Ann Intern Med 1993; 118: 424–8. 10. Kim HJ, Kim BH, Han YS, Yang I, Kim KJ, Dong SH, Kim HJ, Chang YW, Lee JI, Chang R. The incidence and clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study. Am J Gastroenterol 2001; 96: 165–9. 11. Seligman VA, Bolton PB, Sanchez HC, Fye KH. Propylthiouracil-induced microscopic polyangiitis. J Clin Rheumatol 2001; 7: 170–4.

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12. Colakovski H, Lorber DL. Propylthiouracil-induced perinuclear-staining antineutrophil cytoplasmic autoantibody-positive vasculitis in conjunction with pericarditis. Endocr Pract 2001; 7: 37–9. 13. Meister LH, Guerra IR, Carvalho GD. Images in thyroidology. Vasculitis secondary to treatment with propylthiouracil. Thyroid 2001; 11: 199–200. 14. Martin-Denavit T, Edery P, Plauchu H, AttiaSobol J, Raudrant D, Aurand JM, Thomas L. Ectodermal abnormalities associated with methimazole intrauterine exposure. Am J Med Genet 2000; 94: 338–40. 15. Clementi M, Di Gianantonio E, Pelo E, Mammi I, Basile RT, Tenconi R. Methimazole embryopathy: delineation of the phenotype. Am J Med Genet 1999; 83: 43–6. 16. Di Gianantonio E, Schaefer C, Mastroiacovo PP, Cournot MP, Benedicenti F, Reuvers M, Occupati B, Robert E, Bellemin B, Addis A, Arnon J, Clementi M. Adverse effects of prenatal methimazole exposure. Teratology 2001; 64: 262–6. 17. Sinniah R, Lye WC. Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid. Clin Nephrol 2001; 55: 254–8.

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Insulin, glucagon, and hypoglycemic drugs

Diagnosis of hypoglycemia It is easy to read glucose meters wrongly (SEDA-25, 508). Hypoglycemia was missed when a patient inadvertently switched the glucose meter from mmol/l to mg/dl and read 266 mg/dl as 26.6 mmol/l and 158 mg/dl as 15.8 mmol/l (1A ). Three diabetic patients on chronic ambulatory peritoneal dialysis (CAPD) had symptoms of hypoglycemia when glucose readings on strips were higher than 4 mmol/l (2c ). Venous testing showed glucose concentrations as low as 1.8 mmol/l. Large amounts of glucose are used in CAPD, which not only affects the regulation of diabetes but can also affect the peritoneal wall. Since 1999 icodextrin has been used in dialysis fluids. Icodextrin is glucose free and reduces the need for insulin. However, it is also absorbed systematically and can be metabolized to maltose and maltotriose. Paper systems that use either glucose oxidase or glucose dehydrogenase overestimate glucose readings when icodextrin is used, and patients and their carers are not able to measure low blood glucose concentrations. Another factor is that during end-stage renal insufficiency insulin catabolism is reduced. This contributes to the problems when CAPD is changed to automated (overnight) peritoneal dialysis, in which daytime hypoglycemia can be prevented by reducing the amount of insulin used during the day. In Raynaud’s phenomenon blood glucose concentrations measured by finger prick are often lower than the real values (13r ). The arm reacts more slowly to rapid changes in glucose concentrations. When glucose is monitored in the arm, changes in glucose concentrations are later seen than when monitored by finger prick (4r ). Rubbing the arm reduces the differences (5r ). © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

The development of glucose sensor systems has been reviewed (6R ). A new automated device for sampling in the arm (7C ) and a new microdialysis based glucose sensor system (8A ) have been developed. Management of hypoglycemia The Epipen (a pen filled with a solution of adrenaline) is not a good substitute for the glucagon pen (in which glucagon must be dissolved before it can be used) in the treatment of hypoglycemia (9C ). Infusion of too much glucose over an extended period in the treatment of hypoglycemia is dangerous (10A ). Glucose utilization in the postabsorptive state is 2 mg/kg/min and can increase, if insulin concentrations are high, to 6 mg/kg/min (about 600 g/day in a 70 kg individual). It is better to infuse glucose in concentrations of 10% or 20% rather than 40%.

INSULIN (SED-14, 1501; SEDA-23, 454; SEDA-24, 487; SEDA-25, 507) Metabolism Hypoglycemia Hypoglycemia is the most frequent adverse effect of insulin. The various symptoms of hypoglycemia have been reviewed, including detailed descriptions of autonomic symptoms, neuroglycopenic symptoms, general malaise, unawareness, symptoms in adults, children, pregnancy, elderly people, and type 2 diabetes, and combinations with other medications (11R ). In healthy volunteers hypoglycemia caused significant deterioration in short-term attention, whereas sustained attention and intelligence scores did not deteriorate (12C ). In 304 insulin-treated patients 8.2% of those with type 1 diabetes and 2.2% of those with type 2 diabetes had blood glucose concentrations below 4 mmol/l on arrival in the clinic

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462 (13r ). None had complained of symptoms of hypoglycemia or had taken glucose, but when questioned 59% had autonomic symptoms and 12% had neuroglycopenic symptoms; 29% were asymptomatic. Hypoglycemia was retrospectively monitored in 1055 patients who had had type 2 diabetes for more than 2 months, and who visited the clinic at least twice in 6 months (14C ). They all received aggressive treatment to reach near-normal blood glucose concentrations. Hypoglycemic symptoms were mentioned by 12% of those treated with diet alone, 16% of those using oral agents, and 30% of those using any form of insulin. In only five patients, all using insulin, was there severe hypoglycemia. A low HbA1c concentration at follow-up, hypoglycemic symptoms at the initial visit, and younger age were independently associated with an increased incidence of symptoms. A Medline search between 1966 and 1999 identified 46 papers containing 69 cases of factitious hypoglycemia; 46 were women, 52 were not diabetic, 29 had no close links with diabetes in their environment (15cr ). In 47 the hypoglycemia was induced by insulin. Two patients died and one had severe impairment of intellectual function and short-term memory. In 32 cases unnecessary surgical procedures were performed. Body weight The Diabetes Control and Complications Trial Research Group has reported that patients in the intensive treatment group had substantial excess weight gain (16c ). In the first 9 months a group of patients who received intensive treatment gained 3.3 kg, compared with 1.2 kg in the control group; the percentage of people who gained more than 5 kg/m2 was consistently higher with intensive therapy. This weight gain was related to both lean body mass and fat. Fluid balance Two cases of insulin edema in newly discovered diabetic children have been described (17A ). • A 13-year-old girl with diabetes was given insulin 2 U/kg/day. She developed generalized edema and gained 20 kg over 2 weeks. With less insulin, furosemide, and later ephedrine the edema disappeared within 1 month. • A 14-year-old girl with diabetes was given insulin up to 1.5 U/kg/day and gradually developed edema and gained 8.5 kg over 9 days. With furosemide the edema gradually disappeared in 1 month.

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Both of these children received rather high doses of insulin and they lacked the extreme acidosis that often occurs in young people when diabetes first appears. Liver Acute liver damage has been attributed to insulin overdose followed by excessive glucose administration (10A ). • In a suicide attempt a 48-year-old woman took clomipramine 225 mg, diazepam 50 mg, oxazepam 150 mg, flurazepam 120 mg, and aspirin 10 g and injected insulin subcutaneously (1000 U shortacting and 1000 U long-acting). Her blood glucose was undetectable. She was intubated and given 40% glucose 20 ml and an infusion of 20% glucose (total 100 g over 2 hours). She continued to receive intravenous glucose 40% with potassium chloride for 36 hours (total 4430 g) in spite of high glucose concentrations. Her AsT and AlT activities rose to 420 and 610 U/l respectively, the total bilirubin to 147 µmol/l (mainly unconjugated), the alkaline phosphatase to 178 U/l, and the serum lactate to 6.8 mmol/l. An ultrasound scan of the liver was normal. When the glucose infusion was stopped, everything normalized rapidly

Acute steatosis of the liver may have explained this presentation. In insulin overdose the combination of greatly increased hepatic production of triglycerides from glucose and reduced production of apolipoprotein B 100 results in an insufficient increase in the transport of triglycerides in VLDL particles from liver to muscle and adipose tissue and contributes to the steatosis. Skin Hypertrophy of the subcutaneous tissues after insulin injections leads to delayed and variable insulin absorption. Of 282 children (160 boys and 122 girls, median age 12 years) prospectively evaluated for 3 months, 29% had mild skin hypertrophy and 18% had massive hypertrophy (18c ). The latter had higher HbA1c concentrations and longer durations of diabetes and required more daily injections. There was no relation to the length of the needles used. Immunologic The treatment of hypersensitivity reactions to insulin is often difficult. Continuous subcutaneous insulin infusion with fastacting insulin is feasible, as has been shown in two cases. • A 43-year-old man with type 1 diabetes developed local pruritus, redness, and swelling 4–5 times a week, 15–20 minutes after an injection, subsiding

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within 1–2 hours (19A ). Later he had a generalized urticarial reaction 5 minutes after an injection. Lispro insulin did not help. When checked for allergens, he was positive for all types of insulin and negative for additives. With oral mizolastine the local reactions abated for a week, but then reappeared with every injection. Generalized urticaria recurred later. With continuous subcutaneous insulin infusion the local reactions immediately disappeared and metabolic control was improved. • A 79-year-old man, who used mixed insulin for 2 months developed swelling at injection sites, lasting 48 hours (20A ). The lesions persisted despite switching to various types of insulin. He was allergic to insulin, as demonstrated by a raised eosinophil count, a markedly increased IgE concentration, and antibodies to human, bovine, and porcine insulins in the RAST test. He was not allergic to needles or additives. With subcutaneous bolus doses of lispro insulin and Humulin® he developed induration and wheal-and-flare reactions. When hydrocortisone 10 mg was added to each injection the allergic reactions disappeared, but they recurred after 2 months. With continuous subcutaneous insulin infusion there were no allergic responses for 3 months. His raised IgE concentrations fell.

Leukocytoclastic vasculitis has been attributed to human insulin. • A 48-year-old woman with type 1 diabetes developed tender induration within 2–6 hours and persisting for 1–3 days after injection of both NPH and regular insulins (21A ). This was succeeded by intense itching and redness, but no wheal-and-flare reaction. Switching to semisynthetic insulin and other insulin analogues or continuous subcutaneous insulin infusion had no effect. After 3 years the condition became incapacitating. Humalog® 5–6 times a day, including an injection at 03.00 hours was the best tolerated regimen. Intradermal tests showed allergy to human, porcine, and bovine insulins, but no reaction to protamine or other additives. Skin biopsies showed a leukocytoclastic vasculitis. Prednisolone 10 mg/day plus azathioprine 50 mg/day, later replaced by methotrexate 7–15 mg/week, produced complete resolution within 8 weeks.

Pregnancy In a longitudinal cohort survey of 278 pregnant women with type 1 diabetes, the frequency of severe hypoglycemia increased two to three times compared with the last 4 months before pregnancy (25%, including 9% with hypoglycemic coma, before pregnancy and 41%, including 19% with coma, during pregnancy) (22C ). A history of severe hypoglycemia before pregnancy, a longer duration of diabetes, a HbA1c concentration of 6.5% or less, and a daily insulin dose of over 0.1 unit/kg were indicators of increased risk.

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Risk factors In 3805 children and adolescents with type 1 diabetes in 21 pediatric centers in 17 countries, feedback was given on the overall mean HbA1c concentration in all the centers (23C ). After 3 years insulin therapy was more intensive, but glycemic control improved in only three centers. The relative risk of severe hypoglycemia was lowest in the center with the best glycemic control.

NEW SYNTHETIC INSULINS (SED-14, 1506; SEDA-23, 446; SEDA-24, 489; SEDA-25, 509)

Aspart insulin The new short-acting insulin aspart has been reviewed (24M ). Its adverse effects do not differ from those of human insulin. Immunologic When short-acting insulins are given to patients who are allergic to regular insulin the allergic reactions can disappear. Although the short-acting insulins often have the same immunogenic epitopes, rapid dissociation of the fast-acting insulins into monomers can reduce their antigenic effects. Lispro insulin is known to be beneficial, and now this has also been reported for aspart insulin (25A ). • A 45-year-old man with type 2 diabetes treated with glibenclamide and metformin received combined chemotherapy for non-Hodgkin lymphoma and was given premixed insulin. He developed local wheal-and-flare reactions immediately after the injections. Skin prick tests were positive for various types of insulin but weakly positive for lispro and negative for insulin aspart. He tolerated aspart insulin without any allergic reactions.

Glargine insulin The new long-acting insulin analogue glargine insulin has been reviewed (26M ). In general one daily injection gives more constant insulin concentrations and fewer nightly attacks of hypoglycemia than NPH insulin. Treatment satisfaction appeared to be constantly better with glargine in 517 patients (27C ). There was a consistent mean reduction in the perceived

464 frequency of attacks of hypoglycemia. Other adverse effects were not mentioned. Glargine and NPH-insulin have been compared in 349 children and adolescents in a multicenter, open, randomized study (28C ). Besides the usual thrice-daily regimen of regular insulin they used either glargine at bedtime or NPH at bedtime or twice daily. HbA1c did not differ. The target for fasting blood glucose was 4.4–8.8 mmol/l, and 5% more patients who used glargine reached the target (44% compared with 39% of the patients who used NPH). Symptomatic hypoglycemia was similar with the two treatments. In contrast to most long-acting formulations, glargine is a clear solution. Confusion with lispro insulin has been reported. • A 25-year-old woman and a 52-year-old woman injected lispro instead of glargine insulin (29A ). The first realized her mistake and managed to prevent severe hypoglycemia by eating continuously, despite a fall in blood glucose to 3.7 mmol/l. The other had a blood glucose of 3.1 mmol/l and recovered after intravenous dextrose.

Lispro insulin Insulin aspart, lispro, and buffered regular insulin in continuous subcutaneous insulin infusion have been compared in an open, randomized, parallel-group study in 146 (30C ). HbA1c , hypoglycemic episodes, and blockages of pumps or infusion sets did not differ. Lispro insulin and repaglinide were given to seven patients with diabetes related to cystic fibrosis (31C ). They had normal fasting blood glucose and insulin concentrations, but postprandial glucose concentrations were substantially raised. Lispro had a larger and more sustained effect in lowering postprandial glucose than repaglinide. However, the doses of lispro (0.1 U/kg) and repaglinide (1 mg) may not have been comparable. The newer insulins are not yet registered for use in children in many countries. A report of the use of postprandial lispro versus preprandial regular insulin in an open, cross-over, randomized study in 24 prepubertal children showed no large differences (32C ). Fasting blood glucose was higher with lispro. The number of hypoglycemic episodes was almost the same with

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both insulins. There was one case of severe hypoglycemia. In an open, crossover, randomized study in 33 patients with type 1 diabetes who used regular or lispro insulin the latter was associated with a lower incidence of severe hypoglycemia, mostly due to reduced nocturnal hypoglycemia; HbA1c was not different (33C ).

Modes of administration of insulin (SED-14, 1507; SEDA-23, 457; SEDA-24, 488; SEDA-25, 508) The American Diabetes Association has published revised guidelines on insulin administration, including storage of insulin, use and reuse of needles, alternatives to syringes, injection techniques, and patient management related to dosing of insulin, self-monitoring, and hypoglycemia (34S ). Developments in the administration of insulin through the skin, the mouth, the nose, and the lung have been reviewed (35R ). Transdermal administration Application to the skin, a highly efficient general barrier, did not result in sufficient and reproducible absorption (35R ). Oral administration Metabolism of insulin and the lack of a specific carrier to transport insulin through the gut made the oral route impossible (35R ). Nasal administration Insulin is rapidly absorbed after nasal administration, but even with absorption enhancers its systemic availability is low and its metabolic effect very short (35R ). Gelified nasal insulin has been compared with twice daily NPH insulin and three times daily subcutaneous regular insulin in 16 patients with type 1 diabetes (36C ). Three patients had to withdraw because of nasal burning and one because of persistent sinusitis. One patient had purulent sinusitis after 6 months. The efficacy of gelified insulin was comparable to that of regular insulin. Lung administration In the lungs insulin has to be absorbed from the alveoli (35R ). Enhancers to give the particles the right size and

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constituency to reach the alveoli improve the systemic availability of insulin (37C ). The relative potency of inhaled insulin is about 10%, which means that a 10-fold increase in dose is necessary. The effects of inhaled insulin are comparable to those of injected regular or fast-acting insulins or even faster. However, it is difficult to get a good action profile. The anatomy of the pharynx affects the transport of the particles. In smokers the permeability of the lung epithelium is much greater and absorption from the alveoli is faster and higher than in non-smokers; during actual smoking uptake is reduced. In the short term the excipients in the sprays have no adverse effects. More participants in a study of inhaled human insulin were satisfied with inhaled insulin than they were with subcutaneous insulin (38C ). Ten severely hyperglycemic patients with type 2 diabetes taking oral agents were treated at random with two injections of NPH daily or with lyophilized nasal insulin before each meal, with an added injection of subcutaneous NPH when necessary (39C ). The periods were separated by 2 months. Nasal insulin accomplished control of diabetes comparable to NPH, except in three patients. Adverse effects included transient pruritus, sneezing and rhinorrhea, and chronic nasal crusts. One patient was withdrawn because of cough and dizziness after each nasal dose. Continuous subcutaneous insulin infusion Continuous subcutaneous insulin infusion has been reviewed (40R , 41R ). Probably more than 100 000 patients in the USA are using it. Some studies have shown no difference in mean glucose concentration or HbA1c compared with intensive treatment, but most have shown a slight difference favoring continuous subcutaneous infusion. With fast-acting analogues the postprandial glucose peaks are lower. In one study, when insulin delivery was intentionally interrupted, the increase in glucose concentrations or the development of ketonuria was later with regular insulin, but in another study there was no difference in the development of hyperglycemia or beta-hydroxybutyric acid between fast-acting analogues and regular insulin. Patients preferred to continue treatment with pumps. When continuous subcutaneous insulin infusion and sulfonylureas were compared in nine normolipidemic patients with type 2 diabetes,

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HbA1c was not different but triglycerides and small LDL particles were reduced by the continuous infusion (42C ). Continuous subcutaneous insulin infusion treatment is feasible in obese patients (BMI over 30 kg/m2 ) with type 2 diabetes and severe insulin resistance, as has been shown in a study in 10 patients over 40 weeks (43c ). HbA1c improved from 12% to 9.6% and weight was reduced by 2.5 kg. There were no adverse effects. The clogging of insulin in pumps was substantially reduced when the Hoechst 21 PH neutral semisynthetic insulin 400 U/ml was changed to Hoechst 21 PH ETP insulin (Genapol stabilized) (SEDA-24, 489). Hoechst 21 PH insulin in intraperitoneal pumps increases the production of antibodies to insulin, in contrast to the same insulin in subcutaneous pumps (44C ). It is not clear whether the intraperitoneal route or modification of insulin during storage in the implanted reservoir causes greater antigenicity. When a newly designed side-port catheter on the Minimed pump was used in 40 patients for 450 days per patient, there was one catheter encapsulation, one clogging, and six cases of catheter/pump related underdelivery (45c ). This was comparable to the position before 1994, when the formula of the Hoechst 21 PH insulin was changed for the first time. Drug tolerance Insulin resistance has been reported with continuous subcutaneous infusion. • Diabetes mellitus in a 36-year-old man with acute pancreatitis could not be controlled with continuous subcutaneous insulin infusion, even with doses up to 1800 units/day, because of insulin resistance (46A ). Intravenous insulin by pump had to be stopped because of a catheter infection. The continuous subcutaneous infusion of freezedried insulin and the addition of aprotinin, a protease inhibitor, soluble dexamethasone or prednisolone, and intravenous immunoglobulin was ineffective. An implantable pump for intraperitoneal delivery established good regulation at a dose of 30 units/day. • A 23-year-old diabetic woman had severe subcutaneous insulin resistance for 11 years (47A ). Continuous subcutaneous insulin infusion with regular or lispro insulin did not prevent periods of fluctuating responses to insulin. The addition of heparin to lispro in the pump improved serum insulin concentrations and metabolic control. The addition of heparin to regular insulin gave no improvement.

Heparin may improve the transport of lispro insulin but not of regular insulin.

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Pregnancy Continuous subcutaneous insulin infusion in pregnancy has been studied retrospectively in a nested case–control study (48C ). Those who used the pump had higher fasting blood glucose concentrations at the start, came sooner to the pregnancy clinic, used more insulin, put on more weight, and were more likely to have the baby admitted to the special baby care unit. Birth weights and neonatal hypoglycemia were similar.

GLUCAGON

(SED-14, 1508)

Glucagon increases blood glucose concentrations by stimulating glucose output from the liver and is used to treat hypoglycemia. Hypoglycemia often occurs in premature children and can usually be treated by intravenous glucose. For intractable hypoglycemia an infusion of glucagon can be used. However, it can cause hyponatremia with convulsions and thrombocytopenia, as has been recently reported (49A ). • A female triplet was born at 35 weeks by cesarean section after a normal pregnancy, during which her mother had had normal glucose tolerance. At 2 hours the baby’s serum glucose was 1.0 mmol/l. Intravenous glucose was not effective. At 36 hours dexamethasone was added but 24 hours later her blood glucose was below 2.0 mmol/l. Dexamethasone was withdrawn and glucagon 1 mg/day was added to the infusion. After 4 hours the blood glucose became stable at 4.0 mmol/l. Her serum sodium fell from 138 to 116 mmol/l at about 120 hours, her potassium rose to 7.6 mmol/l, and her platelet count fell to 13 × 109 /l. The glucagon infusion was stopped and within 24 hours her sodium and platelets normalized.

Glucagon infusion in premature babies should be avoided until more information is available.

INSULIN-LIKE GROWTH FACTOR-I (SEDA-23, 457; SEDA-24, 491) The addition of insulin-like growth factor-I to insulin therapy improves glycemic control and may reduce insulin requirements. In 14 adolescents the addition of insulin-like growth factorI to diabetic treatment for 12 weeks did not

H.M.J. Krans

change leptin concentrations, an indicator of adiposity (50c ).

ORAL HYPOGLYCEMIC DRUGS A retrospective analysis of a pharmacy database of over 60 million Americans has shown that many do not persist in taking particular oral hypoglycemic drugs (51C ). Of 11.6 million patients identified as continuously benefit-eligible for mail and retail prescriptions, 136 466 had received a first prescription for an oral hypoglycemic drug between 1 October 1997 and 31 March 1999. The 12-month persistence rate ranged from 31% for a-glucosidase inhibitors to 60% for metformin. Compliance rates were 70–80%, and 36% of the patients who continued to use oral drugs changed treatment one or more times. The number of changes increased with increased follow-up, and more than half of the patients had at least one change in therapy.

ALPHA-GLUCOSIDASE INHIBITORS (SED-14, 1513; SEDA-23, 460; SEDA-24, 495; SEDA-25, 513) Voglibose and acarbose have been compared in 32 patients insufficiently treated by diet in an open crossover study (52C ). The metabolic results were identical. There were fewer adverse reactions in those who took voglibose. There was increased flatulence with acarbose in 96% and with voglibose in 57%; abdominal distension was reported in 17% and 10% respectively. Metabolism In 36 Japanese patients who were relatively lean but had excess abdominal fat, glibenclamide and voglibose caused loss of weight and abdominal fat (53c ). The loss of abdominal fat was related to glycemic control. The ratio of subcutaneous to abdominal fat shifted towards subcutaneous fat only in those who took voglibose. Both voglibose and glibenclamide improved insulin sensitivity and the acute response to insulin. In an open study in 57 patients acarbose and gliclazide had the same effects on HbA1c , blood glucose, and lipids, but the ratio of HDL to

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LDL cholesterol increased with acarbose (54C ). Acarbose caused flatulence in 30% and diarrhea in 3% and gliclazide caused at least one mild attack of hypoglycemia in 10%. When patients with inadequately controlled type 2 diabetes used glibenclamide plus metformin, miglitol, or placebo for 24 weeks in addition to their earlier therapy, fasting blood glucose concentrations improved with miglitol (55C ). Flatulence and diarrhea were significantly more common with miglitol. No patient stopped taking miglitol because of adverse effects. Gastrointestinal Most cases of ileus with acarbose have been reported in Japan. • A 73-year-old man with diabetic gangrene who had used insulin and acarbose 300 /day for 15 months developed ileus with abdominal pain and vomiting after he took PL® granules (containing salicylamide, paracetamol, anhydrous caffeine, and promethazine methylene disalicylate) for a common cold (56A ). The ileus subsided after acarbose and the other drugs were withdrawn.

Although the ileus in this case was not clearly related to the use of acarbose, the combination of acarbose, which can cause ileus, with the other drugs that the patient was taking, may have caused it. The anticholinergic effect of promethazine methylene disalicylate may have contributed. Liver There have been two cases of hepatitis associated with acarbose. • A 74-year-old woman who had used acarbose for 3 months developed progressive weakness and jaundice (57A ). Her bilirubin was 152 µmol/l (direct bilirubin 96 µmol/l). All of her liver enzymes were substantially raised. All other investigations were normal, except that she was positive for hepatitis C antigen. After withdrawal of acarbose everything became normal within 1 month. • A 73-year-old woman who had taken acarbose 450 mg/day for 3 months became very tired and icteric (58A ). Her total bilirubin was 427 µmol/l (direct bilirubin 335 µmol/l) and her liver enzymes were very high. Liver biopsy showed cholestasis and cytolysis without eosinophils. Acarbose was continued for 3 days and her condition did not change. When the acarbose was withdrawn she improved rapidly.

In the first case it is not clear whether the hepatitis C virus could have contributed to the effect of the acarbose.

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In a double-blind study in 100 patients with compensated non-alcoholic liver cirrhosis and type 2 diabetes, acarbose for 28 weeks did not alter liver function (59C ). The number of hypoglycemic episodes was reduced. Drug interactions Miglitol did not reduce the tmax or Cmax of glibenclamide, but the 9-hour AUC was significantly reduced (60c ). As reported before acarbose reduces the absorption of metformin (SEDA-18, 426; SEDA19, 399; SED-14, 1513), glibenclamide, warfarin, and digoxin (SED-14, 1513). Miglitol may have similar effects (60c ).

BIGUANIDES

(SED-14, 1512; SEDA-23, 459; SEDA-24, 495; SEDA-25, 513)

Metformin In a retrospective study of 1874 patients with type 2 diabetes taking metformin 25% had contraindications, including acute myocardial infarction, cardiac failure, renal impairment, and chronic liver disease (61c ). However, the development of contraindications often did not lead to withdrawal of metformin: in 621 episodes only 10% stopped taking it. Only 25% and 18% stopped taking metformin when they developed renal impairment or myocardial infarction respectively. One patient developed lactic acidosis, but this may have been a consequence of myocardial infarction. Metformin and troglitazone have been compared in 21 patients with type 2 diabetes unresponsive to glibenclamide 10 mg bd (62C ). Metformin stabilized weight and reduced adipocyte size, leptin concentrations, and glucose transport. GLUT1 and GLUT4 in isolated adipocytes were not changed. Insulin-stimulated wholebody glucose disposal rate increased by 20%. Troglitazone caused increases in body weight, adipocyte size, leptin concentrations, and basal and insulin stimulated glucose transport. GLUT4 protein expression was increased twofold and insulin-stimulated whole-body glucose disposal rate increased by 44%. In a placebo-controlled study in 40 patients with impaired glucose tolerance metformin 500 mg bd for 6 months increased

468 insulin-stimulated glucose metabolism by 20% with minimal improvement in glucose tolerance; this effect was maintained after 12 months (63C ). In 82 children (aged 10–16 years) with type 2 diabetes metformin lowered HbA1c and fasting blood glucose compared with placebo (64C ). More patients who took placebo had to drop out because more medication was necessary. Most of the adverse events (abdominal pain, diarrhea, nausea, vomiting) occurred during metformin treatment. Metabolism Whether metformin in therapeutic doses can cause lactic acidosis in the absence of renal insufficiency has been investigated by studying case histories of metforminassociated lactic acidosis in various databases published from May 1995 to January 2000 (65R ). Overdoses and lactic acidosis caused by contrast media were excluded. There were 21 reports of 26 cases, of which five did not comply with the criteria (lactate over 5 mmol/l, pH 7.35 or less). Plasma metformin concentration was only measured in four cases. The authors distinguished between lactic acidosis precipitated by metformin, which was defined as occurring without accumulation of metformin, and lactic acidosis that occurred during primary acute or chronic renal insufficiency, with accumulation of metformin. In the first group, six of the eight patients died. In the second group, notwithstanding a mean lactate concentration of nearly 15 mmol/l, only one of the 12 patients died, having refused dialysis. They concluded that there is no relation between the use of metformin and lactic acidosis, except when metformin accumulates. This has been illustrated by the case of a 76year-old woman taking 850 mg metformin bd who developed lactic acidosis due to metformin accumulation during deteriorating kidney function (66A ). Gastrointestinal A 49-year-old woman developed chronic diarrhea after using metformin 850 mg tds and insulin for 5 years (67A ). After 5 months metformin was withdrawn and the diarrhea resolved within 3 days. On rechallenge the diarrhea returned. A 44-year-old non-diabetic man took metformin 1700 mg/day for some weeks for obesity (68A ). He developed severe gastrointestinal hemorrhage needing blood transfusion.

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A bleeding Meckel’s diverticulum was removed and he had no further hemorrhage. Coagulation studies, to investigate whether reduced platelet aggregation or altered coagulation factors (increased tissue plasminogen activator (tPA) or reduced tPA-Ag, or PAI-1) could have contributed, were not done. Liver A 64-year-old man developed cholestatic jaundice 2 weeks after starting to take metformin 500 mg bd (69A ). It resolved slowly over several months after withdrawal. Death In 2275 diabetic patients aged 45–74 years compared with 9047 non-diabetics with proven coronary artery disease, 32% of those taking metformin and 44% of those taking combined metformin and glibenclamide died during 7.7 years (70C ). After 4 years the risks of death with metformin alone and combined therapy were equal, but after 7 years combined therapy had a worse prognosis. Drug interactions It has previously been concluded that metformin can be effectively combined with miglitol (SEDA-25, 514). It has subsequently been suggested that metformin accumulates in the gastrointestinal wall, that the combination of acarbose with metformin results in a substantial reduction in early serum metformin concentrations, Cmax , and AUC, and that miglitol could have the same effect (60c ). The effects of acarbose on the absorption of metformin have previously been reported (SED-14, 1513; SEDA-18, 426; SEDA-19, 399).

MEGLITINIDES

(SEDA-23, 462; SEDA-24, 494; SEDA-25, 512)

Nateglinide Nateglinide is a phenylalanine-derived insulin secretagogue that increases insulin secretion and lowers fasting blood glucose in eight patients with type 2 diabetes (71C ). There were no attacks of hypoglycemia even with a dosage of 180 mg/day; other adverse effects were not mentioned. When given 5 minutes before a meal nateglinide reduced the postprandial blood glucose excursion by 64%.

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Repaglinide The pharmacokinetics, pharmacodynamics, and clinical efficacy of repaglinide, and its role in the management of type 2 diabetes have recently been reviewed (72M ). The overall incidence of hypoglycemia was similar to that reported with sulfonylureas, but the incidence of serious hypoglycemia was lower. Other adverse effects were respiratory tract infections and headache. Cardiovascular events and cardiovascular mortality were not different from those in users of sulfonylureas. In Europe repaglinide is contraindicated in patients with severe liver dysfunction and it is not recommended in people over 75 years old; in America the advice is to use repaglinide cautiously in patients with impaired liver function and there is no restriction on its use in elderly patients. Repaglinide interacts with the ATP-sensitive potassium channel in beta cells, muscle, and heart. MgADP potentiated the effect in beta cells but not in cardiac cells (73E ), which may explain the reduced cardiovascular adverse effects of repaglinide in vivo. Metabolism Repaglinide has a short duration of action and improves postprandial hyperglycemia, a potential risk factor for cardiovascular changes (74C ). In a double-blind, multiple-dose, parallel-group study repaglinide stimulated mealtime insulin secretion (75C ). Bouts of hypoglycemia were equally frequent with placebo and repaglinide. When repaglinide was added to NPH monotherapy in patients with HbA1c over 7.1% for 3 months, 38% of the patients had a HbA1c below 7.1% (76c ). The incidence of hypoglycemia did not change. Lispro insulin and repaglinide were given to seven patients with diabetes related to cystic fibrosis (31C ). They had normal fasting blood glucose and insulin concentrations, but postprandial glucose concentrations were substantially raised. Lispro had a larger and more sustained effect in lowering postprandial glucose than repaglinide. However, the doses of lispro (0.1 U/kg) and repaglinide (1 mg) may not have been comparable. When glipizide was compared with repaglinide in 75 patients there were no major hypoglycemic events; minor events were the same in both groups, but after the start of therapy the events occurred much later with repaglinide than glipizide (77C ).

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Factitious hypoglycemia has been attributed to repaglinide in an 18-year-old man who had bouts of hypoglycemia for 2 months (78A ). After glucose administration he recovered promptly and was sent home, but the next night his glucose was 1 mmol/l with high concentrations of insulin (395 pmol/l), C-peptide (2966 pmol/l), and proinsulin (81 pmol/l). The plasma concentrations of repaglinide in three specimens were 4.8–21 ng/ml. Metformin was below the detection limit. He finally admitted to taking repaglinide 4 mg regularly. Risk factors In renal impairment the half-life of repaglinide is prolonged. Patients with mild to moderate impairment can be treated with repaglinide. In severe impairment adjustment of the dose may be necessary (79C ). Drug interactions Clarithromycin, an inhibitor of CYP3A4, increases the plasma concentrations and the effect of repaglinide; this can enhance the blood glucose lowering effect and increase the risk of hypoglycemia (80C ).

SULFONYLUREAS

(SED-14, 1508; SEDA-23, 457; SEDA-24, 492; SEDA-25, 511) The addition of hydroxychloroquine to sulfonylureas has been investigated in a placebocontrolled study in 125 adipose patients whose diabetes was not well enough controlled with a sulfonylurea alone (81C ). During the first six months HbA1c was significantly reduced by 1.02%. There were no significant differences in adverse effects, but those who took hydroxychloroquine had a greater incidence of minor corneal changes.

Glibenclamide In 36 Japanese patients who were relatively lean but had excess abdominal fat, glibenclamide and voglibose caused loss of weight and abdominal fat (53c ). The loss of abdominal fat was related to glycemic control. The ratio of subcutaneous to abdominal fat shifted towards subcutaneous fat only in those who took voglibose. Both voglibose and glibenclamide improved insulin sensitivity and the acute response to insulin.

470 Pancreas In a case-control study in 1.4 million people in Sweden, 462 who were hospitalized for pancreatitis without gall-bladder disease were compared with 1781 randomly selected controls; 6% of the cases and 3% of the controls had diabetes (82C ). Diet and insulin therapy were not associated with an increased risk, but the risk of pancreatitis with glibenclamide had a crude odds ratio of 3.2 and was higher in people aged over 70 years and in those taking beta-blockers. Death Of 2275 diabetic patients aged 45–74 years with proven coronary artery disease, followed for 7.7 years, 990 were treated with diet alone, 79 with metformin, 953 with glibenclamide, and 253 with a combination of metformin and glibenclamide (70C ). They were compared with 9047 non-diabetics. Mortality was lowest in the non-diabetics; death rates in the others were: diet alone 26%, metformin 32%, glibenclamide 34%, and combined therapy 44%. Drug interactions Miglitol did not reduce the tmax or Cmax of glibenclamide, but the 9-hour AUC was significantly lower (60c ).

Gliclazide Nervous system Cerebral damage can occur after severe or repeated hypoglycemia. • A 75-year-old man taking gliclazide 80 mg bd and metformin 850 mg tds became hypoglycemic and was treated successfully (83A ). All hypoglycemic drugs were withdrawn, but he received more through his doctor’s prescription computer and again became hypoglycemic on two occasions. On the second he became unconscious for 4.5 hours and his plasma glucose was 1.2 mmol/l. After resuscitation his abbreviated mental test was 5/10 and did not improve. He later became very aggressive and died of bronchopneumonia.

Metabolism In an open comparative study in 57 patients acarbose and gliclazide had the same effects on HbA1c , blood glucose, and lipids, although the ratio of HDL : LDL cholesterol increased during acarbose therapy (54C ). Of those who took gliclazide 10% reported at least one mild hypoglycemic reaction.

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Drug overdose Permanent right-sided hemiplegia, dysphasia, and hepatitis occurred after a suicide attempt with gliclazide (84A ). • A 14-year-old non-diabetic girl took 15 tablets of gliclazide (1200 mg) and had gastric lavage 6 hours later. She developed lethargy, vomiting, and generalized tonic–clonic convulsions. Her blood glucose concentration was 0.8 mmol/l, AsT 147 U/l (2.45 µkat/l), AlT 102 U/l (1.07 µkat/l), bilirubin 78 µmol/l (direct 31 µmol/l), and alkaline phosphatase 63 U/l. Electroencephalography showed voltage suppression in the left hemisphere and generalized slow-wave activity. A CT scan showed cerebral edema. Hypoglycemia was controlled within 24 hours with intravenous glucose. The convulsions could not be controlled with phenytoin; dexamethasone, or mannitol, given for cerebral edema. The convulsions stopped on day 9. After 3.5 months of follow-up she could perceive words but could not speak and was severely hemiplegic.

Glimepiride In an 8-week non-interventional cohort study in 22 045 patients with type 2 diabetes, of whom 4.9% discontinued therapy, adverse advents occurred in 2.3% (85C ). There were attacks of hypoglycemia in 0.3%. Of the 6547 patients taking glimepiride, 2.5% had adverse reactions and 0.4% had hypoglycemic reactions. In an open multicenter study 849 patients with poorly controlled diabetes were treated with glimepiride monotherapy for 6 months in doses that were titrated from 1 to 6 mg (86C ). The authors tried to identify factors that could predict the response to glimepiride. Patients who achieved a fasting blood glucose below 7.7 mmol/l and HbA1c below 7.5% or a reduction in fasting blood glucose of over 20% and/or in HbA1c of at least 10% were defined as responders (57% of the 849 patients). Earlier treatment with other oral hypoglycemic drugs or long-standing diabetes increased the rate of non-responders. In 9.2% of the patients there were episodes of hypoglycemia, 1.4 per patient, and third-party or medical assistance was required five times as often. A family history of type 2 diabetes doubled the risk; a high HbA1c reduced the risk.

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Glipizide In a comparison of glipizide and repaglinide there were no major hypoglycemic events; minor events were the same in each group but after the start of the therapy the events occurred much sooner with glipizide than repaglinide (77C ).

THIAZOLIDINEDIONES

(SED-14, 1514; SEDA-23, 461; SEDA-24, 496; SEDA-25, 515) Reviews of one or all of the thiazolidinediones have recently been published (87R , 88M , 89M ).

Pioglitazone The literature on pioglitazone as monotherapy and in combination therapy has been reviewed (89M ). Edema was reported in 1.5–12% and there was often a fall in hemoglobin concentration due to hemodilution. An increase in weight was seen in all studies. There was an increase in creatine phosphokinase activity to over 10 times the upper limit of the reference range in seven of 1510 patients in the USA. Four normalized during treatment, two normalized after withdrawal, and one had fallen but not normalized at follow-up. In 561 patients with HbA1c of at least 8.0% on stable treatment with a sulfonylurea, pioglitazone was added for 16 weeks in a doubleblind study (90C ). The incidence of edema increased from 2% in the placebo group to 7%. There were more episodes of hypoglycemia, a dose-related increase in body weight, and a dose-related fall in hemoglobin with pioglitazone. The frequency of adverse cardiovascular effects was the same. The safety profile of monotherapy and combined therapy with pioglitazone has been evaluated in 3500 patients over 2500 patient-years, and some data from post-marketing surveillance were included (91R ). Peripheral edema and hemodilution were common. When patients taking troglitazone were switched to equivalent amounts of rosiglitazone

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(60 patients) or pioglitazone (60 patients) there were no changes in HbA1c or other parameters, except that with pioglitazone there was a significant improvement in lipid profile, with an average fall in total cholesterol of 0.5 mmol/l (92C ). Liver Hepatocellular injury has been attributed to pioglitazone. • A 67-year-old man took pioglitazone 30 mg/day after having taken glibenclamide 2.5 mg/day for 10 years and voglibose 0.6 mg/day for 5 years (93A ). His liver function was normal before and during 6 months of pioglitazone therapy, but at 7 months he had abnormal liver function tests (total bilirubin 10 µmol/l, AsT 1.95 µkat/l, AlT 5.65 µkat/l, alkaline phosphatase 17 µkat/l, gglutamyltransferase 8 µkat/l). He was asymptomatic, with negative viral serology and normal liver ultrasonography. After withdrawal of pioglitazone his liver function normalized within a month.

Immunologic Angio-edema has been reported in an obese woman after she had taken pioglitazone 30 mg/day for 7 days (94A ). She developed a sore throat followed by dyspnea and swelling of the lips and tongue. There was no rash. After intravenous steroids her symptoms rapidly abated.

Rosiglitazone Clinical and pharmaceutical aspects of rosiglitazone have recently been reviewed (88M ). Frequently reported adverse effects in many studies include weight gain, upper respiratory tract infection, injury, and headache for which no cause can be found. Fluid retention can lead to or exacerbate heart failure and pulmonary and general edema (see under Fluid balance). Hematocrit and hemoglobin are reduced. Changes in liver enzymes and bilirubin have not been reported, and although there have been some reports of hepatic-related adverse effect they have not been definitive (see also SEDA-25, 515). There are no drug interactions with other hypoglycemic agents. Rosiglitazone monotherapy has been studied double-blind in 493 patients for 26 weeks (95C ). There was a dose-related fall in hemoglobin. Rosiglitazone caused more mild to moderate edema. One patient had a temporary rise

472 in aminotransferases, which normalized spontaneously. The addition of rosiglitazone to insulin for 26 weeks in a double-blind study in 315 patients with inadequately controlled type 2 diabetes improved glycemic control and was well tolerated (96C ). There was a significant fall in hemoglobin, and some patients in both the rosiglitazone and placebo groups developed edema. Fluid balance Two cases of pulmonary and general edema have been reported (97A ). • A 78-year-old man became short of breath. He had been taking rosiglitazone 8 mg/day for 6 months. He had renal insufficiency, atrial fibrillation, hypertension, and congestive heart failure, with pitting edema and bilateral pleural effusions. He was refractory to intravenous furosemide and metolazone. Withdrawal of rosiglitazone and administration of bumetanide gave a net fluid output of 9.5 l and the edema resolved. • A 67-year-old man, who had taken troglitazone 600 mg/day for 4 months and who had renal insufficiency, stroke, and cardiomyopathy, developed pitting edema, hepatomegaly, ascites, and a pleural effusion. The edema was resistant to treatment until troglitazone was changed to glipizide 10 mg/day, when he had a diuresis of 18 l in 6 days. Later he took rosiglitazone 4 mg bd for 3 weeks and had weight gain of 5 kg and pitting edema. Diuretic therapy failed until rosiglitazone was withdrawn, after which he reached his baseline weight in 4 days.

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Troglitazone Troglitazone has been withdrawn because of hepatotoxicity. However, some data that may be relevant to other thiazolidinediones have recently been reported. In one study body weight, adipocyte size, leptin concentrations, GLUT4 protein expression, basal and insulin-stimulated glucose transport, and insulin-stimulated whole-body glucose disposal rate were increased by troglitazone (62C ). In a 24-week study, in which 40 patients taking troglitazone and glibenclamide were compared with patients taking glibenclamide, serum fasting insulin, serum triglycerides, and insulin resistance were reduced when troglitazone was added. Fat deposition in the liver and the visceral fat area were reduced, but deposition in skeletal muscle was not (98C ).

ALDOSE REDUCTASE INHIBITORS (SED-14, 1514) Fidarestat is an aldose reductase inhibitor of the same class as sorbinil, which was withdrawn because of hypersensitivity reactions in more than 10% of patients. In 279 patients in a multicenter, double-blind, placebo-controlled study for 1 year nerve conduction and subjective symptoms improved [99C ]. There were no skin rashes or changes in liver enzymes or kidney function.

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474 40. Zinman B. Insulin pump therapy and rapid acting insulin: what have we learned? Int J Clin Pract Suppl 2001; 123: 47–50. 41. Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years. Diabetes Care 2002; 25: 593–8. 42. Rivellese AA, Patti L, Romano G, Innelli F, Di Marino L, Annuzzi G, Iavicol M, Coronel GA, Riccardi G. Effect of insulin and sulfonylurea therapy, at the same level of blood glucose control, on low density lipoprotein subfractions in type 2 diabetic patients. J Clin Endocrinol Metab 2000; 85: 4188–92. 43. Wainstein J, Metzger M, Wexler ID, Cohen J, Raz I. The use of continuous insulin delivery systems in severely insulin-resistant patients. Diabetes Care 2001; 24: 1299. 44. Jeandidier N, Boullu S, Busch-Brafin M-S, Chabrier G, Sapin R, Gasser F, Pinget M. Comparison of the antigenicity of Hoechst 21 PH insulin using either implantable intraperitoneal pump or subcutaneous external pump infusion in type 1 diabetic patients. Diabetes Care 2002; 25: 84–8. 45. Gin H, Melki V, Guerci B, Catargi B, for The Evidiac Study Group. Clinical evaluation of a newly designed compliant side port catheter for an insulin implantable pump. Diabetes Care 2001; 24: 175. 46. Riveline J-P, Capeau J, Robert J-J, Varroud-Vial M. Extreme insulin resistance successfully treated by an implantable pump. Diabetes Care 2001; 24: 2155. 47. Tokuyama Y, Nozaki O, Kanatsuka A. A patient with subcutaneous insulin resistance treated by insulin lispro plus heparin. Diabetic Res Clin Pract 2001; 54: 209–12. 48. Simmons D, Thompson CF, Conroy C, Scott DJ. Use of insulin pumps in pregnancies complicated by type 2 diabetes and gestational diabetes in a multiethnic community. Diabetes Care 2001; 24: 2078–82. 49. Belik J, Musey J, Trussell RA. Continuous infusion of glucagon induces severe hyponatremia and thrombocytopenia in a premature neonate. Pediatrics 2001; 107: 595–7. 50. Thrailkill KM, Fowkles JL, Hyde JF, Litton JC. The effects of co-therapy with recombinant human insulin-like growth factor I and insulin on serum leptin levels in adolescents with type 1 diabetes mellitus. Pediatr Diabetes 2001; 2: 25–9. 51. Boccuzzi SJ, Wogen J, Fox J, Sung JCY, Shah AB, Kim J. Utilization of oral hypoglycemic agents in a drug-insured US population. Diabetes Care 2001; 24: 1411–15. 52. Vichayanrat A, Ploybutr S, Tunlakit M, Watanakejorn P. Effects and safety of voglibose in comparison with acarbose in type 2 diabetic patients. Diabetic Res Clin Pract 2002; 55: 99–103. 53. Takami K, Takeda N, Nakashima K, Takami R, Hayashi M, Ozeki S, Yamada A, Kokubo Y, Sato M, Kawachi S-I, Sasaki A, Yasuda K. Effect of dietary treatment alone or diet with voglibose or gliburide on abdominal adipose tissue and metabolic abnormalities in patients with newly di-

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agnosed type 2 diabetes. Diabetes Care 2002; 25: 658–62. 54. Salman S, Salman F, Satman I, Yilmaz Y, Özer E, Sengül A, Ozer-Demirel HO, Karsidag K, Dinççag N, Yulmaz MT. Comparison of acarbose and gliclazide as first-line agents in patients with type 2 diabetes. Curr Med Res Opin 2001; 16: 296– 306. 55. Standl E, Schernthaner G, Rybka J, Hanefeld M, Raptis SA, Naditch L. Improved glycaemic control with miglitol in inadequately-controlled type 2 diabetics. Diabetic Res Clin Pract 2001; 52: 205–13. 56. Oba K, Kudo R, Yano M, Watanabe K, Ajiro Y, Okazaki K, Suzuki T, Nakano H, Metori S. Ileus after administration of cold remedy in an elderly diabetic patient with acarbose. J Nippon Med Sch 2001; 68: 61–4. 57. Madonia S, Pietrosi G, Pagliaro L. Acarboseinduced liver injury in an anti-hepatitis C virus positive patient. Dig Liver Dis 2001; 33: 615–16. 58. Fernández AB, Gacia AM, Fabuel AT, Merino AB. Hepatitis aguda inducida por acarbosa. Med Clin 2001; 117: 317–18. 59. Gentile S, Turco S, Guarino G, Oliviero B, Annunziata S, Cozzolino D, Sasso FC, Turco A, Salvatore T, Torella R. Effect of treatment with acarbose and insulin in patients with non-insulindependent diabetes mellitus associated with nonalcoholic liver cirrhosis. Diab Obesity Metabol 2001; 3: 33–40. 60. Scheen AJ, Lefèbvre PJ. Potential pharmacokinetics interference between a-glucosidase inhibitors and other oral antidiabetic agents. Diabetes Care 2002; 25: 247–8. 61. Emslie-Smith AM, Boyle DIR, Evans JMM, Sullivan F, Morris AD. Contraindications to metformin therapy in patients with type 2 diabetes – a population-based study of adherence to prescribing guidelines. Diabetic Med 2001; 18: 483–8. 62. Ciaraldi TP, Kong APS, Chu NV, Kim DD, Baxi S, Loviscach M, Plodkowski R, Reitz R, Caulfield M, Mudaliar S, Henry RR. Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects. Diabetes 2002; 51: 30–6. 63. Lehtovirta M, Forsén B, Gullström M, Häggblom M, Eriksson JG, Taskinen M-R, Groop L. Metabolic effect of metformin in patients with impaired glucose tolerance. Diabetic Med 2001; 18: 578–83. 64. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes. Diabetes Care 2002; 25: 89–94. 65. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of ‘metformin-associated lactic acidosis’. Diab Obesity Metabol 2001; 3: 195–201. 66. Kruse JA. Metformin associated lactic acidosis. J Emerg Med 2001; 20: 267–72. 67. Foss MT, Clement KD. Metformin as a cause of late-onset chronic diarrhea. Pharmacotherapy 2001; 21: 1422–4.

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68. Burull-Madero MA, Del-Villar-Ruiz A, GrauCerrato S, Andreu-Garcia M, Goday-Arno A. Digestive hemorrhage caused by a Meckel’s diverticulum in a metformin-treated patient: is there any connection? Pharm World Sci 2001; 23: 120–1. 69. Desilets DJ, Shorr AF, Moran KA, Holtzmuller KC. Cholestatic jaundice associated with the use of metformin. Am J Gastroenterol 2001; 96: 2257–8. 70. Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, Kohanovski M, Rotzak R, Schneider H, Behar S, Motro M. Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year followup. Clin Cardiol 2001; 24: 151–8. 71. Gribble FM, Manley SE, Levy JC. Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166). Diabetes Care 2001; 24: 1221–5. 72. Culy CR, Jarvis B. Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 2001; 61: 1625–60. 73. Dabrowski M, Wahl P, Holmes WE, Ashcroft FM. Effect of repaglinide on cloned beta cell, cardiac and smooth muscle type of ATP-sensitive potassium channels. Diabetologia 2001; 44: 747– 56. 74. Schmitz O, Lund S, Andersen PH, Jønler M, Pørksen N. Optimizing insulin secretagogue therapy in patients with type 2 diabetes. Diabetes Care 2002; 25: 342–6. 75. Van Gaal LF, Van Acker KL, De Leeuw IH. Repaglinide improves blood glucose control in sulphonylurea-naive type 2 diabetes. Diabetic Res Clin Pract 2001; 53: 141–8. 76. De Luis DA, Aller R, Cuellar L, Terroba C, Ovale H, Izaola O, Romero E. Effect of repaglinide to NPH monotherapy of glycemic control in patients with type 2 diabetes. Diabetes Care 2001; 24: 1844–5. 77. Madsbad S, Kilhovd B, Lager I, Mustajoki P, Dejgaard A. Comparison between repaglinide and glipizide in type 2 diabetes mellitus: a 1-year multicentre study. Diabetic Med 2001; 18: 395–401. 78. Hirshberg B, Skarulis MC, Pucino F, Csako G, Brennan R, Gorden P. Repaglinide-induced factitious hypoglycemia. J Clin Endocrinol Metab 2001; 86: 475–7. 79. Schumacher S, Abbasi I, Weise D, Hatorp V, Sattler K, Sieber J, Hasslacher C. Single- and multiple-dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment. Eur J Clin Pharmacol 2001; 57: 147–52. 80. Niemi M, Neuvonen PJ, Kivisto KT. The cytochrome P450 3A4 inhibitor clarithromycin increases the plasma concentrations and the effects of repaglinide. Clin Pharmacol Ther 2001; 70: 58–65. 81. Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hydroxychloroquine inpatients with type 2 diabetes mellitus who are refractory to sulfonylureas—a randomized trial. Diabetic Res Clin Pract 2002; 55: 209–19. 82. Blomgren KB, Sundström A, Steineck G, Wiholm BE. Obesity and treatment of diabetes with

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476 99. Hotta N, Toyota T, Matsuoka K, Shigeta Y, Kikkawa R, Kaneko T, Takahashi A, Sugimura K, Koike Y, Ishii J, Sakamoto N. Clinical efficacy of

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fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy. Diabetes Care 2001; 24: 1776–82.

P. Coates

43

Miscellaneous hormones

Calcitonin

(SED-14, 1520; SEDA-23, 466; SEDA-24, 503; SEDA-25, 520) Immunologic Calcitonin allergy, which is rare, has again been reported (1A ). • A 65-year-old woman, who had previously tolerated calcitonin nasal spray, developed eye and nose congestion, an itchy nose, and sneezing minutes after using intranasal salmon calcitonin. She was later given intramuscular salmon calcitonin and developed generalized urticaria and nasal itching within minutes. Skin testing was positive with eel and salmon calcitonins but not human calcitonin, and she was treated with human calcitonin without adverse effects.

Gonadotrophin-releasing hormone (GnRH, gonadorelin) and analogues (SED-14, 1523; SEDA-23, 466; SEDA-24, 503; SEDA-25, 520) Gonadorelin causes an initial surge in gonadotrophins and gonadal steroids, followed by receptor down-regulation and gonadotrophin suppression. Adverse effects and quality of life have been compared in 431 men with prostate cancer treated with a gonadorelin agonist or orchidectomy (2C ). Of the men who reported normal sexual function before treatment, 51% had reduced libido and 69% became impotent. Of those given gonadorelin, 57% had hot flushes. Breast swelling was more common in those given gonadorelin (25% compared with 10% after orchidectomy). Of 547 men randomized to leuprorelin plus flutamide for 3 or 8 months, those treated for 8 months had a higher overall rate of adverse events, and 87% had hot flushes, compared with 72% of those who were treated for 3 months (3C ). © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

Ear, nose, and throat Local irritation or rhinitis occurs uncommonly when gonadorelin agonists are taken intranasally. A 34-year-old woman had to stop using nafarelin nasal spray after 14 days because of exacerbation of maxillary sinusitis (4A ). Nervous system Pituitary apoplexy (hemorrhagic infarction presenting with sudden severe headache, often followed by pituitary hormone deficiency) occasionally occurs after intravenous gonadorelin testing to investigate a pituitary macroadenoma. Two further cases have been reported, in which gonadorelin was administered alone (5A ) or with insulin (6A ). A 67-year-old man with prostate cancer and an unsuspected pituitary macroadenoma developed a severe frontal headache, nausea and vomiting, and blindness within 12 hours of insertion of a goserelin implant (7A ). The mechanism of pituitary apoplexy in these cases is unclear. Gonadorelin may have a direct effect on vascular tone or may increase tumor metabolic activity.

Ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) affects up to 33% of women undergoing ovulation induction with gonadorelin agonists and gonadotrophins given in combination (8R ), or with gonadotrophins alone (9A ). Gonadotrophins are usually withheld if the diagnosis is made before conception (8R , 10R ). OHSS is characterized by cystic ovarian enlargement, increased capillary permeability, and third space fluid accumulation (i.e. in an extracellular compartment that is not in equilibrium with either the extracellular or intracellular fluid, e.g. the bowel lumen, subcutaneous tissues, retroperitoneal space, or peritoneal cavity). Risk factors include a previous history of OHSS, age under 30 years (probably

477

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because more follicles are available), and polycystic ovary syndrome. Non-pregnant patients usually recover within 14 days with supportive treatment. The severe form (with ascites or pleural effusion and hemoconcentration) occurs in 1–10% of patients (10R , 11C ). In critical cases, hypoxemia, renal insufficiency, thromboembolism, and rarely death can occur (12C ).

Skin Injection site reactions are common. In 119 women randomized to subcutaneous triptorelin a local reaction (redness, pain, or bruising) was present after 1 hour in 24% and persisted for 24 h in 9.5% (22C ). In another study in 105 women randomized to leuprorelin acetate, moderate local reactions occurred in 24% and severe reactions in 1% (23C ).

• A 29-year-old woman with polycystic ovary syndrome had her first in vitro fertilization cycle of leuprorelin acetate, follicle-stimulating hormone, and human chorionic gonadotrophin (13A ). Within 2 days she complained of abdominal distension, shortness of breath, and abdominal pain. Over the next few days she developed massive ovarian enlargement, ascites, hyponatremia, respiratory failure, and renal insufficiency. This was further complicated by duodenal perforation, probably due to severe physical stress.

• A 48-year-old woman developed an itchy skin eruption and spotted dark brown pigmentation 3 weeks after starting nasal buserelin 900 µg/day. The lesions resolved when buserelin was withdrawn, and recurred with re-challenge; some persisted for up to 2 years (24A ). • A 78-year-old man treated with subcutaneous leuprorelin acetate had repeated local reactions, with erythema, induration, abscesses, and an ulcer on one hip (25A ).

Gonadorelin receptor antagonists have been reported to lower the risk of OHSS significantly. A meta-analysis showed that cetrorelix but not ganirelix reduced the incidence of OHSS by 75%, both overall and the severe form (14M ). Thromboembolism is a serious complication of OHSS (15A –18A ).

Altered skin pigmentation has been previously reported in pregnancy and after sex hormone administration, so the initial surge in gonadotropins after gonadorelin treatment was a probable cause for the first patient’s presentation. In the second case the lactic acid/glycolic acid vehicle may have caused the reaction rather than leuprorelin.

• A previously healthy 34-year-old woman who underwent ovulation induction with leuprorelin acetate and follicle-stimulating hormone developed abdominal ascites due to OHSS, followed by acute aphasia and right hemiparesis (19A ). The stroke was caused by a large intracardiac thrombus.

A review identified 54 other reports of thromboembolic disease associated with ovulation induction; 60% were in upper limb veins and two-thirds of the patients had OHSS (20R ). The mechanism for the increased risk of thrombosis in these patients has not been determined, but hemoconcentration or a hypercoagulable state associated with high estrogen concentrations could be responsible. Metabolism In 20 premenopausal women treated with triptorelin for 8 weeks, the mean LDL concentration rose from 2.7 to 3.9 mmol/l and HDL fell from 1.6 to 1.5 mmol/l (21c ). Although the change in HDL was not clinically relevant in isolation, the increased LDL and LDL : HDL ratio were significant, suggesting an increased risk of atherogenesis. “Add-back” conjugated equine estrogen did not reverse these changes over 24 weeks.

Musculoskeletal Osteoporosis is common in both sexes after gonadorelin agonist therapy, and the duration of therapy for prostate cancer is inversely related to bone mineral density (26C , 27C ). Intravenous pamidronate may prevent bone loss in these patients (28C , 29C ). • A 44-year-old woman with no previous history of widespread pain, depression, or anxiety developed a diffuse pain syndrome consistent with fibromyalgia after leuprorelin treatment. Her symptoms increased in severity with three successive monthly injections, and persisted for several months (30A ).

Symptoms of this sort have not been previously reported with gonadorelin.

Gonadotrophin-releasing hormone antagonists (SED-14, 1523; SEDA-24, 504; SEDA-25, 521) Competitive gonadorelin receptor antagonists inhibit gonadotrophin secretion without the initial flare seen with gonadorelin agonists, and

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without receptor down-regulation. Potential applications include treatment of prostate cancer and prevention of premature LH surges in in vitro fertilization. Skin Injection sites reactions (pain, itching, redness, swelling, or bruising) are common. In 226 women randomized to subcutaneous ganirelix and 111 to triptorelin there were local symptoms in 12% of those given ganirelix 1 hour after injection and 4.6% still had symptoms after 24 hours (22C ). In another study of ovarian stimulation there were moderate local reactions in 12% of 197 women treated with ganirelix (23C ). Teratogenicity Of 232 infants conceived after ovarian stimulation using cetrorelix seven had major malformations and six had minor malformations; this rate was similar to that in the general population (31C ). Mental development was normal during 2 years of follow-up. After the use of combined ganirelix and folliclestimulating hormone in 68 pregnancies, one child had Beckwith–Wiedemann syndrome (exophthalmos and macroglossia); five had minor malformations, including torticollis, asymmetrical head shape, nevus, skin tags, talipes, pyloric stenosis, and sacral sinus (32C ). Although the numbers were too small to definitely exclude an increase in malformations, the rate of both major and minor defects was consistent with expected values.

Growth hormone (human growth hormone, hGH, somatotropin) (SED-14, 1520; SEDA-23, 467; SEDA-24, 504; SEDA-25, 521) Cardiovascular A 7-year-old boy developed cardiomegaly and edema within a month of starting human growth hormone, 0.7 IU/kg/week; when the dose was reduced to 0.35 IU/kg/week his heart size returned to normal (33A ). This is a reminder that growth hormone adverse effects are dose related and that dose escalation should be gradual.

479 Nervous system In a recent review 139 cases of Creutzfeldt–Jakob disease were identified worldwide in people treated with cadaveric human growth hormone before recombinant human growth hormone became available in the mid-1980s (34CR ). The prevalence of this fatal neurodegenerative condition in human growth hormone recipients ranges from 0.3% in the USA to 4.4% in France. New cases continue to be reported (35A ). • An 18-year-old man from Qatar presented with a 3-month history of unsteadiness, dysarthria, and left-sided weakness, followed by visual, hearing, and memory loss, 13 years after human growth hormone therapy.

This is the first case from Qatar, but it is possible that other cases there have not been reported. Benign intracranial hypertension (pseudotumor cerebri) has been associated with human growth hormone therapy (36A ). • A non-obese 6-year-old girl with Ullrich–Turner syndrome developed headache, vomiting, and blurred vision, with papilledema and increased cerebrospinal fluid (CSF) pressure, 5 months after starting human growth hormone 0.9 IU/kg/week. The CSF pressure normalized after growth hormone was withdrawn, and increased again when therapy was restarted. Her visual acuity was reduced to less than 30% in the right eye.

According to the authors there have been 40 cases of pseudotumor cerebri associated with human growth hormone therapy worldwide, owing to stimulation of CSF production or reduced CSF drainage. Headache was reported in 13% of 75 prepubertal children treated with a modified-release formulation of human growth hormone over 12 months (37C ). Endocrine Fasting and glucose-stimulated insulin concentrations increase with human growth hormone therapy, especially in the first 6–12 months, indicating relative insulin resistance (38C , 39C ). In 78 children treated with human growth hormone for 7 years the mean fasting glucose concentration increased significantly compared with baseline after both 1 and 6 years of growth hormone treatment, but remained within the reference range and was not higher at 6 years than at 1 year (38C ). In a high-dose study in eight HIV-positive men,

480 oral glucose tolerance worsened in the first month of human growth hormone 3 mg/day, then improved towards baseline. Mild glucose intolerance was still present after 6 months, despite a reduction in visceral fat. One man with pre-existing glucose intolerance developed symptomatic diabetes within 2 weeks of starting human growth hormone (40C ). Hypothyroidism developed in 11 of 46 growth hormone-deficient children treated with human growth hormone (41C ). Prior abnormalities in hypothalamic–pituitary function and alterations in thyroid hormone metabolism probably both contributed to the high incidence of hypothyroidism, which was similar to that in previous studies. Skin Injection site reactions are common and include nodules, pain, and erythema. These usually resolve spontaneously (37C , 41C ). Lipoatrophy, a transient loss of subcutaneous fat identifiable as skin dimpling, occurred in 11% of injections in 75 children who were given modified-release human growth hormone for 12 months (37C ) and in one of 68 children in another study (41C ). Immunologic Antibody formation is very common during human growth hormone treatment, but it does not limit its efficacy. There were low titers of anti-growth hormone antibody with no reduction in growth response in 44% of children injecting modified-release growth hormone once a month and in 68% using it twice a month (37C ). Drug interactions In eight post-menopausal growth hormone-deficient women randomized to estradiol, either orally 2 mg/day or transdermally 100 µg/day, together with incremental doses of growth hormone in an 8-week crossover study, oral but not transdermal estrogen reduced IGF-1 concentrations, protein synthesis, and post-prandial lipid oxidation rates (42C ). This confirms the results of a previous report (43c ). The mechanism is not known, but high portal estrogen concentrations after oral estrogen administration probably alter hepatic growth hormone metabolism.

