Side Effects Of Drugs Annual 27 (Side Effects of Drugs Annual)

SIDE EFFECTS OF DRUGS ANNUAL 27 Side Effects of Drugs Annual 27 HONORARY EDITOR Prof. M.N.G. Dukes, Oslo, Norway ADV...

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SIDE EFFECTS OF DRUGS ANNUAL 27

Side Effects of Drugs Annual 27 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 27 A worldwide yearly survey of new data and trends in adverse drug reactions and interactions EDITOR

J. K. ARONSON MA, DPhil, MBChB, FRCP Reader in Clinical Pharmacology University Department of Clinical Pharmacology Radcliffe Inﬁrmary, Oxford OX2 6HE, United Kingdom

2004

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

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© 2004 Elsevier B.V. All rights reserved. This work is protected under copyright by Elsevier B.V., 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 Rights Department in Oxford, UK: phone (+44) 1865 843830, fax (+44) 1865 853333, e-mail: [email protected]. Requests may also be completed on-line via the Elsevier homepage (http://www.elsevier.com/locate/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) 20 7631 5555; fax: (+44) 20 7631 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 the Publisher 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 Rights Department, at the 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 2004 Library of Congress Cataloging in Publication Data A catalog record is available from the Library of Congress. British Library Cataloguing in Publication Data A catalogue record is available from the British Library. ISBN: 0-444-51356-6 ISSN: 0378-6080 (Series) ∞ 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, P HARM , P H D University of Derby, School of Health and Community Studies, Pharmacy Academic Practice Unit, Kingsway House, Derby, DE22 3HL, UK. E-mail: [email protected] J.K. ARONSON, MA, MBC H B, D PHIL , FRCP University Department of Clinical Pharmacology, Radcliffe Inﬁrmary, Woodstock Road, Oxford, OX2 6HE, UK. E-mail: [email protected] S. ARROYO, MD, P H D Neurology Department, 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, MD University of Oslo, Department of Pharmacotherapeutics, P.O. Box 1065 Blindern, N-0316 Oslo, Norway. E-mail: [email protected] A.M. BALDACCHINO, MD, MRCP SYCH , MP HIL , D IP A DD B EH Centre for Addiction Studies, St. George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 0RE, UK. M. BEHREND, MD, P H D Klinik fur Viszeral-, Gefäß-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Strasse 41, D-94469 Deggendorf, Germany, E-mail: [email protected] A. CARVAJAL, MD, P H D Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] R. CATHOMAS, MD Department of Internal Medicine, University Hospital, 8091 Zurich, Switzerland. N.H. CHOULIS, MD, P H D LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania (Attika), Greece. E-mail: [email protected] P. COATES, MBBS, FRACP, FRCPA Burnside Diabetes Centre, 2 Kensington Road, Rose Park, South Australia, Australia 5067. E-mail: [email protected] J. COSTA, MD Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra de Canyet, 08916 Badalona, Spain. E-mail: [email protected] P.J. COWEN, MD University Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK. E-mail: [email protected]

v

vi

Contributors

S. CURRAN, BS C , MBC H B, M MED S C , MRCP SYCH , P H D Professor of Old Age Psychopharmacology, Ageing and Mental Health Research Group, Room HW3-02, Harold Wilson Building, School of Human and Health Sciences, University of Huddersﬁeld, UK. E-mail: [email protected] H.J. DE SILVA, MBBS, MD, DP HIL , FRCP, FRCPE, FCCP University of Kelaniya, Department of Medicine, Faculty of Medicine, P.O. Box 6, Ragama, Sri Lanka. E-mail: [email protected] F.A. DE WOLFF, MA, P H D, E UR C LIN C HEM , ERT, FATS Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] A. DEL FAVERO, MD Istituto di Medicina Interna e Science Oncologiche, Policlinico Monteluce, 06122 Perugia, Italy. E-mail: [email protected] H.C.S. DALY, MBC H B, FRCA Department of Pharmacology, University of Western Australia, and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. J. DESCOTES, MD, P H D, P HARM D Hôpital Edouard Herriot, Centre Antipoison – Centre de Pharmacovigilance, 5 Place d’Arsonval, 69347 Lyon cedex 03, France. E-mail: [email protected] S. DITTMANN, MD, DS C M ED 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, MB, FRCP, FRACP Uppsala Monitoring Centre, The WHO Collaborating Centre for International Drug Monitoring, Stora Torget 3, S-753 20 Uppsala, Sweden. E-mail: [email protected] E. ERNST, MD, P H D, FRCP, FRCP (E D ) Department of Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, 25 Victoria Park Road, Exeter, EX2 4NT, UK. E-mail: [email protected] M. FARRÉ, MD Unitat de Farmacologia, Institut Municipal d’Investigació Mèdica (IMIM-IMAS), Universitat Autònoma de Barcelona, Doctor Aiguader 80, 08003 Barcelona, Spain. E-mail: [email protected] J.A. FRANKLYN, MD, P H D, FRCP, FM ED S CI University of Birmingham, Queen Elizabeth Hospital, Department of Medicine, Edgbaston, Birmingham, B15 2TH, UK. E-mail: [email protected] M.G. FRANZOSI, P H D Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] A.H. GHODSE, MD, P H D, FRCP, FRCP SYCH Centre for Addiction Studies, St. George’s Hospital Medial School, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 0RE, UK. E-mail: [email protected]

Contributors

vii

G. GIRISH, FRCR Department of Diagnostic Imaging, Northern General Hospital, Shefﬁeld Teaching Hospitals (NHS) Trust, Shefﬁeld, S5 7AU, UK. A.I. GREEN, MD Harvard Medical School, Commonwealth Research Center and Massachusetts Mental Health Center, Department of Psychiatry, 74 Fenwood Road, Boston, MA 02115, U.S.A. E-mail: [email protected] A.H. GROLL, MD Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, Muenster, Germany. E-mail: [email protected] J.T. HARTMANN, P H D, MD 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] K. HARTMANN, MS C P HARM Berna Biotech Ltd, Head Global Pharmacovigilance, 3000 Bern, Switzerland. A. IMHOF, MD Program in Infectious Disease, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D3-100, Seattle, WA 98109-1024, U.S.A. E-mail: [email protected], [email protected] J.W. JEFFERSON, MD University of Wisconsin Medical School, Madison Institute of Medicine, 7617 Mineral Point Road, Madison, WI 53717, U.S.A. E-mail: [email protected] H. JICK, MD Boston University School of Medicine, 11 Muzzey Street, Lexington, MA 02421, U.S.A. E-mail: [email protected] P. JOUBERT, BS C , MBB CH , M MED S C , FCP(SA), MD Honorary Professor of Pharmacology and Therapeutics, Medical University of Southern Africa (MEDUNSA), Pretoria, South Africa, Eikerstrasse 9, 4325 Schupfard, Switzerland. E-mail: [email protected] H. KOLVE Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, Muenster, Germany. H.M.J. KRANS, MD Leiden University Medical Center, Vlietpark 2, 2355 CT Hoogmade, The Netherlands. E-mail: [email protected] M. KUHN, MD Department of Internal Medicine, Kantonsspital, 7000 Chur, Switzerland. E-mail: [email protected] R. LATINI, MD Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected]

viii

Contributors

M. LEUWER, MD The University of Liverpool, University Department of Anaesthesia, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail: [email protected] H.-P. LIPP, P H D Eberhard-Karls-University Tübingen, Department of Clinical Pharmacy, Röntgenweg 9, 72076 Tübingen, Germany. C. LUDWIG, MD Abt. Thoraxchirurgie, Universitatsklinikum Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. P. MAGEE, BS C , MS C , MRP HARM S Director of Pharmaceutical Sciences, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK. E-mail: [email protected] A.P. MAGGIONI, MD Istituto di Ricerche Farmacologiche “Mario Negri”, Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] L.H. MARTÍN ARIAS, MD, P H D Instituto de Farmacoepidemiologia, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] M.M.H.M. MEINARDI, MD, P H D Academic Medical Centre, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: [email protected] R.H.B. MEYBOOM, MD, P H D Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands. E-mail: [email protected] T. MIDTVEDT, MD, P H D Karolinska Institutet, Laboratory of Medical Microbial Ecology, Von Eulers v. 5, Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden. E-mail: [email protected] S.K. MORCOS, FRCS, FFRRCSI, FRCR Northern General Hospital, Shefﬁeld Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Shefﬁeld, S5 7AU, UK. E-mail: [email protected] W.M.C. MULDER, MD, P H D Academic Medical Center, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. S. MUSA, MB C H B, MRCP SYCH Consultant Old Age Psychiatrist. South West Yorkshire Mental Health NHS Trust, Chantry Unit, Fieldhead, Wakeﬁeld, UK. J.N. PANDE, MD, FAMS Professor of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. E-mail: [email protected] J.K. PATEL, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, U.S.A. E-mail: [email protected]

Contributors

ix

K. PEERLINCK, MD University of Leuven, Center for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] B.C.P. POLAK, MD VU University Medical Center, Department of Ophthalmology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected] T.E. RALSTON, MA Department of Psychiatry, University of Massachusetts Medical School, 361 Plantation Street, Worcester, Massachusetts 01605, U.S.A. E-mail: [email protected] H.D. REUTER, P H D Siebengebirgsallee 24, D-50939 Köln, Germany. E-mail: [email protected] M. SCHACHTER, MD Department of Clinical Pharmacology, National Heart and Lung Institute, Imperial College, St. Mary’s Hospital, London, W2 1NY, UK. E-mail: [email protected] M. SCHNEEMANN University Hospital Zürich, Department of Medicine, Medical Clinic B, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected] S.A. SCHUG, MD, FANZCA, FFPMANZCA Department of Pharmacology, University of Western Australia and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected] R.P. SEQUEIRA, P H 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] D.A. SICA, MD 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, P H D, MRP HARM S Birmingham Oncology Centre, St Chad’s Unit, City Hospital, Dudley Road, Birmingham B18 7QH, UK. K.J.D. STANNARD, BS C , MBBS, FRCA Department of Pharmacology, University of Western Australia and Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. W.G. VAN AKEN, MD Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] G.B. VAN DER VOET, P H D, ERT Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected]

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Contributors

P.J.J. VAN GENDEREN, MD, P H D Harbour Hospital, Department of Internal Medicine, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail: [email protected] R. VERHAEGHE, MD University of Leuven, Center for Vascular and Molecular Biology, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] T. VIAL, MD 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, P H D Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] DR. G.M. WALSH, MS C , P H D Department of Medicine & Therapeutics, IMS Building, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. E-mail: [email protected] T.J. WALSH, MD Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20891, U.S.A. E-mail: [email protected] E.J. WONG, MD Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Boston, MA 02115, U.S.A. E-mail: [email protected] Y. YOUNG, MBBS, MRCP(UK), FRCA Department of Anaesthesia, Auckland Hospital, Private Bag 92024, Auckland, New Zealand, E-mail: [email protected] A. ZINKERNAGEL, MD University Hospital Zürich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected] O. ZUZAN, MD Royal Liverpool University Hospital, Department of Anaesthesia, Prescot Street, Liverpool, L7 8XP, UK. 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: Louis Lewin—Meyler’s predecessor J.K. Aronson

xxv

Essay: The General Practice Research Database H. Jick

xxxi

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, T.E. Ralston, and J.K. Patel

29

5.

Hypnosedatives and anxiolytics S. Curran and S. Musa

43

6.

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

49

7.

Antiepileptic drugs S. Arroyo

72

8.

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

88

9.

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

102

10.

General anesthetics and therapeutic gases Y. Young

118

11.

Local anesthetics S.A. Schug, K.J.D. Stannard, and H.C.S. Daly

124

xi

xii 12.

Contents

Neuromuscular blocking agents and skeletal muscle relaxants

138

O. Zuzan and M. Leuwer 13.

Drugs that affect autonomic functions or the extrapyramidal system

145

M. Schachter 14.

Dermatological drugs and topical agents

156

W.M.C. Mulder and M.M.H.M. Meinardi 15.

Antihistamines (H1 receptor antagonists)

165

G.M. Walsh 16.

Drugs acting on the respiratory tract

172

M. Kuhn, R. Cathomas, and K. Hartmann 17.

Positive inotropic drugs and drugs used in dysrhythmias

185

J.K. Aronson 18.

Beta-adrenoceptor antagonists and antianginal drugs

203

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

Drugs acting on the cerebral and peripheral circulations

209

R. Verhaeghe 20.

Antihypertensive drugs

213

P. Joubert 21.

Diuretics

219

D.A. Sica 22.

Metals

224

G.B. van der Voet and F.A. de Wolff 23.

Metal antagonists

233

R.H.B. Meyboom 24.

Antiseptic drugs and disinfectants

239

P. Magee 25.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

242

T. Midtvedt 26.

Miscellaneous antibacterial drugs

251

A. Imhof 27.

Antifungal drugs

276

A.H. Groll, H. Kolve, and T.J. Walsh 28.

Antiprotozoal drugs A.S. Zinkernagel and M. Schneemann

289

Contents

xiii

29.

303

Antiviral drugs J.K. Aronson

30.

Drugs used in tuberculosis and leprosy

323

J.N. Pande 31.

Antihelminthic drugs

326

P.J.J. van Genderen 32.

Vaccines

334

S. Dittmann 33.

Blood, blood components, plasma, and plasma products

342

P.J.M. Vossebeld and W.G. van Aken 34.

Intravenous infusions— solutions and emulsions

353

M.C. Allwood 35.

Drugs affecting blood coagulation, ﬁbrinolysis, and hemostasis

358

K. Peerlinck 36.

Gastrointestinal drugs

362

H.J. de Silva 37.

Drugs acting on the immune system

373

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

Vitamins

405

H.D. Reuter 39.

Corticotrophins, corticosteroids, and prostaglandins

414

J. Costa and M. Farré 40.

Sex hormones and related compounds, including hormonal contraceptives

420

M.N.G. Dukes 41.

Thyroid hormones and antithyroid drugs

442

J.A. Franklyn 42.

Insulin, glucagon, and hypoglycemic drugs

446

H.M.J. Krans 43.

Miscellaneous hormones

465

P. Coates 44.

Drugs that affect lipid metabolism

473

I. Aursnes 45.

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

477

xiv

Contents

46.

Radiological contrast agents S.K. Morcos and G. Girish

496

47.

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

509

48.

Treatments used in complementary and alternative medicine E. Ernst

512

49.

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

525

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

535

Index of drugs

549

Index of adverse effects

563

Special reviews

Prenatal cocaine exposure and perinatal effects Beneﬁcial uses of lithium other than in bipolar disorder Use of antipsychotic drugs in conditions other than schizophrenia Comparing typical and atypical antipsychotic drugs Psychosis and antiepileptic drugs Epilepsy and bone loss The effects of NSAIDs on blood pressure Has Helicobacter pylori a role in upper gastrointestinal damage associated with non-steroidal anti-inﬂammatory drugs? Assessing the beneﬁt–harm balance of low-dose aspirin in preventing strokes and heart attacks Hypersensitivity reactions to muscle relaxants Residual paralysis Sleep disorders with dopamine receptor agonists Botulinum toxin A in the treatment of primary axillary hyperhidrosis Aerosol delivery Risks of inhaled corticosteroids in children Leukotriene receptor antagonists and Churg–Strauss syndrome Amiodarone and thyroid disease Diuretics, diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial Future use of antimicrobial drugs: the lesson from avoparcin and vancomycin Nephrotoxicity due to amphotericin Antituberculosis drug regimens containing pyrazinamide in the treatment of latent pulmonary tuberculosis infection Surveillance of adverse events following immunization Multiple immunizations Immunization and autoimmune disease Smallpox vaccination Erythropoietin and pure red cell aplasia Safety aspects of folic acid Genotoxicity and carcinogenicity of antiestrogens Combinations of hypoglycemic drugs Lorenzo’s oil Inhibitors of topoisomerase I and topoisomerase II Contrast medium-induced renal damage Liver damage from kava kava Indirect risks of complementary/alternative therapies

1 19 49 50 72 74 102 105 109 138 139 149 161 172 174 177 192 219 242 276 323 334 334 336 339 348 407 429 458 475 477 500 518 521

xv

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Cumulative index of special reviews, Annuals 15–26 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 Acetylsalicylic acid, 21.100 co-medication, 26.423 gastrointestinal effects, 17.95, 18.90 Reye’s syndrome, 15.85 rhinosinusitis/asthma, 17.94 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, 15.268, 17.305 and ribostamycin, 15.270 Amiodarone, dysrhythmias, 25.211 respiratory toxicity, 15.168 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 prescribing, 15.254 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, 26.180 drowsiness/sedation, 21.170, 23.171, 26.182 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 weight gain, 26.56 Antituberculosis drugs, 16.341 liver damage, 25.363, 26.339 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

xvii

xviii

Cumulative index of special reviews, Annuals 15–26

Aspirin, see Acetylsalicylic acid Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Azoles, see antifungal drugs

Ecstasy, see MDMA EDTA, pseudothrombocytopenia, 21.250 Endothelin receptor antagonists, in hypertension, 26.233 Enzyme inhibitors, 15.337 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 Fertility drugs malignant melanoma, 26.434 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

Baclofen, withdrawal syndrome, 26.152 Bambuterol, cardiac failure, 23.181 Benzodiazepines, depression, 17.43 Beta2 -adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 Beta-adrenoceptor antagonists, sexual function, 15.188 Beta-carotene, see also Vitamin A alcohol, vitamin A, interaction, 24.442 carcinogenicity, 25.454 Beta-lactams, pregnancy, 25.280 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carotenoids, carcinogenicity, 25.454 Ceftriaxone, 15.258 Charcoal, activated, in digitalis overdose, 24.201 Chloramphenicol, children, 15.267 Chloroquine, 15.286 Ciclosporin, urinary system, 19.348 Clozapine, 15.50 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 delayed reactions, 26.513 in magnetic resonance imaging, 20.419 Corticosteroids bone, 16.447, 22.182, 25.195 contact allergy, 15.139, 21.158 effective dose and therapeutic ratio, 23.175 inhaled, growth inhibition, 26.186 inhaled, systemic availability, 24.185, 26.187 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, 26.116 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 Dofetilide, 26.208 Dopamine receptor agonists, sleep disorders, 26.160

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 Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Heroin, see diamorphine Histamine (H2 ) receptor antagonists, 15.393 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530 Hormones, sex, tumors, 22.465 5-HT, see serotonin Hypnotics, 20.30 avoiding adverse effects, 21.37 Immunization adverse effects, 24.364 bioterrorism, 25.378, 26.354 surveillance after, 15.340, 22.333, 23.335, 24.364, 25.376, 26.353 Immunotherapy, in leishmaniasis, 15.299 Indomethacin, fetal and neonatal complications, 18.102 Insulin human, and hypoglycemia, 15.452 modes of administration, 26.464 resistance, and growth hormone, 24.504 synthetic analogs, 24.489

xix

Cumulative index of special reviews, Annuals 15–26 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 Lipid-lowering drugs, 15.479 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 MDMA cognitive effects, 26.32 deaths, 24.32 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 Mibefradil, drug interactions, 23.210 Midazolam, 15.112 Midodrine, 26.159 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387 Crohn’s disease, 23.350, 25.387 Morphine, managing adverse effects, 26.98 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 intensive care, 19.140 Niacin, extended-release, 16.440 Non-depolarizing neuromuscular blockers, 15.127 NSAIDs blood pressure, 19.92 children, 19.96 COX2 inhibitors, 24.115, 25.126, 26.116 current controversies, 17.102 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, 26.111 topical, 18.163 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 and breast cancer, 15.426 formulations, 24.472 third-generation, 25.484, 26.442 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 Phentermine, cardiac valvulopathies, 24.4 Platinum compounds, 26.490 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Propofol, infusion syndrome, 26.135 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 PUVA, malignant melanoma, 22.166 Quinidine, versus quinine, 15.295 Quinine, versus quinidine, 15.295 Ribostamycin, and aminoglycosides, 15.270 Rocuronium, allergic reactions, 26.150 Rotashield, intussusception, 23.354 Salmeterol, tolerance, 24.187 Sex hormones, tumors, 22.465 Serotonin receptor antagonists, 15.391 selective serotonin reuptake inhibitors, drug interactions, 22.13 Somatostatin, 15.468 Statins, see HMG co-A reductase inhibitors Steroids, see corticosteroids Sumatriptan, 17.171 Suramin, patients with prostate cancer, 20.283 Tetracyclines adverse effects, 26.268 comparative toxicity, 22.268 and metalloproteinases, 26.266 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

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Cumulative index of special reviews, Annuals 15–26

Topiramate, cognitive effects, 26.81 Total parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 L-tryptophan, eosinophilia-myalgia syndrome, 15.514

visual ﬁeld defects, 21.78, 24.95, 25.98, 26.82 Valproate, polycystic ovary syndrome, 26.81 Vitamin A, 17.436 alcohol, beta-carotene, interaction, 24.442 hypervitaminosis, 15.411 in pregnancy, 21.405 Vitamin B6 , debate, 23.420 Vitamin E, co-medication, 26.423 Vitamin K cancer, 23.424 skin reactions, 25.461 Vitamins, in old age, 22.431

Vaccines, poliomyelitis, 22.352 Vigabatrin psychosis and abnormal behavior, 18.71

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, 26.180 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 cardiotoxicity, propofol, 26.135 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 amiodarone, 15.168 asthma, acetylsalicylic acid, 17.94 asthma, fenoterol, 23.182 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, acetylsalicylic acid, 17.94 Nervous system demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness/sedation, antihistamines, 21.170, 23.171, 26.182 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

seizures, antibiotics, 18.261 sleep disorders, dopamine receptor agonists, 26.160 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, 26.82 Psychiatric antiepileptic drugs, 22.82 autism, MMR/measles immunization, 23.350, 25.387 cognitive effects, MDMA, 26.32 cognitive effects, topiramate, 26.78 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 ovarian hyperstimulation syndrome, valproate, 26.477 polycystic ovary syndrome, valproate, 26.81 Metabolism hypoglycemia, insulin, 15.452 lactic acidosis, metformin, 23.459 metabolic acidosis, propofol, 26.135 lipodystrophy, HIV-protease inhibitors, 22.317 polyvinylpyrrolidone storage disease, 22.522 weight gain, antipsychotic drugs, 26.56 Hematologic agranulocytosis, clozapine, 22.59 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 eosinophilia-myalgia syndrome, tryptophan, 15.514 pseudothrombocytopenia, EDTA, 21.250 Gastrointestinal bleeding, acetylsalicylic acid, 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

Cumulative index of special reviews, Annuals 15–26 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, antituberculosis drugs, 25.363, 26.339 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, paracetamol, 17.98, 18.94 Reye’s syndrome, acetylsalicylic acid, 15.85 Urinary tract cystitis, tiaprofenic acid, 18.106 nephrotoxicity, aminoglycosides, 15.268, 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, 26.111 renal cell carcinoma, diuretics, 23.225 renal insufﬁciency, diuretics, 25.250 Skin contact allergy, 23.160 contact allergy, corticosteroids, 15.139 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 eosinophilia-myalgia syndrome, tryptophan, 15.514 growth in children, inhaled corticosteroids, 26.186 osteoporosis and osteonecrosis, corticosteroids, 16.447, 19.377, 20.374, 21.417, 22,182 rhabdomyolysis, propofol, 26.135 Sexual function and beta-adrenoceptor antagonists, 15.188 fertility, male, antibiotics, 16.262 Immunologic allergic reactions, antibiotics, 23.251 allergic reactions, rocuronium, 26.150 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

xxi 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 Drug withdrawal baclofen, 26.152 Carcinogenicity alcohol/vitamin A/beta-carotene, 24.442 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474, 26.434 growth hormone, 23.468 omeprazole, 16.423 oral contraceptives, 15.426 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 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

xxii lithium, 16.13 lithium/speciﬁc serotonin reuptake inhibitors, 18.30 mibefradil, 23.210

Cumulative index of special reviews, Annuals 15–26 speciﬁc serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods Post-marketing surveillance, 15.266, 24.274

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 2002. During the production of this Annual, some more recent papers have also been included; older literature has also been cited when it is relevant. 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. Some conﬁrmatory reports are also described. 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 the Special Reviews that were published in SEDA-15 to SEDA-26 and a list of the Special Reviews that appear 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 is 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 or as a combination product. DRUG NAMES Drugs are usually called by their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a ﬁxed combina-

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How to use this book

tion 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. SYSTEM OF REFERENCES References in the text are tagged using the following system, which was introduced in SEDA-24: M A meta-analysis or other form of systematic review; E An experimental study (animal or in vitro); A An anecdote or set of anecdotes (i.e. case histories); R A major review, including non-systematic statistical analyses of published studies; r A brief commentary (e.g. an editorial or a letter); C A major randomized controlled trial or observational study; c A minor randomized controlled trial or observational study or a non-randomized study; S 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 1–26 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

Louis Lewin—Meyler’s predecessor J.K. Aronson

“It is a paradox, but whoever has known, honoured, and loved Louis Lewin experiences a feeling of redemption that he is one of the greatest of the many great Jews in the German history of medicine who were allowed to die before 1933.” Erwin Ackerknecht

After suffering the adverse effects of one or more antituberculosis drugs that he received after the war, the Dutch physician Leopold Meyler, discovered that there was no single contemporary text to which medical practitioners could turn for information about unwanted effects of drugs, and determined to make such information available. He persuaded the Netherlands publishing ﬁrm of Van Gorcum to publish a book, “Schadelijke Nevenwerkingen van Geneesmiddelen”, entirely devoted to descriptions of the adverse effects that drugs could cause. The book appeared in 1951 and an English translation, “Side Effects of Drugs”, in 1952. I have previously given a detailed account of the history of the publication of subsequent volumes and editions (SEDA-23, xxiii), and since then a brief account of how Meyler came to write the ﬁrst volume has appeared (1). It is generally assumed that Meyler was the ﬁrst to write such a book about adverse drug reactions. However, he had an illustrious predecessor, the toxicologist and pharmacologist Louis Lewin (1850–1929), who in 1881 published his book “Die Nebenwirkungen der Arzneimittel”, in a format very similar to that of Meyler. Here I brieﬂy review Lewin’s life and career. In doing so I have relied heavily on articles about Lewin by Brigitte Hoppe (2, 3).

Louis Lewin: toxicologist and pharmacologist Louis Lewin (pronounced Leveen) (Figure 1) was born on 9 November 1850 in Tuchel (Konitz) in West Prussia. His parents, Rahel and Hirsch, originally came from Suwalki, a Polish province in Russia, but they ﬂed westward during the Russian pogroms, and changed their name from Appelbaum to Lewin. In 1856 the Lewin family moved to Berlin and lived in the so-called Shed Quarter (Scheunenviertel) in the Grenadierstraße, close to the Alexanderplatz. Lewin attended a Jewish school, but he later graduated to the Friedrich–Werderschen Gymnasium, where he was taught by Paul de

Fig. 1. Louis Lewin aged.

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xxvi Lagarde, who urged him to go to university and supported him ﬁnancially. Attendance at the Friedrich–Werdersche Gymnasium meant that Lewin had to leave the orthodox Jewish milieu in the Grenadierstraße to assume a western lifestyle more suited to his professional education. In 1871, he left the Gymnasium to read medicine at the Friedrich– Wilhelm Universität in Berlin (now the Humboldt University). In July 1875 he obtained an MSc and in the same year a PhD, with an award-winning piece of work entitled “Experimentelle Untersuchungen über die Wirkung des Aconitin auf das Herz” (“Experiments on the action of aconitine on the heart”). In 1876, he qualiﬁed as a physician and joined the Kaiser– Alexander–Garde Regiment as a volunteer for 1 year. He then served as Assistant Physician with the Railway Regiment, and in the autumn of 1877 moved to Munich, where he became an assistant in the laboratory of Carl von Voit (1831–1909) and Max von Pettenkofer (1818– 1901). Here he began the pharmacological work that led him to obtain a position with Oskar Liebreich (1839–1909) at the Pharmacological Institute of the Friedrich–Wilhelm Universität in Berlin in 1878. Lewin’s work at the Pharmacological Institute was fraught with difﬁculties. Although he was allowed to do research there, his eccentric behaviour and his refusal to be baptized led to his being denied promotion and a full position on the faculty. A cartoon of the Berlin Medical Faculty in 1920 shows Lewin’s isolated position: he is pictured on the far right-hand side, carrying a bottle of poison, his back turned on the other professors (Figure 2). In 1881, Lewin qualiﬁed in medicine, toxicology, and hygiene in Berlin, and married Clara Wolff, whom he had met in Hamburg. In the same year he published his book on the adverse effects of drugs, “Die Nebenwirkungen der Arzneimittel”. In 1893, Lewin received the title of Professor (his inaugural lecture was on disinfectants), but still not a full professorship. However, using private means, he had already established a laboratory in the Ziegelstraße, where he gave lectures and practical classes free. Although Lewin did not have a full Chair, nor ofﬁcial permission to hold examinations, students, medical and non-medical, ﬂocked to learn about pharmacology and toxicology, preferring his enthusiasm

J.K. Aronson

and the anecdotes with which he enlivened his lectures to the boring presentations of the ofﬁcial lecturer. His lectures, announced in the ofﬁcial curriculum but given in his own laboratories, encompassed the following topics: • the theory of medicine, with experiments and demonstrations; • exercises for writing prescriptions, formulating medicines, and calculating their costs; • the effects and adverse effects of drugs; • toxicology, including environmental toxicology and forensic practice, with experiments in blood spectroscopy and proof of poisons. In his research Lewin concentrated on hallucinogens and the symptoms and treatment of poisoning in factory workers. The importance of his work became recognized; in 1919 he was appointed “extraordinary Professor” at the Technical University of Berlin and in 1924 became an honorary member of the Technical University, where he lectured on the theory of toxins, industrial toxins, industrial accidents, and occupational diseases. At last, in 1922, at the age of 72, he was belatedly credited with a full professorship by Friedrich–Wilhelm Universität. The stipend that Lewin received from the university was barely enough to cover the costs of his private laboratory, and although time and again he tried to move it to within the university, time and again he was rejected. However, in 1924, when he donated his collection of toxins and medicines, the university ﬁnally agreed to pay the costs for his private institute. Lewin’s collection contained many arrowheads, rare tropical substances (such as hashish, Anhalonium Lewinii, and kava-kava), several devices for the use of narcotics or stimulants (such as opium pipes, hashish pipes made of potter’s clay, maté equipment, and individual devices for chewing betel), highly perfumed resins, and many herbal medicines that had been sent to him from all over the world. In 1926, Lewin had a stroke from which he never fully recovered. Despite failing health, he worked with unﬂagging zeal until his death from sepsis on 1 December 1929, at the age of 79.

Louis Lewin—Meyler’s predecessor

Fig. 2. A cartoon of the Berlin Medical Faculty, drawn by A Wolotzky in 1927.

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Lewin’s “Untoward Effects of Drugs” In 1881 Lewin published “Die Nebenwirkungen der Arzneimittel. Pharmakologisch–klinisch Handbuch”. Three subsequent editions appeared in 1893, 1899, and 1909. In 1883 the book appeared in a so-called “second edition” as “The Untoward Effects of Drugs”, having been translated into cumbersome English by J.J. Mulheron, Professor of the Principles of Medicine, Materia Medica, and Therapeutics in the Michigan College of Medicine in Detroit (4). Lewin’s interest in adverse effects sprang from his interest in the actions of drugs. “From time to time”, he wrote in the Preface, “during the therapeutic use of certain drugs, abnormal actions occur, the correct signiﬁcance of which is not always understood. But a knowledge of these is of the utmost importance to the physician, since they explain the causes of certain symptoms and show him how to manage them”. The book begins with a long introduction, in which Lewin discusses the nature of adverse drug reactions, and continues with eight chapters on the adverse effects of tonics, astringents, alteratives, excitants, narcotics, evacuants, emollients, and ﬁnally rubefacients and vesicants. Lewin’s text was described in Garrison and Morton’s “Medical Bibliography” (1943) as “the only book of its kind. It deals with the borderline between the pharmacological and the toxicological action of drugs with the untoward or side-effects of all kinds of medicaments”. Meyler’s 1951 text had no introduction, but otherwise followed the same general pattern as Lewin’s text, with 25 chapters, ordered by groups of drugs. Lewin was more discursive than Meyler and he gave fewer references to primary literature. Furthermore, the passage of 70 years shows itself markedly when one compares the two texts. For example, much of Meyler’s two-page description, with 20 references, of the adverse effects of digitalis could be reproduced, with little change, in a modern textbook. Lewin’s two-page description, on the other hand, includes many supposed adverse reactions that we do not recognize today, and he cites only three references. The invention of clinical science by John Burdon-Sanderson and others in the early twentieth century [5] had clearly made its mark.

J.K. Aronson

Conclusions No other toxicologist was as productive or had such an effect on the subject of toxicology as Louis Lewin. His work encompassed almost 300 publications in journals and several monographs on toxicological, forensic, ethnographic, pharmacological, and historical topics. His experimental contributions covered chronic morphinism, dual addiction to morphine and cocaine, narcotics in general, and other alkaloids, such as mescaline from Anhalonium Lewinii (the peyote plant, named after him), the harmala alkaloids, and the constituents of Piper methysticum (kava-kava) and Chavica betel. Extensive research in the ﬁeld of experimental toxicology, the ﬁrst results of which he described in his book “Die Nebenwirkungen der Arzneimittel”, as well as his “Gifte und Vergiftungen—Lehrbuch der Toxikologie” (“Poisons and Poisoning—a Textbook of Toxicology”), published in 1885, underpinned Lewin’s reputation as an internationally recognized scientist. In “Phantastica. Die betäubenden und erregenden Genussmittel für Ärzte und Nichtärzte” (1924) he classiﬁed psychoactive drugs as euphorics, phantastics, inebriants, hypnotics, and excitants (6, 7). The book contained detailed information on all the major such drugs of the time, including opium, cocaine, heroin, cannabis, peyote, ﬂy agaric, henbane, datura, alcohol, kava-kava, betel, coffee, tea, cocoa, and tobacco. His other books included “Die Gifte in der Weltgeschichte” (“Poisons in World History”), “Fruchtabtreibung durch Gifte” (“Toxin-Induced Abortion”), and “Die Pfeilgifte. Historische und Experimentelle Untersuchungen” (“Arrow Toxins. Historical and Experimental Investigations”). Lewin always advocated a basic scientiﬁc and experimental approach to the practice of medicine and the use of drugs. His approach had a deeply religious origin, as he clearly stated in a 1909 article about religion and science: “In my opinion, there is only one basic religious thought, a belief in one God, an inconceivable, incredible, multifarious power, a predominantly systematic order working in nature, an omnipresence. I regard this power as being the basis of experimental biological research, and it has moulded my scientiﬁc attitude towards drugs and toxins”.

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Louis Lewin—Meyler’s predecessor

Louis Lewin has been called the father of toxicology. He undoubtedly wrote the ﬁrst textbook on the adverse effects of drugs, anticipating Meyler by 70 years. However, unlike Meyler, Lewin did not pursue his studies of adverse drug reactions further. And by the time Meyler came to write his book, Lewin’s seems to have been forgotten. Had Lewin continued to survey the adverse reactions literature in the careful way that Meyler did, we would probably now be referring to “Lewin’s Side Effects of Drugs”, not Meyler’s.

Acknowledgements I am grateful to Ms Joke Zwetsloot for help in translating Dr Hoppe’s papers and to Dr Matthias Brockstedt, last President of the erstwhile Berlin–Brandenburgische Louis Lewin– Gesellschaft, for providing me with much material about Lewin and for giving me permission to reproduce the photograph of Louis Lewin and the cartoon.

REFERENCES 1. Van Grootheest AC. Leopold Meyler (1903– 1973): a pioneer in the study of adverse effects of drugs. In: Improving Pharmacovigilance and the Role of the Pharmacist. Doctoral Thesis, Rijksuniversiteit Groningen, 2003: 43–8. 2. Hoppe B. Louis Lewin, 1850–1929. Sein Beitrag zur Entwicklung der Ethnopharmakologie, Toxikologie und Arbeitsmedizin, Dissertationsschrift, Freie Universität Berlin, Fachbereich Medizin, 1985. 3. Hoppe B. Leben und Werk Lewins. In: Louis Lewin (1850–1929), Leben—Werk—Wirkung. Symposion am 17 Oktober 1992 im Kulturforum Berlin–Hellersdorf, Berlin. Heimathefte 1993; 3:

10. (http://www.giftnotruf.de/lewin/hoppe.htm; last accessed 26 January, 2004.) 4. Lewin L. The Untoward Effects of Drugs. Translated from the German by Mulheron. 1882. 5. Romano TM. Making Medical Science: John Burdon Sanderson and the Culture of Victorian Science. Baltimore: The Johns Hopkins University Press, 2003. 6. Lewin L. Phantastica. Die betäubenden und erregenden Genussmittel für Ärzte und Nichtärzte. Georg Stilke: Berlin, 1926. 7. Lewin L. Phantastica. Translated from the second German edition by PHA Wirth. Rochester, Vermont: Inner Traditions International, 1998.

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SIDE EFFECTS OF DRUGS ESSAY

The General Practice Research Database Hershel Jick∗ The General Practice Research Database (GPRD) is a name now generally given to a large data resource that consists of information recorded on hundreds of general practitioners’ computers in the United Kingdom. The effort to build such a resource was initiated in the middle 1980s by VAMP Health, a proﬁt-making corporation. The nature, scope, and utility of the GPRD is complex, and a knowledge of what it actually represents is necessary in order to understand its various uses and to interpret published articles that have been based on the different systems that have all been referred to as the “GPRD”. The GPRD originated from a combination of two separate and independent occurrences that came together in the late 1980s. First, a general practitioner, Dr. Alan Dean, derived an ofﬁce computer-based tool for recording routine medical information. It was designed to replace most of the paper records that had been used for many years by general practitioners. Dean teamed up with a group of business people to form VAMP Health, which built and planned to sell computers containing the software designed by Dean. The second contribution to the eventual creation of the GPRD took place in the early 1980s in a village in the Cotswolds named Minster Lovell, at a time when few people were publishing research papers in the ﬁeld of drug safety epidemiology. Before that time, the general lack of attention paid to formal drug safety research was reﬂected by the fact that the ﬁrst, and until recently only, journal paper that speciﬁcally described the principles and methods of this ∗ This year’s guest contributor of the Side Effects of Drugs Essay is Hershel Jick, who is Associate Professor of Medicine, Boston University School of Medicine, Boston, MA, USA, and Director of the Boston Collaborative Drug Surveillance Program.

research area was published in 1978 (1). The Minster Lovell Workshop, which was designed to describe and discuss the principles and methods of formal drug safety epidemiology, was sponsored by the Boston Collaborative Drug Surveillance Program (BCDSP) and took place over 4 days. The workshop was attended primarily by medical directors of drug companies keenly interested in learning about research resources and techniques to address drug safety issues. More than 20 companies were represented. The designs and results of many previously published studies were presented. The ﬁrst workshop took place some 5 years after investigators began to use the ﬁrst computerized medical database derived from Group Health Cooperative (GHC) in Seattle, Washington, for drug safety research. With this resource it was possible to increase by orders of magnitude the efﬁciency and types of such research that could be accomplished. Over a dozen papers were published in the ﬁrst few years of access to this database (2). In light of the experience with the GHC database, it was logical to suggest at the Minster Lovell Workshop that the UK was an ideal setting for establishing a large computerized medical database derived from patient information held by general practitioners. This was because in the UK the GP is the repository for virtually all the medical information about each patient. A few years after the ﬁrst workshop, Vamp Health became aware of the history of the BCDSP, which had begun a drug safety research program in 1966, had published well over 100 articles in peer reviewed journals, and had used computerized medical data for drug safety research (3). The staff of the BCDSP met with the directors of VAMP Health, and after some discussion VAMP Health agreed to a cooperative effort of research that recognized the

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xxxii scientiﬁc independence of the BCDSP. Vamp Health began an extensive program of instruction and training of GP participants who were willing to join in the standardized collection of the medical data for research purposes. Vamp Health collected newly computerized GP medical data ﬁles, which were subsequently sent to the BCDSP for evaluation of the quality and completeness of the information contained therein. After the BCDSP had organized the ﬁles in a format suitable for efﬁcient access, extensive studies documented that the information about medicines prescribed, clinical diagnoses, and other medical data recorded on computer were of entirely satisfactory quality and completeness for research, and that anonymized referral letters were obtainable (4). Thus, research projects were begun. The database, initially referred to as Vamp Research and more recently as GPRD, was the source of over 100 papers, primarily related to drug safety, over the next decade (3). The next important event in the history of the GPRD occurred in the mid-1990s, when VAMP Health was sold to Reuters, who promptly donated the VAMP Health GP-based data resource to the UK Department of Health (DH). At that time, the DH accepted responsibility for maintaining and continuing data collection, provided that it was ﬁnancially self-supporting. The BCDSP and Alan Dean each signed 7-year license agreements with the DH at a fee of £500 000 per year, and the name of the data resource was changed to the General Practice Research Database or GPRD. At that time there were already two different versions of the GPRD. One resided at the ofﬁces of the BCDSP, which organized and formatted the raw data for research purposes. The second version was held by Alan Dean, who had formed a company called The Epidemiology and Pharmacology Information Core (EPIC) from the GP Database Research Company, which provided access to the data by outside parties for a fee. These data ﬁles were in an entirely different format, and so there were in effect two GPRDs in existence. It should be noted that while the raw data items were the same for each practice, the numbers of practices included in the two versions were substantially different, since the BCDSP had excluded practices based on failure to provide full information of satisfactory quality and

Hershel Jick

completeness, and in some instances changes in the software used by certain general practices. In early 2000, the then Medicines Control Agency (MCA), now called the Medicines and Healthcare products Regulatory Agency (MHRA), since the union of the MCA with the Medical Devices Agency in April 2003, offered to invest some millions of pounds sterling into the GPRD and to take over the responsibility of maintaining and continuing data collection. The MCA’s plan was to create an online system that could be accessed by many people, at a fee, over the internet. The plan included the discontinuation of sending raw data ﬁles to the previous two licensees. However, this was unacceptable to the licensees, and after discussion the relationship between the BCDSP and MCA was ended. This created three versions of the GPRD. One has a unique computer format derived from the raw data by the BCDSP and is based at their ofﬁces, a second resides at EPIC, which, as I understand it, is a slight modiﬁcation of the raw data, and a third is accessible on line at the MHRA. File structures and access modes of these sources are entirely different. The research staff of the BCDSP and their colleagues have now published over 150 papers based on their version of the GPRD (3). Together these publications provide a comprehensive description of the types and validity of the data that the GPRD contains (4) and a wide variety of study designs that can be used to address numerous epidemiological research questions based on the data ﬁle format that has been created. The data provided by EPIC has resulted in some published drug safety studies (5, 6). I am unaware of any published drug safety studies based on the on-line system of data access provided by MHRA. Since the raw data provided by the GPs who participate is identical in basic content, welldesigned studies that are properly implemented should provide closely similar results, regardless of the format. However, a successful study is not only related to the basic GP data. It also depends on an ability to access the ﬁles properly and, of course, the use of professional standard research design and implementation. It is important for those who read publications that purport to be based on the GPRD to understand that they may be derived from different quantities and types of data recorded

The General Practice Research Database

in different computer formats. The evolution of the initial version of the database created by VAMP Health and the BCDSP has been substantially modiﬁed by others, and this has inevitably created confusion and controversy among researchers. In the past 3–5 years the GPRD has seen changes in the software and drug and diagnosis codes used by GPs. After considerable effort, these have been integrated into the original data ﬁle structure at the BCDSP, and our version of what is called the GPRD is now functioning smoothly. Over the years, the BCDSP has provided training to investigators and graduate students who have used and continue to use the version of the GPRD as it has existed in-house and been updated since 1990. Three of those investigators have set up independent research units in Spain (7), Switzerland (8), and Scotland (9),

xxxiii and they continue to use subsets of the data located at the BCDSP. Altogether researchers have published more than 150 articles in peer review journals (3). The GPRD, properly used by researchers experienced and trained in the many characteristics of the data resource itself, as well as the scientiﬁc disciplines that provide professional quality research, is a unique and extraordinary resource, providing high-quality information covering more than 25 million years of human medical experience. There are current uncertainties about future data collection and support for the GPRD, but those who have worked with this resource for over a decade are conﬁdent that, whatever its name, it will continue to produce important scientiﬁc ﬁndings for years to come.

REFERENCES 1. Jick H, Vessey MP. Case-control studies in the evaluation of drug-induced illness. Am J Epidemiol 1978; 107: 1–7. 2. Jick H, Watkins RN, Hunter JR, Dinan BJ, Madsen S, Rothman KJ, Walker AM. Replacement estrogens and endometrial cancer. New Engl J Med 1979; 300: 218–22. 3. Boston Collaborative Drug Surveillance Program. http://www.bu.edu/bcdsp. 4. Jick SS, Kaye JA, Vasilakis-Scaramozza C, Garcia Rodriguez LA, Ruigómez A, Meier CR, Schlienger RG, Black C, Jick H. Validity of the General Practice Research Database. Pharmacotherapy 2003; 23: 686–9. 5. Farmer RDT, Lawrenson RA, Todd J-C, Williams TJ, MacRae KD, Tyrer F, Leydon GM. A comparison of the risks of venous thromboem-

bolic disease in association with different combined oral contraceptives. Br J Clin Pharmacol 2000; 49: 580–90. 6. van Staa T, Abenhaim L, Cooper C. Upper gastrointestinal adverse events and cyclical etidronate. Am J Med 1997; 103: 462–7. 7. Ruigómez A, Johansson S, Wallander MA, Garcia Rodriguez LA. Incidence Of chronic atrial ﬁbrillation in general practice and its treatment pattern. J Clin Epidemiol 2002; 55: 358–63. 8. Schlienger RG, Haefeli WE, Jick H, Meier CR. Risk of cataract in patients treated with statins. Arch Int Med 2001; 161: 2021–6. 9. Jick H, Kaye JA, Black C. Changes in risk of autism in the UK for birth Cohorts 1990–1998. Epidemiology 2003; 14: 630–2.

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Central nervous system stimulants and drugs that suppress appetite

METHYLXANTHINES

(SED-14, 1; SEDA-24, 1; SEDA-25, 1; SEDA-26, 1)

Theophylline Drug interactions In seven healthy volunteers taking modiﬁed-release theophylline, intravenous pazuﬂoxacin mesilate increased serum theophylline concentrations; analysis of the urinary excretion of theophylline and its metabolites suggested that CYP1A2 had been inhibited (1c ). Theophylline concentrations need to be monitored if pazuﬂoxacin is coadministered.

STIMULANT DRUGS (SED-14, 12; SEDA-24, 2; SEDA-25, 2; SEDA-26, 3) Cocaine Cardiovascular Myocardial infarction has been documented in 6% of patients who present to emergency departments with cocaine-associated chest pain (2C , 3R ). Treatment of cocaine-associated myocardial infarction has previously generally been conservative, using benzodiazepines, aspirin, glyceryl trinitrate, calcium channel blockers, and thrombolytic drugs. In the context of 10 patients with cocaineassociated myocardial infarction, who were treated with percutaneous interventions, including angioplasty, stenting, and AngioJet mechanical extraction of thrombus, the authors © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

suggested that percutaneous intervention can be performed in such patients safely and with a high degree of procedural success (4cr ). Patients with cocaine-associated chest pain and electrocardiographic ST segment elevation should ﬁrst undergo coronary angiography, if available, followed by percutaneous intervention. Alternatively, thrombolytic drugs can be used. However, the relative safety and efﬁcacy of thrombolytic drugs compared with percutaneous intervention is undeﬁned in patients with cocaine-associated myocardial infarction.

Prenatal cocaine exposure and perinatal effects The complex interplay between the relative effects of prenatal cocaine exposure and perinatal and environmental factors on development has been evaluated, using a structural model to describe the direct and indirect effects of prenatal drug exposure on developmental outcome from birth to age 6 months (5CR ). Key variables included prenatal drug exposure, perinatal medical characteristics, maternal/caregiver/family characteristics, the home environment, and neurobehavioral outcomes. The study was based on 154 predominantly crack-using women and 154 control subjects matched for pregnancy risk, parity, race, and socioeconomic status. Prior exclusion criteria included age under 18 years, a major illness diagnosed before pregnancy, chronic use of legal drugs, and any use of illicit drugs other than cocaine and marijuana. Urine specimens were collected at two unanticipated times and positive serum samples were

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2 conﬁrmed by gas chromatography/mass spectroscopy. Measures analysed by blinded evaluators included medical assessment at birth and developmental assessments at birth, 1 month, and 6 months, as well as caregiver characteristics and environmental factors at birth and 1 month. Exposure to cocaine affected development at birth. Increasing exposure was signiﬁcantly related to poor developmental outcomes, as measured by the Brazelton qualiﬁer scores. Although no direct effects of cocaine were found at either 1 month or 6 months analysed separately, time-dependent analysis showed an effect on development at 6 months. The indirect effects of cocaine exposure were mediated through maternal psychosocial well-being at delivery and birth head circumference. In addition, indirect effects of prenatal cocaine exposure were also related to concomitant alcohol and tobacco use and the birth head circumference. Neither maternal nor caregiver factors at 1 month was directly related to developmental outcome at any time. These ﬁndings support previous ﬁndings (6CR , 7MR , 8C ) that suggest that cocaine is a mild teratogen with regard to neurodevelopmental outcome. The presence of cocaine during the prenatal period disrupts the development of neural systems involved in mediating visual attention. Of 14 cocaine-exposed children and 20 control children aged 14–60 months, whose visual attention, cognition, and behavior were assessed, the cocaine-exposed children had slower reaction times, supporting the hypothesis that impairment in disengagement and sustained attention are associated with prenatal cocaine exposure (9Cr ). There was a trend to slower reaction times to targets presented in the right visual ﬁeld, but not the left visual ﬁeld. Cocaineexposed children also had greater difﬁculties in behavioral regulation, especially related to an ability to cope with heightened levels of positive and negative emotions (10C ). An association between prenatal cocaine exposure and deﬁcits in total language functioning was found in 236 cocaine-exposed and 207 non-cocaine exposed full-term children (11C ). The link between prenatal cocaine exposure and language deﬁcits during early childhood was not related to cocaine-associated deﬁcits in birth weight, length, or head circumference. Three different but potentially interacting mechanisms whereby maternal cocaine use might

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affect early language development have been proposed (12CR ): • subtle dysregulation of attentional systems, with potential for disrupting an infant’s ability to extract and process available linguistic information; • disruptions in parental–child linguistic interactions due to cocaine and other drug use; • impoverished, unstable, and endangering social and care-giving environments. Early detection of language deﬁcits allowed ameliorative intervention aimed at improving academic performance and social adaptation in preschool and school-aged children.

Amphetamines Nervous system The existence of a previous neurological disorder may be a risk factor for treatment-resistant psychosis in metamphetamine abusers (13c ). It is of particular interest that most of these patients sustained their disorder during childhood. It is not uncommon for metamphetamine patients to continue with psychotic symptoms despite extended periods of abstinence (14c ). These patients often are labelled as being schizophrenic. This study has shown the importance of considering a history of neurological disorders, especially during childhood, in such patients. Skin The severe form of erythema multiforme known as toxic epidermal necrolysis has been attributed to a mixture of dexamphetamine and ephedrine (15A ). • A 27-year-old woman developed peripheral target plaques, papules, blisters, and lip erosions, consistent with erythema multiforme, 9 days after using ”speed” (dexamphetamine and ephedrine), and 3 days later developed widespread lesions with large areas of blistering affecting 40% of her body surface area. She was given intravenous ciclosporin and improved within 24 hours.

Drug abuse There is a high prevalence of the use of amphetamine-like drugs in Brazil, particularly among women, owing to the “culture of slimness as a symbol of beauty” (16C ). Of 2370 subjects in Sao Paulo and Brasilia,

Central nervous system stimulants and drugs that suppress appetite

72% had already undergone from one to more than 10 previous courses of treatment, usually with amphetamine-like anorectic drugs. Over half of them had taken amphetamine-like drugs in compound formulations containing four or more substances, such as benzodiazepines and/or laxatives, diuretics, and thyroid hormones. There were adverse reactions to the amphetamine-like drugs in 86% and 37% sought medical advice; 3.9% required hospitalization. The authors argued the need for more rigorous legislation and enforcement strategies to stop such misuse of drugs. Drug interactions A man taking long-term dexamphetamine had two episodes of serotonin syndrome while taking ﬁrst venlafaxine and later citalopram (17A ). • A 32-year-old man, who was taking dexamphetamine 5 mg tds for adult attention deﬁcit hyperactive disorder, developed marked agitation, anxiety, shivering, and tremor after taking venlafaxine for 2 weeks (75 mg/day increased after a week to 150 mg/day). His heart rate was 140/min, blood pressure 142/93 mmHg, and temperature 37.3◦ C. His pupils were dilated and reactive. There was generalized hypertonia, hyper-reﬂexia and frequent myoclonic jerking. Dexamphetamine and venlafaxine were withdrawn and cyproheptadine (doses of 8 mg up to a total of 32 mg over 3 hours) was given. His symptoms completely resolved within a few hours. Dexamphetamine was restarted 3 days later and citalopram was started a few days later. Two weeks later he reported similar symptoms and stopped taking citalopram. He was successfully treated again with cyproheptadine.

Methylphenidate Cardiovascular Ambulatory blood pressure monitoring showed changes in blood pressure and heart rate in boys aged 7–11 years taking stimulant therapy (18c ). This preliminary study with chronic methylphenidate or Adderrall (dexamphetamine/levamphetamine) for attention deﬁcit hyperactive disorder showed alterations in awake and asleep blood pressures, with profound nocturnal dipping. Modiﬁedrelease formulations of methylphenidate and Adderall now allow more sustained blood concentrations in children. The effects of these newer formulations on cardiovascular indices should be evaluated.

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Endocrine Methylphenidate has been reported to cause stunting of growth by impairing growth hormone secretion (19A ). • A 10-year-old boy with attention deﬁcit hyperactive disorder and chronic asthma, who was using inhaled corticosteroids, developed almost complete growth arrest during methylphenidate treatment. Growth hormone stimulation tests and measurement of growth hormone-dependent growth factors suggested that methylphenidate had altered growth hormone secretion and had impaired growth. Determination of growth velocity was a sensitive marker for the evaluation of growth.

Modaﬁnil Modaﬁnil signiﬁcantly improves fatigue and is well tolerated by patients with multiple sclerosis. In a 9-week, single-blind, placebocontrolled pilot study in 72 patients who took modaﬁnil 200 mg/day for 2 weeks, there was signiﬁcant improvement in fatigue compared with placebo run-in treatment (20C ). The most frequent adverse effects were headache, nausea, and anxiety, and these were rated as either mild or moderate. Drug interactions Clozapine Clozapine toxicity occurred after modaﬁnil administration to reverse sedation associated with clozapine (21A ). • A 42-year-old man with schizophrenia, taking haloperidol, quetiapine, divalproex, gabapentin, benzatropine, and lorazepam, was given clozapine 25 mg at bedtime titrated to 400 mg/day over 13 days. His non-psychotropic medications included levothyroxine, furosemide, potassium, and docusate sodium. All other psychotropic drugs were tapered and withdrawn by day 69. On day 70 the serum clozapine concentration was 761 ng/ml. Because of persistent psychotic symptoms, the dose of clozapine was increased to 450 mg/day on day 77, but this resulted in severe sedation. He was given modaﬁnil 100 mg/day on day 82, titrated to 300 mg/day by day 101; this produced slight improvement in sedation. On day 116 he complained of dizziness, had an unsteady gait, and fell twice. He was afebrile and tachycardic but had a normal blood pressure; his blood oxygen saturation was 86%. His serum clozapine concentration on day 112 was 1400 ng/ml. Clozapine and modaﬁnil were withdrawn. His gait disturbance and hypoxemia resolved. Clozapine 100 mg/day was restarted on day 121 and increased to 300 mg/day by day 122. The clozapine concentration 21 days later was 1236 ng/ml and 5 weeks later 960 ng/ml.

4 It is possible that inhibition of CYP2C19 by modaﬁnil interfered with clozapine clearance in this case (22E ). Despite the potential of modaﬁnil for reversing clozapine-associated sedation (23c ), caution is required when prescribing this drug combination. Dexamphetamine The potential for an interaction of modaﬁnil with dexamphetamine, each at steady state, has been investigated in an open, randomized study in 32 healthy subjects (24c ). All took modaﬁnil orally once daily for 28 days (200 mg on days 1–7 and 400 mg on days 8– 28). On days 22–28, half of them also took dexamphetamine 20 mg orally 7 hours after modaﬁnil. The steady-state pharmacokinetics of modaﬁnil and its metabolites, modaﬁnil acid and modaﬁnil sulfone, were unaltered by lowdose dexamphetamine. Adverse events (abdominal pain, headache, and insomnia) were similar in the two groups and mild or moderate in nature.

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crises and severe hyperthermia, and labetalol or sodium nitroprusside are reasonable choices for rapid stabilization of blood pressure.

Prolintane Drug interactions An interaction of prolintane with diphenhydramine has been reported (26A ). • A young man developed visual hallucinations after taking prolintane and diphenhydramine. He had started to take prolintane 20 mg/day 2 months before, in order to enhance his intellectual performance and academic grades. Soon afterwards he had sleep disturbance and resorted to a hypnotic containing diphenhydramine 25 mg. Despite this, insomnia preceded the acute psychotic episode. Prolintane and diphenhydramine were withdrawn and he was given oral haloperidol and clorazepate. The symptoms gradually abated.

Pharmacological kindling resulting from increased dopaminergic activity could have explained this psychotic episode (27c ).

Pemoline Drug overdose Five children who took excessive amounts of pemoline have been described (25cr ). They had a relatively benign course and their symptoms appeared to be primarily accentuated pharmacological effects on the central nervous and cardiovascular systems. Sinus tachycardia, hypertension, hyperactivity, choreoathetoid movements, and hallucinations were most commonly observed, consistent with previous reports. Possible rhabdomyolysis, manifested by raised serum CPK activity, was also observed in three of four patients in whom it was measured; this appears to be common in acute pemoline poisoning. After ingestion, symptoms occurred within 6 hours and lasted up to 48 hours in all cases. Gastric lavage and activated charcoal are considered to be effective decontamination measures, whereas ipecac-induced emesis should be avoided after massive ingestion, because of the risk of seizures. Aggressive use of benzodiazepine is a reasonable ﬁrst choice to treat associated involuntary movements, tremor, hyperactivity, and agitation. Chlorpromazine or haloperidol can also be used, especially for serious, lifethreatening symptoms, including hypertensive

DRUGS THAT SUPPRESS APPETITE (SEDA-23, 2; SEDA-24, 4; SEDA-25, 5; SEDA-26, 6)

Fenﬂuramines and phentermine Cardiovascular Valvulopathy associated with the use of diet drugs, such as fenﬂuramines and phentermine, has been reviewed (28R ). The use of fenﬂuramine or dexfenﬂuramine, alone or in combination with phentermine, in 2524 adult participants in the population-based Hypertension Genetic Epidemiology Network Study, was associated with aortic regurgitation independent of aortic dilatation or ﬁbrocalciﬁcation (29C ). Association between use of phenﬂuramine/dexfenﬂuramine (alone or with phentermine) and aortic regurgitation adjusted for potential confounders was analyzed. Nineteen participants, all of whom had hypertension, were being treated with fenﬂuramine/ dexfenﬂuramine (5 on these agents alone, 14 also with phentermine). Aortic regurgitation was present in 32% (n = 6) of those taking fenﬂuramine/dexfenﬂuramine versus 6%

Central nervous system stimulants and drugs that suppress appetite

(162/2505) of remaining subjects (p = 0.001). In multivariate-adjusted analyses, after adjusting for important confounders, in particular aortic root structure, treatment with fenﬂuramine or dexfenﬂuramine was associated with aortic regurgitation (OR = 5.2; 95% CI: 1.7 to 14) and ﬁbrocalciﬁcation (OR = 5.2; 95% CI: 1.9 to 15). Of 120 patients who had follow-up echocardiography at least twice after stopping fenﬂuramine–phentermine, 99 met FDA criteria for valvulopathy (30c ). On second echocardiography, 57 of these 99 had no change in valvulopathy, 33 had improved, and nine had deteriorated; nine patients no longer met FDA criteria for valvulopathy. The authors suggested that physicians must continue to be vigilant with patients who develop valvulopathy after taking fenﬂuramine–phentermine. The autopsy ﬁndings in the heart and lungs of a patient with pulmonary hypertension associated with fenﬂuramine and phentermine have been described (31A ). • A 36-year-old woman with a body mass index of 47.5 kg/m2 , took fen–phen for 7 months and developed pulmonary hypertension. Her pulmonary arterial pressure was 56 mmHg and echocardiography showed right ventricular dilatation and hypokinesia. She had a cardiopulmonary arrest during right-heart catheterization and died 3 days later. At autopsy, there was right ventricular dilatation with a ﬁbroproliferative tricuspid valve. The pulmonary arteries had ﬁbroproliferative plaques, which were more severe and prominent in the upper lobes than in the lower lobes.

More autopsy cases of patients with a history of fen–phen use are warranted, to document the frequency of combined cardiac valvular disease and pulmonary hypertension. Drug contamination There have been reports of herbal remedies adulterated with fenﬂuramine. There was public health concern in the UK after the referral of a 44-year-old woman with new-onset hypertension, palpitation, anxiety, and a body mass index of 19 kg/m2 . It became apparent that an alarming number of the local population had been attending a particular Chinese herbalist for weight loss remedies. Most had been taking multiple formulations and described “spectacular” results. Several reported considerable cardiovascular symptoms, but they were reassured that

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Chinese medicines are natural and can cause no harm. Analysis by gas chromatography showed a high concentration of fenﬂuramine in two of the products (sold as Qian Er and Ma Zin Dol, presumably mimicking the brand name Mazindol). Fenﬂuramine was also found in the patients’ urine. Subsequently, a student nurse was admitted with severe fenﬂuramine toxicity, which developed 2 hours after her ﬁrst dose of a herbal slimming remedy (32A ). Following an investigation of this case the Medicines Control Agency published a report on traditional ethnic medicines and the current law (33S ). Stringent regulation of traditional medicines, at least to the standards of conventional practice, is urgently needed. The hazards associated with the use of dietary supplements containing ma huang, a herbal source of ephedrine, have also been reported (34A ). Use in pregnancy In a prospective cohort study of 98 women who had taken fenﬂuramine/phentermine at the recommended daily dose during the ﬁrst trimester of pregnancy and 233 women who had not taken it, there was no evidence of an increased risk of spontaneous abortion or of major or minor anomalies in the offspring of women who took fenﬂuramine/phentermine (35C ). These ﬁndings are similar to those of a previous French Collaborative Study (36C ). However, the risk to the offspring of women who take fenﬂuramine/phentermine for more prolonged periods and at higher dosages during pregnancy is unknown.

Sibutramine Clinical trials have conﬁrmed the efﬁcacy of sibutramine as a weight-loss agent in doses of 10–20 mg/day. The beneﬁt of sibutramine is not only in its ability to induce weight loss, but also to maintain the weight loss effect for up to 2 years. However, once sibutramine is withdrawn, weight gain commonly occurs. Thus, sibutramine is considered effective in the management of obese patients who require pharmacotherapy as part of a multimodal approach to weight reduction (37R ).

6 Cardiovascular Sibutramine was approved in Italy in April 2001, but was taken off the market there on 6 March 2002, after 50 reported adverse reactions (mainly tachycardia, hypertension, and dysrhythmias, in seven cases serious), and two deaths from cardiac arrest (38S ). The Secretariat of the European Medicines Evaluation Agency has begun a comprehensive beneﬁt:harm assessment of sibutramine, which remains on the market in several European countries; these include the UK (where there have been 215 reports of 411 adverse events, 95 serious and two deaths) and France (where there have been 99 reports of adverse events, 10 serious but no deaths). From February 1998 to September 2001, the FDA in the USA received reports of 397 adverse events (143 cardiac dysrhythmias and 29 deaths, 19 due to cardiovascular causes, 10 involving people under 50 years of age, and three involving women under 30 years of age) (39r ). In Canada, 28 adverse reactions (mainly hypertension and dysrhythmias, but no deaths) were reported from December 2000 to February 2002, including one case of chest pain, one of stroke, and two of eye hemorrhage; in three of these cases, the patients were concurrently taking a contraindicated antidepressant (40r ). The safety of sibutramine needs further post-marketing surveillance. In a placebo-controlled study, sibutramine 10 mg/day for 6 months caused weight loss and a reduction in left ventricular mass in 86 obese hypertensive patients with no changes in blood pressure or antihypertensive therapy (41C ). Baseline investigations included echocardiography, 24-hour ambulatory blood pressure monitoring, and hepatic enzyme measurements. Compared with placebo sibutramine produced greater weight loss, an increase in heart rate, and a reduction in left ventricular mass/height index. The two groups had comparable increases in alkaline phosphatase activity and comparable adjustments in antihypertensive therapy. The most frequent adverse effects associated with sibutramine were dry mouth and arthralgia; higher frequencies of insomnia and irritability, as suggested in other studies, were not found. The alterations reported in alkaline phosphatase may be associated with mobilization of visceral adipose tissue (42c ) and cannot be attributed to the use of sibutramine.

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The observation that sibutramine, which blocks the reuptake of noradrenaline and serotonin and to a lesser extent dopamine (37R ), causes a raised blood pressure has been a cause of concern (43C , 44C ). Some insight into this problem and its magnitude comes from two recent studies (45C , 46C ). Most studies have shown a positive relation between blood pressure and weight (47R ). The failure of the blood pressure to fall with weight loss in normotensive and hypertensive patients treated with sibutramine differs from the fall seen with orlistat (48C –50C ) or weight loss induced by life-style modiﬁcations (51C , 52C ). In the case of sibutramine, the potentially detrimental effect due to the failure of the blood pressure to fall with weight loss may be offset by the reductions in lipids, insulin, and uric acid that occur with weight loss (53r ). Intermittent use of sibutramine has been proposed to reduce potential concerns about its effect on blood pressure. An alternative strategy would be to identify those patients who respond to sibutramine with weight loss, but who have minimal changes in blood pressure (53r ). The effects of sibutramine on weight loss, blood pressure, and pulse rate in hypertensive obese patients, whose blood pressure was well controlled with a beta-blocker either alone or with a thiazide diuretic, has been evaluated in a 12-week, double-blind, placebo-controlled, parallel-group, randomized study in 69 patients (45C ). Sibutramine was effective and welltolerated and did not exacerbate pre-existing hypertension controlled with beta-blockers. Despite the presence of apparently effective betablockade, there were modest increases in pulse rate in those who took sibutramine, suggesting that mechanisms other than increased sympathetic tone may, at least in part, mediate this effect. Based on the potential for increased blood pressure and pulse rate, obese patients with well-controlled hypertension who are taking sibutramine should be monitored periodically (45C ). In a 52-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 220 obese (BMI 27–40 kg/m2 ) hypertensive patients, whose hypertension was well controlled with an ACE inhibitor with or without a thiazide diuretic, sibutramine 20 mg/day safely and effectively achieved weight loss without compromising blood pressure control

Central nervous system stimulants and drugs that suppress appetite

(46C ). Blood pressure remained in the target range in patients who took sibutramine or placebo, although sibutramine was associated with a small mean increase in blood pressure and a modest increase in pulse rate. Metabolic In a multicenter, double-blind, randomized, parallel-group, placebo-controlled trial in 22 European centers for specialist diabetes care over 6 months, sibutramine, in conjunction with moderate caloric restriction, enabled obese patients with type 2 diabetes taking sulfonylureas to achieve clinically signiﬁcant weight loss (54C ). This was associated with additional improvement in glycemic control in a limited number of patients who lost at least 10% of their baseline body weight. Drug interactions Citalopram Hypomania in a unipolar depressed woman has been attributed to concomitant use of sibutramine and citalopram (55A ). The close temporal relation between the onset and disappearance of hypomania with the introduction and withdrawal of sibutramine suggested a causal link. This report suggests that combining sibutramine with a serotonin reuptake inhibitor could cause hypomania in people with unipolar major depressive disorder with a family history of bipolar disorder.

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7

Alzheimer’s disease (57M ). Patients taking active treatment will have more favorable ADAS– Cog scores for at least 6 months, after which their scores will begin to converge with those who are taking placebo. The cost-effectiveness data were inconclusive.

Idebenone versus tacrine In a prospective randomized, double-blind, parallel-group, multicenter comparison of idebenone 360 mg/day (n = 104) or tacrine up to 160 mg/day (n = 99) for 60 weeks in 203 patients with mild to moderate dementia of the Alzheimer’s type, idebenone produced more beneﬁt than tacrine (58C ). The beneﬁt:harm ratio was favorable for idebenone compared with tacrine. More patients taking tacrine (65%) reported adverse events than those taking idebenone (50%). The drop-out rate in those taking tacrine was also higher. There were statistically signiﬁcant differences between tacrine and idebenone for gastrointestinal adverse events (nausea, vomiting) and hepatobiliary toxicity (raised serum transaminase activity).

Rivastigmine Finasteride Soon after the introduction of ﬁnasteride to treat alopecia, a 30-year-old man taking sibutramine developed paranoid psychotic behavior (56A ). This drug interaction was demonstrated by careful clinical follow-up and the use of Naranjo’s algorithm.

DRUGS USED IN ALZHEIMER’S DISEASE (SED-14, 435; SEDA-24, 6; SEDA-25, 7; SEDA-26, 7)

Donepezil versus rivastigmine A meta-analysis of various drugs approved for the treatment of Alzheimer’s disease in the USA and Canada has suggested that donepezil and rivastigmine can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild to moderate

The efﬁcacy and safety of rivastigmine have been investigated in several new studies (59cr , 60c –62c ). Neurologists generally titrated this drug more slowly than recommended in the prescribing information (59c ). In daily practice, over 50% of the patients were unable to tolerate rivastigmine, mainly owing to cholinergic gastrointestinal adverse effects (60c ), whereas others have found that the adverse events were most frequently mild and transient (61c , 62c ). It has been suggested that early treatment with rivastigmine (6–12 mg/day) is associated with sustained long-term (up to 52 weeks) cognitive beneﬁt in patients with Alzheimer’s disease (62c ). Cardiovascular Based on an electrocardiographic analysis of pooled data from four 26-week, phase III, multicenter, double-blind, placebo-controlled trials of rivastigmine (n = 2791), there were no adverse effects on

8 cardiac function (63C ). Rivastigmine can therefore be safely given to patients with Alzheimer’s disease without the need for cardiac monitoring. Gastrointestinal The transient use of centrally-acting antiemetics during rivastigmine titration may be useful in combination with dosewithholding and titration strategies to allow

Chapter 1

Reginald P. Sequeira

more patients to reach higher doses, resulting in a rapid and robust therapeutic effect. Patients who were treated with trihexyphenidyl and trimethobenzamide were more likely to be able to maintain or to increase their dose of rivastigmine than patients who were treated with glycopyrrolate or ondansetron (64c ).

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inner-city children of cocaine- and other drug-using mothers. J Appl Dev Psychol 1999; 20: 159–80. 13. Fujii D. Risk factors for treatment resistive methamphetamine psychosis. J Neuropsychiatry Clin Neurosci 2002; 14: 239–40. 14. Iwanami A, Sugiyama A, Kuroki N, Toda S, Kato N, Nakatani Y, Horita N, Kaneko T. Patients with methamphetamine psychosis admitted to a psychiatric hospital in Japan. Acta Psychiatr Scand 1994; 89: 428–32. 15. Yung A, Agnew K, Snow J, Oliver F. Two unusual cases of toxic epidermal necrolysis. Australas J Dermatol 2002; 43: 35–8. 16. Nappo SA, Tabach R, Noto AR, Galduroz JCF, Carlini EA. Use of anorectic amphetamine-like drugs by Brazilian women. Eating Behav 2002; 3: 153–65. 17. Prior FH, Isbister GK, Dawson AH, Whyte IM. Serotonin toxicity with therapeutic doses of dexamphetamine and venlafaxine. Med J Aust 2002; 186: 240–1. 18. Stowe CD, Gardner SF, Gist CC, Schulz EG, Wells TG. 24-hour ambulatory blood pressure monitoring in male children receiving stimulant therapy. Ann Pharmacother 2002; 36: 1142–9. 19. Hottkamp K, Peters-Wallraf B, Wuller S, Pfaafﬂe R, Herpertz-Dahlmann B. Methylphenidaterelated growth impairment. J Child Adolesc Psychopharmacol 2002; 12: 55–61. 20. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efﬁcacy and safety of modaﬁnil (Provigil® ) for the treatment of fatigue in multiple sclerosis: a two center phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72: 179–83. 21. Dequardo JR. Modaﬁnil-associated clozapine toxicity. Am J Psychiatry 2002; 159: 1243–4. 22. Robertson P, DeCory HH, Madan A, Parkinson A. In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modaﬁnil. Drug Metab Dispos 2000; 28: 664–71. 23. Teitelman E. Off-label uses of modaﬁnil. Correction. Am J Psychiatry 2001; 158: 970–1. 24. Hellriegel ET, Arora S, Nelson M, Robertson P, Jr. Steady-state pharmacokinetics and tolerability of modaﬁnil administered alone or in combination with dextro-amphetamine in healthy volunteers. J Clin Pharmacol 2002; 42: 450–60.

Central nervous system stimulants and drugs that suppress appetite 25. Nakamura H, Blumer JL, Reed MD. Pemoline ingestion in children: a report of ﬁve cases and review of the literature. J Clin Pharmacol 2002; 42: 275–82. 26. Paya B, Guisado JA, Vaz FJ, Crespo-Facorro B. Visual hallucinations induced by the combination of prolintane and diphenhydramine. Pharmacopsychiatry 2002; 35: 24–5. 27. Moskovitz C, Moses H, Klawans HL. Levodopa-induced psychosis: a kindling phenomenon. Am J Psychiatry 1978; 135: 669–75. 28. Murthy TH, Weissman NJ. Diet–drug valvulopathy. ACC Curr J Rev 2002; 11: 17–20. 29. Palmieri V, Arnett DK, Roman MJ, Liu JE, Bella JN, Oberman A, Kitzman DW, Hopkins PN, Morgan D, de Simone G, Devereux RB. Appetite suppressants and valvular heart disease in a population-based sample: the HyperGEN study. Am J Med 2002; 112: 710–15. 30. Dahl CF, Allen MR. Regression and progression of valvulopathy associated with fenﬂuramine and phentermine. Ann Intern Med 2002; 136: 489. 31. Tomita T, Zhao Q. Autopsy ﬁndings of heart and lungs in a patient with primary pulmonary hypertension associated with use of fenﬂuramine and phentermine. Chest 2002; 121: 649–52. 32. Metcalfe K, Corns C, Fahie-Wison M, Mackenzie P. Chinese medicines for slimming still cause health problems. Br Med J 2002; 324: 679. 33. Medicines Control Agency. Traditional ethnic medicines: public health and compliance with medicines law. London: MCA, 2001. 34. Samenuk D, Link MS, Homoud MK, Contreras R, Theohardes TC, Wang PJ, Estes NAM II. Adverse cardiovascular events temporally associated with Ma Huang, an herbal source of ephedrine. Mayo Clin Proc 2002; 77: 12–16. 35. Jones KL, Johnson KA, Dick LM, Felix RJ, Kao KK, Chambers CD. Pregnancy outcomes after ﬁrst trimester exposure to phentermine/fenﬂuramine. Teratology 2002; 65: 125–30. 36. Vial T, Robert E, Cartier P, Bertolotti E, Burn A. First-trimester in utero exposure to anorectics: a French collaborative study with special reference to dexfenﬂuramine. Int J Risk Saf Med 1992; 3: 207– 14. 37. Luque CA, Rey JA. The discovery and status of sibutramine as an anti-obesity drug. Eur J Pharmacol 2002; 440: 119–28. 38. Advisory: Health Canada investigates safety of Meridia (sibutramine). Ottawa: Health Canada, 27 Mar 2002. www.hc-sc.gc.ca/english/protection/ warnings/2002/2002-21e.htm. 39. Wooltoron E. Obesity drug sibutramine (Meridia): health and drug alert. Can Med Assoc J 2002; 166: 1307–8. 40. Deitel M. Sibutramine warning: hypertension and cardiac arrhythmias reported. Obes Surg 2002; 12: 422. 41. Faria AN, Filho FFR, Lerario DDG, Kohlmann N, Ferreira SRG, Zanella MT. Effects of sibutramine on the treatment of obesity in patients with arterial hypertension. Arq Bras Cardiol 2002; 78: 176–80.

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42. Luyckx FH, Desaive C, Thiry A, Dewe W, Scheen AJ, Gielen JE, Lefebvre PJ. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord 1998; 22: 222–6. 43. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF. Effect of sibutramine on weight maintenance after weight loss: a randomized trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 2000; 356: 2119–25. 44. Fanghanel G, Cortinas L, Sanchez-Reyez L, Berber A. A clinical trial of the use of sibutramine for the treatment of patients suffering essential obesity. Int J Obes 2000; 24: 144–50. 45. Sramek JJ, Leibowitz MT, Weinstein SP, Rowe ED, Mendel CM, Levy B, McMahon FG, Mullican WS, Toth PD, Cutler NR. Efﬁcacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by β-adrenergic blocking agents: a placebo-controlled, double-blind randomized trial. J Hum Hypertens 2002; 16: 13–19. 46. McMahon FG, Weinstein SP, Rowe E, Ernst KR, Johnson F, Fujioka K, and the Sibutramine in Hypertensive Clinical Study Group. Sibutramine is safe and effective for weight loss in obese patients whose hypertension is well controlled with angiotensin-converting enzyme inhibitors. J Hum Hypertens 2002; 16: 5–11. 47. Cutler JA. Randomized clinical trials of weight reduction in nonhypertensive persons. Ann Epidemiol 1991; 1: 363–70. 48. Rossner S, Sjostrom L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Study Group. Obes Res 2000; 8: 49–61. 49. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J, Heymﬁeld SB. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. J Am Med Assoc 1999; 281: 235–42. 50. Hauptman J, Lucas C, Boldrin MN, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med 2000; 9: 160–7. 51. Stamler R, Stamler J, Grimm R, Gosch FC, Elmer P, Dyer A, Berman R, Fishman J, Van Heel N, Civinelli J, et al. Nutritional therapy for high blood pressure. Final report of a four-year randomized control trial—hypertension control program. J Am Med Assoc 1987; 257: 1484–91. 52. Hypertension Prevention Trial Research Group. The Hypertension Prevention Trial: three year effects of dietary changes on blood pressure. Arch Intern Med 1990; 150: 153–62. 53. Bray GA. Sibutramine and blood pressure: a therapeutic dilemma. J Hum Hypertens 2002; 16: 1–3. 54. Serrano-Rios M, Melchionda N, MorenoCarretero E. Role of sibutramine in the treatment

10 of obese type 2 diabetic patients receiving sulphonylurea therapy. Diabetic Med 2002; 19: 119–24. 55. Benazzi F. Organic hypomania secondary to sibutramine–citalopram interaction. J Clin Psychiatry 2000; 63: 165. 56. Sucar DD, Sougey EB, Neto JB. Psychotic episode induced by potential drug interaction of sibutramine and ﬁnasteride. Rev Bras Psiquiatr 2002; 24: 30–3. 57. Wolfson C, Oremus M, Shukla V, Momoli F, Demers L, Perrault A. Donepezil and revastigmine in the treatment of Alzheimer’s disease: a best evidence synthesis of the published data on their efﬁcacy and cost-effectiveness. Clin Ther 2002; 24: 862–86. 58. Gutzmann H, Kuhl KP, Hadler D, Rapp MA. Safety and efﬁcacy of idebenone versus tacrine in patients with Alzheimer’s disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry 2002; 35: 12–18. 59. Schmidt R, Lechner A, Petrovic K. Rivastigmine in outpatient services: experience of 114 neurologists in Austria. Int Clin Psychopharmacol 2002; 17: 81–5. 60. Richard E, Walstra GT, Van Campen J, Vissers E, Van Gool WA. Rivastigmine in Alzheimer’s

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disease; evaluation of the ﬁrst experience and of structured measurement of efﬁcacy. Ned Tijdschr Geneeskd 2002; 146: 24–7. 61. Bilikiewicz A, Opala G, Podemski R, Puzynski S, Lapin J, Soltys K, Ochudlo S, Barcikowska M, Pfeffer A, Bilinska M, Paradowski B, Parnowski T, Gabryelewicz T. An open-label study to evaluate the safety, tolerability and efﬁcacy of rivastigmine in patients with mild to moderate probable Alzheimer’s disease in the community setting. Med Sci Monit 2002; 8: P15–19. 62. Doraiswamy PM, Krishnan KRR, Anand R, Sohn H, Danyluk J, Hartman RD, Veach J. Longterm effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained beneﬁts? Progr Neuropsychopharmacol Biol Psychiatry 2002; 26: 705–12. 63. Morganroth J, Graham S, Hartman R, Anand R. Electrocardiographic effect of rivastigmine. J Clin Pharmacol 2002; 42: 558–68. 64. Jhee SS, Shiovitz T, Hartman RD, Messina J, Anand R, Sramek J, Cutler NR. Centrally acting antiemetics mitigate nausea and vomiting in patients with Alzheimer’s disease who receive rivastigmine. Clin Neuropharmacol 2002; 25: 122–3.

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2

Antidepressant drugs

TRICYCLIC ANTIDEPRESSANTS (SED-14, 44; SEDA-24, 12; SEDA-25, 13; SEDA-26, 11) Treatment guidelines for depression and anxiety increasingly emphasize the value of longerterm maintenance treatment with antidepressants in order to prevent recurrence of illness. It is therefore important to assess the adverse effects burden of longer-term medication. The change in adverse effects proﬁle over 1 year of treatment has been studied in a doubleblind, placebo-controlled study of maintenance imipramine treatment (average dose 160 mg) in 53 patients with panic disorder (1C ). Adverse effects of imipramine, such as sweating, dry mouth, and increased heart rate, persisted over the year of treatment, while rates of sexual dysfunction fell. Weight gain became increasingly problematic, and by the end of the trial imipramine-treated patients had a mean increase in weight of 4.5 kg, signiﬁcantly more than the placebo-treated subjects, who gained only 1.3 kg. Data of this kind are helpful when advising patients which adverse effects may remit and which are likely to persist during longer-term treatment. These data suggest that relative to SSRIs, such as ﬂuoxetine and sertraline, maintenance treatment with imipramine is less likely to cause sexual dysfunction but has a greater risk of weight gain. Susceptibility factors Age Elderly people have high rates of depression but tend to be excluded from randomized trials of antidepressant treatment. In general, older people metabolize tricyclic antidepressants more slowly and have higher steady-state plasma concentrations. The adverse effects proﬁle of ﬁxed-dose clomipramine (150 mg/day) has been assessed © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

in 112 hospitalized depressed patients (aged 22–70 years), of whom 38 were over 55 years of age (2C ). The only adverse effect that distinguished patients over 55 years was orthostatic hypotension: older subjects had a significantly greater fall in systolic blood pressure on standing. Orthostatic hypotension can lead to falls and injuries, particularly in patients being treated at home, and this suggests that blood pressure should be monitored in older patients who are taking psychiatric doses of tricyclic antidepressants. It is also worth noting that the upper age limit of patients in this study was only 70 years, so it is unclear how more elderly patients would fare with this rather substantial dose of clomipramine. Drug interactions Tricyclic antidepressants are highly bound to plasma proteins. Theoretically, other drugs that are highly protein bound could displace tricyclic antidepressants from protein binding sites; this would be expected to lead to increased plasma concentrations of unbound antidepressant and a greater likelihood of adverse effects. In practice, however, important interactions of this kind are unusual, probably because these drugs have high apparent volumes of distribution, and the amount of drug that can be displaced from plasma proteins is very small compared with tissue concentrations. Salicylates are highly protein bound, and the effect of adding acetylsalicylic acid 1 g/day for 2 days on the plasma availability of imipramine (150 mg/day) has been studied in 20 depressed patients (3c ). Acetylsalicylic acid reduced the protein binding of imipramine and while the total plasma concentration of imipramine was not altered, the unbound concentration rose almost four-fold. The number of characteristic adverse effects of imipramine also increased signiﬁcantly. However, this study was not blind and the results must be in doubt, since it is unlikely that brain concentrations of the drug changed signiﬁcantly.

11

12 Maprotiline is a quadricyclic antidepressant that is pharmacologically closely related to the tricyclic antidepressants. It requires careful dosing, because of the risk of seizures. In three patients plasma concentrations of maprotiline were increased by concomitant treatment with the atypical antipsychotic drug, risperidone (4A ). The data suggest that risperidone is a modest inhibitor of CYP2D6 and should therefore be used with caution in combination with drugs such as maprotiline where increased plasma concentrations have the potential to cause serious toxicity.

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-14, 67; SEDA-24, 14; SEDA-25, 14; SEDA-26, 11) Many patients with recurrent depressive disorders are now advised to continue to take antidepressant medication indeﬁnitely if such treatment is effective and well-tolerated. Two patients who had been maintained successfully on ﬂuoxetine (20 mg/day) for 6 and 10 years respectively began to have agitation, tension, and sleep disturbance (5A ). There had been no recent changes in medication status or life events to explain these symptoms, which closely resembled the kind of adverse effects that can occur shortly after the start of SSRI treatment. Both patients improved after downward titration of the dose of ﬂuoxetine. Blood concentrations of ﬂuoxetine were not reported, so it is possible that for some reason (for example, a change in diet or activity) plasma ﬂuoxetine concentrations had recently increased in these subjects. However, the development of characteristic adverse effects after such a long trouble-free period suggests that patients taking maintenance medication need long-term follow-up, or at least ready access to specialist advice. Nervous system SSRIs have been associated with a variety of extrapyramidal symptoms (SEDA-23, 17), but their propensity to produce these effects relative to other antidepressants has been unclear. Spontaneous reports received

Chapter 2

P.J. Cowen

by the Netherlands Pharmacovigilance Foundation between 1985 and 1999 have been analysed in a case-control study (6C ). Relative to other antidepressants, SSRIs were about twice as likely to be implicated in spontaneous reports of extrapyramidal reactions (OR = 2.2; 95% CI = 1.2, 3.9). The risk was greater in patients who were also taking antipsychotic drugs. This result suggests that SSRIs have a modestly increased risk of producing extrapyramidal reactions compared with other antidepressants. However, increased reporting can be inﬂuenced by increased awareness. In addition, no account was apparently taken in this study of relative prescription rates of different antidepressants. The serotonin syndrome is a recognized complication of SSRI treatment. Usually it occurs as part of a drug interaction, when the serotonergic effects of SSRIs are augmented by medications that also have serotoninpotentiating properties (SEDA-22, 14; SEDA25, 16). Occasionally, however, the serotonin syndrome can occur after SSRI monotherapy. • A 23-year-old Japanese woman with major depression took a single dose of paroxetine (20 mg) and 1 hour later had agitation, myoclonus, mild hyperthermia (37.5◦ C), sweating, and diarrhea, symptoms that meet the criteria for the serotonin syndrome; she recovered with supportive treatment over 3 days (7A ).

Blood concentrations of paroxetine were not obtained, but the authors reported that the patient was homozygous for the 10* form of the CYP2D6 allele, which is associated with low CYP2D6 activity in vivo. While this is an interesting observation, it is unlikely by itself to explain the patient’s sensitivity to paroxetine, because this genotype is not uncommon in the Japanese population, and if a lot of Japanese have this genotype, the serotonin syndrome with SSRI monotherapy would be quite common, given the widespread prescription of SSRIs. However, it reinforces clinical advice that in patients new to SSRI treatment it is advisable to start therapy with half the standard dose. Electrolyte balance SSRIs can reportedly cause hyponatremia (SEDA-18, 20; SEDA-26, 13), but the risk relative to other antidepressants is not clear. In a case control study of hyponatremia in 39 071 psychiatric in-patients and

Antidepressant drugs

Chapter 2

out-patients, the incidence of antidepressantinduced hyponatremia was 2.1% (8C ). SSRI users had a three times higher risk of developing hyponatremia relative to users of other antidepressant drugs (OR = 3.1; 95% CI = 1.3, 8.6). Additional risk factors included older age and concomitant treatment with diuretics. Hyponatremia can sometimes cause severe disturbances of consciousness. • A 47-year-old woman with multiple sclerosis took citalopram 20 mg/day for 4 weeks and was found unconscious in her apartment (9A ). The main ﬁnding was a low plasma sodium (108 mmol/l). As a result of prolonged coma, she had rhabdomyolysis and required intubation for 3 days as well as sodium replacement therapy. She eventually made a full recovery.

It is possible in this case that the underlying demyelinating disease may have made the patient more susceptible to the sodium-lowering effects of the SSRI. Reproductive system Vaginal bleeding and menorrhagia have been rarely reported with SSRI treatment and the mechanism is uncertain. SSRIs have been associated with bleeding diatheses, which might explain these observations (SEDA-24, 15; SEDA-25, 14). Another possibility is an action of serotonin pathways on the neural regulation of gonadotropin release. More cases have been reported. • A 67-year-old woman developed vaginal bleeding after taking sertraline 25 mg/day for 3 days (10A ). The sertraline was withdrawn and the bleeding stopped 48 hours later. • A 41-year-old woman developed vaginal bleeding after taking venlafaxine 75 mg/day, a dose at which selective serotonin blockade is the predominant pharmacological action (11A ). The vaginal bleeding stopped 24 hours after venlafaxine withdrawal and occurred again on re-challenge.

Fetotoxicity Fluoxetine can occasionally cause cardiac dysrhythmias in adults, and may have done so in a fetus whose mother took ﬂuoxetine during pregnancy. • A woman took ﬂuoxetine (20–30 mg/day) from the 28th week of pregnancy (12A ). The ﬂuoxetine was withdrawn during the 37th week, and at 38 weeks a male infant (2700 g) was born by spontaneous vaginal delivery. Both before and after delivery the baby was noted to have multiple atrial and ventricular extra beats. Echocardiography showed a normal heart and the baby was otherwise well. By

13 discharge on day 5 the frequency of extra beats had fallen, and on follow-up 1 month later they were no longer present.

The long half-life of ﬂuoxetine and its active metabolite, norﬂuoxetine, means that active drug would have been present in the mother and baby for some weeks after withdrawal. However, as the authors pointed out, the baseline incidence of atrial extra beats in a fetus in utero is about 1–2%. It is therefore possible that treatment with ﬂuoxetine in this case was coincidental. Drug overdose One reason for the popularity of SSRIs is their safety in overdose compared with tricyclic antidepressants. As noted previously, however, there are concerns that citalopram may be less safe in acute overdose than other SSRIs (SEDA-21, 12). Among all fatal poisonings in one forensic district of Sweden, citalopram was the fourth most commonly used drug (22 of 358 cases) (13C ). However, when correction was made for prescription rate, citalopram was less toxic than amitriptyline, dextropropoxyphene, or nitrazepam. This study has conﬁrmed that citalopram is less toxic than tricyclic antidepressants such as amitriptyline. However, whether it is more toxic than other SSRIs is still uncertain. Drug interactions SSRIs inhibit hepatic CYP isozymes and can thereby increase the activity of co-administered drugs that are metabolized by this route (SEDA-22, 13; SEDA-24, 15). In healthy volunteers randomly allocated to ﬂuoxetine (20 mg/day), sertraline (100 mg/day), or paroxetine (20 mg/day) the activity of CYP2D6 was measured by dextromethorphan testing once steady state had been achieved and the medication was withdrawn (14C ). Extrapolated calculations showed that the mean time for full CYP2D6 recovery after ﬂuoxetine (63 days) was signiﬁcantly longer than that for sertraline (25 days) or paroxetine (20 days). Accordingly, even after SSRIs have been withdrawn, the potential for drug interactions persists for substantial periods of time, particularly in the case of ﬂuoxetine. SSRIs can also cause pharmacodynamic drug interactions for some time after withdrawal, through residual serotonin re-uptake blocking activity.

14 • A 56-year-old woman with a postoperative wound infection developed the serotonin syndrome when she was given the antibiotic linezolid intravenously (15A ). The dose of paroxetine had been tapered and it had been withdrawn 5 days before.

Linezolid inhibits monoamine oxidase activity and has been reported to cause serotonin toxicity in combination with paroxetine. While some patients have apparently taken the combination of linezolid and an SSRI safely, this report suggests that patients taking combined treatment should be monitored for serotonin toxicity. Monoamine re-uptake inhibitors can also potentiate the serotonergic effects of SSRIs. • A 43-year-old woman who had taken citalopram 40 mg/day for 2 years was given sibutramine for obesity and a few hours after the ﬁrst dose of 10 mg had irritability, racing thoughts, pressure of speech, agitation, shivering, and sweating (16A ). These symptoms persisted for 3 days, during which time she continued to take sibutramine. The day after sibutramine was withdrawn the symptoms resolved.

The serotonin syndrome can present with hypomanic features, and the clinical picture and rapid onset in this case suggested that the addition of sibutramine to citalopram provoked serotonin toxicity. Sibutramine blocks the re-uptake of serotonin, dopamine, and noradrenaline. Whether the serotonin toxicity seen here resulted purely from the combined effects of both citalopram and sibutramine in blocking serotonin re-uptake is unclear. It is possible, for example, that potentiation of dopamine and noradrenaline activity by sibutramine might also have been involved. Combined treatment with atypical antipsychotic drugs and SSRIs is common. Case reports have suggested that SSRIs can increase risperidone concentrations and increase the risk of extrapyramidal disorders (SEDA-23, 18). In a systematic open study in 11 hospitalized patients taking a steady dose of risperidone (4–6 mg/day), ﬂuoxetine (20 mg/day) increased plasma concentrations of active antipsychotic medication (combined concentrations of risperidone and 9-hydroxyrisperidone) by 50% after treatment for 25 days (17C ). Despite this, the treatment was well tolerated and there were improvements in rating scales of psychosis and depressed mood. Whether this

Chapter 2

P.J. Cowen

was due to the introduction of ﬂuoxetine or the higher plasma concentrations of risperidone is not clear. Fluoxetine and norﬂuoxetine would require at least a further 2 weeks to reach steady state, so additional increases in risperidone concentrations might be anticipated over this time. Methadone maintenance treatment is now established by controlled trials as effective in managing patients with opioid dependence. SSRIs are often co-prescribed for such patients, and there have been reports that SSRIs can increase methadone concentrations, presumably by inhibition of CYP2D6 (SEDA-25, 15). The effect of adding paroxetine (20 mg/day) to the treatment regimen has been studied in 10 opiate-dependent patients taking methadone maintenance (18C ). Methadone concentrations increased on average by about one-third, although there was much individual variation. There were no obvious clinical consequences, presumably because the patients were fairly tolerant to the effects of methadone. However, the authors cautioned that sudden withdrawal of an SSRI in methadone users has the potential to trigger opioid withdrawal symptoms. When a drug has a relatively narrow therapeutic index, such as acenocoumarol, pharmacokinetic interactions can have serious clinical consequences. • A 63-year-old woman taking acenocoumarol 18 mg/week (INR 1.8) started to take citalopram 20 mg/day and 10 days later noted spontaneous bleeding from her gums; the INR had risen to more than 15 (19A ). She was treated with two units of whole blood and the citalopram was withdrawn. Five days later the INR had returned to the target range.

Citalopram is said to be less likely than other SSRIs to cause drug interactions, because it is a relatively weak inhibitor of CYP isozymes. However, even slight inhibition may have produced serious consequences in this case.

OTHER ANTIDEPRESSANTS Amfebutamone (bupropion) (SED-14, 60; SEDA-24, 16; SEDA-25, 17; SEDA-26, 15) Amfebutamone has been used as an antidepressant for many years in the USA and Canada

Antidepressant drugs

Chapter 2

and is now licensed in Europe for smoking cessation. There has been concern about the number of serious adverse reactions associated with amfebutamone, with particular emphasis on the risk of seizures. Deaths have also been reported from myocarditis and liver failure (20r ). A problem in determining the role of amfebutamone in these adverse effects is that it is prescribed for heavy smokers who are at risk of serious co-morbid disorders, particularly cardiovascular and respiratory disease. However, it has been clear for some time that the use of amfebutamone is associated with an increased risk of seizures, though this is less with the modiﬁed-release formulation (SEDA-23, 20). Cardiovascular The UK Committee on Safety of Medicines has received over 200 reports of chest pain in patients taking amfebutamone, and a case of myocardial infarction has now been reported. • A 43-year-old man who had smoked up to 20 cigarettes daily for several years and had a family history of heart disease was given amfebutamone and stopped smoking after reaching the recommended dose (300 mg/day) (21A ). Three days later he developed central chest and arm pain and 1 day later stopped taking amfebutamone. Three days after this he developed classical symptoms of acute inferoposterolateral myocardial infarction. He was treated with thrombolytic therapy and discharged taking secondary prevention therapy.

It is difﬁcult to know how far amfebutamone might have contributed to this acute cardiac event. However, continuing vigilance and case– control studies are warranted. Nervous system Of 279 patients who presented to a hospital emergency service between 1994 and 1998 with a ﬁrst tonic–clonic seizure, 17 (6.1%) had seizures that were thought to be drug related (22c ). The most common druginduced causes were cocaine intoxication (6/17) and benzodiazepine withdrawal (5/17) followed by amfebutamone use (4/17). While one amfebutamone-associated seizure occurred in a 26-year-old woman without any other risk factors, the three other patients (all women) had additional risk factors, such as concomitant treatment with antidepressants that also lower seizure threshold and a history of bulimia nervosa. These results suggest that amfebutamone is a not infrequent cause of de novo

15 seizures. However, because of the time frame of the study, many of the patients would have been taking standard-release amfebutamone. It would be of interest to repeat the study now that modiﬁed-release amfebutamone is available. Acute dystonia is a recognized complication of treatment with antipsychotic drugs and it can also occur with SSRIs and the anxiolytic drug buspirone. • A 44-year-old man took amfebutamone 300 mg/day and buspirone 45 mg/day for depression (23A ). Over 2–3 weeks he developed increasing neck stiffness, with tightening and spasm of the jaw muscles and pain in the left temporomandibular joint. He stopped taking his medications, and all his symptoms resolved over the next 3 weeks. Rechallenge with buspirone (45 mg/day) failed to reproduce the dystonic symptoms. The buspirone was withdrawn and amfebutamone 150 mg/day was started; the dystonic symptoms did not recur. However, 24 hours after the dose of amfebutamone was increased to 300 mg/day there was a return of neck stiffness and jaw spasm.

Amfebutamone has dopaminergic properties, which seem to have played a part in this dystonia. Whether the effect was initiated by concomitant buspirone therapy is unclear, but subsequently amfebutamone alone was sufﬁcient to produce the dystonic symptoms. Drug interactions Amfebutamone is sometimes used to augment the action of other antidepressant drugs, but there are few data on the pharmacokinetic effects of this strategy. In an open study in 19 consecutive patients (7 men and 12 women), amfebutamone (150 mg/day for 8 weeks) did not alter plasma concentrations of paroxetine or ﬂuoxetine (24c ). Plasma concentrations of venlafaxine increased, but concentrations of its active metabolite, O-desmethylvenlafaxine, fell. Overall tolerability was good and there was a signiﬁcant reduction in depression rating scales. Sexual function, particularly orgasmic function in women, improved. These data suggest that adding amfebutamone to SSRI treatment does not alter plasma concentrations of SSRIs. The addition of amfebutamone to venlafaxine seems unlikely to cause pharmacokinetic problems in practice, because the increase in plasma concentration of the parent compound was offset by a reduction in the concentration of its major active

16

Chapter 2

metabolite. However, there is scope for an interaction of venlafaxine with amfebutamone and the effects in individual patients might be hard to predict. This study also supports clinical suggestions that the addition of amfebutamone to SSRI treatment can enhance antidepressant efﬁcacy and improve sexual function. However, controlled trials are needed to conﬁrm this view.

Mirtazapine Drug interactions In patients who do not respond to SSRI treatment, the addition of mirtazapine is an increasingly popular option. Mirtazapine is an alpha2 -adrenoceptor antagonist, so its acute pharmacological effects predominantly involve potentiation of noradrenergic function. This might be expected to enhance the serotonergic actions of SSRIs. • A 48-year-old woman unresponsive to ﬂuoxetine (20–40 mg/day for 8 weeks) was given additional mirtazapine (30 mg/day) (25A ). Over the next month her depression remitted, but after taking the combined treatment for 7 weeks she slept less, spent more, and was more sociable than usual. She was also argumentative and agitated. Mirtazapine and ﬂuoxetine were withdrawn and valproate introduced as a mood stabilizer. Within 2 weeks her mood had settled but she subsequently became depressed again.

The manic episode here could have been due to mirtazapine alone or to the combination of ﬂuoxetine and mirtazapine. The case also demonstrates the common clinical observation that when an antidepressant treatment has apparently caused mania, withdrawal of antidepressant therapy often results in re-emergence of depressive symptoms, even when mood stabilizer treatment has been introduced.

Reboxetine

(SED-14, 64; SEDA-24, 18)

Urinary tract One of the adverse effects of reboxetine is difﬁculty in passing urine (SEDA-21, 13). Eight patients taking reboxetine (4–8 mg/day) had troublesome urinary hesitancy (26c ). They were successfully treated

P.J. Cowen

with tamsulosin (0.4 mg/day), and in two patients tamsulosin was withdrawn after 2 weeks without recurrence of the urinary symptoms. Reboxetine is a selective noradrenaline reuptake inhibitor and may therefore produce urinary symptoms by activating alpha1 -adrenoceptors in the bladder, which tamsulosin would be expected to reverse. However, tamsulosin is also effective for urinary symptoms caused by other mechanisms, for example, benign prostatic hyperplasia. Whether its apparent effectiveness in reboxetine-induced dysuria represents speciﬁc pharmacological antagonism is therefore uncertain.

Venlafaxine

(SED-14, 66; SEDA-24, 18; SEDA-25, 18; SEDA-26, 16)

Sensory systems Tricyclic antidepressants predispose to acute angle closure glaucoma, probably through an anticholinergic action. However, acute angle closure has also been reported with SSRIs, suggesting that serotoninpotentiating drugs can also cause glaucoma (SEDA-21, 13; SEDA-23, 17). Acute angle closure glaucoma has been reported in a 45-yearold woman taking venlafaxine (75 mg/day) and chlorpromazine (150 mg/day) (27A ). She had previously taken low-dose dosulepin (75 mg/day), chlorpromazine, and SSRIs without ophthalmic problems. Chlorpromazine has mild anticholinergic properties and may have contributed to the angle closure in this case. She also had hypermetropia, which is another risk factor for glaucoma. However, this case supports the view that potent blockade of serotonin re-uptake can cause glaucoma in predisposed subjects. Drug interactions Psychostimulants, such as dexamphetamine, are being increasingly prescribed for patients who meet the criteria for adult attention deﬁcit disorder. Many such patients also have co-morbid major depression. • A 32-year-old man taking dexamphetamine 15 mg/day developed the serotonin syndrome, with shivering, sweating, myoclonus, and pyrexia, following the addition of venlafaxine 150 mg/day (28A ). Venlafaxine and dexamphetamine were withdrawn, and he was given the serotonin receptor antagonist, cyproheptadine (32 mg over

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Chapter 2

3 hours). His symptoms remitted a few hours later and he subsequently restarted dexamphetamine without incident. A later trial of citalopram, while he was still taking dexamphetamine, also led to symptoms of serotonin toxicity.

The combination of stimulants and SSRIs is not uncommon in clinical practice, but reports of serotonin toxicity are unusual, per-

17 haps because drugs such as dexamphetamine and methylphenidate predominantly release dopamine and noradrenaline rather than serotonin. However, psychostimulants do cause some degree of serotonin release, which might have been sufﬁcient to cause serotonin toxicity in this case.

REFERENCES 1. Mavissakalian M, Perel J, Guo S. Speciﬁc side effects of long-term imipramine management of panic disorder. J Clin Psychopharmacol 2002; 22: 155–61. 2. Stage KB, Bech P, Kragh-Sørensen P, Danish University Antidepressant Group. Age-related adverse drug reactions to clomipramine. Acta Psychiatr Scand 2002; 105: 55–9. 3. Juárez-Olguin H, Jung-Cook H, Flores-Pérez J, Asseff IL. Clinical evidence of an interaction between imipramine and acetylsalicylic acid on protein binding in depressed patients. Clin Neuropharmacol 2002; 25: 32–6. 4. Normann C, Lieb K, Walden J. Increased plasma concentration of maprotiline by coadministration of risperidone. J Clin Psychopharmacol 2002; 22: 92– 4. 5. Buchman N, Strous RD, Baruch Y. Side effects of long-term treatment with ﬂuoxetine. Clin Neuropharmacol 2002; 25: 55–7. 6. Schillevoort I, Van Puijenbroek EP, De Boer A, Roos RAC, Jansen PAF, Leufkens HGM. Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: a case-control study using spontaneous reports. Int Clin Psychopharmacol 2002; 17: 75–9. 7. Kaneda Y. Serotonin syndrome—“potential” role of the CYP2D6 genetic polymorphism in Asians. Int J Neuropsychopharmacol 2002; 5: 105–6. 8. Movig KLL, Leufkens HGM, Lenderink AW, Van den Akker VGA, Hodiamont PPG, Goldschmidt HMJ, Egberts ACG. Association between antidepressant drug use and hyponatraemia: a casecontrol study. Br J Clin Pharmacol 2002; 53: 363–9. 9. Hüll M, Kottlors M, Braune S. Prolonged coma caused by low sodium and hypo-osmolarity during treatment with citalopram. J Clin Psychopharmacol 2002; 22: 337–8. 10. Smith M, Robinson D. Sertraline and vaginal bleeding—a possible association. J Am Geriatr Soc 2002; 50: 200–1. 11. Linnebur SA, Saseen JJ, Pace WD. Venlafaxine-associated vaginal bleeding. Pharmacotherapy 2002; 22: 652–5. 12. Abebe-Campino G, Offer D, Stahl B, Merlob P. Cardiac arrhythmia in a newborn infant associated with ﬂuoxetine use during pregnancy. Ann Pharmacother 2002; 36: 533–4.

13. Jonasson B, Saldeen T. Citalopram in fatal poisoning cases. Forensic Sci Int 2002; 126: 1–6. 14. Liston HL, DeVane CL, Boulton DW, Risch SC, Markowitz JS, Goldman J. Differential time course of cytochrome P450 2D6 enzyme inhibition by ﬂuoxetine, sertraline, and paroxetine in healthy volunteers. J Clin Psychopharmacol 2002; 22: 169–73. 15. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis 2002; 34: 1651–2. 16. Benazzi F. Organic hypomania secondary to sibutramine–citalopram interaction. J Clin Psychiatry 2002; 63: 165. 17. Bondolﬁ G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The effect of ﬂuoxetine on the pharmacokinetics and safety of risperidone in psychotic patients. Pharmacopsychiatry 2002; 35: 50–6. 18. Begre S, Von Bardeleben U, Ladewig D, JaquetRochat S, Cosendai-Savary L, Golay KP, Kosel M, Baumann P, Eap CB. Paroxetine increases steadystate concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol 2002; 22: 211–15. 19. Borrás-Blasco J, Marco-Garbayo JL, BoscaSanleon B, Navarro-Ruiz A. Probable interaction between citalopram and acenocoumarol. Ann Pharmacother 2002; 36: 345. 20. Wooltorton E. Bupropion (Zyban, Wellbutrin SR): reports of deaths, seizures, serum sickness. Can Med Assoc J 2002; 166: 68. 21. Patterson RN, Herity NA. Acute myocardial infarction following bupropion (Zyban). QJM Mon J Assoc Phys 2002; 95: 58–9. 22. Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med 2002; 22: 235–9. 23. Detweiler MB, Harpold GJ. Bupropion-induced acute dystonia. Ann Pharmacother 2002; 36: 251– 4. 24. Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB. Combining bupropion SR with venlafaxine, paroxetine, or ﬂuoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry 2002; 63: 181–6. 25. Ng B. Mania associated with mirtazapine augmentation of ﬂuoxetine. Depression Anxiety 2002; 15: 46–7.

18 26. Kasper S, Wolf R. Successful treatment of reboxetine-induced urinary hesitancy with tamsulosin. Eur Neuropsychopharmacol 2002; 12: 119– 22. 27. Ng B, Sanbrook GMC, Malouf AJ, Agarwal SA. Venlafaxine and bilateral acute angle closure glaucoma. Med J Aust 2002; 176: 241.

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28. Prior FH, Isbister GK, Dawson AH, Whyte IM. Serotonin toxicity with therapeutic doses of dexamphetamine and venlafaxine. Med J Aust 2002; 176: 240–1.

J.W. Jefferson

3 In a 2-year, double-blind study, lithium was superior to carbamazepine in prophylactic efﬁcacy, although it caused more adverse effects (Table 1) (1C ).

Beneﬁcial uses of lithium other than in bipolar disorder Some collateral drug effects that are not related to the intended therapeutic effect are potentially beneﬁcial. Several beneﬁcial effects of lithium, beside its action in bipolar disorder, have been described. Nervous system There has been a spate of publications describing the neuroprotective effects of lithium. By inhibiting glycogen synthase kinase-3, lithium inhibits tau hyperphosphorylation and protects against β-amyloid-induced cell death, suggesting a possible role in the treatment of Alzheimer’s disease (2E , 3E ). Studies in mice and cell lines show that lithium reduces gp120-associated neurotoxicity, suggesting that it may be useful in preventing progression of HIV-associated cognitive deterioration (4E ). Low-dose lithium reduced infarct volume and neurological deﬁcits in a rat model of transient focal cerebral ischemia (5E ). Overall the evidence that lithium has neuroprotective and neurotropic effects through a variety of mechanisms is striking (6R ), although whether those ﬁndings will evolve into therapies of practical clinical value remains to be seen. Sensory systems In cultured mouse retinal ganglion cells lithium supported the survival and regeneration of axons (7E ). This led the authors to the very speculative suggestion that lithium might be useful in treating conditions © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Lithium such as glaucoma, optic neuritis, and other neuron loss disorders. Endocrine The antithyroid effects of lithium continued to be explored as adjunctive treatment in thyrotoxic patients who have received radioiodine. Lithium enhanced the efﬁcacy of radioiodine in 23 patients (8c ), but was ineffective in a larger comparison of lithium (n = 175) or radioiodine alone (n = 175) (9C ). In 24 patients with Grave’s disease lithium attenuated or prevented increases in thyroid hormone concentration after methimazole withdrawal and radioiodine treatment (10c , 11r ). Metabolism Lithium therapy in a 17-year-old man with Kleine–Levin syndrome led to remission of the characteristic manifestations, including hyperphagia (12A ). Hematologic Reports continue to accrue of beneﬁcial granulocytopoietic effects of lithium (13A ). For example, lithium carbonate (800– 900 mg/day) effectively corrected neutropenia due to chemotherapy or radiotherapy in over 85% of 100 cancer patients (14C ). A 29year-old man with agranulocytosis who could not tolerate granulocyte-colony stimulating factor had normalization of peripheral granulocyte counts when he took lithium carbonate 800 mg/day (15A ). Skin A topical 8% lithium gluconate ointment was more effective than a placebo ointment in treating 129 patients with facial seborrheic dermatitis (complete remission in 29% vs. 3.8%) (16C ). Immunologic and infections Comments on the generally favorable effects of lithium on immune function have been summarized (17R ). The antiviral and neuroprotective properties of lithium were mentioned in a review of the immune system and bipolar disorder (18R ). The potential beneﬁt of lithium in treating AIDS and

19

20

Chapter 3

Table 1. Adverse effects of lithium and carbamazepine in a double-blind trial (1C ) Adverse effect Difﬁculty concentrating Thirst Hand tremor Blurred vision Reduced appetite Increased appetite Weakness

Lithium (n = 42)

Carbamazepine (n = 46)

45%

33%

41% 31% 26% 21% 17% 14%

22% 4% 11% 9% 33% 4%

AIDS-related dementia, owing in part to its cytokine regulating and neuroprotective effects, has been reviewed (19R ). Cardiovascular Reports of lithium-related cardiovascular adverse effects range across the ages. • A 9-year-old boy whose serum lithium concentration was 1.29 mmol/l had a sinus bradycardia with a junctional escape rhythm (40 beats/min), which normalized at a lower lithium concentration (20A ). • A 52-year-old man with a serum lithium concentration of 4.58 mmol/l had sinus node dysfunction with multiple atrial extra beats and an intraventricular conduction delay, which normalized following hemodialysis (21A ). • A 58-year-old woman with lithium toxicity developed an irregular bradycardia (as low as 20 beats/ min), which resolved during hemodialysis; persistent sinoatrial conduction delay suggested that she was predisposed to the bradydysrhythmia (22A ). • Two patients, a 58-year-old woman and a 74-yearold woman, developed sick sinus syndrome while taking lithium but were able to continue taking it after pacemaker implantation (23A , 24A ). • A 78-year-old woman developed a cardiomyopathy while taking lithium, imipramine, amineptine, levomepromazine, and lorazepam; it resolved when the medications were withdrawn (25A ). Whether lithium was causally involved is not known.

Nervous system Reports of overdose-related neurological symptoms abound (26A –36A ). Among these reports are cases of neurotoxicity at therapeutic serum lithium concentrations (26A , 34A , 36A ) and neurotoxicity associated with non-convulsive status epilepticus (30A , 32A ). Tremor was reported as an adverse effect of lithium in 12 of 22 men and 10 of 38 women who had taken it for at least 1 year (37c ). In an

J.W. Jefferson

open study there was full remission of lithium tremor in four of ﬁve patients treated with vitamin B6 (38A ). A 17-year-old woman developed pseudotumor cerebri with headache after she had taken lithium for 6.5 weeks (39A ). Papilledema and increased intracranial pressure resolved fully when lithium was withdrawn and she was given acetazolamide. Two patients developed Parkinsonism after taking lithium for many years, but it did not improve when the drug was withdrawn and a causal relation could not be established (24A ). A review of drug-induced Parkinsonism provided references to case reports of lithium’s “occasionally inducing or exacerbating Parkinsonism” (40R ). Five patients taking lithium for unspeciﬁed durations developed multifocal action myoclonus without reﬂex activation, which resolved fully when the drug was withdrawn (41A ). A report rather inconclusively suggested that lithium caused periodic alternating nystagmus in a 61-year-old man (42A ), and another report suggested a link between lithium and reversible tardive dystonia (43A ). Sensory systems A 21-year-old woman developed temporary blindness possibly related to lithium toxicity (44A ). Psychological Assessment of cognitive performance in 43 patients with bipolar I disorder showed no correlation between the use of lithium, carbamazepine, or valproate and fullscale IQ or general and working memory (all of which were impaired by antipsychotic drugs) (45C ). When a deﬁcit in sustained attention was noted in 19 euthymic patients with bipolar disorder (17 taking medications, 11 taking lithium alone or in combination), there was no difference between those taking and not taking lithium (46c ). Neuropsychological testing in a 51-year-old woman with a serum lithium concentration of 2.4 mmol/l showed striking cortical and subcortical deﬁcits, which had only partially resolved when she was retested 4 and 14 weeks later (33A ). Endocrine Thyroid Both goiter and hypothyroidism continue to be reported as complications of lithium therapy (24c , 47c , 48C ).

Lithium

Chapter 3

Lithium has been cited as both a cause (49A ) and a treatment of hyperthyroidism. • A 30-year-old man who had taken lithium for 16 years developed subacute thyroiditis associated with a diffusely enlarged gland that showed heterogeneous echogenicity (50A ). • A 52-year-old woman became thyrotoxic 2 months after stopping long-term lithium therapy; the authors brieﬂy reviewed 10 previous reports (51Ar ).

Parathyroid When compared with 12 healthy matched controls, 13 women who had taken lithium for a mean of 8 (range 3–16) years had higher mean ionized and total calcium concentrations, but mean plasma parathormone concentrations did not differ. In eight of the women taking lithium the calcium concentration was above the upper end of the reference range, and in one the parathormone concentration was abnormally high (52c ). Of 15 patients taking long-term lithium who had surgery for primary hyperparathyroidism, 14 had adenomas (11 single, 3 double) and one had four-gland hyperplasia. All restarted lithium successfully after surgery, except one who again developed hyperparathyroidism, resulting in removal of another adenoma (53A ). Other reports have included: • a 74-year-old man who had an adenoma resected (24A ); • two 77-year-old women who developed hyperparathyroidism, which was managed medically (24A ); • a 39-year-old (sex unspeciﬁed) whose adenoma was resected after taking lithium for 10 years (53A ); • a 59-year-old woman with hyperparathyroidism (54A ).

Hypothalamic–pituitary–adrenal axis Two studies (n = 25, n = 24), possibly reporting many of the same patients, showed that lithium augmentation of antidepressant-resistant unipolar depression increased hypothalamic–pituitary–adrenal axis activity, measured by the dexamethasone suppression test, either alone or combined with the corticotropin releasing hormone test (55c , 56c ). However, the tests did not distinguish between lithium responders and non-responders. Hypothalamic–pituitary–adrenal axis function in bipolar disorder has been reviewed, but lithium was mentioned only in passing (57r ).

21 Metabolism Hypoglycemia requiring temporary glucagon and glucose supplementation was noted in a neonate whose mother had taken lithium throughout pregnancy (cord lithium concentration 1.73 mmol/l) (58A ). Difﬁculty in attaining a therapeutic serum concentration of lithium despite increased doses was attributed to increased renal clearance due to the osmotic effect of glycosuria in a 44year-old man with poorly controlled diabetes mellitus (59A ). Weight gain continues to be associated with lithium therapy. An open chart review of 74 hospitalized patients showed a mean weight gain of 6.3 kg and an increase in body mass index of 2.1 kg/m2 after they had taken lithium for a mean of 89 days (60C ). Of 47 lithium-treated patients 14 gained at least 5% of their baseline body mass index, six gained over 10%, and two gained over 15% during an acute treatment phase of unspeciﬁed duration, while during the 1-year maintenance phase 11 gained over 5% and two gained over 10% (61C ). In 15 consecutive patients serum leptin concentrations were measured at baseline and after 8 weeks of lithium treatment. There was a signiﬁcant mean increase of 3.5 ng/ml and serum leptin correlated positively with weight gain (5.9 kg), increased body mass index (24 to 27), and clinical efﬁcacy (62C ). The authors suggested that leptin might play a role in lithiuminduced weight gain. In a double-blind study of 344 patients inadequately responsive to lithium or valproate who were randomized to olanzapine or lithium for 6 weeks, 21% gained weight on lithium plus olanzapine compared with 4.9% taking lithium and placebo (63C ). Whether lithium contributed to weight gain in the olanzapine group is unclear. Two reviews of weight gain with psychotropic drugs mentioned lithium, but neither provided new information (64r , 65R ). Nutrition In a review of naturally occurring dietary lithium (food and water sources) the author acknowledged that human lithium deﬁciency states have not been identiﬁed, but concluded that lithium should be considered an essential element, a conclusion reached on rather shaky grounds (66R ).

22 Mouth and teeth A review of dental ﬁndings and their management in patients with bipolar disorder brieﬂy mentioned that xerostomia, sialadenitis, dysgeusia, and stomatitis have been attributed to lithium (67R ). Urinary tract In 28 of 75 patients taking lithium 24-hour urine volumes were over 3 l/day, and this group had a greater duration of lithium exposure (6.0 vs. 3.9 years) (68C ). There was no relation between polyuria and serum lithium concentrations or dosing regimens, but there was an association with the concurrent use of serotonergic antidepressants (odds ratio 4.25). Chronic renal insufﬁciency (creatinine clearance under 80 ml/min), for which there was no apparent alternative explanation, developed in 53 patients taking long-term lithium (mean 17.7 years); seven required periodic dialysis (69C ). After taking lithium for 6 years, a 55-yearold woman developed mild renal insufﬁciency (serum creatinine 1.6 mg/dl) and lithium was withdrawn (70A ). Lithium-induced interstitial nephritis (serum creatinine 2.3 mg/dl) occurred in an 89-yearold woman who had taken lithium for 29 years (24A ). An 11-year-old boy who had taken lithium for an unstated duration developed nephrotic syndrome with focal glomerulosclerosis, which remitted fully after lithium was withdrawn (71A ). Nephrogenic diabetes insipidus resulted in dehydration and hypernatremia in a 78-year-old man who had taken lithium for 30 years (72A ). Nephrogenic diabetes insipidus in a 63-year-old woman was treated successfully with lithium withdrawal and amiloride (73A ). Skin In a review of skin reactions to mood stabilizers a wide variety of reactions attributed to lithium were mentioned, but the authors did not critically evaluate the data on which the reports had been based (74R ). A 42-year-old woman taking lithium developed psoriasis, which resolved when the drug was withdrawn (75A ). Brief mention was made of two patients (age and sex unstated) taking lithium whose psoriasis improved with oral omega-3 fatty acids (76A ). Despite previous reports that follicular keratosis (Darier’s disease) is worsened by lithium,

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a 52-year-old man noted no exacerbation despite taking lithium for many years (77A ). A 60-year-old man developed systemic swelling, redness, and pruritus 1 month after starting to take lithium; it was attributed to the drug based on positive patch and challenge tests (78A ). Sexual function In a brief review of the sexual adverse effects of psychotropic drugs, reduced libido and arousal with lithium were mentioned in passing, particularly when it was combined with other drugs (which, of course, makes it difﬁcult to implicate lithium) (79r ). Withdrawal The observation that rapid or abrupt lithium withdrawal might be associated with a more immediate or higher likelihood of recurrence has gathered further support from a reanalysis of data from a double-blind lithium maintenance study, in which the beneﬁts of low serum concentrations (0.4–0.6 mmol/l) and standard serum concentrations (0.8–1.0 mmol/l) were compared (80C ). Recurrence rates were greater only in those whose concentrations were abruptly reduced from standard to low at the start of the study. The authors suggested that rapid dosage reduction, rather than a low maintenance concentration itself, accounted for their initial conclusion that standard concentrations were more effective than low concentrations. Pregnancy Lithium deﬁciency in goats was associated with reduced conception rates and a higher incidence of spontaneous abortion (66E ) However, lithium deﬁciency has not been identiﬁed in humans. Reviews dealing with the risks and beneﬁts of treating bipolar disorder during pregnancy and postpartum continue to appear, and while the topic is important, no new information has emerged (58R , 81R –85R , 86r ). Teratogenicity In a review of all pregnancies in Leiden in The Netherlands between 1994 and 2002, none of the 20 children of mothers who had taken lithium had major problems or congenital anomalies (87c ). The cardiovascular teratogenicity of lithium has been summarized in a review of managing bipolar disorder during pregnancy and postpartum (81R ). While the risk of Ebstein’s anomaly

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is increased, being 10–20 times more likely than in the general population, the absolute risk (0.05 to 0.10%) was felt to be small. Fetotoxicity A neonate whose mother had taken lithium throughout pregnancy developed a supraventricular tachycardia (240 beats/minute), which was treated successfully with adenosine (88A ). Another newborn girl exposed to lithium in utero had asymptomatic cardiomegaly that resolved by 1 month of age (59A ). Transient polyuria in two newborns was attributed to the lithium their mothers had taken throughout pregnancy (58A , 88A ). Neonates born to mothers taking lithium included a boy with a goiter and chemical hypothyroidism who required temporary treatment with oral thyroxine for 11 weeks (89A ), a girl with respiratory distress, cardiomegaly, hyperbilirubinemia, nephrogenic diabetes insipidus, and hypoglycemia who responded to various treatments and eventually remitted fully (58R ), and a preterm infant with a supraventricular tachycardia and temporary polyuria associated with 20% weight loss (88A ). The mother of the preterm infant developed polyhydramnios during pregnancy, which was attributed to lithiuminduced fetal polyuria. Lactation While most authors continue to discourage breast feeding if a mother is taking lithium, such a restriction may be too harsh. Breast-milk lithium concentrations were measured in 11 women taking lithium carbonate 600–1500 mg/day (90C ). Maternal serum concentrations were available in only three and infant concentrations in two. No infants had adverse effects that could be attributed to lithium, and the authors calculated that infant lithium exposure was low, leading them to challenge the general contraindication to breast-feeding under such circumstances. In its 2001 Policy Statement the American Academy of Pediatrics Committee on Drugs modiﬁed its earlier contraindication to lithium during breast-feeding by listing it with “drugs that have been associated with signiﬁcant effects on some nursing infants, and should be given to nursing mothers with caution” (91R ). Drug formulations A modiﬁed-release formulation (Carbolithium Once-A-Day) produced

23 a reduction in peak/trough lithium ratio compared with a standard formulation (92c ), and an interim analysis of an open switch to the modiﬁed-release formulation suggested better tolerability and efﬁcacy at 4 weeks (n = 27) and 6 weeks (n = 15) (93c ). A paucity of detail, however, prevents ﬁrm conclusions. A modiﬁed-release multiparticulate lithium capsule has been described consisting of ﬁve copolymer-coated prolonged-release tablets and one standard tablet, each 6 mm in size (94E ). Drug administration route When 10 volunteers were given 500 ml of a 0.1% lithium carbonate solution (13.5 mmol of lithium) intravenously over 1 hour, the peak serum concentration was 0.93 mmol/l, the elimination half-life was 7.8 hours, and there were no adverse effects (95c ). Drug overdose The term “overdose” encompasses acute intentional and accidental ingestion, and gradual intoxication secondary to factors such as dehydration, renal impairment, and drug interactions. Neurotoxicity occurring at therapeutic serum concentrations, as well as various neurological manifestations of highserum concentration intoxication, is discussed under Nervous system. Forty of 133 patients who had begun treatment with lithium died over an observation period of 16 years. Suicide in 11 was twice as common as in the general population, but it was more likely to occur in lithium non-compliant patients (96C ). It is important to be aware that suicidal behavior is actually reduced in patients who are compliant with long-term lithium therapy (although still somewhat higher than in the general population). The 2001 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System included six fatal exposures to lithium, three of which were intentional suicides. A total of 4607 exposures to lithium were reported, and death was the outcome in eight (97R ). A retrospective review of eight cases of lithium poisoning included one death (27C ). Product monographs written by pharmaceutical companies and published by the Canadian Pharmacists Association in the Compendium of Pharmaceutical Specialties have been reviewed with regard to the adequacy of lithium overdose

24 management advice (98R ). All ﬁve were rated “fair” for listing essential interventions for managing overdose but “poor” for warning against contraindicated interventions, and all contained misleading or dangerous information. All in all, a dismal showing. When the Marseilles Poisons Centre analysed information on lithium overdose between 1991 and 2000, in addition to an unspeciﬁed number of suicide attempts and accidental poisonings in children, the next most frequent reports were prescription misinterpretation (n = 43), dehydration in the elderly (n = 35), renal insufﬁciency (n = 15), and diuretic interactions (n = 8) (99c ). Several reports have described severe poisoning responding to treatment that included hemodialysis or hemodiaﬁltration: • a 57-year-old man, serum lithium concentration 3.1 mmol/l (100Ar ); • a 52-year-old woman, serum lithium concentration 3.2 mmol/l (100Ar ); • a 58-year-old woman, serum lithium concentration 4.0 mmol/l (22A ); • a 52-year-old man, serum lithium concentration 4.6 mmol/l (21A ); • a 40-year-old man, serum lithium concentration 5.4 mmol/l (101A ); • a 39-year-old man, serum lithium concentration 5.9 mmol/l, with renal insufﬁciency associated with a polydrug overdose (102A ).