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Growth hormone release-inhibiting hormone (somatostatin) and analogues (SED-14, 1522; SEDA-23, 469; SEDA-24, 505; SEDA-25, 522) Endocrine Somatostatin and its analogues inhibit insulin secretion in the short term, before receptor down-regulation. Mild hyperglycemia occurs during octreotide infusion in up to 23% of adults (44M , 45R ), and occasionally in children (46cR ). This is not usually clinically significant. Children are generally not given long-term octreotide because of concerns about its effect on growth. Although growth was reported as normal in a few case series, “catch-up” growth was also described after octreotide was withdrawn (46cR ). Gastrointestinal Diarrhea and abdominal bloating are common in the first 1–2 weeks of octreotide therapy, but usually resolve spontaneously, owing to receptor down-regulation. One of ten patients with rheumatoid arthritis in an open study stopped using long-acting octreotide because of severe diarrhea and weight loss of 3 kg (47c ). Biliary Octreotide often causes gallstones by suppressing cholecystokinin and impairing gall bladder emptying. Fasting gall bladder volumes increased progressively in seven acromegalic patients treated with once-monthly long-acting octreotide; gallstones formed de novo in six patients within 8 months and one had symptomatic biliary colic (48c ). Gallstones have also been reported in children receiving prolonged octreotide therapy (46cR ). Immunologic A 64-year-old woman, who had had monthly intramuscular injections of long-acting octreotide in the buttocks for 6 years, had increased uptake of 111 In-pentetreotide in both buttocks, thought to represent granuloma formation at the injection sites (49A ). Localized granulomas have previously been described in isolated cases after intramuscular somatostatin analogues, and somatostatin receptors are expressed in high density in activated lymphocytes.

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Allergic reactions to somatostatin are rare. Of 97 cirrhotic patients randomized to subcutaneous octreotide, one stopped therapy because of erythematous itchy skin, which then resolved (45R ). Pregnancy Only 14 pregnancies have been reported in women taking somatostatin analogues, and only three continued therapy after the first trimester. Placental transfer was significant in the first reported pregnancy with longacting octreotide (50A ). The dose of octreotide was reduced after an ultrasound suggested intrauterine growth retardation. The female infant had a low birth weight (11th percentile) but caught up to the 50th percentile by 3 months of age. Her development was normal during 18 months of follow-up.

Oxytocin

(SED-14, 1523)

A 36-year-old multiparous woman had a ruptured uterus after labor was induced at 24 weeks with misoprostol 200 µg and augmented with oxytocin (51A ). The risk of uterine rupture is increased by previous cesarean section, fetal weight over 4 kg, and the use of oxytocin (SEDA-24, 506; 52C , 53C ). In 24 women with uterine rupture after oxytocin, the dose and duration of use of oxytocin were 10% higher than in controls; this difference was not statistically significant, but the power of the study was limited by the small sample size (54C ).

481 Cardiovascular Parathyroid hormone lowers the blood pressure by a direct effect on vascular smooth muscle, and there are isolated instances of hypotension or tachycardia (56R ). Pre-injection blood pressure was normal in 1093 women randomized to parathyroid hormone (PTH1–34), and dizziness was reported infrequently in 541 women taking 20 µg/day but not in 552 taking 40 µg/day (55C ). Mineral balance Transient hypercalcemia is common and dose related. Hypercalcemia was present in 11% of 541 women 4–6 hours after parathyroid hormone 20 µg and in 28% of 552 women after 40 µg (55C ). The dose was halved because of hypercalcemia in 3% and 11% of the women taking 20 µg and 40 µg respectively. Nine of the women taking 40 µg/day stopped treatment because hypercalcemia persisted after dosage reduction. Combining parathyroid hormone with antiresorptive agents may prevent or minimize hypercalcemia. None of 27 women randomized to estrogen plus parathyroid hormone (PTH1–34) 25 µg/d became hypercalcemic during a 3-year study (57C ). Skin Mild discomfort and redness at the injection site are common. Two of 27 women randomized to parathyroid hormone developed nodules at injection sites; however, this could have been due to a contaminant, as both women received parathyroid hormone from the same batch (57C ). Immunologic Dose-dependent antiparathyroid hormone antibodies developed in under 10% of 1093 women in one study; however, there was no reduction in efficacy (55C ).

Parathyroid hormone (PTH) (SED-14, 1520; SEDA-25, 525) Parathyroid hormone, a principal regulator of calcium homeostasis, has an anabolic effect on the skeleton when given intermittently. Both the intact hormone and the (1–34) N-terminal fragment are undergoing clinical trials. Nausea was reported in 18% and headache in 13% of 552 women who took parathyroid hormone 40 µg, compared with 8% of the 544 women who took placebo (55C ).

Thyroid stimulating hormone (TSH, thyrotropin) (SED-14, 1489) Recombinant human TSH stimulates iodine uptake, and this facilitates the diagnosis and treatment of recurrent disease or metastases in the follow-up of differentiated thyroid cancer. It is used as an alternative to thyroid hormone withdrawal, to avoid symptomatic hypothyroidism (58R ). Headache and nausea occur in 6–40% of

482 patients after intramuscular administration, but are usually mild and transient (59C , 60C ). Rapid tumor expansion has been occasionally reported after TSH, including four of 55 patients with central nervous system metastases enrolled in a compassionate use protocol (61Ar ). Two patients with locally recurrent papillary carcinoma had tumor growth 12–48 h after their second injection of rTSH; rapid improvement in neck pain, stridor, and dysphonia after glucocorticoids suggested an inflammatory etiology (61Ar ). There were no features to suggest an allergic reaction; only one such case has been reported and there are no reports of antibody formation even after repeated dosing (58R ).

Thyrotropin-releasing hormone (TRH, protirelin) (SED-14, 1523) The addition of TRH to glucocorticoid therapy to accelerate fetal lung maturation has been the subject of a recent meta-analysis (62M ). In 1134 premature infants the serum TSH concentration was increased for the first 6 h after the last maternal dose of TRH, then suppressed for 36 h before returning to control values (63C ). The largest controlled trial (in 1368 infants) reported a small delay in development at 12 months (64C ). However, developmental assessment was by questionnaire, with incomplete ascertainment, and these findings have been questioned (65r ). In the mothers, there was a three-fold increase in nausea, vomiting, or flushing and a two-fold increase in hypertension compared with glucocorticoid therapy alone.

VASOPRESSIN AND ANALOGUES (SED-14, 1522; SEDA-23, 469; SEDA-24, 506; SEDA-25, 525)

Desmopressin (N-deamino-8-d-arginine vasopressin, DDAVP) Children with nocturnal enuresis treated with desmopressin have fewer wet nights per week,

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but this effect does not persist after therapy is stopped. A recent meta-analysis showed an overall rate of 7.1 adverse events per 100 children (66M ). These were almost all local nasal reactions, including nasal irritation and epistaxis. In an open trial of high-dose desmopressin 1.5 mg intranasally to control bleeding in 278 patients with congenital bleeding disorders, headache occurred in 3.6% and flushing in 3.2% of patients (67C ). Dizziness and nausea were reported in 1–1.5% and edema in 0.3% of patients. Cardiovascular Myocardial infarction has been attributed to desmopressin (68A ). • A 59-year-old woman with hemolytic–uremic syndrome and a recent history of atypical chest pain was given prophylactic desmopressin 0.4 µg/kg immediately before a renal biopsy. Within 30 minutes she developed chest pain and bradycardia due to myocardial infarction.

Three other cases of myocardial infarction in the absence of desmopressin have been reported in patients with hemolytic–uremic syndrome, who already have an increased risk of thrombosis. Electrolyte balance Desmopressin has an antidiuretic effect through vasopressin V2 receptors in the renal tubule. Water intoxication and hyponatremia can occur if fluid intake is not restricted (69A ). • A 37-year-old woman with primary enuresis continued her customary daily fluid intake (2 liters) when she started intranasal desmopressin 30 µg at night. Within 2 days she became severely hyponatremic, with loss of consciousness, generalized seizures, and cerebral edema.

Excess water intake during desmopressin therapy was implicated in seven cases of cerebral edema in children, which occurred over a 5-year period in the Czech Republic (70A ). A non-metered dropper was used for the desmopressin, so overdosage may have contributed. Drug interactions Of 103 children with cranial diabetes insipidus included in a retrospective analysis, 10% became hyponatremic (71c ). The risk of hyponatremia increased three-fold when desmopressin and carbamazepine were

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given in combination, probably because carbamazepine also has a significant antidiuretic effect, by stimulating vasopressin release. In the same study, three children who started or had an increase in dose of lamotrigine needed a larger dose of desmopressin, suggesting an effect either on the renal tubule or on drug clearance.

483 appeared (72A ), although there are several reports with the native hormone. • A 61-year-old man with coronary artery stenosis became hypotensive during elective surgery, refractory to ephedrine (cumulative dose of 36 mg over 45 minutes). Immediately after terlipressin 1 mg, he developed hypertension and bradycardia, with evidence of myocardial ischemia.

Terlipressin (triglycyl–lysine vasopressin) Cardiovascular The first report of myocardial ischemia associated with terlipressin has

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adults. J Clin Endocrinol Metab 1999; 84: 3956– 60. 44. Corley DA, Cello JP, Adkisson W, Ko W-F, Kerlikowske K. Octreotide for acute esophageal variceal bleeding: a meta-analysis. Gastroenterology 2001; 120: 946–54. 45. Erstad BL. Octreotide for acute variceal bleeding. Ann Pharmacother 2001; 35: 618–26. 46. Lam JC, Aters S, Tobias JD. Initial experience with octreotide in the pediatric population. Am J Ther 2001; 8: 409–15. 47. Paran D, Elkayam O, Mayo A, Paran H, Amit M, Yaron M, Caspi D. A pilot study of a long acting somatostatin analogue for the treatment of rheumatoid arthritis. Ann Rheum Dis 2001; 60: 888–91. 48. Moschetta A, Stolk MFJ, Rehfeld JF, Portincasa P, Slee PHThJ, Koppeschaar HPF, Van Erpecum KJ, Vanberge-Henegouwen GP. Severe impairment of postprandial cholecystokinin release and gallbladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR. Aliment Pharmacol Ther 2001; 15: 181–5. 49. Rideout DJ, Graham MM. Buttock granulomas. A consequence of intramuscular injection of Sandostatin detected by In-111 octreoscan. Clin Nucl Med 2001; 26: 650. 50. Fassnacht M, Capeller B, Arlt W, Steck T, Allolio B. Octreotide LAR treatment throughout pregnancy in an acromegalic woman. Clin Endocrinol 2001; 55: 411–15. 51. Al-Hussaini TK. Uterine rupture in second trimester abortion in a grand multiparous woman. A complication of misoprostol and oxytocin. Eur J Obstet Gynecol Reprod Biol 2001; 218–19. 52. Aboyeji AP, Ijaiya MD, Yahaya UR. Ruptured uterus: a study of 100 consecutive cases in Ilorin, Nigeria. J Obstet Gynaecol Res 2001; 27: 341–8. 53. Diaz SD, Jones JE, Seryakov M, Mann WJ. Uterine rupture and dehiscence: ten-year review and case-control study. South Med J 2002; 95: 431–5. 54. Goetzl L, Shipp TD, Cohen A, Zelop CM, Repke JT, Lieberman E. Oxytoxin dose and the risk of uterine rupture in trial of labor after cesarean. Obstet Gynecol 2001; 97: 381–4. 55. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. New Engl J Med 2001; 344: 1434–41. 56. Morley P, Whitfield JF, Willick GE. Parathyroid hormone: an anabolic treatment for osteoporosis. Curr Pharm Des 2001; 7: 671–87. 57. Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, Lindsay R. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001; 16: 925–31. 58. McDougall IR, Weigel RJ. Recombinant human thyrotropin in the management of thyroid cancer. Curr Opinion Oncol 2001; 13: 39–43.

485 59. Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GH, Ross DS, Luster M, Samuels MH, Becker DV, Maxon HR III, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD, Ridgway EC. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84: 3877–85. 60. Durski JM, Weigel RJ, McDougall IR. Recombinant human thyrotropin (rhTSH) in the management of differentiated thyroid cancer. Nucl Med Commun 2000; 21: 521–8. 61. Braga M, Ringel MD, Cooper DS. Sudden enlargement of local recurrent thyroid tumor after recombinant human TSH administration. J Clin Endocrinol Metab 2001; 86: 5148–51. 62. Gross I, Moya FR. Is there a role for antenatal TRH therapy for the prevention of neonatal lung disease? Semin Perinatol 2001; 25: 406–16. 63. Ballard PL, Ballard RA, Ning Y, Cnann A, Boardman C, Pinto-Martin J, Polk D, Phibbs RH, Davis DJ, Mannino FL, Hart M. Plasma thyroid hormones in premature infants: effect of gestational age and antenatal thyrotropin-releasing hormone treatment. Pediatr Res 1998; 44: 642–9. 64. Crowther CA, Hiller JE, Haslam RR, Robinson JS. Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone: adverse effects at 12-month follow-up. Pediatrics 1997; 99: 311–17. 65. McCormick MC. The credibility of the ACTOBAT follow-up study. Pediatrics 1997; 99: 476–8. 66. Glazener CMA, Evans JHC. Desmopressin for nocturnal enuresis in children. Cochrane Database System Rev 2000; 2: CD002217. 67. Leissinger C, Becton D, Cornell C Jr, Gill JC. High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A. Haemophilia 2001; 7: 258–66. 68. Stratton J, Warwicker P, Watkins S, Farrington K. Desmopressin may be hazardous in thrombotic microangiopathy. Nephrol Dial Transplant 2001; 16: 161–2. 69. Odeh M, Oliven A. Coma and seizures due to severe hyponatremia and water intoxication in an adult with intranasal desmopressin therapy for nocturnal enuresis. J Clin Pharmacol 2001; 41: 582–4. 70. Lebl J, Kolska M, Zavacka A, Eliasek J, Gut J, Biolek J. Cerebral oedema in enuretic children during low-dose desmopressin treatment: a preventable complication. Eur J Pediatr 2001; 160: 159–62. 71. Rizzo V, Albanese A, Stanhope R. Morbidity and mortality associated with vasopressin replacement therapy in children. J Pediatr Endocrinol Metab 2001; 14: 861–7. 72. Medel J, Boccara G, Van de Steen E, Bertrand M, Godet G, Coriat P. Terlipressin for treating intraoperative hypotension: can it unmask myocardial ischemia? Anesth Analg 2001; 93: 53–5.

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FIBRATES

(SED-14, 1527; SEDA-23, 472; SEDA-24, 510, SEDA-25, 533) Metabolic The conclusion of a study of fenofibrate and atorvastatin was that increased concentrations of plasma homocysteine result from an action of the fibrates themselves and not indirectly via their lipid-lowering effect (1c ). Concomitant administration of folic acid, at least in part, offset this adverse effect (2c ). The degree of rise in homocysteine differs among the various fibrates. It has previously been reported with fenofibrate and bezafibrate, and a more recent study of fenofibrate and gemfibrozil substantiated a difference between the drugs (3c ). Because the concentration of plasma homocysteine depends on renal function, increased plasma homocysteine concentrations could result from renal function impairment caused by fenofibrate. In contrast, gemfibrozil does not affect renal function. This was tested in a crossover study in 22 patients who had hypertriglyceridemia, by giving them gemfibrozil 900 mg/day or fenofibrate 200 mg/day for 6 weeks. Lipids were altered similarly, but homocysteine, creatinine, and cystatin C were raised by fenofibrate but not by gemfibrozil. In another report there was a 57% increase in homocysteine in 26 individuals treated with ciprofibrate and a 17% reduction in homocysteine in 12 patients treated with bezafibrate (4c ). Urinary system A new observation is that fibrates can cause impaired renal function (5A ). Fenofibrate was the probable cause of rises in serum creatinine concentrations in six patients in one clinic. The authors therefore recommended routine serum creatinine monitoring at © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

486

baseline and at 1–2 months after starting fenofibrate. This is in keeping with an earlier report of unexpected acute renal insufficiency in four patients after uncomplicated cardiac surgery. Each was taking a fibrate at the time of surgery (SEDA-25, 533). Immunologic Allergic reactions have been reported with some fibrates. • A 61-year-old woman with penicillin allergy suffered generalized urticaria, chest tightness, wheezing, nausea, vomiting, hypotension, and loss of consciousness (6A ). Two hours earlier she had taken Eulitop Retard after lunch. She had intense positive responses to intradermal Eulitop Retard and its active component, bezafibrate; skin tests in control subjects were negative. Specific IgE tests (RAST) to Eulitop Retard were negative. The positive skin tests suggested that an IgE mechanism was responsible for this adverse reaction. • A 69-year-old woman developed a major allergic reaction after taking fenofibrate 300 mg/day for 10 days (7A ). The clinical features included weakness, hyperthermia, and slight muscular pain. Biological abnormalities were mildly raised muscle enzymes and pancytopenia, which developed rapidly.

Drug interactions Interactions between fibrates and statins occur, but there may be differences between the various fibrates (8c ). Eleven healthy volunteers took bezafibrate 400 mg/day, gemfibrozil 1200 mg/day, or placebo for 3 days. On day 3, each took a single dose of lovastatin 40 mg. Plasma concentrations of lovastatin, lovastatin acid, gemfibrozil, and bezafibrate were measured for up to 24 hours. Gemfibrozil markedly increased plasma concentrations of lovastatin acid, but bezafibrate did not. The increased risk of myopathy observed during concomitant treatment with statins and fibrates may be partly pharmacokinetic in origin. The risk of myopathy during concomitant therapy with lovastatin and a fibrate may be smaller with bezafibrate than with gemfibrozil.

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HMG COENZYME-A REDUCTASE INHIBITORS (SED-14, 1530; SEDA-23, 472; SEDA-24, 510: SEDA-25, 533) Nervous system Previous reports have not connected sleep disturbances with the use of statins (SED-14, 1530), but there has been one recent report (9A ). • Three months after starting to take metoprolol 100 mg bd and simvastatin 10 mg/day, a 55-yearold man reported restless nights and nightmares, which he had not previously experienced. The dose of metoprolol was reduced to 50 mg bd, with no observable benefit. Simvastatin was withdrawn 2 weeks later and pravastatin 20 mg/day was prescribed, with substantial improvement in the quality of sleep; however, some unpleasant nightmares still occurred. Four weeks later, metoprolol was also withdrawn and atenolol 100 mg/day was prescribed. Thereafter, the quality of sleep was significantly improved, and 6 months later the patient did not report any nightmares. Sleep disturbances recurred after a later attempt to reintroduce simvastatin in place of pravastatin. The same effect occurred when, during treatment with pravastatin, substitution of atenolol with metoprolol was attempted.

In this case the statins may have interacted with metoprolol, and it may have been relevant that metoprolol is more lipid soluble than atenolol. Hematologic Hematological adverse effects can occur during treatment with both simvastatin and atorvastatin, according to a brief review (10r ). They include thrombotic thrombocytopenic purpura and severe thrombocytopenic purpura. Liver The use of HMG-CoA reductase inhibitors may be associated with mild rises in aminotransferase activities, but this has not been definitely correlated with severe morbidity involving altered hepatic function. There seems to be no major difference between the various drugs in this respect (11R ), but when simvastatin and atorvastatin, each at a dose of 80 mg/day, were compared in 826 hypercholesterolemic patients there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase rises with simvastatin (12C ).

Skin A series of skin reactions have been described in patients using statins (13r ), among them an ichthyosiform eruption in a patient taking lovastatin (SED-14, 1530) and now also linear IgA bullous dermatosis in a patient using atorvastatin (14A ) and dermographism in a patient taking atorvastatin (13c ). Musculoskeletal Four cases of tendinopathy have been reported in three men and one woman taking statins (15A ). The diagnoses were extensor tenosynovitis in the hands, tenosynovitis of the tibialis anterior tendon, and Achilles tendinopathy. Two patients were taking simvastatin and two atorvastatin. The tendinopathy developed 1–2 months after the start of treatment. The outcome was consistently favorable within 1–2 months after drug withdrawal. Drug interactions Although the statins seem to be similar in their ability to lower LDL concentrations, there are also dissimilarities, for instance different interactions with other drugs. St John’s wort induces CYP3A4 and reduces blood concentrations of CYP3A4 substrates. In one study St John’s wort reduced plasma concentrations of simvastatin but not pravastatin (16c ). Most drug interactions associated with rhabdomyolysis occur when ciclosporin is combined with simvastatin or lovastatin. It has been suggested that if a statin is to be combined with ciclosporin, pravastatin or fluvastatin should be chosen instead (17A ). The interactions of statins with fibrates are discussed above, under fibrates.

Cerivastatin Cerivastatin was withdrawn from the market in 2001 after 31 people in the USA died of severe rhabdomyolysis related to therapy with the drug; 12 of them had also taken gemfibrozil (18r ).

Fluvastatin Liver A woman presented with clinical and laboratory signs of cholestatic and necrotic acute hepatitis (19A ).

488 • A 61-year-old woman developed symptoms of acute hepatitis 6 weeks after she began to take fluvastatin sodium 20 mg/day for hypercholesterolemia. Ultrasonography and liver biopsy confirmed the diagnosis of non-obstructive intrahepatic jaundice. Studies of viral markers and autoimmune factors excluded viral hepatitis and autoimmune hepatitis. There was a high serum concentration of a metabolite of fluvastatin, suggesting a possible anomaly of drug metabolism. All liver function tests normalized 8 weeks after the withdrawal of fluvastatin.

Fluvastatin should be considered as a potential cause of cholestatic hepatitis with a favorable clinical outcome after drug withdrawal. Drug formulations Once-daily administration of modified-release fluvastatin 80–320 mg/day was generally safe and well tolerated in 40 patients with primary hypercholesterolemia over 13 days (20c ). However, fluvastatin 640 mg in this formulation was not well tolerated: six of seven patients had adverse events, including diarrhea, headache, and clinically relevant rises in serum transaminase activities. In addition, the pharmacokinetics of fluvastatin were non-linear at this dose, possibly due to saturation of first-pass metabolism, causing higher than expected serum drug concentrations.

Pravastatin Respiratory A 41-year-old man, who had been taking pravastatin for 2 years, developed a hypersensitivity pneumonitis with eosinophilia; the symptoms gradually resolved after withdrawal of pravastatin (21A ).

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I. Aursnes

Simvastatin Drug interactions Diltiazem interacts with lovastatin but not with pravastatin (SEDA-24, 511). An interaction has now also been observed with simvastatin in a 75-year-old man when he developed impaired renal function (22A ). He had extreme weakness and muscle pain. Lovastatin has previously been reported to interact with clarithromycin (SED-14, 1531), and a similar reaction has now been observed with simvastatin (23AR ). • A 64-year-old African–American man developed worsening renal insufficiency, raised creatine phosphokinase, diffuse muscle pain, and severe muscle weakness. He had been taking simvastatin for about 6 months and clarithromycin for sinusitis for about 3 weeks. He was treated aggressively with intravenous hydration, sodium bicarbonate, and hemodialysis. A muscle biopsy showed necrotizing myopathy secondary to a toxin. He continued to receive intermittent hemodialysis until his death from infectious complications 3 months after admission.

ION-EXCHANGE RESINS Colestipol

(SED-14, 1530)

Liver A 65-year-old man with type IIa dyslipidemia who took flavored colestipol granules 2 scoops/day for 3 months developed asymptomatic hepatotoxicity (24A ). Several of his liver enzymes were raised 10 times the upper limit of normal. One week after withdrawal of colestipol, his serum transaminases fell dramatically and 3 weeks later all liver function tests were normal. Rechallenge was not attempted, but other potential causes of hepatocellular injury were evaluated.

REFERENCES 1. Giral P, Bruckert E, Jacob N, Chapman MJ, Foglietti M-J, Turpin G. Homocysteine and lipid lowering agents. A comparison between atorvastatin and fenofibrate in patients with mixed hyperlipidemia. Atherosclerosis 2001; 154: 421–7. 2. Stulc T, Melenovsky V, Grauova B, Kozich V,

Ceska R. Folate supplementation prevents plasma homocysteine increase after fenofibrate therapy. Nutrition 2001; 17: 721–3. 3. Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001; 358: 39–40.

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4. Harats D, Yodfat O, Doolman R, Gavendo S, Marko D, Shaish A, Sela B-A. Homocysteine elevation with fibrates: Is it a class effect? Isr Med Assoc J 2001; 3: 243–6. 5. Ritter JL, Nabulsi S. Fenofibrate-induced elevation in serum creatinine. Pharmacotherapy 2001; 21: 1145–9. 6. De Barrio M, Matheu V, Baeza ML, Tornero P, Rubio M, Zubeldia JM. Bezafibrate-induced anaphylactic shock: unusual clinical presentation. J Invest Allergol Clin Immunol 2001; 11: 53–5. 7. Rabasa-Lhoret R, Rasamisoa M, Avignon A, Monnier L. Rare side-effects of fenofibrate. Diabetes Metab 2001; 27: 66–8. 8. Kyrklund, C. Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001; 69: 340–5. 9. Boriani G, Biffi M, Strocchi E, Branzi A, Orsola PS. Nightmares and sleep disturbances with simvastatin and metoprolol. Ann Pharmacother 2001; 35: 1292. 10. Groneberg DA, Barkhuizen A, Jeha T. Simvastatin-induced thrombocytopenia. Am J Hematol 2001; 67: 277. 11. Farmer JA. Learning from the cerivastatin experience. Lancet 2001; 358: 1383–5. 12. Illingworth DR, Crouse JR, Hunninghake DB, Davidson MH, Escobar ID, Stalenhoef AFH, Paragh G, Ma PTS, Liu M, Melino MR, O’Grady L, Mercuri M, Mitchel YB. A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial. Curr Med Res Opin 2001; 17: 43–50. 13. Adcock BB, Hornsby LB, Jenkins K. Dermographism: an adverse effect of atorvastatin. J Am Board Fam Pract 2001; 14: 148–51. 14. Konig C, Eickert A, Scharfetter-Kochanek K, Krieg T, Hunzelmann N. Linear IgA bullous der-

489 matosis induced by atorvastatin. J Am Acad Dermatol 2001; 44: 689–92. 15. Chazerain P, Hayem G, Hamza S, Best C, Ziza J-M. Four cases of tendinopathy in patients on statin therapy. Jt Bone Spine 2001; 68: 430–3. 16. Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, Arakawa M, Sakamoto K, Masada M, Miyamori I, Fujimura A. Different effects of St John’s wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther 2001; 70: 518–24. 17. Stirling CM, Isles CG. Rhabdomyolysis due to simvastatin in a transplant patient: are some statins safer than others? Nephrol Dial Transplant 2001; 16: 873–4. 18. Anonymous. Cerivastatin withdrawn from market. Am J Health-Syst Pharm 2001; 58: 1685. 19. Wachi K, Ishii K, Ikehara T, Shinohara M, Kawafune T, Sumino Y, Nonaka H. A case of acute cholestatic hepatitis associated with fluvastatin sodium. J Med Soc Toho 2001; 48: 153–8. 20. Sabia H, Prasad P, Smith HT, Stoltz RR, Rothenberg P. Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia. J Cardiovasc Pharmacol 2001; 37: 502–11. 21. Liscoet-Loheac N, Andre N, Couturaud F, Chenu E, Quiot JJ, Leroyer C. Hypersensitivity pneumonitis in a patient taking pravastatin. Rev Mal Respir 2001; 18: 426–8. 22. Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem. Nephron 2001 89: 117–18. 23. Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother 2001; 35: 26–31. 24. Sirmans SM, Beck JK, Hoan Linh Banh, Freeman DA. Colestipol-induced hepatotoxicity. Pharmacotherapy 2001; 21: 513–16.

Hans-Peter Lipp, Carsten Bokemeyer, Jörg Thomas Hartmann, and Andrew Stanley

45

Cytostatic drugs

Editor’s note: The wide range of cytostatic drugs, the multitude of their adverse effects, and the fact that they are generally used in combinations of several agents all make it impossible to provide as detailed a review of the adverse effects of all the drugs in this field as the Annual gives in others. This year most of this chapter is devoted to a special review of the adverse effects of the platins by Drs Lipp, Bokemeyer, and Hartmann. The rest of the chapter is by Dr Stanley, who thanks those clinicians and researchers who have sent him copies of their original research papers.

Platinum compounds Although the lead platinum compounds, cisplatin, carboplatin, and oxaliplatin, share some structural similarities, there are marked differences between them in therapeutic uses, pharmacokinetics, and adverse effects profiles (1R –3R , 4c ). Compared with cisplatin, carboplatin has inferior efficacy in germ-cell tumors, head and neck cancers, and bladder and esophageal carcinomas, whereas the two drugs appear to have comparable efficacy in ovarian cancer, extensive small-cell lung cancers (SCLC), and advanced non-small-cell lung cancers (NSCLC) (5R , 6R , 7r ). Oxaliplatin belongs to the group of diaminocyclohexane (DACH) platinum compounds. It is the first platinum-based drug that has marked efficacy in colorectal cancer when given in combination with 5-fluorouracil and folinic acid (8R , 9R ). Nedaplatin has been registered in Japan, whereas other derivatives, like JM216 (which is the only orally available platinum derivative), ZD0473, BBR3464, and SPI-77 (a liposomal formulation of cisplatin), are still under investigation (10r , 11R –13R ). The adverse effects of platinum compounds have recently been reviewed (14R ). © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

490

Cisplatin, carboplatin, and oxaliplatin Mechanism of action Although the precise mechanism of the cytotoxic action of the platinum compounds has not yet been fully elucidated, they are thought to act by causing interstrand and intrastrand cross-links in DNA, particularly including two adjacent guanine or two adjacent guanine–adenine bases (15c –17c , 18E ). In comparison with cisplatin- or carboplatin-induced DNA lesions, diaminocyclohexane (DACH) platinum DNA adduct formation has been associated with greater cytotoxicity and inhibition of DNA synthesis. In addition, there appears to be a complete lack of cross-resistance between oxaliplatin and cisplatin, which may be related to the bulky DACH carrier ligand of oxaliplatin, hindering DNA repair mechanisms within tumor cells (8R , 9R ). Pharmacokinetics There are significant pharmacokinetic differences among cisplatin, carboplatin, and oxaliplatin. Cisplatin is the most highly protein bound (>90%), followed by oxaliplatin (85%) and carboplatin (24–50%). The negligible nephrotoxicity of oxalipatin and carboplatin compared with cisplatin may be related to their slower rates of conversion to reactive species. As a result, intensive hydration is not warranted during carboplatin or oxaliplatin infusion, in contrast to cisplatin

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(1R , 8R , 9R , 10r ). In the case of macromolecular platinum–protein complex formation, decomposition proceeds rather slowly, which may explain why the urinary excretion of total platinum is increased for a long time after treatment, particularly in patients who have been given cisplatin (19A , 20A ). In contrast to cisplatin, carboplatin is primarily eliminated (about 75%) by glomerular filtration, whereas tubular secretion appears to be of minor importance (2R , 3R , 4c ). It has therefore been recommended that the dose of carboplatin be adjusted according to the individual GFR, in order to avoid high plasma drug concentrations when the dose is calculated according to body surface area (21C , 22r , 23r ). Individualized carboplatin therapy helps to avoid abnormally high drug concentrations in patients with renal dysfunction and subtherapeutic concentrations in patients with an unexpectedly high GFR (24r , 25c ). Pharmacokinetic–pharmacodynamic correlations between AUC, response rates, and the extent of myelosuppression have been examined retrospectively (21C , 24r ). AUC values below 4 min.mg.ml−1 and exceeding 7 min.mg.ml−1 cannot be recommended; the former is associated with low response rates and the latter is associated with more pronounced neutropenia and thrombocytopenia without higher response rates. Doses of carboplatin are generally calculated by the Calvert formula (26C ): carboplatin dose = AUC (min.mg.ml−1 ) × (GFR + 25). However, it is still debatable which method most accurately predicts individual values of GFR or creatinine clearance. Whereas the Cr-EDTA method is the most accurate method of estimating GFR, most clinicians do not use it routinely, preferring to collect urine for estimation of creatinine clearance. Alternatively, the use of special formulae has been recommended. A new formula (Wright’s formula) may provide a more accurate estimate of GFR than the formulae of Cockcroft & Gault or Jelliffe (27C , 28C , 29c ). Furthermore, the formulae used for conventional carboplatin chemotherapy cannot translate into high-dose chemotherapy in terms of prediction of myelosuppression or of response rates, because there is a poor correlation between the calculated and the real serum concentrations of carboplatin.

491 After intravenous administration of oxaliplatin, about 33% and 40% of the dose is bound to erythrocytes and plasma proteins. The halflife averages 26 days, which is in accordance with the normal life expectancy of erythrocytes (12–50 days). Oxaliplatin undergoes rapid nonenzymatic biotransformation to form a variety of reactive platinum intermediates, which bind rapidly and extensively to plasma proteins and erythrocytes. The antineoplastic and toxic properties appear to reside in the non-protein bound fraction, whereas platinum bound to plasma proteins or erythrocytes is considered to be pharmacologically inactive. Biotransformation produces DACH-platinum dichloride, 1,2-DACH-platinum dicysteinate, 1,2-DACH platinum diglutathionate, 1,2-DACH-platinum monoglutathionate, and 1,2-DACH-platinum methionine. The erythrocyte contains only thiol derivatives, whereas all derivatives can be recovered from the plasma. The platinum-containing metabolites of oxaliplatin are predominantly excreted in the urine (about 50% of the dose within 3 days), whereas drug excretion via the feces is of minor importance (about 5% of the dose after 11 days). The mean total platinum half-life averages 9 days after oxaliplatin administration (130 mg/m2 intravenously) (8R , 9R ). There is a strong negative correlation between the mean plasma concentration of unbound oxaliplatin and renal function; however, there is no direct relation between moderate renal impairment and the acute toxicity associated with oxaliplatin (30C ).

Adverse effects profile of platinum compounds—general aspects Of the clinically established platinum compounds, cisplatin has the most toxic effects on organs like the nervous system, the organ of Corti, and the kidneys in a dose-dependent fashion. The dose per cycle has therefore usually been limited to 100–120 mg/m2 intravenously, in order to avoid drug-induced irreversible organ dysfunction (12R , 13R ). In contrast to cisplatin, myelotoxicity represents the most prominent adverse effect of carboplatin. Based on its lower organ toxicity and its better predictable pharmacokinetic behavior, carboplatin

492 has extensively replaced cisplatin in combination chemotherapy for the treatment of ovarian cancer and extensive SCLC and NSCLC. For other indications, one has to weigh the more or less inferior efficacy of carboplatin against the more pronounced undesirable adverse effects of cisplatin, which may limit its long-term use. Based on its marked organ toxicity, high-dose cisplatin-containing regimens are not feasible, in contrast to carboplatin, which is part of several dose-intensified combination chemotherapy regimens (12R , 13R ). Like carboplatin, oxaliplatin does not usually cause nephrotoxicity. In addition, both drugs are only moderately emetogenic, in contrast to cisplatin. The most important doselimiting adverse effect of oxaliplatin is a sensory peripheral neuropathy, which has two different forms: (i) a unique acute peripheral sensory (and motor) toxicity that often occurs during or within hours after drug infusion and which is rapidly reversible, and (ii) a peripheral sensory neuropathy related to the cumulative dose, which is generally moderate and slowly reversible, in contrast to the forms that have been described after cisplatin administration.

BBR3464 BBR3464 is the first congener of a novel group of platinum compounds, the so-called cationic trinuclear platins. It binds to DNA more rapidly than cisplatin, which results in long-range interstrand and intrastrand cross-links. It is more potent than cisplatin, and very low dosages were effective in phase I trials. With a 1-hour intravenous infusion of 1.1 mg/m2 every 28 days, diarrhea (preceded by abdominal cramps), nausea/vomiting, and neutropenia were the most prominent drug-related adverse effects. There were no signs of drug-related nephrotoxicity, neurotoxicity, or lung dysfunction (12R , 13R , 31r ).

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Hans-Peter Lipp et al.

lines, including cisplatin-resistant tumor cells. Preliminary results suggested that it is less nephrotoxic than cisplatin. However, a comparative trial showed that intravenous heptaplatin 400 mg/m2 was more nephrotoxic than intravenous cisplatin 60 mg/m2 in terms of uremia and proteinuria, which occurred despite the use of hyperosmolar mannitol and appropriate concomitant hydration (fluid intake at least 3500 ml/day) (32c , 33c ).

Nedaplatin Nedaplatin (CDGP, 254-S, cis-diammineglycolatoplatinum) has some structural similarities to cisplatin and carboplatin. Since 1995 it has been available for therapeutic use in Japan. In phase II trials it had promising antineoplastic activity in patients with head and neck cancers, NSCLC, esophageal cancer, testicular tumors, and cervical cancer. A distinct number of patients with ovarian cancer have responded to nedaplatin (e.g. 100 mg/m2 intravenously) even after relapsing following treatment with cisplatin/carboplatin and cyclophosphamide. Its pharmacokinetic behavior is similar to that of carboplatin. It causes less nephrotoxicity than cisplatin, but hematological toxicity is doselimiting. Other adverse effects include nausea/vomiting and mild peripheral neuropathy (12R , 13R , 34R ). Although nedaplatin is less nephrotoxic than cisplatin, incidental cases of severe nephrotoxicity have occurred. In addition, ototoxicity, similar to that observed after cisplatin, has been documented. Nedaplatin is excreted primarily unchanged by glomerular filtration, and there is a formula for predicting the clearance of unbound platinum after its administration (35c ).

Sartraplatin Heptaplatin Heptaplatin (SKI-2053R, cis-malonate[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II), Sunpla) has high antitumor activity against various cancer cell

Sartraplatin (JM 216, BMS-182751, bis-acetatoammine-dichloro-cyclohexylamine-platinum) is the first oral platinum compound among the third-generation platinum complexes with activity in platinum-sensitive and some platinumresistant preclinical models. Adverse effects

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were generally modest (grades I and II), including nausea, fatigue, anorexia, diarrhea, and altered taste. In addition, myelosuppression and rare cases of grades II and III increases in serum creatinine were reported. During phase II trials sartraplatin was given in a dose of 120 mg/m2 /day for 5 consecutive days every 3 weeks in untreated patients with lung cancer or 30 mg/m2 /day for 14 consecutive days every 5 weeks in patients with metastatic squamous cell carcinoma. There was no nephrotoxicity or neurotoxicity (36c –38c ). Pharmacokinetic studies showed that very little intact parent compound reached the systemic circulation after oral administration, perhaps because of extensive metabolic biotransformation or rapid reaction of platinum(II) species with DNA or other compounds. One of the intermediate compounds released during biotransformation is JM118, which has a longer half-life than the parent compound. Its particular role in the overall activity of sartraplatin is still being investigated (39c ).

encouraging compared with conventional cisplatin. However, despite its favorable pharmacokinetic behavior, enhanced platinum accumulation in tumor tissue has not yet been detected (40c –42c ).

Tetraplatin The further development of the third-generation platinum derivative tetraplatin (ormaplatin, trans-d,l-1,2-diaminocyclohexane tetrachloroplatinum) has been abandoned, because druginduced severe motor and sensory peripheral neuropathy occurred even at low cumulative doses. The high neurotoxic potential of tetraplatin may be associated with its pharmacokinetics: it is rapidly metabolized to 1,2-DACH-platinum dichloride, which was 3.8 times more neurotoxic than oxaliplatin in a neurite outgrowth assay (43E ).

ZD0473 SPI-77 SPI-77 is a stealth liposomal dosage form of cisplatin. One of the main features of stealth liposomes is that they are pegylated on the liposomal surface. Compared with conventional liposomes (e.g. DaunoXome or Myocet) the half-life of the liposome and its embedded drug in plasma is significantly increased by this modification, because degradation by cells of the mononuclear phagocytic system is impaired; the cells are thereby, as it were, tricked. Liposomal encapsulation of cisplatin has been suggested to reduce systemic drug exposure and may help to increase drug delivery into tumor tissue. Pharmacokinetic studies have shown a slow rate of release of cisplatin from the liposomes, resulting in low systemic exposure to unbound drug. In contrast to conventional cisplatin, the incidence of gastrointestinal toxicity after SPI-77 was low, and so prophylactic antiemetics can be avoided. In addition, renal toxicity has not been observed, which also makes hydration before or after chemotherapy unnecessary. Extensive neurological measurements did not show any adverse effects. In conclusion, the toxicity profile of SPI-77 is

ZD0473 (formerly AMD473, JM473) was developed in order to overcome acquired or intrinsic (de novo) resistance to cisplatin. Based on its steric bulk methyl-substituted pyridine moiety, thiol substitution and drug inactivation is hindered compared with cisplatin. In several in vitro studies ZD0473 was active even in cisplatin-refractory tumor cells, whose key mechanism of resistance was based on thiol substitution. In addition, ZD0473 is also active in cisplatin-resistant tumor cells, in which resistance is based on altered drug transport mechanisms or enhanced DNA repair. Based on encouraging preclinical results, ZD0473 entered clinical phase I/II trials in several solid tumors, including NSCLC, mesothelioma, head and neck cancers, and ovarian carcinoma. Its most prominent adverse effects included myelosuppression and nausea/vomiting. Thrombocytopenia and neutropenia were the dose-limiting adverse effects at intravenous doses of 130–150 mg/m2 . In contrast to cisplatin, neurotoxicity, ototoxicity, and renal toxicity have not yet been reported during or after treatment with ZD0473 (12R , 13R , 31r , 34R ).

494

Specific adverse effects of platinum compounds Cardiovascular Asymptomatic sinus bradycardia (e.g. 30–40 beats/minute) is observed within 30 minutes to 2 hours after the start of cisplatin infusion. When cisplatin is withdrawn normal rhythm is restored. Because patients who receive platins are not routinely monitored, drug-induced sinus bradycardia may not be detected in practice. However, several case reports have included heavily pretreated patients, which makes a direct correlation between cisplatin administration and the onset of cardiotoxic symptoms much more difficult to assess. In conclusion, no dosage adjustment appears to be warranted in patients with cisplatininduced sinus bradycardia; however, attention should be paid to patients with resting bradycardia or those using medications known to slow the heart rate (44A , 45A ). Platinum compounds have rarely been described to cause phlebitis after intravenous administration (46R ). Nervous system The mechanism of cisplatininduced neurotoxicity has not been fully explained yet. Cisplatin appears to affect neurons in the dorsal root ganglia. It has also been suggested that it can act as a calcium channel blocker, altering intracellular calcium homeostasis and leading to apoptosis of exposed neurons, such as those of the dorsal root ganglia. Cisplatin-induced sensory neuropathy is predominantly characterized by symptoms such as numbness and tingling, paresthesia of the upper and lower extremities, reduced deep-tendon reflexes, and leg weakness with gait disturbance. The first symptoms are often observed after a cumulative dose of 300–600 mg/m2 . Risk factors include diabetes mellitus, alcohol consumption, or inherited neuropathies. Advanced age has not been identified as an independent risk factor when there is no co-morbidity (47R –50R ). In a study of the time-course and prognosis of cisplatin-induced neurotoxicity (e.g. sural nerve sensory action, conduction velocity, and vibration threshold in the left big toe) in 29 patients with metastatic germ cell tumors, the onset of paresthesia was delayed (51c ). After completion of chemotherapy (3–4 cycles) only 11% of the patients had neurotoxic symptoms,

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whereas 3 months later the proportion was 65%. Cisplatin-induced neurological disorders should therefore be evaluated at 1–4 months after the end of weekly cisplatin administration, because during this time the most severe form of cisplatin neurotoxicity is to be expected. There was resolution of symptoms in most of the patients over the next 12 months, suggesting that in some individuals a long period of regeneration is required to restore axonal sensory function. In patients with mild signs of cisplatin-related neuropathy, retreatment is generally feasible after several months (52C , 53c ). Among several thiol compounds, glutathione may provide neuroprotection in patients treated with cisplatin without altering its antineoplastic activity. This protective role may be based on blockade of the accumulation of p53 protein in response to platinum in dorsal root ganglia, thereby hindering platinum-based apoptosis (54E , 55E ). The melanocortin Org 2766, an ACTH analogue, which is not yet available for clinical use, alleviates neurotoxicity due to vinca alkaloids and cisplatin, perhaps by enhancing neural repair. However, whereas preliminary results suggested some neuroprotection in women with ovarian cancer treated with cisplatin, these results were not confirmed in a randomized, multicenter, double-blind, placebo-controlled dosefinding study, even with higher doses of Org 2766 (56R ). There is evidence that amifostine can reduce the frequency of cisplatin-induced peripheral neuropathy, allowing higher mean cumulative doses to be used. However, some of the results should be interpreted with caution, because the studies included patients who differed in respect to treatment regimen, disease states, and pretreatment status. The underlying protective effect of amifostine may be based on its capacity to scavenge free radicals and prevent cisplatin DNA adduct formation in several organs, including the dorsal root ganglia (55E ). Oxaliplatin is the platinum compound with the highest potential for causing a sensory neuropathy. This correlates with experimental measurements of sensory nerve conduction velocity: oxaliplatin caused the most impairment, followed by cisplatin, carboplatin, and sartraplatin (JM216) (57E ).

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In about 90% of patients oxaliplatin is associated with acute neurosensory toxicity, including dysesthesia and paresthesia. Neurosensory toxicity affects the fingers, toes, perioral and oral regions, and the pharyngolaryngeal tract (in about 1–2% of cases), which is generally induced or aggravated by coldness. As a result, patients should be instructed to avoid exposure to cold. Such symptoms can occur during or shortly after the first course of oxaliplatin. The symptoms are commonly mild and disappear within a few hours or days. Some patients also develop muscle cramps or spasms. The risk of acute neuropathy appears to be lower if oxaliplatin is given in a dosage of 85 mg/m2 every 2 weeks rather than 130 mg/m2 every 3 weeks. A further strategy to reduce the risk of acute recurrent pseudolaryngospasm is to increase the infusion duration from 2 to 6 hours during subsequent cycles (58r , 59r ). The acute neurotoxic effects of oxaliplatin may result from drug-related inhibition of voltage-gated sodium currents (60E ). It has been suggested that oxalate ions, which are released during oxaliplatin metabolism, might be responsible for the inhibitory effects on the voltage-gated sodium channels, because of their calcium chelating activity. Whether there are calcium-sensitive voltage-gated sodium channels that can be affected by oxalateinduced calcium depletion or whether an indirect effect through changes in intracellular calcium-dependent regulatory mechanisms contributes to oxaliplatin-induced sensory neuropathy needs further investigation (61E ). There is increasing evidence that acute oxaliplatin-induced neurotoxicity can be improved by intravenous infusion of calcium gluconate 1000 mg and magnesium sulfate 1000 mg before and after oxaliplatin. It has recently been shown that this strategy could reduce the incidence of acute neurotoxic symptoms, including laryngopharyngeal dysesthesia. Of 101 patients with advanced colorectal cancers who received folinic acid (leucovorin), 5-fluorouracil, and oxaliplatin (85 mg/m2 /2 weeks, 20 patients; 100 mg/m2 /2 weeks, 22 patients; 130 mg/m2 /3 weeks, 59 patients), 63 received infusions of calcium and magnesium (1 g each) before and after oxaliplatin administration (treatment group); 38 patients (control group) did not receive infusions of calcium + magnesium. The median cumulative dose of oxaliplatin was 910 (range 255–2340) mg/m2 in

495 the calcium/magnesium group and 650 (range 255–1450) mg/m2 in the control group. At the end of treatment, 27% had neuropathy (any grade) compared with 75% in the control group; 1.6% and 26% had pharyngolaryngeal dysesthesia; and 5% and 24% had grade III neuropathy. However, further studies are warranted before this regimen can be generally recommended for reducing the risk of acute neurosensory symptoms associated with oxaliplatin infusion (59r , 62c ). Carbamazepine is a potent sodium channel blocker. It has therefore been studied in the prevention of oxaliplatin-induced neuropathy (63E ). The doses of carbamazepine were adjusted to produce serum concentrations in the range 30–60 mg/l. None of the patients who took carbamazepine reported symptoms of peripheral neurotoxicity; however, two patients (one who forgot to take carbamazepine and one who stopped taking it because he felt tired) developed grade I peripheral sensory neurotoxicity. These symptoms were abolished when carbamazepine was restarted. One can therefore speculate that the concomitant use of carbamazepine may allow the use of a higher cumulative dose of oxaliplatin without the occurrence of grade IV neuropathy. However, a multicenter trial is warranted to confirm these encouraging preliminary results (64c ). In addition to the acute neurotoxic symptoms caused by oxaliplatin, about 10–15% of patients develop a moderate neuropathy, particularly after cumulative intravenous doses of 700–800 mg/m2 . The symptoms of cumulative neuropathy include non-cold-related dysesthesia, paresthesia, superficial and deep sensory loss, and eventually sensory ataxia and functional impairment, which persists between treatment cycles. Most of these symptoms usually resolve a few weeks or months after oxaliplatin withdrawal. Lower cumulative doses (e.g. 510–765 mg/m2 ) and higher cumulative doses exceeding 1020 mg/m2 have been associated with incidences of cumulative grade III neurotoxicity of 3.2% and 50% respectively (8R , 9R , 58r , 59r ). In addition higher cumulative doses, exceeding 1000 mg/m2 , have been associated with severe, atypical neurotoxic symptoms, such as micturition disturbances and L’Hermitte’s sign, mimicking cord disease. However, these signs have been observed in only a few patients so far (3.3% in phase III

496 trials). Both symptoms appear to be reversible after oxaliplatin withdrawal (65A ). In some patients oxaliplatin treatment is feasible for as long as 18 months (e.g. cumulative oxaliplatin dose > 3000 mg/m2 ) with no signs of dysesthesia or paresthesia causing functional impairment, indicating high interindividual variability with respect to sensitivity to oxaliplatin-induced cumulative neuropathy (58r , 59r ). Whether cumulative sensory neuropathy can occur as a result of accumulation of dichloro-DACH-platinum, a biotransformation product of DACH-platinum, in the axonal and dorsal root ganglia neurons, needs further investigation (43E ). The risk of oxaliplatin-induced neurosensory toxicity may be increased after surgery. Of 12 patients with metastatic colorectal cancer, seven reported immediate postoperative aggravation of pre-existing neurotoxicity. Before surgery they had only acral paresthesia without any functional impairment, whereas after surgery they complained of major worsening of symptoms, including loss of hand grip strength, leading to dependence in dressing, eating, and use of the toilet, or loss of sensitivity, interfering with walking, which could persist for several months (66c ). The authors speculated that perioperative hemolysis had caused an increase in unconjugated bilirubin and the release of ultrafilterable oxaliplatin, which had previously been confined to the intraerythrocytic compartment. In addition, diffusion of ultrafilterable oxaliplatin out of erythrocytes into the plasma during hemodilution can contribute to the undesirable perioperative increase in unbound oxaliplatin in the plasma. In 15 patients with metastatic colorectal cancer who were given gabapentin (100 mg bd or tds) if neuropathic symptoms developed with oxaliplatin, the symptoms disappeared in all patients, even in those who received up to 14 courses of oxaliplatin. Withdrawal of gabapentin resulted in recurrence. However, a controlled trial is required to verify these encouraging preliminary results. It has been suggested that chronomodulated delivery of oxaliplatin might reduce the incidence of platinum-induced neurotoxicity (67c , 68R ). In a randomized multicenter trial in patients with previously untreated metastases from colorectal cancer, 93 patients were assigned chronotherapy and 93 were assigned constantrate infusion (69C ). Chronotherapy reduced the

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rate of severe mucositis five-fold and halved the rate of functional impairment from peripheral sensitive neuropathy. Median and 3-year survival times were similar in the two groups. Preliminary results have suggested that glutathione may be neuroprotective in patients receiving oxaliplatin (70C ). In a pilot study in 15 patients, subcutaneous amifostine was given 20 minutes before oxaliplatin, in order to counteract oxaliplatininduced peripheral neurosensory toxicity. In 10 patients, this regimen reduced the severity of cumulative neuropathy without compromising antitumor efficacy; the amifostine was well tolerated (71c ). Conventional dosages of carboplatin have been associated with the lowest risk of peripheral neuropathy (e.g. mild paresthesia) among the approved platinum compounds. It has been estimated that about 4–6% of patients who receive carboplatin develop a peripheral neuropathy. Patients over 65 years of age or patients pretreated with other neurotoxic agents may be at a slightly higher risk (72A ). CNS effects are uncommon after treatment with cisplatin. However, there have been case reports of cerebral herniation and coma, severe encephalopathy, tonic–clonic seizures with concomitant visual disturbances and changed mental state, insomnia, anxiety, and Parkinsonian symptoms. The symptoms generally resolved within several weeks (47R –49R , 50A , 73A ). In some studies the CNS effects were the consequence of cisplatin-induced electrolyte disturbances (e.g. hyponatremia, hypocalcemia, or hypomagnesemia) rather than a direct action of the platinum derivative in the CNS (74A – 76A ). For example, mental status improved in one patient who was given 3% sodium chloride in order to increase the serum sodium from 118 to 128 mmol/l, whereas diazepam, phenytoin, phenobarbital, and dexamethasone were ineffective (77A ). Sensory systems Ototoxicity Cisplatin is ototoxic. Tinnitus and bilateral high-frequency hearing loss (threshold 3000 Hz) have been observed in up to 31% of patients treated with initial intravenous doses of cisplatin of 50 mg/m2 . Single doses exceeding 150 mg given over a short period of time and higher cumulative doses have been reported to be associated with bilateral, symmetrical, progressive, and

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irreversible hearing disorders, which suggests that peak plasma concentrations as well cumulative effects contribute to this adverse effect. Other risk factors include young age, previous cranial irradiation, pre-existing renal dysfunction or inner ear damage, and the concomitant use of other potentially ototoxic agents, such as aminoglycosides, loop diuretics, or tirapazamine (78C –82C , 83R , 84r , 85r ). The mechanisms of cisplatin-induced damage to the outer hairy cells of the cochlea may include the formation of highly reactive oxygen radicals and depletion of glutathione (86E ). The role of amifostine and glutathione in preventing cisplatin-induced ototoxicity has therefore been studied (87R , 88c ). The data are not sufficient to support the use of glutathione in this indication. In contrast, there is some evidence that amifostine may provide protection (89R ). No ototoxicity developed in 18 patients who received amifostine over 15 minutes, 15–20 minutes before the intravenous administration of cisplatin 50–120 mg/m2 over 20 minutes. There was transient hearing loss and mild persistent audiometric abnormalities in only 30% of the patients who received cisplatin 150 mg/m2 . Ototoxicity after carboplatin therapy is thought to be rare (90A ). Only 1.1% of evaluable patients had symptoms, such as tinnitus, or subclinical audiographic changes. Routine audiometric monitoring is therefore not recommended during carboplatin therapy. However, after otoacoustic emission testing in 19 children who received cisplatin the authors suggested that this is better at detecting the early cochlear damage associated with cisplatin ototoxicity than traditional pure-tone audiometry, particularly in children, in whom early detection is of the utmost importance (91C ). Previous use of aminoglycosides increases the risk of ototoxicity. In patients who receive high-dose carboplatin, preliminary results suggest that there may be a correlation between the risk of ototoxicity and carboplatin serum concentrations (AUC) during the first course. Patients with high-grade ototoxicity had higher median carboplatin AUCs than patients without any symptoms (92R , 93R ). There is as yet no evidence that oxaliplatin causes ototoxicity (94E ). Visual disturbances Ocular effects, including optic neuritis, papilledema, and retrobulbular neuritis, are uncommon adverse effects

497 of cisplatin-containing cancer chemotherapy. The risk of retinal toxicity is restricted to highdose cisplatin therapy (e.g. 200 mg/m2 over 5 days) and can result in blurred vision and altered color perception, which can persist for several months. In contrast to cisplatin, carboplatin is seldom involved in drug-induced visual disturbances. In two cases there was a relation between the administration of carboplatin (800–1200 mg/m2 ) and the occurrence of clinical cortical blindness (92R ). However, both patients had impaired renal function before the start of therapy with carboplatin. Endocrine The long-term effects of chemotherapy in 244 patients with germ cell tumors on Leydig cell function have been studied by measuring concentrations of sex hormonebinding globulin, luteinizing hormone, and follicle-stimulating hormone at least 74 months after chemotherapy (95C ). The population was divided into groups by cumulative cisplatin exposure (above and below 400 mg/m2 ). Lowdose cisplatin exposure had no effect on Leydig cell function, but cumulative high-dose chemotherapy caused persistent impairment. Electrolyte balance About 75% of patients treated with cisplatin develop hypomagnesemia (serum concentrations below 1.5 mmol/l), which appears to be associated with druginduced renal tubular damage (96A , 97A , 98c ). The symptoms include tetany, muscular weakness, tremulousness, dizziness, personality changes, and perioral and peripheral paresthesia (99R ). Magnesium supplementation is generally recommended during treatment courses with cisplatin (97A , 100R ). Sometimes hypomagnesemia resolves rather slowly and can last several weeks. A significant reduction in serum magnesium and other effects associated with progressive renal dysfunction appear to correlate with high cumulative doses of carboplatin (e.g. a median cumulative dose of 2590 mg/m2 in children or in adults undergoing high-dose chemotherapy with peripheral blood stem cell support). Other electrolyte disturbances induced by cisplatin include hypocalcemia, hypophosphatemia, hyponatremia, and hypokalemia (101R , 102R ). However, these changes are rarely associated with symptoms (103C , 104A ).

498 Hematologic Compared with cisplatin and oxaliplatin, carboplatin has the highest myelotoxic potential. Carboplatin-induced myelosuppression is dose-related and results in thrombocytopenia and neutropenia. At conventional doses (AUC 4–7 min.mg.ml−1 ) about 20–40% of patients develop thrombocytopenia (platelet counts below 50 × 1012 /l). In contrast, severe neutropenia is less pronounced with conventional doses; about 16–21% of patients develop neutrophil counts less than 1 × 109 /l. The lowest leukocyte and platelet counts usually occur at 14–28 days after drug administration. The hemoglobin concentration was below 11 g/dl in 71–91% of patients and below 8 g/dl in 8–21% (93R ). The severity of drug-induced thrombocytopenia is inversely correlated with the endogenous formation and release of thrombopoietin, which is an important cytokine for de novo platelet formation in the bone-marrow. In contrast to conventional dosages, high-dose chemotherapy containing carboplatin is generally associated with severe and life-threatening forms of hematological toxicity, requiring the prophylactic use of recombinant hemopoietic growth factors, such as G-CSF, and peripheral blood stem cell support (105r ). Underlying risk factors, which predispose patients to more severe forms of myelosuppression, include lower initial blood cell counts, renal impairment, poor performance status, extensive prior chemotherapy, and advanced age. There is a strong correlation between carboplatin pharmacokinetics and the severity of myelosuppressive adverse effects; an AUC-adapted dosage of carboplatin is therefore highly recommended during conventional dose chemotherapy (22r , 23r , 93R ). Cisplatin belongs to the most important causative agents for the induction of treatmentrelated anemia requiring the prophylactic use of erythropoietin or intermittent transfusion of erythrocytes, whereas drug-induced leukopenia and thrombocytopenia are generally mild and transient (105r , 106C ). In a pharmacokinetic study non-protein-bound platinum concentrations in patients with significant falls in hemoglobin (3 g/dl or more) were significantly higher (mean 53 ng/ml) than in patients who did not have significant falls in hemoglobin. The authors suggested that early and simple platinum pharmacokinetic control on the day after first drug administration might be useful

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in targeting patients who are likely to develop more severe forms of cisplatin-related anemia (107R ). Myelosuppression caused by oxaliplatin is generally mild. Grade III/IV anemia, neutropenia, and thrombocytopenia are observed in only 2–3% of patients. In combination with fluorouracil/folinic acid the frequency is slightly higher, depending on the dose of fluorouracil (8R , 9R ). Gastrointestinal Of the approved platinum compounds, cisplatin has the greatest emetogenic potential (108R ). Whereas about 65–94% of patients who receive conventional dosages of carboplatin complain of mild to moderate nausea or vomiting, more than 90% of those who receive cisplatin have more than 10 vomiting episodes within the first day of administration in the absence of effective antiemetic therapy. An emetogenic episode occurring within 24 hours after drug administration is usually classified as acute emesis; nausea and vomiting that occur thereafter are classified as delayed emesis and may persist over several days. There appears to be a correlation between the time of cisplatin administration and the severity of drug-induced vomiting (109C ). When cisplatin was given in the morning (0500 h) vomiting was greater than when it was given in the evening (1700 h). However, the prophylactic use of a 5-HT3 receptor antagonist reduced the time-ofday dependency. 5-HT3 receptor antagonists, such as dolasetron, granisetron, ondansetron, or tropisetron, particularly in combination with dexamethasone, reduce the severity of acute emesis occurring within the first 24 hours after cisplatin. In contrast, the satisfactory prevention of delayed emesis remains a challenge. There is increasing evidence that the introduction of a novel class of antiemetic agents, the neurokinin-1-receptor antagonists, such as MK869 (aprepitant), may be associated with additional benefit in combination with a 5-HT3 receptor antagonist in reducing cisplatin-induced nausea and vomiting, both acute and delayed (110C ). Nausea, vomiting, and diarrhea are common adverse effects of oxaliplatin and carboplatin, but they are generally mild to moderate, and both are less emetogenic than cisplatin. However, patients who have previously received cisplatin may be at greater risk of vomiting with carboplatin or oxaliplatin (1R , 8R , 9R ).

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Liver Mild reversible increases in liver function tests can occur in patients who have received platinum compounds (111A ). However, the platinum compounds are generally not classified as hepatotoxic drugs. Urinary tract Of the approved platinum compounds cisplatin has the greatest nephrotoxic potential. If dosages exceed 100 mg/m2 per course or per day, nephrotoxicity is the most severe drug-related adverse effect. Irreversible renal insufficiency has been described after accidental overdosage with cisplatin. Cisplatininduced degenerative renal lesions are primarily observed in the proximal tubules, and are characterized by hydropic degeneration, necrosis, and occasional tubular atrophy. Sensitive indicators of cisplatin-related renal tubular toxicity include changes in creatinine clearance or in urinary alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase activities. Blood urea nitrogen and serum creatinine are poor indicators of early renal damage. The exact mechanisms of cisplatin-induced nephrotoxicity have not been fully elucidated. Like several nephrotoxic heavy metals (e.g. mercury), cisplatin may accumulate in the kidney, where it can interact with sulfhydryl compounds, resulting in increased membrane fragility and depletion of intracellular glutathione. There is some evidence that cisplatin can induce apoptosis and necrosis of kidney cells dose-dependently. In vitro studies have suggested that the constitutive expression of antiapoptotic proteins (e.g. bcl-X) might be inversely correlated with the sensitivity of renal tubular cells (87R , 112R , 113E , 114E ). Several supportive measures have been proposed in order to circumvent cisplatin-induced nephrotoxicity. These include: • adequate hydration before and during cisplatin administration and afterwards, in combination with an osmotic diuretic such as mannitol (the current standard method); • prolongation of the infusion time (e.g. 6 hours instead of 2 hours); • fractionation over several days; • the use of a chronomodulated schedule; • the use of nephroprotective agents, such as organic thiosulfate compounds. Experimental study drugs that may be useful in renal protection include BNP7787

499 (dimesna), selenium, and silibinin (87R , 115R , 116R , 117c –121c , 122E , 123E ). Regarding prolongation of infusion, it has been suggested that there is a correlation between higher plasma platinum concentrations and the risk of cisplatin-induced nephrotoxicity. If platinum concentrations exceed 6 μg/ml more patients develop nephrotoxicity. These drug concentrations were measured shortly after the end of infusion (e.g. 5 minutes after intravenous infusions of 100–120 mg/m2 ), suggesting that high blood concentrations rather than trough concentrations may be predictively important. As a result, prolongation of cisplatin infusion (e.g. 6 hours) has been proposed to reduce the risk of cisplatin-induced renal insufficiency (88c , 124C ). However, in practice a 1-hour infusion remains the common standard. Dose fractionation over several days has been associated with less kidney damage. The glomerular filtration rate was maintained in patients who received cisplatin 20 mg/m2 /day over 5 consecutive days (125c , 126C ). However, patients still had a significant increase in sensitive urinary markers, such as low molecular weight proteins, N-acetyl-beta-Dglucosaminidase (NAG), and alpha-1-microglobulin, showing that conventional approaches can reduce but not completely prevent nephrotoxicity (87R , 112R ). Chronomodulated administration of cisplatin can also reduce drug-induced organ toxicity, e.g. nephrotoxicity (127R , 128E ). Administration of cisplatin in the evening caused markedly less nephrotoxicity and neurotoxicity than morning administration. There is also increasing evidence that all platinum-based anticancer drugs are better tolerated if they are given in the late afternoon or early evening, with less frequent and severe nephrotoxicity, thrombocytopenia, and cumulative peripheral neuropathy after cisplatin, carboplatin, and oxaliplatin. As chronomodulated scheduling appears to affect the adverse effects of all platinum compounds, the mechanism may be based on circadian variation in renal tubular excretion and plasma filtration of platinum compounds, increased plasma protein binding, and reduced tissue susceptibility at about 1600 h (127R , 128E , 129C ). Intensified carboplatin-containing regimens can predispose patients to drug-induced renal dysfunction when cisplatin has previously been

500 used or when renal function is already impaired (104A , 130r ). Amifostine (WR-2721, ethyofos, 2-[3-aminopropyl)amino]ethylphosphorothioic acid) is an organic thiophosphate. It is a prodrug, because dephosphorylation by tissue-bound alkaline phosphatase is necessary to form its active metabolite, WR-1065. Its cytoprotective role in the alleviation of drug-induced or radiationinduced toxicity in normal cells appears to be based on free radical scavenging, hydrogen ion donation, and the prevention or removal of DNA platinum adducts (131R ). In a randomized study, 242 patients with advanced ovarian cancer received intravenous cisplatin 100 mg/m2 and cyclophosphamide 1000 mg/m2 once every 3 weeks with or without amifostine 910 mg/m2 . Besides a significant reduction in chemotherapy-induced neutropenia and thrombocytopenia, amifostine produced significant protection against cisplatin-induced nephrotoxicity. Creatinine clearance fell by more than 40% in 60% of the control group compared with 12% of those in the treated group. In addition, the incidence of cisplatinrelated hypomagnesemia was less pronounced in the patients who received amifostine. In several studies intravenous amifostine (910 mg/m2 ) preserved glomerular filtration rate when it was co-administered with cisplatincontaining regimens (131R ). Even after two cycles containing intravenous cisplatin 50 mg/m2 plus intravenous ifosfamide and etoposide or paclitaxel, GFR can fall by more than 30%, but concomitant use of amifostine prevented this. Even lower dosages of intravenous amifostine (e.g. 740 mg/m2 ) may be effective (132C , 133C ). Because preclinical results suggested that intracellular glutathione may be involved in the modulation of cisplatin-induced toxicity, several trials (two uncontrolled and two randomized) have been conducted to evaluate the efficacy and tolerability of standard doses of cisplatin with concomitant glutathione. In some studies glutathione reduced cisplatinrelated toxicity without impairing its antineoplastic activity (56R ). However, a cisplatin dose-escalation study with concomitant administration of glutathione had to be terminated prematurely because of unacceptable ototoxicity. Glutathione has not yet received FDA approval for chemoprotection. In contrast to cisplatin, severe nephrotoxicity is less common or absent in patients who

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receive carboplatin. In addition, carboplatininduced alterations in creatinine clearance or electrolytes are usually mild and transient. Concomitant intravenous hydration and monitoring is not needed when carboplatin is given in conventional dosages. However, during doseintensified treatment with carboplatin the risk of impaired renal function increases. In addition, other nephrotoxic drugs, such as ifosfamide, are often part of those high-dose combination regimens. During a study of the use of highdose carboplatin (1500 mg/m2 /day or more) on 3 consecutive days the nephrotoxic profile was comparable to a standard single dose of cisplatin (126C ). In a randomized study of the prophylactic use of amifostine during dose-intensified chemotherapy including carboplatin and ifosfamide, patients in the control arm had a median loss of GFR of 37% compared with baseline after one cycle, and 35% of these patients had GFRs below 60 ml/min on day 10 after treatment. In patients who received amifostine during dose-intensified chemotherapy the GFR fell only by a median of 10% and no patient developed a GFR below 60 ml/min by day 10 (134C ). Oxaliplatin, when given alone or in combination with fluorouracil, is considered not to be nephrotoxic (103C , 104A , 130r ). There has been a single case of acute tubular necrosis probably caused by oxaliplatin and not related to dehydration or pre-renal failure (135c ). Skin Even in cases of accidental extravasation the risk of skin ulceration is low. Severe cisplatin-related extravasation injury appears to be primarily restricted to the use of high concentrations (e.g. 0.75 mg/ml) and infusion over a short time. In such circumstances it is advisable to give a local injection of isotonic thiosulfate solution (0.16 mol/l). Since carboplatin is more slowly activated than cisplatin to active DNA binding moieties and is more water soluble, there have been no reports of severe carboplatin extravasation and no antidote is necessary (136A , 137A ). Accidental subcutaneous administration of oxaliplatin resulted in a red-brown painful swelling and sclerosis of the skin within 8 days (138A ). The symptoms were worst 1 week after extravasation and lasted for about 5 weeks, but the patient, a 52-year-old woman, recovered

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fully. Acute intervention included local fluid instillation to dilute the extravasation, removal of the cannula, cold packs, and a gel containing aescin and diethylamine salicylate. Recently two other cases of oxaliplatin extravasation have been reported (139A ). Both occurred when the intraport needle disconnected. The initial symptoms were swelling and tenderness at the port site. The patients developed severe inflammation after 3 days. Treatment included local cool packs, diclofenac ointment, and oral indomethacin, morphine, or dexamethasone. The authors avoided saline instillation because sodium chloride and oxaliplatin may be incompatible in combination (68R ). Both patients recovered without any sign of local necrosis and long-term sequelae (139A ). Immunologic Cisplatin can cause anaphylactic shock, asthma, or urticaria (140A ). Hypersensitivity reactions, probably of type I, have also been reported after the administration of cisplatin, carboplatin, and oxaliplatin (141A –144A , 145c , 146c ). These allergic reactions can include respiratory dysfunction (e.g. wheezing, dyspnea), gastrointestinal discomfort (e.g. abdominal cramps, diarrhea), and rashes (e.g. pruritus, urticaria, facial erythema, and swelling). The risk of exfoliative dermatitis is very low. In most patients the first signs of hypersensitivity reactions usually occurred after the administration of multiple intravenous courses containing platinum compounds. Whether patients who are hypersensitive to one platinum compound also react to another cannot be excluded, since some case reports have suggested possible cross-reactions among platinum compounds (147c ). Sometimes, successful retreatment may be feasible through premedication with steroids and antihistamines (142A ). The risk of carboplatin-induced hypersensitivity reactions is 2–9%. According to one retrospective analysis mild carboplatin-related hypersensitivity reactions, with itching and mild erythema, occurred in 20 of 194 patients, whereas 12 patients developed severe forms of reactions, including diffuse erythroderma, rigor, facial swelling, throat and chest tightness, tachycardia, bronchospasm, and hypertension or hypotension (146c ). The most important interventive measures in patients with severe

501 forms of hypersensitivity reactions include intravenous adrenaline, corticosteroids, and antihistamines. Severe anaphylaxis has been reported in five patients who had already received several cycles (5–12) containing oxaliplatin 100 mg/m2 every 2 weeks (144A ). The predominant symptoms included reduced systolic blood pressure, flushing, sweating, headache, tachycardia, and respiratory distress. If retreatment with the causative platinum compound is required in such cases, premedication with a glucocorticoid and antihistamine may prevent recurrence. However, symptoms can occur despite premedication, making drug withdrawal necessary. The term “oxaliplatin-induced hypersensitivity reaction” can refer to (a) acute neurosensory symptoms, (b) a cytokine release syndrome related to increased plasma concentrations of interleukin-6 and TNF-alpha, and (c) an immunological reaction involving antibody formation and histamine release (141A ). In order to prove an underlying allergic disorder an intradermal skin test with commercial formulations of the platinum compound in different concentrations (e.g. 0.003 mg/ml to 1 mg/ml) can be done (148A ). An effective carboplatin desensitization protocol has been reported in a child with hypersensitivity, allowing additional months of carboplatin treatment (149A ). After premedication with diphenhydramine, ranitidine, and methylprednisolone, eight dilutions of carboplatin (0.01–50.0 mg) were given intravenously at 15-minute intervals at a rate of 1 mg/min. Subsequently, carboplatin 600 mg was given as a continuous infusion over 3 hours without adverse effects. Whether desensitization is generally suitable for overcoming allergic adverse events should be tested prospectively (150A ). Body temperature Oxaliplatin is generally well tolerated. Some patients develop fever, which appears to be related to a transient increase in cytokines, particularly interleukin6 (IL-6) and TNF-alpha. In one study the oxaliplatin-induced increase in body temperature correlated with a marked increase in IL-6 serum concentrations (peak 133 pg/ml) (151c ). IL-6 is a proinflammatory cytokine, which stimulates acute phase proteins and B lymphocytes. Premedication with metamizol, dexamethasone, and clarithromycin, which interferes with IL-6,

502 did not prevent the fever. The roles of IL-6 and TNF-alpha in the development of fever is strengthened by the observation that their serum concentrations fell during resolution of the fever (152E ). Mutagenicity and carcinogenicity There is some evidence that platinum compounds are mutagenic in bacteria and can cause chromosomal aberrations in animal cells in tissue culture (153E ). The risk of secondary leukemia in 28 971 patients with ovarian cancers receiving platinum-based chemotherapy has been evaluated; 96 developed a secondary leukemia (154C ). The authors concluded that the risk of developing a secondary leukemia while receiving a platinum-based protocol may be increased four-fold. The relative risks for carboplatin and cisplatin were estimated at 6.5 and 3.3 respectively. The relative risks of leukemia after cumulative doses of platinum of less than 500 mg, 500–749 mg, 750–999 mg and 1000 mg were 1.9, 2.1, 4.1, and 7.6 respectively. The delay between the start of platinum-containing chemotherapy and the occurrence of secondary malignancies was 2.8–7.7 years. In children who received an average cumulative dose of cisplatin of 600 mg/m2 , the estimated incidence of chemotherapy-induced leukemia was 1.5% (155C ). Concomitant radiation therapy or administration of other carcinogenic agents increases the risk. Fertility There is experimental evidence that several anticancer drugs can cause abnormalities of sperm chromosomes. Preliminary data have suggested that after platinum-containing chemotherapy for testicular cancer, penetration of eggs can be severely impaired. Cytogenetic study of the spermatozoa has shown that many of the abnormalities correspond to structural aberrations that may not have a pathogenic effect in the production of abortions or children with chromosome abnormalities (156R ). Teratogenicity Cisplatin and related compounds cross the placenta and can therefore cause fetal damage. Cisplatin is teratogenic in mice and embryotoxic in mice and rats. The platins should only be used during pregnancy in life-threatening situations. The patient should be informed of the potential hazard to the fetus (157R ).

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Drug overdose In a 68-year-old woman who received an accidental overdose of cisplatin 480 mg there was severe vomiting and myelosuppression, irreversible renal failure, and deafness; other effects included seizures, hallucinations, loss of vision, and hepatotoxicity (158A ). Drug interactions Antiepileptic drugs Cisplatin caused subtherapeutic carbamazepine and valproic acid concentrations in a 38-yearold woman with epilepsy undergoing cytotoxic cancer chemotherapy with doxorubicin and cisplatin, resulting in tonic–clonic seizures (159R ). The mechanism was not clear. Plasma concentrations of antiepileptic drugs (e.g. carbamazepine, valproic acid, phenytoin) should be measured more frequently during cisplatincontaining cancer chemotherapy (159R , 160A ). Irinotecan The concomitant use of irinotecan as a 1-hour infusion immediately following a 2-hour infusion of oxaliplatin resulted in more severe hypersalivation and abdominal pain than irinotecan monotherapy (161A ). Acute intervention with atropine alleviated these adverse effects. When the drugs were separated by 1 day, the cholinergic symptoms were not exacerbated. The authors postulated that oxaliplatin might have some acetylcholinesterase inhibitory activity. Lithium Some data have suggested that cisplatin-containing chemotherapy can alter lithium clearance through impaired renal function, and lithium therapy should be closely monitored during treatment with cisplatincontaining regimens (162A ). Nephrotoxic drugs Based on its considerable nephrotoxic potential, cisplatin should be given after, rather than before, other anticancer drugs and other drugs with a low therapeutic index (e.g. aminoglycoside antibiotics) that are primarily excreted in the urine in unchanged form. Concomitant use of potentially nephrotoxic agents (e.g. conventional amphotericin, tacrolimus) with cisplatin should be avoided (163A , 164A ). Neurotoxic drugs The concomitant or previous use of potentially neurotoxic drugs (e.g. paclitaxel, vinca alkaloids, or hexamethylmelamine) may increase the risk of peripheral neuropathy due to platinum compounds (48R , 49R ).

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Paclitaxel There is some evidence that there is a clinically significant pharmacokinetic interaction of paclitaxel with cisplatin. When cisplatin was given before paclitaxel, the clearance rate of paclitaxel was 25% less than when the two drugs were given in the opposite sequence. In addition, neutropenia was more profound with the former schedule (165C ). In addition, in experimental studies cytotoxicity increased when human ovarian carcinoma cells were exposed to paclitaxel before cisplatin, whereas the interaction was antagonistic when a 1-hour exposure to cisplatin was followed by a 20-hour exposure to taxol, or when the cells were exposed to cisplatin and taxol for 1 hour concurrently (166E ). The biochemical basis of this interaction has not been elucidated. The pharmacodynamic interaction may be related to cisplatin-induced alterations in cell-specific and non-specific binding sites for paclitaxel (167E ). In view of these results, paclitaxel should be given before cisplatin (168R ). There is no similar interaction of paclitaxel with carboplatin (169R ).

GENERAL Recent reviews have increased our understanding not only of the adverse effects profiles of individual drugs (170R ) but also of the factors that contribute to the adverse effects of chemotherapy, which are not purely related to the pharmacology of the cytostatic drugs themselves. For example, there are some dramatic scheduling effects, particularly in hematological toxicity, depending on whether the patient receives doxorubicin followed by docetaxel or the same doses but in reverse order (171c ). Sex also has an effect: women suffer more frequent and more severe toxicity with fluorouracil than men (172M ). Finally, there has long been debate in oncology circles about whether toxicity is a surrogate for efficacy, based on the premise that the greater the toxicity and the effect on the organ or hematological cell line, the greater the effect on the cancer cells. Two recent papers have supported this premise (173c , 174R ). Cardiovascular The cardiotoxicity of anthracyclines still continues to be teased apart. The authors of a recent study used MRI scans

503 to assess the subclinical effects of the anthracyclines. They concluded that increased MRI enhancement equal to or greater than 5 on day 3 compared with the baseline predicted significant reduction in ejection fraction at day 28 (175c ). In 1000 patients given doxorubicin chemotherapy and irradiation there were six cases of congestive heart failure and three cases of myocardial infarction; there was a cumulative cardiac mortality of 0.4% in all anthracycline-exposed patients (176C ). Respiratory Various authors have discussed the differences in busulfan-induced idiopathic pneumonia syndrome, as a result of either chronic low-dose or short-course high-dose therapy. One group found that chronic low-dose therapy (even at cumulative doses of busulfan of up to 3 g) caused different lung damage from the clinical characteristics, radiological, and pathological features of the idiopathic pneumonia syndrome (177c ). Nervous system The sensory neuropathy caused by paclitaxel is well documented. A high-dose study has shown dose-related toxicity, with a dose-limiting ceiling at 775 mg/m2 , when paresthesia occurs (178c ). The late effect of chemotherapy and radiotherapy for CNS lymphoma has been studied in 15 patients, of whom 10 had severe symptomatic diffuse changes in the white matter within 8 months of completing treatment (179c ). Metabolism Hyperglycemia was reported in 21 of 56 patients who received weekly paclitaxel with oral estramustine and carboplatin (four-weekly); less than 10% required pharmacological intervention (180c ). There was mild hyperphosphatemia in 24. Fasting hypoglycemia was noted in 19 of 35 children with acute lymphoblastic leukemia receiving maintenance therapy of daily oral 6-mercaptopurine and weekly oral methotrexate; the authors noted that all the children improved on withdrawal of chemotherapy and 10 of 15 normalized (181c ). Liver Of 54 patients with non-small-cell lung cancers treated with a combination of gemcitabine 1000 mg/m2 on days 1 and 8 and paclitaxel 200 mg/m2 on day 1, six had abnormal but significantly raised liver enzymes (AsT

504 or AlT) (182C ). The authors believed that this was drug induced, but could not rule out underlying liver disease. Skin and nails Of 99 patients who received low-dose docetaxel (60 mg/m2 every 3 or 4 weeks), 25 had skin toxicity, mainly erythema and nail changes (183C ). Of a subset of 25 patients who received irradiation before docetaxel, four had recall dermatitis during their first infusion of docetaxel. All had previously received doxorubicin, which may in part have explained some of the toxicity. Hydroxyurea has featured prominently in recent reports of skin toxicity, including reports of Behçet’s disease, hyperpigmentation of the nails and palmar creases, and leg ulcers (184A , 185A , 186c ). Acral erythema, dermatomyositislike changes on the backs of the hands, squamous cell neoplasms on sun-exposed sites, and ulcers on the legs, genitalia, and oral mucosae have also been reported (187M ). Musculoskeletal In 26 men who took androgen deprivation therapy for prostate cancer for 10 years there was reduced bone mineral density with increasing duration of androgen deprivation therapy across the whole 10-year period (188c ). The authors also noted that patients taking intermittent therapy had similar loss of bone mineral density at years 2 and 4, but less bone loss from year 6 onwards. Reproductive system The gynecological consequences of antiestrogens (tamoxifen and toremifene) have been evaluated in 167 postmenopausal breast cancer patients in a 3-year prospective study (189C ). There was a proliferative endometrium more often in the tamoxifen group than in the toremifene group, but this did not translate into an increase in the rate of endometrial cancer. The authors did not recommend routine surveillance of the endometrium. Immunologic Asparaginase is well known to cause allergic reactions, which increase with the number of doses within a cycle and the number of exposures, irrespective of drug-free intervals. There is now a pegylated formulation (PEG-ASNase; Oncaspar™) with supposedly improved pharmacokinetics and lower allergenic properties. These claims have been investigated, and the authors concluded that although

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the hypersensitivity rate was lower it was still significant; furthermore, there was no crosssensitivity in previously treated patients (190C ). Carcinogenicity Among 679 patients receiving chemotherapy for advanced Hodgkin’s disease there were four deaths due to secondary malignancies (191C ). There were 75 deaths in all during 3 years, of which the vast majority were related to disseminated Hodgkin’s disease. Exposure to diethylstilbestrol during pregnancy in 4836 women has been reported to carry a relative risk of 1.27 of breast cancer later in life (192c ). However, the authors found no evidence to support the link between diethylstilbestrol exposure and ovarian, endometrial, or other cancers. Fertility Of 17 adult men who had been treated before puberty for sarcoma with highdose pulse cyclophosphamide (median dose 20.5 m/m2 ) as part of regimens containing vincristine, actinomycin, and cyclophosphamide, with or without doxorubicin, 10 had azoospermia, five had oligospermia, and only two had normal sperm counts (193c ). The authors concluded that the previous suggestion that puberty acts as a protection to infertility was not borne out and that the risk of infertility was proportional to the cumulative dose of cyclophosphamide. Drug administration route In the UK guidance on the safe administration of intrathecal chemotherapy has been issued (194S ), following a case in which vincristine was fatally injected into the cerebrospinal fluid (195S ). Two reports have reported the safe administration of etoposide intraventricularly (196c ) and a new long-acting formulation of cytarabine intrathecally (197c ). Of course, neither of these interventions is completely free from adverse effects, and mild reversible CNS effects are predictable. Drug interactions Diarrhea ameliorated in six of seven patients treated with irinotecan in combination with oral neomycin at 1000 mg tds (198C ). Neomycin had no effect on the pharmacokinetics of irinotecan and its major metabolites.

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505

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511 O. Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women. Br J Cancer 2001; 84: 897–902. 190. Vieira Pinheiro JP, Muller HJ, Schwabe D, Gunkel M, Casimiro da Palma J, Henze G, Von Schutz V, Winkelhorst M, Wurthwein G, Boos J. Drug monitoring of low-dose PEG-asparaginase (Oncaspar™) in children with relapsed acute lymphoblastic leukaemia. Br J Haematol 2001; 113: 115–19. 191. Hancock BW, Gregory WM, Cullen MH, Vaughan-Hudson G, Burton A, Selby P, Maclennan KA, Jack A, Bessell EM, Smith P, Linch DC, on behalf of the British National Lymphoma Investigation and Central Lymphoma Group. ChiVPP alternating with PABIOE is superior to PABIOE alone in the initial treatment of advanced Hodgkin’s disease: results of a British National Lymphoma Investigation/Central Lymphoma Group randomized controlled trial. Br J Cancer 2001; 84: 1293–300. 192. Titus-Ernstoff L, Hatch EE, Hoover RN, Palmer J, Greenberg ER, Ricker W, Kaufman R, Noller K, Herbst AL, Colton T, Hartge P. Longterm cancer risk in women given diethylstilbestrol (DES) during pregnancy. Br J Cancer 2001; 84: 126–33. 193. Kenny LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 2001; 91: 613–21. 194. Toft B. Toft Report. External enquiry into the adverse incident that occurred at Queen’s Medical Centre, Nottingham, 4 March, 2001. London: Department of Health, 2001. 195. NHS Executive. National guidance on the safe administration of intrathecal chemotherapy. HSC 2001: 022. 196. Fleischhack G, Reif S, Hasan C, Jaehde U, Hettmer S, Bode U. Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours. Br J Cancer 2001; 84: 1453–9. 197. Jaeckle KA, Phuphanich S, Van den Bent MJ, Aiken R, Batchelor T, Campbell T, Fulton D, Gilbert M, Heros D, Rogers L, O’Day SJ, Akerley W, Allen J, Baisdas S, Gertler SZ, Greenberg HS, LaFollette S, Lesser G, Mason W, Recht L, Wong E, Chamberlain MC, Cohn A, Glantz MJ, Gutheil JC, Maria B, Moots P, New P, Russell C, Shapiro W, Swinnen L, Howell SB. Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 2001; 84: 157–63. 198. Kehrer DFS, Sparreboom A, Verweij J, De Bruijn P, Nierop CA, Van de Schraaf J, Ruijgrok EJ, De Jonge MJA. Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 2001; 7: 1136–41.

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Radiological contrast agents

TYPES OF CONTRAST AGENTS Iodinated water soluble contrast agents are of four types: • High-osmolar ionic monomer (e.g. diatrizoate, iothalamate, metrizoate). • Low-osmolar ionic dimers (e.g. ioxaglate). • Low-osmolar non-ionic monomers (e.g. iopitridole, iohexol, iomeprole, iopamidole, iopromide, ioversol). • Iso-osmolar non-ionic dimer (e.g. iodixonal, iotrolan). They are mainly used intravascularly, but can also be injected into body cavities, particularly the low-osmolar contrast agents. The high-osmolar water-soluble contrast agent diatrizoate (Gastrografin) is suitable only for oral or rectal administration. Oil-based iodinated contrast agents, such as Lipiodol, are also available and can be used to outline the ducts of the salivary glands and the lacrimal ducts. Currently the low-osmolar contrast agents are routinely used for these applications. There are also contrast agents that enhance the diagnostic information provided by ultrasound scanning and magnetic resonance imaging. The latter are mainly based on gadolinium, but new non-gadolinium paramagnetic contrast agents have recently become available. Ultrasound contrast agents are microbubbles that provide acoustic enhancement. Liposomal contrast agents have recently been developed, mainly for hepatic CT imaging. They are not yet available for routine clinical use and their safety is currently being evaluated. Adverse reactions to contrast agents are generally few, and serious reactions are uncommon. Ultrasound contrast agents are particularly safe.

© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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INTRAVASCULAR IODINATED CONTRAST AGENTS Water-soluble iodinated contrast agents for intravascular use (SEDA-23, 494; SEDA-24, 519; SEDA-25, 557) Adverse reactions to intravascular iodinated contrast agents can be minor, intermediate, or severe and life-threatening. All types of reactions to low-osmolar contrast agents are five times less common than reactions to highosmolar contrast agents. There are no important differences in the safety profiles of low-osmolar non-ionic monomers (SEDA-25, 557). In a study from Taiwan the incidence of adverse reactions has been investigated in 28 364 patients after intravenous injection of contrast agents during intravenous urography and CT scanning (1CR ). There were adverse reactions in 495 patients (1.75%), including 467 patients of 20 260 (2.03%) examined with ionic contrast agents and 28 of 8076 patients (0.34%) examined with non-ionic contrast agents. The authors concluded that the risk of adverse reactions to non-ionic contrast agents is significantly lower than with ionic agents. Skin rashes, such as urticaria, were the most common adverse effects, followed by nausea and vomiting. Shock requiring cardiopulmonary resuscitation was rare and occurred in only six patients (0.02%); there were no deaths in this series. The safety of the non-ionic contrast agents has also been emphasized in a review from Germany, in which the authors documented a reduced risk of adverse drug reactions with nonionic contrast agents during interventional cardiology (2CR ). According to reports to the FDA, the incidence of lethal complications was 3.9% with ionic monomers, 6.39% with the ionic dimer ioxaglate, and 2.07% with non-ionic monomers. The authors also stated that nonionic contrast agents do not have thrombogenic

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potential, a previous concern; currently most authors would support this view (SEDA-22, 501; SEDA-23, 497). Adverse reactions to contrast agents have been linked to an in vivo interaction with enzymes involved in cholinergic activity. However, experimental results on this topic are conflicting. A study of the in vivo effects of the non-ionic monomer iohexol and the high-osmolar ionic monomer diatrizoate on human plasma acetylcholinesterase and butyrylcholinesterase has shown that both contrast agents significantly reduce the activities of these enzymes (3C ). The effect was more pronounced with iohexol, which has a lower incidence of adverse effects than diatrizoate. The significance of this observation is not certain, but activation of these enzymes is not likely to be important in mediating the adverse effects of contrast agents.

Delayed reactions to iodinated water-soluble contrast agents (SEDA-23, 495; SEDA-25, 558) Delayed contrast reactions usually occur after 1 hour but within 7 days of contrast injection. Several of the reported delayed adverse effects, such as headache, musculoskeletal pain, and flu-like symptoms, may not be caused by the contrast agents, but delayed allergic-like skin reactions are most likely to be. Delayed skin reactions tend to be commoner with non-ionic dimers than with other types of contrast agents (SEDA-22, 499). Delayed reactions are generally benign, but not always. The incidence of delayed adverse reactions has been investigated in 2001 patients who underwent cardiac angiography with either iopamidole 340 (a non-ionic monomer; n = 738, ages 22–88 years, mean dose 1.79 ml/kg), ioxaglate 320 (an ionic dimer; n = 644, ages 28–86 years, mean dose 1.8 ml/kg) or iodixanol 320 (a non-ionic dimer; n = 619, ages 26–85 years, mean dose 1.74 ml/kg) (4CR ). The authors considered reactions that occurred within 24 hours as early reactions and those that occurred after 24 h but within 1 week of the cardiac catheterization as late reactions. The incidences of early reactions

513 were 22% with ioxaglate, 8.8% with iopamidol, and 7.6% with iodixanol. The commonest early reactions were urticaria and nausea and vomiting, the respective incidences being 6.8% and 4.0% with ioxaglate, 0.8% and 1.0% with iopamidole, and 0.5% and 1.1% with iodixanol. A few patients developed sudden hypotension, 0.5% with iopamidole, 1.4% with ioxaglate, and 0.3% with iodixanol. Cardiac arrest occurred in two patients with iopamidole, three with ioxaglate, and one with iodixanol. The frequencies of delayed skin reactions, which were generally benign, were 12% with iodixanol, 4.3% with ioxaglate, and 4.2% with iopamidol. The authors concluded that selection of a contrast agent for diagnostic cardiac catheterization should take account of adverse effects. Iodixanol was the best tolerated agent in the early phase of the study, but it was associated with a higher incidence of delayed skin reactions. The authors did not consider that the skin reactions represented a contraindication to iodixanol, although patients should be advised of this particular adverse effect. Furthermore, no contrast agent was free from these effects. Ioxaglate was the least well tolerated agent in the early phase, with a much greater chance of causing nausea/vomiting and allergic reactions. Delayed adverse reactions to ioxaglate have been documented after coronary angiography with ioxaglate (5A ). • A 63-year-old housewife had an acute myocardial infarction. Diagnostic coronary angiography was performed with ioxaglate and repeated 1 week later. On the morning after she had intense shivering and generalized malaise, a temperature of 39.2◦ C, and hypotension. Several hours later she developed a non-pruritic maculopapular rash, starting on the face and extending within the next 48 hours to cover the entire body but sparing the mucous membranes. She had a mild eosinophilia (600 × 106 /l) with a raised erythrocyte sedimentation rate (52 mm at 1 hour). Her IgE concentration was raised at 1593 kU/l. Blood cultures were negative. The initial clinical impression was that she had sepsis and she was therefore given vancomycin, netilmicin, and cefotaxime (dosages not stated). She improved rapidly and the fever and the rash resolved completely. She was discharged taking atenolol 100 mg/day and lysine acetylsalicylate 250 mg/day, but 3 days later she returned with a temperature of 39.8◦ C and recurrence of the skin rash. She had a marked eosinophilia (1.4 × 109 /l) and raised liver enzymes (AsT 125 IU/l, AlT 116 IU/l, alkaline phosphatase 374 mIU/l). Lactate dehydrogenase

514 (116 mU/ml) and aldolase (125 mU/ml) were raised, but creatine kinase was in the reference range. She had a significantly raised concentration of circulating immune complexes (107 mg/l; reference range below 25 mg/l). Her IgE was 1479 kU/l. Atenolol and lysine acetylsalicylate were withdrawn and she was given acenocoumarol 2 mg/day and amlodipine 5 mg/day. The inflammatory syndrome rapidly disappeared and the enzymes and eosinophil count returned to normal. She had immunological investigations 2 months later. The total IgE was still raised at 1649 kU/l. The leukocyte count and C reactive protein concentration were within the reference ranges. The serum antinuclear antibody titer was 1/256 and the antimitochondrial antibody titer was 1/128. Tests for anti-native DNA, antihistone, and antismooth muscle antibodies were negative. Skin prick tests, intradermal tests, and patch tests with lysine acetylsalicylate, atenolol, heparins, vancomycin, netilmicin, cefotaxime, and the contrast agents ioxaglate, sodium ioxathalamate, iopamidol, and iohexol were negative at 15 minutes, but at 48 hours indurated erythematous papules were observed with ioxaglate, ioxothalamate, and iopamidol. Histological examination of a biopsy from the ioxaglate skin reaction showed discrete spongiosis of the epidermis associated with slight lymphocytic exocytosis. The basal layer contained numerous apoptotic keratinocytes. The superficial dermis was edematous and there was a perivascular inflammatory infiltrate composed mainly of T lymphocytes. There were no mast cells or eosinophils. Immunohistological examination showed no staining with anti IgE, IgG, IgM, C1q, C3, or C4. During follow-up she was completely normal at up to 1 year, with a normal eosinophil count and an IgE concentration of 440 kU/l.

This report documents a rare clinical reaction to ioxaglate, with a combination of a maculopapular rash, fever, hepatic and muscle involvement, eosinophilia, and a very high serum IgE concentration. The intradermal tests confirmed a delayed hypersensitivity reaction to ioxaglate. Histological examination of a skin biopsy identified the predominantly T lymphocyte nature of the infiltrate. A contributing role of the beta-blocker atenolol to the seriousness of the clinical syndrome must also be considered. Delayed skin reactions after intravascular iodinated contrast agents have previously been documented and showed the features of true delayed hypersensitivity reactions with positive skin tests (SEDA-24, 523; SEDA-25, 561). Cardiovascular It is well established that low-osmolar contrast agents are in general bet-

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ter tolerated than high-osmolar ionic agents in cardiac and coronary angiography, and it has recently been suggested that the non-ionic iso-osmolar dimer iodixanol has minimal cardiotoxic effects (SEDA-25, 558). The safety of iodixanol 320 and iohexol 350 has been investigated in Swedish patients undergoing cardiac angiography for suspected coronary artery disease (6C ). Of 1020 patients, 502 aged 25–83 years received iohexol (median dose 105 ml, range 20–440) and 518 aged 18–85 years received iodixanol (median dose 115 ml, range 30–400). There were 134 patients with unstable angina in the iohexol group and 167 in the iodixanol group. Cardiac adverse events (angina pectoris, dysrhythmias, and dyspnea) within 24 hours of the examination were reported by 9% of the patients who received iohexol and 7% of patients who received iodixanol. There were two cases of ventricular fibrillation, both after iohexol. Cardiac adverse events in patients aged 65 years or more occurred in 11% with iohexol and 7% with iodixanol. The proportions of patients with unstable angina and cardiac adverse events were 18% with iohexol and 12% with iodixanol. The authors concluded that iodixanol could be advantageous in old patients and in those with unstable angina. Nervous system Transient cortical blindness is a well recognized complication of vertebral angiography (SEDA-23, 497; SEDA-24, 521; SEDA-25, 559). Now transient contrast encephalopathy has been reported after carotid artery stenting (7A ). • An 82-year-old right-handed man was given 50 ml of the ionic low-osmolar contrast agent ioxaglate 320 for carotid angiography. The next day his right internal carotid artery was stented and a total of 180 ml of ioxaglate was used. Aspirin, ticlopidine, and heparin 5000 units were given during the procedure. While he was still on the table he developed rapidly worsening confusion and a left hemiparesis. A CT scan without contrast 4 h later showed marked cortical enhancement and cerebral edema in the distribution of the right anterior and middle cerebral arteries. He rapidly improved and had complete neurological recovery after 48 hours; 1 month later he was asymptomatic.

The cerebral contrast enhancement on the CT scan suggested disruption of the blood– brain barrier. This could have been due to the large volume of contrast medium used during

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the stenting procedure. This complication must be differentiated from massive cerebral infarction and hyperperfusion syndrome: the rapid radiological resolution and clinical recovery excluded cerebral infarction; hyperperfusion syndrome would have involved the carotid distribution exclusively, rather than both the ipsilateral carotid and posterior circulations. The authors recommended close follow-up of patients after such procedures. The safety of subsequent cerebral angiography in a patient with a history of such a reaction has not been studied extensively, and extreme caution must be exercised should the need for repeat angiography arise later. Sensory systems A few cases of hearing impairment attributed to contrast agents have previously been reported. A case of severe sensorineural hearing loss after drip intravenous pyelography with iohexol has now been reported (8A ). • A 37-year-old man with recurrent attacks of low back pain underwent drip intravenous pyelography to exclude the possibility of stones of the urinary tract. Iohexol 300 was used, but the total volume was not documented. He had had drip intravenous pyelography for suspected urinary calculi 5 years before. A few hours after the procedure he suddenly had bilateral hearing loss and tinnitus in the right ear. He complained of dizziness and nausea but had no rotatory vertigo or skin rash. A puretone audiogram 2 days later showed complete right-sided and partial left-sided deafness. CT and MRI scans showed no abnormalities in the inner ear, internal auditory canal, or posterior fossa. He was given intravenous high-dose hydrocortisone sodium succinate, 10% dextran, and batroxobin, but there was no improvement in hearing. The dizziness and tinnitus in the right ear persisted, as did the deafness, for a further 2 months.

Hearing disturbances attributable to contrast agents are extremely rare. The hearing loss in this patient developed more than 1 hour after the injection of iohexol, without any evidence of other causes. The authors suggested that the hearing disturbance might have been attributable to cochlear impairment caused by a delayed allergic reaction or chemical toxicity of the contrast medium. Endocrine Hyperthyroidism and hypothyroidism have both reportedly been precipitated by iodinated contrast agents (SEDA-21, 478; SEDA-23, 497; SEDA-25, 559). Thyroid

515 metabolism has been prospectively investigated in 102 patients undergoing diagnostic coronary angiography (9C ). Thyroid function tests (T3 , rT3, T4 , free T4 , and TSH) and urinary iodine excretion were measured before and 3 weeks after diagnostic intra-arterial administration of iodinated contrast agents. Only euthyroid patients were included, in order to determine whether the administration of non-ionic iodinecontaining contrast agents causes significant thyroid function changes in euthyroid patients and whether thyroid morphology is a prognostic factor for the risk of hyperthyroidism. Serum concentrations of thyroid autoantibodies (TPO-Ab, Tg-Ab, TSH-receptor-Ab) were measured. Thyroid ultrasound showed that 37 patients had normal thyroid glands. The gland was of normal size but nodular in 16 patients, there was a diffuse goiter in 15 patients, and a nodular goitre in 34 patients. In 25 patients Tg-Ab was positive and in 13 patients TPO-Ab was positive; TSH-receptor-Ab was not detected in any patient. T3 concentrations did not change significantly after the administration of iodine. T4 and free T4 concentrations underwent significantly different changes in the four groups. The amount of iodine given did not affect the changes in the serum concentrations of TSH, T3 , T4 , free T4 , or rT3. Raised concentrations of urinary iodine correlated with the amount of contrast medium given. There were no cases of hyperthyroidism. The study showed that thyroid function was significantly altered after coronary angiography, independent of antibody status and the amount of contrast agent given, but dependent on thyroid morphology. Hematologic Iodinated water-soluble contrast agents have traditionally been contraindicated in patients with sickle cell disease, because of possible shrinkage of erythrocytes secondary to the high osmolality of these agents, which can lead to impaired blood flow through the microcirculation and can precipitate or exacerbate a sickle cell crisis. The hematological and rheological effects in vitro of four contrast agents of different osmolalities (iodixanol 290 mmol/kg, ioxaglate 600 mmol/kg, iohexol 844 mmol/kg, and diatrizoate 1940 mmol/kg) have been compared (10E ). Blood was tested from 10 healthy and 10 sickle cell donors at drug concentrations of

516 0, 1, 10, and 30% w/v in an attempt to approximate the circulating concentrations of contrast medium that might occur during bolus injection. There were significant hematological effects in the blood of both the healthy and sickle cell donors: there was a concentration-related reduction in hematocrit and MCV and an increase in MCHC, all of which varied directly with the osmolality of the contrast medium (diatrizoate > iohexol > ioxaglate > iodixanol). Only with diatrizoate at concentration of 10–30% was there marked echinocytosis. There was no significant increase in the number of irreversibly sickled cells in donors with hemoglobin S. The filterability of erythrocyte suspensions through capillary sized pores was impaired in both healthy and sickle cell samples in direct proportion to the osmolality of the contrast medium. Filterability effects were greater with sickle cells than healthy erythrocytes. Iodixanol, which is iso-osmolar with blood, had little effect on erythrocyte volume and had no significant effect on the filterability of healthy or sickle cells. These results suggest that microcirculatory impairment after infusion of contrast agents can occur in sickle cell disease because of the unusual rheological sensitivity of HbSS erythrocytes and may be avoided by using low-osmolar or iso-osmolar contrast agents. In another study the effects of contrast agents on leukocytes, platelets, and endothelium have been investigated in 19 subjects (mean age 63 years) undergoing angiography with the non-ionic contrast medium iohexol 350 (median volume 40–160 ml) for leg ischemia (11c ). Blood was obtained from the external iliac vein before and at several intervals after the injection of the contrast agent into the ipsilateral femoral artery. Markers of endothelial cell injury (von Willebrand factor), platelet activation (soluble P-selectin), and leukocyte activation (neutrophil elastase and soluble L-selectin) were measured in citrated plasma. Soluble intracellular adhesion molecule-1 and thromboxane B2, which are non-specific markers of inflammation, were also measured. Compared with the sample before angiography, concentrations of soluble L-selectin and soluble intracellular adhesion molecule-1 were reduced immediately after passage of the last bolus of contrast medium; 15 min later the concentrations returned to normal, but the concentration

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of von Willebrand factor had increased. After 30 minutes only thromboxane B2 concentrations were increased. On the next day both von Willebrand factor and soluble P-selectin were increased. These data point to both early and late effects of contrast agents on markers of endothelial, platelet, and leukocyte function. The authors suggested that these adverse changes may increase the risk of coagulopathy and thrombosis after contrast examination and increase the risk of re-stenosis after angioplasty. Gastrointestinal Iodinated water-soluble contrast agents can be used for imaging the gastrointestinal tract, particularly when leakage from the bowel lumen is suspected. The use of the high-osmolar sodium diatrizoate (Gastrografin) as an agent for pre-operative mechanical bowel preparation has been investigated in 58 patients (aged 45–80 years) listed for elective colorectal operations (12C ). One group (30 patients, mean age 67 years) was given oral Gastrografin 200 ml and 3 liters of water for 2 days before the operation. The rest (28 patients, mean age 65 years) were given Ringer’s solution 5–20 l, warmed to body temperature, through a nasogastric tube; preparation was considered complete when the patient excreted clear fluid. All were given metronidazole and cefuroxime as antibiotic prophylaxis during the perioperative period. There were no significant adverse effects in the Gastrografin group, apart from nausea in six patients. In the Ringer’s solution group there was nausea in 15 patients and vomiting in eight. A clean colon was found at operation in 93% of patients in both groups. The authors concluded that Gastrografin is well tolerated and can be used successfully for mechanical bowel preparation before elective colorectal surgery. The rectal administration of Gastrografin 400–1000 ml in patients with suspected diverticulitis before CT examination of the abdomen has been investigated in 308 patients (aged 19–97 years) (13C ). None of the CT scans showed extravasated contrast material in the peritoneal cavity as a sign of bowel perforation. No patient had sudden clinical deterioration after the examination. All tolerated the contrast medium well and there were no allergic reactions. High-quality diagnostic examinations were obtained in all patients.

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Urinary tract Renal insufficiency induced by contrast agents remains a source of concern. The renal effects of low-osmolar contrast agents (iopromide, ioversole, and ioxaglate) have been evaluated in 45 patients who underwent cardiac angiography (14C ). Iopromide (370 mg I/ml, mean dose 1.9 g/kg) was used in 15 patients (mean age 62 years, mean serum creatinine 107 µmol/l, mean creatinine clearance 67 ml/min), ioversole (320 mg I/ml, mean dose 1.8 g/kg) in 15 patients (mean age 62 years, mean serum creatinine 103 µmol/l, mean creatinine clearance 71 ml/min), and ioxaglate (320 mg I/ml, mean dose 1.8 g/kg) in 15 patients (mean age 63 years, mean serum creatinine 100 µmol/l, mean creatinine clearance 71 ml/min). All were normally hydrated and none had been examined with contrast agents in the months before the study or had been treated with nephrotoxic drugs. There were minor increases in serum creatinine 24 h after ioversole (from 103 to 107 µmol/l) and ioxaglate (from 100 to 106 µmol/l) and at 48 hours after iopromide (from 107 to 115 µmol/l). Plasma concentrations of beta2 microglobulin increased only with ioxaglate (from 1.9 to 2.0 mg/l at 24 hours). There was a reduction in creatinine clearance from 71 to 55 ml/min only with ioxaglate 6 h after the administration, but it returned to baseline 24 hours later. There were no significant variations in creatinine clearance at 48 hours after angiography. There were increases in the activities of different tubular enzymes in the urine after angiography with all the contrast agents, but the changes were larger after ioxaglate. The tubular effects were maximum at 6–24 hours and returned to baseline within 72 hours after angiography. In summary all three low-osmolar contrast agents caused reversible tubular damage, indicated by increased enzymuria, which was higher after ioxaglate. In addition, ioxaglate slightly impaired glomerular function. None of the observed changes in renal function were clinically relevant and they were not statistically significant. In summary, none of the three low-osmolar contrast agents caused significant changes in renal function. However, the authors suggested that ioxaglate is probably more nephrotoxic than non-ionic monomeric agents, and that other physicochemical properties beside osmolality play a role in nephrotoxicity due to contrast agents.

517 Acute reduction in renal perfusion is considered important in the pathophysiology of contrast agent-induced nephrotoxicity. Colorcoded duplex sonography has been used in assessing intrarenal vascular resistance in 10 patients (mean age 51 years) after intravenous injection of 100 ml of the low-osmolar contrast medium iopamidole (300 mg I/ml) (15C ). The resistive index was measured at 1 minute intervals over 10 minutes after injection in each patient. There was a statistically significant rise in resistive index at 2, 3, 4, and 5 minutes after injection, mean values 0.74, 0.75, 0.72, and 0.75 respectively. The resistive index then fell progressively to baseline values (mean 0.70) within 10 minutes. The authors concluded that colorcoded duplex sonography is a simple method for checking changes in renal flow resistance after intravascular contrast agents. They suggested that arterial Doppler flow measurement is ideal for investigating the pathophysiological mechanism of contrast agent-induced nephrotoxicity. The pharmacokinetics and safety of the lowosmolar non-ionic contrast agent iomeprole have been investigated in healthy volunteers and patients with various degrees of renal impairment (16C ). Six patients had normal renal function (glomerular filtration rate over 100 ml/min, aged 22–58 years), six had mild renal impairment (glomerular filtration rate 51–75 ml/min, aged 36–74 years), six had moderate renal insufficiency (glomerular filtration rate 26–50 ml/min, aged 58–79 years), and four had severe renal impairment (glomerular filtration rate below 25 ml/min; aged 34–73 years). Eight patients (aged 24–62 years) with end-stage renal disease who were receiving chronic hemodialysis were also studied. All received a single intravenous 50-ml bolus injection of iomeprole 400 mg I/ml and dialysis was performed about 2 hours later. The halflife of iomeprol increased progressively with increasing renal impairment. The half-life was 2 hours in patients with normal renal function, 4–6 hours in those with mild renal impairment, and 16–48 hours in those with severe renal impairment. Fecal excretion over 120 h ranged from 1.6% of the total dose in healthy subjects to 7.2% in those with severe renal impairment. Thus, the pharmacokinetics of iomeprole are similar to those of other water-soluble contrast agents.

518 In patients receiving hemodialysis the mean plasma iomeprole concentration fell by 36% at 2 hours after administration when hemodialysis was started. The mean half-life on dialysis was 4.4 hours. The effective fall in plasma iomeprole concentration after a single dialysis was about 70%. The mean fraction of the dose recovered in the dialysate was 58%. The mean dialysis clearance was 81 ml/min. The extraction efficiency of the dialyser was about 40%. The only adverse effect was infection of an arteriovenous fistula in a patient with end-stage renal disease, which was unrelated to the contrast agent. There were also mild to moderate adverse effects, but all resolved without sequelae. The most common adverse effects were headaches and sensations of warmth. Others were paresthesia, abdominal pain, taste disturbance, and nausea. None of the events was considered to be clinically important. There were no clinically important changes in vital signs, physical examination, electrocardiography, or clinical laboratory evaluations. The authors concluded that iomeprole is safe and well tolerated and can be almost completely eliminated both in patients with renal impairment and in patients receiving dialysis. The use of hemodialysis immediately after intravascular administration of contrast agents to prevent the development of nephrotoxicity in patients with renal impairment has been investigated in 15 patients with a mean serum creatinine of 234 µmol/l before contrast injection (17c ). The patients were randomized to receive either conservative treatment or hemodialysis for 2–3 hours, starting as early as possible (mean 106 minutes) after administration of the contrast agent. The increase in serum creatinine on days 2 and 3 after contrast injection was higher in the dialysed group. The incidence of nephrotoxicity, defined as an increase in serum creatinine by more than 44 µmol/l within 48 hours after administration of the contrast agent, was significantly higher in the dialysed group (43% versus 13%). The authors concluded that hemodialysis performed within 2 hours after contrast injection did not prevent the development of nephrotoxicity in patients with reduced renal function; indeed, it seems to have made things worse.

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The use of prophylactic hemodialysis, in most cases starting more than 20 minutes after injection of a contrast agent, has been investigated in 113 patients with renal insufficiency (serum creatinine concentration over 200 µmol/l) (18C ). Hemodialysis did not reduce the incidence of contrast nephrotoxicity. This failure could have been related to the rapid onset of renal injury after the administration of the contrast agent. Skin Delayed skin reactions after intravascular administration of contrast agents have previously been reported (SEDA-24, 523; SEDA-25, 561). There has now been a report of toxic epidermal necrolysis after intravenous injection of the non-ionic monomer iohexol (19A ). • A 33-year-old man had three contrast-enhanced CT scans with iohexol over about 2 weeks, and developed a disseminated erythematous skin rash. Because drug allergy was suspected, all drugs were withdrawn. Because of a persistent fever a fourth CT scan was performed with iohexol, and 2 hours later he developed malaise, pruritic erythema, hypotension, and cutaneous bullae affecting 50% of his body surface and his oral mucosa. He was treated for toxic epidermal necrolysis and his skin healed without scarring or altered pigmentation. Skin patch tests, prick tests, intradermal tests, and intravenous and oral single-blind challenges with the antibiotics he had received were negative. However, a patch test with iohexol 300 mg I/ml was positive at 48 hours: erythema and multiple small flaking blisters appeared in the patch area. Identical patch tests in healthy controls were negative.

The authors concluded that the patient had had a delayed hypersensitivity reaction to iohexol, causing toxic epidermal necrolysis. Oil-based contrast agents have been used regularly in the past for sialography and dacrocystography. Extravasation of these contrast agents can cause lipogranuloma formation (20A ). • A four-year-old boy with epiphora had a left dacrocystogram with the iodinized oil-based contrast agent Lipiodol under general anesthesia. During injection a false passage was inadvertently formed, with extravasation of the contrast agent from the lacrimal duct into the surrounding tissues. This was confirmed radiographically. He developed swelling and erythema, which gradually resolved over 6 months.

Currently, iso-osmolar non-ionic dimers, such as iotrolan or iodixanol, are the safest contrast

Radiological contrast agents

Chapter 46

agents for such a procedure. Extravasation of these agents causes minimal tissue reaction. Immunologic French workers investigating the causes of severe reactions to iodinated contrast agents suggested that any patient who has had a severe anaphylactoid or anaphylactic reaction after the injection of a contrast agent should undergo immunological assessment (21CR ). The diagnosis of drug anaphylaxis is usually based on the history, proof of mediator release, and the presence of drug-specific IgE antibodies or positive skin tests. In five patients with severe anaphylactoid reactions after the intravascular injection of an iodinated contrast agent, the clinical symptoms, biology, and skin tests were consistent with anaphylaxis. The authors also reported that no premedication has proved effective in preventing subsequent allergic reactions to contrast agents. Drug formulations There are several new formulations of liposome-encapsulated iodinated contrast agents under evaluation, particularly for liver imaging by CT (SEDA-25, 561). A new formulation of liposome-encapsulated iodixanol has been evaluated as part of a phase 1 assessment of diagnostic efficacy and safety (22C ). The formulation is a ready-to-use suspension of multilamellar liposomes with a mean size of 340 nm. The main constituents of the liposome wall are phosphatidylcholine and phosphatidylserine. The concentration of iodixanol in the formulation is 200 mg I/ml (80 mg encapsulated I/ml). The encapsulated iodine to lipid ratio is 1 : 5. This new formulation was injected in doses of 10, 30, 70, and 100 mg of encapsulated I/kg in 5, 8, 8, and 8 healthy volunteers (mean age 30 years). Saline was given to two volunteers in each dose group, in a volume matching that of iodixanol at the 70 mg dose. The intravenous injection was carried out using a power injector at a rate of 2 ml/s. There were dose-dependent changes in leukocyte counts. During the first 2 hours the leukocyte count fell and then rose. At 10 and 30 mg doses the changes were small and in most of the volunteers did not exceed the reference range. At higher doses there was a prominent increase in neutrophils with rod-shaped nuclei, suggesting increased release from the bone-marrow. C-reactive protein also rose dosedependently, suggesting a cytokine-mediated

519 reaction. Leukocyte count and C-reactive protein normalized spontaneously after 24 hours. The volunteers had subjective adverse events at doses of 70 and 100 mg; these included chills (88%), back pain (25%), flu-like symptoms (13%), and nausea and vomiting (38%); they started within 1 hour and recovered spontaneously within 3 hours. No adverse events were interpreted as severe, but they were judged to be too pronounced to be clinically acceptable. Research is needed to find a formulation that causes fewer adverse events without compromising diagnostic quality. Another new hepatocyte-specific contrast formulation, dysprosium-ethoxybenzyltris(carboxylatomethyl)triazaundecanedioic acid-diethylenetriaminepenta-acetic acid (Dy-EOBDTPA), has been used for liver CT imaging (23C ). It contains calcium-EOB-DTPA (0.5 mg/ml), trometamol (1.2 mg/ml), and hydrochloric acid (final pH 7.4). It has been described as a stable metal chelate with high tolerability in vitro and in animal studies, in which a long-lasting increase in CT density of about 30 Hounsfield units has been reported. A total of 40 healthy male volunteers (mean age 33 years) received intravenous infusions of Dy-EOB-DTPA, 0.05, 0.1, 0.25, 0.375, or 0.5 mmol/kg over 10 minutes (n = 6 in each group), or placebo (n = 2 in each group). There were adverse effects in four of the 10 patients who were given placebo and 22 of the 30 who were given Dy-EOB-DTPA. The most common adverse events were nausea (25%), headache (18%), paresthesia (15%), loss of appetite, allergic reactions, back pain, and injection site hemorrhage (7.5%). The adverse effects were generally mild or moderate, but there was a slight increase in intensity at the higher doses. There were gastrointestinal adverse events in all six of the volunteers who received 0.5 mmol/kg. Nausea was the longest lasting and in one case it was severe. The results of laboratory tests did not exceed the reference ranges. Vital signs, hemodynamic parameters, and electrocardiography were not affected by the contrast agent. Over 50% of the adverse events were considered to be unrelated to the drug. The authors concluded that this liverspecific contrast formulation has a good safety profile.

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Chapter 46

MRI CONTRAST AGENTS Gadolinium

(SEDA-24, 256; SEDA-25,

562) Adverse events associated with the non-ionic gadolinium-based contrast agent gadodiamide have been reported in 1–2% of patients. Most of the commonly reported adverse events have been headache, dizziness, or nausea and vomiting. The safety and effectiveness of gadodiamideenhanced magnetic resonance angiography (MRA) with single and triple doses in the assessment of abdominal arterial stenosis has been investigated in 105 patients, of whom 53 (aged 45–83 years) received 0.1 mmol/kg and 52 (aged 38–85 years) received 0.3 mmol/kg (24C ). There were no serious adverse events. Six patients in the single-dose group felt a sensation of heat or warmth in the abdomen, lumbar spine, upper legs, hips, or groin; five of these events were mild and one was moderate; one patient felt a mild cold sensation at the injection site. Six patients in the triple-dose group felt a warm discomfort in the abdomen, pelvis, or buttocks (two mild and four moderate); four other patients felt a cold sensation at the injection site or in the arm (three mild and one moderate). The authors concluded that gadodiamide-enhanced MRA performed with single and triple doses is safe and effective in assessing major abdominal arterial stenosis. Triple-dose MRA was better at evaluating image quality and the degree of arterial stenosis. The safety of gadodiamide-enhanced MRI in staging suspected or recurrent soft tissue tumors of the head and neck has been investigated in 48 patients (aged 37–86) (25C ). There was only one adverse event, moderate thirst. The authors concluded that the use of gadodiamide for MRI contrast-enhanced examination of the head and neck is safe and provides more diagnostic information than unenhanced images. Gadobenate dimeglumine (Multihance, Gd-BOPTA) is a new gadolinium-based contrast agent that has been approved for MRI contrast enhancement of the central nervous system and liver. It is eliminated from the body by renal and hepatobiliary excretion. It binds weakly to serum albumin, and has an in vivo T1 relaxivity that approaches twice that of the conventional extracellular gadolinium chelates

Sameh K. Morcos

used as MRI contrast agents. The safety of gadobenate dimeglumine has been evaluated in 2367 adults aged 18–88 years and 173 children. The overall incidence of adverse events was 20%. Events related to the contrast agent were reported in 15% of the adults. Most of the adverse events were mild and transient and resolved spontaneously. Headache, injection site reactions, nausea, taste disturbance, and vasodilatation were the most common, with frequencies of 1–2.6%. Serious adverse events potentially related to the contrast agent were reported in 0.2%. These events included laryngospasm, which developed 10 minutes after the contrast injection in a 51-year-old woman, severe vomiting in a 5-year-old child, and pulmonary edema in a 65-year-old patient. In controlled studies gadobenate dimeglumine has been compared with gadolinium chelates in 222 patients and with placebo in 189 patients (26C ). There were no serious events and no differences in the incidence of adverse effects between the groups. Adverse effects included vomiting, dizziness, and rashes. Similarly, there were no differences between children and adults or between subjects with renal or liver insufficiency. The authors concluded that gadobenate dimeglumine is safe, with a very low incidence of serious events, and that it compares favorably with other MR contrast agents, such as gadolinium DTPA. Gadobenate dimeglumine, in cumulative doses of 0.15 and 0.2 mmol/kg, has been compared with gadodiamide (Omniscan) 0.3 mmol/kg in 205 patients (aged 20–88 years) with suspected central nervous system lesions (27C ). Gadobenate dimeglumine was well tolerated and the safety profile was similar to that observed with gadodiamide. In the three groups adverse effects occurred in 28%, 23%, and 32% respectively. The most common adverse events of gadobenate dimeglumine were headache (16%), dizziness (4.6%), and taste disturbances (4.6%); the most common adverse events of gadodiamide were headache (7.2%), nausea (5.8%), and taste disturbances (5.8%). All adverse events were classified as mild to moderate. There were no significant changes in vital signs, hematology, or serum chemistry in any group. There were no significant differences in the diagnostic quality of the examination.

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Chapter 46

MS-325 is an intravascular MRI contrast agent that binds strongly but reversibly to human serum albumin in plasma (28C ). Because of albumin binding it has a long half-life and increased relaxivity. These properties are particularly useful for contrast-enhanced threedimensional MRA. The safety and diagnostic efficacy of MS-325 in MRA of the carotid arteries has been investigated in 26 patients aged 42–81 years with suspected carotid artery stenosis. It was given intravenously to 4, 9, and 13 patients in single doses of 0.01, 0.03, or 0.05 mmol/kg respectively. There were no serious or severe adverse events. Two patients who received 0.05 mmol/kg had five adverse events within 3 h after the injection (nausea, cramps, metallic taste, and pruritus), which were rated as mild. There were no significant changes in serum chemistry. High-quality MRA scans were obtained in all the patients. Pancreas Although several studies have shown that intravascular gadolinium-based contrast agents have favorable safety profiles in patients with renal insufficiency, severe adverse reactions can still occur, even with standard doses (maximum 0.3 mmol/kg). Acute pancreatitis with acute renal insufficiency complicating angiography with a gadolinium-based contrast agent has been reported (29A ). • A 68-year-old woman with long-standing peripheral vascular disease and chronic renal insufficiency (serum creatinine 334 µmol/l) had peripheral angiography with gadodiamide (dose not stated) and 6 hours later developed nausea, epigastric pain, and two episodes of vomiting, with further epigastric pain 5 hours later. Her serum amylase and lipase activities were 246 U/l and 1314 U/l respectively (reference ranges 0–140 and 0–200 U/l). The next morning they were 684 U/l and 1646 U/l respectively. Ultrasound scan of the liver and gallbladder was normal. She subsequently developed acute renal insufficiency, electrolyte imbalance, and pulmonary edema. Urine microscopy showed muddy brown casts consistent with acute tubular necrosis. Her pancreatitis resolved without any further complications.

The authors highlighted the fact that there is no recommended maximum safe dose of gadolinium, nor a minimum creatinine clearance below which gadolinium should not be used. Urinary tract Although the use of gadolinium-based contrast agents in patients with a

521 history of serious adverse reactions to iodinated contrast agents seems to be reasonable, these agents can be nephrotoxic in doses over 0.3 mmol/kg. Several reports have unwisely recommended them as alternatives to iodinated contrast agents in patients with renal impairment (SEDA-25, 563). Intravenous gadoterate meglumine 35 ml has been used as a contrast agent for arm venography using digital fluorography in 45 patients with end-stage renal insufficiency (age 26–88 years, serum creatinine 262–1360 µmol/l) before the creation of an arteriovenous fistula (30C ). The mean serum creatinine did not change significantly. There were no significant adverse effects. Only one patient developed vomiting. A good diagnostic examination was obtained in all cases. The use of gadolinium as a contrast agent has been described in a patient with chronic renal insufficiency who required a stent for an infrarenal aortic aneurysm (31A ). • A 64-year-old obese man with a history of radiocontrast-induced nephropathy had an MRI scan, which confirmed the presence of an aortic aneurysm from just below the renal arteries to the aortic bifurcation. Percutaneous stenting of the aortic aneurysm was carried out with 0.5 mol/l gadoteridol solution 90 ml (0.375 mmol/kg) instead of an iodinated contrast agent. There was no further deterioration in renal function.

The authors erroneously concluded that gadolinium-containing contrast agents are not nephrotoxic, and they recommended their use in patients in whom conventional iodinated contrast agents are contraindicated. However, gadolinium-based contrast agents have more nephrotoxic potential than iodinated contrast agents in equimolar concentrations. Their use in patients with renal impairment should be carried out with care and the dosage should not exceed 0.3 mmol/kg. The use of a gadolinium-based contrast agent for renal angiography has been described in France (32A ). • A 67-year-old woman with chronic renal insufficiency secondary to interstitial nephritis had rapid deterioration over several months, with a rise in serum creatinine from 150 to 290 µmol/l. Renal artery stenosis was suspected. She had anaphylaxis during spiral CT angiography with an iodinated contrast medium (details not given), which showed right renal artery stenosis. After further

522 deterioration in renal function (serum creatinine 480 µmol/l) she underwent renal arteriography with 30 ml of a gadolinium-based contrast agent (0.3 mmol/kg) injected into the abdominal aorta just above the renal arteries. Her renal function was monitored for 15 days after the procedure, and there was no further rise in serum creatinine.

There is still misunderstanding about the nephrotoxic potential of gadolinium-based contrast agents. They should not replace iodinated contrast agents in patients with renal insufficiency. The recommended doses of up to 0.3 mmol/kg will not give satisfactory radiographic diagnostic information in most cases. In addition, gadolinium-based contrast agents are not licensed for radiography. Immunologic The use of gadolinium-based contrast agents as an alternative to iodinated contrast agents has been reported in a patient with a history of allergy to the latter (33A ). • A 77-year-old woman had a gadolinium-enhanced MRI scan followed by gadolinium-enhanced spiral CT pulmonary angiography for suspected pulmonary embolism. Gadodiamide 0.4 mmol/kg (60 ml) was injected intravenously at a rate of 2 ml/s. There were no adverse reactions.

Chapter 46

Sameh K. Morcos

hyperplasia (one patient) (34C ). The dose of iron was 6–11.7 µmol/kg. Patients under 60 kg received 0.9 ml as a bolus intravenous injection and patients over 60 kg received 1.4 ml. None of the 19 patients reported any pain or discomfort at the injection site. One had a diffuse erythematous rash associated with a feeling of pressure in the thorax, which lasted for 30 minutes. There was a significant increase in systolic blood pressure (from 137 to 141 mmHg) 5 minutes after injection; it returned to normal within 4 hours. There was a statistically significant fall in diastolic blood pressure from 75 to 70 mmHg at 4 hours after the injection. These changes were not considered to be of clinical importance. There were also minimal changes in the results of blood tests, which were not of clinical importance. High-quality diagnostic information was provided by the MRI examination.

ULTRASOUND CONTRAST AGENTS (SEDA-23, 501; SEDA-24, 529; SEDA-25, 564)

Optison SUPERPARAMAGNETIC IRON OXIDE PARTICLES (SPIO) MRI CONTRAST AGENTS (SEDA-25, 564) SH U 555 A (Resovist) is a new contrast agent that consists of iron oxide microparticles coated with carboxydextran. After intravenous injection it is sequestered by the reticuloendothelial system, mostly in the liver and spleen. MRI iron oxide causes loss of signal intensity, especially on T1 and T2 weighted images and the contrast between the lesions and the surrounding tissues is increased owing to loss of signal in the healthy tissues. The diagnostic efficacy and safety of SH U 555 A has been investigated in 19 patients aged 43–89 years who had been referred for investigation of hepatocellular carcinoma (eight patients), liver metastases (four patients), liver hemangioma (four patients), cholangiocarcinoma (two patients), and focal nodular

Optison is a second-generation ultrasound contrast agent based on sonicated human albumin. Its safety has been demonstrated in previous studies (SEDA-25, 565). In 50 patients (mean age 59 years) in an intensive care unit who underwent echocardiography examination with intravenous Optison (dose 0.5–1.5 ml), there were no contrastrelated adverse effects (35C ). Good quality echocardiography was obtained in all cases.