Some patients recovered from severe intoxication without dialysis: • a 55-year-old woman, serum lithium concentration 4.5 mmol/l, who was left with residual slurred speech (103A ); • a 52-year-old woman, serum lithium concentration 10.6 mmol/l after an acute overdose (104A ).

In an in vitro study bentonite was an effective adsorbent of lithium; the authors suggested that it be explored as an overdose treatment (103E ). Drug interactions Anticonvulsants Reviews have generally been favorable regarding the combination of lithium with anticonvulsants (105R –107R ), although further study is clearly indicated. For example, in a 42-year-old woman the serum lithium concentration rose from 0.5 to 1.4 mmol/l after she increased her topiramate dose from 500 to 800 mg/day (108A ). The authors speculated that topiramate had interfered with lithium excretion. On the other

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hand, in a crossover study in healthy volunteers, 6 days of treatment with topiramate did not signiﬁcantly alter serum lithium concentrations; however, the maximum topiramate dose was only 200 mg/day and one subject did have about a 70% fall in lithium Cmax and AUC (109c ). Antidepressants When polyuria (over 3 l/day) was detected in 28 of 75 patients taking lithium, it was strongly correlated with concomitant use of serotonergic antidepressants (odds ratio 4.25) (68C ). Six patients taking a stable dose of ﬂuvoxamine had a minor increase in plasma ﬂuvoxamine concentration (from 67 ng/ml to 76 ng/ml) 2 weeks after starting to take unspeciﬁed doses of lithium; this is unlikely to be of clinical signiﬁcance (110c ). Antipsychotic drugs A review of aripiprazole included a brief mention of no apparent pharmacokinetic interaction with lithium (111R ). A pharmacodynamic drug interaction could not be excluded when a 60-year-old man developed delirium at a serum lithium concentration of 0.97 mmol/l when taking lithium and haloperidol (34A ). It was suggested that lithium may have contributed to the risk of neuroleptic malignant syndrome in a 16-year-old boy who developed the syndrome when his olanzapine dose was increased (112A ). A brief discussion of serotonin syndrome included lithium as a possible contributor when combined with serotonergic drugs (113r ). In an open study in 10 patients, the addition of quetiapine 250 mg tds did not signiﬁcantly alter serum lithium concentrations (114c ). In an in vitro study there was no visible precipitate formation when lithium citrate syrup was mixed with risperidone solution (115E ). Neuromuscular blocking drugs The authors of a review of interactions between psychotropic drugs, anesthetics, and ECT referred to previous reports of lithium-associated prolongation of the effects of depolarizing and nondepolarizing neuromuscular block agents (116R ). NSAIDs The serum lithium concentration nearly doubled to 1.3 mmol/l after a 57-yearold woman started to take diclofenac (117A ). There have been several reports of raised serum lithium concentrations and neurotoxic

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symptoms when COX-2 inhibitors (celecoxib and rofecoxib) were added to an otherwise stable lithium regimen (20A , 118A , 119A ). In 10 patients taking lithium who took rofecoxib 50 mg/day for 5 days, serum lithium concentrations increased in nine and reached 1.26, 1.47, and 1.63 mmol/l in three (details not provided) (120c ). All in all, the COX-2 inhibitors appear to be similar to non-speciﬁc NSAIDs with

25 regard to the likelihood of increasing lithium concentrations. Interference with diagnostic routines In blood samples from 32 subjects, TSH and free T4 concentrations were no different in collection tubes that contained a lithium heparin anticoagulant compared with dry tubes, but free T3 concentrations were signiﬁcantly lower (121E ).

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41. Caviness JN, Evidente VGH. Cortical myoclonus during lithium exposure. Arch Neurol 2003; 60: 401–4. 42. Lee MS, Lessell S. Lithium-induced periodic alternating nystagmus. Neurology 2003; 60: 344. 43. Chakrabarti S. Chand PK. Lithium-induced tardive dystonia treated with clozapine. Neurol India 2002; 50: 473–5. 44. Fabisiak DB, Murray GB, Stern TA. Central pontine myelinolysis manifested by temporary blindness: a possible complication of lithium toxicity. Ann Clin Psychiatry 2002; 14: 247–51. 45. Donaldson S, Goldstein LH, Landau S, Raymont V, Frangou S. The Maudsley Bipolar Disorder Project: the effect of medication, family history, and duration of illness on IQ and memory in bipolar I disorder. J Clin Psychiatry 2003; 64: 86–93. 46. Harmer CJ, Clark L, Grayson L, Goodwin GM. Sustained attention deﬁcit in bipolar disorder is not a working memory impairment in disguise. Neuropsychologia 202; 40: 1586–90. 47. Schiemann U, Hengst K. Thyroid echogenicity in manic-depressive patients receiving lithium therapy. J Affect Disord 2002; 70: 85–90. 48. Cayköylü ¸ A, Capo˘ ¸ glu ˙I, Ünüvar N, Erdem F, Cetinkaya ¸ R. Thyroid abnormalities in lithiumtreated patients with bipolar affective disorder. J Int Med Res 2002; 30: 80–4. 49. Scanello G. A case of lithium associated thyrotoxicosis [Italian; English Abstract]. Recenti Prog Med 2002; 93: 100–3. 50. Obuobie K, Al-Sabah A, Lazarus JH. Subacute thyroiditis in an immunosuppressed patient. J Endocrinol Invest 2002; 25: 169–71. 51. Dang AH, Hershman, JM. Lithium-associated thyroiditis. Endocr Pract 2002; 8: 232–6. 52. El Khoury A, Petterson U, Kallner G, AbergWistedt A, Stain-Malmgren R. Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1063–9. 53. Morillas Arino C, Jordán Lluch M, Solá Izquierdo E, Serra Cerdá M, Garzón Pastor S, Gómez Balaguer M, Hernández Mijares YA. Parathyroid adenoma and lithium therapy. [Spanish; English abstract.] Endocrinol Nutr 2002; 49: 56–7. 54. Gómez Moreno R, Lobo Fresnillo T, Calvo Cebrián A, Monge Ropero N. Hyperparathyroidism and lithium. [Spanish.] Aten Primaria 2003; 31: 337. 55. Bschor T, Baethge C, Adli M, Eichmann U, Ising M, Uhr M, Müller-Oerlinghausen B, Bauer M. Lithium augmentation increases postdexamethasone cortisol in the dexamethasone suppression test in unipolar major depression. Depression Anxiety 2003; 17: 43–8. 56. Bschor T, Adli M, Baethge C, Eichmann U, Ising M, Uhr M, Modell S, Künzel H, MüllerOerlinghausen Bauer M. Lithium augmentation increases the ACTH and cortisol response in the combined DEX/CRH test in unipolar major depression. Neuropsychopharmacology 2002; 27: 470–8. 57. Watson S, Young AH. Hypothalamic-pituitaryadrenal-axis function in bipolar disorder. Clinical Approaches in Bipolar Disorders 2002; 1: 57–64.

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27 ceiving chronic lithium therapy. J Am Geriatr Soc 2002; 50: P397. 73. Finch CK, Kelley KW, Williams RB. Treatment of lithium-induced diabetes insipidus with amiloride. Pharmacotherapy 2003; 23: 546–50. 74. Warnock JK, Morris DW. Adverse cutaneous reactions to mood stabilizers. Am J Clin Dermatol 2003; 4: 21–30. 75. Lozano García MC, Baca Garcia E. Psoriasis and lithium treatment: a common physiopathology? [Spanish; English abstract.] Actas Esp Psiquiatr 2002; 30: 400–3. 76. Akkerhuis GW, Nolen WA. Lithium-associated psoriasis and omega-3 fatty acids: two case reports. Bipolar Disord 2002; 4: 117. 77. Wang S-L, Yang S-F, Chen C-C, Tsai P-T, Chai C-Y. Darier’s disease associated with bipolar affective disorder: a case report. Kaohsiung J Med Sci 2002; 18: 622–6. 78. Arakaki T, Miyahira Y, Miyazato H, Arakaki H, Asato Y. A case of serious systemic swelling and erythema following lithium carbonate treatment. Int Clin Psychopharmacol 2002; 17 Suppl 2: S69. 79. Kristensen E. Sexual side effects induced by psychotropic drugs. Dan Med Bull 2002; 49: 349– 52. 80. Perlis RH, Sachs GS, Lafer B, Otto MW, Faraone SV, Kane JM, Rosenbaum JF. Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data. Am J Psychiatry 2002; 159: 1155–9. 81. Viguera AC, Cohen LS, Baldessarini RJ, Nonacs R. Managing bipolar disorder during pregnancy: weighing the risks and beneﬁts. Can J Psychiatry 2002; 47: 426–36. 82. Amsterdam JD, Brunswick DJ, O’Reardon J. Bipolar disorder in women. Psychiatric Annals 2002; 32: 397–404. 83. Harris B. Postpartum depression. Psychiatric Annals 2002; 32: 405–15. 84. Krüger S, Bräunig P. Clinical issues in bipolar disorder during pregnancy and the postpartum period. Clin Approaches Bipolar Disord 2002; 1: 65–71. 85. Kusumaker V, MacMaster FP, Kutcher SP, Shulman KI. Bipolar disorder in young people, the elderly and pregnant women. In: Yatham LN, Kusmakar V, Kutcher SP, editors. Bipolar Disorder: A Clinician’s Guide to Biological Treatments, New York: Brunner-Routledge, 2002; 85–113. 86. Ward RK, Zamorski MA. Beneﬁts and risks of psychiatric medications during pregnancy. Am Fam Phys 2002; 66: 629–36, 639. 87. Knoppert van der Klein EAM, Van Kamp IL. A pilot risk evaluation of lithium in pregnancy. Bipolar Disord 2002; 4 Suppl 1: 127. 88. Zegers B, Andriessen P. Material lithium therapy and neonatal morbidity. Eur J Pediatr 2003; 162: 348–9. 89. Frassetto F, Tourneur Martel F, Barjhoux C-E, Villier C, Le Bot B, Vincent F. Goiter in a newborn exposed to lithium in utero. Ann Pharmacother 2002; 36: 1745–8. 90. Moretti ME, Koren G, Verjee Z, Ito S. Monitoring lithium in breast milk: an individualized

28 approach for breast-feeding mothers. Ther Drug Monit 2003; 25: 364–6. 91. Ward RM, Bates BA, Benitz WE, Burchﬁeld DJ, Ring JC, Walls RP, Walson PD. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. 92. Castrogiovanni P. A novel-slow-release formulation of lithium carbonate (Carbolithium Once-ADay® ) vs. standard Carbolithium® : a comparative pharmacokinetic study. Clin Ter 2002; 153: 107– 15. 93. Durbano F, Mencacci C, Dorigo D, Riva M, Buffa G. The long-term efﬁcacy and tolerability of Carbolithium Once A Day: an interim analysis at 6 months. Clin Ter 2002; 153: 161–6. 94. Pietkiewicz P, Sznitowska M, Dorosz A, Lukasiak J. Lithium carbonate 24-hour extendedrelease capsule ﬁlled with 6 mm tablets. Boll Chim Farm 2003; 142: 69–71. 95. Waring WS, Webb DJ, Maxwell SRJ. Lithium carbonate as a potential pharmacological vehicle: intravenous kinetics of single-dose administration in healthy subjects. Eur J Clin Pharmacol 2002; 58: 431–4. 96. Brodersen A, Licht RW, Vestergaard P, Olesen AV, Mortenson PB. Mortality in patients with affective disorder who commenced treatment with lithium: a 16-year follow-up. [Danish; English abstract.] Ugeskr Laeger 2001; 163: 6428–32. 97. Litovitz TL, Kelin-Schwartz W, Rodgers GC, Cobaugh DJ, Youniss J, Omslaer JC, May ME, Woolf AD, Benson BE. 2001 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2002; 22: 391–452. 98. Brubacher JR, Purssell R, Kent DA. Salty broth for salicylate poisoning? Adequacy of overdose management advice in the 2001 Compendium of Pharmaceuticals and Specialties. Can Med Assoc J 2002; 167: 992–6. 99. Anonymous. Lithium overdose. Prescrire Int 2003; 12: 19. 100. Ilagan MC, Carlson D, Madden JF. Lithium toxicity: two case reports. Del Med J 2002; 74: 263–70. 101. De Ridder K, De Meester J, Demeyer I, Verbeke J, Nollet G. Management of a lithium intoxication. [Dutch; English abstract.] Tijdschr Geneeskd 2002; 58: 769–72. 102. Kerbusch T, Mathô RAA, Otten HMMB, Meesters EW, Van Kan HJM, Schellens JHM, Beijnen JH. Bayesian pharmacokinetics of lithium after an acute self-intoxication and subsequent haemodialysis: a case report. Pharmacol Toxicol 2002; 90: 243–5. 103. Ponampalam R, Otten EJ. In vitro adsorption of lithium by bentonite. Singapore Med J 2002; 43: 86–9. 104. Nagappan R, Parkin WG, Holdsworth SR. Acute lithium intoxication. Anesth Intensive Care 2002; 30: 90–2.

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105. Wang PW, Ketter TA. Pharmacokinetics of mood stabilizers and new anticonvulsants. Psychopharmacol Bull 2002; 36: 44–66. 106. Spina E, Perucca E. Clinical signiﬁcance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia 2002; 43 Suppl 2: 37–44. 107. Pies R. Combining lithium and anticonvulsants in bipolar disorder: a review. Ann Clin Psychiatry 2002; 14: 223–32. 108. Pinninti NR, Zelinski G. Does topiramate elevate serum lithium levels? J Clin Psychopharmacol 2002; 22: 340. 109. Doose DR, Kohl KA, Desai-Krieger D, Natarajan J, Van Kammen DP. The effect of topiramate of lithium serum concentration. Presented at the 37th Annual Meeting of the American College of Neuropsychopharmacology, Las Croabas, Puerto Rico, December 14–18, 1998. 110. Takano A, Suhara T, Yasuno F, Ichimiya T, Inoue M, Sudo Y, Suzuki K. Characteristics of clomipramine and ﬂuvoxamine on serotonin transporter evaluated by PET. Int Clin Psychopharmacol 2002; 17 Suppl 2: S84–5. 111. Taylor DM. Aripiprazole: a review of its pharmacology and clinical use. Int J Clin Pract 2003; 57: 49–54. 112. Berry N, Pradhan S, Sagar R, Gupta SK. Neuroleptic malignant syndrome in an adolescent receiving olanzapine-lithium combination therapy. Pharmacotherapy 2003; 23: 255–9. 113. Sternbach H. Serotonin syndrome: how to avoid, identify, & treat dangerous drug interactions. Current Psychiatry 2003; 2: 15–6, 19, 24. 114. Munera PA, Perel JM, Asata M. Medication interaction causing seizures in a patient with bipolar disorder and cystic ﬁbrosis. J Child Adolesc Psychopharmacol 2002; 12: 275–6. 115. Park SH, Dopheide JA, Gill MA. Visual compatibility of risperidone solution and lithium citrate syrup. Am J Health-Syst Pharm 2003; 60: 612–13. 116. Naguib M, Koorn R. Interactions between psychotropics, anaesthetics and electroconvulsive therapy: implications for drug choice and patient management. CNS Drugs 2002; 16: 229–47. 117. Monji A, Maekawa T, Miura T, Nishi D, Horikawa H, Nakagawa Y, Tashiro N. Interactions between lithium and non-steroidal antiinﬂammatory drugs. Clin Neuropharmacol 2003; 25: 241–2. 118. Gunja N, Graudins A, Dowsett R. Lithium toxicity: a potential interaction with celecoxib. Intern Med J 2002; 32: 494. 119. Lundmark J, Gunnarsson T, Bengtsson F. A possible interaction between lithium and rofecoxib. Br J Clin Pharmacol 2002; 53: 403–4. 120. Sajbel TA, Carter GW, Wiley RB. Pharmacokinetics/pharmacodynamics/pharmacometrics/drug metabolism. Pharmacotherapy 2001; 21: 380. 121. He GR, Cheng W, Huang YY. Effect of heparin lithium as anticoagulant in assay of FT3, FT4 and TSH. [Chinese; English abstract]. Di Yi Jun Yi Da Xue Xue Bao 2002; 22: 721–3.

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel

4

Drugs of abuse

AMPHETAMINES

(SED-14, 100; SEDA-24, 32; SEDA-25, 34; SEDA-26, 30)

Methylenedioxymethamphetamine (MDMA, ecstasy)

Methamphetamine

Respiratory Two cases of pneumomediastinum occurred in people who took ecstasy at the same rave party (2A ).

Psychiatric A paranoid hallucinatory state similar to schizophrenia has been reported in women with a history of methamphetamine abuse in a study of ﬂashbacks in 81 female inmates in Japan (1c ). Details of symptoms of initial methamphetamine psychosis, stressful experiences, and patterns of abuse were obtained. Plasma monoamine concentrations were also measured during ﬂashback states and in control abusers who had never experienced them. The researchers reported that concreteness of abstract thought and impaired goaldirected thought characteristic of schizophrenia was not usually seen in methamphetamineinduced psychosis. Moreover, it was the use of methamphetamine and not a severe stressor that caused the initial psychotic state, but the ﬂashbacks appeared to be due to mild environmental stressors. The authors described this pattern as “spontaneous psychosis due to previous methamphetamine psychosis”. They also observed that plasma concentrations of noradrenaline were signiﬁcantly higher in women with ﬂashbacks both during ﬂashbacks and during remissions. This suggests a possible role of noradrenergic hyperactivity in sensitivity to mild stress and susceptibility to ﬂashbacks. Furthermore, these noradrenergic ﬁndings could be used to predict relapse to a paranoid hallucinatory state in schizophrenia.

© 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

• A 23-year-old woman developed chest, back, and neck pain, and surgical emphysema over the chest and neck 7 hours after taking ecstasy. She had surgical emphysema in the mediastinum and neck and was given intravenous ﬂuids and antibiotics. • A 22-year-old man developed anterior chest and neck pain and surgical emphysema over the neck and chest 8 hours after taking four ecstasy tablets. He had surgical emphysema in the mediastinum and neck and contrast swallow showed a leak at the posterolateral aspect of the mid-esophagus. He was given intravenous ﬂuids and antibiotics.

These symptoms were possibly related to the use of ecstasy, but it is also possible that a corrosive additive in the ecstasy was responsible. Ecstasy can cause gastrointestinal dysmotility, which could have resulted in esophageal rupture. Psychological With increasing use of ecstasy, there is considerable interest in its effects on psychopathology and cognition. The residual effects of ecstasy on psychopathology and cognition have been examined in 18 current regular users, 15 ex-users with an average abstinence of 2 years, 16 ecstasy-naïve polydrug users, and 15 non-drug users (3c ). Both current and previous users had signiﬁcantly worse psychopathology than the controls and polydrug users. Ecstasy users had higher scores on the Symptoms Check List (SCL-90-R), Global Severity Index, and the Positive Symptom Distress Index. They also scored signiﬁcantly higher on eight speciﬁc factors on the SCL-90-R: somatization, obsessive–compulsive disorder, anxiety, phobic anxiety, interpersonal sensitivity, depression, paranoid ideation, and altered appetite/restless sleep. Current users had higher scores across

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more categories, but the values were not signiﬁcantly different from ex-users. Current and ex-users had lower working memory and verbal learning abilities than the controls and polydrug users, but there were no signiﬁcant differences between the two groups. Using regression analyses, the investigators found that the best indicator of increased psychopathology was a high consumption of cannabis, while cognitive deﬁcits were best predicted by the amount of previous ecstasy use. Thus, the investigators propose that ecstasy-induced cognitive impairment may not be reversible over time and with abstinence, suggesting that ecstasy is a potent neurotoxin. The neuropsychological effects of ecstasy have been studied in 20 polydrug users (4c ). Various functions and processes throughout the brain, such as verbal ﬂuency, spatial working memory, and attention, were assessed. Ecstasy users showed a signiﬁcant deﬁcit in complex visual pattern recognition and spatial working memory compared with the polydrug abusers who were not taking ecstasy. Since these tests are sensitive to temporal lobe functioning, the authors suggested that there is a selective temporal lobe deﬁcit in ecstasy users, with relative sparing of executive functioning. Based on previous studies, they postulated that serotonin dysfunction in the temporal lobe may be associated with impaired visuospatial working memory. However, they did not study a drugfree control group and the ecstasy group used higher amounts of drugs in general. In addition, the sample size was small. The neurotransmitter systems involved in the psychological and information processing effects of ecstasy have been studied in 16 ecstasy-naïve subjects (5C ). Ecstasy produced a state of enhanced mood, well-being, increased emotional sensitiveness, little anxiety, moderate thought disturbances, but no hallucinations or panic reactions. It caused thought disturbances, such as difﬁculty in concentrating, thought blocking, and difﬁculty in reaching decisions. Women had greater subjective responses to ecstasy than men. For instance, they scored higher on ratings of anxiety, adverse effects, and thought disturbances, suggesting differences in the metabolism of ecstasy between men and women. Prepulse inhibition of the startle response was used to measure physiological changes. Prepulse inhibition and startle habituation have been used as operational measures

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel

of sensorimotor gating and habituation functions in investigations of attention. Moreover, some studies have associated prepulse inhibition with endogenous serotonin release. Ecstasy 1.7 mg/kg increased prepulse inhibition, suggesting that the overﬂow of endogenous serotonin caused by ecstasy may interfere with the startle response and cause a breakdown of cognitive integrity. This effect further advocates serotonin dysregulation in response to ecstasy. Electrolyte balance In a retrospective analysis of all cases of hyponatremia associated with ecstasy (SEDA-25, 37) at the London Center of the National Poisons Information Service from December 1993 to March 1996, 17 patients were identiﬁed with a serum sodium concentration under 130 (range 107–128 mmol/l (6A ). In ten, ecstasy was identiﬁed analytically and six of them had the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The clinical presentation was very consistent, with initial vomiting and delirium, and 11 had seizures. There was complete recovery in 14, but two died of cerebral edema 5 hours after ingestion. • A 20-year-old woman attended a “rave”, where she took ecstasy and drank large amounts of water (often suggested to prevent dehydration and other life-threatening consequences) (7A ). She felt drowsy and had a headache. After lying still for 3 hours she had a tonic–clonic seizure and was brought to the hospital, where her plasma sodium concentration was 112 mmol/l and she had cerebral edema. She was treated with hypertonic saline and recovered fully.

These reports show that hyponatremia due to ecstasy occurs primarily due to inappropriate secretion of antidiuretic hormone and relative excess liquid intake, usually in the setting of a warm environment and possible hyperthermic effects of ecstasy. Excess water ingestion should be discouraged in ecstasy users. Two deaths in patients with hyponatremia after ecstasy intoxication have been reported (8A ). • A 15-year-old woman developed impaired consciousness and psychomotor agitation and 10 minutes later reactive bilateral mydriasis and decerebration. A CT scan showed diffuse brain edema and subarachnoid hemorrhage. She had hyponatremia (119 mmol/l) and was considered brain dead 32 hours later.

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• A 19-year-old woman became disoriented and had hyponatremia (131 mmol/l) and a serum ethanol concentration of 2.4 mmol/l. Her serum sodium had fallen to 120 mmol/l 10 hours later, and 5 hours later she suddenly deteriorated and had a respiratory arrest, coma, and sinus tachycardia of 180/minute with bigeminy. A CT scan showed diffuse edema in the posterior fossa. She was considered brain dead 23 hours after taking the ecstasy.

Hematologic Transient anemia has been associated with ecstasy (9A ). • A 36-year-old HIV-positive man taking zidovudine, lamivudine, and indinavir was noticed to have a mild asymptomatic anemia (hemoglobin 10.2 g/l, white cell count 10.4 × 109 /l with a normal differential count, and platelets 237 × 109 /l). The blood ﬁlm suggested hemolysis. He had taken ecstasy 2 weeks earlier for the ﬁrst time. The anemia was reportedly “secondary to oxidative stress, probably due to drug toxicity”. Three weeks later his hemoglobin returned to normal.

In the absence of other explanations, the authors concluded that this syndrome had probably been caused by ecstasy toxicity. Liver Ecstasy can cause liver damage (SEDA26, 35). • A 21-year-old soldier had nausea, vomiting, abdominal pain, and fever, having taken 7–8 ecstasy tablets a week (10A ). He was treated with intravenous ﬂuids and paracetamol (650 mg/day) for 3 days. His symptoms did not improve and he developed jaundice. He had increased transaminase activities and total bilirubin concentrations and all tests for viral hepatitis were negative. He was considered for liver transplantation, but over the next 2 weeks improved spontaneously.

The authors postulated a hyperthermic effect of ecstasy on the liver or a direct toxic effect of ecstasy on hepatocytes as possible mechanisms. Three organ recipients had ecstasy-induced fulminant hepatic failure (8A ). • A 25-year-old woman developed abdominal pain, jaundice, and vomiting 5 days after consuming ecstasy. She had hepatocellular failure with a prothrombin ratio of 6.5, cytolysis, cholestasis, renal insufﬁciency, and encephalopathy. She had a liver transplant 2 days later and recovered fully. • A 17-year-old man developed toxic subacute hepatitis with grade II encephalopathy and coagulation disorders a few days after consuming ecstasy. Liver transplantation was performed and he recovered fully.

31 • A 16-year-old woman consumed ecstasy and developed jaundice, hepatic failure, a prothrombin ratio of 9, and grade I encephalopathy. She had a liver transplant and was asymptomatic at 11 months.

Immunologic Because other drugs of abuse can cause immune dysfunction in regular users, the effects of acute administration of ecstasy on the immune system have been studied in both controlled and natural settings (11c ). In the controlled study 18 male ecstasy users were given two doses of ecstasy 100 mg at intervals of 4 or 24 hours. There were signiﬁcant reductions in CD4 T-helper cells (30%) and the lymphoproliferative response to phytohemagglutinin mitogenic stimulation (68%) 1.5 hours after the ﬁrst dose, and a 103% increase in the number of natural killer cells. At 4 hours CD4 T-helper cells and lymphocyte proliferative responses were reduced by 40% and 87%, respectively, but natural killer cell numbers increased to 141%. At 24 hours the second dose augmented the alterations in the numbers of CD4 T-helper cells and natural killer cells about three fold. The authors suggested that this large effect after repeated administration of ecstasy increases the interval during which the immune response is compromised, leading to a higher risk of illness and infection in ecstasy abusers. In the uncontrolled study 30 recreational users of ecstasy (mean age 24 years) were observed for 2 years and had lymphocyte counts at yearly intervals. The ecstasy users tended to have lower white blood cell counts over time. Lymphocyte counts were signiﬁcantly lower than in healthy controls by year 1 and signiﬁcantly lower than that the following year. CD4 and CD19 cell numbers fell signiﬁcantly from basal to year 1 and from year 1 to year 2. Natural killer cell numbers were always lower than in healthy controls but did not fall with time. The authors extended these results to suggest a possible role of serotonin dysregulation caused by ecstasy in compromising immune function. These ﬁndings suggest that ecstasy abusers may be at a signiﬁcantly higher risk of infectious diseases. Death In a study of all ecstasy-positive deaths (22 of 19 366 deaths) in New York City from January 1997 to June 2000 18 were men, average age 27 years (12A ). The deaths fell into three categories: acute drug intoxication (n =

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13), mechanical injury (n = 7), and a combination of natural causes and acute drug intoxication (n = 2). Only two of the deaths due to acute drug intoxication were caused by ecstasy alone, and one death was caused by a combination of ecstasy and coronary artery disease. Seven deaths were caused by a combination of cocaine/opiates and ecstasy. Acute ecstasy poisoning includes symptoms such as hypertension, hyperthermia, and delirium, and can progress to intracranial hemorrhage, status epilepticus, and death. Based on reports from harm-reduction organizations and previous studies, the authors discussed the lack of standardization of ecstasy tablets and the danger of harmful additives that could react with other drugs to cause life-threatening symptoms. Drug interactions The pharmacokinetic and pharmacodynamic interactions of single doses of ecstasy 100 mg and ethanol 0.8 g/kg have been investigated in nine healthy men (mean age 23 years) in a double-blind, double-dummy, randomized, placebo-controlled crossover design (13c ). Each underwent four 10-hour experimental sessions, including blood sampling, with 1 week between each. For the task used to test the recognition and recording of visual information, the conditions involving ethanol yielded signiﬁcantly more errors and fewer responses than ecstasy alone or placebo alone. The combination of ecstasy with ethanol reversed the subjective effect of sedation caused by alcohol alone. In addition, the combination extended the sense of euphoria caused by ecstasy to 5.25 hours. The addition of ethanol caused plasma ecstasy concentrations to rise by 13%. These results show that the combination of ecstasy with alcohol potentiates the euphoria of ecstasy and reduces perceived sedation. However, psychomotor impairment of visual processing caused by alcohol is not reversed. This is a concern for road safety, as people who take both drugs would feel sober, but their driving would still be compromised, although the extent of driving impairment under these conditions is not known. The increase in plasma concentrations of ecstasy caused by alcohol could exacerbate the adverse effects of ecstasy.

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel

CANNABINOIDS (SED-14, 95; SEDA-24, 36; SEDA-25, 43; SEDA-26, 36) Respiratory Three patients with large bullae in the upper lung lobe have been reported (14A ). All had been heavy marijuana smokers over 10– 24 years. However, they all had at least nine pack-years of cigarette exposure, so marijuana may not have been the only cause of their lung bullae. Nevertheless, the authors recommended that all those who present with upper lung bullae should be screened for cannabis use. Nervous system The effects of oral cannabinoids (dronabinol or Cannabis sativa plant extract) in relieving pain and muscle spasticity have been studied in 16 patients with multiple sclerosis (mean age 46 years, mean duration of disease 15 years) in a double-blind, placebocontrolled, crossover study (15A ). The initial dose was 2.5 mg bd, increasing to 5 mg bd after 2 weeks if the dose was well tolerated. The plant extract was more likely to cause adverse events; ﬁve patients had increased spasticity and one rated an adverse event of acute psychosis as severe. All physical measures were in the reference ranges. There were no signiﬁcant differences in any measure of efﬁcacy score that would indicate a therapeutic beneﬁt of cannabinoids. This study is the largest and longest of its kind, but the authors acknowledged some possible shortcomings. The route of administration could affect subjective ratings, since the gastrointestinal tract is a much slower and more inefﬁcient route than the lungs. Another possibility is that the dose was too small to have the desired therapeutic effects. Sensory systems The effect of tetrahydrocannabinol, 7.5 mg and 15 mg, on auditory functioning has been investigated in eight men in a double-blind randomized, placebo-controlled, crossover trial (16c ). Blood concentrations of tetrahydrocannabinol were measured for up to 48 hours after ingestion, and audiometric tests were carried out at 2 hours. There were no signiﬁcant differences across treatments, suggesting that cannabis does not affect the basic unit of auditory perception. However, more investigations in this area are needed.

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Psychological The safety and possible beneﬁts of long-term marijuana use have been studied in four seriously ill patients in the Missoula Chronic Clinical Cannabis Use Study with a quality-controlled sample of marijuana (17c ). They were evaluated using an extensive neurocognitive battery. • A 62-year-old woman with congenital cataracts smoked marijuana illicitly for 12 years (current use 3–4 g/day smoked and 3–4 g/day orally). She had mild-to-moderate difﬁculty with attention and concentration and minimal-to-mild difﬁculty with acquisition and storage of very complex new verbal material. Her executive functioning was not affected. • A 50-year-old man with hereditary osteo-onychodysplasia had smoked marijuana since 1974 to alleviate muscle spasms and pain (current use 7 g/day of 3.75% tetrahydrocannabinol). He had mild-to-moderate impairment of attention and concentration and reduced ability to acquire new verbal material. He scored poorly on the California Verbal Learning Test (CVLT), a measure of shortterm memory recall, and had difﬁculty with motor tasks. • A 48-year-old man with multiple congenital cartilaginous exostoses had smoked marijuana since the late 1970s (current use 9 g/day of 2.7% tetrahydrocannabinol). His neurocognitive scores suggest mild difﬁculty in sustaining attention and a minimal-to-mild deﬁcit in the acquisition of new verbal material. • A 45-year-old woman with multiple sclerosis had smoked cannabis since 1990 to control pain and muscle spasms (current use of marijuana cigarettes containing 3.5% tetrahydrocannabinol 10/day). She had impairment of concentration, learning, and memory efﬁciency. Her ability to acquire new verbal information was also impaired.

The authors attributed these cognitive deﬁcits not to marijuana use but rather to the patients’ illnesses, arguing that it is difﬁcult for patients with painful debilitating diseases to concentrate on neurocognitive tasks. Any abnormalities in MRI imaging and electroencephalography were attributed to age-related brain deterioration. There were no signiﬁcant abnormalities of respiratory function, apart from a “slight downward trend in FEV1 and FEV1 /FVC ratios, and perhaps an increase in FVC” in three patients, interpretation of these ﬁndings being complicated by concomitant tobacco smoking. One patient had mild polycythemia and a raised white cell count. None had abnormal endocrine tests. This was a comprehensive study of the long-term effects of cannabis, but concomitant illnesses and use of tobacco made the results difﬁcult to interpret.

Drug interactions Myocardial infarction has been attributed to the combination of cannabis and sildenaﬁl. • A 41-year-old man developed chest tightness radiating down both arms (18A ). He had taken sildenaﬁl and cannabis recreationally the night before. His vital signs were normal and he had no signs of heart failure. However, electrocardiography showed an inferior evolving non-Q-wave myocardial infarct and his creatine kinase activity was raised (431 U/l).

Cannabis inhibits CYP3A4 isoenzyme, which is primarily responsible for the metabolism of sildenaﬁl, increased concentrations of which may have caused this cardiac event.

COCAINE

(SED-14, 106; SEDA-24, 37; SEDA-25, 40; SEDA-26, 27)

Cardiovascular In a review of emergency visits to a hospital during a 20-year period, 14 of 38 cases of acute aortic dissection involved cocaine use; six were of type A and eight of type B (19c ). Crack cocaine had been smoked in 13 cases and powder cocaine had been snorted in one case. The mean time of onset of chest pain was 12 hours after cocaine use. The chronicity of cocaine use was not known in most of the cases. The cocaine users were typically younger than the non-cocaine users. Chronic untreated hypertension and cigarette smoking were often present. • A 43-year-old man with untreated hypertension developed transient mild chest pressure followed by shortness of breath for 4 hours (20A ). He had long used tobacco, alcohol, and cocaine and admitted to having used cocaine within the last 12 hours. He had a tachycardia with a pansystolic murmur suggesting mitral regurgitation. Urine drug screen was positive for cocaine metabolites. A chest X-ray showed mild cardiomegaly and prominent upper lobe vasculature. An electrocardiogram showed atrial ﬂutter at a rate of 130/minute and nonspeciﬁc T wave changes. The diagnoses were myocardial infarction due to cocaine, with mild congestive heart failure, mitral regurgitation and atrial ﬂutter. However, transesophageal echocardiography showed severe aortic insufﬁciency and a dissection ﬂap in the ascending aorta. He underwent emergency repair of the aortic root and resuspension of the aortic valve.

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Respiratory In healthy crack cocaine users, there is evidence of cocaine-related injury to the pulmonary microcirculation, from ﬁberoptic bronchoscopy and examination of the bronchoalveolar ﬂuid in 10 cocaine-only smokers, six cocaine-plus-tobacco smokers, 10 tobacco smokers, and 10 non-smokers, all with normal respiratory function (21c ). The percentages of hemosiderin-positive alveolar macrophages (a marker of recent alveolar hemorrhage) were markedly increased in the cocaine smokers compared with the others. Furthermore, the concentrations of endothelin (ET-1), an indicator of cell damage, were signiﬁcantly raised in the cocaine smokers and to a lesser extent in the cocaine-and-tobacco smokers. These ﬁndings suggest that many asymptomatic healthy crack users have chronic alveolar hemorrhage that is not clinically evident. Handling cocaine pipes can cause thermal injury to the ﬁngertips. The presence of bilateral thumb burns raised suspicion of crack lung in a young woman with suspected communityacquired pneumonia (22A ). When confronted with urine toxicology positive for cocaine, she admitted to having smoked large quantities of free-base cocaine only a few hours before the onset of symptoms. Ear, nose, and throat Chronic use of intranasal cocaine is associated with complications, including nasal septal perforation, saddle-nose deformity, and palatal perforation. Cocaine-related erosion of the external nasal structures has been described (23A ). • A 43-year-old woman with a T12 paraplegia due to a car accident 24 years earlier and a sublabial abscess 2 years before developed progressive erosion of both the internal and external portions of her nose over 6 months, with nasal crusting and nose bleeds. Several antibiotics were unhelpful. There was partial destruction of the external nasal structure and two oronasal ﬁstulae in the upper gingival sulcus. Intranasal biopsy showed acute and chronic inﬂammation. On two occasions urine drug screening was positive for cocaine, although she denied using cocaine.

Midline nasal and hard palate destruction have been reported in two chronic users of intranasal cocaine (24A ). The pathophysiology of these lesions is multifactorial, including ischemia secondary to vasoconstriction, chemical irritation from adulterants, impaired mucociliary transport, reduced immunity, and infection secondary to trauma.

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel

Nervous system Aneurysmal subarachnoid hemorrhage can occur with acute use of cocaine. Of 440 patients with aneurysmal subarachnoid hemorrhage, 27 (6.1%) were cocaine users (25M ). Either urine toxicology was positive or there was a history of use within 72 hours of subarachnoid hemorrhage. There was an increased incidence of vasospasm, deﬁned as a delayed clinical deﬁcit 3–16 days after subarachnoid hemorrhage, among cocaine users compared with the non-users (63% versus 30%). Cocaine may increase the risk of subarachnoid hemorrhage directly by increasing the reactivity of cerebral vessels to vasoconstrictors and indirectly by reducing cerebral blood ﬂow. Cocaine users were also younger and more likely to have anterior circulation aneurysms. Chronic cocaine exposure and long-term adaptation at the molecular level are being investigated; changes in transcription factor gene expression may be involved (26c ). NURR1 is a key factor that regulates transcription of the gene that encodes the cocaine-sensitive dopamine transporter and functions in the development of dopamine neurons. In a recent study, postmortem human midbrain specimens from cocaine users and controls underwent various analyses. Human NURR1 gene expression was markedly reduced in dopamine neurons in the cocaine users and normal in the controls. NURR1-deﬁcient cocaine abusers also had dopamine neurons with markedly reduced dopamine transporter gene expression. NURR1 appears to have a critical role in the brain’s adaptation to repeated cocaine exposure and in maintenance of dopamine neurons. Neuromuscular function A second case of cocaine-induced periodic paralysis has been reported (27A ). • A healthy 33-year-old man suddenly developed generalized weakness and became unable to walk or lift his limbs; he also had mild chest pain. He had had similar episodes 10 days and 5 years before, with spontaneous resolution. He had no spontaneous motor activity and his strength was 2/5 in all major muscle groups with a very mild left upper limb predominance. Cardiac enzymes and neuroimaging of the brain and spinal cord were normal. Creatinine kinase was raised (395 iu/l). Acetylcholine receptor antibodies were in the reference range. His serum potassium concentration was 1.9 mmol/l. Urine toxicology screen showed cocaine, cannabinoids, and benzodiazepines and

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Chapter 4

he admitted to a cocaine binge the previous night and also before the previous two episodes. With potassium supplements his strength gradually improved.

Such severe generalized weakness and hypokalemia may be due to intracellular shift of potassium due to adrenergic stimulation by cocaine or a direct effect on potassium channels. Brown–Sequard syndrome after esophageal sclerotherapy and recent crack cocaine abuse has been reported (28A ). • A 44-year-old man with hepatitis C and cirrhosis, esophageal varices, and poorly controlled hypertension, who was also a chronic alcoholic and crack cocaine abuser, had his varices injected at endoscopy and developed right-sided weakness and numbness up to T4. There was ﬂaccid right leg weakness, right T4–6 hypalgesia, left leg hypalgesia up to L1, and reduced sweating on the left up to T4–6. An MRI scan of the thoracic spine showed a lesion at T4–6 involving the anterior and central portions of the spinal cord. Urine screen was positive for cocaine. He recovered spontaneously 2 weeks later.

Cocaine-induced ischemia was the most likely cause of this adverse outcome. Sensory systems Eyes Orbital infarction has been described after cocaine use (29A ). • A 36-year-old woman drank alcohol and snorted cocaine and heroin at a party. She lost consciousness, with her head positioned down with her left face pressed against a desk. She awoke 3 hours later with severe left orbital pain. Her right eye was normal but there was complete visual loss in the left eye and a nearly complete left ptosis. The left pupil did not react to light but reacted consensually. Movements in the right eye were full, but movements in the left eye were severely limited in all directions. In the left fundus there was retinal edema and retinal pigment epithelium disruption. An orbital MRI scan showed diffuse swelling of all the extraocular muscles in the left orbit. A week later the pain had abated and there was mild improvement in the eye movements and ptosis, but no change in vision. She was instructed to wear protective polycarbonate lenses at all times.

Central retinal artery occlusion has previously been reported in cases of intravenous and intranasal cocaine abuse and has now been reported in a man who smoked crack cocaine (30A ). • A 42-year-old man smoked crack and developed sudden painless loss of vision in his right eye for

35 9 hours. He had smoked cigarettes for 20 years and crack cocaine twice a week for the previous 4 years. Visual acuity in the right eye was counting ﬁngers at one meter, and in the left eye 6/4. There was a right relative afferent papillary defect. In the right fundus there was evidence of central retinal artery occlusion and the left fundus was unremarkable. Treatment included intravenous acetazolamide, intermittent ocular massage, and rebreathing into a paper bag. He was found to have sickle cell trait, a risk factor for central retinal artery occlusion.

Psychological The effect of cocaine on cognitive functioning (SEDA-25, 41; SEDA-24, 25; SEDA-23, 21) has been studied in 20 crack users, 37 crack and alcohol users, and 29 controls at 6 weeks and 6 months of abstinence (31c ). The two substance-dependent groups had signiﬁcant cognitive impairment in a range of neuropsychological tests compared with the controls at both times. Drug dose was strongly associated with the extent of impairment. Abstinent substance users were more depressed than controls during the test period, but depression had only a slight effect on neuropsychological performance. Gastrointestinal The esophagus can undergo thermal injury, in which the inner esophageal wall has a “candy-cane” appearance (alternating pink and white linear bands), when boilinghot liquids are consumed. This reversible condition is associated with chest pain, difﬁculty in swallowing, odynophagia, and abdominal pain. Candy-cane esophagus secondary to smoking crack cocaine has been reported (32A ). • A 55-year-old man accidentally sucked into his mouth and swallowed a portion of boiling water during his last smoke of free base cocaine and 2 days later developed sudden constant pain in the left shoulder and arm accompanied by sweating. He had melena, a hematocrit of 30%, a blood urea nitrogen of 35 mmol/l, and a serum creatinine of 1.1 mmol/l. The initial electrocardiogram showed sinus rhythm, left atrial enlargement, and borderline left ventricular hypertrophy. However, 2 hours later he started to sweat and became hypotensive (blood pressure 85/50 mmHg). An electrocardiogram showed new biphasic T waves and T-wave inversion. Urgent cardiac catheterization showed patent coronary arteries. Esophagogastroduodenoscopy within the hour showed a candycane appearance in the distal esophagus, patchy erythema and erosions in the gastric antrum, and an ulcer in the base of the duodenal bulb. Biopsies of the esophagus tissue showed parakeratosis, squamous hyperplasia with regeneration, and

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minimal inﬂammation. Biopsies of the stomach showed chronic gastritis and bacteria consistent with Helicobacter pylori. Later that day, the electrocardiogram normalized.

The most likely cause of the chest pain was microvascular spasm of the epicardial coronary arteries, due to either thermal injury to the esophagus or an effect of cocaine. Body temperature Cocaine can cause hyperthermia, primarily in hot weather, perhaps through a hypermetabolic state; impaired heat dissipation may be another contributing factor. Seven healthy, cocaine-naïve subjects participated in tests of progressive passive heat stress, during which each received intranasal cocaine or lidocaine as placebo (33c ). Esophageal temperature, skin blood ﬂow, sweat rate, and perceived thermal sensation were measured. Cocaine augmented the temperature increase during heat stress and also increased the temperature threshold for the onset of both cutaneous vasodilatation and sweating. It also impaired the perception of heat. This study elicited commentary, in which it was pointed out that measured effects of small doses of cocaine may not be reﬂective of true cocaine poisoning (34r ). Also, the subjects in the study did not have psychomotor agitation, which is often prominent in cocaine toxicity and which improves with sedatives. Death (SEDA-18, 38; SEDA-21, 32) The smuggling of illicit drugs, known as “body packing” carries medical risks. Drug packages can rupture and digestive secretions can seep into packets and allow drug absorption. Consequently, drug intoxication, intestinal obstruction, peritonitis, and death can occur. A man carrying 99 cocaine powder packages weighing 10 g died as a result (35A ), and the death of a drug dealer has been reported (36A ). • A 17-year-old man swallowed a small plastic bag of cocaine in order to avoid arrest. After 1 hour he complained of a headache and 30 minutes later developed palpitation and agitation and collapsed. Histological examination of his heart showed myocardial necrosis. The blood concentration of cocaine was high at 98 μg/ml. The tissue concentrations of cocaine and its metabolites in various organs and ﬂuids were recorded; the highest concentrations of cocaine and metabolites were detected in the liver, lungs, brain, and blood (in descending order).

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel

The cause of sudden death in this case was probably a cardiac dysrhythmia. Pregnancy Research on the impact of cocaine exposure on pregnancy and neonatal outcomes continues (37c ). Cocaine has been associated with both preterm delivery and premature rupture of the membranes. In a review, 85 of 604 expectant mothers with premature rupture of the membranes with documented cocaine exposure were compared with women with no drug exposure for six conditions of major neonatal morbidity. Cocaine users were older and of higher parity. The non-cocaine users had more morbidity, in particular neonatal infection and sepsis. The authors proposed that the mechanism of premature rupture of the membranes in the presence of cocaine may not be related to infection. Instead, cocaine may have a direct effect on the myometrium, stimulating uterine contractility. The Maternal Lifestyle Study has reported that the prevalence of adverse perinatal complications associated with the use of cocaine or opiates during pregnancy was lower than has been previously reported (38C ). In 11 811 mother–infant pairs followed prospectively, 11% of the exposed and non-exposed groups were hospitalized at least once. However, violence was a factor (20%) in admissions among the cocaine-exposed women. Teratogenicity Intrauterine cocaine exposure is associated with neonatal cardiovascular dysfunction and malformations. The long-term effects of cocaine on the neonate’s cardiovascular system and development are unknown. The effect of cocaine on the infant’s autonomic function and subsequent development has been reported (39c ). Heart rate variability, a noninvasive test of autonomic function, was evaluated in 77 prenatally cocaine-exposed infants, 77 healthy controls, and 89 infants who had been exposed prenatally to drugs other than cocaine (alcohol, marijuana, and/or nicotine). Within the ﬁrst 72 hours of life, the cocaineexposed infants were asymptomatic but had lower heart rate variability and lower vagal tone than the two comparison groups. At follow-up, the cocaine-exposed infants had recovered at 2–6 months of age and now had higher heart rate variability and vagal tone than the two nonexposed groups. Most of the increase in heart

Drugs of abuse

Chapter 4

rate variability and vagal tone was seen in the infants who had had light cocaine exposure and was not apparent in those who had had heavy exposure. The same researchers have published two reports on the cardiovascular effects of intrauterine cocaine. In the ﬁrst study, 82 healthy neonates with intrauterine cocaine exposure, 108 exposed to drugs other than cocaine, and 87 healthy controls were evaluated for global and segmental systolic and diastolic cardiac function (40c ). During the ﬁrst 48 hours of life, the neonates with intrauterine cocaine exposure had signiﬁcant left ventricular diastolic segmental abnormalities. They had a higher index of asynchrony and global and segmental fractional area changes in contrast to the other two groups. The degree of abnormality in the index of asynchrony was greater in the neonates with heavier cocaine exposure. In a second study at 2–6 months of age, 56 cocaine-exposed infants were compared with 72 who had been exposed to drugs other than cocaine and 60 healthy controls (41c ). The cocaine-exposed infants had recovered left ventricular diastolic function. Only in infants with heavy cocaine exposure was there an alteration in septal wall diastolic ﬁlling. The effect of intrauterine cocaine exposure on visual attention, cognition, and behavior has been further investigated in 14 cocaineexposed children and 20 controls aged 14– 60 months (42c ). The cocaine-exposed children were slower in tests of disengagement and sustained attention. They also had greater difﬁculties in behavioral regulation. Research on the effects of prenatal cocaine exposure on development in the ﬁrst 2 years of life has been reported in 203 full-term infants (43C ). Some previous studies have shown a signiﬁcant effect, whereas others have shown none (SEDA-18, 39; SEDA-21, 26; SEDA24, 39; SEDA-25, 42). The infants, who were deﬁned as having had no cocaine exposure, light exposure, or heavy exposure, were tested with the Bayley Scales of Infant Development at 6, 12, and 24 months. Assays of neonatal meconium for cocaine metabolites along with mothers’ self-reports were used to evaluate the dose–response relation. There were no signiﬁcant adverse effects due to cocaine exposure on scores in the major tests up to 24 months of age. Cocaine-exposed infants

37 with the lowest 10th percentile birth weight and those placed with kinship caregivers had less optimal development. Cocaine-exposed infants who participated in child-focused early intervention programs scored higher than the others. The behavioral effects of prenatal cocaine exposure at age 5 years have been studied in 140 children exposed to cocaine, 61 exposed to alcohol, tobacco, and/or marijuana, and 120 not exposed to any drugs (44C ). They were evaluated with the Achenbach Child Behavior Checklist. There was no association between behavior and intrauterine cocaine exposure. However, the current behavioral health of the mother, including recent drug use and psychological functioning, did affect the child’s internalizing and externalizing behavior. Drug interactions Abuse of mixtures of substances accounts for several reports of adverse outcomes. Cocaine plus alcohol The adverse effects of the combined use of alcohol and cocaine have been reviewed (45R ). There is little evidence that this combination acts synergistically or that either drug enhances the negative effects of the other. However, the combination leads to the formation of cocaethylene, which may potentiate cardiotoxic effects and the combination has a greater than additive effect on heart rate. Lastly, cocaine antagonizes the learning and psychomotor performance deﬁcits and driving impairment caused by alcohol. Reports of liver complications after cocaine use are infrequent. However, fulminant hepatitis with acute renal insufﬁciency requiring liver transplantation occurred after the use of cocaine and alcohol (46A ). • A 33-year-old chronic alcoholic with hepatitis C developed acute liver and renal insufﬁciency with grade III encephalopathy. Hemodialysis was begun and emergency liver transplantation was performed. The explanted liver showed marked diffuse macrovesicular steatosis with massive coagulativetype necrosis. The postoperative course included a persistently raised gamma-glutamyltransferase, but he recovered fully after 60 days.

Macrovesicular steatosis can be attributed to alcohol or cocaine, but massive liver necrosis is more probably due to cocaine. The mechanisms of cocaine hepatotoxicity, such as increased lipid peroxidation, free radical activity,

38

Chapter 4

and impaired calcium sequestration, may be potentiated by alcohol. Cocaine plus diamorphine Rhabdomyolysis and ventricular ﬁbrillation has been attributed to cocaine plus heroin ingestion (47A ). • A 28-year-old man went into cardiorespiratory arrest after using intravenous cocaine and heroin. He was intubated and ventilated and given adrenaline, naloxone, and sodium bicarbonate. During a thoracotomy he developed ventricular ﬁbrillation and was electrically converted to sinus rhythm. He had hyperkalemia and myoglobinuria. He developed acute renal insufﬁciency, disseminated intravascular coagulopathy, and a right leg compartment syndrome. There were cocaine metabolites and opioids in his urine. Hemodialysis and fasciotomy were performed, but he died 2 months later with a complicating bronchopneumonia.

The authors discussed the possibility that naloxone, an effective opioid antidote, may have been harmful in this case.

OPIATES

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

SEDA-25, 37)

Diamorphine (heroin) Respiratory “Chasing the dragon”, or inhaling heroin vapor through a straw, is a technique by which heroin users avoid the risks of injection. In Amsterdam, 85% of heroin users smoke or chase the drug. Pulmonary function can be affected by heroin inhalation. It can depress the respiratory center, release histamine (which can trigger asthma), result in septic emboli, and increase susceptibility to infectious diseases, such as tuberculosis and pneumonia. In a recent study of 100 methadone maintenance users lung function and shortness of breath were evaluated using spirometry and clinical history (48c ). Impaired lung function and shortness of breath correlated with chronic heroin smoking. Heroin-induced pulmonary edema or “heroin lung” (SEDA-19, 29; SEDA-25, 39) is a serious complication, which may be due to release of histamine, with increased pulmonary lymph ﬂow and capillary permeability. There have been 27 reports of non-fatal heroin overdose associated with non-cardiogenic pulmonary edema (49M ).

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel

Nervous system Leukoencephalopathy and death have been reported (SEDA-22, 35; SEDA24, 40). The presentation includes apathy, bradyphrenia, motor restlessness, and progressive cerebellar ataxia. Heroin-induced leukoencephalopathy has been misdiagnosed as psychiatric illness (50A ). • A 47-year-old woman, with a history of amphetamine abuse, depression, and paranoia, smoked heroin for 4 weeks after stopping amphetamines and 10 days later became drowsy and confused with increased paranoia and depression. She was disoriented and restless. Her speech was garbled. She had frequent non-purposeful movements and an unsteady gait. A CT brain scan was normal. She was given chlorpromazine, doxepin, and diazepam, but her ataxia and incontinence worsened, her speech and all her movements slowed, with increased tone in all limbs and cogwheel rigidity. Her power and sensation were normal. Truncal ataxia impaired walking. An MRI brain scan showed diffuse high-intensity signals in both cerebral hemispheres, and review of the CT scan showed hypodensities in the same regions. She was treated with coenzyme Q and regained mobility and continence, but with no improvement in cognitive impairment.

Endocrine The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been attributed to heroin (51A ). • A 23-year-old pregnant woman developed antepartum bleeding at 35 weeks and a tonic–clonic convulsion and hypothermia at 39 weeks, having used heroin 4 hours before. She had further tonic– clonic seizures, became obtunded, and required intubation. She had occasional runs of ventricular bigeminy. A cesarean section was performed. The neonate had poor respiratory effort and required ventilation. Blood chemistry suggested inappropriate secretion of antidiuretic hormone, acute renal insufﬁciency, and acute pancreatitis. She and the baby recovered after 2 weeks.

Pregnancy The outcomes in 100 chronic opiate-dependent pregnant women who received levomethadone substitution treatment have been reported (52M ). The average gestational age at delivery was 38 weeks and the mean birth weight was 2869 g. The rate of premature labor was 19% and the risk of premature delivery 11%. There were withdrawal symptoms in 74% of the neonates at a mean of 39 hours and all responded well to levomethadone. Drug formulations Psychomotor and cognitive performance has been studied in 18 opi-

Drugs of abuse

39

Chapter 4

oid-dependent methadone maintenance patients and 21 non-substance abusers (53c ). Abstinence from heroin and cocaine for the previous 24 hours was veriﬁed by urine testing. The methadone maintenance patients had a wide range of impaired functions, including psychomotor speed, working memory, decision making, and metamemory. There was also possible impairment of inhibitory mechanisms. In the areas of time estimation, conceptual ﬂexibility, and long-term memory, the groups performed similarly.

or over in 41 cases (56M ). In the 21 with low concentrations, respiratory tract infections occurred more often, and plausible causes of death were identiﬁed in 19.

Drug administration route Among heroin users, the annual rate of mortality is 1–4% and overdose and HIV infection are the leading causes. The effect of the frequency and route of heroin administration on the occurrence of nonfatal heroin overdose has been studied (54M ). Among 2556 subjects with heroin dependence, 10% had taken overdoses requiring emergency care in the prior 12 months. The cumulative risk of overdose increased as the frequency of heroin use fell. Among daily heroin users, the risk was greater with increased frequency of heroin injection, but not among non-daily users. The risk of overdose was greater with injection than with other routes of administration.

• A 41-year-old woman who had taken 11 alprazolam tablets and heroin mixed with an unknown substance developed slurred speech and a staggering gait. She was also taking paroxetine. Her pupils were dilated, her skin warm and dry. Electrocardiography showed a sinus bradycardia. She was given intravenous naloxone 2.0 mg and became acutely agitated and combative. She was delirious, agitated, and disoriented, and was given an intravenous sedative and intubated. Her urine contained codeine, morphine, and atropine.

Death (SEDA-14,198; SEDA-18, 40; SEDA24, 40; SEDA-25, 37) An increase in the number of deaths of all body packers in New York has been associated with an increase in deaths among opiate body packers: of 50 deaths among body packers from 1990 to 2001, 42 were due to opiates (55R ). Four were related to cocaine and four to both opiates and cocaine. In 37 cases open or leaking drug packets in the gastrointestinal tract resulted in acute intoxication and death. Five cases involved intestinal obstruction or perforation, one a gunshot wound, one an intracerebral hemorrhage due to hypertensive disease, and one was undetermined. The number of packets recovered was 1–111 (average 46). An unbound morphine blood concentration of 100 ng/ml or more is considered potentially fatal. However, fatal cases of heroin intoxication occur in patients with blood morphine concentrations below 100 ng/ml. In 62 cases of heroin intoxication death was associated with unbound morphine heart blood concentrations below 100 ng/ml in 21 cases and 100 ng/ml

Drug interactions Combining opiates with anticholinergic drugs is a common practice in recreational abuse (SEDA-21, 34). Heroin mixed with hyoscine (scopolamine) is nicknamed “polo” and “point on point”. Mixed drug toxicity, with atypical signs and symptoms of opiate abuse, has been reported (57A ).

This case exempliﬁes the difﬁculty in identifying anticholinergic drugs such as atropine, and unfortunately the ﬁnding of dilated pupils did not raise the suspicion of mixed drug toxicity. The use of naloxone uncovered ﬂorid agitation due to anticholinergic drug toxicity.

MISCELLANEOUS DRUGS OF ABUSE Gammahydroxybutyrate (SEDA-26, 542) Nervous system In a double-blind, doubledummy comparison of clomethiazole and gammahydroxybutyrate in ameliorating the symptoms of alcohol withdrawal, alcohol-dependent patients were randomized to receive either clomethiazole 1000 mg or gammahydroxybutyrate 50 mg/kg (58C ). There was no difference between the treatments in ratings of alcohol withdrawal symptoms or requests for additional medications. After tapering the active medication, there was no increase in withdrawal symptoms, suggesting that physical tolerance did not develop to either clomethiazole or gammahydroxybutyrate during the 5-day treat-

40

Chapter 4

ment period. The most frequently reported adverse effect of gammahydroxybutyrate was

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel

transient vertigo, particularly after the evening double dose.

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a case series and review of the literature. J Forensic Sci 2002; 47: 121–6. 13. Hernandez-Lopez C, Farre M, Roset PN, Menoyo E, Pizarro N, Ortuno J, Torrens M, Cami J, De la Torre. 3,4-Methylenedioxymethamphetamine (ecstasy) and alcohol interactions in humans: psychomotor performance, subjective effects, and pharmacokinetics. J Pharmacol Exp Ther 2002; 300: 236–44. 14. Thompson CS, White RJ. Lung bullae and marijuana. Thorax 2002; 57: 563. 15. Killestein J, Hoogervorst ELJ, Reif M, Kalkers NF, Van Loenen AC, Staats PGM, Gorter RW, Uitdehaag BMJ, Polman CH. Safety, tolerability, and efﬁcacy of orally administered cannabinoids in MS. Neurology 2002; 58: 1404–7. 16. Mulheran M, Middleton P, Henry JA. The acute effects of tetrahydrocannabinol on auditory threshold and frequency resolution in human subjects. Hum Exp Toxicol 2002; 21: 289–92. 17. Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, Kirlin KA. Chronic cannabis use in the compassionate investigational new drug program: an examination of beneﬁts and adverse effects of legal clinical cannabis. J Cannabis Ther 2002; 2: 3–57. 18. McLeod AL, McKenna CJ, Northridge DB. Myocardial infarction following the combined recreational use of Viagra® and cannabis. Clin Cardiol 2002; 25: 133–4. 19. Hsue PY, Salinas CL, Bolger AF, Benowitz NL, Waters DD. Acute aortic dissection related to crack cocaine. Circulation 2002; 105: 1592–5. 20. Riaz K, Forker AD, Garg M, McCullough PA. Atypical presentation of cocaine-induced type A aortic dissection: a diagnosis made by transesophageal echocardiography. J Invest Med 2002; 50: 140–2. 21. Baldwin GC, Choi R, Roth MD, Shay AH, Kleerup EC, Simmons MS, Tashkin DP. Evidence of chronic damage to the pulmonary microcirculation in habitual users of alkaloidal “crack” cocaine. Chest 2002; 121: 1231–8. 22. Gatof D, Albert RL. Bilateral thumb burns leading to the diagnosis of crack lung. Chest 2002; 121: 289–91. 23. Vilela RJ, Langford C, McCullagh L, Kass ES. Cocaine-induced oronasal ﬁstulas with external nasal erosion but without palate involvement. Ear Nose Throat J 2002; 81: 562-3. 24. Smith JC, Kacker A, Anand VK. Midline nasal and hard palate destruction in cocaine abusers and cocaine’s role in rhinologic practice. Ear Nose Throat J 2002; 81: 172–7.

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25. Conway JE, Tamargo RJ. Cocaine use is an independent risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2002; 33: 1747–8. 26. Bannon MJ, Pruetz B, Manning-Bog AB, Whitty CJ, Michelhaugh SK, Sacchetti P, Granneman JG, Mash DC, Schmidt CJ. Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers. Proc Natl Acad Sci USA 2002; 99: 6382–5. 27. Lajara-Nanson WA. Cocaine-induced hypokalaemic periodic paralysis. J Neurol Neurosurg Psychiatry 2002; 73: 92. 28. Mueller D, Gilden DH. Brown–Sequard syndrome after esophageal sclerotherapy and crack cocaine abuse. Neurology 2002; 58: 1129–30. 29. Van Stavern GP, Gorman M. Orbital infarction after cocaine use. Neurology 2002; 59: 642–3. 30. Michaelides M, Larkin G. Cocaine-associated central retinal occlusion in a young man. Eye 2002; 16: 790–2. 31. Di Sclafani V, Tolou-Shams M, Price LJ, Fein G. Neuropsychological performance of individuals dependent on crack-cocaine or crack-cocaine and alcohol at 6 weeks and 6 months of abstinence. Drug Alcohol Depend 2002; 66: 161–71. 32. Cohen ME, Kegel JG. Candy cocaine esophagus. Chest 2002; 121: 1701–3. 33. Crandall CG, Vongpatanasin W, Victor RG. Mechanism of cocaine-induced hyperthermia in humans. Ann Intern Med 2002; 136: 785–91. 34. Schier JG, Hoffman RS, Nelson LS. Cocaine and body temperature regulation. Ann Intern Med 2002; 10: 855. 35. Furnari C, Ottaviano V, Sacchetti G, Mancini M. A fatal case of cocaine poisoning in a body packer. J Forensic Sci 2002; 47: 208–10. 36. Fineschi V, Centini F, Monciotti F, Turillazzi E. The cocaine “body stuffer” syndrome: a fatal case. Forensic Sci Int 2002; 126: 7–10. 37. Refuerzo JS, Sokol RJ, Blackwell SC, Berry SM, Janisse JJ, Sorokin Y. Cocaine use and preterm premature rupture of membranes: improvement in neonatal outcome. Am J Obstet Gynecol 2002; 186: 1150–4. 38. Bauer CR, Shankaran S, Bada HS, Lester B, Wright LL, Krause-Steinrauf H, Smeriglio VL, Finnegan LP, Maza PL, Verter J. The Maternal Lifestyle Study: drug exposure during pregnancy and short-term maternal outcomes. Am J Obstet Gynecol 2002; 186: 487–95. 39. Mehta SK, Super DM, Connuck D, Kirchner HL, Salvator A, Singer L, Fradley LG, Kaufman ES. Autonomic alterations in cocaine-exposed infants. Am Heart J 2002; 144: 1109–15. 40. Mehta SK, Super DM, Salvator A, Singer L, Connuck D, Fradley LG, Harcar-Sevcik RA, Thomas JD, Sun JP. Diastolic ﬁlling abnormalities by color kinesis in newborns exposed to intrauterine cocaine. J Am Soc Echocardiogr 2002; 15: 447–53. 41. Mehta SK, Super DM, Connuck D, Kirchner HL, Salvator A, Singer L, Fradley LG, Thomas JD, Sun JP. Diastolic alterations in infants exposed to

41 intrauterine cocaine: a follow-up study by color kinesis. J Am Soc Echocardiogr 2002; 15: 1361–6. 42. Heffelﬁnger AK, Craft S, White DA, Shyken J. Visual attention in preschool children prenatally exposed to cocaine: implications for behavioral regulation. J Int Neuropsychol Soc 2002; 8: 12–21. 43. Frank DA, Jacobs RR, Beeghly M, Augustyn M, Bellinger D, Cabral H, Heeren T. Level of prenatal cocaine exposure and score on the Bayley scales of infant development: modifying effects of caregiver, early intervention, and birth weight. Pediatrics 2002; 10: 1143–52. 44. Accornero VH, Morrow CE, Bandstra ES, Johnson AL, Anthony JC. Behavioral outcome of preschoolers exposed prenatally to cocaine: role of maternal behavioral health. J Pediatr Psychol 2002; 27: 259–69. 45. Pennings, EJM, Leccese AP, Wolff FA. Effects of concurrent use of alcohol and cocaine. Addiction 2002; 97: 773–83. 46. Hurtova M, Duclos-Vallee JC, Saliba F, Emile JF, Benelmans M. Liver transplantation for fulminant hepatic failure due to cocaine intoxication in an alcoholic hepatitis C virus-infected patient. Transplantation 2002; 73: 157–8. 47. McCann B, Hunter R, McCann J. Cocaine/heroin induced rhabdomyolysis and ventricular ﬁbrillation. Emerg Med J 2002; 19: 264–5. 48. Buster M, Rook L, Van Brussel G, van Ree J, Van den Brink W. Chasing the dragon, related to the impaired lung function among heroin users. Drug Alcohol Depend 2002; 68: 221–8. 49. Sporer KA, Dorn E. Heroin-related noncardiogenic pulmonary edema: a case series. Chest 2001; 120: 1628–32. 50. Sayers GM, Green MC, Shaffer RE. Heroininduced leucoencephalopathy misdiagnosed as psychiatric illness. Int J Psychiatry Clin Pract 2002; 6: 53–5. 51. Cooley S, Lalchandani S, Keane D. Heroin overdose in pregnancy: an unusual case report. J Obstet Gynaecol 2002; 22: 219–20. 52. Kastner R, Hartl K, Lieber A, Hahlweg BC, Knobbe A, Grubert T. Substitutionsbehandlung von opiatabhängigen schwangeren—Analyse der Behandlungverläufe an der 1. Ufk München. Geburtschilfe Frauenheilkd 2002; 62: 32–6. 53. Mintzer MZ, Stitzer ML. Cognitive impairment in methadone maintenance patients. Drug Alcohol Depend 2002; 67: 41–51. 54. Brugal MT, Barrio GB, de la Fuente L, Regidor E, Royuela L, Suelves JM. Factors associated with non-fatal heroin overdose: assessing the effect of frequency and route of heroin administration. Addiction 2002; 97: 319–27. 55. Gill JR, Graham SM. Ten years of “body packers” in New York City: 50 deaths. J Forensic Sci 2002; 47: 843–6. 56. Koch A, Reiter A, Meissner C, Oehmichen M. Ursache des Todes von Heroinkonsumenten mit niedrigen Morphin-Konzentrationen im Blut. Arch Kriminol 2002; 209: 76–87. 57. Wang HE. Street drug toxicity resulting from opiates combined with anticholinergics. Prehosp Emerg Care 2002; 6: 351–4.

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58. Nimmerrichter AA, Walter H, Gutierrez-Lobos KE, Lesch OM. Double-blind controlled trial of gamma-hydroxybutyrate and clomethiazole in the

Eileen Wong, Timothy E. Ralston, and Jayendra K. Patel treatment of alcohol withdrawal. Alcohol Alcoholism 2002; 37: 67–73.

Stephen Curran and Shabir Musa

5

Hypnosedatives and anxiolytics

Insomnia is a common disorder and has a number of physiological, physical, and psychological causes. Jet lag, excessive physical exercise, and caffeine-containing drinks are common causes. Psychiatric conditions, such as depression and anxiety, are also frequent causes. Hypnotics have a role to play in the management of insomnia, but initially the underlying cause should be treated and sleep hygiene should be tried, for example, by making sure that the room is not too warm, cold, noisy, etc; a regular sleep pattern and modest exercise can be very helpful.

AZASPIRONES

(SED-14, 133; SEDA-22, 39; SEDA-23, 45; SEDA-26, 49)

Buspirone Drug interactions Clinicians should inform their patients about the risks associated with taking St John’s wort if they are taking psychotropic drugs that can cause the serotonin syndrome. • A 27-year-old married woman developed symptoms of generalized anxiety disorder and was given buspirone 30 mg/day (1A ). During treatment she felt depressed and decided to take St John’s wort. Two months later she started to have nervousness, aggressiveness, hyperactivity, insomnia, blurred vision, and very short periods of confusion and disorientation. The symptoms were consistent with serotonin syndrome. St John’s wort was withdrawn and her symptoms resolved after 1 week.

Buspirone is a partial agonist at 5HT1A receptors; St John’s wort is a non-selective inhibitor of 5HT reuptake and also upregulates postsynaptic 5HT1A and 5HT2A receptors; it therefore causes overstimulation of 5HT1A receptors, leading to the serotonin syndrome. © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

BENZODIAZEPINES

(SED-14, 122; SEDA-24, 46; SEDA-25, 47; SEDA-26, 46)

Psychological In a prospective study, 1389 people aged 60–70 years were recruited from the electoral rolls of the city of Nantes (Epidemiology of Vascular Aging Study) (2C ). A range of symptoms was examined, including cognitive functioning and symptoms of depressive anxiety, and data were also collected on psychotropic and other drugs, as well as tobacco use and alcohol consumption at baseline and thereafter at 2 years and 4 years. Users of benzodiazepines were divided into episodic users, recurrent users, and chronic users. Chronic users of benzodiazepines had a signiﬁcantly higher risk of cognitive decline in the global cognitive test and two attention tests than non-users. Overall, episodic and recurrent users had lower cognitive scores compared with non-users, but the differences were not statistically signiﬁcant. These ﬁndings suggest that long-term use of benzodiazepines is a risk factor for increased cognitive decline in elderly people. Drug overdose Overdosage of benzodiazepines alone is generally thought to be safe, but deaths have occasionally been reported (3A , 4c , 5A ). Death has again been reported, attributed to an overdose of triazolam (6A ). • A 77-year-old woman was found dead in her bathtub. She had a history of depression, liver disease, spinal stenosis, and diabetes mellitus. An empty bottle of triazolam was found in the bin. At autopsy there was no injury or evidence of drowning. There was triazolam 0.12 mg/l in the heart blood.

In 204 consecutive suicides seen by the San Diego County Coroner during 1981–2, drugs were detected in 68%, and anxiolytics and hypnotics in 11% and 12% respectively; although benzodiazepines were found in under 10% of the group as a whole, they were found in onethird of those who died by overdose (7C ). In a

43

44 retrospective analysis of 352 consecutive cases of fatal overdose, temazepam accounted for 65% of all deaths from benzodiazepine overdose (8c ). In one series of 2827 intentional cases of poisoning, in which there were ten deaths, three were associated with benzodiazepines; death was related to a delay between ingestion and medical intervention (9C ), and advanced age has also been described as a risk factor (10c ). In other cases death has been attributed to combined overdose with other drugs, such as alcohol (4c ), oxycodone (11A , 12A ), tramadol (13A ), and amitriptyline (14A ). Concomitant benzodiazepine overdose has also been reported to be an independent risk factor in the development of hepatic encephalopathy (OR = 1.91; CI = 1.00, 3.65) and renal dysfunction (OR = 1.81; CI = 1.00, 3.22) in patients who take a paracetamol overdose (15C ). Drug interactions The question of whether starting a benzodiazepine in patients taking levodopa is followed by a faster increase in antiparkinsonian drug requirements has been studied using drug dispensing data for all the residents in six Dutch cities (16C ). All were 55 years old or older and had used levodopa for at least 360 days. There were 45 benzodiazepine starters and 169 controls. Antiparkinsonian drug doses increased faster in the benzodiazepine group, but the difference was not signiﬁcant (RR = 1.44; 95% CI = 0.89, 2.59).

Alprazolam Psychiatric Alprazolam is a recognized treatment for panic disorder, and abrupt withdrawal from prolonged treatment is associated with panic attacks.

Chapter 5

Stephen Curran and Shabir Musa

This case illustrates the potential severity of alprazolam rebound and how its long-term use can exacerbate the symptoms for which it was originally administered. Drug withdrawal A 39-year-old woman had withdrawal symptoms after her dose of alprazolam was reduced (18A ). Cognitive symptoms made it almost impossible for her to stop taking alprazolam or to continue psychotherapeutic treatment. The medication was stopped by means of a behavioral experiment, in which both patient and therapist were unaware of the way in which the medication was reduced, after which continuation of treatment became possible.

Bromazepam Drug interactions The interaction of bromazepam with ﬂuconazole has been studied in 12 healthy men in a randomized, double-blind, four-way crossover study (19C ). The subjects took a single oral or rectal dose of bromazepam (3 mg) after pretreatment for 4 days with oral ﬂuconazole 100 mg/day or placebo. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, the continuous number addition test, and electroencephalography. After rectal administration there was a higher AUC (1.7-fold) and a higher Cmax (1.6-fold) than after oral administration; there were electroencephalographic effects and subjective drowsiness after rectal bromazepam, and the electroencephalographic effects correlated closely with mean plasma bromazepam concentrations. However, ﬂuconazole caused no signiﬁcant changes in the pharmacokinetics or pharmacodynamics of oral or rectal bromazepam.

• A 77-year-old married woman with panic attacks did not experience them while she took alprazolam 0.5 mg bd for 5 months; however, the attacks recurred after an increase in dose to 0.5 mg qds (17A ).

Diazepam

The authors suggested that the duration of action of alprazolam is too brief to prevent rebound anxiety with administration four times a day, but this explanation is highly speculative.

Immunologic Diazepam hypersensitivity is probably very rare: a MEDLINE search showed no reports between 1982 and 2002, but a case has now been reported (20A ).

Hypnosedatives and anxiolytics

45

Chapter 5

• A 28-year-old nurse had generalized urticaria and collapsed while she was undergoing a gastroscopy for suspected Helicobacter pylori infection. Before the start of the procedure she was given lidocaine oral spray and intravenous diazepam 10 mg, and at the end intravenous ﬂumazenil 1 mg. Skin prick tests and intradermal tests with diazepam 5 mg/ml produced a weal-and-ﬂare reaction; ﬂumazenil 0.1 mg/ml and lidocaine 2% had no effect.

Although for safety reasons a challenge test was not performed, the author suggested that the reaction had been IgE-mediated.

Lormetazepam Psychiatric Auditory hallucinations been attributed to lormetazepam (21A ).

have

• A 45-year-old woman with moderate depression and anxiety took lormetazepam 4 mg/day. After a few days, she noticed musical auditory hallucinations like children’s songs. There were no neurological, otological, or psychiatric causes for the hallucinations. When the dose of lormetazepam was reduced to 2 mg the auditory experience changed to “classic tinnitus”. The lormetazepam was eventually withdrawn, but a slight degree of tinnitus remained.

Quazepam Drug–food interactions The disposition of quazepam 20 mg, fasted and 30 minutes after the consumption of meals containing different amounts of dietary fat, has been studied in a three-arm, randomized, crossover study in nine healthy men (22C ). Plasma concentrations of quazepam and its metabolite, 2-oxoquazepam, were measured for up to 48 hours after dosing. The peak concentrations of quazepam 30 minutes after low-fat and high-fat meals were 243% and 272% respectively of those in the fasted state. The AUCs of quazepam from 0 to 8 hours and from 0 to 48 hours were increased by both the low-fat and highfat meals by 1.4–2 fold times. Quazepam was well tolerated, with no signiﬁcant difference in the Stanford Sleepiness Scale between fasted and fed conditions. Thus, food signiﬁcantly increased the absorption of quazepam but did not prolong the half-life. Quazepam is lipophilic; it would therefore be more highly dissolved in a fatty meal and more available for absorption.

Temazepam Drug abuse Inadvertent intra-arterial injection of temazepam can cause tissue damage. • A 29-year-old unemployed man developed pain and swelling of the right hand following inadvertent intra-arterial injection of temazepam capsules (23A ). Over 10 days, necrotic areas involving the index, middle, and little ﬁngers developed and the ﬁngers had to be amputated. He reported episodes of intravenous drug use during the previous 3 days—a single heroin dose followed by temazepam four times (10 mg gel capsules dissolved in hot water). He had injected the drugs into a superﬁcial blood vessel on the back of the right hand.

Drug dosage regimens Benzodiazepine prescribing for sleep induction in an elderly medical in-patient population has been examined, to determine if hospital prescribing increases the use of benzodiazepines after discharge (24c ). The secondary objectives included monitoring for adverse effects and assessment of the quality of sleep in hospital compared with the quality of sleep at home. In-patient and out-patient prescribing of benzodiazepines used for insomnia was recorded over 3 months. Benzodiazepines were prescribed for 20% of patients, and 94% of the prescriptions were for temazepam. Of the 57 patients who were given benzodiazepines during a hospital admission, 57% had not taken a benzodiazepine at home before admission. Benzodiazepines were effective in the short-term for inducing sleep in hospital, with little evidence of adverse effects.

Triazolam Liver Liver damage has been attributed to triazolam (25A ). • A 64-year-old woman developed anorexia, fatigue, and jaundice. She had occasionally taken triazolam 0.25 mg for insomnia, and her liver function tests had been normal 5 months before. There was no history of liver disease or alcohol misuse or other serious medical history. She was jaundiced, with spider angiomata, and gradually deteriorated over the next 16 days, ﬁnally losing consciousness. Liver histology was consistent with submassive necrosis, extensive coagulation necrosis, and marked inﬂammation secondary to triazolam. She had a liver transplant 31 days after the initial presentation and 2 years later was in good health.

46

OTHER HYPNOTICS AND SEDATIVES

Chapter 5

Stephen Curran and Shabir Musa

neuropsychological tests scores. Thus, clomethiazole did not improve or worsen cerebral outcome after coronary artery bypass surgery.

Chloral hydrate

(SED-14, 133; SEDA-24, 49; SEDA-25, 49)

Immunologic Several reports have highlighted the importance of gelatin allergy in young children, with some deaths due to anaphylaxis. A 2-year-old boy and a 4-year-old boy developed anaphylactic symptoms after being given a chloral hydrate suppository, which contained gelatin, for sedation before electroencephalography (26A ). Chloral hydrate suppositories are often used to sedate children during various examinations and the authors suggested using gelatin-free formulations.

Zaleplon

(SEDA-24, 49; SEDA-25, 50;

SEDA-26, 49) A review of published studies of zaleplon has shown that it has a quick onset of action and undergoes rapid elimination, which results in a better safety proﬁle than previously available agents (29R ). In additional, rebound insomnia and other withdrawal effects have not been demonstrated with zaleplon, and it is well tolerated in both young and older patients. These characteristics may be clinically advantageous for patients who should not receive benzodiazepines.

Clomethiazole

(SED-14, 133; SEDA-24, 49; SEDA-25, 49; SEDA-26, 49)

Nervous system In a double-blind, doubledummy, placebo-controlled comparison of clomethiazole and gamma-hydroxybutyrate in ameliorating the symptoms of alcohol withdrawal, alcohol-dependent patients were randomized to receive either clomethiazole 1000 mg or gamma-hydroxybutyrate 50 mg/kg (27C ). There was no difference between the three treatments in ratings of alcohol withdrawal symptoms or requests for additional medication. After tapering the active medication, there was no increase in withdrawal symptoms, suggesting that physical tolerance did not develop to either clomethiazole or gamma-hydroxybutyrate during the 5-day treatment period. The most frequently reported adverse effect of gammahydroxybutyrate was transient vertigo, particularly after the evening double dose. The effect of clomethiazole on cerebral outcome in patients undergoing coronary artery bypass surgery has been investigated in 245 patients, who were randomized double-blind to placebo or clomethiazole (1800 mg over 45 minutes followed by 800 mg/hour until the end of surgery) (28C ). A battery of eight neuropsychological tests was administered preoperatively and repeated 4–7 weeks after surgery. There were no differences between the clomethiazole and placebo groups in postoperative

Zolpidem

(SED-14, 132; SEDA-24, 50; SEDA-25, 50; SEDA-26, 50)

Nervous system Three patients had improvements in dystonia and parkinsonism after taking zolpidem 10 mg (30c ). The improvement in dystonia began at 15–45 minutes and optimal beneﬁts were observed after 1–2 hours. The mean duration of action was 4.5 hours initially, falling to 2–3 hours with chronic use. This is similar to that reported in patients with progressive supranuclear palsy, and corresponds to the drug’s half-life (2.5 hours). Sleepiness was noted at doses over 10 mg bd. Psychiatric Delirium has been attributed to zolpidem (31A ). • Zolpidem 5 mg caused temporary delirium in an 86-year-old woman after 5 hours, when she became very restless and would not follow the directions of the nursing staff. She climbed out of bed over the rails and began to walk with an unsteady gait. She knew her name but was not oriented in time or place. Her symptoms resolved 2 days later with haloperidol. The zolpidem was withdrawn without recurrence of the delirium. A CT scan a few days later showed no signiﬁcant changes.

Improvement in cognitive function has been attributed to zolpidem (32A ).

Hypnosedatives and anxiolytics

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Chapter 5

• A recovering 60-year-old alcoholic woman developed reduced cognitive function, including considerable memory loss, praxis disorders, and an inability to join in conversation. A CT scan showed non-speciﬁc cerebral atrophy. She was given zolpidem 10 mg for insomnia, which she took at ﬁrst at 2200 hours, but then earlier, at 1900 hours. After starting to take it at the earlier time she talked more easily and could wash the dishes and do the housework, things that she had lost the ability to do. This beneﬁcial effect was detectable 45–60 minutes after the dose of zolpidem, lasted for 3 hours after each administration, and then abated. The subjective improvement in cognitive function was conﬁrmed several times by her general practitioner.

Zopiclone

(SED-14, 132; SEDA-24, 50;

SEDA-26, 51) Nervous system In a two-part, placebo-controlled, crossover comparison of the effects of zopiclone and zaleplon on car driving, memory, and psychomotor performance, zaleplon 10 mg had no residual effect on driving when taken at bedtime, 10 hours before driving (33C ). In contrast, zopiclone 7.5 mg caused marked residual impairment. Patients should be advised to avoid driving the morning after taking zopiclone.

REFERENCES 1. Dannawi M. Possible serotonin syndrome after combination of buspirone and St John’s wort. J Psychopharmacol 2002; 16: 401. 2. Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin Psychopharmacol 2002; 22: 285–93. 3. Michalodimitrakis M, Christodoulou P, Tsatsakis AM, Askoxilakis I, Stiakakis I, Mouzas I. Death related to midazolam overdose during endoscopic retrograde cholangiopancreatography. Am J Forensic Med Pathol 1999; 20: 93–7. 4. Drummer OH, Syrjanen ML, Cordner SM. Deaths involving the benzodiazepine ﬂunitrazepam. Am J Forensic Med Pathol 1993; 14: 238–43. 5. Aderjan R, Mattern R. Eine todlich verlaufene Monointoxikation mit Flurazepam (Dalamadorm). Probleme bei der toxikologischen Beurteilung. Arch Toxicol 1979; 43: 69–75. 6. Levine B, Grieshaber A, Pestaner J, Moore KA, Smialek JE. Distribution of triazolam and α-hydroxytriazolam in a fatal intoxication case. J Anal Toxicol 2002; 26: 52–4. 7. Mendelson WB, Rich CL. Sedatives and suicide: the San Diego study. Acta Psychiatr Scand 1993; 88: 337–41. 8. Obafunwa JO, Busuttil A. Deaths from substance overdose in the Lothian and Borders region of Scotland (1983–1991). Hum Exp Toxicol 1994; 13: 401–6. 9. Bruyndonckx RB, Meulemans AI, Sabbe MB, Kumar AA, Delooz HH. Fatal intentional poisoning cases admitted to the University Hospitals of Leuven, Belgium from 1993 to 1996. Eur J Emerg Med 2002; 9: 238–43. 10. Shah R, Uren Z, Baker A, Majeed A. Trends in suicide from drug overdose in the elderly in England and Wales, 1993-1999. Int J Geriatr Psychiatry 2002; 17: 416–21.

11. Burrows DL, Hagardorn AN, Harlan GC, Wallen ED, Ferslew KE. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci 2003; 48: 683–6. 12. Drummer OH, Syrjanen ML, Phelan M, Cordner SM. A study of deaths involving oxycodone. J Forensic Sci 1994; 39: 1069–75. 13. Michaud K, Augsburger M, Romain N, Giroud C, Mangin P. Fatal overdose of tramadol and alprazolam. Forensic Sci Int 1999; 105: 185–9. 14. Kudo K, Imamura T, Jitsufuchi N, Zhang X-X, Tokunaga H, Nagata T. Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs. Forensic Sci Int 1997; 86: 35– 41. 15. Schmidt LE, Dalhoff K. Concomitant overdosing of other drugs in patients with paracetamol poisoning. Br J Clin Pharmacol 2002; 53: 535–41. 16. Van de Vijver DAMC, Roose RAC, Jansen PAF, Porsius AJ, De Boer A. Inﬂuence of benzodiazepines on antiparkinsonian drug treatment in levodopa users. Acta Neurol Scand 2002; 105: 8–12. 17. Bashir A, Swartz C. Alprazolam-induced panic disorder. J Am Board Fam Pract 2002; 15: 69–72. 18. Meesters Y, Van Velzen CJM, Horwitz EH. A cognitive aspect related to the withdrawal of alprazolam; a case study [in Dutch]. Tijdschr Psychiatrie 2002; 44: 199–203. 19. Ohtani Y, Kotegawa T, Tsutsumi K, Morimoto T, Hirose Y, Nakano S. Effect of ﬂuconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam; an application of electroencephalography as the pharmacodynamic method. J Clin Pharmacol 2002; 42: 183–91. 20. Asero R. Hypersensitivity to diazepam. Allergy Eur J Allergy Clin Immunol 2002; 57: 1209. 21. Curtin F, Remund C. Musical hallucinations during a treatment with benzodiazepine: case report. Can J Psychiatry 2002; 47: 789–90.

48 22. Yasui-Furukori N, Kondo T, Takahata T, Mihara K, Ono S, Kaneko S, Tateishi T. Effect of dietary fat content in meals on pharmacokinetics of quazepam. J Clin Pharmacol 2002; 42: 1335–40. 23. Feeney GFX, Gibbs HH. Digit loss following misuse of temazepam. Med J Aust 2002; 176: 380. 24. Ramesh M, Roberts G. Use of night-time benzodiazepines in an elderly inpatient population. J Clin Pharm Ther 2002; 27: 93–7. 25. Kanda T, Yokosuka O, Fujiwara K, Saisho H, Shiga H, Oda S, Okuda K, Sugawara Y, Makuuchi M, Hirasawa H. Fulminant hepatic failure associated with triazolam. Dig Dis Sci 2002; 47: 1111–14. 26. Yamada A, Ohshima Y, Tsukahara H, Hiraoka M, Kimura I, Kawamitsu T, Kimura K, Mayumi M. Two cases of anaphylactic reaction to gelatin induced by a chloral hydrate suppository. Pediatr Int 2002; 44: 87–9. 27. Nimmerrichter AA, Walter H, Gutierrez-Lobos KE, Lesch OM. Double-blind controlled trial of gamma-hydroxybutyrate and clomethiazole in the

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treatment of alcohol withdrawal. Alcohol Alcohol 2002; 37: 67–73. 28. Kong RS, Butterworth J, Aveling W, Stump DA, Harrison MJG, Hammon J, Stygall J, Rorie KD, Newman SP. Clinical trial of the neuroprotectant clomethiazole in coronary artery bypass graft surgery. Anaesthesiology 2002; 7: 585–91. 29. Israel AG, Kramer JA. Safety of zaleplon in the treatment of insomnia. Ann Pharmacother 2002; 36: 852–9. 30. Evidente VGH. Zolpidem improves dystonia in “Lubag” or X-linked dystonia–parkinsonism syndrome. Neurology 2002; 58: 662–3. 31. Shuster J. ISMP adverse drug reactions. Hosp Pharm 2002; 37: 242–9, 333. 32. Jarry C. Beneﬁcial effect of zolpidem for dementia. Ann Pharmacother 2002; 36: 1808. 33. Vermeeren A, Riedel WJ, Van Boxtel MPJ, Darwish M, Paty I, Patat A. Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 2002; 25: 224–31.

Alfonso Carvajal and Luis H. Martín Arias

6

Antipsychotic drugs

GENERAL Use of antipsychotic drugs in conditions other than schizophrenia There is enormous interest in the effectiveness of antipsychotic drugs in conditions other than schizophrenia, such as autism (1R ) and psychosis in patients with dementia (2R ). Antipsychotic medication for treatment of psychosis and agitation in patients with dementia was generally effective; in double-blind, placebocontrolled trials; mean improvement rates were 61% with antipsychotic drugs and 35% with placebo. However, the number of well-designed studies in this area has been small so far. Amisulpride In a randomized, double-blind, multicenter trial for 8 weeks in 278 patients with depression there were no differences in efﬁcacy or tolerability between amisulpride 50 mg and SSRIs (3C ). Clozapine Special subgroups of patients can beneﬁt from clozapine (SEDA 24, 61). Of 10 adolescent inpatients (aged 12–17 years) with severe acute manic or mixed episodes, who did not improve after treatment with conventional drugs and who were given clozapine (mean dose 143 mg/day), all responded positively after 15–28 days and adverse effects (increased appetite, sedation, enuresis, sialorrhea) were frequent but not severe enough to require reduced dosages (4c ). Mean weight gain after 6 months was 7 kg (11%), and neither reduced white cell counts nor epileptic seizures were reported during follow-up for 12–24 months. In a case series in which clozapine was used as add-on medication, two patients with bipolar disorder and one with schizoaffective disorder © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

had marked reductions in affective symptoms after clozapine had been added to pre-treatment with a mood stabilizer; transient and moderate weight gain and fatigue were the only adverse effects (5A ). Olanzapine The efﬁcacy and safety of olanzapine in disorders other than schizophrenia have been studied (SEDA-24, 67; SEDA-25, 64; SEDA-26, 61). In a 3-week, randomized, double-blind clinical trial, the effects of a ﬂexible dose of olanzapine (5-20 mg/day) and divalproex (500-2500 mg/day) for the treatment of patients with acute bipolar manic or mixed episodes have been compared (6C ). The olanzapine treatment group (n = 125) had significantly greater mean improvements in mania rating and a signiﬁcantly greater proportion of patients achieved protocol-deﬁned remission. With olanzapine there was signiﬁcantly more weight gain (12% vs. 7.9%), dry mouth (34% vs. 6.3%), increased appetite (12% vs. 2.4%), and somnolence (39% vs. 21%), while more cases of nausea (29% vs. 10%) were reported with divalproex. The efﬁcacy of adding olanzapine to either valproate or lithium alone in acute manic or mixed bipolar episodes has been studied in a 6-week, double-blind, randomized, placebocontrolled trial (7C ). Compared with valproate or lithium alone, the addition of olanzapine provided better efﬁcacy. Olanzapine was associated with somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. Olanzapine, mean dose 5.4 mg/day, has been given to 21 patients with apathy in the absence of depression after long-term treatment with selective serotonin reuptake inhibitors for non-psychotic depression in an open, ﬂexibledose study (8c ). The more frequent adverse effects were sedation (n = 12), increased appetite (n = 8), stiffness (n = 7), edema (n = 6), and dry mouth (n = 5).

49

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Chapter 6

The medical records of ten patients with a DSM-IV diagnostic of cluster B personality disorder (narcissistic personality disorder) who had received olanzapine 2.5–20 mg/day for 8 weeks have been reviewed (9c ). The mean Social Dysfunction and Aggression Scale score was 29 for the 8 weeks before olanzapine therapy and improved to 14 after 8 weeks of treatment. Five of the 10 patients developed severe weight gain. Risperidone Risperidone has been used in bipolar disorder, dementia, disruptive behavior disorder with subaverage intelligence, Tourette’s syndrome, and autism (SEDA-23, 69; SEDA-25, 67; SEDA-26, 64). The efﬁcacy and safety of low doses of risperidone in the treatment of autism and serious behavioral problems have been studied in 101 children aged 5–17 years with autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior, who were randomly assigned to risperidone for 8 weeks (n = 49; dosage 0.5 to 3.5 mg/day) or placebo (n = 52) (10C ). Risperidone produced a 57% reduction in the Irritability Score, compared with a 14% reduction in the placebo group; all other parameters were also signiﬁcantly improved. Risperidone was associated with an average weight gain of 2.7 kg, compared with 0.8 kg with placebo; increased appetite, fatigue, drowsiness, dizziness, and drooling were more common with risperidone. In two-thirds of the children with a positive response to risperidone at 8 weeks, the beneﬁt was maintained at 6 months.

Comparing typical and atypical antipsychotic drugs In recent years there has been particular interest in comparing typical and atypical antipsychotic drugs (SEDA-25, 53). In a consensus meeting on the pharmacotherapy of schizophrenia, four of six participants who disclosed ﬁnancial interests had relationships with various pharmaceutical companies (11R ). The participants addressed issues such as the role of ﬁrstand second-generation antipsychotic drugs as ﬁrst-line agents and the risk of tardive dyskinesia with these drugs.

Alfonso Carvajal and Luis H. Martín Arias

Therapeutic comparisons of antipsychotic drugs In a randomized double-blind trial in 157 inpatients with chronic schizophrenia, clozapine (n = 40), olanzapine (n = 39), and risperidone (n = 41), but not haloperidol (n = 37), produced statistically signiﬁcant improvements in total scores on the Positive and Negative Syndrome Scale after 14 weeks (12C ). Patients who had failed to respond to any typical antipsychotic drug were eligible, including patients who had previously failed to respond to haloperidol. High doses were used (the mean daily doses achieved during the last period of study were: clozapine 525 mg, olanzapine 30 mg, risperidone 12 mg, and haloperidol 26 mg). There was a signiﬁcant fall in the Extrapyramidal Symptom Rating Score with the three atypical drugs at the end of the study and no change with haloperidol. One patient developed agranulocytosis, two had hypertensive episodes, and four had seizures while taking clozapine. In other studies, outcome variables have been discontinuation, relapse, and compliance (13c ) or quality of life (14R ). A re-analysis of data from two large double-blind comparisons of olanzapine with haloperidol (n = 1996) and of olanzapine with risperidone (n = 336) showed that in patients who had an initial response, there was no signiﬁcant difference between olanzapine and haloperidol when outcome was measured using either 52-week relapse rates or the time to ﬁrst non-compliance; after 12 months, the estimated mean times to discontinuation were 271 days and 241 days respectively (13C ). There were no differences between olanzapine and risperidone. However, while the dose of olanzapine was well within the recommended range, the dose of haloperidol was too high (modal doses, 13 and 12 mg/day respectively). In a double-blind trial, 28 patients with paranoid schizophrenia who had had a partial response to typical antipsychotic drugs were randomized to receive either olanzapine or haloperidol in ﬂexible doses for 14 weeks (15C ). The two groups showed similar improvement on the Brief Psychiatric Rating Scale positive symptoms subscale, while improvement in the same negative symptoms subscale was signiﬁcant only with olanzapine. There were no signiﬁcant differences between the two groups on the Simpson and Angus rating Scale

Antipsychotic drugs

Chapter 6

scores, but there was a signiﬁcant difference in the Barnes Akathisia Rating Scale. No patient taking olanzapine had akathisia, while a few patients taking haloperidol did. Apart from the small sample, patients with a partial response to typical antipsychotic drugs were included, which precludes ﬁrm conclusions. In a double-blind, placebo-controlled, doseresponse trial 270 acutely agitated patients were randomized to receive 1–3 intramuscular injections of olanzapine (2.5, 5, 7.5, or 10 mg), haloperidol (7.5 mg), or placebo within 24 hours (16C ). Olanzapine had a doserelated effect in reducing agitation; olanzapine was better than placebo but not better than haloperidol; the most frequently reported adverse event was hypotension, which occurred with olanzapine (n = 7) but not haloperidol or placebo. Acute dystonias did not occur in patients given olanzapine or placebo but occurred in two patients given haloperidol. In a previous comparison of risperidone and haloperidol in patients with chronic schizophrenia, those taking risperidone had greater reductions in the mean severity of both psychotic symptoms and extrapyramidal adverse effects than those taking haloperidol (17C , SEDA-26, 53). The conclusion was that “the preponderance of the evidence now supports the use of risperidone as a ﬁrst-line treatment for patients with schizophrenia” (18r ). Nevertheless, the use of “higher-than-optimal doses of conventional drugs” was also mentioned as a caveat of the study. Others emphasized that those who took haloperidol received a relatively high mean modal dose (12 mg per day) and 81% of the patients taking haloperidol took a daily dose of 7.5–20 mg (19r –21r ). Many studies have shown that doses of haloperidol over 3.75–7.5 mg/day have no increased clinical efﬁcacy but are associated with a signiﬁcantly increased risk of extrapyramidal effects. A meta-analysis has further compared risperidone and haloperidol (22M ). Almost all the randomized controlled clinical trials of risperidone versus haloperidol (number of studies = 18; number of patients = 3591) used a 20% improvement on the Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale to deﬁne a clinical response. An overall analysis showed that risperidone was better than haloperidol (OR = 1.6; 95% CI = 1.4, 1.8).

51 Meta-regression did not ﬁnd that the dose of the haloperidol comparator had a signiﬁcant effect on positive or negative symptoms. The authors stated that previous meta-analyses had underestimated the risperidone–comparator difference, because they included the suboptimal 1 or 2 mg dose in their comparisons, which were not included in this one. Both ziprasidone and haloperidol reduced overall psychopathology in 301 schizophrenic outpatients aged 18–64 years who were randomized to ﬂexible-dose oral ziprasidone 80– 160 mg/day (n = 148) or haloperidol 5–15 mg/day (n = 153) for 28 weeks in a doubleblind, multicenter study (23C ). The median duration of treatment was 113 days with ziprasidone and 139 days with haloperidol; the rates of withdrawal due to insufﬁcient clinical response were the same in the two groups (18%), but twice as many patients discontinued haloperidol (16%) as ziprasidone (8%) because of treatment-related adverse effects; the percentage of patients in whom any movement disorder emerged was markedly higher with haloperidol (41%) than with ziprasidone (15%). Mean changes in body weight from baseline to endpoint were small and similar with ziprasidone (+0.31 kg) and haloperidol (+0.22 kg). With regard to electrocardiographic changes, the mean baseline and endpoint QTc intervals were 398 and 404 ms with ziprasidone and 389 and 387 ms with haloperidol; no patient had a QTc interval over 500 ms at any time. It must be stated that some patients included in the study had already been taking haloperidol, 26% in the ziprasidone group and 25% in the haloperidol group. The study was funded by Pﬁzer, the marketing authorization holder for ziprasidone. Quality of life is said to be superior with atypical antipsychotic drugs, from an analysis of seven controlled trials and eight open trials (14R ). However, in a comparison of olanzapine and haloperidol in 335 patients there was no signiﬁcant change in quality of life (24C ). Moreover, in all the studies, mean doses of haloperidol were higher than 12 mg/day, and in some studies as high as 28 mg/day. This is in accordance with the results of a double-blind, randomized, comparison of olanzapine (mean dosage 11 mg/day; n = 159) and haloperidol (mean dosage 11 mg/day; n = 150) in 309 schizophrenic patients (25C ). There were

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Chapter 6

no signiﬁcant differences between the groups in positive, negative, or total symptoms of schizophrenia, quality of life, extrapyramidal symptoms, or withdrawals. Olanzapine was associated with less akathisia but there were more reports of weight gain and signiﬁcantly higher costs. Cardiovascular QTc prolongation due to antipsychotic drugs (SEDA-21, 54; SEDA-26, 54) has recently been reviewed (26R ). It is not a class effect: among currently available agents, thioridazine and ziprasidone are associated with the greatest prolongation. Dysrhythmias are more likely to occur if drug-induced QTc prolongation co-exists with other risk factors, such as individual susceptibility, congenital long QT syndromes, heart failure, bradycardia, electrolyte imbalance, overdose of a QTc prolonging drug, female sex, restraint, old age, hepatic or renal impairment, and slow metabolizer status; pharmacokinetic or pharmacodynamic interactions can also increase the risk of dysrhythmias. In an open study in 164 patients with schizophrenia of the effect of several antipsychotic drugs on the QT interval, the study drugs were given for 21–29 days and three separate electrocardiograms were obtained after steady state had been achieved and drug concentrations were at their maximum (27c ). The mean changes in the QTc interval were: • thioridazine 36 ms (95% n = 30); • ziprasidone 20 ms (95% n = 31); • quetiapine 15 ms (95% n = 27); • risperidone 12 ms (95% n = 20); • olanzapine 6.8 ms (95% n = 24; • haloperidol 4.7 ms (95% n = 20).

CI = 31, 41; CI = 14, 26; CI = 9.5, 20; CI = 7.4, 16; CI = 0.8, 13; CI = −2, 11;

Nervous system In a consensus meeting the risk of tardive dyskinesia with typical and atypical antipsychotic drugs was addressed (11R ). There is sufﬁcient evidence to conclude that atypical antipsychotic drugs are less likely to

Alfonso Carvajal and Luis H. Martín Arias

cause tardive dyskinesia than typical drugs, and that atypical antipsychotic drugs, apart from clozapine or ziprasidone, should be selected before typical drugs for patients with a ﬁrst episode of schizophrenia or for patients whose history of response to antipsychotic drugs is not available. However, a meta-analysis has shown that atypical antipsychotic drugs have advantages over conventional drugs only in studies in which haloperidol in relatively high doses was used as the comparison drug; when doses of haloperidol were below 12 mg/day, there were no advantages of the newer agents (28M ). Furthermore, clinical studies have not shown an advantage of haloperidol in dosages over 5 mg/day, which leads to a high occupancy of dopamine D2 receptors, as demonstrated by positron emission tomography and single-photon emission computed tomography (29c ). Antiparkinsonian drugs are more often required in patients taking conventional neuroleptic drugs, but they can cause objective and subjective deﬁcits (30c , 31c ). Psychiatric Cognitive function is reduced in schizophrenia, and antipsychotic drugs can cause further impairment (SEDA-25, 58). A comparison between haloperidol (n = 25) and new antipsychotic drugs (clozapine, n = 24; olanzapine, n = 26; risperidone, n = 26) has been conducted in patients with treatmentresistant schizophrenia in a 14-week, randomized, double-blind trial (32c ). Global neurocognitive function improved signiﬁcantly with olanzapine and risperidone, by about 8–9 “IQequivalent” points. According to the authors, the ﬁnding was not mediated by changes in symptoms, adverse effects, or blood drug concentrations. In the haloperidol group, higher blood concentrations were associated with less improvement in motor function. In another study there was a small but significant negative correlation between the dosages of conventional neuroleptic drugs and “mental functioning” when the data were controlled for psychopathology; this correlation was also seen for risperidone and clozapine, but there were no signiﬁcant differences between patients taking low or high dosages of atypical agents. The authors pointed out that the dosage range in patients taking atypical agents was rather narrow

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and it is possible that higher doses of atypical neuroleptic drugs may give different results (33c ). In 207 schizophrenic patients who answered the short form of a questionnaire entitled “Subjective Well-Being under Neuroleptic Treatment” (SWN-S), those taking risperidone (n = 26) and olanzapine (n = 40) took part in a study with random assignment after a washout period of at least 3 days, whereas patients taking conventional neuroleptic drugs (n = 106; predominantly haloperidol and ﬂupenthixol) were assessed during treatment (34c ). Endocrine The effects of haloperidol and quetiapine on serum prolactin concentrations have been compared in 35 schizophrenic patients after a 2-week washout period in a randomized study (35c ). There was no signiﬁcant difference in prolactin concentration between the groups at the start of the study, although prolactin concentrations were signiﬁcantly lower with quetiapine than haloperidol. After 6 weeks, the mean prolactin concentration was signiﬁcantly increased in those taking haloperidol but not in those taking quetiapine. Two patients taking haloperidol had galactorrhea related to hyperprolactinemia. Metabolism Excessive weight gain is an important shortcoming of atypical antipsychotic drugs (SEDA-26, 56). Obesity is associated with increased risks of dyslipidemia, hypertension, cardiovascular disease, osteoarthritis, sleep apnea, type 2 diabetes mellitus, and many other disorders. Antipsychotic drug treatment of non-diabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, as has been suggested by the results of a study in which modiﬁed oral glucose tolerance tests were performed in schizophrenic patients (n = 48) taking clozapine, olanzapine, risperidone, or typical antipsychotic drugs, and untreated healthy control subjects (n = 31) (36c ). Newer antipsychotic drugs, such as clozapine and olanzapine, compared with typical agents, are associated with adverse effects on blood glucose regulation, which can vary in severity regardless of adiposity and age. In contrast, serum leptin, a peripheral hormone secreted by fat, correlates inversely with body

53 weight; in 22 patients taking clozapine who gained weight those who had the most pronounced 2-week increase in leptin had the least gain in body weight after 6 and 8 months (37c ). The association between clozapine-related weight gain and increased mean arterial blood pressure has been examined in 61 patients who were randomly assigned to either clozapine or haloperidol in a 10-week parallel group, double-blind study, and in 55 patients who chose to continue to take clozapine in a subsequent 1-year, open, prospective study (38C ). Clozapine was associated with signiﬁcant weight gain in both the double-blind trial (mean 4.2 kg) and the open trial (mean 5.8 kg), but haloperidol was not associated with significant weight gain (mean 0.4 kg). There were no signiﬁcant correlations between change in weight and change in mean arterial blood pressure for clozapine or haloperidol. Psychiatric The effects of newer antipsychotic drugs on cognitive functioning and the implications for functional outcome have recently been summarized and methodological and conceptional issues addressed (39R ). Metabolism The charts of 94 long-term inpatients have been reviewed retrospectively to examine the changes in weight, fasting glucose, and fasting lipids in those taking either risperidone (n = 47) or olanzapine (n = 47) (40c ). The patients had increased weight, triglycerides, and cholesterol, and the changes were signiﬁcantly higher with olanzapine; olanzapine but not risperidone considerably increased glucose concentrations. One case of new-onset diabetes mellitus occurred in a patient taking olanzapine. Weight should be monitored in patients taking maintenance atypical antipsychotic drugs, especially dibenzodiazepines. The genetic basis of some reactions associated with antipsychotic drugs is of particular interest. An important association between weight gain and a 5-HT2C receptor gene polymorphism has now been identiﬁed in 123 Chinese Han schizophrenic patients taking chlorpromazine (n = 69), risperidone (n = 46), clozapine (n = 4), ﬂuphenazine (n = 3), or sulpiride (n = 1) (41C ). Weight gain was substantially greater in the patients with the wild-type genotype than in those with a

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variant genotype (−759C/T), at both 6 and 10 weeks; this effect was seen in men and women. In addition, homozygous CYP2D6∗ 4, a non-functional genotype, was found in a 17year-old schizophrenic patient who developed severe akathisia, parkinsonism, and drowsiness after taking risperidone 6 mg/day for 3 months; he had a high plasma concentration of risperidone and an active metabolite (42A ). Sexual dysfunction Priapism, although infrequent, can occur during treatment with neuroleptic drugs. It necessitates prompt urological consultation and sometimes even surgical intervention (SEDA-14, 149). A 31-year-old man who took zuclopenthixol developed an acute, painful erection (43A ). In another case priapism followed the use of ﬁrst risperidone and then ziprasidone (44A ). • A 22-year-old African–American man with chronic undifferentiated schizophrenia developed priapism after taking risperidone 4 mg bd, clonazepam 0.5 mg bd, vitamin E 400 IU bd, and a multivitamin for over 6 months. He did not respond to subcutaneous terbutaline 0.25 mg. Irrigation of the corpora with phenylephrine 200 μg resulted in detumescence; risperidone was withdrawn. A few months later he took ziprasidone 20 mg bd for 1 week, clonazepam 1 mg bd, and vitamin E 400 IU bd. The ziprasidone dosage was increased to 40 mg bd, but early the next morning he developed a ﬁrm erection with some discomfort that lasted about 2 hours and resolved when he urinated; the next morning he had a similar erection that also lasted 2 hours and resolved.

INDIVIDUAL DRUGS Alimemazine Nervous system Neuroleptic malignant syndrome has been reported with alimemazine (45A ). • A 4-year-old girl with damage in the basal ganglia who was receiving increasing doses of alimemazine for sedative purposes developed neuroleptic malignant syndrome. The alimemazine was withdrawn and she received dantrolene and supportive measures, including ventilation under sedation and paralysis with midazolam and vecuronium. As her symptoms were unchanged, she was given increasing doses of bromocriptine

Alfonso Carvajal and Luis H. Martín Arias

and improved. A few days after bromocriptine withdrawal, the neuroleptic malignant syndrome recurred and was complicated by cardiorespiratory arrest.

Amisulpride

(SEDA-23, 58; SEDA-24;

60; SEDA-26, 58) In an extensive review of 19 randomized studies for the Cochrane Library (n = 2443), most of the trials were small and of short duration (46M ). The data from four trials with 514 participants with predominantly negative symptoms suggested that low-dose amisulpride (up to 300 mg/day) was more acceptable than placebo (n = 514; RR = 0.6; 95% CI = 0.5, 0.8). Amisulpride was more likely to cause extrapyramidal symptoms than placebo in two studies (n = 269; RR = 2.2; 95% CI = 1.2, 4.2). Compared with typical antipsychotic drugs, the pooled results of a total of 14 trials suggested that amisulpride was more effective in improving global state (n = 651), general mental state (n = 695), and the negative symptoms of schizophrenia (n = 506). Amisulpride was as effective as typical antipsychotic drugs in relieving positive symptoms. It was less likely to cause at least one general adverse event (n = 751), to cause one extrapyramidal symptom (n = 771), or to require the use of antiparkinsonian drugs (n = 851). There were no clear differences in other adverse events compared with typical drugs. Amisulpride also seemed to be more acceptable than conventional drugs, as measured by early withdrawal (n = 1512) than conventional drugs, but this result may have been overestimated owing to publication bias, which could not be excluded with certainty. In a comparison of amisulpride with another atypical antipsychotic drug, risperidone, there were no signiﬁcant differences in efﬁcacy or acceptability, with the exception of agitation, which was more frequent with amisulpride (n = 228). A further meta-analysis of 10 randomized controlled clinical trials of amisulpride in “acutely ill patients” (n = 1654) has recently been published, supported in part by a grant from Sanoﬁ–Synthélabo, the marketing authorization holder (47M ). Amisulpride was signiﬁcantly better than conventional antipsychotic drugs by

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about 11 percentage points on the Brief Psychiatric Rating Scale. In four studies in patients with “persistent negative symptoms”, amisulpride was signiﬁcantly better than placebo (n = 514), but there was no signiﬁcant difference between amisulpride and conventional drugs (only three trials; n = 130). Low doses of amisulpride (50–300 mg/day) were not associated with signiﬁcantly more use of antiparkinsonian drugs than placebo (n = 507), and usual doses caused fewer extrapyramidal adverse effects than conventional antipsychotic drugs (n = 1599). In studies in acutely ill patients, signiﬁcantly fewer patients taking amisulpride dropped out compared with patients taking conventional drugs, mainly owing to fewer adverse events; there were no signiﬁcant differences in dropout rates between amisulpride and conventional antipsychotic drugs (three small studies). In these two meta-analyses, data were independently extracted and analysed on an intention-to-treat basis. Additionally, two narrative reviews of amisulpride have been published (48R , 49R ). The authors emphasized that amisulpride in low dosages (below 300 mg/day) causes a similar incidence of adverse effects to placebo; nevertheless, at higher dosages (400–1200 mg/day), the overall incidence of adverse events in those taking amisulpride was similar to that in patients taking haloperidol, ﬂupenthixol, or risperidone. The most commonly reported adverse events associated with higher dosages of amisulpride were extrapyramidal symptoms, insomnia, hyperkinesia, anxiety, increased body weight, and agitation. The incidence of extrapyramidal symptoms was dose related. In elderly people, amisulpride can cause hypotension and sedation. There are no systematic published data on efﬁcacy in children aged under 15 years.

Clozapine

(SED-14, 140; SEDA-24, 61; SEDA-25, 60; SEDA-26, 59) Rates of hospitalization with clozapine have previously been analysed by Novartis, the manufacturers (SEDA-24, 62), and now in a study in Ohio (50c ). Patients with chronic borderline personality disorder who were in hospital for an average of 110 days/year were given clozapine (mean daily dosage at time of discharge

55 334 mg; range 175–550 mg). None stopped taking clozapine and few adverse effects were reported. Among the seven patients who were taking clozapine when they were discharged, hospitalization fell to a mean of 6.3 days per patient per year. There was no control group in this study. Clinical predictors of response have been examined in 37 partially treatment-refractory outpatients who had been assigned to clozapine in a double-blind, haloperidol-controlled, longterm (29-week) study (51c ). Clozapine responders were rated as less severely ill, had fewer negative symptoms, and had fewer extrapyramidal adverse effects at baseline compared with non-responders. In an open study in 37 patients (27 men and 10 women; mean age 35 years) with treatmentresistant schizophrenia treated with clozapine for 18 weeks, there was no correlation between plasma clozapine concentrations and percentage improvement on the Positive and Negative Syndrome Scale (52c ). Plasma clozapine concentrations were not signiﬁcantly different between those who responded to clozapine (n = 19) and those who did not (n = 18), nor between patients who smoked (n = 28) and those who did not (n = 9). Dosages were adjusted according to clinical response, and plasma concentrations of clozapine and its metabolites were measured weekly. The mean end-point clozapine dosage was 487 mg/day and there was a signiﬁcant correlation between the daily dosage of clozapine and the plasma concentrations of clozapine and its metabolites. Three patients dropped out of the study owing to adverse effects (two because of signiﬁcant sedation and one because of hypersalivation); there were no cases of agranulocytosis. Cardiovascular Cardiovascular adverse effects of clozapine are not uncommon, and it has been associated with cardiomyopathy, including myocarditis (SED-14, 142; SEDA-24, 62; SEDA-25, 61; SEDA-26, 59). Now pericardial effusion and pericarditis have been reported. • A 43-year-old man developed a pericardial effusion after taking clozapine for 7 years (53A ). The condition resolved when the drug was withdrawn. • A 16-year-old girl developed pericarditis associated with clozapine (54A ). There were electrocardiographic changes and serial rises in serum troponin I, a highly sensitive and speciﬁc marker of myocardial injury.

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This is said to be the ﬁrst reported case of pericarditis due to clozapine, demonstrating rises in troponin I, which resolved despite continuation of therapy. The authors suggested that troponin I is the preferred marker for monitoring the cardiac adverse effects of clozapine. A particular concern is the association of clozapine with venous thromboembolism (SEDA-25, 61; SEDA-26, 59). Between February 1990, when clozapine was ﬁrst marketed in the USA, and December 1999 the FDA received 99 reports of venous thromboembolism (83 mentioned pulmonary embolism with or without deep vein thrombosis and 16 mentioned deep vein thrombosis alone) (55c ). In 63 cases death had resulted from pulmonary embolism; 32 were conﬁrmed by necropsy. Of 36 nonfatal cases, only seven had been documented objectively by such diagnostic techniques as perfusion–ventilation lung scanning and venography. Thus, in 39 of the 99 reports there was objective evidence of pulmonary embolism or deep vein thrombosis. The median age of the 39 individuals was 38 (range 17–70) years and 20 were women. The median daily dose was 400 (range 125–900) mg. The median duration of clozapine exposure before diagnosis was 3 months (range 2 days to 6 years). Information on risk factors for pulmonary embolism and deep vein thrombosis varied; however, 18 of the 39 patients were obese. The frequency of fatal pulmonary embolism in this study is consistent with that described in the labeling for clozapine in the USA. As of 31 December 1993, there were 18 cases of fatal pulmonary embolism in association with clozapine therapy in users aged 10–54 years. Based on the extent of use recorded in the Clozapine National Registry, the mortality rate associated with pulmonary embolism was 1 death per 3450 person-years of use. This rate was about 28 times higher than that in the general population of a similar age and sex (95% CI = 17, 42). Whether pulmonary embolism can be attributed to clozapine or some characteristic(s) of its users is not clear (56S ). Nervous system Several cases of stuttering have been associated with clozapine; one occurred before a generalized epileptic seizure and recovered after antiepileptic drug treatment (SEDA-25, 64). Now, a further case of clozapine-associated stuttering has been described (57A ).

Alfonso Carvajal and Luis H. Martín Arias

• A 28-year-old man taking clozapine 300 mg/day developed severe stuttering and subsequently had a generalized tonic–clonic seizure while taking 425 mg/day. There were electroencephalographic abnormalities, especially left-sided slowing.

The authors suggested that in patients taking clozapine, electroencephalographic abnormalities and stuttering may be harbingers of seizures. Although clozapine is thought to increase the risk of seizures, six patients with epilepsy and severe psychosis taking clozapine had no increases in seizure frequency, and three had a substantial reduction (58c ). The addition of lamotrigine to clozapine therapy has been associated with rapid improvement of psychiatric symptoms (59A ); this has been observed in three cases of poor response or resistance to clozapine monotherapy. It is said that clozapine causes less tardive dyskinesia than haloperidol and even that it can improve pre-existing tardive dyskinesia (SEDA-25, 61). • A 45-year-old woman developed tardive dyskinesia while taking clozapine (60A ). She had never had any of the symptoms before she started to take 223 mg/day and ﬁrst experienced involuntary tongue movements and akathisia 5 months after the start of treatment.

Psychiatric Suicide, suicidality, and suicidal ideation are very serious problems in patients with schizophrenia. Based on general observations that 1–2% of schizophrenic patients complete suicide within 1 year after initial attempts, the authors of a retrospective study of 295 antipsychotic drug-resistant schizophrenics who had taken clozapine monotherapy for at least 6 months would have expected as many as 10 or 11 successful suicides or suicide attempts, but none was observed (61c ). Metabolism Weight gain has been commonly associated with clozapine (SEDA-25, 62), and there is increasing evidence that it is associated with an increased risk of many other disorders, including hypertension (SEDA-26, 57). This has been the subject of a recent study, in which the association between clozapinerelated weight gain and increased mean arterial blood pressure has been examined in 61 patients who were randomly assigned to either clozapine or haloperidol in a 10-week parallel

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group, double-blind study, and in 55 patients who chose to continue to take clozapine in a subsequent 1-year, open, prospective study (38C ). Clozapine was associated with signiﬁcant weight gain in both the double-blind trial (mean 4.2 kg) and the open trial (mean 5.8 kg). There was no signiﬁcant correlation between change in weight and change in mean arterial blood pressure. There were no signiﬁcant associations between cycle length and weight change during clozapine treatment in 13 psychotic premenopausal women (62c ). Phenylpropanolamine 75 mg/day did not promote weight loss in a randomized, placebocontrolled study in 16 patients with schizophrenia who had gained at least 10% of their body weight while taking clozapine (63c ). A case of sleep apnea associated with clozapine-induced obesity has been reported (64A ). • A 45-year-old woman with schizophrenia who took clozapine 300 mg/day for 16 months gained 18 kg and had hypertriglyceridemia and glucose intolerance. She had daytime sedation, difﬁculty in sleeping at night, loud snoring, and periods of apnea during sleep.

Nasal continuous positive airway pressure produced improvement. Endocrine Diabetic ketoacidosis and other cases of new-onset diabetes mellitus have previously been reported in patients taking clozapine (SEDA-24, 64; SEDA-25, 62). Now, another case of new-onset diabetes mellitus has been reported in a 49-year-old man taking olanzapine, who had recovered after withdrawal (65A ). Opposite data have been found in a casecontrol study in 7227 patients with new diabetes and 6780 controls, all with psychiatric disorders (66C ). Clozapine was not signiﬁcantly associated with diabetes (adjusted OR = 0.98; 95% CI = 0.74, 1.31) and there was no suggestion of relations between larger dosages or longer durations of clozapine use and an increased risk of diabetes. Among individual non-clozapine antipsychotic drugs, there were signiﬁcantly increased risks for two phenothiazines: chlorpromazine (OR = 1.31; 95% CI = 1.09, 1.56) and perphenazine (OR = 1.34; 95% CI = 1.11, 1.62). The authors suggested that, in contrast to earlier reports, these results provided some reassurance that clozapine does not increase the

57 risk of diabetes. However, cases of diabetes were identiﬁed by the new use of antidiabetic drugs, and it is therefore possible that clozapine was associated with less pronounced glucose intolerance that did not require drug therapy. Hematologic Agranulocytosis associated with clozapine therapy has been extensively studied and discussed (SEDA-24, 62; SEDA-26, 59). Agranulocytosis after long-term clozapine therapy has been reported (67A ). • A 41-year-old man suddenly developed agranulocytosis after taking clozapine nearly continuously for 89 months. During this time, his white blood cell and granulocyte counts remained stable. The white blood cell and granulocyte counts returned to baseline shortly after withdrawal of clozapine and administration of sargramostim.

There is a potentially dangerous interaction with cancer treatment in patients with schizophrenia taking clozapine, because of the unpredictable risk of myelotoxicity. However, a 37-year-old patient taking clozapine for schizophrenia was given full-dose cisplatin and concomitant radiotherapy for an undifferentiated nasopharyngeal carcinoma, without signiﬁcant neutropenia (68A ). Gastrointestinal Constipation is an adverse effect that has often been associated with clozapine; it may be serious and even fatal, and it has therefore been suggested that diet modiﬁcation and regular exercise should be encouraged in patients taking clozapine in order to prevent this serious event (SEDA-25, 63). Another fatal case of clozapine-induced constipation has been reported (69A ). • A 43-year-old man took clozapine 750 mg/day for 6 years and developed vomiting and epigastric pain. He had ulcerative esophagitis, and a CT scan was “normal apart from constipation”. He was given omeprazole 20 mg/day and psyllium bd. Six months later he developed abdominal pain with feculent vomiting. Emergency laparotomy revealed large-bowel obstruction secondary to severe fecal impaction. He died 3 weeks later with septic shock and progressive multisystem organ failure.

Drug overdose The features of clozapine overdose have again been described (70A ). • A 41-year-old woman took 12.5 g of clozapine (125 tablets of 100 mg each) in a suicide attempt. She developed agitation, hallucinations, diminished distrust, and lethargy; she was given physostigmine 2 mg and recovered completely within 1 week.

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Drug interactions Clozapine toxicity occurred in a 42-year-old man after he was given modaﬁnil 300 mg/day, a central stimulant, to combat sedation associated with clozapine (450 mg/day) (71A ). He complained of dizziness, had an unsteady gait, and fell twice, and his clozapine serum concentration was 1400 ng/ml, which suggested a metabolic interaction between clozapine and modaﬁnil. The authors suspected that inhibition of CYP2C19 by modaﬁnil reduced clozapine clearance. Fluvoxamine increases clozapine plasma concentrations (SEDA-24, 65; SEDA-25, 63). In two studies of short duration (18 patients each) there were beneﬁts of using low doses of clozapine plus ﬂuvoxamine, and the authors suggested taking advantage of this interaction (72r ). Patients taking ﬂuvoxamine required relatively low doses of clozapine and had clinically signiﬁcant reductions in the symptoms of their illness while avoiding the sedative adverse effects associated with the usual doses of clozapine. Plasma concentrations of clozapine are lower in smokers than in non-smokers (see Drug interactions under olanzapine).

Droperidol

(SEDA-24, 66)

Nervous system Balance disturbances have been described with droperidol in 120 women undergoing gynecological dilatation and curettage, who were randomly assigned to receive either 0.9% saline (placebo) or droperidol 0.625 mg intravenously before surgery (73c ). Body sway above its pre-anesthesia baseline was signiﬁcantly greater in the droperidol group (61%) than in the placebo group (33%).

Haloperidol

(SEDA-22, 63)

Cardiovascular A 39-year-old man died suddenly 1 hour after taking a single oral dose of haloperidol 5 mg (74A ). He had myasthenia, alcoholic hepatitis, and electrolyte abnormalities due to inadequate nutritional state. His electrocardiogram showed prolongation of the QTc interval (460 ms). Autopsy showed a cardiomyopathy but no explanation for sudden death.