Sono Vue

(SEDA-25, 565)

Sono Vue is an ultrasound contrast agent that consists of microbubbles containing sulfur hexafluoride gas stabilized by phospholipids. Its safety has been demonstrated in previous studies (SEDA-25, 565). The safety of Sono Vue as an intravenous bolus injection of 0.3, 0.6, 1.2, or 2.4 ml in

Radiological contrast agents

Chapter 46

transcranial Doppler examination of the cerebral arteries has been investigated in 40 patients (mean age 64 years) (36C ). The interval between each dose was at least 10 minutes or until total disappearance of the contrast effect from the previous dose. Eight patients reported 12 adverse events. There were no serious adverse events and no patient withdrew because of an adverse event. The most common adverse events were pain at the injection site, headache, and a feeling of warmth; all were mild. The safety of Sono Vue has been evaluated in 36 healthy volunteers who were given a single dose of isotonic saline or Sono Vue, 0.003, 0.01, 0.03, 0.06, 0.09, or 0.12 ml/kg and in 30 volunteers who were given cumulative doses of 0.15–0.6 ml/kg (37C ). The volunteers were

523 aged 20–35 years. Another 12 subjects, patients with chronic obstructive airways disease, were given a single dose of Sono Vue 4 ml and placebo (isotonic saline 4 ml) in two sessions separated by 48–72 h. All adverse events were minor or mild and rapidly resolved. The adverse effects in the healthy volunteers were heat at the injection site, facial flushing, headache, and a tingling sensation in the hand (one patient each). There were no differences in the frequencies of adverse events in the different dosages groups or between Sono Vue and placebo. In the patients with chronic obstructive airways disease, vomiting and lethargy occurred in one patient each. There were no significant changes in respiratory function tests (FEV1 , FVC, forced mid-expiratory flow, and oxygen saturation).

REFERENCES 1. Yang HC, Lee RC, Teng MMH, Chang CY. Adverse reactions to intravenous administration iodinated contrast media. Experience in a medical center. Chin J Radiol 2001; 26: 17–21. 2. Schraeder R. Contrast media selection in interventional cardiology. J Clin Basic Cardiol 2001; 4: 245–8. 3. Mironidou M, Katsimba D, Kokkas B, Kaitartzis C, Karamanos G. Effetti in vivo dello iohexolo e del diatrizoato sull’attivita plasmatica umana dell’acetil- e della butiril-colinesterasi. Radiol Med 2001; 101: 183–6. 4. Sutton AGC, Finn P, Grech ED, Hall JA, Stewart MJ, Davies A. Early and late reactions after the use of iopamidol 340, ioxaglate 320 and iodixanol 320 in cardiac catheterisation. Am Heart J 2001; 141: 677–83. 5. Kanny G, Marie B, Hoen B, Trechot P, MoneretVautrin DA. Delayed adverse reaction to sodium ioxaglic acid-meglumine. Eur J Dermatol 2001; 11: 134–7. 6. Flinck A, Gottfridsson B. Experiences with iohexol and iodixanol during cardioangiography in an unselected patient population. Int J Cardiol 2001; 80: 143–51. 7. Dangas G, Monsein LH, Laureno R, Peterson MA, Laird JR Jr. Transient contrast encephalopathy after carotid artery stenting. J Endovasc Ther 2001; 8: 111–13. 8. Karino S, Fukaya T. Sudden hearing loss following drip intravenous pyelography with iohexol: a case report. Auris Nasus Larynx 2001; 28: 95–7. 9. Fassbender WJ, Schluter S, Stracke H, Bretzel G. Wass W, Tillmanns H. Schilddrusenfunktion nach gabe jodhaltigen Röntgenkontrastmittels bei Koronarangiographie–eine prospektive Unter-

suchung euthyreoten Patienten. Z Kardiol 2001; 90: 751–9. 10. Losco P, Nash G, Stone P, Ventre J. Comparison of the effects of radiographic contrast media on dehydration and filterability of red blood cells from donors homozygous for haemoglobin A or haemoglobin S. Am J Hematol 2001; 68: 149–58. 11. Blann AD, Adams R, Ashleigh R, Naser S, Kirkpatrick U, McCollum CN. Changes in endothelial, leucocyte and platelet markers following contrast medium injection during angiography in patients with peripheral artery disease. Br J Radiol 2001; 74: 811–17. 12. Koussidis GA, Koussidis A. Preoperative bowel preparation with meglumine and sodium diatrizoate (Gastrografin): a prospective randomised comparison. Eur J Surg 2001; 167: 899–902. 13. Kircher MF, Kihiczak D, Rhea JT, Novelline RA, Maglinte DDT. Safety of colon contrast material in (helical) CT examination of patients with suspected diverticulitis. Emerg Radiol 2001; 8: 94–8. 14. Donadio C, Lucchesi A, Ardini M, Tramonti G, Chella P, Magagnini E, Bianchi C. Renal effects of cardiac angiography with different low-osmolar contrast media. Renal Fail 2001; 23: 385–96. 15. Hetze GR, May P, Hollenbeck M, Voiculescu A, Modder U, Grabensee B. Assessment of radiocontrast media induced renal vasoconstriction by color coded duplexsonography. Renal Fail 2001; 23: 77–83. 16. Lorusso V, Taroni P, Alvino S, Spinazzi A. Pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with renal impairment or end-stage renal disease requiring hemodialysis. Invest Radiol 2001; 36: 309–16. 17. Berger ED, Bader BD, Bosker J, Risler T, Erley CM. Kontrastmittelinduziertes Nierenversagen

524 lasst sich durch Hämodialyse nicht verhindern. Dtsch Med Wochenschr 2001; 126: 162–6. 18. Vogt B, Ferrari P, Schonholzer C, Marti H-P, Mohaupt M, Wiederkehr M, Cereghetti C, Serra A, Huynh-Do U, Uehlinger D, Frey FJ. Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful. Am J Med 2001; 111: 692–8. 19. Rosado A, Canto G, Veleiro B, Rodriguez J. Toxic epidermal necrolysis after repeated injections of iohexol. Am J Roentgenol 2001; 176: 262–3. 20. Delaney Y, Khooshabeh R. Lipogranuloma following traumatic dacryocystography in a 4-year-old boy. Eye 2001; 15: 683–4. 21. Dewachter P, Moulton-Faivre C. Reactions sévères avec les produits de contraste iodes: l’anaphylaxie est-elle responsable? J Radiol 2001; 82: 973–7. 22. Leander P, Hoglund P, Borseth A, Kloster Y, Berg A. A new liposomal liver-specific contrast agent for CT: first human phase-I clinical trial assessing efficacy and safety. Eur Radiol 2001; 11: 698–704. 23. Krause W, Mahler M, Hanke B, Milius W, Kaufmann J, Rogalla P, Hamm B. Dy-EOB-DTPA: tolerance and pharmacokinetics in healthy volunteers and preliminary liver imaging in patients. Invest Radiol 2001; 36: 431–44. 24. Thurnher SA, Capelastegui A, Herraiz del Olmo F, Dondelinger RF, Gervas C, Jassoy AG, Keto P, Loewe C, Ludman CN, Marti-Bonmati L, Meusel M, Palmero da Cruz J, Pruvo JP, Sanjuan VM, Vogl T. Safety and effectiveness of singleversus triple-dose gadodiamide injection-enhanced MR angiography of the abdomen: a phase III double-blind multicenter study. Radiology 2001; 219: 137–46. 25. Ekholm SE, Bjork-Eriksson T, Western A, Nellstrom H, Jonsson E, Johansson A, Lonn L, Mercke C, Tollesson PO. MRI staging using gadodiamide for soft-tissue tumors of the head and neck region. Results from a phase II trial and a 5-year clinical follow-up. Eur J Radiol 2001; 39: 168–75. 26. Kirchin MA, Pirovano G, Venetianer C, Spinazzi A. Safety assessment of gadobenate dimeglumine (MultiHance® ): extended clinical experience from phase I studies to post-marketing surveillance. J Magn Reson Imaging 2001; 14: 281–94. 27. Runge VM, Armstrong MR, Barr RG, Berger BL, Czervionke LF, Gonzalez CF, Halford HH, Kanal E, Kuhn MJ, Levin JM, Low RN, Tanenbaum LN, Wang A-M, Wong W, Yuh WTC, Zoarski GH. A clinical comparison of the safety and efficacy of

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MultiHance (gadobenate dimeglumine) and Omniscan (gadodiamide) in magnetic resonance imaging in patients with central nervous system pathology. Invest Radiol 2001; 36: 65–71. 28. Bluemke DA, Stillman AE, Bis KG, Grist TM, Baum RA, D’Agostino R, Malden ES, Pierro JA, Yucel EK. Carotid MR angiography: Phase II study of safety and efficacy for MS-3251. Radiology 2001; 219: 114–22. 29. Schenker MP, Solomon JA, Roberts DA. Gadolinium arteriography complicated by acute pancreatitis and acute renal failure. J Vasc Intervent Radiol 2001; 12: 393. 30. Geoffroy O, Tassart M, Le Blanche A-F, Khalil A, Duedal V, Rossert J, Bigot J-M, Boudghene FP. Upper extremity digital subtraction venography with gadoterate meglumine before fistula creation for hemodialysis. Kidney Int 2001; 59: 1491–7. 31. Wagner H-J, Storck M. Endovaskulare stentgraftgestutzte Exklusion eines infrarenalen Aortenaneurysmas mit Gadolinium als Kontrastmittel bei Niereninsuffizienz. Dtsch Med Wochenschr 2001; 126: 616–20. 32. Bassilios N, Vantelon C, Cluzel P, Baumelou A, Deray G. Use of gadolinium-based contrast agent for renal angiography: case report and review of the literature. Renal Fail 2001; 23: 857–61. 33. Coche EE, Hammer FD, Goffette PP. Demonstration of pulmonary embolism with dynamic gadolinium-enhanced spiral CT. Eur Radiol 2001; 11: 2306–9. 34. Kehagias DT, Gouliamos AD, Smyrniotis V, Vlahos LJ. Diagnostic efficacy and safety of MRI of the liver with superparamagnetic iron oxide particles (SH U 555 A). J Magn Reson Imaging 2001; 14: 595–601. 35. Daniel GK, Chawla MK, Sawada SG, GradusPizlo I, Feigenbaum H, Segar DS. Echocardiographic imaging of technically difficult patients in the intensive care unit: Use of optison in combination with fundamental and harmonic imaging. J Am Soc Echocardiogr 2001; 14: 917–20. 36. Kaps M, Legemate DA, Ries F, Ackerstaff RGA, Markus H, Pezzoli C, Llull J-B, Spinazzi A. SonoVue™ in transcranial Doppler investigations of the cerebral arteries. J Neuroimaging 2001; 11: 261–7. 37. Bokor D, Chambers JB, Rees PJ, Mant TGK, Luzzani F, Spinazzi A. Clinical safety of SonoVue™, a new contrast agent for ultrasound imaging, in healthy volunteers and in patients with chronic obstructive pulmonary disease. Invest Radiol 2001; 36: 104–9.

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47

Drugs used in ocular treatment

ANTIGLAUCOMATOUS DRUGS Adrenoceptor agonists Brimonidine is a third-generation alpha2 selective adrenoceptor agonist. It is distinguished from clonidine by a chemical modification that reduces its ability to cross the blood–brain barrier. Its adverse effects include allergic conjunctivitis and ocular pruritus (1r ). There is a potential for serious toxic effects, especially in children. • An one-month-old infant with Peters anomaly had recurrent episodes of unresponsiveness, hypotension, hypotonia, and bradycardia (2r ). Extensive medical evaluation showed that these episodes were caused by the ophthalmic use of brimonidine.

Beta-adrenoceptor antagonists (SED 14, 1639) It has been more than a quarter of a century since the discovery that oral propranolol reduces intraocular pressure in patients with glaucoma. However, the use of propranolol for glaucoma was limited by its local anesthetic action (membrane-stabilizing activity). Topical timolol was released for general use in 1978. That timolol is systemically absorbed was suggested by early reports of reduced intraocular pressure in the untreated eyes of patients using monocular treatment. About 80–90% of a topically administered drop drains through the nasolacrimal duct and enters the systemic circulation through the highly vascular nasal mucosa, without the benefit of first-pass © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

metabolism in the liver; only a small fraction is swallowed. Thus, topical ophthalmic dosing is probably more akin to intravenous delivery than to oral dosing, and systemic adverse reactions are potentially serious. However, although patients may give their physicians a detailed list of current medications, they often fail to mention the use of eye drops, about which physicians are often either unaware or do not have time to ask specific questions. Betaxolol is a beta1 -selective adrenoceptor antagonist without significant membranestabilizing activity or intrinsic sympathomimetic activity. It may be no more effective than other drugs in reducing intraocular pressure, but it may be safer for some patients, particularly those with bronchospastic disease (but see Respiratory below) (3R ). Partial agonist activity (intrinsic sympathomimetic activity) of beta-blockers may help to prevent ocular nerve damage and subsequent visual field loss associated with glaucoma. Such damage may be related to a reduction in ocular perfusion, as might occur if an ocular betablocker caused local vasoconstriction. An agent with intrinsic sympathomimetic activity might preserve ocular perfusion through local vasodilatation or by minimizing local vasoconstriction. The data are sparse and inconclusive, but carteolol appears to have no effect on retinal blood flow or may even increase it, making it suitable as a neuroprotective drug (3R , 4R ). Cardiovascular Significant cardiovascular adverse effects have been reported after topical administration of timolol maleate. Bradycardia with frank syncope can occur, especially in elderly patients (3R ). After topical administration its action begins in 20 minutes, peaks in 4 hours, and lasts 24 hours. Episodes of dizziness and occasional falls can occur 1–2 hours after instillation of timolol, as has been described in an otherwise healthy elderly patient (5A ).

525

526 • An 80-year-old woman with gastrointestinal bleeding had a sinus bradycardia (52 beats/minute) despite acute blood loss. The only drug she had used that was an AV nodal depressant was timolol maleate 0.5%, one drop to both eyes every day. Continuous electrocardiography showed transient complete AV block without ventricular escape for nearly 6 seconds about 1 hour after instillation of timolol eye drops. She also reported having previously had episodes of dizziness and occasional falls 1–2 hours after instillation of her eye drops. Timolol was withheld and a temporary pacemaker was inserted. Rechallenge with timolol was associated with recurrence of third-degree AV block. She subsequently had a permanent dual chamber pacemaker implanted.

Respiratory Bronchospasm, which can be life-threatening, can be precipitated by betablocker eye drops. Even beta1 -selective antagonists, such as betaxolol, can cause a substantial reduction in forced expiratory volume. Wheezing and dyspnea have been reported among patients using betaxolol: the symptoms resolved after withdrawal. A cross-sectional study has shown that ophthalmologists were more aware than chest physicians about the use of betablocker eye drops by patients with obstructive airways disease; patient awareness was also poor (3R , 6c ). Psychiatric Depressive symptoms were reported in 17 of 165 patients after the administration of timolol over two decades (7A ). Depression accounted for 17% of 369 central nervous system reactions to timolol reported to a National Registry of Drug-induced Ocular Side Effects during 7 years: of these, 20 cases were of acute suicidal depression. Metabolism Topical beta-blockers can cause rises in serum triglyceride concentrations and falls in serum high-density lipoprotein concentrations; this makes them less suitable in patients with coronary heart disease (3R , 8c ). Inhibition of glycogenolysis and glucose mobilization can occur (3R ). This makes topical beta-blockers less suitable for patients with insulin-dependent diabetes mellitus prone to hypoglycemia. Immunologic Contact allergy to topical betablockers can occur. A 68-year-old woman developed contact allergy after many year of using befunolol (9A ). Patch-testing showed cross-

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sensitivity to carteolol. Evidence of such crosssensitivity has not previously been reported.

Prostaglandin analogues Travoprost is a synthetic prostaglandin analog, believed to reduce intraocular pressure by increasing uveoscleral outflow. Its adverse effects include gradual darkening of the color of the iris and the eyelid skin, increased thickness, number, and darkness of the eyelashes, conjunctival hyperemia, and ocular pruritus (1r ). Latanoprost is a prostaglandin F analogue used to treat open-angle glaucoma, targeting the uveoscleral outflow of ocular aqueous humor. Ocular adverse effects include conjunctival hyperemia, iris pigmentation, periocular skin color changes, anterior uveitis, and cystoid macular edema in pseudophakic patients (10R , 11A ). Herpes simplex dendritic keratitis has been reported after treatment with latanoprost (12r ). In patients with uveitic glaucoma latanoprost can cause increased intraocular pressure and recurrence of inflammation (13c ). Cardiovascular Recently exacerbation of angina pectoris has been described in association with latanoprost (14r ). Prostaglandin F is a vasoconstrictor, and systemic absorption of topically applied latanoprost can cause vasoconstriction in coronary arteries. Nervous system Three patients had new onset of migraine after using latanoprost, perhaps through activation of the trigeminal vascular system (15A ).

Prostamides Bimatoprost is the first synthetic prostamide analog. It is believed to lower intraocular pressure by increasing the outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Its adverse effects include gradual darkening of the color of the eyes and the eyelid skin, increased thickness, numbers and darkness of eyelashes, conjunctival hyperemia, and ocular pruritus (16R ).

Drugs used in ocular treatment

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REFERENCES 1. Chernin T. The eyes have it. FDA clears several ophthalmic drops for glaucoma in a row. Drug Topics 2001; 145: 20. 2. Berlin RJ, Lee UT, Samples JR, Rich LF, TangLiu DDS, Sing KA, Steiner RD. Ophthalmic drops causing coma in an infant. J Pediatr 2001; 138: 441–3. 3. Frishman WH, Kowalski M, Nagnur S, Warshafsky S, Sica D. Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension. Focus on beta-adrenergic blockade. Heart Dis 2001; 3: 386–97. 4. Girkin CA. Neuroprotection: does it work for any neurological diseases? Ophthalmic Pract 2001; 19: 298–302. 5. Sharifi M, Koch JM, Steele RJ, Adler D, Pompili VJ, Sopko J. Third degree AV block due to ophthalmic timolol solution. Int J Cardiol 2001; 80: 257–9. 6. Malik A, Memon AM. Beta-blocker eye drops related airway obstruction. J Pak Med Assoc 2001; 51: 202–4. 7. Schweitzer I, Maguire K, Tuckwell V. Antiglaucoma medication and clinical depression. Aust NZ J Psychiatry 2001; 35: 569–71. 8. Gavalas C, Costantino O, Zuppardi E, Scaramucci S, Doronzo E, Aharrh-Gnama A, Nubile M, Di Nuzzo S, De Nicola GC. Variazioni della colesterolemia in pazienti sottoposti a terapia topica con

il timololo. Ann Ottalmol Clin Ocul 2001; 127: 9–14. 9. Nini M, Suppa F, Ayala F, Balato N. Allergic contact dermatitis due to the beta-blocker befunolol in eyedrops, with cross-sensitivity to carteolol. Contact Dermatitis 2001; 44: 369. 10. Linden C. Therapeutic potential of prostaglandin analogues in glaucoma. Expert Opin Invest Drugs 2001; 10: 679–94. 11. Wand M, Ritch R, Isbey EK, Zimmerman TJ. Latanoprost and periocular skin color changes. Arch Ophthalmol 2001; 119: 614–15. 12. Ekatomatis P. Herpes simplex dendritic keratitis after treatment with latanoprost for primary open angle glaucoma. Br J Ophthalmol 2001; 85: 1008–9. 13. Sacca S, Pascotto A, Siniscalchi C, Rolando M. Ocular complications of latanoprost in uveitic glaucoma: three case reports. J Ocul Pharmacol Ther 2001; 17: 107–13. 14. Mitra M, Chang B, James T. Exacerbation of angina associated with latanoprost. Br Med J 2001; 323: 783. 15. Weston BC. Migraine headache associated with latanoprost. Arch Ophthalmol 2001; 119: 300–1. 16. Cantor LB. Bimatoprost: a member of a new class of agents, the prostamides, for glaucoma management. Expert Opin Invest Drugs 2001; 10: 721–31.

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Complementary and alternative forms of medicine remain popular. Numerous surveys are being published, showing that the prevalence of use is high and increasing. For instance, 43% of all patients attending an emergency department in the USA had used at least one such therapy at some time and 24% were current users (1R ). All complementary treatments were considered to be safe by 16% of the patients and 33% of all users failed to tell their physicians. Furthermore, 15% of the women and 7% of the men believed that complementary therapies do not interact with other medications. As the popularity of complementary medicine rises, so does the research interest in this subject (2R ), including research into direct and indirect risks (3R –5R ).

almost six-fold (7R ). And survey data from the USA have suggested that herb–drug interactions may be a significant problem in a sizeable proportion of patients (8R ). Several herbal medicines pose serious problems for surgical patients, for example through an increased bleeding tendency (9R , 10R ). Vulnerable populations also include children (11R ), and too few safety data are available to recommend herbal medicines during pregnancy or lactation (2R ). Several investigators have pointed out the potential of herbal medicines to harm certain organs, e.g. the liver (12R ) or the skin (13R ). Laxatives are often based on herbal extracts, and the risks of herbal laxatives have been emphasized (14R ). Many authors have reviewed the risks of herbal medicines in general terms (15R , 16R ).

HERBAL MEDICAMENTS (SED-14, 1651; SEDA-23, 506; SEDA-24, 537; SEDA-25, 567) Herbal medicines, often self-prescribed by patients, are particularly popular. The myth that they are devoid of risk continues to be promoted, not least by the popular press. However, a hospital-based study from Oman has suggested that 15% of all cases of self-poisoning seen in this setting are with traditional medicines (6R ). A case series from Thailand has suggested that in patients with oral squamous cell carcinoma the use of herbal medicines before the first consultation with a healthcare professional increases the risk of an advanced stage © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

528

ASIAN HERBAL MIXTURES Nervous system An 8-year-old boy became agitated, vomited repeatedly, and became unrousable (17A ). His mother had applied a homemade paste topically for his eczema, according to a recipe in a Bangladeshi book. The paste was made from a mixture of ground tobacco leaves, lime, and lyophilized coffee. Acute nicotine poisoning was confirmed through blood and urine analyses. The boy recovered fully within 2 days. Drug contamination A total of 54 samples of Asian remedies, purchased in Vietnam, Hong Kong, Florida, New York, and New Jersey, were analysed for heavy metal contamination (18A ). They contained concentrations of arsenic, lead, and mercury that ranged from merely exceeding

Treatments used in complementary and alternative medicine

published guidelines (74%) to toxic (49%). The authors concluded that “the public health hazards of traditional herbal Asian remedies should be identified and disclosed”.

Allium sativum (garlic)

(SED-14,

1652) Skin A 50-year-old Romanian man was advised by his herbalist to treat his asthma with a compress of freshly crushed garlic (19A ). He wore the compress on his forehead overnight and subsequently developed second-degree burns in this area. Specific Jg E RAST tests for garlic were negative. He was treated conservatively and made an uneventful recovery. Two Korean patients used topical garlic for the treatment of pruritus and subsequently developed irritant contact dermatitis of the treated skin areas (20A ). Withdrawal of this folk remedy resulted in full recovery.

Anso Comfort The California State Health Director has warned consumers to stop using the herbal product Anso Comfort capsules immediately, because the product contains the undeclared prescription drug chlordiazepoxide. Chlordiazepoxide, available by prescription either by its generic name or under the brand name of Librium, is used for anxiety and as a sedative and can be dangerous if not taken under medical supervision (21Ar ). Anso Comfort capsules, available by mail or telephone order from the distributor in 60-capsule bottles, are clear with dark green powder inside. The label is yellow with green English printing and a picture of a plant. An investigation by the California Department of Health Services Food and Drug Branch and Food and Drug Laboratory showed that the product contains chlordiazepoxide. The ingredients for the product were imported from China and the capsules were manufactured in California. Advertising for the product claims that the capsules are useful for the treatment of a wide variety of illnesses, including high blood pressure and high cholesterol, in addition to claims

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that it is a natural herbal dietary supplement. The advertising also claims that the product contains only Chinese herbal ingredients and that consumers may reduce or stop their need for prescribed medicines. No clear medical evidence supports any of these claims. The distributor, NuMeridian (formerly known as Top Line Project), is voluntarily recalling the product nationwide. Metabolic A San Francisco woman with a history of diabetes and high blood pressure was hospitalized in January 2001 with lifethreatening hypoglycemia after she consumed Anso Comfort capsules. This may have been due to an interaction of chlordiazepoxide with other unspecified medications that she was taking.

Aristolochia

(SED-14, 1654; SEDA-25,

568) Urinary tract In June 2001, the FDA issued a nationwide alert, recalling 13 “Treasure of the East” herbal products containing aristolochic acid. Aristolochic acid, found in certain plants and botanicals is a potent carcinogen and can cause serious kidney damage (22R ). Before this alert, the FDA had issued several warnings: 1. On 4 April 2001 a “Dear Health Professional” letter was sent, drawing attention to serious renal disease associated with the use of aristolochic acid-containing dietary supplements or “traditional medicines”. Health professionals were urged to review patients who had had unexplained renal disease, especially those with urothelial tract tumors and interstitial nephritis with end-stage renal insufficiency, to determine if such products had been used. 2. On 9 April 2001 a letter was sent to industry associations, detailing the reported cases of renal disease associated with aristolochic acid. 3. On 11 April 2001 the FDA cautioned consumers to immediately discontinue any dietary supplements or “traditional medicines” that contain aristolochic acid, including products with “Aristolochia”, “Bragantia”, or “Asarum” listed as their ingredients.

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In a related action, Health Canada has warned consumers not to use the pediatric product Tao Chih Pien. This Chinese product, which is sold in the form of tablets, is said to be a diuretic and a laxative. It is not labelled to contain aristolochic acid. However the Chinese labelling says that it contains Mu Tong, a traditional term used to describe numerous herbs, including aristolochia; subsequent product analysis has shown that Tao Chih Pien does indeed contain aristolochic acid. Health Canada has now advised individuals in possession of this product not to consume it and to return it to the place of purchase. It has also issued a Customs Alert for the product to prevent the importation and sale of Tao Chih Pien. Chinese herb nephropathy, a rapidly progressive fibrosing interstitial nephritis, was first reported in 1993 after Belgian patients took Chinese herbal mixtures containing aristolochic acid. Numerous reports from many countries have confirmed that plants from the Aristolochia species are the cause (23A , 24A ), and the toxic agent has been confirmed to be aristolochic acid (25A ). • A 46-year-old Chinese woman, living in Belgium and China, developed subacute renal insufficiency (26A ). Her creatine concentrations had increased from 80 µmol/l (November 1998) to 327 µmol/l (January 2000). During the preceding 6 months she had taken a patent medicine bought in China “for waste discharging and youth keeping”. The package insert did not list any herbs of the Aristolochia species. Kidney biopsy showed extensive hypocellular interstitial fibrosis, tubular atrophy, and glomerulosclerosis. Analysis of the Chinese medicine demonstrated the presence of aristolochic acid. She required hemodialysis in June 2000 and received a renal transplant 4 months later. • A 58-year-old Japanese woman with CREST syndrome (calcinosis, Raynaud’s syndrome, esophageal sclerosis, sclerodactyly, and telangiectasia) developed progressive renal dysfunction (27A ). Renal biopsy showed changes typical of Chinese herb nephropathy. Analyses of Chinese herbs she had taken for several years demonstrated the presence of aristolochic acid. Oral prednisolone improved her renal function and anemia.

Arnica montana (arnica)

(SED-14,

1654) Skin Of 443 individuals who were tested for contact sensitization, five had a positive reac-

E. Ernst

tion to arnica and nine to marigold (28C ). Both plants are compositae, and a mixture of the two was positive in 18 cases. Sensitization was often accompanied by reactions to nickel, Myroxylon pereirae resin, fragrance mix, propolis, and colophon.

Calendula officinalis (marigold) Skin Of 443 individuals who were tested for contact sensitization, nine had a positive reaction to marigold and five to arnica (28C ). Both plants are compositae, and a mixture of the two was positive in 18 cases. Sensitization was often accompanied by reactions to nickel, Myroxylon pereirae resin, fragrance mix, propolis, and colophon.

Cardiac glycosides Cardiovascular A 26-year-old woman had taken a herbal supplement for stress-relief which contained Scutellaria lateriflora, Pedicularis canadensis, Cimicifuga racemosa, Humulus lupulus, Valeriana officinalis, and Capsicum annuum (29A ). She was admitted with chest pain of 7 hours duration. Her medical history was otherwise unremarkable. Examination of her heart showed no abnormality, but during monitoring her heart rate fell to 39 beats/min and her blood pressure to 59/36 mmHg. Her serum digoxin concentration was 0.9 ng/ml. The authors therefore concluded that the herbal remedy contained digoxin-like factors that had caused digitalis toxicity.

Citrus auranticum (bergamot) Skin In aromatherapy volatile plant oils (often incorrectly termed “essential oils”) are used and are usually applied by gentle massage. Bergamot oil (Citrus auranticum spp. bergamia) is often used in this way. It has photosensitive and melanogenic properties and is potentially phototoxic and photomutagenic. Two patients had localized and disseminated bullous phototoxic skin reactions 48–72 hours

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after exposure to bergamot aromatherapy and ultraviolet light (30A ). One developed bullous skin lesions after exposure to aerosolized aromatherapy oil in a sauna.

Ecballium elaterium (squirting cucumber) (SED-14, 1658) Ecballium elaterium is used in the Mediterranean as a purgative and in treating sinusitis. In a retrospective chart analysis in a Greek ENT department 42 patients with allergic reactions to this remedy, including upper airway edema, were identified (31c ). Treatment with corticosteroids and antihistamines resulted in full recovery in all cases.

Echinacea

(SED-14, 1658; SEDA-25,

569) A 41-year-old man, who had taken Echinacea intermittently for the previous 18 months, had four episodes of erythema nodosum, preceded by myalgia and arthralgia, fever, headache, and malaise (32A ). The skin lesions resolved within 2–5 weeks and responded to oral prednisolone. He was advised to discontinue Echinacea and 1 year later remained free from further recurrence.

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A 56-year-old man had a stroke without apparent risk factors (34A ). A CT scan confirmed a right parietal hematoma. He had not taken any medications, except for a Ginkgo extract (3×40 mg/day) which he had started 18 months before. The authors argued that the antiplatelet effects of Ginkgo might have contributed to this case of intracerebral bleeding. Hematologic A 34-year-old woman had a laparoscopic cholecystectomy and started bleeding into the surgical wound postoperatively (35A ). This led to a fall in hemoglobin from 16.5 to 12.4 g/dl. She was given blood transfusions and recovered uneventfully. The surgeons believed that self-medication with Ginkgo had caused the postoperative bleeding. Skin A 40-year-old Afro-American woman developed an exfoliative rash and blistering and swelling of the tongue (36A ). A diagnosis of Stevens–Johnson syndrome was made. She had not taken any medications other than two doses of a Ginkgo-containing formulation. Her condition responded to treatment with prednisolone, clotrimazole, and famotidine. Ginkgo was withdrawn and no further events occurred. However, 5 months later she still had tenderness in the soles of the feet, peeling of the nails, and discoloration of the skin.

Glycyrrhiza radix (licorice) (SED-14, 1659; SEDA-25, 569)

Ginkgo biloba (maidenhair tree) (SED-14, 1658) Nervous system A 78-year-old man and an 84-year-old woman with previously well controlled epilepsy presented with recurrent seizures (33A ). There were no obvious reasons for these events, and the investigator suspected self-medication with Ginkgo biloba extracts. Both patients had started taking Ginkgo within 2 weeks of the start of the seizures. The herbal remedy was withdrawn and both patients remained seizure-free several months later. No other change of medication was made. The author postulated that 4-0-methylpyridoxine, a constituent of Ginkgo and a known neurotoxin, had caused the seizures.

In healthy volunteers who took licorice corresponding to glycyrrhetinic acid 75–540 mg/day for periods of 2–4 weeks, there was an average increase in systolic blood pressure of 3.1–14.4 mmHg (37c ). The increase in blood pressure was dose related and the authors concluded that as little as 50 g/day of licorice for 2 weeks would have caused a significant rise in blood pressure.

Hydroxycut Hydroxycut is a US dietary supplement that contains ephedra and guarana extract; both have sympathomimetic properties, which may be problematic.

532 • A 22-year-old man had taken hydroxycut for muscle-enhancing purposes for 2 weeks when he developed a seizure-like episode without tonic– clonic movements, followed by coma (38A ). He required mechanical ventilation and was treated with intravenous methylprednisolone. He became arousable only 2 days later, after which he made a full recovery within 3 days but had no memory of the event. After 2 years he was free of adverse sequelae.

Hypericum perforatum (St John’s wort) (SED-14, 1660; SEDA-25, 570) Nervous system Delirium and serotonin syndrome have been attributed to St John’s wort. • A 76-year-old woman began taking an extract of St John’s wort (75 mg/day) and developed delirium and psychosis 3 weeks later (39A ). She had no relevant medical history and did not take any other medications. She was given risperidone and donepezil hydrochloride, and her paranoid delusions and visual hallucinations improved. The final diagnosis was acute psychotic delirium associated with St John’s wort in a woman with underlying Alzheimer’s dementia. • A 40-year-old man with a history of anxiety disorder and depression presented with flushing, sweating, agitation, weakness of the legs, dry mouth, tightness in the chest, and inability to focus (40A ). He was taking clonazepam (0.5 mg bd) and had started to take St John’s wort 10 days before. He had previously had two similar episodes after having taken sertraline. The authors concluded that self-medication with St John’s wort, which has SSRI activity, had caused the serotonin syndrome.

Endocrine In a retrospective case–control study, 37 patients with raised TSH concentrations were compared with 37 individuals with normal TSH concentrations (41c ). Exposure to St John’s wort during the previous 3–6 months increased the odds of a raised TSH concentration by a factor of 2.12 (95% CI = 0.36, 12). The authors concluded that an association between St John’s wort and raised TSH concentrations is probable. Hair A 24-year-old schizophrenic patient who self-medicated with St John’s wort while also taking olanzapine (5–10 mg/day) developed hair loss on her scalp and eyebrows 5 months later; it persisted for 12 months (40A ). Her medical history was otherwise unremarkable and the authors speculated that, like SSRIs, St John’s wort can cause hair loss.

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Drug interactions Oral contraceptives A 36-year-old woman became pregnant whilst taking an oral contraceptive, ethinylestradol/ dienogest (doses not stated) (42A ). She had also taken St John’s wort extract, which is a hepatic enzyme inducer. As no other cause for contraceptive failure could be identified, the authors concluded that the St John’s wort had been responsible. Ciclosporin Two patients who took ciclosporin after kidney transplantation self-medicated with St John’s wort, and their ciclosporin concentrations became subtherapeutic (43A ). One subsequently had an acute transplant rejection. Withdrawal of St John’s wort resulted in normalization of ciclosporin concentrations. This effect of St John’s wort was probably due to enzyme induction. After a kidney transplant for end-stage renal insufficiency a 58-year-old man was given ciclosporin, azathioprine, and prednisolone (44A ). Four years later he started to take St John’s wort (300 mg bd) for depression, and 2 weeks later his previously stable ciclosporin concentrations had halved. Withdrawal of the St John’s wort resulted in normalization of his ciclosporin concentrations.

Larrea tridentata (chaparral) (SED-14, 1660) Liver In four patients who were given topical chaparral tincture there was no evidence of liver damage (45A ).

Laurus nobilis (laurel oil) Laurel (Laurus nobilis) has well-known analgesic, diaphoretic, antipyretic, and diuretic effects (46R ), and is widely used in rheumatic, pyrexial, and infective disorders (47R ), as well as in the perfume and soap industries (46R ). Skin Laurel contact allergy is usually seen in aromatherapists or their clients (48A , 49C , 50A ).

Treatments used in complementary and alternative medicine • A 55-year-old woman developed erythema and edema over her knees (48A ). She had applied laurel oil, obtained from a herbalist, to her knees to relieve joint pain 15 days earlier. After 3 days, the erythema and edema had begun to appear. She had erythema, edema, and papules over her patellae, and eczema around the eye. She was treated with an oral antihistamine and a topical corticosteroid. Two days later, the lesions worsened and systemic corticosteroid therapy was needed. The lesions started to heal, leaving slight post-inflammatory hyperpigmentation. Patch testing was performed with a European standard series and commercial laurel oil 1 month later. There was a reaction to the oil only, and no reaction to either fragrance mix or Myroxylon Pereirae Resin in the standard series. The same preparation of laurel oil was negative on patch testing in 15 control subjects.

Lycium barbarum (Chinese wolfberry) Drug interactions A 61-year-old woman, who had taken warfarin for atrial fibrillation in weekly doses of 18–19 mg for years and had been completely stable, developed a raised INR after she consumed a tea made from Chinese wolfberry (51A ). Four days after drinking the tea (180 ml/day), she had an INR of 4.1. After discontinuation of the herbal tea her INR returned to within the target range and remained stable. No mechanism was suggested.

Piper methysticum (kava)

(SED-14,

1663; SEDA-25, 571) Nervous system Kava and valerian are herbal remedies, claimed to have anxiolytic and sedative properties respectively, without dependence potential or any appreciable adverse effects. Kava is an extract of the roots of the Polynesian plant Piper methysticum. Valerian is derived from Valeriana officinalis. In a pilot study, 24 patients with stress-induced insomnia were treated for 6 weeks with kava 120 mg/day, followed by a 2-week washout period and then treatment with valerian 600 mg/day for another 6 weeks (52c ). Stress was measured in three areas, including social, personal, and life events, and insomnia was assessed by evaluating the time taken to fall asleep, the number of hours

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slept, and waking mood. Total stress severity and insomnia were significantly improved by both compounds, with no significant differences. The most commonly reported adverse events were vivid dreams with valerian (16%) and dizziness with kava (12%). In 24 patients treated with kava for generalized anxiety disorder for 4 weeks in an open, crossover, randomized trial, two dosage schedules were compared: 120 mg od and 45 mg tds (53c ). There were significant reductions in mean Hamilton Anxiety Rating Scale scores, irrespective of dose schedule, treatment order, or sex. The impact of adverse effects was relatively low, and only one patient had to withdraw from the study (tds schedule) because of nausea. There was daytime drowsiness in 33% of patients taking the thrice-daily regimen compared with 9% in those taking a once-daily dose. A 45-year-old woman with a family history of essential tremor developed severe and persistent Parkinsonism after taking kava extract (65 mg/day) for 10 days (54A ). Her symptoms responded to anticholinergic drugs, but slowness and tremor at rest persisted. The authors concluded that kava might cause Parkinsonism in individuals with a genetic susceptibility. Liver Three cases of liver damage have been attributed to kava. • A 33-year-old woman took a kava extract equivalent to 210 mg of kavalactones daily for 3 weeks (55A ). She developed malaise, loss of appetite, and jaundice. Her liver enzymes were raised 3to 60-fold. Viral hepatitis was excluded and liver biopsy confirmed toxic hepatitis. Kava was withdrawn, and within 8 weeks the liver enzymes returned to normal. A lymphocyte transformation test showed strong concentration-dependent T-cell reactivity to kava. Phenotyping of CYP2D6 activity showed that she was a poor metabolizer.

The authors concluded that the liver damage in this case was due to an immune-mediated reaction, possibly mediated by a reactive metabolite of kava, although she was a poor metabolizer. • A 60-year-old patient, who had taken no medications other than kava extract, developed liver and kidney failure and progressive encephalopathy (56A ). Viral, metabolic, and autoimmune causes were excluded. Liver biopsy was consistent with toxic liver damage. The patient eventually received an orthotopic liver transplant and made a good recovery.

534 • A 50-year-old man developed jaundice. He had noticed fatigue for a month, a “tanned” skin, and dark urine (57A ). The medical history was unremarkable, apart from slight anxiety, for which he had been taking three or four capsules of kava extract daily for 2 months. He took no other drugs and did not consume alcohol. Liver function tests showed 60-fold and 70-fold increases in AsT and alanine AlT respectively. He subsequently developed stage IV encephalopathy but made a good recovery after a liver transplant operation.

Polygonum multiflorum (Shou wu Pian) Liver Polygonum multiflorum was prescribed by a Chinese herbalist for a 46-year-old woman with graying hair (58A ). After taking it for 2 weeks she developed signs and symptoms of hepatitis. The history revealed no plausible cause for hepatitis and viral infection was ruled out. After withdrawal of the Polygonum multiflorum her liver enzymes normalized and she recovered fully.

Scutellaria lateriflora (skullcap) (SED-14, 1665) Respiratory A 53-year-old Japanese man, who had taken skullcap intermittently for hemorrhoids, developed recurrent interstitial pneumonitis (59A ). Re-challenge, after he had discontinued the herbal remedy and had become symptom free, resulted in a high fever and signs and symptoms of interstitial pneumonitis. Transbronchial lung biopsy showed lymphocytic alveolitis with eosinophilic infiltration. The symptoms subsided again after withdrawal.

Selaginella doederleinii Hematologic A 52-year-old woman with cholangiocarcinoma developed severe bonemarrow suppression after taking Selaginella doederleinii daily for 2 weeks (60A ). She developed severe pancytopenia with skin ecchymoses and gum bleeding. A bone-marrow smear and biopsy showed severe hypocellularity without malignant cell infiltration. One week

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E. Ernst

after withdrawal her blood count became normal.

Serenoa repens (saw palmetto) Hematologic A 53-year-old man, who had self-medicated with a saw palmetto supplement for benign prostatic hyperplasia, had profuse bleeding (estimated blood loss 2 liters) after resection of a meningioma and required 4 units of packed red cells, 3 units of platelets, and 3 units of fresh frozen plasma (61A ). Postoperatively his bleeding time was 21 min (reference range 2–10 min) but all other coagulation tests were normal. He made an uneventful recovery. The authors concluded that the cyclo-oxygenase inhibitory activity of saw palmetto had caused platelet dysfunction, which had resulted in abnormal bleeding.

Uncaria tomentosa (cat’s claw) Liver A 59-year-old woman with mantle-cell lymphoma and no hepatic involvement took a range of unconventional medicines (62A ). During a routine check-up she had raised liver enzymes, and self-medication with cat’s claw was deemed the most likely cause. Cat’s claw was withdrawn and her liver tests normalized within 60 days.

Vaccinium macrocarpon (cranberry) Hematologic After transurethral resection of his prostate, a 68-year-old man developed immune thrombocytopenic purpura (platelet count 1 × 109 /l). He had self-medicated with cranberry juice for 10 days before the operation and had also taken amlodipine and aspirin (63A ). He had oral petechiae, bleeding gums, hematuria, and bruises. He recovered within 3 days of being given human immunoglobulin and oral prednisolone, and 18 months later his platelet count was still normal. Cranberry juice may contain small amounts of quinine, which can cause immune thrombocytopenia.

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ACUPUNCTURE (SED-14, 1673; SEDA-23, 511; SEDA-24, 540; SEDA-25, 573) A systematic review of all prospective studies of adverse effects associated with acupuncture included nine primary investigations (64M ). The most commonly reported adverse events were needle pain (1–45%), tiredness (2–41%), and bleeding (0.03–38%). Pneumothorax was the only serious complication in these studies; it was reported twice in about 250 000 patients. Two prospective UK studies with a total of about 70 000 consultations have confirmed that serious adverse events of acupuncture are true rarities in Britain (65C , 66C ). Bleeding and needle pain were the most frequent adverse events, with a prevalence of about 1 : 1000. A systematic review of all adverse events associated with acupuncture in the Japanese medical literature located 124 cases (67M ). These included 25 cases of pneumothorax, 18 cases of spinal cord injury, 11 cases of hepatitis B, and 10 cases of localized argyria. An 82-year-old woman was scheduled for gastrectomy with an epidural anesthetic (68A ). She had previously had many acupuncture treatments with a Japanese technique (okibari), in which small needles are left in situ. Her preoperative chest and abdominal X-rays showed hundreds of needles around the vertebrae. The anesthesiologists feared that an epidural anesthetic might lead to spinal cord injury or pneumothorax, and general anesthesia was chosen instead. Respiratory Two further cases of pneumothorax have been reported in association with acupuncture (69A , 70A ). • A 28-year-old Chinese woman developed bilateral pneumothoraces after receiving acupuncture in the upper thoracic and paraspinal regions (70A ). She was treated conservatively and was discharged after 2 days.

Skin A 59-year-old woman presented with a 1-month history of non-pruritic papules on the dorsa of both feet (71A ). During the previous year she had repeatedly received acupuncture in this area. A biopsy showed mixed lichenoid, spongiotic, and granulomatous dermatitis. Ultrastructural examination showed macrophages containing silicone. At follow-up new lesions on her mid calves were noted, and again she

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explained she had recently received acupuncture at these sites. It was discovered that the acupuncturist used silicone-coated needles and silicone deposition was thus caused by acupuncture. Infection risk Infection is a well-known risk of acupuncture and cases continue to be reported. • A 79-year-old woman presented with induration of the right leg three months after receiving acupuncture in this area (72A ). Radiography showed a focal dystrophic calcification at this point and histological studies showed suppurative granulomatous inflammation with microabscesses and caseous necrosis due to infection with Mycobacterium chelonae. She made a full recovery after antibiotic treatment. • A 42-year-old woman with Marfan’s syndrome, who had previously had an aortic root and valve replacement, presented with fever and polyarthralgia 6 days after receiving acupuncture for back pain (73A ). Examination of the valve showed no abnormalities, but Staphylococcus aureus was grown from blood cultures. Extensive investigations did not identify a cause for the infection. Her condition deteriorated despite antibiotic therapy, and emergency aortic root and valve replacement became necessary. She eventually made a full recovery. The authors concluded that the acupuncture had been the most likely cause of the infection.

LEECH THERAPY Skin Leeches are still used in complementary medicine to treat a large variety of conditions. A 69-year-old patient with polyarthralgia was treated with leeches in the lumbar region (74A ). She developed pruritus in that area and treatment was discontinued. One year later she returned with keloid-like skin lesions at the sites of the leech bites. Biopsy showed pseudolymphomatous inflammatory infiltrates with follicular hyperplasia and eosinophilic infiltration. The authors concluded that the lesions were a reaction to arthropods.

MASSAGE THERAPY An 80-year-old Japanese man with a recent history of cerebral infarction received a shiatsu

536 massage in the neck area to relieve a headache (75A ). Immediately after he had right visual field impairment. Thorough ophthalmological and neurological tests show multiple branch occlusions of the central retinal artery and multiple small infarctions in the right frontoparietal lobe. He was given urokinase for 7 days, and made an almost complete recovery. The authors concluded that the forceful neck massage had caused his problem.

SPINAL MANIPULATION (SED-14, 1674; SEDA-23, 512; SEDA-24, 540; SEDA-25, 575) A systematic review of all prospective studies of the risks associated with spinal manipulation included five primary investigations (76M ). The most valid studies suggested that about half of all patients who see a chiropractor will have adverse effects, which are usually mild and transient. No reliable data about serious adverse events were uncovered. However, a review of recent case reports has shown that spinal manipulation was associated with several serious adverse effects, including dissection of the vertebral and internal carotid arteries, resulting in strokes and at least one death (77M ). Other recent instances relate to epidural hematoma, intracranial aneurysm, cauda equina syndrome, contusion of the spinal cord, myelopathy, radiculopathy, and palsy of the long thoracic nerve. Nervous system A survey of 323 UK neurologists disclosed 35 previously unreported cases of serious neurological complications of spinal manipulation (78c ). This means that in this particular series, under-reporting of adverse events had been 100%.

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• A 34-year-old man with a whiplash injury consulted a chiropractor for his neck pain, and 36 hours after one particularly painful treatment he experienced throbbing, positional headache, dizziness, diplopia, otorrhea, and rhinorrhea (79A ). After thorough neurological examination the author concluded that the patient had suffered a dural tear due to cervical manipulation. • A 34-year-old woman had memory loss, ataxia, and poor co-ordination of the right arm associated with right neck pain after consulting a chiropractor (80A ). An MRI scan confirmed a right cerebellar infarct, most probably caused by upper spinal manipulation. She made a full recovery within 1 month. • A 41-year-old man with neck pain sought chiropractic care and the evening after felt unable to breathe in the recumbent position (81A ). Diaphragmatic paralysis was attributed to phrenic nerve injury during cervical manipulation. He remained short of breath and had persistent difficulties breathing in the supine position.

UNCONVENTIONAL DIETS Kwashiorkor unrelated to chronic illness has been reported in 12 cases over 9 years by US pediatric dermatologists (82c ). The children had the characteristic rash and the overall clinical presentation typical of kwashiorkor. Most of the cases were due to nutritional ignorance, perceived milk intolerance, and food faddism. • A 10-year-old boy developed a cognitive disorder, pyramidal symptoms in his legs, involvement of the posterior spinal cord, and peripheral motor and sensory degeneration (83A ). He was a member of a religious community adhering to a strict vegan diet. The cause of the problems was identified as vitamin B12 hypovitaminosis.

REFERENCES 1. Weiss SJ, Takakuwa KM, Ernst AA. Use, understanding, and beliefs about complementary and alternative medicines among emergency department patients. Acad Emerg Med 2001; 8: 41–7. 2. Ernst E, Pittler MH, Stevinson C, White AR,

Eisenberg D. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby, 2001. 3. Ernst E. Investigating the safety of complementary medicine. In: Lewith G, Jonas W, Walach H,

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24. Tamaki K, Okuda S. Chinese herbs nephropathy: a variant form in Japan. Intern Med 2001; 40: 267–8. 25. Lebeau C, Arlt VM, Schmeiser HH, Boom A, Verroust PJ, Devuyst O, Beauwens R. Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells. Kidney Int 2001; 60: 1332–42. 26. Gillerot G, Jadoul M, Arlt VM, Van Ypersele De Strihou C, Schmeiser HM, But PPH, Bieler CA, Cosyns JP. Aristolochic acid nephropathy in a Chinese patient: time to abandon the term “Chinese herbs nephropathy”? Am J Kidney Dis 2001; 38: 1–5. 27. Nishimagi E, Kawaguchi Y, Terai C, Kajiyama H, Hara M, Kamatani N. Progressive interstitial renal fibrosis due to Chinese herbs in a patient with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome. Intern Med 2001; 40: 1059–63. 28. Reider N, Komericki P, Hausen BM, Fritsch P, Aberer W. The seamy side of natural medicines: contact sensitization to arnica (Arnica montana L.) and marigold (Calendula officinalis L.). Contact Dermatitis 2001; 45: 269–72. 29. Scheinost ME. Digoxin toxicity in a 26-year-old woman taking a herbal dietary supplement. J Am Osteopath Assoc 2001; 101: 444–6. 30. Kaddu S, Kerl H, Wolf P. Accidental bullous phototoxic reactions to bergamot aromatherapy oil. J Am Acad Dermatol 2001; 45: 458–61. 31. Kloutsos G, Balatsouras DG, Kaberos AC, Kandiloros D, Ferekidis E, Economou C. Upper airway edema resulting from use of Ecballium elaterium. Laryngoscope 2001; 111: 1652–5. 32. Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol 2001; 44: 298–9. 33. Granger AS. Ginkgo biloba precipitating epileptic seizures. Age Ageing 2001; 30: 523–5. 34. Benjamin J, Muir T, Briggs K, Pentland B. A case of cerebral haemorrhage—can Ginkgo biloba be implicated? Postgrad Med J 2001; 77: 112–13. 35. Fessenden JM, Wittenborn W, Clarke L. Ginkgo biloba: a case report of herbal medicine and bleeding postoperatively from a laparoscopic cholecystectomy. Am Surg 2001; 67: 33–5. 36. Davydov L, Stirling AL. Stevens–Johnson syndrome with Ginkgo biloba. J Herbal Pharmacother 2001; 1: 65–9. 37. Sigurjónsdóttir HA, Franzson L, Manhem K, Ragnarsson J, Sigurdsson G, Wallerstedt S. Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens 2001; 15: 549–52. 38. Kockler DR, McCarthy MW, Lawson CL. Seizure activity and unresponsiveness after hydroxycut ingestion. Pharmacotherapy 2001; 21: 647–51. 39. Laird RD, Webb M. Psychotic episode during use of St John’s wort. J Herbal Pharmacother 2001; 1: 81–7. 40. Parker V, Wong AHC, Boon HS, Seeman SV. Adverse reactions to St John’s wort. Can J Psychiatry 2001; 46: 77–9.

538 41. Ferko N, Levine MAH. Evaluation of the association between St John’s wort and elevated thyroid-stimulating hormone. Pharmacotherapy 2001; 21: 1574–8. 42. Schwarz UI, Büschel B, Kirch W. Failure of oral contraceptive because of St John’s wort. Eur J Clin Pharmacol 2001; 57: A25. 43. Turton-Weeks SM, Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. St John’s wort: a hidden risk for transplant patients. Prog Transplant 2001; 11: 116–20. 44. Moschella C, Jaber BL. Interaction between cyclosporine and Hypericum perforatum (St John’s wort) after organ transplantation. Am J Kidney Dis 2001; 38: 1105–7. 45. Heron S, Yarnell E. The safety of low-dose Larrea tridentata (DC) coville (creosote bush or chaparral): a retrospective clinical study. J Altern Complement Med 2001; 7: 175–85. 46. Ilisulu K. Ilac ve Baharat Bitkileri. 1st edition, 1992: 63–75. 47. Yesilada E, Ustun O, Sezik E, Takaishi Y, Ono Y, Honda G. Inhibitory effects of Turkish folk remedies on inflammatory cytokines: interleukin1a, interleukin-1b and tumor necrosis factor a. J Ethnopharmacol 1997; 58: 59–73. 48. Ozden MG, Oztas P, Oztas MO, Onder M. Allergic contact dermatitis from Laurus nobilis (laurel) oil. Contact Dermatitis 2001; 45: 178. 49. Schaller M, Korting HC. Allergic airborne contact dermatitis from essential oils used in aromatherapy. Clin Exp Dermatol 1995: 20: 143–5. 50. Keane FM, Smith HR, White IR, Rycroft RJG. Occupational allergic contact dermatitis in 2 aromatherapists. Contact Dermatitis 2000: 43: 49–51. 51. Lam AY, Elmer GW, Mohutsky MA. Possible interaction between warfarin and Lycium barbarum L. Ann Pharmacother 2001; 35: 1199–201. 52. Wheatley D. Kava and valerian in the treatment of stress-induced insomnia. Phytother Res 2001; 15: 549–51. 53. Wheatley D. Kava-kava (LI 150) in the treatment of generalized anxiety disorder. Prim Care Psychiatry 2001; 7: 97–100. 54. Meseguer E, Taboada R, Sánchez V, Mena MA, Campos V, De Yébenes JG. Life-threatening Parkinsonism induced by kava-kava. Mov Disord 2002; 17: 195–6. 55. Russmann S, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001; 135: 68–9. 56. Kraft M, Spahn TW, Menzel J, Senninger N, Dietl KH, Herbst H, Domschke W, Lerch MM. Fulminantes Leberversagen nach Einnahme des planzlichen Antidepressivums Kava-Kava. Dtsch Med Wochenschr 2001; 126: 970–2. 57. Escher M, Desmeules J, Giostra E. Hepatitis associated with kava, a herbal remedy for anxiety. Br Med J 2001; 322: 139. 58. Park GJ-H, Mann SP, Ngu MC. Acute hepatitis induced by Shou–Wu–Pian, a herbal product derived from Polygonum multiflorum. J Gastroenterol Hepatol 2001; 16: 115–17. 59. Takeshita K, Saisho Y, Kitamura K, Kaburagi N, Funabiki T, Inamura T, Oyamada Y, Asano K,

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Yamaguchi K. Pneumonitis induced by Ou–gon (skullcap). Intern Med 2001; 40: 764–8. 60. Pan KY, Lin JL, Chen JS. Severe reversible bone marrow suppression induced by Selaginella doederleinii. Clin Toxicol 2001; 39: 637–9. 61. Cheema P, El-Mefty O, Jazieh AR. Intraoperative haemorrhage associated with the use of extract of saw palmetto herb: a case report and review of literature. J Intern Med 2001; 250: 167–9. 62. Gertz MA, Bauer BA. Caring (really) for patients who use alternative therapies for cancer. J Clin Oncol 2001; 19: 4346–9. 63. Davies JK, Ahktar N, Ranasinge E. A juicy problem. Lancet 2001; 358: 2126. 64. Ernst E, White AR. Prospective studies of the safety of acupuncture: a systematic review. Am J Med 2001; 110: 481–5. 65. White A, Hayhoe S, Hart A, Ernst E. Adverse events following acupuncture: prospective survey of 32 000 consultations with doctors and physiotherapists. Br Med J 2001; 323: 485–6. 66. MacPherson H, Thomas K, Walters S, Fitter M. The York acupuncture safety study: prospective survey of 34 000 treatments by traditional acupuncturists. Br Med J 2001; 323: 486–7. 67. Yamashita H, Tsukayama H, White AR, Tanno Y, Sugishita C, Ernst E. Systematic review of adverse events following acupuncture: the Japanese literature. Complement Ther Med 2001; 9: 98–104. 68. Koga K, Noguchi T. Should epidurals be avoided in acupunctured patients? Anaesthesia 2001; 56: 291–2. 69. Shen D, Zhang M. A case of pneumothorax caused by acupuncture. Int J Clin Acupunct 2001; 12: 79. 70. Kao CL, Chang JP. Bilateral pneumothorax after acupuncture. J Emerg Med 2002; 22: 101–2. 71. Alani RM, Busam K. Acupuncture granulomas. J Am Acad Dermatol 2001; 45: 225–6. 72. Woo PCY, Li JHC, Tang WM, Yuen KY. Acupuncture mycobacteriosis. New Engl J Med 2001; 345: 842–3. 73. Nambiar P, Ratnatunga C. Prosthetic valve endocarditis in a patient with Marfan’s syndrome following acupuncture. J Heart Valve Dis 2001; 10: 689–90. 74. Beer A-M, Fey S, Kuhnen C, Mentzel T. Kutane Arthropodenreaktion nach Blutegeltherapie. Aktuel Dermatol 2001; 27: 42–6. 75. Ernst E. Prospective investigations into the safety of spinal manipulation. J Pain Symptom Manage 2001; 21: 238–42. 76. Ernst E. Life-threatening complications of spinal manipulation. Stroke 2001; 32: 809–10. 77. Stevinson C, Honan W, Cooke B, Ernst E. Neurological complications of cervical spine manipulation. J R Soc Med 2001; 94: 107–10. 78. Jeret JS. More complications of spinal manipulation. Stroke 2001; 32: 1936–7. 79. Ng KPL, Doube A. Stroke after neck manipulation in the post partum period. NZ Med J 2001; 114: 498. 80. Schram DJ, Vosik W. Diaphragmatic paralysis following cervical chiropractic manipulation: case report and review. Chest 2001; 119: 638–40.

Treatments used in complementary and alternative medicine 81. Tsuboi K. Retinal and cerebral artery embolism after “Shiatsu” on the neck. Stroke 2001; 32: 2441. 82. Liu T, Howard RM, Mancini AJ, Weston WL, Paller AS, Drolet BA, Esterly NB, Levy ML, Schachner L, Frieden IJ. Kwashiorkor in the United

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States. Arch Dermatol 2001; 137: 630–6. 83. Cornejo W, Gonzalez F, Toro ME, Cabrera D. Degeneración combinada subaguda. Descriptión de un caso en un nino vegetariano estricto. Rev Neurol 2001; 33: 1154–7.

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Miscellaneous drugs, materials, and medical devices

Acamprosate Acamprosate (calcium acetylhomotaurinate) has been postulated to act by restoring the alcohol-induced neurotransmission imbalance of inhibition–excitation inputs believed to underlie alcohol dependence (1R , 2r ). The molecular structure of acamprosate explains its specificity towards the basic molecular mechanisms involved in the pathophysiology of alcohol dependence. A competitive interaction has been described between spermidine and acamprosate, suggesting a specific binding site for acamprosate on N -methyl-D-aspartate receptors (3r ). To test the role of acamprosate as an aid in preventing relapse after detoxification, 296 alcohol-dependent patients entered a prospective, multicenter, randomized, doubleblind, placebo-controlled study of acamprosate 666 mg tablets tds for 180 days (4C ). Unlike previous studies, acamprosate was prescribed from the start of alcohol withdrawal, rather than after the detoxification process. During the treatment period, 110 patients dropped out. The two treatment groups were balanced with regard to baseline values and reasons for discontinuation. There was no difference between the groups in the severity of withdrawal symptoms, as measured by the CIWA–Ar (Clinical Institute Withdrawal Assessment for Alcohol scale). Acamprosate given during withdrawal did not cause unwanted effects. The overall incidence of adverse events was similar in the two groups. The number of patients who presented at least one new adverse event (not present at baseline) during the course of the study was 99 with acamprosate and 94 with placebo. Nevertheless, there was a trend for gastrointestinal © 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

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adverse events to be reported more often in the acamprosate-treated patients (n = 61) compared with placebo (n = 46). The individual adverse events that were reported more often with acamprosate were diarrhea, dyspepsia, constipation, and flatulence. Pruritus was reported by seven of those who took acamprosate and five of those who took placebo.

Buffergel Since there is an urgent need for topical microbicides that women can administer vaginally to protect themselves from HIV infection and possibly other sexually transmitted diseases and pregnancy, BufferGel (ReProtect LLC, Baltimore, MD), an aqueous gel of a spermicidal microbicide, formulated at pH 3.9, which acidifies twice its volume of semen to a pH of 5 and maintains the protective acidity of the vagina, should be ideal. The safety of BufferGel has been evaluated in a high-dose tolerance trial in 98 women, of whom 91 (26 sexually abstinent and 65 sexually active) completed the study (5c ). Reasons for withdrawal included: an inability to adhere to the protocol (one woman); breakthrough menstrual bleeding (two women); the presence of yeast on day 7 (two asymptomatic cases and one symptomatic case); and refusal to continue (one woman). The percentage of women with at least one sign or symptom judged by a clinician as potentially related to the product was 29% in India, 33% in Thailand, 35% in Malawi, and 33% in Zimbabwe. There were no differences in the proportions of sexually abstinent and sexually active women with at least one potentially product-related sign or symptom at each study site. In all, there were 45 potentially product-related signs and symptoms. Two were judged to be definitely related

Miscellaneous drugs, materials, and medical devices

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to the product (vaginal itching after product insertion) and 43 as possibly or probably related. All were categorized as mild (84%) or moderate (16%). Excluding participants who withdrew by day 7, 71% of the signs and symptoms resolved during the trial and 24% within 3 days of product withdrawal at the end of the trial; 5% persisted at the end of the trial (one woman was given treatment for a yeast infection and one was not re-evaluated for itching). Minor self-reported symptoms of irritation of limited duration accounted for 64% of reported signs and symptoms and were approximately equally distributed across study sites. They included vulvar and vaginal itching or burning, burning when urinating, and genital rash. The overall rate of symptoms of irritation for all sites combined was 0.58 events per woman-week of observation (95% CI = 0.3, 0.88). Other signs and symptoms included lower abdominal pain or backache, symptomatic yeast infection, and vaginal discharge.

Because of the short duration and severity of the metabolic acidosis, together with a near-normal lactate concentration, acid ingestion was the most likely cause for his acid-base disorder. This diagnosis was confirmed once the composition of the ingested fluid was known.

Citric acid

Cyanamide

Cardiovascular Citric acid toxicity has been reported previously, but only after intravenous administration. It was originally seen with massive transfusion of blood products with citrate as the anticoagulant. Two case reports have described accidental intravenous administration of citrate or citric acid, and at a maximum serum concentration of citrate (4.1 mmol/l) there were profound alterations in blood pressure and QT interval; these were reversed by calcium infusion (6Ac ). Metabolism Although there is a long list of causes of metabolic acidosis with an increased anion gap (7A , 8c ), clinical clues may help diagnosis. A case report has illustrated the acute metabolic and hemodynamic effects of ingestion of a massive load of oral citric acid. The principal findings included a metabolic acidosis accompanied by an increase in the plasma anion gap, not due to lactic acidosis, hyperkalemia, and the abrupt onset of hypotension (9C ). • A 42-year-old previously healthy male prisoner drank a large volume of a commercial solution of unknown composition. His medical history was non-contributory, except for severe epigastric pain.

Within an hour, his condition deteriorated; he was ashen, his blood pressure was 80/40 mmHg, and his pulse rate was 102 beats/min. His neck vessels were flat and his breath sounds were equal bilaterally, with occasional expiratory wheezes at both bases. There were no cardiac murmurs. The abdomen was soft and the bowel sounds were active. His extremities were warm with no cyanosis or edema. There were no neurological abnormalities. Fortuitously, because of therapy to avoid cardiac complications of hyperkalemia, he was given 1 g of calcium chloride, 50 mmol of sodium bicarbonate, 25 g of glucose, and 10 units of regular insulin intravenously. His blood pressure immediately increased to 116/76 mmHg and his pulse rate fell to 90 beats/min. By the next morning his plasma acid-base balance was normal, as was his ionized calcium concentration (1.1 mmol/l).

Skin Rashes due to cyanamide have been reported in two cases (10c ). • A 37-year-old man developed itchy erythema on his trunk and legs after taking cyanamide (dose not specified) for 3 days. He had an eosinophilia of 22%. Patch testing with cyanamide was positive. The eruption subsided after withdrawal of cyanamide. • A 60-year-old man developed keratotic erythema on his trunk and extremities after taking cyanamide (dose not specified) for 1 month. Patch testing with cyanamide was positive. The eruption subsided after withdrawal of cyanamide, but itch and redness persisted for 9 months.

Disulfiram

(SED-14, 1697; SEDA-23, 516; SEDA-25, 580) Disulfiram (tetraethylthiuram) has been widely used since the late 1940s to facilitate abstinence from alcohol. Concomitant use of alcohol during disulfiram therapy results in an autonomic symptom complex that can involve headache, flushing, nausea and vomiting,

542 sweating, tachycardia, hypotension, and confusion. The mechanism of action of disulfiram is inhibition of aldehyde dehydrogenase; alcohol is metabolized to acetaldehyde, which accumulates (11A ). Nervous system A 20-year-old woman was referred for implantation of an intrathecal baclofen pump (12c ). She had had severe dystonia and spasticity following a suicide attempt with disulfiram at age 14 years. T1-weighted MRI scanning of her brain showed bilateral globus pallidus infarction. She had profound relief of spasticity after intrathecal test injections of baclofen and underwent implantation of an intrathecal baclofen pump. Her spasticity subsequently improved. Disulfiram-induced neurotoxicity caused Parkinsonism in a man who had been an alcoholic for 10 years (13c ). • A 52-year-old alcoholic stopped drinking in August 1996 and started to take disulfiram 500 mg/day. His usual medications had been aspirin 300 mg/day and levothyroxine 100 microgram/day. He had had severe loss of visual acuity (2/10) in the left eye 3 months before admission. He was admitted to hospital because of drowsiness. Neurological examination showed severe hypophonia, difficulty in swallowing, and mild rigidity of the limbs. Disulfiram was withdrawn but the other medications were maintained. His drowsiness improved over 5 days, but he remained bradykinetic, with extrapyramidal hypertonia, facial hypomobility, and abnormal posture. His gait was slow and shuffling.

Psychiatric Neuropsychiatric effects of disulfiram have been reported, and have been characterized by symptoms such as paranoia, impaired memory and concentration, ataxia, dysarthria, and frontal release signs (signs that can be indicative of permanent structural damage or temporary metabolic or infectious changes to the brain’s frontal lobes), such as snout and grasp reflexes (11A , 14R ). Prolonged toxic delirium related to disulfiram and alcohol intake has been reported (15c ). The predominant presenting feature was neuropsychiatric rather than autonomic symptoms. • A 50-year-old woman with a history of bipolar disorder type I and alcohol dependence taking disulfiram had a 4-day history of a change in mental status, including visual hallucinations and deficits in orientation and concentration. Other features included a tachycardia and non-focal neurological

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signs. Extensive metabolic, infectious, and neurological investigations revealed no abnormalities that alone could explain her acute confusional state. It was subsequently discovered that she had drunk alcohol on at least two separate occasions while taking disulfiram before her change in mental status, and that a similar, although shorter, episode had occurred previously.

Fluorescein Fluorescein retinal angiography was first described in 1961 (16A ) and has since proved to be a valuable clinical investigation. Rapid intravenous injection has become the standard method of administering the dye. This technique displays retinal circulation velocity and the fine architecture and integrity of the blood retinal barrier. This is associated with minor adverse events in 21% of cases and potential life-threatening adverse events in 0.5% (17c ). The fluorescein is always diluted in cerebrospinal fluid, resulting in a hyperdense solution. For this reason it is necessary to put the patient in the Trendelenburg position for 30–40 minutes so that the fluorescein reaches the cerebral cisterns and is visualized at the level of the fistulae. Complications of the use of fluorescein, all of which were reversible in a few hours or days, have been reported (18c , 19c ). Most of the complications were associated with the use of a larger quantity of fluorescein than recommended. Three patients out of 84 in another study had urticaria, which settled within half an hour of administration of an oral antihistamine, and one had nausea, which subsided without treatment (20c ).

Gammahydroxybutyrate The Expert Advisory Committee on Drugs (EACD) in New Zealand has advised the New Zealand Medicines and Medical Devices Safety Authority to schedule gammahydroxybutyrate, 1,4 butanediol, and other “party drugs” under the Misuse of Drugs Act 1975 (21A ).

Miscellaneous drugs, materials, and medical devices

Isosulfan blue Isosulfan blue 1% aqueous solution (Lymphazurin 1%), a triphenylmethane-based dye, is the dye most commonly used for injection when sentinel node mapping is used to detect the lymphatic drainage basin of a primary malignancy. Isosulfan blue, one of the rosaniline dyes, has other names, including 129-17-9, patent blue, patent blue violet, alphazurine 26, alphazurine 2G, and Lymphazurin 1%. This dye was popular for lymphography in the 1960s and 1970s, but it has largely been replaced by newer techniques. During that period there were a few reports of severe allergic reactions (22r , 23r ). Currently, the reported incidence of allergic reactions is as high as 2.5% (24c ). Two cases of anaphylaxis and three cases of “blue hives” occurred after injection with isosulfan blue in 267 patients who had intraoperative lymphatic mapping (25c ). The two patients with anaphylaxis had cardiovascular collapse, erythema, perioral edema, urticaria, and uvular edema. The blue hives in three patients resolved and transformed to blue patches during the course of the procedures. Urticaria has also been described in three other patients. • A 52-year-old woman with history of ulcerative colitis, hypertension, and asthma underwent preoperative lymphoscintigraphy and 45 min after intraparenchymal peritumoral injections of 2 ml of 1% isosulfan blue dye her right arm and right chest became covered with blue hives (25c ). • A 57-year-old woman with a history of gastroesophageal reflux underwent preoperative lymphoscintigraphy and 25 min after intraparechymal peritumoral injections of 2 ml of 1% isosulfan blue dye she developed widespread blue urticaria involving both breasts and the entire interior abdominal wall, extending to her groin (26c ). • A 52-year-old woman with a previously removed invasive breast carcinoma had 5 ml of 1% isosulfan blue injected and the breast gently massaged, for lymphatic mapping prior to further breast surgery (27c ). She developed diffuse urticaria and was given diphenhydramine hydrochloride; hypotension responded to ephedrine. A blue-stained histologically positive lymph node was identified within a small axillary incision. Because of the hypotension, mammoplasty was abandoned, but segmental mastectomy was performed. Postoperatively, she had severe edema. She was monitored in the intensive care unit, extubated, and discharged the next

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day. Axillary node dissection and bilateral reduction mammoplasty were performed 2 weeks later with no reaction to the antibiotic and anesthetic agents.

Menthol Menthol is a cyclic alcohol, obtained from the volatile oils of various species of Mentha. It is largely used as a flavoring or olfactory agent in a variety of products, including cigarettes, liqueurs, cough drops, mouthwashes, toothpastes, and shampoos. Menthol has been used in different medications to relieve symptoms of asthma and rhinitis. It can cause perioral dermatitis, urticaria, and stomatitis (28A ). Respiratory Some reports have pointed out a relation between menthol present in toothpaste and worsening of asthma in some patients, most of them sensitive to aspirin (29R , 30R ). Cases of menthol-induced asthma are almost always associated with sensitivity to aspirin (31C ), but an exception has been reported (32c ). • A 40-year-old woman with no personal or family history of asthma had dyspnea, wheezing, and nasal symptoms for 2 years whenever she used toothpaste and/or ingested mint confections. She had no history of aspirin sensitivity, and a challenge test with a menthol solution diluted in alcohol ruled out any possibility that the asthma had been caused by preservatives, dyes, or other additives.

Skin There have been reports of urticaria and contact reactions due to menthol (28A , 29R ).

Para-phenylenediamine (Mehindi tattooing) Mehindi is an ancient art of painting the skin using a paste made from the leaves of Lawsonia inermis. This is the botanical denomination of a small shrub that grows in Egypt, Tunisia, Iran, India, Arabia, and tropical Africa, also known as henne, al-Khanna, and alhenna. The leaves of the plant are dried and then powdered, in order to obtain a yellow-green powder, which is dissolved in hot water at the time of use. Application of this paste to the skin

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for 30–40 minutes leaves a temporary tattoo. The most probable cause of contact dermatitis due to mehindi is the presence of paraphenylenediamine, which is added to the paste to strengthen its color. Among numerous mixtures that contain henna and chemical coloring agents, there is the so-called “black henna” used to perform skin drawings; it may contain natural henna, a rare and weak sensitizer, which probably contains para-phenylenediamine. • A 39-year-old housewife developed acute blistering eruptions on her upper back and left arm, the shape of which corresponded exactly to temporary tattoos made with “black henna” during a holiday in Egypt (33c ). She complained of intense itching and burning localized at the side of the dermatitis.

Silicone

(SEDA-25, 583)

Silicone has been used for more than 30 years in various medical applications, including the construction of joint prostheses and breast implants, and in tissue augmentation procedures. Foreign body giant cell granulomas were first reported after liquid silicone injection in 1965 (34A ). Since then, numerous reports have been published demonstrating granulomatous reactions to silicone at application sites and distal sites after hematogenous or lymphatic migration (35R ). • An otherwise healthy 59-year-old woman had received acupuncture for a sprained ankle several times over the previous year (36c ). She had numerous 2–5 mm waxy orange-brown papules on the dorsal aspects of both feet and ankles. A punch biopsy of one of these showed a mixed lichenoid, spongiotic, and granulomatous dermatitis. Macrophages, including many foreign body-type giant cells, were arranged in a granuloma annulare-like pattern around dermal collagen with focal mucinous alteration. Ultrastructural examination showed macrophages containing amorphous foreign material consistent with silicone. The acupuncturist had switched to silicone-plated acupuncture needles over the recent months, and she was believed to have cutaneous granulomas secondary to silicone deposition. She was treated with potent topical steroids and continued acupuncture with non-coated needles. The lesions slowly resolved over the ensuing months.

This case raises the possibility of silicone deposition from cutaneous manipulation with silicone-coated instruments over a relatively

N.H. Choulis

short duration of time. In addition, the case is remarkable in that the latency from exposure to the foreign material to the onset of lesions was relatively short (6–12 months).

Talc Pleurodesis with talc has been used for more than 50 years in the USA and Europe, and has proven to be a secure and effective method in patients with malignant pleural effusions. Malignant pleural effusions represent 25–50% of all pleural effusions seen in a general hospital (37A ). Lung, breast, ovarian, genitourinary, and gastrointestinal tract malignancies are often associated with pleural effusions, and malignant effusion is often the first manifestation of malignancy (38R , 39R ). Of 51 patients with malignant pleural effusions 14 underwent slurry talc pleurodesis via a chest tube, 14 had talc poudrage during Video-Assisted Thoracoscopic exploration of the pleural cavity for suspected malignant effusion, and 24 underwent chemical pleurodesis with bleomycin via a chest tube (40c ). The most common adverse effects were chest pain and fever. The duration of adverse effects after talc pleurodesis was longer (2–3 days) than after bleomycin. There was chest pain in 15 of the 28 patients who received talc, with a duration of 18–52 (median 31) hours. There was fever in 22 of those who received talc, with a duration of 5–34 (median 12.5) hours. Complications were more common in those who received talc, such as thoracic empyema (n = 1), wound infection (n = 2) and respiratory distress (n = 5).

Thiuram Thiurams are a group of chemicals that have been in commercial use since the 1920s. Their main uses are as accelerators and vulcanizing agents during rubber processing and as fungicides on seeds and plants. Skin Allergic contact dermatitis following exposure to thiuram compounds in rubber products, such as disposable rubber gloves, is well recognized (41R ).

Miscellaneous drugs, materials, and medical devices

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Table 1. Miscellaneous reports Drug

Adverse effect(s)

Blue dye Butyl hydroxyanisole Cinnamic aldehyde Enoxolone Fluoride Indigo carmine Indocyanine green Laureth-A (polidocanol) Methyl glucose dialate Polyoxyethylene lauryl ether Rasburicase

Contact dermatitis Allergic contact dermatitis Cutaneous vasodilatation Allergic contact dermatitis Hyperparathyroidism Allergic alveolitis Burning sensation Allergic contact dermatitis Erythematous dermatitis Contact dermatitis Skin rash, respiratory reaction, hemolysis Contact dermatitis Anaphylactic reactions Contact dermatitis Foreign body reactions, tumors, pulmonary complications Contact dermatitis

Stearyl alcohol Sulfan blue Tetraethylthiuramdisulfide Walnut oil White flower

• A 49-year-old man developed acute pruritic dermatitis of the hand, which settled quickly with oral corticosteroids and antibiotics (42c ). Six months later he developed a similar eruption, which became more widespread, involving the trunk and limbs. He had no personal or family history of atopy, and had no known allergies or previous history of skin disease. He had a widespread dry eczematous eruption, most marked in exposed areas. The rash had developed soon after he had handled plants that had been sprayed with a fungicide. The safety data sheet for this product indicated that it contained 80% thiuram. Full blood count and serum electrolytes were normal, and autoantibodies and a porphyrin screen were negative. Biopsy of the lesion showed significantly sun-damaged skin with a superficial perivascular chronic inflammatory infiltrate, confluent surface parakeratosis, and epidermal acanthosis with moderate spongiosis, consistent with a spongiotic dermatitis. He denied any previous contact with rubber gloves in both occupational and social settings and had not had dermatitis before. He was treated with sun protection, topical and oral corticosteroids, and a moisturizer. He had no further contact with the fungicide and the eruption resolved completely. He was advised to avoid all thiuram products, including rubber products and fungicides, in the future. Despite this, he subsequently developed one recurrence of hand dermatitis when he again used rubber gloves for protection at work.

MISCELLANEOUS SUBSTANCES Reports on adverse effects of other miscellaneous substances are listed in Table 1.

Reference (43c ) (44c ) (45c ) (46c ) (47R ) (48R ) (49c ) (50c ) (51c ) (52c ) (53A ) (54c ) (55c ) (56c ) (57c ) (58c )

MEDICAL DEVICES Central venous catheters

(SEDA-25,

583) Central venous catheters are reluctantly used as blood access for hemodialysis because of safety concerns and frequent complications, e.g. sepsis, thrombosis, and vessel stenosis. Nevertheless, 20% or more of all patients rely on atrial catheters for chronic dialysis because of lack of other access. Potentially fatal risks related to central venous catheters include air embolism (59c ), severe blood loss (60c ), and electric shock (61c ). These specific risks have been substantially eliminated by the inherent design and implantation of Dialock (Biolink Corporation, USA). Dialock is a subcutaneous device consisting of a titanium housing with two passages with integrated valves connected to two silicone catheters. The system is implanted subcutaneously below the clavicle. The tips of the catheters are placed in the right atrium. The port is accessed percutaneously with needle cannulas. The results of a study of Dialock® /CLS, the first study using an antimicrobial catheter locking solution in a large number of patients, have been reported in 70 patients (29 men, 41 women; mean age at implantation 63 (range 30–88) years), of whom 42 had no infection (45 when infections occurring within 30 days after implantation were omitted) (62R ). Excluding these early events, 25 patients had a total of

546 30 infections. The majority (22 events in 20 patients) were pocket infections. The first seven of these pocket infections caused loss of the Dialock. After local treatment with gentamicin no further devices were lost through pocket infection. No infections were recorded during the last 3 months, although the expected rate calculated on the basis of previous occurrences

Chapter 49

N.H. Choulis

would have been about four. This may have been related to increased nursing care. Immunologic Anaphylaxis to a central venous catheter (ARROWg+ ard Blue® Catheter) coated with chlorhexidine and sulfadiazine has been reported in a 50-year-old man (63A ).

REFERENCES 1. Littleton J. Acamprosate in alcohol dependence: how does it work? Addiction 1995; 90: 1179–88. 2. Zeise ML, Kasparov S, Capogna M, Zieglgänsberger W. Acamprosate (calcium acetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acids receptors. Eur J Pharmacol 1993; 231: 47–52. 3. Naassila M, Hammoumi S, Legrand E, Durbin P, Daoust M. Mechanism of action of acamprosate. Part 1. Characterization of spermidine-sensitive acamprosate binding site in rat brain. Alcoholism Clin Exp Res 1988; 22: 1–8. 4. Gual A, Lehert Ph. Acamprosate during and after acute alcohol withdrawal: a double-blind placebocontrolled study in Spain. Alcohol Alcohol 2001; 36: 413–18. 5. Van de Wijget J, Fullem A, Kelly C, Mehendale S, Rugpao S, Kumwenda N, Chirenje Z, Joshi S, Taha T, Padian N, Bollinger R, Nelson K. Phase 1 trial of the topical microbicide BufferGel: safety results from four international sites. J Acquired Immune Defic Syndr 2001; 26: 21–7. 6. Bunker JP, Bandixen HH, Murphy A. Hemodynamic effects of intravenously administered sodium citrate. New Engl J Med 1962; 268: 372–7. 7. Emmeh M, Narins RG. Clinical use of the anion gap. Medicine 1977; 56: 38–54. 8. Oh MS, Carroll HJ. The anion gap. New Engl J Med 1979; 297: 814–17. 9. DeMars CS, Hollister K, Tomassoni A, Himmelfarb J, Halperin ML. Citric acid ingestion: a life-threatening cause of metabolic acidosis. Ann Emerg Med 2001; 38: 588–91. 10. Tsunoda T, Iguchi M, Watanabe M. Two cases of drug eruption due to cyanamide. Skin Res 2001; 43: 97–100. 11. Bosch J, Burroughs AK, Clinical manifestations and management of bleeding episodes in cirrhotics. In: Bircher J, Benhamou JP, McIntyre N, Rizzetto M, Rodes J, editors. Clinical Hepatology, 2nd edition New York: Oxford University Press, 1999: 671–93. 12. Mesiwala AH, Loeser JD. Bilateral globus pallidus infraction secondary to disulfiram ingestion. Pediatr Neurosurg 2001; 34: 224. 13. Boukriche Y, Weisser I, Pascale A, Masson C. MRI findings in a case of late onset disulfiraminduced neurotoxicity. J Neurol 2001; 247: 714–15.

14. Gostout CJ. Patient assessment and resuscitation. Gastrointest Endosc Clin N Am 1999; 9: 175–87. 15. Park CW, Riggio S. Disulfiram–ethanol induced delirium. Ann Pharmacother 2001; 35: 32–5. 16. Novotny HR, Alvis DL. A method of photographing fluorescein circulating blood in the human retina. Circulation 1961; 24: 82–6. 17. Watson AP, Rosen ES. Oral fluorescein angiography: reassessment of its relative safety and evaluation of optimum conditions with use of capsules. Br J Ophthalmol 1990; 74: 458–61. 18. Mahaley Jr MS, Odom GL. Complication following intrathecal injection of fluorescein. J Neurosurg 1966; 25: 298–9. 19. Wallace JD, Weintriaub MI, Mattson RH, Rosnagle R. Status epilepticus as a complication of intrathecal fluorescein. J Neurosurg 1972; 36: 659–60. 20. Razvi FM, Kritzinger EE, Tsaloumas MD, Ryder REJ. Use of oral fluorescein angiography in the diagnosis of macular oedema within a diabetic retinopathy screening programme. Diabetic Med 2001; 18: 1003–6. 21. Anonymous. Gamma hydroxybutyrate. Fantasy drugs to be classified. WHO Pharm Newslett 2001; 2/3: 5–6. 22. Hepps S, Dollinger M. Anaphylactic death after administration of a trimethylmethane dye to determine burn depth. New Engl J Med 1965; 272; 24: 1281. 23. Kopp WL. Anaphylaxis from alphazurine 2G during lymphography. J Am Med Assoc 1966; 198: 668–9. 24. Vervloet D, Pradal M, Castelian M. Patent blue dye. In: Vervloet D, Pradal M, Castelain M, editors. Drug allergy, 3rd edition. Marseille: Pharmacia Upjohn, 1999: 206–7. 25. Cimmino VM, Brown AC, Szocik JF, Pass HA, Moline S, De Summit K, Domino EF. Allergic reactions to isosulfan blue during sentinel node biopsy—a common event. Surgery 2001; 130: 439–42. 26. Saliq TS, Burns WW, Taber GJ, Damitz L, Ollila DW. Blue urticaria. A previously unreported adverse event associated with isosulfan blue. Arch Surg 2001; 136: 1433–5. 27. Kuerer HM, Wayne JD, Ross MI. Anaphylaxis during breast cancer lymphatic mapping. Surgery 2001; 129: 119–20.

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28. Morton CA, Garioch J, Todd P, Lamey PJ, Forsyth A. Contact sensitivity to menthol and peppermint in patients with intra-oral symptoms. Contact Dermatitis 1995; 32: 281–4. 29. McGowan EM. Menthol urticaria. Arch Dermatol 1966; 94: 62–3. 30. Kwane H. Aspirin-induced asthma and artificial flavors. Chest 1994; 106: 654–5. 31. Kwane H. Menthol and aspirin-induced asthma. Respir Med 1996; 90: 247–9. 32. Dos Santos MA, Galrao CES, Castro FM. Menthol-induced asthma: a case report. J Invest Allergol Clin Immunol 2001; 11: 56–8. 33. Schiera A, Battifoglio ML, Rossi L, Nicoletti A, Galbiati G. Contact dermatitis caused by mehindi. Acta Dermatovenereol Alp Panonica Adriat 2001; 10: 57–61. 34. Ballantyne DL Jr, Rees TD, Seldman I. Silicone fluid: response to massive subcutaneous injections of dimethylpolysiloxane fluid in animals. Plast Reconstr Surg 1965; 6: 330–8. 35. Travis WD, Balogh K, Abraham JL. Silicone granulomas: report of three cases and review of the literature. Hum Pathol 1985; 16: 19–27. 36. Alani RM, Busam K. Acupuncture granulomas J Am Acad Dermatol 2001; 45: S225–6. 37. Deslauriers J, Beauchamp J, Desmeules M. Pleural neoplasms and malignant pleural effusion. In: Baue AE, Geha AS, Hammond GL, Laks H, Naunheim KS, editors. Glenn’s Thoracic and Cardiovascular Surgery, 5th edition, volume 1. Prentice-Hall International Inc, 1991; 473–8. 38. Sahn SA. Malignant pleural effusions. In: Shields TW, LoCicero J, Ponn RB, editors. General Thoracic Surgery, 5th edition, volume 1. Philadelphia: Lippincott Williams and Wilkins, 2000: 795–803. 39. Rodrigeuz-Panadero F, Borderas Naranjo F, Lopez Mejias J. Pleural metastatic tumors and effusions. Frequency and pathogenic mechanisms in a post-mortem series. Eur Resp J 1989; 2: 366–9. 40. Foroulis CN, Kotoulas C, Konstantinou M, Lioulias A. The management of malignant pleural effusions: talc pleurodesis versus bleomycin pleurodesis. J BUON 2001; 6: 397–400. 41. Von Hinzenstern J, Heese A, Koch HU, Peters KP, Hornstein OP. Frequency, spectrum and occupational relevance of type IV allergies to rubber chemicals. Contact Dermatitis 1991; 24: 244– 52. 42. Saunders H, Watkins F. Allergic contact dermatitis due to thiuram exposure from a fungicide. Aust J Dermatol 2001; 42: 217–18. 43. Guin JD. Seat-belt dermatitis from disperse blue dyes. Contact Dermatitis, 2001; 44: 263. 44. Orton DI, Shaw S. Allergic contact dermatitis from pharmaceutical grade BHA in Timodine® , with no patch test reaction to analytical grade BHA. Contact Dermatitis 2001; 44: 191–2. 45. VemderEude DS, Morrow JD. Release of markedly increased quantities of prostaglandin D2 from the skin in vivo in humans after the application of cinnamic aldehyde. J Am Acad Dermatol 2001; 45: 62–7.

46. Tanaka S, Oksuki T, Matsumoto Y, Hayakawa R, Sugiura M. Allergic contact dermatitis from enoxolone. Contact Dermatitis 2001; 44: 192. 47. Gupta SK, Khan TI, Gupta RC, Gupta AB, Gupta KC, Jain P, Gupta A. Compensatory hyperparathyroidism following high fluoride ingestion. A clinico-biochemical correction. Indian Pediatr 2001; 38: 139–46. 48. Steurich F, Feyerabend R. Campari-/Karmin/Cochenille-Allergie. Farbstoffe in Lebensuitteln, Medikamenten und Kosmetika. Allergologie 2001; 24: 66–72. 49. Szeimies RM, Lorenzen T, Karrer S, Abels C, Plettenberg A. Photochemotherapy of cutaneous AIDS-related Kaposi sarcoma with indocyanine green and laser light. Hautarzt 2001; 54: 322–6. 50. Gallo R, Basso M, Voltolini S, Guarrera M. Allergic contact dermatitis from laureth-9 and polyquaternium-7 in a skin-care product. Contact Dermatitis 2001; 45: 356–7. 51. Corazza M, Levratti A, Virgili A. Allergic contact dermatitis due to methyl glucose dioleate. Contact Dermatitis 2001; 45: 308. 52. Kimura M, Kawada A. Follicular contact dermatitis due to polyoxyethylene laurylether. J Am Acad Dermatol 2001; 42: 879–80. 53. Easton J, Noble S, Jarvis B. Rasburicase. Paediatr Drugs 2001; 3: 433–7. 54. Yesudian PD, King CM. Allergic contact dermatitis from stearyl alcohol in Efudix cream. Contact Dermatitis 2001; 45: 313–14. 55. Gimenez J, Botella-Estrada R, Hernandez D, Carbenell M, Martinez MA, Guillen C, Vazquez C. Anaphylaxis after peritumoral injection of sulpham blue 1% for identification of the sentinel node in lymphatic mapping of the breast: case report. Eur J Surg 2001; 167: 921–3. 56. Gutgesell C, Fuchs T. Orally elicited allergic contact dermatitis to tetraethylthiuramdisulfide. Am J Contact Dermatitis 2001; 12: 235–6. 57. Munch IC, Hvolris JJ. Intramuscular injection of walnut oil as an aid to body-building. Ugeskr Laeg 2001; 163: 6758. 58. Saary MJ, Holness DL. Contact dermatitis from white flower embrocation. Contact Dermatitis 2001; 44: 100. 59. Orebaugh SL. Venous air embolism: clinical and experimental considerations. Crit Care Med 1992; 20: 1169–77. 60. Lau G. Iatrogenically-related, fatal haemorrhage occurring in end-stage renal failure: a series of three cases. Forens Sci Int 1995; 73: 117–24. 61. Jonsson P, Stegmayr BG. Current leakage in haemodialysis machines varies. Int J Artif Organs 1999; 22: 425. 62. Sodemann K, Polaschegg HD, Feldmer B. Two years experience with Dialock® and CLS™ (a new antimicrobial lock solution). Blood Purif 2001; 19: 251–4. 63. Stephens R, Mythen M, Kallis P, Davies DW, Egner W, Rickards A. Two episodes of life-threatening anaphylaxis in the same patient to a chlorhexidine–sulphadiazine-coated central venous catheter. Br J Anaesth 2001; 87: 306–8.

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The WHO International Drug Monitoring Programme

History The WHO International Drug Monitoring Programme was established in 1968 as a pilot project, with the participation of ten countries that had organized national pharmacovigilance systems at that time. The intention was to develop international collaboration to make it easier to detect rare adverse drug reactions not revealed during clinical trials. The International Drug Monitoring Centre was moved from WHO headquarters in Geneva, Switzerland, to a WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, in 1978. This was the result of an agreement between the WHO and the Swedish Government, by which Sweden assumed the operational responsibility for the Programme. WHO headquarters in Geneva retained the responsibility for policy matters. The Collaborating Centre is often referred to as the Uppsala Monitoring Centre (UMC). Information about the WHO and the UMC can be obtained from their websites: www.who.int/medicines and www.whoumc.org. A new negotiation between the WHO and the Swedish Government was completed in 2001, and the Uppsala Monitoring Centre is now a non-profit-making foundation, with a Board appointed partly by the WHO and partly by the Swedish Government, as well as having a jointly agreed Director.

Vision and goals of the Uppsala Monitoring Centre It is the aim of the Uppsala Monitoring Centre to support WHO’s leadership in the field of world health by providing excellence: • in the science and concepts of all aspects of pharmacovigilance; • to prevent harm to humans from the effects of medicines; • to gather and share objective intelligence and opinion in the field of drug safety through open and transparent means of communication; • to support the promotion of the rational use of drugs, and the achievement of improved patient therapy and public health; • in global education and communications in benefit, harm, effectiveness, and risk in medical therapy. This will be achieved by the following activities: • developing leading-edge systems and science for the identification and communication of safety hazards from drugs and other substances used in medicine; • carrying out research that pushes forward the ethical, intellectual, and scientific boundaries of theory and practice in pharmacovigilance; • pursuing active collaboration and communication with all stakeholders; • pursuing the goal of a single global database for drug safety data. The Uppsala Monitoring Centre will particularly:

© 2003 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 26 J.K. Aronson, ed.

548

• ensure that effective, timely, international collective effort will never miss a signal of a potential hazard;

The WHO International Drug Monitoring Programme

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Chapter 50

Table 1. Members of the WHO International Drug Monitoring Programme and their year of entry Country

Year of entry

Country

Year of entry

Country

Year of entry

Argentina Armenia Australia Austria Belgium Brazil Bulgaria Canada Chile China, PR Costa Rica Croatia Cuba Cyprus Czech Republic Denmark Egypt Estonia Fiji Islands Finland France Germany Ghana Greece

1994 2001 1968 1991 1977 2001 1975 1968 1996 1998 1991 1992 1994 2000 1992 1968 2001 1998 1999 1974 1986 1968 2001 1990

Guatemala Hungary Iceland India Indonesia Iran Ireland Israel Italy Japan Jordan Korea, Republic of Latvia Macedonia Malaysia Mexico Moldova Morocco Netherlands New Zealand Norway Oman Peru Philippines

2002 1990 1990 1998 1990 1998 1968 1973 1975 1972 2002 1992 2002 2000 1990 1998 2003 1992 1968 1968 1971 1995 2002 1995

Poland Portugal Romania Russia Singapore Slovak Republic South Africa Spain Sri Lanka Sweden Switzerland Tanzania Thailand Tunisia Turkey Ukraine United Kingdom Uruguay USA Venezuela Vietnam Yugoslavia FR Zimbabwe

1972 1993 1976 1998 1993 1993 1992 1984 2000 1968 1991 1993 1984 1993 1987 2002 1968 2001 1968 1995 1999 2000 1998

Associated member countries: Netherlands Antilles Bahrain

Belarus Kyrgyztan

• ensure that all stakeholders evaluate and learn from decisions and actions through positive impact assessment, follow-up, and debate; • encourage the growth of pharmacovigilance activities around the world, in particular the establishment of new National Centres; • promote existing National Centres and other stakeholders in the field; • contribute actively to the global vision of the WHO Programme; • use and share available information openly and transparently; • sponsor and support others in their pharmacovigilance activities; • exploit fully the resources of the Uppsala Monitoring Centre; • stimulate the development of coherent, harmonized systems worldwide for pharmacovigilance, through education, training, promoting and participating in international forums, promoting best practice, and the publication of guidelines; • maintain and develop useful products, services, and tools in pursuit of the vision and

Pakistan Zambia

goals of the WHO Programme and the Uppsala Monitoring Centre.

Current programme structure At present 71 countries are active members of the WHO Programme. Six countries have formally applied for membership, and they are considered as associated members while the issue of the technical compatibility of their reports with the WHO requirements is established. Member countries and associated member countries are listed in Table 1. In each country a national centre or system, designated by the competent health authority, is responsible for collecting, processing, and evaluating adverse reaction case reports submitted by health professionals. Information obtained from these reports is passed back to the professionals on a national basis, but is also submitted to the WHO Centre for inclusion in the international database. Collectively the centres

550 annually provide over 200 000 individual reports to the WHO of reactions suspected of being drug-induced. The cumulative database of the WHO Programme now comprises nearly 3 million case reports. Case reports submitted to the WHO are checked for technical correctness and are then incorporated into the international database in a daily routine. Reports may be submitted either in the format recommended by the E2b working party of ICH (International Conference on Harmonization) or in the format previously agreed within the WHO Drug Monitoring Programme. In 2002 a new database that allows the storage of much more information, as proposed by the Council of Organizations of Medical Sciences (CIOMS) monograph 1(a) (1S ) and adapted by the ICH project E2b, was introduced.

Signal finding Each national centre reasonably focuses on its own country’s issues and data, turning to international information for secondary support. The WHO Programme has the only international repository of adverse drug reaction reports, in which one can look at the pooled information for signals on all reported medicinal products from around the world. The need for automated tools to help deal with all this information is great, but the tools must be such that they do not obscure the tentative nature of the information and conclusions. The tools must aid human review and not replace it. It is a truism that people do not cope with large amounts of information, let alone multiple variables, missing data, and data of variable quality. A combination of automatic signalling devices and scanning by experienced medical personnel is now considered by the Uppsala Monitoring Centre most advantageous in successfully fulfilling the original aim of the programme, i.e. the early identification of new adverse drug reactions. In 1998 a new method developed at the Uppsala Monitoring Centre, using a Bayesian Confidence Propagation Neural Network (BCPNN) (2, 3) in analysing the database, was put into routine use. This method provides a quantitative measure of the strength of association of a drug/reaction combination in the database (4).

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I. Ralph Edwards and Sten Olsson

The BCPNN method has been tested as a routine tool for finding new adverse drug reactions in the WHO database; its positive predictive value is a little less than 50%, but its negative predictive value is about 85% (5). When the new data have been processed and entered into the database, a BCPNN scan is run to generate statistical measurements for each combination of drug and adverse reaction. The resulting combinations database is made available to national centres and pharmaceutical companies, in the latter case as a subscription service on selected drugs. The database is presented in a computerized form, with software that facilitates searching and sorting of the information. Associations are selected from the combinations database based on a preset threshold. Based on the results of the test runs of the BCPNN, the threshold for associations is set to the lower 95% confidence limit of the Information Component (IC) crossing zero when a new batch of reports is added. The Information Component in information theory is a measure of disproportionality, indicating how strongly a data field or complex of data fields stands out from the background of information value. The UMC puts greatest emphasis on identifying early signals concerning serious, potentially fatal reactions reported with new medicines. A series of criteria are used for focusing on the prioritized areas: • drugs first entered into the WHO database in the last 1–2 years; • serious reactions included in the WHO List of Critical Terms; • at least one report having a fatal outcome; • the drug–ADR combination exceeds the statistical threshold of having a lower 95% confidence limit of the IC above zero; • few reports about the combination. In addition, attention is given to drug–reaction combinations that fulfil the statistical threshold mentioned above, when the IC has increased at least two-fold since the last quarterly analysis. Special consideration is also given to certain reactions that are often drug induced e.g. Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, and rhabdomyolysis. The combinations selected by any of the above criteria are checked by the UMC staff for

The WHO International Drug Monitoring Programme

occurrence in the available product information literature, e.g. the Physician’s Desk Reference or Martindale’s Extra Pharmacopoeia or using Medline and Reactions Weekly. If the reaction is not found or not sufficiently well described, case reports are retrieved from the WHO database. The collected documentation is submitted to the most appropriate expert in the UMC panel of signal reviewers, who is asked to assess the evidence that the reaction was caused by the suspected drug. Short summaries of reviewers’ findings are circulated to participating national centres in a memorandum called “Signal”. Selected associations are followed for 2 years, the data being checked at 6-monthly intervals. After the final listing, an association may be reintroduced for another 2-year follow-up. Investigations have shown that the WHO Programme is successful in finding new drug– reaction associations at an early stage and in providing useful information about them to national centres. Individualized sections of the “Signal” document are provided to companies (only on their patented products). Companies are invited to provide an analysis of the suspected drug problem for inclusion in the “Signal” document. A larger number of variables than the routine drug–reaction combinations can also be considered using the Bayesian approach described above. Searching and sorting of the associations data can be done, not only on drug, adverse reaction, and the various statistical measurements, but also on System Organ Class and on therapeutic drug groups using the Anatomical– Therapeutic–Chemical (ATC) classification (6). The system can be used in other ways. For example, the effects of including drugs reported as “concomitant medications” can be studied using the BCPNN. One of the outcomes of these analyses might be to identify patient subgroups at particularly high risk of a specific adverse reaction to a specific drug. Another possibility is to establish that a drug safety problem is related to a particular country, region, or time period. However, it should be pointed out that, in order for these data to be useful, a substantial number of case reports is required. The BCPNN has also been used for the first time for “unsupervised pattern recognition” of multiple variables in the database. This is being developed into a routine tool.

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Reference source and database The database of the WHO Programme is a unique reference source that is used in many different circumstances. When a national centre receives the first report of an unfamiliar drug– reaction association, the WHO database is often consulted to find out whether a similar observation has been made elsewhere in the world. If so, the initial signal may be strengthened. National centres are provided with an annual reference document on CD-ROM that provides summary figures of suspected drug–reaction associations reported to the WHO. On-line search facilities, accessible over the Internet, are also at the disposal of national centres for up-to-date checking of what has been reported. In order to speed up the accrual of useful case data, a primary consideration is the structure of databases. In the past, database structure has been limited in the number of fields provided, partly because of limited computer storage capacity, but also because single-sheet reporting forms have been thought to be user friendly and that reporters would be put off reporting by what appeared to be a lengthy questionnaire. This has meant that the information sent to national centres has been limited by the design of the forms used, and that sent to the WHO database has been further limited because of storage capacity. In the modern world all that has changed. It is possible to capture information for reporting from the doctor’s notes and prescribing information in an automated way, thus making the reporting of more data much easier. We have collaborated with ICH on international agreement on information technology standards for the transmission of data in a secure way. With first CIOMS (1) and then ICH we have developed a comprehensive set of data fields; these have been included in our new database, Vigibase (7, 8). The new database has great complexity, and it seems unlikely that many of the available fields will be completed until a “paperless” system comes into operation in several countries. The new database is fully compatible with the old one. To provide flexibility for users with varying requirements and sophistication is a great challenge, but we are hopeful that Vigibase will pave the way for the international availability of much more useful case data, without recourse to the original provider for more details.

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Quantification There is a general need to quantify adverse drug reactions information. Under-reporting of adverse reactions in routine monitoring is the norm. However, the degree of under-reporting differs from time to time, from place to place, and from drug to drug. The WHO centre is working jointly with IMS International, to analyse adverse reaction reports together with drug use data from different countries. This allows national differences in reporting rates to be further analysed for reasons that may be due to differences in indications for use, medical practice, demographics, etc. Several new signals have been evaluated in this way, often making it clearer what biases might be present both geographically and over time. Bearing such problems in mind, cautious comparisons of reporting rates between medicinal products are often revealing (9–12). This type of analysis of international data serves as a guide to the need for more precise pharmacoepidemiological investigations.

A clearing house for information The Uppsala Monitoring Centre has an important role to play as a communication centre—a clearing house for information on drug safety at the service of drug regulatory agencies, the pharmaceutical industry, researchers, and other groups in need of drug safety information (13). Requests for special database searches and investigations are received from these parties at a rate of around 300 per year. In addition, flexible on-line retrieval programmes are made available through Internet, by which database users can perform a variety of standardized searches by themselves. Access for non-member parties is subjected to confidentiality restrictions agreed by Programme members. Countries have the right to refuse the release of their own information if they so wish, and some do. Use of the information released is subject to a caveat document as to its proper use. Detailed manuals for the on-line service and the customized retrievals on request are available from the Uppsala centre.

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WHO member countries are provided with the WHO Pharmaceuticals Newsletter, distributed by the Health Technology & Pharmaceuticals department of WHO headquarters. The Uppsala Monitoring Centre is responsible for the information that is included in the drug safety section of this newsletter, which is also available from the WHO web site. An agreement with Adis International has allowed information from newsletters produced by members of the WHO Programme to be printed in “Reactions Weekly”. The agreement includes making this journal available to national centres at heavily discounted subscription rates, greatly enhancing their access to up-to-the-minute information on adverse drug reactions. “Uppsala Reports” is the name of a bulletin that is made freely available to all interested parties by the Uppsala Monitoring Centre. It provides an easy-to-read account of news about pharmacovigilance in general, the WHO Programme, and its members and services. Communications within the WHO Programme have improved with the increasing use of electronic communications media. The Uppsala Monitoring Centre maintains an e-mail discussion group called “Vigimed”, which allows rapid exchange of information around the world on drug safety matters. Membership is restricted to persons connected with national pharmacovigilance centres. The Internet home page of the WHO Programme (http://www.who-umc.org) was introduced in 1996. It is intended to be developed into a dynamic tool for communications with all clients of the Uppsala Monitoring Centre. Recently, internet-based seminars and training courses were introduced on the Uppsala Monitoring Centre web site. The Uppsala Monitoring Centre publishes a book, “National Pharmacovigilance Systems— Country Profiles and Overview” (14), in which the operating procedures of the national centres that participate in the WHO Programme are described.

Terminology and standards The WHO Programme has assumed responsibility for developing a standardized adverse

The WHO International Drug Monitoring Programme

reactions terminology (WHO–ART) and a comprehensive index of reported drugs (WHO– DD), both of which have a utility beyond their importance to the monitoring system. These tools are used in the premarketing safety area, as well as for postmarketing studies by many pharmaceutical companies. WHO–ART has also been adopted by the International Programme on Chemical Safety as the medical terminology to describe poisoning incidents. The WHO Drug Dictionary (WHO–DD) is unique in its coverage of drugs marketed throughout the world. It is available in hard copy or as computer files. The Uppsala Centre is developing it further, to incorporate more detailed information and to make it compatible with the prestandard proposed by the European Committee for Standardization (CEN). In response to the challenge to safety monitoring offered by traditional herbal remedies, the WHO centre has taken initiatives to improve the classification systems for such medicines. In a joint project (15–18) with institutions such as the Royal Botanical Gardens, Kew, in the UK, others in South Africa and the Netherlands, and including the phytotherapy industry, a system compatible with the ATC system used for modern synthetic medicines has been developed. This is now being implemented in the WHO–DD. Input from experts from all parts of the world, representing different therapeutic traditions, will be indispensable for the further development of this project. The way in which adverse drug reactions terminology is used is an important factor in data mining. The development of definitions and guidelines for the use of terms is paramount. We have worked with CIOMS in this area, resulting in the publication of definitions that are useful in pharmacovigilance (19). It is hoped that this work can be extended. In data mining, the hierarchical linkage between terms is less important. On the other hand we are aware of the need by many people for some harmony in this area. The advent of MedDRA as a commercial terminology has caused some difficulties, since it is not yet clear that it represents a clear overall improvement. The WHO and Uppsala Monitoring Centre are actively looking at ways in which the different types of terminology can be used in a parallel fashion, while we find a way forward that will offer clear benefits. One obvious proposal is to link WHO–ART

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with the world standard, the International Classification of Disease (ICD 9 and 10). We are pursuing this, since ICD has the advantage of having a core structure on to which variants can be grafted in a transparent way. There are already domain versions of ICD, for example in neurology and psychiatry, which follow the common ICD logic. Definitions for terms are already available in ICD. The advantage to WHO in maintaining such a unbiased normative terminology, which can be used for any aspect of public health epidemiology in any country in the world, and at minimal cost, must be clear. Within the WHO Programme a number of definitions of commonly used terms (such as adverse reaction, side effect, adverse event, signal) have been worked out. These definitions contribute to a harmonized way of communicating both inside and outside the Programme (20). However, approaches to, and the extent of, pharmacovigilance are being considered all the time. New definitions therefore need to be considered (21R ).

Education In order to foster education and communication in pharmacovigilance, every second year the WHO Centre offers a 2-week training course in “Pharmacovigilance—the Study of Adverse Drug Reactions” in Uppsala, to which 25 health-care professionals are accepted. The course is divided into two modules. The first is about spontaneous monitoring and the practicalities of managing a drug monitoring centre. This section also offers hands-on experience in using the database of the WHO Programme. The second module is an introduction to wider issues in pharmacoepidemiology. There is an increasing trend towards local and regional meetings and courses in pharmacovigilance. The WHO Programme often takes part in such meetings, particularly those organized in developing countries, to provide support and technical advice.

Support to national centres Along with the provision of the new database, Vigibase (which is also offered as a singlestop repository for industry reports, rather than

554 their sending them to each national centre), we have developed a computer software suitable for processing and managing adverse reaction reports at a National Centre. The UMC has been collaborating with the Swiss medicines agency, Swissmedic, on the challenge of improving ADR reporting and feedback in the age of the Internet. The web has made possible the creation of a channel for improved communication between reporting physicians and a pharmacovigilance centre. The system accesses Vigibase over the Internet; thus, no local installations are required, and therefore no licenses of database systems and servers. Reports can be entered and assessed via a secure Internet connection by the individual who reports an ADR. Assessors from a regional centre and the national centre then access the report. The collaboration with the Swiss agency has guaranteed a solution that solves the basic needs of a National Centre, and it can be developed to add new useful functionality. When the report is completed it is downloaded to the Vigibase database, where it will be available for searching by the reporting centre and all other National Centres. It will also be available for statistical analysis by the UMC.

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Communication Through its consultants, the Uppsala Monitoring Centre continues to offer advice and training on all aspects of the communication of the complex messages of benefit and harm, effectiveness and risk to all stakeholders in drug safety (25). The WHO and the Uppsala Monitoring Centre have recently developed and published several guidelines and position documents, with the aims of improving general knowledge of basic concepts in benefit/harm assessment and pharmacovigilance, and of expanding the horizons beyond searching for new signals to new medicinal products (26, 27). This includes issues that vary from new professional concerns (such as poisoning by drugs, fraudulent drugs, and adverse reactions to herbal remedies) to promoting the view that consumer reports have unique importance in telling us what patients feel about the adverse events they experience. They may not be telling us about new adverse reactions, but they are giving us their concerns, which must be considered and acted upon (28, 29). A new UMC monograph on key issues of communication in the medicines safety area was published in 2002 (30).

Annual meetings Harm and risk The consideration of benefit/effectiveness versus harm/risk has so far been almost entirely at a descriptive level. Most of the work so far in this area is confined to describing the benefits and the risks separately for each medicinal product. The more difficult task of deriving a useful analysis and then a synthesis of the information is accorded much less attention. The situation is changing and there is an increasing effort to give semi-quantitative tabular summaries of information for all medicines that might be used for a specific indication. On the other hand, there is a need for an improved conceptual approach to what is benefit and harm, effectiveness and risk, as well as more technical thinking over how to improve comparisons between medicinal products (22–24).

Every year representatives of national centres are invited to a meeting arranged jointly by the WHO and one of the participating countries. At these meetings technical issues are discussed, in relation to how to improve global drug monitoring in general and concerning individual drug safety problems. Since the meetings have very high attendance rates, they are important for establishment and maintenance of personal relationships and subsequently contribute to good communications.

Collaboration with other organizations Co-operation with organizations that are interested in developing early signals of significance is of importance in achieving safer drug

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therapy. The International Society for Pharmacoepidemiology (ISPE) is specifically interested in the science of pharmacovigilance, and the Council for International Organizations of Medical Sciences (CIOMS) is pivotal in bringing interested parties together to mount various collaborative projects. Much support has been given to the International Society of Pharmacovigilance (ISoP). The WHO is also involved in the ICH processes, as observers at all meetings, and the Uppsala Monitoring Centre provides additional technical advice to WHO when required.

Developments needed in the immediate future Given the considerations discussed above, the biggest challenge we face is how to manage efficiently the large amount of risk information that accumulates while a medicinal product is being aggressively marketed (31). Our failure to cope with this challenge can have two opposite consequences: failure to recognize a signal early, causing unnecessary exposure of patients to harm, and deletion of a medicinal product due to hasty action on poorly considered information. Many will argue that pharmacoepidemiology and the use of, mainly, case-control studies will provide a surer answer to safety questions. The extent to which this is true is very limited, for the following reasons. Most medicines safety signals, including those that arise from how the particular product was used, come from experience contained in accumulated single case reports. It is not possible to perform an epidemiological analysis of each signal: the cost is prohibitive. Case–control studies suffer from biases, just as case reports do. Case– control studies, while very suitable for rare events, often have problems of power from a practical standpoint. Rare but clinically serious events are not easily investigated without long multicentre studies, and sometimes cannot be reasonably investigated at all by this method. The use of continuous, comprehensive, and rigorously collected data on medicinal products, and their use to provide information on benefit and harm, has long been seen as attractive. Postmarketing surveillance of a restricted

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number of medicines (used as a continuous method in New Zealand and the UK) has provided useful new information on a limited range of medical products, with limited comparative opportunities. Health-care databases mainly in the USA and UK have also been useful. Their limitations are size and their structure, which does not necessarily allow all the relevant information to be collected, nor for the finding of new signals relating to properties of medicines or their use: their role has been restricted to hypothesis testing using nested studies. Almost the whole effort of this vast collection machinery for clinical case report information is directed towards finding new adverse reactions signals. Little use is made of the data for other signal work, such as finding atrisk groups (do some adverse reactions occur disproportionately with age?), interactions (do known reactions occur more frequently with certain drug combinations?), or use-related adverse reactions (do certain reactions occur more often in certain countries? at higher doses?). This is not surprising, since the quantity of data is so great and most national centres have few resources. Several needs are apparent if we are to meet the challenges of the future. Amongst the most important are: I. To encourage clinicians to report their clinical experience. The concentration only on new and rare adverse reactions to new drugs is not going to help us get information that will allow us to tackle avoidable reactions adequately (32). II. To give advice about the diagnosis and management of adverse reactions. III. To improve the rapid transmission of quality information to national centres and industry, and thence to the WHO database. IV. To bridge the gap between a tentative signal from raw adverse reactions data to observational studies that use specific protocols and to clinical outcomes (33). V. To link genetic information with adverse reactions. In 2002 the World Health Assembly passed a resolution on Quality of Care–Patient Safety emphasizing the need to establish and strengthen science-based systems for improving patient safety and monitoring of adverse events.

556 Whether or not this kind of work should be linked to the current work of national regulatory agencies and the WHO Programme for International Drug Monitoring is a consideration. Perhaps the overlap in the work will be regarded as large enough to warrant using the existing adverse reactions monitoring machinery, but much depends on how far there will be monitoring of other medical misadventures and the attitude of national monitoring agencies. It is clear to any clinical pharmacologist that causation of disease by medicines is often missed in the differential diagnosis. Failure to take an adequate medication history is one reason, but the complexities of polypharmacy in elderly patients with multiple diseases make diagnosis difficult. Education of undergraduates and postgraduates in the logical approach to a diagnosis of medicine-related injury has been neglected. The reason for failure to report adverse drug reactions is an old topic. Redoubled efforts with new initiatives are required. Modern communications theory throws some light on reasons for under-reporting. Failure to understand the motivation of doctors and the need for health professionals to understand the adverse drug reactions reporting schemes and to see why they

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are important to them in their clinical practice are critical issues. It is likely that modern information technology can contribute to better reporting in some countries. This need not be only in the most developed countries. Argentina had one of the first e-mail adverse drug reactions reporting systems to function on a routine basis, linking regional centres, based in hospitals, to the national regulatory authority. The gap between the analysis of raw data to find a signal and the need to perform more formal studies is of great importance. The decision to perform the latter must be based on the seriousness of the event, the strength of the causal relation, and an idea of the medicine-related fraction of that event. The latter piece of information is much helped by having information on where, how, and how widely a medicine is used. Unfortunately, there still seem to be problems in obtaining full information on the use of medicines. The advent of genotyping technology throws open the possibility of not only genotyping for pharmacokinetic phenotypic variation, but also of examining pharmacodynamic phenotypes. This should allow the identification of people at risk and the possibility of preventing some adverse reactions.

REFERENCES 1. CIOMS. Harmonization of data fields for electronic transmission of case-report information internationally. Public report. Geneva: CIOMS, 1995. 2. Orre R, Lansner A, Bate A, Lindquist M. Bayesian neural networks with confidence estimations applied to data mining. Comput Stat Data Analysis 2000; 34: 473–93. 3. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 1998; 54: 315–21. 4. Lindquist M, Edwards IR, Bate A, Fucik H, Nunes AM, Ståhl M. From Association to Alert— a revised approach to International Signal Analysis. Pharmacoepidemiol Drug Saf 1999; 8: S15–25. 5. Lindquist M, Ståhl M, Bate A, Edwards IR, Meyboom RHB. A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf 2000; 23: 533–42. 6. Bate A, Lindquist M, Orre R, Edwards IR, Meyboom RHB Data mining analyses of pharmacovig-

ilance signals in relation to relevant comparison drugs. Eur J Clin Pharmacol 2002; 58: 483–490. 7. Lindquist M, Edwards IR. The WHO Programme for International Drug Monitoring, its database, and the technical support of the Uppsala Monitoring Center. J Rheumatol 2001; 28: 1180–7. 8. Lindquist M. The WHO Programme for International Drug Monitoring: the Present and Future. In: Mitchard M (editor). Electronic Communication Technologies. Buffalo Grove: Interpharm Press Inc, 1998; 527–49. 9. Lindquist M, Edwards IR. Risks of non-sedating antihistamines. Lancet 1997; 349: 1322. 10. Lindquist M, Pettersson M, Edwards IR, Sanderson J, Taylor N, Fletcher P, Schou J, Fraunfelder FT. Omeprazole and visual disorders: seeing alternatives. Pharmacoepidemiol Drug Saf 1996; 5: 27–32. 11. Lindquist M, Pettersson M, Edwards IR, Sanderson J, Taylor N, Fletcher P, Schou JS, Savage R. How does cystitis affect a comparative risk profile of tiaprofenic acid with other non-steroidal antiinflammatory drugs? An international study based

The WHO International Drug Monitoring Programme on spontaneous reports and drug usage data. Pharmacol Toxicol 1997; 80: 211–17. 12. Lindquist M, Sanderson J, Claesson C, Imbs JL, Rohan A, Edwards IR. New pharmacovigilance information on an old drug—an international study of spontaneous reports on digoxin. Drug Invest 1994; 8: 73–80. 13. Olsson, S. The role of the WHO Programme on International Drug Monitoring in coordinating worldwide drug safety efforts. Drug Saf 1998; 19: 1–10. 14. Olsson S (editor). National Pharmacovigilance Systems: Uppsala Monitoring Centre. 2nd edition. Uppsala: The Uppsala Monitoring Centre, 1999. 15. Edwards IR. Monitoring the safety of herbal remedies: WHO project is under way. Br Med J 1995; 311: 1569–70. 16. Farah MH. Consumer protection and herbal remedies. WHO Drug Inf 1998; 12: 141. 17. Farah MH, Edwards IR, Lindquist M, Leon C, Shaw D. International monitoring of adverse health effects associated with herbal medicines. Pharmacoepidemiol Drug Saf 2000; 9: 105–12. 18. Fucik H, Farah MH, Meyboom RHB, Lindquist M, Edwards IR, Olsson S. Vigilance of herbal medicines at the Uppsala Monitoring Centre. Minerva Med 2001; 92: 24–6. 19. CIOMS. Reporting of adverse drug reactions: definitions of terms and criteria for their use. Report No. 9290360712. Geneva: CIOMS, 1999. 20. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994; 10: 93–102. 21. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255–9. 22. Edwards IR, Lindquist, M. Understanding and communication of key concepts in therapeu-

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tics. In: Velo G (editor). Moments of truth— communicating drug safety. Verona: Elsevier Science, 2000: 9–14. 23. Edwards IR, Wiholm B-E, Martinez C. Concepts in risk–benefit assessment. Drug Saf 1996; 15: 1–7. 24. CIOMS, editor. Benefit-risk balance for marketed drugs: evaluating safety signals, 1st edition. Geneva: World Health Organization, 1998. 25. Edwards IR, Hugman B. The challenge of effectively communicating risk–benefit information. Drug Saf 1997; 17: 216–27. 26. WHO Collaborating Centre for International Drug Monitoring, Viewpoint—Watching for safer medicines. Part 1. Uppsala, Sweden: Uppsala Monitoring Centre, 2002. 27. World Health Organization. The Importance of Pharmacovigilance. Geneva: World Health Organization, 2002. 28. Edwards IR. Who cares about pharmacovigilance? Eur J Clin Pharmacol 1997; 53: 83–8. 29. Edwards IR. Spontaneous reporting—of what? Clinical concerns about drugs. Br J Clin Pharmacol 1999; 48: 138–41. 30. WHO Collaborating Centre for International Drug Monitoring. Dialogue in Pharmacovigilance—More Effective Communication. Uppsala, Sweden: Uppsala Monitoring Centre, 2002. 31. Edwards IR. The accelerating need for pharmacovigilance. J R Coll Phys Lond 2000; 34: 48–51. 32. Biriell C, Edwards IR. Reasons for reporting adverse drug reactions—some thoughts based on an international review. Pharmacoepidemiol Drug Saf 1997; 6: 21–6. 33. Edwards IR, Fucik H. Impact and credibility of the WHO adverse reaction signals. Drug Inf J 1996; 30: 461–4.