Alfonso Carvajal and Luis H. Martín Arias

The effects of haloperidol dose and plasma concentration and CYP2D6 activity on the QTc interval have been studied in 27 Caucasian patients taking oral haloperidol (aged 23–77 years, dosages 1.5–30 mg/day) (75c ). Three patients had a QTc interval longer than 456 ms, which can be considered as the cut-off value for a risk of cardiac dysrhythmias. There was no correlation between QTc interval and haloperidol dosage or plasma concentrations or CYP2D6 activity. Nervous system Neuroleptic malignant syndrome has again been reported with haloperidol (76A ). • A 21-year-old Turkish man with succinic semialdehyde dehydrogenase deﬁciency and mental retardation developed neuroleptic malignant syndrome after a single dose of haloperidol 10 mg for anxiety and agitation, having never received a neuroleptic drug before.

Several reports have suggested a higher incidence and severity of extrapyramidal symptoms during haloperidol treatment in congenitally poor metabolizers of substrates of CYP2D6 and even a case of a patient with a poor metabolizer polymorphism of the CYP2D6 gene who developed neuroleptic malignant syndrome after receiving haloperidol (77c ). All frequent polymorphisms of CYP2D6 were therefore investigated in the second patient, who was a carrier of the wild-type genotype CYP2D6∗ 1/∗ 1, which is common in subjects of Caucasian origin. The authors concluded that a genetic defect of haloperidol metabolism via CYP2D6 was unlikely as a reason for the neuroleptic malignant syndrome in this case. Endocrine The effects of haloperidol and quetiapine on serum prolactin concentrations have been compared in 35 schizophrenic patients during a drug-free period for at least 2 weeks in a randomized study (35c ). There was no signiﬁcant difference in prolactin concentration between the groups at the start of the study, control prolactin concentrations were signiﬁcantly lower with quetiapine than haloperidol. Two patients taking haloperidol had galactorrhea related to hyperprolactinemia. Skin Haloperidol has been reported to have caused a widespread skin rash (78A ).

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• A 41-year-old man who had been taking weekly methotrexate 15 mg for 10 months for psoriasis started to take haloperidol 1.5 mg bd for a psychotic illness, and 2 weeks later developed sudden redness and swelling of the face and hands accompanied by redness and watering of both eyes. He had diffuse erythema, edema, scaling, and erosions over his face, the anterior aspect of the neck, and the backs of both hands. A skin biopsy showed parakeratosis, acanthosis, spongiosis, focal epidermal cell degeneration, and dermal edema, accompanied by a moderate lymphomononuclear inﬁltrate, consistent with subacute dermatitis. A diagnosis of pellagra-like photosensitivity dermatitis, caused by combined deﬁciency of niacin, riboﬂavin, and other water-soluble vitamins, probably precipitated by haloperidol, was therefore considered. Haloperidol was withdrawn, vitamins were administered, and the condition resolved in the next 5 days.

Drug interactions An interaction between valproate and haloperidol has been reported (79A ). • A 30-year-old man with bipolar affective disorder was given intravenous sodium valproate 20 mg/kg/day without any major problem. Later, he was given oral haloperidol 10 mg bd for persistent aggressive behavior and manic symptoms. The next day he developed a sense of imbalance and started swaying. He was drowsy and had cerebellar ataxia. Haloperidol was withdrawn and within 1 day his ataxia had disappeared completely in spite of continuing valproate.

Olanzapine

(SEDA-23, 64; SEDA-24, 66; SEDA-25, 64; SEDA-26, 61) The efﬁcacy and safety of switching 108 Asian patients from their regimen of antipsychotic medications to olanzapine (initial dose of 10 mg/day) for 6 weeks has been studied in an open, multicenter, randomized study (80C ). They were randomly assigned to one of two groups: the direct switch group (n = 54) received only olanzapine, while the start-taper switch group (n = 54) received olanzapine and their usual antipsychotic drug in decreasing doses for the ﬁrst 2 weeks. There were statistically signiﬁcant improvements from baseline to end-point in both switch groups in the Clinical Global Impressions–Severity of Illness Scale score and the Positive and Negative Syndrome Scale total score. Nevertheless, there were

59 no signiﬁcant differences between the switch groups in any measure of efﬁcacy. Weight gain occurred in both switch groups and both showed statistically signiﬁcant improvement from baseline to end-point on the Simpson– Angus Scale and Barnes Akathisia Scale. Cardiovascular Olanzapine often causes QT interval prolongation (SEDA-25, 64; SEDA-26, 61). Two recent cases of light-headedness or “fainting” in patients taking olanzapine have been reported (81A ). Electrocardiograms showed ﬁrst-degree heart block and AV conduction delay, which normalized after dosage reduction. • A 44-year-old man took olanzapine 10 mg/day and the dose was increased to 50 mg/day, after which he complained of episodes of light-headedness. An electrocardiogram showed prolongation of the PR interval to 227 ms. The dosage was reduced to 30 mg and the PR interval returned to 187 ms within 2 days. • A 36-year-old man took olanzapine 20 mg/day and within 2 weeks began to complain of intermittent, unpredictable “fainting” attacks. An electrocardiogram showed a prolonged PR interval at 230 ms. The dose of olanzapine was reduced to 17.5 mg/day, and a repeat electrocardiogram 1 week later was normal.

Nervous system Olanzapine has fewer extrapyramidal effects than typical antipsychotic drugs such as haloperidol (SEDA-24, 66). Even some cases of tardive dystonia have been successfully managed with atypical antipsychotic drugs. The antidystonic efﬁcacy of olanzapine has been studied in an open video-blinded study in four patients with tardive cervical dystonia after several years of neuroleptic drug treatment (82c ). There was moderate to marked improvement in dystonia in all of them, and no serious adverse effects at the maximum dosage reached (7.5 mg/day). However, cases of olanzapine-induced tardive dyskinesia have been reported, and it has been estimated that this adverse effect may occur in 1% of treated patients (SEDA-24, 68; SEDA-25, 64). • A 55-year-old man with Huntington disease took olanzapine 5 mg/day and rapidly developed tardive dyskinesia (83A ). After 2 months, his chorea improved markedly, but orofacial dyskinesia, which he had never had in the past, appeared. Olanzapine was withdrawn, and 1 week later the orofacial dyskinesia improved while the chorea worsened.

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Neuroleptic malignant syndrome has also been associated with olanzapine (SEDA-24, 68; SEDA-25, 64; SEDA-26, 62). • A 53-year-old man developed atypical neuroleptic malignant syndrome, with fever, altered mental status, and autonomic dysfunction, but without rigidity (a usual feature of this condition) while taking olanzapine (84A ).

The authors pointed out that such atypical cases may support either a spectrum concept of neuroleptic malignant syndrome or the theory that neuroleptic malignant syndrome secondary to atypical antipsychotic drugs differs from that caused by conventional neuroleptic drugs. They suggested that more ﬂexible diagnostic criteria than currently mandated in DSM-IV may be warranted. Following a case of olanzapine-associated weight gain, hyperglycemia, and neuroleptic malignant syndrome in a 64-year-old woman the authors suggested that neuroleptic malignant syndrome might occur more often in patients aged 60 years or older (85A ). However, this patient had previously had welldocumented neuroleptic malignant syndrome secondary to haloperidol, and on another occasion ﬂuphenazine decanoate. Seizures associated with olanzapine have been estimated to occur in 0.9% of patients, and the incidence is probably comparable to that of other typical antipsychotic drugs (SEDA-25, 64). • A 27-year-old woman had a seizure while taking a stable dosage of olanzapine 15 mg/day 1 day after the introduction of quetiapine 100 mg in the evening (86A ). She suddenly fell to the ground and had generalized shaking and inarticulate vocalization for about 30–60 seconds.

Alfonso Carvajal and Luis H. Martín Arias

or risperidone and to establish whether the duration of antipsychotic treatment is related to the severity of obsessive–compulsive symptoms (88C ). At baseline and week 6 assessments, obsessive–compulsive symptoms were found in 32 of 106 evaluable cases and 16 met DSM-IV criteria for obsessive–compulsive disorder, but there were no differences in patients taking olanzapine or risperidone. However, the severity of obsessive-compulsive symptoms was associated with the duration of treatment with olanzapine. Sleep-related eating disorder, a recently described syndrome, consists of partial arousal from sleep followed by rapid ingestion of food, commonly with at least partial amnesia for the episode on the next day; this disorder has been reported, purportedly for the ﬁrst time, in association with an atypical antipsychotic drug (89A ). • A 52-year-old man with bipolar I disorder and a family history of sleepwalking took olanzapine 10 mg/day and after several days had episodes of sleep-related eating disorder, witnessed by his wife; he had no memory of these episodes. After olanzapine withdrawal, the episodes disappeared rapidly.

Endocrine Olanzapine can cause increased serum prolactin concentrations and galactorrhea, but probably to a lesser extent than haloperidol, and paradoxical cases of improvement in galactorrhea have also been observed (SEDA-23, 67).

• A 42-year-old woman with bipolar II disorder who had taken olanzapine 5 mg/day for 5 weeks began to have severe enduring panic-like anxiety and serious obsessive–compulsive symptoms (87A ).

• A depressed 27-year-old woman taking mirtazapine developed hyperprolactinemia and galactorrhea after taking olanzapine 10 mg/day for 5 weeks (90A ). • A 19-year-old woman with mild mental retardation and a history of birth anoxia who took olanzapine 15 mg/day for 3 weeks developed euprolactinemic galactorrhea (91A ). Laboratory tests were all normal, including a normal thyroid-stimulating hormone concentration and a prolactin concentration of 13 ng/ml (reference range 3–30 ng/ml). She had mild to moderate akathisia. Both the galactorrhea and the akathisia abated after substitution by quetiapine.

The aims of a recent prospective study in 113 consecutively hospitalized young patients (mean age 22 years) were to determine whether the severity of obsessive–compulsive symptoms differs during treatment with olanzapine

The authors stated that the reason why galactorrhea occurred is unclear but suggested that it may have been due to structural damage and greater sensitivity to prolactin resulting from the patient’s anoxia at birth.

Psychiatric Olanzapine can cause both de novo and worsening obsessive–compulsive symptoms (SEDA-24, 68; SEDA-25, 65).

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Metabolism It has previously been reported that signiﬁcant weight gain occurs more often with olanzapine than with other antipsychotic drugs, such as haloperidol or risperidone (SEDA-24, 69; SEDA-25, 65; SEDA-26, 57). In a retrospective chart review, 20 consecutive patients, who requested a switch from their previous antipsychotic drug therapy to olanzapine, were monitored over 12 months to note changes in weight. After 12 months of olanzapine treatment, 13 had a mean weight gain of 7.3 kg and three had no signiﬁcant change in weight (92c ). Paradoxically, four patients lost weight when taking olanzapine, and the authors claimed that this is the ﬁrst report of patients who had weight loss with olanzapine, although in these cases it is difﬁcult to determine which factors contributed to the weight loss. Taking advantage of this effect on weight, olanzapine 10 mg has been used in an open trial in 20 patients with anorexia nervosa (93c ). Of the 14 patients who completed the 10-week study, 10 gained an average of 3.9 kg and three of these attained their ideal body weight. The other four patients who completed the study lost a mean of 1.0 kg. The most common adverse effects were sedation (n = 13), headache (n = 5), fatigue (n = 4), and hypoglycemia (n = 4). Whether hyperglycemia and diabetes associated with olanzapine therapy are associated with weight gain or obesity is a matter of debate (SEDA-24, 69; SEDA-25, 65; SEDA-26, 62). • A 51-year-old woman with an 18-year history of type II diabetes mellitus developed glucose dysregulation with persistent hyperglycemia within 3 weeks of starting treatment with olanzapine, in the absence of weight gain (94A ).

The author suggested that olanzapine can cause glucose dysregulation by a mechanism other than weight gain. A previous study in 14 patients showed that both increased insulin secretion and hyperleptinemia may be mechanisms that underlie olanzapine-induced weight gain (95c , SEDA25, 65). There has since been an open study in seven men and four women taking olanzapine (mean daily dose 12 mg and mean treatment duration 23 months) (96c ). Although the mean fasting triglyceride concentrations and mean fasting plasma glucose concentrations were similar to those found in the previous study, the mean fasting insulin concentrations were lower

61 (143 pmol/l vs. 228 pmol/l), and four of the subjects had hyperinsulinemia, compared with ten in the other study. However, the small sample sizes precluded any clear conclusions. The genetic basis of some reactions associated with antipsychotic drugs is of particular interest. Different polymorphisms have been studied in connection with atypical antipsychotic drug-induced weight gain (SEDA-26, 57). The relation between the CYP2D6 genotype and weight gain in patients taking atypical antipsychotic drugs has been addressed in a new study in 11 Caucasian patients taking a ﬁxed dose of olanzapine 7.5–20 mg/day for up to 47 weeks (97c ). They had their DNA analysed for the CYP2D6∗ 1, CYP2D6∗ 3, and CYP2D6∗ 4 alleles; six had two ∗ 1 alleles and the other 5 had either ∗ 1/∗ 3 or ∗ 1/∗ 4. Subjects with a heterozygous genotype (∗ 1/∗ 3 or ∗ 1/∗ 4) had a statistically signiﬁcantly larger percentage change in body mass index than those who were homozygous for the ∗ 1 allele. Death from olanzapine-induced hyperglycemia has been reported (98A ). • A 31-year-old man took olanzapine 10 mg/day for 1 week and his fasting blood glucose rose to 11 mmol/l (200 mg/dl). For more aggressive treatment of his psychosis, the dosage of olanzapine was increased to 20 mg/day, and his fasting blood glucose rose to 16 mmol/l (280 mg/dl). He became progressively weaker and developed polydipsia and polyuria and died 3 weeks after starting to take olanzapine. He had no personal or family history of diabetes mellitus and was taking no other drugs at the time of his death. Death was attributed to hyperosmolar non-ketotic hyperglycemia.

The authors recommended including vitreous glucose and gamma-hydroxybutyrate analysis as part of postmortem toxicology work-up when the drug screen reveals either olanzapine or clozapine. Hematologic Olanzapine is relatively free of hematological adverse effects (SEDA-24, 69), although cases of neutropenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia have been published (SEDA-25, 65; SEDA-26, 62). Eosinophilia can now be added to that list. • Eosinophilia occurred in a 30-year-old man taking olanzapine 22.5 mg/day (99A ). After 5 weeks, the white blood cell count increased to 15 × 109 /l, of which 7.9 × 109 /l were eosinophils. Olanzapine was withdrawn, and 5 weeks later the white blood cell count was 8.5 × 109 /l with 14% eosinophils.

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Drug overdose Several cases of death from overdosage of olanzapine have previously been reported (SEDA-24, 70; SEDA-25, 66). • A 24-year-old man took a presumed cumulative dose of 420 mg of olanzapine and 10 mg of alprazolam (100A ). He had a cardiac arrest with asystole, from which he was initially resuscitated. Recurrent cardiac arrest, probably caused by hyperkalemia, occurred in the intensive care unit and he died within 1 hour.

Drug interactions Carbamazepine reduces olanzapine concentrations (SEDA-24, 71). The effect of carbamazepine on the glucuronidation of olanzapine has been studied in 30 patients taking olanzapine monotherapy (dosage 2.5–30, median 15, mg/day) and in 15 patients being co-medicated with carbamazepine (dosage 5–50, median 20, mg/day) (101c ). The median ratio of unbound olanzapine concentration to daily dose in the carbamazepine group was 38% lower than in the monotherapy group, conﬁrming that carbamazepine accelerates the metabolism of olanzapine. Furthermore, in the carbamazepine group the median glucuronidated olanzapine fraction was 79% of the unbound fraction, compared with 43% in the monotherapy group, which suggests that an increased rate of olanzapine glucuronidation contributes to the increased rate of metabolism of olanzapine induced by carbamazepine. Plasma concentrations of olanzapine and clozapine are lower in smokers than in nonsmokers, mainly because of induction of CYP1A2. Two patients who smoked tobacco and cannabis have been reported (102A ). One took olanzapine and had extrapyramidal motor symptoms after reducing his consumption of tobacco. The second, who was taking clozapine, developed confusion after he stopped smoking tobacco and cannabis, related to increased clozapine concentrations. The authors recommended that when patients stop smoking, appropriate dosage adjustments should be made to ensure that the plasma antipsychotic drug concentrations remain within the usual target range.

Quetiapine

(SEDA-24, 71; SEDA-25, 66;

SEDA-26, 63) Endocrine The effects of haloperidol and quetiapine on serum prolactin concentrations

Alfonso Carvajal and Luis H. Martín Arias

have been compared in 35 schizophrenic patients during a drug-free period of at least 2 weeks in a randomized study (35c ). There was no signiﬁcant difference in prolactin concentration between the groups at the start of the study, and control prolactin concentrations were signiﬁcantly lower with quetiapine than haloperidol. No patients taking quetiapine had galactorrhea.

Risperidone

(SEDA-24, 71; SEDA-25, 67; SEDA-26, 63)

Risperidone was effective and well tolerated in 118 children aged 5–12 years with subaverage intelligence and severely disruptive behavior in a 6-week, multicenter, double-blind, randomized trial (103C ). Risperidone produced significantly greater improvement than placebo on the conduct problem subscale of the Nisonger Child Behavior Rating Form from week 1 (respective reductions in score of 15 and 6). The most common adverse effects of risperidone (mean dose at end-point 1.16 mg/day) were headache and somnolence; the extrapyramidal symptom proﬁle of risperidone was comparable to that of placebo, and there were respective mean weight increases of 2.2 kg and 0.9 kg. Nervous system Pisa syndrome, an axial dystonia with ﬂexion of the trunk towards one side, is a rare dystonic reaction that occurs during treatment with antipsychotic drugs (SED14, 146; SEDA-24, 57). Two cases related to risperidone have been published. • A 24-year-old woman with mental retardation and an unspeciﬁed psychosis took risperidone 2 mg/day and trihexyphenidyl 2 mg/day and after 2 weeks developed symptoms that included tilting of her body backwards and to the left and tremors and cogwheel rigidity of the limbs (104A ). Risperidone was withdrawn and olanzapine 5 mg/day started; after 4 weeks there was no improvement and she was then lost to follow-up. • A 25-year-old man with auditory hallucinations took risperidone 7 mg/day for 15 months plus biperiden 6 mg/day (105A ). He then complained of leaning to the right and being unable to straighten up. He had tonic ﬂexion of the trunk to the right with slight backward axial rotation. After 5 months of risperidone withdrawal, the condition had not resolved; it later improved with co-beneldopa 400/100 mg/day and then after the addition of cabergoline 0.75 mg/day.

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Restless legs syndrome has been reported in association with risperidone (106A ). • A 31-year-old woman with schizoaffective disorder taking risperidone 6 mg/day complained of uncomfortable tingling and tearing sensations deep inside the calves and less severe sensations in her arms after 5 days; the symptoms vanished after replacement by quetiapine 400 mg/day.

Rabbit syndrome, a late-onset extrapyramidal adverse effect associated with antipsychotic drugs, characterized by a rapid tremor of the lips and occasionally of the jaw, has been reported in association with risperidone (107A ). • A 38-year-old man with major depressive disorder and psychotic features developed rabbit syndrome after taking risperidone 4 mg/day and paroxetine 40 mg/day for 4 months; he was also taking simvastatin 10 mg/day, thiamine 100 mg/day, and folic acid 1 mg/day.

Two patients with hydrocephalus and learning difﬁculties developed headache, nausea, vomiting, drowsiness, lethargy, and episodes of collapse after starting to take risperidone for aggressive outbursts; the condition mimicked increased intracranial pressure (108A ). Withdrawal of the drug resulted in complete resolution of all the symptoms within 72 hours. The authors pointed out the striking degree of overlap between the adverse effects proﬁle of risperidone and the symptoms of raised intracranial pressure due to shunt malfunction, which has not been previously highlighted. Psychiatric Risperidone has been used in the treatment of mania in combination with mood stabilizers (SEDA-23, 69; SEDA-26, 64), even though risperidone has also been reported to cause mania (SEDA-23, 71; SEDA-24, 72). Two new cases of risperidone-induced mania have been reported in a 23-year-old man and a 21-year-old woman, who developed acute mania with euphoria, psychomotor agitation, and hypersexuality, at dosages of 4–8 mg/day (109A ). Endocrine When 20 women with schizophrenia who were taking risperidone and had menstrual disturbances, galactorrhea, and sexual dysfunction (SEDA-24, 72; SEDA-26, 65) were switched from risperidone to olanzapine over 2 weeks and then took olanzapine

63 5–20 mg/day for 8 further weeks, serum prolactin concentrations fell signiﬁcantly (110c ). Scores on the Positive and Negative Syndrome Scale, Abnormal Involuntary Movement Scale, and Simpson–Angus Scale for extrapyramidal symptoms at the end-point were also significantly reduced. There were improvements in menstrual functioning and patients’ perceptions of sexual adverse effects. Metabolism Weight gain can be a problem with atypical antipsychotic drugs, even risperidone (SEDA-26, 56). In a multicenter, open study in 127 elderly psychotic patients (median age 72, range 54–89, years) taking risperidone (mean dose 3.7 mg/day) there was no signiﬁcant weight gain after 12 months (111c ). Sleep apnea has been associated with risperidone-induced obesity (64A ). • A 50-year-old man with schizophrenia gained 29 kg over 31 months and developed diabetes while taking risperidone 6 mg/day. He reported difﬁculty in sleeping and frequent daytime napping that left him unsatisﬁed, and his wife reported prominent snoring and apnea at night.

Nasal continuous positive airway pressure produced improvement. Fluid balance Water retention and edema occur very rarely during treatment with antipsychotic drugs. • A 27-year-old woman with schizophrenia took risperidone 4 mg/day for 3 weeks and developed moderate pitting edema in both legs and moderate periorbital and facial edema and gained 5 kg (112A ). She had no history of edema, congestive heart failure or any other cardiac dysfunction, thyroid disorders, or peripheral vascular disease; laboratory tests were normal. The dosage of risperidone was reduced to 3 mg/day, and the edema resolved within 1 week.

The manufacturers’ monograph mentions the risks of risperidone-induced edema: 16% (n = 147; dosage 0.5 mg/day), 13% (n = 147; dosage 1 mg/day), and 18% (n = 162; dosage 2 mg/day) compared with 6% in placebotreated patients (n = 161) (113S ). In one study, 16% of 462 risperidone recipients developed peripheral edema, in contrast to 5.5% of placebo cases (114C ). Polydipsia with hyponatremia have been reported in patients taking risperidone (SED-14, 149).

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• A 28-year-old man complained of unbearable thirst 2 weeks after starting risperidone 8 mg/day, and would drink 4–5 liters of water within a variable period of a few minutes to 8 hours; he did not develop hyponatremia (115A ). The condition lasted about 2 years and remitted after withdrawal of risperidone. After a drug-free interval of 2 weeks, clozapine was started and the condition had not recurred after 6 months.

The mechanism of this effect was unclear. The authors thought that SIADH was unlikely, considering the features of polyuria, a low urine osmolality (172 mosmol/kg), and absence of hyponatremia during polydipsia. Sexual function Erectile dysfunction and priapism have previously been associated with risperidone (SEDA-24, 71; SEDA-25, 70; SEDA-26, 65). In one case priapism followed the use of ﬁrst risperidone and then ziprasidone (44A ). In two other cases, presumed to be due to risperidone (116A , 117A ), penile irrigation with isotonic saline and phenylephrine injection resulted in detumescence. Risperidone has a high afﬁnity for alpha-1 adrenoceptors, and alpha-1 blockade leads to direct arteriolar dilatation, which results in increased blood inﬂow and reduced outﬂow secondary to effacement and subsequent obstruction of emissary veins. Pregnancy All antipsychotic agents cross the placenta and reach the fetus in potentially signiﬁcant amounts; the best recommendation is to avoid any drug during the ﬁrst trimester and only to use drugs thereafter if the beneﬁts to the mother and fetus outweigh any possibility of risk (SED-14, 152; SEDA-22, 54). Risperidone has been used in two cases before and throughout pregnancy without developmental abnormalities in the children after 9 months and 1 year; the dosages started at 2 mg/day and were increased to 4–6 mg/day (118A ). In a large postmarketing study of 7684 patients who took risperidone, nine women took it during 10 pregnancies; there were seven live births and three therapeutic terminations of pregnancy (SEDA23, 69; 119C ). Drug interactions The most important drug interactions with risperidone are with serotonin re-uptake inhibitors and with carbamazepine (SEDA-25, 70; SEDA-26, 65). When 10 schizophrenic patients stabilized on risperidone 4–6 mg/day took ﬂuoxetine 20

Alfonso Carvajal and Luis H. Martín Arias

mg/day for concomitant depression the mean plasma risperidone concentration increased from 12 to 56 ng/ml at week 4; the concentration of 9-hydroxyrisperidone was not signiﬁcantly affected (120c ). One patient dropped out after 1 week because of akathisia associated with a markedly increased plasma risperidone concentration. In an open 30-day trial, the pharmacokinetics, safety, and tolerability of a combination of risperidone 4 or 6 mg/day with ﬂuoxetine 20 mg/day were evaluated in 11 psychotic inpatients (121c ). CYP2D6 genotyping showed that three were poor metabolizers and eight were extensive metabolizers. The mean AUC of risperidone increased from 83 and 398 h.ng/ml to 341 and 514 h.ng/ml when risperidone was co-administered with ﬂuoxetine in extensive and poor metabolizers respectively. However, despite this pharmacokinetic interaction, the severity and incidence of extrapyramidal symptoms and adverse events did not increase signiﬁcantly when ﬂuoxetine was added; 10 of the 11 patients improved clinically. Other authors have described an increased risk of adverse effects in poor metabolizers of risperidone (122c ). Whether the risk is increased in poor metabolizers or not, risperidone interacts with paroxetine and with other serotonin re-uptake inhibitors. • A 24-year-old woman with auditory hallucinations taking risperidone 6 mg/day developed neuroleptic malignant syndrome after adding ﬂuvoxamine 50 mg/day (123A ).

Carbamazepine, on the other hand, lowers plasma concentrations of risperidone and 9-hydroxyrisperidone (124c ). Mean plasma concentrations of risperidone and 9-hydroxyrisperidone (5 ng/ml and 35 ng/ml) signiﬁcantly fell during carbamazepine co-administration (2.5 ng/ml and 19 ng/ml). In 11 schizophrenic patients taking risperidone 6 mg/day and then carbamazepine 400 mg/day for 1 week, the changes in risperidone concentrations correlated positively with the concentration ratio of risperidone/9-hydroxyrisperidone, which was closely associated with CYP2D6 genotype. Conversely, carbamazepine concentrations can increase when risperidone is added; when risperidone 1 mg/day was added in eight patients taking carbamazepine (mean dose 625 mg/day) carbamazepine plasma concentrations increased

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from 6.7 μg/ml at baseline to 8.0 μg/ml 2 weeks later (125c ). In three patients maprotiline plasma concentrations increased when risperidone was added (126A ). The rise was explained by inhibition of CYP2D6, by which maprotiline is mainly metabolized. An interaction of risperidone with ritonavir and indinavir has been reported (127A ). • A 34-year-old man with AIDS took risperidone 4 mg/day for a Tourette-like tic disorder. Ritonavir and indinavir were added, and 1 week later he developed signiﬁcantly impaired swallowing, speaking, and breathing, and worsening of his existing tremors. The authors hypothesized that inhibition of CYP2D6 and CYP3A4 by ritonavir and indinavir may have resulted in accumulation of the active moiety of risperidone.

Thioridazine Sensory systems Phenothiazines can cause pigment changes in the ocular fundus and can remain bound to retinal pigment epithelium for years, with progressive visual loss, despite withdrawal (SED-14, 151; SEDA-23, 56; SEDA-26, 55). • A 51-year-old woman with a long history of psychiatric problems and no family history of hereditary retinal degeneration had reduced vision in both eyes for several years while she was taking thioridazine 300 mg/day and chlorpromazine 600 mg/day (128A ). She had large patches of atrophy outside the arcades and within the macula, with sparing of foveal pigmentation; there were diffuse increases in hyperpigmentation in the peripheries of both eyes, and hypopigmented or unpigmented retinal epithelium.

The authors thought that the pigmentary changes were probably due to thioridazine, as adverse effects on the retina are rare with chlorpromazine. Death Thioridazine has been associated with sudden unexplained death, and regulatory action was accordingly taken (SEDA-24, 55). A retrospective case–control study conducted by the same group who ﬁrst identiﬁed a relation effect of pimozide and thioridazine on the QT interval (SEDA-24, 55) has been published (129C ). The study was carried out in ﬁve large

65 psychiatric hospitals in England and included all inpatients with sudden unexplained death over a period of 12 years (1984–95) and two controls for each case from the same hospital matched for age, sex, and duration of inpatient stay, one of whom was also matched for primary psychiatric diagnosis. The patients were aged 18–74 years, and there were 69 cases and 132 controls (63 matched for diagnosis). Since the presence of an organic disorder was signiﬁcantly associated with sudden unexpected death, this was adjusted for; sudden death was associated with hypertension, ischemic heart disease, and thioridazine therapy (OR = 5.3; 95% CI = 1.7, 15). Among the limitations of this study was the incompleteness of the records, which often lacked information about important risk factors, including underlying cardiac disease, smoking, or the use of alcohol or illicit drugs; furthermore, the low rate of postmortem examination raises the possibility that some of the deaths were from causes other than cardiac dysrhythmias, although other causes were found in only three of 30 cases when a post-mortem examination was done. Drug withdrawal The consequences of restricting the indications for thioridazine (SEDA24, 54) in patients with learning disabilities have been a matter of reﬂection (130r ). Of 155 psychiatric patients, 18 were regularly taking thioridazine at the time of the directive; all stopped taking it and seven had moderate or severe difﬁculties during the following 3 months and one developed probable neuroleptic malignant syndrome 4 weeks after switching to an alternative drug. According to the authors, the Committee on Safety of Medicines in the UK should take account of the adverse consequences of drug changes when making judgements about the beneﬁt:harm balance, especially in vulnerable patients, such as those with learning disabilities and psychiatric illnesses. Other consequences of banning thioridazine have been reported in a rural general practice in Ireland, in which 29 of 40 GPs responded to a questionnaire and 17 reported management problems and adverse reactions (131r ). There was increased service demand, as 44% of the GPs described up to a 50% increase in referrals to the mental health service; although most of the GPs (67%) reported satisfaction with alternative agents, 37% described

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adverse effects associated with the alternative agents. It seems reasonable that directives should incorporate the ﬂexibility required to accommodate the needs of patients who are already successfully stabilized on these drugs.

Ziprasidone

(SEDA-23, 73; SEDA-24, 74; SEDA-25, 71) Ziprasidone 20 mg (n = 30) has been compared with diazepam 10 mg (n = 30) and placebo (n = 30) in a randomized, parallelgroup, double-blind study in non-psychotic subjects who were anxious before undergoing minor dental surgery (132C ). The peak anxiolytic effect of ziprasidone compared with placebo was similar to that of diazepam but had a later onset. However, at 3 hours after the dose, the anxiolytic effect of ziprasidone was signiﬁcantly greater than that of placebo and somewhat greater than that of diazepam. The sedative effect of ziprasidone was never greater than that of placebo, whereas diazepam was signiﬁcantly more sedative than placebo 1–1.5 hours after the dose. Ziprasidone was generally well tolerated; only one patient reported treatment-related adverse events (nausea and vomiting) and, unlike diazepam, ziprasidone did not reduce the blood pressure. Dystonia, extrapyramidal syndrome, akathisia, and postural hypotension were not seen with ziprasidone. Ziprasidone may therefore have anxiolytic effects in addition to its antipsychotic properties.

Cardiovascular Three extensive reviews of ziprasidone have devoted particular attention to the possibility of QT interval prolongation (133R –135R ). Ziprasidone up to 160 mg/day prolongs the QTc interval on average 5.9– 9.7 ms (data from 4571 patients); a QTc interval of over 500 ms was seen in two of 2988 ziprasidone recipients and in one of 440 placebo recipients. In an open study in 31 patients with schizophrenia, ziprasidone given for 21– 29 days prolonged the QTc interval by 20 ms (95% CI = 14, 26).

Alfonso Carvajal and Luis H. Martín Arias

• A 38-year-old woman with a psychosis who took 4020 mg of ziprasidone had borderline intraventricular conduction delay (QRS duration 111 ms); the QTc interval was 445 ms (136A ). She oscillated between being drowsy and calm, and alert and agitated; her blood pressure fell from 129/81 to 99/34 mmHg 4 hours later. She also had diarrhea and urinary retention.

Nervous system Tardive dyskinesia has been associated with ziprasidone in a 49-year-old man with bipolar disorder (137A ). Psychiatric Three cases of hypomania in patients with depression have been reported (138A ). Musculoskeletal Rhabdomyolysis with pancreatitis and hyperglycemia has been reported in a middle-aged woman with schizoaffective disorder (139A ).

Zuclopenthixol Sexual dysfunction Priapism, although infrequent, can occur during treatment with neuroleptic drugs. It necessitates prompt urological consultation and sometimes even surgical intervention (SEDA-14, 149). A case has been associated with zuclopenthixol (43A ). • A 31-year-old man developed priapism after taking zuclopenthixol 30 mg/day for 8 days, the dose having been increased to 75 mg the day before, while he was still taking oral carbamazepine 600 mg/day and clorazepate dipotassium 30 mg/day. He had a history of perinatal anoxic encephalopathy with severe motor sequelae and dyslalia, alcohol dependence, and a personality disorder. On the day before the priapism occurred, he had been physically restrained and given an extra dose of intramuscular clorazepate dipotassium 50 mg. When priapism occurred, all drugs except clorazepate were withdrawn and about 6 hours later the corpora cavernosa were washed and infused with noradrenaline in glucose (8 doses of 40 μg), after which the priapism resolved.

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69 76. Neu P, Seyfert S, Brockmöller J, Dettling M, Marx P. Neuroleptic malignant syndrome in a patient with succinic semialdehyde dehydrogenase deﬁciency. Pharmacopsychiatry 2002; 35: 26–8. 77. Mihara K, Suzuki A, Konto T, Yasui N, Furokori H, Nagashima U, Otani K, Kaneko S, Inoue Y. Effects of the CYP2D6∗ 1 allele on the steady-state plasma concentrations of haloperidol in Japanese patients with schizophrenia. Clin Pharmacol Ther 1999; 653: 291–4. 78. Thami GP, Kaur S, Kanwar AJ. Delayed reactivation of haloperidol induced photosensitive dermatitis by methotrexate. Postgrad Med J 2002; 78: 116–17. 79. Ranjan S, Jagadheesan K, Nizamie SH. Cerebellar ataxia with intravenous valproate and haloperidol. Aust NZ J Psychiatry 2002; 36: 268. 80. Lee C-T, Conde BJL, Mazlan M, Visanuyothin T, Wang A, Wong MMC, Walker DJ, Roychowdhury SM, Wang H, Tran PV. Switching to olanzapine from previous antipsychotics: a regional collaborative multicenter trial assessing 2 switching techniques in Asia Paciﬁc. J Clin Psychiatry 2002; 63: 569-76. 81. Kosky N. A possible association between high normal and high dose olanzapine and prolongation of the PR interval. J Psychopharmacol 2002; 16: 181–2. 82. Lucetti C, Bellini G, Nuti A, Bernardini S, Dell’Agnello G, Piccinni A, Maggi L, Manca L, Bonuccelli U. Treatment of patients with tardive dystonia with olanzapine. Clin Neuropharmacol 2002; 25: 71–4. 83. Benazzi F. Rapid onset of tardive dyskinesia in Huntington disease with olanzapine. J Clin Psychopharmacol 2002; 22: 438–9. 84. Reeves RR, Torres RA, Liberto V, Hart RH. Atypical neuroleptic malignant syndrome associated with olanzapine. Pharmacotherapy 2002; 22: 641–4. 85. Malyuk R, Gibson B, Procyshyn RM, Kang N. Olanzapine associated weight gain, hyperglycemia and neuroleptic malignant syndrome: case report. Int J Geriatr Psychiatry 2002; 17: 326–8. 86. Hedges DW, Jeppson KG. New-onset seizure associated with quetiapine and olanzapine. Ann Pharmacother 2002; 36: 437–9. 87. Jonkers F, De Haan L. Olanzapine-induced obsessive–compulsive symptoms in a patient with bipolar II disorder. Psychopharmacology 2002; 162: 87–8. 88. De Haan L, Beuk N, Hoogenboom B, Dingemans P, Linszen D. Obsessive–compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of 113 patients with recent-onset schizophrenia or related disorders. J Clin Psychiatry 2002; 63: 104–7. 89. Paquet V, Strul J, Servais L, Pelc I, Fossion P. Sleep-related eating disorder induced by olanzapine. J Clin Psychiatry 2002; 63: 597. 90. Licht RW, Arngrim T. Olanzapine-induced galactorrhea. Psychopharmacology 2002; 162: 94–5. 91. Kingsbury SJ, Castelo C, Abulseoud O. Quetiapine for olanzapine-induced galactorrhea. Am J Psychiatry 2002; 159: 1061.

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110. Kim K-S, Pae C-U, Chae J-H, Bahk W-M, Jun T-Y, Kim D-J, Dickson RA. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002; 63: 408–13. 111. Barak Y. No weight gain among elderly schizophrenia patients after 1 year of risperidone treatment. J Clin Psychiatry 2002; 63: 117–19. 112. Tamam L, Ozpoyraz N, Unal M. Oedema associated with risperidone. Clin Drug Invest 2002; 22: 411–14. 113. Risperidal product monograph. www.janssenortho.com/JOI/pdf_ﬁles/Risperdal_E.pdf. 114. Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry 1999; 60: 107–11. 115. Kar N, Sharma PSVN, Tolar P, Pai K, Balasubramanian R. Polydipsia and risperidone. Aust NZ J Psychiatry 2002; 36: 268–70. 116. Ankem MK, Ferlise VJ, Han K-R, Gazi MA, Koppisch AR, Weiss RE. Risperidone-induced priapism. Scand J Urol Nephrol 2002; 36: 91–2. 117. Freudenreich O. Exacerbation of idiopathic priapism with risperidone–citalopram combination. J Clin Psychiatry 2002; 63: 249–50. 118. Ratnayake T, Libretto SE. No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry 2002; 63: 76–7. 119. Mackay FJ, Wilton GL, Pearce SN, Freemantle SN, Mann RD. The safety of risperidone a postmarketing study on 7,684 patients. Hum Psychopharmacol 1998; 13: 413–18. 120. Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E. Inhibition of risperidone metabolism by ﬂuoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. J Clin Psychopharmacol 2002; 22: 419–23. 121. Bondolﬁ G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The effect of ﬂuoxetine on the pharmacokinetics and safety of risperidone in psychotic patients. Pharmacopsychiatry 2002; 35; 50–6. 122. Bork JA, Rogers T, Wedlund P, De Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A. J Clin Psychiatry 1999; 60: 469–79. 123. Reeves RR, Mack JE, Beddingﬁeld JJ. Neurotoxic syndrome associated with risperidone and ﬂuvoxamine. Ann Pharmacother 2002; 36: 440–3. 124. Ono S, Mihara K, Suzuki A, Kondo T, YasuiFurukori N, Furukori H, De Vries R, Kaneko S. Signiﬁcant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes. Psychopharmacology 2002; 162: 50–4. 125. Mula M, Monaco F. Carbamazepine– risperidone interactions in patients with epilepsy. Clin Neuropharmacol 2002; 25: 97–100.

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71 pared with diazepam in subjects anxious before dental surgery. J Clin Psychopharmacol 2002; 22: 206–10. 133. Stimmel GL, Gutierrez MA, Lee V. Ziprasidone: An atypical antipsychotic drug for the treatment of schizophrenia. Clin Ther 2002; 24: 21–37. 134. Gunasekara NS, Spencer CM, Keating GM. Ziprasidone: a review of its use in schizophrenia and schizoaffective disorder. Drugs 2002; 62: 1217–51. 135. Caley CF, Cooper CK. Ziprasidone: the ﬁfth atypical antipsychotic. Ann Pharmacother 2002; 36: 839–51. 136. House M. Overdose of ziprasidone. Am J Psychiatry 2002; 159: 1061–2. 137. Rosenquist KJ, Walker SS, Ghaemi SN. Tardive dyskinesia and ziprasidone. Am J Psychiatry 2002; 159: 1436. 138. Davis R, Risch SC. Ziprasidone induction of hypomania in depression? Am J Psychiatry 2002; 159: 673–4. 139. Yang SH, McNeely MJ. Rhabdomyolysis, pancreatitis, and hyperglycemia with ziprasidone. Am J Psychiatry 2002; 159: 1435.

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Antiepileptic drugs

GENERAL TOPICS

(SED-14, 164; SEDA-24, 82; SEDA-25, 78; SEDA-26, 70) Nervous system Antiepileptic drugs have sometimes been associated with a paradoxical increase in seizures. The evidence for this comes from isolated reports and clinical impressions. Somerville asked ﬁve pharmaceutical companies responsible for the development of new antiepileptic drugs to provide data concerning increases in seizure frequency during randomized, placebo-controlled, add-on trials in patients with uncontrolled partial seizures (1M ). Seizure frequency in individual patients taking the active drug or placebo was compared with the baseline pretreatment seizure frequency. More than 40% of the patients in trials of tiagabine, topiramate, and levetiracetam had an increase in seizures while taking a placebo. Increased seizure frequency was no more likely to occur when they were taking any of the three drugs than when they were taking placebo. A doubling or more of seizure frequency was signiﬁcantly less likely to occur with topiramate or levetiracetam than with placebo, but more likely with tiagabine. There was some evidence of a dose-response effect with tiagabine, but a negative effect with topiramate (aggravation less likely with increasing dose). Unfortunately, the author did not obtain data on gabapentin and lamotrigine. Thus, aggravation of seizures in patients using some of the new antiepileptic drugs occurs no more often than with placebo and probably represents spontaneous ﬂuctuation of seizure frequency.

© 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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Psychosis and antiepileptic drugs Patients with chronic epilepsy have a higher likelihood of psychosis than the healthy population (2c , 3C ). Psychosis is especially frequent in patients with temporal lobe epilepsy (4c ). Anticonvulsant drugs have been reported to precipitate psychosis, although the literature is confounded by the inclusion of affective and confusional psychoses in this category. Moreover, the purported association has mostly been made through isolated case reports or small non-controlled case series. In fact, most antiepileptic drugs have been associated with psychosis: phenytoin and phenobarbital (5M ), carbamazepine and valproate (6A ), felbamate (7A ), gabapentin (8A ), levetiracetam (9A ), topiramate (10A ), vigabatrin (11c ), and zonisamide (12A ). There have been no reports of psychosis associated with lamotrigine. A retrospective chart review of 44 consecutive patients with epilepsy who had psychotic symptoms with clear consciousness has shown the difﬁculties in associating psychosis with drug effects (13c ). These patients were divided into two groups based on the presence or absence of changes in their drug regimen before the onset of the ﬁrst episode of psychosis. In 27 patients the ﬁrst episode of psychosis was unrelated to changes in their antiepileptic drug regimen, and in 23 of them the psychosis was temporally related to changes in seizure frequency. In 17 patients the ﬁrst episode of psychosis developed in association with changes in their antiepileptic drug treatment, and in 12 them the psychosis was temporally related to seizure attenuation or aggravation. This study therefore highlights the fact that psychosis can occur in relation to changes in seizure frequency, sometimes due to lack of effect of the new medication or to concomitant withdrawal of an efﬁcacious medication. In addition, withdrawal of anticonvulsants with favorable mood stabilization properties, such as carbamazepine, has often been associated with

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acute psychosis (14A , 15A ). Moreover, the phenomenon of “forced normalization”, by which complete seizure freedom in a patient with previous refractory epilepsy can lead to a psychotic state, may also contribute to the apparent association between drugs and psychosis (16M ). Double-blind studies Information from double-blind studies of psychosis as an adverse event is relatively scarce. A double-blind, randomized, add-on, placebo-controlled trial with carbamazepine showed that there was no increase in chronic psychotic symptoms in patients with suspected temporal lobe seizures (17C ). The relation between psychosis and tiagabine has been assessed in an analysis of data from two multicenter, double-blind, randomized, placebo-controlled trials of add-on tiagabine therapy (32 or 56 mg/day) in 554 adolescents and adults with complex partial seizures during 8–12 weeks (18M ). There were psychotic symptoms (hallucinations) in three (0.8%) of 356 patients taking tiagabine and none of the 198 taking placebo, a non-signiﬁcant difference. Thus, it appears that tiagabine does not increase the risk of psychosis, but the result is inconclusive. An analysis of double-blind, placebo-controlled trials of vigabatrin as add-on therapy for treatment-refractory partial epilepsy showed that compared with placebo patients taking vigabatrin had a signiﬁcantly higher incidence of events coded as psychosis (2.5% versus 0.3%) (19M ). There were no signiﬁcant differences between treatment groups for aggressive reaction, manic symptoms, agitation, emotional lability, anxiety, or suicide attempts. In an open trial of topiramate, psychosis was seen in 30/1001 (3%) of the patients, and was severe enough to require withdrawal in eight (20M ). Implications Should certain antiepileptic drugs be contraindicated in patients with active psychosis? Unfortunately there is not enough solid information to answer this question. Undoubtedly, anticonvulsants that are less likely to cause psychosis (lamotrigine, carbamazepine, oxcarbazepine, valproate) should be preferred (21M , 22M ). However, patients with psychoses have been successfully treated even with drugs that are believed to be associated with psychosis, such as vigabatrin. For example, in a prospective study in 10 patients with psychosis

73 and epilepsy to whom vigabatrin was added, there was no aggravation of the psychiatric disorder (23c ). Endocrine The risk of anovulatory cycles and its association with epilepsy syndrome and antiepileptic drugs has been assessed in a crosssectional cohort study in women with epilepsy and non-epileptic controls (24c ). There were 59 patients with localization-related epilepsy and 35 with idiopathic generalized epilepsy. They were treated with monotherapy and followed for 6 months or more. Anovulatory cycles occurred in 11% of cycles in controls, 14% of cycles in women with focal epilepsy, and 27% of cycles in women with idiopathic generalized epilepsy. Anovulatory cycles were more frequent in women taking valproate: 38% had at least one anovulatory cycle in contrast to 11% of women not taking valproate. Predictors of ovulatory failure included generalized idiopathic epilepsy syndrome, use of valproate currently or within 3 years, high concentrations of unbound testosterone, and fewer numbers of luteinizing hormone pulses, but not polycystic-like ovaries. However, the crosssectional design of the study did not allow ﬁrm conclusions to be drawn, especially since previous antiepileptic drug exposure was not controlled. Hematologic In a large cohort study of the occurrence of bleeding complications in neonates exposed to maternal enzyme-inducing antiepileptic drugs in utero in 662 pregnancies in women with epilepsy, 463 had been exposed to carbamazepine, 212 to phenytoin, 44 to phenobarbital, 11 to primidone, and 7 to oxcarbazepine (25C ). Another 1324 “non-epileptic” pregnancies (1334 neonates) were matched for maternal age, parity, number of fetuses, and delivery date. None of the mothers had received vitamin K1 during pregnancy, but all the infants received vitamin K1 1 mg intramuscularly at birth. There were bleeding complications in ﬁve (0.7%) of the neonates exposed to maternal enzyme-inducing antiepileptic drugs and in ﬁve (0.4%) of the control subjects. Logistic regression analysis showed that bleeding was associated with premature birth and alcohol abuse, but not with exposure to enzymeinducing antiepileptic drugs. These results contradict the widely held view, based on anecdotal evidence, that maternal enzyme-inducing

74 antiepileptic drugs increase the risk of bleeding in the offspring. Thus, antenatal administration of vitamin K to mothers treated with enzymeinduced drugs may not be needed in most cases. However, prophylaxis may be worth considering when premature delivery is imminent in a woman who uses antiepileptic drugs. It is worth noting that the ﬁndings described in this article are only relevant to patients taking carbamazepine or phenytoin monotherapy. Therefore, extrapolation to individuals on polytherapy or to those taking other enzyme-inducing drugs is not possible.

Epilepsy and bone loss Epilepsy and osteoporosis are very common and frequently overlap. Nevertheless, the prevalence of low bone density appears to be disproportionately higher in patients with epilepsy, and patients with epilepsy have an excessive risk of fractures. A recent meta-analysis of 94 cohort studies and 72 case-control studies has shown that anticonvulsant treatment is highly associated with fractures (relative risk over 2) (26M ). Other risk factors were low body weight, weight loss, physical inactivity, consumption of corticosteroids, primary hyperparathyroidism, type 1 diabetes mellitus, anorexia nervosa, gastrectomy, pernicious anemia, and age over 70 years. The effects on bone metabolism of carbamazepine, valproate, or phenobarbital as monotherapy have been analysed in a casecontrol study in 118 ambulatory children with epilepsy and corresponding controls (27c ). Patients taking carbamazepine or phenobarbital had signiﬁcantly raised alkaline phosphatase and bone and liver isoenzyme activities compared with controls. Although the authors concluded that children who take antiepileptic drugs may have their bone metabolism affected, this conclusion is based on abnormal values of a surrogate marker for bone disease. There has only been one prospective study of bone mineral density in patients with epilepsy (28C ). Femoral neck bone mineral density was analysed by dual-energy X-ray absorptiometry in 81 men with epilepsy. Bone mineral density was more than one standard deviation below normal in 47%, indicating an increased

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risk of fractures (29c ). Age and duration of therapy were the most signiﬁcant risk factors associated with a low bone mineral density. Vitamin D deﬁciency was not a signiﬁcant risk factor. Longitudinal analysis showed that only those in the youngest age group (25–44 years) had signiﬁcant reductions in bone mineral density (1.8% annualized loss) while taking anticonvulsants. There was no evidence that a speciﬁc type of antiepileptic drug was more causally related to bone loss, although most patients were taking phenytoin or carbamazepine. Predisposing factors for bone disease In patients with epilepsy, several factors can inﬂuence bone health, including poor mobility and anticonvulsant drug treatment. Limitations to physical activity that result from neurological deﬁcits or cerebral palsy underlying symptomatic epilepsies clearly constitute a risk factor for osteoporosis (30c ). Of 117 children with moderate to severe cerebral palsy, 77% had osteopenia, but the rate was 97% among those who were unable to stand and were over 9 years old; fractures occurred in 26% of the children who were over 10 years old (31c ). Similarly, adults with neurodevelopmental disorders residing in long-term care facilities have a high rate of both low bone mass and skeletal fractures, especially with concomitant use of anticonvulsant drugs (32c ). Reduced activity and participation in sports, because of frequent seizures, might also have an impact on bone mineralization. Certain antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, primidone) are inducers of cytochrome P450 isozymes and increase the breakdown of vitamin D (33c , 34c ). Although low vitamin D has been thought to be the cause of low bone density and osteomalacia, a reduction in bone density in the absence of vitamin D deﬁciency has been also found in children taking either enzyme-inducing agents (33c , 35c ) or valproate (36c ). Moreover, there is recent evidence that although subjects taking enzyme-inducing drugs tend to have lower bone mineral density than those taking non-inducers (clonazepam, ethosuximide, gabapentin, lamotrigine, topiramate, and valproic acid), this is not necessarily due to low vitamin D concentrations. In fact, even though 50% of patients with epilepsy have low vitamin D concentrations, there is no good correlation with bone mineral density (33c ).

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Pathophysiology The drug-related mechanisms that cause bone loss in patients with epilepsy are not completely understood. Although low vitamin D concentrations may play a part, a direct increase in the proliferation rate of human osteoblast-like cells (observed with phenytoin) might lead to impairment of bone formation (34c ). Consequences Low bone density leads to an increased risk of fractures. There was a 30% increased risk of non-seizure-related fractures in 348 non-institutionalized patients with epilepsy compared with a large control population (37c ). For non-seizure-related fractures the crude fracture rate was 1.6 fractures per 100 patientyears of observation; a similar rate (1.4) has been found in men with epilepsy (29c ). In addition, in children with epilepsy, treatment with valproic acid and/or lamotrigine for more than 2 years is associated with short stature, possibly in relation to a low bone mass and reduced bone formation (38c ). Assessment The results of multiple investigations suggest that patients with epilepsy and certain risk factors should be assessed for mineral loss: these include those taking enzyme-inducing agents or long-term treatment (especially polytherapy), those with low or lack of physical activity, postmenopausal women, and elderly people (33c , 34c ). Assessment should be done with dual-energy X-ray absorptiometry scanning of the hip (28C ) and measurement of several biochemical markers (serum total calcium, phosphate, alkaline phosphatase, gamma-glutamyltranspeptidase, aspartate transaminase, 25-hydroxycolecalciferol, and 1,25-dihydroxycolecalciferol). Patients with abnormal ﬁndings should have parathyroid hormone and sexual hormone concentrations assayed or be referred to an endocrinologist for further assessment. Despite increasing evidence of bone disease in patients with epilepsy, few pediatric (41%) and adult (28%) neurologists routinely evaluate it (39c ). A recent survey among neurologists showed that of those who detect bone disease through diagnostic testing, only 40% of pediatric and 37% of adult neurologists prescribed calcium or vitamin D, and about half referred patients to specialists (39c ). Under 10% of neurologists prescribed prophylactic calcium or

vitamin D for patients taking anticonvulsants. This also reﬂects the fact that evidence about the indications for evaluating and treating bone disorders in patients with epilepsy is currently scarce. Treatment Calcium and vitamin D supplementation alone, although necessary to meet normal nutritional guidelines, may be inadequate in preventing bone loss in epilepsy. Bone loss associated with other chronic diseases and other bone-depleting medications has prompted a search for more aggressive therapy. Osteoporosis can be effectively treated with bisphosphonates, which disrupt osteoclastic bone resorption by causing apoptosis of osteoclasts. Oral bisphosphonates are typically administered daily. Third-generation intravenous agents, such as zoledronic acid, can be just as effective when administered once a year. However, there is not currently enough information to support the use of bisphosphonates in patients at risk who are taking antiepileptic drugs. However, potential therapeutic interventions clearly require randomized prospective studies. Variables that might be addressed in such trials include: the impact of monotherapy and polytherapy on the attainment of peak bone mass in adolescence and adulthood; bone health in women; characterization of the impact of limitations in physical activity on bone density in patients with epilepsy who have cerebral palsy or those with developmental disabilities or mental retardation; the effects of newer antiepileptic drugs on bone metabolism; standardization of the workup for bone disease in patients with epilepsy; and the effectiveness of the current recommendations for supplementation with calcium and vitamin D.

Benzodiazepines (SED-14, 186; SEDA-24, 84; SEDA-25, 81; SEDA-26, 72; see also Chapter 5) Psychiatric A literature review of behavioral adverse effects associated with benzodiazepines (clonazepam, diazepam, and lorazepam) has shown that 11–25% of patients with mental retardation have these adverse effects (40R ).

76 Teratogenicity The occurrence of congenital abnormalities associated with the use of benzodiazepines (alprazolam, clonazepam, medazepam, nitrazepam, and toﬁsopam) during pregnancy has been analysed in a matched casecontrol study (41C ). The cases and controls were drawn from the Hungarian Case-Control Surveillance of Congenital Abnormalities from 1980 to 1996. Of the 38 151 pregnant women who delivered babies without congenital anomalies, 75 had taken benzodiazepines during pregnancy, compared with 57 of 22 865 who delivered offspring with anomalies. Thus, treatment with these benzodiazepines during pregnancy did not cause a detectable teratogenic risk. However, the true relevance of these ﬁndings needs to be supported by prospective case ascertainment. Susceptibility factors Neonates The safety of benzodiazepines in neonates has been assessed in a retrospective chart review of 63 infants who received benzodiazepines (lorazepam and/or midazolam) as sedatives or anticonvulsants (42c ). Five infants had hypotension and three had respiratory depression. In all cases of respiratory depression, ventilatory support was initiated or increased. Signiﬁcant hypotension was treated with positive inotropic drugs in two cases. Thus, respiratory depression and hypotension are relatively common when benzodiazepines are prescribed in these patients. However, both depression and hypotension could also have been due to the severe underlying illnesses and concomitant medications. Matched controls were not studied.

Carbamazepine

(SED-14, 172; SEDA-24, 84; SEDA-25, 81; SEDA-26, 72) Cardiovascular There has been a report of carbamazepine-induced hypertension (43A ).

• A 33-year-old man with complex partial seizures was switched from phenytoin to carbamazepine. His blood pressure was 118/70, but 4 months later, while he was taking carbamazepine 600 mg bd, his blood pressure was 150/112 and 1 month later 142/110. He was taking no medications beside carbamazepine. Secondary causes of hypertension were ruled out. Carbamazepine was withdrawn and gabapentin prescribed. One month later his blood pressure was normal, and it remained so at subsequent follow-up appointments over the next 2 years.

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Musculoskeletal Markers of collagen and bone turnover in 60 children and adolescents with epilepsy taking carbamazepine monotherapy were measured at different pubertal stages after 2 years of treatment (35c ). Compared with age-matched healthy children, there was an increase in several markers of bone turnover. In particular, there was a nearly 10-fold increase in postpubertal patients of N-telopeptides of type I collagen excretion, indicating increased bone resorption due to excessive osteoclastic activity. These data suggest that carbamazepine can cause increased bone turnover independent of pubertal age. Drug administration route The suitability of a modiﬁed-release formulation of carbamazepine (Carbatrol) for administration through feeding tubes in six children has been assessed (44A ). Carbatrol was administered as follows: ﬁrst, the tube was ﬂushed with 10 ml of water, then the granular contents of a capsule of Carbatrol were added to 15 ml of water and administered via the tube; this was followed by an additional ﬂush with 10 ml of water. Two of the six children had to be withdrawn from the study because of frequent tube occlusions, attributed to the Carbatrol granules. Teratogenesis Data from various studies in 1255 patients exposed to carbamazepine have been analysed to evaluate its potential teratogenicity (45M ). There was an increased rate of congenital anomalies, mainly neural tube defects, cardiovascular and urinary tract anomalies, and cleft palate. The combination of carbamazepine with other antiepileptic drugs was more teratogenic than carbamazepine monotherapy. Because this study was retrospective, the conclusions should not be seen as deﬁnitive. Drug interactions Risperidone signiﬁcantly increases serum carbamazepine concentrations (46c ) and carbamazepine signiﬁcantly reduces serum risperidone concentrations (47c ). The clinical relevance of these changes is uncertain. Serum carbamazepine concentrations were reduced in a 44-year-old woman who also took rifampicin (48A ).

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Gabapentin

(SED-14, 188; SEDA-24, 86; SEDA-25, 84; SEDA-26, 73)

In a double-blind comparison of gabapentin and lamotrigine in 309 patients with new-onset partial or generalized seizures, the target doses were gabapentin 1800 mg/day and lamotrigine 150 mg/day (49C ). Severe adverse events were reported in 11% of patients taking gabapentin and 9.3% of patients taking lamotrigine. Two patients has serious adverse events thought to be related to the study drug; one took an overdose of gabapentin and the other had convulsions with lamotrigine. The most frequent treatment-related adverse events in both treatment groups were dizziness, weakness, and headache; 11% of patients taking gabapentin and 15% of those taking lamotrigine withdrew because of adverse events. There was an increase of over 7% in body weight from baseline in 14% of the patients taking gabapentin and 6.6% of those taking lamotrigine. There were benign skin rashes in 4.4% of those taking gabapentin and 11% of those taking lamotrigine. In a non-interventional observational cohort study using the technique of prescription-event monitoring patients taking gabapentin were identiﬁed from dispensed National Health Service prescriptions (50C ). Outcome data were obtained from questionnaires sent to the doctor 6 months after the initial gabapentin prescription. The cohort included 3100 patients, of whom 136 (4%) were children. The median duration of treatment was 8.1 months. The most frequently reported adverse events during the ﬁrst month of treatment were neurological: drowsiness/sedation (6.7% of patients), headache/migraine (3.6%), malaise/lassitude (3.5%), dizziness (2.4%), and nausea/vomiting (2.6%). These events were also the commonest reasons for withdrawal of gabapentin and were reported as suspected adverse drug reactions. There were no congenital anomalies in the 11 babies born to women who used gabapentin during the ﬁrst trimester of pregnancy. The crude mortality rate was ﬁve times that in the general population but similar to that in other published studies in patients with epilepsy. Thus, this report does not disclose new unrecognized adverse effects of gabapentin.

Liver Gabapentin-induced cholestasis has been reported (51A ). • A 50-year-old man was given gabapentin for diabetic neuropathic pain. He had also taken metformin, amitriptyline, dihydrocodeine (30 mg as required), and ramipril for over 12 months. After taking the gabapentin for 2 weeks, he developed clinical and biochemical evidence of cholestasis. Liver function tests were: bilirubin 199 μmol/l, aspartate transaminase 104 U/l, alkaline phosphatase 210 U/l, and gamma-glutamyltransferase 839 U/l. He had negative hepatitis A, B, and C serology and negative antinuclear antibody and anti-smooth muscle antibody. A blood count, renal proﬁle, and liver ultrasound scan were also normal. A liver biopsy showed normal liver architecture with evidence of patchy steatosis, cholestasis, and some foci of chronic inﬂammation, thought to be consistent with a drug-induced etiology. Gabapentin was withdrawn and his symptoms and liver function tests improved gradually over 7–12 weeks.

The authors attributed the cholestasis to gabapentin because of the temporal relation. However, the authors failed to mention whether they withdrew other concomitant medications that could also have caused liver damage, a more likely explanation. Moreover, the number of dihydrocodeine tablets the patient took before admission was not stated. Sexual function Gabapentin-induced anorgasmia and reduced libido have been reported in two women (52A ). Both were taking relatively low doses of gabapentin (900–1800 mg). In one case the symptoms disappeared with dosage reduction but in the other gabapentin had to be withdrawn. This adverse event, although infrequent, has been reported before (53A ).

Lamotrigine

(SED-14, 188; SEDA-24, 87; SEDA-25, 85; SEDA-26, 74) Nervous system Cognitive adverse effects of lamotrigine and valproate have been compared in a double-blind, randomized, placebocontrolled study in 30 healthy volunteers who took lamotrigine 50 mg, valproic acid 900 mg, or placebo for 12 days (54C ). Lamotrigine had a relatively good cognitive proﬁle but no different from that of valproic acid at the doses tested. Lamotrigine was associated with a selective general psychostimulant effect. As this

78 study was performed in healthy volunteers taking a low dose, and conducted over a very short time, its conclusions are not generalizable to patients with epilepsy taking long-term treatment. Hematologic Lamotrigine has been associated with agranulocytosis (55A ). • A 59-year-old woman, with seizures after resection of a low-grade glioma, chemotherapy, and radiotherapy 2 years before, took lamotrigine 300 mg/day for 9 weeks and developed an agranulocytosis. The lamotrigine serum concentration was 2.2 mg/l (usual target range 1–15 mg/l). A bone marrow biopsy showed a hypocellular marrow with reduced myelopoiesis, a shift to the left, and normal cytogenetics. Over the next few days she developed a fever but no infection. She recovered after 10 days, having been given granulocyte-colony-stimulating factor and prophylactic antibiotics for 7 days.

Skin The rates of lamotrigine-related rash have been analysed from 12 multicenter studies of bipolar depression in 1955 patients taking open-label lamotrigine, 1198 taking lamotrigine in controlled studies, and 1056 taking placebo (56M ). In controlled studies, the rates of benign rash were 8.3% for lamotrigine and 6.4% for placebo. There were no serious rashes. In the open studies 13% (n = 257) had rashes with lamotrigine and one was reported as a mild form of Stevens–Johnson syndrome that did not require hospitalization. Thus, the risk of severe allergic rashes with lamotrigine is low, provided that there is a low initial dose and slow upward titration. Drug withdrawal Psychomotor inhibition after rapid withdrawal of lamotrigine has been reported (57A ). • A 26-year-old man with refractory generalized seizures had taken lamotrigine since the age of 22. At age 26, during pre-surgical evaluation with video-electroencephalography, lamotrigine was withdrawn and valproic acid 1200 mg/day and levetiracetam 1000 mg/day were continued. After 5 days he become anhedonic and had hyperhidrosis of the hands. He claimed that he had the impression that he was ﬂoating or that he was drunk. He had visual hallucinations, with stars in both visual ﬁelds, but no diplopia. He had a tremor and a slight tachycardia. Biological and toxicological results were unremarkable. An electroencephalogram ruled out status epilepticus.

The interpretation of this case is confounded by the use of levetiracetam at the onset of the

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symptoms. In addition, his symptoms appeared just after an admission for video-electroencephalography, during which he suffered at least one generalized tonic–clonic seizure. Thus, his symptoms could have been a mild form of postictal psychosis. Pregnancy Changes in lamotrigine clearance before, during, and after pregnancy were retrospectively analysed in 12 pregnancies (58c ). There was a signiﬁcant (over 65%) increase in apparent clearance between preconception and the second and third trimesters. In 11 pregnancies higher doses of lamotrigine were required to maintain therapeutic concentrations. In the postpartum period, apparent clearance returned to the preconception baseline, and lamotrigine doses had to be reduced. Teratogenicity The results of a prospective study on the outcomes in pregnant women exposed to lamotrigine have been published (59C ). The report included 168 outcomes in women exposed to lamotrigine monotherapy and 166 after pregnancies exposed to lamotrigine polytherapy during the ﬁrst trimester. Three of 168 neonates (1.8%) exposed to lamotrigine monotherapy had major birth defects (95% CI = 0.5, 5.5%). There were ﬁve major birth defects in 50 neonates (10%) after lamotrigine polytherapy with valproic acid during the ﬁrst trimester (95% CI = 3.7, 23%). The proportion of major defects on exposure to lamotrigine polytherapy without valproate during the ﬁrst trimester was ﬁve of 116 (4.3%) (95% CI = 1.6, 10%). There were no speciﬁc patterns of major birth defects in any subgroup or within the register as a whole. Thus, it appears that lamotrigine-exposed women have a relatively low frequency of major birth defects and that the combination of lamotrigine and valproic acid could potentially be especially detrimental in this respect. However, the wide conﬁdence intervals preclude a ﬁrm conclusion. Moreover, there were several methodological limitations to this study, such as lack of standardization in outcome ascertainment and other potential sources of bias. Drug interactions In a study of 400 serum concentrations from 372 patients taking lamotrigine and valproic acid, lamotrigine was associated with a slight reduction in valproate serum

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concentrations (60c ). However the size of the effect was probably of no clinical signiﬁcance. The time–course of de-induction following the step-wise withdrawal of enzyme inducers in patients treated concomitantly with lamotrigine has been analysed (61c ). This study was part of an active-control, monotherapy trial. Patients taking carbamazepine or phenytoin were given lamotrigine to attain a target dose of 500 mg/day, while carbamazepine or phenytoin were withdrawn in weekly 20% decrements. After inducer withdrawal, lamotrigine was continued as monotherapy for a further 12 weeks. Of 156 patients, 76 were assigned to lamotrigine, 43 of them completed the withdrawal to monotherapy, and 28 of these 43 successfully completed the study. In a subset analysis of completers, lamotrigine concentration increased by 160% in patients who had previously taken phenytoin and by 62% in those who had taken carbamazepine. These differences were signiﬁcantly different and occurred when carbamazepine and phenytoin plasma concentrations were very low or undetectable.

Drug interactions Four patients with refractory epilepsy taking carbamazepine were given added levetiracetam and developed central nervous system effects (ataxia, diplopia, nystagmus) suggestive of carbamazepine toxicity (64A ). Reduction of the dose of carbamazepine resolved the symptoms in three cases. Carbamazepine and carbamazepine-epoxide blood concentrations were not altered during levetiracetam co-medication. Thus, a pharmacodynamic interaction between carbamazepine and levetiracetam is likely. In a double-blind, crossover study 18 healthy women taking an oral contraceptive containing ethinylestradiol 30 μg plus levonorgestrel 150 μg took levetiracetam 500 mg/day or placebo (65C ). The plasma concentration-time curves and pharmacokinetics of ethinylestradiol and levonorgestrel were not altered.

Levetiracetam

Oxcarbazepine

(SED-14, 190; SEDA-24, 90; SEDA-25, 88; SEDA-26, 75)

Susceptibility factors Children The safety of levetiracetam has been assessed in 24 children with uncontrolled partial-onset seizures in an open study (62c ). The most commonly reported adverse events were headache (33%), infection (33%), anorexia (25%), and somnolence (25%). The adverse events proﬁle of levetiracetam was similar to that seen in adults. Owing to a dispensing error, one patient received an accidental overdose of 71 mg/kg/day, rather than 40 mg/kg/day, during the last 4 weeks of the evaluable phase of the study. No ill-effects were reported or observed on examination or laboratory testing, and the patient completed the trial. Drug overdose Overdosage of levetiracetam can cause respiratory depression. • A 38-year-old woman took 60 tablets of levetiracetam 500 mg (63A ). She vomited 4 hours later, and 2 hours after that was obtunded with respiratory depression. Her levetiracetam serum concentration was 400 μg/ml at 6 hours, 72 μg/ml at 18 hours,

and 60 μg/ml at 20.5 hours (target serum concentration 10–37 μg/ml). The half-life was 5.1 hours, similar to the usually reported half-life. She was extubated the next day and recovered without sequelae.

(SED-14, 190; SEDA-24, 90; SEDA-25, 90; SEDA-26, 76)

Electrolyte balance Low serum sodium concentrations have been reported in patients taking oxcarbazepine; 25% had concentrations below 135 mmol/l and 3% had concentrations below 125 mmol/l (66R ). In most patients, the hyponatremia was asymptomatic and only rarely resulted in morbidity or led to drug withdrawal. In a prospective study 11 patients with epilepsy and 10 controls taking oxcarbazepine 600–1800 mg/day for 3 weeks were subjected to a water-load test (67c ). Oxcarbazepine signiﬁcantly reduced serum osmolality and serum sodium concentration after a water-load test in both healthy volunteers and patients with epilepsy. The hyponatremia was hypotonic and not associated with a signiﬁcant change in serum concentrations of arginine vasopressin; thus, it could not be attributed to inappropriate secretion of ADH. There was a statistically signiﬁcant negative correlation between the trough plasma concentration of the monohydroxyderivative of oxcarbazepine and the percentage

80 of the water load excreted at 1 hour. The hyponatremia appears to result from both a relative inability to dilute the urine and a reduction in the percentage of water excreted. The underlying mechanism might be related to a direct effect of the drug on the renal collecting tubules or enhancement of their responsiveness to circulating antidiuretic hormone. Susceptibility factors A 28-year-old man with porphyria cutanea tarda took oxcarbazepine without adverse effects, suggesting that oxcarbazepine may be used in patients with this disorder (68A ); most other antiepileptic drugs cannot. Drug interactions In human liver microsomes with cDNA-expressed CYP2C19, oxcarbazepine and its 10-monohydroxy metabolite inhibited CYP2C19-mediated phenytoin metabolism at therapeutic concentrations (69E ). Thus, co-administration of oxcarbazepine with phenytoin could signiﬁcantly increase serum phenytoin concentrations.

Phenytoin and fosphenytoin (SED-14, 180; SEDA-24, 90; SEDA-25, 90; SEDA-26, 76) Intravenous phenytoin and intravenous fosphenytoin have been compared in an open, randomized study in 256 emergency department patients who were given 279 doses (70C ). The mean phenytoin-equivalent dose was similar in the two groups. Adverse events occurred with similar frequencies, but slightly more often with fosphenytoin (phenytoin 9.1%, fosphenytoin 16%). The most common events were pruritus, pain on infusion, and paresthesia. Only one patient developed hypotension, with fosphenytoin. Thus, this study has not demonstrated obvious advantages of fosphenytoin. Cardiovascular Fosphenytoin-induced QT interval prolongation has been reported (71A ). • A 23-year-old man was given intravenous fosphenytoin (equivalent to phenytoin 1500 mg or 20.5 mg/kg) over 85 minutes. He was normocalcemic before the infusion. During the infusion he had prolongation of the QT interval and reductions in the concentrations of total and ionized

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serum calcium. Plasma phenytoin concentrations were within the target range during the electrocardiographic changes, and the blood pressure was stable.

Fosphenytoin is metabolized by phosphatases to yield phenytoin plus inorganic phosphate. Binding of calcium by phosphate could have lowered the serum concentration of ionized calcium. Nervous system Five patients with Down syndrome and dementia, aged 44–67 years, taking phenytoin had progressive cognitive decline (72A ). This resolved once the drug was withdrawn. Cognitive decline was not related to high serum concentrations. Older patients with Down syndrome might be especially sensitive to the effects of phenytoin. Skin Subacute cutaneous lupus erythematosus has been reported in a patient taking phenytoin (73A ). • A 73-year-old woman who had taken phenytoin for 5 years developed erythematous, macular, annular lesions over her upper chest, back, and arms. She was also taking propafenone and nifedipine. Routine hematology and biochemistry were normal, except for leukopenia and a raised gammaglutamyltranspeptidase. There were no antinuclear antibodies, but antibodies against Ro, La, and histone proteins were detectable. A skin biopsy was consistent with subacute cutaneous lupus erythematosus. She was given topical steroids, and all medications, apart from phenytoin, were withdrawn. However, as her eruption persisted, the phenytoin was tapered and withdrawn. Her rash cleared within 6 months. Over the next year there was no photosensitivity or recurrence, but Ro and La antibodies remained positive.

Interpretation of this report is confounded by the presence of concomitant treatments and the lack of quick resolution of the symptoms on phenytoin withdrawal. Furthermore, the autoantibodies did not normalize at 6 months. Drug interactions The interaction of losartan with phenytoin has been studied in a randomized, crossover study in 16 healthy volunteers (74C ). Losartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9mediated conversion of losartan to its active metabolite, thus potentially reducing its efﬁcacy.

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Chapter 7

Isradipine, an inhibitor of CYP450, provoked phenytoin intoxication in one patient (75A ).

Remacemide

(SEDA-25, 91)

In a double-blind, randomized study of remacemide in 262 patients with partial seizures there was a trend for efﬁcacy, but not signiﬁcantly different from placebo (76C ). The most frequent adverse events were headache, fatigue, dizziness, diplopia, and somnolence. There were no signiﬁcant changes in vital signs, electrocardiograms, or biochemistry. In another double-blind, placebo-controlled study in patients with refractory epilepsy undergoing in-patient video-electroencephalographic monitoring, the pattern of adverse events was similar (77C ).

Tiagabine

(SED-14, 190; SEDA-24, 91; SEDA-25, 92; SEDA-26, 77)

Nervous system A few more cases of nonconvulsive status epilepticus associated with tiagabine have been reported (78A , 79Ar , 80A ). Drug overdose Tiagabine overdose (1 g) was associated with convulsive status epilepticus in a 39-year-old man, previously well controlled (81A ). The tiagabine plasma concentration was 2620 ng/ml, over ten times higher than the concentrations found in trials.

Topiramate

(SED-14; 191; SEDA-23, 90; SEDA-24, 92; SEDA-25, 780)

Nervous system Reversible hemiparesis occurred in a boy taking topiramate (82A ). • A 5.5-year-old boy with partial motor seizures secondary to heterotopic gray matter in the atrium of the left lateral ventricle and postictal Todd’s paresis was given topiramate in addition to baseline valproate and carbamazepine, and became seizure-free for 6 months. However, he then started to have a new type of seizures, characterized as complex partial. The dosage of topiramate was

81 increased and carbamazepine was withdrawn. He then had a change in behavior, clumsiness, and persistent right hemiparesis. Electroencephalography showed continuous independent left and right centrotemporal epileptiform discharges. There were no changes on an MRI scan. Topiramate was withdrawn and ethosuximide was added. He become seizure-free and his hemiparesis resolved after 1 month. The electroencephalogram improved remarkably.

It is very difﬁcult to ﬁnd a causal relation between topiramate and this patient’s hemiparesis. An alternative interpretation is that he had complex partial status (as suggested by his electroencephalogram) when carbamazepine was withdrawn, associated with reversible hemiparesis. Psychiatric Two adult patients with refractory partial seizures without a previous history of psychosis had an acute psychotic episode with hallucinations and psychomotor agitation after taking topiramate 200–300 mg/day (10A ). Metabolism Metabolic acidosis developed in eight of nine infants and toddlers aged 5 months to 2.3 years, weights 8.2–26 (median 11) kg, taking topiramate (83A ). Five patients were taking other antiepileptic drugs. The metabolic acidosis developed early in treatment (after 8– 26 days). Four of the nine children had hyperventilation. This study suggests that metabolic acidosis may not be rare in young children taking topiramate, although is often asymptomatic. However, the very rapid titration and high doses used make it difﬁcult to generalize the data. In a retrospective chart review, weight loss has been assessed in 214 patients with psychiatric disorders taking topiramate (84c ). Patients taking either lithium or valproate gained a mean (SD) of 6.3 (9.0) kg and 6.4 (9.0) kg respectively, whereas patients taking topiramate lost 1.2 (6.3) kg. Similar statistically signiﬁcant results were found in the bone mass index. Pregnancy/lactation The concentrations of topiramate have been measured in plasma and breast milk in ﬁve women with epilepsy during pregnancy and lactation (85A ). The umbilical cord plasma/maternal plasma ratios were close to unity, suggesting extensive transplacental transfer of topiramate. The mean milk/maternal plasma concentration ratio was 0.86 (range 0.67–1.1) at 2–3 weeks after delivery. The

82 milk/maternal plasma concentration ratios at sampling 1 and 3 months after delivery were similar. Two of the breastfed infants had detectable (>0.9 μmol/l) concentrations of topiramate 2–3 weeks after delivery, although they were below the limit of quantiﬁcation (2.8 μmol/l), and one had an undetectable concentration. Thus, breast-fed infants had very low topiramate concentrations. No adverse effects were observed in the infants. Drug interactions In 12 patients taking phenytoin monotherapy, topiramate 400–800 mg/ day was added progressively; after stabilization phenytoin was tapered and withdrawn (86c ). Although there were no changes in phenytoin serum concentrations in nine patients, in three of them the peak phenytoin plasma concentrations increased (from 60 to 84 μmol/l, from 112 to 144 μmol/l, and from 108 to 164 μmol/l). Human liver microsomal studies showed that topiramate partially inhibits CYP2C19 at very high concentrations (about 5–15 times higher than the recommended dose). Topiramate clearance was about two-fold higher during coadministration of phenytoin. Three children taking valproate developed hyperammonemia after topiramate was added (87A ). Ammonia was normalized after topiramate was reduced or withdrawn. Thus, topiramate could potentially enhance the risk of hyperammonemia in patients taking valproate. The authors did not discuss the mechanism of this purported interaction.

Valproate sodium and semisodium (SED-14, 182; SEDA-24, 93; SEDA-25, 95; SEDA-26, 80) Endocrine The endocrine consequences of valproate or carbamazepine monotherapy have been evaluated in a cross-sectional study in two groups of women with epilepsy, who were treated for at least 2 years with valproate (n = 52) or carbamazepine monotherapy (n = 53) (88c ). Menstrual disturbances were reported by 29 of the women, 12 of those taking valproate and 17 of those taking carbamazepine. Polycystic ovaries were found in 28 patients, of whom 13 were taking valproate and 15

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carbamazepine. Postprandial concentrations of insulin, C-peptide, and proinsulin were signiﬁcantly higher with valproate than carbamazepine, but there were no differences in the fasting state. In conclusion, this study did not show an increase in the frequency of polycystic ovaries in valproate-treated women, although valproate does appear to increase glucosestimulated pancreatic insulin secretion. Metabolic Valproate-induced hyperammonemic encephalopathy has been reviewed (89R ). Proton magnetic resonance spectroscopy was performed in a patient with valproate-induced hyperammonemic encephalopathy; there was a signiﬁcant fall in the choline and myoinositol resonances and an increase in glutamine in the hyperintense basal ganglia lesions (90A ). A similar pattern has been observed in other hyperammonemic encephalopathies, such as hepatic encephalopathy. In another study in seven patients with valproate-related hyperammonemia serum or cerebrospinal ﬂuid glutamine concentrations were initially raised in most patients, sometimes in the absence of hyperammonemia (91A ). In a prospective cohort study of the role of insulin and leptin (a signal factor that regulates body weight and energy expenditure) in valproate-related obesity, 81 patients with epilepsy taking valproate and 51 healthy controls were analysed (92c ). Mean serum insulin concentrations were signiﬁcantly higher in the valproate-treated patients than in the controls, despite similar body mass indexes. Furthermore, serum insulin concentrations were significantly higher both in lean men and lean women compared with lean controls of same sex and similar body mass indexes. This implies that the hyperinsulinemia seen in obese people taking valproate is not merely a consequence of insulin resistance induced by weight gain. Serum leptin concentrations did not differ between the valproate-treated patients and the controls. Thus, both obese and lean patients taking valproate have hyperinsulinemia, suggesting insulin resistance. This may be one of the factors that leads to weight gain during valproate treatment. Similar ﬁndings, i.e. increased insulin concentrations without changes in leptin concentrations, have also been published in three other reports from one center (88c , 93c , 94c ).

Antiepileptic drugs

83

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Nutrition Chronic valproate treatment did not change serum concentrations of lipids, vitamin B12 , or folic acid in 26 children with epilepsy (95c ).

ﬂuctuation during the dosage interval, with divalproex DR.

Pancreas A review of valproate-induced pancreatitis has been published (96R ). The author discouraged routine checking of amylase activity in the absence of other clinical signs and symptoms.

Vigabatrin

Urinary tract A child with developmental delay and epilepsy developed glycosuria about 16 months after starting to take valproic acid (97A ). Laboratory evaluation showed global defects in proximal tubule function, consistent with the De Toni–Debré–Fanconi syndrome. The authors reviewed the literature on this rare complication, which is reversible on valproate withdrawal. Drug formulations Extended-release (ER) divalproex (valproate semisodium) is not bioequivalent to delayed-release (DR) divalproex. In a randomized, crossover study in 36 healthy volunteers the bioequivalence of divalproex ER once a day and divalproex DR at 14% and 20% lower daily doses given twice a day were compared (98C ). The two formulations gave equivalent exposure (AUC) with lower peak and higher trough concentrations, i.e. less

(SED-14, 192; SEDA-24, 94; SEDA-25, 98; SEDA-26, 82)

Sensory systems There have been several further reports of visual ﬁeld deﬁcits in patients taking vigabatrin (99c –105c ). For a review see last year’s Annual (SEDA-26, 82). The prevalence of visual ﬁeld constriction associated with vigabatrin has been evaluated in 91 children aged 5.6–18 years (106c ). There were visual ﬁeld defects in 17, but there was wide intrasubject variation between successive test sessions, and children often performed better in later test sessions, making evaluation difﬁcult.

Zonisamide

(SED-14, 193; SEDA-25, 100; SEDA-26, 84) Lactation Zonisamide concentrations in plasma and breast milk were measured, in order to investigate the transfer of zonisamide through the placenta and breast milk in two neonates (107A ). The transfer rates were 92% via the placenta and 41–57% via breast milk.

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104. Besch D, Kurtenbach A, Apfelstedt-Sylla E, Sadowski B, Dennig D, Asenbauer C, Zrenner E, Schiefer U. Visual ﬁeld constriction and electrophysiological changes associated with vigabatrin. Doc Ophthalmol 2002; 104: 151–70. 105. Arndt CF, Salle M, Derambure PH, DefoortDhellemmes S, Hache JC. The effect on vision of associated treatments in patients taking vigabatrin: carbamazepine versus valproate. Epilepsia 2002; 43: 812–17. 106. Vanhatalo S, Nousiainen I, Eriksson K, Rantala H, Vainionpaa L, Mustonen K, Aarimaa T,

87 Alen R, Aine MR, Byring R, Hirvasniemi A, Nuutila A, Walden T, Ritanen-Mohammed UM, Karttunen-Lewandowski P, Pohjola LM, Kaksonen S, Jurvelin P, Granstrom ML. Visual ﬁeld constriction in 91 Finnish children treated with vigabatrin. Epilepsia 2002; 43: 748–56. 107. Kawada K, Itoh S, Kusaka T, Isobe K, Ishii M. Pharmacokinetics of zonisamide in perinatal period. Brain Dev 2002; 24: 95–7.

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8

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Sexual function Although long-term administration of low-dose opioids, especially intrathecally, improves quality of life through improved pain control, it may compromise it by causing impaired sexual function. Low testosterone concentrations have been reported in heroin addicts (1c ) and subjects in a methadone maintenance program (2c ). A prospective non-randomized non-blinded evaluation of the effects of a 12-week course of intrathecal opioids for the control of chronic non-cancer pain on the hypothalamic–pituitary– gonadal axis in 12 men has conﬁrmed what was known from animal studies and retrospective human studies: the hypothalamic–pituitary– gonadal axis was suppressed and serum testosterone concentrations fell (3c ). This effect not only reduces quality of life through sexual dysfunction but can also increase the risk of spinal osteoporosis in men, with an increased risk of vertebral and hip fractures. Patients receiving long-term intrathecal opioid therapy need to be informed of potential hypothalamic–pituitary– gonadal axis suppression as a result of the treatment, and testosterone replacement after hypothalamic–pituitary–gonadal axis surveillance during treatment should be considered if indicated.

OPIOID RECEPTOR AGONISTS Alfentanil (SED-14, 211; SEDA-24, 104; SEDA-25, 110; SEDA-26, 89) In a non-comparative study of 24 consecutive out-patients undergoing extracorporeal © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

88

shock-wave lithotripsy, alfentanil (initial dose 15 μg/kg followed by 0.38 μg/kg/min) and propofol (initial dose 1 mg/kg followed by 59 μg/kg/min) were used for sedation (4c ). Both alfentanil and propofol were effective and safe, provided respiratory and cardiovascular parameters were routinely monitored.

Dextromethorphan (SED-14, 212; SEDA-24, 104; SEDA-25, 111; SEDA-26, 90) In a double-blind, placebo-controlled, crossover pilot study in three patients with cancer-associated post-amputation phantom limb pain, oral dextromethorphan 60–90 mg bd or placebo were given for 1 week each, followed by dextromethorphan or placebo again (5c ). Dextromethorphan satisfactorily improved phantom limb pain at a dosage of 60 mg bd in two patients and 90 mg bd in the third. Even though a relatively high total dose of dextromethorphan was used, there were no adverse effects. There have been two randomized placebocontrolled, double-blind trials in 19 patients with painful diabetic neuropathy and 17 with postherpetic neuralgia (6C ). In the ﬁrst trial dextromethorphan was compared with memantine and/or lorazepam. Among the patients with diabetic neuropathy, dextromethorphan (median dose 400 mg/day) reduced pain intensity by a mean of 33% from baseline; memantine reduced pain by a mean of 17% and lorazepam by 16%, showing no signiﬁcant difference to placebo. Among the patients with postherpetic neuralgia, dextromethorphan (median dose 400 mg/day) reduced pain intensity by a mean of 6.5%, which was not different from the effects of memantine and lorazepam. In the second trial the 10 patients with diabetic neuropathy who had responded to dextromethorphan shared a signiﬁcant dose-response effect

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89

on pain intensity; the highest dose was signiﬁcantly better than that of lorazepam. The median dose was 520 (range 240–920) mg/day. The adverse effects proﬁles were uneventful. These results conﬁrm the long-term safety of high-dose dextromethorphan for selected patients with painful diabetic neuropathy (7M ).

vomiting, and pruritus occurred relatively infrequently, with no differences between the groups; sedation was more frequent with fentanyl.

Dextropropoxyphene

• A 53-year-old man with a 7-year history of heroin abuse presented with confused speech and unsteady gait (11A ). A CT scan showed low attenuation in the white matter tracts and an MRI scan showed increased signal intensity in the white matter tracts extending from the centrum semiovale, corpus callosum, corona radiata, posterior limbs of the internal capsules, cerebral and cerebellar peduncles, and pyramidal tracts, suggestive of spongiform demyelination. He became bedbound and tetraplegic and died of a chest infection. • A 47-year-old woman with a history of depression and amphetamine misuse started smoking heroin in order to “lift her spirits” (12A ). She became increasingly drowsy, confused, panicky, and paranoid. She was initially given chlorpromazine, doxepin, and diazepam, but remained disoriented in time and place and became very restless. She had an unsteady gait, slurred speech, and non-purposeful movements. A CT brain scan was normal. She became increasingly ataxic and incontinent, with increased tone in both arms and legs, cogwheel rigidity, and truncal ataxia. An MRI scan showed diffuse high-intensity signals in both cerebral hemispheres. Heroin pyrolase syndrome with Parkinsonism and global cognitive impairment was diagnosed, and she was given coenzyme Q 30 mg tds. She subsequently became independently mobile and continent but without improvement in cognition.

(SED-14, 212;

SEDA-24, 104; SEDA-25, 112) Liver Dextropropoxyphene has been implicated in hepatic injury in four patients taking co-proxamol (dextropropoxyphene plus paracetamol) (8A ). The cases were recorded at the Regional Centre of Pharmacovigilence in St Etienne, France between 1985 and 2000 and were similar to 29 cases published in the international literature between 1971 and 1994. The risk factors identiﬁed in the conﬁrmed cases included age over 50 years, female sex, and a history of excessive alcohol consumption or previous pathology that might have caused liver damage. Drug withdrawal produced good outcomes.

Diamorphine (heroin)

(SED-14, 214; SEDA-24, 105; SEDA-25, 112; SEDA-26, 91) In a randomized, double-blind study, 64 patients undergoing total knee arthroplasty received either intrathecal morphine 0.3 mg or intrathecal diamorphine, 0.3 mg in 0.3 ml, with 2–2.5 ml of 0.5% heavy spinal bupivacaine (9C ). The patients given morphine had significantly greater analgesia at 4, 8, and 12 hours postoperatively. The incidence of opioid-related adverse effects was not signiﬁcantly different between the groups. In a single-blind, randomized, controlled study, 70 patients scheduled for elective cesarian section under spinal anesthesia using hyperbaric bupivacaine 0.5% received intrathecal fentanyl 20 μg, intrathecal diamorphine 300 μg, or 0.9% saline (10C ). Signiﬁcantly less intraoperative and postoperative “analgesic control” was required in the opioid groups, especially in those given diamorphine. Diamorphine produced longer-lasting analgesia than fentanyl (12 hours vs 1 hour). Nausea,

Nervous system The inhalation of contaminated heroin vapor can cause a leukoencephalopathy.

Intravenous administration of pure heroin did not cause a leukoencephalopathy in a patient in whom inhalation had caused it (13A ), and toxicity in these cases may have been due to the heating of the heroin. This might have implications for young heroin users who, because of the known increased risk of HIV infection, prefer to “chase” (smoke) the drug, rather than to inject it intravenously. • A 23-year-old pregnant woman at 39 weeks gestation developed tonic–clonic seizures and hypothermia after taking excessive heroin intravenously (14A ). She developed Cheyne-Stokes respiration needing intubation and a cesarian section was performed, after which she developed inappropriate secretion of antidiuretic hormone and acute renal insufﬁciency. She made a complete recovery.

90 Drug overdose Risk factors associated with non-fatal heroin overdose have been identiﬁed in 2556 subjects treated for heroin dependence in 164 out-patient facilities in Spain (15C ). The frequency of non-fatal overdose was 10%. The risk of overdose increased as the frequency of heroin injection increased. Other signiﬁcant risk factors included combined use of tranquillizers, alcohol, and/or cocaine, and being HIV-positive. Being a non-daily injector significantly increased the risk of non-fatal episodes of overdose.

Fentanyl (SED-14, 213; SEDA-24, 105; SEDA-25, 113; SEDA-26, 92) The use of a continuous epidural infusion of lidocaine 0.4% plus fentanyl 1 μg/ml in combination with intravenous metamizol 40 mg/kg provided signiﬁcantly better analgesia than epidural morphine 20 μg/kg plus intravenous metamizol 40 mg/kg during the ﬁrst 3 postoperative days in 30 children undergoing orthopedic surgery, without increasing the incidence of adverse effects; however, the difference in beneﬁcial effect was small (16c ). Prophylactic nalbuphine 4 mg and droperidol 0.625 mg with minidose lidocaine–fentanyl spinal anesthesia in a randomized, doubleblinded, controlled study in 62 patients having out-patient knee arthroscopy provided signiﬁcantly better analgesia and reduced nausea and pruritus compared with 62 patients who received only nalbuphine 4 mg with minidose lidocaine + fentanyl spinal anesthesia (17c ). Prophylactic intravenous ondansetron 8 mg with hyperbaric bupivacaine 7–10 mg and fentanyl 25 μg signiﬁcantly reduced the incidence of intrathecal fentanyl-induced pruritus in 125 patients undergoing knee arthroscopy or urological surgery in a randomized, double-blind, placebo-controlled trial (18c ). The incidence of pruritus was 39% with ondansetron and 68% with placebo. Pregnancy The efﬁcacy of intrathecal fentanyl and sufentanil for labor analgesia has been studied in 75 nulliparous women in a two-part comparison (19c ). In the ﬁrst phase, 20 subjects received varying doses of fentanyl; the ED50

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of intrathecal fentanyl for 60 minutes of labor analgesia was 18 μg, with a potency ratio of intrathecal sufentanil to intrathecal fentanyl of 4.4. In the second phase, 55 subjects participated in a double-blind, randomized comparison of the efﬁcacy and safety of either intrathecal fentanyl 36 μg or sufentanil 8 μg. Sufentanil gave 25 minutes longer analgesia than fentanyl. There were no signiﬁcant differences in adverse effects between the two groups: 83% had pruritus and 27% of those given sufentanil and 10% of those given fentanyl group had nausea. In a randomized, double-blind, placebocontrolled study of whether patient-controlled epidural fentanyl could produce effective and safe postoperative analgesia following 25 μg of spinal fentanyl at cesarian section in 36 patients, the fentanyl group used a mean of 23 μg/hour of fentanyl compared with 27 μg/hour in the control group (20c ). There was pruritus in 15 patients given fentanyl compared with one control; nine given fentanyl had mild or moderate drowsiness during the operation compared with eight controls. Postoperative nausea, pruritus, and drowsiness did not differ between the two groups. In a randomized, controlled trial, 52 patients in labor were randomly given either intrathecal fentanyl 25 μg with saline or fentanyl 25 μg with magnesium sulfate 50 mg as part of a combined spinal–epidural technique (21C ). The incidence of pruritus with fentanyl alone was 65%, signiﬁcantly lower than with fentanyl plus magnesium sulfate (77%). However, fentanyl plus magnesium sulfate produced signiﬁcantly better and longer-lasting pain control, potentially reducing postoperative opioid requirements. Drug administration route Transdermal fentanyl has been extensively reviewed in patients with chronic cancer pain (22M ). The long-term use of transdermal fentanyl in patients with chronic non-cancer pain (back pain, leg pain, arthritic pain, trigeminal neuralgia, and intestinal cystitis), which is controversial, has been discussed (23A ). Transdermal fentanyl was effective and safe and improved quality of life and independent living. However, these case reports were collected by authors closely associated with the company that manufactures transdermal fentanyl patches; a degree of case selectivity and bias might have occurred.

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In a prospective study, 64 patients with a recent history of at least one vertebral fracture caused by primary and secondary osteoporosis were recruited from six osteoporosis centers in Germany between December 1999 and April 2001 (24c ). Transdermal fentanyl 25 μg/hour was the recommended starting dose, with incremental steps of 25 μg/hour if there was insufﬁcient analgesia. Treatment was stopped after less than 28 days in 15 patients (23%). In 10 of these fentanyl was stopped because of nausea and/or vomiting and/or dizziness. In 49 patients, pain at rest (55% reduction) and on motion (47% reduction) abated signiﬁcantly from baseline. The starting dose of 25 μg/hour of fentanyl was sufﬁcient in most patients (70%). The use of transdermal fentanyl in 113 patients with undertreated chronic cancer pain was studied in a non-randomized, uncontrolled, open study for 42 days (25c ). The mean dose of fentanyl increased from 25 μg/hour to 117 μg/hour between the start and end of the study. By day 3, six patients reported sleepiness and two reported dizziness; ﬁve reported nausea and two had vomiting, and by days 21–42 four of the 100 patients who completed the study had severe nausea and vomiting. Non-compliance was not related to the adverse effects of fentanyl, but to insufﬁcient pain control (nine patients) and/or death (three patients). Oral transmucosal fentanyl citrate has two advantages: it is more acceptable as a ﬂavored lozenge than an oral elixir or tablet would be, especially in children, and 25% goes directly into the systemic circulation without ﬁrst-pass metabolism. Its main adverse effect is dosedependent nausea and/or vomiting, which occurs in 25–50% of patients. In a double-blind, placebo-controlled comparison of oral transmucosal fentanyl citrate (10 μg/kg) and oral oxycodone (0.2 mg/kg) in out-patient wound care procedures in 22 children there were similar outcomes and no adverse effects in either group (26c ). Drug overdose Accidental overdose can be caused by fentanyl patches. • A 71-year-old woman was found unconscious, with reduced respiration and miotic pupils, having previously had nausea, dizziness, and drowsiness (27A ). She had inappropriately applied a fentanyl patch 100 μg/hour a day before the symptoms occurred. She recovered fully after treatment with intravenous naloxone 0.4 mg.

Hydrocodone

(SEDA-24, 106;

SEDA-25, 115) Ear, nose, and throat Five patients who abused prescribed opioids intranasally have been described (28A ). All took hydrocodone bitartate plus cocaine (n = 2), codeine phosphate (n = 2), oxycodone hydrochloride (n = 2), or methadone hydrochloride (n = 1). The symptoms included nasal obstruction and congestion, foul smelling nasal crusting and discharge, headaches and nasal pain, and in one case dysphagia with odynophagia. Physical ﬁndings included a perforated septum, soft palate erosion, and a mucopurulent exudate. All except one patient had positive fungal cultures and two had invasive rhinitis. Not only can intranasal opioids cause septal perforation, commonly associated with intranasal cocaine, but it is also possible that intranasal abuse of opioids, especially hydrocodone, can cause localized immunosuppression, supporting the growth of fungal organisms.

Methadone

(SED-14, 214; SEDA-24, 106; SEDA-25, 115; SEDA-26, 94) Cardiovascular In a retrospective case study in methadone maintenance treatment programs in the USA and a pain management center in Canada, 17 methadone-treated patients developed torsade de pointes during 5 years (29c ). The dose of methadone was 65–1000 mg/day. Six patients had had an increase in methadone dose in the months just before the onset of torsade de pointes. One patient had taken nelﬁnavir, a potent inhibitor of CYP3A4, begun just before the development of torsade de pointes. The above two risk factors (increased drug dosage and drug interactions) are important when eliciting the cause of torsade de pointes in patients taking methadone.

Death In a retrospective study of cases from the Jefferson County Coroner/Medical Examiners Ofﬁce, Alabama, USA between January 1982 and December 2000 there were 101 deaths in patients in whom methadone was detected in the blood (30c ). Methadone was the sole intoxicant in 15 cases, with a mean concentration of 0.27 mg/l. A benzodiazepine was

92 the most frequently detected co-intoxicant in 60 of the 101 cases and the only co-intoxicant in another 30 cases. In 26 cases methadone had been taken with a range of non-benzodiazepine substances, including antidepressants, antipsychotic drugs, antiepileptic drugs, and cocaine. The high incidence of benzodiazepine–methadone related deaths can be explained by synergistic respiratory depression. Higher concentrations of methadone can occur with chronic abuse of methadone plus benzodiazepines, because over time benzodiazepines inhibit the hepatic enzymes that metabolize methadone. This might explain why the mean methadone concentration in the 30 deaths attributed to methadone plus a benzodiazepine was only 0.6 mg/l. Fetotoxicity A newborn girl born of an HIVpositive mother who took antiretroviral drugs and methadone during pregnancy developed a methadone abstinence syndrome at day 7 (31A ). She was HIV-negative and was treated symptomatically for 15 days with chlorpromazine. The platelet count was 1049 × 109 /l on day 17 and fell progressively to 290 × 109 /l at 8 weeks. The authors suggested that the thrombocytosis had been secondary to intrauterine methadone exposure. Drug dosage regimens The role of opioid rotation in cancer pain management has been described, highlighting the limitations of equianalgesic tablets and the need for monitoring and individualization of dose. This is particularly important when methadone is used as the opioid for conversion. The authors referred to a greater than expected potency of methadone, with excessive sedation and opioid related adverse effects, if the switch is done on a one-toone basis. They suggested that the calculated equianalgesic dose of methadone should be reduced by 75–90% and the dose then titrated upwards if necessary (32A , 33r ). Drug administration route Of 90 patients undergoing abdominal or lower limb surgery randomly assigned double-blind to two groups, 60 received racemic methadone in initial doses of 3–6 mg followed by 6–12 mg by continuous infusion over 24 hours, and 30 received repeated boluses of 3–6 mg every 8 hours (34c ). In both groups the highest visual analogue score

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occurred 2 hours after surgery. From then on the pain diminished gradually and signiﬁcantly at each recording. Opioid-related adverse effects were not different between the two groups, except for miosis, which was signiﬁcantly more common in the bolus group. The results suggested that both epidural methadone protocols used in this study provide effective and safe postoperative analgesia. However, the infusion method should be preferred, as the doses of methadone can be reduced after the ﬁrst day of treatment. Drug interactions Paroxetine 20 mg/day, a selective CYP2D6 inhibitor, was given for 12 days to 10 patients on methadone maintenance (35c ). Eight were genotyped as CYP2D6 homozygous extensive metabolizers and two as poor metabolizers. Paroxetine increased the steady-state concentrations of R-methadone and S-methadone, especially in the extensive metabolizers.

Morphine

(SED-14, 215; SEDA-24, 107; SEDA-25, 115; SEDA-26, 97) The practical administration of morphine has been reviewed in relation to dose (initial dose with titration and rescue), formulations (indication and costs), routes of administration, and adverse effects (36M ).

Death A 14-year-old boy with infectious mononucleosis was given intravenous morphine 10 mg for pain relief with good effect, but 2 hours later was found unresponsive, lying on his back, and not breathing (37A ). An autopsy showed marked bilateral tonsillar enlargement with considerable narrowing of the upper airway. The blood morphine concentration was 0.08 mg/l. The coroner concluded that the morphine had contributed to respiratory compromise and death. Susceptibility factors Genetic Morphine6-glucuronide (glucuromorphine) is an active metabolite of morphine. Accumulation of glucuromorphine is a risk factor for opioid toxicity during morphine treatment. However, it does not occur in all patients with renal insufﬁciency,

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Chapter 8

which is the most common reason for glucuromorphine accumulation; this suggests that other risk factors can contribute to glucuromorphine toxicity. • Two men, aged 87 and 65 years, both with renal insufﬁciency, took oral morphine 30 mg/day for pain management (38A ). While the 65-year-old tolerated morphine well despite a high plasma glucuromorphine concentration of 1735 nmol/l, the 87-year-old had severe sleepiness and drowsiness, even though the plasma glucuromorphine concentration was only 941 nmol/l.

The patients were screened for genetic polymorphisms in the OPRM1-gene (coding for μ-opioid receptors), P glycoprotein, and other candidate genes that code for transporters that may play an important role in determining the central nervous system concentration of morphine or glucuromorphine. The 65-year-old patient was a homozygous carrier of the mutated G118 allele of the μ-opioid receptor gene, which has previously been related to reduced glucuromorphine potency (a protector gene). In contrast, the 87-year-old patient was a homozygous carrier of the wild-type allele A118. This observation implies that a single nucleotide polymorphism, the G118 allele, has a protective effect against glucuromorphine toxicity. Age Morphine, as an intravenous bolus of 2 or 3 mg every 5 minutes until pain relief or adverse effects occurred, was given to 875 patients who were under 70 years old and 175 patients who were over 70 years old in a prospective, uncontrolled, non-blinded study (39c ). The total dose of morphine was not signiﬁcantly different between the groups. There was no signiﬁcant difference in the incidence of morphine-related adverse effects, the number of sedated patients, and the number of patients in whom dose titration had to be stopped. The results only applied to the immediate and short-term postoperative periods and the patients studied had a variety of surgical procedures unrelated to age. The results suggested that intravenous morphine can be safely given to elderly patients using the same protocol that is used in younger ones. The generalizability of this study is limited because the sample size was small. Of 44 children undergoing major genitourinary or lower abdominal surgery in a randomized, single-blind study, 24 were given morphine 0.1 mg/kg epidurally and 20 were given

93

the same dose intravenously immediately after intubation (40c ). Postoperatively PCA boluses were administered to both groups. Both techniques provided sufﬁcient pain relief. Of the children given epidural morphine one required treatment for pruritus and seven vomited more than once, compared to none in those given intravenous morphine. Drug administration route The systemic availability of morphine from an aerosol is low (about 10%). A nasal solution containing morphine and chitosan, a linear polysaccharide, has been tested in a pilot study in healthy volunteers and patients with cancer (41c ). The formulation was well tolerated and could be a useful delivery system for morphine. In a double-blind, randomized, uncontrolled study in 150 women to compare intrathecal morphine 100 μg plus ketoprofen, intrathecal morphine 200 μg, or epidural morphine 3 mg, postoperative nausea or vomiting occurred in 16%, 28%, and 26% respectively (42c ). The incidence of itching was least in those given intrathecal morphine 100 μg. The results were unequivocal and did not justify preferring any one of the techniques as better or safer. In a double-blind randomized study in 60 patients undergoing elective knee arthroscopy, direct intrasynovial injection of morphine 1 mg provided better long-term analgesia (12–24 hours) than intra-articular morphine 1 mg, with no adverse effects (43c ).

Oxycodone

(SED-14, 216; SEDA-24, 107; SEDA-25, 116; SEDA-26, 99)

Drug formulation In a systematic review of the safety and efﬁcacy of modiﬁed-release oxycodone 16 trials were identiﬁed; seven addressed the safety and efﬁcacy of oxycodone for the treatment of non-cancer pain (44M ). In these studies modiﬁed-release oxycodone offered no signiﬁcant advantage over immediate-release oxycodone. There was no consistent beneﬁcial effect on quality of life, despite adequate analgesia. Opioid adverse effects, such as constipation, nausea, vomiting, and drowsiness, were more frequent and severe with oxycodone than with placebo. In six studies, modiﬁed-release

94 oxycodone was compared with immediaterelease oxycodone in cancer and non-cancer pain. In only one study was modiﬁed-release oxycodone superior; in the other ﬁve there were no signiﬁcant differences in analgesic effect. In ﬁve randomized, double-blind comparisons there was no advantage in analgesic efﬁcacy nor a consistent reduction in adverse effects with modiﬁed-release oxycodone compared with modiﬁed-release morphine, hydromorphone, or methadone.

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Fetotoxicity Pethidine 50 mg plus promethazine 25 mg given intravenously to 14 mothers in labor caused a signiﬁcant change in fetal heart rate indices 40 minutes after administration (48c ). There were signiﬁcant changes in fetal heart rate acceleration of at least 10 beats/minute, acceleration of at least 15 beats/minute, time spent in episodes of high variation, and short-term variation.

Remifentanil

(SED-14, 217; SEDA-24, 108; SEDA-25, 118; SEDA-26, 99)

Pethidine (meperidine) (SED-14, 217; SEDA-24, 107; SEDA-25, 117; SEDA-26, 99) In a double-blind, randomized, placebo-controlled study 40 patients who were scheduled for elective cesarian section under spinal anesthesia were given intrathecal 0.5% hyperbaric bupivacaine 2 ml together with either 5% pethidine 0.2 ml or isotonic saline (45C ). The pethidine group had a signiﬁcantly greater incidence of intraoperative nausea or vomiting, with signiﬁcantly better immediate postoperative analgesia, which was not sustained 4 hours after surgery. In a randomized, controlled study in 611 mothers, 310 were randomized to intramuscular pethidine up to 300 mg and 301 to epidural 0.25% bupivacaine 10 ml with an infusion of 0.125–0.25% bupivacaine (46C ). There were no signiﬁcant differences in analgesic efﬁcacy, adverse effects, or the incidence of backaches. Nervous system In a retrospective survey of 355 medical records of patients who received intravenous PCA pethidine between 1988 and 1994 the mean consumption by patients who had used over 600 mg/day of pethidine was 13.3 mg/kg/day in asymptomatic patients and 16.9 mg/kg/day in the 2% of patients who presented with central nervous system excitatory signs and symptoms (muscle twitches, jitteriness, agitation, and hallucinations) (47R ). The authors recommended a maximum safe dose of pethidine by PCA of 10 mg/kg/day for no more than 3 days.

The respiratory depressant and gastrointestinal adverse effects of remifentanil have again been observed in two randomized, single-blind studies. In the ﬁrst study, 125 patients undergoing elective orthopedic and urological surgery under spinal or brachial plexus anesthesia were randomized to either remifentanil (a bolus of 0.5 μg/kg plus an infusion of 0.1 μg/kg/min) or propofol (a bolus of 500 μg/kg plus an infusion of 50 μg/kg/min) (49c ). Owing to a signiﬁcantly higher rate of respiratory depression with remifentanil (46%) than with propofol (19%), the mean remifentanil infusion rate was reduced to 0.078 ± 0.028 μg/kg/min. The incidence of intraoperative nausea and vomiting with remifentanil was 27% compared with 2% with propofol. Postoperatively there was no signiﬁcant difference in the incidence of gastrointestinal symptoms. Remifentanil may be considered as an alternative if propofol is contraindicated (e.g. because of amnesic episodes). In the second study 60 patients receiving cervical plexus block during carotid endarterectomy were given either remifentanil 3 μg/kg/hour or propofol 1 mg/kg/hour (50c ). There was a higher incidence of adverse respiratory effects with remifentanil and a similar sedative effect. The authors suggested that when using remifentanil for sedation in patients undergoing carotid endarterectomy, the initial dose of remifentanil should be reduced to 1.5– 2 μg/kg/hour to minimize cardiovascular and respiratory adverse effects. In two randomized, double-blind, controlled comparisons of anesthetic techniques for extracorporeal shock wave lithotripsy remifentanil infusion had no advantage over the combination

Opioid analgesics and narcotic antagonists

Chapter 8

of fentanyl bolus plus propofol infusion, but caused more adverse effects (nausea and vomiting) (51c ). In another study remifentanil infusion provided comparable analgesia and caused less respiratory depression and fewer gastrointestinal symptoms than intravenous boluses of sufentanil (52c ). Cardiovascular There has been an increasing number of reports of remifentanil-induced bradycardia and asystole, but this may be useful as a protective effect in patients with atrial ﬁbrillation (53A ). • A 90-year-old woman with atrial ﬁbrillation was given digoxin for 3 days before surgery for a pelvic mass. Following anesthesia induced with thiopental and atracurium, her heart rate rose to 105 beats/minute and her electrocardiogram showed fast atrial ﬁbrillation and ST segment depression. She was given remifentanil 0.25 μg/kg/ min and her heart rate fell to 95 beats/minute.

Death A nurse was found dead at home with a syringe and empty vials of remifentanil (2 mg) and midazolam (1 mg/ml); toxicological studies showed that she had not been a chronic user of remifentanil (54A ). Pregnancy In a dose-ﬁnding study in 17 healthy pregnant women in the ﬁrst stage of labor the PCA bolus of remifentanil was increased from 0.2 μg/kg in 0.2 μg/kg increments during 60 minutes until analgesia was considered adequate (55c ). The median effective dose of remifentanil was 0.4 (range 0.2–0.8) μg/kg and consumption was 0.066 (range 0.027– 0.207) μg/kg/min. All the women reported slight sedation; ﬁve had slight to moderate nausea throughout the study. Supplementary oxygen 2 l/min via nasal cannula was given to three women who had repeated episodes of oxygen desaturation. Two women reported difﬁculties in reading and visual focusing and one woman had difﬁculty in swallowing towards the end of remifentanil administration. In ﬁve cases there were changes in fetal heart rate indices within 30 minutes of the ﬁrst dose. The neonates had Apgar scores of 8–10. The authors concluded that remifentanil is a potentially effective obstetric analgesic but that adverse effects will limit its use. A similar observation was made in an open pilot study in 36 women randomized during

95

the early stages of labor to either intramuscular pethidine 100 mg or remifentanil given as patient-controlled analgesia (20 μg bolus over 20 seconds) (56c ). Remifentanil provided better pain relief but a higher risk of lower oxygen saturation compared with pethidine. Remifentanil was given only a cautious welcome by the authors, owing to its respiratory depressant effects. Drug interactions In eight subjects the concentration of remifentanil was signiﬁcantly increased when therapeutic concentrations of propofol were present in the body (57c ). The combination of propofol and remifentanil can cause cardiovascular depression. As with other opioids, remifentanil competes with propofol for hydrophobic binding in the lungs and heart.

Sufentanil

(SED-14, 217; SEDA-24, 109; SEDA-25, 188; SEDA-26, 101)

In 41 patients undergoing abdominal hysterectomy randomly allocated in a double-blind, controlled study to sufentanil 50 μg for 8– 16 hours via a lumbar epidural catheter before or at the end of surgery (58c ) the pre-emptive group (n = 20) used less sufentanil compared with the control group (n = 21). The frequency of adverse effects was similar in the two groups; nine patients in the pre-emptive group and ten in the control group complained of nausea or vomiting and four patients in the pre-emptive group and ﬁve patients in the control group complained of mild pruritus. Respiratory Respiratory arrest has been attributed to sufentanil (59A ). • A healthy 22-year-old woman at 41 weeks gestation presented for urgent cesarian section following fetal heart rate deceleration. She was given sufentanil 10 μg plus 0.1% bupivacaine 10 mg intrathecally and 8 minutes later became unrousable and apneic. After 3 minutes spontaneous ventilation resumed.

The authors suggested that giving the local anesthesia ﬁrst and then the sufentanil later might have contributed to this presentation of spontaneous reversal of short-lived early-onset respiratory arrest.

96 Drug interactions In a randomized, doubleblind, controlled study the addition of adrenaline (100 μg/ml) signiﬁcantly reduced the incidence of sedation and light-headedness after epidural sufentanil (40 μg) in 43 women who received epidural analgesia during early labor (60c ). However, adrenaline did not help in preventing maternal oxygen desaturation.

Tramadol

(SED-14, 218; SEDA-24, 109; SEDA-25, 119; SEDA-26, 102)

Tramadol produces a similar analgesic effect to pethidine and is about one-tenth as potent as morphine. The use of tramadol for postoperative analgesia by intravenous patient-controlled analgesia (PCA) has gained popularity, mostly because it is less likely to cause sedation and respiratory depression (61c ). However, it is associated with nausea, vomiting, dry mouth, and sweating. The addition of droperidol to tramadol PCA reduces the incidence of gastrointestinal symptoms without signiﬁcantly increasing sedation (62c ). In a double-blind, randomized study 40 patients undergoing coronary artery bypass grafting and/or valve replacement surgery were given droperidol 0.1 mg/ml plus either tramadol 10 mg/ml or morphine 1 mg/ml. The results in the two groups were comparable in efﬁcacy, adverse effects proﬁles, and dose requirements, and the authors argued that there may be no advantage in using tramadol rather than morphine in conjunction with droperidol (63c ). In another double-blind, randomized, controlled study, the addition of a tramadol infusion to morphine for PCA in 69 patients undergoing elective abdominal surgery resulted in improved analgesic efﬁcacy and reduced morphine requirements, with a relative lack of adverse effects (64c ). In a randomized, placebocontrolled study the addition of an intravenous bolus of dexamethasone 150 μg/kg with a PCA system programmed to deliver tramadol 20 mg in a 1 ml solution on demand in 50 patients after major abdominal surgery signiﬁcantly reduced the incidence of nausea, vomiting, and subsequent administration of rescue antiemetic therapy (65c ). In a similar study in 66 patients the addition of magnesium sulfate 30 mg/ml or ketamine 1 mg/ml to PCA tramadol both

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A.H. Ghodse and A.M. Baldacchino

signiﬁcantly reduced the consumption of tramadol at 6, 12, and 24 hours postoperatively, with no differences in the incidence of nausea and sedation (66c ). Diplopia was reported by two patients in the tramadol/ketamine group (n = 22). In a recent review of the use of tramadol in musculoskeletal pain the authors concluded that tramadol can be used at Step 2 of the analgesic ladder, recent publications having conﬁrmed its efﬁcacy, alone or in conjunction with NSAIDs, in the management of chronic musculoskeletal pain without increasing the frequency of adverse effects (67M , 68C ). Tramadol has been used in the treatment of shivering after anesthesia. In one study 150 patients scheduled for general anesthesia and surgery were randomly allocated to intravenous tramadol 1 or 2 mg/kg or 0.9% saline given at the time of wound closure (69C ). The authors concluded that both doses of tramadol were effective and safe. Of the patients in the higher-dose group, 2% had shivering, compared with 4% in the lower-dose group and 48% in the control group. In a similar study in 96 patients the optimal dose of tramadol in preventing shivering after anesthesia was 0.5–1 mg/kg intravenously (70c ). Drug interactions Serotonin syndrome occurred in an 88-year-old woman who took sertraline 50–100 mg/day and tramadol 200–400 mg/day for 10 days; the symptoms subsided 15 days after withdrawal of tramadol (71A ). In a randomized, controlled study of postoperative PCA using tramadol with or without ondansetron in 59 patients undergoing ear, nose, and throat surgery, ondansetron reduced the overall analgesic effect of tramadol, increased the doses of tramadol needed in the ﬁrst 12 hours after surgery. This increase in tramadol requirements in those given ondansetron resulted in a signiﬁcantly higher vomiting scores at 4 and 8 hours postoperatively and an overall increase in the number of episodes of vomiting, despite the use of ondansetron (72C ).

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Chapter 8

PARTIAL OPIOID RECEPTOR AGONISTS Buprenorphine

(SED-14, 220; SEDA-24, 110; SEDA-25, 120; SEDA-26, 104)

Drug tolerance The effects of buprenorphine (sublingually or by injection) in an opioiddependent population have been studied again (73c , 74c ). In both studies there was beneﬁt in using buprenorphine to counteract opioid withdrawal effects in patients with chronic heroin use and subsequent dependence. However, the results are limited and the beneﬁts short-term if psychosocial support is not in place as part of an overall treatment package before buprenorphine is prescribed (75C ). • A 35-year-old man with a 10-year history of heroin use was given sublingual buprenorphine 24 mg/day (76A ). Although it was dispensed daily by a pharmacist, he was not adequately supervised: he collected the buprenorphine and continued to use heroin. He then decided to take buprenorphine 40 mg and stopped using heroin; he immediately developed opioid withdrawal symptoms. In an attempt to relieve these symptoms, he took a further two doses of buprenorphine 24 mg in 24 hours. He subsequently came to a drug treatment clinic, where he was given another 16 mg of buprenorphine, with no effect. After 3 days, having taken in all 106 mg of sublingual buprenorphine, he was transferred to methadone and his withdrawal symptoms resolved.

In this case buprenorphine precipitated opioid withdrawal symptoms after heroin use. This highlights the importance of regular monitoring and supervision of community-dispensed buprenorphine. Drug formulations A transdermal therapeutic system (TTS) for rate-controlled delivery of buprenorphine is now available in three strengths, with release rates of 35, 52.5, and 70 μg/hour for 72 hours. This is equivalent to daily doses of 0.8, 1.2, and 1.6 mg respectively. In a double-blind, randomized, controlled study using one of three dosage strengths of buprenorphine TTS in 445 patients with chronic pain the adverse effects were mild and typical of the opioid analgesics; they included nausea (17%), vomiting (9.3%), dizziness (6.8%), tiredness (5.6%), constipation (5.3%), and sweating (3.7%) (77c ). There was

erythema in 25% and pruritus in 22%. More than half of the cases of erythema and onethird of the cases of pruritus resolved within 24 hours. In a single-blind, randomized study sublingual buprenorphine 0.2 mg provided an effective and convenient alternative in the treatment of acute renal colic compared with pethidine 50 mg intramuscularly (78c ). There was a slightly but non-signiﬁcantly higher incidence of nausea, vomiting, and dizziness in those given buprenorphine.

OPIOID RECEPTOR ANTAGONISTS Naloxone

(SED-13, 179; SEDA-26, 104)

In a randomized, double-blind study in 40 patients with moderate to severe acute traumatic brain injury, intravenous naloxone, 0.3–4.8 mg/kg/day for 10 days, reduced morbidity and mortality (79c ). Drug administration route The authors of two review papers both concluded that there is no evidence that subcutaneous or intramuscular administration of naloxone is less effective in restoring respiration in patients with opioid overdose than the intravenous route (80R , 81R ).

Naltrexone

(SED-14, 200; SEDA-24, 111; SEDA-25, 121; SEDA-26, 104) The Health Technology Board of Scotland has concluded that in people with alcohol dependence naltrexone reduces drinking (82M ). In a multicenter, double-blind, placebo-controlled, 12-week study of naltrexone 50 mg/day in 202 patients with alcohol dependence naltrexone was well tolerated, with few adverse effects: abdominal pain (8.6%), headache (7.5%), nausea (6.5%), and dizziness (5.4%); there were no changes in liver function tests (83c ). However, those who took naltrexone did not have signiﬁcant improvements in drinking history or fewer relapses.

98 Psychiatric In studies of its use in treating alcohol, opioid, and nicotine dependence, naltrexone has not been reported to cause depression or dysphoria. Patients who complain of naltrexone-associated dysphoria often have co-morbid depressive disorders or depression resulting from opioid or alcohol withdrawal states (84M ). Co-morbid depression is not a contraindication to naltrexone. Small pilot studies have supported the use of naltrexone in combination with antidepressants for the treatment of patients with co-morbid depression. The risk of non-fatal overdose is signiﬁcantly increased after naltrexone treatment, as a result of reduced tolerance, compared with patients taking substitution methadone (85M ). Drug administration route Six cases of complications loosely related to the use of naltrexone pellet implantation during the highly controversial rapid and ultra-rapid opioid detoxiﬁcation procedures have been reported (86A ). These included pulmonary edema, prolonged opioid withdrawal states, drug toxicity, withdrawal from cross-dependence to alcohol and

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benzodiazepines, aspiration pneumonia, and death. The risk of these controversial procedures and of naltrexone in this novel delivery system are high; a robust scientiﬁcally validated program of research is needed to justify such treatment packages.

MISCELLANEOUS COMPOUNDS Nefopam

(SEDA-26, 106)

Drug abuse Three cases of nefopam abuse have been reported (87A ). The patients had the same pattern of a history of chronic pain, concomitant anxiolytic and antidepressant drug therapy, and abuse of nefopam due to its primarily psychostimulant-like symptoms. The recommended dose of nefopam is 20 mg intramuscularly every 6 hours, with a maximum recommended dose of 120 mg/day. Daily consumption in the three patients was 120–1840 mg/day.