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Address list of national centres that participate in the WHO Drug Monitoring Programme Editor’s note: The details given here were correct at the time of going to press in January 2003. However, details of this sort often change, and readers should contact the WHO Monitoring Programme at Uppsala if they are unable to reach any of the agencies listed using the information given. Argentina (ARG) Dra Mabel Teresa Foppiano Head Tel: +54-1-340 0866 Fax: +54-1-340 0866 E-mail: [email protected] Website: anmat.gov.ar Armenia (ARM) Dr Samvel Azatyan Deputy director Tel: +374-1-584 020, 584 120 Fax: +374-1-542 406 E-mail: [email protected] Website: pharm.am Australia (AUS) Dr John McEwen Director Tel: +61-2-6232 8113 Fax: +61-2-6232 8392 E-mail: [email protected] Website: www.health.gov.au

Administración Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT) Sistema Nacional de Farmacovigilancia Avenida de Mayo 869, piso 11o (1084) Buenos Aires, Argentina

Department of Pharmacovigilance and Rational Use of Drugs Armenian Drug and Medical Technology Agency 15, Moskowian Street Yerevan 375001, Armenia Adverse Drug Reactions Unit Therapeutic Goods Administration PO Box 100 Woden, ACT 2606, Australia

Austria (AUT) Eugen Obermayr Head Tel: +43-1-711 00, ext 4638 Fax: +43-1-712 0823 E-mail: [email protected] Website: bmsg.gv.at

Federal Ministry for Social Security and Generations Pharmacovigilance Unit VIII/A/3 Radetzkystrase 2 A-1031 Vienna, Austria

Bahrain (BHR) Ms Layla Abdur-Rahman Director Tel: +973-25 86 68 Fax: +973-27 93 57 E-mail: [email protected]

Ministry of Health Pharmacy and Drug Control PO Box 12 Manama, Bahrain

559

560 Belarus, Republic of (BLR) Mr Godovalnikov Tel: +7-017-289 55 14 Fax: +7-017-289 53 48

Address list of national centres

Ministry of Health Center for Examinations and Test Health Service Republican Unitary Enterprise 22 0037 Minsk, 2-a Tovarishcheskij Per Republic of Belarus

Belgium (BEL) Mr André Pauwels Head Tel: +32-2-227 5567 Fax: +32-2-227 5528 E-mail: [email protected]

Federal Ministry Social Affairs, Public Health and Environment, Pharmaceutical Inspectorate National Centre for Pharmacovigilance Boulevard Bischoffsheim 33, 1st floor B-1000 Brussels, Belgium

Brazil (BRA) Mr Murilo Freitas Dias Pharmacovigilance Manager Tel: +55-61-448 1219 Fax: +55-61-448 1275 E-mail: [email protected]

Brazilian Pharmacovigilance Center Unidade de Farmacovigilancia (UFARM) Agência Nacional de Vigilância Sanitárita SEPN 515 Bl.B Ed. Omega 2 Andar, Sala 2 CEP 70770-502 Brasilia DF, Brazil

Brazil (BRA) Dr Anthony Wong Tel: +55-11-3088 9431 Fax: +55-11-3088 9431 E-mail: [email protected]

Bulgaria (BUL) Ms Daniela Encheva Head Tel: +359-2-4347 356 Fax: +359-2-9434 487 E-mail: [email protected] Website: bda.bg Canada (VAR) Dr Wikke Walop Head, Vaccine Safety Epidemiologist Tel: +1-613-954 5590 Fax: +1-613-957 1340 or 998 6413 E-mail: [email protected] Website: hc-sc.gc.ca

Canada (CAN) Ms Heather Sutcliffe Head Tel: +1-613-946 1138 or 957 0337 Fax: +1-613-957 0335 E-mail: [email protected] Website: hc-sc.gc.ca

CEATOX, Sao Paulo Regional Poison and Pharmacovigilance Centre Inst. Crianca Reference Centre Avenida Dr Enéas de Carvalho Aguiar, 647 05403-903 Sao Paulo SP, Brazil

Bulgarian Drug Agency Department of Pharmacovigilance Eurointegration and Pharmacopoeia 26 Yanko Sakazov Boulevard BG-1504 Sofia, Bulgaria

VAAE Surveillance Section Division of Immunization Centre for Infectious Diseases, Prevention & Control Population and Public Health Branch Tunney’s Pasture 0603EI Ottawa Ontario K1A OL2, Canada

Marketed Health Products Directorate Health Canada Finance Bldg, 1st Floor, Tunney’s Pasture A/L 0201 C2 Ottawa Ontario K1A 1B9, Canada

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Address list of national centres

Chile (CHL) Dr Q F Cecilia Morgado-Cadiz Head Tel: +56-2-239 8769 Fax: +56-2-239 8760 E-mail: [email protected] China, People’s Republic of (CHN) Prof Li Shaoli Director-General Tel: +86-10-6716 4982 Fax: +86-10-6716 4984 E-mail: [email protected] Website: cdr.gov.cn Costa Rica (COR) Dra Jetty Murillo Ocampo Farmacéutica responsable Tel: +506-222 1878 Fax: +506-257 7004 E-mail: [email protected] Croatia (CRO) Dr Igor Francetic Head Tel: +385-1-2421 875 Fax: +385-1-2388 279 E-mail: [email protected]

Cuba (CUB) Lic Francisco Debesa García Head Tel: +53-7-24 09 24 Fax: +53-7-24 72 27 E-mail: [email protected]

Cyprus (CYP) Dr Athos Tsinontides Clinical Pharmacist Tel: +357-240 7101 Fax: +357-233 9623 E-mail: [email protected] Czech Republic (CZE) Dr Ivana Koblikova Head Tel: +42-2-7218 5848, 7218 5111 Fax: +42-2-7143 2377, 7218 5816 E-mail: [email protected]

Instituto de Salud Publica de Chile CENIMEF Avenida Marathon 1000 3 piso, Nuñoa-Casilla 48 Santiago, Chile

Center for Drug Re-evaluation (CDR) National Center for ADR Monitoring Building 11, Fa-Hua-Nan-Li Chongwen District Beijing 100061, People’s Republic of China

Caja Costarricense de Seguro Social Centro Nacional de Farmacovigilancia Avenida Segunda San José 1000, Costa Rica

Croatian Adverse Reaction Monitoring Centre of Drugs and Medical Devices Division of Clinical Pharmacology Department of Medicine University Hospital Centre 12 Kispaticeva 10000 Zagreb, Croatia

National Coordinating Unit of Pharmacovigilance Pharmacoepidemiology Development Center 44 No 502 esq 5a Ave Miramar, Playa Havana CP 11300, Cuba

Pharmaceutical Services Ministry of Health 1475 Lefkosia, Cyprus

Branch of Clinical Trials and Pharmacovigilance State Institute for Drug Control Srobarova 48 10041 Prague 10, Czech Republic

562 Denmark (DEN) Ms Margit Handlos Head of Pharmacovigilance Tel: +45-44-88 91 11 Fax: +45-44-91 73 73 E-mail: [email protected] Website: dkma.dk Egypt (EGY) Prof Abdulla Molokhia Chairman, NODCAR Tel: +20-2-7484 989 Fax: +20-2-3379 445 E-mail: [email protected] Estonia (EST) Dr Maia Uusküla Head Tel: +372-7-374 140 Fax: +372-7-374 142 E-mail: [email protected] Website: sam.ee

Address list of national centres

Danish Medicines Agency Department of Medicines Evaluation 378, Frederikssundsvej DK-2700 Bronshoj, Denmark

Ministry of Health National Organization for Drug Control and Research PO Box 29 51 Wezaret Al-Ziraa, Agouza Cairo, Egypt Ravimiamet State Agency of Medicines 19 Ravila Street 50411 Tartu, Estonia

Fiji (FJI) Mr Peter Zinck Chief Pharmacist Tel: +679-315 022 Fax: +679-304 199 E-mail: [email protected]

Business and Essential Drugs (BED) Fiji Pharmaceutical Services Box 106 Suva, Fiji

Finland (FIN) Prof Erkki Palva Research Director Tel: +358-9-4733 4288 Fax: +358-9-4733 4297 E-mail: [email protected] Website: nam.fi

National Agency for Medicines—Lääkelaitos Drug Information Centre PO Box 55 Mannerheimintie 166 SF-00301 Helsinki, Finland

France (FRA) Dr Carmen Kreft Jaïs Head Tel: +33-1-5587 3533 Fax: +33-1-5587 3532 E-mail: [email protected] Website: agmed.sante.gouv.fr/fr/htm/2/2000.htm

Agence Francaise de Securité Sanitaire des Produits de Sonti (AFSSAPS) 143-147, Boulevard Anatole France Unité de Pharmacovigilance F-93285 Saint-Denis, Cedex, France

Germany (GFR) Dr Jürgen Beckmann Head Tel: +49-30-4548 3311 Fax: +49-30-4548 3515 E-mail: [email protected] Website: bfarm.de

Pharmacovigilance Department Federal Institute for Drugs and Medical Devices Kurt-Georg-Kiesinger-Allee 3 53113 Bonn, Germany

563

Address list of national centres

Ghana (GHA) Dr Alex Dodoo Tel: +233-21-675 885 Fax: +233-21-666 8219 E-mail: [email protected]

Greece (GRC) Dr Georgia Athanassiou Head of Pharmacovigilance Unit Tel: +30-1-06507 337 Fax: +30-1-0654 9585 E-mail: [email protected] Website: eof.gr Guatemala (GTM) Licda Yanira Gicela Ruano Muños Tel: +502-471 9842 Fax: +502-440 8267 E-mail: [email protected]

Hungary (HUN) Dr Sándor Elek Head Tel: +36-1-266 2874 Fax: +36-1-266 6073 E-mail: [email protected] Iceland (ICE) Prof. Magnús Jóhannsson Tel: +354-5-20 2114 Fax: +354-5-61 2170 E-mail: [email protected] Website: lyfjastofnun.is India (IND) Prof Suresh K Gupta Chief Tel: +91-11-659 3633 Fax: +91-11-686 2663 or 652 10 41 E-mail: [email protected]; [email protected] Indonesia (INO) Dra Engko Sosialine M Head Tel: +62-21-4245 459 Fax: +62-21-4243 605 E-mail: [email protected]

Centre for Tropical Clinical Pharmacology & Therapeutics University of Ghana Medical School Korle-Bu Teaching Hospital Accra, Ghana

National Organization for Medicines Adverse Drug Reactions Section 284 Messogion Avenue GR-155 62 Athens-Holargos, Greece

Coordinadora del Programa Nacional de Farmacovigilancia Ministerio de Salud y Asistencia Social 11 Ave. “A” 11-57 zona 7 Finca La Verbena Guatemala, Guatemala

National Institute of PharmacyAdverse Drug Reactions Monitoring Centre Zrínyi u. 3-1051 PO Box 450 H-1372 Budapest, Hungary

The Icelandic Medicines Control Agency Eidistorg 13-15 172 Seltjarnarnes, Iceland

National Pharmacovigilance Centre Department of Pharmacology All India Institute of Medical Sciences Ansari Nagar New Delhi 110029, India

Section of Adverse Drug Reaction Surveillance Directorate of Drug and Biological Product Evaluation National Agency for Drug and Food Control Jalan Percetakan Negara 23 Jakarta 10560, Indonesia

564 Iran, Islamic Republic of (IRN) Dr Gloria Shalviri Director Tel: +98-21-640 5569 Fax: +98-21-641 7252 E-mail: [email protected]

Ireland (IRE) Ms Niamh Arthur Pharmacovigilance Co-ordinator Tel: +353-1-676 4971 Fax: +353-1-676 7836 E-mail: [email protected] Website: imb.ie Israel (ISR) Dr Dina Hemo Head Tel: +972-2-568 1219 Fax: +972-2-672 5820 E-mail: [email protected] Italy (ITA) Dr Roberto Raschetti Tel: +39-06-599 41 Fax: +39-6-5994 3554 E-mail: [email protected]

Japan (JPN) Dr Tatsuo Kurokawa Director, Safety Division Tel: +81-3-3595 2435 Fax: +81-3-3508 4364 E-mail: [email protected] Jordan (JOR) Ms Nancy Ghabboun Tel: +962-6 5660 028 Fax: +962-6 5660 028 E-mail: [email protected] Korea, Republic of (KOR) Dr Joon-Shik Chang Head Tel: +82-2-382 0185 Fax: +82-2-386 0843 E-mail: [email protected] Website: kfda.go.kr

Address list of national centres

Ministry of Health and Medical Education Iranian ADR Centre Under-Secretary for Food and Drug Affairs Building no. 3 Fakhr-e-Razi Street, Enghlab Avenue Teheran 13145, Islamic Republic of Iran

Pharmacovigilance Unit Irish Medicines Board Earlsfort Terrace Earlsfort Centre Dublin 2, Ireland

Ministry of Health Department of Clinical Pharmacology Drug Monitoring Center 29 Rivka Street, PO Box 1176 Jerusalem 91010, Israel

Ministry of Health Medicines Evaluation and Pharmacovigilance General Direction Pharmacovigilance Centre Viale della Civilta Romana 7 I-00144 Rome, Italy

Pharmaceutical and Medical Safety Bureau Ministry of Health, Labor and Welfare 1-2-2, Kasumigaseki, Chiyoda-Ku Tokyo 100-8916, Japan

Drug Directorate Ministry of Health PO Box 86 Amman, Jordan

Korea Food and Drug Administration Pharmaceutical Safety Bureau 5 Nokbun-dong Eunpyong-ku Seoul 122-704, Republic of Korea

565

Address list of national centres

Kyrgyzstan (KGZ) Saliya Karimbaeva Tel: +996-312-54 29 40 Fax: +996-312-54 29 10 E-mail: [email protected]

Drug Information Centre Ministry of Health 3rd Liniya Street 720044 Bishkek, Kyrgyzstan

Latvia (LVA) Dr Inese Studere Tel: +371-2-707 8442 Fax: +371-2-707 8442 E-mail: [email protected]

State Agency of Medicine of Latvia (SAM) ADR Monitoring Department Jersikas St. 15 LV-1003 Riga, Latvia

Macedonia, Republic of (MKD) Ms Biljana Celevska Tel: +389-2-11 93 75, 23 76 69 Fax: +389-2-23 08 57, 11 30 14 E-mail: [email protected] Malaysia (MAL) Mr Mohd Zin Che Awang Director of Pharmaceutical Services Tel: +60-3-4045 7389 Fax: +60-3-7968 2222 E-mail: [email protected] Website: madrac.gov.my/madrac Mexico (MEX) Dr Carmen Becerril Martinez Head Tel: +52-5-203 4378 Fax: +52-5-203 4378 E-mail: [email protected]

Ministry of Health ul. 50 Divizija bb 1000 Skopje, Republic of Macedonia

Pharmaceutical Services Division Ministry of Health 11th floor Bangunan Perkim Jalan IPOM 51200 Kuala Lumpur, Malaysia

Ministry of Health Gauss No 4, 7 piso Col. Casa Blanca Mexico City, DF CP 11590, Mexico

Moldova (MDA) Dr Lucia Tsurcan Head Tel: +373-2-73 70 02, 73 87 86 Fax: +373-2-73 70 45 E-mail: [email protected]

National Centre for Adverse Reaction Monitoring of the Republic of Moldova National Institute of Pharmacy Str. Korolenko 2/1 Chisinau 2028, Moldova

Morocco (MOR) Dr Rachida Soulaymani-Bencheikh Head Tel: +212-37-68 64 64 or 6110 47 45 (gsm) Fax: +212-37-77 60 87 or 77 20 67 E-mail: [email protected]

Centre Anti Poisons et de Pharmacovigilance Rue Lamfedel Cherkaoui Rabat Institute Medinate AP Irfane BP 769 Rabat, Morocco

Netherlands Antilles (ANT) Dr Peter H. M. Fontilus Director Tel: +599-9-737 4877 Fax: +599-9-737 4844 E-mail: [email protected]

Bureau of Pharmaceutical Affairs Groot Davelaar K-139-140 PO Box 3824 Curacao, Netherlands Antilles

566

Address list of national centres

Netherlands (NET) Dr A. C. van Grootheest Director Tel: +31-73-646 9700 Fax: +31-73-642 6136 E-mail: [email protected] Website: lareb.nl

Netherlands Pharmacovigilance Foundation LAREB Goudsbloemvallei 7 NL-5237 MH S-Hertogenbosch The Netherlands

New Zealand (NEZ) Dr Michael Tatley Head Tel: +64-3-479 7247 Fax: +64-3-479 0509 E-mail: [email protected]

Centre for Adverse Reactions Monitoring Dunedin School of Medicine PO Box 913 Dunedin 9000, New Zealand

Norway (NOR) Ms Ingebjorg Buajordet Head Tel: +47-22-89 77 00 Fax: +47-22-89 77 99 E-mail: [email protected] Website: slk.no Oman (OMN) Dr Sawsan Ahmad Jaffar Head Tel: +968-600 016 Fax: +968-602 287 E-mail: [email protected] Pakistan (PAK) Prof Akhlaque Un-Nabi Khan Tel: +92-21-588 2997, 589 2801 Fax: +92-21-588 1444, 589 3062 E-mail: [email protected]

Norwegian Medicines Agency Statens Legemiddelverk Adverse Drug Reaction Section Sven Oftedals vei 6 N-0950 Oslo, Norway

Ministry of Health Directorate General of Pharmaceutical Affairs and Drug Control PO Box 393 Muscat, Sultanate of Oman 113

College of Physicians & Surgeons Pakistan (CPSP) Department of Clinical Pharmacology 7th Central Street Phase II Phase II, Defence Housing Authority Karachi 75500, Pakistan

Peru (PER) Dra Susana Vasquez Lezcano Jefe de CENAFIM Tel: +51-14-71 62 46 Fax: +51-14-71 63 53 E-mail: [email protected] Website: minsa.gob.pe

Presidenta del Comite Tecnico Nacional de Farmacovigilancia CENAFIM, DIGEMID Ministerio de Salud 11 Avenue Arenales # 1302 - Of. 318-319 Lima 11, Peru

Philippines (PHL) Ms Marissa Macaraeg Information Officer Tel: +63-2-807 8517 Fax: +63-2-807 8285 E-mail: [email protected]

Adverse Drug Reaction Monitoring Bureau of Food and Drugs Department of Health Filinvest Corporate City, Alabang Muntinlipa City 1770, Philippines

567

Address list of national centres

Poland (POL) Dr Agata Maciejczyk Head Tel: +48-22-841 6742 Fax: +48-22-851 4366 E-mail: [email protected] Website: il.waw.pl

Drug Institute Pharmacoepidemiology Centre Centre for Adverse Drug Reactions Monitoring 30/34 Chelmska Street PL-00725 Warsaw, Poland

Portugal (POR) Dr Regina Carmona Head Tel: +351-21-798 7153 Fax: +351-21-798 7155 E-mail: [email protected] Website: infarmed.pt

National Pharmacovigilance Centre INFARMED Parque de Saúde de Lisboa Avenida do Brasil, no. 53 1749-004 Lisboa, Portugal

Romania (ROM) Dr Juliana Daniela Stanciu Head Tel: +40-1-224 1102, 224 1710 Fax: +40-1-224 3497 E-mail: [email protected] Russia (RUS) Prof Victor Cheltsov Head Tel: +7-95-434 52 44 Fax: +7-95-434 02 92 E-mail: [email protected] Singapore (SIN) Ms Chan Cheng Leng Head of Pharmacovigilance Tel: +65-325 5604, 325 5610 Fax: +65-325 5448 E-mail: [email protected] Slovakia (SVK) Dr Pavol Gibala Head Tel: +421-2-5293 1735, 5293 1732 Fax: +421-2-5293 1734 E-mail: [email protected] Website: sukl.sk South Africa (SOA) Ms Ushma Mehta Head Tel: +27-21-447 1618 Fax: +27-21-448 6181 E-mail: [email protected]

National Medicines Agency Str Aviator Sanatescu no 48 Sector 1 R-71 324 Bucuresti, Romania

Department of Clinical Pharmacology Miklukho-Maklay Street, 8 117198 Moscow, Russia

Centre for Pharmaceutical Administration Health Sciences Authority No. 2 Jalan Bukit Merah, Singapore 169547

National Centre for Monitoring Adverse Reactions to Drugs State Institute for Drug Control Kvetná 11 825 08 Bratislava 26, Slovakia

National Adverse Drug Event Monitoring Centre Division of Pharmacology, Medical School Faculty of Medicine University of Cape Town, K45 Old Main Building Observatory 7925, South Africa

568 Spain (SPA) Dr Francisco José de Abajo Head Tel: +34-91-596 7711 Fax: +34-91-596 7891 E-mail: [email protected] Website: msc.es/agemed Sri Lanka (LKA) Dr Bernadette Mignonne Rohini Fernandopulle Senior lecturer Tel: +94-1-695 300 ext. 41 03 17 Fax: +94-1-695 300 E-mail: [email protected] Sweden (SWE) Prof Ingemar Persson Head Tel: +46-18-17 46 44 Fax: +46-18-54 85 66 E-mail: [email protected] Website: mpa.se Switzerland (SCH) Dr Ruedi Stoller Head Tel: +41-31-322 0348 Fax: +41-31-322 0418 E-mail: [email protected] Website: iks.ch

Address list of national centres

Agencia Española del Medicamento División de Farmacoepidemiología y Farmacovigilancia Carretera a Pozuelo, Km 2 E-28220 Majadahonda (Madrid), Spain

Faculty of Medicine University of Colombo Kynsey Road PO Box 271 Colombo 8, Sri Lanka

Adverse Drug Reaction Unit Pharmacovigilance Unit Medical Product Agency PO Box 26 S-751 03 Uppsala, Sweden

Swissmedic, Schweizerisches Heilmittelinstitut Pharmacovigilance Zentrum Erlachstrasse 8 CH-3000 Bern 9, Switzerland

Tanzania (TAN) Mr Henry Irunde Tel: +255-22-2450 512, 245 07 51 Fax: +255-22-2450 793 E-mail: [email protected]

Tanzania Drug and Toxicology Information Service (TADATIS) PO Box 77150 Dar Es Salaam, Tanzania

Thailand (THA) Ms Pornpit Silkavute Director Tel: +66-2-590 72 81 Fax: +66-2-591 84 57 E-mail: [email protected] Website: fda.moph.go.th/APR

Thai National ADRM Centre Technical Division Food and Drug Administration Ministry of Public Health Ti-wa-nondh Road Nonthaburi 1100, Thailand

Tunisia (TUN) Prof Chalbi Belkahia Head Tel: +216-1-562 098 Fax: +216-1-571 390 or 57 81 96 E-mail: [email protected]

Centre National de Pharmacovigilance Sis Hôpital Ch Nicolle Bd du 9 Avril Tunis 1006, Tunisia

569

Address list of national centres

Turkey (TUR) Prof Dr Orban Canbolat Head Tel: +90-312-230 1674, 230 2769 Fax: +90-312-230 1610 E-mail: [email protected]

General Directorate of Drugs and Pharmacy Ministry of Health Ilkiz Sokak No 4 Sihhiye Ankara 06430, Turkey

Ukraine (UKR) Dr Marina Sharayeva Head Tel: +7-358 4468 2500 Fax: +7-358 4468 2500 E-mail: [email protected]

Pharmacovigilance Department State Pharmacological Center Ministry of Health of Ukraine 18 Chygorina Str. 01042 Kiev, Ukraine

United Kingdom (UNK) Dr June Raine Head Tel: +44-207-273 0400 Fax: +44-207-273 0282, 273 0675 E-mail: [email protected] Website: open.gov.uk/mca/ United States of America (USA) Dr M Miles Braun Director Tel: +1-301-827 3974 Fax: +1-301-827 3529 E-mail: [email protected] United States of America (USA) Dr Paul Seligman Director Tel: +1-301-827 6276 Fax: +1-301-827 6276 E-mail: [email protected]

Uruguay (URY) Dr Carolina Seade Fournie Tel: +598-2 487 27 02 Fax: +598-2 6226 969 E-mail: [email protected] Uruguay (URY) Dra Mabel Burger Tel: +598-2-480 4000 Fax: +598-2-487 0300 E-mail: [email protected] Website: ciat.hc.edu.uy

Post-licensing Division Medicines Control Agency Market Towers 1 Nine Elms Lane London SW8 5NQ, United Kingdom

Food and Drug Administration Center for Biologics Evaluation and Research Division of Epidemiology 1401 Rockville Pike, HFM-220 Rockville, MD 20852-1448, USA

Office of Pharmacoepidemiology and Statistical Science Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane, Room 15 B33 Rockville, MD 20857, USA

Departamento de Farmacologia Hospital de Clinicas Avda Italia s/n piso 1, 11600 Montevideo, Uruguay

Deptartamento de Toxicologia Hospital de Clínicas Avda Italia s/n, piso 7 11600 Montevideo, Uruguay

570 Venezuela (VEN) Dr Jesús Querales Castillo Head Tel: +58-2-6624 797 Fax: +58-2-6624 797, 693 1455

Vietnam (VNM) Prof Hoang Tich Huyên Head Tel: +84-4-245 292 Fax: +84-4-823 1253 E-mail: [email protected] Yugoslavia, Federal Republic of (YUG) Prof Vaso Antunovic Head Tel: +381-11-361 5531 Fax: +381-11-361 56 30

Zimbabwe (ZWE) Mrs Sakhile Dube-Mwedzi Regulatory Officer Tel: +263-4-736981-5 Fax: +263-4-736980 E-mail: [email protected]

Address list of national centres

Presidente, Instituto Nac. de Higiene “Rafael Rangel” Apartado Postal 60.412-Ofic. del Este Ciudad Universitaria Caracas, Venezuela

Adverse Drug Reaction Centre Institute for Drug Quality Control Ministry of Health 48 Hai Ba Trung Street Hanoi, Vietnam

Clinical Centre of Serbia National Centre for Adverse Drug Reactions Visegradska 26 YU-11000 Belgrade Federal Republic of Yugoslavia

Medicines Control Authority of Zimbabwe 106 Baines Ave Harare, Zimbabwe

Institutions EMEA Ms Priya Bahri Tel: +44-207-418 8454 Fax: +44-207-418 8668 E-mail: [email protected]

EC Emer Cooke Tel: +32-2-296 7072 Fax: +32-2-296 1520 E-mail: [email protected] WHO Dr Mary Couper Tel: +41-22-791 3643 Fax: +41-22-791 4730 E-mail: [email protected]

EMEA—The European Agency for the Evaluation of Medicinal Products Pharmacovigilance Section 7 Westferry Circus, Canary Wharf London E14 4HB, UK

European Commission Directorate General III—Industry Rue de la Loi 200 B-1049 Brussels, Belgium

World Health Organization Department of Essential Drugs & Medicines Policy Quality Assurance & Safety Medicines CH-1211 Geneva 27, Switzerland

Index of drugs Notes: For any therapy, see under the specific item and the class; for example lisinopril and angiotensin-converting enzyme inhibitors. Boldface page numbers refer to main discussions. abacavir, 330 acamprosate, 540 acarbose gastrointestinal system, 467 liver, 467 metabolic effects, 467 metformin concentration, 468 ACE inhibitors. see angiotensin converting enzyme inhibitors aceclofenac, 115 acetaminophen. see paracetamol acetazolamide electrolyte balance, 238 immunologic system, 239 overdose, 239 urinary tract, 238 acetylcholinesterase inhibitors, 164 acetylsalicylic acid (aspirin) antiplatelet activity, +ibuprofen, 115 asthma, 118 furosemide inhibition, 240 gastrointestinal system, 113 liver, 113 renal insufficiency, 112 vitamin E, concomitant use, 423 aciclovir, 329 acitretin, 175 activated charcoal, 387 acupuncture, 535 adefovir, 335 adenosine adverse drug reactions, management, 203–204 cardiovascular system, 203 death, 203 respiratory system, 203 adrenaline, 143 alfa- and beta-adrenoceptor agonists cardiovascular system, 156 gastrointestinal system, 157 interactions, 157 psychiatric effects, 157 alfa2 -adrenoceptor agonists, 525 beta-adrenoceptor agonists cardiovascular system, 159, 190–191, 525–526 immunologic system, 526 metabolic effects, 223, 526 psychiatric effects, 526

respiratory system, 526 beta-adrenoceptor antagonists amphetamine interaction, 30 ajmaline, 204 alatrofloxacin, 276 albendazole, 344–345 albumin, 363 alcohol hepatotoxicity, +paracetamol, 114–115 performance impairment, +zaleplon, 49 aldose reductase inhibitors, 472 alfentanil, 89 alkylammonium amidobenzoate, 169 all-trans retinoic acid cardiovascular system, 417 mineral balance, 417–418 pancreas, 418 retinoic acid syndrome, 417 toxicity, 418 urinary tract, 418–419 Allium sativum (garlic), 529 allopurinol, 125–126 alosetron concomitant alprazolam, 46 concomitant fluoxetine, 383 gastrointestinal system, 383 alpha-glucosidase inhibitors gastrointestinal system, 467 interactions, 467 liver, 467 metabolic effects, 466–467 alprazolam, 46 alprostadil (prostaglandin E1 ), 430 alteplase, 49 aluminium, 243–244 aluminium hydroxide, 457 amantadine nervous system, 162 psychiatric effects, 334 AMD473. see ZD0473 amfebutamone death, 15 myocardial ischemia, +pseudoephedrine, 157 overdose, 15–16 seizures, +lithium, 25–26 amikacin nephrotoxicity, +amphotericin B deoxycholate (DAMB), 302

sensory systems, 271 urinary tract, 271 amiloride electrolyte balance, 240 lithium toxicity, 291 aminoethanolamine, 169 aminoglycosides, 271 aminosalicylates, 387 amiodarone administration route, 206–207 cardiovascular system, 204 vs. dofetilide, 210 efficacy, 202 endocrine systems, 205–206 fetotoxicity, 206 overdose, 207 respiratory system, 204–205, 207 risk factors, 206 skin, 206 special senses, 205 amisulpride, 58–59 amlodipine, 225 amodiaquine, 315 amoxicillin, 263. see also co-amoxiclav amphetamine cardiovascular system, 30 ecstasy interaction, 32 nervous system, 30 amphetamines cardiovascular system, 3 nervous system, 3–4 overdose, 4 risk factors, 4 teratogenicity, 4 amphotericin B colloidal dispersion (ABCD), 302 amphotericin B deoxycholate (DAMB), 302 amphotericin B lipid complex (ABLC), 302–303 amphotericin B liposomal, 303 amprenavir, 332 anabolic steroids, 450 anakinra, 397–398 androgenic anabolic steroids, 450 androgens, 437 anesthesia. see specific agents, such as benzocaine; ropivacaine anesthetic vapors. see specific gases, such as halothane; nitrous oxide

571

572 angiotensin converting enzyme inhibitors, 234. see also specific drugs, such as captopril; lisinopril angiotensin II receptor antagonists. see irbesartan Anso Comfort general effects, 529 recall, 47 antacids, 279 anthracyclines cardiovascular system, 503 liver, 503–504 metabolic effects, 503 nervous system, 503 respiratory system, 503 anthrax vaccine, 354 anti-inflammatory drugs, 280 antiandrogens, 451 antibiotics. see also specific drugs and classes, such as cephalosporins; minocycline anticholinergic drugs, 165 antidysrhythmic drugs, 202–203 antiepileptics. see also specific drugs and classes, such as benzodiazepines; gabapentin death, 71 endocrine system, 70 metabolic effects, 71 musculoskeletal, 71 psychiatric effects, 70 reproductive, 70–71 teratogenicity, 71 antihistamines (H1 ). see also specific drugs such as fexofenadine; loratadine cardiotoxicity, 180–182 central nervous system, 182–183 antimony, 244 antipsychotic drugs body temperature, 58 cardiovascular system, 54 vs. clozapine, 53 endocrine system, 56 gastrointestinal system, 58 metabolic effects, 56 nervous system, 54 overdose, 58 sensory systems, 55 skin, 58 weight gain, 56–58 antispasmodic agents (gastrointestinal), 389 antithrombin III, 363 antituberculous agents, 339–340 antiviral drugs methadone concentration, 96 skin, 168 aprindine, 207 aristolochic acid, 529–530 Arnica montana skin, 530

Index of drugs arsenic, 244 Artemisia derivatives, 319–320 articaine, 144 ASA. see acetylsalicylic acid ascorbic acid. see vitamin C Asian herbal mixtures, 528 aspart insulin, 463 aspirin. see acetylsalicylic acid atorvastatin clearance, nelfinavir, 333 erythromycin interaction, 287 hematologic system, 487 musculoskeletal system, 487 skin, 487 atovaquone general effects, 320 +proguanil, adherence, 317 +proguanil, neuropsychiatric effects, 319 azathioprine +aminosalicylate, leukopenia, 388 gastrointestinal system, 404 hematologic system, 404 azithromycin cardiovascular system, 285 clearance, fexofenadine, 181 concomitant desloratadine, 181 hematologic system, 285 immunologic system, 285 interactions, 286 pregnancy, 285 +pyrimethamine, general effects, 322–323 risk factors, 286 sensory systems, 285 tolerability, 284–285 Bacille Calmette-Guérin vaccine administration route, 355 skin, 354 bacitracin, 292 baclofen clinical presentation, 153 effects of renal impairment, 153 fetotoxicity, 154 withdrawal syndrome, 152–154 barnidipine, 225 Basic Red 22, 169 BBR3464, 492 BCG. see Bacille Calmette-Guérin vaccine befunolol, 526 benzimidazoles, 344–345 benzocaine, 144–145 benzodiazepines effects, 72 overdose, 72 sedation, +macrolides, 284 sedation, +miocamycin, 288 trauma, 46 benzyl alcohol, 173 bergamot, 530–531

betaxolol, 525, 526 bile acids, 389 bimatoprost, 430, 526 biotin. see vitamin H bismuth, 244–245 black iron oxide, 169 beta-blockers. see beta-adrenoceptor antagonists blood substitutes, 363 blue dye, 545 brachial plexus anesthesia, 140–141 branched-chain fatty acid esters, 168 Brighton Collaboration, 354 bromazepam, 46 Bryostatin I, 409 bucillamine, 254 BufferGel, 540–541 buprenorphine, 104 bupropion. see amfebutamone buserelin, 478 buspirone, 49 busulfan, 503 butylhydroxyanisole, 169, 545 cabergoline, 160 caffeine cardiovascular system effects, 1 lithium interaction, 26 musculoskeletal system, 1–2 nervous system, 1 calciferol. see vitamin D calcineurin inhibitors, 306 calcitetracemate, 253 calcitonin, 477 calcitriol, 422 calcium carbonate, 457–458 calcium channel blockers. see specific drugs, such as felodipine; verapamil Calendula officinalis (marigold), 530 cannabinoids cardiovascular system, 36–37 nervous system, 37 cannabis animal toxicology, xxxiii–xxxiv cardiovascular system, xxxvi cognitive function, xxxv–xxxvi, xxxviii–xxxix dependence, xxxix–xli MDMA interaction, 33–34 memory, xxxv neurotoxicity claims, xxxvi–xxxvii in pregnancy, xli psychiatric illness, xxxvii–xxxviii psychoactive effects, xxxiv psychomotor impairment, xxxiv–xxxv smoke and cancer, xlii–xliv smoke and lung effects, xlii

573

Index of drugs smoke and smoking behavior, xli–xlii tolerance, xxxix–xli captopril digoxin interaction, 199 pancreas, 234 carbamazepine cardiovascular system, 72 clonazepam interaction, 47 concentration, cisplatin + doxorubicin, 502 concomitant lamotrigine, 73 electrolyte balance, 72–73 hyponatremia, desmopressin, 482–483 vs. lamotrigine, 74 lincomycin interaction, 284 lithium interaction, 25, 26 metabolic effects, 72 miocamycin interaction, 288 psychiatric effects, 72 risperidone concentration, 65 skin, 73 teratogenesis, 73 carbimazole, 459 carbohydrate-rich diet, 349 carboplatin adverse effects, 491–492 hematologic system, 498 immunologic system, 501 mechanism of action, 490 pharmacokinetics, 490–491 urinary tract, 499–500 cardiac glycosides cardiovascular system, 198, 530 contamination of herbal products, 199 endocrine system, 198 interactions, 199 metabolic effects, 198–199 psychiatric effects, 198 reproductive system, 199 risk factors, 199 carvedilol, 223 caspofungin, 311 catechol-O-methyl transferase inhibitors, 163 cat’s claw, 534 caudal anesthesia, 141 cefaclor, 264 cefazolin, 264 cefdinir, 264 cefepime, 264–265 celecoxib gastrointestinal system, 123–124 hemorrhage, +clopidogrel, 124 liver, 124 psychiatric effects, 123 skin, 124 urinary tract, 124 central venous catheters, 545–546 cerivastatin, 487

cetrorelix, 479 chaparral, 532 Chinese wolfberry, 533 chiropractic, 536 chitosan, 280 chloramphenicol gastrointestinal system, 274 general effects, 273–274 hematologic system, 273 chlordiazepoxide in Anso Comfort, 47, 529 formulations, 47 hematologic system, 46–47 chlorhexidine, 256 chlorhexidine digluconate, 169 2-chloro-paraphenylenediamine, 169 chloroquine cardiovascular system, 315 formulations, 317 nervous system, 315–316 overdose, 316–317 pregnancy, 316 +proguanil, adherence, 317 sensory systems, 316 skin, 316 chloroxylenol, 169 chlorprocaine, 145 chlorquinaldol, 169 cholestyramine, 457 chromium, 245 cibenzoline, 207 cicloproxolamine, 169 ciclosporin carcinogenicity, 406 concentration, fluconazole, 306 concentration, methylphenidate, 5 concentration, oxcarbazepine, 76 concentration, St. John’s wort, 532 concomitant ketoconazole, 304 hematologic system, 405 interactions, 405 metabolic effects, 404 musculoskeletal system, 405 nervous system, 404 pregnancy, 406 rhabdomyolysis, +lovastatin, 487 rhabdomyolysis, +simvastatin, 487 urinary tract, 405 cidofovir, 328 cilomilast, 200 cilostazol, 230 cimetidine clarithromycin absorption, 286 dofetilide concentration, 212 dystonic reaction, 384 praziquantel concentration, 349 cinchocaine, 145–146 cinnamic aldehyde, 545

ciprofloxacin gastrointestinal system, 276 interactions, 277 lithium interaction, 26 liver, 276 musculoskeletal system, 276–277 nervous system, 276 psychiatric effects, 276 risk factors, 277 sensory systems, 276 skin, 276 urinary tract, 276 cisapride cardiovascular system, 382 digoxin concentration, 200 interactions, 382 cisplatin adverse effects, 491–492 electrolyte balance, 497–498 endocrine system, 497 gastrointestinal system, 498 hematologic system, 498 immunologic system, 501 lithium clearance, 502 mechanism of action, 490 nephrotoxicity, 502 nervous system, 494–496 neurotoxicity, 502 ototoxicity, 496 overdose, 502 paclitaxel clearance, 503 pharmacokinetics, 490–491 skin, 500 teratogenicity, 502 urinary tract, 499–500 visual disturbances, 497 citalopram cardiovascular system, 12 concomitant digoxin, 200 concomitant ketoconazole, 304 concomitant methylphenidate, 5 ejaculation, 14 sexual function, 13 citric acid, 541 Citrus auranticum (bergamot), 530–531 clarithromycin cardiovascular system, 286 circulation, +ergotamine, 164 immunologic system, 286 interactions, 286–287 psychiatric effects, 286 repaglinide concentration, 469 rifabutin concentration, 341 skin, 286 clenbuterol, 191 clindamycin gastrointestinal system, 284 pregnancy, 284 sensory systems, 283–284 skin, 284 clomethiazole, 49

574 clomiphene citrate, 434 clomipramine, 11 clonazepam, 47 clopidogrel hematologic system, 380 hemorrhage, +celecoxib, 124 immunologic system, 380 clotting factors. see also factors; porcine factors; recombinant factor VIII:C body temperature, 368 cardiovascular system, 366 hematologic system, 366–367 immunologic system, 367 infection risk, 367–368 respiratory system, 366 skin, 367 clozapine vs. antipsychotic drugs, 53 cardiovascular system, 59 concentration, nefazodone, 16 concentration, risperidone, 60, 65–66 concomitant ketoconazole, 304 hematologic, 59–60 interactions, 60–61 lisinopril interaction, 236 liver, 60 metabolic effects, 59 vs. olanzapine, 61 salivary glands, 60 co-amoxiclav, 379 co-trimoxazole anticoagulation, 379 concentration, rifampicin, 342 dosage regimen, 322 drug tolerance, 292 effectiveness, 320–321 electrolyte balance, 291–292, 321 hematologic system, 292 immunologic system, 292 interactions, 292, 322 metabolic effects, 321 nervous system, 291, 321 reproductive system, 321–322 respiratory system, 291 skin, 292, 321 coagulation factor gene therapy, 368 cocaine cardiovascular system, 37–38 drug abuse, 40 ear, nose, throat, 38 fetotoxicity, 40–41 nervous system, 38–39 pregnancy, 41–42 psychological effects, 39 respiratory system, 38 sexual function, 40 urinary tract, 39 cocamidopropyl betaine, 168 codeine drug abuse, 90

Index of drugs nervous system, 89 skin, 90 colchicine, 286 colestipol, 488 colistin, 289 colophonium, 168 Compositae species, 171–172 contrast agents, iodinated renal insufficiency, + IV immunoglobulin, 366 contrast agents, oil-based iodinated erythema, 518 swelling, 518 contrast agents, water-soluble iodinated cardiovascular system, 514 delayed reactions, 513–514 endocrine system, 515 formulations, 519 gastrointestinal system, 516 hematologic system, 515–516 immunologic system, 519 nervous system, 514–515 sensory systems, 515 skin, 518–519 urinary tract, 517–518 contrast agents, water-soluble iodinated, intravascular cholinesterase activity, 513 general effects, 512–513 copper, 245 corticosteroids concomitant, praziquantel, 349 hiccups, 450 corticosteroids, inhaled endocrine system, 188 growth in children, 186–187 immunologic system, 190 infection risk, 190 musculoskeletal system, 188–190 sensory systems, 188 skin, 188 systemic availability, 187 cough syrup. see codeine coumarin interactions, 379 potentiation, co-trimoxazole, 292 COX-2 inhibitors. see also celecoxib; rofecoxib angio-edema, 122–123 cardiovascular system, 117–118 gastrointestinal system, 119–121 lithium interaction, 26 reproductive system, 123 respiratory system, 118–119 safe prescribing, comparison with non-selective NSAIDs, 116 sulfonamide-like allergic adverse reactions, 122

urticaria, 122–123 “crack.” see cocaine cranberry, 534 cryotherapy, 345 Cucurbicin, 422 cyanamide, 541 cyclophosphamide amiodarone interaction, 207 carcinogenicity, 406 reproductive system, 406 cytotoxic drugs. see anthracyclines dacluzumab, 402 dairy products, 280 dapsone, 340 daptomycin, 292 darbepoetin, 368 daunorubicin. see anthracyclines DDAVP. see desmopressin deferiprone, 253 deferoxamine general effects, 253–254 nervous system, 254 delta-9-tetrahydrocannabinol, 37 denileukin diftitox, 398 depolarizing neuromuscular blocking agents electrolyte balance, 151–152 nervous system, 151 desensitization therapy, 195 desloratadine cardiotoxic effects, 181 CNS effects, 182 desmopressin cardiovascular system, 482 electrolyte balance, 482 interactions, 482–483 dexamethasone, 429–430 dextrans, 374 dextromethorphan general effects, 90–91 neuromuscular, 91 pregnancy, 91 diamorphine drug use, 42 vs. morphine, 91–92 nervous system, 42, 92 sensory systems, 42, 92 diatrizoate cholinesterase activity, 513 described, 512 safety, 516 diazepam nervous system, 47, 137 overdose, 47 diclofenac, 115 didanosine, 329 diethylcarbamazine, 345–346 diethylstilbestrol, 436 diets, unconventional, 536 digoxin absorption, alpha-glucosidase inhibitors, 467 concentration, fluoxetine, 14

575

Index of drugs concentration, cisapride, 382 concomitant itraconazole, 308 concomitant moxifloxacin, 279 dofetilide interaction, 211–212 interactions, 199 management of toxicity, 200–201 reproductive system, 199 toxicity, clarithromycin, 286–287 dihydrocodeine, 92 dihydroergotamine, 288 diltiazem concentration, sirolimus (rapamycin), 408 digoxin concentration, 199 impaired renal function, simvastatin, 488 interactions, 226 nervous system, 225 overdose, 225–226 skin, 225 diphtheria-tetanus vaccine (DT, Td), 356 dipyridamole, 380 disopyramide efficacy, 202 macrolide interaction, 287 disulfiram, 542 ditrizoate, 516 diuretics, 238. see also specific drugs and classes, such as furosemide; loop diuretics dobutamine, 159 dofetilide adverse effects, 210 vs. amiodarone, 210 cardiovascular system, 210–211 clinical pharmacology, 208–209 concentration, +verapamil, 228 effectiveness, +digoxin, 200 efficacy, 202 vs. flecainide, 210 interactions, 211–212 open clinical studies, 209 pharmacology, 208 vs. propafenone, 210 vs. sotalol, 210 ventricular tachydysrhythmias, 210 donepezil, 7 dopamine receptor agonists cardiovascular system, 159–160 nervous system, 160 psychiatric, 162 respiratory system, 160 sleep disorders, 160–162 dorzolamide, 239 doxepin, 170 doxorubicin. see anthracyclines doxycycline, 265

droperidol, 383 DTP-Hib vaccine cardiovascular system, 357 pre-term infants, 356 sensory systems, 357 skin, 357 dysprosium-ethoxybenzyltris (carboxylatomethyl) triazaundecanedioic aciddiethylenetriaminepenta-acetic acid (Dy-EOB-DTPA), 519 ebastine, 181 Ecballium elaterium (squirting cucumber), 531 Echinacea (coneflower), 531 echinocandins, 311 ecstasy. see methylenedioxymethamphetamine (MDMA, ecstasy) edetate, 254 efavirenz immunologic system, 331 interactions, 331 methadone concentration, 96 psychiatric effects, 331 reproductive system, 331 skin, 331 Elohes® , 374–375 emedastine cardiotoxicity, 181 concomitant ketoconazole, 304 EMLA cream, 144 enalapril, 235 endothelin receptor antagonists, 233–234 enoximone, 201 enoxolone, 170, 545 Ephedra, 531–532 ephedrine cardiovascular system, 156 gastrointestinal system, 157 interactions, 157 psychiatric effects, 157 epidural anesthesia, 141–142 epirubicin. see anthracyclines epoetin. see also erythropoietin in children, 370 effectiveness, 368 ergot alkaloids cardiovascular system, 163 interactions, 164 ritonavir interactions, 333 ergotamine ergotism, +miocamycin, 288 ergotism, +troleandomycin, 288 erythromycin interaction, 287 lincomycin interaction, 284 metabolism, clarithromycin, 287 erythromycin cardiovascular system, 287 digoxin availability, 200

dysrhythmia, +verapamil, 228 interactions, 287 ritonavir/saquinavir concentration, 334 erythropoietin body temperature, 370 cardiovascular system, 369 gastrointestinal system, 369 general effects, 368–369 hair, 369 hematologic system, 369 immunologic system, 370 nervous system, 369 risk factors, 370 skin, 369 esomeprazole, 385 estradiol, 480 etanercept endocrine system, 399 hematologic system, 399–400 immunologic system, 400 infection risk, 400 nervous system, 399 risk factors, 400 skin, 400 ethmozine. see moricizine ethyl alcohol. see alcohol ethylene oxide, 256 ethylmercury, 248 etomidate, 135 everolimus, 406 factor VIIa (recombinant) myocardial infarction, 366 thrombophlebitis, 366 factor VIII:C, 367 factor VIII:C (porcine), 367 factor IX:C shortness of breath, 366 urticarial rash, 367 factor IX (recombinant), 366 famciclovir, 329–330 felbamate, 73 felodipine skin, 226 telangiectases, 174 fenfluramine cardiovascular system, 6 hematologic, 6–7 fenofibrate, 486 fentanyl effectiveness, 92–94 formulations, 94 lithium interaction, 25 respiratory system, 94 skin, 94 urinary tract, 94 ferrous sulfate, 457 fexofenadine cardiotoxic effects, 181–182 concentration, azithromycin, 286 fibrates, 486 filgrastim, 399 finasteride, 451

576 flecainide cardiovascular system, 212 vs. dofetilide, 210 efficacy, 202 overdose, 213 sensory systems, 212–213 Fleet enema, 387 fleroxacin, 277 fluconazole cardiovascular system, 305 concomitant oral contraceptives, 445 concomitant ritonavir, 333 interactions, 306 metabolic effects, 305 teratogenicity, 305 fluorescein, 542 fluoride, 545 fluoroquinolones cardiovascular system effects, 274 diagnostic tests, interference, 275 dosage regimens, 275 infection risk, 275 interactions, 275 musculoskeletal system, 275 nervous system, 274–275 skin, 275, 340–341 5-fluorouracil, 347–348 fluoxetine cardiovascular system, 12 endocrine, 13 mania, +tramadol, 103 QT interval prolongation, 11–12 skin, 13 flutamide gastrointestinal system, 452 hematologic system, 451 fluvastatin formulations, 488 liver, 487–488 fluvoxamine in breast milk, 14 ejaculation, 14 mexiletine clearance, 213 nervous system, 12–13 olanzapine interaction, 63 sex drive, 13 fomivirsen, 328 formoterol, 191 foscarnet, 328 fosfomycin effectiveness, 292 hematologic system, 292 kidney protection, +glycopeptides, 281–282 liver, 292 fosinopril, 235–236 fosphenytoin drug administration route, 77 immunology, 76 skin, 77

Index of drugs furazolidone, 386 furosemide, 363 fusidic acid, 281 gabapentin drug administration, 74 drug withdrawal, 74 immunologic system, 74 nervous system, 73–74 psychiatric effects, 74 urinary tract, 74 gadobenate dimeglumine, 520 gadodiamide, 520 gadolinium general effects, 520–521 immunologic system, 522 pancreas, 521 urinary tract, 521 gadoterate meglumine, 521 gallium, 245 gammahydroxybutyrate, 542 ganciclovir, 329 ganirelix, 479 garlic, 529 gatifloxacin, 277 gelatin, 24 gemeprost, +mifepristone, 430 gemfibrozil, 486 gemifloxacin intestinal flora, 278 liver, 277–278 gemtuzumab ozogamicin, 402 gene therapy, 368 general anesthetics effectiveness trials, 131 gastrointestinal system, 131–132 nervous system, 131 gentamicin dosage regimens, 272 immunologic system, 272 interactions, 272 nervous system, 271 sensory systems, 271 urinary tract, 272 Ginkgo biloba (maidenhair tree), 531 glargine insulin, 463–464 glibenclamide alpha-glucosidase inhibitors interaction, 467 death, 470 interactions, 470 introduction, 469–470 metabolic effects, 467 pancreas, 470 gliclazide metabolic effects, 467, 470 nervous system, 470 overdose, 470 potentiation, fluconazole, 306 glimepiride potentiation, fluconazole, 306 studies, 470

glipizide, 471 glucagon, 466 glucocorticoids, 482 glucocorticosteroids, systemic death, 429 fetotoxicity, 429–430 immunologic system, 429 infection risk, 429 metabolic effects, 427 musculoskeletal system, 428–429 psychiatric effects, 427 respiratory system, 427 risk factors, 429 skin, 427 glutathione, 500 glyburide. see glibenclamide glyceryl trinitrate (nitroglycerin), 224 glycopeptides drug tolerance (antibacterial resistance), 282 urinary tract, 281–282 Glycyrrhiza (licorice), 531 GnRH. see gonadrotrophin-releasing hormone gold hematologic system, 246 nails, 246–247 nervous system, 246 respiratory system, 246 sensory systems, 246 gonadorelin. see gonadrotrophin-releasing hormone gonadotrophin-releasing hormone antagonists, 479 gonadotrophin-releasing hormone (GnRH, gonadorelin) ear, nose and throat, 477 metabolic effects, 478 musculoskeletal system, 478 nervous system, 477 ovarian hyperstimulation syndrome, 477–478 skin, 478 gonadotrophins, 434 granisetron, 383–384 granulocyte colony-stimulating factor (G-CSF) gastrointestinal system effects, 398 musculoskeletal system, 399 skin, 399 urinary tract, 399 granulocyte-macrophage colony-stimulating factor (GM-CSF), 398 grapefruit juice fexofenadine availability, 181 irbesartan concentration, 236 grepafloxacin, 278 griseofulvin, 176

577

Index of drugs growth hormone (human growth hormone, hGH, somatotropin) cardiovascular system, 479 endocrine system, 479–480 immunologic system, 480 interactions, 480 nervous system, 479 skin, 480 growth hormone release-inhibiting hormone (somatostatin) biliary, 480 endocrine system, 480 gastrointestinal system, 480 immunologic system, 480–481 pregnancy, 481 guarana general effects, 531–532 ventricular fibrillation, 1 gum resins, 168, 171 halofantrine, 317 haloperidol psychoactive effects, +lithium, 26 vs. risperidone, 64 halothane, 132 Helicobacter pylori eradication therapies, 386–387 hemodialyis, 73 hemoglobin-based oxygen carriers, 363–364 henna tattoos, 543–544 heparins, 379 hepatitis A and B vaccines, 358 hepatitis A vaccine, 358 hepatitis B vaccine hematologic system, 358 immunologic system, 358 mouth, 358 nervous system, 357–358 optic neuritis, +hepatitis A vaccine, 358 sensory systems, 358 hepatitis E vaccine, 358 heptaplatin, 492 herbal diuretics, 26 herbal medications, 528 heroin. see diamorphine hetastarch. see hydroxyethyl starch hirudin, 379 histamine H2 receptor agonists comparison, 384 dofetilide interaction, 212 HMG coenzyme-A reductase inhibitors, 487 metabolism, clarithromycin, 287 rhabdomyolysis, +macrolides, 284 rhabdomyolysis, +miocamycin, 287–288 hormone replacement therapy

cardiovascular system, 437–438, 441 general effects, 436–437 hematologic system, 439–440 metabolic effects, 438–439 musculoskeletal system, 440 nervous system, 438 prolactin release, 13 reproductive system, 440–441 skin, 440 urinary tract, 440 5-HT3 receptor antagonists, 382–383 human growth hormone. see growth hormone human papilloma virus vaccine, 358 hydrocortisone aceponate cream, 427 hydromorphone, 94 hydroquinone, 170 hydroxychloroquine, 469 Hydroxycut, 531–532 hydroxyethyl starch hematologic system, 374–375 reproductive system, 375–376 skin, 374 urinary tract, 375 Hypericum perforatum. see St. John’s wort hypochlorite, 259 hypoglycemic drugs, oral, 466 ibuprofen gentamicin interaction, 272 interactions, 115 lithium interaction, 26 ibutilide, 202 idarubicin. see anthracyclines ifosfamide, 304–305 iloprost, 430 immunizations. see vaccines immunomodulators, 172 indigo carmine, 545 indinavir amprenavir concentration, 332 cardiovascular system, 332 interactions, 333 liver, 333 metabolic effects, 333 skin, 333 urinary tract, 333 indocyanine green, 545 indomethacin, 240 infiltration anesthesia, 143 infliximab cardiovascular system, 400–401 immunologic system, 401–402 infection risk, 402 nervous system, 401 respiratory system, 401 skin, 401 influenza vaccine

general effects, 358–359 skin, 359 insulin. see also aspart insulin; glargine insulin; lispro insulin fluid balance, 462 immunologic system, 462 liver, 462 metabolic effects, 461–462 modes of administration, 464–466 pregnancy, 463, 466 risk factors, 463 skin, 462 insulin-like growth factor-I, 466 interferon, 23 interferon alfa endocrine system, 394–395 hematologic system, 395 immunologic system, 396 interactions, 396–397 musculoskeletal system, 396 nervous system, 393–394 neuromuscular function, 394 pregnancy, 396 psychiatric effects, 394 respiratory system, 393 sensory systems, 394 skin, 395–396 interferon beta, 397 interleukin-1 receptor antagonist, 397–398 interleukin-2 (IL-2) concentration, lithium, 23 general effects, 397–398 interleukin-4 (IL-4), 23 interleukin-10 (IL-10), 23 interleukin-11 (IL-11), oprelvekin, 398 interscalene catheterization, 140 intrathecal (spinal) anesthesia, 142–143 intravenous immunoglobulin cardiovascular system, 365 general effects, 364–365 hematologic system, 365 immunologic system, 366 infection risk, 366 interactions, 366 nervous system, 365 respiratory system, 365 skin, 366 urinary tract, 365 intravenous regional anesthesia, 144 iodine. see also contrast agents, water-soluble iodinated fetotoxicity, 194 overdose, 459 iodixanol cardiac arrest, 513 cardiovascular system, 514 iodixanol, liposome-encapsulated, 519

578 3-iodo-2propynylbutylcarbamate, 170 iohexol cardiovascular system, 514 cholinesterase activity, 513 hearing impairment, 515 toxic epidermal necrolysis, 518 iopamidole, 513 ioxaglate general effects, 513–514 urinary tract, 517 irbesartan, 236 irinotecan, 502 iron, 247 isepamicin, 272 isoniazid hepatotoxicity, 340 musculoskeletal system, 341 pancreas, 341 isosulfan blue, 543 isotretinoin gastrointestinal system, 176 hematologic, 176 liver, 176 metabolic effects, 176 psychiatric effects, 175–176 respiratory system, 175 itraconazole cardiovascular system, 307 digoxin concentration, 200 dosage regimen, 307 general effects, 306–307 interactions, 308 liver, 307 skin, 308 ivermectin, 346–347 Japanese encephalitis vaccine, 359 JM473. see ZD0473 josamycin, 287 kava (Piper methysticum), 533–534 ketamine, 135 ketoconazole effectiveness, 304 hematologic system, 304 interactions, 304 liver, 304 ritonavir/saquinavir concentration, 334 ketolides, 283 ketoprofen respiratory system, 116 skin, 172 ketorolac, 134 LAAM. see levomethadyl acetate HCl labetalol, 223–224 Lactobacillus GG, 387

Index of drugs lactulose, 387 lamotrigine bone metabolism, +valproate, 71 vs. carbamazepine, 74 clearance, desmopressin, 483 concentration, oral contraceptives, 75 concomitant carbamazepine, 73 interactions, 75 metabolic effects, 75 overdose, 75 psychiatric effects, 74–75 lanoconazole, 170 Larrea tridentata (chaparral), 532 latanoprost cardiovascular system, 526 hair, 431 infection risk, 431 nervous system, 430–431, 526 ocular effects, 526 sensory systems, 431 skin, 431 laureth-A (polidocanol), 545 Laurus nobilis (laurel), 532–533 laxatives, 387 lead, 248 leech therapy, 535 lenograstim, 399 lepirudin, 379–380 letrozole, 445 leucovorin, 347 leuprorelin, 478 levalbuterol. see levosalbutamol levamisole aphthous ulcers treatment, 348 colorectal cancer treatment, 347–348 head and neck carcinoma treatment, 348 nephrotic syndrome treatment, 348 nervous system, 347 pediculosis capitis treatment, 347 warts treatment, 347 levetiracetam concomitant warfarin, 76 interactions, 76 psychiatric effects, 75–76 levobupivacaine, 146 levocetirizine, 182 levodopa cardiovascular system, 159–160 methylphenidate interaction, 5 nervous system, 160 respiratory system, 160 levofloxacin cardiovascular system, 278 interactions, 279 liver, 278 musculoskeletal system, 279 nervous system, 278

pancreas, 279 risk factors, 279 seizures, 274 sensory systems, 278 skin, 279 theophylline interaction, 2 levomethadyl acetate HCl (LAAM), 95 levonorgestrel, 447–448 levosalbutamol (levalbuterol), 191–192 licorice, 531 lidocaine cardiovascular system, 146 comparison trials, 142 hematologic, 146 interactions, 147 skin, 146–147 lignocaine. see lidocaine lincomycin, 284 linezolid, 288–289 liposome-encapsulated iodixanol, 519 lisinopril, 236 lispro insulin, 464 lithium additives, 24 administration route, 24 cardiovascular system, 19–20 cisplatin clearance, 502 death, 23 diabetes mellitus, 21 dosage regimens, 24 electrolyte balance, 21 endocrine system, 20–21 formulations, 24 hair, 22–23 hematologic system, 21–22 immunologic system, 23 interactions, 25–26 intoxication, 25 lactation, 23 mouth and teeth, 22 nervous system, 20 neuromuscular system, 20 overdose, 24–25 pancreas, 22 parathyroid gland, 21 pregnancy, 23 reproductive system, 23 respiratory system, 20 risk factors, 23–24 sexual function, 23 skin, 22–23 toxicity, 25 toxicity, trimethoprim, 291 urinary tract, 22 withdrawal, 23 LJP 394, 409 local anesthetics, 172–173 lopinavir/ritonavir fluid balance, 333 gastrointestinal system, 333 sensory systems, 333

579

Index of drugs loratadine cardiotoxic effects, 182 nefazodone interaction, 16 lorazepam administration route, 48 hip fractures, 46 metabolic effects, 48 nervous system, 47–48, 48 neuroleptic malignant syndrome, 55 lovastatin concentration, gemfibrozil, 486 pain and weakness, +clarithromycin, 488 rhabdomyolysis, +ciclosporin, 487 rhabdomyolysis, +miocamycin, 288 skin, 487 loxapine, 61 loxoprofen, 116 Lycium barbarum (Chinese wolfberry), 533 Lyme disease vaccine, 357 Ma-huang. see ephedrine macrolides. see specific drugs such as clindamycin; josamycin maidenhair tree, 531 manganese, 248 manidipine, 226–227 mannitol psychiatric effects, 376 skin, 376–377 marigold, 530 marijuana. see cannabinoids; cannabis massage therapy, 535–536 MDMA. see methylenedioxymethamphetamine (MDMA) measles-mumps-rubella (MMR) vaccine hematologic system, 359–360 nervous system, 359 psychiatric effects, 359 measles vaccine, 359 mebendazole, 324 medroxyprogesterone described, 448 general effects, 444 mefloquine concomitant ritonavir, 333 neuropsychiatric, 317–318 vs. pyrimethamine + sulfadoxine, 318 risk factors, 318 mehindi tattooing, 543–544 melarsoprol, 323 meloxicam, 116 Mentha spicata, 170 menthol respiratory system, 543

skin, 543 meperidine. see pethidine mercaptopurine, 388 mercury, 248 meropenem, 265 mesalazine, 388 metalloproteinases, 266–267 metformin alpha-glucosidase inhibitors interaction, 467 concomitant miglitol, 468 contraindications, 467 death, 468 gastrointestinal system, 468 interactions, 468 liver, 468 metabolic effects, 468 methadone cardiovascular system, 95 concentration, amprenavir, 332 concentration, efavirenz, 331 concentration, nevirapine, 332 interactions, 96 neuromuscular, 96 psychological, 96 respiratory system, 95 risk factors, 96 methamphetamine amphetamine interaction, 30 drug dependence, 31 psychiatric effects, 30–31 methandrostenolone, 450 methimazole hematologic system, 458 teratogenicity, 459 methotrexate carcinogenicity, 407 ciprofloxacin clearance, 277 clearance, rofecoxib, 125 hematologic system, 406–407 methoxamine, 157 methoxy polyethylene glycol, 170 methoxypsoralens, 173 methyl glucose dialate, 170, 545 methyldibromoglutamate, 170 methylenedioxymethamphetamine (MDMA, ecstasy) cardiovascular system, 32 drug contamination, 36 liver, 35 pregnancy, 35–36 psychiatric effects, 34 respiratory system, 32 reversal with diamorphine, 42 risk factors, 34 methylphenidate, 5 methylprednisolone, 308 metoclopramide, 383 metoprolol, 487 metronidazole in children, vs. mebendazole, 324 contact allergy, 170 general effects, 323–324

nervous system, 324 pregnancy, 324 mexazolam, 48 mexiletine, 213 midazolam cardiovascular system, 137 nervous system, 131, 137 vs. propofol, 131 temperature regulation, 137 midodrine, 157–158 mifepristone plus gemeprost, 430 mifepristone (RU 486) introduction, 448–449 mineral balance, 449 reproductive system, 449 miglitol alpha-glucosidase inhibitors interaction, 467 concomitant metformin, 468 glibenclamide clearance, 470 metabolic effects, 467 milrinone, 201 minocycline, 265–266 miocamycin, 287–288 Mirena, 447, 448 misoprostol general effects, 431–432 reproductive system, 432 uterine rupture, +oxytocin, 481 mizolastine, 182 modafinil, 5–6 moricizine, 213 morphine adverse effects management, 98–99 vs. diamorphine, 91–92 effectiveness, 97 pregnancy, 97 moxifloxacin cardiovascular system, 279 concomitant theophylline, 3 interactions, 279–280 skin, 279 MS-325, 521 mumps vaccine. see measles-mumps-rubella (MMR) vaccine mycophenolate mofetil immunologic system, 407 infection risk, 407 pregnancy, 407–408 myrrh, 348–349 N-deamino-8-d-argenine vasopressin. see desmopressin nadroparin, 379 nafarelin, 477 nalbuphine, 104–105 nalidixic acid, 280 nalmefene effects, 21 safety, 105 naloxone, 105 naltrexone, 105–106 naproxen

580 vs. COX-2 inhibitors, 117–118 hematologic system, 116 nateglinide, 468 nedaplatin, 492 nefazodone concentration, zopiclone, 51 liver, 16 loratadine concentration, 182 nefopam, 106 nelfinavir, 333 neomycin, 273 netilmicin, 273 neuromuscular blocking agents electrolyte balance, 151–152 irreversibility, +polymyxins, 289 nervous system, 151 nevirapine, 332 niacin. see nicotinic acid nicardipine children, 227 digoxin concentration, 199 nickel, 248–249 nicotine, 528 nicotinic acid (niacin) and nicotinamide, 419–420 nifedipine digoxin concentration, 199 mouth and teeth, 227 pregnancy, 227 nilutamide, 452 nimesulide lithium interaction, 26 liver, 125 nimodipine, 227 nitrofurantoin, 288 nitroglycerin. see glyceryl trinitrate nitrous oxide, 134 nizatidine, 384 non-steroidal anti-inflammatory drugs (NSAIDs). see also specific drugs such as ketoprofen anaphylaxis, 121–122 angio-edema, 122–123 cardiovascular system, 117–118 chronic renal disease, 111–112 gastrointestinal system, 119–121 immunologic system, 121 pregnancy and teratogenicity, 112–113 pseudoporphyria, 175 renal insufficiency, 111–112 reproductive system, 123 skin, 174 urticaria, 122–123 19-nor-1α, 25-dihydroxycholecalciferol. see paricalcitol norfloxacin, 280 Norplant, 444

Index of drugs noxurol, 170 NSAIDs. see non-steroidal anti-inflammatory drugs (NSAIDs) nucleoside analogue reverse transcriptase inhibitors (NRTI), 330 octreotide, 480 ofloxacin endocrine system, 280 formulations, 280 interactions, 280 salivary glands, 280 skin, 280 for tuberculosis, safety, 339 olanzapine cardiovascular system, 61–62 vs. clozapine, 61 concentration, fluvoxamine, 14 hair loss, St. John’s wort, 532 hematologic, 62–63 immunologic system, 63 interactions, 63 lithium interaction, 26 metabolic effects, 62 nervous system, 62 pancreas, 63 psychiatric effects, 62 sexual function, 63 olsalazine, 389 omalizumab, 402–403 omeprazole in children, 385–386 clarithromycin metabolism, 286 interactions, 386 skin, 386 urinary tract, 386 ondansetron, 103 oprelvekin, 398 Optison, 522 oral contraceptives concentration, +fluconazole, 306 failure, +St. John’s wort, 532 formulations, 444–445 interactions, 445 lamotrigine concentration, 75 liver, 443–444 skin, 174 third-generation assessment, 442–443 oral hypoglycemic drugs, 466 oseltamivir, 334 ovulation induction, 478 oxaliplatin acetylcholinesterase activity, 502 body temperature, 501–502 hematologic system, 498 immunologic system, 501 interleukin-6 concentration, 501

mechanism of action, 490 nervous system, 494–496 pharmacokinetics, 490–491 skin, 500–501 TNF-alpha concentration, 501 oxazepam, 48 oxazolidinones effectiveness, 288–289 hematologic system, 289 interactions, 289 oxcarbazepine, 76 oxybenzone, 174 oxybuprocaine, 147 oxycodone, 99 oxygen carriers, 363–364 oxymetholone, 450 oxytocic drugs, 431–432 oxytocin, 481 paclitaxel clearance, cisplatin, 503 concentration, ciclosporin, 406 palivizumab, 403 pancreatic enzyme supplements, 389 pantoprazole, 386 para-phenylenediamine general effects, 543–544 skin, 173 paracetamol hematological system, 113 interactions, 114–115 overdose, 114 renal insufficiency, 112 paramethoxyamphetamine (PMA), 36 parathyroid hormone (PTH), 481 parecoxib, 124 parenteral nutrition, 377 paricalcitol, 422 paromomycin, 273 paroxetine endocrine, 13 and interferon alfa, 394 lithium interaction, 25 risperidone concentration, 65 sexual function, 13 skin, 13 Passiflora incarnata (passion flower), 48 pefloxacin arthropathy, 275 immunologic system, 281 risk factors, 281 pemoline, 7 penicillamine endocrine system, 255 liver, 255 pregnancy, 256 skin, 256 urinary tract, 256 penicillins immunologic reaction, 262–263 liver, 262

581

Index of drugs pentamidine, 323 perfluorocarbons, 364 pethidine, 99 phenolic compounds, 260 phenoxyethanol, 173 phenylpropanolamine, 158–159 phenytoin concentration, fluvoxamine, 14 drug administration route, 77 immunology, 76 skin, 77 phototherapy, 175 phytomenadione. see vitamin K pimozide potentiation, clarithromycin, 286 vs. risperidone, 63 pioglitazone, 471 Piper methysticum (kava), 533–534 piperacillin, 263–264 piracetam, 7–8 piroxicam, 286 platinum compounds body temperature, 501–502 effectiveness, 490 electrolyte balance, 497–498 endocrine system, 497 fertility, 502 gastrointestinal system, 498 general effects, 491–492 hematologic system, 498 immunologic system, 501 interactions, 502–503 liver, 499 mutagenicity and carcinogenicity, 502 nervous system, 494–496 overdose, 502 sensory systems, 496–497 skin, 500–501 teratogenicity, 502 urinary tract, 499–500 visual disturbances, 497 PMA. see paramethoxyamphetamine polidocanol, 545 poliomyelitis vaccine. see DTP-HiB vaccine polyestradiol phosphate, 451 polygeline, 376 Polygonum multiflorum (Shou wu Pian), 534 polymyxins, 289 polyoxyethylene lauryl ether, 545 polyvalent cations, 279 porcine factor VIII:C bronchospasm, 366 periorbital edema, 367 safety, 367 urticaria, 367 potassium iodide, 459 potassium persulfate, 173 pramipexole, 160

pravastatin, 488 praziquantel cysticercosis treatment, 344 interactions, 349 neurocysticercosis treatment, 349–350 paragonimiasis treatment, 350 prednisolone, 427 prednisone, 427 primaquine, 318–319 pristinamycin, 289–290 probenecid, 134 procainamide, 213 procaine, 147 progesterone, 450 progestogens, 447–448 proguanil adherence, +atovaquone, 317 adherence, +chloroquine, 317 neuropsychiatric effects, +atovaquone, 319 promethazine, 55 propafenone cardiovascular system, 214 vs. dofetilide, 210 efficacy, 202 overdose, 214 risk factors, 214 proparacaine, 147 propofol anti-nausea effectiveness, 131 bradycardia, +lithium, 25 cardiovascular system, 135 -infusion syndrome, 135–136 liver, 136 vs. midazolam, 131 nervous system, 135 pancreas, 136 respiratory system, 135 propylthiouracil immunologic system, 459 liver, 458 prostaglandin analogues, 526 prostamides, 526 protease inhibitors concentration, fluconazole, 306 metabolic effects, 332 protirelin. see thyrotropin-releasing hormone (TRH) proton pump inhibitors, 384–385 pseudoephedrine. see ephedrine psyllium, 387 PTH. see parathyroid hormone PUVA, 175 pyrazinamide, 339–340 pyridoxine. see vitamin B6 pyrimethamine, 320, 322 quetiapine, 63 quinidine digoxin concentration, 199 efficacy, 202 interactions, 214

skin, 214 quinine, 318 quinupristin/dalfopristin, 290 rabeprazole, 386 raloxifene, 445–446 ranitidine concomitant moxifloxacin, 280 skin, 384 urinary tract, 384 rapacuronium, 150 rapamycin. see sirolimus rasburicase, 545 recombinant factor IX, 366 recombinant factor VIIa, 366–367 recombinant human activated protein C, 363 recombinant human chorionic gonadotrophin (RhCG), 435–436 Red Bull, 1 remacemide, 77 remifentanil cardiovascular system, 101 general effects, 99–101 nervous system, 101 pregnancy, 101 repaglinide vs. glipizide, 471 interactions, 469 metabolic effects, 469 risk factors, 469 retinol. see vitamin A ribavirin clotting disorders, +interferon alfa, 395 didanosine concentration, 329 hematologic system, 329 metabolic effects, 329 rifabutin interactions, 341 metabolism, clarithromycin, 286 musculoskeletal system, 341 rifampicin co-trimoxazole concentration, 292, 322 concomitant ritonavir, 334 interactions, 342 liver function, +paracetamol, 115 ritonavir/saquinavir concentration, 334 urinary tract, 341–342 rimonabant, xxxiv risperidone clozapine clearance, +nefazodone, 16 clozapine concentration, 60–61 concentration, paroxetine, 15 effectiveness, 63–64 endocrine system, 65 interactions, 65 liver, 65 nervous system, 64

582 overdose, 65 vs. pimozide, 63 salivary glands, 65 sexual function, 65 ritodrine, 192 ritonavir. see also lopinavir/ritonavir amprenavir concentration, 332 clarithromycin metabolism, 286 concentration, fluconazole, 306 ergotamine metabolism, 164 indinavir concentration, 333 interactions, 333–334 rituximab, 403 rivastigmine, 8 rocuronium, 150–151 rofecoxib interactions, 125 nervous system, 124–125 urinary tract, 125 urticaria/angio-edema safety, 122 ropinirole interactions, 162 sleep disorders, 160 ropivacaine concomitant itraconazole, 308 nervous system, 147–148 rosiglitazone, 472 rotavirus vaccine, 360 roxithromycin, 288 RU 486. see mifepristone rubella vaccine, 360. see also measles-mumps-rubella (MMR) vaccine salmeterol, 192–193 saquinavir amprenavir concentration, 332 concentration, fluconazole, 306 concentration, ritonavir, 334 sartraplatin, 492–493 saw palmetto, 534. see also Cucurbicin Scutellaria lateriflora (skullcap), 534 Selaginella doederleinii, 534 selective serotonin re-uptake inhibitors (SSRIs) cardiovascular system, 12 death risks, 11–12 electrolyte balance, 13 endrocrine, 13 interactions, 14 lactation, 14 nervous system, 12–13 sexual function, 13–14 skin, 13 selegiline, 308 selenium, 249 Serenoa repens (saw palmetto), 534. see also Cucurbicin sertindole, 66

Index of drugs sertraline oxazolidinones interaction, 289 Parkinsonism, 12 sevelamer concomitant digoxin, 200 concomitant warfarin, 379 sevoflurane cardiovascular system, 132 interactions, 134 liver, 133 musculoskeletal system, 134 nervous system, 132–133 psychiatric effects, 133 respiratory system, 132 urinary tract, 133–134 SH U 555 A, 522 Shou wu pian, 534 sibutramine, 7 sildenafil death, +glyceryl nitrate, 225 interactions, 231 nervous system, 231 sensory systems, 231 silicone, 544 silver, 249 simvastatin concentration, ciclosporin, 405 concentration, diltiazem, 226 concentration, nelfinavir, 333 hematologic system, 487 interactions, 488 musculoskeletal system, 487 rhabdomyolysis, +ciclosporin, 487 rhabdomyolysis, +miocamycin, 288 sleep disturbance, +metoprolol, 487 sirolimus (rapamycin), 226, 408 sitafloxacin, 281 skullcap, 534 sodium diatrizoate, 516 sodium dihydroxyacetyl phosphate, 171 sodium fusidate. see fusidic acid sodium polystyrene sulfonate, 256 somatostatin endocrine system, 480 immunologic system, 480 pregnancy, 481 somatotropin. see growth hormone Sono Vue (sulfur hexafluoride), 522–523 sotalol cardiovascular system, 224 comparison with dofetilide, 210 efficacy, 202 risk factors, 224 soybean extract, 171 sparfloxacin cardiovascular system, 281

phototoxicity, 341 risk factors, 281 skin, 281 spearmint, 170 SPI-77, 493 spinal manipulation, 536 spironolactone digoxin concentration, 199 liver, 240 skin, 240 squirting cucumber, 531 SSRIs. see selective serotonin re-uptake inhibitors (SSRIs) St. John’s wort concentration, ciclosporin, 405–406 endocrine system, 532 hair, 532 interactions, 532 nervous system, 532 nevirapine concentration, 332 statin concentration, 487 tricyclic antidepressant concentration, 11 statins. see HMG coenzyme-A reductase inhibitors stavudine, 331 stearyl alcohol, 171, 545 streptomycin, 273 strychnine, 6 succinylcholine, 151–152 sucralfate, 279 sufentanil, 101–102 sulfadiazine, 323 sulfadoxine, 320, 322 sulfamethoxazole. see co-trimoxazole sulfan blue, 545 sulfasalazine, 389 sulfonamides immunologic system, 290 interactions, 290–291 skin, 290 teratogenicity, 290 sulfonylureas, 115 sumatriptan, 15 sunscreen, 174 suramin glioma, recurrent high-grade, 350–351 prostate cancer, hormone-refractory, metastatic, 350 renal cell carcinoma treatment, 351 tacrine, 8 tacrolimus concentration, fluconazole, 306 concentration, itraconazole, 308 infection risk, 409 liver, 408 metabolic effects, 408 nervous system, 408

583

Index of drugs sildenafil concentration, 231 skin, 408 talc, 544 tamoxifen carcinogenicity, 447 cardiovascular system, 446 hair, 446 metabolic effects, 446 reproductive system, 446–447 tea tree oil, 171 tegaserod concomitant theophylline, 3 digoxin availability, 200 teicoplanin adverse reactions, management, 283 administration route, 283 drug tolerance (antibacterial resistance), 283 formulations, 283 hematologic system, 282 immunologic system, 282–283 skin, 282 telithromycin, 283 temazepam nervous system, 48 vs. zolpidem, 50 tenofovir, 331 terbinafine dosage regimen, in children, 310–311 hair, 310 hematologic system, 309 immunologic system, 310 interactions, 311 liver, 309–310 musculoskeletal system, 310 skin, 310 terfenadine, 16 terlipressin (triglycyl-lysine vasopressin), 483 testosterone, 449–450 tetanus/pertussis vaccine, 356 tetracyclines, chemically modified, 268 tetraethylthiuramdisulfide, 545 tetraplatin, 493 thalidomide neurotoxicity, +interferon alfa, 397 thrombosis, 176 theophylline clearance, +fluoroquinolones, 275 clearance, levofloxacin, 279 concomitant moxifloxacin, 280 diagnostic test interference, 2 interactions, 2–3 in neonates, 2 overdose, 2 risk factors, 2 thiazide diuretics carcinogenicity, 239–240 cardiovascular system, 239

electrolyte balance, 239 interactions, 240 skin, 239 urinary tract, 239 thimerosal bacitracin allergy, 292 vaccines, 259–260 thionamides hematologic system, 458 immunologic system, 458–459 teratogenicity, 459 thiuram, 544–545 thyroid stimulating hormone (TSH, thyrotropin), 481–482 thyrotropin-releasing hormone (TRH, protirelin), 482 thyroxine cardiovascular system, 457 drug abuse, 457 interactions, 457–458 tiagabine, 77–78 tibolone, 452 ticlopidine, 381 timolol, 525–526 titanium, 249–250 tobramycin, 273 tocopherols. see vitamin E tolbutamide fluvoxamine interaction, 14 inhibition, sulfonamides, 290 tonic water, 318 topical anesthesia, 144 topiramate acid-base balance, 80 body temperature, 80 cognitive effects, 78–79 administration, 80 effects, 78 lithium interaction, 25 psychiatric effects, 79 sensory systems, 79 toremifene, 447 tosufloxacin, 281 tramadol dependence, 103 efficacy, 102–103 interactions, 103–104 overdose, 103 tranexamic acid, 381 trastuzumab, 403 travoprost general effects, 432 ocular effects, 526 tretinoin, 419 triamterene risk factors, 241 teratogenicity, 240–241 urinary tract, 240 triazolam zaleplon interaction, 49 vs. zopiclone + zolpidem, 51 tribavirin. see ribavirin trichloroethylene, 134 triclosan, 171

tricyclic antidepressants, 11 triethanolamine, 171 trimebutine, 171 trimethoprim. see also co-trimoxazole concomitant theophylline, 3 electrolyte balance, 291 interactions, 291 lithium concentration, 25 triphenylmethane dyes, 259 triptans SSRI interaction, 15 teratogenicity, 230 triptorelin, 478 troglitazone, 472 troleandomycin, 288 tropicamide, 147 tropisetron, 384 trovafloxacin, 276 TSH. see thyroid stimulating hormone (TSH, thyrotropin) tylosin, 288 Uncaria tomentosa (cat’s claw), 534 ursodeoxycholic acid, 389 vaccines monitoring needs, 353–354 trial size, 353 Vaccinium macrocarpon (cranberry) hematologic system, 534 valaciclovir, 330 valerian, 533 valproate bone metabolism, +lamotrigine, 71 polycystic ovary syndrome, 81 valproate sodium body temperature, 81–82 fetotoxicity, 82 infection risk, 81 liver, 80–81 metabolic effects, 80 nervous system, 80 skin, 81 valproic acid, 502 Varicella vaccine, 360 venlafaxine drug withdrawal, 17 hair, 16–17 indinavir concentration, 333 lithium interaction, 25–26 overdose, 17 verapamil cardiovascular system, 227–228 digoxin concentration, 199 dofetilide concentration, 212 interactions, 228 musculoskeletal system, 228 nervous system, 228 vertebral angiography, 514–515

584 vigabatrin general effects, 82 long term safety, 83 visual field defects, 82–84 vinca alkaloids, 308 virginiamycin drug tolerance (antibacterial resistance), 293 resistance to quinupristin/dalfopristin, 290 vitamin A, 416 vitamin B2 (riboflavin), 420 vitamin B5 , 424 vitamin B6 (pyridoxine), 420–421 vitamin C (ascorbic acid), 421 vitamin D (calciferol), 421 vitamin E acetylsalicylic acid, concomitant use, 423 hematologic system, 422 vitamin H (biotin), 424 vitamin K, 424 voglibose, 466–467 voriconazole, 309

Index of drugs walnut oil, 545 warfarin absorption, alpha-glucosidase inhibitors, 467 clearance, +raloxifene, 445–446 clearance, +rifampicin, 342 concentration, fluvoxamine, 14 concomitant digoxin, 200 concomitant levetiracetam, 76 concomitant suramin, 350 dosage, nevirapine, 332 efficacy, rofecoxib, 125 hypoprothrombinemia, +macrolides, 284 hypoprothrombinemia, +miocamycin, 288 INR, Chinese wolfberry, 533 INR, +clarithromycin, 287 INR, +Cucurbicin, 422 INR, +doxycycline, 265 INR, +ropinirole, 162 metabolism, quinidine, 214 white flower, 545

withdrawal levofloxacin interaction, 279 xenon, 134–135 zafirlukast, 194 zaleplon, 49 zanamivir, 334–335 ZD0473, 493 zinc, 250 zinc ricinoleate, 171 zolpidem drug abuse, 50–51 nervous system, 50 overdose, 51 psychiatric effects, 50 vs. zopiclone + triazolam, 51 zonisamide, 84 zopiclone bitter taste, 50 interactions, 51 nervous system, 51 overdose, 51 vs. zolpidem, 50

Index of adverse effects ABCR gene chloroquine, 316 abdominal discomfort anticholinergic drugs, 164 deferiprone, 253 famciclovir, 329–330 hemoglobin-based oxygen carriers, 363 abdominal distension antipsychotic drugs, 58 leuprorelin acetate, 478 octreotide, 480 voglibose, 466 abdominal fat glibenclamide, 466, 469 voglibose, 466 abdominal pain amphotericin B liposomal, 303 antipsychotic drugs, 58 Artemisia derivatives, 320 atovaquone, 320 azathioprine, 404 BufferGel, 541 celecoxib, 123 erythromycin, 284 irinotecan + oxaliplatin, 502 itraconazole, 307 leuprorelin acetate, 478 levofloxacin, 278 mesalazine, 387 metformin, 468 methotrexate, 407 methylphenidate, 5 moxifloxacin, 279 naltrexone, 105 NRTIs, 330 oral contraceptives, 444 primaquine, 319 progestogens, 448 proton pump inhibitors, 385 pseudoephedrine, 157 quinine, 318 rabeprazole, 386 suramin, 351 abdominal tenderness antipsychotic drugs, 58 lead, 248 propofol, 136 abnormal posture disulfiram, 542 abnormal stools cilostazol, 230 lopinavir/ritonavir, 333 abscesses leuprorelin acetate, 478 absence seizures

valproate sodium, 80 acanthosis silver, 249 acanthosis nigricans fusidic acid, 281 acetylcholinesterase activity contrast agents, 513 aches interleukin-11 (oprelvekin), 398 acidosis cocaine, 39 diclofenac, 115 propofol, 135–136 topiramate, 80 acne lithium, 22 Mirena, 447 acral erythema docetaxel, 504 acute respiratory distress syndrome (ARDS) all-trans retinoic acid, 417, 418 amiodarone, 204 infliximab, 401 tetracycline therapy, 268 addiction methamphetamine, 30 adenocarcinoma hormone replacement therapy, 441 adrenal insufficiency fluconazole, 305 inhaled corticosteroids, 188 aggression amfebutamone, 16 androgenic anabolic steroids, 450 cannabis in animals, xxxiii gabapentin, 74 gliclazide, 470 midazolam, 136 piracetam, 8 vigabatrin, 82 agitation amfebutamone, 16 baclofen, 153 cefepime, 265 haloperidol, 53 infiltration anesthesia, 143 levetiracetam, 76 midazolam, 136 nicotine poisoning, 528 paracetamol + rifampicin, 115 piracetam, 8 risperidone, 53

rofecoxib, 123 sevoflurane, 133 St. John’s wort, 532 theophylline, 2 zolpidem, 50, 51 agranulocytosis clozapine, 59–60 dapsone, 340 olanzapine, 62, 63 terbinafine, 309 thionamide drugs, 458 air embolism central venous catheters, 545 airway obstruction triphenylmethane dyes, 259 akathisia antipsychotic drugs, 54 cocaine, 38 diphenhydramine, 54 haloperidol, 64 prochlorperazine, 54, 55 risperidone, 64 alkaline phosphatase blood activity quinupristin/dalfopristin, 290 allergic conjunctivitis adrenoceptor agonists, 525 allergic reaction albumin, 363 asparaginase, 504 calcitonin, 472 Dy-EOB-DTPA, 519 epoetin, 370 fibrates, 486 inhaled corticosteroids, 190 iodinated water-soluble contrast agents, 513 isosulfan blue, 543 Japanese encephalitis vaccine, 359 mercury, 248 nickel, 248 para-phenylenediamine, 173 penicillin, 262–263 rocuronium, 150–151 squirting cucumber, 531 steroids, 450 vitamin B6 , 420 alopecia epoetin, 369 lithium, 23 Mirena, 447 Norplant, 444 St. John’s wort + olanzapine, 532 tamoxifen, 446

585

586 terbinafine, 310 venlafaxine, 16–17 alveolitis indigo carmine, 545 amenorrhea Mirena, 447 risperidone, 65 aminotransferase activity HMG-CoA reductase inhibitors, 487 linezolid, 289 MDMA, 35 amnesia efavirenz, 331 lorazepam, 48 anaphylaxis/anapylactoid reactions acetazolamide, 239 albumin, 363 anthrax vaccine, 355 cefazolin, 264 chlorhexidine, 258 chlorhexidine + sulfadiazine, 290 cisplatin, 501 diphtheria vaccine, 356 etomidate, 135 intravenous immunoglobulin, 366 iodinated contrast agents, 519 iron dextran, 247 isosulfan blue, 543 5-methoxypsoralen, 173 NSAIDs, 121–122 oxaliplatin, 501 polygeline, 376 rocuronium, 150–151 sulfan blue, 545 thiazide + loop diuretics, 239 vancomycin, 282–283 vitamin B2 , 420 anemia ACE inhibitors, 234 arsenic, 244 cisplatin, 498 interleukin-11, oprelvekin, 398 methotrexate, 407 ribavirin, 329 suramin, 351 vitamin D, 421 anemia, aplastic anthrax vaccine, 355 chloramphenicol, 273 clopidogrel, 380 ketoconazole, 303 anemia, hemolytic intravenous immunoglobulin, 365 anemia, sideroblastic chemically modified tetracyclines, 268 linezolid, 289 anencephaly triamterene, 241

Index of adverse effects aneurysmal subarachnoid hemorrhage cocaine, 39 gold, 246 anger prednisone, 427 angina see also cardiac ischemia dipyridamole, 380 hormone replacement therapy, 438 iodixanol, 514 iohexol, 514 latanoprost, 526 nitroglycerin, 224 thyroxine, 457 angio-edema meloxicam, 116 NSAIDs, 121–122, 122–123 pioglitazone, 471 vitamin B2 , 420 anhidrosis brachial plexus anesthesia, 140 anorexia Artemisia derivatives, 320 clozapine, 60 digoxin, 198 ecstasy, 35 phenytoin + fosphenytoin, 76 vitamin A, 416 zonisamide, 84 anorgasmia SSRIs, 13–14 anovulatory cycles valproate sodium, 81 anteroseptal defects dipyridamole, 380 antibacterial resistance chemically modified tetracyclines, 269 fusidic acid, 281 glycopeptides, 282 quinupristin/dalfopristin, 290 virginiamycin, 293 antibody formation epoetin, 370 human growth hormone, 480 interferon alfa, 394 lepirudin, 379–380 parathyroid hormone, 481 antibody function factor VIII:C, 367 anxiety antituberculous agents, 339 cannabis, xxxiv, xxxviii cefepime, 265 cisplatin, 496 efavirenz, 331 gabapentin, 74 levofloxacin, 278 lithium, 20 MDMA, 34 mefloquine, 318 methamphetamine, 30

nefazodone, 16 remifentanil, 100 zolpidem, 51 aortic dissection cocaine, 37 aortic regurgitation fenfluramine, 6 aphasia gonadorelin receptor antagonists, 478 leuprorelin, 478 aplasia cutis congenita carbimazole, 459 apnea alprostadil, 430 DTP-Hib vaccines, 356 methadone, 95 apoptosis cisplatin, 499 appetite, change in cannabis in animals, xxxiii Dy-EOB-DTPA, 519 fentanyl, 94 kava, 533 methylphenidate, 4, 5 moricizine, 213 piracetam, 8 risperidone, 64 ARDS see acute respiratory distress syndrome (ARDS) argyria acupuncture, 535 argyrosis, vaginal silver, 249 artery vasculitis hepatitis B vaccine, 358 arthralgia all-trans retinoic acid, 417 anthrax vaccine, 355 Echinacea, 531 intravenous immunoglobulin, 365 nicardipine, 228 propylthiouracil, 458 quinupristin/dalfopristin, 290 rubella vaccine, 360 terbinafine, 310 arthritis Lyme vaccine, 358 rubella vaccine, 360 arthropathy ciprofloxacin, 277 fluoroquinolones, 275 arthrosis rubella vaccine, 360 ascites albumin, 363 leuprorelin acetate, 478 aseptic meningitis allopurinol, 125 co-trimoxazole, 291, 321 gentamicin, 271 infliximab, 401

587

Index of adverse effects intravenous immunoglobulin, 365 rofecoxib, 124–125 valaciclovir, 330 aseptic necrosis systemic glucocorticosteroids, 429 asthma aspirin-induced, 117–118 cisplatin, 501 cocaine, 38 ketoprofen, 116 menthol, 543 NSAIDs, 121–122 asymmetrical head shape ganirelix + follicle stimulating hormone, 479 asystole acetylcholinesterase inhibitors, 164 ergot alkaloids, 163 remifentanil, 101 ataxia disulfiram, 542 gabapentin, 74 heroin, 92 lamotrigine, 74 macrolides, 284 miocamycin, 288 oxcarbazepine, 76 remacemide, 77 spinal manipulation, 536 zonisamide, 84 atherogenesis triptorelin, 478 atherosclerotic plaque rupture cannibinoids, 36 atopic dermatitis titanium, 250 atopy and immunizations, 355 atrial fibrillation dofetilide, 209 fluoroquinolones, 274 milrinone, 202 venlafaxine, 17 atrial flutter dofetilide, 209 moricizine, 213 atrioventricular block adenosine, 203 propafenone, 214 sotalol, 224 atrium, heart see entries at heart– auditory disturbance see entries at hearing– autism measles-mumps-rubella vaccine, 359 valproate sodium, 82 autonomic symptoms insulin, 461, 462 avascular necrosis

systemic glucocorticosteroids, 429 azoospermia cyclophosphamide, 406, 504 azotemia lithium, 21, 22 baboon syndrome nickel, 248 terbinafine, 310 back pain denileukin diftitox, 398 Dy-EOB-DTPA, 519 hormone replacement therapy, 440 liposome-encapsulated iodixanol, 519 backache BufferGel, 541 intravenous immunoglobulin, 364 balance amphetamine, 30 cannabis, xxxv streptomycin, prenatal, 273 zolpidem, 50 balanitis co-trimoxazole, 321–322 Beckwith-Weidemann syndrome ganirelix + follicle stimulating hormone, 479 behavioral changes topiramate, 79 behavioral control vigabatrin, 82 Behçet’s disease docetaxel, 504 bilirubin concentration all-trans retinoic acid, 418 celecoxib, 124 bioterrorism anthrax vaccine, 354–355 birth defects antiepileptic drugs, 71, 73 cetrorelix, 479 fluconazole, 305–306 losartan, 236 nalidixic acid, 280 birth weight antiepileptic drugs, 73 cocaine, 40 dexamethasone, 429 somatostatin, 481 bitter taste azelastine, 183 zolpidem, 50 black tongue arsenic, 244 bladder diverticula copper, 245 bladder stones felbamate, 73 bleeding

acupuncture, 535 recombinant human activated protein C, 363 saw palmetto, 534 bleeding tendency, increased herbal medicines, 528 blepharoconjunctivitis dorzolamide, 239 blindness gonadorelin, 477 mexiletine, 213 blistering Ginkgo biloba, 531 henna tattooing, 544 blood, dark-colored benzocaine, 145 blood clots MDMA, 35 blood dyscrasias dapsone, 340 terbinafine, 309 blood glucose control pancreatic enzyme supplements, 389 blood loss central venous catheters, 545 blood pressure changes citric acid, 541 intravenous immunoglobulin, 364 “blue hives” isosulfan blue, 543 blurred vision brachial plexus anesthesia, 140, 141 cisplatin, 497 flecainide, 213 human growth hormone, 479 latanoprost, 431 mexazolam, 48 bone dysplasia deferiprone, 254 bone loss G-CSF, 399 systemic glucocorticosteroids, 428 bone marrow suppression pyrimethamine + azithromycin, 322 Selaginella doederleinii, 534 thionamide drugs, 458 bone metabolism ciclosporin, 405 valproate + lamotrigine, 71 bone mineral density androgen deprivation therapy, 504 antiandrogens, 450 inhaled corticosteroids, 186, 188–190 bone pain all-trans retinoic acid, 417, 418 bowel sounds dextromethorphan, 91

588 bradycardia adrenoceptor agonists, 525 alprostadil, 430 cisplatin, 494 desmopressin, 482 diltiazem, 226 DTP-Hib vaccines, 356 ergot alkaloids, 163 labetalol, 164 lithium, 24, 25 milrinone, 202 propafenone, 214 propofol, 136 remifentanil, 100 sotalol, 224 terlipressin, 483 timolol, 525 bradypnea diltiazem, 226 breakthrough bleeding, menstrual BufferGel, 540 breakthrough infections voriconazole, 309 breakthrough pain fentanyl, 92 breast enlargement finasteride, 450 penicillamine, 255 breast pain antiandrogens, 450 breast swelling gonadotrophin-releasing hormone, 477 breast tenderness finasteride, 450 hormone replacement therapy, 436 progestogens, 448 risperidone, 65 breathing, difficulty in adenosine, 203 leuprorelin acetate, 478 spinal manipulation, 536 vitamin B6 , 424 vitamin H, 424 bronchiolitis obliterans mesalazine, 388 bronchoconstriction propofol, 135 bronchopneumonia gliclazide, 470 bronchopulmonary dysplasia cocaine, 41 bronchospasm adenosine, 203 beta-adrenoceptor agonists, 526 carboplatin, 501 clarithromycin, 286 hypochlorite, 259 intravenous immunoglobulin, 365 rapacuronium, 150 zanamivir, 334–335

Index of adverse effects bronzing of the skin antituberculous agents, 339 Brugada syndrome flecainide, 212 bruising cranberry, 534 ganirelix, 479 bruxism paramethoxyamphetamine (PMA), 36 buccal movement methylphenidate, 4 bullous emphysema cocaine, 38 bullous erruptions melarsoprol, 323 bullous pemphigoid influenza vaccine, 359 Td-IPV vaccine, 358 bullous phototoxic skin reactions bergamot, 530 burning, skin henna tattooing, 544 tacrolimus, 408 burning eyes aminoglycosides, 273 bimatoprost, 430 flecainide, 213 burning mouth clonazepam, 47 inhaled corticosteroids, 188 burning sensation calcineurin inhibitors, 172 griseofulvin, 176 indocyanine green, 545 burns, second degree garlic, 529 butyrylcholinesterase activity contrast agents, 513 calcinosis aristolochic acid, 530 heparins, 377 calcium blood concentration vitamin A, 416 cancer ethylene oxide, 258 cancer, breast diethylstilbestrol (stilbestrol), 436 hormone replacement therapy, 441 cancer, colon thiazide + loop diuretics, 239 cancer, endometrial hormone replacement therapy, 441 tamoxifen, 447 cancer, esophageal trichloroethylene, 134 cancer, skin cyclophosphamide, 406 cancer, vaginal

diethylstilbestrol (stilbestrol), 436 Candida infection fluoroquinolones, 275 inhaled corticosteroids, 187, 190 carcinogenic effects nitroglycerin, 224 carcinoma, renal cell thiazide + loop diuretics, 239 cardiac see also entries at coronary–; heart– cardiac arrest see also myocardial infarction depolarizing neuromuscular blocking agents, 151, 152 diltiazem, 226 iodixanol, 513 iopamidol, 513 ioxaglate, 513 pethidine, 99 propofol, 136 cardiac collapse polygeline, 376 cardiac dysfunction ecstasy, 32 cardiac dysrhythmia adenosine, 203 ajmaline and derivatives, 204 antihistamines, 181 beta-adrenoceptor agonists, 190 carbamazepine, 72 dobutamine, 159 flecainide, 212 ritodrine, 192 sertindole, 65 cardiac ischemia nitrous oxide, 134 pseudoephedrine + amfebutamone, 157 terlipressin, 483 thyroxine, 457 cardiogenic shock nicardipine, 228 pranlukast, 193 cardiomegaly human growth hormone, 479 infiltration anesthesia, 143 cardiomyopathy antipsychotic drugs, 54 chloroquine, 315 clozapine, 59 lithium, 19 olanzapine, 63 cardiotoxicity antihistamines, 180–181 loratadine + nefazodone, 16 trastuzumab, 403 cardiovascular collapse isosulfan blue, 543 propofol, 135–136 cardiovascular events darbepoetin, 368

589

Index of adverse effects epoetin, 368 erythropoietin, 368, 369 cardiovascular teratogenesis lithium, 19 carotid artery dissection spinal manipulation, 536 caseous necrosis acupuncture, 535 cataracts erythromycin + statins, 287 inhaled corticosteroids, 188 catatonia alprazolam, 46 bromazepam, 46 catecholaminergic neurotransmission cocaine, 39 cauda equina syndrome lidocaine, 143 spinal manipulation, 536 central retinal artery, branch occlusions massage therapy, 536 cerebellar infarct spinal manipulation, 536 cerebellar sequelae lithium, 20 cerebral damage gliclazide, 470 cerebral edema desmopressin, 482 sildenafil, 231 cerebral hemorrhage phenylpropanolamine, 158–159 cerebral herniation cisplatin, 496 cerebral infarction tamoxifen, 446 cerebral ischemic symptom gold, 246 cerebral sinus thrombosis tamoxifen, 446 cerebral venous thrombosis oxymetholone, 450 cerebrospinal fluid pressure all-trans retinoic acid, 417 cervical cancer trichloroethylene, 134 cervical lacerations misoprostol, 432 cheilitis glyceryl hydrogenated rosinate, 171 chest discomfort intravenous immunoglobulin, 365 chest pain cardiac glycosides, 530 cocaine, 37 desmopressin, 482 dipyridamole, 380 dobutamine, 159 Ephedra, 156 iloprost, 230

MDMA, 32 talc, 544 vitamin B6 , 424 vitamin H, 424 chest tightness amphotericin B liposomal, 303 carboplatin, 501 fibrates, 486 intravenous immunoglobulin, 364 chewing methylphenidate, 4 Cheyne-Stokes respiration lithium, 25 chiasmal herniation cabergoline, 160 chills all-trans retinoic acid, 417 interferon alfa, 397 intravenous immunoglobulin, 364 liposome-encapsulated iodixanol, 519 misoprostol, 431 quinine, 318 Chinese herb nephropathy aristolochic acid, 530 choanal atresia methimazole, 459 cholangitis MDMA, 35 cholestasic jaundice, 377 cholestasis ecstasy, 35 cholestatic hepatitis celecoxib, 124 cholestatic jaundice metformin, 468 cholesterol blood concentration testosterone, 449–450 cholesterol ratio acarbose, 466–467 antipsychotic drugs, 56 gliclazide, 466–467 gonadorelin receptor antagonists, 478 triptorelin, 478 choluria celecoxib, 124 chorea interferon alfa, 393–394 choreiform movements methadone, 96 choreoathetosis cocaine, 38 Churg-Strauss syndrome pranlukast, 193 clotting disorders fenfluramine, 6–7 interferon alfa + ribavirin, 395 coagulation, intravascular piperacillin, 263–264 coagulopathy contrast agents, 516

ecstasy, 32 cognitive deficits carbamazepine, 72 gabapentin, 72 cognitive function cannabis, xxxv ecstasy, 33 lithium, 25 topiramate, 78–79 unconventional diets, 536 cold, sensation of gadolinium, 520 cold extremities methoxamine, 157 colds levetiracetam, 75 colitis isotretinoin, 176 meloxicam, 116 collapse benzocaine, 145 colonic necrosis sodium polystyrene sulfonate, 256 colonic ulceration loxoprofen, 116 color vision cisplatin, 497 coma benzocaine, 145 cefepime, 265 cisplatin, 496 Hydroxycut, 531 insulin, 463 lithium, 25 melarsoprol, 323 zolpidem, 51 concentration, difficulty chlorpromazine, 53 clozapine, 53 disulfiram, 542 lithium, 25 morphine, 97 salmeterol, 192 conduction disturbances chloroquine, 315, 316–317 confusion amantadine, 162 amfebutamone, 16 efavirenz, 331 etanercept, 399 mefloquine, 318 paracetamol + rifampicin, 115 rofecoxib, 123 sildenafil, 231 topiramate, 79 conjunctival hyperemia bimatoprost, 430, 526 brachial plexus anesthesia, 140 latanoprost, 526 conjunctival inflammation clindamycin, 284 conjunctival injection co-trimoxazole, 321

590 interleukin-11 (oprelvekin), 398 conscious recollection diazepam, 47–48 lorazepam, 47–48 consciousness alteration baclofen, 153 constipation acamprosate, 540 alosetron, 383 anticholinergic drugs, 164 antipsychotic drugs, 58 codeine, 90 ecstasy, 35 fentanyl, 92 granisetron, 384 linezolid, 289 morphine, 97 olanzapine, 61 contact allergies antiviral drugs, 168 befunolol, 526 branched-chain fatty acid esters, 168 cocamidopropyl betaine, 168 colophonium, 168 Compositae species, 172 gum resins, 168, 171 laurel oil, 532 para-phenylenediamine, 173 sesquiterpene lactones, 172 topical drugs and cosmetics, 169–171 contact blepharoconjunctivitis dorzolamide, 239 contact dermatitis azithromycin, 285 benzocaine, 145 blue dye, 545 butyl hydroxyanisole, 545 cefepime, 265 cinchocaine, 145–146 DoloPosterine, 173 enoxolone, 545 gentamicin, 272 henna tattooing, 544 hormone replacement therapy, 440 hydrocortisone aceponate cream, 427 inhaled corticosteroids, 188 ketoprofen, 172 laureth-A (polidocanol), 545 NSAIDs, 174 oxybenzone, 174 polidocanol, 545 polyoxyethylene lauryl ether, 545 proparacaine, 147 stearyl alcohol, 545 talc, 544–545 tetraethylthiuramdisulfide, 545 vitamin B6 , 420 vitamin C, 421

Index of adverse effects white flower, 545 contact hypersensitivity vitamin B6 , 420 contact leukoderma para-phenylenediamine, 173 contact pemphigus ketoprofen, 172 contact reactions menthol, 543 contact sensitization arnica, 530 marigold, 530 contact vasculitis ketoprofen, 172 contusion of the spinal cord spinal manipulation, 536 convulsions baclofen, 153 cannabis, animals, xxxiv ecstasy, 32 fentanyl, 93 fluoroquinolones, 274 gliclazide, 470 glucagon, 466 levetiracetam, 75 levofloxacin, 278 melarsoprol, 323 paramethoxyamphetamine (PMA), 36 sevoflurane, 132 cooperation midazolam, 137 coordination codeine, 90 spinal manipulation, 536 zolpidem, 50 copper deficiency zinc, 250 corneal deposits flecainide, 212–213 corneal microprecipitates ciprofloxacin, 276 coronary see also entries at cardi–; heart– coronary arteritis anthrax vaccine, 355 coronary artery dissection cocaine, 37 coronary thrombosis all-trans retinoic acid, 417 coronary vasoconstriction triptans, 230 cough ACE inhibitors, 234 arsenic, 244 fentanyl, 94 inhaled corticosteroids, 187, 188 nasal insulin, 465 primaquine, 319 crabbiness methylphenidate, 4 cramps

MS-325, 521 cramps (abdominal) BBR3464, 492 cisplatin, 501 cramps (muscle) oxaliplatin, 495 cranial nerve palsy measles-mumps-rubella vaccine, 359 craniosynostosis valproate sodium, 82 creatine kinase activity baclofen, 153 isoniazid, 341 tenofovir, 331 creatine phosphokinase concentration pioglitazone, 471 creatinine concentration amphotericin B liposomal, 303 carboplatin, 500 ciclosporin, 404 cidofovir, 328 cisplatin, 500 lithium, 22 penicillamine, 256 propofol, 136 suramin, 351 tenofovir, 331 CREST syndrome aristolochic acid, 530 Creutzfeldt-Jakob disease human growth hormone, 479 crystal accumulation sodium polystyrene sulfonate, 256–257 cutaneous bullae iohexol, 518 cutaneous granulomas silicone, 544 cutaneous lupus erythematosus etanercept, 400 cutaneous necrosis interferon alfa, 395 cutaneous polyarteritis minocycline, 266 cutaneous pseudolymphoma valproate sodium, 81 cutaneous vasculitis infliximab, 401 cutaneous vasodilatation cinnamic aldehyde, 545 cutis laxa penicillamine, 256 cyanosis benzocaine, 145 cocaine, 37 EMLA cream, 144 lidocaine, 146 CYP1A2 fluvoxamine, 12 inhibition, fluvoxamine, 63 inhibition, olanzapine, 14 inhibition, risperidone, 60–61

591

Index of adverse effects mexiletine, 213 norfloxacin, 280 risperidone, 65 CYP2C9 co-trimoxazole, 321 fluconazole, 306 inhibition, fluvoxamine, 14 sulfonamides, 290 voriconazole, 309 CYP2C19 inhibition, fluvoxamine, 14 inhibition, risperidone, 60–61 risperidone, 66 voriconazole, 309 CYP2D6 almotriptan, 15 inhibition, risperidone, 60–61 mexiletine, 213 risperidone, 15, 65 terbinafine, 311 CYP2E1 alcohol + paracetamol, 114 CYP3A4 clarithromycin, 286, 287 efavirenz, 331 erythromycin, 228 inhibition, nefazodone, 16 macrolides, 284 mexiletine, 213 miocamycin, 287–288 nevirapine, 332 quinupristin/dalfopristin, 290 sildenafil, 231 St. John’s wort, 487 substrate, benzodiazepines, 16 substrate, carbamazepine, 16 substrate, ciclosporin, 16 verapamil, 228 voriconazole, 309 CYP3A (unspecified) everolimus, 406 cystoid macular edema latanoprost, 526 cytochrome C oxidase activity propofol, 136 cytokine release syndrome oxaliplatin, 501 cytomegalovirus reaction dacluzumab, 402 rituximab, 403 cytotoxicity paclitaxel + cisplatin, 502 dapsone syndrome dapsone, 340 dark urine celecoxib, 124 entacapone, 163 darkening of the iris bimatoprost, 430 latanoprost, 431 deafness cisplatin, 502 heroin, 41, 92

death adenosine, 203 antiepileptic drugs, 71 benzocaine, 145 beta-adrenoceptor agonists, 190 bromocriptine, 160 chemotherapy, 504 dacluzumab, 402 dofetilide, 210 gold, 246 hormone replacement therapy, 438 insulin, 462 itraconazole, 307 lithium, 24 methadone, 96 nitrogen + sildenafil, 225 paramethoxyamphetamine (PMA), 36 propylthiouracil, 458, 459 thyroxine, 457 vincristine, 504 deep vein thrombosis cocaine, 37 erythropoietin, 369 tamoxifen, 446 defiance vigabatrin, 82 deformities losartan, 236 dehydration lithium, 21 déjà vu amantadine + phenylpropanolamine, 334 delayed follicular rupture COX-2 inhibitors, 123 delirium ciprofloxacin, 276 cocaine, 39 digitalis, 198 disulfiram, 542 lithium, 20, 22 sevoflurane, 132, 133 St. John’s wort, 532 demyelination etanercept, 399 heroin, 92 dependence zolpidem, 50–51 depersonalization zaleplon, 49 depression androgenic anabolic steroids, 450 antituberculous agents, 339 buspirone, 49 cannabis, xxxviii digitalis, 198 ecstasy, 34 isotretinoin, 175 levetiracetam, 75 mefloquine, 318 pimozide, 64

risperidone, 64 timolol, 526 topiramate, 79 dermatitis see also contact dermatitis; eczematous dermatitis; exfoliative dermatitis antiviral drugs, 168 azithromycin, 285 benzocaine, 145 cinchocaine, 145–146 diltiazem, 225 DoloPosterine, 173 dorzolamide, 239 gentamicin, 272 henna tattooing, 544 inhaled corticosteroids, 187, 188 ketoprofen, 172 lidocaine, 146–147 nickel, 248–249 NSAIDs, 174 oxybenzone, 174 oxybuprocaine, 147 proparacaine, 147 titanium, 250 dermatomyositis docetaxel, 504 dermographism atorvastatin, 487 dermopathy penicillamine, 256 desaturation DTP-Hib vaccines, 356 deterioration vigabatrin, 82 diabetes insipidus lithium, 21, 22 ofloxacin, 280 diabetes mellitus interferon alfa, 394 medroxyprogesterone, 444 olanzapine, 62 tacrolimus, 408 diabetes (unspecified) tamoxifen, 446 dialysis azithromycin, 286 dialysis-associated encephalopathy aluminium, 243 diaphragmatic paralysis spinal manipulation, 536 diarrhea acamprosate, 540 acarbose, 467 all-trans retinoic acid, 417 amprenavir, 332 anorexia, 493 Artemisia derivatives, 319, 320 atovaquone, 320 azathioprine, 404 azithromycin + rifabutin, 285 BBR3464, 492

592 buspirone, 49 carboplatin, 498 celecoxib, 123 cilostazol, 230 ciprofloxacin, 276 cisplatin, 501 clarithromycin, 286 clindamycin, 284 dipyridamole, 380 enalapril, 235 entacapone, 163 erythromycin, 284 famciclovir, 329–330 fentanyl, 92 fluvastatin, 488 granisetron, 384 iloprost, 430 irinotecan + neomycin, 504 itraconazole, 306, 307 lactulose, 387 levamisole, 348 levofloxacin, 278 linezolid, 289 lithium, 20, 24, 25 lopinavir/ritonavir, 333 mesalazine, 387 metformin, 468 mifepristone, 448 miglitol, 467 misoprostol, 431 moxifloxacin, 279 nicotinic acid, 420 norfloxacin, 280 octreotide, 480 olsalazine, 389 oxaliplatin, 498 phenytoin + fosphenytoin, 76 proton pump inhibitors, 384, 385 pseudoephedrine, 157 quinine, 318 quinupristin/dalfopristin, 290 rabeprazole, 386 roxithromycin, 288 salmeterol, 192 suramin, 351 telithromycin, 283 thiabendazole, 345 diarrhea, bloody phenytoin + fosphenytoin, 76 digitalis toxicity cardiac glycosides, 530 digoxin concentration cardiac glycosides, 530 fluoxetine, 15 diplopia diazepam, 47 lamotrigine, 74 spinal manipulation, 536 discoid lupus etanercept, 400 disorientation amfebutamone, 16 baclofen, 153

Index of adverse effects ecstasy, 35 lithium, 25 zolpidem, 50 disseminated intravascular coagulation lamotrigine, 74 disulfiram-like reaction with alcohol metronidazole, 323 divergent gaze amphetamine, 30 diverticula, bladder copper, 245 dizziness benzocaine, 145 buspirone, 49 cilostazol, 230 cisplatin, 497 desmopressin, 482 dextromethorphan, 91 diazepam, 47 diltiazem, 226 dobutamine, 159 epoetin, 369 famciclovir, 329–330 fluoroquinolones, 274 gabapentin, 74 gadobenate dimeglumine, 520 gadolinium, 520 kava, 533 lamotrigine, 74 levetiracetam, 75 levofloxacin, 278 linezolid, 289 manganese, 248 5-methoxypsoralen, 173 mexazolam, 48 misoprostol, 431 nasal insulin, 465 nefazodone, 16 nicardipine + erythromycin, 228 olanzapine, 61 oxcarbazepine, 76 parathyroid hormone, 481 praziquantel, 350 propafenone, 214 quinine, 318 remacemide, 77 spinal manipulation, 536 strychnine, 6 telithromycin, 283 thiabendazole, 344, 345 tiagabine, 77 timolol, 525, 526 topiramate, 78 tramadol, 103 vitamin B2 , 420 zonisamide, 84 dream disturbance isotretinoin, 175 valerian, 533 drowsiness cannabis, xxxv

clozapine, 61 diazepam, 47 disulfiram, 542 intravenous immunoglobulin, 365 mexazolam, 48 naltrexone, 105 vitamin B2 , 420 zopiclone, 51 dry eyes bimatoprost, 430 flecainide, 213 dry mouth anticholinergic drugs, 164, 165 clarithromycin, 286 dihydrocodeine, 92 entacapone, 163 inhaled corticosteroids, 188 olanzapine, 61 risperidone, 64 dry skin all-trans retinoic acid, 417, 418 Duchenne’s muscular dystrophy androgenic anabolic steroids, 450 dull/listless appearance methylphenidate, 4 dural tear spinal manipulation, 536 dynamic compliance rapacuronium, 150 dysarthria amphetamine, 30 cocaine, 38 diazepam, 47 disulfiram, 542 heroin, 92 human growth hormone, 479 infiltration anesthesia, 143 metronidazole, 324 dysdiadochokinesis metronidazole, 324 dysesthesia oxaliplatin, 495 phenolic compounds, 260 dysgeusia levamisole, 348 dyskinesia ciprofloxacin, 276 dextromethorphan, 91 entacapone, 163 gabapentin, 73 dyslexia hepatitis B vaccine, 358 dysmetria amphetamine, 30 cocaine, 38 heroin, 92 metronidazole, 324 dysosmia levamisole, 348 dyspepsia acamprosate, 540

593

Index of adverse effects buspirone, 49 mesalazine, 387 sildenafil, 231 sulfasalazine, 387 dysphagia methimazole, 458 dysphasia gliclazide, 470 dysphonia inhaled corticosteroids, 187 dyspnea all-trans retinoic acid, 417 amphotericin B liposomal, 303 benzocaine, 145 betaxolol, 526 carboplatin, 501 cisplatin, 501 denileukin diftitox, 398 iodixanol, 514 iohexol, 514 iron dextran, 247 lidocaine, 146 menthol, 543 oxaliplatin, 501 pergolide, 160 pioglitazone, 471 suramin, 351 tobramycin, 273 vitamin B2 , 420 dysrhythmia adenosine, 203 benzocaine, 145 cisapride, 382 COX-2 inhibitors, 117 dobutamine, 159 flecainide, 212 iodixanol, 514 iohexol, 514 nicardipine + erythromycin, 228 propafenone, 214 dystonia cimetidine, 384 cocaine, 38 disulfiram, 542 tiagabine, 77 dystrophic calcification acupuncture, 535 echinocytosis sodium diatrizoate, 516 eczema aceclofenac, 115 inhaled corticosteroids, 188 intravenous immunoglobulin, 366 vitamin B6 , 420 vitamin C, 421 edema barnidipine, 225 denileukin diftitox, 398 desmopressin, 482 EMLA cream, 144

hormone replacement therapy, 436 human growth hormone, 479 inhaled corticosteroids, 188 isosulfan blue, 543 laurel oil, 533 lopinavir/ritonavir, 333 manidipine, 227 mesalazine, 387 morphine, 97 olanzapine, 63 pioglitazone, 471 rosiglitazone, 471, 472 edema, ankle manidipine, 227 ejaculatory dysfunction diuretics, 238 finasteride, 450 risperidone, 65 SSRIs, 13–14 electric shock central venous catheters, 545 electrocardiographic changes see also QT interval prolongation clozapine, 59 salmeterol, 192 electrolyte disturbances pentamidine, 323 embryopathy antiepileptic drugs, 71 methimazole, 459 emesis see vomiting emotional lability gabapentin, 73 emphysema MDMA, 32 empty sella syndrome androgenic anabolic steroids, 450 thyroid hormones, 457 encephalitis systemic glucocorticosteroids, 429 encephalocele triamterene, 241 encephalopathy albendazole, 344 aluminium, 243 cisplatin, 496 erythropoietin, 369 kava, 534 lamotrigine, 75 melarsoprol, 323 paracetamol + rifampicin, 115 tacrolimus, 408 endometrial disorders hormone replacement therapy, 440 mifepristone, 449 tamoxifen, 447 tamoxifen + toremifene, 504 toremifene, 447

endomyocarditis pranlukast, 193 endothelial impairment iron dextran, 247 enlarged spleen gabapentin, 74 enophthalmos brachial plexus anesthesia, 140 enuresis chlorpromazine, 53 dibucaine, 143 enzymuria ioxaglate, 517 eosinophilia clozapine, 60 cyanamide, 541 ioxaglate, 513, 514 MDMA, 35 olanzapine, 63 pranlukast, 193 trovafloxacin, 276 eosinophilic endomyocarditis pranlukast, 193 eosinophilic folliculitis foscarnet, 328 eosinophilic gastroenteritis clofazimine, 235 enalapril, 235 naproxen, 235 eosinophilic infiltration leech therapy, 535 eosinophilic pleural effusion with eosinophilic pericardial tamponade vitamin B6 , 424 vitamin H, 424 eosinophilic pneumonia levofloxacin epidural hematoma spinal manipulation, 536 epigastric pain oral contraceptives, 444 epileptiform activity alfentanil, 89 baclofen, 153 sevoflurane, 132–133 erectile dysfunction diuretics, 238 risperidone, 65 ergotism erythromycin + ergotamine, 287 macrolides, 284 miocamycin, 288 ritonavir + ergotamine, 333 troleandomycin + ergotamine, 288 erythema cisplatin, 501 cyanamide, 541 docetaxel, 504 etanercept, 400 griseofulvin, 176 human growth hormone, 480

594 inhaled corticosteroids, 188 intravenous immunoglobulin, 366 iodinized oil-based contrast agent, 518 iohexol, 518 isosulfan blue, 543 laurel oil, 533 leuprorelin acetate, 478 lidocaine, 147 oral contraceptives, 174 suramin, 351 tacrolimus, 408 erythema, facial carboplatin, 501 cisplatin, 501 oxaliplatin, 501 erythema exsudativum multiforme lenograstim, 399 erythema multiforme para-phenylenediamine, 173 erythema nodosum Echinacea, 531 erythematous dermatitis methyl glucose dialate, 545 erythematous lesions fentanyl, 94 erythematous rash interferon beta, 397 SH U 555 A, 522 erythrocyte folate concentrations antiepileptic drugs, 72 erythroderma carboplatin, 501 olanzapine, 63 omeprazole, 386 esophageal atresia methimazole, 459 esophageal dysfunction hemoglobin-based oxygen carriers, 363 esophageal laceration activated charcoal, 387 esophageal sclerosis aristolochic acid, 530 exanthematous pustulosis mexiletine, 213 teicoplanin, 282 terbinafine, 310 excitability efavirenz, 331 excitation dopamine receptor agonists, 162 exercise intolerance topiramate, 80 exfoliative dermatitis all-trans retinoic acid, 417 carboplatin, 501 denileukin diftitox, 398 oxaliplatin, 501 explicit memory

Index of adverse effects temazepam, 48 explosive behavior methylphenidate, 4, 5 external ophthalmoplegia cocaine, 40 extrapyramidal effects antipsychotic drugs, 56 disulfiram, 542 pimozide, 64 risperidone, 64 extravasation cisplatin, 500 mannitol, 376–377 eyelash changes bimatoprost, 526 latanoprost, 431 misoprostol, 432 travoprost, 526 eyelid pigmentation changes bimatoprost, 526 travopost, 526 facial hypomobility disulfiram, 542 facial paresis sildenafil, 231 factitious hypoglycemia repaglinide, 469 failure to capture flecainide, 212 failure to thrive silver, 249 falls clozapine, 61 levamisole, 347 timolol, 525, 526 fat deposits tamoxifen, 446 fatigue acarbose, 467 amprenavir, 332 anorexia, 493 azithromycin + rifabutin, 285 celecoxib, 124 deferiprone, 253 digoxin, 198 gabapentin, 74 kava, 534 lithium, 24 myrrh, 349 nicardipine + erythromycin, 228 oxcarbazepine, 76 pergolide, 160 pimozide, 64 risperidone, 64 sartraplatin, 493 suramin, 350, 351 topiramate, 79 zaleplon, 49 zonisamide, 84 fatty liver disease tamoxifen, 446 febrile reactions

albumin, 363 feeding intolerance DTP-Hib vaccines, 356 fertility (male) sulfasalazine, 387 fetal hypothroidism amiodarone, 206 fetal valproate syndrome valproate sodium, 82 FEV1 colistin, 289 fever acupuncture, 535 all-trans retinoic acid, 417, 418 alprostadil, 430 amphotericin B liposomal, 303 arsenic, 244 caspofungin, 311 clozapine, 60 co-trimoxazole, 322 diethylcarbamazine + ivermectin, 346 diethylcarbamazine, 345 Echinacea, 531 epoetin, 370 interferon alfa, 397 intravenous immunoglobulin, 364 ioxaglate, 513–514, 514 itraconazole, 307 melarsoprol, 323 mesalazine, 387 misoprostol, 431 olanzapine, 63 phenytoin + fosphenytoin, 76 pranlukast, 193 praziquantel, 349 primethamine, 290 propylthiouracil, 458 quinine, 318 suramin, 351 talc, 544 topiramate, 80 vancomycin, 283 fibroadenomata ciclosporin, 406 fibrosing colonopathy mesalazine, 388 fibrosis pergolide, 160 fidgetiness levamisole, 347 fixed drug eruption clarithromycin, 286 co-trimoxazole, 292, 321 fexofenadine, 183 terbinafine, 310 flank pain amphotericin B liposomal, 303 flatulence acamprosate, 540 acarbose, 467 lactulose, 387 miglitol, 467

595

Index of adverse effects rabeprazole, 386 tenofovir, 331 voglibose, 466 flu-like symptoms darbepoetin, 368 denileukin diftitox, 398 epoetin, 368 erythropoietin, 368 iodinated water-soluble contrast agents, 513 levamisole, 348 liposome-encapsulated iodixanol, 519 tacrolimus, 408 fluid retention rosiglitazone, 471 flushing alprostadil, 430 barnidipine, 225 desmopressin, 482 heroin, 91 intravenous immunoglobulin, 3634 iron dextran, 247 misoprostol, 431 nicardipine, 227 nicotinic acid, 419, 420 oxaliplatin, 501 sildenafil, 231 Sono Vue, 523 St. John’s wort, 532 thyrotropin-releasing hormone, 482 vitamin B2 , 420 zolpidem, 51 focal dystrophic calcification acupuncture, 535 follicular hyperplasia leech therapy, 535 follicular mycoses fungoides lithium, 22–23 follicular rupture COX-2 inhibitors, 123 foreign body reaction walnut oil, 545 fractures benzodiazepines, 46 inhaled corticosteroids, 189 systemic glucocorticosteroids, 428 frontal release signs disulfiram, 542 frontoparietal lobe infarctions massage therapy, 536 gait disturbance cannabis, xxxv heroin, 92 levamisole, 347 methadone, 96 olanzapine, 61 galactorrhea risperidone, 65 SSRIs, 13

gallbladder disease Norplant, 444 gallstones octreotide, 480 ganglion cells tobramycin, 273 gangrene ergotamine + erythromycin, 287 ergotamine + troleandomycin, 288 gastric irritation zinc, 250 gastric nodules omeprazole, 385 gastric upset levamisole, 348 salmeterol, 192 gastritis antituberculous agents, 339 gastrointestinal bleeding naproxen, 116 timolol, 526 gastrointestinal discomfort acamprosate, 540 azithromycin, 285 azithromycin + rifabutin, 341 carboplatin, 501 chloroquine, 315 cisplatin, 501 denileukin diftitox, 398 fentanyl, 92 oseltamivir, 33 oxaliplatin, 501 propafenone, 214 pyrimethamine + azithromycin, 322 remacemide, 77 tramadol, 102 gastrointestinal hemorrhage COX-2 inhibitors, 120–121 metformin, 468 gastrointestinal toxicity flutamide, 450 levamisole, 348 gastrotoxicity aspirin, 113 giddiness diethylcarbamazine + ivermectin, 346 myrrh, 349 glaucoma promethazine, 183 topiramate, 79 glomerular filtration test results theophylline, 2 glomerular function ioxaglate, 517 glomerulosclerosis aristolochic acid, 530 glucose concentration human growth hormone, 479 nicotinic acid, 420 salmeterol, 192

glucose intolerance human growth hormone, 480 tacrolimus, 408 glucose tolerance digoxin, 198 glucose transporter type I (Glut 1) deficiency syndrome caffeine, 2 glutathione-S-transferase T1 null genotype ethylene oxide, 258 glycogenolysis inhibition beta-adrenoceptor agonists, 526 goiter lithium, 20 zafirlukast, 194 graft-vs.-host disease interferon alfa, 396 granulocytopenia clozapine, 60 lithium, 21–22 olanzapine, 62 granuloma formation octreotide, 480 granulomatosis of the lung infliximab, 401 granulomatous dermatitis acupuncture, 535 silicone, 544 granulomatous reaction silicone, 544 growth retardation deferiprone, 254 gum bleeding cranberry, 534 Selaginella doederleinii, 534 gynecomastia antiandrogens, 450 risperidone, 65 hair cells tobramycin, 273 hair loss see alopecia hallucinations (auditory) cefepime, 265 valaciclovir, 330 hallucinations (unspecified) amfebutamone, 16 anticholinergic drugs, 164 baclofen, 153 cefepime, 265 celecoxib, 123 cisplatin, 502 dextromethorphan, 90, 91 disulfiram, 542 dopamine receptor agonists, 162 entacapone, 163 fentanyl, 93 levetiracetam, 76 mefloquine, 318 rofecoxib, 123 topiramate, 79 valaciclovir, 330

596 voriconazole, 309 zaleplon, 49 hallucinations (visual) cefepime, 265 disulfiram, 542 valaciclovir, 330 headache all-trans retinoic acid, 417, 418 amphetamine, 30 amprenavir, 332 anthrax vaccine, 355 anticholinergic drugs, 164 Artemisia derivatives, 320 articaine, 144 azithromycin + rifabutin, 285 barnidipine, 225 benzocaine, 145 bromocriptine, 160 buspirone, 49 caspofungin, 311 ciclosporin, 404 cilostazol, 230 codeine, 89 colistin, 289 darbepoetin, 368 deferiprone, 253 desmopressin, 482 diethylcarbamazine, 345 diethylcarbamazine + ivermectin, 346 dihydrocodeine, 92 dipyridamole, 380 dobutamine, 159 Dy-EOB-DTPA, 519 Echinacea, 531 epoetin, 368, 369 famciclovir, 329–330 fentanyl, 94 fluvastatin, 488 gadobenate dimeglumine, 520 gadodiamide, 520 gadolinium, 520 gonadorelin, 477 heroin, 91 human growth hormone, 479 iloprost, 430 interferon alfa, 397 intravenous immunoglobulin, 364, 365 iodinated water-soluble contrast agents, 513 latanoprost, 430 levamisole, 348 levetiracetam, 75 levofloxacin, 278 linezolid, 289 lithium, 25 manganese, 248 melarsoprol, 323 mesalazine, 387, 388 methoxamine, 157 methylphenidate, 5 metoclopramide, 383 milrinone, 201

Index of adverse effects misoprostol, 431 naltrexone, 105 Norplant, 444 omeprazole, 386 oxaliplatin, 501 oxcarbazepine, 76 parathyroid hormone, 481 praziquantel, 349, 350 primaquine, 319 progestogens, 448 propafenone, 214 proton pump inhibitors, 384, 385 rabeprazole, 386 repaglinide, 469 rosiglitazone, 471 sildenafil, 231 Sono Vue, 523 sulfasalazine, 387 tacrolimus, 408 thyroid stimulating hormone, 481–482 topiramate, 78 zolpidem, 50 zonisamide, 84 headache, positional spinal manipulation, 536 hearing disturbance streptomycin, prenatal, 273 hearing disturbances deferiprone, 254 iohexol, 515 hearing loss aminoglycosides, 271 azithromycin, 285 deferiprone, 254 gentamicin, 271 heroin, 41 human growth hormone, 479 streptomycin, 273 heart see also entries at cardi–; coronary– heart beat see cardiac dysrhythmias; tachycardia; specific conditions, such as sinus node dysfunction heart block cardiac glycosides, 198 moricizine, 213 heart failure all-trans retinoic acid, 417 cibenzoline, 207 doxorubicin, 503 intravenous immunoglobulin, 365 rosiglitazone, 471 trastuzumab, 403 heart failure, congestive doxorubicin, 503 infliximab, 400 itraconazole, 307 heart rate increase

cannabis, xxxvi cannibinoids, 36 deferiprone, 254 heat, sensation of gadolinium, 520 heat intolerance topiramate, 80 heat stroke zonisamide, 84 hematuria cranberry, 534 felbamate, 73 hemianopia hepatitis B vaccine, 358 hemidiaphragm paralysis brachial plexus anesthesia, 140 hemiparesis gonadorelin receptor antagonists, 478 infiltration anesthesia, 143 leuprorelin, 478 sildenafil, 231 hemodialysis vancomycin, 283 hemodilution pioglitazone, 471 rosiglitazone, 471 hemoglobin concentration pioglitazone, 471 hemolysis primaquine, 318 quinine, 318 rasburicase, 545 hemolytic uremic syndrome quinine, 318 hemopoietic suppression co-trimoxazole, 292 hemorrhage antithrombin III, 363 bromocriptine, 160 clopidogrel, 124 cocaine, 41 GM-CSF, 398 milrinone, 202 paramethoxyamphetamine (PMA), 36 sildenafil, 231 hemostasis hydroxyethyl starch, 375 hepat– see also entries at liver– hepatic insufficiency lamotrigine, 74 hepatic veno-occlusive disease, 402 gemtuzumab ozogamicin, 402 hepatitis acarbose, 467 acupuncture, 535 buprenorphine, 104 cetirizine, 183 ciprofloxacin, 276 clozapine, 60 dapsone, 340

597

Index of adverse effects ecstasy, 35 fluvastatin, 487–488 gatifloxacin, 277 gliclazide, 470 kava, 533 MDMA, 35 minocycline, 268 olanzapine, 63 propofol, 136 propylthiouracil, 458 Shou wu Pian, 534 spironolactone, 240 zafirlukast, 194 hepatitis, fulminant rabeprazole + terbinafine, 386 terbinafine, 310 hepatitis B, fulminant rituximab, 403 hepatitis C infection intravenous immunoglobulin, 366 hepatocellular injury pioglitazone, 471 propofol, 136 hepatomegaly ecstasy, 35 hepatosplenomegaly dapsone, 340 hepatotixicity dapsone, 340 insulin, 462 kava, 533 propylthiouracil, 458 hepatotoxicity alcohol + paracetamol, 114 amphotericin B liposomal, 303 antituberculous agents, 339–340 benzylpenicillin, 262 cisplatin, 502 colestipol, 488 fosfomycin, 293 imipenem/cilastatin, 262 isoniazid, 340 levofloxacin, 278 MDMA, 35 nefazodone, 16 nimesulide, 125 paracetamol + rifampicin, 115 pemoline, 7 penicillin, 262 piperacillin, 262 pyrimethamine + azithromycin, 322 risperidone, 65 sevoflurane, 133 tacrine, 8 tolcapone, 163 troglitazone, 472 trovafloxacin, 276 zafirlukast, 193 herpes simplex dendritic keratitis latanoprost, 526

herpes simplex retinitis methotrexate, 407 hiccups anabolic steroids, 450 corticosteroids, 450 progesterone, 450 hirsutism valproate sodium, 81 histiocytes MDMA, 35 histological damage lidocaine, 143 histoplasmosis infliximab, 402 hoarseness arsenic, 244 inhaled corticosteroids, 187 homicidal ideation interferon alfa, 394 homocysteine concentration antiepileptic drugs, 72 atorvastatin, 486 co-trimoxazole, 321 fenofibrate, 486 Horner’s syndrome brachial plexus anesthesia, 140 interscalene catheterization, 140 hostility gabapentin, 73 levetiracetam, 75 hot flushes gonadotrophin-releasing hormone, 477 polyestradiol phosphate, 450 hydropic degeneration cisplatin, 499 21 β-hydroxylase antibodies interferon alfa, 394 hydroxyurea docetaxel, 504 hyperandrogenism valproate sodium, 81 hyperbilirubinemia amphotericin B liposomal, 303 indinavir, 333 itraconazole, 307 quinupristin/dalfopristin, 290 hypercalolcemia all-trans retinoic acid, 417 calcitriol, 422 lithium, 19, 21 parathyroid hormone, 481 vitamin A, 416 vitamin D, 421 hypercapnia intravenous immunoglobulin, 365 zolpidem, 51 hypercholesterolemia all-trans retinoic acid, 417 hyperesthesia articaine, 144 hyperglycemia

abacavir, 330 clozapine, 59 indinavir, 333 insulin, 461 olanzapine, 62 oxcarbazepine, 76 paclitaxel + estramustine + carboplatin, 503 pentamidine, 323 somatostatin, 480 hyperinsulinemia co-trimoxazole, 321 valproate sodium, 81 hyperkalemia amiloride, 240 beta-adrenoceptor antagonists, 223–224 citric acid, 541 co-trimoxazole, 291, 321 depolarizing neuromuscular blocking agents, 151–152 diclofenac, 115 ecstasy, 32 trimethoprim, 291 hyperkalemic cardiac arrest depolarizing neuromuscular blocking agents, 151, 152 hyperkeratotic follicular papules lithium, 22–23 hyperkinesia haloperidol, 53 levamisole, 347 risperidone, 53 hyperlactatemia lorazepam, 48 hyperlipidemia ciclosporin, 404 tacrolimus, 408 vitamin D, 421 hypernatremia lithium, 21, 22 olanzapine, 62 hyperostosis alprostadil, 430 hyperparathyroidism fluoride, 545 lithium, 21 hyperphosphatemia paclitaxel + estramustine + carboplatin, 503 hyperpigmentation aluminium, 243 buserelin, 478 diltiazem, 225 docetaxel, 504 EMLA cream, 144 hyperplastic polyp omeprazole, 385 hyperprolactinemia antipsychotic drugs, 56 risperidone, 65 hyperpyrexia ecstasy, 32