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A. Del Favero

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Anti-inﬂammatory and antipyretic analgesics and drugs used in gout

The effects of NSAIDs on blood pressure NSAIDs can adversely affect cardiovascular function in many ways (SEDA-22, 107; SEDA24, 120). In particular they can cause or aggravate hypertension and interact negatively with the effects of antihypertensive drugs, including diuretics, although contrasting data from experimental and clinical studies have been published (1R ). This problem is clinically relevant, since hypertension is common and is a major determinant of cardiovascular diseases, while NSAIDs are among the most commonly prescribed drugs world wide. Consequently any potential drug– drug and drug–disease interactions should be carefully evaluated. Two meta-analyses and two prospective studies deserve attention. The ﬁrst meta-analysis (2M ) was performed to determine the hypertensive effects of NSAIDs or aspirin (1.5 g/day or greater) in shortterm intervention studies; 54 studies and 123 NSAID treatment arms were included. Of the 1324 participating subjects, 92% were hypertensive; they had a mean age of 46 years and none was over 65 years. The major outcome studied was the change in mean arterial pressure. The effects of NSAIDs on blood pressure were found solely in hypertensive subjects; among these, the increase in mean arterial pressure, after adjusting for possible confounders (e.g. dietary salt intake) was different among different NSAIDs. The increase in mean arterial pressure was 3.59 mmHg for indomethacin © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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(57 treatment arms), 3.74 mmHg for naproxen (four arms), and 0.45 mmHg for piroxicam (four arms). However, mean arterial pressure fell by 2.59 mmHg with placebo (10 arms), by 0.83 mmHg with ibuprofen (6 arms), 1.76 mmHg with aspirin (four arms), and 0.16 mmHg with sulindac (23 arms). Overall, only the effects of indomethacin on mean arterial pressure were statistically signiﬁcantly different from those found with placebo, showing that in this population the effects of NSAIDs on blood pressure were modest and varied considerably among different drugs. However, one must take into account the important limitations of the analysis: the patients were mostly young, the studies included in the meta-analysis were small and short-term, and information on possible confounders was incomplete. The signiﬁcance of the results of this study is therefore doubtful. The second meta-analysis provided more complete and useful results (3M ). Its primary aim was to produce an estimate of the overall effect of NSAIDs on blood pressure, and its secondary aims were to evaluate the mechanisms by which NSAIDs alter blood pressure and to determine susceptibility factors. Moreover, as NSAIDs have been associated with raised blood pressure in normotensive individuals and in both treated and untreated hypertensive subjects, the authors tried to discover different effects in these subgroups. Finally, they studied whether different NSAIDs alter blood pressure to the same degree. In all, 50 randomized placebo-controlled trials and 16 randomized comparisons of two or more NSAIDs met the selection criteria. These studies included 771 young volunteers or patients aged 47 years or younger. The studies were small (the mean sample size per trial

Anti-inﬂammatory and antipyretic analgesics and drugs used in gout

was 16); many different NSAIDs and antihypertensive drugs were used, but indomethacin was used in more than half of all the trials; the duration of therapy with NSAIDs or antihypertensive drugs was 1 week or longer, but in most studies it was less than 3 months. NSAIDs raised supine mean blood pressure by 5.0 mmHg (95% CI = 1.2, 8.7), but had no signiﬁcant effect on variables measured to assess possible mechanisms (such as body weight, daily urinary sodium output, creatinine clearance, or urinary prostaglandin excretion). Overall, the data suggested that NSAIDs do not appear to increase blood pressure primarily by increasing salt and water retention, because weight and urinary sodium were not altered by NSAIDs and inhibition of blood pressure control was not more marked in patients taking diuretics compared with other antihypertensive drugs. In addition NSAIDs did not signiﬁcantly alter plasma renin activity or 24-hour urinary excretion of prostaglandin E2 and 6-ketoprostaglandin F1α. Other factors may therefore contribute to the increase in blood pressure caused by NSAIDs. In particular, a potential effect of NSAIDs on peripheral vascular resistance should be considered (4c , 5c ). There is good evidence to suggest an important role for prostaglandins in the modulation of two major determinants of blood pressure, vasoconstriction of arteriolar smooth muscle and control of extracellular volume. NSAIDs inhibited the effects of all antihypertensive drug categories. However, in patients taking beta-blockers and vasodilators, NSAIDs produced a greater increase in supine mean blood pressure than in patients taking diuretics, but only the pooled inhibitory effect of NSAIDs on the effects of beta-blockers achieved statistical signiﬁcance. When the data were analysed by type of NSAID the meta-analysis showed that all NSAIDs increased supine blood pressure, and that piroxicam, indomethacin, and ibuprofen produced the most marked increases. However, only piroxicam had a statistically signiﬁcant effect with respect to placebo. Aspirin, sulindac, and ﬂurbiprofen caused the smallest increases in blood pressure. In conclusion this meta-analysis has provided more clear evidence that, as a group, NSAIDs signiﬁcantly increase arterial pressure and can antagonize the blood pressurelowering effect of some antihypertensive drugs,

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by mechanisms that are still unclear. Although the hypertensive effect of NSAIDs was more marked in hypertensive subjects taking antihypertensive drugs than in normotensive subjects not taking antihypertensive drugs, the difference was not statistically signiﬁcant and its clinical relevance is unclear. It is worth noting that the effects of NSAIDs on blood pressure were similar in patients taking antihypertensive drugs for months or only a few days. This study also had two main limitations: ﬁrst, most of the trials were small, which precluded deﬁnitive conclusions about the effects of individual NSAIDs or individual antihypertensive drug classes; secondly, in most studies therapy was short-term and the patients were relatively young, making generalization of the results difﬁcult, as NSAIDs are most often prescribed long-term and for elderly people. Useful additional data have come from two prospective clinical studies. The ﬁrst was a case–control study of the effects of NSAID therapy on arterial pressure in subjects aged 65 years and over, drawn from a large database (the State of New England Medicaid Program) (6C ). To determine whether NSAIDs affect blood pressure the investigators calculated the odds ratio (OR) for the initiation of antihypertensive therapy in patients taking NSAIDs relative to non-users after adjusting for possible confounding factors. The 9411 patients had started taking antihypertensive drugs between 1981 and 1990, and a similar number of controls were randomly selected. The date of the ﬁrst prescription for an antihypertensive drug was deﬁned as the index date. Of those who took antihypertensive drugs, 41% had taken an NSAID during the year before the index date, compared with 26% of the control subjects. This risk increased with the recency of NSAID therapy, and was greatest among recent users (those with a supply of NSAIDs ending less than 60 days before the index date) (OR = 2.10; 95% CI = 1.95, 2.26). For former users (those with a supply of NSAIDs ending more than 60 days before the index date) the adjusted OR compared with non-users was 1.66 (1.54, 1.80). There was a dose–response relation, with adjusted ORs of 1.55 (1.38, 1.74), 1.64 (1.44, 1.87), and 1.82 (1.62, 2.05) for low, medium, and high daily doses of NSAIDs respectively. The unadjusted ORs for ibuprofen, piroxicam,

104 meclofenamate, and indomethacin, were separately calculable, and for each of these drugs the OR increased with increasing dose. The relation between cumulative duration of NSAID use and the initiation of antihypertensive therapy was also examined in recent users. The risk was greatest in those who had used an NSAID for 30–90 days and was less for those who had used an NSAID for less than 30 days or for more than 90 days. The results of this study suggest that the effects of NSAIDs on blood pressure in older patients taking NSAIDs may be clinically important. Given that 15% of the control group were recent users of NSAIDs, and assuming that the adjusted OR of 1.66 represents a causal association of these drugs with the initiation of antihypertensive therapy, the proportion of cases attributable to the use of these drugs in this sample of elderly population was nearly one in ten. Despite the high prevalence of the use of minor analgesics (aspirin and paracetamol) there is little information available on the association between the use of these analgesics and the risk of hypertension. A recent prospective cohort study in 80 020 women aged 31–50 years has provided some useful information (7C ). The women had participated in the Nurses’ Health Study II and had no previous history of hypertension. The frequency of use of paracetamol, aspirin, and NSAIDs was collected by mailed questionnaires. and cases of physiciandiagnosed hypertension were identiﬁed by selfreport. During 164 000 person-years of followup, 1650 incident cases of hypertension were identiﬁed. Overall 73% of the cohort had used paracetamol at least 1–4 days/month, 51% had used aspirin, and 77% had used an NSAID. Compared with non-users of paracetamol the age-adjusted relative risk (RR) of hypertension was signiﬁcantly increased even in women who had used paracetamol for only 1–4 days/month (RR = 1.22; 1.07, 1.39). There seemed to be a dose–response relation, as the RR of hypertension compared with non-users was 2.00 (1.52, 2.62) in women who had taken paracetamol for 29 days/month or more. For women using aspirin or NSAIDs at a frequency of 1–4 days/month the RRs were 1.18 (1.02, 1.35) and 1.17 (1.02, 1.36) respectively. However, after adjusting for age and other potential risk factors only paracetamol and

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NSAIDs, but not aspirin, remained signiﬁcantly associated with a risk of hypertension. In summary, the data from this study support the view that paracetamol and NSAIDs are strongly associated with an increased risk of hypertension in women, the risk increasing with increasing frequency of use. Aspirin did not seem to be associated with an increased risk. This conclusion contrasts with the results of some short-term studies that have shown no effect of paracetamol on blood pressure (8C , 9C ). However, the results from this study must be interpreted with caution, as there were some limitations: the assessments of analgesic use and hypertension were made using a selfreported questionnaire; relative risk can be inﬂuenced by many potentially confounding variables; the results are relevant only for young women and cannot be extrapolated to the general population. Conclusions The overall results of the abovementioned studies have provided convincing evidence that NSAIDs and paracetamol can raise arterial blood pressure in a dose-related fashion, interfere with the actions of antihypertensive drugs, and prompt the need for new antihypertensive therapy. Even if the increase in mean blood pressure is probably modest (less than 5.0 mmHg) the clinical relevance of such an increase can be large, especially in elderly people. In fact, an overview of randomized clinical trials of antihypertensive treatment has shown that a 5–6 mmHg increase in diastolic blood pressure over a few years can be associated with a 67% increase in the incidence of strokes and a 15% increase is coronary heart disease (10R ). These effects are apparent in both normotensive and hypertensive patients. Whether these results apply with certainty to patients taking NSAIDs is not known, because these studies included patients not taking NSAIDs, but it is wise to consider this probability. The type and dose of NSAID may be important, but more studies are needed to document this. Hypertensive and elderly patients seem to be particularly at risk. In patients taking long-term NSAIDs, or even paracetamol, periodic monitoring of blood pressure appears to be warranted. These considerations apply also to the COX-2 selective NSAIDs (SEDA-26, 116).

Anti-inﬂammatory and antipyretic analgesics and drugs used in gout

Has Helicobacter pylori a role in upper gastrointestinal damage associated with non steroidal anti-inﬂammatory drugs? Helicobacter pylori and non-steroidal antiinﬂammatory drugs (NSAIDs) account for nearly all gastroduodenal ulcers and serious ulcer complications, but the interaction between infection with Helicobacter pylori and the use of NSAIDs in the pathogenesis of NSAID-induced gastropathy is matter of controversy. In fact, studies that have examined these two susceptibility factors have yielded conﬂicting results about whether Helicobacter pylori infection increases the risk of toxicity in NSAID users, has no effect, or even is protective (11R , 12r , 13r ). Since this topic was reviewed 10 years ago (SEDA-16, 103; SEDA-17, 105) a large amount of information has accumulated and merits further attention. The pathophysiological mechanisms Among possible common pathophysiological mechanisms of importance are those that compromise the effectiveness of the gastroduodenal mucus– bicarbonate barrier, those that cause recruitment and activation of neutrophils, and those that can interfere with the process of mucosal adaptation (11R ). Both NSAIDs and aspirin can reduce the effectiveness of mucosal defences, by inhibiting gastroduodenal prostaglandin synthesis and by reducing mucosal blood ﬂow (14E ). On the other hand Helicobacter pylori infection can damage the mucus–bicarbonate barrier, by increasing gastric acid secretion and reducing the viscosity of gastric mucus (15E ). Contrasting data have been reported on the effect of Helicobacter pylori on mucosal blood ﬂow (16c , 17c ) and on mucosal prostaglandin production. However, although Helicobacter pylori increases mucosal prostaglandin synthesis, the combination of Helicobacter pylori with NSAIDs or aspirin causes a marked fall in mucosal prostaglandin synthesis, showing that the stimulatory effect of prostaglandin production by Helicobacter pylori is insigniﬁcant in the presence of NSAIDs or aspirin (17c , 18C ). Gastric ulceration induced by NSAIDs is a neutrophil-dependent process (19E ) and the association of Helicobacter pylori infection with

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neutrophil inﬁltration has also been well documented. Gastric injury by NSAIDs is minimal in neutropenic animals, and the cumulative incidence of peptic ulcers in long term NSAID users is increased in the presence of neutrophil inﬁltration in the mucosa of patients who are Helicobacter pylori positive, suggesting a possible link between NSAIDs and Helicobacter pylori in the pathogenesis of peptic ulcers (20c , 21c ). The ability of the gastroduodenal mucosa to adapt to repeated exposure to NSAIDs and aspirin is well documented, and recent reports have shown the possible involvement of Helicobacter pylori in this process (17c , 22c ). In one endoscopic study in volunteers, mucosal adaptation to naproxen after 4 weeks of treatment occurred in 53% of Helicobacter pyloripositive subjects and in 81% in Helicobacter pylori-negative subjects (23C ). Similar results were found in another study in volunteers who took aspirin for 2 weeks; mucosal adaptation to the injury caused by aspirin was clearly impaired in the presence of Helicobacter pylori and was restored after Helicobacter pylori eradication (24c ). In summary, NSAIDs and Helicobacter pylori can causing adverse effects on gastroduodenal mucosal protective mechanisms in different ways, and so the interaction between these two susceptibility factors might allow damage to occur more readily when NSAIDs are taken in the presence of Helicobacter pylori infection. However, despite this experimental evidence, the interaction between Helicobacter pylori infection and use of NSAIDs in the pathogenesis of peptic ulcers and their complications is still unclear from clinical studies. Clinical studies Most of the early studies of the interaction between Helicobacter pylori infection and the use of NSAIDs were based on observational studies in long-term NSAID users and gave conﬂicting results (25c –33c ). In some studies there were signiﬁcantly more ulcers in NSAID users who were Helicobacter pylori-positive then in users who were not infected (25c –27c ). However, these ﬁndings were not conﬁrmed by other investigators (28c –31c ), and they probably reﬂect a complex relation between Helicobacter pylori infection and NSAID-associated gastropathy as well as heterogeneity of methods across studies.

106 For example, differences in population studied (e.g. the type of NSAID exposure, the age of the patient) and even in the deﬁnition of ulcer at endoscopy make direct comparison of results difﬁcult. Most of the few published prospective trials did not show that Helicobacter pylori is a susceptibility factor for NSAIDinduced gastroduodenal damage (34C –37C ), and two long-term longitudinal studies (38C , 39C ) gave conﬂicting results, although the data have mostly been derived from studies in small numbers of young healthy volunteers at very low risk of gastropathy, and the results must therefore be treated with great caution. Thus, despite numerous studies we do not have convincing evidence for or against a link between Helicobacter pylori and NSAIDs in the development of peptic ulcers. A recent meta-analysis has helped to clarify this issue (40M ). The aim was to assess the presence and magnitude of any possible interaction in peptic ulcer disease between these two susceptibility factors, with particular attention to bleeding peptic ulcer disease, the sites of ulceration, and the effect of Helicobacter pylori eradication. In all, 61 relevant studies were identiﬁed, 36 of which were excluded for various reasons. Thus, 25 studies were left for analysis, of which 16 observational studies (8 crosssectional studies, 7 case–control studies, and 1 cohort study) provided data on the prevalence of peptic ulcer disease in 1633 NSAID users, with data on Helicobacter pylori status for 1625 patients. The pooled frequency of peptic ulcer disease in NSAID users was 42% in those who were Helicobacter pylori-positive and 25% in those who were Helicobacter pylori-negative (OR = 2.12; 95% CI = 1.68, 2.67). The frequencies of uncomplicated peptic ulcer disease in NSAID users and non-users were compared in eight case–control studies; however, the NSAID users and controls were not matched by age in three studies and so, because Helicobacter pylori infection is age-dependent, the prevalence of infection was analysed in only ﬁve studies. Overall Helicobacter pylori infection was diagnosed in 47% of the NSAID users and 46% of the controls, but peptic ulcer disease was signiﬁcantly more common in the NSAID users (36% vs 8.3%; OR = 5.14; CI = 1.35, 20). Compared with patients who were Helicobacter pylori-negative and were not

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taking NSAIDs, the risk of ulcer in Helicobacter pylori-infected NSAID users was very high (OR = 61; CI = 10, 373). Helicobacter pylori infection increased the risk of peptic ulcer disease in NSAID users 3.53 times in addition to the risk associated with NSAID use (OR = 19). Similarly, in the presence of a risk of peptic ulcer disease associated with Helicobacter pylori infection (OR = 18) the use of NSAIDs increased the risk of peptic ulcer disease 3.55 times. Helicobacter pylori infection and NSAID use respectively increased the risk of ulcer bleeding 1.79 times and 4.85 times; the risk of ulcer bleeding increased to 6.13 when both factors were present. From these data we can conclude that both Helicobacter pylori infection and NSAID use independently and signiﬁcantly increase the risk of peptic ulcer and ulcer bleeding and that there is synergism in the development of peptic ulcer and ulcer bleeding between Helicobacter pylori infection and NSAID use. The meta-analysis also showed that onethird of patients taking long-term NSAIDs have gastric or duodenal ulcers, irrespective of Helicobacter pylori status and study design. However, peptic ulcer disease was signiﬁcantly more common in Helicobacter pylori-infected NSAID users than in non-infected users, suggesting a possible interaction between NSAID use and Helicobacter pylori infection for the development of peptic ulcers. Moreover, the meta-analysis clariﬁed another uncertainty: whether in NSAID takers Helicobacter pylori infection is as important a risk factor for gastric ulcer as it is for duodenal ulcer. A pooled analysis of four studies (41C –44C ) showed that Helicobacter pylori infection is less closely associated with gastric ulcer than with duodenal ulcer in both NSAID users and non-users, and that while NSAID use has a major role in the development of gastric ulcer, duodenal ulcer is more closely related to Helicobacter pylori infection. Further convincing evidence for the existence of a possible interaction between Helicobacter pylori and NSAIDs in the pathogenesis of ulcer has been obtained by investigating the effects of Helicobacter pylori eradication on the occurrence of NSAID-related ulcers and their complications (e.g. bleeding), although some divergent ﬁndings have been reported from these studies (45C , 46C ).

Anti-inﬂammatory and antipyretic analgesics and drugs used in gout

In a prospective randomized trial of the effect of eradication of Helicobacter pylori before the start of NSAID therapy on the subsequent risk of ulcer occurrence, patients who required new NSAID treatment and who had Helicobacter pylori infection but no pre-existing ulcers on baseline endoscopy were recruited (45C ). Of these patients 100 were randomly allocated to naproxen for 8 weeks, either alone or preceded by a 1-week course of Helicobacter pylori eradication. Endoscopy was repeated after 8 weeks or if naproxen was withdrawn early because of adverse effects. The primary end-point of the study was the cumulative rate of gastric and duodenal endoscopic ulcers. At 8 weeks Helicobacter pylori was eradicated in 40 patients (89%) who took eradication therapy and in none of those who had no pretreatment. Twelve (26%) of those who had no eradication therapy developed ulcers compared with three (7%) who had eradication therapy, two of whom had failure of eradication. Thus, only one patient with successful eradication developed ulcers with naproxen. These data suggest that NSAID-induced ulceration can be reduced by eradication of Helicobacter pylori before naproxen administration and suggest that Helicobacter pylori infection is a susceptibility factor for NSAID-induced ulcer disease. In my opinion, determination of Helicobacter pylori infection and eradication in infected patients should be recommended before starting NSAID therapy. However, the data from this study contrasted with those from another randomized controlled trial, the HELP study, in which the effect of Helicobacter pylori eradication was investigated in a different population of 285 patients who had used long-term NSAID therapy, those with current or previous peptic ulcers, or dyspepsia, or both (46C ). The patients were randomly assigned to omeprazole plus 1 week of eradication therapy (n = 142) or to omeprazole plus placebo for 1 week (n = 143). They took omeprazole until their ulcer healed or dyspepsia resolved, after which they continued taking the NSAID, with follow-up assessment of ulcer and dyspepsia at 1, 3, and 6 months. The estimated probabilities of being ulcer-free at 6 months were similar in the two groups: 0.56% (95% CI = 047, 065) with eradication treatment and 0.53 (0.44, 062) with control treatment. Moreover, fewer gastric ulcers healed in

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those who had taken eradication therapy than in the controls (7% vs 100% at 8 weeks). These data suggest that Helicobacter pylori eradication therapy not only did not reduce the rate of development of peptic ulcer or dyspepsia at 6 months, but also led to impaired healing of gastric ulcers. Helicobacter pylori eradication therefore seems not to be justiﬁed. These conﬂicting results can probably be explained by important differences in the characteristics of the patients and the study methods. The inclusion criteria in the two studies were mutually exclusive: patients with longterm NSAID use and a history of ulceration were excluded in the ﬁrst study and included in the second. Furthermore, there were differences in the deﬁnition of endoscopic ulcers, the eradication regimen, the deﬁnition of Helicobacter pylori infection, and the length of follow-up. Data from a more recent eradication study have helped to clarify these uncertainties. The aim of the study was to determine whether among NSAID-naive patients positive for Helicobacter pylori who have dyspepsia or a history of ulcer and who are about to start long-term NSAID treatment, eradication of Helicobacter pylori infection reduces the risk of ulcers (47C ). Bismuth was replaced by omeprazole in the eradication regimen, the observation period was increased to 6 months, and the frequencies of both complicated and symptomless ulcers were assessed. Patients were randomly assigned to omeprazole triple therapy (eradication group, n = 51) or omeprazole with placebo antibiotics (control group, n = 51) for 1 week. All took diclofenac 100 mg/day for 6 months. The 6-month probability of having ulcers was 12% (95% CI = 3.1, 21) in the eradication group and 34% (21, 48) in the placebo group. The 6-month probability of complicated ulcers was 4.2% (1.3, 9.7) in the eradication group and 27% (15, 40) in the placebo group. These statistically signiﬁcant differences suggested that screening and treatment for Helicobacter pylori infection signiﬁcantly reduces the risk of ulceration and bleeding in patients who take long-term NSAIDs. However, these conclusions may not be valid for patients who take low-dose aspirin for prevention of cardiovascular events, as there are data that suggest that Helicobacter pylori increases (48C ), has no effect (49C , 50C ), or even reduces (51C ) the risk of bleeding among users of low-dose aspirin as well

108 as other NSAIDs. This question has been addressed in 400 patients with a history of upper gastrointestinal bleeding who were infected with Helicobacter pylori and who were taking low-dose aspirin (n = 250) or other NSAIDs (n = 150) (52C ). Their ulcers were healed with omeprazole 20 mg/day for 8 weeks. Those who had been taking aspirin were given aspirin 80 mg/day, and those who had been taking other NSAIDs were given naproxen 500 mg bd for 6 months. The patients in each group were then randomly assigned separately to receive omeprazole 20 mg/day for 6 months or 1 week of eradication therapy followed by placebo for 6 months. Among patients taking aspirin the probability of recurrent bleeding during the 6 months was 1.9% for patients who had taken eradication therapy and 0.9% for patients who had taken omeprazole, a non-statistically signiﬁcant difference of 1% (95% CI = −1.9, 3.9). Among users of naproxen the probability of recurrent bleeding was signiﬁcantly greater for patients who had taken eradication therapy (19%) than for those who had taken omeprazole (4.4%). Unfortunately the absolute reduction in the risk of recurrent bleeding attributable to eradication of Helicobacter pylori could not be determined, because a placebo group was not included. This study has therefore shown that in patients infected with Helicobacter pylori who take low-dose aspirin, eradication of Helicobacter pylori is as effective as prophylactic therapy with omeprazole in preventing recurrent upper gastrointestinal bleeding. Therefore, patients taking aspirin for cardiovascular prophylaxis could be tested for Helicobacter pylori infection and treated for it if infection is conﬁrmed. In contrast, omeprazole is superior to eradication of Helicobacter pylori for the secondary prevention of upper gastrointestinal bleeding in Helicobacter pylori-infected users of naproxen and presumably other non-aspirin NSAIDs. Conclusions Whether the eradication of Helicobacter pylori can reduce the risk of ulcers appears to vary according to the characteristics of the patient. For people who have never taken a non-aspirin NSAID, eradication of Helicobacter pylori before NSAID treatment is begun reduces the risk of ulcers (45C ). However, for

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long-term users of non-aspirin NSAIDs, eradication of Helicobacter pylori has not been shown to prevent gastroduodenal injury. Moreover, eradication alone is not sufﬁcient to prevent recurrent bleeding in susceptible long-term users. The divergent outcomes in patients taking aspirin or other NSAIDs suggest that Helicobacter pylori may have a more important role in ulcer bleeding associated with low-dose aspirin than in bleeding associated with other NSAIDs. A possible explanation is that infection with Helicobacter pylori impairs gastric adaptation to aspirin (17c ); eradication restores this capability and increases the mucosal resistance to aspirin. There are several conclusions from these results. First, eradication of Helicobacter pylori is a useful strategy in preventing upper gastrointestinal damage caused by NSAIDs or aspirin in some patients. Secondly, there are doubts about the correct interpretation and generalizability of the results of some relevant studies on the efﬁcacy of omeprazole and misoprostol in the prevention of gastroduodenal ulcer in chronic NSAID users. In fact in these studies, OMNIUM (53C ), ASTRONAUT (54C ), and MUCOSA (55C ), the patients’ Helicobacter pylori status was not considered and may have modiﬁed their outcomes (ulcer recurrence and ulcer healing). Some evidence supporting this hypothesis come from a reanalysis of the data, taking into account the presence or absence of Helicobacter pylori (56R ). The superiority of omeprazole over ranitidine or misoprostol claimed in OMNIUM and ASTRONAUT in preventing NSAID-induced ulcers was markedly affected by Helicobacter pylori status. In a dosage of 40 mg/day, omeprazole was not superior to the full dose of misoprostol in healing unequivocal NSAID-induced gastric ulcers in chronic NSAID users, but it was superior in those whose NSAID use was complicated by Helicobacter pylori infection. Duodenal ulcers were markedly over-represented as a cause of ulcer recurrence in the Helicobacter pylori-infected patients and most of the effect of omeprazole occurred in this population. Therefore, the therapeutic advantages of using omeprazole to prevent recurrent ulcers or their complications in chronic NSAID users may be different in

Anti-inﬂammatory and antipyretic analgesics and drugs used in gout

those with and without Helicobacter pylori infection. We have no data on the possible interaction between Helicobacter pylori status and the ability of COX-2 selective inhibitors to cause gastrointestinal toxicity. However, one would expect that when patients use COX-2 inhibitors Helicobacter pylori infection would remain a source of continuing ulcer risk, requiring eradication. Although there are no trials, this approach is supported by data from the VIGOR study, in which the residual risk of ulcers in patients taking rofecoxib was approximately doubled in Helicobacter pylori-infected compared with non-infected patients (57R ).

INDIVIDUAL DRUGS AND CLASSES Acetylsalicylic acid (aspirin) and related compounds (SED-14, 233; SEDA-24, 121; SEDA-25, 132; SEA-26, 113)

Assessing the beneﬁt–harm balance of low-dose aspirin in preventing strokes and heart attacks Although there is clear evidence of beneﬁt of acetylsalicylic acid (aspirin) in secondary prevention of strokes and heart attacks, the question of whether aspirin should also be prescribed for primary prevention in asymptomatic people is still debatable. Trials in primary prevention have given contrasting results (58C , 59C ), and aspirin can cause major harms (e.g. severe gastrointestinal bleeding and hemorrhagic stroke). Furthermore, despite evidence of the efﬁcacy of aspirin in secondary prevention, its use in patients at high risk of strokes and heart attacks remains suboptimal (60C ). A possible explanation for this underuse may be concern about the relative beneﬁt in relation to the potential risk for serious hemorrhagic events. Accurate evaluation of the beneﬁts and harms of aspirin is therefore warranted. Two recent meta-analyses have provided some information. The ﬁrst examined the beneﬁt and harms of aspirin in subjects without known

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cardiovascular or cerebrovascular disease (primary prevention) (61M ). The authors selected articles published between 1966 and 2000—ﬁve large controlled studies of primary prevention that lasted at least 1 year and nine studies of the effects of aspirin on gastrointestinal bleeding and hemorrhagic stroke. The ﬁve randomized placebo-controlled trials included more than 50 000 patients and the meta-analysis showed that aspirin signiﬁcantly reduced the risk of the combined outcome (conﬁrmed non-fatal myocardial infarction or death from coronary heart disease) (OR = 0.72; 95% CI = 0.60, 0.87). However, aspirin increased the risk of major gastrointestinal bleeding (OR = 1.7; 1.4, 2.1) signiﬁcantly, while the small increase found for hemorrhagic stroke (OR = 1.4; 0.9, 2.0) was not statistically signiﬁcant. All-cause mortality was not signiﬁcantly affected (OR = 0.93; 0.84; 1.02). Most important was the ﬁnding that the net effect of aspirin improved with increasing risk of coronary heart disease. The meta-analysis showed that for 1000 patients with a 5% risk of coronary heart disease events over 5 years, aspirin would prevent 6–20 myocardial infarctions but would cause also 0–2 hemorrhagic strokes and 2–4 major gastrointestinal bleeds. For patients at lower risk (1% over 5 years), aspirin would prevent 1–4 myocardial infarctions but would still cause 0–2 hemorrhagic strokes and 2–4 major gastrointestinal bleeds. Therefore when deciding to use aspirin in primary prophylaxis one should take account of the relative utility of the different outcomes that are prevented or caused by aspirin. The other meta-analysis (62M ) compared the beneﬁts of aspirin in secondary prevention with the risk of gastrointestinal bleeding. An earlier analysis of this problem included patients at various levels of risk and doses of aspirin that would currently be regarded as too high (63C ), and may therefore have either underrepresented the beneﬁt or exaggerated the risk. In another analysis there was no difference in the risk of gastrointestinal bleeding across the whole range of doses used (64M ). The meta-analysis reviewed all randomized, placebo-controlled, secondary prevention trials of at least 3 months duration published from 1970 to 2000. The dosage of aspirin was 50–325 mg/day. Six studies that contributed 6300 patients to the analysis (3127 on aspirin

110 and 3173 on placebo). Aspirin reduced allcause mortality by 18%, the number of strokes by 20%, myocardial infarctions by 30%, and other “vascular events” by 30%. On the other hand, patients who took aspirin were 2.5 times more likely than those who took placebo to have gastrointestinal tract bleeds. The number of patients needed to be treated (NNT) to prevent one death from any cause was 67 and the NNT to cause one gastrointestinal bleeding event was 100. In other words 1.5 lives can be saved for every gastrointestinal bleed attributed to aspirin. Although the risk of gastrointestinal bleeding was increased by aspirin the hemorrhagic events were manageable and led to no deaths. On the basis of these data we can conclude that the beneﬁt–harm balance for low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events is highly favorable. The same conclusions have been drawn from the systematic overview published by the Antithrombotic Trialists Collaboration Group, which analysed data from 287 studies involving 135 000 patients (65M ). As far as primary prevention of cardiovascular events is concerned, it appears that aspirin can reduce heart attacks and strokes but increases gastrointestinal and intracranial bleeding. The decision to use aspirin in primary prevention should therefore take into account the fact that the net effect of aspirin improves with increasing risk of coronary heart disease as well as the values that patients attach to the main favorable and unfavorable outcomes.

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

Paracetamol and combinations Drug overdose Paracetamol is one of the most commonly ingested medications in deliberate self-poisoning and accidental ingestion by children. Its easy availability is reported to be the most common reason for its use in this way (66C ), and so reducing its availability might be an effective strategy. However, unless the availability of other medications is also controlled, the removal of

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one readily available medication, such as paracetamol, could lead to an increase in the use of other compounds with similar or even greater toxicity (e.g. aspirin, ibuprofen). In Australia paracetamol-containing medications were recalled during two periods in 2000, presenting a unique opportunity for a retrospective observational study of the effect of reduced availability of paracetamol on the incidence of deliberate self-poisoning and accidental pediatric poisoning with paracetamol and other over-the-counter analgesics (67C ). During the recall periods there was a signiﬁcant increase in ibuprofen deliberate self-poisoning (RR = 1.86; 95% CI = 1.41, 2.44), while there was no statistically signiﬁcant change in paracetamol and aspirin deliberate self-poisoning. In children there was a signiﬁcant increase in the proportion of ibuprofen accidental poisoning but no signiﬁcant change for aspirin and paracetamol. These results suggest that reduced paracetamol availability increased poisoning with alternative analgesics (in particular ibuprofen) but had little effect on the incidence of paracetamol poisoning. Restriction of paracetamolcontaining medications should be critically reconsidered as an effective strategy for preventing deliberate and accidental poisoning. A 20-hour treatment protocol for acute paracetamol overdose using oral acetylcysteine has been proposed (68C ) and was effective in preventing hepatic injury after an acute overdose of paracetamol when therapy was begun within 8 hours after ingestion. Paracetamol plus dextropropoxyphene, the combination known as co-proxamol, is available as a prescription-only analgesic in many countries. Self-poisoning can be lethal, as respiratory depression can occur from an excessive dose of dextropropoxyphene. In England and Wales co-proxamol alone accounts for 5% of all suicides, and overdose is more likely to result in death than overdose with paracetamol alone or tricyclic antidepressants (69C ). Furthermore, although it is often prescribed it is no more effective than paracetamol for short-term relief of pain. It should not be prescribed without good reason. Drug interactions The thrombin inhibitor argatroban had no effect on the pharmacokinetics of ﬁve oral doses of paracetamol 1 g 6-hourly in

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12 healthy volunteers; the argatroban was given as an intravenous infusion of 1.5 μg/kg/min from hours 12 to 30 (70c ).

PYRAZOLONE DERIVATIVES Dipyrone

(SED-14, 260)

Hematologic The publication of the results of a Swedish study on agranulocytosis related to dipyrone (71C ) stimulated comments and criticisms (72r , 73r ). The study was based on spontaneous reports of serious blood dyscrasias associated with dipyrone and on an analysis of prescription data. The incidence of agranulocytosis was 1 per 1439 prescriptions, a higher estimate than has previously been reported. Despite criticisms about the small number of cases identiﬁed in the study, this result conﬁrms earlier ones (73r ). Furthermore, one must remember that dipyrone is also associated with other blood dyscrasias, serious immune reactions, and severe hypotension.

ARYLALKANOIC ACID DERIVATIVES (SED-14, 268;

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Ibuprofen Drug interactions Treatment with ibuprofen might limit the cardioprotective effects of aspirin, because concomitant administration antagonizes the irreversible platelet inhibition that aspirin causes (SEDA-26, 115). This hypothesis has now been supported in a study of over 7000 patients who were discharged after a ﬁrst admission for cardiovascular disease between 1989 and 1997 and who took lowdose aspirin and survived for at least 1 month (76C ). The adjusted hazard ratios for all-cause mortality (1.93; 95% CI = 1.30, 287) and for cardiovascular mortality (1.73; 1.05, 2.84) were signiﬁcantly raised in patients who took ibuprofen (mean dose 1210 mg/day) in addition to the aspirin. There was no increase in hazard in patients who combined aspirin with diclofenac, which is consistent with the in vitro data. However, this study had many limitations (77r ), and further epidemiological studies are needed to address this potentially important interaction. In the meantime, when patients taking lowdose aspirin for cardioprotection also require long-term treatment with an NSAID, diclofenac would be preferable to ibuprofen.

SELECTIVE COX-2 INHIBITORS (SEDA-25, 122; SEDA-26, 116)

SEDA-24, 122; SEDA-25, 133; SEDA-26, 115)

Amtolmetin Amtolmetin is a pro-drug of tolmetin with claims of better gastric tolerability. A renal sparing effect has now been reported, but clinical experience with this compound is limited (74c ).

Urinary tract The use of NSAIDs to treat and prevent bladder spasms has been documented in clinical trials (78C ) and their role in relaxing bladder smooth muscle has experimental support (79E ). Three elderly patients who used rofecoxib or celecoxib developed acute but reversible urinary retention (80A ). Each had comorbidities likely to cause bladder dysfunction, and the administration of a COX-2 inhibitor may have caused further relaxation of the detrusor muscle, resulting in urinary retention.

Dexibuprofen Nervous system Meningoencephalitis has been attributed to dexibuprofen in a 22-yearold woman with systemic lupus erythematosus (75A ). Patients with systemic lupus erythematosus have increased susceptibility to NSAIDinduced aseptic meningitis or encephalitis.

Celecoxib Cardiovascular There have been reports of celecoxib-associated torsade de pointes in three patients who had never had it before celecoxib administration; the dysrhythmia did not recur

112 after the drug was withdrawn (81A ). However, all three patients had cardiac abnormalities that might have predisposed them to the development of torsade de pointes, and the follow-up period was too short to evaluate possible spontaneous recurrence. The hypothesis that celecoxib is dysrhythmogenic requires conﬁrmation. Urinary tract As more experience accumulates, it appears that selective COX-2 inhibitors can cause the same renal syndromes that nonselective NSAIDs do (82R ). In a recent randomized comparison of celecoxib and diclofenac plus omeprazole, renal adverse events, including hypertension, peripheral edema, and renal insufﬁciency, were common and similar in the two groups (83C ). They occurred in the 24% of the patients who took celecoxib and in 31% of those who took diclofenac plus omeprazole. Among patients with renal impairment at baseline, 51% of those who took celecoxib and 41% of those who took diclofenac plus omeprazole had renal adverse events. Careful monitoring of renal function in patients taking COX-2 inhibitors or traditional NSAIDs is mandatory, especially in high-risk subjects (e.g. those with pre-existing renal disease, diabetes, or heart failure). Celecoxib can induce non-oliguric acute renal insufﬁciency (84A ). • A 43-year-old woman with rheumatoid arthritis developed dizziness having taken celecoxib 200 mg/day for 2 weeks. At the start of treatment she had normal renal function. Her serum creatinine was 670 μmol/l (7.4 mg/dl) and blood urea nitrogen 30 mmol/l (90 mg/dl). Creatinine clearance was 16 ml/min. Urinalysis was normal and casts were not present. Urinary chemical analysis showed a sodium concentration of 18 mmol/l, a fractional excretion of sodium of 0.3, and a renal failure index of 0.493, consistent with prerenal acute renal insufﬁciency. Celecoxib was withdrawn. Although her renal function then improved, her serum creatinine was still abnormal (4.7 mg/dl) 1 month later.

Skin There have been new reports of maculopapular rash (85A ) and severe erythema multiforme (toxic epidermal necrolysis) (86A ) with celecoxib. Immunologic Anaphylaxis due to celecoxib has been described (SEDA 26, 121). Lifethreatening anaphylaxis, with urticaria, angio-

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edema, and bronchospasm, has now been described 30 minutes after a dose of celecoxib for arthritis of the hip (87Ac ). Allergic vasculitis has been reported in association with various NSAIDs, and has recently been attributed to celecoxib (88A , 89A ), including one case with a fatal outcome (90A ). Whether allergic reactions to celecoxib occur more often in patients who report a previous reaction to sulfonamides, and should therefore be contraindicated in such patients, is still unknown (91r ).

Rofecoxib Nervous system Aseptic meningitis is a rare complication of NSAID therapy. Five serious cases of aseptic meningitis associated with rofecoxib have been reported (92A ). • A 55-year-old woman who had taken rofecoxib for 1 month reported numbness and tingling on the left side of the tongue and left hand (93A ). The association between paresthesia and rofecoxib was supported by the time-course of the reaction and resolution after withdrawal. Because she was using other medications (paroxetine, zolpidem, and sumatriptan), which can have a similar effect, this report requires conﬁrmation.

Gastrointestinal Little is known about the effects of COX-2 inhibitors on the colon, although animal evidence suggests that they can worsen or precipitate acute colitis. Now features similar to those seen in cases of ischemic colitis have been reported in a patient taking rofecoxib (94A ). • A 52-year-old woman with a colostomy for a tumor of the sigmoid colon developed low back pain that radiated to the legs. A bone scan showed no evidence of tumor. She was given rofecoxib 25 mg/day and 4 days later noticed bloody diarrhea from the colostomy. At colonoscopy a large portion of the transverse colon was seen to be hemorrhagic, with nodularity, a superﬁcial exudate, and mucosal edema, with a well demarcated transition to normal areas. Despite extensive investigations, no plausible cause of the bloody diarrhea and colitis were found, except the possible involvement of rofecoxib. She stopped taking it and was given intravenous ﬂuids. After 4 days the colostomy stopped oozing blood; colonoscopy showed no evidence of hemorrhage and the mucosa was regenerative. Bleeding did not recur.

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Skin Swelling and wrinkling of the palms soon after exposure to water occurred in an 18-year-old-woman taking rofecoxib for mixed connective tissue disease (95A ). The swelling followed exposure for 1 to a few minutes to water at any temperature. The swelling developed rapidly and was accompanied by symptoms of mild pain and discomfort. Over the following 2 hours, the palms would return to normal. Because of the temporal correlation with the use of rofecoxib, it was withdrawn, and 3 weeks later her symptoms had almost completely resolved. The authors speculated that this phenomenon might have been due to increased salt content of the skin caused by the rofecoxib, resulting in increased water-binding capacity of keratin. Several drugs, including NSAIDs, have been implicated in cases of erythema multiforme, and rofecoxib can be added to the list. Three patients developed erythema multiforme while taking rofecoxib (96A ). All were well documented, and oral rechallenge with rofecoxib, positive in two of them, conﬁrmed the role of rofecoxib in the pathogenesis of this adverse reaction. Immunologic Angio-edema is a recognized adverse effect of rofecoxib (SEDA-26, 121). • A 60-year-old man developed angio-edema after taking two doses of rofecoxib 12.5 mg 18 and 12 hours before (97A ). Despite intensive treatment he developed pulmonary hemorrhagic edema and died a day later. He had ﬁbrotic lung disease, which may have predisposed him to the lethal event.

The tolerability of rofecoxib in patients with cutaneous allergic and pseudo-allergic adverse reactions to non-selective NSAIDs has been conﬁrmed in another study in 139 patients with NSAID-induced adverse reactions: 60 with urticaria alone (43%), 34 with angioedema (25%), 34 with angio-edema plus ur-

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ticaria (2.9%), and two with Stevens–Johnson syndrome (1.4%) (98C ). They all underwent a single-blind, placebo-controlled oral challenge with increasing doses of rofecoxib, and 138 of them tolerated it without adverse reactions. Only one had mild urticaria on the arms. Rofecoxib may be a useful alternative in patients with NSAID hypersensitivity. Drug interactions Rofecoxib did not cause any clinically important changes in ethinylestradiol and norethindrone pharmacokinetics in 18 subjects (99c ). A possible interaction of rofecoxib with lithium has been reported (100A ). • A 73-year-old man with manic-depressive illness, who had taken lithium for 40 years, underwent coronary bypass surgery and was given long-term warfarin. He developed signs of lithium intoxication (confusion, irritability, tremor, and gait disturbance) after having taken rofecoxib 12.5 mg/day for 9 days for arthritis. Rofecoxib had been chosen in order to avoid a possible drug interaction with warfarin. Lithium and rofecoxib were withdrawn and the signs resolved within 1 week. His serum lithium concentration was 1.5 mmol/l and his serum creatinine 1430 μmol/l.

Both lithium and rofecoxib have been associated with nephrotoxicity, and it is likely that lithium intoxication was caused by concomitant administration of rofecoxib, causing a reversible reduction in renal function.

Parecoxib Drug interactions A single perioperative dose of parecoxib did not alter the disposition or the clinical effects of a bolus of propofol (101C ).

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inﬂuencing analgesic poison. Med J Aust 2002; 176: 162–5. 68. Luke Y, Dart RC. A 20-hour treatment for acute acetaminophen overdose. New Engl J Med 2003; 348: 2471–2. 69. Hawton K, Simkin S, Deeks J. Co-proxamol and suicide: a study of national mortality statistics and local non-fatal self poisonings. Br Med J 2003; 326: 1006–8. 70. Inglis AML, Sheth SB, Hursting MJ, Tenero DM, Graham AM, DiCicco RA. Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin. Am J Health-Syst Pharm 2002; 59: 1258–66. 71. Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol 2002; 58: 265– 74. 72. Edwards JE, McQuay HJ. Dipyrone and agranulocytosis: what is the risk? Lancet 2002; 360: 1438. 73. Schönhöfe P, Offerhaus L, Herxheimer A. Renal tolerability of three commonly employed nonsteroidal anti-inﬂammatory drugs in elderly patients with osteoarthritis. Lancet 2003; 361: 968. 74. Niccoli L, Bellino S, Cantini F. Renal tolerability of three commonly employed non-steroidal anti-inﬂammatory drugs in elderly patients with osteoarthritis. Clin Exp Rheumatol 2002; 20: 201–7. 75. Obermoser G, Bellmann R, Pfausler B, Schmutzhard E, Sepp N. Aseptic meningo-encephalitis related to dexibuprofen use in a patient with systemic lupus erythematosus: a case report with MR ﬁndings. Lupus 2002; 11: 451–3. 76. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin Lancet 2003; 361: 573–4. 77. Fitzgerald GA. Parsing an enigma: the pharmacodynamics of aspirin resistance. Lancet 2003; 361: 542–4. 78. Park JM, Houch CS, Sethna NF, Sullivan LJ, Atala A, Borer JG, Cilento BG, Diamond DA, Peters CA, Retik AB, Bauer SB. Ketorolac suppresses postoperative bladder spasms after pediatric ureteral reimplantation. Anesth Analg 2000; 91: 11–15. 79. Park JM, Schnermann JB, Briggs JP. Cyclooxygenase-2. A key regulator of bladder prostaglandin formation. Adv Exp Med Biol 1999; 462: 171–81. 80. Gruenenfeldern J, McGuire EJ, Faerber GJ. Acute urinary retention associated with the use of cyclooxygenase-2 inhibitors. Urology 2002; 168: 1106. 81. Pathak A, Boveda S, Defaye P, Mansourati J, Mallaret M, Thebault L, Galinier M, Blanc JJ, Montastruc JL. Celecoxib associated torsade de pointes. Ann Pharmacother 2002; 36: 1290–1. 82. Noroian G, Clive D. Cyclo-oxygenase 2 inhibitors and the kidney: a case for caution. Drug Saf 2002; 25: 165–72. 83. Chan FKL, Hung LCT, Suen BY, Wu JCY, Lee KC, Leung VKS, Hui AJ. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. New Engl J Med 2002; 347: 2104–10.

Anti-inﬂammatory and antipyretic analgesics and drugs used in gout 84. Alkhuja S, Menkel RA, Alwarshetty M, Ibrahimbacha AM. Celecoxib-induced nonoliguric acute renal failure. Ann Pharmacother 2002; 36: 52–4. 85. Verbeiren S, Morant C, Charlanne H, Ajebbar K, Caron J, Modiano P. Celecoxib induced toxiderma with positive patch-test. Ann Dermatol Venereol 2002; 129: 203–5. 86. Berger P, Dwyer D, Corallo CE. Toxic epidermal necrolysis after celecoxib therapy. Pharmacotherapy 2002; 22: 1193–5. 87. Grob M, Pichler WJ, Wuthrich B. Anaphylaxis to celecoxib. Allergy Eur J Allergy Clin Immunol 2002; 57: 264–5. 88. Skowron F, Berard F, Bernard N, Balme B, Perrot H. Cutaneous vasculitis related to celecoxib. Dermatology 2002; 204: 305. 89. Jordan KM, Edwards CJ, Arden NK. Allergic vasculitis associated with celecoxib. Rheumatology 2002; 41: 1453–5. 90. Schneider F, Meziani F, Chartier C, Alt M, Jaeger A. Fatal allergic vasculitis associated with celecoxib. Lancet 2002; 359: 852–3. 91. Wiholm BE, Shear NH, Knowles S, Shapiro L. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Drug Saf 2002; 25: 297–300. 92. Bonnel RA, Villalba ML, Karwoski CB, Beitz J. Aseptic meningitis associated with rofecoxib. Arch Intern Med 2002; 162: 713–15. 93. Daugherty KK, Gora-Harper ML. Idiopathic paresthesia reaction associated with rofecoxib. Ann Pharmacother 2002; 36: 264–6.

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94. Freitas J, Farricha V, Nascimento I, Borralho P, Parames A. Rofecoxib: a possible cause of acute colitis. J Clin Gastroenterol 2002; 34: 451–3. 95. Carder KR, Weston WL. Rofecoxib-induced instant aquagenic wrinkling of the palms. Pediatr Dermatol 2002; 19: 353–5. 96. Sarkar R, Kaur C, Kanwar AJ. Erythema multiforme due to rofecoxib. Dermatology 2002; 204: 304–5. 97. Kumar NP, Wild G, Ramasamy KA, Snape J. Fatal haemorrhagic pulmonary oedema and associated angioedema after the ingestion of rofecoxib. Postgrad Med J 2002; 78: 439–40. 98. Nettis E, Di Paola R, Ferrarnini A, Tursi A. Tolerability of rofecoxib in patients with cutaneous adverse reactions to nonsteroidal anti-inﬂammatory drugs. Ann Allergy Asthma Immunol 2002; 88: 331–4. 99. Schwartz JI, Wong PH, Porras AG, Ebel DL, Hunt TR, Gertz BJ. Effect of rofecoxib on the pharmacokinetics of chronically administered oral contraceptives in healthy female volunteers. J Clin Pharmacol 2002; 42: 215–21. 100. Lundmark J, Gunnarsson T, Bengtsson F. A possible interaction between lithium and rofecoxib. Br J Clin Pharmacol 2002; 53: 403–4. 101. Ibrahim A, Park S, Feldam J, Karim A, Kharasch ED. Effects of parecoxib, a parenteral COX-2-speciﬁc inhibitor, on the pharmacokinetics and pharmacodynamics of propofol. Anesthesiology 2002; 96: 88–95.

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10

General anesthetics and therapeutic gases

GENERAL TOPICS Sedation for endoscopy Gastrointestinal endoscopy is one of the most commonly performed invasive procedures in clinical practice (for example, about 500 000 procedures per annum in Australasia). Propofol is a short-acting intravenous anesthetic with a rapid onset of action and a short half-life, making it eminently suitable for day procedures. However, the use of propofol by non-anesthetists has been controversial because of the perceived risks of its low therapeutic ratio. The incidence of adverse events related to an endoscopy sedation regimen that included propofol (in addition to midazolam and fentanyl), delivered by specially trained general practitioners has been examined in a prospective audit (1C ); 28 472 procedures were performed over 5 years. There were 185 sedation-related adverse events, 107 with airway or ventilation problems; 123 interventions were necessary to maintain ventilation. No patients required tracheal intubation and there were no deaths. The authors concluded that appropriately trained general practitioners encountered a low incidence of adverse events and could safely use propofol for sedation during endoscopy. It should be noted that all the general practitioners had some experience in anesthesia or intensive care and were individually trained by the Director of Anesthesia. Sedation during surgery under regional anesthesia Sedation during prolonged surgical procedures under regional anesthesia can be quite challenging. The beta-2 adrenoceptor agonist dexmedetomidine has potent sedative and analgesic-sparing properties. In therapeutic © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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doses it does not cause respiratory depression, making it attractive for infusion sedation. However, it causes reduced sympathetic outﬂow, which might cause untoward hemodynamic upset during intraoperative sedation. Dexmedetomidine has been compared with propofol in a prospective randomized trial in 40 patients (2c ). Dexmedetomidine provided slightly slower onset and offset of sedation, higher intraoperative blood pressure, and better postoperative analgesia. Remifentanil is a highly selective μ-opioid receptor agonist with an extremely short onset and offset of action, allowing rapid and accurate titration of infusion rate to drug effect with rapid down-titration in case of respiratory adverse effects. This makes it attractive for sedation. The efﬁcacy and adverse effects proﬁles of remifentanil and propofol have been compared in a randomized, single-blind trial in 125 patients undergoing surgery with regional anesthesia (3c ). In those given remifentanil nausea and vomiting were more frequent (27% vs 2%) and there was signiﬁcantly more respiratory depression (46% vs 19%). Sedation in intensive care It has been proposed that a combination of propofol and midazolam may have advantages over either drug alone, reducing adverse effects while preserving the potential beneﬁts (“co-sedation”). Propofol combined with a constant low dose of midazolam (1.0 mg/hour) has been compared with propofol alone for postoperative sedation in a randomized, placebo-controlled, doubleblind trial in 60 patients undergoing coronary artery surgery under high-dose fentanyl anesthesia (4c ). Target sedation was achieved more readily with co-sedation (91% vs 79%) but at the expense of prolonged weaning from mechanical ventilation (432 vs 319 min). However, it is not clear whether this slightly pro-

General anesthetics and therapeutic gases

Chapter 10

longed time on the ventilator affected length of stay in the ICU.

ANESTHETIC VAPORS (SED-14, 318; SEDA-24, 128; SEDA-25, 139; SEDA-26, 132)

Sevoﬂurane Sevoﬂurane is pleasant to breathe and has a rapid onset and offset of action. It has become popular in day surgery, despite little evidence of clear advantages over current alternatives. Sevoﬂurane and isoﬂurane have been compared in a randomized study in 180 patients undergoing knee arthroscopy (5C ). In those given sevoﬂurane there were signiﬁcantly more respiratory and cardiovascular complications and increased nausea and vomiting. Nervous system Convulsions during anesthesia are of concern, because with the use of muscle relaxants they may go unrecognized. They can cause postoperative delirium. Sevoﬂurane can cause epileptiform activity on the electroencephalogram, especially during induction of and emergence from anesthesia. It has also been associated with epileptiform discharges in volunteers, but clinical convulsions appear to be very rare. Little is known about the electroencephalogram during maintenance of anesthesia with sevoﬂurane after intravenous induction of anesthesia. In a prospective observational study in 30 children undergoing adenoidectomy anesthesia was induced with midazolam and thiopental (both potent anticonvulsants) and maintained with sevoﬂurane; no electroencephalographic epileptiform activity was observed (6c ). Sevoﬂurane often causes postoperative delirium and agitation in children, and this can be severe. The effects of intravenous and caudal epidural clonidine on the incidence and severity of postoperative agitation have been assessed in a randomized, double-blind study in 80 children, all of whom received sevoﬂurane as the sole general anesthetic for induction and maintenance (7C ). A caudal epidural block was performed before surgery for analgesia with

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0.175% bupivacaine 1 ml/kg. The children were assigned randomly to four groups: (I) clonidine 1 μg/kg added to the caudal bupivacaine; (II) clonidine 3 μg/kg added to the caudal bupivacaine; (III) clonidine 3 μg/kg intravenously; and (IV) no clonidine. The incidences of agitation were 22, 0, 5, and 39% in the four groups respectively. Thus, clonidine 3 μg/kg effectively prevented agitation after sevoﬂurane anesthesia independent of the route of administration. The effect of a single preoperative dose of the opioid oxycodone on emergence behavior has been studied in a randomized trial in 130 children (8C ). Oxycodone prophylaxis, compared with no premedication, signiﬁcantly reduced the incidence of post-halothane agitation, but had no effect on post-sevoﬂurane delirium. Urinary tract Sevoﬂurane can contribute to the development of renal insufﬁciency, by toxicity from either inorganic ﬂuoride ions or the haloalkene degradation product Compound A. Fluoride ions are produced as a result of metabolism of sevoﬂurane and can reach high concentrations after prolonged anesthesia. Compound A is produced in carbon dioxide absorbers (soda lime and barium hydroxide lime in particular) and has been proven to be nephrotoxic in rats but not in humans. The effect of the nephrotoxic aminoglycoside antibiotic amikacin on renal function during low-ﬂow sevoﬂurane anesthesia has been studied in a randomized study in 37 men undergoing orthopedic surgery (9c ). Markers of renal tubular injury (urinary N-acetyl-betaD-glucosaminidase and beta-2-microglobulin) were not abnormally raised and urine volume, creatinine clearance, and serum creatinine and urea concentrations were unaffected. The duration of anesthesia and compound A concentrations were similar in the two groups. Again, no human evidence of sevoﬂurane nephrotoxicity has been demonstrated. Musculoskeletal Rhabdomyolysis triggered by sevoﬂurane in a child with Duchenne muscular dystrophy has been reported in one case (10A ).

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Isoﬂurane Liver Hepatitis or hepatocellular injury has been described with all current volatile anesthetics. Among these, halothane-associated hepatitis has been best characterized and is probably caused by an immune reaction induced by hepatocyte proteins that have been covalently triﬂuoracetylated by the triﬂuoracetyl metabolite of halothane. In an interesting case report, clinical, histochemical, and immunohistochemical evidence supporting the role of triﬂuoracetyl-modiﬁed proteins has been presented in a patient with hepatitis associated with isoﬂurane (11A ). Patients with increased activity of CYP2E1 or CYP2A6 appear to be at higher risk.

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Y. Young

from anesthesia. The development of closed rebreathing systems has led to further interest. However, its high cost limits its use. The subjective, psychomotor, and physiological properties of subanesthetic concentrations of xenon have been studied in 10 volunteers (15c ). Xenon sedation was well tolerated and was not associated with any adverse physiological effects. In particular, there was no nausea or vomiting. It was preferred to sedation with nitrous oxide and was subjectively dissimilar (xenon was more pleasant).

INTRAVENOUS AGENTS BARBITURATE ANESTHETICS

NITROUS OXIDE

(SED-14, 325; SEDA-24, 132; SEDA-25, 142; SEDA-26, 134)

(SED-14, 327; SEDA-25, 143)

Thiopental Sensory systems Nitrous oxide is 34 times more soluble than nitrogen in enclosed body cavity gas spaces and it enters such spaces rapidly, causing expansion and a rise in pressure. Vitreoretinal surgery often uses intraocular gases to replace vitreous humor, in order to internally tamponade the neuroretina to the retinal pigment epithelium. Various longacting inert gases, such as sulfur hexaﬂuoride or perﬂuoropropane, can be used as intraocular tamponading agents. Several cases of blindness and severe visual loss associated with nitrous oxide in people with intraocular gas bubbles have been reported (12A –14A ). It has been suggested that all such patients should have warning bracelets detailing the presence of intraocular gas and that nitrous oxide be avoided until it has been shown that the gas bubble has been absorbed.

Electrolyte balance Life-threatening hyperkalemia following therapeutic barbiturate coma with thiopental has been described in three patients; it was fatal in one (16A ). All the episodes occurred after the withdrawal of thiopental. Hypokalemia that is resistant to potassium replacement is common during thiopental coma and clinicians may choose to manage asymptomatic barbiturate-induced hypokalemia expectantly in an attempt to avoid rebound hyperkalemia.

MISCELLANEOUS NON-BARBITURATE ANESTHETICS Ketamine

XENON

(SED-14, 329; SEDA-24, 134; SEDA-25, 143; SEDA-26, 135)

Xenon is receiving renewed interest, because it has many characteristics of the ideal anesthetic. In addition to its lack of effects on the cardiovascular system, xenon has low solubility, enabling faster induction of and emergence

When added to standard doses of morphine and a non-steroidal analgesic, S-ketamine 0.5 mg/kg had no additional beneﬁt in a randomized, double-blind study in 30 patients undergoing anterior cruciate ligament repair (17c ).

General anesthetics and therapeutic gases

Chapter 10

Psychological Subanesthetic low-dose ketamine is being used increasingly often for acute pain therapy, day-case surgery, and chronic pain management. Ketamine is now available in chiral (S+ and R−) forms as well as the standard racemic form. S-ketamine has twice the analgesic potency of racemic ketamine and four times that of R-ketamine. Thus, low dose Sketamine may avoid adverse effects while providing high-quality analgesia. This hypothesis has been explored in a randomized, doubleblind, crossover study of cognitive impairment in 24 volunteers who received S-ketamine 0.25 mg/kg, racemic ketamine 0.5 mg/kg, or R-ketamine 1.0 mg/kg (18c ). The ketamine isomers caused less tiredness and cognitive impairment than equianalgesic doses of racemic ketamine. In addition, S-ketamine caused less reduction in concentration capacity and primary memory.

Etomidate

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

SEDA-26, 135) Nervous system When etomidate was given to 12 patients who had seizures of short duration during electroconvulsive therapy conducted previously under propofol anesthesia, mean seizure duration was signiﬁcantly increased with etomidate anesthesia (19A ). However, there is no evidence that this observation is associated with an improved psychiatric outcome.

Propofol

(SED-14, 330; SEDA-24, 135; SEDA-25, 144; SEDA-26, 135)

Cardiovascular Propofol caused marked prolongation of the QTc interval in a 71-year-old woman with an acute myocardial infarction who required ventilatory support (20A ). Substituting midazolam for propofol was associated with normalization of the QTc interval. Rechallenge with propofol was associated with further prolongation. There were no malignant ventricular dysrhythmias.

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Nervous system Dystonic movements induced by propofol occurred in a patient undergoing elective cardioversion (21A ). Benzatropine 2 mg intravenously terminated the abnormal movements. The authors also reviewed all other reports of abnormal movements after propofol. Pain on injection is a sometimes severe adverse effect of propofol, and numerous agents have been tried to prevent it. The effects of different doses of ketorolac, with or without venous occlusion, on the incidence and severity of pain after propofol injection have been studied in a randomized, double-blind study in 180 patients (22C ). Pretreatment with intravenous ketorolac 15 mg and 30 mg reduced the pain after propofol injection. A lower dose of ketorolac 10 mg with venous occlusion for 120 seconds achieved the same effect. Ondansetron and tramadol have been compared in patients being given propofol in a randomized, double-blind study in 100 patients (23C ). Tramadol 50 mg intravenously was as effective as ondansetron 4 mg intravenously with 15 seconds of venous occlusion at preventing propofol injection pain. However, there was signiﬁcantly less nausea and vomiting in those given ondansetron. Pancreas A healthy 21-year-old woman developed acute pancreatitis a day after an anesthetic that lasted 138 minutes, with propofol for induction (24A ). She recovered after supportive therapy for 6 days. There was no evidence of gallstones on abdominal imaging and there was no defect in lipid metabolism. Metabolic Propofol infusion syndrome was discussed at length in SEDA-26 (p. 135). It is a syndrome of myocardial failure (bradycardia, hypotension, low cardiac output), metabolic acidosis, and rhabdomyolysis, ﬁrst described in children receiving high-dose propofol infusions for more than 48 hours in pediatric ICUs. There are few descriptions of propofol kinetics in critically ill children. In a study in 21 critically ill children aged 1 week to 12 years, who were also receiving morphine by infusion, propofol kinetics were altered in very small babies and in children of all ages recovering from cardiac surgery (25c ). Increased volume of distribution and reduced metabolic clearance caused a prolonged half-life. The combination of morphine 20–40 μg/kg and 2% propofol 4–6 mg/kg/h for up to 28 hours appears to be safe.

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BENZODIAZEPINES

(SED-14, 327; SEDA-24, 133; SEDA-25, 145; SEDA-26, 137; see also Chapter 5)

Diazepam Respiratory Apnea after emergency treatment of seizures by paramedics in the pre-

Chapter 10

Y. Young

hospital setting with benzodiazepines can be a signiﬁcant problem. The efﬁcacy and adverse effects of diazepam and midazolam administered by paramedics for seizure control have been studied retrospectively in 107 children (26c ). Diazepam was associated with a signiﬁcantly higher incidence of apnea (29% vs 20%).

REFERENCES 1. Clarke AC, Chiragakis L, Hillman LC, Kaye GL. Sedation for endoscopy: the safe use of propofol by general practioner sedationists. Med J Aust 2002; 176: 158–61. 2. Arain SR, Ebert TJ. The efﬁcacy, side-effects, and recovery characteristics of dexmedetomidine versus propofol when used for intraoperative sedation. Anesth Analg 2002; 95: 461–6. 3. Servin FS, Raeder JC, Merle JC, Wattwil M, Hanson AL, Lauwers MH, Aitkenhead A, Marty J, Reite K, Martisson S, Wostyn L. Remifentanil sedation compared with propofol during regional anaesthesia. Acta Anaesthesiol Scand 2002; 46: 309–15. 4. Walder B, Borgeat A, Suter PM, Romand JA. Propofol and midazolam versus propofol alone following coronary artery bypass grafting: a randomized, placebo-controlled trial. Anaesth Intensive Care 2002; 30: 171–8. 5. Elcock DH, Sweeney BP. Sevoﬂurane vs isoﬂurane: a clinical comparison in day surgery. Anaesthesia 2002; 57: 52–6. 6. Niminen K, Westeren-Punnonen S, Kokki H, Ypparila H, Hyvarinen A, Partanen J. Sevoﬂurane anaesthesia in children after induction of anaesthesia with midazolam and thiopental does not cause epileptiform EEG. Br J Anaesth 2002; 89: 853–6. 7. Bock M, Kunz P, Schreckenberger R, Graf BM, Martin E, Motsch J. Comparison of caudal and intravenous clonidine in the prevention of agitation after sevoﬂurane in children. Br J Anaesth 2002; 88: 790–6. 8. Murray DJ, Cole JW, Shrock CD, Snider RJ, Martini JA. Sevoﬂurane versus halothane: effect of oxycodone premedication on emergence behaviour in children. Paediatr Anaesth 2002; 12: 308–12. 9. Higuchi H, Adachi Y. Renal function in surgical patients after administration of low-ﬂow sevoﬂurane and amikacin. J Anesth 2002; 16: 17–22. 10. Takahashi H, Shimokawa M, Sha K, Sakomoto T, Kawaguchi M, Kitaguchi K, Furuya H. Sevoﬂurane can induce rhabdomyolysis in Duchenne’s muscular dystrophy. Jpn J Anesthesiol 2002; 51: 190–2. 11. Njoku DB, Shrestha S, Soloway R, Duray PR, Tsokos M, Abu Asab MS, Pohl LR, West AB. Subcellular localization of trﬂuoracetylated liver proteins in association with hepatitis following isoﬂurane. Anesthesiology 2002; 96: 757–61.

12. Yang YF, Herbert L, Ruschen H, Cooling RJ. Nitrous oxide anaesthesia in the presence of intraocular gas can cause irreversible blindness. Br Med J 2002; 325: 532–3. 13. Seaberg RR, Freeman WR, Goldbaum MH, Manecke GR Jr. Permanent postoperative vision loss associated with expansion of intraocular gas in the presence of a nitrous oxide-containing anesthetic. Anesthesiology 2002; 97: 1309–10. 14. Fu AD, McDonald HR, Eliott D, Fuller DG, Halperin LS, Ramsay RC. Complications of general anesthesia using nitrous oxide in eyes with preexisting gas bubbles. Retina 2002; 22: 569–74. 15. Bedi A, McCarroll C, Murray JM, Stevenson MA, Fee JPH. The effects of subanaesthetic concentrations of xenon in volunteers. Anaesthesia 2002; 57: 233–41. 16. Cairns CJS, Thomas B, Fletcher S, Parr MJA, Finfer SR. Life-threatening hyperkalaemia following therapeutic barbiturate coma. Intensive Care Med 2002; 28: 1357–60. 17. Jaksch W, Lang S, Reichhalter R, Raab G, Dann K, Fitzal S. Perioperative small-dose S(+) ketamine has no incremental beneﬁcial effects on postoperative pain when standard-practice opioid infusions are used. Anesth Analg 2002; 94: 981–6. 18. Pfenninger EG, Durieux ME, Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology 2002; 96: 357–66. 19. Stadtland C, Erfurth A, Rata U, Michael N. A switch from propofol to etomidate during an ECT course increases EEG and motor seizure duration. J ECT 2002; 18: 22–5. 20. Sakabe M, Fujiki A, Inoua H. Propofol induced marked prolongation of QT interval in a patient with acute myocardial infarction. Anesthesiology 2002; 97: 265–6. 21. Schramm BM, Orser BA. Dystonic reaction to propofol attenuated by benztropine (Cogentin). Anesth Analg 2002; 94: 1237–40. 22. Huang YW, Buerkle H, Lee TH, Lu CY, Lin CR, Lin SH, Chou AK, Muhammad R, Yang LC. Effect of pre-treatment with ketorolac on propofol injection pain. Acta Anaesthesiol Scand 2002; 46: 1021–4.

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23. Memis D, Turan A, Karamanlioglu B, Kaya G, Pamukcu Z. The prevention of propofol injection pain by tramadol or ondansetron. Eur J Anaesthesiol 2002; 19: 47–51. 24. Jawaid Q, Presti ME, Neuschwander-Tetri BA, Burton FR. Acute pancreatitis after single-dose exposure to propofol. A case report and review of the literature. Dig Dis Sci 2002; 47: 614–18.

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25. Rigby-Jones AE, Nolan JA, Priston MJ, Wright PMC, Sneyd JR, Wolf AR. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97: 1393–400. 26. Rainbow J, Browne GJ, Lam LT. Controlling seizures in the prehospital setting: diazepam or midazolam? J Paediatr Child Health 2002; 38: 582–6.

Stephan A. Schug, Kathryn J.D. Stannard, and Helen C.S. Daly

11

Local anesthetics

EFFECTS RELATED TO MODES OF USE

Each patient’s symptoms settled with supplementary oxygen, and surgery proceeded uneventfully. In both instances a chest X-ray showed a raised hemidiaphragm on the side of the block, but pneumothorax was excluded. The respiratory compromise was probably caused by paresis of the ipsilateral diaphragm due to blockade of the phrenic nerve, which is likely to occur after an infraclavicular plexus block but is well tolerated in most patients. Dyspnea in these two patients may have resulted from several factors. Both had been lightly sedated with benzodiazepines (although both were alert and cooperative, so this probably had a minimal contribution). The ﬁrst had emphysema, which may have been an important factor; in such patients diaphragmatic function is important for sufﬁcient gas exchange and a 50% loss of function can result in signiﬁcant impairment. The second woman was obese, and obesity is associated with a reduction in functional residual capacity and respiratory function, so she may have had reduced respiratory reserve. The authors suggested that in patients with reduced pulmonary reserve infraclavicular brachial plexus blockade should be avoided and an axillary approach considered. In addition they speculated that a smaller volume of local anesthetic may reduce the risk of phrenic nerve blockade.

Brachial plexus anesthesia Cardiovascular Pulmonary embolism has been attributed to brachial plexus block. • A 43-year-old man with end-stage renal disease became acutely hypoxic after an interscalene brachial plexus block with 35 ml of 1.5% mepivacaine for primary placement of an arteriovenous ﬁstula in the left arm (1A ). He had been undergoing hemodialysis for 1 month using subclavian and internal jugular vascular catheters for temporary access. Immediately after an apparently straightforward block, his oxygen saturation fell from 99% to 85%, he complained of chest pain and shortness of breath, and he developed hemoptysis. A CT scan suggested acute pulmonary embolism.

The authors proposed that manipulations and vasodilatation related to the interscalene block may have facilitated the dislodgement of a pre-existing thrombus in the arm. Respiratory Two cases of respiratory compromise after infraclavicular brachial plexus blockade have been described (2A ). • An 84-year-old 74 kg woman had a past history of hypertension, emphysema, and ischemic heart disease. She had an infraclavicular brachial plexus block with 40 ml (400 mg) of prilocaine 1% and 10 ml (75 mg) of ropivacaine 0.75%, and 20 minutes later developed difﬁculty in breathing and became desaturated. She had received midazolam 2 mg before the block. • A 47-year-old woman with a history of hypertension, gastric reﬂux, and obesity was premedicated with oxazepam 10 mg and had an infraclavicular brachial plexus block with the same doses of ropivacaine and prilocaine as in the ﬁrst case; 10 minutes later she developed dyspnea and became desaturated. © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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Nervous system Interscalene block can cause paralysis of the arm. • A 33-year-old woman received combined regional and general anesthesia for a shoulder repair (3A ). Pre-operatively an interscalene catheter was placed uneventfully. The next day she had almost complete paralysis of the arm with hypesthesia of dermatomes C5–7. The symptoms persisted and 4.5 months later, during surgical exploration of the brachial plexus, electrical stimulation of the three trunks was possible and there were electrophysiological signs of recovery. Despite extensive neurophysiological tests a clear cause could not be established and there was no improvement at 2 years.

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Chapter 11

Caudal, epidural, and spinal anesthesia Caudal anesthesia Respiratory Awake regional anesthesia for inguinal hernia repair in former preterm infants has been suggested, in order to avoid life-threatening respiratory complications that can occur after general anesthesia. Caudal anesthesia is becoming a more popular technique for this purpose. To prolong the duration of anesthesia and to reduce the postoperative need for analgesics in these infants, caudal clonidine has been considered useful. • A former preterm infant, had two awake caudal anesthetics for herniotomy within 3 weeks (4A ). The ﬁrst was uneventful with bupivacaine 0.25% at 35 weeks of age. At 38 weeks, the baby had intraoperative and postoperative bouts of apnea after inadvertent administration of bupivacaine 0.125% plus clonidine.

Neuromuscular function Racemic bupivacaine has been the most commonly used local anesthetic in pediatric regional anesthesia; however, postoperative motor block and more serious complications, such as seizures and cardiac dysrhythmias are associated with its use. Ropivacaine and levobupivacaine are available and are reported to be associated with a lower risk of unwanted motor blockade and toxicity. In a recent study in 60 anesthetized children undergoing minor subumbilical surgery caudal blocks, 0.2% ropivacaine, 0.25% racemic bupivacaine, and 0.25% levobupivacaine (all 1 ml/kg) were compared (5C ). All the blocks were successful in terms of intraoperative and early postoperative analgesia. Ropivacaine, but not levobupivacaine, was associated with less motor block during the ﬁrst postoperative hour compared with racemic bupivacaine. However, the lower concentration of ropivacaine will have biased this result.

Epidural anesthesia Cardiovascular An asystolic cardiac arrest has been described in a 55-year-old man who underwent partial hepatectomy under combined general and epidural anesthesia (6A ). During

postoperative recovery he developed asystole followed by ventricular ﬁbrillation. Resuscitation was unsuccessful and the authors concluded that in the absence of any other abnormality the arrest had been the result of an autonomic imbalance due to spreading sympathetic block, although other postoperative causes of death should not be discarded. Nervous system High spinal block has previously been reported as a rare complication of epidural anesthesia. • A 31-year-old woman in labor had an epidural catheter sited at L3/4 (7A ). A test dose of 0.25% bupivacaine 10 ml was followed 90 minutes later by another 10 ml. After a further 90 minutes she required cesarean section, had a block to T7, and was topped up with 0.75% ropivacaine 10 ml. Within minutes she developed arm weakness, and over the next 15 minutes developed further ascending block requiring intubation. Three hours later the block had regressed to T8 and she had no further complications.

The cause was thought to be subdural injection, although other mechanisms could not be excluded; for example, the catheter could have been partly intrathecal and the ultimate distribution of the dose could have been related to the speed of injection or catheter migration before the ﬁnal dose was given. A left-sided Horner’s syndrome has been reported following a lumbar epidural with ropivacaine for cesarean section (8A ). The symptoms resolved after 5 hours. The most likely cause was high sympathetic block, possibly facilitated by left lateral positioning, leading to cephalad spread of the local anesthetic. The authors also wondered whether the physicochemical properties of ropivacaine favor its effect on sympathetic ﬁbers over bupivacaine.

Intrathecal (spinal) anesthesia Intrathecal blockade for cesarean section using 0.5% hyperbaric bupivacaine at three different doses of 7.5 mg, 8.75 mg, and 10 mg has been studied in a double-blind comparison in 60 patients (9C ). There was no signiﬁcant difference in maximum block height, but more of the patients who were given the two lower doses had moderate visceral pain requiring rescue

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ketamine. Bupivacaine 10 mg was associated with signiﬁcantly more bradycardia, and 7.5 and 8.75 mg with signiﬁcantly more hypotension. Motor block lasted signiﬁcantly longer with 10 mg. The outcome was good in all the infants, although one baby whose mother had received bupivacaine 10 mg had an Apgar score of <10 at 5 minutes. The authors concluded that the use of bupivacaine 7.5 mg avoids hypotension, bradycardia, and prolonged block. Cardiovascular The effect of intrathecal clonidine has been evaluated in a prospective randomized study in 45 children aged 6–15 years, who were randomized to receive either 0.5% hyperbaric bupivacaine or 0.5% hyperbaric bupivacaine plus clonidine 2 micrograms/kg (10C ). Clonidine was associated with nonsigniﬁcant prolongation of motor block, from an average of 150 to 190 min. Postoperative analgesia was signiﬁcantly longer with clonidine (490 vs 200 min). Clonidine was associated with higher incidences of hypotension (54 vs 36%) and bradycardia (30 vs 0%). Respiratory Immediate respiratory arrest has been reported after the administration of intrathecal bupivacaine and fentanyl (11A ). • A 26-year-old woman in labor was given an epidural for analgesia. After 2 hours and total doses of bupivacaine 77.5 mg and fentanyl 190 micrograms, the epidural was removed owing to failure. A subsequent intrathecal injection of bupivacaine 2.5 mg plus fentanyl 10 micrograms was followed 4 minutes later by apnea and loss of consciousness. She was rapidly intubated and regained consciousness after 15 minutes, at which time her sensory level was T8 to pinprick. She was extubated after 30 minutes.

The authors concluded that the respiratory depression had been due to excessive cephalad spread of fentanyl, possibly facilitated by the volume of bupivacaine that had previously been injected epidurally. Nervous system Transient radicular irritation, often also incorrectly named transient neurological symptoms, despite the absence of any neurological disturbances, continues to be reported after neuraxial anesthesia. The incidence seems to be highest with lidocaine, but other local anesthetics can also cause it. In a prospective audit of 100 patients having spinal anesthesia with 5% hyperbaric lidocaine

in a mean dose of 73 mg there was an unusually low incidence of 4% (12C ). All the patients recovered completely, which led the authors to conclude that 5% hyperbaric lidocaine is acceptable for spinal anesthesia in patients in whom rapid recovery from the block is desired. The low incidence in this study might have been due to the fact that the patients were placed in the supine or lateral position, as patient position has previously been reported to be a risk factor for the development of transient radicular irritation, the lithotomy position and knee arthroscopy having a higher incidence, possibly owing to excessive stretching of the nerve roots, leading to ischemic damage. This impression has been conﬁrmed by three recent reports of patients who developed transient radicular irritation after intrathecal anesthesia, as all these patients had surgery in positions that could have caused excessive stretching of nerve roots. • A 44-year-old man developed transient pain in the buttocks and thighs 4 hours after 4% hyperbaric mepivacaine had been used to provide anesthesia for knee arthroscopy (13A ). The symptoms resolved after 2 days. • A 46-year-old woman had an epidural placed at L4/5 (14A ). As there was insufﬁcient block 20 minutes after injection of 300 mg mepivacaine, the epidural catheter was removed and an intrathecal injection of 0.5% tetracaine 2 ml dissolved in 5% glucose was performed. She was then placed in the lithotomy position for 30 minutes. One day postoperatively she developed pain and numbness in her left leg, and the numbness spread to the lower back, buttocks, and thighs. The symptoms disappeared after 4 days. • A 50-year-old man had an intrathecal injection of 2% lidocaine 40 mg diluted to 1% with sterile water, while in the prone jack-knife position for excision of a pilonidal cyst (15A ). About 7 hours after the start of the block he developed acute sharp lower back pain radiating to the right buttock. There were no accompanying neurological signs. The pain settled with ketorolac and was gone after 5 days.

The last case is the ﬁrst report of transient radicular irritation after the use of hypobaric lidocaine, but it again suggests the importance of sciatic stretching. The cause of transient radicular irritation is obscure. Neurotoxicity of local anesthetics has been postulated as a mechanism, and there are again some experimental data to conﬁrm this. An animal study of the histological and physiological effects of intrathecal lidocaine at

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varying concentrations from 3 to 20% showed the presence of lesions in the posterior roots and columns characterized by axonal degeneration (16E ). The lesions were severe at higher concentrations, but even at the lower concentration of 7.5% there were mild lesions that did not correlate with the presence of neurofunctional deﬁcit. In a study of the effect of clinically relevant concentrations of lidocaine, bupivacaine, mepivacaine, and ropivacaine on cultured neurons, the local anesthetics caused destruction of the growth cones, implying that they have a toxic effect on the growth and regeneration of neuronal tissue (17E ). Lidocaine had the most marked effect and mepivacaine the least. While this might not be of direct relevance to the etiology of transient radicular irritation, the authors pointed out the potential risks of using local anesthetics in very young children, taking into consideration the difﬁculties of extrapolating from in vitro studies to in vivo use. In a careful meta-analysis 29 randomized, controlled studies of the incidence of transient radicular irritation were identiﬁed (18M ). Lidocaine and mepivacaine were identiﬁed as the two local anesthetics that most commonly cause transient radicular irritation, while prilocaine, bupivacaine, and ropivacaine had the lowest incidences. Owing to insufﬁcient data, deﬁnitive statements could not be made about the effects of the baricity of the local anesthetic, the concentration, and the effect of vasoconstrictors, although all these factors seemed not to be relevant. With regard to intrathecal ropivacaine, the incidence in the formal studies was zero. However, there has been one previous report after intrathecal administration, and now a recent report of transient radicular irritation following epidural anesthesia with ropivacaine; the symptoms resolved within 24 hours (19A ). Cauda equina syndrome has been reported after a spinal anesthetic using dibucaine (20A ). • A 64-year-old man with a history of borderline diabetes who had undergone two previous operations uneventfully under spinal anesthetic received a spinal anesthetic with hyperbaric 0.24% dibucaine 2.2 ml and then a general anesthetic because of unilateral block. The next day he complained of difﬁculty in defecation and urination, with abnormal anal sensation. A diagnosis of cauda equina syndrome was made. He made a gradual recovery, but mild hypesthesia remained after 4 months.

A possible cause for this adverse event may have been maldistribution in the intrathecal space of the high concentration of dibucaine, affecting the cauda equina and resulting in nerve damage; the incomplete block achieved in this case is suggestive of this. Elderly patients undergoing urological surgery often have risk factors for cauda equina syndrome, such as intraoperative lithotomy position, frequent spinal anesthetics, old age, and diabetes mellitus. The authors suggested that dibucaine should be avoided for spinal anesthesia in these patients, because of its high neurotoxicity compared with other local anesthetics.

Dental anesthesia Nervous system Cranial nerve motor effects, facial paralysis, and ophthalmic complications from intraoral anesthesia are rare, but well documented. Four cases of persistent lingual paresthesia or hyperesthesia after inferior dental block with articaine have been reported (21A ). Neurological complications with articaine have previously been described, but the product information suggests that resolution usually occurs within 2 weeks. The authors reported that the symptoms in their cases persisted for 6–18 months and noted that they were aware of another four cases of persistent paresthesia with articaine that had not been formally reported. In seven subjects articaine with adrenaline caused distortion of lingual nerve function with effects on vowel pronunciation and therefore the potential to impair speech (22c ). • A 49-year-old man developed uvular deviation as a result of palatal muscle paralysis following intraoral mandibular block of the inferior alveolar nerve with 1.8 ml of 2% lidocaine with adrenaline 1 in 100 000 (23A ). A few minutes after injection he had swallowing difﬁculties and a foreign body sensation in his throat. There was paralysis of the velum palatinum, with deviation of the uvula towards the non-paralysed side opposite the point of anesthetic inﬁltration. This resolved after the anesthetic had worn off.

The authors suggest that a high inferior alveolar nerve block can easily affect the mandibular nerve if the anesthetic solution diffuses to the internal trunk of the third trigeminal branch and the supply to the tensor veli palatini.

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Immunologic Allergic reactions to local anesthetics are rare, but both immediate and delayed hypersensitivity reactions have been reported. • A 39-year-old man was investigated for three episodes of facial swelling following dental procedures over 2 years (24A ). The swelling always occurred on the same side as the dental procedure and about 12 hours after it, took a couple of days to resolve, did not respond to antihistamines, and was not associated with a rash, laryngeal edema, or bronchospasm. He was admitted twice and treated with intravenous antibiotics for cellulitis. He also reported a history of a rash after penicillin but no previous reactions to local anesthetics. All blood tests, including full blood count, C3 and C4 concentrations, and C1 esterase inhibitor activity and function were normal; an antinuclear antibody test was negative, IgE concentrations were not raised, and latex-speciﬁc IgE was not detected. Skin prick, intradermal, and subcutaneous tests were carried out with isotonic saline, lidocaine, prilocaine, and procaine; these did not show immediate reactions, but 2 days later a wheal appeared at the lidocaine site. There was a less intense reaction with prilocaine and none with saline or procaine.

The authors concluded that sensitization to lidocaine must have taken place during previous procedures and that cross-reactivity with the other amide type local anesthetic, prilocaine, had also occurred.

Inﬁltration anesthesia Skin inﬁltration with local anesthetics can produce pain. The pain experienced during skin inﬁltration of lidocaine, chloroprocaine, and buffered solutions of both has been studied in 22 volunteers in a double-blind, randomized study (25C ). The pH of the solutions was unrelated to the pain score, but both formulations of chloroprocaine were signiﬁcantly less painful than lidocaine.

adrenaline 1 in 200 000. During recovery she was anxious and moderately hypotensive and had a ﬂaccid paralysis from T4 down. An MRI scan was normal. She gradually recovered motor function, sensation, and pain at the wound site.

The authors concluded that the local anesthetic may have passed down a ﬁstulous track into the subarachnoid space, producing spinal block.

Intravenous regional anesthesia Intravenous regional anesthesia is associated with rare but serious complications, such as seizures, cardiac arrest, and death. It has been suggested that ropivacaine, with its lower risk of toxicity and relatively long duration of action, may be a good choice of local anesthetic for this technique. Nervous system The correlation of CNS adverse effects with plasma concentrations after the intravenous administration of 40 ml of lidocaine 0.5% plus ropivacaine 0.2% for regional anesthesia has been examined in 10 volunteers (27c ). The double-cuffed tourniquet was inﬂated for as long as it could be tolerated. The incidence, duration, and intensity of CNS adverse effects were recorded at 3, 10, and 30 minutes after tourniquet release and correlated with venous samples. There was a lower incidence and shorter duration of CNS adverse effects with ropivacaine than lidocaine; however, the dose of ropivacaine was much lower than that of lidocaine and therefore no clear conclusions can be drawn. In view of the availability of safer and effective alternatives for intravenous regional anesthesia, such as prilocaine and lidocaine, the reasons for using ropivacaine are hard to comprehend.

Nervous system Inﬁltration anesthesia has reportedly caused transient paralysis. • Transient paraplegia occurred after wound site inﬁltration with bupivacaine in a 35-year-old woman during removal of a lumboperitoneal shunt that had been inserted 2 years previously for benign intracranial hypertension (26A ). Under general anesthesia with the patient in the left lateral position, a small incision was made over the right ﬂank and the drain was easily removed. The site was inﬁltrated with 7.5 ml of 0.5% bupivacaine with

Lower limb block The combination of lumbar plexus and posterior sciatic nerve block represents an alternative to a neuraxial technique. • An 80-year-old 41 kg woman was given a combination of a posterior lumbar plexus block and

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a posterior sciatic nerve block for dynamic hip screw repair of a fractured right neck of femur (28A ). The lumbar plexus block was technically difﬁcult, requiring three attempts, and 25 ml of ropivacaine 0.75% (187.5 mg), adrenaline (1 in 400 000), and clonidine 50 μg was slowly injected, aspirating after every 3 ml. The sciatic nerve block was straightforward, and 20 ml of a solution containing mepivacaine 1.5% (300 mg), adrenaline 1 in 400 000 and clonidine 50 μg was injected slowly. She had seizures and dysrhythmias 20 minutes after completion of the block. Cardiopulmonary resuscitation was successful, surgery proceeded under general anesthesia, and she made a full recovery. Blood samples taken 5 minutes after the seizures contained ropivacaine 1.9 μg/ml and mepivacaine 3.7 μg/ml.

The authors suggested that the timing of events (the neurological signs preceded cardiac toxicity) suggested a toxic reaction to one of the local anesthetics or an overdose from their combination.

Ocular anesthesia Cardiovascular Two cases of cardiopulmonary arrest after retrobulbar block for corrective squint surgery have been described (29A ). Both the patients were ﬁt healthy young men and they received a retrobulbar block with 2% lidocaine 2 ml via a 23G 1.5 needle after negative aspiration. Three minutes later both complained of breathlessness and rapidly became apneic and unresponsive, with unrecordable pulse and blood pressure. Both were resuscitated and became fully alert within 40 minutes. Possible reasons suggested were an allergic reaction, a direct toxic effect, a vasovagal attack, intraarterial injection, or injection directly into the optic nerve sheath with spread of the local anesthetic into the CSF. The latter seemed to be the most likely in these cases. Since then the authors have altered their technique, including changing the position of gaze and using a short blunt needle. These cases illustrate the need for careful monitoring, knowledge of potential complications, and the ready availability of resuscitation facilities (including appropriately trained personnel familiar with the equipment), even when performing what many regard as minor local anesthetic blocks.

129 Sensory systems Complications from retrobulbar blocks can arise from accidental scleral perforation and intraocular injection of local anesthetic. • An 86-year-old man scheduled for cataract surgery sustained an inadvertent occult single perforating needle injury with an intraocular injection of 0.5% plain bupivacaine during a retrobulbar block using a long (38 mm) needle (30A ). He had pain on injection and a raised intraocular pressure, with corneal edema, poor iris detail, and a reduced red reﬂex. Paracentesis lowered the intraocular pressure and surgery proceeded uneventfully. At 6 weeks he had a reduction in visual acuity, and a scan identiﬁed a vitreous hemorrhage and retinal detachment. Prompt vitreoretinal surgery was performed with reasonable success.

The authors added that retinal toxicity of the local anesthetic agent did not affect the visual outcome in this patient. Scleral perforation is a well-known complication of eye blocks for ophthalmic surgery. The incidence with retrobulbar techniques is 0.075% and with peribulbar blocks 0.0002%. When recognized, ocular perforation usually requires a vitreoretinal procedure and is associated with a poor visual outcome. Risk factors include an anxious or oversedated patient, long sharp needles, superior injection, incorrect angle of needle insertion, and myopic eyes. If the intraocular pressure is increased, paracentesis may acutely reduce it, preventing retinal and optic nerve ischemia and possible permanent visual loss. In view of the complications described above, sub-tenon inﬁltration of local anesthesia has recently become increasingly popular for cataract and vitreoretinal surgery; presumed advantages are its safety, speed of onset, and patient compliance. Three cases of persistent diplopia following sub-tenon local anesthesia have been reported (31A ). Two of the patients were given injections of 4 ml of a mixture of lidocaine 1% or 2% with adrenaline 1 in 100 000 and hyaluronidase 1500 units, and the third was given 4 ml of 0.75% bupivacaine with lidocaine. All had vertical diplopia, consistent with restriction of the inferior rectus muscle, which persisted for 2–9 months. The authors suggested possible mechanisms, including direct trauma to the muscle, inﬂammation and adhesions, infection, and myotoxicity of local anesthetics. They have since modiﬁed their technique, reducing the rate and force of inﬁltration.

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Intracameral injection of local anesthetics is another technique that is being used increasingly often in the modern minimally invasive techniques for cataract surgery. The endothelial toxicity of local anesthetics has been assessed in pigs, as this might be relevant to the safety of agents used in this way (32E ). Lidocaine, mepivacaine, and prilocaine were safe, while bupivacaine in clinically effective concentrations resulted in signiﬁcant cell reduction. Infection risk The ﬁrst infectious complication of sub-tenon anesthesia has been reported (33A ). • A 63-year-old woman underwent phacoemulsiﬁcation and lens implantation under sub-tenon block. After the local anesthetic was injected, the eye was prepared with an aqueous solution of betadine and the surgery proceeded uneventfully. At the end, gentamicin and betamethasone were injected subconjunctivally. Over the next few days she developed orbital cellulitis, requiring intravenous antibiotics.

The authors concluded that bacterial contamination of the episcleral space from the ocular surface or skin ﬂora had occurred during or after the sub-tenon injection. They recommended applying topical betadine before the episcleral space is opened, in order to reduce this risk. Drug abuse Corneal complications have been reported in three patients following abuse of topical anesthetics (34A ). Abuse of these medications often results in irreversible corneal damage and visual loss. Two patients continued to instill their topical 0.5% tetracaine eye-drops, despite medical advice. The result was bilateral corneal perforation in the ﬁrst case and a large unilateral descemetocele in the second. Surgery was required to correct the perforations, but the long-term anatomical and functional results were poor. The third patient had obtained 0.5% tetracaine hydrochloride drops over the counter to relieve discomfort in his eye after colleagues at work had attempted to remove a foreign body from his eye. He had developed chronic toxic keratitis and was persuaded to discontinue the eye-drops. With appropriate treatment the cornea returned to normal. The local adverse effects of topical anesthetics depend on the agent and on other constituents added to the commercially available formulations. Toxic reactions are usually due to

overdose or individual hypersensitivity. It appears that the ﬁrst sign of topical anesthetic abuse is an epithelial defect, which may mimic other diagnoses, such as acanthameba keratitis. Patients may report a current or past history of psychiatric problems or substance abuse; persistent abuse results in a poor visual outcome.

Stellate ganglion block Stellate ganglion block is a selective sympathetic block that affects the ipsilateral head, neck, arm, and upper part of the thorax. It is sometimes used to treat vascular insufﬁciency, sympathetically maintained pain syndromes, and painful Herpes zoster infections. Nervous system Convulsions are a recognized complication of inadvertent intra-arterial injection during stellate ganglion block; two such cases have been described (35A ). • A 28-year-old 75 kg woman underwent stellate ganglion block for symptomatic treatment of Raynaud’s syndrome. An anterolateral approach was used, guarding the carotid artery and jugular vein. After an aspiration test was negative in two planes, 5 ml of 1% lidocaine was injected over 2–3 seconds using a 20 G needle. However, a second aspiration test was positive for blood, the needle was pulled back, and on reinjection the patient immediately had a severe generalized tonic–clonic seizure. The patient made a rapid recovery with no further treatment and was fully conscious after 2 minutes. • A 31-year-old 72 kg man with diabetes, who had a below-knee amputation in the past, developed Buerger’s disease affecting his hands, particularly on the right. He underwent his third stellate ganglion block for symptomatic treatment. An anterior paratracheal approach was used with a 20 G 3.5 cm needle; after an aspiration test was negative in two planes, 1 ml of 1% lidocaine was injected every 2–3 seconds. After one injection he had an abrupt seizure, which was treated with diazepam 10 mg. He made a full recovery and later completed his course of stellate ganglion blocks uneventfully.

It was thought that inadvertent vertebral arterial injection had occurred, with subsequent rapid elimination due to high cerebral blood ﬂow. The authors suggested several precautions to minimize this risk, including using a largediameter needle and using less than the calculated minimum arterial toxic dose of lidocaine (16.8 mg) as the initial test dose; for subsequent doses they suggested 5 mg.

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Topical anesthesia Lidocaine is now being used successfully as a topical analgesic in a new adhesive patch formulation for the pain of postherpetic neuralgia; this indication now has FDA approval. The pharmacokinetics and safety of the 5% lidocaine patches have been studied in 20 healthy volunteers, who applied four patches to the skin either every 24 hours or every 12 hours for 3 days (36c ). Mean steady-state plasma concentrations were 186 and 225 ng/ml respectively, well below those required for an antidysrhythmic effect (1500 ng/ml) or a risk of toxicity (5000 ng/ml). The patches were well tolerated, with no major cutaneous adverse effects. This is in line with data from post-marketing surveillance studies, which have shown that since the availability of lidocaine patches in 1999 no adverse cardiac or other serious adverse event has been reported (37r ). Sensory systems Double vision and difﬁculty in focusing have been attributed to lidocaine applied to the tongue (38A ). • A 22-year-old man developed double vision and difﬁculty in focusing after using 2% viscous lidocaine for a painful tongue ulcer. He used viscous 2% lidocaine 10 ml hourly and developed symptoms when the daily dose exceeded 240 ml (4800 mg of lidocaine hydrochloride) after 10 days of use. At that time his serum lidocaine concentration was 6.7 μg/ml. His symptoms persisted when the serum concentration of lidocaine fell to below toxic concentrations, implying that metabolites of lidocaine had contributed.

Hematologic There have again been several reports of methemoglobinemia following topical anesthesia (39A , 40A ). Most have been associated with topical benzocaine, and the patients recovered fully after the administration of methylene blue. • A neonate born at 24 weeks had a rectal biopsy under general anesthesia and was intubated with an endotracheal tube that had been lubricated with lidocaine jelly 1 g and after the biopsy a rectal pack soaked in about 1 g of benzocaine lubricant; 30 minutes after surgery she developed cyanosis, with a methemoglobin concentration of 45% (41A ).

The authors postulated that either local anesthetic could have been responsible, but that the oxidant effects of the two agents may have been

additive. They highlighted the need for awareness of seemingly minor uses of medications in neonates. • A 7-month-old girl was ventilated with inhaled nitric oxide 40 ppm and developed methemoglobinemia after the application for 5 hours of Emla to an 8 cm2 area of skin (42A ). Shortly after removal she developed cyanosis, with a methemoglobin concentration of 16%, which resolved with two doses of methylene blue.

The prolonged duration of Emla application was thought to be the cause, but the concomitant use of inhaled nitric oxide may have contributed. Skin A 6-year-old boy developed contact dermatitis following the application of Emla for a skin biopsy to diagnose graft–versus–host disease (43A ). The histopathological features of the contact dermatitis were similar to graft– versus–host disease. The use of Emla to provide topical anesthesia should be documented in order to avoid misdiagnosis. Granuloma gluteale adultorum is a rare skin condition of unknown etiology, characterized by reddish purple granulomatous nodules on the gluteal surfaces and groin areas. It has been reported in a 40-year-old woman who presented with a 3-year history of the condition associated with the use of topical benzocaine (44A ).

INDIVIDUAL COMPOUNDS Bupivacaine

(SED-14, 351; SEDA-24, 151; SEDA-25, 156)

Cardiovascular All studies of the cardiotoxic effects of local anesthetics on the isolated heart published from 1981 to 2001 have been reviewed (45M ). Thirteen studies were identiﬁed, all of which studied bupivacaine, either alone or compared with another local anesthetics. The general conclusions were: • Highly lipid-soluble, extensively proteinbound, highly potent local anesthetics, such as tetracaine, bupivacaine, and etidocaine, are much more cardiotoxic than less lipidsoluble, protein-bound, and potent local anesthetics, such as lidocaine and prilocaine.

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• Bupivacaine has a potent depressant effect on electrical conduction in the heart, primarily via an action on voltage-gated sodium channels that govern the initial rapid depolarization of the cardiac action potential. • The S(−) isomer of bupivacaine is less cardiotoxic than the R(+) form. • Bupivacaine predisposes the heart to reentrant dysrhythmias. • The actions of bupivacaine on channels other than voltage-gated sodium channels probably contribute to the dose-dependent cardiotoxic effects of bupivacaine. A comparison of the cardiotoxicity of the two stereoisomers of ropivacaine and bupivacaine on the isolated heart showed that both compounds had negative inotropic and negative chronotropic effects irrespective of the stereoisomer used, but bupivacaine had greater effects compared with ropivacaine at equal concentrations (46E ). Atrioventricular conduction time showed stereoselectivity for bupivacaine at clinical concentrations; the R(+) isomer had a greater effect in lengthening atrioventricular conduction time, but the less fat-soluble ropivacaine only showed stereoselectivity at concentrations far greater than those used clinically. Similar to the negative inotropic and chronotropic effects, bupivacaine produced greater effects on atrioventricular conduction time than ropivacaine at equal concentrations. This important study has conﬁrmed speculations that not only the stereospeciﬁcity of ropivacaine but also its physicochemical properties contribute to its cardiac safety. In another general review of the systemic toxicity of local anesthetics interesting trends were identiﬁed (47M ). The incidence of systemic toxicity has been falling during the last 20 years, most probably due to increased awareness of the potential cardiotoxicity of longacting aminoamide local anesthetics. Steps to guard against unintentional intravascular injection have been increasingly used. These include aspiration, incremental injection, dose limitation, and the use of test doses. The most studied test dose is adrenaline 15 μg, which reliably produces a tachycardia in healthy subjects within 20 seconds of intravascular injection. Speciﬁcally, the incidence of cardiotoxicity has also fallen; several case series of systemic toxicity have been published in recent years, report-

ing only CNS toxicity but no cases of cardiotoxicity. This contradicts previous estimates of the risk of cardiotoxicity, which suggested an incidence of 10% of all systemic toxicity reactions, reconﬁrming the impression of increased carefulness of healthcare professionals. In another review current concepts of resuscitation after local anesthetic cardiotoxicity have been scrutinized (48R ). Vasopressin may be a logical vasopressor in the setting of hypotension, rather than adrenaline, in view of the dysrhythmogenic potential of the latter. Amiodarone is probably of use in the treatment of dysrhythmias. Calcium channel blockers, phenytoin, and bretyllium should be avoided. In terms of new modes of therapy targeted at the speciﬁc action of local anesthetics, lipid infusions, propofol, and insulin/glucose/potassium infusions may all have a role, but further research is necessary. Inadvertent administration of bupivacaine can lead to fatal cardiovascular collapse that may be refractory to conventional resuscitation. A recent study in rats has suggested that in addition to its direct cardiotoxic effect, bupivacaine may have a toxic action on the brainstem and that cardiovascular collapse may result from dysfunction of vital cardiorespiratory control systems (49E ). Nervous system Most reactions to local anesthetics occur as a result of inadvertent overdose or accidental intravenous injection. • A 53-year-old woman received postoperative epidural analgesia by nurse-administered bolus doses after a total knee replacement (50A ). She received her ﬁrst epidural bolus of 0.25% bupivacaine 6 ml with morphine 2 mg 2 hours after the operation, with good effect. Six hours later she was accidentally given a second top-up dose intravenously. She became distressed and complained of tinnitus, palpitation, and dizziness. She was able to cooperate and was in sinus rhythm with a tachycardia of 120 bpm. She was observed overnight on ICU and made a full recovery.

Despite correct epidural placement, this complication arose as a result of human error, and the authors believed that the low concentration and volume of the top-up had protected the patient from more serious sequelae.

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Dibucaine

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(SED-14, 352)

Immunologic An anaphylactic reaction to dibucaine has been described. • A 71-year-old man received spinal anesthesia using 0.3% dibucaine 2 ml for a transurethral prostatectomy (51A ). He had a history of allergic rhinitis, and 2 months before had an uneventful prostate biopsy and cystoscopy, also under spinal anesthesia with isobaric bupivacaine. Within 45 minutes of the spinal injection he complained of periorbital itching, started to shake, and developed muscle rigidity. He rapidly became unconscious, with a systolic blood pressure of 40 mmHg and widespread erythema. He was treated with hydrocortisone and antihistamines and required an infusion of adrenaline. Intradermal testing after full recovery was positive with dibucaine.

Levobupivacaine

(SEDA-26, 146)

Levobupivacaine has been introduced as a longacting local anesthetic with potentially reduced cardiac toxicity compared with racemic bupivacaine. This is in line with the previous success of ropivacaine, whose S(−) enantiomer was shown to have increased safety. Cardiovascular Several animal studies have shown that levobupivacaine on an equivalent dose basis is safer than bupivacaine; 32–57% more levobupivacaine is required to cause death (52ER ). In sheep the mean lethal dose of levobupivacaine was 78% higher than bupivacaine; the author suggested that there may be a similar trend in humans and concluded that levobupivacaine should be used in preference to bupivacaine, based on safety data alone. Nervous system Tonic–clonic seizures have been attributed to levobupivacaine. • A 60-year-old 70 kg woman with a fractured radius had an axillary brachial plexus block for postoperative analgesia after uneventful general anesthesia (53A ). A 50 mm insulated regional block needle attached to a nerve stimulator was used to locate the brachial plexus, and after negative aspiration levobupivacaine 125 mg was injected with intermittent aspiration. Within 30 seconds the patient had a generalized tonic–clonic seizure, which lasted about 30 seconds and self-terminated. She remained cardiovascularly stable and made an uneventful recovery.

The authors proposed that some or all of the local anesthetic had been inadvertently injected intravascularly, despite negative aspiration tests. There were no cardiovascular complications, underlining the proposed greater cardiovascular safety of levobupivacaine over bupivacaine. The authors accepted that if the patient had been awake during the procedure, earlier detection of neurological symptoms might have been possible.

Lidocaine

(SED-14, 349; SEDA-24, 152;

SEDA-26, 146) Sensory systems Acute CNS toxicity of local anesthetics usually presents with perioral tingling, confusion, seizures, coma, and possibly death, depending on the initial dose. Temporary blindness is an unusual feature and has been reported in an otherwise healthy young woman (54A ). • A 21-year-old 50 kg woman, previously ﬁt, was to have an open reduction and ﬁxation of a fractured proximal phalanx with intravenous regional anesthesia. As a result of misreading the vial label 30 ml (600 mg) of 2% lidocaine was injected, and this inadvertent error was immediately recognized. The decision was made to continue with the procedure, which was uneventful, with a tourniquet time of 45 minutes. At this point the patient complained of severe tourniquet pain, and without the anesthesiologist’s knowledge the cuff was deﬂated. Immediately she developed a tachycardia, complained of visual disturbances, and became unconscious. She had a seizure, which lasted 30 seconds and resolved with midazolam. She became more alert, but complained of reduced vision. Neurological examination was normal, apart from temporary blindness; this fully resolved within 10 minutes. There were no long-term neurological or visual sequelae.

The authors suggested that the visual symptoms could have occurred as a result of occipital lobe seizure activity or subcortical stimulation, due to the acute high cerebral concentration of lidocaine. The speed of spontaneous resolution was consistent with the pharmacokinetics of lidocaine. Two cases have illustrated the effects of lidocaine in precipitating partial seizures in patients with a previous history of epilepsy (55A ).

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• A 36-year-old woman developed chest pain and ventricular tachycardia. She had a 14-year history of right-sided focal motor seizures controlled with phenytoin. After receiving intravenous lidocaine 100 mg to treat the dysrhythmias she developed a typical seizure involving the right side of her face and arm. She was given a loading dose of phenytoin and the seizure abated. However, the ventricular tachycardia persisted and was treated with additional lidocaine 50 mg followed by an infusion of 3.3 mg/minute; 6 hours later she had a generalized seizure with a venous blood lidocaine concentration of 21 μg/ml. The infusion was stopped and the seizure was treated with intravenous diazepam 10 mg. • A 41-year-old woman with a long-standing history of focal and secondarily generalized seizures controlled with carbamazepine underwent cerebral arteriography, during which she was inadvertently given lidocaine 20 mg via an intra-arterial catheter in the right internal carotid artery; within 20 seconds she had a focal seizure.

These two patients had their typical partial seizures triggered by high doses of lidocaine. In both cases the serum concentrations of their usual anticonvulsants were initially low. The ﬁrst patient received a loading dose of phenytoin after the partial seizure, was then given a second bolus of lidocaine and an infusion, and then had a second seizure, which was generalized. There was no evidence that this second seizure evolved from the left seizure focus. The authors concluded that lidocaine can activate seizure foci in patients with a history of partial seizures and that this may be more likely if the serum concentrations of anticonvulsants are low. However, therapeutic concentrations of antiepileptic drugs may not prevent generalized seizures that result from the widespread lowering of seizure threshold caused by high concentrations of lidocaine. Drug overdose Fatal accidental overdose has been reported in a child. • An 18-month-old infant died after swallowing an unknown amount 2% viscous lidocaine (56A ). He rapidly became unwell at home, with convulsions, followed by an asystolic cardiorespiratory arrest. He was intubated and resuscitated by paramedics, but continued to have seizures. He was given anticonvulsants and cardiorespiratory resuscitation unsuccessfully. Toxicological tests identiﬁed high concentrations of lidocaine and its metabolites.

Owing to the rare but serious poisonings reported to date, 2% viscous lidocaine should not be prescribed for children under 6 years of age.

An unusual case of homicide using an overdose of intravenous lidocaine has been described (57A ). • A 32-year-old man, who had been in hospital for several months because of acute intermittent porphyria and chronic pancreatitis, had a seizure and an asystolic cardiac arrest. Resuscitation was unsuccessful. There was a suspicion of patient mistreatment by one of the attending nurses, and toxicological analyses showed high blood concentrations of lidocaine, diazepam, phenytoin, and promethazine. Diazepam and phenytoin had been administered during resuscitation but lidocaine had not.

The cause of death was given as ventricular dysrhythmia caused by a lidocaine overdose (total dose about 1500 mg), and a nurse was later arrested and tried for murder.

Ropivacaine

(SED-14, 353; SEDA-25, 156; SEDA-26, 147) Nervous system Three patients suffered convulsions as a result of inadvertent intravascular injection of ropivacaine during placement of local blocks.

• A 75-year-old woman received ropivacaine 160 mg intravenously through an epidural catheter (58A ). After completion of the injection, she suddenly became unresponsive and had a generalized tonic– clonic convulsion accompanied by a sinus tachycardia of 120 bpm but no other cardiac dysrhythmias. • A 56-year-old 70 kg woman with a Colles fracture received a brachial plexus block at the humeral canal with 0.75% ropivacaine 40 ml using a nerve stimulator (59A ). The local anesthetic was administered slowly with negative intermittent aspiration. However, 15 minutes later she had two generalized convulsions, which were treated with diazepam. The total venous ropivacaine concentration measured 2 hours after the block was 2.3 μg/ml. • A 25-year-old man received ropivacaine 75 mg intravenously during sciatic nerve block (60A ). The nerve was located using a nerve stimulator and the injection was performed after elicitation of a distal extensor response. Numerous aspirations were performed during the procedure, but 1 minute after injection he suddenly became unresponsive and developed a tonic–clonic seizure, which resolved after treatment with midazolam and propofol. The only cardiovascular effect was a sinus tachycardia of 130 bpm.

Local anesthetics

Chapter 11

In the last case, the authors noted that the motor response to stimulation was maintained throughout the injection; it is generally felt that the motor response to stimulation should disappear after the injection of the ﬁrst milliliters of local anesthetic and if the response does not disappear the injection should be stopped.

135 In all three cases nervous system toxicity occurred with minimal or no cardiovascular toxicity, which is in keeping with previous reports, conﬁrming the relative safety of ropivacaine; there has still not been one single fatal outcome reported with this agent.

REFERENCES 1. Rose M, Ness TJ. Hypoxia following interscalene block. Reg Anesth Pain Med 2002; 27: 94–6. 2. Heid FM, Kern T, Brambrink AM. Transient respiratory compromise after infraclavicular vertical brachial plexus blockade. Eur J Anaesthesiol 2002; 19: 693–4. 3. Dullenkopf A, Zingg P, Curt A, Borgeat A. Funktionsverlust der oberen Extremität nach Bankart– Schulteroperation unter Interscalenus-blockade und Allgemeinanästhesie. Anaesthesist 2002; 51: 547– 51. 4. Fellmann C, Gerber AC, Weiss M. Apnoea in a former preterm infant after caudal bupivacaine with clonidine for inguinal herniorrhaphy. Paediatr Anaesth 2002; 12: 637–40. 5. Ivani G, DeNegri P, Conio A, Grossetti R, Vitale P, Vercellino C, Gagliardi F, Eksborg S, Lonnqvist PA. Comparison of racemic bupivacaine, ropivacaine, and levo-bupivacaine for pediatric caudal anesthesia: effects on postoperative analgesia and motor block. Reg Anesth Pain Med 2002; 27: 157–61. 6. Lopez Galera S, Fernandez Galinski D, Echevarria Martin J, Aguilar Sanchez JL. Asistolia despues de anestesia combinada. Rev Esp Anestesiol Reanim 2002; 49: 334–6. 7. Britts R, Wadsworth R. Unexpectedly high block during total lunar eclipse. Int J Obstet Anesth 2002; 11: 71–2. 8. Zahn PK, Van Aken HK, Marcus AE. Horner’s syndrome following epidural anesthesia with ropivacaine for cesarean delivery. Reg Anesth Pain Med 2002; 27: 445–6. 9. Kiran S, Singal NK. A comparative study of three different doses of 0.5% hyperbaric bupivacaine for spinal anaesthesia in elective caesarean section. Int J Obstet Anesth 2002; 11: 185–9. 10. Kaabachi O, Ben-Rajeb A, Mebazaa M, Saﬁ H, Jelel C, Ben-Ghachem M, Ben-Ammar M. La rachianesthésie chez l’enfant: étude comparative de la bupivacaïne hyperbare avec et sans clonidine. Ann Fr Anesth Réanim 2002; 21: 617–21. 11. Kuczkowski KM. Respiratory arrest in a parturient following intrathecal administration of fentanyl and bupivacaine as part of a combined spinalepidural analgesia for labour. Anaesthesia 2002; 57: 939–40. 12. Davies MJ, Cook RJ, Quach K. Transient lumbar pain after 5% hyperbaric lignocaine spinal

anaesthesia in patients having minor vascular surgery. Anaesth Intensive Care 2002; 30: 782–5. 13. Bang-Vojdanovski B, Hannibal H, Eberhardt M. Vorübergehende neurologische Symptome nach einer Spinalanästhesie mit 4%igem hyperbarem Scandicain® (Mepivacain). Anaesthesist 2002; 51: 989–92. 14. Takenami T, Kondou Y, Kimotsuki H, Okamoto H, Hoka S. A case of transient neurologic symptoms following epidural mepivacaine and spinal tetracaine. J Anesth 2002; 16: 336–8. 15. Alley EA, Pollock JE. Transient neurologic syndrome in a patient receiving hypobaric lidocaine in the prone jack-knife position. Anesth Analg 2002; 95: 757–9. 16. Takenami T, Yagishita S, Asato F, Arai M, Hoka S. Intrathecal lidocaine causes posterior root axonal degeneration near entry into the spinal cord in rats. Reg Anesth Pain Med 2002; 27: 58–67. 17. Radwan IA, Saito S, Goto F. The neurotoxicity of local anesthetics on growing neurons: a comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine. Anesth Analg 2002; 94: 319–24. 18. Eberhart LH, Morin AM, Kranke P, Geldner G, Wulf H. Transiente neurologische Symptome nach Spinalanästhesie. Eine quantitative systematische Übersicht (Metaanalyse) randomisierter kontrollierter Studien. Anaesthesist 2002; 51: 539–46. 19. Al-Nasser B, Negre M, Hubert C. Transient neurological manifestations after epidural analgesia with ropivacaine. Anaesthesia 2002; 57: 306–7. 20. Yorozu T, Matsumoto M, Hayashi S, Yamada T, Nakaohji T, Nakatsuka I. [Dibucaine for spinal anesthesia is a probable risk for cauda equina syndrome.] (in Japanese) Masui 2002; 51: 1151–4. 21. Van Eeden SP, Patel MF. Re: Prolonged paraesthesia following inferior alveolar nerve block using articaine. Br J Oral Maxillofac Surg 2002; 40: 519–20. 22. Niemi M, Laaksonen JP, Vahatalo K, Tuomainen J, Aaltonen O, Happonen RP. Effects of transitory lingual nerve impairment on speech: an acoustic study of vowel sounds. J Oral Maxillofac Surg 2002; 60: 647–52; discussion 53. 23. Sanchis JM, Penarrocha M. Uvular paralysis after dental anesthesia. J Oral Maxillofac Surg 2002; 60: 1369–71. 24. Evans LA, Pointing J, Wills EJ, Michalopoulos J, Adelstein S. Recurrent facial swelling fol-

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lowing dental procedures. Med J Aust 2002; 177: 522. 25. Marica LS, O’Day T, Janosky JE, Nystrom EU. Chloroprocaine is less painful than lidocaine for skin inﬁltration anesthesia. Anesth Analg 2002; 94: 351–4. 26. Imison A, Nunan P. An unusual case of transient paraplegia. Anaesth Intensive Care 2002; 30: 102–3. 27. Atanassoff PG, Hartmannsgruber MW. Central nervous system side effects are less important after iv regional anesthesia with ropivacaine 0.2% compared to lidocaine 0.5% in volunteers. Can J Anaesth 2002; 49: 169–72. 28. Mullanu C, Gaillat F, Scemama F, Thibault S, Lavand’homme P, Auffray JP. Acute toxicity of local anesthetic ropivacaine and mepivacaine during a combined lumbar plexus and sciatic block for hip surgery. Acta Anaesthesiol Belg 2002; 53: 221–3. 29. Bharti N, Shende D. Transient cardiopulmonary arrest following retrobulbar block with lignocaine. Anaesth Intensive Care 2002; 30: 388–9. 30. Wadood AC, Dhillon B, Singh J. Inadvertent ocular perforation and intravitreal injection of an anesthetic agent during retrobulbar injection. J Cataract Refract Surg 2002; 28: 562–5. 31. Adams W, Morgan SJ. Diplopia following subtenon’s inﬁltration of local anesthesia. J Cataract Refract Surg 2002; 28: 1694–7. 32. Wubbolt I, Winter R, Brockmann D, Sistani F. Endotheltoxizität verschiedener Lokalanästhetika. Spektrum Augenheilkd 2002; 16: 206–10. 33. Dahlmann AH, Appaswamy S, Headon MP. Orbital cellulitis following sub-tenon’s anaesthesia. Eye 2002; 16: 200–1. 34. Pharmakakis NM, Katsimpris JM, Melachrinou MP, Koliopoulos JX. Corneal complications following abuse of topical anesthetics. Eur J Ophthalmol 2002; 12: 373–8. 35. Mahli A, Coskun D, Akcali DT. Aetiology of convulsions due to stellate ganglion block: a review and report of two cases. Eur J Anaesthesiol 2002; 19: 376–80. 36. Gammaitoni AR, Alvarez NA, Galer BS. Pharmacokinetics and safety of continuously applied lidocaine patches 5%. Am J Health-Syst Pharm 2002; 59: 2215–20. 37. Galer BS. Effectiveness and safety of lidocaine patch 5%. J Fam Pract 2002; 51: 867–8; author’s reply 868. 38. Yamashita S, Sato S, Kakiuchi Y, Miyabe M, Yamaguchi H. Lidocaine toxicity during frequent viscous lidocaine use for painful tongue ulcer. J Pain Symptom Manage 2002; 24: 543–5. 39. Abdallah HY, Shah SA. Methemoglobinemia induced by topical benzocaine: a warning for the endoscopist. Endoscopy 2002; 34: 730–4. 40. Margulies DR, Manookian CM. Methemoglobinemia as a cause of respiratory failure. J Trauma 2002; 52: 796–7. 41. Voelker CA, Brown L, Hinson RM. Perioperatively acquired methaemoglobinaemia in a preterm infant. Paediatr Anaesth 2002; 12: 284–6.

42. Sinisterra S, Miravet E, Alfonso I, Soliz A, Papazian O. Methemoglobinemia in an infant receiving nitric oxide after the use of eutectic mixture of local anesthetic. J Pediatr 2002; 141: 285–6. 43. Dong H, Kerl H, Cerroni L. Emla cream-induced irritant contact dermatitis. J Cutaneous Pathol 2002; 29: 190–2. 44. Dytoc MT, Fiorillo L, Liao J, Krol AL. Granuloma gluteale adultorum associated with use of topical benzocaine preparations: case report and literature review. J Cutaneous Med Surg 2002; 6: 221–5. 45. Heavner JE. Cardiac toxicity of local anesthetics in the intact isolated heart model: a review. Reg Anesth Pain Med 2002; 27: 545–55. 46. Graf BM, Abraham I, Eberbach N, Kunst G, Stowe DF, Martin E. Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology 2002; 96: 1427–34. 47. Mulroy MF. Systemic toxicity and cardiotoxicity from local anesthetics: incidence and preventive measures. Reg Anesth Pain Med 2002; 27: 556–61. 48. Weinberg GL. Current concepts in resuscitation of patients with local anesthetic cardiac toxicity. Reg Anesth Pain Med 2002; 27: 568–75. 49. Pickering AE, Waki H, Headley PM, Paton JF. Investigation of systemic bupivacaine toxicity using the in situ perfused working heart-brainstem preparation of the rat. Anesthesiology 2002; 97: 1550–6. 50. Karaca S, Unlusoy EO. Accidental injection of intravenous bupivacaine. Eur J Anaesthesiol 2002; 19: 616–17. 51. Mizuno Y, Esaki Y, Kato H. [Anaphylactoid reaction to dibucaine during spinal anesthesia.] (in Japanese) Masui 2002; 51: 1254–6. 52. Gristwood RW. Cardiac and CNS toxicity of levobupivacaine: strengths of evidence for advantage over bupivacaine. Drug Saf 2002; 25: 153–63. 53. Pirotta D, Sprigge J. Convulsions following axillary brachial plexus blockade with levobupivacaine. Anaesthesia 2002; 57: 1187–9. 54. Sawyer RJ, Von Schroeder H. Temporary bilateral blindness after acute lidocaine toxicity. Anesth Analg 2002; 95: 224–6. 55. DeToledo JC, Minagar A, Lowe MR. Lidocaine-induced seizures in patients with history of epilepsy: effect of antiepileptic drugs. Anesthesiology 2002; 97: 737–9. 56. Nisse P, Lhermitte M, Dherbecourt V, Fourier C, Leclerc F, Houdret N, Mathieu-Nolf M. Intoxication mortelle après ingestion accidentelle de Xylocaine visqueuse a 2% chez une jeune enfant. Acta Clin Belg 2002; 1: 51–3. 57. Kalin JR, Brissie RM. A case of homicide by lethal injection with lidocaine. J Forensic Sci 2002; 47: 1135–8. 58. Cherng C-H, Wong C-S, Ho S-T. Ropivacaineinduced convulsion immediately after epidural administration—a case report. Acta Anaesthesiol Sinica 2002; 40: 43–5. 59. Ould-Ahmed M, Drouillard I, Fourel D, Roussaly P, Almanza L, Segalen F. Convulsions induites

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par 1a ropivacaine lors d’un bloc au canal humeral. Fr Anesth Reanim 2002; 21: 681–4. 60. Petitjeans F, Mion G, Puidupin M, Tourtier JP, Hutson C, Saissy JM. Tachycardia and convulsions

137 induced by accidental intravascular ropivacaine injection during sciatic block. Acta Anaesthesiol Scand 2002; 46: 616–17.

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Neuromuscular blocking agents and skeletal muscle relaxants

Hypersensitivity reactions to muscle relaxants The diagnosis of an allergic reaction to a muscle relaxant is based on clinical features, measurement of histamine and tryptase concentrations in the plasma during the reaction, and subsequent skin testing a few weeks later. However, during general anesthesia isolated symptoms can occur, most often hypotension or bronchospasm. Therefore, the clinical features of anaphylaxis may not be recognized as such. Also, histamine and tryptase concentrations may be ambiguous. The detection of drug-speciﬁc IgE is valuable, but the sensitivity of IgE testing is variable and reached 90–97% in selected specialized centers only (1E ). Skin testing is therefore essential to conﬁrm the diagnosis and to identify the causative agent (2r ). The sensitivity of skin testing for reactions to muscle relaxants is thought to be greater than 95% (2r ), although signiﬁcantly lower for opioids, barbiturates, and synthetic colloids (3R ). Additional biological tests have been suggested to improve the accuracy further. The leukocyte histamine release test has been found helpful (4E ) but it is expensive and time-consuming. Flow cytometry has been suggested for the detection of basophil activation. Several surface molecules have been studied as markers, for example CD63. Recently, an assay for CD63 and CCR3 was reported to have a sensitivity of 54% compared with 63% for the detection of speciﬁc IgE (5E ). Combined, these tests had a sensitivity of 80% and a speciﬁcity of 100%. The authors regarded this as a © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

138

promising approach to the diagnosis of muscle relaxant allergy in cases in which there were discrepancies between the clinical presentation and the laboratory results. More information about allergic reactions during anesthesia is given in a recent review (3R ). Another case of an anaphylactic reaction to cisatracurium (6c ) and more cases of anaphylactic reactions to rocuronium (7c –9c ) have been published. One patient died after developing multiorgan failure due to a reaction to rocuronium (10c ). • A 64-year-old obese man, scheduled for a hernia repair, had previous episodes of venous thromboembolism, for which he was still taking an oral anticoagulant. Previous general anesthesia had been uneventful. General anesthesia was induced with sufentanil 15 μg and propofol 400 mg. He was given rocuronium 50 mg to facilitate endotracheal intubation, and shortly after developed bronchospasm, severe hypotension, tachycardia, and generalized erythema. He was resuscitated with adrenaline, hydrocortisone, and colloid infusion. However, his further course after admission to the intensive care unit was complicated by persistent hypotension, acute respiratory distress syndrome, acute renal insufﬁciency, disseminated intravascular coagulation, and pancreatitis, and he died 7 days after the incident. Blood samples drawn at 30 and 60 minutes after the initial presentation showed increased concentrations of histamine and tryptase. Speciﬁc IgE antibodies against quaternary ammonium groups were detected, with a positive radioimmunoassay inhibition by rocuronium.

Death caused by an anaphylactic reaction to a muscle relaxant seems to be rare, although mortality rates from intraoperative anaphylaxis in the range of 3.4–6% have been reported (11Cr , 12c –14c ). The incidence of cardiac arrest was 4.9% among patients with anaphylactic reactions to muscle relaxants referred to the

Neuromuscular blocking agents and skeletal muscle relaxants

French GERAP centers for further testing, but these patients all survived (15C ). In a recent publication from the same group the incidence of allergic reactions to several muscle relaxants was also assessed in relation to the number of vials sold in France (16C ). In line with a previous publication (15C ) the proportion of reported reactions to rocuronium was higher than its corresponding market share. Based on that, the authors suggested classifying the risk of allergic reactions to neuromuscular blocking agents as high (succinylcholine, rocuronium), intermediate (pancuronium, vecuronium, mivacurium), and low (atracurium, cisatracurium). We should like to stress that this classiﬁcation is based on the assumption that the ratio of used/sold vials is similar for each agent, which may or may not be true. The authors themselves insisted that they did not recommend one muscle relaxant over another on the basis of their allergic potential (17r ). As highlighted before (SEDA-26, 150), there are signiﬁcant methodological and statistical problems when such rare events are compared. What we need is an international network of clinics specialized in investigating patients after suspected intraoperative allergic reactions, and the French GERAP centers are an excellent example of this. Allergic reactions to muscle relaxants have received considerable attention in the anesthetic literature over the last couple of years. This has prompted some anesthetists to reconsider the use of neuromuscular blocking agents in general, and it has been suggested that advances in anesthetic technique, in combination with newer anesthetic drugs, might justify a much more restrictive use of muscle relaxants (18r ). On the other hand, endotracheal intubation is less traumatic when it is facilitated by a muscle relaxant. Vocal cord hematoma after intubation occurred in six of 36 patients when only fentanyl plus propofol was used, compared with one of 37 when atracurium was added (19c ). The incidence of allergic reactions to muscle relaxants has been estimated as 1 in 6500 or 15 in 100 000 cases (20C ). In other settings clinicians do not hesitate to use substances with a similar or higher incidence of anaphylaxis if the patient is expected to beneﬁt. For example, the incidence of anaphylaxis has been

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estimated as 32 in 100 000 for parenteral penicillin, 35 in 100 000 for non-ionic contrast media, and 55 in 100 000 for blood (21C ). We therefore believe that the risk of anaphylaxis should not stop us from using muscle relaxants for endotracheal intubation.

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 371; SEDA-24, 159; SEDA-25, 160; SEDA-26, 150)

Residual paralysis Residual paralysis after the use of long-acting muscle relaxants, such as pancuronium, is not uncommon and can result in signiﬁcant pulmonary complications (22C ). Many anesthetists have assumed that this was less of a problem with agents of intermediate duration. However, a surprisingly high incidence of residual neuromuscular impairment has been reported after a single intubating dose of muscle relaxants of intermediate duration as well (23c ). Two hours after either rocuronium, vecuronium, or atracurium, the train-of-four ratio was still below 0.7 in 10% of patients and below 0.9 in 37%, which was not reliably detected by clinical evaluation (head lift, tongue depressor test) or qualitative measurements (repetitive nerve stimulation with tactile evaluation of fade). Similar results have been reported by others (24c –27c ). Pharyngeal dysfunction with a risk of aspiration has been observed in partially paralysed awake volunteers at trainof-four ratios below 0.9 (28c , 29c ). Therefore, patients with a train-of-four ratio below 0.9 at the end of the operation should receive a cholinesterase inhibitor, such as neostigmine, in order to reduce the impact of residual paralysis. This obviously implies that quantitative monitoring of neuromuscular transmission should be used routinely. Only if this is not possible should a cholinesterase inhibitor be given blindly. This represents a change in our opinion: we had previously stated that anticholinesterase drugs should be used to reverse residual neuromuscular block detected by monitoring of neuromuscular transmission or producing clinical symptoms (SEDA-24, 157).

140 Now we acknowledge that a reversal agent is justiﬁed, even in asymptomatic patients, because residual dysfunction of certain muscle groups may still be present. For the time being there is nothing to support the routine use of an anticholinesterase drug if spontaneous recovery with a train-of-four ratio of 0.9 or above can be demonstrated. We should like to stress that attempts to reverse intense neuromuscular blockade must be avoided. Therefore, some evidence of recovery of neuromuscular transmission (e.g. spontaneous ventilation, voluntary movements, twitch response to nerve stimulation) should be observed before any anticholinesterase is given. In addition, it should be mentioned that large doses of cholinesterase inhibitors can cause deterioration rather than improvement of neuromuscular function (30c , 31c ). It is unnecessary to use more than 2.5 mg of neostigmine or equivalent (32c ). Neostigmine 1.25 mg or equivalent may be as effective (33c ) and is associated with a reduced incidence of postoperative nausea and vomiting (34M ).