598 hypersalivation clozapine, 60 irinotecan + oxaliplatin, 502 olanzapine, 61 risperidone, 65 hypersensitivity lung disease co-trimoxazole, 291 hypersensitivity pneumonitis with eosinophilia pravastatin, 488 hypersensitivity reaction abacavir, 330 allopurinol, 125–126 azithromycin, 285 cisplatin, 501 clopidogrel, 380 co-trimoxazole, 292 denileukin diftitox, 398 gabapentin, 74 infliximab, 401 insulin, 462–463 interferon alfa, 396 iohexol, 518 ioxaglate, 514 lidocaine, 147 local anesthetics, 172 olanzapine, 63 oxybenzone, 174 suramin, 351 thimerosal, 259 vitamin B6 , 420 hypersplenism G-CSF, 398 hypertension amphetamine, 30 amphetamines, 3 buspirone, 49 cannibinoids, 36 carboplatin, 501 ciclosporin, 404 clozapine, 59 cocaine, 39 diltiazem, 225 entacapone, 163 epoetin, 368 erythropoietin, 368, 369 hemoglobin-based oxygen carriers, 363 indinavir, 332 intravenous immunoglobulin, 365 MDMA, 34 midodrine, 158 milrinone, 201 moricizine, 213 Norplant, 444 olanzapine, 62 pseudoephedrine, 156–157 remifentanil, 100 tacrolimus, 408 terlipressin, 483 testosterone, 449 thyrotropin-releasing hormone, 482

Index of adverse effects hypertension, intracranial mesalazine, 388 hypertension, pulmonary artery interferon alfa, 393 hypertensive crisis moxifloxacin, 279 hypertensive encephalopathy erythropoietin, 369 hyperthermia baclofen, 153 cocaine, 39 fenofibrate, 486 olanzapine, 62 paramethoxyamphetamine (PMA), 36 sevoflurane, 134 topiramate, 80 zonisamide, 84 hyperthyroidism amiodarone, 205–206 etanercept, 399 human growth hormone, 480 iodinated contrast agents, 515 lithium, 20 hypertrichosis measles vaccine, 359 hypertriglyceridemia all-trans retinoic acid, 417 tamoxifen, 446 hypertrophy of subcutaneous tissues insulin, 462 hyperventilation topiramate, 80 hypoactivity EMLA cream, 144 hypoalbuminemia caspofungin, 311 denileukin diftitox, 398 hypocalcemia cisplatin, 497 ecstasy, 32 hypocellularity Selaginella doederleinii, 534 hypogammaglobulinemia systemic glucocorticosteroids, 429 hypoglycemia Anso Comfort, 529 chlordiazepoxide, 529 cibenzoline, 207 co-trimoxazole, 321 diagnosis, 461 disopyramide, 208 glargine insulin, 464 gliclazide, 467, 470 glimepiride, 470 insulin, 463 pentamidine, 323 pioglitazone, 471 quinine, 318 repaglinide, 469 hypokalemia amphotericin B liposomal, 303

caffeine, 1 chloroquine, 316–317 cisplatin, 497 clenbuterol, 191 mifepristone, 449 milrinone, 201 hypokalemic paralysis lithium, 21 hypokinesis cocaine, 37 hypomagnesemia clenbuterol, 191 hypomobility, facial disulfiram, 542 hyponatremia antiepileptic drugs, 72–73 cisplatin, 497 co-trimoxazole, 291–292 desmopressin, 482 glucagon, 466 leuprorelin acetate, 478 oxcarbazepine, 76 SSRIs, 13 thiazide and loop diuretics, 239 hypophonia disulfiram, 542 hypophosphatemia cisplatin, 497 clenbuterol, 191 cocaine, 38 stavudine, 331 hypopigmented retinal spots vigabatrin, 82 hypoprothrombinemia macrolides, 284 miocamycin, 288 hyporeflexia cannibinoids, 37 hypotension adrenoceptor agonists, 525 all-trans retinoic acid, 417, 418 alprostadil, 430 amfebutamone, 15 amphotericin B liposomal, 303 cannabinoids, 36 cannabis, xxxvi cannibinoids, 36 carboplatin, 501 chloroquine, 316–317 citric acid, 541 clomipramine, 11 cocaine, 37 denileukin diftitox, 398 diltiazem, 226 dopamine receptor agonists, 159–160 ephedrine, 156 epidural anesthesia, 141 fentanyl, 93 fibrates, 486 heroin, 91 iloprost, 430 intravenous immunoglobulin, 365

599

Index of adverse effects iohexol, 518 ioxaglate, 513 iron dextran, 247 ivermectin, 346 licorice, 531 lidocaine, 146 melarsoprol, 323 midazolam, 136 milrinone, 202 nefazodone, 16 NSAIDs, 121–122 oxaliplatin, 501 parathyroid hormone, 481 pentamidine, 323 propafenone, 214 remifentanil, 100 risperidone, 65 sotalol, 224 sufentanil, 101 suramin, 351 thiazide and loop diuretics, 239 tricyclic antidepressants, 11 vitamin B2 , 420 hypotension, arterial all-trans retinoic acid, 417, 418 hypothalamic-pituitary-adrenal axis function inhaled corticosteroids, 188 hypothermia antipsychotic drugs, 58 bromazepam, 46 midazolam, 136 valproate sodium, 81–82 hypothyroidism amiodarone, 205, 206 iodinated contrast agents, 515 lithium, 19, 20 hypotonia adrenoceptor agonists, 525 diazepam, 47 hypoventilation fentanyl, 92 hypoxemia all-trans retinoic acid, 417 cocaine, 37 pranlukast, 193 hypoxia all-trans retinoic acid, 417 benzocaine, 145 zolpidem, 51 ichthyosiform eruption lovastatin, 487 idiopathic pneumonia syndrome busulfan, 503 idiopathic pulmonary fibrosis lithium, 20 ileus acarbose, 467 illusions zaleplon, 49 immune thrombocytopenic purpura

cranberry, 534 impotence carbamazepine, 70 finasteride, 450 gonadotrophin-releasing hormone, 477 risperidone, 64 indurated plaques aluminium, 243 induration acupuncture, 535 insulin, 463 leuprorelin acetate, 478 infarctions see cerebral infarction; myocardial infarction infection acupuncture, 535 articaine, 144 cannabis smoking, xlii talc, 544 voriconazole, 309 inferior defects dipyridamole, 380 infertility COX-2 inhibitors, 123 thyroid hormones, 457 inflammatory bowel disease celecoxib, 123 infusion-related reactions amphotericin B deoxycholate (DAMB), 302 amphotericin B lipid complex (ABLC), 302–303 amphotericin B liposomal, 303 voriconazole, 309 infusion site reactions deferiprone, 254 inhibitor formation clotting factors, 367 injection site reactions darbepoetin, 368 Dy-EOB-DTPA, 519 epoetin, 368 erythropoietin, 368 etanercept, 400 gadobenate dimeglumine, 520 ganirelix, 479 gentamicin, 272 human growth hormone, 480 influenza vaccine, 359 interferon alfa, 395 interferon beta, 397 octreotide, 480 omalizumab, 402–403 oxaliplatin, 501 palivizumab, 403 parathyroid hormone, 481 quinine, 318 Sono Vue, 523 triptorelin, 478 injury cannabis, xxxv rosiglitazone, 471

insomnia cisplatin, 496 efavirenz, 331 felbamate, 73 fentanyl, 94 fluoroquinolones, 274 levofloxacin, 278 linezolid, 289 mexazolam, 48 prednisone, 427 theophylline, 2–3 topiramate, 78 vigabatrin, 82 insulin dependent diabetes mellitus interferon alfa, 394 insulin release tacrolimus, 408 insulin resistance human growth hormone, 479 infused insulin, 465 medroxyprogesterone, 444 intention tremor cocaine, 38 interferon concentration lithium, 23 interleukin-2 concentration lithium, 23 interleukin-4 concentration lithium, 23 interleukin-10 concentration lithium, 23 interstitial fibrosis aristolochic acid, 530 interstitial nephritis aristolochic acid, 529, 530 mesalazine, 388 omeprazole, 386 ranitidine, 384 rifampicin, 341–342 interstitial pneumonia interferon alfa, 393 interstitial pneumonitis amiodarone, 204–205 pranlukast, 193 skullcap, 534 interstitial pulmonary disease mesalazine, 388 intestinal dilatation antipsychotic drugs, 58 intestinal discomfort lactulose, 387 intestinal pseudo-obstruction antipsychotic drugs, 58 intoxication digitalis, 198 lithium, 25 manganese, 248 tramadol, 103 vitamin D, 421 intracellular inclusions amiodarone, 205 intracranial aneurysm spinal manipulation, 536

600 intracranial hemorrhage bromocriptine, 160 sildenafil, 231 intracranial hypertension human growth hormone, 479 praziquantel, 349 intracranial pressure all-trans retinoic acid, 418 androgenic anabolic steroids, 450 depolarizing neuromuscular blocking agents, 151 intramural hematoma of the ascending aorta cocaine, 37 intraocular inflammation fomivirsen, 328 intravascular papillary endothelial hyperplasia interferon beta, 397 intussusception rotavirus vaccine, 360 invasive pulmonary aspergillosis infliximab, 402 iris pigmentation changes bimatoprost, 526 latanoprost, 526 misoprostol, 432 travoprost, 526 irritability efavirenz, 331 fentanyl, 94 levetiracetam, 75 palivizumab, 403 piracetam, 8 prednisone, 427 topiramate, 79, 80 valproate sodium, 82 vigabatrin, 82 irritation BufferGel, 541 gold, 246 ischemia sildenafil, 231 ischemic colitis alosetron, 383 meloxicam, 116 pseudoephedrine, 157 ischemic necrosis cocaine, 37–38, 38 ergot alkaloids, 163 ischemic nephropathy cocaine, 39 islet cell-specific autoantibodies interferon alfa, 394 isolated lung masses amiodarone, 205 itching all-trans retinoic acid, 418 Artemisia derivatives, 319 buserelin, 478 calcitonin, 477 flecainide, 213

Index of adverse effects ganirelix, 479 henna tattooing, 544 lidocaine, 147 nickel, 248 nicotinic acid, 420 propylthiouracil, 458 quinupristin/dalfopristin, 290 somatostatin, 481 itchy eyes aminoglycosides, 273 jaundice, 377 acarbose, 467 buprenorphine, 104 celecoxib, 124 ecstasy, 32 fosinopril, 236 hemoglobin-based oxygen carriers, 363 kava, 533, 534 MDMA, 35 metformin, 468 propylthiouracil, 458 joint disease rubella vaccine, 360 joint pain all-trans retinoic acid, 418 deferiprone, 253 hormone replacement therapy, 436 interleukin-11, oprelvekin, 398 keloid-like skin lesions leech therapy, 535 keratopathy amiodarone, 205 gold, 246 keratotic erythema cyanamide, 541 ketosis acetazolamide, 238 kidney see also entries at nephro-; renalkidney stones felbamate, 73 kwashiorkor unconventional diets, 536 lactic acidemia ribavirin, 329 lactic acidosis acetazolamide, 238 NRTIs, 330 vancomycin, 282 language difficulty sildenafil, 231 laryngospasm gadobenate dimeglumine, 520 laryngotracheitis triphenylmethane dyes, 259 leaning olanzapine, 61

learning disabilities antiepileptic drugs, 71–72 prenatal cocaine exposure, 41 left bundle branch block cibenzoline, 207 moxifloxacin, 279 lesions, skin aluminium, 243 fentanyl, 94 infiltration anesthesia, 143 lethargy alprostadil, 430 benzocaine, 145 clozapine, 60 codeine, 90 diltiazem, 226 EMLA cream, 144 gliclazide, 470 infiltration anesthesia, 143 interferon alfa, 397 risperidone, 65 Sono Vue, 523 suramin, 350 valproate sodium, 82 vitamin A, 416 leukemia carboplatin, 502 cisplatin, 502 platinum compounds, 502 leukocytoclastic vasculitis insulin, 463 leukocytosis all-trans retinoic acid, 417, 418 alprostadil, 430 clozapine, 60 cocaine, 38 leukoderma para-phenylenediamine, 173 leukoencephalitis hepatitis B vaccine, 358 leukopenia alatrofloxacin, 276 arsenic, 244 intravenous immunoglobulin, 365 mesalazine, 388 methotrexate, 407 mycophenolate, 235 olanzapine, 62 oxcarbazepine, 76 suramin, 351 teicoplanin, 282 libido, reduced carbamazepine, 70 diuretics, 238 finasteride, 450 gonadotrophin-releasing hormone, 477 lichen planus amlodipine, 225 lichenoid dermatitis acupuncture, 535 diltiazem, 225 silicone, 544

601

Index of adverse effects lichenoid eruptions ursodeoxycholic acid, 389 lichenoid lesions hepatitis B vaccine, 358 lichenoid purpura diltiazem, 225 lightheadedness buspirone, 49 dextromethorphan, 90 fentanyl, 92 strychnine, 6 zaleplon, 49 limp olanzapine, 61 linear IgA bullous disease lovastatin, 487 vancomycin, 282 lipid changes hormone replacement therapy, 438 isotretinoin, 176 lipoatrophy human growth hormone, 480 lipodystrophy syndrome protease inhibitors, 332 stavudine, 331 lipogranuloma formation iohexol, 518 listeriosis infliximab, 402 liver see also entries at hepat– liver, occlusive disease GM-CSF, 398 liver adenomatosis oral contraceptives, 443 liver atrophy ecstasy, 35 liver dysfunction dapsone, 340 manganese, 248 quinine, 318 roxithromycin, 288 liver enzyme activities acarbose, 467 all-trans retinoic acid, 417 antituberculosis protocol, 340 azithromycin, 285 caspofungin, 311 cat’s claw, 534 celecoxib, 124 ciprofloxacin, 276 gemcitabine + paclitaxel, 503–504 gemifloxacin, 277–278 ioxaglate, 513 isotretinoin, 176 kava, 533 moricizine, 213 pefloxacin, 281 tacrolimus, 408 valproate sodium, 80–81 voriconazole, 309 liver failure

ecstasy, 32 kava, 533 ketoconazole, 303 paracetamol + rifampicin, 115 roxithromycin, 288 terbinafine, 309–310 liver focal nodular hyperplasia itraconazole, 307 liver function itraconazole, 307 moxifloxacin, 279 liver injury fosinopril, 235–236 liver iron content penicillamine, 255–256 liver necrosis buprenorphine, 104 nitrofurantoin, 288 propylthiouracil, 458 lower limb weakness colistin, 289 lung masses amiodarone, 205 lupus-like syndrome chemically modified tetracyclines, 268–269 etanercept, 400 minocycline, 266, 268 procainamide, 213 terbinafine, 310 ticlopidine, 380 zonisamide, 84 lupus vulgaris BCG vaccine, 355 lymphadenopathy carbamazepine, 71 lymphopenia suramin, 350 lymphoproliferative disorders antiepileptic drugs, 73 macrophage activation syndrome etanercept, 399–400 maculopapular rash codeine, 90 efavirenz, 331 ioxaglate, 513–514 phenytoin + fosphenytoin, 76 primethamine, 290 maculopathy chloroquine, 316 malaise Echinacea, 531 ecstasy, 35 heroin, 91 insulin, 461 kava, 533 lithium, 25 NRTIs, 330 suramin, 350 malignancy albendazole therapy, 345 methotrexate, 407

malignant hyperthermia sevoflurane, 134 mammary hyperplasia, benign ciclosporin, 406 mania olanzapine, 62 Red Bull, 1 risperidone, 64 tramadol + fluoxetine, 104 maxillary sinusitis nafarelin, 477 medullary injury infiltration anesthesia, 143 medullary nephrocalcinosis thiazide and loop diuretics, 239 melanoma fertility treatment, 434 phototherapy, 175 melatonin concentration nervous system, 12–13 memory impairment cannabis, xxxv disulfiram, 542 ecstasy, 32–33 human growth hormone, 479 methadone, 96 morphine, 97 spinal manipulation, 536 meningism praziquantel, 349 meningitis co-trimoxazole, 321 menopause-like problems tamoxifen, 446 menstrual disturbances levonorgestrel, 448 morphine, 97 valproate sodium, 81 mental status alteration gabapentin, 74 metabolic acidosis co-trimoxazole, 321 diclofenac, 115 lorazepam, 48 propofol, 135–136 topiramate, 80 metallic taste levamisole, 347 metronidazole, 323 MS-325, 521 propafenone, 214 methemoglobin concentration benzocaine, 144–145 dapsone, 340 EMLA cream, 144 flutamide, 450 lidocaine, 146 primaquine, 319 MI see myocardial infarction microalbuminuria hormone replacement therapy, 440 microangiopathic hemolytic anemia

602 quinine, 318 microvesicular steatosis buprenorphine, 104 migraine latanoprost, 526 miscarriage NSAIDs, 112 mitochondrial dysfunction NRTIs, 330 mitochondrial myopathy propofol, 136 mitral regurgitation fenfluramine, 6 mood changes progestogens, 448 motor degeneration unconventional diets, 536 motor peripheral neuropathy tetraplatin, 493 mouth, burning clonazepam, 47 movement disorders dextromethorphan, 91 mucosal toxicity amiodarone, 206 mucosal ulceration triphenylmethane dyes, 259 mucositis levamisole, 348 methotrexate, 407 mucous membrane irritation hypochlorite, 259 muscle pain all-trans retinoic acid, 418 muscle rigidity baclofen, 153 remifentanil, 100 muscle spasm lithium, 25 oxaliplatin, 495 muscular hypotonia diazepam, 47 musculoskeletal pain iodinated water-soluble contrast agents, 513 vitamin D, 421 mutagenicity nitroglycerin, 224 mutism alprazolam, 46 bromazepam, 46 myalgia ciclosporin, 404 diethylcarbamazine, 345 Echinacea, 531 interferon alfa, 397 intravenous immunoglobulin, 364 norfloxacin, 280 quinupristin/dalfopristin, 290 myasthenia cocaine, 40 myasthenia gravis interferon alfa, 394

Index of adverse effects penicillamine, 255 mydriasis tropicamide, 147 myelopathy nitrous oxide, 134 spinal manipulation, 536 myelosuppression anorexia, 493 azathioprine, 404 cisplatin, 502 clarithromycin + rifabutin, 341 oxaliplatin, 498 ZD0473, 493 myelotoxicity carboplatin, 491–492 myocardial damage ecstasy, 32 myocardial infarction see also cardiac arrest amphetamine, 30 atropine, 165 cannibinoids, 36 cocaine, 37 COX-2 inhibitors, 117–118 desmopressin, 482 dipyridamole, 380 doxorubicin, 503 Ephedra, 156 erythropoietin, 369 hormone replacement therapy, 438 intravenous immunoglobulin, 365 methadone, 95 nitroglycerin, 224 recombinant factor VIIa, 366 thyroxine, 457 myocarditis antipsychotic drugs, 54 clozapine, 59 myoclonic jerks aluminium, 243 myoclonic-like movements midazolam, 136 myoclonic seizures nicardipine, 228 myoclonus amantadine, 162 entacapone, 163 gatifloxacin, 277 morphine, 98 myoglobinuria ecstasy, 32 lamotrigine, 74 myopathy caffeine, 1 myopericarditis Td-IPV vaccine, 357 myopia topiramate, 79 myosis brachial plexus anesthesia, 140 myotoxicity erythromycin + statins, 287

nail changes docetaxel, 504 gold, 246 nasal congestion naltrexone, 105 sildenafil, 231 nasal symptoms desmopressin, 482 menthol, 543 nausea albumin, 363 alfentanil, 89 all-trans retinoic acid, 417 amphetamine, 30 amprenavir, 332 Artemisia derivatives, 320 atovaquone, 320 BBR3464, 492 buspirone, 49 cannibinoids, 37 carboplatin, 498 cidofovir, 328 cisplatin, 498 clarithromycin, 286 cocaine, 37 deferiprone, 253 desmopressin, 482 dextromethorphan, 90 diltiazem, 226 dobutamine, 159 dopamine receptor agonists, 162 Dy-EOB-DTPA, 519 ecstasy, 35 epoetin, 369 fentanyl, 92, 93, 94 fibrates, 486 fluorescin, 542 gadobenate dimeglumine, 520 gadodiamide, 520 gadolinium, 520 gemeprost + mifepristone, 430 gonadorelin, 477 heroin, 91 hydromorphone, 94 iloprost, 430 intravenous immunoglobulin, 364, 365 iopamidol, 513 ioxaglate, 513 iron dextran, 247 itraconazole, 306, 307 josamycin, 287 lactulose, 387 levamisole, 347, 348 levofloxacin, 278 linezolid, 289 liposome-encapsulated iodixanol, 519 lithium, 20, 25 lopinavir/ritonavir, 333 metformin, 468 metronidazole, 323 mexazolam, 48 mifepristone, 448

603

Index of adverse effects misoprostol, 431 morphine, 97 moxifloxacin, 279 MS-325, 521 naltrexone, 105 nefopam, 106 nicotinic acid, 420 NRTIs, 330 olanzapine, 61 oseltamivir, 334 oxaliplatin, 498 oxcarbazepine, 76 parathyroid hormone, 481 praziquantel, 350 primaquine, 319 propafenone, 214 propofol, 136 proton pump inhibitors, 384 quinine, 318 rabeprazole, 386 remifentanil, 100, 101 Ringer’s solution, 516 risperidone, 64 salmeterol, 192 sartraplatin, 493 sodium diatrizoate, 516 sufentanil, 101 telithromycin, 283 thiabendazole, 344, 345 thyroid stimulating hormone, 481–482 thyrotropin-releasing hormone, 482 topiramate, 78 tramadol, 103 vitamin B2 , 420 water-soluble iodinated contrast agents, 512 ZD0473, 493 zonisamide, 84 neck pain spinal manipulation, 536 necrosis cisplatin, 499 cocaine, 37, 38 ecstasy, 35 necrosis of kidney cells cisplatin, 499 needle pain acupuncture, 535 neonatal goiter zafirlukast, 194 nephr– see also entries at kidney–; renal– nephritic syndrome dapsone, 340 nephrocalcinosis gentamicin, 272 nephrolithiasis indinavir, 333 sulfadiazine, 323 triamterene, 240 nephrotic syndrome

bucillamine, 254 lithium, 22 nephrotoxicity adefovir, 335 amikacin, 271 aminoglycosides, 271 amphotericin B deoxycholate (DAMB), 302 ciclosporin, 405 cidofovir, 328 cisplatin, 499, 502 colistin, 289 contrast agent, 518 gadolinium, 521 gentamicin, 272 glycopeptides, 281–282 isepamicin, 272 itraconazole, 307 lithium, 22 nedaplatin, 492 paromomycin, 273 sevoflurane, 133 vancomycin, 283 voriconazole, 309 nervousness felbamate, 73 palivizumab, 403 sildenafil, 231 neural tube defects triamterene, 240 neuroglycopenic symptoms insulin, 461, 462 neuroleptic malignant syndrome antipsychotic drugs, 55 baclofen, 153 chlorpromazine, 53 olanzapine, 62 SSRIs, 11–12 neurological disturbances dapsone, 340 iron dextran, 247 praziquantel, 349 propafenone, 214 neuromuscular blockade chlorprocaine, 145 neuropathy interleukin-11, oprelvekin, 398 oxaliplatin, 495 neurosarcoidosis interferon beta, 397 neurosensory symptoms oxaliplatin, 495, 501 neurotoxicity aluminium, 243 amphetamines, 3–4 arsenic, 244 cisplatin, 494 lithium, 24 methamphetamines, 3–4 oxaliplatin, 495, 496 ropivacaine, 148 neutropenia albendazole, 345

arsenic, 244 azithromycin, 285 azithromycin + rifabutin, 285 BBR3464, 492 chlorpromazine, 53 cidofovir, 328 co-trimoxazole, 321 cyclophosphamide, 348 enalapril, 235 interferon alfa, 393, 395 intravenous immunoglobulin, 365 linezolid, 289 olanzapine, 62 oxaliplatin, 498 paclitaxel + cisplatin, 502 rifabutin, 341 ZD0473, 493 neutropenic sepsis suramin, 351 neutrophil count deferiprone, 253 neutrophilic dermatoses G-CSF, 399 nevus ganirelix + follicle stimulating hormone, 479 night sweats fentanyl, 94 nightmares cefepime, 265 nocturia vitamin A, 416 non-Hodgkin’s lymphoma cyclophosphamide, 406 trichloroethylene, 134 non-pruritic papules acupuncture, 535 non-sustained ventricular tachycardia moricizine, 213 numbness cocaine, 37 nystagmus cocaine, 38 obesity clozapine, 59 valproate sodium, 81 obsessive-compulsive symptoms methylphenidate, 5 obtundation amphetamine, 30 olanzapine, 62 ocular dysmetria cocaine, 38 ocular effects travoprost, 526 ocular pain topiramate, 79 ocular pigmentation antipsychotic drugs, 55 ocular pruritus adrenoceptor agonists, 525

604 bimatoprost, 430, 526 travoprost, 526 ocular syndrome topiramate, 79 odynophagia inhaled corticosteroids, 188 Ogilvie’s syndrome antipsychotic drugs, 58 OHSS see ovarian hyperstimulation syndrome oligohidrosis zonisamide, 84 oligohydramnios losartan, 236 oligospermia cyclophosphamide, 406, 504 oliguria amlodipine, 225 diltiazem, 225, 226 milrinone, 202 propofol, 136 onycholysis gold, 246 ophthalmic changes mexiletine, 213 opiate testing fluoroquinolones, 275 opisthotonos strychnine, 6 opportunistic infections ciclosporin, 404 systemic glucocorticosteroids, 429 opposition vigabatrin, 82 optic atrophy vigabatrin, 82 optic neuritis cisplatin, 497 etanercept, 399 hepatitis A and B vaccines, 358 Td-IPV vaccine, 358 optic neuropathy deferiprone, 254 sildenafil, 231 oral candidiasis inhaled corticosteroids, 190 oral pemphigus interferon alfa, 395 oral petechiae cranberry, 534 orthostatic hypertension entacapone, 163 orthostatic hypotension clozapine, 61 ephedrine, 156 osteoarticular tuberculosis etanercept, 400 osteocartilaginous erosion cocaine, 38 osteomyelitis cocaine, 38 osteonecrosis

Index of adverse effects all-trans retinoic acid, 418 systemic glucocorticosteroids, 429 osteopenia G-CSF, 399 osteoporosis gonadotropin agonist therapy, 478 systemic glucocorticosteroids, 428 otorrhea spinal manipulation, 536 ototoxicity amikacin, 271 azithromycin, 285 cisplatin, 496 isepamicin, 272 lopinavir/ritonavir, 333 nedaplatin, 492 paromomycin, 273 pyrimethamine + azithromycin, 322 tobramycin, 273 ovarian cysts tamoxifen, 446 ovarian enlargement leuprorelin acetate, 478 ovarian hyperstimulation syndrome gonadotrophins, 477–478 hydroxyethyl starch, 375–376 ovarian stimulation gonadotrophins, 434 oversleeping lithium, 20 ovulation induction thromboembolic disease, 478 oxygen requirements DTP-Hib vaccines, 356 P50 auditory evoked response cocaine, 39 pain cocaine, 37 fenofibrate, 486 ganirelix, 479 iodinated water-soluble contrast agents, 513 simvastatin + clarithromycin, 488 pain scores remifentanil, 100 pallor EMLA cream, 144 palpitation cilostazol, 230 dobutamine, 159 nicardipine, 227 salmeterol, 192 palsy of the long thoracic nerve spinal manipulation, 536 pancerebellar dysfunction cocaine, 38–39 pancreatitis

all-trans retinoic acid, 418 amphotericin B liposomal, 303 antimony, 244 captopril, 234 glibenclamide, 470 isoniazid, 341 levofloxacin, 279 olanzapine, 63 pentamidine, 323 propofol, 136 pancytopenia fenofibrate, 486 hepatitis B vaccine, 358 methotrexate, 407 olanzapine, 63 Selaginella doederleinii, 534 thionamide drugs, 458 panic cannabis, xxxiv topiramate, 79 panlobular liver necrosis buprenorphine, 104 panniculitis interferon beta, 397 papilledema all-trans retinoic acid, 417 cisplatin, 497 human growth hormone, 479 paralysis brachial plexus anesthesia, 136 lithium, 21 paralysis, diaphragmatic spinal manipulation, 536 paranoia disulfiram, 542 mefloquine, 318 parathyroid hormone concentration lithium, 21 parathyroid tumors lithium, 21 paresthesia articaine, 144 colistin, 289 Dy-EOB-DTPA, 519 etanercept, 399 levamisole, 347 oxaliplatin, 495 propafenone, 214 topiramate, 78 Parkinson’s disease risperidone, 15 Parkinsonian symptoms cisplatin, 496 diltiazem, 225 disulfiram, 542 haloperidol, 64 kava, 533 risperidone, 64 risperidone + paroxetine, 65 paronychia indinavir, 333 paroxysmal atrial fibrillation cannibinoids, 37

605

Index of adverse effects paroxysmal atrial tachycardia digoxin, 198 parvovirus-induced red cell aplasia rituximab, 403 pathogen transmission albumin, 363 peak expiratory flow rate rapacuronium, 150 peak inflating pressure rapacuronium, 150 peak inspiratory flow rate rapacuronium, 150 pedal edema interleukin-11, oprelvekin, 398 pemphigoid spironolactone, 240 pemphigus ketoprofen, 172 phenolic compounds, 260 pemphigus foliaceus thiazide and loop diuretics, 239 pemphigus vulgaris enalapril, 235 perceptual changes MDMA, 34 pericardial effusions all-trans retinoic acid, 418 pericarditis mesalazine, 388 perineal sensation dibucaine, 143 periobital dermatitis dorzolamide, 239 periocular skin color change latanoprost, 431, 526 perioral dermatitis inhaled corticosteroids, 187 menthol, 543 perioral edema isosulfan blue, 543 perioral paresthesia cisplatin, 497 peripheral edema proton pump inhibitors, 385 peripheral eosinophilia pranlukast, 193 peripheral motor and sensory degeneration unconventional diets, 536 peripheral neuropathy antituberculous agents, 339 dapsone, 340 metronidazole, 323 platinum compounds, 499, 502 peripheral paresthesia cisplatin, 497 periportal hepatic edema MDMA, 35 peritonitis iron dextran, 247 pernicious anemia interferon alfa, 395 personality changes

cisplatin, 497 petechiae interleukin-11, oprelvekin, 398 pharyngitis rabeprazole, 386 phlebitis bryostatin I, 409 caspofungin, 311 clarithromycin, 286 vancomycin, 283 photoallergic dermatitis ketoprofen, 172 NSAIDs, 174 photomutagenicity bergamot, 530 photophobia gold, 246 intravenous immunoglobulin, 365 latanoprost, 431 photosensitivity aceclofenac, 115 chloroquine, 316 dapsone, 340 efavirenz, 331 oral contraceptives, 174 tretinoin + prochlorperazine + fluorouracil, 419 vitamin B6 , 420 phototoxicity bergamot, 530 fluoroquinolones, 340–341 ketoprofen, 172 levofloxacin, 279 lincomycin, 284 oxybenzone, 174 pefloxacin, 281 phrenic nerve blockade brachial plexus anesthesia, 136 phrenic nerve injury spinal manipulation, 536 pigmentary retinopathy mexiletine, 213 piloerection methoxamine, 157 midodrine, 158 pituitary apoplexy gonadorelin, 477 placental transfer somatostatin, 481 platelet count vancomycin, 282 pleural effusion all-trans retinoic acid, 417, 418 pleuropulmonary disease pergolide, 160 pneumatosis intestinalis lactulose, 387 pneumocystosis infliximab, 402 pneumomediastinum cocaine, 38 MDMA, 32 pneumonia

ecstasy, 32 hypochlorite, 259 methyl-prednisolone sodium succinate, 427 nitrofurantoin, 288 sildenafil, 231 pneumonia, aspiration ecstasy, 32 pneumonitis disopyramide, 208 gold, 246 itraconazole, 307 pneumoperitoneum lactulose, 387 pneumothorax acupuncture, 535 cocaine, 38 pocket infections central venous catheters, 545 polyangiitis propylthiouracil, 459 polyarteritis nodosa hepatitis B vaccine, 358 polyarthralgia acupuncture, 535 rifabutin, 341 polycystic ovary syndrome valproate sodium, 81 polycythemia isotretinoin, 176 polydipsia vitamin D, 422 polymorphic ventricular tachycardia dofetilide, 210, 211 polyneuropathy, Guillain–Barré type nitrous oxide, 134 suramin, 350 polyradiculoneuropathy hepatitis B vaccine, 358 polyuria vitamin D, 422 polyuria-polydipsia syndrome lithium, 19 poor handling DTP-Hib vaccines, 356 porcine factor VIII:C safety, 367 positional headache spinal manipulation, 536 postoperative myocardial ischemia nitrous oxide, 134 postoperative vomiting general anesthetics, 131–132 postural hypotension cannabis, xxxvi dopamine receptor agonists, 159–160 potassium concentration propofol, 136 salmeterol, 192 premature birth

606 ciclosporin, 406 cocaine, 40 prerenal azotemia lithium, 22 priapism cocaine, 40 olanzapine, 63 risperidone, 65 prickly erythema, diffuse oral contraceptives, 174 prolactin concentration antipsychotic drugs, 56 SSRIs, 13 proliferative endometrium tamoxifen + toremifene, 504 prolonged QT interval see QT interval prolongation prolonged reaction times ecstasy, 33 proprioception levodopa and dopamine receptor agonists, 160 prosthetic valves, inflammatory reactions silver, 249 prostration alprazolam, 46 proteinuria cidofovir, 328 colistin, 289 penicillamine, 256 pruritic erythematous dermatitis benzocaine, 145 pruritus all-trans retinoic acid, 417 anthrax vaccine, 355 antiviral drugs, 168 carboplatin, 501 celecoxib, 124 chloroquine, 315, 316 cisplatin, 501 co-trimoxazole, 321 dapsone, 340 fentanyl, 93 fosinopril, 236 hydromorphone, 94 hydroxyethyl starch, 374 inhaled corticosteroids, 188 intravenous immunoglobulin, 366 iron dextran, 247 ivermectin, 346 ketoprofen, 172 leech therapy, 535 local anesthetics, 172 5-methoxypsoralen, 173 midodrine, 158 Mirena, 447 morphine, 97 MS-325, 521 nasal insulin, 465 nelfinavir, 333 olanzapine, 63

Index of adverse effects oxaliplatin, 501 procaine, 147 propylthiouracil, 458 remifentanil, 101 sufentanil, 101, 102 tacrolimus, 408 “pseudo-myocardial infarct pattern” lithium, 19 pseudolymphomatous inflammatory infiltrates leech therapy, 535 pseudomembranous colitis clarithromycin + metronidazole + omeprazole, 387 pristinamycin, 289–290 pseudopheochromocytoma clozapine, 59 pseudoporphyria causes, 175 pseudotumor cerebri all-trans retinoic acid, 417 psychiatric effects dapsone, 340 psychological symptoms hormone replacement therapy, 436 psychomotor effects lorazepam, 48 psychomotor retardation digoxin, 198 psychomotor skills cannabis, xxxiv–xxxv psychomotor slowing topiramate, 78–79, 79 psychomotor speed temazepam, 48 psychosis cannabis, xxxvii dapsone, 340 ecstasy, 34 fluoroquinolones, 274 isotretinoin, 175 methamphetamine, 30 St. John’s wort, 532 psychotic delirium St. John’s wort, 532 psychotic reactions melarsoprol, 323 ptosis brachial plexus anesthesia, 140 ptosis, bilateral cocaine, 40 pulmonary alveolar proteinosis isotretinoin, 175 pulmonary artery hypertension interferon alfa, 393 pulmonary complications walnut oil, 545 pulmonary edema diltiazem, 225 ecstasy, 32 gadobenate dimeglumine, 520 hypochlorite, 259

iloprost, 230 thiazide and loop diuretics, 239 pulmonary embolism tamoxifen, 446 pulmonary fibrosis nitrofurantoin, 288 pulmonary function brachial plexus anesthesia, 140 pulmonary function, reductions in brachial plexus anesthesia, 140 pulmonary infarction cocaine, 37, 38 pulmonary infiltration all-trans retinoic acid, 417, 418 amiodarone, 204 BCG vaccine, 356 pranlukast, 193 tosufloxacin, 281 pulmonary interstitial infiltrates efavirenz, 331 pulmonic regurgitation fenfluramine, 6 pupil dilatation dextromethorphan, 91 propafenone, 214 pupils, fixed lithium, 25 pupils, fluctuating diameter olanzapine, 62 purpuric hemorrhage naproxen, 116 pyloric stenosis ganirelix + follicle stimulating hormone, 479 nalidixic acid, 280 pyramidal symptoms unconventional diets, 536 pyrexia baclofen, 153 dextromethorphan, 91 infiltration anesthesia, 143 QT interval prolongation, 19 amiodarone, 206, 207 amisulpride, 58–59 amodiaquine, 315 antipsychotic drugs, 54 azithromycin, 285 cisapride, 382 citric acid, 541 clozapine, 59 dofetilide, 208, 211 flecainide, 212 fluconazole, 305 fluoroquinolones, 274 fluoxetine, 11–12 halofantrine, 317 haloperidol, 54 levofloxacin, 278 loratadine, 182 methadone, 95 moxifloxacin, 279

607

Index of adverse effects nicardipine + erythromycin, 228 olanzapine, 61–62 pefloxacin, 281 sertindole, 65 sevoflurane, 132 SSRIs, 12 terfenadine, 16 quadriparesis diclofenac, 115 radiation recall dermatitis interferon alfa, 395 radiculopathy spinal manipulation, 536 raised body temperature olanzapine, 62 raised hepatic enzymes quetiapine, 63 rash aciclovir, 329 Artemisia derivatives, 319 articaine, 144 carboplatin, 501 caspofungin, 311 celecoxib, 124 cisplatin, 501 co-trimoxazole, 321, 322 codeine, 90 cyanamide, 541 darbepoetin, 368 deferiprone, 253 epoetin, 368, 369 erythromycin, 284 erythropoietin, 368 fentanyl, 94 gadobenate dimeglumine, 520 Ginkgo biloba, 531 iohexol, 518 ioxaglate, 513–514 itraconazole, 306 ivermectin, 346 lamotrigine, 74 levamisole, 348 levofloxacin, 278 linezolid, 289 mesalazine, 387 moricizine, 213 nelfinavir, 333 nevirapine, 332 olanzapine, 63 oxilaplatin, 501 propylthiouracil, 458 pyrimethamine + sulfadoxine, 322 rasburicase, 545 SH U 555 A, 522 sulfasalazine, 387 suramin, 350 teicoplanin, 282 vitamin B2 , 420 water-soluble iodinated contrast agents, 512 Raynaud’s phenomenon

aristolochic acid, 530 nitroglycerin, 224 re-stenosis after angioplasty contrast agents, 516 rectal bleeding celecoxib, 123 red cell hypoplasia linezolid, 289 red eyes aminoglycosides, 273 red man disease vancomycin, 282 redness diphtheria, tetanus vaccines, 356 EMLA cream, 144 ganirelix, 479 reflex sympathetic dystrophy heroin, 41 rejection methotrexate, 407 rejection site reactions phenolic compounds, 260 renal see also entries at kidney –; nephr– renal cell carcinoma thiazide and loop diuretics, 239 renal cortical necrosis tranexamic acid, 380 renal disease aristolochic acid, 529–530 renal dysfunction carboplatin, 499 G-CSF, 399 quinine, 318 renal function fibrates, 486 lithium + cisplatin, 502 mesalazine, 387 renal impairment and baclofen withdrawal syndrome, 153 ecstasy, 32 pefloxacin, 281 pentamidine, 323 renal infarction cocaine, 39 renal insufficiency all-trans retinoic acid, 418 amphotericin B liposomal, 303 aristolochic acid, 529, 530 aspirin, 111–112 ciprofloxacin, 276 cisplatin, 499, 502 cocaine, 39 copper, 245 dextrans, 374 gentamicin + ibuprofen, 272 hydroxyethyl starch, 375 intravenous immunoglobulin, 365 irbesartan, 236 kava, 533

lamotrigine, 74 leuprorelin acetate, 478 lithium, 25 losartan, 236 milrinone, 201 paracetamol, 111–112 rofecoxib, 125 sevoflurane, 134 suramin, 350 renal lesions cisplatin, 499 renal papillary necrosis dapsone, 340 renal toxicity cisplatin, 497 renal tubular acidosis acetazolamide, 238 renal tubular damage cisplatin, 497 renal tubular dysfunction stavudine, 331 renal vasoconstriction cocaine, 39 respiratory burst anti-inflammatory drugs + ofloxacin, 280 respiratory depression alprostadil, 430 epidural anesthesia, 141 remifentanil, 100 sufentanil, 102 zolpidem, 51 respiratory distress infiltration anesthesia, 143 oxaliplatin, 501 talc, 544 respiratory distress syndrome diltiazem, 225 respiratory dysfunction carboplatin, 501 cisplatin, 501 Norplant, 444 oxaliplatin, 501 respiratory failure diazepam, 47 leuprorelin acetate, 478 respiratory function rapacuronium, 150 respiratory reaction rasburicase, 545 respiratory tract infection etanercept, 400 levetiracetam, 75 methotrexate, 407 rosiglitazone, 471 salmeterol, 192 respiratory tract infections repaglinide, 469 restlessness gabapentin, 74 risperidone, 64 theophylline, 2 retinal injury vigabatrin, 82–84

608 retinal pigmentation fomivirsen, 328 vigabatrin, 82 retinoic acid syndrome all-trans retinoic acid, 418 retinopathy chloroquine, 316 interferon beta, 397 retrobulbular neuritis cisplatin, 497 Reye’s syndrome aspirin, 113 rhabdomyolysis cerivastatin, 487 ciclosporin + lovastatin, 487 ciclosporin + simvastatin, 487 clarithromycin + simvastatin, 287 cocaine, 39 depolarizing neuromuscular blocking agents, 151 diltiazem + simvastatin, 226 ecstasy, 32 interferon alfa, 396 interferon beta, 397 isoniazid, 341 lamotrigine, 74 miocamycin, 287–288 propofol, 135–136 theophylline, 2 rheumatoid arthritis doxycycline trials, 267–268 rhinitis buspirone, 49 gonadotrophin-releasing hormone, 477 rabeprazole, 386 zonisamide, 84 rhinorrhea nasal insulin, 465 spinal manipulation, 536 rhinorrhea, CSF cabergoline, 160 right bundle branch block dofetilide, 211 rigidity baclofen, 153 disulfiram, 542 olanzapine, 62 remifentanil, 100 rigor carboplatin, 501 rosacea Mirena, 447 rosacea fulminans vitamin B6 , 420–421 ruptured uterus oxytocin + misoprostol, 481 saddle-nose deformities cocaine, 38 salivary gland function ofloxacin, 280 sarcoidosis

Index of adverse effects interferon alfa, 395–396 scaling nickel, 248 sclerodactyly aristolochic acid, 530 scleroderma-pulmonary-renal syndrome penicillamine, 256 sclerosis of the skin oxaliplatin, 500–501 secondary bone infection cocaine, 38 sedation codeine, 90 dextromethorphan, 90, 91 diphenhydramine, 54 dopamine receptor agonists, 162 droperidol, 383 fentanyl, 94 hydromorphone, 94 macrolides, 284 metoclopramide, 383 miocamycin, 288 nefopam, 106 risperidone, 64 topiramate, 78 tramadol, 103 vigabatrin, 82 seizures aluminium, 243 amfebutamone, 15–16 antipsychotic drugs, 54 benzocaine, 145 brachial plexus anesthesia, 140 cefepime, 265 chloroquine, 315–316 chlorpromazine, 53 ciclosporin, 404 cisplatin, 496, 502 clozapine, 54 desmopressin, 482 epoetin, 369 fluoroquinolones, 274 gatifloxacin, 277 Ginkgo biloba, 531 interferon alfa, 397 lithium, 20 nicardipine, 228 olanzapine, 54 propafenone, 214 remifentanil, 101 ropivacaine, 147–148 strychnine, 6 sulfasalazine, 389 tramadol, 103 selective auditory attention chlorpheniramine, 183 self-injurious behavior vigabatrin, 82 sensitization bismuth, 245 sensory ataxia oxaliplatin, 495

sensory degeneration unconventional diets, 536 sensory impairment lidocaine, 143 sensory loss oxaliplatin, 495 sensory neuropathy carboplatin, 494 cisplatin, 494 metronidazole, 324 oxaliplatin, 494 paclitaxel, 503 sartraplatin, 494 tetraplatin, 493 sepsis central venous catheters, 545 sepsis-like hypersensitivity reaction co-trimoxazole, 292 septal perforation cocaine, 38 serotonin neurotoxicity ecstasy, 33 serotonin syndrome ecstasy, 32 linezolid + sertraline, 289 lithium, 20, 25 St. John’s wort, 532 tramadol + fluoxetine, 104 serotonin toxicity SSRIs, 12 serum sickness amoxicillin, 263 cefaclor, 264 co-amoxiclav, 263 minocycline, 265 penicillin, 263 severe acute necrotizing eosinophilic endomyocarditis pranlukast, 193 severe gait deterioration clozapine, 61 sexual arousal piracetam, 8 sexual desire SSRIs, 13 sexual function carvedilol, 223 diuretics, 238 morphine, 97 SSRIs, 13 shivering ioxaglate, 513 remifentanil, 100 shock acetazolamide, 239 nicardipine, 228 water-soluble iodinated contrast agents, 512 shortness of breath factor IX:C, 366 sialorrhea haloperidol, 64 risperidone, 64

609

Index of adverse effects sick sinus syndrome lithium, 19 sickle cell disease iodinated water-soluble contrast agents, 515–516 silicone deposition acupuncture, 535 silicone, 544 sinonasal structural damage cocaine, 38 sinus bradycardia amisulpride, 58–59 amodiaquine, 315 cisplatin, 494 lithium, 19, 20 timolol, 526 sinus node dysfunction lithium, 19, 20 sinus rhythm cannibinoids, 37 sinus tachycardia lead, 248 moxifloxacin, 279 theophylline, 2 sinusitis cocaine, 38 skin discoloration amiodarone, 206 skin ecchymoses Selaginella doederleinii, 534 skin hypertrophy insulin, 462 skin irritation calcineurin inhibitors, 172 skin lesions dapsone, 340 skin pigmentation amiodarone, 206 skin problems lithium, 19 skin reaction dapsone, 340 fentanyl, 92 primethamine + sulfadoxine, 290 skin tags ganirelix + follicle stimulating hormone, 479 skin toxicity docetaxel, 504 sleep disorders dopamine receptor agonists, 160–162 fluvoxamine, 12 methadone, 95 modafinil, 5–6 nervous system, 12–13 pramipexole, 160 ropinirole, 160 sleep disturbance methylphenidate, 4 metoprolol + simvastatin, 487 slow reactions dopamine receptor agonists, 162

zolpidem, 50 slurred speech dextromethorphan, 90 sildenafil, 231 topiramate, 79 zolpidem, 50 sneezing calcitonin, 477 nasal insulin, 465 social withdrawal digoxin, 198 somnolence buspirone, 49 clozapine, 61 dopamine receptor agonists, 161 ecstasy, 35 felbamate, 73 gabapentin, 73, 74 haloperidol, 53 levetiracetam, 75 myrrh, 349 nervous system, 13 nicotine poisoning, 528 pimozide, 64 progesterone, 448 risperidone, 53, 64 tiagabine, 77 zonisamide, 84 sore throat deferiprone, 253 methimazole, 458 phenytoin + fosphenytoin, 76 pioglitazone, 471 salmeterol, 192 spastic paraparesis methadone, 96 spasticity disulfiram, 542 sperm motility lithium, 23 spina bifida triamterene, 241 spinal cord injury acupuncture, 535 spinal cord ischemia intravenous immunoglobulin, 365 spleen, enlarged gabapentin, 74 splenomegaly carbamazepine + phenytoin, 76 G-CSF, 398 spongiotic dermatitis acupuncture, 535 silicone, 544 squamous cell neoplasms docetaxel, 504 squamous erythematous plaques local anesthetics, 172 ST segment depression remifentanil, 100 status epilepticus

lithium, 25 tiagabine, 77 steatosis of the liver insulin, 462 stenosis cocaine, 39 ergot alkaloids, 163 stenosis, vessel central venous catheters, 545 Stevens–Johnson syndrome celecoxib, 124 Ginkgo biloba, 531 nevirapine, 332 pyrimethamine + sulfadoxine, 290, 322 ranitidine, 384 suramin, 350 stillborn fetus losartan, 236 stimulation theophylline, 2–3 stomach ache methylphenidate, 4 stomach discomfort roxithromycin, 288 stomatitis all-trans retinoic acid, 417 menthol, 543 stool, light-colored MDMA, 35 stooped posture olanzapine, 61 stroke Ginkgo biloba, 531 sildenafil, 231 stromal edema gold, 246 stuttering antipsychotic drugs, 55 lithium, 20 subacute cutaneous lupus erythematosus terbinafine, 310 subcapsular blebs quetiapine, 63 subcortical hemorrhage sildenafil, 231 subdural hematoma oxymetholone, 450 subependymal cyst formation cocaine, 41 sudden cardiac death clozapine, 59 sudden death adenosine, 203 antipsychotic drugs, 54 beta-adrenoceptor agonists, 190 dofetilide, 210 olanzapine, 61 sertindole, 65 suicidal ideation isotretinoin, 175 suicide antipsychotic drugs, 58 isotretinoin, 175

610 sulfonamide hypersensitivity COX-2 inhibitors, 122 supine hypertension midodrine, 158 suppurative granulomatous inflammation acupuncture, 535 supraventricular tachycardia digoxin, 198 swallowing difficulty disulfiram, 542 sweating baclofen, 153 clozapine, 59 cocaine, 37 gabapentin, 74 lithium, 20 morphine, 97 nefopam, 106 olanzapine, 62 oxaliplatin, 501 St. John’s wort, 532 tramadol, 102 sweating, reduced topiramate, 80 zonisamide, 84 Sweet’s syndrome celecoxib, 124 swelling carboplatin, 501 cisplatin, 501 cocaine, 37 diphtheria, tetanus vaccines, 356 ganirelix, 479 Ginkgo biloba, 5310 heroin, 91 insulin, 463 iodinized oil-based contrast agent, 518 oxaliplatin, 500–501 pioglitazone, 471 swelling (facial) co-trimoxazole, 321 swelling (neck) brachial plexus anesthesia, 140, 141 MDMA, 32 syncope lithium, 19 methadone, 95 systemic contact dermatitis cinchocaine, 146 systemic lupus erythematosus etanercept, 400 penicillamine, 255 terbinafine, 310 systolic hypotension melarsoprol, 323 T lymphocyte proliferation pefloxacin, 281 T wave changes caudal anesthesia, 141

Index of adverse effects tachycardia amfebutamone, 16 anticholinergic drugs, 164 antihistamines, 181 benzocaine, 145 cannibinoids, 37 carboplatin, 501 cardiac glycoside, 198 cilostazol, 230 clenbuterol, 191 dextromethorphan, 91 digoxin, 198 disulfiram, 542 dobutamine, 159 dofetilide, 210, 211 ecstasy, 32 gabapentin, 74 heroin, 91 intravenous immunoglobulin, 364 lithium, 19 milrinone, 202 moricizine, 213 nefopam, 106 nicardipine, 227 olanzapine, 62 orphenadrine, 165 oxaliplatin, 501 parathyroid hormone, 481 risperidone, 65 sevoflurane, 132 theophylline + levofloxacin + clarithromycin, 2 vitamin B2 , 420 tachydysrhythmia methadone, 95 theophylline, 2 tachypnea benzocaine, 145 talipes ganirelix + follicle stimulating hormone, 479 tardive dyskinesia antipsychotic drugs, 55, 56 antipsychotics, 53 clozapine, 53 haloperidol, 64 risperidone, 64 taste disturbance anorexia, 493 clarithromycin, 286 codeine, 90 gadobenate dimeglumine, 520 gadodiamide, 520 levofloxacin, 278 metronidazole, 323 penicillamine, 255 tearfulness methylphenidate, 4 tearing flecainide, 213 telangiectasia aristolochic acid, 530 felodipine, 174, 226

temperature body, increased zonisamide, 84 temperature instability DTP-Hib vaccines, 356 tenderness oxaliplatin, 501 tendinitis ciprofloxacin, 276–277 fluoroquinolones, 275 tendinopathy atorvastatin, 487 levofloxacin, 279 simvastatin, 487 tendon rupture fluoroquinolones, 275 teratogenesis THC, no effect, xxxiii tetany cisplatin, 497 strychnine, 6 thinking, difficulty in morphine, 97 thirst inhaled corticosteroids, 187 vitamin A, 416 thoracic empyema talc, 544 throat tightness carboplatin, 501 throbbing spinal manipulation, 536 thrombocytopenia aspirin, 113 carboplatin, 498 cidofovir, 328 clotting factors, 366 darbepoetin, 368 epoetin, 368 erythropoietin, 368 glucagon, 466 interferon alfa, 395 intravenous immunoglobulin, 365 linezolid, 289 naproxen, 116 neutropenia, 498 olanzapine, 62 oxaliplatin, 498 penicillamine, 255 platinum compounds, 499 quinine, 318 rituximab, 403 ZD0473, 493 thrombocytopenic purpura clordiazepoxide, 46–47 measles-mumps-rubella vaccine, 359–360 quinine, 318 thromboembolic complications apomorphine, 160 thromboembolic disease epoetin, 369 ovulation induction, 478 thromboembolism

611

Index of adverse effects gonadorelin receptor antagonists, 478 thrombophlebitis darbepoetin, 368 epoetin, 368 thrombosis central venous catheters, 545 contrast agents, 516 erythropoietin, 368 hormone replacement therapy, 438 intravenous immunoglobulin, 365 thalidomide, 176 thrombosis, arterial infliximab, 400–401 thrombotic events all-trans retinoic acid, 417 thrombotic microangiopathy ciclosporin, 405 thrombotic thrombocytopenic purpura atorvastatin, 487 simvastatin, 487 thyroid dysfunction amiodarone, 205 lithium, 20–21 thyroid immunity interferon alfa, 394–395 thyrotoxicosis lithium, 20, 21 thyrotropin concentration thyroxine, 457 tics methylphenidate, 5 tingling sensation Sono Vue, 523 tinnitus buspirone, 49 cisplatin, 496 hepatitis B vaccine, 358 heroin, 41 lidocaine, 144 quinine, 318 tiredness acupuncture, 535 dihydrocodeine, 92 ecstasy, 35 risperidone, 64 tongue, black arsenic, 244 tongue hypertrophy inhaled corticosteroids, 187 tonic-clonic seizures ciclosporin, 404 cisplatin, 496 cisplatin + doxorubicin, 502 torsade de pointes amiodarone, 204, 207 antipsychotic drugs, 54 arsenic, 244 dofetilide, 210, 211 erythromycin, 287 fluoroquinolones, 274

grepafloxacin, 278 haloperidol, 54 levomethadyl acetate HCl (LAAM), 95 methadone, 95 mosapride, 212 olanzapine, 61 sevoflurane, 132 sotalol, 224 torticollis ganirelix + follicle stimulating hormone, 479 Tourette syndrome methylphenidate, 5 toxic delirium disulfiram, 542 toxic epidermal necrolysis antipsychotic drugs, 58 chloroquine, 316 co-trimoxazole, 292, 321 iohexol, 518 ofloxacin, 280 toxicity gabapentin, 74 lithium, 25 mercury, 248 silver, 249 transaminase activity adefovir, 335 all-trans retinoic acid, 418 fluvastatin, 488 heparins, 377 interferon alfa, 395 transient cortical blindness vertebral angiography, 514–515 transient dysrhythmia propafenone, 214 transient polycythemia isotretinoin, 176 transient radicular irritation intrathecal (spinal) anesthesia, 142 trembling lithium, 25 tremor haloperidol, 64 lithium, 19, 20, 24 methadone, 96 moricizine, 213 olanzapine, 62 risperidone, 64 salmeterol, 192 zolpidem, 51 tremor, intention metronidazole, 324 tremulousness cisplatin, 497 tricuspid regurgitation fenfluramine, 6 triglyceride concentration all-trans retinoic acid, 418 antipsychotic drugs, 56 beta-adrenoceptor agonists, 526 trigonocephaly

valproate sodium, 82 truncal ataxia cocaine, 38 TSH concentration St. John’s wort, 532 TT virus infection intravenous immunoglobulin, 366 tuberculosis etanercept, 400 infliximab, 402 tubular atrophy aristolochic acid, 530 cisplatin, 499 tubular damage ioxaglate, 517 tubular necrosis cocaine, 39 oxaliplatin, 500 tubulointerstitial nephritis cefdinir, 264 copper, 245 rofecoxib, 125 thiazide and loop diuretics, 239 tumor expansion thyroid stimulating hormone, 481–482 tumor lysis syndrome rituximab, 403 tumors walnut oil, 545 tumors, parathyroid lithium, 21 ulcerative colitis isotretinoin, 176 lamotrigine, 74 ulcers (aphthous) Fleet enema, 387 ulcers (gastrointestinal) NSAIDs, 120 ulcers (genital) co-trimoxazole, 321–322 ulcers (hip) leuprorelin acetate, 478 ulcers (leg) docetaxel, 504 ulcers (oral) articaine, 144 deferiprone, 253 methotrexate, 407 ultraviolet recall tobramycin, 273 ultraviolet sensitivity fluoroquinolones, 275 unawareness insulin, 461 unconsciousness bromocriptine, 160 cannibinoids, 37 cocaine, 37 desmopressin, 482 fibrates, 486 unresponsiveness

612 adrenoceptor agonists, 525 ergot alkaloids, 163 zolpidem, 51 unsteadiness human growth hormone, 479 lithium, 25 urea concentration itraconazole, 307 propofol, 136 uremia see azotemia urethral obstruction suramin, 351 urethral stones felbamate, 73 urinary retention codeine, 90 felbamate, 73 fentanyl, 94 midodrine, 158 urinary tract infection methotrexate, 407 urinary urgency midodrine, 158 urine discoloration celecoxib, 124 deferiprone, 253 entacapone, 163 kava, 534 MDMA, 35 urothelial tract tumors aristolochic acid, 529 urticaria carboplatin, 501 cisplatin, 501 factor IX:C, 367 fibrates, 486 fluorescein, 542 heroin, 91 inhaled corticosteroids, 188 insulin, 463 intravenous immunoglobulin, 365, 366 iodixanol, 513 iopamidol, 513 ioxaglate, 513 isosulfan blue, 543 meloxicam, 116 menthol, 543 NSAIDs, 121–122, 122–123 omalizumab, 403 oxaliplatin, 501 oxybenzone, 174 praziquantel, 350 rare antigens in cosmetic products and drugs, 173 systemic glucocorticosteroids, 427 urticaria, consort amoxicillin, 263 urticarial rash factor IX:C, 367 uterine bleeding hormone replacement therapy, 440

Index of adverse effects uterine rupture misoprostol, 432 UV photosensitivity efavirenz, 331 uveitis cidofovir, 328 uveitis, anterior latanoprost, 526 uvular edema isosulfan blue, 543 vaginal argyrosis silver, 249 vaginal bleeding hormone replacement therapy, 437 vaginal discharge BufferGel, 541 vaginal discomfort BufferGel, 541 vaginal dryness toremifene, 447 valvular regurgitation fenfluramines, 6 Varicella zoster rituximab, 403 vascular degeneration copper, 245 vascular disruption cocaine, 40 vascular leak syndrome denileukin diftitox, 398 vascular sheathing vigabatrin, 82 vasculitis cocaine, 39 doxycycline, 265 ketoprofen, 172 minocycline, 266 SSRIs, 13 thionamides, 458–459 vasoconstriction nitroglycerin, 224 vasodilatation gadobenate dimeglumine, 520 vasomotor symptoms toremifene, 447 vasospasm ergot alkaloids, 163 venous thromboembolism clozapine, 59 oral contraceptives, 442–443 venous thrombosis hormone replacement therapy, 438 ventricular dysrhythmia dobutamine, 159 ventricular extra beats milrinone, 201 moricizine, 213 ventricular fibrillation digoxin, 198 ergot alkaloids, 163 iohexol, 514

ventricular tachycardia dofetilide, 210, 211 levofloxacin, 278 sevoflurane, 132 ventricular tachydysrhythmias methadone, 95 vertebral artery dissection amphetamines, 3 amphetamine, 30 verticillate epithelial keratopathy amiodarone, 205 vertigo dihydrocodeine, 92 vesiculopapular dermatitis nickel, 248–249 vessel stenosis central venous catheters, 545 vestibular dysfunction heroin, 41 vestibulopathy heroin, 41 vestibulotoxicity isepamicin, 272 violent behavior midazolam, 136 viral infection clotting factors, 367 viral pneumonia etanercept, 400 virus dermatitis latanoprost, 431 vision disturbances cisplatin, 496 deferiprone, 254 mefloquine, 317–318 voriconazole, 309 vision loss amphetamine, 30 cisplatin, 502 human growth hormone, 479 interferon alfa, 394 visual acuity disulfiram, 542 mexiletine, 213 topiramate, 79 visual field impairment massage therapy, 536 vitamin B12 hypovitaminosis unconventional diets, 536 vomiting albumin, 363 all-trans retinoic acid, 417 amphetamine, 30 antipsychotic drugs, 58 arsenic, 244 Artemisia derivatives, 320 BBR3464, 492 cannibinoids, 37 carboplatin, 498 chloramphenicol, 274 cidofovir, 328 cisplatin, 498, 502 dextromethorphan, 90 digoxin, 199

613

Index of adverse effects erythromycin, 284 famciclovir, 329–330 fentanyl, 92 fibrates, 486 gadobenate dimeglumine, 520 gadolinium, 520 gadoterate meglumine, 521 general anesthetics, 131–132 gliclazide, 470 gonadorelin, 477 human growth hormone, 479 hydromorphone, 94 iloprost, 430 infiltration anesthesia, 143 intravenous immunoglobulin, 364 iodixanol, 513 iopamidol, 513 ioxaglate, 513 iron dextran, 247 itraconazole, 306, 307 josamycin, 287 levamisole, 348 levofloxacin, 278 linezolid, 289 liposome-encapsulated iodixanol, 519 lithium, 20 MDMA, 32, 35 mefloquine, 318 metformin, 468 mifepristone, 448 misoprostol, 431 morphine, 97 nicotine poisoning, 528 NRTIs, 330 oxaliplatin, 498 oxcarbazepine, 76 praziquantel, 350 propofol, 136 quinine, 318 quinupristin/dalfopristin, 290 remifentanil, 100, 101 salmeterol, 192 sildenafil, 231 Sono Vue, 523 telithromycin, 283 theophylline, 2 thiabendazole, 344 thyrotropin-releasing hormone, 482 tramadol, 103 vitamin D, 422

water-soluble iodinated contrast agents, 512 ZD0473, 493 zonisamide, 84 von Willebrand’s disease hydroxyethyl starch, 374–375 vulvar discomfort BufferGel, 541 warmth, sensation of gadolinium, 520 Sono Vue, 523 water intoxication desmopressin, 482 weakness acarbose, 467 anthrax vaccine, 355 cisplatin, 497 colistin, 289 diethylcarbamazine + ivermectin, 346 ecstasy, 35 enalapril, 235 fenofibrate, 486 fosinopril, 236 granisetron, 384 levetiracetam, 75 propafenone, 214 simvastatin + clarithromycin, 488 St. John’s wort, 532 tiagabine, 77 weakness (facial) amphetamine, 30 weeping dermatitis cinchocaine, 146 weight changes antiepileptic drugs, 71 weight gain all-trans retinoic acid, 417, 418 antipsychotic drugs, 56–58 beta-adrenoceptor antagonists, 223 chlorpromazine, 53 clozapine, 53 haloperidol, 53 lithium, 19 medroxyprogesterone, 444 mexazolam, 48 morphine, 97 pioglitazone, 471 quetiapine, 63 risperidone, 53, 64 rosiglitazone, 471

troglitazone, 472 valproate sodium, 80 weight loss felbamate, 73 fosinopril, 236 glibenclamide, 466, 469 MDMA, 35 pergolide, 160 topiramate, 78 voglibose, 466 wheal-and-flare reactions insulin, 463 wheezing betaxolol, 526 carboplatin, 501 cisplatin, 501 fibrates, 486 intravenous immunoglobulin, 364 menthol, 543 oxaliplatin, 501 white matter changes paclitaxel, 503 WHO Uppsala Monitoring Center origins, xxvii–xxviii wind see flatulence withdrawal alprazolam, 46 androgenic anabolic steroids, 450 baclofen, 152–153 caffeine + lithium, 25 cannabis, xxxix–xl levofloxacin interaction, 279 lithium, 19 nitroglycerin, 224 olanzapine, 46 venlafaxine, 17 withdrawal bleeding hormone replacement therapy, 436 withdrawal symptoms fentanyl, 93 Wolbachia bacteria after diethylcarbamazine therapy, 345 wound infection talc, 544 yeast infection BufferGel, 540, 541