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14, 361; SEDA-24, 158; SEDA-25, 161; SEDA-26, 151)

Succinylcholine Electrolyte balance Succinylcholine can be expected to produce an increase in serum potassium concentration of 0.5–1.0 mmol/l. It is therefore contraindicated in patients with hyperkalemia (i.e. a serum potassium concentration over 5.5 mmol/l). This, however, has recently been questioned (35c ). In an analysis of their anesthetic database, the authors identiﬁed 38 patients with a preoperative serum potassium concentration over 5.5 mmol/l who subsequently received succinylcholine. In no case were dysrhythmias or any complications documented and there were no deaths. While they admitted that minor complications might not have found their way into the database, the authors felt that major problems caused by succinylcholine in these patients were unlikely. They suggested that the use of succinylcholine

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O. Zuzan and M. Leuwer

in patients with serum potassium concentrations above 5.5 mmol/l may be acceptable when other muscle relaxants have inappropriate proﬁles. As their analysis included only a few patients with serum potassium concentrations above 6.0 mmol/l they recommended the use of antihyperkalemic treatment before succinylcholine in these patients. Susceptibility factors The choice of muscle relaxants for rapid sequence induction of anesthesia in patients at risk of aspiration has been controversial for many years. Succinylcholine has been used for decades, because it has a fast onset and a short duration of action, although it can have severe adverse effects. Alternatives have been suggested, all of which have their own pros and cons, but succinylcholine has withstood the test of time and is still widely used. On this background, the use of rocuronium versus succinylcholine has been subjected to a Cochrane review, in which 40 studies addressing the issue were identiﬁed, 26 of which were combined for analysis (36R ). For rocuronium, the relative risk of excellent intubating conditions was 0.87 (95% CI = 0.81, 0.94) compared with succinylcholine. In a subgroup of patients who had been given propofol as an induction agent, there was no difference between rocuronium and succinylcholine. The reviewers concluded that overall succinylcholine creates excellent intubation conditions more reliably than rocuronium and should still be used as a ﬁrst line muscle relaxant for rapid sequence intubation. Rocuronium, when used with propofol, reliably created excellent intubation conditions and was consequently suggested as a second-line alternative to succinylcholine. In addition, we suggest that intubating under deep anesthesia without a neuromuscular blocker is an acceptable third-line alternative if neither succinylcholine nor rocuronium is considered appropriate. To allow rapidsequence intubation of the trachea without a muscle relaxant, adequate doses of propofol (2.0–2.5 mg/kg) or etomidate (0.3 mg/kg) and a fast-onset opioid, such as alfentanil (50 μg/kg) or remifentanil (4 μg/kg) are required (37c – 42c ). Drug interactions Donepezil is an acetylcholinesterase inhibitor used to improve cognitive function in patients with Alzheimer disease. It has been hypothesized that donepezil

Neuromuscular blocking agents and skeletal muscle relaxants

like other cholinesterase inhibitors could prolong the action of succinylcholine (43r , 44r ). The authors of a recent report suggested that their case might have been an example of this interaction (45r ). • A 72-year-old woman with a symptomatic hiatus hernia, osteoarthritis, and Alzheimer’s disease was taking ﬂuoxetine 20 mg/day, donepezil hydrochloride 10 mg/day, nimesulide 12.5 mg/day, and omeprazole 20 mg/day. There still was no twitch response to peripheral nerve stimulation 20 minutes after rapid-sequence induction of anesthesia with propofol 2.5 mg/kg and succinylcholine 1 mg/kg. She then gradually developed a weak twitch response, and 50 minutes after induction of anesthesia four twitches with a fade were elicited by train-of-four stimulation. No additional medication was given and after the end of the procedure 10 minutes later she was extubated uneventfully. She refused further blood testing and so her plasma cholinesterase activity at that time is not known. However, her anesthetic notes from a previous operation did not reveal any problems with prolonged paralysis after succinylcholine.

It is not proven that donepezil was the cause of the prolonged duration of action of succinylcholine in this case. However, a case with some similarities has been reported before (46c ). In addition, there has been another report linking donepezil therapy to both prolonged duration of action of succinylcholine and reduced sensitivity to atracurium (47c ). Recovery of neuromuscular function should therefore be monitored when succinylcholine is given to patients taking donepezil. The withdrawal of donepezil 2–3 weeks before an operation cannot be supported, because this might have adverse effects on cognitive function. The issue has been highlighted in a recent letter, and we agree with the author’s conclusion that “a brief prolongation of muscle relaxation is very rarely a problem (although its mismanagement may be)” (48r ).

SKELETAL MUSCLE RELAXANTS (SED-14, 390; SEDA-24, 159; SEDA-25, 163; SEDA-26, 152)

Baclofen Nervous system The systemic effects of baclofen can cause a reduced level of consciousness. Intrathecal application via a catheter is

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therefore widely used to avoid systemic effects. However, because a continuous infusion is required, implantable pumps containing a very concentrated solution of baclofen are used to avoid frequent reﬁlls. Inadvertent subarachnoid bolus administration of a concentrated solution will produce cranial spread of baclofen within the CSF, resulting in cerebral effects. This is most likely to occur when a new catheter or pump is implanted or during surgical revision of a catheter or implantable pump in cases of malfunction. A report of coma after implantation of a baclofen pump in ﬁve out of nine consecutive children illustrates this (49c ). The authors suggested that these children should be monitored in the recovery room for 5 hours postoperatively, in order to cover both the peak effect of any baclofen bolus and the additive effects of other perioperative CNS suppressants, such as opioids, benzodiazepines, or sedative antiemetics. In another recent report of transient coma after perioperative intrathecal bolus administration it was shown that the management of this complication can require admission to an intensive care unit (50c ). Gastrointestinal A possible effect of intrathecal baclofen on intestinal motility has been proposed (51c ). Triggered by two cases of paralytic ileus in patients receiving continuous intrathecal baclofen, the authors reviewed the case notes of 14 patients and summed the days without bowel movements before and after intrathecal baclofen therapy. Intestinal function deteriorated in ten patients, was unchanged in one, and improved in three. They therefore advised that intestinal activity should be closely observed in patients receiving intrathecal baclofen. However, they felt that treatment could be continued, even in particularly sensitive patients, if prokinetic, laxative, or eubiotic drugs were used to promote peristaltic function. Body temperature Febrile reactions after intrathecal baclofen stopped a patient from receiving this treatment for spinal spasticity (52c ). • A 33-year-old woman with spasticity caused by a myelopathy after numerous operations on her spine received a single bolus dose of baclofen 50 μg via a lumbar puncture, which resulted in complete resolution of her spasticity for almost

142 24 hours. However, her temperature increased to 39.0◦ C within 2 hours after the injection, and she had ﬂu-like symptoms. Inﬂuenza was assumed to be the most likely explanation, as a child in her house had inﬂuenza at that time. Subsequently, an intrathecal catheter was placed and a baclofen pump implanted. However, her temperature rose again after baclofen administration had been started and the pump was halted. Subsequently, several attempts were made to restart the infusion, followed each time by spikes of fever. In the end, continuous intrathecal baclofen therapy had to be abandoned, and the fever did not recur. Several investigations to identify other causes of fever were mostly negative. However, based on bilateral hilar adenopathy on the chest X-ray and increased concentrations of angiotensinconverting enzyme, sarcoidosis was suspected.

The authors claimed that this was the ﬁrst report of this problem. Referring to the observation that baclofen injection into the cerebral ventricles can produce fever in rats (53E ) they assumed that rostral spread of baclofen could have initiated a thermoregulatory response via the chemotrigger zone in the third ventricle. They suggested that a percutaneous subarachnoid catheter could facilitate the decision to either proceed with or abort surgical catheter or pump implantation when baclofen is associated with fever. Drug withdrawal A withdrawal syndrome, with muscular hyperactivity, hyperthermia, metabolic derangements, and rhabdomyolysis, can occur when baclofen therapy is abruptly discontinued, and several deaths have occurred (54cr ). Because early diagnosis is crucial a high level of suspicion is justiﬁed if patients receiving continuous baclofen treatment present with these symptoms. The ﬁrst-line treatment should be administration of baclofen if feasible. As a second step, a benzodiazepine can be used. Only if hyperthermia and muscular hyperactivity still persist despite this treatment should dantrolene be considered. • A 14-year-old child receiving continuous intrathecal baclofen treatment developed a fever of up to 40◦ C and painful muscle spasms, attributed to baclofen withdrawal due to failure of the intrathecal catheter. The symptoms resolved promptly after reintroduction of intrathecal baclofen (55r ).

If intrathecal baclofen has to be interrupted or cannot be restarted immediately, enteral baclofen should be given. However, ﬁnding the

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appropriate dose for this can be difﬁcult and close observation of the patient is required, as illustrated in the following report (56c ). • A 34-year-old man who was receiving continuous intrathecal baclofen (700 μg/day) for muscle spasticity after a spinal cord injury developed a fever, and infection of the implanted baclofen pump was suspected. The device was removed and he was given replacement therapy with oral baclofen (40 mg tds). He developed a tremor 12 hours after pump removal and his heart rate increased to 120/min. Another 12 hours later he was somnolent, agitated, and confused, and had visual hallucinations. His blood pressure rose to 198/108 mmHg and his temperature to 40◦ C. This was followed by atrial ﬁbrillation with a ventricular rate of 170/min. The dose of oral baclofen was increased to 80 mg tds and he was given intravenous lorazepam 6–8 mg every four hours. During the following 24 hours his blood pressure, pulse, and temperature normalized and he recovered fully.

It has been hypothesized that the baclofen withdrawal syndrome might have similarities with the serotonin syndrome caused by overdose of serotonin reuptake inhibitors or amphetamines (57c ). Consequently, the authors used the serotonin receptor antagonist cyproheptadine in combination with oral baclofen and a benzodiazepine in four patients with baclofen withdrawal syndrome after continuous intrathecal baclofen therapy. They claimed that their patients improved signiﬁcantly when cyproheptadine was given. Body temperature fell by at least 1.5◦ C and heart rate fell from 120–140/min to under 100/min. Muscular tone and myoclonus improved. Two patients also reported that itching was less intense. All this was felt to be temporarily related to the repeated administration of cyproheptadine. The authors concluded that cyproheptadine was a useful adjunct for the treatment of baclofen withdrawal syndrome. However, one of their patients suffered severe brain damage during withdrawal and subsequently died of pulmonary complications. This illustrates that early intensive care is required.

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anesthesia in France in 1999–2000. Anesthesiology 2003; 99: 536–45. 17. Laxenaire M, Mertes P. Anaphylaxis during anaesthesia. Br J Anaesth 2002; 88: 605–6. 18. Baillard C, Larmignat P, Fournier JL, Denantes C, Cupa M, Samama CM. Anesthesia: with or without curare? Can J Anaesth 2003; 50: 522. 19. Mencke T, Echternach M, Kleinschmidt S, Lux P, Barth V, Plinkert PK, Fuchs-Buder T. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology 2003; 98: 1049–56. 20. Laxenaire MC. Epidémiologie des réactions anaphylactoïdes peranesthésiques. Quatrième enquête multicentrique (juillet 1994–décembre 1996). Ann Fr Anesth Reanim 1999; 18: 796–809. 21. The International Collaborative Study of Severe Anaphylaxis. Risk of anaphylaxis in a hospital population in relation to the use of various drugs: an international study. Pharmacoepidemiol Drug Saf 2003; 12: 195–202. 22. Berg H, Viby-Mogensen J, Roed J, Mortensen CR, Engbaek J, Skovgaard LT, Krintel JJ. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand 1997; 41: 1095–103. 23. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003; 98: 1042–8. 24. Appelboam R, Mulder R, Saddler J. Atracurium associated with postoperative residual curarization. Br J Anaesth 2003; 90: 523. 25. Hayes AH, Mirakhur RK, Breslin DS, Reid JE, McCourt KC. Postoperative residual block after intermediate-acting neuromuscular blocking drugs. Anaesthesia 2001; 56: 312–18. 26. Baillard C, Gehan G, Reboul-Marty J, Larmignat P, Samama CM, Cupa M. Residual curarization in the recovery room after vecuronium. Br J Anaesth 2000; 84: 394–5. 27. Fawcett WJ, Dash A, Francis GA, Liban JB, Cashman JN. Recovery from neuromuscular blockade: residual curarisation following atracurium or vecuronium by bolus dosing or infusions. Acta Anaesthesiol Scand 1995; 39: 288–93. 28. Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, Kuylenstierna R. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997; 87: 1035–43. 29. Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna R, Eriksson LI. The incidence and mechanisms of pharyngeal and upper esophageal

144 dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology 2000; 92: 977–84. 30. Payne JP, Hughes R, Al Azawi S. Neuromuscular blockade by neostigmine in anaesthetized man. Br J Anaesth 1980; 52: 69–76. 31. Goldhill DR, Wainwright AP, Stuart CS, Flynn PJ. Neostigmine after spontaneous recovery from neuromuscular blockade. Effect on depth of blockade monitored with train-of-four and tetanic stimuli. Anaesthesia 1989; 44: 293–9. 32. Jones JE, Hunter JM, Utting JE. Use of neostigmine in the antagonism of residual neuromuscular blockade produced by vecuronium. Br J Anaesth 1987; 59: 1454–8. 33. Jones JE, Parker CJ, Hunter JM. Antagonism of blockade produced by atracurium or vecuronium with low doses of neostigmine. Br J Anaesth 1988; 61: 560–4. 34. Tramèr MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and risk of residual paralysis. A systematic review. Br J Anaesth 1999; 82: 379–86. 35. Schow AJ, Lubarsky DA, Olson RP, Gan TJ. Can succinylcholine be used safely in hyperkalemic patients? Anesth Analg 2002; 95: 119–22. 36. Perry J, Lee J, Wells G. Rocuronium versus succinylcholine for rapid sequence induction intubation (Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Oxford: Update Software. 37. Beck GN, Masterson GR, Richards J, Bunting P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia 1993; 48: 876–80. 38. Scheller MS, Zornow MH, Saidman LJ. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg 1992; 75: 788–93. 39. Wong AKH, Teoh GS. Intubation without muscle relaxant: an alternative technique for rapid tracheal intubation. Anaesth Intensive Care 1996; 24: 224–30. 40. Stevens JB, Vescovo MV, Harris KC, Walker SC, Hickey R. Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important? Anesth Analg 1997; 84: 1222–6. 41. Klemola UM, Mennander S, Saarnivaara L. Tracheal intubation without the use of muscle relaxants: remifentanil or alfentanil in combination with propofol. Acta Anaesthesiol Scand 2000; 44: 465– 9. 42. Erhan E, Ugur G, Alper I, Gunusen I, Ozyar B. Tracheal intubation without muscle relax-

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ants: remifentanil or alfentanil in combination with propofol. Eur J Anaesthesiol 2003; 20: 37–43. 43. Heath ML. Donepezil, Alzheimer’s disease and suxamethonium. Anaesthesia 1997; 52: 1018. 44. Walker C, Perks D. Do you know about donepezil and succinylcholine? Anaesthesia 2002; 57: 1041. 45. Crowe S, Collins L. Suxamethonium and donepezil: a cause of prolonged paralysis. Anesthesiology 2003; 98: 574–5. 46. Sprung J, Castellani WJ, Srinivasan V, Udayashankar S. The effects of donepezil and neostigmine in a patient with unusual pseudocholinesterase activity. Anesth Analg 1998; 87: 1203–5. 47. Sanchez Morillo J, Demartini Ferrari A, Roca de Togores Lopez A. Interacción entre donepezilo y bloqueantes musculares en la enfermedad de Alzheimer. Rev Esp Anestesiol Reanim 2003; 50: 97–100. 48. Heath ML. Donepezil and succinylcholine. Anaesthesia 2003; 58: 202. 49. Anderson KJ, Farmer JP, Brown K. Reversible coma in children after improper baclofen pump insertion. Paediatr Anaesth 2002; 12: 454–60. 50. Lyew MA, Mondy C, Eagle S, Chernich SE. Hemodynamic instability and delayed emergence from general anesthesia associated with inadvertent intrathecal baclofen overdose. Anesthesiology 2003; 98: 265–8. 51. Koﬂer M, Matzak H, Saltuari L. The impact of intrathecal baclofen on gastrointestinal function. Brain Inj 2002; 16: 825–36. 52. Wu SS, Dolan KA, Michael Ferrante F. Febrile reaction to subarachnoid baclofen administration. Anesthesiology 2002; 96: 1270–2. 53. Zarrindast MR, Oveissi Y. GABAA and GABAB receptor sites involvement in rat thermoregulation. Gen Pharmacol 1988; 19: 223–6. 54. Coffey RJ, Edgar TS, Francisco GE, Graziani V, Meythaler JM, Ridgely PM, Sadiq SA, Turner MS. Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially lifethreatening syndrome. Arch Phys Med Rehabil 2002; 83: 735–41. 55. Alden TD, Lytle RA, Park TS, Noetzel MJ, Ojemann JG. Intrathecal baclofen withdrawal: a case report and review of the literature. Child’s Nerv Syst 2002; 18: 522–5. 56. Greenberg MI, Hendrickson RG. Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement. J Toxicol Clin Toxicol 2003; 41: 83–5. 57. Meythaler JM, Roper JF, Brunner RC. Cyproheptadine for intrathecal baclofen withdrawal. Arch Phys Med Rehabil 2003; 84: 638–42.

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Drugs that affect autonomic functions or the extrapyramidal system

The volume of publications in this area is not diminishing. Although some are concerned with new drugs or novel adverse effects of old drugs, others show that precautions are not always taken and potential hazards are sometimes treated too casually. Parkinson’s disease remains interesting and controversial.

DRUGS THAT STIMULATE BOTH ALPHA- AND BETA-ADRENOCEPTORS (SED-14, 414; SEDA-24, 163; SEDA-25, 166; SEDA-26, 156)

Adrenaline Cardiovascular Adrenaline is occasionally used as a hemostatic agent, with rare complications. However, they do occur, as noted in a report from Lyon (1A ). • A 64-year-old man with diabetes and hypertension bled from a site in the lower rectum. A local injection of adrenaline 0.2 mg successfully stopped the hemorrhage, but very soon after he became hypotensive, with rapid atrial ﬁbrillation (ventricular rate not given), the ﬁrst time he had experienced this. He reverted spontaneously to sinus rhythm within 24 hours.

The authors suggested that if this type of procedure is contemplated in elderly patients with cardiovascular disease an anesthetist should be present to monitor cardiovascular status; it may © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

in any case be wiser to avoid adrenaline altogether in favor of other means of hemostasis. A more unusual site of adrenaline injection has been described in a Canadian report. • A 79-year-old woman developed pituitary apoplexy in an adenomatous gland and was being prepared for trans-sphenoidal hypophysectomy (2A ). Topical adrenaline (1 : 1000) was applied to both nostrils and then 1.5 ml of 1% lidocaine containing 1 : 100000 adrenaline was injected into the nasal mucosa. The blood pressure immediately rose from 100/50 to 230/148 mmHg and the pulse rate from 48 to 140 beats/minute. Although she was treated immediately with esmolol and intravenous glyceryl trinitrate, resulting in normalization of her blood pressure, subsequent investigations showed that she had a painless myocardial infarction. She made a full recovery after pituitary surgery.

The authors suggested that if adrenaline is to be used in such cases, even lower concentrations might be advisable. This is reasonable, although one also wonders in this case whether her blood pressure may have been lowered too rapidly.

Ephedra, ephedrine, and pseudoephedrine Cardiovascular Both ephedrine and pseudoephedrine remain worryingly popular (3M ) and are widely available without prescription. Cardiologists and pharmacologists from Boston have reviewed cases of possible cardiovascular toxicity associated with the use of ma huang, a herbal source of ephedrine. Among over 900 cases of possible toxicity reported to the Food and Drug Administration, they identiﬁed 37 patients (23 women) in whom stroke (16 cases),

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146 myocardial infarction (10), and sudden death (11) appeared to be temporally related to consumption of ma huang. The authors noted that in all but one of these cases the doses used were within the range recommended by the manufacturers. In the seven patients on whom autopsies were performed, coronary artery disease was found in three and cardiomyopathy in another three, with features suggesting sympathomimetic toxicity. The authors emphasized the toxicity of ma huang in relatively young individuals—the mean age of the 37 patients was about 43 years—even though the relevant pathogenic mechanisms remain to be fully deﬁned. Ephedrine is sometimes used to treat vasovagal episodes and has been reported to cause coronary artery spasm and myocardial infarction in these circumstances (4A ). • Two apparently healthy women, aged 26 and 34 years, who were given spinal anesthesia for pelvic or hip surgery, both developed hypotension and bradycardia and were given intravenous ephedrine in divided doses, in one case a total of 20 mg and in the other 30 mg. In both cases this resulted in ventricular tachycardia and raised troponin I concentrations and creatine kinase activity, but Q waves did not follow. Coronary angiography showed normal arteries in both cases and the women recovered, apparently fully.

The authors rightly pointed out that atropine is a safer and more appropriate intervention in circumstances such as these. The largest manufacturer of Ephedra-containing supplements is Metabolife. The ﬁrm has repeatedly insisted that it was not aware of adverse events associated with its products, and claimed that they were “absolutely safe” (5S ). An investigation by the US Justice Department into the truth of these statements showed that between 1997 and 2002 the company had received over 13 000 reports of suspected adverse drug reactions; they included nearly 2000 reports of signiﬁcant adverse reactions. • A 33-year-old man had a stroke while taking a herbal remedy (Thermadrene) containing Ephedra alkaloids and guaraná for “boosting his energy” (6A ). He was immediately treated with alteplase and was referred for rehabilitation 9 days later. At follow-up 5 months later he still had a minor neurological deﬁcit.

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Psychiatric Ephedrine and pseudoephedrine can also produce neuropsychiatric adverse effects. • A 37-year-old New Zealand woman took a total of 480 mg of pseudoephedrine in various cold remedies over 4 days (7A ). She had also been taking ﬂuoxetine 20 mg/day for seasonal affective disorder. She developed rapidly swinging mood changes, alternating between laughing and crying, and was sweating and shaking violently. Although her pulse rate was only 70/minute her blood pressure was 220/130 mmHg. She recovered within 4 hours and had no recurrence of her behavioral disturbance.

Although pseudoephedrine toxicity was a possible diagnosis, the authors concluded that serotonin syndrome was more likely, from an interaction of pseudoephedrine with ﬂuoxetine. Patients should be warned about the hazards of taking selective serotonin reuptake blockers and then self-medicating with ephedrine or pseudoephedrine. Immunologic Pseudoephedrine can cause hypersensitivity, as in three cases reported by allergy specialists from Spain (8A ). • A 33-year-old man developed anaphylaxis on a second exposure to pseudoephedrine, having developed urticaria after a ﬁrst exposure. • A 24-year-old woman developed severe urticaria and fever, but no other systemic reaction, after a single dose of pseudoephedrine. • A 67-year-old woman developed urticaria and angio-edema of the eyelids after a single dose of pseudoephedrine.

In all three cases skin testing was performed; it was positive in the ﬁrst two instances but not the third. The authors noted that such cases are reportedly uncommon and that cross-sensitivity is to be expected between pseudoephedrine and ephedrine. Overdose Based on increasing evidence of the risks of Ephedra self-medication, various national regulatory authorities are currently considering recalling Ephedra products from over-the-counter sales. • In a suicide attempt, a 32-year-old woman took 60 tablets of a weight-loss supplement containing Ephedra (9A ). She was delivered to hospital comatose. Her symptoms resolved over the next 5 days without treatment. At follow-up 5 months later she was euthymic, had no suicidal ideation, and was not taking any psychotropic medications.

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DRUGS THAT PREDOMINANTLY STIMULATE ALPHA-ADRENOCEPTORS

DRUGS THAT STIMULATE PREDOMINANTLY BETA1 -ADRENOCEPTORS

(SED-14, 417; SEDA-24, 164; SEDA-25, 167; SEDA-26, 157)

(SED-14, 420; SEDA-24, 165; SEDA-25, 167; SEDA-26, 159)

Phenylephrine

Dobutamine

It can never be emphasized enough that the eyes are a potential route for systemic drug administration. This has been illustrated by a British case of pulmonary edema in a child, apparently attributable to systemic absorption of phenylephrine eye-drops (10A ). • An 8-year-old boy was admitted for unilateral retinal detachment surgery. Phenylephrine 2.5% and cyclopentolate 1% as premedication were prescribed but not given. In theatre the assistant surgeon administered 2–5 drops of 10% phenylephrine to the right eye. During the operation the boy developed bradycardia and was given glycopyrrolate, but shortly afterwards the systolic arterial pressure rose to 211 mmHg and the pulse rate to 160 beats/minute, with multifocal atrial and ventricular ectopic beats. Labetalol was given and the pulse and blood pressure fell to normal, but he then developed clinical and radiological signs of pulmonary edema, which resolved spontaneously.

The management of this case was subsequently criticized by correspondents in the same journal (11r ). They suggested that a lower ocular dose of phenylephrine should be used routinely, that oxymetazoline might in any case be safer, and that labetalol might have been hazardous, owing to its beta-blocking properties. In their reply the authors pointed out that they used the lowest concentration of phenylephrine available for ocular use, that oxymetazoline is not licensed for use as a mydriatic agent, and that the patient had tachycardia and ventricular extra beats, which made the beta-blocking properties of labetalol clinically desirable. In a less dramatic context, German allergologists have described a case of contact dermatitis induced by phenylephrine eye-drops in a 62-year-old man (12A ). The inﬂammation affected both eyelids symmetrically and resolved rapidly on withdrawal of the eye-drops and application of topical corticosteroids. Skin testing conﬁrmed hypersensitivity to phenylephrine but no cross-sensitization to ephedrine or adrenaline.

Cardiovascular The value and safety of dobutamine stress echocardiography has been studied in 135 patients aged 70 years or older (mean 74 years; 58% men) soon after myocardial infarction (13C ). A diagnostic endpoint was reached in 83% of patients, a ﬁgure comparable to younger populations. No major complications were reported. The procedure was terminated prematurely because of symptomatic hypotension (n = 8), non-sustained ventricular tachycardia (n = 2), systolic hypertension (n = 2), atrial ﬁbrillation (n = 1), or bladder discomfort (n = 1). All of these problems resolved rapidly after the procedure was stopped. At the time of discontinuation, seven of these 16 patients had objective evidence of myocardial ischemia. In the PRECEDENT study dobutamine was compared with nesiritide (B natriuretic peptide) in patients with acutely decompensated congestive heart failure (14C ). The primary objective of the study was to assess the risk of ventricular dysrhythmias with the two therapies. Altogether 255 patients (mean age 61 years, 67% men) were randomized to receive dobutamine 5 μg/kg/hour or one of two doses of nesiritide 0.015 or 0.03 μg/kg/hour. Dobutamine signiﬁcantly increased the number of episodes of ventricular tachycardia by 48 per day, ventricular extra beats by 69 per hour, and overall heart rate by 5 beats per minute. These parameters were unchanged or improved by nesiritide. Since the two drugs had similar effects on the hemodynamic features of heart failure and its symptoms, the authors concluded that nesiritide should be considered as an alternative to dobutamine in this type of patient.

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DRUGS THAT ACT ON DOPAMINE RECEPTORS

Hiccups, an unusual form of dyskinesia, have been attributed to levodopa (19A ).

(SED-14, 421; SEDA-24, 165; SEDA-25, 168; SEDA-26, 159)

• An 80-year-old man with Parkinson’s disease and dementia developed worsening bradykinesia, and the dose of co-careldopa was increased from 12.5/50 mg bd to 25/100 mg bd. Two days later he developed hiccups, which lasted for 1 week and which ceased when the dosage was reduced to the previous level.

Levodopa and dopamine receptor agonists Respiratory Two men with Parkinson’s disease, aged 66 and 78 years, developed abnormal respiration (tachypnea and irregularity in the depth of breathing) when levodopa was either introduced at a dose of 300 mg/day in the ﬁrst case or increased from 300 to 600 mg/day in the other (15Ar ). The authors cited a number of earlier similar reports. Nervous system The long-term consequences of levodopa therapy have been considered in a review by predominantly Canadian authors, but whose senior author was Oleh Hornykiewicz, the doyen of the dopamine concept of Parkinson’s disease (16R ). Their conclusions were not at all unexpected. Levodopa was given to 42 patients (30 men, mean disease duration of 16 years, mean follow-up about 9 years). There were adverse effects in over 70%: dyskinesias in 62%, on-off effects in about 17%, and end-of-dose wearing-off in about 7% (the last perhaps surprisingly low). Dyskinesia was not only the most common but also the earliest adverse effect. It should be noted that the mean levodopa dosage in this population was rather low, only 500 mg/day. In a more general review the advantages and disadvantages of levodopa have been summarized, with particular focus on adverse effects and their management (17R ). The author concluded that there is no convincing evidence for neurotoxicity of levodopa in humans. Neurologists from New York and Yugoslavia have noted the variable time to the development of motor complications after starting levodopa (18C ). Of 40 patients (21 men, mean age 67 years) 17 were at Hoehn and Yahr stage I at the start of levodopa therapy, 13 at stage II, and 10 at stage III. The median times to the development of motor ﬂuctuations were respectively 64, 55, and 14 months in the three groups and the times to onset of dyskinesias were similar. This reinforces the clinical experience of neurologists in general.

Ocular dyskinesias have been described in a 60-year-old Spanish man who showed intermittent upward and leftward deviations of gaze associated with peak concentrations of levodopa, in doses of up to 800 mg/day plus benserazide (20A ). It should be noted that the patient was and apparently still is taking pramipexole and amantadine in addition to levodopa. The pathophysiology of the restless legs syndrome is poorly understood, but it often responds well to dopaminergic therapy. However, augmentation of symptoms has also been described, especially with levodopa. Of 60 patients (mean age 58 years) with this syndrome who were treated with pramipexole (0.25– 1.0 mg/day) ﬁve had augmentation of symptoms over a period of at least 6 months during continuous treatment and four had what was described as a secondary syndrome, in other words with co-existing and possibly causative neurological disease (21C ). There was no relation to the initial severity of the syndrome or to the dosage of drug, although the authors suggested that the very low dose of 0.25 mg/day is probably optimal. It is almost universally accepted that directly acting dopamine receptor agonists have less efﬁcacy than levodopa, although the reasons are not clear. Neurologists from London have sought to question this assumption by using cabergoline (n = 11) and pergolide (n = 7) at considerably higher doses than recommended (22c ). The actual mean doses were 8.8 and 9.4 mg/day, compared with recommended maxima of 6 and 5 mg/day respectively. The high doses were tolerated by the patients for 2.3– 2.5 years; mild dyskinesias (n = 7), ankle edema (n = 3), and hallucinations (n = 1) were the only reported adverse effects. The authors concluded that the therapeutic window for these drugs is apparently much greater than is generally accepted, and that higher doses may be given safely with potentially enhanced efﬁcacy.

Drugs that affect autonomic functions or the extrapyramidal system

Sleep disorders with dopamine receptor agonists The problem of sleep disorders associated with dopamine receptor agonists (SEDA-26, 160) continues to generate many articles. Daytime sleepiness and nocturnal wakefulness can both occur in relation to dopaminergic drug therapy, but sleep attacks are rare (23R ). Many factors beside drug treatment can lead to sleep disorders in Parkinsonian patients, including the disease process itself and episodes of sleep apnea; some are skeptical about the existence of sleep attacks as a phenomenon distinct from increased general drowsiness (24R ), although others disagree. Neurologists from King’s College London have concluded that all dopaminergic drugs are capable of causing sleepiness and that in a minority of patients it may take the form of a narcolepsy-like phenotype, possibly amenable to improvement by selegiline or modaﬁnil; they have recommended that affected individuals should not drive (25R ). Although it was their view that this is a class effect of dopamine agonists, they nevertheless suggested that switching from one agonist to another may sometimes be helpful. In a Canadian survey of 638 Parkinsonian patients who were fully independent and with no evidence of dementia, just over half (327) had excessive daytime sleepiness, as assessed by the Epworth Sleepiness Scale and the Inappropriate Sleep Composite Score (26C ). Only 16 patients had fallen asleep while driving and of these three had no warning; all had high scores on the scales mentioned. Unfortunately, the structure of the survey did not allow conclusions regarding drug therapy, although all the patients were taking levodopa (80%), or a dopamine receptor agonist, or both. In another survey, from Texas, Epworth scores were studied in 368 patients with Parkinson’s disease and 243 with other neurological disorders, mostly other movement disorders, including other causes of Parkinsonian syndromes (27C ). The former had scores 25% higher: however, it should be noted that matching for age and other parameters was not clearly described. Using a multivariate model the authors calculated that levodopa dosage, the use of dopamine receptor agonists, and the severity of the disease accounted for only a minor extent (about 9%) of the variation in

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scores in the Parkinsonian group. Even so, they concluded that progression of the disease, the dosage of levodopa, and the use of dopamine receptor agonists are contributory factors in increased daytime somnolence. Several smaller-scale studies and case reports have also been published. An Italian group have reported polysomnographic studies in a 44-year-old woman with a 5-year history of idiopathic Parkinson’s disease (28A ). She was taking modiﬁed-release levodopa, to which pergolide 3 mg/day was added, titrating up from a lower dose. After taking this dosage for 5 days she developed irresistible sleep attacks up to 5 times a day with no warning or obvious triggers. Polysomnography showed that these episodes closely resembled narcolepsy. The episodes ceased after pergolide withdrawal. Six German patients (aged 36–68 years, disease duration 7–12 years, four men) were studied after reporting sleep attacks following the addition of pramipexole or ropinirole to a levodopa-based treatment regimen (29c ). Five had abnormal results in the multiple sleep latency test, and three of these also had increased errors in a test of driving vigilance. The authors concluded that patients should be assessed individually in terms of their safety to drive. They also suggested that sleep attacks are at the extreme end of the spectrum of daytime sleepiness, although it is not clear that such a conclusion can be reached so unequivocally from such a small study. A French group has tested the effects of ropinirole 3 mg on sleep latency in 20 healthy men (mean age 24 years) compared with placebo (30c ). The time to sleep onset was signiﬁcantly quicker in the ropinirole-treated subjects (2.6 vs 4.8 minutes), but sleep attacks did not occur. Clearly this is a very different group of individuals from the usually much older group with Parkinson’s disease, so again deﬁnite conclusions are elusive.

Psychiatric It is a pharmacological truism that exogenous dopamine is not a central dopamine receptor agonist, because it cannot cross the blood–brain barrier. However, the possibility that it might, and could thus contribute to the development of delirium, has been examined (31R ). Of over 21 000 in-patients in Stanford

150 University Hospital, 1164 were given intravenous dopamine. Although the authors conceded that the methods that they used to assess the presence of delirium were imprecise, they nevertheless calculated that intravenous administration of dopamine nearly triples the likelihood of the need for subsequent antipsychotic medication. This raises at least the possibility that in some pathological states signiﬁcant amounts of exogenous dopamine can enter the brain. A prospective study is needed to clarify this. Meanwhile the authors have proposed that it might be useful to give dopamine receptor antagonists to patients who are about to receive dopamine infusions. However, most clinicians would probably be reluctant to do this on the existing evidence. Hair Treatment with levodopa, pergolide, and bromocriptine has very rarely been associated with reversible alopecia. • Two women in New York, aged 66 and 68 years, took pramipexole 15 and 3.5 mg/day (32A ). Both developed progressive hair loss 2–12 months later. When pramipexole was withdrawn there was partial regrowth of hair. Ropinirole and levodopa did not provoke hair loss in these women.

The authors noted that this problem appears to be conﬁned to women, at least according to published reports. The mechanism is unknown. Serosae Intrathoracic ﬁbrosis is a rare but well recognized complication of the use of dopaminergic ergoline derivatives, such as pergolide. Dutch authors have described four patients, men aged 63–65 years, who had been treated for Parkinson’s disease for 3–5 years with various doses (not all speciﬁed) of pergolide (33A ). In three cases pleural ﬁbrosis was demonstrated on biopsy, while in the fourth there was pleural effusion with no histological evidence. On drug withdrawal there was clinical and radiological improvement in three cases but not the fourth. On reviewing reports of similar adverse drug reactions the authors noted that the age and male preponderance of their patients was in keeping with previous reports. They observed that the dosage was generally higher in patients with retroperitoneal ﬁbrosis compared with those with pleuropulmonary ﬁbrosis. The duration of drug exposure was also a signiﬁcant risk factor. Clearly, the fact that changes are often irreversible emphasizes the need for early

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detection and high levels of awareness of these problems. • A 67-year-old man developed pericardial ﬁbrosis and thickening while taking pergolide for Parkinson’s disease (34A ). The symptoms and signs of heart failure emerged after 11 months, but the possible causative role of the drugs was not suspected for some months while the pericardial changes progressed, as did cardiac failure. In this case the changes appeared to be wholly reversible on drug withdrawal.

Sexual function Czech neurologists have described seven men, aged 35–70 years, in whom sexual behavior was greatly increased and who had frequent spontaneous penile erections (35A ). All had been taking levodopa, to which pergolide 3 mg/day had been added, and all had advanced ﬂuctuating Parkinson’s disease. In one case the dosage of pergolide was halved and in two others ropinirole or entacapone were used as alternatives, in all cases with reduction of the hypersexual symptoms. The other four patients continued to take pergolide, with persistence of the symptoms, to which they and their partners adjusted. Other more unusual forms of hypersexuality can also occur (36A ). • A 72-year-old man who had taken levodopa for over 20 years started to take selegiline 10 mg/day. He developed a strong impulse for cross-dressing, which he had never experienced before. The behavior ceased when the selegiline was withdrawn.

It is not clear whether this effect was due to an interaction of levodopa with selegiline or due to a direct effect of selegiline itself. Pregnancy Parkinson’s disease is very rare in pregnancy, but has been described (37A ). • A 36-year-old woman with a 4-year history of Parkinson’s disease, who had been taking pergolide 3 mg/day and levodopa 200 mg/day continued to take it during pregnancy. The end-ofdose wearing-off effect completely disappeared, and reappeared at their previous intensity after delivery. There were no adverse effects in the mother. The baby was healthy at birth and remained so at the time of the report, at the age of 13 months.

Drugs that affect autonomic functions or the extrapyramidal system

OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY (SED-14, 424; SEDA-24, 167; SEDA-25, 171; SEDA-26, 162)

Catechol-O-methyl transferase inhibitors After the problems experienced with tolcapone, it is not surprising that the safety of its successor entacapone continues to receive attention. In a placebo-controlled study in Germany and Austria, 301 patients with Parkinson’s disease were randomized to receive placebo or entacapone 200 mg with each dose of levodopa, together with their other usual therapy (38C ). The mean age was 61 years and 40% of the entacapone group and 48% of the placebo group were men: the groups were also unequal in size (197 vs 104), for reasons that were not clearly deﬁned. Entacapone reduced the Uniﬁed Parkinson’s Disease Rating Scale score, increased “on” periods, and reduced “off” periods. In the patients who took entacapone there was more frequent dyskinesia (34 vs 26%), nausea (10 vs 4.8%), and diarrhea (8.1 vs 3.8%). All of these ﬁndings are consistent with enhanced dopaminergic activity. There was no evidence of hepatotoxicity in any of the patients. Liver Whether entacapone is hepatotoxic is debatable. • A 76-year-old Australian woman complained of nausea, anorexia, and malaise 2 weeks after starting to take entacapone 200 mg ﬁve times a day (39A ). A week later her bilirubin, alanine transaminase, alkaline phosphatase, and γ -glutamyl transpeptidase were all raised (2–8 times higher than the upper limits of the reference ranges). Clotting was normal. Over the next 3 days her liver function tests deteriorated and the entacapone was withdrawn. All the laboratory data improved within 2 days, but not all were fully normal 4 weeks later. She refused a rechallenge.

The authors noted that two other patients in the Australian adverse reactions database also appeared to have had hepatotoxicity related to entacapone. In response, representatives of the manufacturers (Novartis) strongly contested the conclusion that any of the three reported cases

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demonstrated entacapone-induced hepatotoxicity, and concluded that two of the three patients had cholestasis, which is unlikely to be related to entacapone, while the third had no real evidence of hepatic dysfunction (40r ). These arguments were in turn rebutted by the original authors, and the possible hepatotoxicity of entacapone remains a matter of debate, although there can be no doubt that it is safer than tolcapone.

THE ERGOT ALKALOIDS AND RELATED AGENTS (SED-14, 431; SEDA-24, 168; SEDA-25, 171; SEDA-26, 163) Cardiovascular There is no shortage of data to discourage the continued use of ergotamine in the treatment of migraine. • A 63-year-old Canadian woman who had been taking ergotamine (dosage unspeciﬁed) for migraine for 20 years developed acute ischemia of the right arm, with no palpable pulses below the axilla (41A ). Angiography showed multiple ﬁlling defects in upper limb arteries, partially reversible with intravenous phentolamine. She was given prazosin 2 mg/day and became pain-free after 5 days. Treatment was continued for 3 months and during this time attacks of migraine were treated with sumatriptan without adverse effects. Her pulses were entirely normal after 3 months, as was angiography.

Psychiatric Unlike the dopamine-mimetic ergolines, ergotamine is not usually regarded as a drug with major effects on the brain. However, this may not always be true. • A 75-year-old woman in Arizona developed progressive confusion, auditory hallucinations, and aggressive behavior (42A ). Her systolic pressure was raised (194 mmHg). She had a history of migraine and many other problems, including hypertension. Her headaches had become more severe over the weeks before admission and she had been gradually increasing her intake of a formulation containing ergotamine 1 mg and caffeine 100 mg: just before the emergence of her psychiatric symptoms she was taking 14 tablets per week. After withdrawal of the ergotamine/caffeine, her mental state and blood pressure returned to normal, without antihypertensive medication, and remained so 12 months later.

Although there has been extensive discussion of the phenomenon of ergotism in medieval

152 and early modern times, its features do not closely resemble this case, perhaps because of the co-administration of caffeine. However, regardless of that, there does seem to be a strong case for a drug effect here.

DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SED-14, 436; SEDA-24, 168; SEDA-25, 172; SEDA-26, 164)

Anticholinergic drugs Cardiovascular The potential dysrhythmogenic effect of anticholinergic drugs has been examined retrospectively in nearly 4000 patients taking ﬂavoxate, oxybutynin, and hyoscyamine between 1991 and 1995, compared with over 10 000 patients who had no exposure to these drugs (43c ). All the patients were over 65 years old and they were reasonably matched for co-morbidities, although not surprisingly more women than men were taking the antispasmodic drugs (75% women in the treated group vs 67% in the control population). The encouraging conclusion was that there was no evidence that these drugs promote ventricular dysrhythmias or sudden death. However, the authors noted that more detailed analysis of these data is needed and that it may also be advisable to consider data from newer drugs.

Atropine When parasympathicolytic or anticholinergic agents are used to dilate the pupils, it is important to recognize systemic anticholinergic intoxication, because the outcome can be fatal without treatment. In patients who are confused or have difﬁculty speaking, large ﬁxed pupils, and fever, anticholinergic intoxication has to be considered. • A 3-year-old boy with amblyopia was vomiting, had difﬁculty in walking, had fever, was agitated, and had a warm red skin and dilated pupils that did not respond to light. An empty bottle of atropine eye-drops was found in his home, and suspected anticholinergic intoxication was conﬁrmed. He made a full recovery following treatment with physostigmine.

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• A 52-year-old woman was confused and had dysarthria and difﬁculty in walking and swallowing. That same day she had eaten berries that she thought were bilberries, but were instead Atropa belladonna (deadly nightshade) (44A ).

Hyoscine Nervous system Transdermal hyoscine is used by some anesthetists to minimize postoperative nausea and vomiting. The safety and efﬁcacy of this form of treatment has been reviewed in an analysis of data from 23 trials involving 979 patients treated with hyoscine and 984 with placebo (45M ). The authors concluded that of 100 patients who are treated with hyoscine, 17 will escape postoperative nausea and vomiting that would otherwise have occurred; however, 18 will have visual disturbances, eight will complain of dry mouth, two of dizziness, and one will become agitated. Although these are not necessarily prohibitive problems they certainly do need to be considered when choosing a drug for this indication. Pregnancy Two Japanese primigravidae, aged 25 and 28 years, developed the HELLP syndrome, a severe variant of pre-eclampsia in which there is Hemolysis, Elevated Liver enzymes, and a Low Platelet count. They were given parenteral hyoscine butyl bromide for abdominal pain and had seizures 60–90 minutes later (46A ). One died from intracerebral hemorrhage some days later and the other survived after a cesarean section soon afterwards. The authors speculated that anticholinergic drugs may enhance sympathetic nervous system activity, and in particular vasoconstriction, and should be avoided in pre-eclampsia. It is not clear how widespread their use is in other countries in managing abdominal pain in these circumstances.

Oxybutynin Drug formulations An extended-release formulation of oxybutynin has been compared with an immediate-release formulation; it had similar efﬁcacy but fewer adverse effects (47R ).

Drugs that affect autonomic functions or the extrapyramidal system

The overall conclusion of an unsystematic review was that, as expected, dry mouth is very common; it occurred in about two-thirds of those taking the extended-release formulation (up to a dose of 30 mg/day) and in nearly 90% of those who took the immediate-release formulation. In about 25% of those who took the extended-release formulation the dry mouth was classiﬁed as severe, compared with nearly 50% of those who took the immediate-release formulation. Other adverse effects were very uncommon and signiﬁcant toxicity was not reported. In total the two comparative trials involved 331 patients, and an open-label study of 256 patients was also discussed.

Tolterodine Immunologic Anticholinergic drugs can rarely cause immunological reactions.

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• An 81-year-old Swiss woman took immediaterelease tolterodine 2 mg bd and 18 days later had fever, malaise, and nausea with vomiting (48A ). Liver function tests showed a mixed hepatitic and cholestatic pattern and she also had leukocytosis and eosinophilia.

The authors suggested that this was a hypersensitivity reaction; if so it is the ﬁrst of its kind to be reported with tolterodine. Drug formulations A total of 1077 patients continued to take extended-release tolterodine 4 mg/day after participating in a randomized trial, about 78% of those who completed the double-blind phase of the study (49C ). Of the patients who took open-label treatment 71% were still doing so after 12 months. The only signiﬁcant adverse effect was a dry mouth in 13%, while 3.3% complained of constipation. There was no serious systemic toxicity of any kind and efﬁcacy was judged to be at least equivalent to that of the immediate-release formulation.

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Drugs that affect autonomic functions or the extrapyramidal system 47. Michel MC. A beneﬁt–risk assessment of extended-release oxybutynin. Drug Saf 2002; 25: 867– 75. 48. Schlienger RG, Keller MJ, Krähenbühl S. Tolterodine-associated acute mixed liver injury. Ann Pharmacother 2002; 36: 817–19.

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

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.

Botanical extracts Natural botanical extracts are being increasingly used in cosmetics. Consumers tend to regard these natural substances as safe. However, patients with positive patch tests to Aloe vera, Arnica, Centella asiatica, chamomile, cucumber, lavender oil, peppermint, rosemary, sage, St John’s wort (photosensitivity), tea tree oil, and witch hazel have been reported (20R ).

Fragrances and essential oils (SEDA-25, 175) The fragrance mix, introduced in 1977 by Larsen, is used to detect sensitivity to fragrances in, for example, cosmetics and household products. The mix contains eight widely used fragrance compounds. Additional indicators of fragrance allergy are balsam of Peru and colophony. The frequency of positive patch tests to the fragrance mix has increased over recent years. However, the mix has been estimated to miss 15% of relevant contact allergies (21R ). In a study of 1855 consecutive patients, patch tests with additional fragrance allergens has shown that lyral (2.7% positive reactions), citral (1.1%), and farnesol P © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

156

(0.5%) are valuable additions when patch testing to detect a fragrance allergy. Several other compounds that were tested at the same time were positive less often (22C ). A similar study in 1606 consecutively tested patients showed that ylang-ylang oil I (2.6% positive patch tests), ylang-ylang oil II (2.5%), lemongrass oil (1.6%), narcissus absolute (1.3%), jasmine absolute (1.2%), and sandalwood oil (0.9%) are the most important ingredients (23C ). In this series, limonene was positive in 0.6% of cases, but in another series of 2273 consecutive patients it was positive in 2.8%, of whom 57% did not react to the fragrance mix (24C ). These and other compounds were patch tested in another series of fragrance-sensitive patients (25C ). Of the 218 subjects tested, 76% were positive to the fragrance mix. Ten fragrances were not detected by the fragrance mix: benzenepropanol, beta, beta, 3-methyl, hexylsalicylate, dl-citronellol, synthetic ylang-ylang oil, benzyl mixture (containing benzyl alcohol, benzyl salicylate, and benzyl acetate), cyclohexylacetate, eugenyl methyl ether, isoeugenyl methyl ether, 3-phenyl-1-propanol, and 3,7-dimethyl-7-methoxyoctan-2-ol. In earlier studies by this group, signiﬁcant additional reactions were found to sandela, geranium oil bourbon, spearmint oil, galaxolide (1,3,4,6,7,8hexahydro-4,6,6,7,8,8-hexamethyl-cyclopentagamma-2-benzopyran), omega-6-hexadecenlactone, and tripal (dimethyltetrahydrobenzaldehyde) (26C , 27C ).

Hair dyes

(SEDA-26, 173; SEDA-25, 177)

Contact allergy to the paraphenylene group of hair dyes is well established (28C ). To test for cross-reactivity between these oxidative dyes and the new generation of hair dyes, 40 hairdressers allergic to paraphenylenediamine were

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

Use

Test conc. & vehicle

Number studied

Comments

Reference

Bronopol (2-bromo-2nitropropane-1,3-diol)

Metrogel

not stated

1

Calcipotriol

Antipsoriatic

0.4–10 μg/ml isopropanol

1

(SEDA-24, 173)

(2A )

Caprylic/capric triglyceride

Emulsiﬁer

1% (vehicle not stated)

1

Rare allergen

(3r )

Carvone

Toothpaste

5% pet

1

Cheilitis

(4r )

Hydrophilized ceramide

Moisturizer

0.25% pet

1

First report

(5r )

Clobetasone butyrate

Corticosteroid

0.5 and 1% pet

1

Rare allergen

(6r )

Coathylene

Mascara

10% pet

1

First case

(7r )

Dibutyl phthalate

Timodine® cream

5% pet

1

Rare allergen

(8r )

Dicaprylyl maleate

Emulsiﬁer

10% (vehicle not stated)

2

Rare allergen

(3r )

Diclofenac

Treatment for actinic keratosis

2.5% pet

1

Fourth case

(9r )

Ethylhexylglycerin

Skin conditioner

10% pet

1

First case

(10r )

Glyceryl stearate

Emolient and emulsiﬁer

10% pet

1

Hydroxyethyl salicylate

Hypostasis

5% aqua

1

Iodoform

Otitis externa

10% pet

3

Nitroglycerin

Transdermal therapeutic system

0.2% aqua 0.5% ethanol

1

Rare allergen, generalized reaction

(14r )

Phthalic anhydride/ trimellitic anhydride/ glycols copolymer

Nail varnish

1% pet

1

First case in nail varnish

(15r )

Prime yellow carnauba wax

Mascara

50% mineral oil

1

First case

(7r )

Polyvinylpyrrolidone (PVP)/1-triacontene copolymer

Sunscreen

10% pet

1

First report

(16r )

Shellac

Mascara

20% ethanol

6

Rare allergen

(17A )

Sodium metabisulﬁte

Corticosteroid

2% pet

1

Rare allergen

(6r )

Sodium myristoyl sarcosinate

Facewash

1% aqua

1

First report

(18r )

Stearic acid

Emolient and emulsiﬁer

10% pet

1

Rare allergen

(11r )

Trideceth-2carboxamide monoethanolamine

Stabilizer in hair dye

0.5% aqua

1

First case

(19r )

(1r )

(11r ) Second case

(12r ) (13A )

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selected; none reacted to any of the four acid dyes, two FD&C dyes, or four D&C dyes, suggesting that these newer hair dyes are safe alternatives to the paraphenylene-based hair dyes (29C ).

Iodopropynylbutylcarbamate (SEDA-26, 170) Initially used as a preservative in wood paints and metal-working ﬂuids, iodopropynylbutylcarbamate is being increasingly used in cosmetics (30R ). In the past, four contact allergic reactions were reported in a series of 3168 consecutively patch tested patients (31R ). In a recent publication, 16 positive reactions (0.3%) were observed in 4883 consecutive patients (32R ).

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

cases of contact allergy to formaldehyde and MCI/MI. These preservatives are currently avoided in cosmetics. However, the frequency of positive reactions to MDBGN has risen, from 0.7% in 1991 to 3.5% in 2000. The authors suggested that the concentration of this preservative should be reduced in leave-on cosmetic products (33C ). DMDM hydantoin is a preservative that is used mainly in cosmetics. In 1808 consecutive patients DMDM hydantoin was patch tested in a concentration of 2% in petroleum, and in a further 34 321 patients it was tested in a concentration of 2% in water. The proportion of positive reactions was 0.39–0.65%, with no evidence of a signiﬁcant time trend. In the 180 positive cases cosmetics (30%) or topical drugs (22%) were considered causal (34C ).

CONTACT URTICARIA AND IMMEDIATE REACTIONS

Preservatives Preservatives are important causes of allergic contact dermatitis in cosmetics. In a 10-year analysis in 16 centers in 11 countries, 73 818 consecutive patients were patch tested, including formaldehyde, quaternium-15, imidazolidinyl urea, diazolidinyl urea, parabens mix, 5-chloro-2-methyl-4-isothiazolin-3-one + 2-methyl-4-isothiazolin-3-one (Kathon CG, MCI/MI), and methyldibromoglutaronitrile (Euxyl K400, MDBGN). There were several

Reports of contact urticaria to relatively rare antigens in both cosmetic products and drugs are shown in Table 2. Hair bonds and hair extensions are being increasingly used both as cosmetic hair alterations and in localized or diffuse alopecia. The commercial glues used to afﬁx the exogenous hair are gelatinous liquids that contain pigments, antioxidants, and natural latex. Two patients developed severe type I reactions to a hair bond.

Table 2. Reports of contact urticaria to relatively rare antigens in both cosmetic products and drugs Allergen

Allergencontaining product

20-minute patch test

Skin prick tests

Remarks

Reference

2-Phenoxyethanol

Various cosmetics

2-Phenoxyethanol 1% pet + Euxyl K 400 1.5% + Own cosmetics +

2-Phenoxyethanol 1% + Euxyl K 400 1.5% +

Second report of immediate hypersensitivity

(35A )

Benzophenone-3

Sunscreens

Benzophenone-3 + (concentration not stated)

n.d.

Contact urticaria rare

(36A )

Geraniol

Various cosmetics

Geraniol + (concentration not stated)

n.d.

First report of contact urticaria

(37A )

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• A 37-year-old atopic patient had generalized pruritus, diffuse urticaria, angioedema, rhinoconjunctivitis, and tachycardia within minutes of having glued a hair bond to her scalp. Skin tests with the glue (diluted 1 : 10 000 in saline) were positive, as was an IgE RAST on latex proteins (38A ). • A 40-year-old woman noted palmar irritation, followed by generalized pruritus, a feeling of faintness, facial edema, and difﬁculty in breathing. A latex skin prick test was positive (39A ).

in guinea-pigs (43E ). Ketoprofen and benzophenone were the strongest photosensitizers. Cross-reactivity was most frequent after sensitization with ketoprofen. Benzophenone photosensitization did not induce cross-reactivity. The benzoyl radical was identiﬁed as the key structure for both photosensitization and crossreactivity among the NSAIDs.

Sunscreens PHOTOSENSITIVITY Phototherapy Body temperature Inﬂuenza-like symptoms, have been attributed to psoralens (40A ). • A 54-year-old man treated with photochemotherapy for disabling hand eczema developed ﬂu-like symptoms, which lasted for 48 hours and occurred repeatedly within 2 hours after oral methoxsalen 50 mg. In addition to a fever up to 39◦ C, he had headache, nausea and vomiting, fatigue, dyspepsia, and muscle aches.

Although no attempt was made to isolate any viruses, the multiple positive rechallenges, in combination with a time-course compatible with methoxsalen pharmacokinetics, suggested a drug-related event.

(SEDA-26, 174)

Photo-induced contact urticaria to benzophenone-3 and benzophenone-10, possibly in combination with delayed hypersensitivity, has been described (44A ). Urticaria occurred within minutes of UVA irradiation (10 J), 24 hours after the application of the benzophenones. Octyl triazone is a UVB absorber structurally unrelated to the benzophenones. Photocontact allergy to this agent in a sunscreen has been described (45A ).

RETINOIDS (SED-14, 449; SEDA-25, 179; see also Chapter 38)

NSAIDs

Neuromuscular function A new case of stiff man syndrome has been described. It started 10 days after the start of oral isotretinoin treatment (1 mg/kg/day) and resolved completely within 2 weeks of withdrawal (46A ). There were no motor or sensory nerve conduction abnormalities. There were no conditions known to be associated with stiff man syndrome, either at the time or during 5 years of follow up.

Photocontact dermatitis has been reported after topical application of dexketoprofen (Enangel® ), with positive photopatch tests to dexketoprofen 1% and piketoprofen 2% (41A ). Local pharyngeal treatment with benzydamine hydrochloride 0.15% (Tantum® verde) by a 67-year-old man resulted in systemic photocontact dermatitis in the third week of treatment (42A ). Photopatch tests with Tantum® verde as is and in 10% aqueous solution were positive: D1 +, D2 +, D3 ++. Photosensitization potentials and cross-reactivities of ketoprofen, suprofen, tiaprofenic acid, and benzophenone have been studied

Metabolism Symptoms of hyperlipidemia and the metabolic syndrome have been investigated in a cross-sectional study in young adults who had used isotretinoin for acne for at least 4 weeks (mean dosage 0.56 mg/kg). Those in whom triglyceride concentrations increased by at least 1.0 mmol/l during therapy were termed hyper-responders (n = 102), and those in whom triglyceride concentrations changed by 0.1 mmol/l or less were termed non-responders (n = 100) (47c ). Despite similar pretreatment body weights and plasma lipid concentrations, 4 years after completion of isotretinoin therapy the hyper-responders

PHOTOCONTACT DERMATITIS

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were more likely to have hypertriglyceridemia (OR = 4.8; 95% CI = 1.6, 14), hypercholesterolemia (OR = 9.1; CI = 1.9, 43), truncal obesity (OR = 11.0; CI = 2.0, 59), and hyperinsulinemia (OR = 3.0, CI = 1.6, 5.7) than non-responders. In addition, more hyperresponders had at least one parent with hypertriglyceridemia. Genotypes containing apoE ε2 and apoE ε4 alleles were over-represented among hyper-responders. Although a comparison of hyper-responders with non-responders may lead to overestimation of the risk, these data suggest that those who develop hyperlipidemia while taking isotretinoin are those who are already at risk of hyperlipidemia and the metabolic syndrome. An increase in the frequency of attacks of familial Mediterranean fever has been reported after the start of systemic therapy with isotretinoin for nodulocystic acne (48A ). • A 32-year-old man with familial Mediterranean fever, who took colchicine twice daily for 10 years, had one or two attacks per year. During the ﬁrst month after starting to take isotretinoin 50 mg/day he had three typical attacks, increasing to one attack a week after dosage increments to 60 mg/day and later 80 mg/day. Isotretinoin was withdrawn and he had no further attacks of familial Mediterranean fever during the following 10 months. Rechallenge was not performed.

MISCELLANEOUS DRUGS Minoxidil

(see also Chapter 20)

Topical minoxidil stimulates new hair growth and arrests loss of hair in androgenic alopecia. Its adverse effects include irritant contact dermatitis, allergic contact dermatitis, and exacerbation of seborrheic dermatitis and are usually limited to the application site on the scalp. These effects are seen in 5.7% of patients who use a 5% solution and in 1.9% of those who use a 2% formulation (49C ). The results with the 2% solution are variable, and experience has suggested that higher concentrations may be more effective. Topical twice-daily minoxidil 2% and 5% have therefore been compared for 48 weeks in a doubleblind, randomized, placebo-controlled, multicenter trial in 393 men (aged 18–49 years) with

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

androgenic alopecia (50C ). The higher concentration of minoxidil was signiﬁcantly more effective than both the lower concentration and placebo in terms of change from baseline in non-vellus hair count, patient rating of scalp coverage and treatment beneﬁt, and investigator rating of scalp coverage; the response to treatment occurred earlier with 5% minoxidil. However, there was more pruritus and local irritation with 5% minoxidil. In 11 patients allergic to topical minoxidil lotion, patch tests showed that four were positive to minoxidil itself (51A ). Propylene and butylene glycol are used as solvents for minoxidil in topical formulations. Nine of the 11 patients appeared to have positive patch tests to propylene glycol and one of the 11 reacted to its alternative butylene glycol. • Allergic contact dermatitis occurred in a 54-yearold man who had used 1% minoxidil on the scalp for 8 months (52A ). He had positive patch tests to minoxidil (2,4-diamino-6-piperidinopyrimidine-3oxide) in alcohol, but not to minoxidil in petrolatum, piperidine, pyrimidine, or diaminopyrimidine.

The authors suggested that the whole structure of minoxidil is required for sensitization and that propylene glycol in the formulation of minoxidil that is used therapeutically increases the penetration of minoxidil into the skin, enhancing the risk of a reaction. • A 57-year-old man developed a pigmented contact dermatitis after using topical minoxidil 5% for 2 years (53A ). Patch tests were negative with the European standard series and with a textile and ﬁnishes series, but positive with minoxidil 5% on days 3 and 7. However, withdrawal of the minoxidil did not lead to improvement after 10 months.

Immunologic A 24-year-old woman with androgenic alopecia became sensitized to topical minoxidil after using minoxidil 4% with retinoic acid in a propylene glycol base (54A ). She subsequently also became sensitized to saw palmetto (Serenoa repens), a topical herbal extract commonly promoted for the treatment of hair loss. Teratogenicity Caudal regression syndrome is a rare anomaly, a continuum of congenital malformations ranging from isolated sacral agenesis to absence of the lumbosacral spine

Dermatological drugs and topical agents

Chapter 14

and major visceral anomalies. While the exact cause of this syndrome is unclear, maternal diabetes, genetic factors, teratogens, and vascular anomalies that alter blood ﬂow have been hypothesized to play a role. A case has been attributed to maternal minoxidil exposure (55A ). • A fetus had an extremely hypotrophic caudal body pole, aplasia of the lower spine, and complete renal agenesis diagnosed in the second trimester by ultrasound. The mother had used minoxidil solution to prevent hair loss for 4 years before and during gestation. She had also taken co-trimoxazole during the ﬁrst trimester. She was not diabetic and had no history of familial genetic disorders.

Thalidomide

(SEDA-24, 171; SEDA-26, 176, 397)

Nervous system The incidence and susceptibility factors for thalidomide neuropathy have been studied in a prospective cohort study in 135 patients (56C ). Structured questionnaires were administered, standardized neurological and electrophysiological examinations were performed, and neuropathic signs and symptoms were classiﬁed by investigators who did not know the dose of thalidomide or the treatment duration. Deﬁnite thalidomide neuropathy occurred in 25% of patients, and another 30% developed atypical neuropathy, discordant clinical and electrophysiological features, or typical clinical signs without electrophysiological investigation. The only signiﬁcant susceptibility factor was the daily dose: neuropathy did not develop at dosages below 25 mg/day.

Botulinum toxin A in the treatment of primary axillary hyperhidrosis (SEDA-19, 144, SEDA-24, 160) Primary hyperhidrosis is a chronic idiopathic disorder of excessive, uncontrollable sweating that mainly affects the axillae, the palms of the hands, the soles of the feet, and the face. Skin maceration and secondary microbial infection can result from profuse sweating. Treatment is aimed at reducing sweat production. Therapeutic options involve topical aluminium chloride

161

or aluminium chloride hexahydrate in ethanol (57R ), iontophoresis (58R ), or anticholinergic or beta-blocking drugs (59R ). Botulinum toxin is a potent neurotoxin that inhibits acetylcholine release in cholinergic autonomic neurons and at the neuromuscular junction (60R ). It is used in the treatment of excessive muscle contraction disorders (dystonias), such as strabismus, blepharospasm, focal dystonias, and spasticity. One of its uses is in the removal of facial wrinkles by paralysing mimic muscles. Botulinum toxin can reduce sweat production by blocking cholinergic innervation of eccrine sweat glands. In small trials intradermal injection of botulinum toxin A has been shown to be effective in patients with axillary sweating, palmoplantar sweating, or compensatory sweating. Several larger placebo-controlled trials have now been published. In a multicenter, randomized placebo-controlled trial in 145 patients with axillary hyperhidrosis, refractory to treatment with topical aluminium chloride, both 100 and 200 U of botulinum toxin reduced sweat production by about 80% (61C ). After 24 weeks, sweat production in the treated axillae was about 45% of baseline. Temporary adverse events during the ﬁrst 14 weeks included headache, soreness of the muscles of the shoulder girdle, axillary itching, and increased facial sweating. A multicenter, double-blind, randomized, placebo-controlled study in 320 patients with untreated hyperhidrosis showed a more than 50% reduction in sweat production at 4 and 16 weeks after treatment respectively in 94% and 82% of patients treated with botulinum toxin (50 U per axilla) and in 36% and 21% of placebo-treated patients (62C ). The major treatment-related adverse effect was an increase in sweating in non-axillary sites after treatment. Open treatment with botulinum toxin A was offered to patients in whom sweat production was at least 50% of baseline values (63C ). Of 207 study subjects, 39% had one treatment, 45% had two treatments and 15% had three treatments. Response rates 4 weeks after treatment were 96%, 91% and 83% after the ﬁrst, second, and third treatments respectively. In one of 207 patients there was possible transient seroconversion from negative to positive for neutralizing antibodies to botulinum toxin, and subsequent treatment with botulinum

162 toxin resulted in complete disappearance of axillary sweating 7 days after injection. The long-term effectiveness of high-dose botulinum toxin (200 U per axilla) has been evaluated in an open study in patients with axillary hyperhidrosis unresponsive to previous therapies (64c ). In 34 patients follow-up was for at least 12 months. Four relapsed within 12 months and two relapsed after 16 and 19 months. Mild pain and a burning sensation, sometimes lasting up to 1 hour after injection, were the most frequent adverse effects. No compensatory hyperhidrosis at other body sites was reported. Nervous system Pain due to injection of botulinum toxin has been reported to be less severe with botulinum toxin reconstituted in preservative-containing saline 0.9% (benzyl alcohol 0.9% w/w) than with botulinum toxin reconstituted in preservative-free saline 0.9% in patients with glabella frown lines (65c ). Five cases of severe headache refractory to oral analgesics have been reported in patients treated with 10–38 U of botulinum toxin for

Chapter 14

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

glabella frown lines (n = 4) and in a patient treated with 120 U for palmar hyperhidrosis (66A ). The headache lasted for 8 days to 4 weeks, did not respond to oral prednisolone, and in some patients was accompanied by photophobia, ear tenderness, or nasal congestion. Two patients had a similar headache after a previous treatment with botulinum toxin and in another patient a similar headache occurred after the next treatment. None of the patients had a history of severe headaches. Neuromuscular A case of generalized muscular weakness associated with signs of systemic cholinergic autonomic impairment has been reported. • A 25-year-old woman was treated with botulinum toxin for hyperhidrosis of the axillae and hands in one session with a total amount of 1400 U. Six days later she complained of diffuse weakness, diplopia, mild bilateral ptosis, severe weakness in the ﬁngers, and reduced lacrimation, salivary production, and sweating (67A ). She recovered completely within 2 months.

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16. Stone N, Varma S, Hughes TM, Stone NM. Allergic contact dermatitis from polyvinylpyrrolidone (PVP)/1-triacontene copolymer in a sunscreen. Contact Dermatitis 2002; 47: 49. 17. Le Coz C-J, Leclere J-M, Arnoult E, RaisonPeyron N, Pons-Guiraud A, Vigan M, Members of Revidal-Gerda. Allergic contact dermatitis from shellac in mascara. Contact Dermatitis 2002; 46: 149–52. 18. Malanin KEN. Allergic contact dermatitis caused by a mixture of sodium myristoyl sarcosinate and sodium myristoate in a cosmetic product. Contact Dermatitis 2002; 47: 50. 19. Bowling JCR, Scarisbrick J, Warin AP, Downs AM. Allergic contact dermatitis from trideceth-2carboxamide monoethanolamine (MEA) in a hair dye. Contact Dermatitis 2002; 47: 116–17. 20. Kiken DA, Cohen DE. Contact dermatitis to botanical extracts. Am J Contact Dermatitis 2002; 13: 148–52. 21. De Groot AC, Weyland JW, Nater JP. Unwanted Effects of Cosmetics and Drugs Used in Dermatology. 3rd edition. Amsterdam: Elsevier, 1994. 22. Frosch PJ, Johansen JD, Menné T, Pirker C, Rastogi SC, Andersen KE, Bruze M, Goossens A, Lepoittevin JP, White IR. Further important sensitizers in patients sensitive to fragrances. I. Reactivity to 14 frequently used chemicals. Contact Dermatitis 2002; 47: 78–85. 23. Frosch PJ, Johansen JD, Menné T, Pirker C, Rastogi SC, Andersen KE, Bruze M, Goossens A, Lepoittevin JP, White IR. Further important sensitizers in patients sensitive to fragrances. II. Reactivity to essential oils. Contact Dermatitis 2002; 47; 279–87. 24. Matura M, Goossens A, Bordalo O, GarciaBravo B, Magnusson K, Wrangsjo K, Karlberg AT. Oxidized citrus oil (R-limonene): a frequent skin sensitizer in Europe. J Am Acad Dermatol 2002; 47: 709–14. 25. Larsen W, Nakayama H, Fischer T, Elsner P, Frosch P, Burrows D, Jordan W, Shaw S, Wilkinson J, Marks J, Sugawara M, Nethercott M, Nethercott J. Fragrance contact dermatitis—a world wide multicenter investigation (Part III). Contact Dermatitis 2002; 46: 141–4. 26. Larsen W, Nakayama H, Lindberg M, Fischer T, Elsner P, Burrows D, Jordan W, Shaw S, Wilkinson J, Marks J Jr, Sugawara M, Nethercott J. Fragrance contact dermatitis—a world wide multicenter investigation (Part I). Contact Dermatitis 1996; 7: 77–83. 27. Larsen W, Nakayama H, Fischer T, Elsner P, Frosch P, Burrows D, Jordan W, Shaw S, Wilkinson J, Marks J Jr, Sugawara M, Nethercott M, Nethercott J. Fragrance contact dermatitis – a world wide multicenter investigation (Part II). Contact Dermatitis 2001; 6: 344–6. 28. Sosted H, Agner T, Andersen KE, Menné T. 55 Cases of allergic reactions to hair dye: a descriptive, consumer complaint-based study. Contact Dermatitis 2002; 47: 299–303. 29. Fautz R, Fuchs A, Van der Walle H, Henny V, Smits L. Hair dye-sensitized hairdressers: the cross-

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reaction pattern with new generation hair dyes. Contact Dermatitis 2002; 46: 319–24. 30. Badreshia S, Marks JG Jr. Iodopropynyl butylcarbamate. Am J Contact Dermatitis 2002; 13: 77–9. 31. Bryld LE, Agner T, Rastogi SC, Menné T. Iodopropynyl butylcarbamate: a new contact allergen. Contact Dermatitis 1997; 36: 156–8. 32. Schnuch A, Geier J, Brasch J, Uter W. The preservative iodopropynyl butylcarbamate: frequency of allergic reactions and diagnostic considerations. Contact Dermatitis 2002; 46: 153–6. 33. Wilkinson JD, Shaw S, Andersen KE, Brandao FM, Bruynzeel DP, Bruze M, Camarasa JM, Diepgen TL, Ducombs G, Frosch PJ, Goossens A, Lachappelle JM, Lahti A, Menne T, Seidenari S, Tosti A, Wahlberg JE. Monitoring levels of preservative sensitivity in Europe. A 10-year overview (1991–2000). Contact Dermatitis 2002; 46: 207– 10. 34. Uter W, Frosch PJ, IVDK Study Group and the German Contact Dermatitis Research Group, DKG. Contact allergy from DMDM hydantoin, 1994– 2000. Contact Dermatitis 2002; 47: 57–8. 35. Hernandez B, Ortiz-Frutos FJ, Garcia M, Palencia S, Garcia MC, Iglesias L. Contact urticaria from 2-phenoxyethanol. Contact Dermatitis 2002; 47: 54. 36. Yesudian PD, King CM. Severe contact urticaria and anaphylaxis from benzophenone-3 (2hydroxy-4-methoxy benzophenone). Contact Dermatitis 2002; 46: 55–6. 37. Yamamoto A, Morita A, Tsuji T, Suzuki K, Matsunaga K. Contact urticaria from geraniol. Contact Dermatitis 2002; 46: 52. 38. Cogen FC, Beezhold DH. Hair glue anaphylaxis: a hidden latex allergy. Ann Allergy Asthma Immunol 2002; 88: 61–3. 39. Wakelin SH. Contact anaphylaxis from natural rubber latex used as an adhesive for hair extensions. Br J Dermatol 2002; 146: 340–1. 40. Van Coevorden AM, Coenraads PJ. Severe inﬂuenzalike symptoms associated with methoxsalen photochemotherapy. Arch Dermatol 2002; 138: 840–1. 41. Valenzuela N, Puig L, Barnadas MA, Alomar A. Photocontact dermatitis due to dexketoprofen. Contact Dermatitis 2002; 47: 237. 42. Henschel R, Agathos M, Breit R. Photocontact dermatitis after gargling with a solution containing benzydamine. Contact Dermatitis. 2002; 47: 53. 43. Sugiura M, Hayakawa R, Xie Z, Sugiura K, Hiramoto K, Shamoto M. Experimental study on phototoxicity and the photosensitization potential of ketoprofen, suprofen, tiaprofenic acid and benzophenone and the photocross-reactivity in guinea pigs. Photodermatol Photoimmunol Photomed 2002; 18: 82–9. 44. Bourrain JL, Amblard P, Béani JC. Contact urticaria photoinduced by benzophenones. Contact Dermatitis 2003; 48: 45–6. 45. Sommer S, Wilkinson SM, English JSC, Ferguson J. Photoallergic contact dermatitis from the sunscreen octyl triazone. Contact Dermatitis 2002; 46: 304–5.

164 46. Chroni E, Sakkis T, Georgiou S, Monastirli A, Pasmatzi E, Paschalis C, Tsambaos D. Stiff-person syndrome associated with oral isotretinoin treatment. Neuromuscul Disord 2002; 12: 886–8. 47. Rodondi N, Darioli R, Ramelet AA, Hohl D, Lenain V, Perdrix J, Wietlisbach V, Riesen WF, Walther T, Medinger L, Nicod P, Desvergne B, Mooser V. High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study. Ann Intern Med 2002; 136: 582–9. 48. Alli N, Toy GG. Familial Mediterranean fever: attacks during isotretinoin treatment. J Am Acad Dermatol 2002; 47: 967. 49. Rogaine extra strength for men slide lecture kit. Pharmacia & Upjohn Company, 1998: M-7909P. 50. Olsen EA, Dunlap FE, Funicella T, Koperski JA, Swinehart JM, Tschen EH, Trancik RJ. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol 2002; 47: 377–85. 51. Friedman ES, Friedman PM, Cohen DE, Washenik K. Allergic contact dermatitis to topical minoxidil solution: etiology and treatment. J Am Acad Dermatol 2002; 14: 309–12. 52. Suzuki K, Suzuki M, Akamatsu H, Matsungaga K. Allergic contact dermatitis from minoxidil: study of the cross-reaction to minoxidil. Am J Contact Dermatitis 2002; 13: 450–6. 53. Trattner A, David M. Pigmented contact dermatitis from topical minoxidil 5%. Contact Dermatitis 2002; 46: 246. 54. Sinclair RD, Mallari RS, Tate B. Sensitization to saw palmetto and minoxidil in separate topical extemporaneous treatments for androgenetic alopecia. Australas J Dermatol 2002; 43: 311–12. 55. Rojansky N, Fasouliotis SJ, Ariel I, Nadjari M. Extreme caudal agenesis. Possible drug-related etiology? J Reprod Med 2002; 47: 241–5. 56. Bastuji-Garin S, Ochonisky S, Bouche P, Gherardie RK, Duguet C, Djerradine Z, Poli F, Revuz J, on behalf of the Thalidomide Neuropathy Study Group. Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients. J Invest Dermatol 2002; 119: 1020– 6.

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57. Shelley WB, Hurley HJ Jr. Studies on topical antiperspirant control of axillary hyperhidrosis. Acta Derm-Venereol 1975; 55: 241–60. 58. Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands and their disorders. II. Disorders of sweat gland function. J Am Acad Dermatol 1989; 20: 713–26. 59. Mack GW, Shannon LM, Nadel ER. Inﬂuence of beta-adrenergic blockade on the control of sweating in humans. J Appl Physiol 1986; 61: 1701–5. 60. Hambleton P. Clostridium botulinum toxins: a general review of involvement in disease, structure, mode of action and preparation for clinical use. J Neurol 1992; 239: 16–20. 61. Heckmann M, Ceballos-Baumann AO, Plewig G, for the Hyperhidrosis Study Group. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). New Engl J Med 2001; 344: 488–93. 62. Naumann M, Lowe NJ, on behalf of the Hyperhidrosis Clinical Study Group. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. Br Med J 2001; 323: 596–9. 63. Naumann M, Lowe NJ, Kumar CR, Hamm H, for the Hyperhidrosis Clinical Investigators Group. Botulinum toxin type A is a safe and effective treatment for axillary hyperhidrosis over 16 months: a prospective study. Arch Dermatol 2003; 139: 731–6. 64. Wollina U, Karamﬁlov T, Konrad H. Highdose botulinum toxin type A therapy for axillary hyperhidrosis markedly prolongs the relapse-free interval. J Am Acad Dermatol 2002; 46: 536–40. 65. Alam M, Dover JS, Arndt KA. Pain associated with injection of botulinum A exotoxin reconstituted using isotonic sodium chloride with and without preservative: a double-blind, randomized controlled trial. Arch Dermatol 2002; 138: 510–14. 66. Alam M, Arndt KA, Dover JS. Severe, intractable headache after injection with botulinum A exotoxin: report of 5 cases. J Am Acad Dermatol 2002; 46: 62–5. 67. Tugnoli V, Eleopra R, Quatrale R, Capone JG, Sensi M, Gastaldo E. Botulism-like syndrome after botulinum toxin type A injections for focal hyperhidrosis. Br J Dermatol 2002; 147: 808–9.

Garry M. Walsh

15

Antihistamines (H1 receptor antagonists)

Second-generation antihistamines are highly effective in the treatment of atopic disease, including both seasonal and perennial allergic rhinitis, urticaria, and atopic dermatitis (1R ). The newer antihistamines are a heterogeneous group of compounds, having markedly differing chemical structures, a spectrum of antihistaminic properties, half-lives, tissue distribution, and metabolism, and varying degrees of antiinﬂammatory effects. Although they are among the most frequently prescribed and safest drugs in the world, the second-generation drugs are not free from adverse effects. Indeed, they may be administered or selected inappropriately and may be a source of drug-related morbidity (2R ). Recently, the desire for improved drugs with enhanced potency, duration, and onset of action, together with greater predictability and safety, has led to the emergence of several novel antihistamines. These are either metabolites or enantiomers of existing drugs and include fexofenadine, desloratadine, and levocetirizine, all of which appear to be effective for several allergic conditions. Cardiovascular Many of the second-generation antihistamines (e.g. terfenadine, ebastine, astemizole, and loratadine) undergo extensive ﬁrst-pass metabolism to pharmacologically active metabolites; as a common feature, their metabolism is primarily supported by the CYP3A4 isozyme of the cytochrome P450 family. Although this extensive metabolism leads to low or undetectable plasma concentrations of the parent drug, metabolism of the parent compound can sometimes be compromised. Accumulation of unmetabolized terfenadine and astemizole can result in blockade of cardiac potassium channels in the ventricular myocytes © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

that regulate the duration of the action potential; subsequent prolongation of the QT interval can result in potentially life-threatening polymorphous ventricular tachycardias (3R ), ﬁrst reported with astemizole (4r ) and later with terfenadine (5r ), of which the latter has been the most widely prescribed (6R ). Predisposing factors to the induction of cardiac dysrhythmias by antihistamines include: liver disease; concomitant prescribing of drugs such as macrolide antibiotics; overdose; congenital QT interval prolongation; ischemic heart disease; congestive cardiac failure; and electrolyte imbalance. Furthermore, certain foods, such as grapefruit juice, can alter the systemic availability of some antihistamines by interactions with enzymes such as cytochrome P450 or active transporter systems (1R ). Nervous system The potential for sedation by some of the newer antihistamines is still an issue. This is important, as many patients using antihistamines want to remain alert and active and may also be taking other medications, with the potential for drug–drug interactions. First-generation H1 receptor antagonists readily cross the blood–brain barrier, and their consequent sedative and anticholinergic effects are well documented; however, they are still widely used, mainly as over-the-counter products, often in combination with other drugs. While second-generation H1 antagonists lack signiﬁcant CNS effects, there is a widespread tendency to consider them to be completely non-sedative. For example, when used at their recommended dosages in objective studies in healthy volunteers, the CNS depressant effects of loratadine (7R ), mizolastine (8R ), and fexofenadine (9C , 10C ) appear to be no greater than those of placebo. However, the issue is complicated by evidence that suggests that sedation in allergic disease—and subsequent

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impairment in performance and learning—may be consequences of the condition itself, as opposed to being wholly induced by antihistamines (1R , 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 (11R ). Another issue is the tendency of patients with allergies to self-medicate, titrating their antihistamine dosage upwards to achieve symptom relief; impairment does in fact occur if the dose of loratadine, mizolastine, or cetirizine is increased sufﬁciently (1R , 2R ). Thus, it is more correct to describe the second-generation antihistamines as having minimal sedative effects when taken in their recommended doses.

Cetirizine

(SED-14, 486; SEDA-22, 178)

Seasonal allergic rhinitis affects about 10% of school-age children, and there is evidence of a signiﬁcant impact of the disease on healthrelated quality of life. The effect on healthrelated quality of life of once-daily cetirizine syrup 10 mg/day for 4 weeks has been studied in 544 children with seasonal allergic rhinitis in a multicenter, open, non-comparative study (12C ). In addition to improvements in symptom scores the authors also reported signiﬁcant improvements in health-related quality of life, with good tolerability of the drug. Treatmentrelated adverse effects were reported in 22 subjects, of which somnolence was the most frequent problem, reported by six of the subjects. Only 12 of subjects discontinued treatment owing to an adverse effect. Health-related quality of life and clinical outcomes in 865 adult patients with seasonal allergic rhinitis treated with cetirizine or placebo for 2 weeks have been evaluated in a double blind, randomized, parallel-group study (13C ). Cetirizine signiﬁcantly improved both symptoms and health-related quality of life, while treatment-related adverse effects were comparable with those in the placebo group. Psychological The Early Treatment of the Atopic Child (ETAC) Study has provided evidence that cetirizine may be able to halt the progression to asthma in high-risk groups of

Garry M. Walsh

young children and infants with atopic dermatitis (14C ). However, the study involved giving relatively high doses of cetirizine to very young children (aged 1–2 years at study entry) over a long period of time. Therefore, the impact of prolonged use of high-dose cetirizine (0.25 mg/kg bd over 18 months) on behavior and cognitive ability in young children and infants has been assessed in a recent double-blind, randomized, placebo-controlled study (15C ). Well-validated and standardized assessments of behavior or cognition were used, and the ages at which psychomotor milestones were attained were established. The authors concluded that, compared with placebo, cetirizine had no signiﬁcant effects on behavior, cognition, or psychomotor milestones in young children with atopic dermatitis. Skin There have been several case reports of skin intolerance of cetirizine, including cases of urticaria. • A 32-year-old woman with recurrent idiopathic urticaria, asthma, and metal-induced contact dermatitis had 5–10 episodes of urticaria a year, with pruritic wheals of less than 24 hours duration (16A ). Cetirizine 10 mg/day was associated with the appearance of pruritic wheals on her neck, forehead, and arms. The symptoms resolved on drug withdrawal and reappeared on rechallenge. Double-blind challenge tests with mizolastine, loratadine, fexofenadine, dexchlorphenamine, ebastine, ketotifen, and placebo were negative, whereas hydroxyzine and its active metabolite, cetirizine, reproduced the urticaria.

The authors concluded that identiﬁcation of uncommon adverse reactions to H1 antihistamines is important, particularly because they may mimic the underlying disease. • A 36-year-old woman noted intense exacerbation of urticarial wheals and facial edema 3–4 hours after taking cetirizine 10 mg (17A ). Skin tests with cetirizine produced an urticarial reaction 5 hours after challenge. Placebo-controlled oral challenge resulted in generalized urticaria, edema of the hands, and intense pruritus 90 minutes after administration of cetirizine, with symptoms lasting up to 12 hours. Skin biopsies showed inﬂammation typical of urticaria.

The authors concluded that the patient had suffered a non-immunological adverse reaction to cetirizine and that reactions to cetirizine may be interpreted as lack of responsiveness in patients with skin disease.

Antihistamines (H1 receptor antagonists)

• In a 45-year-old man cetirizine caused multiple ﬁxed erythematous lesions on the trunk (18A ). Cetirizine was withdrawn for 15 days and an oral challenge test was performed. The same skin lesions developed in the previously affected skin sites when cetirizine was taken. • A 14-year-old girl with house dust mite allergy had generalized skin eruptions after taking cetirizine. She also had symptoms of acute hepatitis, which also resolved after withdrawal of cetirizine (19A ). • A 73-year-old man had skin eruptions associated with cetirizine and hydroxyzine therapy, which healed after drug withdrawal (20A ).

Desloratadine

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(SEDA-26, 181, 182)

Desloratadine is the primary metabolite of loratadine, with superior H1 receptor binding, potent antihistaminic activity compared with the parent compound, and proven efﬁcacy in allergic disease (21R ). It is effective and well tolerated in seasonal allergic rhinitis, including relief of nasal congestion (22C –24C ). In a randomized, open, four-way crossover study in 20 healthy men desloratadine was given as single doses (5, 7.5, 10, and 20 mg) in four different treatment periods with 14 days between each dose. The Cmax for all doses occurred at 4 hours after administration, with a half-life of 21 to 24 hours. There were no doserelated differences in drug absorption rate, and even the 20 mg dose was well tolerated (25C ). The systemic availability of desloratadine was unaffected by food in healthy adult volunteers (26C ). Cardiovascular The electrocardiographic safety of desloratadine in combination with the CYP3A4 inhibitor ketoconazole has been assessed in a randomized, two-way crossover, third-party blind, multiple-dose, placebo-controlled study over ten days in 24 healthy volunteers (27C ). Compared with desloratadine alone there were no signiﬁcant or clinically important changes in QTc , QT, PR, or QRS intervals when desloratadine (7.5 mg/day, i.e. 50% higher than the recommended dose) was co-administered with ketoconazole (200 mg bd). There was a 1.3-fold increase in desloratadine Cmax when it was co-administered with ketoconazole, but this was judged not to be clinically important. The authors concluded that co-administration of

desloratadine with ketoconazole has no clinically relevant electrocardiographic or pharmacodynamic implications. In a similar study in 12 male and 12 healthy female volunteers there was no prolongation of the QTc interval after co-administration of desloratadine with erythromycin (28C ). Susceptibility factors The effects of race and age on desloratadine pharmacokinetics at steady state have been examined in two studies (29C , 30C ). The authors concluded that no dosage adjustments for desloratadine were required; nor were there any clinically relevant electrocardiographic changes. Drug interactions In a non-blinded, randomized, single-dose, crossover study in 24 healthy adults, grapefruit juice had no effect on the systemic availability of oral desloratadine (31C ). There were no clinically signiﬁcant electrocardiographic changes after co-administration of grapefruit juice with desloratadine compared with desloratadine alone.

Diphenhydramine

(SED-14, 488;

SEDA-22, 178) Nervous system Diphenhydramine is still widely used, mainly in over-the-counter products, often in combination with other drugs. This is a cause for concern, as it can cause signiﬁcant daytime neurological impairment comparable to intoxication with alcohol (32R ). In a recent study to assess injury rates in 12 106 patients taking diphenhydramine compared with 24 968 patients taking loratadine, using a health-care claims database that included employees, dependents, and retirees who ﬁled claims from January 1991 to December 1998, there was a strong association between diphenhydramine use and the occurrence of injuries: 55% of all injuries were associated with its use. The loratadine and diphenhydramine groups had similar pre-drug intake injury rates. The authors concluded that a substantial number of excess injuries and costs had been incurred as the result of the use of diphenhydramine (33M ).

168 Psychiatric Visual hallucinations occurred in an otherwise healthy 19-year-old man who took the stimulant prolintane and diphenhydramine (34A ). The psychiatric complications occurred 2 months after he started to take the two drugs and resolved quickly once they were withdrawn. Drug tolerance In 15 healthy men tolerance to diphenhydramine developed rapidly in a randomized, placebo-controlled, crossover study (35C ). Diphenhydramine 50 mg or placebo was given twice a day for 4 days and tests of objective and subjective sleepiness together with computer-based tests of psychomotor performance were carried out. Compared with placebo on day 1 diphenhydramine caused signiﬁcant impairment. However, by day 4 sleepiness and impairment of performance were indistinguishable from placebo.

Ebastine

(SED-14, 488; SEDA-21, 175; SEDA-26, 181) Ebastine is a second-generation antihistamine with proven efﬁcacy in the treatment of allergic disease (36R ). It is rapidly absorbed after oral administration, and undergoes extensive ﬁrstpass metabolism to its active carboxylic acid metabolite, carebastine. Like other antihistamines that rely on activation by metabolism, the systemic availability of ebastine may be affected by food. In a double-blind, placebocontrolled, parallel-group study, 215 patients with seasonal allergic rhinitis took ebastine with solid food (immediately after breakfast), while 218 took the drug 1–2 hours after breakfast (37C ). Food taken at the time of dosing did not alter the therapeutic or adverse effects of ebastine for 2 weeks in seasonal allergic rhinitis. Although carebastine steady-state concentrations were 15% higher when ebastine was taken with food this was not considered clinically important. Psychological The effects of ebastine 10 mg on cognitive impairment have been assessed in 20 healthy volunteers who performed six types of attention-demanding cognitive tasks, together with objective measurements of reaction times and accuracy (38C ). Ebastine was

Chapter 15

Garry M. Walsh

compared with placebo and a positive control, chlorphenamine (chlorpheniramine, 2 mg and 6 mg). Compared with placebo, ebastine had no effect on any objective cognitive test nor any effect on subjective sleepiness. In contrast, chlorphenamine signiﬁcantly increased reaction times, decreased accuracy in cognitive tasks, and increased subjective sleepiness. The effect of chlorphenamine increased with plasma concentration.

Emedastine

(SEDA-26, 181)

Nervous system Emedastine is a potent antihistamine with proven efﬁcacy in allergic conjunctivitis (39C ). However, it is currently only registered for the treatment of seasonal allergic rhinitis in its country of origin (Japan). The potential sedative effects of single and repeated doses of emedastine 2 mg and 4 mg bd on actual driving performance have been assessed in healthy volunteers (nine men and ten women, aged 21–45 years) (40C ). The study was a four-period, double-blind, crossover design, and driving performance was measured in a standardized test at 3–4 h after administration of the morning dose on days 1, 4, and 5. Emedastine signiﬁcantly impaired driving in every test at both doses and the authors concluded that the drug could constitute a trafﬁc hazard and that its users should be warned accordingly.

Fexofenadine (SED-14, 488; SEDA-21, 177; SEDA-26, 181, 183) Fexofenadine is the active metabolite of terfenadine and is efﬁcacious and well-tolerated in seasonal allergic rhinitis (41R ) with positive effects on nasal blockade (42C ) and chronic idiopathic urticaria (43R ). Drug interactions In a non-blinded, randomized, single-dose, crossover study in 24 healthy adults, grapefruit juice reduced the rate of absorption and the systemic availability of oral fexofenadine by 30% (30C ). However, there were no clinically signiﬁcant electrocardiographic changes after co-administration of

Antihistamines (H1 receptor antagonists)

Chapter 15

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. St John’s wort (Hypericum perforatum) is a popular and widely available herbal extract used as a remedy for anxiety, depression, and sleep disorders. Fexofenadine is transported by P glycoprotein in vitro (44E ) and there is evidence that St John’s wort may alter P glycoprotein activity (45E ). The effects of St John’s wort on the pharmacokinetics of fexofenadine have therefore been studied (46C ). Fexofenadine 60 mg was given orally twice—before a single dose of St John’s wort 900 mg and again after 3 weeks treatment with 300 mg tds. A single dose of St John’s wort signiﬁcantly inhibited intestinal P glycoprotein activity and increased the maximum plasma concentration of fexofenadine by 45%. In contrast, long-term St John’s wort caused a 35% reduction in the Cmax of fexofenadine and increased its oral clearance. However, the authors concluded that these pharmacokinetic changes alone are unlikely to be clinically signiﬁcant. In addition to their effects on P glycoprotein, fruit juices and St John’s wort may also inhibit organic anion transporting polypeptides (47E ). These ﬁndings suggest new models of intestinal drug absorption and mechanisms of drug interactions.

169

such adverse effects (1R ), it is unlikely that levocetirizine is any different in this regard. Nervous system There have been relatively few studies of the sedative effects of levocetirizine, although two comprehensive studies have suggested a favorable proﬁle (50C , 51C ). The effect of levocetirizine 5 mg/day on actual driving performance by 48 healthy volunteers has been compared with the effect of the ﬁrst-generation antihistamine diphenhydramine 50 mg/day in a double-blind, placebocontrolled, randomized study (52C ). Treatments were administered on days 1, 2, 3, and 4, 90 minutes before the start of a standardized driving test on day 1 and day 4. In contrast to diphenhydramine, driving performance was not signiﬁcantly affected by levocetirizine. Psychological A double-blind, placebo-controlled, randomized trial examined the effects of levocetirizine 5 mg and diphenhydramine 50 mg on objective measurements (a wordlearning test, the Sternberg Memory Scanning Test, a tracking test, and a divided attention test that measured both tracking and memory scanning simultaneously) in 48 healthy volunteers (24 men and 24 women). Levocetirizine had no effect, while diphenhydramine signiﬁcantly affected divided attention and tracking after acute administration (53C ). However, on day 4 the effects of diphenhydramine did not reach significance, suggesting a degree of tolerance to this ﬁrst generation drug (see also above).

Loratadine Levocetirizine

(SEDA-26, 182, 183)

Levocetirizine is the R enantiomer of cetirizine dihydrochloride and, like cetirizine, undergoes minimal hepatic metabolism. Levocetirizine has twice the afﬁnity for the H1 receptor as cetirizine (48E ). It is efﬁcacious and well tolerated in patients with seasonal allergic rhinitis (49C ). Cardiovascular To date, there have been no studies of the potential cardiotoxic effects of levocetirizine. However, since cetirizine is free of

(SED-14, 488; SEDA-22, 178; SEDA-26, 182)

Skin Loratadine caused erythematous, edematous, pruriginous skin eruptions in a 19-yearold woman who complained of at least three episodes of eruptions located at the same sites each time (54A ). An oral challenge with loratadine was positive, and cetirizine and ebastine caused no cutaneous reaction. Histopathology suggested a ﬁxed drug eruption.

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Chapter 15

Garry M. Walsh

REFERENCES 1. 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. 2. Casale TB, Blaiss MS, Gelfand E, Gilmore T, Harvey PD, Hindmarch I, Simons FE, Spangler DL, Szeﬂer SJ, Terndrup TE, Waldman SA, Weiler J, Wong DF. Antihistamine Impairment Roundtable. First do no harm: managing antihistamine impairment in patients with allergic rhinitis. J Allergy Clin Immunol 2003; 111: S835–42. 3. 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. Clin Allergy Immunol Series. Marcel Dekker Inc, 1996: 383–412. 4. Simons FER, Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-induced torsade de pointes. Lancet 1988; 2: 624. 5. Davies AJ, Harinda V, McEwan A, Ghose RR. Cardiotoxic effect with convulsions in terfenadine overdose. Br Med J 1989; 298: 325. 6. Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996; 36: 233–52. 7. Kay GG, Harris AG. Loratadine, a non-sedating antihistamine. Clin Exp Allergy 1999; 29 Suppl 3: 147–50. 8. 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. 9. 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. 10. Nicholson AN, Stone BM, Turner C, Mills SL. Antihistamines and aircrew: usefulness of fexofenadine. Aviation Space Environ Med 2000; 71: 2–6. 11. 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. Marcel Dekker Inc, 1996: 357–81. 12. Gillman SA, Blatter M, Condemi JJ, Collins M, Olufade AO, Leidy NK, Chapman D, Kramer B. The health-related quality of life effects of oncedaily cetirizine HCl syrup in children with seasonal allergic rhinitis. Clin Pediatr 2002; 41: 687–96. 13. Murray JJ, Nathan RA, Bronsky EA, Olufade AO, Chapman D, Kramer B. Comprehensive evaluation of cetirizine in the management of seasonal allergic rhinitis: impact on symptoms, quality of life, productivity and activity impairment. Allergy Asthma Proc 2002; 23: 391–8. 14. ETAC Study Group. Allergic factors associated with the development of asthma and the inﬂuence of cetirizine on this progression in a double-blind, randomised, placebo-controlled trial: ﬁrst results of ETAC. Pediatr Allergy Immunol 1998; 9: 116–24.

15. Stevenson J, Cornah D, Evrard P, Vanderheyden V, Billard C, Bax M, Van Hout A, for the ETAC Study Group. Long-term evaluation of the impact of the H1 -receptor antagonist cetirizine on the behavioral, cognitive, and psychomotor development of very young children with atopic dermatitis. Pediatr Res 2002; 52: 251–7. 16. Tella R, Gaig P, Bartra J, Garcia-Ortega P. Urticaria to cetirizine. J Invest Allergol Clin Immunol 2002; 12: 136–7. 17. Schroter S, Damveld B, Marsch WC. Urticarial intolerance reaction to cetirizine. Clin Exp Dermatol 2002; 27: 185–7. 18. Inamadar AC, Palit A, Athanikar SB, Sampagavi VV, Deshmukh NS. Multiple ﬁxed drug eruptions due to cetirizine. Br J Dermatol 2002; 147: 1025–6. 19. Sanchez-Lombrana JL, Perez Alvarez R, Rodrigo Saez L, Perez Oliva N, Simo Martinez RM. Acute hepatitis associated with cetirizine intake. J Clin Gastroenterol 2002; 34: 493–5. 20. Assouere M-N, Mazereeuw-Hautier J, Bonafe J-L. Cutaneous drug eruption with two antihistaminic drugs of a same chemical family: cetirizine and hydroxyzine. Ann Dermatol Venereol 2002; 129: 1295–8. 21. McCellan K, Jarvis B. Desloratadine. Drugs 2001; 61: 789–96. 22. Horak F, Stubner UP, Zieglmayer R, Ing D, Harris AG. Effect of desloratadine versus placebo on nasal airﬂow and subjective measures of nasal obstruction in subjects with grass pollen-induced allergic rhinitis in an allergen-exposure unit. J Allergy Clin Immunol 2002; 109: 956–61. 23. Bachert C, Virchow CJ Jr, Plenker A. Desloratadine in the treatment of seasonal allergic rhinitis: results of a large observational study. Clin Drug Invest 2002; 22: 43–52. 24. Wilson AM, Haggart K, Sims EJ, Lipworth BJ. Effects of fexofenadine and desloratadine on subjective and objective measures of nasal congestion in seasonal allergic rhinitis. Clin Exp Allergy 2002; 32: 1504–9. 25. Gupta S, Banﬁeld C, Affrime M, Marco A, Cayen M, Herron J, Padhi D. Desloratadine demonstrates dose proportionality in healthy adults after single doses. Clin Pharmacokinet 2002; 41: 1–6. 26. Gupta S, Banﬁeld C, Affrime M, Marbury T, Padhi D, Glue P. Oral bioavailability of desloratadine is unaffected by food. Clin Pharmacokinet 2002; 41: 7–12. 27. 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: 37–44. 28. Banﬁeld C, Hunt T, Reyderman L, Statkevich P, Padhi D, Affrime M. Lack of clinically relevant interaction between desloratadine and erythromycin. Clin Pharmacokinet 2002: 41: 29–35.

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29. Affrime M, Gupta S, Banﬁeld C, Cohen A. A pharmacokinetic proﬁle of desloratadine in healthy adults, including elderly. Clin Pharmacokinet 2002; 41: 13–19. 30. Affrime M, Banﬁeld C, Gupta S, Cohen A, Boutros T, Thonoor M, Cayen M. Effect of race and sex on single and multiple dose pharmacokinetics of desloratadine. Clin Pharmacokinet 2002; 41: 21–8. 31. 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. 32. O’Hanlon JF, Raemaekers JG. Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989-94. Allergy 1995; 50: 234–42. 33. Finkle WD, Adams JL, Greenland S, Melmon KL. Increased risk of serious injury following an initial prescription for diphenhydramine. Ann Allergy Asthma Immunol 2002; 89: 244–50. 34. Paya B, Guisado JA, Vaz FJ, Crespo-Facorro B, Vaz Leal FJ. Visual hallucinations induced by the combination of prolintane and diphenhydramine. Pharmacopsychiatry 2002; 35: 24–5. 35. Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002; 22: 511–15. 36. Wiseman LR, Faulds D. Ebastine: a review of its pharmacological properties and clinical efﬁcacy in the treatment of allergic disorders. Drugs 1996; 51: 260–77. 37. Hampel F Jr, Gillen M, Rohatagi SS, Lim J, Georges G. A double-blind, placebo-controlled study of the efﬁcacy and safety of ebastine 20 mg once daily given with and without food in the treatment of seasonal allergic rhinitis. J Clin Pharmacol 2002; 41: 1097–104. 38. Tagawa M, Kano M, Okamura N, Higuchi M, Matsuda M, Mizuki Y, Arai H, Fujii T, Komemushi S, Itoh M, Sasaki H, Watanabe T, Yanai K. Differential cognitive effects of ebastine and (+)chlorpheniramine in healthy subjects: correlation between cognitive impairment and plasma drug concentration. Br J Clin Pharmacol 2002; 53: 296– 304. 39. 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. 40. Vermeeren A, Ramaeders JG, O’Hanlon JF. Effects of emedastine and cetirizine, alone and with alcohol, on actual driving of males and females. J Psychopharmacol 2002; 16: 57–64. 41. 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.

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42. Wilson AM, Orr LC, Coutie WJR, Sims EJ, Lipworth BJ. A comparison of once daily fexofenadine versus the combination of montelukast plus loratadine on domiciliary nasal peak ﬂow and symptoms in seasonal allergic rhinitis. Clin Exp Allergy 2002; 32: 126–32. 43. Kawashima M, Harada S, Tango T. Review of fexofenadine in the treatment of chronic idiopathic urticaria. Int J Dermatol 2002; 41: 701–6. 44. Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 1999; 27: 866– 71. 45. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with a herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66: 338–45. 46. Wang Z, Hamman MA, Huang S-M, Lesko LJ, Hall SD. Effect of St John’s wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 2002; 71: 414–20. 47. Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, Kim RB. Fruit juices inhibit organic anion transporting polypeptidemediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002; 71: 11–20. 48. Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H-1 histamine receptors: contribution of Lys(191) and Thr(194). Mol Pharmacol 2002; 61: 391–9. 49. Leynadier F, Mees K, Arendt C, Pinelli ME. Efﬁcacy and safety of levocetirizine in seasonal allergic rhinitis. Acta Otorhinolaryngol Belg 2001; 55: 305–12. 50. 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. 51. 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. 52. Verster JC, De Weert AM, Bijtjes SI, Aarab M, Van Oosterwijck AW, Eijken EJ, Verbaten MN, Volkerts ER. Driving ability after acute and subchronic administration of levocetirizine and diphenhydramine: a randomized, double-blind, placebocontrolled trial. Psychopharmacology (Berl) 2003; 169: 84–90. 53. Verster JC, Volkerts ER, Van Oosterwijck AW, Aarab M, Bijtjes SI, De Weert AM, Eijken EJ, Verbaten MN. Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood. J Allergy Clin Immunol. 2003; 111: 623–7. 54. Ruiz-Genao DP, Hernandez-Nunez A, SanchezPerez J, Garcia-Diez A. Fixed drug eruption due to loratadine. Br J Dermatol 2002; 146: 528–9.

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Drugs acting on the respiratory tract

Aerosol delivery Propellants Pulmonary delivery of drugs is the administration route of choice in respiratory diseases such as chronic obstructive pulmonary disease and asthma. Different devices are available, including metered dose inhalers, dry powder inhalers, and nebulizers, and nearly 80% of asthmatic patients worldwide use metered dose inhalers (1R ). Chloroﬂuorocarbon has been used as an aerosol propellant in metered dose inhalers; however, it depletes the ozone layer and is being replaced by more environment-friendly propellants. The ﬁrst chloroﬂuorocarbon-free metered dose inhaler for asthma treatment was approved by the FDA in 1996 (2R ) and the European Union has set 2005 as a target date for the withdrawal of all chloroﬂuorocarbon-based inhalers (1R ). In the USA, prescriptions for chloroﬂuorocarbon-free medications rose from 16.4 million in 1996 to 33.8 million in 2000 (2R ). Most of the chloroﬂuorocarbon-free medications were steroids for nasal use (27.2 million). However, chloroﬂuorocarbon-containing medications still represented two-thirds of all prescriptions and increased from 63.0 to 67.6 million dispensed (2R ). The search for ozone-friendly propellants has concentrated on two hydroﬂuoroalkanes with physicochemical properties similar to the chloroﬂuorocarbons: hydroﬂuoroalkane 134a and hydroﬂuoroalkane 227 (1R ). A new generation of chloroﬂuorocarbon-free metered dose inhalers has been designed by the pharmaceutical industry to be equivalent to the currently marketed chloroﬂuorocarbon-containing inhalers in terms of efﬁcacy, safety, and dose © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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delivered. This goal was achieved by using the Modulite® technology, by dissolving the drug in the propellant with the aid of a glycerol-like co-solvent (3R ). Beclomethasone dipropionate and budesonide Modulite® formulations have been compared with equivalent chloroﬂuorocarbon products in small groups of healthy volunteers and asthmatic patients (4c ): there was no signiﬁcant difference in morning serum cortisol or urinary cortisol excretion, suggesting that the systemic availability of the inhaled corticosteroids with different propellants is similar. Moreover, plasma proﬁles of beclomethasone dipropionate and B17MP were similar after inhalation of beclomethasone dipropionate Modulite® and beclomethasone dipropionatechloroﬂuorocarbon, suggesting that pulmonary delivery to the lung is comparable with the two propellants (4c ). There have been three randomized, doubleblind studies in adult asthmatics of the efﬁcacy and safety of a new beclomethasone dipropionate-hydroﬂuoroalkane 134a formulation, equivalent in dose per actuation to the currently marketed beclomethasone dipropionate chloroﬂuorocarbon products (5C –7C ). Daily doses of beclomethasone dipropionate hydroﬂuoroalkane 134a 1000 μg over 12 weeks given by metered dose inhaler (5C ) or a spacer jet device (6C ) were equivalent in terms of safety and efﬁcacy compared with beclomethasone dipropionate chloroﬂuorocarbon 1000 μg. The same was true for doses of 400 μg (7C ). In another study different doses of ﬂunisolide hydroﬂuoroalkane were tested in 21 healthy adult volunteers for 4.5 days (170 μg, 340 μg, 680 μg); there was a dose-related response after both single- and multiple-dose administration (8c ). There was no accumulation of ﬂunisolide with repeated dosing, suggesting that the systemic availability of ﬂunisolide hydroﬂuoroalkane is low. A randomized, double-blind,

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placebo-controlled study with daily doses of 80 μg and 160 μg over 12 weeks in 353 asthmatic children gave similar results (9C ). Hydroﬂuoroalkane 134a and chloroﬂuorocarbon have been compared in two randomized, double-blind, placebo-controlled studies with salbutamol. Salbutamol 180 μg in hydroﬂuoroalkane 134a given 30 minutes before an exercise challenge was as safe and effective as 180 μg in chloroﬂuorocarbon in 24 patients with documented exercise-induced bronchospasm (10c ). In 63 patients with mild to moderate asthma salbutamol in hydroﬂuoroalkane 134a or chloroﬂuorocarbon were of comparable efﬁcacy without any difference in the incidence of adverse events (11c ). These results suggest that the transition from chloroﬂuorocarbon-containing to chloroﬂuorocarbon-free metered dose inhalers is possible without concerns about safety and efﬁcacy

of the hypothalamic–pituitary–adrenal axis. As effective inhaled corticosteroid therapy is expected to cause detectable reductions in the physiological secretion of cortisol (12r ), lowdose budesonide by pressurized metered dose inhaler is probably not effective. In another study budesonide inhalation suspension, developed for nebulization to meet the speciﬁc needs of infants and young children, did not cause signiﬁcant suppression of hypothalamic– pituitary–adrenal axis function (basal plasma cortisol concentrations and ACTH test) in doses from 0.25 to 1.0 mg (16C ). However, inhaled ﬂuticasone propionate by pressurized metereddose inhaler with a spacer in 62 children resulted in abnormal morning cortisol concentrations in 36% (17 using a low dose of 176 μg/day; 43 using a high dose, over 880 μg/day) (17c ). The equivalence of inhaled corticosteroids based on equipotent (cortisol suppression) effects has been studied by the Asthma Clinical Research Network (ACRN). Six different inhaled corticosteroids and matched placebos (beclomethasone chloroﬂuorocarbon, budesonide dry powder inhaler, ﬂuticasone dry powder inhaler, ﬂuticasone-chloroﬂuorocarbon metered dose inhaler, ﬂunisolide chloroﬂuorocarbon, and triamcinolone chloroﬂuorocarbon) were compared by measuring their systemic effects (18c ). Steroid naïve people with asthma (n = 156) were enrolled at six centers and a 1week doubling dose design was used for each of the six inhaled corticosteroids and matched placebos to a total of four doses. The best outcome variable for the reliable assessment of a systemic effect was the 12-hour AUC of the hourly overnight plasma cortisol measurements from 8 p.m. to 8 a.m. Microgram comparisons of the corticosteroids could only be performed at 10% cortisol suppression, because ﬂuticasone did not cause higher suppression. The following equipotent doses (i.e. doses producing equal systemic cortisol suppression) were found: ﬂunisolide 936 μg; triamcinolone 787 μg; beclomethasone 548 μg; ﬂuticasone dry powder: 445 μg; budesonide 268 μg; ﬂuticasone metered dose inhaler 111 μg. The ranking of systemic effects was very similar to that found earlier in a large meta-analysis (19M ). In a randomized, double-blind study adult asthmatic patients took budesonide 800 μg/day

Drugs acting on the respiratory tract

Systemic availability of inhaled corticosteroids (SEDA-23, 175; SEDA-24, 185; SEDA-26, 187) The systemic availability of an inhaled corticosteroid represents the additive and complex combination of pulmonary and gastrointestinal drug absorption. Absorption is inﬂuenced by many factors, including delivery device, the use of a spacer, the particle size of the inhaled drug, and the absorption and metabolism of the swallowed drug (12r ). The different methods of assessing hypothalamic–pituitary–adrenal axis activity in patients using inhaled corticosteroids have been compared (13C ). The AUC of serum cortisol concentrations was the most reliable method. There were signiﬁcant positive correlations between AUC and the 8 a.m. serum and salivary cortisol concentrations. The authors favored the non-invasive method of salivary concentration measurement. However, 24-hour urine collection is not recommended, as it correlated only moderately well. This ﬁnding is consistent with the results of other studies. Urinary free cortisol estimation based on immunoassay after inhaled corticosteroids may be an unreliable surrogate marker of adrenal suppression, and studies using this method should be interpreted with caution (14c ). Dry powder inhaler and pressurized metered-dose inhaler for administration of low-dose budesonide (400 μg/day) have been compared (15c ). Only the dry powder caused suppression

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over 12 weeks either by Easyhaler® (n = 103) or Turbuhaler® (n = 58) dry powder inhaler. The Easyhaler was equivalent to the Turbuhaler with regards to safety and efﬁcacy, but was more acceptable to the patients (20C ).

INHALED CORTICOSTEROIDS (SED-14, 512; SEDA-23, 178; SEDA-26, 186)

Risks of inhaled corticosteroids in children Inhaled corticosteroids are recommended as ﬁrst-line therapy for persistent asthma in children, to reduce both asthma symptoms and inﬂammatory markers. Treatment should be begun early in the course of the disease, because inhaled corticosteroids can preserve airway function and prevent airway remodelling and subsequent irreversible airway obstruction (21M ). Because asthma is a chronic disease requiring long-term treatment, it is very important to balance the safety and efﬁcacy of inhaled corticosteroids to achieve optimal long-term results. Major safety concerns in children are the potential adverse effects on growth, adrenal function, and bone mass. Overall, the beneﬁts of inhaled corticosteroids clearly outweigh their potential adverse effects and the risks of poor asthma control. However, high doses of inhaled corticosteroids in children are still of concern (22M ). It is of utmost importance to use the lowest effective dose, to limit systemic availability by selecting drugs with high ﬁrst-pass hepatic inactivation, and to instruct patients on proper inhalation technique. Moreover, the use of adjuvant asthma medications acting by different mechanisms can help to reduce inhaled corticosteroid dosages (21M , 22M ). These add-on therapies include leukotriene modiﬁers, long-acting beta2 -agonists, cromoglicate and nedocromil, and in selected cases theophylline. These agents should be added to, but should not in any case replace, inhaled corticosteroid therapy (21M , 22M ). Adrenal suppression in children In recent years inhaled corticosteroids have been prescribed more and more in younger children at an earlier stage of their disease and for

longer periods; children with severe asthma are also treated with larger doses than licensed. Therefore, considerations of their systemic effects are of importance. Symptomatic adrenal insufﬁciency has been reported in children after prolonged high-dose treatment with inhaled corticosteroids. • Four boys 4–8 years old with symptomatic adrenal insufﬁciency had all used consistent high doses of ﬂuticasone propionate 1000–1500 μg/day over extended periods (16 months to 5 years) (23A ). They presented with acute hypoglycemia secondary to iatrogenic adrenal suppression, with abnormal ACTH tests, although none had Cushingoid features. • A 33-year-old man and three children (two girls, one boy, 7–9 years) presented with symptomatic adrenal insufﬁciency (24A ). All three children had seizures because of hypoglycemia, and the man had a low blood pressure, nausea, and fatigue. In all cases ACTH tests were abnormal, showing adrenal insufﬁciency. The children had used ﬂuticasone propionate 500–2000 μg/day and the man had recently switched from ﬂuticasone propionate 1000–2000 μg/day to budesonide dry powder inhaler 800 μg/day. Only one of the children had used oral glucocorticosteroids in the previous year. • A 21-month-old boy had a hypoglycemia-induced seizure in the setting of adrenal suppression (25A ). He had been given increasing doses of budesonide up to 2000 μg qds and oral glucocorticosteroids until the age of 15 months. • A 32-month-old girl developed hypoglycaemic seizures (26A ). She had been given ﬂuticasone propionate 440–880 μg/day and up to 5 months before the incident oral glucocorticosteroids.

In addition to these case reports, there has been a survey of symptomatic adrenal suppression associated with inhaled corticosteroids in the UK (27c ). Only 24% of the questionnaires were returned (709 responses), and there were 28 cases of symptomatic adrenal suppression reported in children and ﬁve in adults (including the 10 cases discussed above). The children presented mostly with hypoglycemia and coma, whereas the adults mainly had lethargy and nausea. No obvious precipitating cause was found in 65% of the cases. In four children diagnosis was delayed by 3 months to 2 years. All but three patients had been treated with ﬂuticasone propionate alone, but at high daily doses (children 500–2000 μg, adults 1000–2000 μg). One child had used both ﬂuticasone propionate and budesonide and one adult and one child used beclomethasone dipropionate. Different inhaled corticosteroids have recently been compared for their suppressing

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effects on the hypothalamic–pituitary–adrenal axis (18c ). In a large meta-analysis budesonide or beclomethasone dipropionate in doses of over 1500 μg/day were associated with adrenal suppression in adults (19M ). In children, ﬂuticasone propionate 200 μg/day or budesonide 400 μg/day caused detectable adrenal gland suppression (28c ). For interpretation of the different studies it is very important to distinguish between detectable indicators for systemic drug action (i.e. reduced morning cortisol) and true suppression of the hypothalamic– pituitary–adrenal axis, as determined by adrenal function tests (standard-dose or low-dose ACTH test), which are more predictive of possible systemic adverse effects (12r ). The fact that ﬂuticasone propionate is involved in the vast majority of the published cases should be discussed further. The systemic concentration of an inhaled glucocorticoid depends on the absorbed fraction of the drug in the gut and in the lung. Swallowed ﬂuticasone propionate is almost completely metabolized in the liver by CYP3A4 (ﬁrst-pass effect over 99.9%) before reaching the systemic circulation; however, its metabolic clearance can be altered in patients with low CYP3A4 expression and activity (29c ). Pulmonary absorbed ﬂuticasone propionate is very potent; because of its pronounced lipophilicity it binds with higher afﬁnity to glucocorticoid receptors and has a larger distribution volume and a longer half-life than other inhaled corticosteroids (30M ). These characteristics give it the potential of accumulating with multiple doses. Other factors that determine the absorbed fraction of inhaled corticosteroids include age of the child, as lung deposition of inhaled drugs increases with age (31M ). Therefore, the minimum effective dose may fall as the child becomes older. Moreover, it is reasonable to hypothesize that systemic absorption will increase once asthma control is established (32r ). Furthermore, patient adherence and inhaler technique are two factors that can have a large inﬂuence on the amount of corticosteroid inhaled and absorbed. However, the most important factor is the dose. The safety and efﬁcacy of ﬂuticasone propionate in children in daily doses of 100– 200 μg have been demonstrated in many studies (33M ). The doses in the case reports of symptomatic adrenal suppression have to be

considered as being excessively high. These reports reﬂect excessive dosing of inhaled corticosteroids, and in some cases a residual effect of previous oral glucocorticosteroid treatment cannot be excluded. The use of excessive doses is empirical and not supported by the literature. All inhaled corticosteroids have a ﬂat dose-response curve (34M ). Extensive clinical experience with inhaled corticosteroids over the past 20 years has suggested that the risk of adrenal insufﬁciency with inhaled corticosteroids alone is very low when recommended doses are used (35M ). To avoid symptomatic adrenal suppression, the lowest effective dose should always be used. Before automatically increasing the dose in refractory patients, the diagnosis should be reconsidered. Furthermore, a reduction in the dosage of inhaled corticosteroid can also be achieved with the addition of adjuvant therapies, such as leukotriene receptor antagonists and long-acting beta2 adrenoceptor agonists (22M ). Monitoring children using inhaled corticosteroids has recently been discussed (12r ). Children using low to moderate doses of inhaled corticosteroids (up to 200 μg of ﬂuticasone propionate or budesonide) do not require routine hypothalamic–pituitary–adrenal axis measurement. In children using consistently higher doses (up to 400 μg of ﬂuticasone propionate or budesonide) or using glucocorticoids by other routes, morning plasma cortisol should be monitored periodically because of the increased risk of clinically signiﬁcant adrenal suppression. If cortisol concentrations are below 276 μmol/l (100 μg/l), functional testing of the hypothalamic–pituitary–adrenal axis should be considered.

Drugs acting on the respiratory tract

Growth inhibition Oral glucocorticoids inhibit growth by blunting pulsatile growth hormone secretion, by decreasing insulin-like growth factor-1 activity, and by directly inhibiting collagen synthesis (36M ). Although inhalation reduces systemic exposure, concerns have been raised regarding the potential effects on growth and ﬁnal height in children, especially when inhaled corticosteroids are used for long periods. A two-part review was published in 2002, addressing the difﬁculties of assessing the effects of asthma therapy on childhood growth and reviewing the published literature based on the authors’ recommendations (37M , 38M ). In

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the ﬁrst part, a simple classiﬁcation system for growth studies was developed: • comparisons with placebo (type 1 studies); • comparisons with non-steroidal asthma therapy (type 2 studies); • comparisons with another inhaled corticosteroid (type 3 studies); • comparisons with “real life” asthma therapy (type 4 studies) (37M ). In the context of these different study types, the authors also discussed the choice of end-point, key trial design issues, the selection and numbers of subjects in the active and control groups, the duration of assessments, and methods for measuring height and data analysis. They also elaborated speciﬁc recommendations regarding study duration, age/sexual maturity of the patients, exclusion criteria for height and growth velocity, permitted therapy during the study, the protocol for height measurement, the numbers of patients for adequate statistical power, and methods for statistical analysis (37M ). In the second part, they selected 18 growth studies that included minimal criteria, such as selected control group, measured height by stadiometry, and at least a 12-month duration; they compared the design attributes of these studies with the described recommendations (38M ). Of the 18 selected studies, 17 were susceptible to one or more important confounding factors; nevertheless, the outcomes of all 18 studies were considered to be consistent. In summary, impaired growth velocity was found with budesonide and beclomethasone dipropionate compared with placebo, non-steroidal treatment, and ﬂuticasone propionate during 1–2 years of therapy, but none of the inhaled corticosteroids appeared to affect ﬁnal height (38M ). Growth in children treated with lowdose ﬂuticasone propionate (up to 200 μg/day) for 1 year is similar to growth in those treated with placebo or non-steroidal therapy. Standard pediatric doses of inhaled corticosteroids (less than 800 μg of budesonide and less than 400 μg of budesonide or ﬂuticasone) are considered not to affect growth adversely (35M , 39r ). The risk of growth suppression depends on the dose, the administration regimen, and the delivery device. An important confounding factor is the inﬂuence of non-adherence to inhaled corticosteroid

treatment (40r ). Sensitive and reliable measures of adherence should be applied when evaluating long-term effects on height. The time of dosing can inﬂuence the effect of inhaled corticosteroids on growth suppression in the prepubertal child, since GH secretion is generally conﬁned to night-time. Therefore, once-daily morning dosing could be advantageous (41M ). For clinical practice, the lowest effective dose should be achieved, and all children using inhaled corticosteroids should have their growth measured every 6 months, as this is a sensitive method of detecting signiﬁcant systemic effects (35M , 41M ). These results apply to children over 4 years of age; for younger children only assumptions can be entertained and age-speciﬁc studies are needed (41M ). Bone mineral density The adverse effects of oral corticosteroids on bone metabolism are well established. However, studies of the effects of inhaled corticosteroids on markers of bone mineral density have provided conﬂicting data (42M ). A cross-sectional study in children (43C ) showed no signiﬁcant difference in total and anteroposterior spine bone mineral density between children with asthma treated with longterm budesonide (200–800 μg for at least 6 months; n = 52) and asthmatic children who had never used inhaled corticosteroids (n = 22). These results are in agreement with those of a larger cross-sectional study of the effects of long-term treatment (3–6 years, mean 4.5 years) with inhaled budesonide on total bone mineral density in children with asthma (n = 157). The results provided evidence that long-term treatment with inhaled corticosteroids in moderate dosages is unlikely to affect bone mineral density adversely in children with asthma (44M ). However, a recent study of the association of clinical risk factors and bone density with fractures in 324 prepubertal children, of whom 32 had a fracture, suggested that for total fracture risk bone mineral density may be less important than clinical risk factors (45C ). In a multivariate model incorporating age, weight, height, breast-feeding history, sports participation, and the use of inhaled corticosteroids, these factors accounted for 10% of the variability in the risk of fracture.

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Surprisingly, bone mineral density in the lumbar spine, femoral neck, and total body bone did not differ between those with or without fractures. More data on the effect of inhaled corticosteroids on bone mineral density in adults has been generated by the large randomized, multicenter, double-blind, placebo-controlled EUROSCOPE (European Respiratory Society Study on Chronic Obstructive Pulmonary Disease) study of 912 patients with chronic obstructive pulmonary disease randomly assigned to treatment for 3 years with budesonide 800 μg/day or placebo (46C ). There were no signiﬁcant differences in bone mineral density at L2–4 vertebrae, the femoral neck, trochanter, or Ward’s triangle; nor did the fracture rate between budesonide-treated and placebo-treated patients differ. These ﬁndings are in contrast to recent data from the Lung Health Study, which showed that triamcinolone 1200 μg/day for 4 years was associated with a statistically signiﬁcant 2% reduction in bone mineral density in the femoral neck compared with placebo (47M ). It can be hypothesized that different corticosteroids have different systemic effects, and therefore different effects on bone metabolism. An alternative hypothesis is that these effects are dose-dependent (22M ), support for which comes from a population-based case-control study of 16 341 older patients with hip fractures (mean age 79 years) and 29 889 controls; recent use of an inhaled corticosteroid was associated with a small dose-dependent increase in the risk of hip fracture (48C ).

inhibitors (n = 53 845) were the controls. Relative to controls oral corticosteroid users (n = 31 864) were more likely to develop diabetes mellitus, but there was no association between the use of inhaled corticosteroids (n = 38 441) and diabetes mellitus. These results suggest that the use of inhaled corticosteroids in elderly people does not signiﬁcantly increase the risk of diabetes mellitus.

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Endocrine Diabetes mellitus The association between inhaled corticosteroids and the risk of diabetes mellitus in elderly people (over 65 years) has been investigated in two Canadian studies. In a nested case-control study of the association between current use of inhaled corticosteroids and the risk of using antidiabetic drugs among 21 645 subjects the risk of diabetes was not statistically signiﬁcant (49C ). Moreover, there was no statistically signiﬁcant increase in risk among users of high-dose beclomethasone compared with non-users. In a retrospective population-based cohort study using administrative databases, the association between oral and inhaled corticosteroid use and the onset of diabetes mellitus in the elderly was quantiﬁed (50C ). Users of proton pump

Skin Contact allergy to corticosteroids is not rare in patients with atopic dermatitis. In patients with known contact allergy to budesonide allergic skin reactions can also occur when inhaled forms of the drug are used, as shown by a randomized, double-blind, placebo-controlled study in 15 non-asthmatic patients with budesonide hypersensitivity on patch testing (51c ). In four of seven patients who used inhaled budesonide, there was reactivation of the 6-week-old patch test sites and they had new distant skin lesions. No ﬂare-up reactions were observed in the other 11 patients (three had used inhaled budesonide and eight placebo for 1 week). None of the patients developed respiratory symptoms; spirometry and peak expiratory ﬂow rates remained normal. Drug interactions Interactions with other drugs can increase plasma concentrations of inhaled corticosteroids. Itraconazole, a potent inhibitor of CYP3A4, markedly increased plasma concentrations of inhaled budesonide (52c ). Ritonavir, another potent inhibitor of CYP3A4, caused Cushing’s syndrome in a patient using ﬂuticasone propionate 1000 μg/day (53A ).

LEUKOTRIENE MODIFIERS (SEDA-24, 184; SEDA-25, 197; SEDA-26, 193)

Leukotriene receptor antagonists and Churg-Strauss syndrome Leukotriene receptor antagonists (montelukast, pranlukast, zaﬁrlukast) were introduced in 1998. They have both anti-inﬂammatory and bronchodilator effects and are increasingly

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being used in patients with moderate to severe asthma in order to reduce corticosteroid dosages. In early clinical trials leukotriene receptor antagonists were generally well tolerated, but in the postmarketing phase they have been associated with the Churg–Strauss syndrome. Churg–Strauss syndrome is a rare disease, ﬁrst described in 1951, characterized by the histological ﬁndings of eosinophilic tissue inﬁltration, extravascular eosinophil granulomas, and necrotizing vasculitis. It develops in patients with a history of upper airway disease (especially allergic rhinitis and sinusitis) and asthma. There are different deﬁnitions of the syndrome, and it is important to know which deﬁnition is being used when the results of different incidence studies are being compared. Clinically the syndrome has been deﬁned (54R ) as a combination of asthma, peripheral eosinophilia (over 1.5 × 109 /l), and a systemic vasculitis involving two or more extrapulmonary organs. Recognized clinical risk factors include moderate to severe asthma, chronic sinusitis, and a recent reduction in systemic corticosteroid therapy (55R ). An important feature is the phasic developmental pattern of the disease, and corticosteroid therapy suppresses some manifestations of the syndrome, leading to incomplete disease. Churg and colleagues labelled these cases “formes frustes” of Churg–Strauss syndrome (56c ). Careful monitoring must be ensured when tapering corticosteroids in steroiddependent patients to avoid development of incomplete disease. In 2002 there were several reports of patients with Churg–Strauss syndrome who were using leukotriene receptor antagonists. • Two 50-year-old men, both using inhaled corticosteroids, presented with Churg–Strauss syndrome after taking montelukast for 4–5 months, not related to steroid tapering (57A ). One had a history of asthma and recurrent sinusitis for 5 years with intermittent short-course oral corticosteroids and continued inhaled steroids, whereas the other had asthma for 1 year treated with only inhaled corticosteroids. • Two women (aged 60 and 62 years) with allergic rhinitis and asthma, one using inhaled corticosteroids and the other oral corticosteroids, developed Churg–Strauss syndrome after taking montelukast (58A ). In the woman using oral steroids dosage reduction preceded the onset of the syndrome; in the woman using inhaled steroids there was no dosage reduction. The authors also presented the case of a 54-year-old man with a history

of Churg–Strauss syndrome who relapsed after taking montelukast. • A 50-year-old man with a history of severe asthma and tapering of prednisone took montelukast and developed an erythematous rash and mononeuritis multiplex; skin biopsy conﬁrmed the diagnosis of Churg–Strauss syndrome (59A ). • A 54-year-old man with no history of corticosteroid therapy presented with systemic symptoms and a purpuric rash after taking zaﬁrlukast; the diagnosis was Churg–Strauss syndrome (60A ). • An 18-year-old woman with childhood asthma using inhaled corticosteroids and zaﬁrlukast developed Churg–Strauss syndrome 10 days after starting to use rokitamycin (61A ).

Of 22 asthmatic patients taking leukotriene receptor antagonists who developed Churg– Strauss syndrome, 13 had used zaﬁrlukast, eight montelukast, and one pranlukast (62M ). All had used inhaled or oral corticosteroids. The onset of the syndrome was at 2 days to 10 months after starting treatment with the leukotriene receptor antagonist; the interval between the last dose of oral steroids and the recognised onset of Churg–Strauss syndrome ranged from 3 days to 8 months. In several patients the signs and symptoms of Churg–Strauss syndrome became manifest after the start of leukotriene receptor antagonist treatment and tapering of inhaled/oral steroids (13 of 23 patients). There are different explanations for the possible association between leukotriene receptor antagonist treatment and Churg–Strauss syndrome. The favored hypothesis is unmasking of Churg–Strauss syndrome (meaning either unmasking of a previously contained pathological condition or the clinical declaration of a “forme fruste”) after reduction of corticosteroid dosage (55R , 63r ). This is supported by the fact that Churg–Strauss syndrome has also been reported in asthmatic patients who are tapering their doses of corticosteroid after the introduction of other antiasthmatic drugs (55R ). It seems unlikely that leukotriene receptor antagonists themselves provoke Churg–Strauss syndrome, since none of the established mechanisms of adverse drug reactions provides a plausible explanation for the association (55R ). The incidence of Churg–Strauss syndrome among asthmatic patients has been calculated in a cohort study of 36 230 patients with asthma (64C ). The incidence rates of deﬁnite Churg– Strauss syndrome were 0–67 cases per million per year, depending on the deﬁnition used. The small number of cases did not allow subgroup

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analysis. The occurrence of Churg–Strauss syndrome during leukotriene receptor antagonist therapy could therefore be coincidental, because the rate of 64 cases per million patients per year in association with leukotriene receptor antagonists is comparable to the estimated rate of 18–74 cases per million patients per year in the asthma population observed before the introduction of these drugs (55R , 62M ), (63r ). Large epidemiological studies, including data on corticosteroid-naive patients using leukotriene receptor antagonists, are needed to address this question further. In summary, to date most authors agree that the most plausible explanation for Churg– Strauss syndrome during therapy with leukotriene receptor antagonists is an unmasking mechanism (i.e. progression of clinical symptoms when oral corticosteroids are avoided, withdrawn, or withheld) rather than a druginduced disease. However, physicians should be aware of the possible development of Churg– Strauss syndrome in patients with moderate to severe asthma who are tapering their corticosteroid dosages, because early recognition and effective treatment of the syndrome is of the utmost importance.

BETA2 -ADRENOCEPTOR AGONISTS (SED-14, 500; SEDA-24, 187; SEDA-25, 192; SEDA-26, 190)

Formoterol (SED-14, 506; SEDA-25, 194; SEDA-26, 191) In a post-marketing surveillance study of the long-acting beta2 -adrenoceptor agonist formoterol in the UK using the technique of prescription event monitoring, exposure and outcome data in 5777 patients aged 3–96 years were collected (67C ). The most commonly reported events, excluding those related to respiratory disease, were headache, tremor, palpitation, cramp, and nausea and vomiting, events known to be associated with beta2 -adrenoceptor agonists (68R ). However, the frequencies of nausea and vomiting (1.3%) and pruritus (0.5%) differed from the frequencies reported in the premarketing trials.

Salbutamol

(SED-14, 502;

SEDA-23, 185)

Montelukast

(SEDA-24, 184;

SEDA-26, 193) Drug overdose Since montelukast is a relatively new drug, few data are available on unintentional poisoning. This makes it difﬁcult to determine which dosages require aggressive decontamination or simple monitoring. Acute montelukast overdose with doses up to at least 150 mg/day have been reported in children. In most of the reports no adverse events were reported; when they occurred, symptoms included thirst, somnolence, mydriasis, hyperkinesia, and abdominal pain. In two cases of unintentional poisoning with montelukast there were no symptoms in a 3-year-old child who took 80 mg or in a 5-year-old child who took 135 mg (65A ). In adults, montelukast doses up to 20- to 90-fold greater than the recommended dose (10 mg/day), given for longer than 1 week, were well tolerated and no unexpected adverse events occurred (66M ).

The short-acting beta2 -adrenoceptor agonists have pharmacologically predictable adverse effects (tachycardia, tremor, plasma altered potassium and blood glucose concentrations) and unpredictable effects, including airway hyper-responsiveness (68R ). Rare adverse reactions to salbutamol are also occasionally reported. Nervous system The often reported observation by parents of asthmatic children that salbutamol causes hyperactivity has been investigated in 19 children before and after the inhalation of 5 ml of a nebulized solution (isotonic saline or salbutamol 5 mg); there was no statistically signiﬁcant difference in activity (69c ). The authors hypothesized that the supposed effect on the children’s activity might be dose related or might reﬂect a propellant effect rather than being a consequence of salbutamol itself.

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Metabolic Transient lactic acidosis/lactatemia has been reported as an adverse effect of inhaled salbutamol. In ﬁve patients who received 5 mg salbutamol by inhalation serum lactate concentrations were 3.2–8.0 mmol/l and arterial blood pH values 7.34–7.43; after 24 h serum lactate concentrations returned to normal without speciﬁc treatment (70A ). In two other cases high-dose salbutamol caused lactic acidosis, contributing to respiratory failure in one patient and complicating the assessment and management of acute severe asthma in the other (71A ). Respiratory compensation for this primary metabolic acidosis, characterized by increased respiratory rate and effort, may be mistaken for increased respiratory distress due to asthma. Lactic acidosis in acute asthma can therefore lead to problems in asthma management, including unwarranted intensiﬁcation of beta2 -adrenoceptor agonist therapy and the initiation of premature or unnecessary mechanical ventilation. Musculoskeletal The question of whether salbutamol can cause a myopathy has recently been discussed (72A ). • A 76-year-old asthmatic woman developed increasing weakness, proximal muscle cramps, and fatigue. She had been using salbutamol spray (600 μg/day) and tablets (10 mg/day) for 2 years, and for 6 months had also used inhaled formoterol 24 μg/day. There were increases in creatine kinase (494 IU/l; reference range 0–130 IU/l), lactate dehydrogenase (350 IU/l; 0–300 IU/l), and aldolase (10 IU/l; 0–7.5 IU/l). Myopathy was conﬁrmed electrophysiologically and histologically. The three medications were withdrawn and 2 days later her condition began to improve; the muscle pain and weakness disappeared within 3 weeks.

The authors concluded that beta2 -adrenoceptor agonist activity had been responsible for the deleterious muscle effects and they proposed that beta2 -adrenoceptor agonists should be added to the list of drugs that can cause myopathies. However, the exact effects of beta2 adrenoceptor agonists on human skeletal muscle are not clear. They have also been reported to increase muscle strength and have been used in patients with muscle weakness, including spinal muscular atrophy (73A ). Drug overdose A 28-year-old woman took an overdose of oral salbutamol (100 mg of salbutamol BP solution) (74A ). She developed

diabetic ketoacidosis, with a serum glucose concentration of 17 mmol/l (308 mg/dl). Diabetic ketoacidosis induced by salbutamol overdose is uncommon in patients without diabetes; however, this patient had a family history of diabetes. A 4-year-old girl with accidental salbutamol intoxication (2.3 mg/kg) developed fever (38◦ C) besides the classical signs of salbutamol intoxication (75A ). Since she had no identiﬁable focus of infection the possibility of a thermogenic effect induced by increased adrenergic stimulation due to salbutamol intoxication was considered.

Terbutaline

(SED-14, 507;

SEDA-23, 186) Nervous system Acute paraparesis occurred after an injection of terbutaline sulfate for premature labor in a 26-year-old woman (76A ).

ANTICHOLINERGIC DRUGS (SED-14, 499; SEDA-24, 192; SEDA-26, 194)

Tiotropium bromide The parasympathetic nervous system plays a major role in regulating bronchomotor tone. Bronchoconstriction due to increased parasympathetic bronchomotor tone is thought to be the major component of airway obstruction in patients with chronic obstructive pulmonary disease. Inhaled anticholinergic drugs, such as the quaternary ammonium compound ipratropium bromide, are therefore recommended as ﬁrstline bronchodilators in the treatment of chronic obstructive pulmonary disease. The most recently developed quaternary ammonium compound, tiotropium bromide, is an anticholinergic bronchodilator that binds with similar afﬁnity to the three muscarinic receptor subtypes (77R ). However, tiotropium dissociates more slowly from M1 and M3 receptors in bronchial smooth muscle than from M2 receptors. This results in a long half-life of the bound complex, allowing once-daily administration.

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The efﬁcacy and safety of tiotropium have been studied in vitro and in early clinical trials, and dose-ranging studies have shown that tiotropium dry powder 18 μg/day is safe and efﬁcacious (77R –79R ). Tiotropium is inhaled from the HandiHaler® , a dry-powder, breathactivated inhaler system that delivers particles to the lung over a wide range of airﬂow limitations in patients with chronic obstructive pulmonary disease; it can be effectively delivered at inspiratory ﬂow rates as low as 20 l/min (80c ). Pharmacodynamic steady-state studies have shown that most of the bronchodilator activity is achieved with one to two doses within 48 hours, although a carryover effect on forced vital capacity was observed beyond 48 hours (81c ). Several large, randomized, double-blind, controlled comparisons of tiotropium with placebo (82C ), ipratropium (83C ), and salmeterol (84C ) have been published. In a multicenter, double-blind, placebo-controlled trial in patients with stable chronic obstructive pulmonary disease tiotropium 18 μg/ day for 1 year (n = 550) signiﬁcantly improved lung function (mean trough FEV1 , FVC, PEFR) and reduced dyspnea compared with placebo (n = 371) (82C ). Moreover, tiotropium recipients had better health status scores, fewer exacerbations of chronic obstructive pulmonary

disease, and fewer hospitalizations. There was no evidence of tachyphylaxis over one year. In a randomized, double-blind trial tiotropium 18 μg/day for 1 year (n = 356) was compared with ipratropium 160 μg/day (n = 179) in patients with chronic obstructive pulmonary disease (83C ). Tiotropium maintained superior efﬁcacy (FEV1 and FVC) throughout the study, improved dyspnea, and reduced the number of exacerbations by 24%. In a placebo-controlled, double-blind study tiotropium 18 μg/day for 6 months (n = 209) was compared with salmeterol 50 μg bd (n = 213) and placebo (n = 201) in 623 patients with moderate to severe chronic obstructive pulmonary disease (84C ). Tiotropium improved dyspnea and trough FEV1 and FVC signiﬁcantly more than salmeterol. The patients who used tiotropium had better quality-of-life scores than those who used salmeterol, but the difference was not statistically signiﬁcant. In all these studies adverse events were comparable to those with placebo, except for dry mouth, which was reported in 10–16% of patients (77R , 82C –84C ). Since the quaternary structure of tiotropium limits its absorption through the mucous membrane of the respiratory and gastrointestinal tract, systemic adverse effects are in general minimal.

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38. Price J, Hindmarsh P, Hughes S, Efthimiou. Evaluating the effects of asthma therapy on childhood growth: what can be learnt from the published literature? Eur Respir J 2002; 19: 1179–93. 39. Wolthers OD. Growth problems in children with asthma. Horm Res 2002; 57 Suppl 2: 83–7. 40. Wolthers OD, Allen DB. Inhaled corticosteroids, growth and compliance. New Engl J Med 2002; 347: 1210–11. 41. Allen DB. Inhaled corticosteroid therapy for asthma in preschool children: growth issues. Pediatrics 2002; 109: 373–80. 42. Wong CA, Subakumar G, Casey PM. Effects of asthma and asthma therapies on bone mineral density. Curr Opin Pulm Med 2002; 8: 39–44. 43. Bahceciler NN, Szegin G, Nursoy NA, Barlan IB, Basaran NM. Inhaled corticosteroids and bone density of children with asthma. J Asthma 2002; 39: 151–7. 44. Agertoft L, Pedersen S. Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide. Am J Respir Crit Care Med 1998; 157: 178–83. 45. Ma DQ, Jones G. Clinical risk factors but not bone density are associated with prevalent fractures in prepubertal children. J Pediatr Child Health 2002; 38: 497–500. 46. Johnell O, Pauwels R, Löfdahl CG, Laitinen LA, Postma DS, Pride NB, Ohlsson SV. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler® . Eur Respir J 2002; 19: 1058–63. 47. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. New Engl J Med 2000; 343: 1902–9. 48. Hubbard RB, Smith CJP, Smeeth L, Harrison TW, Tattersﬁeld AE. Inhaled corticosteroids and hip fracture: a population-based case-control study. Am J Respir Crit Care Med 2002; 166: 1563– 6. 49. Dendukurri N, Blais L, LeLorier J. Inhaled corticosteroids and the risk of diabetes among the elderly. Br J Clin Pharmacol 2002; 54: 59–64. 50. Blackburn D, Hux J, Mamdani M. Quantiﬁcation of the risk of corticosteroid-induced diabetes mellitus among the elderly. J Gen Intern Med 2002; 17: 717–20. 51. Isaksson M, Bruze M. Allergic contact dermatitis in response to budesonide reactivated by inhalation of the allergen. J Am Acad Dermatol 2002; 46: 880–5. 52. Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivistö KT. Plasma concentration of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole. Clin Pharmacol Ther 2002; 72: 362– 9. 53. Clevenbergh P, Corcostegui M, Gérard D, Hieronimus S, Mondain V, Chichmanian RM, Sadoul JL, Dellamonica P. Iatrogenic Cushing’s syndrome in an HIV-infected patient treated with inhaled corticosteroids (ﬂuticasone propionate) and low dose ritonavir enhanced PI containing regimen. J Infect 2002; 44: 194–5.

54. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg–Strauss syndrome. Medicine (Baltimore) 1984: 63; 65–81. 55. Lilly CM, Churg A, Lazarovich M, Pauwels R, Hendeles L, Rosenwasser LJ, Ledford D, Wechsler ME. Asthma therapies and Churg–Strauss syndrome. J Allergy Clin Immunol 2002; 109: S1–20. 56. Churg A, Brallas M, Cronin SR, Churg J. Formes frustes of Churg–Strauss syndrome. Chest 1995; 108: 320–3. 57. Guilpain P, Viallard JF, Lagarde P, Cohen P, Kambouchner M, Pellegrin J-L, Guillevin L. Churg–Strauss syndrome in two patients receiving montelukast. Rheumatology 2002; 41: 535–9. 58. Solans R, Bosch JA, Selva A, Orriols R, Vilardell M. Montelukast and Churg–Strauss syndrome. Thorax 2002; 57: 183–5. 59. Gal AA, Morris RJ, Pine JR, Sparker MK. Cutaneous lesions of Churg–Strauss syndrome associated with montelukast therapy. Br J Dermatol 2002; 147: 618–19. 60. Soy M, Ozer H, Canataroglu A, Gumurdulu D, Erken E. Vasculitis induced by zaﬁrlukast therapy. Clin Rheumatol 2002; 21: 328–9. 61. Richeldi L, Rossi G, Ruggieri MP, Corbetta L, Fabbri M. Churg–Strauss syndrome in a case of asthma. Allergy 2002; 57: 647–8. 62. Jamaleddine G, Diab K, Tabbarah Z, Tawil A, Arayssi T. Leukotriene antagonists and the Churg– Strauss syndrome. Semin Arthritis Rheum 2002; 31: 218–27. 63. Masi AT, Hamilos DL. Leukotriene antagonists: bystanders or causes of Churg–Strauss syndrome? Semin Arthritis Rheum 2002; 31: 211–17. 64. Loughlin JE, Cole JA, Rothman KJ, Johnson ES. Prevalence of serious eosinophilia and incidence of Churg–Strauss syndrome in a cohort of asthma patients. Ann Allergy Asthma Immunol 2002; 88: 319–25. 65. Cobb DB, Abbott CL, Watson WA, Fernandez MC. High-dose montelukast exposures in a 3-year old and a 5-year old child. Vet Hum Toxicol 2002; 44: 91–2. 66. Muijsers RBR, Noble S. Montelukast: a review of its therapeutical potential in asthma in children 2 to 14 years of age. Pediatr Drugs 2002; 4: 123–9. 67. Wilton LV, Shakir SA. A post-marketing surveillance study of formoterol (Foradil® ). Drug Saf 2002; 25: 213–23. 68. Sears MR. Adverse effects of beta-agonists. J Allergy Clin Immunol 2002; 110: S322–8. 69. Hadjikoumi I, Loader P, Bracken M, Milner AD. Bronchodilator therapy and hyperactivity in preschool children. Arch Dis Child 2002; 86: 202–4. 70. Stratakos G, Kalomenidis J, Routsi C, Papiris S, Roussos C. Transient lactic acidosis as a side effect of inhaled salbutamol. Chest 2002; 122: 385–6. 71. Prakash S, Mehta S. Lactic acidosis in asthma: report of two cases and review of the literature. Can Respir J 2002; 9: 203–8. 72. Hellier JP, Baudrimont M, Dussaule JC, Berenbaum F. Reversible selective beta2 -adrenoceptor

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agonist-induced myopathy. Rheumatology 2002; 41: 111–13. 73. Kinali M, Mercuri E, Main MA, De Biasia F, Karatza A, Higgins R, Banks LM, Manzur AY, Muntoni F. Pilot trial of albuterol in spinal muscular atrophy. Neurology 2002; 59: 609–10. 74. Habib GS, Saliba W, Cohen L. Diabetic ketoacidosis associated with oral salbutamol overdose. Am J Med 2002; 113: 701–2. 75. Yilmaz HL, Kucukosmanoglu O, Hennes H, Celik T. Salbutamol intoxication: is salbutamol a fever-inducing drug? A case report and treatment strategy. Eur J Emerg Med 2002; 9: 179–82. 76. Herskowitz A, Herskowitz B. Acute paraparesis due to terbutaline sulfate. South Med J 2002; 95: 275–6. 77. Hvizdos KM, Goa KL. Tiotropium bromide. Drugs 2002; 62: 1195–203. 78. Disse B, Speck GA, Rominger KL, Witek TJ, Hammer R. Tiotropium (Spiriva™ ): mechanistical considerations and clinical proﬁle in obstructive lung disease. Life Sci 1999; 64: 457–64. 79. Beeh KA, Welte T, Buhl R. Anticholinergics in the treatment of chronic obstructive pulmonary disease. Respiration 2002; 69: 372–9. 80. Chodosh S, Flanders JS, Kesten S, Serby CW, Hochrainer D, Witek TJ Jr. Effective delivery of particles with the HandiHaler® dry powder inhalation system over a range of chronic obstructive pulmonary disease severity. J Aerosol Med 2001; 14: 309–15. 81. Van Noord JA, Smeets JJ, Custers FLJ, Korducki L, Cornelissen PJG. Pharmacodynamic

steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J 2002; 19: 639–44. 82. Casaburi R, Mahler DA, Jones PW, Wanner A, San-Pedro G, ZuWallack RL, Menjoge SS, Serby CW, Witek T. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002; 19: 217–24. 83. Vincken W, Van Noord JA, Greefhorst APM, Bantje ThA, Kesten S, Korducki L, Cornelissen PJG, Van de Bosch JMM, Bunnik MCM, Creemers JPHM, Dalinghaus WH, Eland ME, Evers WBM, Gans SJM, Gooszen Hch, Van Harreveld AJ, Van Kasteren JHLM, Kuipers AF, Van Noord JA, Nossent GD, Pannekoek BJM, Pasma HR, Peters A, Pieters WR, Postmus PE, Schreurs AJM, Sinninghe Damste HEJ, Sips AP, Van Spiegel PI, Westbroek J, Aumann JL, Janssens E, Pauwels R, Radermecker M, Slabbynck H, Stappaerts I, Verhaert J, Vermeire P, Vincken W. Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. Eur Respir J 2002; 19: 209–16. 84. Donohue JF, van Noord JA, Bateman ED, Langley SJ, Lee A, Witek TJ Jr, Kesten S, Towse L. A 6month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002; 122: 47–55.

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Positive inotropic drugs and drugs used in dysrhythmias

CARDIAC GLYCOSIDES (SED-14, 523; SEDA-24, 197; SEDA-25, 205; SEDA-26, 198) There has been a multicenter, randomized, placebo-controlled, double-blind comparison of aprindine and digoxin in the prevention of atrial ﬁbrillation and its recurrence in 141 patients with symptomatic paroxysmal or persistent atrial ﬁbrillation who had converted to sinus rhythm (1C ). They were randomized in equal numbers to aprindine 40 mg/day, digoxin 0.25 mg/day, or placebo, and were followed every 2 weeks for 6 months. After 6 months the Kaplan–Meier estimates of the numbers of patients who had no recurrences while taking aprindine, digoxin, and placebo were 33%, 29%, and 22% respectively. The rates of adverse events were similar in the three groups. This conﬁrms that digoxin does not prevent relapse of symptomatic atrial ﬁbrillation after conversion to sinus rhythm. Of 603 adults aged 79 (s.d. 7) years, of whom 59% were women and 18% African– American, 376 patients (62%) were discharged taking digoxin, and 223 (37%) had no indication for its use, based on the absence of left ventricular systolic dysfunction or atrial ﬁbrillation (2C ). After adjustment for various factors, prior digoxin use (OR = 11; 95% CI = 5.7, 23) and pulse over 100/min (OR = 2.33; 95% CI = 1.1, 4.9) were associated with inappropriate digoxin use. Unfortunately, the authors did not report the frequency of adverse effects, and it is not therefore clear whether patients in whom digoxin is used inappropriately are more or less likely to suffer adverse reactions. © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

In a multicenter survey, conducted between 1988 and 1997, of 28 411 patients aged 70 (s.d. 16) years admitted to 81 hospitals throughout Italy, 1704 had adverse drug reactions (3C ). In 964 cases (3.4% of all admissions), adverse reactions were considered to be the cause of admission. Of these, 187 were regarded as severe. Gastrointestinal complaints (19%) were the most common, followed by metabolic and hemorrhagic complications (9%). The drugs most often responsible were diuretics, calcium channel blockers, non-steroidal anti-inﬂammatory drugs, and digoxin. Female sex (OR = 1.30; 95% CI = 1.10, 1.54), alcohol use (OR = 1.39; 95% CI = 1.20, 1.60), and number of drugs (OR = 1.24; 95% CI = 1.20, 1.27) were independent predictors of admission for adverse reactions. For severe adverse reactions, age (for age 65–79, OR = 1.50; 95% CI = 1.01, 2.23; for age 80 and over, OR = 1.53; 95% CI = 1.00, 2.33), co-morbidity (OR = 1.12; 95% CI = 1.05, 1.20 for each point on the Charlson Comorbidity Index), and number of drugs (OR = 1.18; 95% CI = 1.11, 1.25) were predisposing factors. Of the 28 411 patients, about 6700 were taking digoxin, and they suffered 82 adverse effects, either gastrointestinal (n = 28) or unspeciﬁed dysrhythmias (n = 44), or presumably both (data not given); of those, 11 were graded as severe (two gastrointestinal and nine dysrhythmias). Cardiovascular Digoxin has previously been reported to cause atrial tachycardia with Wenckebach atrioventricular block (SEDA-26, 198) and another case has been reported in a patient who in error took three times the recommended dose (4A ). Special senses Early studies suggested that impairment of color vision, measured with sensitive tests, was related to serum digoxin concentrations and peripheral measures of Na/K

185

186 pump function (SEDA-5, 176; SEDA-10, 143). There have also been reports of patients with evidence of digoxin toxicity and serum concentrations in the usual target range who nevertheless had impaired color vision (SEDA23, 194). However, in a study of 30 patients (mean age 81 years) taking digoxin and an agematched control group there was no correlation between color vision impairment and serum digoxin concentration (5c ). There was slight to moderate red–green impairment in 20–30% of those taking digoxin, depending on the test used; about 20% had a severe tritan defect. The authors suggested that color vision testing in elderly patients would have limited value in the detection of digitalis toxicity. However, this conclusion was based on using the digoxin concentration as a standard, while the point of pharmacodynamic tests, such as color vision measurement, is that they are supposed to reﬂect the effect of the drug better than the serum concentration. Death Sex-based differences in the effect of digoxin have been explored in a post-hoc analysis of the data from the Digitalis Investigation Group (DIG) study (SEDA-20, 173; 6c ). There was an absolute difference of 5.8 percent (95 CI = 0.5, 11) between men and women in the effect of digoxin on the case fatality rate from any cause. Women who were randomly assigned to digoxin had a signiﬁcantly higher fatality rate than women who were randomly assigned to placebo (33% vs. 29%), while the fatality rate was similar among men randomly assigned to digoxin or placebo (35% vs. 37%). However, serum digoxin concentrations were higher in the women at 1 month, and this may have contributed to the increased risk of death (7r ). In another post-hoc analysis of the data from the DIG study the patients who had been randomized to digoxin were divided into three groups, according to serum digoxin concentration, 0.5–0.8 ng/ml, 0.9–1.1 ng/ml, and 1.2 ng/ml and over (8c ). Higher concentrations were associated with higher all-cause fatality rates: 30%, 39%, and 48% respectively. Both of these studies suggest that lower serum concentrations of digoxin (0.5–1.0 ng/ml) may be beneﬁcial for routine therapy of heart failure than have traditionally been recommended (0.8–2.0 ng/ml), and this has been discussed in a brief review (9r ).

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Drug interactions Acarbose has previously been reported to reduce the absorption of digoxin after oral administration (SEDA-24, 202). There has been a further anecdotal report of this interaction (10A ) and a formal study of the pharmacokinetics of a single dose of digoxin 0.75 mg before and after the administration of acarbose 50 mg tds for 12 days in healthy volunteers (11c ). Apart from a small increase in Cmax , the pharmacokinetics of digoxin were unaffected by acarbose. It is not uncommon for anecdotal reports of a possible interaction to be unconﬁrmed by formal kinetic studies, and it is possible in such cases that there is a subset of patients who are susceptible to the interaction who have not been included in the formal study. In this case, for example, it may be that the interaction occurs in people with diabetes and not in healthy subjects. There may also be a difference between the effect of acarbose on a single dose of digoxin, compared with steadystate therapy. Advice that acarbose and digoxin should be administered 6 hours apart is still reasonable. The thrombin inhibitor argatroban had no effect on the steady-state pharmacokinetics of oral digoxin 0.375 mg/day in 12 healthy volunteers; the argatroban was given as an intravenous infusion of 2 μg/kg/min on days 11–15 (12c ). Fondaparinux sodium, a selective inhibitor of factor Xa, is eliminated by the kidneys. In a randomized, crossover study in 24 healthy volunteers the pharmacokinetics and pharmacodynamics of digoxin 0.25 mg/day orally for 7 days were unaffected by fondaparinux sodium 10 mg/day subcutaneously for 7 days (13C ). The macrolide antimicrobial drugs can reportedly interact with 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-26, 200). However, in a study of the latter mechanism in nine healthy Japanese men, clarithromycin 200 mg bd and erythromycin 200 mg qds did not alter the plasma concentration vs time curve of a single intravenous dose of digoxin 0.5 mg, but increased its renal clearance (14C ). This contrasts with a previous observation of reduced renal clearance of digoxin in two patients taking clarithromycin (SEDA-23, 194). That inhibition of renal P glycoprotein may not reduce

Positive inotropic drugs and drugs used in dysrhythmias

the renal clearance of digoxin has also been suggested by studies with talinolol (SEDA-25, 172) and atorvastatin (15CE ). Other transport mechanisms for digoxin, including the organic anion-transporting polypeptides, have not been well studied and may play a role in digoxin disposition and hence drug interactions. The quinolone antimicrobial drugs gemiﬂoxacin and sparﬂoxacin have previously been shown not to interact with digoxin (SEDA-24, 203) and another study has shown the same with levoﬂoxacin 500 mg bd for 6 days in 12 healthy volunteers (16C ). The effects of statins on the pharmacokinetics of digoxin have been variable. For example, cerivastatin had no effect on the steady-state pharmacokinetics of digoxin in 20 healthy men (SEDA-24, 202), and rosuvastatin 40 mg/day had no effect on the pharmacokinetics of a single oral dose of digoxin 0.5 mg in 18 healthy men (17C ). In contrast, atorvastatin 80 mg/day increased the AUC and Cmax of digoxin 0.25 mg/day by 15% and 20% respectively during steady-state therapy, without affecting renal digoxin clearance (15C ), and a single dose of ﬂuvastatin increased the steadystate Cmax of digoxin 0.125–0.5 mg/day by 11% and renal clearance by 15%, without changing AUC or tmax (18C ). There is no simple explanation that reconciles these disparate ﬁndings. The alpha1 -adrenoceptor antagonist tamsulosin 0.4 and 0.8 mg/day had no effect on the pharmacokinetics of a single intravenous dose of digoxin 0.5 mg in 10 healthy men (19C ). The effects of nitrates on the pharmacokinetics of digoxin are probably small. Nitroprusside has previously been shown to cause a small increase in the renal clearance of digoxin, perhaps by increasing renal blood ﬂow (SEDA-7, 197). In eight patients with chronic heart failure taking digoxin 0.25 mg/day, isosorbide dinitrate 10 mg tds caused only a small increase in Cmax (15%) and had no effect on the mean steadystate serum concentration or AUC (20C ). Studies of the effects of diltiazem on the pharmacokinetics of digoxin have yielded variable results. In one study, diltiazem reduced the steady-state total body clearance of betaacetyldigoxin in 12 healthy men, perhaps because of reduced renal and non-renal clearances (SEDA-10, 145). In some other studies diltiazem 120–240 mg/day increased steady-state plasma digoxin concentrations by about 20– 40% (SEDA-14, 146; 21C ), although not in

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other studies (SEDA-14, 146), and reduced the total body clearance of digoxin, with changes in both renal and non-renal clearances (SEDA-11, 154), although others did not ﬁnd this (22C ). In at least one case digoxin toxicity was attributed to this interaction (SEDA-17, 216). In a recent study in eight patients with chronic heart failure taking digoxin 0.25 mg/day, diltiazem 180 mg/day increased the AUC and mean steadystate serum concentrations of digoxin by 50% and reduced its total clearance (20C ). Interference with diagnostic tests Crossreaction of spironolactone, canrenone, and their metabolites with antidigoxin antibodies used in radioimmunoassays is well known (SEDA24, 203; 23r ). In most cases this results in falsely high digoxin concentrations, although interference, with apparently reduced digoxin concentrations, has also been reported. In nine assays (AxSYM, IMx, TDx, Emit, Dimension, aca, TinaQuant, Elecsys, and Vitros) interference by spironolactone, canrenone, and three metabolites was sought in vitro, and all routine digoxin measurements using the AxSYM system over 16.5 months (n = 3089) were reviewed (24cE ). There was a reduction in the expected concentrations by canrenone (3125 μg/l) in the following assays: AxSYM (42% of expected), IMx (51%), and Dimension (78%). There was positive bias in aca (0.7 μg/l), TDx (0.62 μg/l), and Elecsys (>0.58 μg/l). Of 669 routinely monitored patients, 25 had falsely low results and 19 of them actually had potentially toxic digoxin concentrations; this was attributable to concurrent therapy with spironolactone, canrenone, hydrocortisone, or prednisolone. However, standard doses of spironolactone (up to 50 mg/day) in patients with heart failure produced less than 11% inhibition. Diagnosis of adverse drug reactions Plasma or serum concentrations In a retrospective analysis of 210 randomly selected digoxin plasma concentration determinations in in-patients, the indications were considered to have been inappropriate in 67, appropriate in 81, and unevaluable in four (25c ). Timing of the blood sample was wrong in 17 cases. Of the measurements whose indications were considered to have been inappropriate, most (52) were performed as part of “routine” monitoring.

188 Management of poisoning Fab fragments of antidigoxin antibodies are considered to be the treatment of choice after self-poisoning with cardiac glycosides, although the evidence of their efﬁcacy is anecdotal (SEDA-25, 173), and another anecdotal report has been published (26A ). It is not known whether the antibody reduces mortality; one randomized controlled study (SEDA-23, 195) was too small to detect an effect on mortality after self-poisoning with seeds of the yellow oleander, which contains cardiac glycosides such as peruvoside. In 401 patients with acute self-poisoning with yellow oleander seeds, the fatality rate was reduced from 8.0% to 2.5% by the administration of repeated doses of activated charcoal, 50 g 6hourly for 3 days (27C ). Activated charcoal, given in this way, should be standard treatment in glycoside self-poisoning in addition to Fab fragments of antibody or when antibody is not available. Because digoxin has a large volume of distribution, one would not expect exchange transfusion to be effective by itself in treating digoxin overdose. However, there have been two reports of the use of exchange transfusion to remove Fab antibody fragment–digoxin complexes in patients with acute anuric renal insufﬁciency (28A , 29A ). • A 70-year-old man with alcoholic cirrhosis was given amiodarone and digoxin for atrial ﬁbrillation after a hemicolectomy for adenocarcinoma (29A ). He developed acute renal insufﬁciency and digoxin toxicity, with a serum concentration of 4.4 ng/ml. A dose of Fab antidigoxin antibody fragments was followed 16 hours later by exchange transfusion and another dose was followed by two exchanges. He recovered slowly over the next few days.

The total digoxin concentration (antibody bound and unbound) rose after the ﬁrst dose of Fab fragments but did not fall until after the second plasma exchange (after the second dose of Fab fragments). Digoxin was recovered from the plasma collection bags, but the total amount recovered seems to have been less than 100 μg, so the efﬁcacy of plasma exchange in this case is not clear. The suggestion that intravenous calcium should be used to treat the hyperkalemia that can occur in digitalis intoxication (30R ) has been challenged, on the grounds that it may increase the risk of cardiac dysrhythmias in such cases (31r ).

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OTHER POSITIVE INOTROPIC DRUGS (SED-14, 532; SEDA-24, 204; SEDA-25, 208; SEDA-26, 201)

Enoximone Enoximone has been used to treat cardiogenic shock in a case of self-poisoning with verapamil 2.4 g in a 40-year-old woman; treatment with calcium and noradrenaline had been unsuccessful (32A ).

Milrinone Intravenous milrinone has been used, with some success, to treat patients with severe cardiac failure (SEDA-22, 203). It can be particularly useful in tiding patients over while they are waiting for deﬁnitive treatment, as another anecdotal report has demonstrated (33A ). • A 48-year-old man with an inﬂammatory aneurysm of the ascending aorta and severe heart failure due to massive aortic regurgitation was given a continuous intravenous infusion of milrinone 0.5 μg/kg/minute. His pulmonary arterial pressure fell and his symptoms improved over 7 weeks while he was taking corticosteroids. The diseased tissue was successfully replaced at operation and the milrinone was tapered uneventfully.

The authors suggested that continuous milrinone infusion may be suitable for patients with surgically correctable inﬂammatory cardiovascular diseases complicating severe heart failure in whom maintenance of optimal hemodynamics is necessary for several weeks before operation. However, milrinone did not prove valuable in a randomized, double-blind, placebocontrolled trial in 78 community and tertiary care hospitals in the USA, in which 951 patients admitted with an exacerbation of systolic heart failure (mean age 65 years; 92% with baseline NYHA class III or IV; mean left ventricular ejection fraction 23%) were randomly assigned to a 48-hour infusion of either milrinone (0.5 μg/kg/minute initially for 24 hours) or saline (34C ). The median number of days in hospital for cardiovascular causes within 60 days after randomization did not differ signiﬁcantly between patients given milrinone

Positive inotropic drugs and drugs used in dysrhythmias

(6 days) or placebo (7 days). Sustained hypotension requiring intervention (11% vs 3.2%) and new atrial dysrhythmias (4.6% vs 1.5%) were more common in the patients who received milrinone. There was no difference in hospital mortality (3.8% vs 2.3%), 60-day mortality (10% vs 8.9%), or the composite incidence of death or readmission (35% vs 35%). The authors concluded that these results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in patients with an exacerbation of chronic heart failure. The disappointing results with positive inotropic drugs in treating acute and chronic heart failure may be due to the fact that they increase both systolic and diastolic calcium concentrations in the myocardium (35r ).

Olprinone Olprinone, an inhibitor of phosphodiesterase type III, is given intravenously and is mostly eliminated by the kidneys. Its pharmacological effects have been reviewed (36R ). Its major adverse effects are cardiac dysrhythmias and thrombocytopenia, the latter with a reported incidence of 0.43%.

DRUGS USED IN DYSRHYTHMIAS Adenosine

(SED-14, 536; SEDA-24, 205; SEDA-25, 210; SEDA-26, 203)

Cardiovascular Adenosine can occasionally cause serious cardiac dysrhythmias (SEDA-20, 175), and more cases of ventricular ﬁbrillation have been reported in four patients with preexcited atrial ﬁbrillation who had been given 12 mg of adenosine (37c ). After resuscitation electrophysiological studies were carried out before catheter ablation of a single accessory pathway. In a control group of ﬁve patients with single accessory pathways, sustained atrial ﬁbrillation was induced by rapid atrial pacing and adenosine 12 mg was given. The patients had shorter antegrade effective refractory periods in the accessory pathways than the controls:

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227 (s.d. 29) vs 289 (s.d. 37) ms respectively. The atrial effective refractory periods were 210 (s.d. 17) vs 219 (s.d. 21) ms respectively. The shortest RR interval during atrial ﬁbrillation was 246 (s.d. 51) ms in the patients and 301 (s.d. 60 ms) in the controls. After adenosine, none of the controls developed ventricular ﬁbrillation. The authors concluded that adenosine can cause ventricular ﬁbrillation when it is given during pre-excited atrial ﬁbrillation, particularly in patients who have accessory pathways with short refractory periods. Nervous system Adenosine has been used intrathecally to treat pain, but can itself cause backache (SEDA-23, 197). In a placebo-controlled study in 40 healthy volunteers, who were given intrathecal adenosine 2 mg in 2 ml of saline, 13 had a mild headache, nine had mild to moderate backache, and one had mild aching in the thigh, compared with none of those who were given saline alone (38C ). No headaches or leg aches occurred later than 6 hours after the injection, but the backaches occurred at 6–24 hours; there were no later symptoms. In a randomized, double-blind study of two doses of intrathecal adenosine in 35 volunteers with experimental hypersensitivity induced by capsaicin, intrathecal adenosine 0.5 or 2 mg in 2 ml of saline, but not saline alone, equally reduced areas of allodynia and hyperalgesia from capsaicin (39C ). There were adverse effects in 1, 2, and 6 of the volunteers who received saline, 0.5 mg, and 2.0 mg of adenosine respectively. The adverse effects were headache, backache, and leg or groin ache. Intravenous aminophylline 5 mg/kg, given 2 hours after the adenosine, did not reverse the effects of adenosine. Backache was also observed in patients with chronic neuropathic pain after intrathecal adenosine (40C ).

Amiodarone (SED-14, 537; SEDA-24, 206; SEDA-25, 211; SEDA-26, 204) In a meta-analysis of ﬁve randomized, placebocontrolled trials of amiodarone 200–1200 mg/ day for 2–7 days in the treatment of postoperative atrial ﬁbrillation and ﬂutter in 764 patients, the incidence of adverse events with

190 amiodarone was no greater than with placebo (41M ). In a meta-analysis of ﬁve randomized, placebo-controlled trials of intravenous amiodarone about 500–2200 mg over 24 hours in the treatment of recent-onset atrial ﬁbrillation in 410 patients, the incidence of adverse events was 27% with amiodarone and 11% with placebo (42M ). Intravenous amiodarone was signiﬁcantly more effective than placebo in producing cardioversion. The most common adverse effects of intravenous amiodarone were phlebitis, bradycardia, and hypotension; most of these effects were not considered to be dose limiting. Of 85 patients with persistent atrial ﬁbrillation after balloon mitral valvotomy given amiodarone (600 mg/day for 2 weeks and 200 mg/day thereafter), 33 converted to sinus rhythm (43C ). Of the other 52 patients, who underwent DC cardioversion at 6 weeks, 41 converted to sinus rhythm. Six patients had adverse effects attributable to amiodarone. Five had mild gastrointestinal symptoms, such as abdominal discomfort and nausea. One developed hypothyroidism after 3 months, which resolved when the dosage of amiodarone was reduced to 100 mg/day. In 83 patients (27 women, 56 men; mean age 61 years) disopyramide, propafenone, or sotalol were used to prevent recurrence after elective electrical cardioversion for persistent atrial ﬁbrillation (44c ). If there was recurrence cardioversion was repeated and the patient was given one of the other antidysrhythmic drugs. If there was further recurrence, amiodarone was used, a third cardioversion was performed, and, if sinus rhythm was restored, amiodarone 100–200 mg/day was continued. Patients in whom the initial cardioversion was not successful were given amiodarone and underwent repeated cardioversion. The follow-up duration was 12 months. The ﬁrst electrical cardioversion was effective in 44 (53%) patients, and after 1 year 23 (52%) of them were still in sinus rhythm. None of the patients who underwent a second cardioversion and received a second antidysrhythmic drug stayed in sinus rhythm. Amiodarone as a third antidysrhythmic agent was effective in 10 (48%) patients. After 12 months of antidysrhythmic drug therapy sinus rhythm was maintained in 75% of patients in whom the ﬁrst cardioversion had been effective, accounting for 40%

Chapter 17

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of all the patients selected for cardioversion. In the 83 patients, sequential antidysrhythmic treatment effectively maintained sinus rhythm in 54 (65%), of whom 31 (57%) took amiodarone. The authors concluded that repeated electrical cardioversion and antidysrhythmic drug therapy enabled maintenance of sinus rhythm in 68% of patients for 1 year, that there was limited efﬁcacy of the ﬁrst antidysrhythmic drug given after a ﬁrst effective electrical cardioversion, regardless of the drug used, excluding amiodarone, and that when atrial ﬁbrillation recurred, a second antidysrhythmic drug, other than amiodarone, was completely ineffective. There were very few adverse events in this study. One patient taking amiodarone developed hyperthyroidism and two had symptomatic bradycardia. Cardiovascular Amiodarone can sometimes cause atrial ﬂutter, even though it is also used to treat it (SEDA-25, 180). There has been a report of seven cases (six men and one woman, aged 34–75 years) of 1 : 1 atrial ﬂutter with oral amiodarone (45c ). Four of them had underlying cardiac disease; none had hyperthyroidism. The initial dysrhythmia was 2 : 1 atrial ﬂutter (n = 4), 1 : 1 atrial ﬂutter (n = 2), or atrial ﬁbrillation (n = 1). One patient was taking amiodarone 200 mg/day and one was taking 400 mg/day plus carvedilol. The other ﬁve all received loading doses of 9200 (s.d. 2400) mg over 10 (s.d. 4) days. There was an adrenergic trigger factor (exertion, fever, esophageal stimulation, or a beta-adrenoceptor agonist aerosol) in ﬁve patients. One required emergency cardioversion. T wave alternans has previously been attributed to amiodarone (SEDA-18, 201; SEDA26, 204), and another case has been reported (46A ). • A 65-year-old man with atrial ﬁbrillation was given intravenous amiodarone 450 mg over 30 minutes followed by 900 mg over 24 hours. He reverted to sinus rhythm, but the electrocardiogram showed giant T wave alternans with a variable QT interval (0.52–0.84 sec). He had a short bout of torsade de pointes and was given magnesium. Two days later the electrocardiogram was normal.

Respiratory Two patients with dilated cardiomyopathy developed pneumonitis after 6 weeks and 8 months while taking amiodarone 400 and 200 mg/day respectively (47A ). Cases

Positive inotropic drugs and drugs used in dysrhythmias

that occurred as rapidly as the ﬁrst of these have previously been reported (SEDA-26, 204). Several techniques have been used in the diagnosis of amiodarone-induced lung damage, including 67 gallium scintigraphy (SEDA-15, 168). • A 75-year-old man, who had taken amiodarone 200 mg/day for 4 years, developed acute dyspnea, chest pain, fever, and sweats (48A ). The chest X-ray showed diffuse alveolar and interstitial inﬁltrates, particularly at the lung bases. No pathogenic organisms were isolated and antibiotics had no effect. There was no evidence of sarcoidosis. Pulmonary 67 gallium scintigraphy showed extensive uptake of tracer throughout both lungs, consistent with amiodarone pneumonitis on a background of asbestosis with interstitial ﬁbrosis. Treatment with corticosteroids after withdrawal of amiodarone resulted in marked clinical improvement.

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correlate with clinical or electromyographic evidence of myopathy. In the peripheral nerves there was demyelination, some axon loss, and a variable number of characteristic lysosomal inclusions. Muscle specimens from two patients showed evidence of a vacuolar myopathy. After withdrawal of amiodarone, two patients improved and one died with a cardiac dysrhythmia. Benign orgasmic headache has been associated with amiodarone (51A ). • A 52-year-old man, who had taken amiodarone 800 mg/day for 7 months, developed acute, severe, throbbing headaches precipitated by coitus and occasionally other forms of exertion. An MRI scan of the brain was normal. When the dose of amiodarone was reduced to 200 mg/day the headaches diminished in frequency and severity. When the dose was increased again to 400 mg/day they increased in frequency and severity. The amiodarone was withdrawn and the headaches resolved.

The authors said that the extensive changes on gallium scanning, not present on the chest X-ray, had helped them to make the diagnosis, although a high-resolution CT scan had also shown widespread changes. Another scanning technique, 99m Tc-diethylene triamine penta-acetic acid (DPTA) aerosol scintigraphy, has been compared with 67 Ga scanning in 26 patients, seven with amiodaroneinduced lung damage, eight taking amiodarone without lung damage, and 11 healthy controls (49c ). 67 Ga scintigraphy was positive in four of the seven patients with lung damage but normal in the others. There was a positive correlation between 99m Tc-DTPA clearance and the cumulative dose of amiodarone. The mean clearance values were 2 percent/min in those with amiodarone-induced lung damage, 1.3 percent/min in those without lung damage, and 0.9 percent/min in the controls. The authors concluded that 67 Ga lung scintigraphy is useful for detecting amiodarone-induced lung damage but that 99m Tc-DTPA aerosol scintigraphy is better.

Special senses Of 22 patients taking longterm amiodarone, two who had otherwise healthy eyes had abnormal blue color vision (52c ); color vision abnormalities have previously been described (SEDA-12, 153). Otherwise, color vision, contrast sensitivity, and visual ﬁelds were normal or could be explained by eye diseases such as cataract. There were corneal drug deposits in all of the eyes, slight anterior subcapsular lens opacities in 22%, and dry eyes in 9%, as previously reported (SEDA-23, 199).

Nervous system Amiodarone-induced neuromyopathy has been studied in three patients by a review of their records, electromyography, and histopathology of muscle and nerve (50Ar ). Two patients had a slightly asymmetric, mixed, but primarily demyelinating sensorimotor polyneuropathy and the third had an acute neuropathy resembling Guillain–Barré syndrome. Creatine kinase activity did not

• A 63-year-old man reduced his dietary sodium intake to combat ﬂuid retention and was taking furosemide 40 mg/day, spironolactone 50 mg/day, and enalapril 2.5 mg/day (54A ). He then took amiodarone 800 mg/day for 7 days and his serum sodium concentration fell to 119 mmol/l; his plasma vasopressin concentration was raised at 2.6 pmol/l. The dose of amiodarone was reduced to 100 mg/day, with ﬂuid restriction; his sodium rose to 130 mmol/l and his vasopressin fell to 1.4 pmol/l.

Amiodarone was originally developed as a vasodilator, and that may have been the cause of headaches in this case.

Endocrine Amiodarone-induced hyponatremia, due to the syndrome of inappropriate secretion of antidiuretic hormone, is rare (SEDA21, 199; 53A ), but another three cases have been reported.

192 • An 87-year-old man reduced his dietary sodium intake to combat ﬂuid retention and was taking furosemide 40 mg/day and spironolactone 25 mg/day (54A ). He then took amiodarone 200 mg/day for 7 days and 100 mg/day for 8 days and his serum sodium concentration fell to 121 mmol/l; his plasma vasopressin concentration was raised at 11 pmol/l. Amiodarone was continued, with ﬂuid restriction; his sodium rose to 133 mmol/l and his vasopressin fell to 2.4 pmol/l. • A 67-year-old man, who had taken amiodarone 200 mg/day for 3 months, developed hyponatremia (serum sodium concentration 117 mmol/l) (55A ). He was also taking furosemide 20 mg/day, spironolactone 25 mg/day, and lisinopril 40 mg/day. His urine osmolality was 740 mosmol/kg with a normal serum osmolality. Fluid restriction was ineffective, but when amiodarone was withdrawn the sodium rose to 136 mmol/l.

In all three cases other factors may have contributed to the hyponatremia that amiodarone seems to have caused. The mechanism of this rare effect is unknown. Unlike other adverse effects of amiodarone, it seems to occur rapidly and to resolve rapidly after withdrawal.

Amiodarone and thyroid disease Many of the adverse effects of amiodarone are a function of both cumulative dose and time of exposure and this may be true of thyroid disease. In a nested case-control analysis of 5522 patients with a ﬁrst prescription for an antidysrhythmic drug and no previous use of thyroid drugs, cases were deﬁned as all patients who had started a thyroid-mimetic or antithyroid drug no sooner than 3 months after the start of an antidysrhythmic drug and controls were patients with a comparable follow-up period who had not taken any thyroid drugs during the observation period (56c ). There were 123 patients who had started antithyroid drugs and 96 who had started a thyroid-mimetic drug. In users of amiodarone there were adjusted odds ratios of 6.3 (95% CI = 3.9, 10) for hyperthyroidism and 6.6 (3.9, 11) for hypothyroidism compared with users of other antidysrhythmic drugs. Patients who were exposed to a cumulative dose of amiodarone over 144 g had an adjusted odds ratio of 13 (6, 27) for hyperthyroidism; the dose relation for hypothyroidism was less pronounced.

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J.K. Aronson

Types of hyperthyroidism Amiodarone-induced hyperthyroidism is of two types (SEDA-23, 199): type 1 occurs in those with latent disease and is due to the iodine that amiodarone contains; type 2 is due to a destructive thyroiditis in a previously normal gland. The distinction may be important, because type 1 typically responds to thionamides and perchlorate while type 2 responds to high-dose corticosteroids. Diagnosis is complicated by the effects that amiodarone has on thyroid hormone metabolism (SEDA-15, 170), and other diagnostic methods have been sought. Color-ﬂow Doppler sonography of the thyroid and measurement of serum interleukin-6 (IL-6) have been studied as diagnostic tools in a retrospective case-note study of patients with amiodarone-associated hyperthyroidism (57c ). There were 37 patients with amiodarone-associated hyperthyroidism (mean age 65, range 20–86 years), and 25 underwent color-ﬂow Doppler sonography. Of those, 10 were classiﬁed as type 1 (based on increased vascularity) and 10 as type 2 (based on patchy or reduced vascularity); ﬁve were indeterminate. In those with type 1 hyperthyroidism, free serum thyroxine tended to be lower (52 vs 75 pmol/l), free serum triiodothyronine was lower (8.8 vs. 16 pmol/l), the cumulative amiodarone dose was lower (66 vs. 186 g), and less prednisolone was used (because the diagnosis of type 1 disease encouraged steroid withdrawal); however, carbimazole doses were not different and the time to euthyroidism was the same in the two groups (81 vs. 88 days). IL-6 was raised in two patients with type 1 and in one patient with type 2 hyperthyroidism. The authors proposed that color-ﬂow Doppler sonography could be used to distinguish the two subtypes, conﬁrming an earlier report (58C ), but that IL-6 measurement was unhelpful. However, others have suggested that the differentiation of amiodarone-induced hyperthyroidism into two types is not helpful in determining suitable therapy (59c ). Of 28 consecutive patients there was spontaneous resolution of hyperthyroidism in ﬁve and 23 received carbimazole alone as ﬁrst-line therapy. Long-term euthyroidism was achieved in 11, ﬁve became hypothyroid and required long-term thyroxine, and ﬁve relapsed after withdrawal of carbimazole and became euthyroid with either longterm carbimazole (n = 3) or radioiodine (n = 2). Four were intolerant of carbimazole and

Positive inotropic drugs and drugs used in dysrhythmias

received propylthiouracil, with good effect in three. One was resistant to thionamides and responded to corticosteroids. There was no difference in presentation or outcome between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 disease (deﬁned clinically and by serum IL-6 measurement). The authors concluded that continuing amiodarone has no adverse effect on the response to treatment of hyperthyroidism and that ﬁrst-line therapy with a thionamide alone, whatever the type of disease, is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. However, it is not clear how good their differentiation of types 1 and 2 disease was. A previous prospective study in 24 patients showed that differentiation predicted response to treatment (60C ). Susceptibility factors It has been suggested that men are more susceptible to hyperthyroidism due to amiodarone (61c ). Of 122 600 patients in 12 practices in the West Midlands in the UK, 142 men and 74 women were taking amiodarone and 27 (12.5%) had thyroid disease. Of those, 11 men (7.7%) and four women (5.4%) had hypothyroidism, a nonsigniﬁcant difference; however, 12 men (8.5%) had hyperthyroidism compared with no women. This difference is particularly striking because hyperthyroidism is usually more common in women. Deaths Not only is amiodarone-induced hyperthyroidism difﬁcult to treat, but it can also be fatal, as has been reported in two cases (62A ): • a 62-year-old man who had taken amiodarone for 2 years; carbimazole 40 mg/day, prednisolone, lithium, and colestyramine were ineffective and he died with hepatic encephalopathy and multiorgan failure; • a 55-year-old man who had taken amiodarone for 4 years; carbimazole 60 mg/day, prednisolone, and lithium were ineffective and he died with septicemia and multiorgan failure;

In three other cases reported in the same paper, severe hyperthyroidism responded severally to treatment with carbimazole, carbimazole plus lithium, or propylthiouracil. In one case amiodarone therapy was restarted after prophylactic subtotal thyroidectomy.

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Treatment Agents used in oral cholecystography, such as ipodate and iopodate, which are rich in iodine and potent inhibitors of 5 -deiodinase, have been used to treat amiodarone-induced hyperthyroidism (SEDA-26, 205). Three patients with type 1 disease, two of whom had not responded to methimazole plus perchlorate, were successfully treated with a short course of iopanoic acid 1 g/day, resulting in a marked reduction in the peripheral conversion of T4 to T3 (63A ). Euthyroidism was restored in 7–12 days, allowing uneventful thyroidectomy. The patients were then treated with levothyroxine for hypothyroidism and amiodarone was safely restarted. The authors suggested that iopanoic acid is the drug of choice for rapid restoration of normal thyroid function before thyroidectomy in patients with drug-resistant type 1 amiodarone-induced hyperthyroidism. The use of local anesthesia for total thyroidectomy in patients with amiodarone-induced hyperthyroidism and cardiac impairment has been reviewed in the context of six patients (64c ). Hematologic Bone-marrow granulomata have rarely been reported in patients taking amiodarone (SEDA-23, 199; SEDA-25, 182), but another case has been reported (65A ). • A 76-year-old man, who had taken amiodarone for an unspeciﬁed time, developed a monoclonal gammopathy with bone-marrow granulomata. After another 2 years he developed hepatic granulomata and the amiodarone was withdrawn. The bone-marrow granulomata resolved within a few months. Infections were excluded and there was no evidence of sarcoidosis.

Skin The severe form of erythema multiforme known as toxic epidermal necrolysis has rarely been attributed to amiodarone (66A ), but another case has been reported (67A ). • A 71-year-old woman, who had taken amiodarone 200 mg/day for 3 months and diltiazem for 8 months, developed extensive erythema, blistering, and erosions affecting 50% of the body surface area, with a maculopapular rash on the limbs. She developed bilateral pneumonia and septicemia and died after 7 days.

Immunologic Lupus-like syndrome has rarely been attributed to amiodarone (SEDA-24, 208), but another case has been reported (68A ).

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Chapter 17

• A 59-year-old man, who had taken amiodarone 200 mg/day for 2 years, developed fever, pleuritic chest pain, dyspnea at rest, a non-productive cough, malaise, and joint pains. He had a verrucous endocarditis and a pleuropericardial effusion. He had raised titers of antinuclear antibodies (1 : 320) with anti-Ro speciﬁcity. Serum complement was normal and there were no circulating immune complexes, no cryoglobulins, and no anti-dsDNA, antiLa, anti-U1 ribonucleoprotein, anti-Sm, anti-Sc1, 70, anti-Jo 1, antihistone, antiphospholipid, anticentromere, anticardiolipin, or anticytoplasmic antibodies. Within 7 days of withdrawal of amiodarone the signs and symptoms started to resolve, and he recovered fully with the addition of prednisolone.

Drug formulations The steady-state plasma concentrations of amiodarone and desethylamiodarone in 77 patients taking two different formulations, a new generic formulation and Cordarone® , were comparable (69c ). Drug interactions The interaction of amiodarone with warfarin is well known (SEDA-24, 210). In a study of this interaction in 43 patients who took both amiodarone and warfarin for at least 1 year, the interaction peaked at 7 weeks and the mean dosage of warfarin fell by 44% from 5.2 to 2.9 mg/day (70C ). The dosage of warfarin correlated inversely with the maintenance dose of amiodarone. There were minor bleeding episodes in ﬁve patients. The authors recommended reducing the daily warfarin dose by about 25%, 30%, 35%, and 40% in patients taking amiodarone 100, 200, 300, and 400 mg/day respectively. The interaction of amiodarone with Class I antidysrhythmic drugs is well known (SEDA18, 203), particularly because of the risk of QT interval prolongation (SEDA-19, 194). In 26 patients taking mexiletine plus amiodarone for 1 month and 155 taking mexiletine alone, there was no signiﬁcant difference in the apparent oral clearance of mexiletine (71c ). However, the lack of a pharmacokinetic interaction does not reduce the risk that dangerous QT interval prolongation may occur with a combination such as this.

Aprindine

(SED-14, 541; SEDA-24, 210;

SEDA-26, 207) There has been a multicenter, randomized, placebo-controlled, double-blind comparison

J.K. Aronson

of aprindine and digoxin in the prevention of atrial ﬁbrillation and its recurrence in 141 patients with symptomatic paroxysmal or persistent atrial ﬁbrillation who had converted to sinus rhythm (1C ). They were randomized in equal numbers to aprindine 40 mg/day, digoxin 0.25 mg/day, or placebo and followed every 2 weeks for 6 months. After 6 months the Kaplan–Meier estimates of the numbers of patients who had no recurrences with aprindine, digoxin, and placebo were 33%, 29%, and 22% respectively. The rates of adverse events were similar in the three groups. This shows that aprindine has a very small beneﬁcial effect in preventing relapse of symptomatic atrial ﬁbrillation after conversion to sinus rhythm. Furthermore, recurrence occurred later with aprindine than with placebo or digoxin (about 60% recurrence at 115 days compared with 30 days).

Bepridil

(SED-14, 541, 605)

Cardiovascular Bepridil is an antidysrhythmic drug with unusual pharmacological properties, in that it belongs to both Class I and Class IV. In other words, it blocks both the fast inward sodium current and the slow outward calcium current in excitable cardiac cells (SEDA-13, 141). Its main adverse effect is torsade de pointes due to QT interval prolongation. The effect of a beta-blocker (metoprolol 30–40 mg/day or bisoprolol 2.5–5.0 mg/day for 1 month) on the change in QT interval, QT dispersion, and transmural dispersion of repolarization caused by bepridil has been studied in 10 patients with paroxysmal atrial ﬁbrillation resistant to various antidysrhythmic drugs (72c ). Bepridil signiﬁcantly prolonged the QTc interval from 0.42 to 0.50 sec, QT dispersion from 0.07 to 0.14 sec, and transmural dispersion of repolarization from 0.10 to 0.16 sec. The addition of a beta-blocker shortened the QTc interval from 0.50 to 0.47 sec, QTc dispersion from 0.14 to 0.06 sec, and transmural dispersion of repolarization from 0.16 to 0.11 sec. The authors therefore suggested that combined therapy with bepridil and a beta-blocker might be useful for intractable atrial ﬁbrillation.

Positive inotropic drugs and drugs used in dysrhythmias

Cibenzoline

(SED-14, 541; SEDA-24, 210; SEDA-25, 217; SEDA-26, 207) Cardiovascular In three patients in whom cibenzoline had caused sinus node dysfunction, normal sinus node recovery time was restored by cilostazol (73c ).

Susceptibility factors Cibenzoline is 60% eliminated by the kidneys, and renal insufﬁciency may therefore reduce its elimination (SEDA-15, 174). The importance of this has been suggested by a report of three patients in whom severe renal insufﬁciency (creatinine clearance 10–16 ml/min) led to increased plasma cibenzoline concentrations during treatment with 300 mg/day (74A ). They developed prolonged QTc intervals, widened QRS complexes, dysrhythmias, hypotension, and hypoglycemia. Their plasma cibenzoline concentrations were 1944–2580 μg/l, 5–10 times higher than the usual target range. The half-lives of cibenzoline immediately after withdrawal were 69, 116, and 198 hours, 3–10 times longer than reported in patients with end-stage renal insufﬁciency (about 20 hours).

Disopyramide

(SED-14, 543; SEDA-24, 211; SEDA-25, 217; SEDA-26, 208)

Nervous system Neuropathy has rarely been attributed to disopyramide (75A ), but another case has been reported (76A ). • A 71-year-old woman, who had taken disopyramide 500 mg/day for 4 years, developed fatigue, paresthesia, pain, and cramps in her legs. She had proximal weakness in all four limbs and an unsteady gait. Electrophysiology showed a sensorimotor polyneuropathy, with reduced motor conduction velocity and muscle denervation. All antibodies were negative. The symptoms did not respond to prednisone but improved in the months after disopyramide withdrawal.

Dofetilide

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disease and sustained ventricular tachycardia (77C ). There were signiﬁcant reductions in heart rate, mean systemic pressure, and cardiac index (−13%) with sotalol, but cardiac index increased signiﬁcantly with dofetilide (11%) with no effect on heart rate or systemic blood pressure. The authors suggested that oral dofetilide could be useful in patients with ventricular tachydysrhythmias associated with impaired left ventricular function. One patient taking dofetilide reported mild dizziness and there were no cardiac dysrhythmias.

Flecainide (SED-14, 545; SEDA-24, 211; SEDA-25, 217; SEDA-26, 212) A systematic review of 22 studies of the effects of ﬂecainide used for at least 3 months in the treatment of supraventricular dysrhythmias suggested that ﬂecainide is associated with a variety of adverse reactions, many of which are well tolerated, but carries a small risk of serious cardiac events (2%), which can lead to death (0.13%) (SEDA-21, 200). In a meta-analysis of 122 prospective studies of the use of ﬂecainide in 4811 patients with supraventricular dysrhythmias, 21 were placebo-controlled and 37 were comparative studies with other antidysrhythmic drugs (78M ). The total exposure time was 2015 patient years, with a mean oral ﬂecainide dose of 216 mg/day. There were eight deaths (total mortality 0.17%, fatality rate per 100 patient years 0.40; 95% CI = 0.17, 0.78), conﬁrming the earlier ﬁnding. Three deaths were noncardiac (cancer, suicide, urinary sepsis). Of the cardiac deaths, all but two occurred in patients with coronary heart disease. In controls, there was one death. There were prodysrhythmic events in 120 patients taking ﬂecainide (2.7%) and 88 controls (4.8%), 58 (7.4%) of which occurred in patients taking placebo. Non-cardiac adverse effects are listed in Table 1. Thus, ﬂecainide is safe in patients with supraventricular dysrhythmias with no cardiac damage, in contrast to patients with ventricular dysrhythmias after myocardial infarction.

(SEDA-26, 208)

The hemodynamic effects of dofetilide 500 μg bd and sotalol 160 mg bd for 3–5 days have been studied in 12 patients with ischemic heart

Cardiovascular In 33 patients with symptomatic and inducible supraventricular tachycardias single doses of placebo, ﬂecainide 3 mg/kg or diltiazem 120 mg plus propranolol

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Table 1. Numbers (%) of cardiac and non-cardiac adverse effects of ﬂecainide in a meta-analysis of 4375 treatment courses compared with 1818 treatment courses in controls (78M ) System

Adverse effect

Flecainide

Controls

Cardiovascular

Angina pectoris Palpitation Hypotension Syncope Heart failure/dyspnea Sinus node dysfunction Bundle branch block Atrioventricular block

43 (1.0) 17 (0.4) 33 (0.8) 5 (0.1) 40 (0.9) 52 (1.2) 29 (0.7) 24 (0.5)

25 (1.3) 6 (0.3) 24 (1.3)∗ 3 (0.2) 13 (0.7) 22 (1.2) 7 (0.4) 7 (0.4)

Nervous system

Total Headache Dizziness Vertigo

412 (9.4) 88 (2.0) 148 (3.4) 137 (3.1)

65 (3.4)∗ 53 (2.9)∗ 45 (2.5) 42 (2.3)

Sensory systems

Visual disturbances

175 (4.0)

16 (0.9)∗

Gastrointestinal

Total Diarrhea Nausea

144 (3.3) 29 (0.7) 71 (1.6)

121 (6.7)∗ 50 (2.8)∗ 33 (1.8)

∗ Signiﬁcantly different.

80 mg were used to terminate the dysrhythmia (79C ). Conversion to sinus rhythm was achieved within 2 hours in 17 patients with placebo, in 20 with ﬂecainide, and in 31 with diltiazem plus propranolol. Time to conversion was shorter with diltiazem plus propranolol (32 minutes) than with ﬂecainide (74 minutes) or placebo (77 minutes). Of those who were given ﬂecainide, two had hypotension and one had sinus bradycardia. Respiratory Interstitial pneumonitis has only rarely been attributed to ﬂecainide (SEDA-16, 181; SEDA-25, 184), but another two cases have been reported (80A ). • A 75-year-old man, who had taken ﬂecainide 100 mg/day for 22 months, developed fever, headache, and a dry cough. A CT scan of the lungs was normal and he responded to prednisone. His symptoms disappeared, but when prednisone was withdrawn they returned, with breathlessness, a dry cough, and weight loss. A chest X-ray showed bilateral patchy opacities and a CT scan subpleural ground-glass opacities and septal thickening. He had impaired lung function, including a reduced diffusion capacity. Biopsy showed diffuse interstitial thickening with lymphocytic and eosinophilic inﬁltrates. Flecainide was withdrawn and prednisone given, and he made a full recovery within 1 month. • A 73-year-old man, who had taken ﬂecainide 100 mg/day for 4 months, developed fever, weight

loss, breathlessness, and a dry cough. A chest X-ray showed patchy inﬁltrates and a CT scan ground-glass opacities and subpleural septal thickening. He had normal lung function, apart from a reduced diffusion capacity. Flecainide was withdrawn and prednisone given, and he made a full recovery within a few months.

Pregnancy Flecainide is occasionally used to treat fetal cardiac dysrhythmias by administration to the mother (81c , 82c ), although occasionally it can cause adverse effects in the child (SEDA-25, 184) and in the mother (83A ). • At 30 weeks of gestation in a 41-year-old woman the fetus had hydrops, ascites, a pericardial effusion, and bilateral hydroceles. A supraventricular tachycardia with 1 : 1 conduction was treated by giving the mother oral ﬂecainide 150 mg bd. However, during the next few weeks the mother developed evidence of hepatic cholestasis. The dosage of ﬂecainide was reduced to 50 mg bd and the liver damage resolved. The child was born healthy but later required sotalol for a re-entry tachycardia.

Lidocaine (lignocaine)

(SED-14, 546;

SEDA-24, 212; SEDA-25, 218) Sensory systems Pupillary mydriasis occurred in a neonate who was given intravenous lidocaine 3 mg/kg/hour as an anticonvulsant (84A ).

Positive inotropic drugs and drugs used in dysrhythmias

Drug administration route The pharmacokinetics of lidocaine in patches have been investigated in two studies. In 20 healthy volunteers 5% lidocaine patches were applied for 18 hours/day on 3 consecutive days (85c ). The mean peak concentrations on days 1, 2, and 3 were 145, 153, and 154 ng/ml respectively; the median values of tmax were 18.0, 16.5, and 16.5 hours; and the mean trough concentrations were 83, 86, and 77 ng/ml. The patches were well tolerated; local skin reactions were generally minimal and self-limiting. In 20 healthy volunteers four lidocaine patches were applied every 12 or 24 hours on 3 consecutive days (86c ). The mean maximum plasma lidocaine concentrations at steady state were 225 and 186 ng/ml respectively. There was no loss of sensation at the site of application. No patient had edema and most cases of erythema were very slight. No systemic adverse events were judged to be related to the patches. Drug overdose Accidental overdose with viscous lidocaine has been reported in a child (87A ). • An 18-month-old child took an unstated amount of 2% viscous lidocaine and developed malaise and had a cardiorespiratory arrest. He was resuscitated but developed seizures and died. Serum concentrations of lidocaine and monoethylglycinexylidide at 7 hours were 1.1 μg/ml and 0.94 μg/ml respectively.

Drug interactions The thrombin inhibitor argatroban had no effect on the pharmacokinetics of intravenous lidocaine 1.5 mg/kg for 10 minutes followed by 2 mg/kg/hour for 16 hours in 12 healthy volunteers; the argatroban was given as an intravenous infusion of 2 μg/kg/min for 16 hours (12c ). An interaction of lidocaine with mexiletine, which resulted in toxic concentrations of lidocaine, has been reported (88A ). • An 80-year-old man with a dilated cardiomyopathy was given a lidocaine infusion started at 90 mg/hour for a ventricular tachycardia. He was already taking mexiletine 400 mg/day, and the plasma concentration was within the usual target range; however, the dose was reduced to 200 mg/day to avoid possible adverse effects. Intermittent ventricular tachycardia persisted, and so the lidocaine infusion was increased to 120 mg/day, but adverse effects (involuntary movements, muscle rigidity) were observed. The lidocaine infusion

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was stopped and within 20 minutes the adverse effects abated; the lidocaine concentration was 6.84 μg/ml. The ventricular tachycardia persisted, lidocaine was restarted at a lower rate, and the oral dose of mexiletine was increased to 450 mg/day. This resulted in an unexpectedly high concentration of lidocaine and the lidocaine concentration was signiﬁcantly higher while the mexiletine dose was high. Further studies suggested that mexiletine had displaced lidocaine from tissue binding sites.

The authors suggested that this ﬁnding has implications for loading doses and acute effects of lidocaine in the concurrent therapy of lidocaine and mexiletine and highlighted the importance of close monitoring of lidocaine concentrations in this setting.

Mexiletine

(SED-14, 547; SEDA-24, 212; SEDA-25, 219; SEDA-26, 213) The analgesic efﬁcacy of mexiletine 600 mg/ day and gabapentin 1200 mg/day has been investigated in 75 patients with acute and chronic pain associated with breast surgery in a doubleblind, randomized, placebo-controlled study for 10 days (89C ). Pain at rest and after movement was reduced by both drugs on the third postoperative day and pain after movement was reduced by gabapentin at 2–5 days postoperatively. Two women given mexiletine withdrew from the study because of adverse events, one with an axillary vein thrombosis and one with nausea and vomiting.

Procainamide

(SED-14, 548; SEDA-24, 213; SEDA-26, 213) Drug overdose Procainamide overdose has been reported (90A ).

• A 14-year-old boy took about 21 g of procainamide and developed abdominal pain, weakness, blurred vision, dry mouth, pain on swallowing, and headache. His pupils were dilated, his skin dry and pale, and his mucous membranes dry. His blood pressure was 106/49 mmHg, his heart rate 91/minute. Following a tonic–clonic seizure his blood pressure was 125/57 mmHg and his heart rate 136/minute in sinus tachycardia. He became lethargic with slurred speech. He was given repeated doses

198 of activated charcoal and made a full recovery. The serum procainamide and acecainide (Nacetylprocainamide) concentrations were 63 and 80 μg/ml respectively.

There have been two previous reports of overdose with procainamide in adults. • A 79-year-old man took about 19 g of procainamide and developed lethargy, vomiting, a wide-complex tachycardia, hypotension, and coma (91A ). His serum procainamide concentration was 77 μg/ml at 3 hours. He was treated with vasopressors and peritoneal dialysis. • A 67-year-old woman took about 7 g of procainamide and developed nausea, vomiting, lethargy, a junctional tachycardia, hypotension, and oliguria (92A ). She was treated with hemodialysis.

Propafenone

(SED-14, 551; SEDA-24, 214; SEDA-25, 220; SEDA-26, 214)

Propafenone 450 mg/day and sotalol 240 mg/ day have been compared in a placebo-controlled study of 300 patients with atrial ﬁbrillation (93C ). The two drugs had similar efﬁcacy. There were adverse events in 38 of the patients who took propafenone, compared with 12 of those who took placebo. These included gastrointestinal discomfort, neurological disturbances, asymptomatic bradycardia, a metallic taste, and general weakness. In nine patients the adverse effects were sufﬁcient to cause withdrawal of propafenone. Cardiovascular In controlled trials in patients with recent-onset atrial ﬁbrillation without heart failure oral propafenone (450–600 mg as a single dose) had a relatively quick effect (within 3–4 hours) and a high rate of efﬁcacy (72–78% within 8 hours) (94R ). A potentially

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harmful effect of propafenone in these cases is the risk of transforming atrial ﬁbrillation into atrial ﬂutter, which occurs in 3.5–5% of patients. However, atrial ﬂutter with 1 : 1 atrioventricular conduction occurred in only two of 709 patients (0.3%) who received propafenone.

Quinidine

(SED-14, 552; SEDA-24, 214; SEDA-25, 221; SEDA-26, 214) Cardiovascular Quinidine causes prolongation of the QT interval, and the relation between serum quinidine concentrations and QT interval dispersion has been studied in 11 patients with atrial dysrhythmias and subtherapeutic or therapeutic serum quinidine concentrations (1.48 and 3.78 μg/ml respectively) (95c ). The baseline QTc interval was 430 msec. At subtherapeutic and therapeutic serum quinidine concentrations, mean QTc intervals were 451 msec and 472 msec respectively. Mean QT dispersion was 47 msec at baseline, 98 msec at subtherapeutic concentrations, and 71 msec at therapeutic concentrations. Despite QT interval lengthening with increasing serum quinidine concentrations, QT dispersion was greatest at subtherapeutic concentrations. Drug interactions In human liver microsomes diclofenac inhibited testosterone 6-betahydroxylation with characteristics that suggested that it inactivated CYP3A4 (96E ). Quinidine, which stimulates CYP3A4-mediated diclofenac 5-hydroxylation, did not affect the inactivation of CYP3A4 assessed by testosterone 6-beta-hydroxylation activity but accelerated the inactivation assessed by diazepam 3-hydroxylation activity.

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202 95. Mathis AS, Gandhi AJ. Serum quinidine concentrations and effect on QT dispersion and interval. Ann Pharmacother 2002; 36: 1156–61.

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96. Masubuchi Y, Ose A, Horie T. Diclofenac-induced inactivation of CYP3A4 and its stimulation by quinidine. Drug Metab Dispos 2002; 30: 1143–8.

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

18

Beta-adrenoceptor antagonists and antianginal drugs

BETA-ADRENOCEPTOR ANTAGONISTS (SED-13, 488; SEDA-24, 220; SEDA-25, 227; SEDA-26, 223)

Carvedilol Cardiovascular Propranolol and other nonselective beta-blockers have been extensively evaluated in the primary prevention of variceal hemorrhage. Meta-analysis of these trials has clearly shown that these drugs are beneﬁcial when compared with placebo, even if many patients could not tolerate the treatment. Alpha-adrenoceptor antagonism was also very effective in reducing hepatic venous pressure gradients, but patients often had symptomatic hypotension and sometimes, as a consequence, renal dysfunction. Carvedilol combines non-selective betablockade with weak alpha1 -blockade. Ten patients with gastro-esophageal varices, none having bled, were treated with oral carvedilol 12.5 mg/day for 4 weeks (1C ). Hemodynamic measurements were performed before the ﬁrst administration and at 1 hour and 4 weeks after. After acute administration, the hepatic venous pressure gradient was signiﬁcantly reduced by 23% (from 16.4 to 12.6 mmHg), with a signiﬁcant reduction in heart rate. After 4 weeks the hepatic venous pressure gradient was further signiﬁcantly reduced to 9.3 mmHg. Carvedilol was well tolerated, and only one patient had asymptomatic hypotension. The results of this study suggest that low-dose carvedilol significantly reduces portal pressure without signiﬁcant systemic hemodynamic effects. The reduction in portal pressure with carvedilol was © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

larger than that obtained with propranolol, encouraging speciﬁc trials of carvedilol for the primary prevention of variceal hemorrhage.

Labetalol Cardiovascular Labetalol is generally used effectively as an antihypertensive drug without reports of high vascular resistance, even in patients with pheochromocytoma. However, a case of pheochromocytoma with increased systemic vascular resistance and reduced cardiac index has been described (2A ). • A 36-year-old man with a pheochromocytoma underwent adrenalectomy. After induction of anesthesia he was given intravenous labetalol 30 mg, and after intubation his blood pressure rose from 147/85 to 247/150 mmHg, his systemic vascular resistance index rose from 1958 to 3458 dyn·sec−1 ·m2 ·cm5 , and his cardiac index fell to 3.6 l·min−1 ·m2 . During tumor resection, he was given sodium nitroprusside to reduce his blood pressure. After tumor resection, his blood pressure fell to 77/52 mmHg and his systemic vascular resistance index to 1635 dyn·sec−1 ·m2 ·cm5 . His blood pressure was effectively controlled with dobutamine.

This case affords a reminder that intravenous labetalol can increase the systemic vascular resistance and cause a hypertensive crisis. In these cases, labetalol should be replaced with a pure alpha-blocker or another vasodilator, to prevent the possibility of cardiovascular complications. Liver Acute hepatitis has previously been described as an adverse effect of labetalol. A new case has been described in an East-Asian man (3A ). • A 50-year-old man with chronic hepatitis B infection, a hemiparesis due to a hemorrhage in the left basal ganglia, and a high systolic blood pressure

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was given intermittent intravenous labetalol followed by oral therapy (200 mg bd). After 1 week, his AsT, AlT, and bilirubin started to rise. Ultrasonography of the liver and gallbladder was normal. Labetalol was withdrawn, and all the liver function tests normalized within a few days.

Prior hepatitis B infection may have predisposed this patient to labetalol-induced liver toxicity. Electrolyte balance Hypertension is common in patients with end-stage renal disease undergoing renal transplantation and can be controlled by labetalol. Life-threatening hyperkalemia has previously been documented in a renal transplant recipient given intravenous labetalol for perioperative hypertension. In a retrospective chart review in 103 transplanted patients from January to November 1994, hypertension requiring perioperative treatment was observed in 51 cases (4C ). Treatment for hyperkalemia was necessary in 13 of the 38 patients who were treated with labetalol, compared with 11 of the 65 who were treated with another antihypertensive treatment. This result conﬁrms that the risk of hyperkalemia after renal transplant is higher in patients taking labetalol.

NITRATE DERIVATIVES (SED-14, 594; SEDA-24, 222; SEDA-25, 228; SEDA-26, 224)

Glyceryl trinitrate (nitroglycerin) Cardiovascular Topical nitrates are used as an alternative to surgical treatment of chronic anal ﬁssures. Their often limiting adverse effect is headache, due to vasodilatation, which is why glyceryl trinitrate ointment has been compared with diltiazem cream in a double-blind study in 60 patients with chronic anal ﬁssures (5C ). After 8 weeks of treatment, 25 of 29 patients who received glyceryl trinitrate and 24 of 31 who received diltiazem had healed or improved; adverse effects were more common with glyceryl trinitrate (21/29) than diltiazem (13/31), the most frequent being headache. The authors suggested that diltiazem might be used as an alternative to glyceryl trinitrate in the treatment of chronic anal ﬁssures, since it has similar efﬁcacy with fewer adverse effects.

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

Pregnancy Transdermal glyceryl trinitrate 5 mg for 16 hours each day has been compared with placebo in 25 mothers in 26 mothers bearing intrauterine growth-retarded fetuses (6c ). It was applied from week 27 to week 35 of gestation until delivery. Three mothers were excluded from the analysis because they did not use the glyceryl trinitrate correctly. Placental ﬂow, measured by Doppler, was improved by glyceryl trinitrate, and there was a better short-term neonatal outcome. Moreover, a biochemical marker of brain distress, the protein S100B, was normalized after glyceryl trinitrate, without an excess of adverse events in either the neonates or the mothers.

Isosorbide-5-mononitrate Cardiovascular Isosorbide-5-mononitrate has been tested with and without propranolol in a placebo-controlled study in 30 patients with liver cirrhosis and esophageal varices (7C ). The aim of the study was to assess the severity of previously reported adverse effects (i.e. renal dysfunction and hepatic encephalopathy) when vasoactive drugs are used to prevent variceal bleeding. Neither isosorbide-5-mononitrate nor propranolol alone or together had any adverse effect on subclinical hepatic encephalopathy or renal function in patients with wellcompensated cirrhosis. Severe headache in those taking isosorbide caused three patients to withdraw.

CALCIUM CHANNEL BLOCKERS (SED-14, 578; SEDA-24, 222; SEDA-25, 229; SEDA-26, 225) Hematologic A hemorrhagic diathesis, including impaired platelet function, develops in chronic renal insufﬁciency, in which calcium channel blockers are used widely as antihypertensive agents. In 156 patients with moderate to severe chronic renal insufﬁciency not on hemodialysis calcium channel blockers prolonged the bleeding time (OR = 3.52; 95% CI = 1.01, 12.3) (8c ). However, despite this effect, there were no clinically serious hemorrhagic events during the study. Among those

Beta-adrenoceptor antagonists and antianginal drugs

taking calcium channel blockers, 21 patients with prolonged bleeding times were randomly assigned to two groups; in one group treatment was withdrawn and bleeding time shortened; in those who continued to take the treatment the bleeding time was unchanged. Drug overdose Five cases of overdose of calcium channel blockers have been reported (9A ): • a 5-month-old girl inadvertently given nifedipine 20 mg; • a 14-year-old girl who took modiﬁed-release verapamil 30 mg/kg; • a 48-year-old man who took an unknown amount of modiﬁed-release diltiazem; • a 34-year-old woman who took amlodipine 0.86 mg/kg; • a 31-year-old man who took modiﬁed-release verapamil 71 mg/kg.

All were successfully treated with hyperinsulinemia/euglycemia therapy. The authors described the mechanism of action of this form of therapy, which is mainly related to improvement in cardiac contractility and peripheral vascular resistance and reversal of acidosis. They proposed indications and dosing for this therapy consisting in most cases of intravenous glucose with an intravenous bolus dose of insulin 1 U/kg followed by an infusion of 0.5– 1 U/kg/hour until the systolic blood pressure is over 100 mm/Hg and the heart rate over 50. Hyperinsulinemia/euglycemia therapy is currently reserved as an adjunct to conventional therapy and is recommended only after an inadequate response to ﬂuid resuscitation, high-dose calcium salts, and pressor agents.

Amlodipine Liver Hepatitis has been attributed to amlodipine (10A ). • A 77-year-old man took amlodipine for 1 month and developed jaundice and raised AsT, AlT, and bilirubin. A liver biopsy suggested a drug-induced hepatitis and the amlodipine was withdrawn. His symptoms and laboratory values normalized. Other drugs (metformin, ﬂuindione, and omeprazole) were not withdrawn.

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Skin Recognized skin eruptions associated with amlodipine include erythematous and maculopapular rashes, skin discoloration, urticaria, dryness, alopecia, dermatitis, erythema multiforme, and lichen planus. A granuloma annulare-like eruption has been reported (11A ). • A 64-year-old Caucasian woman, with a history of ankylosing spondylitis, hypertension, and osteoporosis, took amlodipine for 13 days and developed a rash on her lower legs. Amlodipine was withdrawn, but the rash progressed to involve both of her hands. The eruption consisted of multiple erythematous pruritic papules. Histology showed focal collagen degeneration and a signiﬁcant interstitial histiocytic dermal inﬁltrate, suggestive of granuloma annulare. Within 3 months of withdrawal of amlodipine the reaction cleared and did not recur during follow-up for 3 years.

Drug interactions A possible interaction of amlodipine with chloroquine has been reported (12A ). • A 48-year-old hypertensive physician, who had optimal blood pressure control after taking oral amlodipine 5 mg/day for 3 months, developed a slight frontal headache and fever, thought that he had malaria, and took four tablets of chloroquine sulfate (total 600 mg base). Two hours later he became nauseated and dizzy and collapsed; his systolic blood pressure was 80 mmHg and his diastolic pressure was unrecordable, suggesting vasovagal syncope, which was corrected by dextrose–saline infusion.

There was no malaria parasitemia in this case, and hence the syncope may have resulted from the acute synergistic hypotensive, venodilator, and cardiac effects of chloroquine plus amlodipine, possibly acting via augmented nitric oxide production and calcium channel blockade. Since malaria fever is itself associated with orthostatic hypotension, this possible interaction may be unrecognized and unreported in these patients.

Diltiazem Drug interactions Paralytic ileus has been attributed to the combined use of diltiazem and nifedipine (13A ). • A 62-year-old man with chest pain underwent cardiac catheterization. The diagnosis was vasospastic angina and he was given nifedipine 20 mg bd;

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when his angina attacks persisted he was also given oral diltiazem 100 mg bd. After 2 days, although his angina was well controlled, abdominal distension and vomiting occurred, and an X-ray suggested intestinal ileus. The drugs were withdrawn and the ileus resolved. It recurred when the treatment was resumed and gradually resolved again after withdrawal.

The disorder was suspected to be due to enhanced pharmacodynamic effects caused by the combination of the two calcium channel blockers. However, plasma concentrations of nifedipine have also been reported to increase about three-fold when it is combined with diltiazem (14C ). Rhabdomyolysis and acute hepatitis have been reported in association with the co-administration of diltiazem and atorvastatin (15A ). • A 60-year-old African–American man developed abdominal pain, a racing heart, and shortness of breath over 24 hours. He had also noticed increasing fatigue and reduced urine output over the previous 2–3 days. He had been taking several medications, including atorvastatin, for more than 1 year, but diltiazem had been added 3 weeks before for atrial ﬁbrillation. On the basis of laboratory ﬁndings and physical examination a diagnosis of acute hepatitis and rhabdomyolysis with accompanying acute renal insufﬁciency was made. His renal function gradually normalized and his CK activity reached a maximum of 2092 units/l on day 1 and fell to 623 units/l on discharge. His liver function tests returned to normal by 3 months.

While rhabdomyolysis from statins is rare, the risk is increased when they are used in combination with agents that share similar metabolic pathways. Atorvastatin is metabolized by CYP3A4, which is inhibited by diltiazem.

Isradipine Drug interactions An interaction of isradipine with phenytoin has been reported (16A ). • A 21-year-old white man, who was taking phenytoin and carbamazepine for seizures, developed severe lethargy, ataxia, and weakness after isradipine was prescribed for blood pressure control. The interaction was veriﬁed 2 months later, when he was rechallenged with the same dose of isradipine, 2.5 mg bd, and developed the same symptoms. Phenytoin plasma concentrations were at the upper limit of the usual target range (maximum assayed

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

100 μmol/l) and did not fall when the dose of phenytoin was reduced while he was taking isradipine.

Both pharmacokinetic and pharmacodynamic mechanisms can explain these observations. Isradipine inhibits CYP450 isoforms that are responsible for the metabolism of phenytoin, and both isradipine and phenytoin can bind to calcium channels in the brain and thereby affect neurological function.

Nicardipine Cardiovascular Severe bradycardia has been attributed to nicardipine (17A ). • A 75-year-old man with atrial ﬁbrillation undergoing surgery for esophageal carcinoma developed hypothermia and bradycardia during anesthesia. In an attempt to reduce his blood pressure of over 190/100 mmHg, he was given intravenous nicardipine 1 mg twice, 3 minutes apart. After the second dose, his blood pressure fell and his heart rate fell to 10 bpm. He recovered after cardiopulmonary resuscitation.

The authors suggested that direct suppression of the sinoatrial node by nicardipine in the presence of low sympathetic tone might have been the mechanism of this serious adverse reaction.

Nifedipine Food–drug interactions The effect of food on the systemic availability of two modiﬁedrelease dosage forms of nifedipine for oncedaily administration (Adalat OROS, a tablet with an osmotic push-pull system, and Slofedipine XL, a tablet with an acid-resistant coating) has been investigated in 24 healthy men in an open, randomized, crossover study (18c ). After fasted administration the systemic availability was slightly lower for Slofedipine XL than Adalat OROS, with a point estimate of 82%, mainly resulting from differences in nifedipine concentrations during the ﬁrst 15 hours after administration. Maximum plasma concentrations were lower after Slofedipine XL compared with Adalat OROS (point estimate 84%). After a high-fat breakfast the differences in availability between the two products were greater than

Beta-adrenoceptor antagonists and antianginal drugs

while fasting, with point estimates of 70% for AUC and 81% for Cmax . Most striking was the lag time after food for Slofedipine XL which was more than 15 hours in 15 of 24 subjects. The availability of nifedipine from Slofedipine XL compared with Adalat OROS was only 28% over the intended dosing interval of 24 hours. The delay in nifedipine absorption when Slofedipine XL is administered may be explained by properties of the formulation, since the acid-resistant coating probably confers delayed absorption, due to prolongation of the gastric residence time, while the osmotic push-pull system is not sensitive to food. The same authors conducted a similar study in 24 healthy subjects, in which they compared Adalat OROS with Nifedicron, a product that consists of a capsule containing several mini-tablets (19c ). There was a higher rate of availability for Nifedicron in the fasted state, and after a high-fat breakfast the differences between the products became even more pronounced. The most important effect of concomitant food was reﬂected by a pronounced increase in Cmax after Nifedicron, which resulted in a more than threefold higher mean concentration than Adalat OROS. This phenomenon may result in safety and tolerability problems.

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• Two 19-year-old-girls developed pulmonary edema after taking massive overdoses of verapamil (6000 mg and 7200 mg). In each case a chest Xray showed diffuse bilateral patchy inﬁltration. Left ventricular size and function was normal on transthoracic echocardiography. They were both treated successfully with mechanical ventilatory support.

Several mechanisms may be involved in non-cardiogenic pulmonary edema subsequent to verapamil intoxication, including leaky capillary syndrome attributable to inhibition of prostacyclin, a cellular membrane protector. Prolonged hypotension and a shock-like state may also contribute. The authors recommended pressor/inotropic therapy and mechanical ventilation as therapy. Elsewhere, multiple-dose activated charcoal has been suggested for the treatment of verapamil overdose (SEDA-24, 226). • A 61-year-old woman developed profound hypotension, bradycardia, oliguria, and multifocal myoclonus after verapamil overdose. Her serum verapamil concentration was 800 ng/ml (1760 nmol/l) (usual target range 50–200 ng/ml, 110– 440 nmol/l). She was treated with supportive care, vasopressin, dopamine, and calcium gluconate. After about 60 hours the myoclonus and hemodynamic compromise resolved completely (21A ).

Verapamil Drug overdose Non-cardiogenic pulmonary edema has been reported after the ingestion of a large quantity of verapamil (20A ).

REFERENCES 1. Tripathy D, Therapondos G, Lui HF, Stanley AJ, Hayes PC. Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2002; 16: 373–80. 2. Chung PCH, Li AH, Lin CC, Yang MW. Elevated vascular resistance after labetalol during resection of a pheochromocytoma. Can J Anaesth 2002; 49: 148–50. 3. Marinella MA. Labetalol-induced hepatitis in a patient with chronic hepatitis B infection. J Clin Hypertens 2002; 4: 120–1. 4. McCauley J, Murray J, Jordan M, Scantlebury V, Vivas C, Shapiro R. Labetalol-induced hyperkalemia in renal transplant recipients. Am J Nephrol 2002; 22: 347–51.

5. Kocher HM, Steward M, Leather AJM, Cullen PT. Randomized clinical trial assessing the side-effects of glyceryl trinitrate and diltiazem hydrochloride in the treatment of chronic anal ﬁssure. Br J Surg 2002; 89: 413–17. 6. Gazzolo D, Bruschettini M, Di Iorio R, Marinoni E, Lituania M, Marras M, Sarli R, Bruschettini PL, Michetti F. Maternal nitric oxide supplementation decreases cord blood S100B in intrauterine growth-retarded fetuses. Clin Chem 2002; 48: 647–50. 7. Silva G, Segovia R, Ponce R, Backhouse C, Palma M, Roblero JP, Abadal J, Quijada C, Troncoso M, Iturriaga H. Effects of 5-isosorbide mononitrate and propranolol on subclinical hepatic encephalopathy and renal function in patients with

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liver cirrhosis. Hepato-Gastroenterology 2002; 49: 1357–62. 8. Hayashi K, Matsuda H, Honda M, Ozawa Y, Tokuyama H, Okubo K, Takamatsu I, Kanda T, Tatematsu S, Homma K, Saruta T. Impact of calcium antagonists on bleeding time in patients with chronic renal failure. J Hum Hypertens 2002; 16: 199–203. 9. Boyer EW, Duic PA, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pediatr Emerg Care 2002; 18; 36–7. 10. Khemissa-Akouz F, Ouguergouz F, Sulem P, Tkoub EM, Vaucher E. Amlodipine-induced acute hepatitis. Gastroenterol Clin Biol 2002; 26: 637–8. 11. Lim AC, Hart K, Murrell D. A granuloma annulare-like eruption associated with the use of amlodipine. Australas J Dermatol 2002; 43: 24–7. 12. Ajayi AAL, Adigun AQ. Syncope following oral chloroquine administration in a hypertensive patient controlled on amlodipine. Br J Clin Pharmacol 2002; 53: 404–5. 13. Harada T, Ohtaki E, Sumiyoshi T, Hosoda S. Paralytic ileus induced by the combined use of nifedipine and diltiazem in the treatment of vasospastic angina. Cardiology 2002; 97: 113–14. 14. Toyosaki N, Toyo-Oka T, Natsume T. Combination therapy with diltiazem and nifedipine in patients with effort angina pectoris. Circulation 1988; 77: 1370–5. 15. Lewin III JJ, Nappi JM, Taylor MH, Lugo SI, Larouche M. Rhabdomyolysis with concurrent

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

atorvastatin and diltiazem. Ann Pharmacother 2002; 36: 1546–9. 16. Cachat F, Tufro A, Dalmady-Israel C, Laplante S. Phenytoin/isradipine interaction causing severe neurologic toxicity. Ann Pharmacother 2002; 36: 1399–402. 17. Arima H, Sobue K, Tanaka S, Morishima T, Ando H, Katsuya H. Profound sinus bradycardia after intravenous nicardipine. Anesth Analg 2002; 95: 53–5. 18. Schug BS, Brendel E, Chantraine E, Wolf D, Martin W, Schall R, Blume HH. The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag-time after a high fat breakfast. Br J Clin Pharmacol 2002; 53: 582–8. 19. Schug BS, Brendel E, Wonnemann M, Wolf D, Wargenau M, Dingler A, Blume HH. Dosage formrelated food interaction observed in a marketed once-daily nifedipine formulation after a high-fat American breakfast. Eur J Clin Pharmacol 2002; 58: 119–25. 20. Karti SS, Ulusoy H, Yandi M, Gündüz A, Kosucu M, Erol K, Ratip S. Non-cardiogenic pulmonary oedema in the course of verapamil intoxication. Emerg Med J 2002; 19: 458–9. 21. Vadlamudi L, Wijdicks EFM. Multifocal myoclonus due to verapamil overdose. Neurology 2002; 58: 984–5.

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

(SED-14, 630; SEDA-24, 229; SEDA-25, 236; SEDA-26, 230) The efﬁcacy and safety data of cilostazol in placebo-controlled clinical trials have been repeatedly subjected to meta-analysis, with the same conclusion (1M , 2M ). Cilostazol is well tolerated; headache, bowel complaints, and palpitation are the most common but mild adverse effects.

Cinnarizine and ﬂunarizine (SED-14, 630; SEDA-23, 214) Cinnarizine is used to treat motion sickness because of its antihistamine (H1 ) properties. A study in young volunteers has now established the effects of 15–45 mg of cinnarizine on daytime sleepiness and performance (4c ). Doses of 30 mg or more caused impaired performance and increased sleepiness. The authors therefore advised that cinnarizine should not be used in aircrew involved in tasks that demand attention.

Ginkgo biloba

(SED-14, 631;

SEDA-23, 214) Cardiovascular A report of ventricular tachycardia during cilostazol therapy is new (3A ). • A 92-year-old woman developed sudden runs of ventricular tachycardia, a few days after she started to take cilostazol because of subacute leg ischemia. She was known to have atrial ﬁbrillation and intraventricular conduction delay. The runs did not respond to empirical magnesium therapy but subsided shortly after withdrawal of cilostazol.

The phosphodiesterase III inhibitors have no known direct dysrhythmogenic effects. However, the authors speculated that raised concentrations of cAMP may have contributed to the ventricular tachycardia, mainly because ventricular dysrhythmias have been mentioned with other agents of the same family in patients with heart failure. Whether some populations are particularly vulnerable is unknown. © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Hematologic Clinical trials have suggested that standardized leaf extracts of Ginkgo biloba improve symptoms of age-associated memory impairment and dementia, including Alzheimer’s disease. The extract is largely considered to be innocuous, but recent reports have linked the use of Ginkgo biloba extract to an increased risk of bleeding: • hyphema led to temporarily impaired vision in a man who had taken Ginkgo biloba for 2 weeks; no other cause was found; the lesion regressed after withdrawal and did not recur (5A ); • a large subphrenic hematoma occurred 1 week after a second liver transplant in a 59-year-old man, followed by an episode of vitreous hemorrhage 3 weeks later; he was then discovered to be taking Ginkgo biloba (6A ). • a spontaneous cerebellar bleed occurred in a man who had taken Ginkgo biloba (7A ).

The arguments that implicated the extract in these cases of bleeding were the absence of recurrence after withdrawal (a weak argument) and a potential inhibitory effect of the extract on platelet function.

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Drug overdose Ginkgo biloba seed is also used as an over-the-counter herbal medicine, but rather for its antitussive and expectorant properties. Acute poisoning with Ginkgo seeds is occasionally seen in East Asian countries.

other hand, aseptic meningitis occurs with nonsteroidal anti-inﬂammatory drugs in patients with connective tissue diseases.

• A 2-year-old girl was admitted with vomiting, diarrhea, and irritability a few hours after eating a large quantity of Ginkgo seeds and then developed an afebrile generalized clonic seizure (8A ). Her serum concentration of 4-methoxypyridoxine, the putative toxic agent in the seed, was extremely high.

DRUGS USED IN THE TREATMENT OF MIGRAINE

Administration of pyridoxal phosphate, a competitive antagonist of 4-methoxypyridoxine, which inhibits the formation of gammaaminobutyric acid (GABA), prevented further seizures in this case.

Pentoxifylline

(SED-14, 633)

Pentoxifylline is a methylxanthine derivative, which inhibits phosphodiesterase, but also has anti-inﬂammatory and immunomodulatory properties. The most common adverse effect is gastrointestinal intolerance. Nervous system A case of drug-induced aseptic meningitis has been reported (9A ). • A 37-year-old woman with mixed connective tissue disease was given pentoxifylline 400 mg/day for Raynaud’s phenomenon. After 12 days she complained of headache, myalgia, and neck pain and developed a fever. She recovered promptly after withdrawal of the drug. A few weeks later, she took a single tablet of pentoxifylline and within 1 hour developed the same symptoms, together with chills, vomiting, and diarrhea. Neurological examination was normal, but the cerebrospinal ﬂuid contained a large number of leukocytes. Bacteriological and virological tests were negative.

A diagnosis of aseptic meningitis was made and pentoxifylline was thought to have played a causative role, because of the suggestive symptoms after ﬁrst exposure, the close temporal relation on rechallenge, and the quick recovery after withdrawal. The authors argued that the underlying disease may have had a predisposing role, since aseptic meningitis secondary to pentoxifylline has never been reported in the thousands of patients who have used it for peripheral arterial disease. On the

Triptans

(SED-14, 635; SEDA-24, 229; SEDA-25, 237; SEDA-26, 230) Vasoconstriction leading to organ ischemia has been repeatedly reported with triptans. The risk is very low in the absence of pre-existing arterial disease. Nevertheless, cases of myocardial infarction, mesenteric ischemia, and ischemic colitis all have been described. Splenic infarction has now been added to the list (10A ). • A 48-year-old woman with a low risk of atherosclerotic disease who was not taking oral contraception was admitted with sudden heavy pain in the left hypochondrium. Routine tests were normal, but there was a triangular hypodensity in the spleen on computerized tomography consistent with a splenic infarct. There was a history of postoperative venous thrombosis 15 years before, but tests for thrombophilia were all normal. No source of embolism was identiﬁed in the heart or proximal arteries. She had repeatedly taken zolmitriptan over the previous few months for migraine, and the symptoms started 3 hours after the most recent dose.

The temporal relation and the absence of an alternative cause to explain the infarct led the authors to conclude that zolmitriptan had been causative.

OTHER PERIPHERAL VASODILATORS Sildenaﬁl

(SED-14, 636; SEDA-24, 231; SEDA-25, 238; SEDA-26, 231) Cardiovascular In several reviews, in which the same data have been analysed, sildenaﬁl has been rated as being well-tolerated (11R , 12R ) and extremely safe (13R ). Concerns about its cardiovascular safety proﬁle have stemmed primarily from sporadic reports of myocardial infarction and stroke. The interpretation of these

Drugs acting on the cerebral and peripheral circulations

sporadic cases is controversial, although some have argued that the reported cardiovascular adverse effects occur more often with sildenaﬁl than with other pharmacological treatments of erectile dysfunction. It is at present unclear whether there is an increased risk with sildenaﬁl. Nervous system Unexpected functional disturbances, which occur shortly after the use of sildenaﬁl, are likely to be attributed to the drug. A 51-year-old man had transient global amnesia 30 minutes after taking sildenaﬁl 25 mg (14A ). A 79-year-old man had acute vertigo, vomiting, and tinnitus resembling vestibular neuronitis 2 hours after ﬁrst taking 50 mg; the symptoms lasted for 24 hours (15A ). Generalized tonic–clonic seizures have been reported after a ﬁrst 50 mg tablet in two men aged 54 and 63, neither of whom had organic brain lesions on imaging; one had tonic–clonic seizures again on rechallenge with the drug 3 months later (16A ). Sensory systems Following an initial report (SEDA-26, 231), several new cases of nonarteritic ischemic optic neuropathy in men taking sildenaﬁl have been reported (17A , 18A ). Hematologic Two men developed prolonged epistaxis a few hours after taking sildenaﬁl 50 mg to enhance their sexual performance (before the nose bleeding started); both had wellcontrolled hypertension (19A ). Epistaxis is not an unusual problem in elderly people with hypertension, and venous engorgement is thought to be the main causative factor. Whether this is ampliﬁed by sildenaﬁl (and/or by sexual activity) is an open question. Similarly, a 68year-old man with alcoholic cirrhosis and small

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esophageal varices (degree of severity classiﬁed as Child I) started bleeding after taking sildenaﬁl 25 mg for the ﬁrst time (20A ). Sudden overload of the portal venous system related to splanchnic vasodilatation is a possible provoking factor. Gastro-esophageal reﬂux secondary to a lower esophageal sphincter tone and causing mucosal erosion is an alternative explanation. Drug tolerance Potential tachyphylaxis with long-term use of sildenaﬁl has recently been discussed following a survey in which 200 patients were questioned twice, 2 years apart, about the effects of sildenaﬁl; on the second occasion 20% of them reported needing an increased dose and 17% had discontinued therapy because of lack of effect (21c ). However, others have commented that more likely reasons for the loss of effect over time included worsening of the disease (22r –26r ), reducing testosterone concentrations with age (23r , 24r ), or lack of proper arousal (27r ). Although the mRNA for phosphodiesterase type 5 is downregulated in the retina by long-term administration of sildenaﬁl in rats (28r ), it is not known whether that happens in human corpus cavernosum, nor whether long-term sildenaﬁl use is associated with tachyphylaxis. Drug overdose A case of suspected overdose of sildenaﬁl has been reported (29A ). • A 56-year-old man with a history of diabetes mellitus and hypertension was found dead at home, with an empty package of sildenaﬁl (12 tablets of 50 mg) near the body. The concentration of sildenaﬁl in postmortem blood was high. Autopsy showed a dilated cardiomyopathy and diffuse coronary atherosclerosis, but an overdose of sildenaﬁl was suspected to have provoked a fatal ventricular dysrhythmia.

REFERENCES 1. Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from eight randomised, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol 2002; 90: 1314–19. 2. Regensteiner JG, Ware JE Jr, McCarthy WJ, Zhang P, Forbes WP, Heckman J, Hiatt WR. Effect of cilostazol on treadmill walking, community-

based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomised controlled trials. J Am Geriatr Soc 2002; 50: 1939–46. 3. Gamssari F, Mahmood H, Ho JS, Villareal RP, Liu B, Rasekh A, Garcia E, Massumi A. Rapid ven-

212 tricular tachycardias associated with cilostazol use. Tex Heart Inst J 2002; 29: 140–2. 4. Nicholson AN, Stone BM, Turner C, Mills SL. Central effects of cinnarizine: restricted use in aircrews. Aviat Space Environ Med 2002; 73: 570–4. 5. Schneider C, Bord C, Misse P, Arnaud B, Schmitt-Bernard CF. Hyphéma spontané provoqué par l’extrait de Ginkgo biloba. J Fr Ophtalmol 2002; 25: 731–2. 6. Hauser D, Gayowski T, Singh N. Bleeding complications precipitated by unrecognised Ginkgo biloba use after liver transplantation. Transplant Int 2002; 15: 377–9. 7. Purroy Garcia F, Molina C, Alvarez Sabin J. Hemorragia cerebelosa esponetanea asociada a la ingestion de Ginkgo biloba. Med Clin (Barc) 2002; 119: 596–7. 8. Kajiyama Y, Fujii K, Takeuchi H, Manabe Y. Ginkgo seed poisoning. Pediatrics 2002; 109: 325– 7. 9. Mathian A, Amoura Z, Piette JC. Pentoxifyllineinduced aseptic meningitis in a patient with mixed connective tissue disease. Neurology 2002; 59: 1468–9. 10. Bellaïche G, Radu B, Boucard M, Ley G, Slama JL. Infarctus splénique associé à la prise de zolmitriptan. Gastroenterol Clin Biol 2002; 26: 299. 11. Padma-Nathan H, Eardley I, Kloner RA, Laties AM, Montorsi F. A 4-year update on the safety of sildenaﬁl citrate (Viagra). Urology 2002; 60: 67– 90. 12. Fink HA, Mac Donald R, Rutks IR, Nelson DB, Wilt TJ. Sildenaﬁl for male erectile dysfunction. Arch Int Med 2002; 162: 1349–60. 13. Lim PH, Moorthy P, Benton KG. The clinical safety of Viagra. Ann NY Acad Sci 2002; 962: 378– 88. 14. Savitz SA, Caplan LR. Transient global amnesia after sildenaﬁl (Viagra) use. Neurology 2002; 59: 778. 15. Hamzavi J, Schmetterer L, Formanek M. Vestibular symptoms as a complication of sildenaﬁl:

Chapter 19

R. Verhaeghe

a case report. Wien Klin Wochenschr 2002; 114: 54–5. 16. Gilad R, Lampl Y, Eshel Y, Sadeh M. Tonic– clonic seizures in patients taking sildenaﬁl. Br Med J 2002; 325: 869. 17. Pomeranz HD, Smith KH, Hart WM, Egan RA Jr. Sildenaﬁl-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2002; 109: 584–7. 18. Boshier A, Pambakian M, Shakir SA. A case of nonarteritic optic neuropathy (NAION) in a male patient taking sildenaﬁl. Int J Clin Pharmacol Ther 2002; 40: 422–3. 19. Hicklin RA, Ryan C, Wong DKK, Hinton AE. Nose-bleeds after sildenaﬁl (Viagra). J R Soc Med 2002; 95: 402–3. 20. Tzathas C, Christidou A, Ladas SD. Sildenaﬁl (Viagra) is a risk factor for acute variceal bleeding. Am J Gastroenterol 2002; 97: 1856. 21. El-Galley R, Rutland H, Talic R, Keane T, Clark H. Long-term efﬁcacy of sildenaﬁl and tachyphylaxis effect. J Urol 2001; 166: 927–31. 22. Billups KL. Re: Long-term efﬁcacy of sildenaﬁl and tachyphylaxis effect. J Urol 2002; 168: 204–5. 23. Carson CC. Re: Long-term efﬁcacy of sildenaﬁl and tachyphylaxis effect. J Urol 2002; 168: 205. 24. Guay AT. Re: Long-term efﬁcacy of sildenaﬁl and tachyphylaxis effect. J Urol 2002; 168: 206–7. 25. Mumtaz FH, Khan MA, Mikhailidis DP, Morgan RJ. Re: Long-term efﬁcacy of sildenaﬁl and tachyphylaxis effect. J Urol 2002; 168: 207. 26. Tomera K. Re: Long-term efﬁcacy of sildenaﬁl and tachyphylaxis effect. J Urol 2002; 168: 207. 27. Basson R, Robinow O. Re: Long-term efﬁcacy of sildenaﬁl and tachyphylaxis effect. J Urol 2002; 168: 204. 28. Steers WD. Tachyphylaxis and phosphodiesterase type 5 inhibitors. J Urol 2002; 168: 207. 29. Tracqui A, Miras A, Tabib A, Raul JS, Ludes B, Malicier D. Fatal overdosage with sildenaﬁl citrate (Viagra): ﬁrst report and review of the literature. Hum Exp Toxicol 2002; 21: 623–9.

Pieter Joubert

20

Antihypertensive drugs

ANGIOTENSIN CONVERTING ENZYME INHIBITORS Captopril

(SED-14, 642; SEDA-24, 237; SEDA-25, 242; SEDA-26, 234)

Immunologic A case of lupus-like syndrome associated with captopril has been reported (1A ). The authors believed their patient to be the ﬁfth such published case. • A 54-year-old Caucasian man presented with a 4-week history of chills, fever, malaise, and generalized arthralgia. Following an aortic valve replacement, he had taken aspirin, coumadin, and captopril 25 mg tds for 1 year. He was febrile (temperature 103◦ F), normotensive, with diffuse livedo reticularis, and the physical signs of aortic valve disease. Infective endocarditis was ruled out by appropriate investigations. He had a raised erythrocyte sedimentation rate (142 mm/hour) and a positive antinuclear antibody test (FANA 1 : 2560) with a negative antinative DNA test. Captopril was withdrawn and he was given prednisone for 5 days. His symptoms resolved rapidly and the livedo reticularis cleared within 2 days. The FANA and ESR returned to normal and remained so at follow-up 6 months later.

During early drug development, the occurrence of antinuclear antibodies in 10 of 37 patients taking high doses of captopril was described (2c ).

Fosinopril

• A 64-year-old woman with insulin-dependent diabetes mellitus and pemphigus vulgaris controlled by deﬂazacort 12 mg/day was given fosinopril 10 mg/day for hypertension. Within 1 month her skin lesions worsened and an indirect immunoﬂuorescence test became positive. Fosinopril was withdrawn and her skin lesions improved without modiﬁcation of her steroid regimen; 10 months later the immunoﬂuorescence test was negative.

Following this, normal human skin slices (obtained after informed consent from mammoplasty patients) were incubated with increasing concentrations of either fosinopril or captopril for 2–24 hours. Sera from patients with pemphigus vulgaris, containing anti-desmoglein-3 antibodies (anti-Dsg3) were tested on the skin samples incubated with fosinopril and captopril, as well as control skin samples incubated with 0.9% saline. Indirect immunoﬂuorescence testing showed that captopril, at dilutions as high as 1/10 000 (1.7 × 10−9 mmol/l), blocked the binding of anti-Dsg3 to the keratinocyte surface, probably because captopril blocked adhesion molecules. In contrast, fosinopril only had this effect at a dilution of 1/100 (1.7 × 10−2 mmol/l), at a concentration much higher than would occur in vivo with fosinopril. The authors proposed that captopril produces acantholysis by blocking adhesion molecules, but that fosinopril does not have this effect, and that another mechanism must have been involved in the case that they reported.

(SEDA-26, 235)

Skin There is a recognized association between the use of ACE inhibitors and the development of pemphigus vulgaris, for example with enalapril (SEDA-26, 235). A case of worsening of pemphigus vulgaris with fosinopril, and a subsequent in vitro mechanistic study, has now been published (3AE ). © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Lisinopril (SEDA-22, 228; SEDA-24, 238; SEDA-25, 242; SEDA-26, 236) Skin Worsening of pre-existing cold urticaria has been reported with lisinopril (4A ). • A 43-year-old Caucasian man had a history of mild cold urticaria during the preceding 10 years. Shortly after starting to take lisinopril 20 mg/day and hydrochlorothiazide 25 mg/day for hypertension, his condition worsened considerably and

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he had several bouts of severe cold urticaria. On one occasion, after swimming in water at 24◦ C, he developed severe urticaria and angio-edema, and required emergency hospital admission. Standard ice-cube and cold-water immersion tests were strongly positive within 1 minute. Tests for a variety of causative factors were negative, and a diagnosis of acquired cold urticaria was made. Lisinopril was withdrawn, he was given valsartan 80 mg/day, and the dose of hydrochlorothiazide was reduced to 12.5 mg/day. During the next 24 weeks he had only mild symptoms of cold urticaria. Repeat ice-cube and cold-water immersion tests were negative at 1 and 3 minutes, but positive at 5 minutes.

The authors cited evidence that the kallikrein–kinin system is involved in cold urticaria, that ACE inhibitors increase wheal and ﬂare reactions to cutaneously applied bradykinin, and that ACE inhibitor therapy is associated with raised plasma kinin concentrations. They therefore recommended avoidance of ACE inhibitors in patients with cold urticaria.

Ramipril

Pieter Joubert

Liver Hepatic injury due to losartan is a recognized rare adverse effect. A further conclusive case, with a brief review of the literature, has been published (7Ar ). • A 52-year-old woman developed jaundice, right upper abdominal discomfort, and weakness. She had had a similar problem previously, after taking losartan 50 mg/day for 5 months for hypertension. At that time she was jaundiced with increased serum transaminase activities. The losartan was withdrawn and during the following 3 weeks she improved. Losartan was then reintroduced, and 2 weeks later her symptoms recurred. She was jaundiced, with raised transaminase, alkaline phosphatase, and lactic dehydrogenase activities; tests for viral hepatitis were negative. A liver biopsy showed chronic hepatitis with moderate to severe inﬂammation and mild ﬁbrosis. Losartan was withdrawn and the laboratory tests returned to normal over a period of 4 months. She was healthy with normal laboratory tests 2 years later.

The authors made a strong case for a causal relation, based on the absence of other causes, the return to normality after withdrawal of losartan, and re-occurrence on rechallenge. A literature search revealed four previous reports of losartan-induced liver damage.

(SEDA-24, 239)

Gastrointestinal Diarrhea is a recognized infrequent adverse effect of ACE inhibitors. A convincing case of diarrhea associated with ramipril therapy has been reported (5A ).

ANGIOTENSIN II RECEPTOR ANTAGONISTS Losartan

(SED-14, 645; SEDA-24, 240; SEDA-25, 245; SEDA-26, 236)

Sensory systems A case, thought to be the third reported, of reversible loss of taste discrimination with losartan, has been published (6A ). There have been reports of taste disturbance in patients taking ACE inhibitors, tentatively attributed to chelation of metal ions. However, no mechanism for taste loss due to angiotensin-II receptor blockers has been proposed.

ENDOTHELIN RECEPTOR ANTAGONISTS (SEDA-26, 233) Clinical trials of the effects of endothelin receptor antagonists in patients with heart failure, coronary artery disease, arterial hypertension, and pulmonary hypertension have been reviewed (8R ), as have their uses in treating cancers (9R ) and cerebral vasospasm (10R ), and their potential uses in atherosclerosis, restenosis, myocarditis, shock, and portal hypertension (11R ).

Bosentan The effects of bosentan (62.5 mg bd for 4 weeks followed by either 125 or 250 mg bd for a minimum of 12 weeks) have been studied in a double-blind, placebo-controlled trial in 213 patients with pulmonary arterial hypertension (12C ). The patients who took bosentan had improved exercise capacity, less dyspnea, and

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delayed worsening. There were similar results in 32 patients who took bosentan for a minimum of 12 weeks (62.5 mg bd for 4 weeks then 125 mg bd) (13C ). Bosentan signiﬁcantly reduced pulmonary vascular resistance. The number and nature of adverse events were similar with bosentan and placebo.

Drug tolerance Despite short-term beneﬁts of bosentan in systemic hypertension and congestive heart failure, it increases plasma concentrations of endothelin-1, probably by inhibiting its clearance via endothelin type B receptors. This may mean that its effectiveness is reduced during long-term therapy (11R ).

Cardiovacular In the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) placebo-controlled study, the effects of low dose bosentan (125 mg bd) were evaluated in 1613 patients with severe heart failure (left ventricular ejection fraction <35%, New York Heart Association classes IIIb–IV) (14C ). The primary endpoint of all-cause mortality or hospitalization for heart failure was reached in 321 of 808 patients who took placebo and 312 of 805 who took bosentan. Treatment with bosentan conferred an early risk of worsening heart failure necessitating hospitalization, because of ﬂuid retention. These results throw doubt on the potential beneﬁts of non-speciﬁc endothelin receptor blockade in heart failure. Preliminary data suggest that in heart failure selective endothelin type A receptor antagonists (BQ-123, sitaxsentan) may be more beneﬁcial than non-selective antagonists, especially when there is associated pulmonary hypertension (11R ).

Susceptibility factors The effects of severe renal insufﬁciency on the pharmacokinetics and metabolism of bosentan 125 mg have been studied in an open, parallel-group study in eight patients with creatinine clearances 17–27 ml/min and in eight healthy subjects (creatinine clearances 99–135 ml/min) (16C ). The pharmacokinetics of bosentan did not differ signiﬁcantly, although the concentrations of the three CYP2C9- and CYP3A4-derived metabolites increased about two-fold in the patients with renal insufﬁciency. It is not necessary to adjust the dosage of bosentan in patients with any grade of renal insufﬁciency.

Biliary tract Bosentan can cause dose-dependent reversible cholestasis. The effects of bosentan and its main metabolites, both of which are eliminated in the bile, on biliary secretion have been studied in rats with biliary ﬁstulae and with or without a genetic defect in mrp2 (15E ). Intravenous bosentan 0.1–10 mg/kg caused a dose-dependent increase in biliary bilirubin excretion, and doses of 10 mg/kg or over caused a sustained increase in canalicular bile salt-independent bile ﬂow, combined with signiﬁcant increases in the concentrations and output of glutathione and of bicarbonate in the bile. Phospholipid and cholesterol secretion were profoundly inhibited and uncoupled from bile salt secretion. In mrp2-deﬁcient rats, the choleretic effect of bosentan was markedly reduced. Thus, bosentan alters canalicular bile formation mostly via mrp2-mediated mechanisms. Intermittent uncoupling of lipid from bile salt secretion may contribute to its hepatic adverse effects.

Tezosentan Nervous system The endothelin receptor antagonist tezosentan has been studied in single intravenous doses of 5, 20, 50, 100, 200, 400, and 600 mg for 1 hour in sequential groups of six men in a randomized, placebo-controlled, double-blind design (17c ). Headache was the most frequently reported adverse event and it was more common than with placebo at doses of 100 mg and over. There were no clinically important changes in vital signs, electrocardiography, or clinical laboratory tests. The volume of distribution at steady state, about 16 l, and the clearance, 30 l/hour, were independent of dose. Endothelin-1 concentrations increased dose- and concentration-dependently and returned slowly to baseline after the end of the infusion. During chronic double-blind, placebo-controlled infusion in healthy men of tezosentan 100 mg/hour for 6 hours in six subjects (total dose 600 mg) and 5 mg/hour for 72 h in eight subjects (total dose 360 mg), headache was the most common adverse event (75–100% with tezosentan and 50% with placebo) (18c ).

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DRUGS THAT ACT ON THE SYMPATHETIC NERVOUS SYSTEM (SED-14, 646; SEDA-23, 222; SEDA-24, 242; SEDA-25, 245)

PRESYNAPTIC ALPHA-ADRENOCEPTOR AGONISTS Clonidine

(SED-14, 646; SEDA-24, 242;

SEDA-25, 245) Cardiovascular In three patients with chronic schizophrenia and primary polydipsia given clonidine in doses of up to 800 micrograms/day for 2–5 months, blood pressure and pulse fell signiﬁcantly in a dose-dependent manner, but ﬂuid intake, as assessed by measurements of weight and 24-hour urine volume, was not affected (19A ). Hypotension and bradycardia limited the extent to which the dose of clonidine could be increased. The lack of effect of clonidine on polydipsia in this small sample and the inconsistent results of two other recent studies have provided little overall support for using clonidine to treat primary polydipsia associated with schizophrenia. Clonidine-induced hypertension has been reported in a patient with autonomic dysfunction (20A ). • A 39-year-old quadriplegic man with poorly controlled pain had many features consistent with autonomic dysfunction (e.g. a C4 spinal lesion, orthostatic hypotension, hypertension). He routinely used transdermal clonidine and transdermal glyceryl trinitrate as needed for control of acute hypertensive episodes. The clonidine was discontinued, after which his blood pressure fell (maximum systolic and diastolic pressures by about 50 and 25 mmHg respectively).

Because clonidine relies on central alpha2 adrenoceptor agonist activity for its hypotensive effects, it can cause hypertension in patients with autonomic dysfunction. It should therefore be used with great caution when autonomic dysfunction is suspected. Skin When transdermal clonidine is used to lower blood pressure, systemic adverse effects seem to be fewer than with oral clonidine (21R ).

Pieter Joubert

However, localized skin reactions are common, and the incidence increases with the dose and duration of use. Common signs include erythema, scaling, vesiculation, excoriation, and induration. Allergic contact dermatitis is less frequent but still common. Hyperpigmentation and depigmentation also occur. Pretreatment with 0.5% hydrocortisone is associated with less skin irritation and higher blood concentrations. Drug overdose The effects of exposure to clonidine hydrochloride in chldren, as reported to US poison centers from 1993 to 1999, have been retrospectively reviewed (22R ). There were 10 060 reported exposures, of which 57% were in children under 6 years, 34% in children aged 6–12 years, and 9% in adolescents aged 13–18 years. In 1999 there were 2.5 times as many exposures as in 1993. Clonidine was the child’s medication in 10% of those under 6 years, 35% of those aged 6–12 years, and 26% of the adolescents. Unintentional overdose was most common in those under 6 years, while therapeutic errors and suicide attempts predominated in those aged 6–12-years and the adolescents. In 6042 symptomatic children (60%), the most common symptoms were lethargy (80%), bradycardia (17%), hypotension (15%), and respiratory depression (5%). Most of the exposures resulted in no effect (40%) or minor effects (39%). There were moderate effects in 1907 children (19%), major effects in 230 (2%), and one death in a 23month-old child.

POSTSYNAPTIC ADRENOCEPTOR ANTAGONISTS (SED-14, 648; SEDA-23, 222; SEDA-24, 242; SEDA-25, 246) The pharmacokinetics, mode of action, use, efﬁcacy, and adverse effects of the selective alpha1 -adrenoceptor blockers doxazosin, prazosin, and terazosin in benign prostatic hyperplasia have been reviewed (23R ).

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Doxazosin (SED-14, 649; SEDA-23, 222; SEDA-24, 242; SEDA-25, 246) Phenoxybenzamine and doxazosin have been compared in 35 patients with pheochromocytoma (24c ). Hemodynamic, pharmacological, and biochemical indicators of alpha- and betaadrenoceptor blockade were measured before, during, and after anesthesia and surgery in eight patients pretreated with phenoxybenzamine and in 27 patients pretreated with doxazosin. Doxazosin (2–16 mg/day) was as effective as phenoxybenzamine in controlling arterial blood pressure and heart rate before and during surgery and it caused fewer adverse effects. Cardiovascular Recent data from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have shown that the risk of congestive heart failure is twice as high with doxazosin as with chlortalidone (25C ). Doxazosin, and probably all alpha-blockers, should no longer be used as ﬁrst-line in hypertension. Hypotension is a risk with doxazosin and has been reported to cause stroke (26A ). • A 64-year-old man developed a right hemiparesis after taking one dose of doxazosin 4 mg for prostatic symptoms. A CT scan of the brain and carotid ultrasound studies were normal. He recovered most of his neurological function within a few days. Ambulatory blood pressure monitoring after treatment with doxazosin 2 mg showed striking blood pressure reduction during sleep.

Drug formulations Doxazosin can cause a sharp fall in blood pressure at the start of therapy, and a modiﬁed-release formulation has been developed in an attempt to obviate this. In an open, non-comparative, sequential study in primary care, the ordinary formulation (1–16 mg/day for 3–6 months) was replaced by the modiﬁed-release formulation (4–8 mg/day for 3 months) in 3537 patients (27c ). The most common reasons for withdrawal from the study were loss to follow-up (37%) and adverse events (28%). Blood pressure fell from 160/95 to 139/82 mmHg with the ordinary formulation and to 135/79 mmHg

when the modiﬁed-release formulation was used instead. The most common adverse events were weakness, headache, dizziness, and hypotension, all of which were more common with the ordinary formulation; however, these differences could have been due to a healthy survivor effect, whereby those who had an adverse event early on (i.e. while taking the ordinary formulation) dropped out before taking the modiﬁed-release formulation, which would therefore appear to be safer. Thus, the lack of crossover in this study makes the results hard to interpret, although it appears that the two formulations were at worst no different from each other.

DIRECT VASODILATORS Hydralazine

(SED-14, 650; SEDA-21, 223; SEDA-25, 247) Skin A 44-year-old man taking hydralazine (dose not stated) developed a pruritic rash, attributed to a drug-induced lichenoid eruption, based on biopsy ﬁndings (28A ). The hydralazine was withdrawn and the rash resolved in a few weeks.

Minoxidil

(SED-14, 650; SEDA-22, 231; SEDA-24, 243; SEDA-25, 247; see also Chapter 14)

Cardiovascular Minoxidil can cause pericardial effusion, and another case has been reported (29A ). • A 52-year-old man with a history of chronic hypertension presented with worsening dyspnea and leg edema. He had been taking minoxidil for 10 years. The cardiac silhouette was markedly enlarged. Echocardiography and computed tomography showed a large pericardial effusion. Minoxidil was withdrawn and the effusion resolved within 1 month.

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REFERENCES 1. Ratliff NB, Pieranna F, Manganelli P. Captoprilinduced lupus. J Rheumatol 2002; 29: 1807–8. 2. Reidenberg MM, Case DB, Drayer DE, Reis S, Lorenzo B. Development of antinuclear antibody in patients treated with high doses of captopril. Arthritis Rheum 1984; 27: 579–81. 3. Parodi A, Cozzani E, Milesi G, Drosera M, Rebora A. Fosinopril as a possible pemphigus-inducing drug. Dermatology 2002; 204: 138–41. 4. Kränke B, Mayr-Kanhäuser S. Cold urticaria and angiotensin converting enzyme inhibitor. Acta Dermatol Venereol 2002; 82: 149–50. 5. Tosetti C. Angiotensin-converting enzyme inhibitors and diarrhoea. J Clin Gastroenterol 2002; 35: 105–6. 6. Ohkoshi N, Shoji S. Reversible ageusia induced by losartan: a case report. Eur J Neurol 2002; 9: 315. 7. Tabak F, Mert A, Ozaras R, Biyikli M, Ozturk R, Ozbay G, Senturk H, Aktuglu Y. Losartan-induced hepatic injury. J Clin Gastroenterol 2002: 34: 585– 6. 8. Neunteuﬂ T, Berger R, Pacher R. Endothelin receptor antagonists in cardiology clinical trials. Expert Opin Invest Drugs 2002; 11: 431–43. 9. Wu Wong JR. Endothelin receptor antagonists as therapeutic agents for cancer. Curr Opin Invest Drugs 2002; 3: 1234–9. 10. Chow M, Dumont AS, Kassell NF, Seifert V, Zimmermann M, Elliott JP, Awad IA, Dempsey RJ, Hodge Jr CJ. Endothelin receptor antagonists and cerebral vasospasm: An update. Neurosurgery 2002; 51: 1333–42. 11. Doggrell SA. The therapeutic potential of endothelin-1 receptor antagonists and endothelinconverting enzyme inhibitors on the cardiovascular system. Expert Opin Invest Drugs 2002; 11: 1537– 52. 12. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. New Bosentan therapy for pulmonary arterial hypertension. Engl J Med 2002; 346: 896–903. 13. Badesch DB, Bodin F, Channick RN, Frost A, Rainisio M, Robbins IM, Roux S, Rubin LJ, Simonneau G, Sitbon O, Tapson VF. Complete results of the ﬁrst randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension. Curr Ther Res Clin Exp 2002; 63: 227–46. 14. Kalra PR, Moon JCC, Coats AJS. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol 2002; 85: 195–7. 15. Fouassier L, Kinnman N, Lefevre G, Lasnier E, Rey C, Poupon R, Oude-Elferink RPJ, Housset C. Contribution of mrp2 in alterations of canalicular

bile formation by the endothelin antagonist bosentan. J Hepatol 2002; 37: 184–91. 16. Dingemanse J, Van Giersbergen PLM. Inﬂuence of severe renal dysfunction on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. Int J Clin Pharmacol Ther 2002; 40: 310–16. 17. Dingemanse J, Clozel M, Van-Giersbergen PLM. Entry-into-humans study with tezosentan, an intravenous dual endothelin receptor antagonist. J Cardiovasc Pharmacol 2002; 39: 795–802. 18. Dingemanse J, Clozel M, Van-Giersbergen PLM. Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects. Br J Clin Pharmacol 2002; 53: 355–62. 19. Delva NJ, Chang A, Hawken ER, Lawson JS, Owen JA. Effects of clonidine in schizophrenic patients with primary polydipsia: three single case studies. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 387–92. 20. Backo AL, Clause SL, Triller DM, Gibbs KA. Clonidine-induced hypertension in a patient with a spinal lesion. Ann Pharmacother 2002; 36: 1396–8. 21. Prisant LM. Transdermal clonidine skin reactions. J Clin Hypertens (Greenwich) 2002; 4: 136– 8. 22. Klein-Schwartz W. Trends and toxic effects from pediatric clonidine exposures. Arch Pediatr Adolesc Med 2002; 156: 392–6. 23. Akduman B, Crawford ED. Terazosin, doxazosin, and prazosin: current clinical experience. Urology 2001; 58 Suppl 1: 49–54. 24. Prys-Roberts C, Farndon JR. Efﬁcacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 2002; 26: 1037–42. 25. Messerli FH. Doxazosin and congestive heart failure. J Am Coll Cardiol 2001; 38: 1295–6. 26. Mansoor GA, Tendler BE. Stroke associated with alpha blocker therapy for benign prostatic hypertrophy. J Natl Med Assoc 2002; 94: 1–4. 27. Anegon M, Esteban J, Jimenez Garcia R, Sanz de Burgoa V, Martinez J, Gil de Miguel A. A postmarketing, open-label study to evaluate the tolerability and effectiveness of replacing standardformulation doxazosin with doxazosin in the gastrointestinal therapeutic system formulation in adult patients with hypertension. Clin Ther 2002; 24: 786–97. 28. Bargout R, Malhotra A. A 44-year-old man with a pruritic skin rash. Cleve Clin J Med 2001; 68: 952–3. 29. Shirwany A, D’Cruz IA, Munir A. Very large pericardial effusion attributable to minoxidil: resolution without drainage of ﬂuid. Echocardiography 2002; 19: 513–16.

Domenic A. Sica

21 Diuretics, diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included high-risk hypertensive patients aged 55 years or over. ALLHAT was a large simple trial, designed to mimic clinical practice in high-risk patients. Its goals were to determine whether the incidence of the primary outcome— a composite of fatal coronary heart disease and non-fatal myocardial infarction differed between treatment with a thiazide-like diuretic (chlorthalidone 12.5–25.0 mg/day), and treatment with each of three other types of antihypertensive drugs, a calcium channel blocker (amlodipine 2.5–10.0 mg/day), an angiotensinconverting enzyme inhibitor (lisinopril 10– 40 mg/day), and a peripheral α-adrenoceptor antagonist (doxazosin 1–8 mg/day). Secondary outcomes included all-cause mortality, stroke, and all major cardiovascular disease events. If patients did not meet the blood pressure goal with the maximum tolerated dose of the initial medication, an open-label Step 2 agent (atenolol 25–100-mg/day, reserpine 0.05–0.2 mg/day, or clonidine 0.1–0.3 mg bd) or an open-label Step 3 agent (hydralazine 25–100 mg bd) could be added (1C ). ALLHAT was the ﬁrst hypertension trial in which a large number of people with diabetes mellitus (15 297) were enrolled and prospectively designated for subgroup analyses. In ALLHAT there was no noteworthy difference between the diuretic chlortalidone and the other agents in primary or secondary outcomes between diabetic and non-diabetic patients. This suggests that diuretic-based therapy (without concurrent ACE inhibition or angiotensin © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Diuretics receptor blocker therapy) could be as protective as ACE inhibitor-based therapy (without concurrent diuretic therapy) in high-risk patients similar to those studied in ALLHAT. Because many studies have shown the beneﬁts of ACE inhibitors on multiple adverse outcomes in patients with diabetes, including both macrovascular and microvascular complications, in patients with either mild or more severe hypertension and in both type 1 and type 2 diabetes, the established practice of choosing an ACE inhibitor as the ﬁrst-line agent in most patients with diabetes is still reasonable. ALLHAT showed a sizeable difference between drug classes in the incidence of newonset diabetes (fasting glucose over 126 mg/dl or 7 mmol/l). Those who took an ACE inhibitor, a calcium channel blocker, or a diuretic had 4-year incidences of new-onset diabetes of 8.1, 9.8, and 11.6% respectively. In ALLHAT the favorable effect on outcomes with diuretic therapy occurred despite this greater tendency for glucose homeostasis to deteriorate to frank diabetes. However, in ALLHAT there was a very short period of time for observation of these “newly” developed diabetics, and the long-term risk of diabetes has yet to be deﬁned. Whether, and if so to what degree, an ACE inhibitor or an angiotensin receptor blocker modiﬁes the risk of thiazide-induced diabetes is still unclear; despite this lack of proven beneﬁt it may be advisable to use one of the other of these drug classes as a second antihypertensive medication in patients who are thought to be at risk of diabetes and being considered for diuretic therapy. The presumption is that these drug classes reduce the risk of new-onset diabetes and would thereby minimize the risk from diuretic therapy. In the ALLHAT study the diuretic used was chlorthalidone. The question arises of whether the results of the study can be accepted as evidence for a class-effect for all thiazide-like diuretics. This is a complicated question to answer. It is commonly appreciated that loop diuretics can be differentiated from thiazide-like

219

220 diuretics in terms of diuretic potency (based on their site of action) and that they also have different blood pressure reducing effects. What is less well appreciated is that thiazide diuretics can have different pharmacokinetic properties, in part dictating their patterns of response. For example, chlortalidone is a fairly long-acting diuretic, with a greater tendency than hydrochlorothiazide to reduce extracellular volume and generate electrolyte abnormalities, such as hypokalemia. This being said, the incidence of hypokalemia (below 3.5 mmol/l) was low in the chlorthalidone-treated cohort in ALLHAT—12.7 and 8.5% at the 2-year and 4-year follow-up visits respectively. Hypokalemia is a deceptive term when used to describe the effect of a diuretic, since to be hypokalemic means that the serum potassium concentration has fallen below some threshold value (typically 3.5 mmol/l). If the threshold concentration is not reached, the deﬁnitional criterion is not satisﬁed and patients can then be described only in terms of the absolute fall in serum potassium concentration. In this regard, the chlorthalidone-treated subjects had an overall fall in serum potassium concentration from 4.3 to 4.0 mmol/l at the 2-year follow-up visit. This represents a significant fall in the population average for serum potassium and is consistent with the more prolonged action of chlorthalidone. The relevance of this ﬁnding to the ﬁndings of the ALLHAT trial requires further study.

CARBONIC ANHYDRASE INHIBITORS (SED-14, 669; SEDA-24, 249; SEDA-25, 249; SEDA-26, 238)

Acetazolamide Musculoskeletal A 46-year-old man with hypokalemic periodic paralysis and diabetes mellitus had worse muscle weakness after taking acetazolamide, possibly because of reduced muscle uptake of potassium (2A ).

Dorzolamide In a 3-month prospective study of the adverse effects and efﬁcacy of topical dorzolamide in 39

Chapter 21

Domenic A. Sica

patients intolerant of systemic carbonic anhydrase inhibitors, the effect on mean intraocular pressure was similar to that of acetazolamide, and health assessment scores improved significantly in seven of the eight categories of the SF-36 health assessment questionnaire, used to evaluate changes in well-being and quality of life (3c ). There were no adverse effects with the switch in medication. Electrolyte balance Electrolyte abnormalities, such as metabolic acidosis, have not been previously described with the topical carbonic anhydrase inhibitor dorzolamide. • A 5-day-old boy, weighing 2.3 kg, developed a metabolic acidosis after receiving topical dorzolamide for 1 week for bilateral Peter’s anomaly (a congenital corneal disorder characterized by a central leukoma and adhesions at the periphery of the corneal opacity) (4A ). The maximum base deﬁcit was 20.2 mmol/l. On withdrawal of topical dorzolamide his acidosis resolved within 1 day.

Factors that may have contributed to this metabolic acidosis included low birth weight, renal tubular immaturity, and impaired renal function, which may have resulted in systemic accumulation with repetitive dosing. This case stresses the fact that topical medications can cause systemic effects if a sufﬁcient amount of drug is absorbed in a susceptible subject.

THIAZIDE AND LOOP DIURETICS (SED-14, 656; SEDA-24, 250; SEDA-25, 252; SEDA-26, 239) Respiratory The risks and beneﬁts of distal tubular diuretics have been assessed in preterm infants under 3 weeks of age with or developing chronic lung disease (5c ). Acute and chronic administration of distal diuretics improved pulmonary mechanics; adverse effects were not reported. However, additional studies are needed to assess whether thiazide administration improves mortality, duration of oxygen dependency, ventilator dependency, length of hospital stay, and long-term outcome in patients exposed to corticosteroids and bronchodilators, and whether adding spironolactone to thiazides or adding metolazone to furosemide has any beneﬁcial effect.

Diuretics

221

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Urinary tract Acute renal insufﬁciency carries a high morbidity and mortality. Diuretics continue to be used in this setting, despite absence of evidence of beneﬁt. In a cohort study of 552 patients with acute renal insufﬁciency studied from 1989 to 1995 diuretic use was associated with a signiﬁcant increase in the risk of death or non-recovery of renal function (6C ). This increased risk was largely borne by patients who were relatively unresponsive to diuretics. Although this study was observational, which prohibits causal inference, it is unlikely that diuretics afford any material beneﬁt in the setting of acute renal insufﬁciency. The widespread use of diuretics in critically ill patients with acute renal insufﬁciency should be discouraged.

ALDOSTERONE RECEPTOR ANTAGONISTS (SED-14, 674; SEDA-24, 251; SEDA-25, 254; SEDA-26, 240)

Eplerenone Sexual function Gynecomastia, impotence, and menstrual abnormalities occur with spironolactone and can preclude its continued use. A new aldosterone receptor antagonist, eplerenone, has now been reported to produce less gynecomastia than spironolactone (10C , 11C ). In patients with gynecomastia from spironolactone, eplerenone can be substituted and gynecomastia status reassessed.

Spironolactone Skin A 77-year-old man developed a ﬂorid photosensitive lichenoid eruption, histologically conﬁrmed, while taking thiazide diuretics for heart failure (7A ). The eruption cleared on withdrawal of the drug. Although thiazideinduced photosensitivity is well documented, there have been no histologically proven cases of a lichenoid eruption in light exposed areas. Immunologic Non-life-threatening skin and bone-marrow reactions to sulfa-type diuretics can occur. A history of such a reaction often complicates the use of diuretics, in that ethacrynic acid is the only available non-sulfaderived loop/thiazide diuretic. A furosemide rechallenge protocol, based on a method that has been used to rechallenge with a sulfacontaining antimicrobial agent, safely allowed the long-term reinstitution of loop diuretic therapy with furosemide (8A ). Drug interactions A 60-year-old woman developed moderately severe sensorineural hearing loss bilaterally after receiving ﬁve doses of gentamicin (total 2350 mg) and one of furosemide 20 mg (9A ). The cumulative dose and duration of aminoglycoside therapy are more important than serum concentrations in the development of gentamicin ototoxicity, except when interacting medications such as furosemide are co-administered.

Electrolyte balance Spironolactone is increasingly used for its antiproliferative and antiﬁbrotic effect in patients with congestive heart failure, and now in patients with end-stage renal disease undergoing either peritoneal (12A ) or maintenance hemodialysis (13A ), although there is scant experimental evidence to support such use in advanced dialysis-dependent renal disease. Carefully selected dialysis patients exposed to doses of spironolactone ranging from 25 mg three times a week to 25 mg/day appeared not to have an increased frequency of hyperkalemia. However, these studies were preliminary and the results should not be extrapolated to the general dialysis population. If spironolactone is contemplated in patients with end-stage renal disease, periodic surveillance is necessary and other causes of hyperkalemia, such as ACE inhibitor therapy and/or a high potassium intake, should be controlled. Hematologic Agranulocytosis has been attributed to spironolactone (14A ). • A 43-year-old woman with cirrhosis and hepatocellular carcinoma took spironolactone for 7 days before leukopenia was detected. The leukocyte count returned to normal 8 days after withdrawal of spironolactone. Unlike many of the previously reported cases this one did not involve concurrent administration of furosemide.

This case illustrates the quick onset and equally quick recovery from this hematologic effect of spironolactone.

222 Drug interactions In a population-based, nested, case–control study all patients aged 66 years or over who were taking an ACE inhibitor and who had been hospitalized for hyperkalemia were evaluated for interacting medications (15C ). Compared with controls taking ACE inhibitors who did not have hyperkalemia, before adjusting for confounding variables, the patients were 27 times more likely to have received a prescription for a potassium-sparing diuretic (type not speciﬁed) in the week before hospitalization. There was no such association between hospital admission for hyperkalemia and the use of indapamide in patients taking ACE inhibitors. Interference with diagnostic tests Spironolactone interferes with the analytical determination of digoxin, and falsely low results are commonly observed. Several modern digoxin assays suffer from potentially negative interference from aldosterone receptor antagonists, such as spironolactone and potassium canrenoate (16M ). This analytical interference may allow true toxic digoxin concentrations to go unrecognized and increase the chance of intoxication should the dosage of digoxin be increased because of falsely low values. Assays that have been recently developed may be less prone to interference by spironolactone (17E ). Laboratories should determine the false negative potential of the analytical method that they use.

POTASSIUM-SPARING DIURETICS (SED-14, 674; SEDA-24, 251; SEDA-26, 240)

Amiloride

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Domenic A. Sica

treated with a combination of a thiazide and a potassium-sparing diuretic, without consensus on the preferred potassium-sparing diuretic. A Japanese adult was recently systematically studied to determine the renal effects of hydrochlorothiazide plus amiloride and hydrochlorothiazide plus triamterene (18A ). The combination with amiloride was superior to that with triamterene in preventing excessive urinary potassium loss, hypokalemia, and metabolic alkalosis. These results suggest that amiloride is the preferred add-on therapy to hydrochlorothiazide in nephrogenic diabetes insipidus.

OSMOTIC DIURETICS (SED-14, 1162, 1236)

Mannitol Urinary tract Four cases of acute renal insufﬁciency have been described in a series of men aged 20–42 years who received mannitol 1172 (SD 439) g over 58 (28) hours (19A ). The onset of acute renal insufﬁciency was detected 48 (22) hours after the start of infusion. All the patients had dilutional hyponatremia (average 120 mmol/l), and serum hyperosmolality (osmolar gap 70 mosm/kg water). In the three anuric cases, in which hemodialysis was performed, there was immediate recovery of diuresis. This emphasizes the risk of renal insufﬁciency with mannitol and stresses the importance of early hemodialysis. Mannitol is dialysable and once its suppressive effect on renal perfusion is eliminated functional recovery is prompt.

Electrolyte balance Patients with congenital nephrogenic diabetes insipidus are often

REFERENCES 1. The ALLHAT Ofﬁcers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor therapy or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-

Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Am Med Assoc 2002; 288: 2981–97. 2. Ikeda K, Iwasaki Y, Kinoshita M, Yabuki D, Igarashi O, Ichikawa Y, Satoyoshi E. Acetazolamideinduced muscle weakness in hypokalemic periodic paralysis. Intern Med 2002; 41: 743–5.

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3. Nesher R, Ticho U. Switching from systemic to the topical carbonic anhydrase inhibitor dorzolamide: effect on the quality of life of glaucoma patients with drug-related side effects. Isr Med Assoc J 2003; 5: 260–3. 4. Morris S, Geh V, Nischal KK, Sahi S, Ahmed MA. Topical dorzolamide and metabolic acidosis in a neonate. Br J Ophthalmol 2003; 87: 1052–3. 5. Brion LP, Primhak RA, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons Ltd. 6. Mehta RL, Pascual MT, Soroko S, Chertow GM. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. J Am Med Assoc 2002; 288: 2547–33. 7. Johnson GA. Thiazide-induced lichenoid photosensitivity. Clin Exp Dermatol 2002; 27: 670–2. 8. Earl G, Davenport J, Narula J. Furosemide challenge in patients with heart failure and adverse reactions to sulfa-containing diuretics. Ann Intern Med 2003; 138: 358–9. 9. Bates DE, Beaumont SJ, Baylis BW. Ototoxicity induced by gentamicin and furosemide. Ann Pharmacother 2002; 36: 446–51. 10. Burgess ED, Lacourciere Y, Ruilope-Urioste LM, Oparil S, Kleiman JH, Krause S, Roniker B, Maurath C. Long-term safety and efﬁcacy of the selective aldosterone blocker eplerenone in patients with essential hypertension. Clin Ther 2003; 25: 2388–404. 11. Hollenberg NK, Williams GH, Anderson R, Akhras KS, Bittman RM, Krause SL. Symptoms and the distress they cause: comparison of an aldos-

223 terone antagonist and a calcium channel blocking agent in patients with systolic hypertension. Arch Intern Med 2003; 163: 1543–8. 12. Hausmann MJ, Liel-Cohen N. Aldactone therapy in a peritoneal dialysis patient with decreased left ventricular function. Nephrol Dial Transplant 2003; 17: 2035. 13. Hussain S, Dreyfus DE, Marcus RJ, Biederman RW, McGill RL. Is spironolactone safe for dialysis patients? Nephrol Dial Transplant 2003; 18: 2364–8. 14. Hsiao SH, Lin YJ, Hsu MY, Wu TJ. Spironolactone-induced agranulocytosis: a case report. Kaohsiung J Med Sci 2003; 19: 574–8. 15. Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug–drug interactions among elderly patients hospitalized for drug toxicity. J Am Med Assoc 2003; 289: 1652–8. 16. Steimer W, Muller C, Eber B. Digoxin assays: frequent, substantial, and potentially dangerous interference by spironolactone, canrenone, and other steroids. Clin Chem 2002: 48: 507–16. 17. Datta P, Dasgupta A. A new turbidometric digoxin immunoassay on the ADIVA 1650 Analyzer is free from interference by spironolactone, potassium canrenoate, and their common metabolite canrenone. Ther Drug Monit 2003; 25: 478–82. 18. Konoshita T, Kuroda M, Kawane T, Koni I, Miyamori I, Tofuku Y, Mabuchi H, Takeda R. Treatment of congenital nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride in an adult patient. Horm Res 2004; 61: 63–7. 19. Perez-Perez AJ, Pazos B, Sobrado J, Gonzalez L, Gandara A. Acute renal failure following massive mannitol infusion. Am J Nephrol 2002; 22: 573–5.

Gijsbert B. van der Voet and Frederik A. de Wolff

22 Aluminium

(SED-14, 683; SEDA-24, 253; SEDA-25, 257; SEDA-26, 243)

The role of aluminium as a neurotoxin continues to be investigated (1R ), including its role in Alzheimer’s disease (2R , 3R ). However, more attention is being paid to the adverse effects of aluminium salts as adjuvants in vaccines. Although aluminium adjuvants have proven to be safe over six decades, adverse effects, such as erythema, subcutaneous nodules, and contact hypersensitivity, sometimes occur (4R ). The aluminium body burden has been estimated in infants during the ﬁrst year of life for a standard immunization schedule compared with breast milk and formula diets (5R ). The calculated body burden of aluminium from immunization exceeds that from dietary sources, but is still below the minimal risk level equivalent curve during the brief period after injection. Neuromuscular function Recently two cases of macrophagic myofasciitis have been reported in relation to immunization using an aluminium-based vaccine (6A ). • A 5-year-old boy with chronic intestinal pseudoobstruction required night-time parenteral nutrition. He had abnormal pupillary reﬂexes and urinary retention, suggesting diffuse dysautonomia. A 3-year-old child had developed delay and hypotonia. Both children had received ageappropriate immunizations. Quadriceps muscle biopsies showed the typical patchy, cohesive, centripetal inﬁltration of α-1-antitrypsin+ , α-antichymotrypsin+ , CD68+ , PAS+ , CD1a− , S-100− , factor XIII− granular macrophages with adjacent atrophy of myoﬁbers, dilated blood vessels, and mild endomysial and perimysial ﬁbrosis. There was no myonecrosis and no discrete granulomas. There was a single aluminium peak on energy dispersive X-ray microanalysis. Most infectious causes leading to macrophage activation were © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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Metals ruled out, thus implicating aluminium. Both patients improved gradually with time.

Antimony (SED-14, 683; SEDA-24, 254; SEDA-25, 258; SEDA-26, 244) Antimony compounds, especially pentavalent ones, continue to be used in the treatment of the different forms of leishmaniasis as primary therapy (7R ). However, more attention is being paid to the anticancer potential of antimony compounds (8E , 9R ). Cardiovascular Common adverse effects of antimony treatment include anorexia, nausea, vomiting, muscle ache, headache, lethargy, and bone and joint pain. Changes in the electrocardiogram depend on the cumulative dose of antimony, and sudden death may be related to this; this cumulative effect seldom occurs but is a risk (10A ). • A 4-year-old boy with visceral leishmaniasis was given intravenous sodium stibogluconate 20 mg/ kg/day (1200 mg/day) and oral allopurinol 16 mg/kg/day (100 mg tds). On day 3 he reported chest pain and a persistent cough. Electrocardiography was unremarkable. The drugs were withdrawn and 3 days later he developed petechial rashes on the legs. Sepsis and other causes of petechial rashes were ruled out. Three days after treatment was discontinued he developed ventricular ﬁbrillation and died.

The authors suggested that patients taking antimony compounds should be observed cautiously for signs of cardiological and hematological changes.

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Chapter 22

Arsenic (SED-14, 686; SEDA-24, 254; SEDA-25, 258; SEDA-26, 244) Arsenic compounds are used in the treatment of acute promyelocytic leukemia, chronic myelogenous leukemia, and multiple myeloma (11R ). The use of arsenical paste in dentistry and consumption of indigenous medicines that contain arsenic as contaminants can cause arsenic toxicity. Nervous system In a recent case of a rapidly progressive neuropathy with arsenic, a contributory role of thiamine deﬁciency was implied (12A ). • A 46-year-old woman with acute promyelocytic leukemia was given arsenic trioxide 10 mg/day for 28 days. On day 33 she complained of numbness in the legs and on day 37 all four limbs were paralyzed and areﬂexic. Her speech was inaudible and she had bulbar paralysis. Nerve conduction studies showed a generalized reduction in sensory action potentials. Thiamine deﬁciency was conﬁrmed and she was given parenteral thiamine (100 mg/day). By the next day the power in her arms had dramatically improved and her speech had become audible. Over the next 5 days, she regained full power in the arms. Subsequently she was given arsenic trioxide 5 mg/day for 28 days with oral thiamine, without neurological deterioration this time. The power in her legs continued to improve.

The members of a family in India, in the business of preparing and manufacturing indigenous medicines containing arsenicals, consumed a home-made vitalizer for health which accidentally got contaminated with arsenicals (13A ). • A 50-year-old woman developed severe vomiting, abdominal colic, and diarrhea, which persisted for 5–6 days and 2 weeks later developed tingling, numbness, paresthesia, and gradually progressive weakness of all four limbs. She had gross hyperpigmentation of the face, arms, and upper chest, hyperkeratosis of the palms, and transverse white lines (Mees’ lines) in the ﬁnger nails. She had a symmetrical, predominantly distal, peripheral sensorimotor neuropathy in all four limbs. Meanwhile, her 52-year-old husband and her 28-year-old son developed severe gastrointestinal problems. Her husband died within 48 hours of onset and the son developed severe wasting, weakness, and a sensorimotor ﬂaccid quadriparesis, similar to that of his mother. Two younger sons, aged 22 and 20 years, and an 18-year-old daughter were out of town but returned after the death of their father. They also developed severe

225 diarrhea, vomiting, abdominal pain, and tingling of the hands and feet within 2–3 weeks. Arsenic concentrations were found in the hair and nails, and the concentrations were directly proportional to the severity of the illness. They were given dimercaprol, and 6 months later all had signiﬁcant clinical improvement.

Musculoskeletal The use of arsenical paste in dental medicine can lead to severe toxicity. Severe alveolar bone necrosis has been reported as a result of leakage of an arsenical devitalization paste into the periodontium (14A ). • An 18-year-old woman with dental pain had a tooth devitalized with an arsenical paste and soon after developed excruciating pain and denudation of bone. She had slightly inﬂamed gums and loss of the mesial papillary gingivae. The surrounding bone was exposed to a height of 3–4 mm and the exposed bone had a greyish color. The non-vital tooth was preserved by root canal treatment and ﬂap surgery to remove necrotic bone and the associated root, and 3 months later a deﬁnitive cuspal coverage restoration was placed over the tooth. At 1 year the patient reported that the tooth was functional without any problems.

Bismuth (SED-14, 686; SEDA-24, 255; SEDA-25, 259; SEDA-26, 244) Bismuth compounds continue to be used for gastrointestinal disorders, including eradication of Helicobacter pylori. Bismuth iodoform parafﬁn paste is commonly used in ear, nose, and throat surgery and in oral and maxillofacial surgery. A new area for the use of bismuth compounds may be in oncology as anticancer agents (9R ). Nervous system Encephalopathy has been attributed to bismuth. • A 49-year-old woman with chronic gastric ulcers and 5 years of bismuth abuse developed bismuth encephalopathy, with progressive dementia, dysarthria, and myoclonic jerks 1 week after increasing the dosage of bismuth (15A ). Electroencephalography showed generalized spike–wave complexes, suggesting that the myoclonus was epileptic in nature. Bismuth was withdrawn and she was given valproate, which reduced the frequency of the myoclonic jerks. Administration of the chelator dimercaptopropane sulfonic acid (DMPS) enhanced bismuth elimination but aggravated the clinical symptoms and it was therefore withdrawn. She slowly recovered.

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• An 86-year-old woman underwent partial maxillectomy for squamous cell carcinoma of the right alveolus and hard palate, and the maxillary antrum was packed with a length of bismuth iodoform parafﬁn paste (16A ). Postoperatively she developed delirium and by day 5 was exhausted, lightheaded, and unsteady. She became increasingly aggressive and by day 11 was eating very little and having fainting episodes. Worsening confusion and some paranoid ideation was apparent and tremor was pronounced, but there were no focal neurological signs. The bismuth iodoform parafﬁn pack was removed on day 14 and 7 days later she had improved and was very cooperative and alert when she was discharged 5 days later. The bismuth serum concentration on day 14 was 146 nmol/l (reference range 0–4 nmol/l) and on day 22 was 81 nmol/l. The original peak bismuth concentration was extrapolated to over 300 nmol/l.

Urinary tract Renal damage has been reported in two cases of bismuth overdose. • A 17-year-old girl took 25 tablets of bismuth subcitrate 300 mg (total 7.5 g) in a suicide attempt and developed severe renal insufﬁciency (17A ). Renal biopsy showed evidence of acute tubular necrosis, with epithelial ﬂattening, lumen widening, and atrophic changes in the convoluted tubules and mononuclear cell inﬁltration and edema in the interstitium. She was managed with hemodialysis and recovered. • A 22-year-old woman took 5.4 g of colloidal bismuth subcitrate in a suicide attempt and developed Fanconi’s syndrome and acute renal insufﬁciency (18A ). She received hemodialysis and intravenous sodium 2,3-mercapto-1-propanesulfonate 60 hours after intoxication. Her serum bismuth concentrations fell from 640 μg/l to 15 μg/l within 6 days, her renal function improved, and her tonsillar ulceration healed. Hemodialysis was discontinued on day 14. She had normal renal function 6 weeks later.

Immunologic Anaphylaxis to bismuth subsalicylate (Pepto-Bismol) has been observed for the ﬁrst time (19A ). • A 25-year-old man with symptoms of acute gastroenteritis took PeptoBismol, a total of 8 caplets over 6 hours. About 30 minutes after the last dose, he developed generalized acute urticaria. He had previously tolerated PeptoBismol well, but presumably had become sensitized. He was successfully treated with intravenous ﬂuids and histamine H1 receptor antagonists.

Gijsbert B. van der Voet and Frederik A. de Wolff

Chromium (SED-14, 683; SEDA-24, 255; SEDA-25, 259; SEDA-26, 245) Trivalent chromium compounds (i.e. chromium chloride, chromium nicotinate, and chromium picolinate) are traditionally used as nutritional supplements or support medication in diabetes (for their positive effects on insulin, hemoglobin, and coronary artery disease), and chromium-51 is a radiopharmaceutical. Liver There has been a report of liver damage caused by chromium toxicity (20A ). • A 35-year-old woman complained of nausea, fatigue, pruritus, dark urine, pale stools, and jaundice after taking an supplement containing chromium picolinate for weight loss. Infectious hepatitis was excluded and a liver biopsy was consistent with toxic liver damage. Hepatic chromium concentrations were more than 10 times normal. The chromium supplement was withdrawn and she received supportive treatment with a suspension containing “natural products”, cholestyramine 1 g qds, and hydroxyzine 25 mg tds and fully recovered in 3 months.

Carcinogenicity Hexavalent chromium compounds have no medical uses and are known as mutagens and carcinogens (21R ). In an in vitro study the coordination of chromium by picolinate ligands made chromium picolinate more toxic to cultured cells, leading to enhanced apoptosis (22E ). These observations support the hypothesis that chromium picolinate is a human carcinogen.

Copper (SED-14, 688; SEDA-24, 256; SEDA-25, 259; SEDA-26, 245) There is a host of literature on the molecular mechanism of Wilson’s disease, including the role of copper (23R , 24R ). Copper has also been reported to have a role in neurodegenerative diseases (Alzheimer’s disease, familial amyotrophic lateral sclerosis, prion disease) (25R ). The medically used copper compounds (copper chloride, copper gluconate in common nutritional supplements, and copper histidine in Menkes’ disease) have not caused any newly reported adverse effects. The potential use of novel chelating agents for copper isotopes with short half-lives in radiopharmacy has been discussed (26E ).

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Reproductive system The use of coppercontaining intrauterine contraceptive devices is often reviewed, without any new information on adverse effects of copper (27R ). • A 32-year-old woman, who had a copper intrauterine contraceptive device for more than 5 years, developed acyclic menstrual bleedings and had a uterine biopsy after removal of the intrauterine device (28A ). Histology of the abraded tissue showed an actinomycotic endometritis, with brown to black deposits in or around typical Actinomyces druses, but there was no carcinoma. Electron microscopy showed copper deposits in the shell and matrix of the druses and inside the bacteria. Electron-dense accumulations showed high signals for copper and sulfur, and to a lesser extent also for phosphorus and oxygen.

Copper accumulation in this case may have been caused by active uptake and concentration by the Actinomycetes.

Respiratory Gold-induced lung toxicity is a infrequent adverse effect in patients with rheumatoid arthritis and psoriatic arthritis. There are three types: interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, and bronchiolitis obliterans; the ﬁrst is the most frequent. There have been two reports of gold-induced lung toxicity in psoriatic arthritis (32A ). • A 54-year-old woman with psoriatic polyarthritis was treated with aurothiomalate 50 mg/week. When the cumulative dose reached 250 mg she developed weakness, dyspnea, fever, nausea, vomiting and erythematous skin lesions. Chest X-ray and CT scan showed diffuse interstitial pneumonitis. Gold was withdrawn and she was given prednisone 60 mg/day. She recovered in 6 months. • A 62-year-old woman with psoriatic arthritis was given aurothiomalate 50 mg/week. After a cumulative dose of 135 mg she developed an itchy rash, dyspnea, and fever. Chest X-ray and CT scan suggested pneumonitis and she was given prednisone 40 mg/day. She recovered in 6 months.

Gallium

(SED-14, 690; SEDA-24, 256; SEDA-25, 260; SEDA-26, 245)

Gallium compounds are used in cancer treatment, and the anticancer activity of new compounds, such as gallium maltolate, doxorubicin gallium transferrin conjugate, and trisquinolinolato gallium, is being explored (29R ). Gallium-67 isotope scintigraphy is of great importance in diagnostic imaging, although diagnostic outcomes may sometimes be difﬁcult to interpret. Gallium alloys are still considered to be better alternatives to amalgams in dental medicine in spite of their tendency to corrosion, their controversial biocompatibility, and lack of knowledge about gallium’s environmental impact (30R ).

Gold

(SED-14, 690; SEDA-24, 257; SEDA-25, 260; SEDA-26, 245) The use of gold compounds in arthritic diseases and the use of gold alloys in dental medicine has produced a host of reports on mucocutaneous adverse effects without any new observations. The antitumor activity of novel gold compounds is being pursued (31R ).

Iron

(SED-14, 697; SEDA-24, 257; SEDA-25, 260; SEDA-26, 247)

The molecular basis of iron overload and toxicity has been reviewed (33R , 34R ). Much attention has been paid to mechanisms of hemochromatosis (35R , 36R ). No new adverse effects of the various compounds of iron have been reported. However, current research is concentrating on their comparative tolerance and safety (37C ) and their use in very speciﬁc conditions, such as renal insufﬁciency (38C ). Respiratory Lung damage has been reported in a man who had inhaled an oral iron formulation containing 350 mg of elemental iron (39A ). • A 75-year-old man developed chest discomfort and hemoptysis. A chest X-ray showed left lower lobe collapse and ﬁbreoptic bronchoscopy showed that the left endobronchial mucosa was friable, edematous, and golden-yellow, with interspersed erythematous ulcerated areas with marked contact bleeding. There was heavy deposition of yellow brown pigment on the basement membrane of the superﬁcial bronchial epithelium, on the basement membrane of the bronchial glands, and on ﬁbrillar material in the stroma. Pigment deposition was greatest in the necrotic fragments of mucosa,

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but was also seen in viable mucosa. This material stained strongly for ferric ion with Perls’ stain. Iron was withdrawn and the left lower lobe collapse improved.

Urinary tract Iron deﬁciency is a common and important cause of poor response to erythropoietin in patients with severe chronic renal insufﬁciency, in whom oral iron supplements fail to correct iron deﬁciency (38C ). Ferric gluconate has a low adverse effects proﬁle, but the recommended dose of 62.5–125 mg per treatment is not practical for patients who are not on hemodialysis. In a retrospective analysis of the incidence of adverse effects associated with 250 mg of ferric gluconate infused over 1–4 hours in 40 patients with severe chronic renal insufﬁciency, who received 79 treatments, four treatments in two patients were associated with adverse effects, including diarrhea, vomiting, low back pain, hypotension, and a burning sensation in the feet. The duration of the infusion did not inﬂuence the adverse effects proﬁle. Immunologic Iron dextran administration is associated with a high incidence of adverse reactions, including anaphylaxis and death (37C ). Although it is the dextran rather than the iron that is believed to be the cause of these reactions, it is not known whether patients who are sensitive to iron dextran can be safely given another form of parenteral iron, sodium ferric gluconate in sucrose. In a double-blind, controlled trial sodium ferric gluconate in sucrose or placebo was given to 144 iron dextransensitive patients for comparison with 2194 patients who had been tolerant to iron dextran. Serum tryptase concentrations were also measured. Of 144 patients who were sensitive to iron dextran and who were exposed to sodium ferric gluconate in sucrose, three were intolerant; all had suspected allergic reactions, including one with a serious reaction. One dextran-sensitive patient had a suspected allergic reaction after placebo. In contrast, among the 2194 iron dextran-tolerant patients, reactions to sodium ferric gluconate in sucrose were signiﬁcantly less common, with intolerance in seven patients, including ﬁve who had suspected allergic events, but none who had serious events. Two iron-dextran tolerant patients had allergic-like reactions to placebo. Two of the three suspected allergic events in the iron dextran-sensitive group were conﬁrmed as mast

Gijsbert B. van der Voet and Frederik A. de Wolff

cell-dependent, by a 100% increase in serum tryptase, while there were no conﬁrmed allergic events in the iron dextran-tolerant group. Long-term exposure to sodium ferric gluconate in sucrose in iron dextran-sensitive patients resulted in intolerance in only one additional patient and no serious adverse events. Patients with a history of iron dextran sensitivity had about seven-fold higher rates of reaction to both placebo and sodium ferric gluconate in sucrose compared with iron dextran-tolerant patients. However, logistic regression analysis, performed to account for the higher reaction rate to placebo, suggested that this increased reactivity was neither drug-speciﬁc nor immunologically mediated, but represented host idiosyncrasy. These results support the conclusions that reactions to sodium ferric gluconate in sucrose can be attributed to pseudoallergy, and that it is not a true allergen.

Lead

(SED-14, 701; SEDA-24, 258; SEDA-25, 261; SEDA-26, 248) Herbal medicines, often from Asian manufacture, are sources of lead, and can cause poisoning. The actual symptoms are not new, but their unexpected occurrence can be misleading. Fetotoxicity Intrauterine lead intoxication has been reported.

• A 24-year-old pregnant woman, who had recently emigrated from India, had periodically over the course of 9 years taken tablets prescribed by an Ayurvedic doctor for a gastrointestinal complaint. The tablets had a high lead content. She presented at 30 weeks’ gestation with abdominal pain and progressive confusion, culminating in seizures (40A ). Her erythrocytes showed typical basophilic stippling and her blood lead concentration was 5.2 μmol/l (reference range 0.06–0.6 μmol/l). She was given intramuscular dimercaprol and intravenous calcium disodium edetate and 36 hours later had an antepartum hemorrhage; labor was induced and she gave birth by vaginal delivery to a 1.6 kg girl, who was ﬂaccid and areﬂexic and did not move in response to noxious stimuli, but had spontaneous ocular movements. She had bilateral diaphragmatic palsy. The cord blood lead concentration was 7.6 μmol/l, the erythrocyte porphyrin concentration was 20 μmol/l (reference range 0.4–1.7 μmol/l), and radiography of the long bones showed increased bone density adjacent to the metaphyses. The infant was given chelation

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with dimercaprol (4 mg/kg every 4 hours) and intravenous calcium disodium edetate 50 mg/kg. The blood lead concentration initially rose to 12 μmol/l and then fell rapidly over the next few days. A high urinary lead concentration on day 4 (52 μmol/l) showed that lead was being excreted. Facial, bulbar, proximal limb, and diaphragmatic muscle activity improved.

Manganese

(SED-14, 702; SEDA-24, 259; SEDA-25, 261; SEDA-26, 248) Occupational exposure to manganese counts for many reports of poisoning, including neurotoxicity (1R ). Although manganese compounds are used medically as nutrients and also as diagnostic agents in biomedical imaging, no new adverse effects have been reported.

Mercury (SED-14, 702; SEDA-24, 260; SEDA-25, 262; SEDA-26, 248) The neurotoxicity of amalgams is still controversial. Reports of the toxicity of mercury are often of an occupational or environmental nature. Nephrotoxicity and neurotoxicity of mercury are common, although the exposure route is sometimes remarkable, as in one case in which it resulted from the use of an ointment (41A ). Urinary tract Membranous glomerulonephritis has been attributed to mercury in a patient with diabetes mellitus. • A 21-year-old man with a 16-year history of diabetes mellitus, who had been using an ointment containing 10% mercuric ammonium chloride for eczema for about 3 weeks, became tired, with fasciculation in the limbs and poor control of his diabetes (41A ). Nephrotic syndrome and hypertension were diagnosed 1 month later, and at 2 months he was very weak with tremor of the hands, was almost unable to walk, and had lost 20 kg. His behavior suggested an acute psychosis. The urine mercury concentration was 250 μg/l. He was treated with sodium 2,3-dimercaptopropane1-sulfonate (Dimaval® ) capsules for 12 days (total dose 6.3 g). The highest urine mercury excretion during antidote treatment was 2336 μg/day. He had proteinuria of up to 11 g/day and renal biopsy showed diffuse membranous glomerulonephritis

without diabetic nephropathy. Similarly, his neuropathy did not have typical features of diabetic neuropathy. He improved over the next year.

Immunologic Previous sensitization and the subsequent development of an allergic contact dermatitis from vaccines that contain thimerosal has received more attention than before (42C ). Cross-reactivity, exposure factors, and tolerance to vaccines containing thimerosal have been studied in 125 patients sensitized to mercury derivatives in a cross-sectional study (42C ). Childhood vaccinations, merbromin used as an antiseptic, broken thermometers, and the use of drops were the main sources of previous exposure. There was sensitization to thimerosal in 57 patients and 24 had a positive intradermal reaction. Ammoniated mercury elicited positive reactions in 78% of all patients and merbromin in 66%. In most cases (100/125) there was cross-reactivity among different mercury derivatives. Intramuscular thimerosal caused a mild local reaction in only ﬁve patients (4% of the total, 9% of thimerosal positive reactions). Most of the patients had positive tests to both organic and inorganic mercury derivatives. Vaccination with thimerosal is relatively safe, even for individuals with delayed type hypersensitivity, since more than 90% of allergic patients tolerated intramuscular challenge tests with thimerosal. However, it would be advisable to restrict the use of mercurial antiseptics and mercury thermometers.

Nickel

(SED-14, 704; SEDA-24, 260; SEDA-25, 262; SEDA-26, 248) Nickel is used in alloys in dental medicine (43R ) and implant materials (44R ). Immunologic The main adverse effect of nickel is sensitization and subsequent allergy. • A 13-year-old non-atopic girl with a 1-year history of recurrent itchy eyelid inﬂammation and conjunctivitis in both eyes had been ﬁtted with a removable orthodontic appliance 14 months before (45A ). The metal wires of the orthodontic appliance were made of steel containing 10–13% nickel and 16–19% chromium. Patch testing conﬁrmed allergy to nickel. A low nickel diet improved the dermatitis, but it did not clear. She was advised to stop wearing the orthodontic appliance, and the ocular lesions cleared within 2 weeks.

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Selenium (SED-14, 704; SEDA-24, 260; SEDA-25, 263; SEDA-26, 249) Selenium-based drugs show some promise in several diseases, as orally active antihypertensive, anticancer, antiviral, antimicrobial, and immunosuppressive drugs, and organoselenium compounds reduce oxidative tissue damage and edema (46R ).

Silver

(SED-14, 705; SEDA-24, 261; SEDA-25, 263; SEDA-26, 249) Silver compounds continue to be used as astringents and in antimicrobial drugs. Hematologic Fatal pancytopenia has been reported from the extensive use of topical silver sulfadiazine. • An 11-month-old infant with second- and thirddegree burns over 30% of the body was treated topically with silver sulfadiazine (47A ). From day 2 there was signiﬁcant neutropenia, maximal at day 3. The silver sulfadiazine was withdrawn. The neutropenia was followed by anemia, which was maximal on day 5. Finally, thrombocytopenia developed. In spite blood transfusions and recovery of the neutropenia and thrombocytopenia, infection occurred and the patient died from respiratory failure.

Skin Höllensteinstift 10® (Pharma Winter, Leipzig, Germany) is a stick that contains 90% silver nitrate and 10% potassium nitrate, and has corrosive, germicidal, and astringent characteristics; it is used in the treatment of hypergranulation and common warts. • A 28-year-old woman used Höllensteinstift 10® inappropriately (48A ). Intending to treat her periorbital folds, she removed the outside layer of parafﬁn, moistened the tip, and applied the stick to the lower parts of the lids, accidentally transferring parts of the corrosive agent to the skin in the periorbicular region. After some time, she felt a burning sensation, rinsed her face with water, and so distributed the agent widely to both cheeks and increased the pain. Self-treatment with several ointments did not bring relief. On the next day she developed brown discoloration of the facial skin, particularly in the periorbital region, pain, and torsion of the skin in the affected area. Initial treatment consisted of soap solution (to wash out the silver particles) and panthenol ointment (to

Gijsbert B. van der Voet and Frederik A. de Wolff support the process of healing). The lesions disappeared completely.

Titanium (SED-14, 706; SEDA-24, 261; SEDA-25, 263; SEDA-26, 249) Titanium is used as implant and orthodontic material. Adverse effects are usually in the mechanical area (e.g. fracture of the implant device), but otherwise titanium is very biocompatible (49R ). Recently more attention has been paid to allergic reactions to titanium (50R ). A new area for the use of titanium complexes may be in cancer treatment (51R ).

Zinc (SED-14, 706; SEDA-24, 261; SEDA-25, 264; SEDA-26, 250) Hematologic The use of megadoses of vitamin and mineral supplements has become common, and adverse effects can occur. • A 17-year-old boy developed fatigue after taking large daily doses of zinc supplements for 6– 7 months in an attempt to treat his acne (52A ). He initially took 50 mg/day, but because his acne did not improve he increased the dosage to 100 mg tds. He had anemia and neutropenia. His plasma zinc concentration was 1.95 mg/l (reference range 0.50–0.95 mg/l) 1 month after withdrawal and 1.69 mg/l 1 month later. His plasma copper concentration was 0.12 mg/l (reference value 0.90– 2.35 mg/l). When his anemia and neutropenia had resolved 4 months later, the zinc and copper concentrations had returned to normal.

Mouth and teeth Lichen planus has been attributed to zinc in dental materials. • A 74-year-old woman, who had extensive odontitis treated with root canal disinfection and dental metal restorations, developed painful erosion and erythema of the upper lip mucosa, white streaks on the buccal mucosa, and white lesions on the gums (53A ). Histology showed lichen planus. Her 14 dental metal restorations contained 5.3% zinc, and patch testing was positive with zinc chloride and negative with all the other metal components. The lichen planus resolved 3 months after removal of the metal restorations.

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Chapter 22

231

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19. More D, Whisman B, Johns J, Hagan L. Anaphylaxis to Pepto-Bismol. Allergy Eur J Allergy Clin Immunol 2002; 57: 558. 20. Lanca S, Alves A, Vieira AI, Barata J, De Freitas J, De Carvalho A. Chromium-induced toxic hepatitis. Eur J Intern Med 2002; 13: 518–20. 21. Bagchi D, Stohs SJ, Downs BW, Bagchi M, Preuss HG. Cytotoxicity and oxidative mechanisms of different forms of chromium. Toxicology 2002; 180: 5–22. 22. Manygoats KR, Yazzie M, Stearns DM. Ultrastructural damage in chromium picolinate-treated cells: a TEM study. J Biol Inorg Chem 2002; 7: 791–8. 23. Fatemi N, Sarkar B. Molecular mechanism of copper transport in Wilson disease. Environ Health Perspect 2002; 110 Suppl 5: 695–8. 24. Harada M. Wilson disease. Med Electron Microsc 2002; 35: 61–6. 25. Llanos RM, Mercer JFB. The molecular basis of copper homeostasis and copper-related disorders. DNA Cell Biol 2002; 21: 259–70. 26. Ma D, Lu F, Overstreet T, Milenic DE, Brechbiel MW. Novel chelating agents for potential clinical applications of copper. Nucl Med Biol 2002; 29: 91–105. 27. Bilian X. Intrauterine devices. Best Pract Res Clin Obstet Gynaecol 2002; 16: 155–68. 28. Jonas L, Baguhl F, Wilken HP, Haas HJ, Nizze H. Copper accumulation in Actinomyces druses during and after long-term use of an intrauterine contraceptive device. Ultrastruct Pathol 2002; 26: 323–9. 29. Collery P, Keppler B, Madoulet C, Desoize B. Gallium in cancer treatment. Crit Rev Oncol Hematol 2002; 42: 283–96. 30. Ruiz JI, Baciero GR, Gonzalvo EC, Gil BG. Gamalgamation: current situation. Refuat Hapeh Vehashinayim 2002; 19: 6–15, 88. 31. Tiekink ERT. Gold derivatives for the treatment of cancer. Crit Rev Oncol Hematol 2002; 42: 225– 48. 32. Manero-Ruiz FJ, Larraga-Palacio R, HerreroLabarga I, Ferrer-Peralta M. Neumonitis por sales de oro en la artritis psoriasica: a proposito de dos casos. An Med Interna 2002; 19: 237–40. 33. Trinder D, Fox C, Vautier G, Olynyk JK. Molecular pathogenesis of iron overload. Gut 2002; 51: 290–5. 34. Eaton JW, Qian M. Molecular bases of cellular iron toxicity. Free Radic Biol Med 2002; 32: 833– 40. 35. Whittington CA, Kowdley KV. Haemochromatosis. Aliment Pharmacol Ther 2002; 16: 1963– 75. 36. Bomford A. Genetics of haemochromatosis. Lancet 2002; 360: 1673–81. 37. Coyne DW, Adkinson NF, Nissenson AR, Fishbane S, Agarwal R, Eschbach JW, Michael B, Folkert V, Batlle D, Trout JR, Dahl N, Myirski P, Strobos J, Warnock DG. Sodium ferric gluconate

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complex in hemodialysis patients. II Adverse reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney Int 2003; 63: 217–24. 38. Jain AK, Bastani B. Safety proﬁle of a high dose ferric gluconate in patients with severe chronic renal insufﬁciency. J Nephrol 2002; 15: 681–3. 39. Clarke BE, Kim ST. Iron-induced bronchial injury. Histopathology 2002; 41: 472–3. 40. Tait PA, Vora A, James S, Fitzgerald DJ, Pester BA. Severe congenital lead poisoning in a preterm infant due to a herbal remedy. Med J Aust 2002; 177: 193–5. 41. Pelclova D, Lukas E, Urban P, Preiss J, Rysava R, Lebenhart P, Okrouhlik B, Fenclova Z, Lebedova J, Stejskalova A, Ridzon P. Mercury intoxication from skin ointment containing mercuric ammonium chloride. Int Arch Occup Environ Health 2002; 75 Suppl: S54–9. 42. Audicana MT, Munoz D, Del Pozo MD, Fernandez E, Gastaminza G, Fenandez de Corres L. Allergic contact dermatitis from mercury antiseptics and derivatives; study protocol of tolerance to intramuscular injections of thimerosal. Am J Contact Dermatitis 2002; 13: 3–9. 43. Eliades T, Athanasiou AE. In vivo aging of orthodontic alloys: implications for corrosion potential, nickel release, and biocompatibility. Angle Orthod 2002; 72: 222–37. 44. Shabalovskaya SA. Surface, corrosion and biocompatibility aspects of Nitinol as an implant material. Bio Med Mater Eng 2002; 12: 69–109.

Gijsbert B. van der Voet and Frederik A. de Wolff 45. Mancuso G, Berdondini RM. Eyelid dermatitis and conjunctivitis as sole manifestations of allergy to nickel in an orthodontic appliance. Contact Dermatitis 2002; 46: 245. 46. May SW. Selenium-based pharmacological agents: an update. Exp Opin Invest Drugs 2002; 11: 1261–9. 47. Blangy H, Simon D, Lévy-Cloez A, Feillet F, Fyad JP, Tréchot P, Gillet P, Lascombes P. Sulfadiazine argentique topique et bicytopénie: 1er cas. Therapie 2002; 57: 307–9. 48. Schlepfer H, Kessler J, Hartmann B. Abuse of silver-nitrate solution for planing periorbital folds. Burns 2002; 28: 90–1. 49. Schlegel KA, Eppeneder S, Wiltfang J. Soft tissue ﬁndings above submerged titanium implants—a histological and spectroscopic study. Biomaterials 2002; 23: 2939–44. 50. Farronato G, Tiraﬁli C, Alicino C, Santoro F. Titanium appliances for allergic patients. J Clin Orthodont 2002; 36: 676–9. 51. Meléndez E. Titanium complexes in cancer treatment. Crit Rev Oncol Hematol 2002; 42: 309– 15. 52. Salzman MB, Smith EM, Koo C. Excessive oral zinc supplementation. J Pediatr Hematol Oncol 2002; 24: 582–4. 53. Ido T, Kumakiri M, Kiyohara T, Sawai T, Hagesawa Y. Oral lichen planus due to zinc in dental restorations. Contact Dermatitis 2002; 47: 51.

R.H.B. Meyboom

23 IRON CHELATORS Deferiprone

(SED-14, 719; SEDA-24, 265; SEDA-25, 268; SEDA-26, 253)

In a large-scale programme for the controlled use of deferiprone, established in 1997 by the Italian Ministry of Health, 86 centers collected information about 532 patients (1CR ). In 187 patients 269 events led to interruption of treatment, often transient. Permanent withdrawal because of adverse events occurred in 47 patients (8.9%). Reasons for withdrawal of treatment in 64 patients included non-compliance (n = 30), a serum ferritin concentration above 4000 μg/l (n = 14), and a ferritin concentration below 500 μg/l (n = 3). The most common adverse events were mild to severe granulocytopenia (4.3%), arthralgia (3.9%), gastrointestinal discomfort (3.2%), including nausea, vomiting, and abdominal pain, and transient increases in ALT activity (2.8%); however, the ALT results were not clearly presented in the report. Adverse events that were not established as adverse effects were urticaria, erythema, dermatitis, fever, ﬂu-like symptoms, and “infectious episodes”; the authors did not comment on these. Preliminary results of adding deferiprone to conventional treatment in order to reduce mortality from acute Plasmodium falciparum malaria suggest beneﬁt (2cr ). In 24 patients who were given deferiprone there were two deaths, compared with four in the control group of 21 patients. One patient who was given deferiprone died of unexplained pneumonia. Hematologic In the study of the Italian Ministry of Health, mentioned above (1CR ), agranulocytosis developed in ﬁve patients, three of © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Metal antagonists whom had previously had transient episodes of granulocytopenia, while using deferiprone; deferiprone was permanently withdrawn and all ﬁve recovered. There were episodes of less profound neutropenia in 18 other patients. In eight patients with neutropenia deferiprone was restarted; in one case agranulocytosis recurred and in three there was a relapse of less severe neutropenia; in the other four patients rechallenge was uneventful. Granulocytopenia occurred predominantly in patients with an intact spleen and in the younger age group (under 18 years); however, splenectomy was more frequent in the older patients. The risk of agranulocytosis is higher during the ﬁrst months of exposure and probably falls with time. Liver Since a report in 1998 (SEDA-23, 240; SEDA-25, 268) it has been feared that deferiprone may adversely affect hepatic ﬁbrosis in patients with thalassemia. However, a further study has provided reassurance. Three pathologists evaluated 112 coded liver biopsies obtained from 56 patients before and after deferiprone treatment (median duration 3.5 years). They found no evidence that deferiprone had worsened hepatic ﬁbrosis (3CR ). In view of the history of this problem, it is worth noting that “The International Safety Monitoring Committee that commissioned this study [was] an independent body of scientists”, and that “The members of the Safety Monitoring Committee and the authors [had] no ﬁnancial interest in the development of deferiprone”.

Deferoxamine

(SED-14, 714; SEDA-24, 265; SEDA-25, 267; SEDA-26, 253) In two children with Wilson’s disease liver transplantation was undertaken because of fulminant hepatic injury, after deferoxamine and supportive treatment had failed to control the disease (4cr ).

233

234 Special senses Ocular toxicity Two patients with transfusion-related hemochromatosis, who received deferoxamine 9 g/week and 10 g/ month to a total dose of 39 g, and one with hemodialysis-related aluminum storage, who received 9 g/week, experienced gradual loss of visual acuity (5CR ). There was pigmentary mottling near the maculae and electroretinography was abnormal in the two patients studied. Ototoxicity In an Iranian study the incidence of sensorineural hearing impairment in 128 patients taking deferoxamine was assessed by otological examination and pure tone audiometry (6CR ). Patients who received deferoxamine subcutaneously every other day were compared with those who received it for 6 days a week. In both groups the average daily dose was the same, 21–39 mg/kg/day, since the alternate-day group received double doses. Of the patients in the once-a-day group there was hearing loss at a frequency of 8000 Hz in the right ear in 28% and in the left ear in 23%. In the alternate-day group hearing loss was more common: 45% and 42% respectively. It appears that the maximum plasma deferoxamine concentration is a determinant of sensorineural toxicity. There was no relation between ototoxicity and either the serum ferritin concentration (which was meticulously controlled) or the duration of deferoxamine treatment.

Chapter 23

R.H.B. Meyboom

Kaposi’s sarcoma, and in vitro tests have suggested that it inhibits the growth of sarcomaderived cells (8E ). Unfortunately, the intralesional injection of deferoxamine led to paradoxical exacerbation of Kaposi’s sarcoma of the skin and the development of numerous sarcomatous papules in the area of injection, whereas there were no changes in untreated lesions (9AR ).

Dimercaptopropane sulfonate (DMPS) (SED-14, 721) Dimercaptopropane sulfonate (DMPS) has become the treatment of choice for acute arsenic poisoning and has been used safely in high doses (15.25 g in 12 days, ﬁrst intravenously and later orally) in a 21-year-old man who swallowed about 1000 mg or more of arsenic trioxide (10AR ). There were no adverse effects. A modest transient increase in serum transaminases was thought to have been due to the arsenic.

Ethylenediaminetetraacetic acid (EDTA; edetate) (SED-14, 721; SEDA-25, 268; SEDA-26, 254)

Musculoskeletal Of 41 patients in Hong Kong with transfusion-dependent homozygous beta-thalassemia, who received subcutaneous infusion of deferoxamine in doses not exceeding 50 mg/kg/day, 16 had radiographic evidence of deferoxamine-induced bone dysplasia (7CR ). All 16 had metaphyseal sclerosis of long bones (arms, hands, legs, and/or ribs); three had irregular sclerosis at the costochondral junction; one had platyspondyly. There was osteoporosis (unrelated to deferoxamine), as indicated by thinning of the metacarpal cortex, in 17 patients, eight with and nine without deferoxamine dysplasia. Two patients had evidence of medullary expansion; however, they were from mainland China and had irregular blood transfusions and no chelation therapy, and it was unrelated to deferoxamine. Carcinogenicity Deferoxamine is used experimentally in a variety of diseases, including

In spite of a lack of evidence of efﬁcacy and safety, salts of ethylenediaminetetraacetic acid (Na2 EDTA, CaNa2 EDTA) are still used worldwide as “chelation therapy” in atherosclerosis and several other disorders. Five patients became ill shortly after chelation therapy at an out-patients clinic, where they had received an infusion of Na2 EDTA 3 g, MgCl 2 g, vitamin B1 100 mg, vitamin B complex 1 ml, and vitamin C 15 g in sterile water at a rate of 180 ml/h (11cr ). One patient also received 10 ml of 50% dimethylsulfoxide. All initially had gastrointestinal and musculoskeletal symptoms (trembling, muscle spasms) and complained of dry mouth or excessive thirst. All had fever and hypotension, four had tachycardia and sweating. Laboratory data were collected in four patients, all of whom had varying degrees of thrombocytopenia, leukopenia, and lymphocytopenia,

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reﬂecting transient bone-marrow suppression. Subsequent measurements showed leukocytosis with early cell forms. Urinalysis showed transient proteinuria (in four), microscopic hematuria (in three), hyaline casts (in two), and ketonuria (in four). Three had mild transient rises in serum urea and creatinine concentrations. Three had hypocalcemia, requiring supplementation in one (probably accounting for the muscular symptoms). In these patients acute edetate toxicity appeared to be related to errors in dosage or the rate at which the formulation was administered. Urinary tract Edetate can cause renal damage, with vacuolization of the proximal tubules, loss of the brush border, and eventually degeneration of the proximal tubular cells. A possible mechanism underlying this renal toxicity is an interaction between edetate and endogenous metals in the proximal tubule (11cr ). Drug interactions Reduced anticoagulation has been reported in a patient taking warfarin when he was given chelation therapy (12AR ). • A 64-year-old man with coronary artery disease taking atenolol, lisinopril, atorvastatin, glyceryl trinitrate, triamterene, hydrochlorothiazide, omeprazole, nizatidine, enteric-coated aspirin, and a liquid multivitamin formulation containing spinach and broccoli extracts, was given warfarin for bilateral pulmonary embolism. About 3 weeks later he received chelation therapy with a cocktail including sodium edetate 3 g and heparin 2500 U. The next day his INR had fallen from 2.6 to 1.6. He denied having missed a dose of warfarin, having taken other drugs, or having made dietary changes. The dose of warfarin was increased and the INR reached the target range.

The authors did not propose a mechanism for this interaction, although the rapidity of the effect suggests protein binding displacement of warfarin; nor did they comment on the possible role of the extract of broccoli, which contains vitamin K.

PENICILLAMINE AND RELATED DRUGS Bucillamine

(SED-14, 736;

SEDA-26, 254) Reproductive system The ﬁrst report of gigantism of the breasts, probably induced by bucillamine, a penicillamine-analogue frequently used in Japan, has been published (13CR ). • After attempts with chrysotherapy and lobenzarit, a 24-year-old woman was given bucillamine 300 mg/day and a corticosteroid, predonine, for rheumatoid arthritis. After 10 months she noticed bilateral breast enlargement, which over 6 months progressed to extreme proportions, the left breast ultimately reaching as far as her pubis. The skin of the breasts was thin and erythematous, with marked dilatation of the superﬁcial veins. The nipple areola complexes were elongated and poorly deﬁned from the surrounding skin. There were no abnormalities of prolactin, sex hormones, growth hormone, or TSH (but the values were not stated). Bilateral total mastectomy was performed and the nipple–areola complexes were removed from the resected tissue and grafted on to the breasts after insertion of a tissue expander. The breast tissue removed from the right side weighed 5 kg and that from the left side 7 kg. Histologically there was increased ﬁbrosis and duct dilatation and no malignancy.

This effect, attributed here to bucillamine, is a rare but well established adverse effect of penicillamine (SED-14, 733). Although the patient had also taken isoniazid for pulmonary tuberculosis, that was unlikely to have played a part, since the breast enlargement started earlier and progressed after the isoniazid had been withdrawn.

Penicillamine (SED-14, 723; SEDA-24, 266; SEDA-25, 269; SEDA-26, 255) A 28-year observational study in Austria of the patterns of use of disease-modulating antirheumatic drugs (DMARDs) has illustrated how penicillamine has given way to other drugs, in particular methotrexate and sulfasalazine (14Cr ). In another Austrian study patients with rheumatoid arthritis were followed for a mean of 10 years (15CR ). Of 27 courses of penicillamine, 13 were discontinued because of

236 adverse effects, 12 because of lack of effectiveness, and two because of remission. Furthermore, an analysis of the reasons for DMARD withdrawal in patients in the Czech and Slovak Republics has underlined the fact that lack of effectiveness is, in addition to adverse effects, an important reason for stopping penicillamine (16cr ). General trends in the treatment of rheumatoid arthritis in the past decade have been more aggressive treatment in early disease with DMARDs (17R ) and the use of combinations of DMARDs (18R ). Strategies for improving the long-term outcome in rheumatoid arthritis include early specialist referral for DMARD treatment and the avoidance of NSAID-induced gastrointestinal and renal toxicity (19CR ). The organization and preliminary results of an intensiﬁed voluntary reporting system for rheumatologists in the UK West Midlands for studying the safety of DMARDs have been described (20Cr ). Respiratory The diagnosis and management of lupus-induced pleurisy have been reviewed (21R ). Urinary tract A clinical algorithm for the management of hematuria, for example in patients taking penicillamine or NSAIDs, has been published (22R ). It should be borne in mind that in such patients hematuria may be symptomatic of underlying pathology (e.g. a tumor of the urinary tract). Skin Penicillamine can cause localized scleroderma (also known as morphea), which has been reviewed (23R ). Bullous lesions can occur in scleroderma (localized, generalized, or systemic), and this highlights the diagnostic problems in such patients (24AR ). In one of the four case histories presented in this paper, the bullous eruption, in a patient taking penicillamine for systemic sclerosis, was diagnosed as penicillamine-induced pemphigus foliaceus. Although rarely described, skin reactions that mimic graft–versus–host disease are an established complication of penicillamine (SED14, 731). The similarity of the pathology of these drug-induced eruptions to those that occur after bone marrow transplantation has been reviewed (25CR ). Even though the drug-related eruptions may have different manifestations

Chapter 23

R.H.B. Meyboom

(they can, for example, resemble smallpox, lichen planus, or eczema) their histological features are similar to those seen in cutaneous graft–versus–host disease, in particular eruptions in which liquefactive necrosis is seen at the interface between the epidermis and the cutis. One of the possible mechanisms involved in hypersensitivity reactions to sulfhydryl-containing drugs is based on the immune response of T cells to the sulfhydryl group, which arises when binding of IL-2 to the IL-2 receptor induces autoreactive T cells (26E ). The concentrations of IL-2 and IL-2 receptor were closely associated with the onset and severity of cutaneous graft–versus–host disease, suggesting an etiological similarity between the disease and skin eruptions induced by sulfhydryl-containing drugs. Proliferation of autoreactive T cells is induced by the binding of IL-2 to its receptor in these patients. Reproductive system There has been another report of penicillamine-induced gigantism of the breasts (27CR ). Although it can be debilitating (see bucillamine above), in this case it was mild. • A 55-year-old premenopausal woman took penicillamine 1 g/day for 2 years for localized scleroderma. She used no other drugs. She noticed a gradual enlargement of her breasts, from a size B to size D+ bra cup. There were no palpable masses or tenderness. The only abnormal laboratory test ﬁnding was a positive test for homogeneous antinuclear antibodies (titer > 1 : 80), which is often found in patients with scleroderma. Serum prolactin was normal. Penicillamine was withdrawn and the breast enlargement regressed over 3 months; the bra cup size reverted to B.

Immunologic It has been emphasized that penicillamine is no longer used in juvenile rheumatoid arthritis, in particular because of lack of effect and the possibility of inducing a lupus-like syndrome (28r ).

POLYSTYRENE SULFONATES (SEDA-25, 271; SEDA-26, 256)

Calcium polystyrene sulfonate Gastrointestinal Acute colonic necrosis and, less commonly, upper gastrointestinal damage are occasionally reported with sodium

Metal antagonists

Chapter 23

polystyrene sulfonate, and colonic perforation has now been attributed to calcium polystyrene sulfonate in a premature infant (29A ). • A boy delivered at 28 weeks was given calcium polystyrene sulfonate 0.2 mg rectally for hyperkalemia (7.1 mmol/l). His abdomen, already distended, became larger with abdominal wall discoloration. An X-ray showed distended loops of bowel and at laparotomy he was found to have a perforation at the rectosigmoid junction.

Sodium polystyrene sulfonate Gastrointestinal Further cases of colonic ulceration have been reported in patients taking sodium polystyrene sulfonate. • A 53-year-old woman took sodium polystyrene sulfonate 15 g twice, 8 days apart, and 15 days later developed colonic necrosis and perforation; there were crystals of sodium polystyrene sulfonate in the inﬂammatory debris (30A ). • An 81-year-old woman with chronic renal insufﬁciency, who had taken sodium polystyrene sulfonate 2 spoons/day, developed a 3–4 cm ulcer at 45 cm from the anal margin, with crystals of sodium polystyrene sulfonate in the biopsy (31Ar ). • A 74-year-old woman with chronic renal insufﬁciency, who had taken sodium polystyrene sulfonate 1–2 spoons/day, developed cecal ulceration,

237 with crystals of sodium polystyrene sulfonate in the biopsy (31Ar ).

A giant diverticulum in the sigmoid colon has been attributed to inﬂammation due to sodium polystyrene sulfonate crystals in a 44year-old man who had taken 15 mg/day for 2 years (31Ar ). Esophageal ulceration has occasionally been attributed to sodium polystyrene sulfonate and another case has been reported (32A ). • An 83-year-old man with septic shock and renal insufﬁciency after prostatectomy was given sodium polystyrene sulfonate for hyperkalemia and developed a 3 cm esophageal ulcer. Crystals of sodium polystyrene sulfonate were found in a biopsy.

Drug formulations Drugs that have similar names are not infrequently confused. The name of Sanoﬁ–Synthelabo’s brand of sodium polystyrene sulfonate, Kayexalate, could be confused with the names of proprietary brands of potassium chloride, such as Kay-Cee-L and Kay-Ciel. Furthermore, some formulations of potassium chloride are formulated in packaging that resembles that of Kayexalate. There have been two deaths when potassium chloride was given instead of sodium polystyrene sulfonate for hyperkalemia (33A ).

REFERENCES 1. Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, Galanello R, Maggio A, Masera G, Piga A, Schettini F, Stefano I, Tricta F. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol 2002; 118: 330–6. 2. Mohanty D, Ghosh K, Pathare AV, Karnad D. Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria. Indian J Med Res 2002; 115: 17–21. 3. Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, Gamberini MR, Schwartz E, Cohen AR. Lack of progressive hepatic ﬁbrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood 2002; 100: 1566–9. 4. Komatsu H, Fujisawa T, Inui A, Sogo T, Sekine I, Kodama H, Uemoto S, Tanaka K. Hepatic copper concentration in children undergoing living related liver transplantation due to Wilsonian fulminant hepatic failure. Clin Transplant 2002; 16: 227–32.

5. Szwarcberg J, Mack G, Flament J. Ocular toxicity of deferoxamine: description and analysis of three observations. J Fr Ophtalmol 2002; 25: 609– 14. 6. Karimi M, Asadi-Pooya AA, Khademi B, AsadiPooya K, Yarmohammadi H. Evaluation of the incidence of sensorineural hearing loss in betathalassemia major patients under regular chelation therapy with desferrioxamine. Acta Haematol 2002; 108: 79–83. 7. Chan Y-L, Pang L-M, Chik K-W, Cheng JCY, Li C-K. Patterns of bone diseases in transfusiondependent homozygous thalassaemia major: predominance of osteoporosis and desferrioxamineinduced bone dysplasia. Pediatr Radiol 2002; 32: 492–7. 8. Simonart T, Degraef C, Andrei G, Mosselmans R, Hermans P, Van Vooren JP, Noel JC, Boelaert JR, Snoeck R, Heenen M. Iron chelators inhibit the growth and induce the apoptosis of Kaposi’s sarcoma cells and of their putative endothelial precursors. J Invest Dermatol 2000; 115: 893–900.

238 9. Simonart T, Boelaert JR, Van Vooren JP. Enhancement of classic Kaposi’s sarcoma growth after intralesional injections of desferrioxamine. Dermatology 2002; 204: 290–2. 10. Horn J, Eicher H, Muhlberg W, Platt D. Acute arsenic trioxide poisoning: nonserious course of illness because of high dosage chelation therapy [in German with English summary]. Intensivmed Notf Med 2002; 39: 246–53. 11. Morgan BW, Singleton K, Thomas JD. Adverse effects in 5 patients receiving EDTA at an outpatient chelation clinic. Vet Hum Toxicol 2002; 44: 274–6. 12. Grebe HB, Gregory PJ. Inhibition of warfarin anticoagulation associated with chelation therapy. Pharmacotherapy 2002; 22: 1067–9. 13. Sakai Y, Wakamatsu S, Ono K, Kumagai N. Gigantomastia induced by bucillamine. Ann Plast Surg 2002; 49: 193–5. 14. Aletaha D, Smolen JS. Laboratory testing in rheumatoid arthritis patients taking disease-modifying antirheumatic drugs: clinical evaluation and cost analysis. Arthritis Care Res 2002; 47: 181–8. 15. Skoumal M, Wottawa A. Long-term observation study of Austrian patients with rheumatoid arthritis. Acta Med Austriaca 2002; 29: 52–6. 16. Pavelka K, Forejtova S, Pavelkova A, Zvarova J, Rovensky J, Tuchynova A. Analysis of the reasons for DMARD therapy discontinuation in patients with rheumatoid arthritis in the Czech and Slovak Republics. Clin Rheumatol 2002; 21: 220–6. 17. Parkinson S, Alldred A. Drug regimens for rheumatoid arthritis. Hosp Pharm 2002; 9: 11–15. 18. Sibilia J. Combinaison de traitements de fond dans la polyarthrite rhumatoide. Ann Med Interne (Paris) 2002; 153: 41–52. 19. Capell H, McCarey D, Madhok R, Hampson R. “5D” outcome in 52 patients with rheumatoid arthritis surviving 20 years after initial disease modifying antirheumatic drug therapy. J Rheumatol 2002; 29: 2099–105. 20. Jobanputra P, Maggs F, Homer D, Bevan J. Monitoring and assessing the safety of diseasemodifying antirheumatic drugs: a West Midlands experience. Drug Saf 2002; 25: 1099–105.

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21. Wang D-Y. Diagnosis and management of lupus pleuritis. Curr Opin Pulm Med 2002; 8: 312–16. 22. Mazhari R, Kimmel PL. Hematuria: an algorithmic approach to ﬁnding the cause. Clevel Clin J Med 2002; 69: 870–84. 23. Sehgal VN, Srivastava G, Aggarwal AK, Behl PN, Choudhary M, Bajaj P. Localized scleroderma/morphea. Int J Dermatol 2002; 41: 467–75. 24. Rencic A, Goyal S, Moﬁd M, Wigley F, Nousari HC. Bullous lesions in scleroderma. Int J Dermatol 2002; 41: 335–9. 25. Takatsuka H, Takemoto Y, Yamada S, Mori A, Wada H, Fujimori Y, Okamoto T, Kanamaru A, Kakishita E. Similarity between eruptions induced by sulfhydryl drugs and acute cutaneous graft– versus–host disease after bone marrow transplantation. Hematology 2002; 7: 55–7. 26. Kitamura K, Aihara M, Osawa J, Naito S, Ikezawa Z. Clinical histological study of drug eruptions induced by sulfhydryl drugs. Proc Jpn Soc Investig Dermatol 1988; 12: 136–7. 27. Tchebiner JZ. Breast enlargement induced by D-penicillamine. Ann Pharmacother 2002; 36: 444–5. 28. Chikanza IC. Juvenile rheumatoid arthritis: therapeutic perspectives. Paediatr Drugs 2002; 4: 335– 48. 29. Grammatikopoulos T, Greenough A, Pallidis C, Davenport M. Beneﬁts and risks of Calcium Resonium therapy in hyperkalaemic preterm infants. Acta Paediatr Int J Paediatr 2003; 92: 118–20. 30. Cheng ES, Stringer KM, Pegg SP. Colonic necrosis and perforation following oral sodium polystyrene sulfonate (Resonium A® /Kayexalate® ) in a burn patient. Burns 2002; 28: 189–190. 31. Mulder J-WR, Offerhaus GJA, Drillenburg P, Busch ORC. “Giant diverticulum” sigmoid colon. J Am Coll Surg 2002; 195: 130. 32. Moguelet P, Houdouin L, Bertheau P, Boudaoud S, Hassani Z, Eurin B, Janin A. Une ulceration oesophagienne. Ann Pathol 2002; 22: 487–8. 33. Kaplan M, Summerﬁeld MR, Pestaner JP. Mix-up between potassium chloride and sodium polystyrene sulfonate. Am J Health-Syst Pharm 2002; 59: 1786–7.

Pam Magee

24

Antiseptic drugs and disinfectants

BISBIGUANIDES Chlorhexidine

(SED-14, 764; SEDA-24, 270; SEDA-25, 276; SEDA-26, 258) Respiratory The toxicity of disinfectants when taken in high doses, whether by intent or accidentally, is an important consideration in their development. Chlorhexidine gluconate when ingested usually causes relatively mild symptoms, with poor gastrointestinal absorption, and is considered relatively safe. However, a rare fatality, with acute respiratory distress syndrome, has been reported (1A ).

• An 80-year-old woman with dementia accidentally took about 200 ml of chlorhexidine gluconate 5%. She aspirated her gastric contents and despite intensive treatment died of acute respiratory distress syndrome 12 hours later. The serum concentration of chlorhexidine gluconate was markedly high (25 μg/ml).

It is possible that in this case although chlorhexidine was poorly absorbed from the gastrointestinal tract absorption occurred through the pulmonary alveoli. Special senses Accidental use of chlorhexidine disinfectant in the eye has been reported as the cause of corneal burns and loss of corneal clarity (SEDA-23, 247). The toxicity of chlorhexidine in these cases resulted from strong concentrations of chlorhexidine 4% used for disinfection, and chlorhexidine is usually non-toxic when used in a concentration of 0.02%. However, a case of progressive ulcerative keratitis related to the use of chlorhexidine gluconate 0.02% eye drops has been reported (2A ). © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

• A 45-year-old woman was treated for presumed Acanthamoeba keratitis with chlorhexidine gluconate 0.02% and propamidine 0.1% eye drops. After using the eye drops for 8 weeks she developed a near total loss of the corneal epithelium and progressive ulcerative keratitis, which eventually required penetrating keratoplasty. Histopathological examination of the corneal button showed ulceration and loss of Bowman’s membrane, massive loss of keratocytes with apparent apoptosis, and loss of endothelial cells, with inﬂammatory cells adherent to the remaining cells. These ﬁndings were similar to those seen in chlorhexidine 4% keratopathy. No organisms were seen in stained sections and immune histochemistry showed no signiﬁcant ﬁndings.

Immunologic Chlorhexidine allergy is well documented. However it may still not be suspected as a possible cause of anaphylaxis when several agents are used in the anesthetized surgical patient, and hypersensitivity to chlorhexidine may not be tested for (3r ). If a reaction occurs during anesthesia, there is often doubt about the exact agent responsible; patch testing will help if there is doubt about causality. Chlorhexidine-coated catheters have been developed in the hope of reducing the incidence of central venous line sepsis. Package inserts warn that these should not be used in individuals who are thought to be sensitive to chlorhexidine. Life-threatening anaphylaxis has been reported twice in the same patient, and attributed to a central venous catheter impregnated with chlorhexidine and sulfadiazine (SEDA-26, 258). In another case two episodes of pronounced refractory cardiovascular collapse accompanied the insertion of a chlorhexidine-coated central venous catheter (4r ). Sensitivity to chlorhexidine was not at ﬁrst suspected, but 5 months later a skin prick test with chlorhexidine resulted in a characteristic sustained weal and ﬂare response, strongly suggesting IgE-mediated sensitivity. The patient, a 51-year-old man, subsequently underwent uneventful surgery following strict avoidance

239

240

Chapter 24

Pam Magee

of chlorhexidine exposure. Bronchospasm was not a feature in either of these two cases, nor of previously reported cases (SEDA-22, 262; SEDA-23, 248). It is possible that the potential beneﬁt of reducing the incidence of central venous sepsis by using chlorhexidine-coated catheters is outweighed by the risk of sudden and profound anaphylaxis. Certainly a high degree of suspicion of chlorhexidine allergy should be exercised and skin tests performed.

Urinary tract Povidone iodine sclerosis has been suggested to be safe and effective in treating lymphoceles after renal transplantation, with only minor complications of the procedure, such as pericatheter cutaneous infections. However, a case of acute renal tubular necrosis has been reported (6A ).

IODOPHORS

Iodine-induced renal insufﬁciency has been previously reported after the use of topical povidone iodine on the skin and after intracavity irrigation (SEDA-24, 271).

(SED-14, 768; SEDA-24, 271; SEDA-25; 277)

Povidone iodine Endocrine Topical povidone iodine is often used in the management of burns and resultant iodine resorption can cause suppression of thyroid hormones; hyperthyroidism is less common (SEDA-20, 226; SEDA-24, 271). Thyrotoxicosis related to iodine toxicity in a child with burns occurred after alternate-day povidone iodine washes (5A ). • A 22-month-old boy was admitted to a pediatric intensive care unit after partial and full thickness burns over 80% of his body surface area. After debridement he was given alternate day povidone iodine (Betadine) washes. He became increasingly tachycardic, hypertensive, and hyperpyrexic, with sweating, agitation, and diarrhea and developed neutropenia. Daily sepsis screens were negative. Thyroid function tests showed evidence of iodine-induced thyrotoxicosis. He was given propranolol and carbimazole, and chlorhexidine was substituted for povidone iodine. His tachycardia, hypertension, and diarrhea slowly improved and his neutropenia resolved. By day 42 his free thyroxine concentration was normal and he was given thyroxine. On day 63 the carbimazole, propranolol, and thyroxine were withheld. However thyroid function tests 1 week later showed hypothyroidism, and thyroxine was restarted. Repeat plasma and urine iodine concentrations on day 57 (a month after withdrawal of povidone iodine) continued to show marked urinary excretion of iodine (urine concentration 65 μmol/l, reference range 0.39–1.97) with high but falling plasma iodine concentrations (5.9 μmol/l, reference range 0.32– 0.63).

• In a 23-year-old woman, a kidney allograft recipient with recurrent lymphoceles treated with povidone iodine irrigations (50 ml of a 1% solution bd for 6 days), a metabolic acidosis occurred and renal function deteriorated. After a few days, despite suspension of irrigation, the patient developed oliguria, and dialysis was needed. A renal biopsy showed acute tubular necrosis.

ORGANIC MERCURY COMPOUNDS (SED-14, 771; SEDA-25, 278; SEDA-26, 259)

Thiomersal (thimerosal) Thiomersal was ﬁrst added to childhood vaccines as a preservative in the 1930s. It contains 50% ethyl mercury by weight. It was the potential for infants to be exposed to cumulative doses of mercury from thiomersal in vaccines that prompted the European Medicines Evaluation Agency and the UK’s Committee on Safety of Medicines (CSM) to recommend that it would be prudent to promote the use of vaccines without thiomersal as a precautionary measure (SEDA-26, 259). Psychiatric There is continuing debate that there is an association between autism and thiomersal vaccines. Some authors believe that review of the literature supports the hypothesis that mercury in vaccines may be a factor in the pathogenesis of autism (7r ). The World Health Organization’s Global Advisory Committee on Vaccine Safety (GACvS) has also kept this issue under review and concluded in November 2002 that there is no evidence of toxicity in infants, children, or adults who have been exposed to

Antiseptic drugs and disinfectants

Chapter 24

thiomersal in vaccines. The CSM is also keeping the issue under close review and studies of the possible toxicology of thiomersal continue to appear (8c ). The usual dose of ethyl mercury in pediatric vaccines is small (about 12.5–25 micrograms of mercury). However, the metabolism of ethyl mercury in infants who receive vaccines containing thiomersal is unknown. The mean doses of mercury in 40 full-term infants exposed to thiomersal-containing vaccines were 46 (range 38–63) μg in 2-month-old children and 111 (range 88–175) μg in 6-monthold children. Blood mercury concentrations in the thiomersal-exposed 2-month-old children ranged from less than 3.8 to 21 nmol/l; in 6month-old children all the concentrations were below 7.5 nmol/l. Only one of 15 blood sam-

241 ples from 21 controls contained measurable concentrations of mercury. Urine concentrations of mercury were low after vaccination, but stool concentrations were high in thiomersalexposed 2-month-old children (mean 82 ng/g dry weight). The mean half life of ethyl mercury was 7 days. This study was not designed as a formal assessment of the pharmacokinetics of mercury. However, it showed that the administration of vaccines containing thiomersal did not seem to raise blood concentrations of mercury above safe values in infants. Ethyl mercury seems to be eliminated from the blood rapidly via the stools. The authors concluded that the thiomersal in routine vaccines poses very little risk in full-term infants.

REFERENCES 1. Hirata K, Kurokowa A. Chlorhexidine gluconate ingestion resulting in fatal respiratory distress syndrome. Vet Hum Toxicol 2002; 44: 89–91. 2. Murthy S, Hawksworth NR, Cree I. Progressive ulcerative keratitis related to the use of topical chlorhexidine gluconate (0.02%). Cornea 2002; 21: 237–9. 3. Evans P, Foxell RM. Chlorhexidine as a cause of anaphylaxis. Int J Obstet Anaesth 2002; 11: 145–6. 4. Pittaway A, Ford S. Allergy to chlorhexidinecoated central venous catheters revisited. Br J Anaesth 2002; 88: 304–5. 5. Robertson P, Fraser J, Shield J, Weir P. Thyrotoxicosis related to iodine toxicity in a paediatric burn patient. Intensive Care Med 2002; 28: 1369.

6. Manfro RC, Comerlato L, Berdichevski RH, Ribeiro AR, Denicol NT, Berger M, Saitovitch D, Kott WJ, Goncalves LF. Nephrotoxic acute renal failure in a renal transplant patient with recurrent lymphocoele treated with povidone–iodine irrigation. Am J Kidney Dis 2002; 40: 655–7. 7. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiatry 2002; 7: 42–3. 8. Pichichero ME, Cernictiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal; a descriptive study. Lancet 2002; 360: 1737–41.

Tore Midtvedt

25

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Future use of antimicrobial drugs: the lesson from avoparcin and vancomycin The increasing rate of antimicrobial drug resistance has been a matter of great concern and has been commented upon almost yearly in SEDA as the most serious unwanted effect of these drugs. However, in spite of the fact that the problem is now very well recognized (SEDA-25, 279), it continues to grow. History Most antimicrobial drugs are natural products, i.e. they are produced by microorganisms such as bacteria or fungi, often found in the soil. In fact, they can be looked upon as Mother Nature’s own regulatory principle for the microbial society. Therefore, resistance to antimicrobial drugs is a natural phenomenon. Before the introduction of the ﬁrst antibiotic, penicillin, more than half a century ago, resistance to antimicrobial drugs was not a clinical problem. At that time, the large majority of commensal and infectious bacteria associated to man were susceptible. Over the last ﬁve decades, however, increased use of antimicrobial drugs, not only in human medicine, but also in veterinary medicine, agriculture, ﬁsh farming, etc., has had an enormous impact on the microbial society. Nearly everywhere, the numbers of susceptible strains have reduced and resistant strains or variants have increased in numbers. It has been repeatedly reported that the susceptibility proﬁle of bacteria in any human compartment, © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

242

such as the skin, intestine, and respiratory tract, is very different from what it was in the preantibiotic era, and even 10 years ago. The same trend is reported from hospitals and homes. Multidrug resistance, i.e. resistance to several antimicrobial drugs, is commonly found in bacteria that cause infections as well as in commensal organisms. A few decades ago, it was a common opinion that various compartments in nature have their own ﬂora. As an example, it was claimed that you could use antimicrobial drugs relatively freely in ﬁsh farming without increasing the burden of resistance in humans. Now we have learned the lesson. Micro-organisms circulate everywhere, and there is a continuous exchange of strains between all compartments in nature (humans, animals, birds, ﬁsh, etc.). Even if a bacterial species is host speciﬁc, the genetic material that codes for resistance is not. In fact, antibiotics have shown that bacteria have great genetic adaptability, in terms of their ability to exchange genetic traits among genera and species which are evolutionarily millions of years apart. Antibiotic resistance genes on plasmids and transposons ﬂow to and from nearly all types of bacteria. Sometimes they leave the plasmid and jump into bacterial chromosomes, and sometimes they jump back again. However, this knowledge is not being heeded everywhere. Small doses of antimicrobial drugs as “growth promoters” are still commonly used, even in countries in which the health authorities should be aware of the problems. It is easy to blame developing countries for using antimicrobial drugs as growth-promoters, or for selling antimicrobial drugs over the counter without prescription, but it took the European Community many years before it started to look into the problem of using antimicrobial drugs as growth promoters. To be

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

honest, the sad history of cross-resistance between avoparcin and vancomycin may have provided important background for this alteration in attitude. Avoparcin and vancomycin are both glycopeptide antibiotics. They are large molecules that are produced by a variety of environmental micro-organisms. Consequently, genes that code for antimicrobial drug resistance may also be present. Both drugs are mostly active against Gram-positive bacteria, such as enterococci and staphylococci. In Europe, avoparcin was allowed to be used as an animal food additive in many countries, while the use of vancomycin was limited to humans. Nobody bothered about the possibility of cross-resistance between avoparcin and vancomycin until 10 years ago. After the emergence of vancomycin-resistant enterococci and after more than 2 years of hard lobbying by several groups, avoparcin was withdrawn from the market in the European Community. However, in the meantime, vancomycin-resistant enterococci had become widespread in many European countries and, sorry to say, are still. Instead of focussing on the development of resistance to a speciﬁc antimicrobial drug in a speciﬁc species, we should focus on the microbial community as a single entity or a “metagenome”. Any use of any microbial agent might cause resistance to develop in one or more microbial species. When such genes have ﬁrst become established, they may ﬂoat around and be picked up by other species. This approach to the development and spread of resistance can, and should, be applied to the microbial ﬂora in all mammals, as well as in the environment. The consequence of this approach is that we should, every time we prescribe an antimicrobial drug, try to ﬁnd a drug that hits nothing but the pathogen in the infected organ(s). Of course, this can be difﬁcult and sometimes even close to impossible. But that should not stop us from trying. For example, in nearly all cases, a third-generation cephalosporin for acute pharyngitis caused by Group A streptococci, or of a ﬂuoroquinolone for acute cystitis, are not the best alternatives. Ecology In our struggle for prudent use of antimicrobial drugs, the so-called eco-shadow concept represents a challenging way of following alterations in mammalian and environmental ecosystems produced by exposure of these

Chapter 25

243

systems to antibiotics (1R ). In brief, an ecoshadow (ecological shadow) can be deﬁned as any alteration in any ecosystem following exposure of the system to an antimicrobial drug (or any compound that inﬂuences the system). The alterations can be of variable length and may involve a variable number of species and functions, including the development and spread of resistance. When possible, the sum of all the alterations caused by an antibiotic can be included in an “eco-shadow index”. A large eco-shadow or high eco-shadow index indicates a high tendency to the development of microbial resistance. At present, it seems that Europe has taken the lead in the ﬁght against antimicrobial drug resistance. At the Fourth European Conference on Antibiotic Resistance, organized by the European Commission and held in Rome in November 2003, it was strongly emphasized that only a multidisciplinary approach, involving all stakeholders—physicians, researchers, industry, politicians, and patients—can overcome the problem of increasing resistance. It is to be hoped that this problem will be established as a major objective for the forthcoming European Centre for Disease Prevention and Control. Hematologic Since the days when chloramphenicol was more commonly used, it has been recognized that many antimicrobial drug are associated with severe blood dyscrasias, such as aplastic anemia, neutropenia, agranulocytosis, thrombocytopenia, and hemolytic anemia. Information on this association has come predominantly from case series and hospital surveys (2R –4R ). Some evidence can be extracted from population-based studies that have focused on aplastic anemia and agranulocytosis and their association with many drugs, including antimicrobial drugs (5R , 6R ). Recently, the incidence rates of blood dyscrasias in the general population have been estimated in a cohort study with a nested casecontrol analysis, using data from a General Practice Research Database in Spain (7R ). The study population consisted of 822 048 patients aged 5–69 years who received at least one prescription (in all 1 507 307 prescriptions) for an antimicrobial drug during January 1994 to September 1998. The main outcome measure was a diagnosis of neutropenia, agranulocytosis, hemolytic anemia, thrombocytopenia,

244 pancytopenia, or aplastic anemia. The incidence was 3.3 per 100 000 person–years in the general population. Users of antimicrobial drugs had a relative risk (RR), adjusted for age and sex, of 4.4, and patients who took more than one class of antimicrobial drug had a relative risk of 29. Among individual antimicrobial drugs, the greatest risk was with cephalosporins (RR = 14), followed by the sulfonamides (RR = 7.6) and penicillins (RR = 3.1).

PENICILLINS

(SED-14, 810; SEDA-24, 276; SEDA-25, 282; SEDA-26, 262)

Amoxicillin Skin Allergic contact urticaria has been attributed to amoxicillin. • A 40-year-old male nurse developed facial angioedema, dyspnea, rhinoconjuntivitis, dysphonia, and dysphagia immediately after opening a sachet containing amoxicillin and clavulanic acid (8C ). Skin prick tests were positive for both amoxicillin and ampicillin, and an open test with amoxicillin resulted in a severe immediate-type reaction with large localized wheals and erythema at 10 minutes. Six months later, when he was asymptomatic, erythema was observed during open tests with ampicillin 5%.

Immunologic Consort urticaria has previously been described in a young woman after she kissed her boyfriend, who had taken ampicillin (SEDA-25, 263). It may occur more often than recognized. • Two episodes of urticarial angio-oedema occurred in a 45-year-old woman (9A ). The ﬁrst episode occurred 1 hour after she had taken a ﬁfth dose of bacampicillin 1200 mg. In the second episode, she had mild itching and edema of the lips and moderate cutaneous itching and swelling about 30 minutes after making love with her husband, who was taking bacampicillin 1200 mg bd and had taken a tablet about 2 hours before. He had used a condom as contraception, and so the only contact between their mucosae was by kissing. Her symptoms disappeared 2 h after she took cetirizine 10 mg. Some months later, her husband took placebo or bacampicillin 120, 360, or 520 mg on different days, and 2 hour after taking the tablets kissed his wife. She developed mild intraoral itching and itching and wheals on the face and arms 20 min after kissing her husband after he had taken bacampicillin 360 mg.

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Kissing can cause an allergic reaction if one of the lovers is sensitized to a compound that has just been taken by the other. This holds true for both drugs and food (10A , 11A ). Whether a similar reaction can occur if the lovers have intercourse without using a condom has, to the best of my knowledge, neither been reported nor investigated. However, allergic reactions to penicillin during in vitro fertilization and intrauterine insemination are possible (12C ). The authors recommended “that in patients known to be penicillin sensitive, penicillin should not be used during transfer of gamete and embryo for assisted reproductive procedures”.

Piperacillin Electrolyte balance Urinary loss of potassium and interstitial nephritis are well recognized adverse effects of piperacillin. Since patients in ICU may have increased risks of renal complications, serum electrolyte concentrations have been measured in 43 patients before and after piperacillin administration and in 40 patients who were given other antibiotics (13c ). The groups were comparable in regard to age and severity of disease and all had normal serum creatinine concentrations before the study. Serum concentrations of magnesium, potassium, and, to a lesser degree, calcium fell signiﬁcantly 36 hours after the start of therapy in patients who were given piperacillin, but not in patients who were given other antibiotics. The fall was most pronounced in the subgroup of patients who were also given furosemide. The authors concluded that “treatment with piperacillin may cause or aggravate electrolyte disorders and tubular dysfunction in ICU patients, even when serum creatinine [is] normal” and that “the mechanism is probably exacerbation of pre-existing tubular dysfunction”. Serum concentrations of electrolytes, including magnesium, should be regularly monitored and, if necessary, supplements should be given to patients in ICU who are receiving piperacillin. This may hold true for all patients receiving piperacillin. Hematologic Over the years, several cases of neutropenia after treatment with piperacillin

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

with or without tazobactam have been described, especially in children (14A , 15A , 16c ). Now another adult case can be added (17A ). • A 77-year-old man with chronic obstructive lung disease and pneumonia received piperacillin 4 g + tazobactam 0.5 g every 6 hours. The neutrophil count gradually fell to zero after 24 days. Piperacillin + tazobactam was withdrawn and lenogastrim was given. Within 4 days, the number of neutrophils started to increase. Lenograstim was withdrawn, and the number of neutrophils returned to normal within a week. He made a full recovery.

Whether the rate of hematological adverse effects is higher for piperacillin + tazobactam than for other penicillins is unclear, as is the question of whether neutropenia is more frequent in children than in adults or more frequent in patients with cystic ﬁbrosis than in patients with other conditions (18A ). It would anyway be wise to follow patients treated with piperacillin, either alone or in combination with tazobactam, with particular attention.

CEPHALOSPORINS (SED-14, 821; SEDA-24, 276; SEDA-25, 283; SEDA-26, 264)

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25 mg/l respectively. In the other two patients, the serum concentrations after dialysis were 14 and 54 mg/l, suggesting high concentrations before dialysis. There was complete recovery in four of the patients. One, a 73-year-old woman, died of multi-organ failure with refractory status epilepticus and coma. The authors referred to four other reports of cefepime-induced generalized seizures. They seriously questioned “whether the actual frequency of this complication might not be underestimated, due to insufﬁcient knowledge, underreporting, and/or lack of speciﬁcity of clinical features”. Another recent case report may support their assumption (20A ). • An 82-year-old man on chronic hemodialysis, got pneumonia, for which he was given intravenous cefepime, 1 g/day. After 4 days he developed a seizure and cefepime was withdrawn. Hemodialysis was started and his conscious level improved. On the next day, after a second hemodialysis, he recovered completely.

The authors recommended that in elderly patients with severe renal impairment other agents than cefepime should be considered.

Cefepime

Ceftriaxone

Nervous system Cefepime can cause neuropsychiatric and neurotoxic symptoms, including coma and seizures (SEDA-26, 264). There has been a recent report of ﬁve patients who developed severe symptoms after receiving cefepime (19Ar ). The patients, three men and two women, aged 16–75 years, received 2 g/day, (n = 3), 4 g/day, (n = 1), or 9 g/day, (n = 1). The symptoms started 12–16 days after the start of therapy. In all cases, the initial neurological symptoms (disorientation, confusion, and reduced consciousness) were progressive and were attributed to the infection. Facial or multifocal myoclonic movements occurred subsequently and were rapidly followed by convulsive or non-convulsive status epilepticus. The dose of ceﬁpime had not been adjusted for renal function in any of the patients. Cefepime serum concentrations were measured in three cases, and were 72, 73, and 134 mg/l. All the patients underwent hemodialysis, and the serum concentrations of cefepime fell to 4.3, 21, and

Hematologic Hemolytic anemia due to ceftriaxone is a rare, serious, and potentially fatal adverse effect. Of 10 patients, seven died, six of them children (21A –25A ). Another case has recently been described (26A ). • A 5-year-old girl, who had taken co-trimoxazole prophylaxis for recurrent urinary tract infections since the age of 1 year, received ceftriaxone intramuscularly for 7 days at the age of 5 years, uneventfully. Six months later she was given intramuscular ceftriaxone 50/mg/kg/day and amikacin 20 mg/kg for a new urinary tract infection. After 3 days she became unexpectedly ill and had a generalized seizure 30 min after the administration of both drugs. A day later, her seizures recurred, she rapidly became worse, and she was referred to an ICU for ventilatory support. There she had two cardiac arrests and was resuscitated successfully. Her hematocrit and reticulocyte count were 8% and 0.2% respectively. A direct antiglobulin test was strongly positive. She was given methylprednisone 5 mg/kg/day and three units of red blood cells. The direct antiglobulin test became negative on day 3, and the dose of methylprednisone was reduced to 3 mg/kg/day but then had to be increased again to

246 5 mg/kg/day because of recurring hemolysis. The steroid was withdrawn uneventfully after 8 weeks. She remained well and had no neurological deﬁcit.

According to the authors, this is the only child who has survived after severe ceftriaxoneinduced hemolytic anemia. They also stated that in children the hemolysis usually starts within minutes to some few hours after the administration of the drug, whereas in adults it starts after a period of days. It has previously been found that a degradation product of ceftriaxone can cause hemolysis (SEDA-24, 277). Whether this is the cause in all cases, and whether there is a difference in the breakdown of ceftriaxone in children and adults is not known. Whatever the mechanisms, this adverse effect is very serious. The outcome depends on very rapid intervention, and high-dose corticosteroids appear to be effective. Immunologic An acute, life-threatening, anaphylactic reaction has been described in a child who received his ﬁrst intravenous injection of ceftriaxone (27A ). • A 3-year-old boy developed a high fever and a petechial rash. In the past he has been treated four times with amoxicillin for upper respiratory tract infections without allergic reactions. At presentation he had multiple petechiae over the trunk and limbs. There were no signs of meningeal irritation. He was given intravenous ceftriaxone 100 mg/kg and after 1 minute developed excitation and a generalized papular urticarial rash. His heart rate increased to 160/min and the blood pressure was not measurable. He was given subcutaneous adrenaline 0.15 mg plus intravenous clemastine fumarate 2 mg, dexamethasone 3 mg, and ﬂuids. Within 15 minutes his circulation was restored and the urticarial rash abated. Instead of ceftriaxone, he was given chloramphenicol for 7 days, and no further allergic reaction was observed. Neisseria meningitidis, sensitive to chloramphenicol and ceftriaxone, was cultured from his blood and spinal ﬂuid. He was discharged well 12 days after admission. One month later, skin tests for ceftriaxone and benzylpenicillin were negative, as was a test for ceftriaxone-speciﬁc IgE. Because hypersensitivity could not be demonstrated, a controlled intravenous challenge with ceftriaxone 100 mg/kg was performed, and 20 seconds later there was again excitation and a generalized papular urticarial rash. He was treated as before and recovered within 15 minutes.

According to the authors, anaphylaxis after a single injection of ceftriaxone without previous exposure to the drug is very rare, and

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they referred to only one previous report (28A ). However, despite the fact that hypersensitivity could not be demonstrated by skin testing or the presence of ceftriaxione-speciﬁc IgE, the outcome of the challenge to ceftriaxone very clearly pointed to an anaphylactic reaction.

CARBAPENEMS

(SEDA-26, 265)

Meropenem Of all the drugs that have been implicated in drug-induced toxic epidermal necrolysis, antimicrobial drugs account for 29–42% (now more than 100 in number) (29R , 30R ), and almost all antimicrobial drugs have been implicated. Meropenem can now be added to this long list (31R ). • A 75-year-old woman developed acute pneumonia. She was ﬁrst given oral co-amoxiclav, ﬂuconazole, and ciproﬂoxacin for 10 days, followed by cefotaxime and amikacin, both intravenously. Six days later, she developed a progressive erythematous rash, soon involving 40% of her body surface. The antibiotics were withdrawn and she was rehydrated and given intravenous immunoglobulins 0.75 g/kg for 5 days, but not systemic corticosteroids. She then developed severe septic shock because of a combination of two very resistant bacterial strains and was given meropenem 1 g and teicoplanin 800 mg bd. However, within 2 days her skin lesions recurred, extending to previously uninvolved skin areas and including over 60% of her body. A biopsy showed typical features of toxic epidermal necrolysis. Meropenem was withdrawn and replaced by aztreonam. However, she died 5 days later.

Neither meropenem nor teicoplanin has previously been reported to have caused toxic epidermal necrolysis, but imipenem, which is related to meropenem, has (32R ). The authors stated that to the best of their knowledge, this was the ﬁrst report of a possible crossreaction between two classes of antibiotics in causing toxic epidermal necrolysis. The time between the ﬁrst administration and the epidermal necrolysis is considerable shorter in recurrence or provocation testing (33A , 34R ). They also claimed that it is likely that the beta-lactam ring is responsible for this hypersensitivity reaction, citing the evidence that the patient had been given amoxicillin 15 days before the cephalosporin, and that could have

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

served as the sensitizing event. They did not discuss whether aztreonam, a monobactam, also could have caused a cross-reaction; however, it has been involved in two cases of fatal toxic epidermal necrolysis (35A ).

MONOBACTAMS Aztreonam Immunologic When Escherichia coli was cocultured with mouse peritoneal macrophages and exposed to aztreonam and ceftazidime, there was enhanced secretion of TNF-alpha; imipenem did not do this (36E ). Both aztreonam and ceftazidime enhanced LPS release from E. coli while imipenem did not, consistent with the observed differences in TNF-alpha release. All three antibiotics increased E. coli-induced expression of inducible nitric oxide synthase (iNOS), as assessed by both mRNA and protein.

TETRACYCLINES

(SEDA-14, 906; SEDA-24, 278; SEDA-25, 284; SEDA-26, 265)

Doxycycline Nervous system Peripheral neuropathy from doxycycline has recently been reported (37A ). • A 61-year-old doctor with recurrent bronchopneumonia took two courses of doxycycline. During the ﬁrst course he had persistent numbness in his feet. During the second course, a few months later, he noticed after only 2 or 3 days that the numbness accelerated markedly and was associated with a low threshold for muscle cramps in the feet. He stopped taking doxycycline and during the following weeks noticed slight improvement. However, some symptoms persisted and he had neurological investigations. A wide range of clinical and laboratory tests showed no cause for his neuropathy. A search for an association between doxycycline and polyneuropathy failed to identify any documented cases. He also made an inquiry to the Swedish Adverse Drug Reactions Advisory Committee, resulting in information about three cases of “paresthesia”, two cases of “sensitivity disturbance”, and one case of “neuropathy”. The last was a man who had pain and paresthesia in the feet, arms, and face after taking doxycycline 100 mg/day for 2 weeks for prostatitis. The symptoms began to wane 1 week after treatment was stopped, and disappeared completely 1 week later.

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Minocycline Teeth Staining of permanent teeth by tetracyclines takes place during tooth development by well documented mechanisms. Tetracycline forms a complex with calcium orthophosphate during calciﬁcation, which then darkens with exposure to light. With minocycline, however, the staining occurs after eruption in previously normal-colored fully mineralized adult teeth. There are at least four theories about the mechanisms of this adverse effect. • That minocycline attaches to the acquired pellicle glycoproteins (the “extrinsic theory”) (38A ). This in turn etches the enamel, and cycles of demineralization and remineralization occur. It oxidizes on exposure to air or as a result of bacterial activity, and the ﬁnal product is insoluble black quinine. • That minocycline, bound to plasma proteins, is deposited in collagen-rich tissues, such as pulp, teeth, and bones (the “intrinsic” theory). Minocycline is then slowly oxidized over time with exposure to light (39A , 40E ). • That a breakdown product of minocycline chelates with iron to form insoluble complexes (41c , 42E ). • That minocycline is deposited in dentine during dentinogenesis, accelerating or changing the process (43R ). Whatever the mechanism(s) might be, the sad fact is that staining of adult dentition occurs in 3–6% of patients who take long-term minocycline 100 mg/day (38A , 44R ). The onset of discoloration can occur at any time from 1 month to many years after the start of treatment (41c , 44R ). The importance of avoiding permanent staining of the teeth cannot be over-emphasized, as many patients with acne are already prone to negative psychological effects. Minocycline should therefore be prescribed only with great care. Immunologic Minocycline as a cause of drug-induced lupus-like syndrome was commented on last year (SEDA-26, 266), but new cases continue to appear, including two with acute respiratory failure. • A 16-year-old girl, who had taken minocycline for acne for more than 2 years, developed a severe cough with paroxysms (45A ). She had also a

248 recent history of joint pain with swelling and stiffness, fever, general weakness, and weight loss of 9 kg. She had been treated as an outpatient for presumed pneumonia with multiple antibiotics, but developed progressive dyspnea. Pulmonary lupus was suspected, and minocycline was withdrawn. She was treated with an initial 3-day course of intravenous methylprednisolone 20 mg tds, and then prednisone 40 mg bd for 2 weeks. She improved very rapidly, and the prednisone was gradually reduced over 7 weeks.

According to the authors, the patient fulﬁlled all the criteria for a diagnosis of drug-induced lupus-like syndrome, i.e. no history of lupus erythematosus before minocycline therapy, the presence of antinuclear antibodies, at least one clinical feature of lupus erythematosus, and prompt recovery after withdrawal of minocycline. She also had positive antihistone antibodies, compatible with drug-induced lupus-like syndrome. • A 54-year-old woman with a 2-week history of low-grade fever, dry cough, and dyspnea was given levoﬂoxacin for a presumed community-acquired pneumonia (46A ). Five days later she developed severe respiratory failure and was mechanically ventilated and given antibiotics (imipenem and

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clarithromycin). Microbiological examination of tracheobronchial aspirates was negative for pathogenic organisms, as were serological tests for common agents of atypical pneumonia. She progressively improved and was taken off the ventilator after 6 days and discharged about 10 days later, but 14 days later was readmitted with rapidly progressive pulmonary failure requiring mechanical ventilation. It then transpired that 2 weeks before the ﬁrst episode of respiratory failure, she had started to take oral minocycline for acne vulgaris and had started to take it again 24 hours before the second episode. The minocycline was stopped and she was given intravenous methylprednisolone. She improved rapidly, and for 12 months after minocycline withdrawal has remained free of respiratory symptoms.

It is a good rule of the thumb that these patients should never be re-challenged with minocycline, as symptoms tend to recur (47A , 48A , 49R ). If minocycline is used to treat rheumatoid arthritis, the patient should be followed very carefully, as worsening arthritis may be erroneously attributed to the underlying disease. It should also be emphasized that in the search for a cause of joint pains, minocycline should always be considered (50A ).

REFERENCES 1. Midtvedt T. The ECO-SHADOW concept—a new way of following envitronmental impacts of antimicrobials. In: Kümmerer K, editor. Pharmaceuticals in the environment. Sources, fate, effects and risks. Berlin, Heidelberg, New York: SpringerVerlag, 2001: 230–6. 2. George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne O, Vondracek T. Druginduced thrombocytopenia: systematic review of published case reports. Ann Intern Med 1998; 129: 886–90. 3. Wright MS. Drug-induced hemolytic anemias: increasing complications to therapeutic interventions. Clin Lab Sci 1999; 12: 115–18. 4. Arneborn P, Palmblad J. Drug-induced neutropenia—a survey for Stockholm 1973–1978. Acta Med Scand 1982; 212: 289–92. 5. Baumelou E, Gueguet M, Mary JY. Epidemiology of aplastic anemia in France: a case-control study. I. Medical history and medical use. The French Cooperative Group for Epidemiological Study of Aplastic Anemia. Blood 1993; 81: 1471– 8. 6. Anonymous. Anti-infective drug use in relation to the risk of agranulocytosis and aplastic anemia. A report from the International Agranulocytosis

and Aplastic Anemia Study Group. Arch Intern Med 1989; 149: 1036–40. 7. Huearta C, Rodriguez, LAG. Risk of clinical blood dyscrasia in a cohort of antibiotic users. Pharmacotherapy 2002; 22: 630–6. 8. Conde-Salazar L, Guimaraens D, Gonzales MA, Mancebo E. Occupational allergic contact urticaria from amoxicillin. Contact Dermatitis 2001; 45: 109. 9. Liccardi G, Gilder JA, D’Amato M, D’Amato G. Drug allergy transmitted by passionate kissing. Lancet 2002; 359: 1700. 10. Wuthrich B. Oral allergy syndrome to apple after a lover’s kiss. Allergy Eur J Allergy Clin Immunol 1997; 52: 235–6. 11. Wuthrich B, Dasscher M, Borrelli S. Kiss-induced allergy to peanuts. Allergy Eur J Allergy Clin Immunol 2001; 56: 913. 12. Smith YR, Hurd WW, Menge AC, Sanders GM, Ansbacher R, Randolph JF Jr. Allergic reactions to penicillin during in vitro fertilization and intrauterine insemination. Fertil Steril 1992; 58: 847–9. 13. Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002; 28: 520–2.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines 14. Gerber L, Wing EJ. Life-threatening neutropenia secondary to piperacillin/tazobactam therapy. Clin Infect Dis 1995; 21: 1047–8. 15. Ruitz-Irastorza G, Barreiro G, Aguirre C. Reversible bone marrow depression by high-dose piperacillin/tazobactam. Br J Haematol 1996; 95: 611–12. 16. Reichardt P, Handrick W, Linke A, Schille R, Kiess W. Leucocytopenia, thrombocytopenia and fever related to piperacillin/tazobactam treatment: a retrospective analysis in 38 children with cystic ﬁbrosis. Infection 1999; 27: 355–6. 17. Ortega Garcia MP, Guevara Serrano J, Gil Gomez I, Iglesias Iglesias AA, Fernandez Villalba EM. Neutropenia reversibile secundaria al tratamiento con piperacillina/tazobactam. Atencion Pharmaceutica 2002; 4: 44–8. 18. Thickett, KM, Wildman, MJ, Fegan CD, Stableforth DE. Hemolytic anemia following treatment with piperacillin in a patient with cystic ﬁbrosis. J Antimicrob Chemother 1999; 43: 435–6. 19. Chatellier D, Jourdain M, Mangalaboyi J, Ader F, Chopin C, Derambure P, Fourrier F. Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med 2002; 28: 214–17. 20. Ferrara N, Abete P, Giordano M, Ferrara P, Carnovale V, Leosco D, Beneduce F, Ciarambino T, Varricchio M, Rengo F. Neurotoxicity induced by cefepime in a very old hemodialysis patient. Clin Nephrol 2003; 59: 388–90. 21. Garatty G, Postoway N, Swellenback J, McMahill PC. A fatal case of ceftriaxone (Rocepine)induced hemolytic anemia associated with intravascular immune hemolysis. Transfusion 1991; 31: 176–9. 22. Bernini JC, Mustafa MM, Sutor LJ, Buchanan GR. Fatal hemolysis induced by ceftriaxone in a child with sickle cell anemia. J Paediatr 1995; 126: 813–15. 23. Scimeca PG, Weinblatt ME, Boxer R. Hemolysis after treatment with cefriaxone. J Paediatr 1996; 128: 163–4. 24. Moallem HJ, Garratty G, Wakeham M, Dial S, Oligario A, Gondi A, Rao SP, Fikrig S. Cetriaxonerelated fatal hemolysis in an adolescent with perinatally acquired human immunodeﬁciency virus infection. J Paediatr 1998; 133: 279–81. 25. Meyer O, Hackstein H, Hoppe B, Göbel FJ, Bein G, Salama A. Fatal immune hemolysis due to a degradation product of ceftriaxone. Br J Haematol 1999; 105: 1084–5. 26. Citak A, Garratty G, Ücsel R, Karabocuoglu M, Uzel N. Cetriaxone-induced haemolytic anemia in a child with no immune deﬁciency or haemolytic disease. J Paediatr Child Health 2002; 38: 209–10. 27. Ernst MR, Van Dicken, PJ, Kabel PJ, Draiaisma IMTh. Anaphylaxis after ﬁrst exposure to ceftriaxone. Acta Paediatr 2002; 91: 355–9. 28. Romano A, Piunti E, Di Fonsa M, Viola M, Venuti A, Venemalm L. Selective immediate hypersensitivity to ceftriaxone. Allergy Eur J Allergy Clin Immunol 2000; 55: 415–16.

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29. Roujeau JC, Guillaume JC, Fabre JP, Parsons RW, Krizek TJ. Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France 1981–1985. Arch Dermatol 1990; 126: 37– 42. 30. Schøpf E, Stühmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens–Johnson syndrome: an epidemiologic study from West Germany. Arch Dermatol 1991; 127: 839–42. 31. Paquet P, Jacob E, Damas P, Pierard GE. Recurrent fatal drug-induced toxic epidermal necrolysis (Lyell’s syndrome) after putative beta-lactam cross-reactivity: case report a scrutiny of antibiotic imputability. Crit Care Med 2002; 30: 2580–3. 32. Brand R, Rohr JB. Toxic epidermal necrolysis in Western Australia. Aust J Dermatol 2000; 41: 31–3. 33. Dreyfuss, DA, Gottlieb LJ, Wilkerson D, Guillaume JC. Survival after a second episode of toxic epidermal necrolysis. Ann Plast Surg 1988; 20: 146–7. 34. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990; 23: 1039–58. 35. McDonald BJ, Singer JW, Bianco JA. Toxic epidermal necrolysis possibly linked to aztreonam in bone marrow transplant patients. Ann Pharmacother 1992; 26: 34–5. 36. Cui W, Lei MG, Silverstein R, Morrison DC. Differential modulation of the induction of inﬂammatory mediators by antibiotics in mouse macrophages in response to viable Gram-positive and Gram-negative bacteria. J Endotoxin Res 2003; 9: 225–36. 37. Olsson R. Can doxycycline cause polyneuropathy? J Intern Med 2002; 251: 361–2. 38. Berger RS, Mandel EB, Hayes RR. Minocycline staining of the oral cavity. J Am Acad Dermatol 1989; 21: 1300–1. 39. Bowles WH, Bokmeyer TJ. Staining of adult teeth by minocycline: binding of minocycline by speciﬁc proteins. J Esthet Dent 1997; 9: 30–4. 40. Bowles WH. Protection against minocycline pigment formation by ascorbic acid (vitamin C). J Esthet Dent 1998; 10: 182–6. 41. Rosen T, Hoffmann TJ. Minocycline-induced discoloration of the permanent teeth. J Am Acad Dermatol 1989; 21: 569–70. 42. Poliak SC, DiGiovanna JJ, Gross EG, Gantt G, Peck GL. Minocycline-associated tooth discoloration in young adults. J Am Med Assoc 1985; 254: 2930–2. 43. Good ML, Hussey DL. Minocycline: stain devil? Br J Dermatol 2003; 149: 237–47. 44. Westbury LW, Najera A. Minocycline-induced intraoral pharmacogenic pigmentation: case reports and review of the literature. J Periodontol 1997; 68: 84–91. 45. Christodoulo CS, Emmanuel P, Ray RA, Good RA, Schnapf BC, Cawkwell GD. Respiratory distress due to minocycline-induced pulmonary lupus. Chest 1999; 115: 1471–3.

250 46. Oddo M, Liaudet L, Lepori M, Broccard AF, Schaller MD. Relapsing acute respiratory failure induced by minocycline. Chest 2003; 123: 2146–8. 47. Singer SJ, Piazza-Mepp TD, Girardi LSA, Moledina NB. Lupus-like reaction associated with minocycline. J Am Med Assoc 1997; 227: 295–6. 48. Masson C, Chevailler A, Pascaretti C, Legrand E, Bregeon C, Audra A. Minocycline-related lupus. J Rheumatol 1996; 23: 2160–1.

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49. Lawson TM, Amos N, Bulgen D, Williams HD. Minocycline-induced lupus: clinical features and response to rechallenge. J Rheumatol 2001; 40: 329–35. 50. Bonnotte B, Gresset AC, Chauffert B, Courois JM, Martin F, Collet E, Sgro C, Lorcerie B. Symptomes évocateurs de maladie de système chez des patients prenant du chlorhydrate de minocycline. Presse Méd 1999: 28: 1105–8.

Alexander Imhof

26

Miscellaneous antibacterial drugs

AMINOGLYCOSIDES (SED-14, 837; SEDA-24, 283; SEDA-25, 287; SEDA-26, 271) Sensory systems In a retrospective study in 81 men and 29 women, hearing loss of 15 decibels at two or more frequencies, or at least 20 decibels at at least one frequency, was found in 18% of patients treated with aminoglycosides (amikacin, kanamycin, and/or streptomycin) (1C ). In those treated with kanamycin the rate was 16%. Age, sex, treatment duration, total aminoglycoside dose, and ﬁrst serum creatinine concentration were not associated with hearing loss. Urinary tract In a retrospective study, the rate of nephrotoxicity at the end of treatment with aminoglycosides was 7.5% (kanamycin 4.5%) (1C ). Patients who developed nephrotoxicity had a longer duration of treatment and received larger total doses. In 89 critically ill patients with a creatinine clearance over 30 ml/min who were treated with gentamicin or tobramycin 7 mg/kg/day independent of renal function, with subsequent doses chosen on the basis of the pharmacokinetics of the ﬁrst dose, signs of renal impairment occurred in 14%; in all survivors renal function recovered completely and hemoﬁltration was not needed (2C ). In a prospective, non-interventional surveillance study of 249 patients receiving a once-daily aminoglycoside (17% amikacin and 83% gentamicin), serum creatinine increased by more than 50% in 12%; none developed oliguric renal insufﬁciency (3C ). Renal damage correlated signiﬁcantly with: a high aminoglycoside trough concentration (over 1.1 μg/ml); a

hemoglobin concentration below 10 g/dl; hospital admission for more than 7 days before aminoglycoside treatment; and aminoglycoside treatment for more than 11 days. Immunologic In a prospective study of the results of skin patch testing in 149 patients who were scheduled for ear surgery, 14% of the patients had a positive skin reaction to one of the aminoglycosides (13% for gentamicin, 13% for neomycin) (4C ). In 16% of the patients with chronic otitis media and 6.7% of the patients with otosclerosis there was allergy to one of the aminoglycosides commonly found in antibiotic ear-drops. Patients who had previously received more than ﬁve courses of antibiotic ear-drops had a greater tendency to develop allergy to the aminoglycosides (35%). Cross-reactivity between aminoglycoside antibiotics has long been known. Aminoglycoside antibiotics can be categorized in two groups, depending on the aminocycolitol nucleus: streptidine (streptomycin) and deoxystreptamine (neomycin, kanamycin, gentamicin, paramomycin, spectinomycin, and tobramycin). Another antigenic determinant is neosamine, a diamino sugar present in neomycin and, with minor changes, also in paramomycin, kanamycin, tobramycin, amikacin, and isepamicin. Streptomycin shares no common antigenic structures with the other aminoglycoside antibiotics, and cross-sensitivity with streptomycin has not been reported. Acute contact dermatitis was described in 30-yearold man after rechallenge with gentamicin 80 mg; a patch test was positive for gentamicin, neomycin, and amikacin (5A ).

Amikacin © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Sensory systems Retinal toxicity attributable to intravitreal aminoglycosides for endoph-

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252 thalmitis has previously been reported. Macular toxicity followed the use of intravitreal amikacin 0.2 mg for postoperative endophthalmitis in a 69-year-old white woman (6A ). • A 43-year-old man, who was receiving hemodialysis through a permanent catheter developed severe irreversible sensorineural hearing loss after using an amikacin–heparin lock for 16 weeks (7A ). He suddenly developed a high-frequency sensorineural hearing loss of 40 decibels. His condition progressed over 1 week, despite immediate withdrawal of the amikacin-heparin lock, and he developed severe irreversible hearing loss below 80 decibels for both high and low frequencies.

Arbekacin Skin Contact dermatitis due to arbekacin has recently been reported (8A ).

Gentamicin Sensory systems Gentamicin ear-drops can cause serious adverse effects (e.g. vertigo, imbalance, ataxia, oscillating vision, hearing loss, and tinnitus) when they are used by patients with perforated tympanic membranes or tympanostomy tubes (9R ). The symptom complex known as visual vestibular mismatch can be caused by peripheral vestibular disease. In a retrospective study of 28 patients with Menière’s disease, 17 had visual vestibular mismatch; gentamicin therapy increased the number of positive answers (10c ). In a retrospective analysis of 85 patients treated with intratympanic gentamicin, using a ﬁxed-dose regimen of 26.7 mg/ml tds on 4 consecutive days, hearing loss occurred in 26% of individuals (11C ). In a case of accidental injection of gentamicin 20 mg into the vitreous in a 70-year-old man during vitrectomy, no toxic signs occurred after the operation (12A ). Urinary tract Local gentamicin treatment in surgical revision is well established. Nephrotoxicity is uncommon, but acute renal insufﬁciency occurred in an 83-year-old woman after two-stage revision of an infected knee prosthesis with gentamicin-impregnated beads and

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block spacers (13A ). The combined use of beads and a cement block spacer, both gentamicin impregnated, may have caused this severe complication. A 43-year-old black woman with a 13-year history of lupus developed severe acute tubular necrosis secondary to gentamicin (14A ). In animals melatonin (15E , 16r ) or l-carnitine (17E ) protected the kidneys against oxidative damage and the nephrotoxic effect of gentamicin. Susceptibility factors Several factors can predispose a patient to aminoglycoside ototoxicity: the A1555G chromosomal mutation, pre-existing disorders of hearing and balance, hypovolemia, bacteremia, liver and renal dysfunction, and the co-administration of other ototoxic medications. The cumulative dose and duration of aminoglycoside therapy are more important than serum concentrations. Drug interactions Administration of an aminoglycoside followed by furosemide increases the risk of ototoxicity. A 60-year-old white woman developed ototoxicity after only 5 days of gentamicin therapy (500 mg, 6.8 mg/kg/day) and one dose of furosemide 20 mg (18A ).

Isepamicin The bone tissue penetration of isepamicin has been studied in an open, non-comparative study, and the results compared with microbiologic data to estimate the clinical efﬁcacy of isepamicin in bone infections (19c ). In 12 subjects of similar age, body weight, height, and creatinine clearance, who were undergoing elective total hip replacement, a single parenteral dose of isepamicin 15 mg/kg achieved concentrations in both cancellous and cortical bone tissue greater than the minimum concentrations required to inhibit the growth of 90% of strains of most of the susceptible pathogens commonly involved in bone infections. Urinary tract Fleroxacin had a protective effect on isepamicin-induced nephrotoxicity in rats (20E ).

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Neomycin Immunologic Of 200 patients with psoriasis four had a positive patch test to neomycin (21C ).

Netilmicin Sensory systems In patients with acute bacterial conjunctivitis there were adverse drug reactions in two of 106 patients treated with netilmicin and four of 103 treated with gentamicin (22C ). The adverse effects included redness, itching, and burning, and none was serious.

Streptomycin Immunologic Anaphylaxis has been attributed to transdermal absorption of streptomycin. • A 59-year-old farmer with a 10-year history of chronic hand eczema due to delayed hypersensitivity to thiurams developed anaphylaxis when he absorbed streptomycin through skin lesions on his hand (23A ). While he was giving an injection to a cow, he accidentally spilled some streptomycin solution on his hand, and immediately afterwards developed angio-edema of the hand, followed in a few minutes by generalized urticaria and angioedema, with dyspnea, dizziness, and severe hypotension. Streptomycin-induced anaphylactic shock occurred in a 41-year-old woman during oocyte retrieval procedures for in vitro fertilization (24A ).

Susceptibility factors The A1555G mutation in the mitochondrial 12S ribosomal RNA gene is often found in patients with hearing loss after aminoglycoside exposure. A second pathogenic mutation in this gene, deletion of thymidine at position 961 with varying numbers of cytosine insertions (delT961Cn), has recently been found to predispose patients to aminoglycosideinduced deafness (25E ).

Tobramycin Respiratory Nebulized antipseudomonal antibiotics, such as tobramycin, improve lung

253 function and reduce the frequency of exacerbations of infections in patients with cystic ﬁbrosis (26r ). In a randomized comparison of nebulized tobramycin and nebulized colistin in patients with cystic ﬁbrosis, 26 of 53 patients treated with tobramycin had at least one respiratory adverse event, most commonly pharyngitis (27C ). In 520 patients, inhaled tobramycin (300 mg bd for three 28-day cycles, each cycle being separated by a 28-day period of no treatment) was compared with placebo. Respiratory function was signiﬁcantly improved as early as the second week and remained so for the rest of the study, even during periods without aerosol treatment. There was also a parallel reduction in the relative risk of hospitalization, the number of days of hospitalization, and the number of days of intravenous antibiotic treatment (28C ). In a comparison of different dosage regimens, inhaled tobramycin caused bronchial obstruction (29c ). However, after 10 min of inhalation, lung function returned to baseline; the effect was independent of dose. Sensory systems Of 60 adult patients with cystic ﬁbrosis randomized to tobramycin, either 10 mg/kg/day or 3.3 mg/kg tds, two patients (one in each group) had bilateral impairment in pure tone audiography after treatment (30C ). Urinary tract Toxicity studies have not previously shown nephrotoxicity or ototoxicity with nebulized tobramycin. The introduction or selection of resistant bacteria is relatively rare but remains a matter of concern (31R ). However, the ﬁrst case of nephrotoxicity due to inhaled tobramycin has recently been described in a 20-year-old patient with cystic ﬁbrosis who developed acute non-oliguric renal insufﬁciency after taking inhaled tobramycin 300 mg bd for 1 week; the clinical and renal biopsy ﬁndings were consistent with aminoglycosideinduced changes (32A ). Immunologic Hypersensitivity to inhaled tobramycin has been reported in a 9-year-old boy who developed a rash after a course of gentamicin (33A ). The rash resolved after withdrawal, but returned all over his body when inhaled tobramycin was given. He was desensitized using escalating doses of inhaled tobramycin, tolerated the procedure well, and was still using once-a-day tobramycin 9 months after desensitization.

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CHLORAMPHENICOL AND RELATED DRUGS (SED-14, 848; SEDA-24, 287; SEDA-25, 292; SEDA-26, 273)

Chloramphenicol Hematologic Chloramphenicol causes two types of hemotoxicity. First, reversible bone marrow depression, which is common. Second, aplastic anemia, which is rarer, irreversible, and often fatal (34E , 35M , 36R ). Chloramphenicol inhibits mRNA translation by the 70S ribosomes of prokaryotes, but does not affect 80S eukaryotic ribosomes. Most mitochondrial proteins are encoded by nuclear DNA and are imported into the organelles from the cytosol where they are synthesized. Mitochondria retain the capacity to translate, on their own ribosomes, a few proteins encoded by the mitochondrial genome. True to its prokaryotic heritage, mitochondrial ribosomes are similar to those of bacteria, meaning that chloramphenicol inhibits protein synthesis by these ribosomes. Chloramphenicol-induced anemia is believed to result from this inhibition (37E ).

FLUOROQUINOLONES (SED-14, 852; SEDA-23, 277; SEDA-25, 293; SEDA-26, 274) Several newer quinolones have either been withdrawn from the market, or had their uses severely restricted because of adverse effects: clinaﬂoxacin because of phototoxicity and hypoglycemia; grepaﬂoxacin because of prolongation of the QTc interval and resultant torsade de pointes; sparﬂoxacin because of phototoxicity; and trovaﬂoxacin because of hepatotoxicity (38R ). Cardiovascular Preclinical and clinical trial data and data from phase IV studies have shown that levoﬂoxacin, moxiﬂoxacin, and gatiﬂoxacin cause prolongation of the QTc interval, but the potential for torsade de pointes is rare and is inﬂuenced by several independent variables (e.g. concurrent administration of class Ia and III antidysrhythmic agents) (39R ).

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Musculoskeletal Quinolones can affect the articular cartilage and the epiphyseal growth plate in immature animals; in children they should be restricted to carefully selected indications (such as the use of ciproﬂoxacin in cystic ﬁbrosis). Tendinitis and tendon rupture can also be caused by quinolones (40R , 41R ). In a retrospective analysis, quinolone arthropathy developed during the ﬁrst 3 weeks, and depended on the patient’s age and history (42C ). It resolved fully within 7 days to 3 months after drug withdrawal.

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 indications for trovaﬂoxacin has been restricted. In a multicenter, double-blind, randomized comparison of trovaﬂoxacin 200 mg and clarithromycin 500 mg bd in 176 subjects with acute exacerbations of chronic bronchitis, the most common adverse effects of trovaﬂoxacin were nausea (5%), dizziness (5%), vomiting (3%), and constipation (3%) (43C ).

Ciproﬂoxacin Cardiovascular Ciproﬂoxacin causes prolongation of the QTc interval (39R , 44r ). Psychiatric A 27-year-old woman developed an acute psychotic reaction following the use of ciproﬂoxacin eye-drops (1 drop hourly to each eye) (45A ). Sensory systems Ciproﬂoxacin 0.3% ophthalmic drops can cause microprecipitates of pure ciproﬂoxacin in the corneal epithelium (46c ).

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Hematologic Fatal ciproﬂoxacin-associated thrombotic thrombocytopenic purpura (47A ), thrombocytopenia (48C ), and the ﬁrst case of ciproﬂoxacin-associated hemolytic–uremic syndrome (49A ) have been reported. • A 53-year-old white man was given chemotherapy for acute lymphoblastic leukemia and after 4 weeks recovered his blood cell count but developed a fever and was given oral ciproﬂoxacin 500 mg bd. After four doses he developed the typical features of hemolytic–uremic syndrome with microangiopathic hemolytic anemia. The ciproﬂoxacin was withdrawn, and he received ﬁve sessions of plasma exchange. He recovered completely.

Gastrointestinal Ciproﬂoxacin has been associated with diarrhea due to Clostridium difﬁcile (50r ). Immunologic Angioimmunoblastic lymphadenopathy is a rare disorder characterized by generalized lymphadenopathy, fever, hepatosplenomegaly, immune hemolytic anemia, and polyclonal hypergammaglobulinemia. Biopsyproven angioimmunoblastic lymphadenopathy has been reported in a 79-year-old man who had received ciproﬂoxacin (51A ). A Jarisch–Herxheimer reaction to ciproﬂoxacin has been reported (52A ). • A 14-year-old girl developed tachycardia, hypotension, and disseminated intravascular coagulation after her ﬁrst dose of oral ciproﬂoxacin 500 mg for presumed pyelonephritis. A peripheral blood smear showed spirochetes consistent with Borrelia spp.

Musculoskeletal Ciproﬂoxacin can be associated with Achilles tendinitis or rupture. Of 72 lung transplant recipients who received ciproﬂoxacin, 20 had Achilles tendon involvement (tendinitis 15, rupture ﬁve) (53C ). Tendon rupture occurred at a lower dosage of ciproﬂoxacin than tendinitis and the mean recovery duration was signiﬁcantly longer. Drug interactions Methotrexate elimination can be delayed by ciproﬂoxacin. Two children with malignant diseases had reduced elimination of methotrexate (12 g/m2 4-hourly) when they took ciproﬂoxacin 500 mg bd (54A ). Hypoglycemia occurred in a patient treated with insulin and ciproﬂoxacin 500 mg bd (48C ). There is pharmacokinetic evidence that plasma concentrations of oral contraceptive steroids

are unchanged by co-administration of ciproﬂoxacin (55R ). Food–drug interactions The systemic availability of ciproﬂoxacin is reduced by 30–36% when it is taken with dairy products (56R ).

Clinaﬂoxacin Skin In a phase III, randomized, investigatorblinded comparison of the safety and efﬁcacy of clinaﬂoxacin with those of piperacillin/tazobactam in the treatment of adults with severe skin and soft-tissue infections, four of 84 patients randomized to clinaﬂoxacin developed phototoxicity (57C ).

Garenoxacin Garenoxacin is an orally and parenterally available, 6-des-ﬂuorinated quinolone, which has a high degree of in vitro activity against a broad range of bacterial pathogens (58R ). Musculoskeletal In dogs garenoxacin concentrations in plasma and joint tissue were higher than those of ciproﬂoxacin and norﬂoxacin (59E ). However, the articular toxicity of garenoxacin was much less than that of the other two quinolones.

Gatiﬂoxacin Gatiﬂoxacin has a broader spectrum of antibacterial activity than the older ﬂuoroquinolones and has good activity against many Grampositive and Gram-negative pathogens, atypical organisms, and some anerobes (60R ). Gatiﬂoxacin is well absorbed from the gastrointestinal tract (oral availability almost 100%), and concomitant administration of a continental breakfast, 1050 kcal, had no effect on its availability (61c ).

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Cardiovascular Clinical trial data and data from phase IV studies have shown that gatiﬂoxacin causes prolongation of the QTc interval (39R ). Recently, four cases of gatiﬂoxacinassociated cardiac toxicity have been reported in patients with known risk factors for this adverse event (62A ). Nervous system Gatiﬂoxacin can cause ataxia and generalized seizures (63A ). Gastrointestinal Diarrhea and nausea were the most common adverse events in several clinical studies of gatiﬂoxacin (60R , 64c , 65C , 66C ). Liver 68A ).

Gatiﬂoxacin can cause hepatitis (67A ,

Drug interactions Previous studies have shown a signiﬁcant reduction in the oral availability of trovaﬂoxacin and ciproﬂoxacin when it is co-administered with an opiate, but oral oxycodone and gatiﬂoxacin can be co-administered without a signiﬁcant reduction in systemic availability (70c ). Four cases of severe persistent hypoglycemia due to gatiﬂoxacin 400 mg/day have been reported in adults with diabetes mellitus who were taking oral hypoglycemic agents (repaglinide, glibenclamide, glimepiride) (71A , 72A ). Numerous reports have documented enhanced hypoprothrombinemia when ﬂuoroquinolones (most notably ciproﬂoxacin) were given with warfarin. This has now also been reported with gatiﬂoxacin (73A ).

Gemiﬂoxacin Gastrointestinal In a randomized, doubleblind, multicenter comparison of a 5-day course of gemiﬂoxacin 320 mg/day with a standard 7-day regimen of clarithromycin 500 mg bd in 712 patients with acute exacerbations of chronic bronchitis, the most frequently reported gemiﬂoxacin-related adverse events were diarrhea (5.1%) and nausea (4.3%) (74C ).

Alexander Imhof

Grepaﬂoxacin Grepaﬂoxacin is a synthetic quinolone with extensive tissue distribution and strong antibacterial activity in vivo (75E , 76c ). However, it was withdrawn in 1999 because of its adverse cardiovascular effects, including torsade de pointes (38R ).

Levoﬂoxacin Of 17 individuals with suspected latent multidrug-resistant tuberculosis treated with pyrazinamide and levoﬂoxacin, 11 developed musculoskeletal adverse effects related to therapy, ﬁve had nervous system effects, and 15 had raised liver enzymes, uric acid, or creatinine kinase (77c ). Cardiovascular Preclinical and clinical trial data and data from phase IV studies have suggested that levoﬂoxacin causes prolongation of the QTc interval (39r ). Nervous system In one study convulsions occurred in two per million levoﬂoxacin prescriptions (78C ). Gastrointestinal Levoﬂoxacin can cause pseudomembranous colitis due to Clostridium difﬁcile (79c ). Of 48 patients taking pyrazinamide 30 mg/ kg/day plus levoﬂoxacin 500 mg/day for 1 year, 27 discontinued therapy within 4 months owing to adverse events. Gastrointestinal intolerance was the major adverse event that resulted in early withdrawal (80c ). Urinary tract Two reports have suggested that levoﬂoxacin can cause tubulointerstitial nephritis (81A ). A case of nephrotoxicity and purpura associated with levoﬂoxacin has recently been reported; allergic interstitial nephritis or vasculitis was believed to be the underlying pathologic process (82A ). • A 73-year-old white man took levoﬂoxacin for a lower urinary tract infection for 3 days and developed palpable purpura and erythematous skin lesions over the lower limbs and trunk, with a markedly reduced urine output. Serum creatinine was 560 μmol/l (6.4 mg/dl). Levoﬂoxacin was withdrawn, and prednisone, furosemide, and intravenous ﬂuids were given. The patient recovered fully over the next 4 weeks.

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Skin A 78-year-old woman developed a rash with blistering 2 days after completing a course of levoﬂoxacin (83A ). The rash progressed to toxic epidermal necrolysis in 7 days. She was treated with intravenous ﬂuids and wound dressings. Her condition improved and she was discharged after 22 days. Musculoskeletal Four cases of Achilles tendinitis have been reported in patients taking levoﬂoxacin (84A ). Two were on chronic dialysis, one was a kidney transplant recipient, and one had chronic vasculitis. In all four cases, tendinitis had an acute onset with bilateral involvement and was incapacitating. In three cases the onset was early during levoﬂoxacin treatment and in one case it began 10 days after the end of treatment. All the patients recovered completely after 3–8 weeks. Drug interactions Numerous reports have documented enhanced hypoprothrombinemia when ﬂuoroquinolones (most notably ciproﬂoxacin) are given with warfarin. This has been reported with levoﬂoxacin in four patients (85A ).

Lomeﬂoxacin Gastrointestinal In a multicenter, prospective, randomized study of oral lomeﬂoxacin 400 mg/day in 182 patients with chronic bacterial prostatitis, the most frequent adverse events were gastrointestinal disorders (86C ).

Moxiﬂoxacin

Gastrointestinal In a prospective pharmacokinetic study in 12 healthy men the most frequent adverse events, possibly or probably related to moxiﬂoxacin, were generally mild or moderate and were mostly diarrhea, nausea, and abdominal pain (89c ). Liver A 69-year-old man who took moxiﬂoxacin 400 mg/day for 5 days developed cholestasis (87A ). Immunologic In vitro, moxiﬂoxacin has immunomodulatory activity through its capacity to alter the secretion of IL1-alpha and TNF-alpha by human monocytes (90E ). Moxiﬂoxacin can cause anaphylactic reactions (91A ). A case of simultaneous drug allergies has been reported (92A ). • A 32-year-old woman had a generalized urticaria 15 min after taking co-amoxiclav and 1 year later developed a non-pruritic micropapular rash some hours after taking moxiﬂoxacin 400 mg,

Drug interactions Drug interactions with moxiﬂoxacin have been reviewed (93r ). Drugs that contain sucralfate or multivalent cations (e.g. Mg2+ , Al3+ , and iron, but not Ca2+ ) impair the absorption of moxiﬂoxacin. Moxiﬂoxacin had no effect on the pharmacokinetics of theophylline or warfarin in combination steady-state conditions. The effect of food on the pharmacokinetics of moxiﬂoxacin was not clinically important. • A 76-year-old man with low-risk myelodysplastic syndrome had a major erythroid response to combination therapy with erythropoietin and moxiﬂoxacin (94A ). The immunomodulatory effects of moxiﬂoxacin may have explained the synergy with erythropoietin.

The reported adverse effects of moxiﬂoxacin are primarily gastrointestinal (nausea, diarrhea) and mild to moderate in severity (87A ). Cardiovascular Moxiﬂoxacin carries a greater risk of QT interval prolongation than ciproﬂoxacin, levoﬂoxacin, and oﬂoxacin (88R ). It should be used with caution in patients with prodysrhythmic conditions and avoided in patients taking antidysrhythmic agents.

Norﬂoxacin Hematologic Eosinophilia occurred in a 35year-old man with alcoholic cirrhosis taking norﬂoxacin 400 mg bd for prophylaxis of spontaneous bacterial peritonitis (95A ).

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Gastrointestinal In a prospective study in women with urinary tract infections treated with pivmecillinam 400 mg bd for 3 days (n = 483) or norﬂoxacin 400 mg bd for 3 days (n = 471), 36% of the pivmecillinam-treated patients and 39% of the norﬂoxacin-treated patients reported adverse events (96C ). Gastrointestinal symptoms were most frequent. Of the patients who took norﬂoxacin 4.3% had vaginal candidiasis. Pancreas (97A ).

Alexander Imhof

Peﬂoxacin Musculoskeletal In patients with mucoviscidosis treated with peﬂoxacin the most common adverse event was arthropathy, and the symptoms disappeared 3 days to 3 months after drug withdrawal (101C ). In vitro, peﬂoxacin was more toxic to tendons than oﬂoxacin, ciproﬂoxacin, or levoﬂoxacin (102E ).

Norﬂoxacin can cause pancreatitis

Drug interactions Plasma concentrations of oral contraceptive steroids were unchanged by norﬂoxacin (55R ). Food–drug interactions The systemic availability of norﬂoxacin was reduced by 38–52% by dairy products (56R ).

Pruliﬂoxacin Gastrointestinal In a randomized, doubleblind comparison of pruliﬂoxacin 600 mg/day and ciproﬂoxacin 500 mg bd in 235 patients with acute exacerbations of chronic bronchitis, the most common treatment-related adverse event was gastric pain of mild or moderate intensity, reported in 8.5% of the patients taking pruliﬂoxacin and 6.8% of those taking ciproﬂoxacin (103C ).

Oﬂoxacin Drug interactions Plasma concentrations of oral contraceptive steroids were unchanged by oﬂoxacin (55R ).

Pazuﬂoxacin Skin In in vivo studies in animal models of phototoxicity, pazuﬂoxacin was less potent than nalidixic acid, oﬂoxacin, ciproﬂoxacin, or sparﬂoxacin, and there was no photoallergenicity (98E ). Drug interactions Co-administration of pazuﬂoxacin and theophylline has been studied in rats (99E ). Pazuﬂoxacin reduced the clearance of theophylline by about 25%. In seven healthy volunteers taking modiﬁed-release theophylline, intravenous pazuﬂoxacin mesilate increased serum theophylline concentrations; analysis of the urinary excretion of theophylline and its metabolites suggested that CYP1A2 had been inhibited (100c ). Theophylline concentrations need to be monitored if pazuﬂoxacin is coadministered.

Sparﬂoxacin Cardiovascular Sparﬂoxacin caused greater prolongation of the QT interval than other quinolones (40R ). A 37-year-old woman who was taking sparﬂoxacin as part of modiﬁed antitubercular therapy developed torsade de pointes (104A ).

Tosuﬂoxacin The most common adverse reactions to tosuﬂoxacin are gastrointestinal disorders, including diarrhea, abdominal discomfort, nausea and vomiting, and skin disorders, including rash and pruritus (105R ). Central and peripheral nervous system disorders were observed in 0.36% of patients and the most common symptoms were headache and dizziness. Skin There is a low incidence of phototoxicity with tosuﬂoxacin (105R ). Musculoskeletal Rhabdomyolysis has been reported in 13 cases (105R ).

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Drug interactions The Cmax and AUC of tosuﬂoxacin tosilate 300 mg were signiﬁcantly reduced by aluminum hydroxide gel ﬁne granules 1 g or magnesium oxide 1 g (105R ).

FUSIDIC ACID

(SED-14, 912; SEDA-24, 288; SEDA-25, 303; SEDA-26, 281) Liver Fusidic acid is chemically very similar to bile acids and hence competes with them for elimination and metabolism. A patient with a past history of alcohol-induced cirrhosis developed cholestatic jaundice after taking oral fusidic acid for 2 days (106A ).

Urinary tract Severe hypocalcemia and acute renal insufﬁciency developed in two diabetic patients who took oral fusidic acid 500 mg tds (107A ). Immunologic Positive patch tests occurred in three of 1119 patients who had used topical fusidic acid (108C ). In the second part of this study, all cases of positive patch tests to fusidic acid over the previous 20 years were reviewed; the average frequency was 1.62 patch-tested patients per year (1.45%) of those who were patch tested.

GLYCOPEPTIDES (SED-14, 858; SEDA-24, 288; SEDA-25, 303; SEDA-26, 281) Teicoplanin Hematologic Hemophagocytosis after vancomycin and teicoplanin occurred in a 45-yearold woman (109A ). Teicoplanin caused thrombocytopenia in one of 17 children (110C ). Skin A pustular skin eruption occurred in a 60-year-old woman who was given teicoplanin 400 mg as a loading dose followed by 200 mg/ day (111A ). Following the sixth injection of teicoplanin she developed a pruritic eruption on her chest, which evolved into a widespread maculopapular eruption with tiny pustules and occasional vesicles on an erythematous base

over the face, trunk, and limbs within 2 days. Teicoplanin was withdrawn and she was given prednisolone 60 mg/day. This resulted in improvement of the eruption and relieved the discomfort over the next 7 days. Susceptibility factors The administration of 5 and 10 mg/kg of teicoplanin to seven anuric patients immediately after the end of hemodialysis gave mean values of Cmax of 63 and 122 mg/l, mean AUCs of 526 and 1104 h.mg/l, mean half-lives of 109 and 107 h, mean clearance rates of 13 and 12 ml/min, mean apparent volumes of distribution of 1.68 and 1.68 l/kg, and mean volumes of distribution at steady state of 0.31 and 0.28 l/kg (112c ). Trough serum concentrations were above 10 mg/l for 24 h after the 5 mg/kg dose and for 48 h after the 10 mg/kg dose. Teicoplanin was not detected in the dialysate. Its concentrations in the arterial and the venous lines of the ﬁstulae were similar. Drug interactions Teicoplanin is less nephrotoxic than vancomycin when it is combined with aminoglycosides (113R ).

Vancomycin The adverse effects of once-daily or twice-daily vancomycin were not signiﬁcantly different in 121 hospitalized patients (114C ). Nephrotoxicity developed in 11% and 7.7% of the patients respectively; hearing loss in 3.2% and 16%; phlebitis in 14% and 23%; and red man syndrome in 14% and 9.6%. Cardiovascular Red man syndrome usually occurs after too rapid infusion of vancomycin, because of acute histamine release, but it has also been reported after slow infusion. • A 45-year-old man developed hypotension, bradycardia, a change in consciousness, and an erythematous macular rash 10 min after the slow infusion of 0.1% vancomycin (115A ). After appropriate management, he recovered well and was discharged on the following day.

In 50 patients, in whom vancomycin 15 mg/ kg was continuously infused at a constant rate over 30 min, the occurrence of pruritus suggested that systemic vascular resistance

260 was falling, exposing the patient to a risk of hypotension (116c ). Therapy with a betablocker appeared to confer protection against this hemodynamic effect. Hematologic Vancomycin can cause pancytopenia (117A ). • Neutropenia occurred in a 48-year-old man 16 days after the start of vancomycin therapy (118A ). Vancomycin was withdrawn and he was given a granulocyte-colony stimulating factor. He was then rechallenged with a single dose of vancomycin 1 g. His white blood cell count fell to 600 × 109 /l but returned to normal with continued granulocytecolony stimulating factor therapy.

Gastrointestinal Pseudomembranous colitis is primarily caused by Clostridium difﬁcile. The most common predisposing factor is prior use of antibiotics, including vancomycin (119R ), despite the fact that vancomycin is often used to treat it. Urinary tract Vancomycin-induced nephrotoxicity is clearly related to drug plasma concentrations: trough vancomycin concentrations over 15 μg/ml were associated with signiﬁcantly more nephrotoxicity (120R ). Skin Epidermolysis bullosa acquisita occurred in a 73-year-old man after a course of vancomycin for 15 days (121A ). Vancomycin-induced linear immunoglobulin A bullous disease has been reported (122A ). • A 52-year-old woman was given vancomycin 1 g intravenously bd and within 12 hours developed a generalized pruritic maculopapular rash. Over the next few days, the lesions progressively worsened and transformed into hemorrhagic and non-hemorrhagic vesicles and bullae. Mucosal surfaces, palms, and soles were spared. The skin lesions completely healed without scarring within 2 weeks of vancomycin withdrawal. There was no recurrence 5 months later.

A ﬁxed drug eruption after the ﬁfth dose of vancomycin 1 g occurred in a 45-year-old white woman (123A ). Immunologic An anaphylactic reaction occurred in a 77-year-old woman 5 minutes after the start of a vancomycin infusion, when she had received only 40 mg (124A ). She became unconscious and had a severe cardiovascular collapse, from which she was resuscitated with intravenous ephedrine and adrenaline.

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KETOLIDES (SEDA-24, 294; SEDA-25, 305; SEDA-26, 283) The ketolides cethromycin (ABT-773) and telithromycin are members of a family of the macrolide–lincosamide–streptogramin-B class of antimicrobials, the ketolides (125R , 126R , 127C ). Telithromycin has an absolute oral availability of 57% in young and elderly subjects (128c ) and 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 and ﬂuids, achieves high concentrations at sites of infection, and concentrates within polymorphonuclear neutrophil leukocytes. Telithromycin 800 mg/day 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. Cardiovascular Telithromycin causes prolongation of the QTc interval especially in elderly patients with predisposing conditions (126R ). Food–drug interactions The rate and extent of absorption of telithromycin is unaffected by food (129c ).

LINCOSAMIDES

(SED-14, 871; SEDA-24, 293; SEDA-25, 306; SEDA-26, 283)

Clindamycin Skin The most common adverse events in patients using clindamycin/benzoyl peroxide were dry skin, peeling, erythema, and rash (130R , 131c ). However, withdrawal rates due to adverse events were low (0–0.8%). • A 57-year-old Caucasian woman with a history of ocular toxoplasmosis, treated with intravitreal clindamycin (1 mg/0.1 ml) and dexamethasone (0.4 mg/0.1 ml), developed a generalized erythematous macular rash over the scalp, face, arms, thighs, and trunk 2 days after the start of treatment (132A ).

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Immunologic In a prospective study, truepositive patch tests were seen in four of six patients with known clindamycin hypersensitivity, while 22 healthy controls were negative; there was one false positive and one false negative reaction (133c ).

MACROLIDES

(SED-14, 873; SEDA-24, 295; SEDA-25, 306; SEDA-26, 284) Cardiovascular Increasing age, female sex, concomitant diseases, and co-morbidity are believed to increase the risk of torsade de pointes in patients taking macrolide antimicrobials (134R ).

Respiratory In an animal model, acute lung injury was inhibited by pretreatment with clarithromycin or roxithromycin, which signiﬁcantly ameliorated bleomycin-induced increases in the total cell and neutrophil counts in bronchoalveolar lavage ﬂuids and wet lung weight (135E ). Pretreatment with clarithromycin or roxithromycin also suppressed inﬂammatory cell inﬁltration and interstitial lung edema. Pretreatment with azithromycin was much less effective. Hematologic Clarithromycin and roxithromycin slightly inhibited the downregulation of L-selectin expression on neutrophils induced by interleukin-8 stimulation (136E ). Furthermore, clarithromycin strongly inhibited the interleukin-8-induced upregulation of the expression of Mac-1, an adhesion molecule, on neutrophils. Drug interactions 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) (137C ). This interaction can cause myopathy and rhabdomyolysis, particularly in patients with renal insufﬁciency or in those who are concurrently taking medications associated with myopathy.

Azithromycin In a multicenter, open, randomized comparison of levoﬂoxacin 500 mg/day orally or intravenously and azithromycin 500 mg/day intravenously for up to 2 days plus ceftriaxone 1 g/day intravenously for 2 days in 236 patients, the most common drug-related adverse events in those given azithromycin were diarrhea (4.2%), vein disorders (2.5%), and pruritus (1.7%) (138C ). Cardiovascular In a prospective study of 47 previously healthy people, there was a modest statistically insigniﬁcant prolongation of the QTc interval without clinical consequences after the end of a course of azithromycin 3 g/day for 5 days (139C ). Psychiatric (140A ).

Azithromycin can cause delirium

Gastrointestinal In a review of 12 clinical studies most of the adverse events in those taking azithromycin affected the gastrointestinal system, and were reported in 138 (8.5%) azithromycin-treated patients (141M ). Abdominal pain, diarrhea, nausea, and vomiting were the most frequently reported gastrointestinal adverse events. Liver Two cases of azithromycin-induced cholestasis have been reported. • A 33-year-old woman and a 72-year-old man developed cholestasis after they had taken a 5day course of azithromycin. The woman was given colestyramine and underwent six courses of plasmapheresis; 2 months later, her total bilirubin and serum transaminases were back to normal (142A ). After withdrawal of azithromycin, the man’s symptoms resolved within 1 month and his liver enzymes returned to normal (143A ).

Skin A 19-year-old man with infectious mononucleosis developed a maculopapular, nonpruritic rash after one dose of azithromycin 500 mg (144A ).

Clarithromycin In a multicenter, double-blind, randomized comparison of trovaﬂoxacin 200 mg and clarithromycin 500 mg bd in 176 subjects with

262 acute exacerbations of chronic bronchitis, the most common adverse effects of clarithromycin were nausea (3%), diarrhea (4%), and taste disturbances (4%) (43C ). Cardiovascular QT interval prolongation and a ventricular dysrhythmia occurred in an HIV-positive 30-year-old man at the start of intravenous clarithromycin therapy 500 mg 12hourly (145A ). Sensory systems Ototoxicity was attributed to clarithromycin in a 76-year-old man 4 days after he started to take clarithromycin for atypical pulmonary tuberculosis (146A ). When the clarithromycin was withdrawn his hearing improved subjectively, but it worsened again on re-exposure. Psychiatric Of cases of mania attributed to antibiotics and reported to the WHO, 28% were due to clarithromycin (147S ). Hallucinations caused by clarithromycin are not uncommon. Visual hallucinations with marked anxiety and nervousness occurred after the second dose of oral clarithromycin 500 mg in a 32-year-old woman (148A ). Clarithromycin was withdrawn and the symptoms disappeared a few hours later. Hematologic Thrombotic thrombocytopenic purpura was reported in a 42-year-old man with no past medical history after he had just completed a 30-day course of clarithromycin 250 mg bd (149A ). Liver Idiosyncratic drug-induced fatal fulminant hepatic failure has been reported in 40year-old woman with end-stage renal insufﬁciency taking clarithromycin 500 mg bd (150A ). Fatal drug-induced cholestasis associated with clarithromycin 500 mg bd for 3 days has been reported in a 59-year-old woman with diabetes mellitus and chronic renal insufﬁciency (151A ). Skin Only a few cases of adverse skin reactions to clarithromycin have been reported, to which can be added a case of phototoxicity (152A ).

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Drug interactions Clarithromycin can increase the steady-state concentrations of drugs that depend primarily on CYP3A metabolism, including tacrolimus, as has been reported in a 32-year-old African–American man who took clarithromycin 500 mg bd for 4 days (153A ). Fatal toxic epidermal necrolysis (Lyell’s disease) and fulminant hepatitis occurred shortly after the start of treatment with clarithromycin in a 47-year-old man who was taking disulﬁram (154A ). • A 47-year-old man with a history of chronic alcoholism took disulﬁram 250 mg/day for 1 month. He then took clarithromycin 500 mg bd and paracetamol 500 mg tds and 1 week later noticed nonpruritic cutaneous maculopapular lesions on his legs, extending to the rest of his body, excluding the palms and soles. Previous drug therapy was withdrawn. A skin biopsy showed toxic epidermal necrolysis. During the next several days the skin lesions worsened. Cutaneous blisters became evident, initially covering less than 10% of the body surface, but then extending all over the body. The serum bilirubin concentration was 359 μmol/l (direct bilirubin 213 μmol/l), the partial thromboplastin time longer than 200 seconds, and the prothrombin time 26 seconds. He developed septic shock and, despite supportive measures, died.

Severe hypoglycemia occurred in two elderly men with type 2 diabetes mellitus and mild to moderate impaired renal function, who took clarithromycin 1000 mg/day for respiratory infections, in addition to a sulfonylurea (glibenclamide 5 mg/day in one case and glipizide 15 mg/day in the other) (155A ). Both developed severe hypoglycemia within 48 h of starting clarithromycin.

Erythromycin Gastrointestinal Erythromycin often causes intolerable gastrointestinal effects. One of the more serious of these is infantile hypertrophic pyloric stenosis, which is associated with early postnatal erythromycin exposure; the prominent gastrokinetic properties of erythromycin have been postulated as the mechanism (156R ). In a retrospective study in 314 029 children, very early exposure to erythromycin (at 3– 13 days of life) was associated with a nearly eight-fold increased risk of pyloric stenosis (157C ). There was no increased risk in infants

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exposed to erythromycin after 13 days of life or in infants exposed to antibiotics other than erythromycin. Pyloric stenosis has also been reported in a boy born at 23 weeks’ gestation, weight 690 g, after treatment of the child with three doses of oral erythromycin 10 mg/kg/day (158A ). Skin Topical erythromycin in benzoylperoxide, marketed for acne treatment, must be compounded by a pharmacist and requires subsequent refrigeration, warranting the development of alternative formulations. In a double-blind, parallel-group, multicenter study in 327 patients, a single-use erythromycin/benzoylperoxide combination package was compared with the vehicle alone and the original, reconstituted formulation packaged in a jar. Dry skin was the most frequently reported skin-related adverse event; it occurred in 3.2% of patients who used the preformulated erythromycin/benzoylperoxide and 5.0% of those who used the reconstituted erythromycin/benzoylperoxide (159C ). Drug interactions When erythromycin was co-administered with atorvastatin, the mean maximum blood concentration and the AUC of atorvastatin increased signiﬁcantly (160R ). QT interval prolongation and torsade de pointes occurred after co-administration of cisapride and erythromycin 500 mg qds for 1 week in a 47-year-old woman (161A ). Combined desloratadine 7.5 mg/day plus erythromycin 500 mg qds in 24 healthy volunteers was well tolerated and had no clinically important electrocardiographic effects (162c ). Although co-administration of erythromycin slightly increased plasma concentrations of desloratadine, this change did not correlate with prolongation of the QT interval, and there was no toxicity. Teratogenicity In a retrospective study there was no evidence of an increased risk of pyloric stenosis among infants born to mothers exposed to erythromycin during pregnancy (163C ). Cardiovascular In a prospective study of 550 patients with 1386 peripheral venous catheters, the incidence of phlebitis was 19% with antibiotics and 8.8% without; erythromycin was associated with an increased risk (164C ).

Josamycin Gastrointestinal In female rats josamycin caused bile duct proliferation at a high dose of 1460 mg/kg (165E ).

Rokitamycin Rokitamycin is the latest semisynthetic 16membered ring macrolide to be introduced. It is more hydrophobic, and has better bacterial uptake and slower release, more cohesive ribosomal binding, and a longer post-antibiotic effect than other 14-, 15- and 16-membered ring macrolides (166R ). Immunologic A case of Churg–Strauss syndrome has been reported in an 18-year-old woman taking cysteinyl leukotriene receptor antagonists and oral rokitamicin 400 mg bd for 10 days (167A ).

Roxithromycin Cardiovascular Torsade de pointes has been reported in an 83-year-old man who developed severe prolongation of the QT interval after taking roxithromycin 300 mg/day for 4 days (168A ). Respiratory Eosinophilic pneumonia of acute onset has been attributed to roxithromycin in a 21-year-old woman (169A ). • A 21-year-old woman developed a fever of 39◦ C, a generalized pruritic macular rash, odynophagia, and intense weakness, in conjunction with respiratory difﬁculties 8 days after starting to take roxithromycin 150 mg bd. Her leukocyte count was 15.4 × 109 /l with 9.8% eosinophils and an erythrocyte sedimentation rate of 32 mm/h. Peripheral inﬁltrates were evident on the chest X-ray and CT scan, with multiple areas of consolidation and an air bronchogram, mainly peripherally distributed. Bronchoalveolar lavage showed 50% eosinophils. She improved with corticosteroids and 6 months later was free of respiratory symptoms; a chest Xray was normal.

Liver Cholestatic and hepatocellular liver damage occurred in a previously healthy 20year-old woman after she took roxithromycin 150 mg bd for 4 days (170A ).

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Skin Angio-edema and urticaria occurred in a 22-year-old woman a few hours after a second dose of roxithromycin 150 mg for a sore throat (171A ). The lesions subsided within 12 hours of drug withdrawal and there was no relapse after 3 months of follow-up. A skin prick test was positive for roxithromycin (1 mg/ml) and negative for erythromycin and clarithromycin in the same concentrations. Allergic dermatitis with characteristic distribution pattern called “baboon syndrome” has been reported (172A ).

High resolution CT scans showed groundglass opaciﬁcation in the mid-thoracic region, with patchy ﬁbrosis and traction bronchiectasis. After withdrawal of nitrofurantoin and administration of prednisone, a chest X-ray 3 months later showed resolution of the pulmonary changes.

• A 58-year-old man developed a pruritic skin eruption after he had taken roxithromycin 300 mg/day for 3 days. Large erythematous plaques covered his buttocks. Roxithromycin was immediately withdrawn and following treatment with oral antihistamines and topical corticosteroids the rash resolved within a few days.

Gene toxicity Treatment with nitrofurantoin for 12 months caused a signiﬁcant increase in chromosome aberrations and sister chromatid exchanges in the lymphocytes of 69 children (179C ).

Drug interactions In an open, randomized, crossover study in 12 healthy volunteers, roxithromycin did not alter the pharmacokinetics of lovastatin in such a way that dosage adjustment of lovastatin should be necessary during co-administration (173C ). Plasma concentrations of oral contraceptive steroids were unchanged when roxithromycin was co-administered (55R ). Myopathy occurred in a 73-year-old woman taking simvastatin 80 mg/day and gemﬁbrozil 600 mg bd 4 days after she started to take roxithromycin 300 mg/day (174A ).

Troleandomycin Drug interactions Troleandomycin is an inhibitor of CYP3A4 and can cause carbamazepine toxicity (175R ).

NITROFURANTOIN

(SED-14, 884; SEDA-25, 310; SEDA-26, 288) Respiratory In a 58-year-old woman who took nitrofurantoin 100 mg/day for 11 months, pulmonary toxicity occurred, with bilateral interstitial inﬁltrates in the lower zones of the chest X-ray and loss of lung volume (176A ).

Liver Nitrofurantoin has been associated with fatal liver necrosis (177A ) and can cause chronic hepatitis resembling autoimmune hepatitis if the drug is continued (178A ).

OXAZOLIDINONES

(SEDA-26, 288)

The oxazolidinones represent the ﬁrst truly new class of antibacterial agents to reach the marketplace in several decades. They have a unique 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. The most frequently reported adverse effects are diarrhea, headache, nausea and vomiting, insomnia, constipation, rash, and dizziness; thrombocytopenia has also been documented in a few patients (about 2%) (180R , 181C ). In children the common adverse events have been similar to those found in adult trials, although thrombocytopenia has not been as common (182R ). Plasma linezolid trough concentrations after a 1 h infusion of 600 mg bd were 0.54– 5.3 μg/ml and CSF linezolid trough concentrations were 1.46–7.0 μg/ml; the ratio between CSF and plasma linezolid trough concentrations always exceeded 1 (mean, 1.6; range

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1.2–2.3) (183c ). There was good rapid penetration of linezolid into bone, fat, and muscle (184c , 185c ). Nervous system Peripheral and optic neuropathy occurred in a 76-year-old man after he had taken linezolid for about 6 months (186A ). Hematologic Linezolid has been associated with reversible myelosuppression (187R ), which appears to be related to the duration of therapy, with a higher risk after more than 2 consecutive weeks of treatment (188C ). Pancytopenia in two cases was reported with linezolid 600 mg bd (189A ). Red cell hypoplasia and thrombocytopenia occurred in a 66-year-old man who took linezolid 600 mg bd (190A ). Reversible pure red blood cell aplasia occurred in a 52-year-old black man who had taken linezolid for 8 weeks (191A ). In 19 patients there was thrombocytopenia in six of those who had taken it for more than 10 days; gastrointestinal bleeding was observed in one patient and four required platelet transfusions (192c ). Of 71 patients who took linezolid for 1–44 days, 48 took it for more than 5 days; among those 48, thrombocytopenia, with a 32– 89% reduction in platelet count, occurred in 23; the platelet count fell to below 100 × 109 /l in nine (193C ). Susceptibility factors Children In singledose pharmacokinetic studies children had a greater plasma clearance (0.34 l/h/kg for children aged 3 months to 16 years) than adults (0.10 l/h/kg) (182R ). Drug interactions Serotonin syndrome was reported in 56-year-old white woman who received intravenous linezolid shortly after withdrawal of a selective serotonin reuptake inhibitor, paroxetine (194A ).

Nervous system After intravenous colistin sulfomethate sodium (5 mg/kg/day) the CSF concentration was 25% of the serum concentration in a patient with meningitis (195A ). Urinary tract Nephrotoxicity is the most important adverse effect of colistin. It occurs more often in patients with pre-existing impairment of renal function. Doses must be adjusted in patients with renal insufﬁciency, because colistin is excreted principally by the kidneys, and raised blood concentrations may further impair renal function (196R ).

Mupirocin In a randomized, double-blind, placebo-controlled trial, 97 of 2012 patients treated with mupirocin reported adverse effects, such as rhinorrhea and itching at the site of application (197C ).

STREPTOGRAMINS

(SEDA-24, 300; SEDA-25, 311; SEDA-26, 289)

Pristinamycin Gastrointestinal In a multicenter, open, randomized trial in 204 patients with erysipelas treated with either oral pristinamycin 1 g tds or intravenous then oral penicillin, adverse events related to treatment were signiﬁcantly more common with pristinamycin; they were mostly mild or moderate and mainly involved the gastrointestinal tract (198C ).

Quinupristin/dalfopristin POLYMYXINS

(SED-14, 887; SEDA-24, 300; SEDA-25, 311; SEDA-26, 289) Respiratory In 62 children with cystic ﬁbrosis there was increased dyspnea in seven and pharyngitis in three in response to nebulized colistin sulfomethate (80 mg dissolved in 3 ml of preservative-free isotonic saline, by inhalation bd for 4 weeks) (29C ).

The adverse effects of quinupristin/dalfopristin include arthralgia, myalgias, reversible rises in serum alkaline phosphatase, itching, diarrhea, vomiting, and pain/inﬂammation, edema, or thrombophlebitis at the infusion site; these effects occurred in 2.5–4.6% of patients (199R , 200C ). In healthy volunteers receiving quinupristin/dalfopristin, 7.5 mg/kg infused over 1 h bd,

266 mean fecal antibiotic concentrations were 291 and 42 μg/g of feces for quinupristin and dalfopristin respectively by the ﬁfth day of treatment (201c ). Skin In a retrospective study of children taking quinupristin/dalfopristin, rash (2%) was the most frequent adverse event, but only one patient with rash discontinued quinupristin/dalfopristin because of it (200C ). Musculoskeletal Of seven patients with endstage renal insufﬁciency who received quinupristin/dalfopristin, two developed myalgias (202c ). Drug tolerance (antibacterial resistance) After 5 days’ administration of quinupristin/ dalfopristin 7.5 mg/kg infused over 1 h bd, the fecal microﬂora in 20 healthy volunteers increased signiﬁcantly during treatment and returned within 12 weeks to baseline concentrations after the end of treatment. There were anerobes and enterococci resistant to erythromycin or to quinupristin/dalfopristin, but glycopeptide-resistant enterococci did not emerge (201c ).

SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE (SED-14, 896; SEDA-25, 312; SEDA-26, 290) In a randomized open, multicenter study in 46 patients with sight-threatening ocular toxoplasmosis, those who took sulfadiazine had signiﬁcantly more adverse events, especially malaise (203C ). Liver Increased activities of alanine transaminase and aspartate transaminase to over ﬁve times the upper limit of the reference range were reported in a randomized trial of sulfadiazine in toxoplasmic encephalitis (204C ).

Co-trimoxazole Endocrine Co-trimoxazole 27–31 mg/kg orally bd substantially altered serum total T4 and

Chapter 26

Alexander Imhof

TSH concentrations and neutrophil counts in dogs within as short a time as a few weeks (205E ). Hematologic Hemophagocytosis in the setting of severe drug hypersensitivity syndrome due to co-trimoxazole has been reported (109A ). • A 53-year-old woman with congenital dyskeratosis took co-trimoxazole six double-strength tablets a day (trimethoprim 960 mg/day and sulfamethoxazole 4800 mg/day) for Pneumocystis carinii plus folic acid, and after 9 days developed a fever (39◦ C) accompanied by a morbilliform rash and painful cervical lymphadenopathy. She had a white blood cell count of 1.7 × 109 /l, with 0.5 × 109 /l neutrophils; hemoglobin 7.3 g/dl; platelets 17 × 109 /l; and hemolysis. A myelogram showed extensive hemophagocytosis. Polyvalent intravenous immunoglobulin (1 g/kg/day) was given for 2 days. She became apyrexial within 48 hours, accompanied by marked clinical improvement, and recovered within 1 month.

Severe, life-threatening thrombocytopenia associated with co-trimoxazole has been reported (206A ). • A 54-year-old white woman took a 10-day course of co-trimoxazole (trimethoprim 160 mg, sulfamethoxazole 800 mg) for chronic sinusitis. One day after ﬁnishing the course she developed scattered petechiae on both hands and blood blisters in her mouth. She had a low platelet count of 20 × 109 /l. Other laboratory tests were normal, except for a raised blood glucose. She was treated successfully with a transfusion of two units of platelets and oral prednisone. Her platelet count increased to 110 × 109 /l 4 days after withdrawal of co-trimoxazole.

Skin In a randomized, open trial of long-term intermittent co-trimoxazole on recurrences of toxoplasmic retinochoroiditis, four of 54 patients who took a single tablet of co-trimoxazole (trimethoprim 160 mg, sulfamethoxazole 800 mg) withdrew when they developed mild allergic reactions (cutaneous erythema that resolved when drug treatment was stopped) (207C ). Toxic epidermal necrolysis is a life-threatening, rapidly evolving, mucocutaneous reaction characterized by widespread erythema, necrosis, bullous detachment of the epidermis resembling the effects of scalding, constitutional symptoms, and internal organ involvement. There is widespread apoptosis of keratinocytes, which is generally considered to be due to Fas/CD95–FasLigand interaction, but of unknown primary mechanism.

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• An 86-year-old man developed severe and extensive toxic epidermal necrolysis within 24 hours of taking co-trimoxazole for a urinary infection (208A ). He had an allergic reaction to cotrimoxazole a few years before. He recovered completely without serious sequelae. • A 50-year-old man took oral co-trimoxazole (trimethoprim 160 mg, sulfamethoxazole 800 mg) and developed toxic epidermal necrolysis 13 days later (209A ).

Cross-sensitivity to co-trimoxazole and nimesulide has been reported (210A ). • A 10-year-old-boy developed an extensive ﬁxed drug eruption when he took co-trimoxazole (trimethoprim 200 mg, sulfamethoxazole 40 mg bd) 8 weeks after having had a ﬁxed drug eruption due to nimesulide. An oral provocation test with co-trimoxazole 1 month later showed reactivation within 12 hours in the form of severe itching and erythema at the sites of the lesions with onequarter of the dose.

Immunologic The hydroxylamine and other metabolites of sulfamethoxazole can bind covalently to proteins because of their chemical reactivity, resulting in the induction of speciﬁc adverse immune responses. Therefore, changes in the activity of detoxiﬁcation pathways are associated with a greater risk of allergic reactions to sulfonamides. Allergies to sulfonamides, particularly sulfamethoxazole, are more frequent in patients with AIDS, but the reason for this increased risk is not fully understood. No tools are available to predict which patients have a greater risk for developing allergies to sulfonamides. In a small study in HIV-positive patients with hypersensitivity syndrome reaction, the lymphocyte toxicity assay has a strong potential for use as a diagnostic tool to assess co-trimoxazole hypersensitivity (211c ). Diagnosis is essential to avoid possible progression to severe reactions and readministration of the offending drug. In patients who absolutely require further treatment, successful desensitization can be achieved (212R ). Two patients with chronic granulomatous disease who had previously been intolerant of co-trimoxazole completed a 5-day desensitization protocol with a good clinical outcome (213A ). Drug interactions Co-trimoxazole greatly increased the risk of overanticoagulation in patients taking acenocoumarol and phenprocoumon (214R ).

In an animal model indinavir nephrotoxicity was potentiated by co-trimoxazole but nelﬁnavir alone or in combination with cotrimoxazole was not nephrotoxic (215E ).

Trimethoprim Nervous system Aseptic meningitis is a rare adverse effect of co-trimoxazole. The pathogenic mechanism is still uncertain. A 15-yearold boy developed aseptic meningitis while taking trimethoprim 200 mg in the morning and 100 mg in the evening (216A ).

OTHER ANTIMICROBIAL DRUGS Daptomycin

(SEDA-25, 317;

SEDA-26, 292) 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 (217R ). When daptomycin 4 mg/kg was given intravenously to seven healthy men the mean peak concentrations in plasma and inﬂammatory ﬂuid were 78 and 28 μg/ml respectively; the mean terminal half-lives were 7.7 and 13 h respectively; the overall penetration of total drug into the inﬂammatory ﬂuid was 68% and the mean urinary recovery over 24 h was 60% (218c ).

Fosfomycin

(SED-14, 911; SEDA-24, 302; SEDA-25, 317; SEDA-26, 292) Fosfomycin concentrations in brain interstitium were measured in two patients after the intravenous administration of 4 g (219c ). Brain Cmax values were above MIC for relevant pathogens, such as Streptococcus pneumoniae and Neisseria meningitidis. Variability in brain penetration might be explained by the degree to which the integrity of the blood–brain barrier is disrupted by the underlying disease.

268

Fosmidomycin Fosmidomycin acts by inhibiting 1-deoxy-Dxylulose 5-phosphate reductoisomerase, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis. It inhibits the synthesis of isoprenoids by Plasmodium falciparum and suppresses the growth of multidrug-resistant strains in vitro. In an open, uncontrolled study, fosmidomycin was administered for 3–5 days (1.2 g every 8 h) to 27 adults with malaria, of whom 16 reported possibly drug-related adverse events (220C ). The most frequent adverse events were headache, weakness, myalgia, abdominal pain, and loose stools. There were two cases of raised alanine aminotransferase activity.

Chapter 26

Virginiamycin

Alexander Imhof

(SEDA-24, 302;

SEDA-26, 293) Drug tolerance (antibacterial resistance) 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 (221r ).

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11. Kaplan DM, Nedzelski JM, Al-Abidi A, Chen JM, Shipp DB. Hearing loss following intratympanic instillation of gentamicin for the treatment of unilateral Menière’s disease. J Otolaryngol 2002; 31: 106–11. 12. Burgansky Z, Rock T, Bartov E. Inadvertent intravitreal gentamicin injection. Eur J Ophthalmol 2002; 12: 138–40. 13. van Raaij TM, Visser LE, Vulto AG, Verhaar JA. Acute renal failure after local gentamicin treatment in an infected total knee arthroplasty. J Arthroplasty 2002; 17: 948–50. 14. Fogo AB. Quiz page. Mesangial lupus nephritis, WHO IIb, and severe acute tubular necrosis, secondary to gentamycin toxicity. Am J Kidney Dis 2002; 40: xlix. 15. Sener G, Sehirli AO, Altunbas HZ, Ersoy Y, Paskaloglu K, Arbak S, Ayanoglu-Dulger G. Melatonin protects against gentamicin-induced nephrotoxicity in rats. J Pineal Res 2002; 32: 231–6. 16. Reiter RJ, Tan DX, Sainz RM, Mayo JC, LopezBurillo S. Melatonin: reducing the toxicity and increasing the efﬁcacy of drugs. J Pharm Pharmacol 2002; 54: 1299–321. 17. Kopple JD, Ding H, Letoha A, Ivanyi B, Qing DP, Dux L, Wang HY, Sonkodi S. L-carnitine ameliorates gentamicin-induced renal injury in rats. Nephrol Dial Transplant 2002; 17: 2122–31. 18. Bates DE, Beaumont SJ, Baylis BW. Ototoxicity induced by gentamicin and furosemide. Ann Pharmacother 2002; 36: 446–51. 19. Boselli E, Breilh D, Bel JC, Debon R, Saux MC, Chassard D, Allaouchiche B. Diffusion of isepamicin into cancellous and cortical bone tissue. J Chemother 2002; 14: 361–5. 20. Yazaki T, Yoshiyama Y, Wong P, Beauchamp D, Kanke M. Protective effect of ﬂeroxacin against

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273 reductase inhibitors. Clin Pharmacokinet 2002; 41: 343–70. 161. Kyrmizakis DE, Chimona TS, Kanoupakis EM, Papadakis CE, Velegrakis GA, Helidonis ES. QT prolongation and torsades de pointes associated with concurrent use of cisapride and erythromycin. Am J Otolaryngol 2002; 23: 303–7. 162. Banﬁeld C, Hunt T, Reyderman L, Statkevich P, Padhi D, Affrime M. Lack of clinically relevant interaction between desloratadine and erythromycin. Clin Pharmacokinet 2002; 41 Suppl 1: 29–35. 163. Hussain N, Herson VC. Erythromycin use during pregnancy in relation to pyloric stenosis. Am J Obstet Gynecol 2002; 187: 821–2; author reply 822. 164. Lanbeck P, Odenholt I, Paulsen O. Antibiotics differ in their tendency to cause infusion phlebitis: a prospective observational study. Scand J Infect Dis 2002; 34: 512–19. 165. Kasahara K, Nishikawa A, Furukawa F, Ikezaki S, Tanakamaru Z, Lee IS, Imazawa T, Hirose M. A chronic toxicity study of josamycin in F344 rats. Food Chem Toxicol 2002; 40: 1017–22. 166. Braga PC. Rokitamycin: bacterial resistance to a 16-membered ring macrolide differs from that to 14- and 15-membered ring macrolides. J Chemother 2002; 14: 115–31. 167. Richeldi L, Rossi G, Ruggieri MP, Corbetta L, Fabbri LM. Churg–Strauss syndrome in a case of asthma. Allergy Eur J Allergy Clin Immunol 2002; 57: 647–8. 168. Haffner S, Lapp H, Thurmann PA. [Adverse drug reactions—case report] (in German). Dtsch Med Wochenschr 2002; 127: 1021. 169. Perez-Castrillon JL, Jimenez-Garcia R, Martin-Escudero JC, Velasco C. Roxithromycin-induced eosinophilic pneumonia. Ann Pharmacother 2002; 36: 1808–9. 170. Hartleb M, Biernat L, Kochel A. Drug-induced liver damage—a three-year study of patients from one gastroenterological department. Med Sci Monit 2002; 8: CR292–6. 171. Gurvinder SK, Tham P, Kanwar AJ. Roxithromycin induced acute urticaria. Allergy Eur J Allergy Clin Immunol 2002; 57: 262. 172. Amichai B, Grunwald MH. Baboon syndrome following oral roxithromycin. Clin Exp Dermatol 2002; 27: 523. 173. Bucher M, Mair G, Kees F. Effect of roxithromycin on the pharmacokinetics of lovastatin in volunteers. Eur J Clin Pharmacol 2002; 57: 787–91. 174. Huynh T, Cordato D, Yang F, Choy T, Johnstone K, Bagnall F, Hitchens N, Dunn R. HMG CoA reductase-inhibitor-related myopathy and the inﬂuence of drug interactions. Intern Med J 2002; 32: 486–90. 175. Pauwels O. Factors contributing to carbamazepine–macrolide interactions. Pharmacol Res 2002; 45: 291–8. 176. Hadi HA, Arnold AG. Malaise, weight loss, and respiratory symptoms. Postgrad Med J 2002; 78: 55, 58.

274 177. Amit G, Cohen P, Ackerman Z. Nitrofurantoin-induced chronic active hepatitis. Isr Med Assoc J 2002; 4: 184–6. 178. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis 2002; 6: 467–86. 179. Slapsyte G, Jankauskiene A, Mierauskiene J, Lazutka JR. Cytogenetic analysis of peripheral blood lymphocytes of children treated with nitrofurantoin for recurrent urinary tract infection. Mutagenesis 2002; 17: 31–5. 180. Evans GA. The oxazolidinones. Curr Infect Dis Rep 2002; 4: 17–27. 181. Moise PA, Forrest A, Birmingham MC, Schentag JJ. The efﬁcacy and safety of linezolid as treatment for Staphylococcus aureus infections in compassionate use patients who are intolerant of, or who have failed to respond to, vancomycin. J Antimicrob Chemother 2002; 50: 1017–26. 182. Kaplan SL. Use of linezolid in children. Pediatr Infect Dis J 2002; 21: 870–2. 183. Villani P, Regazzi MB, Marubbi F, Viale P, Pagani L, Cristini F, Cadeo B, Carosi G, Bergomi R. Cerebrospinal ﬂuid linezolid concentrations in postneurosurgical central nervous system infections. Antimicrob Agents Chemother 2002; 46: 936–7. 184. Lovering AM, Zhang J, Bannister GC, Lankester BJ, Brown JH, Narendra G, MacGowan AP. Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement. J Antimicrob Chemother 2002; 50: 73–7. 185. Rana B, Butcher I, Grigoris P, Murnaghan C, Seaton RA, Tobin CM. Linezolid penetration into osteo-articular tissues. J Antimicrob Chemother 2002; 50: 747–50. 186. Corallo CE, Paull AE. Linezolid-induced neuropathy. Med J Aust 2002; 177: 332. 187. Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, Kuter DJ. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother 2002; 46: 2723–6. 188. Hau T. Efﬁcacy and safety of linezolid in the treatment of skin and soft tissue infections. Eur J Clin Microbiol Infect Dis 2002; 21: 491–8. 189. Halpern M. Linezolid-induced pancytopenia. Clin Infect Dis 2002; 35: 347–8. 190. Waldrep TW, Skiest DJ. Linezolid-induced anemia and thrombocytopenia. Pharmacotherapy 2002; 22: 109–12. 191. Monson T, Schichman SA, Zent CS. Linezolid-induced pure red blood cell aplasia. Clin Infect Dis 2002; 35: E29–31. 192. Attassi K, Hershberger E, Alam R, Zervos MJ. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002; 34: 695–8. 193. Orrick JJ, Johns T, Janelle J, Ramphal R. Thrombocytopenia secondary to linezolid administration: what is the risk? Clin Infect Dis 2002; 35: 348–9. 194. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis 2002; 34: 1651–2. 195. Jimenez-Mejias ME, Pichardo-Guerrero C, Marquez-Rivas FJ, Martin-Lozano D, Prados T,

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Pachon J. Cerebrospinal ﬂuid penetration and pharmacokinetic/pharmacodynamic parameters of intravenously administered colistin in a case of multidrug-resistant Acinetobacter baumannii meningitis. Eur J Clin Microbiol Infect Dis 2002; 21: 212–14. 196. Stein A, Raoult D. Colistin: an antimicrobial for the 21st century? Clin Infect Dis 2002; 35: 901– 2. 197. Perl TM, Cullen JJ, Wenzel RP, Zimmerman MB, Pfaller MA, Sheppard D, Twombley J, French PP, Herwaldt LA. Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. New Engl J Med 2002; 346: 1871–7. 198. Bernard P, Chosidow O, Vaillant L. Oral pristinamycin versus standard penicillin regimen to treat erysipelas in adults: randomised, non-inferiority, open trial. Br Med J 2002; 325: 864. 199. Blondeau JM, Sanche SE. Quinupristin/dalfopristin. Expert Opin Pharmacother 2002; 3: 1341–64. 200. Loefﬂer AM, Drew RH, Perfect JR, Grethe NI, Stephens JW, Gray SL, Talbot GH. Safety and efﬁcacy of quinupristin/dalfopristin for treatment of invasive Gram-positive infections in pediatric patients. Pediatr Infect Dis J 2002; 21: 950–6. 201. Scanvic-Hameg A, Chachaty E, Rey J, Pousson C, Ozoux ML, Brunel E, Andremont A. Impact of quinupristin/dalfopristin (RP59500) on the faecal microﬂora in healthy volunteers. J Antimicrob Chemother 2002; 49: 135–9. 202. Schwenger V, Mundlein E, Dagrosa EE, Fahr AM, Zeier M, Mikus G, Andrassy K. Treatment of life-threatening multiresistant staphylococcal and enterococcal infections in patients with end-stage renal failure with quinupristin/dalfopristin: preliminary report. Infection 2002; 30: 257–61. 203. Bosch-Driessen LH, Verbraak FD, SuttorpSchulten MS, van Ruyven RL, Klok AM, Hoyng CB, Rothova A. A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis. Am J Ophthalmol 2002; 134: 34–40. 204. Chirgwin K, Hafner R, Leport C, Remington J, Andersen J, Bosler EM, Roque C, Rajicic N, McAuliffe V, Morlat P, Jayaweera DT, Vilde JL, Luft BJ. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeﬁciency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039. Clin Infect Dis 2002; 34: 1243–50. 205. Williamson NL, Frank LA, Hnilica KA. Effects of short-term trimethoprim-sulfamethoxazole administration on thyroid function in dogs. J Am Vet Med Assoc 2002; 221: 802–6. 206. Yamreudeewong W, Fosnocht BJ, Weixelman JM. Severe thrombocytopenia possibly associated with TMP/SMX therapy. Ann Pharmacother 2002; 36: 78–82. 207. Silveira C, Belfort R Jr, Muccioli C, Holland GN, Victora CG, Horta BL, Yu F, Nussenblatt RB. The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of

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toxoplasmic retinochoroiditis. Am J Ophthalmol 2002; 134: 41–6. 208. Lipozencic J, Milavec-Puretic V, Kotrulja L, Tomicic H, Stulhofer Buzina D. Toxic epidermal necrolysis due to cotrimoxazole. J Eur Acad Dermatol Venereol 2002; 16: 182–3. 209. Nassif A, Bensussan A, Dorothee G, MamiChouaib F, Bachot N, Bagot M, Boumsell L, Roujeau JC. Drug speciﬁc cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 2002; 118: 728–33. 210. Sarkar R, Kaur C, Kanwar AJ. Extensive ﬁxed drug eruption to nimesulide with cross-sensitivity to sulfonamides in a child. Pediatr Dermatol 2002; 19: 553–4. 211. Neuman MG, Malkiewicz IM, Phillips EJ, Rachlis AR, Ong D, Yeung E, Shear NH. Monitoring adverse drug reactions to sulfonamide antibiotics in human immunodeﬁciency virus-infected individuals. Ther Drug Monit 2002; 24: 728–36. 212. Choquet-Kastylevsky G, Vial T, Descotes J. Allergic adverse reactions to sulfonamides. Curr Allergy Asthma Rep 2002; 2: 16–25. 213. Hasui M, Kotera F, Tsuji S, Yamamoto A, Taniuchi S, Fujikawa Y, Nakajima M, Yoshioka A, Kobayashi Y. Successful resumption of trimethoprim-sulfamethoxazole after oral desensitisation in patients with chronic granulomatous disease. Eur J Pediatr 2002; 161: 356–7. 214. Visser LE, Penning-van Bees FJ, Kasbergen AA, De Smet PA, Vulto AG, Hofman A, Stricker

275 BH. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 2002; 88: 705–10. 215. de Araujo M, Seguro AC. Trimethoprim– sulfamethoxazole (TMP/SMX) potentiates indinavir nephrotoxicity. Antiviral Ther 2002; 7: 181– 4. 216. Redman RCt, Miller JB, Hood M, DeMaio J. Trimethoprim-induced aseptic meningitis in an adolescent male. Pediatrics 2002; 110(2 Pt 1): e26. 217. Anonymous. Daptomycin, cidecin, dapcin, LY 146032. Drugs R D 2002; 3: 33–9. 218. Wise R, Gee T, Andrews JM, Dvorchik B, Marshall G. Pharmacokinetics and inﬂammatory ﬂuid penetration of intravenous daptomycin in volunteers. Antimicrob Agents Chemother 2002; 46: 31–3. 219. Brunner M, Reinprecht A, Illievich U, Spiss CK, Dittrich P, van Houte M, Muller M. Penetration of fosfomycin into the parenchyma of human brain: a case study in three patients. Br J Clin Pharmacol 2002; 54: 548–50. 220. Missinou MA, Borrmann S, Schindler A, Issifou S, Adegnika AA, Matsiegui PB, Binder R, Lell B, Wiesner J, Baranek T, Jomaa H, Kremsner PG. Fosmidomycin for malaria. Lancet 2002; 360: 1941–2. 221. Voegel LP. Path of drug resistance from farm to clinic. Science 2002; 295: 625.

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

27 AMPHOTERICIN B

(SED-14, 922; SEDA-24, 315; SEDA-25, 331; SEDA-26, 302)

Nephrotoxicity due to amphotericin Amphotericin remains an important antifungal drug for the management of invasive mycoses. Lipid-based formulations (amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B) are less nephrotoxic than conventional amphotericin B deoxycholate (1R ). Data on the safety and tolerance of the four marketed amphotericin formulations and their usefulness for speciﬁc indications continues to accumulate. Amphotericin B deoxycholate (DAMB) Amphotericin-associated nephrotoxicity has been studied in a retrospective analysis of 69 recipients of blood stem-cell transplants with multiple myeloma who received at least two doses of amphotericin B deoxycholate during 1992–5 (2c ). Nephrotoxicity occurred in 30 patients (43%) and developed rapidly. Patients who developed nephrotoxicity were similar to those who did not in many aspects associated with their treatment. However, baseline estimated creatinine clearance, ciclosporin therapy, nephrotoxic drug therapy within 30 days of starting amphotericin, and the number of concomitant nephrotoxic drugs were signiﬁcant predictors of amphotericin-associated nephrotoxicity. The authors concluded that recipients of bone marrow or peripheral blood stem-cell transplants who have multiple myeloma and are receiving ciclosporin or multiple nephrotoxic drugs at the start of amphotericin therapy should be considered at high risk of amphotericin-associated nephrotoxicity. © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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Antifungal drugs In a randomized, controlled, single-center study continuous infusion of amphotericin reduced nephrotoxicity and infusion-associated reactions compared with the standard infusion over 2–4 hours in patients with neutropenia, refractory fever, and suspected or proven invasive fungal infections (3c ). However, the concentration-dependent pharmacodynamics of antifungal polyenes raise concerns about the antifungal effectiveness of this mode of administration in particular, as its therapeutic efﬁcacy has not been adequately studied in animals or in patients with documented infections. In a retrospective study, renal function was investigated in patients receiving ciclosporin alone or in combination with amphotericin (24-hour infusion) after allogeneic stem-cell transplantation (4c ). Of 84 patients, 22 were treated with amphotericin. There was a statistically signiﬁcant reduction in renal function compared with the 62 patients who received ciclosporin alone. However, renal insufﬁciency in all patients remained in a clinically acceptable range and was reversible in patients who survived to 1 year after transplantation. Continuous infusion of amphotericin has been assessed in an open study in six lung transplant recipients with invasive or semi-invasive bronchopulmonary azole-resistant candidal infections who were treated for 40 (17–73) days by 24-hour continuous infusions of amphotericin 1 mg/kg (5c ). They received at least 1000 ml/day of 0.9% saline intravenously. Apart from ciclosporin, ﬁve patients received aminoglycosides for at least 2 weeks, and four received ganciclovir. Calculated creatinine clearance fell from 57 (43–73) ml/min to a nadir of 35 (28–39) and recovered to 52 (33– 60) after the end of therapy. One patient needed temporary hemoﬁltration for 7 days. Besides three episodes of mild hypokalaemia there were no adverse effects attributable to amphotericin. Asymptomatic candidal colonization persisted for 10 months in one case, but the other ﬁve patients were cured.

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Amphotericin B Colloidal Dispersion (ABCD) In a randomized, double-blind, multicenter trial, amphotericin B colloidal dispersion (Amphotec; 6 mg/kg/day) was compared with liposomal amphotericin (1.0–1.5 mg/kg/day) for the ﬁrst-line treatment of invasive aspergillosis in 174 patients (6C ). The median duration of therapy was 13 (1–357) days in those given ABCD, and 15 (1–87) days in those given liposomal amphotericin. For evaluable patients (n = 103) given ABCD or liposomal amphotericin, the respective rates of therapeutic response (52% vs. 51%), mortality (36% vs. 45%), and death due to fungal infection (32% vs. 26%) were similar. Renal toxicity was signiﬁcantly lower (25% vs. 49%) and the median time to onset of nephrotoxicity longer (301 vs. 22 days;) in the patients who received ABCD. Rates of drug-related toxicity in the patients who received ABCD and liposomal amphotericin were respectively 53% vs 30% (chills), 27% vs 16% (fever), 1% vs 4% (hypoxia) and 22% vs 24% (toxicity requiring study drug withdrawal). Based on the results of this trial, ABCD appears to have equivalent efﬁcacy to liposomal amphotericin, and superior renal safety, in the treatment of invasive aspergillosis. However, infusion-related chills and fever occurred more often with ABCD. Amphotericin B Lipid Complex (ABLC) The rates of ABLC-associated nephrotoxicity in various clinical settings at a university hospital have been estimated retrospectively and compared with previously reported rates of nephrotoxicity (7R ). Data from 33 adult patients (20 men, 13 women; mean age 49 years) with and without neutropenia receiving ABLC were collected, and the degree of nephrotoxicity was determined using two deﬁnitions: (1) doubling of baseline serum creatinine concentration using the peak value within the ﬁrst 7 days, and (2) end-of-therapy doubling of baseline serum concentration using the end-of-therapy value. Using the selected deﬁnitions of ABLCassociated nephrotoxicity, there were only two cases. This rate was signiﬁcantly below the 42% rate reported in the only large published study (95% CI = 1.7, 19.6). The median change in serum creatinine concentration was 8.9 (−97 to 380) μmol/l. The concomitant use of nephrotoxic agents was not associated with signiﬁcant changes in serum creatinine concentration. The authors concluded that ABLC infrequently

277 causes clinically signiﬁcant nephrotoxicity, and that earlier data derived from a single study in febrile patients with neutropenia should be interpreted cautiously. Liposomal Amphotericin (L-AmB) Liposomal amphotericin (3 mg/kg/day) has been compared with conventional amphotericin (0.7 mg/ kg/day) for induction therapy of moderate to severe disseminated histoplasmosis in a randomized, double-blind, multicenter trial in 81 patients with AIDS (8C ). The duration of induction was 2 weeks, to be followed by 10 weeks of itraconazole in the case of a response. Clinical success was achieved in 14 of 22 patients treated with conventional amphotericin compared with 45 of 51 patients who received liposomal amphotericin (difference, 24%; 95% CI = 1%, 52%). Culture conversion rates were similar. Three patients treated with conventional amphotericin and one treated with liposomal amphotericin died during induction. Infusionrelated adverse effects were more common with conventional amphotericin (63%) than with liposomal amphotericin (25%). Nephrotoxicity occurred in 37% of patients treated with conventional amphotericin and 9% of patients treated with liposomal amphotericin. The results of this study suggest that liposomal amphotericin is less toxic than conventional amphotericin and is associated with improved survival.

Liposomal Amphotericin (L-AmB) Pancreas Raised alkaline phosphatase and hepatic transaminase activities can occur during therapy with liposomal amphotericin. In a retrospective analysis, ﬁve of 31 children with cancers, who had received liposomal amphotericin in dosages of 1–3 mg/kg/day, had an isolated transient rise in the serum lipase activity during or shortly after therapy with liposomal amphotericin (9c ). Three of these patients had signs of pancreatitis. While the exact pathogenesis is unclear, the authors proposed fat overload or toxic damage to the pancreas by the liposomes or amphotericin itself as potential mechanisms.

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PYRIMIDINE ANALOGUES

Fluconazole

Flucytosine

In a study using the UK General Practice Research Database (see p. xxxi) to determine rates of drug-induced, rare, serious adverse effects on the liver, kidneys, skin, or blood, occurring within 45 days of completing a prescription or reﬁll in 54 803 users of either ﬂuconazole or itraconazole, three had illnesses for which a ﬂuconazole-induced cause could not be ruled out; one with thrombocytopenia, one with neutropenia, and one with an abnormal liver function test just after receiving ﬂuconazole (12R ). The rates were 2.8/100 000 prescriptions (95% CI = 0.8, 10) for serious, adverse blood events and 1.4/100 000 prescriptions (95% CI = 0.25, 8.2) for serious, adverse liver events. These results suggest that ﬂuconazole does not commonly have serious adverse effects on the liver, kidneys, skin, or blood. In a randomized, double-blind, placebocontrolled study in Saudi Arabia of oral ﬂuconazole (200 mg/day for 6 weeks) in the treatment of cutaneous leishmaniasis 106 patients were assigned to ﬂuconazole and 103 to placebo (13C ). Follow-up data were available for 80 and 65 patients respectively. At the 3-month follow-up, healing of lesions was complete in 63 of the 80 patients who took ﬂuconazole and 22 of the 65 patients who took placebo (relative risk of complete healing, 2.33; 95% CI = 1.63, 3.33). Adverse effects were mild and similar in the two groups.

(SED-14, 926;

SEDA-24, 295) Increases in hepatic transaminases and depressed hemopoiesis are the principal adverse effects of ﬂucytosine (1R ). Hematologic In a pilot study in six patients receiving intravenous ﬂucytosine, hemopoietic toxicity was monitored by measuring platelet and leukocyte counts; 5-ﬂuorocytosine and 5-ﬂuorouracil serum concentrations were measured using hplc (10c ). The concentrations of 5-ﬂuorouracil in the 34 available serum samples were below the limit of quantiﬁcation (0.05 mg/l), but 5-ﬂuorocytosine was detectable in all samples and the 5-ﬂuorouracil metabolite, alpha-ﬂuoro-beta-alanine (FBAL), was detected at low concentrations in several samples. One patient developed thrombocytopenia (50 × 109 /l) during therapy, and one developed leukopenia (2.6 × 109 /l). The fact that 5-ﬂuorouracil was not detected in the serum made it unlikely that the toxic effects of intravenous 5-ﬂuorocytosine resulted from exposure to 5-ﬂuorouracil.

AZOLE DERIVATIVES (SED-14, 928; SEDA-24, 318; SEDA-25, 333; SEDA-26, 304) Skin The risk of serious skin disorders has been estimated in 61 858 users, aged 20–79 years, of oral antifungal drugs identiﬁed in the UK General Practice Research Database (see p. xxxi) (11R ). They had received at least one prescription for oral ﬂuconazole, griseofulvin, itraconazole, ketoconazole, or terbinaﬁne. The background rate of serious cutaneous adverse reactions (corresponding to non-use of oral antifungal drugs) was 3.9 per 10 000 person–years (95% CI = 2.9, 5.2). Incidence rates for current use were 15 per 10 000 person-years (1.9, 56) for itraconazole, 11.1 (3.0, 29) for terbinaﬁne, 10 (1.3, 38) for ﬂuconazole, and 4.6 (0.1, 26) for griseofulvin. Cutaneous disorders associated with the use of oral antifungal drugs in this study were all mild.

Cardiovascular Prolongation of the QT interval is a class effect of the antifungal azoles and can lead to torsade de pointes, which can occur when these drugs are given alone or in conjunction with other medications. • A 25-year-old woman with worsening endocarditis had a prolonged QT interval at baseline and developed monomorphic ventricular dysrhythmias, which were managed successfully with pacing and antiarrhythmic therapy, including amiodarone (14A ). Several days later, she was given high-dose ﬂuconazole (800 mg/day) for fungemia and after 3 days had episodes of torsade de pointes.

In this case torsade de pointes developed in the presence of known risk factors—hypokalemia, hypomagnesemia, female sex, baseline QT interval prolongation, and ventricular dysrhythmias.

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Drug interactions Clinical interaction studies and some in vitro studies have suggested that azole antifungal drugs may inhibit P glycoprotein, and this has again been studied in vitro (15E ). In a cell line in which human P glycoprotein was overexpressed, itraconazole and ketoconazole inhibited P glycoprotein function, with 50% inhibitory concentrations of about 2 and 6 μmol/l respectively; however, ﬂuconazole had no effect. Omeprazole is extensively metabolized in the liver by 5-hydroxylation and sulfoxidation reactions, catalysed predominantly by CYP2C19 and CYP3A4 respectively. Fluconazole is a potent competitive inhibitor of CYP2C19 and a weak inhibitor of CYP3A4. The effect of ﬂuconazole on the pharmacokinetics of a single oral dose of omeprazole 20 mg has been evaluated after a single oral dose of ﬂuconazole 100 mg and after 4 days of oral administration of 100 mg/day in 18 healthy male volunteers (16c ). Fluconazole increased the Cmax and the mean AUC of omeprazole and prolonged its half-life (2.59 vs 0.85 hours). The effect of ﬂuconazole, a potent inhibitor of CYP2C9 and CYP2C19, on the pharmacokinetics of rosuvastatin has been investigated in a randomized, double-blind, two-way, crossover, placebo-controlled study (17c ). Healthy male volunteers (n = 14) were given ﬂuconazole 200 mg/day or matching placebo for 11 days; rosuvastatin 80 mg was co-administered on day 8. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 hours after the dose. Fluconazole, increased the AUC and Cmax of rosuvastatin by 14% and 9% respectively. Limited data available for the N-desmethyl metabolite showed that the Cmax fell by about 25%. Fluconazole did not affect the proportion of circulating active or total HMG-CoA reductase inhibitors accounted for by circulating rosuvastatin. Thus, ﬂuconazole produced only small changes in rosuvastatin kinetics, which were not considered to be of clinical relevance. Carbamazepine serum concentrations increased during concomitant ﬂuconazole administration (400 mg/day) in a 38-year-old man (18A ). Since ﬂuconazole inhibits cytochrome P450, this observation suggests inhibition of carbamazepine metabolism. An interaction between ﬂuconazole and methadone (a substrate of CYP3A4, CYP2C9,

and CYP2C19) has been reported in a 60-yearold man with advanced cancer (19A ). While taking a stable dose of methadone, he developed respiratory depression 2 days after receiving intravenous ﬂuconazole for refractory oral candidiasis. Intravenous naloxone reversed the respiratory depression. The interaction of ﬂuconazole with bromazepam has been studied in 12 healthy men in a randomized, double-blind, four-way, crossover study (20C ). They received single oral or rectal doses of bromazepam (3 mg) after 4-day pretreatment with oral ﬂuconazole (100 mg/day) or placebo. Fluconazole caused no signiﬁcant changes in the pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Susceptibility factors Children In 34 otherwise healthy infants with oral candidiasis randomized to either nystatin oral suspension four times a day for 10 days or ﬂuconazole suspension 3 mg/kg in a single daily dose for 7 days, 6 of 19 were cured by nystatin and all of 15 by ﬂuconazole (21c ). Fluconazole was tolerated without apparent adverse events.

Itraconazole Oral itraconazole solution has been compared with intravenous/oral ﬂuconazole for the prevention of fungal infections in a randomized, controlled trial in adult liver transplant recipients, who were randomized to receive either oral itraconazole solution (200 mg bd) or intravenous/oral ﬂuconazole (400 mg od) (22C ). Prophylaxis was started immediately before transplant surgery and continued for 10 weeks after transplantation. Proven fungal infection developed in nine of 97 patients given itraconazole and in four of 91 patients given ﬂuconazole. Mortality from fungal infection was very low and occurred in only one of the 188 patients. Except for more frequent gastrointestinal adverse effects (nausea, vomiting, diarrhea) with itraconazole, both drugs were well tolerated and neither was associated with hepatotoxicity. Mean trough plasma concentrations of itraconazole were over 250 ng/ml throughout the study and were not affected by H2 histamine receptor antagonists or antacids. In a study using the UK General Practice Research Database (see p. xxxi) to determine rates

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of rare, serious drug-induced, adverse effects on the liver, kidneys, skin, or blood, occurring within 45 days of completing a prescription or reﬁll in 54 803 users of either ﬂuconazole or itraconazole, one patient had an abnormal liver function test while taking itraconazole in whom a drug-induced etiology could not be ruled out, a rate of 3.2 per 100 000 prescriptions (95% CI = 0.6, 18) for serious adverse liver effects (12R ). Thus, itraconazole does not commonly have serious adverse effects on the liver, kidneys, skin, or blood. Liver All itraconazole clinical trials sponsored by Janssen Research Foundation for the treatment of onychomycosis, in which there was an assessment of laboratory safety, have been analysed (23M ). There were no signiﬁcant differences in the number of code 4 abnormalities (baseline value is in the reference range and at least two values, or the last testing in the observation period, exceed twice the upper limit of the reference range) in liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin). The incidence of all the code 4 abnormalities was under 2%. Itraconazole pulse therapy for onychomycosis appears to be safe, especially from the perspective of potential liver damage. In the itraconazole package insert, liver function tests are recommended in patients receiving continuous itraconazole for over 1 month. There is no such monitoring requirement for the pulse regimen, unless the patient has a history of underlying hepatic disease, the liver function tests are abnormal at baseline, or signs or symptoms suggestive of liver dysfunction develop at any time. Drug interactions Clinical interaction studies and some in vitro studies have suggested that azole antifungal drugs may inhibit P glycoprotein, and this has again been studied in vitro (15E ). In a cell line in which human P glycoprotein was overexpressed, itraconazole and ketoconazole inhibited P glycoprotein function with 50% inhibitory concentrations of about 2 and 6 μmol/l respectively; however, ﬂuconazole had no effect. The effects of these azole antifungal drugs on ATP consumption by P glycoprotein (representing transport activity) were also assessed, and the Km values were congruent with the IC50s. Thus, exposure to itraconazole may

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

be modulated by human P glycoprotein, and interactions with other drugs may be due, in part, to inhibition of P glycoprotein transport. Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more and more common in chronic lung disease. In many cases, patients also use topical or systemic glucocorticosteroids. Itraconazole can inhibit the metabolic clearance of glucocorticosteroids by interfering with CYP3A4 and can directly inhibit steroidogenesis, thereby causing serious adverse effects. Two patients with cystic ﬁbrosis developed profound adrenal failure and impairment of inhaled steroid clearance, resulting in paradoxical Cushing’s syndrome, after long-term treatment with itraconazole and inhaled budenoside (24A , 25A ). Pituitary–adrenal axis and gonadal function was then assessed in 37 patients treated with itraconazole with or without budenoside (26c ). An adrenocorticotrophic hormone (ACTH) test (tetracosactid 250 (g) was performed in 25 patients with cystic ﬁbrosis taking itraconazole and budesonide and in 12 patients taking itraconazole alone (six with cystic ﬁbrosis and six with chronic granulomatous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma renin activity and follicle stimulating hormone, luteinizing hormone, progesterone, estradiol, testosterone, and serum inhibin A and B concentrations. ACTH tests performed as part of a pretransplantation program in a further 30 patients with cystic ﬁbrosis were used as controls. Eleven of the 25 patients who took both itraconazole and budesonide had adrenal insufﬁciency. None of the patients taking itraconazole alone and none of the control patients with cystic ﬁbrosis had an abnormal ACTH test. Mineralocorticoid or gonadal insufﬁciency was not observed in any patient. Only one patient with an initial pathological ACTHtest subsequently normalized; the other 10 patients improved but had not achieved normal adrenal function 2–10 months after itraconazole had been withdrawn. The effects of itraconazole on the pharmacokinetics and cortisol suppressing activity of budesonide by inhalation were further investigated in a randomized, doubleblind, two-phase, crossover study in 10 healthy subjects who took oral itraconazole 200 mg/day or placebo for 5 days (27c ). On day 5, 1 hour after the last dose of itraconazole or placebo, they took budesonide 1000 μg by inhalation.

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Plasma budesonide and cortisol concentrations were measured up to 23 hours. Itraconazole increased the mean total AUC of inhaled budesonide 4.2-fold (range 1.7–9.8) and the peak plasma concentration 1.6-fold compared with placebo. The mean half-life of budesonide was prolonged from 1.6 to 6.2 hours. The suppression of cortisol production after inhalation of budesonide was signiﬁcantly increased by itraconazole compared with placebo, with a 43% reduction in the AUC of plasma cortisol from 0.5 to 10 hours and a 12% reduction in the cortisol concentration measured 23 hours after budesonide, at 8 am. Thus, itraconazole markedly increased the systemic exposure to inhaled budesonide. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production. An interaction of itraconazole with fentanyl (a substrate of CYP3A4, CYP2C9, and CYP2C19) has been reported in a 67-year-old man with cancer on a stable dose of transdermal fentanyl 50 μg/hour (28A ). He took itraconazole 200 mg bd for oropharyngeal candidiasis, and 24 hours later developed signs of opioid toxicity, which was reversed by withdrawal of fentanyl and replacement with short-acting opioids. The effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam has been studied in a double-blind, randomized, crossover study in 10 healthy male volunteers, who took oral itraconazole 100 mg/day or placebo for 7 days and on day 4 a single oral dose of estazolam 4 mg (29c ). Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam. There was no signiﬁcant difference between the placebo and itraconazole phases in peak plasma concentration, clearance, and half-life. Similarly, psychomotor function was unaffected. These ﬁndings suggest that cytochrome CYP3A4 is not involved to a major extent in the metabolism of estazolam. Two cases of rhabdomyolysis caused by itraconazole in heart transplant recipients taking long-term ciclosporin and simvastatin have been reported (30A , 31A ). To avoid severe myopathy, ciclosporin concentrations should be monitored frequently and statins should be withdrawn or the dosage should be reduced, as

long as azoles need to be prescribed in transplant recipients. Patients need to be educated about signs and symptoms that require immediate physician intervention. Susceptibility factors Children The safety, pharmacokinetics, and pharmacodynamics of an oral suspension of cyclodextrin itraconazole (2.5 mg/kg od or bd for 15 days) have been investigated in an open, sequential, doseescalation study in 26 children and adolescents, 5–18 years old, infected with HIV (mean CD4 count 128 × 106 /l) with oropharyngeal candidiasis (32c ). Apart from mild to moderate gastrointestinal disturbances in three patients, cyclodextrin itraconazole was well tolerated. Two patients withdrew prematurely because of adverse events. The oropharyngeal candidiasis score fell signiﬁcantly from a mean of 7.46 at baseline to 2.8 at the end of therapy, demonstrating antifungal efﬁcacy in this setting. Based on these results, a dosage of 2.5 mg/kg bd was recommended for the treatment of oropharyngeal candidiasis in children aged 5 years and under.

Voriconazole Voriconazole is a synthetic, intravenous and oral antifungal triazole structurally related to ﬂuconazole. It is active against a wide spectrum of clinically important yeasts and moulds, including Candida spp, Cryptococcus neoformans, Aspergillus, and other hyaline, dematiaceous, and dimorphic moulds (33R , 34R ). Voriconazole has a half-life of about 6 hours, non-linear pharmacokinetics, undergoes complex hepatic metabolism, and has the potential for drug–drug interactions mediated by CYP3A4, CYP2C9, and CYP2C19. Its efﬁcacy has been demonstrated in non-comparative phase I/II studies in patients with oropharyngeal and esophageal candidiasis and acute and chronic invasive aspergillosis. In phase III clinical trials, it was superior to conventional amphotericin for ﬁrst-line therapy of invasive aspergillosis and yielded comparable success rates but less proven and probable breakthrough infections compared with liposomal amphotericin as empirical antifungal therapy in patients with persistent neutropenia (1R ). In an open, non-comparative, multicenter study in immunocompromised patients with

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proven or probable invasive aspergillosis, 116 patients were treated with intravenous voriconazole 6 mg/kg bd twice and then 3 mg/kg bd for 6–27 days, followed by 200 mg bd orally for up to 24 weeks; voriconazole was given as primary therapy in 60 (38C ). There were good responses in 56; 16 had a complete response and 40 a partial response; there was a stable response in 24 patients. There were adverse events in 91% of the patients who received at least one dose of voriconazole, but only 15% were attributed to the drug. The most common adverse events attributed to voriconazole were skin rash (8.7%), reversible visual disturbances (11%), and raised liver function tests (15%). There was evidence of a concentration-dependent incidence of adverse events: six of seven patients with voriconazole plasma concentrations over 10 μg/ml developed adverse events requiring drug withdrawal. The safety, tolerability, and pharmacokinetics of voriconazole have been evaluated in 42 healthy men, 41 of whom completed the study (39c ). Two groups of subjects participated. Group 1 (n = 28) took part in two study periods, each consisting of 14 days separated by a minimum 7-day washout period. During one of the periods, 14 subjects received intravenous voriconazole 6 mg/kg bd on day 1 followed by 3 mg/kg bd on days 2–7 and were then switched to 200 mg orally bd on days 8–14. During the other period, they received 6 mg/kg intravenously bd on day 1 followed by 5 mg/kg bd on days 2 to 7 and were then switched to 400 mg orally bd on days 8–14. The other 14 subjects in group 1 received a matching placebo throughout the study. In group 2 (n = 14), 7 subjects received 6 mg/kg intravenously bd on day 1 followed by 4 mg/kg bd on days 2–7 and were then switched to 300 mg orally bd on days 8–14. The other seven received a matching placebo. Voriconazole had non-linear pharmacokinetics, attributed to saturable metabolism. For intravenous dosing, a 1.7-fold increase in dose resulted in 2.4- and 3.1-fold increases in Cmax and AUC respectively; a 2-fold increase in oral dosing resulted in 2.8- and 3.9-fold increases in Cmax and AUC respectively. The mean Cmax after oral dosing was 63–90% of the intravenous Cmax . After the switch from intravenous to oral dosing, most subjects achieved steady state by day 4. Voriconazole was well tolerated; the most commonly reported adverse events were mild to moderate headache,

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

rash, and abnormal vision. Visual function tests conducted on all subjects detected no further abnormalities during voriconazole treatment and one abnormality (abnormal color vision test) during placebo treatment. All visual disturbances were mild to moderate in intensity, and all resolved spontaneously within 2 days of onset. No subject in any treatment group had a serious adverse event. Special senses Visual adverse events, in particular enhanced brightness of light and color, are common with voriconazole (35c ). These visual adverse effects are transient and reversible. So far, comprehensive ophthalmological investigations have not shown any morphological correlates or long-term visual sequelae in any patient. Voriconazole has been compared with liposomal amphotericin for empirical antifungal therapy in a randomized, international, multicenter trial in 837 patients (415 assigned to voriconazole, 4 mg/kg bd (6 mg/kg bd on day 1) and 422 to liposomal amphotericin, 3 mg/kg/day) (36C ). The overall success rates were similar (26% with voriconazole and 31% with liposomal amphotericin); however, there were signiﬁcantly fewer documented breakthrough fungal infections in patients who received voriconazole (8 vs. 21). Those who received voriconazole had fewer severe infusionrelated reactions, less mild nephrotoxicity, as deﬁned by increases in serum creatinine to over 1.5 times baseline, and less hypokalemia; however, there was no difference whatsoever in the proportion of patients with more profound renal compromise (increased serum creatinine to over 2.0 times baseline; 7.0 vs. 7.6%). The incidence of hepatotoxicity, as measured by raised hepatic transaminases and alkaline phosphatase, was similar in the two groups; increased serum bilirubin to over 1.5 times baseline was more common in patients who took amphotericin. Patients who received voriconazole had more episodes of transient visual changes than those who received liposomal amphotericin (22% vs. 1%) and more episodes of visual hallucinations (4.3% vs. 0.5%). Parenteral voriconazole was changed to the oral formulation in 22%, with a reduction in the mean duration of hospitalization by 1 day in all patients but by 2 days in patients at high risk (with relapsed leukemia or after allogeneic bone-marrow transplant). Toxicity or lack of efﬁcacy caused 9.9% of those

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who received voriconazole and 6.6% of those who received amphotericin to withdraw. In a comparative, randomized, unblinded trial for primary therapy of invasive aspergillosis, 144 patients received either intravenous voriconazole (6 mg/kg bd on day 1, then 4 mg/kg bd for at least 7 days) followed by 200 mg orally bd and 133 received intravenous amphotericin B deoxycholate (1–1.5 mg/kg/ day); other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the ﬁrst drug used (37C ). Most patients had allogeneic hemopoietic cell transplants, acute leukemia, or other hematological diseases. At week 12, 53% of the patients in the voriconazole group and 32% of those in the amphotericin group (difference, 21%; 95% CI = 10, 33%) had a successful outcome. The survival rate at 12 weeks was 71% in the voriconazole group and 58% in the amphotericin group (hazard ratio, 0.59; 95% CI = 0.40, 0.88). Transient visual disturbances were more common with voriconazole (45% vs. 4.3%). The most frequent descriptions of such disturbances were blurred vision, altered visual perception, altered color perception, and photophobia. Of the patients who received voriconazole 9% had hallucinations or confusion considered possibly related to the drug compared with 3.7% of those who received amphotericin. Infusion-related reactions (fever, chills, or both) were more common in those who received amphotericin (3.1% vs. 25%), as were severe, potentially related adverse events (13% vs. 24%); the most frequent events were renal impairment (14%) in those who received amphotericin and liver function abnormalities (4.8%) in those who received voriconazole. In a multicenter, randomized, double-blind, double-dummy, parallel-group, dose-escalation comparison with ﬂuconazole, the safety, tolerability, and pharmacokinetics of oral voriconazole were investigated in 24 subjects at high risk of fungal infections (with hematological malignancies, solid tumors, or autologous bone marrow transplants) (40c ). The subjects were randomized to receive voriconazole 200 mg bd (n = 9), voriconazole 300 mg bd (n = 9), or ﬂuconazole 400 mg od (n = 6) for 14 days. There was an approximate 5-fold accumulation of voriconazole during the dosing period and evidence of non-linear pharmacokinetics.

283 Voriconazole was generally safe and well tolerated. Mild, reversible visual disturbances were the most commonly reported adverse events but they were not associated with treatment withdrawal. No patient developed a breakthrough fungal infection. Drug interactions The interaction of voriconazole with ciclosporin has been investigated in a randomized, double-blind, placebo-controlled, crossover study in kidney transplant recipients with stable renal function (41c ). During the ﬁrst study period (7.5 days), subjects taking ciclosporin 150 mg/day received either concomitant voriconazole (200 mg every 12 hours) or a matching placebo. After a washout period of at least 4 days, they were switched to the other treatment. In the seven subjects who completed both regimens, concomitant administration with voriconazole resulted in a 1.7-fold increase (90% CI = 1.47, 1.96) in mean ciclosporin AUC during a dosage interval. Ciclosporin Cmax and tmax were not signiﬁcantly affected, but Cmin was increased by voriconazole by a mean of 2.48 (range 1.88–3.03) times. Seven subjects withdrew during voriconazole administration, six for reasons that were considered to be drug related; most were attributable to increased ciclosporin concentrations. Although not serious, all causality-related adverse events were more frequent during voriconazole administration than during placebo administration. Thus, when voriconazole is initiated or withdrawn in patients who are already taking ciclosporin, blood ciclosporin concentrations should be carefully monitored and the dose of ciclosporin adjusted as necessary. Susceptibility factors Children The safety and efﬁcacy of voriconazole have been studied in 58 children (aged 9 months to 15 years; median 7 years) who were treated in the manufacturer’s compassionate release program (42c ). They received voriconazole for an invasive fungal infection if they were refractory to or intolerant of conventional antifungal drugs. Voriconazole was given intravenously as a loading dose of 6 mg/kg every 12 hours on day 1 followed by 4 mg/kg every 12 hours thereafter. When feasible, the route of administration was changed from intravenous to oral (100 or 200 mg bd for patients weighing under or over 40 kg respectively). At the end of therapy

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(mean 93 days, range 1–800), 26 patients had a complete or partial response, four had a stable response, 25 failed therapy, and four were withdrawn because of intolerance of voriconazole. Two had treatment-related serious adverse events (ulcerated lips with rash and raised hepatic transaminases or bilirubin). A total of 23 patients had voriconazole-related adverse events, three of which required withdrawal of voriconazole. The most commonly reported adverse events included raised hepatic transaminases or bilirubin (n = 8), skin rashes (n = 8), abnormal vision (n = 3), and a photosensitivity reaction (n = 3). The authors concluded that these data support the use of voriconazole for invasive fungal infections in children who are intolerant of or refractory to conventional antifungal drugs.

ALLYLAMINES

(SED-14, 937; SEDA-24, 314; SEDA-25, 331; SEDA-26, 309)

Terbinaﬁne Hematologic Hematological adverse effects of terbinaﬁne, including neutropenia, thrombocytopenia, and pancytopenia, have been reported anecdotally. The frequency of blood dyscrasias has been estimated at 32 per million patient-years, and that of thrombocytopenia at 1 in 200 000 patients (43R ). • A 53-year-old woman developed severe thrombocytopenia after a 6-week course of terbinaﬁne (250 mg/day) for onychomycosis (44A ). A bone marrow aspirate showed a normocellular marrow. She received a platelet transfusion and recovered after a short course of prednisolone.

Liver Minor abnormalities in liver function tests have been reported in up to 4% of patients taking oral terbinaﬁne (45R ); however, several cases of more severe symptomatic hepatobiliary reactions have been reported in association with terbinaﬁne, including at least two cases of fatal liver failure. • A 56-year-old woman developed chronic biliary ductopenia and portal ﬁbrosis 2 years after a course of terbinaﬁne (46A ). Terbinaﬁne treatment at that time had resulted in jaundice and evidence of cholestasis. After withdrawal of terbinaﬁne, she

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh continued to have pruritus and persistently raised serum alkaline phosphatase activity. Investigations for various types of chronic liver disease were negative and so chronic bile duct loss and periportal ﬁbrosis were attributed to terbinaﬁne.

Skin Baboon syndrome has been attributed to terbinaﬁne (47A ). • A 26-year-old man developed a ﬁxed drug eruption on his hands and inguinal and gluteal areas after oral treatment of onychomycosis with terbinaﬁne. The rash showed the characteristic distribution of the baboon syndrome. Although epicutaneous testing showed no positive reactions, the rash recurred after oral rechallenge with terbinaﬁne.

The underlying pathogenic mechanism for the baboon syndrome has been suggested to be a systemically induced allergic contact dermatitis. Drug interactions Inhibition of CYP2D6 by terbinaﬁne has been evaluated by assessing 48-hour concentration-time proﬁles of the tricyclic antidepressant desipramine in 12 healthy volunteers identiﬁed as extensive CYP2D6 metabolizers by genotyping and phenotyping (48c ). The pharmacokinetics were evaluated at baseline (50 mg oral desipramine given alone), steady state (after 250 mg oral terbinaﬁne for 21 days), and 2 and 4 weeks after terbinaﬁne withdrawal. The pharmacodynamics were evaluated before and 2 hours after each dose of desipramine, using Mini-Mental Status Examination and electroencephalography. Terbinaﬁne inhibited CYP2D6 metabolism, as indicated by signiﬁcant increases in desipramine Cmax and AUC and reductions in the Cmax and AUC of the CYP2D6-mediated metabolite, 2-hydroxydesipramine, both of which were still altered 4 weeks after terbinaﬁne withdrawal. Caution should be exercised when co-prescribing terbinaﬁne and drugs that are metabolized by CYP2D6, particularly those with a narrow therapeutic index. Metabolism by CYP2D6 is of major importance for the hydroxylation of nortriptyline, making it susceptible to competitive inhibition by terbinaﬁne. Nortriptyline intoxication secondary to terbinaﬁne has been observed in a woman with a major depressive disorder (49A ). After rechallenge her serum nortriptyline concentration rose and the serum concentrations of its two hydroxylated metabolites fell. She had a

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normal genotype for CYP2D6, suggesting that this interaction can occur even in people without reduced CYP2D6 activity. Susceptibility factors Children In an open, prospective, uncontrolled study in 81 immunocompetent young children (aged 2–13 years) with tinea capitis due to Microsporum canis, oral terbinaﬁne was given in dosages based on weight (62.5 mg for those weighing 10–20 kg and 125 mg for 20–40 kg), and applied topically to affected areas (1% cream bd) (50c ). Treatment lasted for 4 weeks, followed by an 8-week observation (treatment-free) period. All the subjects were assessed for efﬁcacy and tolerability at 12 weeks. At 12 weeks: 32 had completely recovered, with no evidence of relapse during the observation period, and 21 had mycological cure but residual signs of infection. The effective cure rate was 65%. Terbinaﬁne was well tolerated by these children: 75 had no adverse effects; the other six had abdominal pain (2), vomiting (1), generalized (1) and local (1) itching, and localized erythema (1). Hematological and biochemical parameters remained normal during the study.

ECHINOCANDINS

(SEDA-25, 338;

SEDA-26, 311) The echinocandins are semisynthetic antifungal lipopeptides, which act by non-competitive inhibition of 1,3-beta-D-glucan, a major constituent of the cell wall of many pathogenic fungi, which 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, and micafungin, Fujisawa Inc, Deerﬁeld, IL) have potent and broad-spectrum antifungal activity against Candida and Aspergillus spp, without cross-resistance to existing agents. Their activity against other fungal pathogens in vitro is variable (51R ). All three compounds have dose-independent pharmacokinetics, with half-lives of 10–15 hours and are dosed once a day. They are highly (>95%) protein bound and distribute into all major tissues, including the brain; concentrations in non-inﬂammatory CSF are low. The echinocandins are metabolized by the liver and

are slowly excreted as inactive metabolites into the urine and feces; only small fractions are excreted into the urine unchanged. They lack signiﬁcant potential for drug interactions mediated by CYP450 isozymes and are generally well tolerated (1R , 51R ). The efﬁcacy of anidulafungin, caspofungin, and micafungin against Candida spp has been documented in phase II and phase III studies in immunocompromised patients with mucosal candidiasis. All had efﬁcacy that was at least comparable with standard agents. Caspofungin has promising efﬁcacy as second-line therapy of deﬁnite or probable invasive aspergillosis. It was equally effective as standard therapies in the treatment of invasive candidiasis and for empirical antifungal therapy in patients with persistent febrile neutropenia. Caspofungin is approved in the USA and EU for secondline therapy of deﬁnite or probable invasive aspergillosis and for primary therapy in nonneutropenic patients with invasive Candida infections (51R , 52R ).

Caspofungin The safety and tolerability of caspofungin have been studied in 623 patients, including 295 who received at least 50 mg/day for at least 1 week in clinical studies. In 263 patients who received caspofungin in randomized, doubleblind, active-control trials, there were no serious clinical or laboratory drug-related adverse events; caspofungin was withdrawn in 2% of these patients because of drug-related adverse effects (53R ). In a double-blind, randomized trial, caspofungin was compared with amphotericin B deoxycholate for the primary treatment of invasive candidiasis (54C ). Patients who had clinical evidence of infection and a positive culture for Candida species from blood or another site were enrolled. They were stratiﬁed according to the severity of disease, as indicated by the presence or absence of neutropenia and the Acute Physiology and Chronic Health Evaluation (APACHE II) score, and were randomly assigned to receive either caspofungin (50 mg/day with a loading dose of 70 mg on day 1) or amphotericin (0.6–0.7 mg/kg/day or 0.7–1.0 mg/kg/day for patients with neutropenia). Of the 239 patients enrolled, 224

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were included in the modiﬁed intention-to-treat analysis. Baseline characteristics, including the percentage of patients with neutropenia and the mean APACHE II score, were similar in the two treatment groups. The efﬁcacy of caspofungin was similar to that of amphotericin, with successful outcomes in 73% of the patients treated with caspofungin and in 62% of those treated with amphotericin. There were signiﬁcantly fewer drug-related adverse events associated with caspofungin: fever, chills, and infusion-related events were less frequent with caspofungin. Caspofungin caused less nephrotoxicity, as deﬁned by an increase in serum creatinine of at least twice the baseline value or an increase of at least 88.4 μmol/l) (8.4% vs. 25%). Only 2.6% of those who were given caspofungin were withdrawn because of adverse events, compared with 23% of those who were given amphotericin. Thus, caspofungin was at least as effective as amphotericin for the treatment of mostly non-neutropenic patients with invasive candidiasis but signiﬁcantly better tolerated. The safety, tolerability, and efﬁcacy of caspofungin in patients with oropharyngeal and/or esophageal candidiasis have been investigated in a phase II dose-ranging study (55c ). The patients were randomized double-blind to either caspofungin acetate (35, 50, or 70 mg) or amphotericin (0.5 mg/kg intravenously) once daily for 7–14 days. Of 140 patients, 63% had esophageal involvement and 98% were infected with HIV. Response rates with caspofungin groups were 74–91%, and 63% with amphotericin. Fewer patients receiving any dose of caspofungin had drug-related adverse effects (fever, chills, nausea, vomiting). Two patients who took caspofungin 35 mg and one who was given amphotericin withdrew because of adverse effects. Drug-related laboratory abnormalities were also more common in patients who received amphotericin. The most common drug-related laboratory abnor-

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh

malities in patients who received caspofungin were raised alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, which were typically less than ﬁve times the upper limit of normal and resolved despite continued treatment. None of the patients receiving caspofungin and nine of those who received amphotericin developed drug-related increases in serum creatinine concentrations. No patient withdrew because of drug-related laboratory adverse effects. Caspofungin and ﬂuconazole have been compared in adults with Candida esophagitis in a double-blind randomized trial (56c ). Eligible patients had symptoms compatible with esophagitis, endoscopic mucosal plaques, and microscopic Candida. They were randomized to receive caspofungin (50 mg) or ﬂuconazole (200 mg) intravenously once a day for 7–21 days. Most of them (154/177) had HIV infection, with a median CD4 count of 30 × 106 /l. Favorable response rates were achieved in 66 of the 81 patients in the caspofungin arm and in 80 of the 94 patients in the ﬂuconazole arm; symptoms had resolved in over 50% of the patients in both groups by the ﬁfth day of treatment. Drug-related adverse effects were reported in 41% of patients given caspofungin and 32% of those given ﬂuconazole; the most common events in both groups were phlebitis, headache, fever, nausea, diarrhea, abdominal pain, and rashes. Drug-related laboratory abnormalities developed in 29% of patients given caspofungin and in 34% of those given ﬂuconazole. The most frequent laboratory abnormalities included reduced white blood cell count, hemoglobin concentration, and serum albumin concentration, and increased alkaline phosphatase and aminotransferases. No patient given caspofungin developed a serious drugrelated adverse effect; therapy was withdrawn in only one patient (who was receiving ﬂuconazole), because of an unspeciﬁed adverse effect.

REFERENCES 1. Groll AH, Gea-Banacloche JC, Glasmacher A, Just-Nuebling G, Maschmeyer G, Walsh TJ. Clinical pharmacology of antifungal compounds. Infect Dis Clin North Am 2003; 17: 159–91.

2. Gubbins PO, Penzak SR, Polston S, McConnell SA, Anaissie E. Characterizing and predicting amphotericin B-associated nephrotoxicity in bone marrow or peripheral blood stem cell

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transplant recipients. Pharmacotherapy 2002; 22: 961–71. 3. Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. Br Med J 2001; 322: 579–82. 4. Furrer K, Schaffner A, Vavricka SR, Halter J, Imhof A, Schanz U. Nephrotoxicity of cyclosporine A and amphotericin B-deoxycholate as continuous infusion in allogenic stem cell transplantation. Swiss Med Wkly 2002; 132: 316–20. 5. Speich R, Dutly A, Naef R, Russi EW, Weder W, Boehler A. Tolerability, safety and efﬁcacy of conventional amphotericin B administered by 24-hour infusion to lung transplant recipients. Swiss Med Wkly 2002; 132: 455–8. 6. Bowden R, Chandrasekar P, White MH, Li X, Pietrelli L, Gurwith M, Van Burik JA, Laverdiere M, Safrin S, Wingard JR. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2002; 35: 359–66. 7. Slain D, Miller K, Khakoo R, Fisher M, Wierman T, Jozefczyk K. Infrequent occurrence of amphotericin B lipid complex-associated nephrotoxicity in various clinical settings at a university hospital: a retrospective study. Clin Ther 2002; 24: 1636–42. 8. Johnson PC, Wheat LJ, Cloud GA, Goldman M, Lancaster D, Bamberger DM, Powderly WG, Hafner R, Kauffman CA, Dismukes WE. Safety and efﬁcacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002; 137: 105–9. 9. Stuecklin-Utsch A, Hasan C, Bode U, Fleischhack G. Pancreatic toxicity after liposomal amphotericin B. Mycoses 2002; 45: 170–3. 10. Vermes A, Guchelaar HJ, Van Kuilenburg AB, Dankert J. 5-ﬂuorocytosine-related bone-marrow depression and conversion to ﬂuorouracil: a pilot study. Fundam Clin Pharmacol 2002; 16: 39–47. 11. Castellsague J, Garcia-Rodriguez LA, Duque A, Perez S Risk of serious skin disorders among users of oral antifungals: a population-based study. BMC Dermatol 2002; 2: 14. 12. Bradbury BD, Jick SS. Itraconazole and ﬂuconazole and certain rare, serious adverse events. Pharmacotherapy 2002; 22: 697–700. 13. Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, Faris RM, Maguire JH. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. New Engl J Med 2002; 346: 891–5. 14. Khazan M, Mathis AS. Probable case of torsades de pointes induced by ﬂuconazole. Pharmacotherapy 2002; 22: 1632–7. 15. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother 2002; 46: 160–5. 16. Kang BC, Yang CQ, Cho HK, Suh OK, Shin WG. Inﬂuence of ﬂuconazole on the pharmacokinetics of omeprazole in healthy volunteers. Biopharm Drug Dispos 2002; 23: 77–81.

287 17. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. The effect of ﬂuconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 2002; 58: 527–31. 18. Finch CK, Green CA, Self TH. Fluconazole– carbamazepine interaction. South Med J 2002; 95: 1099–100. 19. Tarumi Y, Pereira J, Watanabe S. Methadone and ﬂuconazole: respiratory depression by drug interaction. J Pain Symptom Manage 2002; 23: 148–53. 20. Ohtani Y, Kotegawa T, Tsutsumi K, Morimoto T, Hirose Y, Nakano S. Effect of ﬂuconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: an application of electroencephalography as the pharmacodynamic method. J Clin Pharmacol 2002; 42: 183–91. 21. Goins RA, Ascher D, Waecker N, Arnold J, Mooreﬁeld E. Comparison of ﬂuconazole and nystatin oral suspensions for treatment of oral candidiasis in infants. Pediatr Infect Dis J 2002; 21: 1165–7. 22. Winston DJ, Busuttil RW. Randomized controlled trial of oral itraconazole solution versus intravenous/oral ﬂuconazole for prevention of fungal infections in liver transplant recipients. Transplantation 2002; 74: 688–95. 23. Gupta AK, Chwetzoff E, Del Rosso J, Baran R. Hepatic safety of itraconazole. J Cutaneous Med Surg 2002; 6: 210–13. 24. Main KM, Skov M, Sillesen IB, Dige-Petersen H, Muller J, Koch C, Lanng S. Cushing’s syndrome due to pharmacological interaction in a cystic ﬁbrosis patient. Acta Paediatr 2002; 91: 1008–11. 25. Parmar JS, Howell T, Kelly J, Bilton D. Profound adrenal suppression secondary to treatment with low dose inhaled steroids and itraconazole in allergic bronchopulmonary aspergillosis in cystic ﬁbrosis. Thorax 2002; 57: 749–50. 26. Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S. Iatrogenic adrenal insufﬁciency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J 2002; 20: 127–33. 27. Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivisto KT. Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole. Clin Pharmacol Ther 2002; 72: 362– 9. 28. Mercadante S, Villari P, Ferrera P. Itraconazole– fentanyl interaction in a cancer patient. J Pain Symptom Manage 2002; 24: 284–6. 29. Otsuji Y, Okuyama N, Aoshima T, Fukasawa T, Kato K, Gerstenberg G, Miura M, Ohkubo T, Sugawara K, Otani K. No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam. Ther Drug Monit 2002; 24: 375–8. 30. Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA. Itraconazole-induced rhabdomyolysis and acute renal failure in a heart transplant recipient treated with simvastatin and cyclosporine. Transplantation 2002; 73: 1962–4. 31. Maxa JL, Melton LB, Ogu CC, Sills MN, Limanni A. Rhabdomyolysis after concomitant use

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of cyclosporine, simvastatin, gemﬁbrozil, and itraconazole. Ann Pharmacother 2002; 36: 820–3. 32. Groll AH, Wood L, Roden M, Mickiene D, Chiou CC, Townley E, Dad L, Piscitelli SC, Walsh TJ. Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. Antimicrob Agents Chemother 2002; 46: 2554–63. 33. Hoffman HL, Ernst EJ, Klepser ME. Novel triazole antifungal agents. Expert Opin Invest Drugs 2000; 9: 593–605. 34. 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. 35. Ally R, Schurmann D, Kreisel W, Carosi G, Aguirrebengoa K, Dupont B, Hodges M, Troke P, Romero AJ. 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. 36. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, Yanovich S, Stiff P, Greenberg R, Donowitz G, Schuster M, Reboli A, Wingard J, Arndt C, Reinhardt J, Hadley S, Finberg R, Laverdiere M, Perfect J, Garber G, Fioritoni G, Anaissie E, Lee J. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. New Engl J Med 2002; 346: 225–34. 37. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New Engl J Med 2002; 347: 408–15. 38. Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E, Haas A, Ruhnke M, Lode H. Efﬁcacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002; 34: 563–71. 39. Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002; 46: 2546–53. 40. Lazarus HM, Blumer JL, Yanovich S, Schlamm H, Romero A. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol 2002; 42: 395–402. 41. Romero AJ, Pogamp PL, Nilsson LG, Wood N. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther 2002; 71: 226–34. 42. Walsh TJ, Lutsar I, Driscoll T, Dupont B, Roden M, Ghahramani P, Hodges M, Groll AH, Perfect JR. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J 2002; 21: 240–8.

Andreas H. Groll, Hedwig Kolve, and Thomas J. Walsh 43. 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. 44. Tsai HH, Lee WR, Hu CH. Isolated thrombocytopenia associated with oral terbinaﬁne. Br J Dermatol 2002; 147: 627–8. 45. Van der Schroeff JG, Cirkel PK, Crijns MB, Van Dijk TJ, Govaert FJ, Groeneweg DA, Tazelaar DJ, De Wit RF, Wuite J. A randomized treatment duration-ﬁnding study of terbinaﬁne in onychomycosis. Br J Dermatol 1992; 126 Suppl 39: 36–9. 46. Anania FA, Rabin L. Terbinaﬁne hepatotoxicity resulting in chronic biliary ductopenia and portal ﬁbrosis. Am J Med 2002; 112: 741–2. 47. Weiss JM, Mockenhaupt M, Schopf E, Simon JC. Reproducible drug exanthema to terbinaﬁne with characteristic distribution of baboon syndrome. Hautarzt 2001; 52: 1104–6. 48. Madani S, Barilla D, Cramer J, Wang Y, Paul C. Effect of terbinaﬁne on the pharmacokinetics and pharmacodynamics of desipramine in healthy volunteers identiﬁed as cytochrome P450 2D6 (CYP2D6) extensive metabolizers. J Clin Pharmacol 2002; 42: 1211–18. 49. Van Der Kuy PH, Van Den Heuvel HA, Kempen RW, Vanmolkot LM. Pharmacokinetic interaction between nortriptyline and terbinaﬁne. Ann Pharmacother 2002; 36: 1712–14. 50. Silm H, Karelson M. Terbinaﬁne: efﬁcacy and tolerability in young children with tinea capitis due to Microsporum canis. J Eur Acad Dermatol Venereol 2002; 16: 228–30. 51. Groll AH, Walsh TJ. Antifungal chemotherapy: recent advances and current perspectives. Swiss Med Wkly 2002; 132: 303–11. 52. Groll AH, Walsh TJ. Caspofungin: pharmacology, safety, and therapeutic potential in superﬁcial and invasive fungal infections. Expert Opin Invest Drugs 2001; 10: 1545–58. 53. Sable CA, Nguyen BY, Chodakewitz JA, DiNubile MJ. Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transplant Infect Dis 2002; 4: 25–30. 54. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, Lupinacci R, Sable C, Kartsonis N, Perfect J. Comparison of caspofungin and amphotericin B for invasive candidiasis. New Engl J Med 2002; 347: 2020–9. 55. Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, DiNubile MJ, Sable CA. Randomized, doubleblind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother 2002; 46: 451–7. 56. Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, Smietana JM, DiNubile MJ, Sable CA. A randomized doubleblind study of caspofungin versus ﬂuconazole for the treatment of esophageal candidiasis. Am J Med 2002; 113: 294–9.

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Antiprotozoal drugs

ANTIMALARIAL DRUGS 4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) (SED-14, 950;

There have been only a few isolated reports of Stevens–Johnson syndrome associated with hydroxychloroquine. Recently a clear temporal relation to the start of treatment with hydroxychloroquine has been documented in a patient with rheumatoid arthritis (4A ).

SEDA-24, 331; SEDA-25, 343; SEDA-26, 315)

Chloroquine and hydroxychloroquine Chloroquine is effective in most cases of nonfalciparum malaria but is now only seldom used for falciparum malaria, owing to widespread resistance. On the other hand, chloroquine is still widely used in rheumatology. Since it is used in higher doses and for longer times, adverse effects are nowadays mainly found in this population. Cardiovascular Chloroquine cardiomyopathy occurred during long-term (7 years) treatment for rheumatoid polyarthritis in a 42-yearold woman, who had an isolated acute severe conduction defect, conﬁrmed by histological study with electron microscopy (1A ). Sensory systems Unilateral sensorineural hearing loss occurred in a 7-year-old girl with idiopathic pulmonary hemosiderosis after she had taken hydroxychloroquine 100 mg bd for 2 years (2A ). Skin An increased frequency of skin reactions to hydroxychloroquine was noted in 11 patients (seven of whom had systemic lupus erythematosus, two discoid lupus, and two a lupus-like syndrome) when a coloring agent (sunshine yellow E110) was removed from the formulation; the authors were unable to explain this unexpected ﬁnding (3r ). © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Susceptibility factors Skin reactions to hydroxychloroquine occur more often in patients with dermatomyositis than in patients with systemic lupus erythematosus, as has been shown in a retrospective, age-, sex-, and race-matched case–control study in 78 patients (5c ). Twelve of 39 patients with dermatomyositis developed a skin reaction to hydroxychloroquine, compared with only one of 39 patients with lupus erythematosus. Drug overdose In Zimbabwe 544 cases of poisoning by a single agent were identiﬁed in a retrospective hospital record review (6c ). Antimalarial drugs accounted for the largest proportion of admissions (53%), and chloroquine accounted for 96% of these (279 cases). The median length of hospital stay in those who took chloroquine was signiﬁcantly shorter (1 vs 2 days) and more patients took chloroquine deliberately (80% vs 69%). The mortality rate from chloroquine poisoning was signiﬁcantly higher than from poisoning with other drugs (5.7% vs 0.7%). Drug interactions Syncope occurred in a hypertensive 48-year-old man who took oral chloroquine sulfate (total 600 mg base) while also taking amlodipine 5 mg/day (7A ). Chloroquine and amlodipine both cause vasodilatation, perhaps by release of nitric oxide, and the syncope in this case was probably due to a synergistic mechanism. Malaria itself can also provoke orthostatic reactions, which may be why syncope is not a reported adverse effect of chloroquine. However, in this patient malaria had been excluded.

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Halofantrine

(SED-14, 968; SEDA-24, 311; SEDA-25, 344; SEDA-26, 317)

Drug interactions Halofantrine is not used any more in many parts of the world, because it prolongs the QT interval. Since halofantrine is metabolized to N-debutyl-halofantrine by CYP3A4, grapefruit juice increases its systemic availability (8c ). Twelve healthy men and women took halofantrine 500 mg with water, orange juice, or grapefruit juice (250 ml/day for 3 days and once 12 hours before halofantrine) in a crossover study. Compared with water, grapefruit juice signiﬁcantly increased halofantrine AUC and Cmax 2.8-fold and 3.2-fold respectively; there was no signiﬁcant change in half-life. Maximum QTc interval prolongation increased signiﬁcantly from 17 ms when halofantrine was taken with water to 31 ms when it was taken with grapefruit juice. Grapefruit juice should be avoided by patients taking halofantrine.

Meﬂoquine

(SED-13, 808; SEDA-24, 332; SEDA-25, 343; SEDA-26, 317)

The frequency and spectrum of adverse events associated with meﬂoquine (750 and 500 mg 6 hours apart) has been assessed in 22 healthy volunteers who were monitored for 21 days after drug administration (9C ). More women than men reported severe adverse reactions. The most commonly reported adverse effects were vertigo (96%), nausea (82%), and headache (73%). The vertigo was severe (grade 3) in 73% and required bed rest and speciﬁc medication for 1–4 days. In most cases (17/22) the symptoms resolved within 3 weeks after drug administration. Biochemical and hematological measures stayed within the reference ranges, but there were nevertheless signiﬁcant rises in serum sodium, chloride, calcium, bilirubin, gamma-glutamyl transpeptidase, and lactate dehydrogenase. Nervous system Neuropsychiatric events have been extensively reviewed, but little is known about the sex-related incidence. Of 179 travellers (mean age 39 years) who took meﬂoquine for a 3-week prophylactic period before travelling, the women reported adverse events

Annelies S. Zinkernagel and Markus Schneemann

signiﬁcantly more often than the men (10C ). There was an increase in fatigue exclusively in the women, especially in ﬁrst-time users of meﬂoquine. Psychiatric In a prospective, double-blind, randomized, placebo-controlled study in 119 healthy volunteers (mean age 35 years) who took either atovaquone 250 mg/day + chloroguanide 100 mg/day or meﬂoquine 250 mg/ week, depression, anger, and fatigue occurred during the use of meﬂoquine but not atovaquone + chloroguanide (11C ).

Piperaquine Gastrointestinal The novel combination (Artekin™) of dihydroartemisinin and piperaquine has been assessed in 106 patients (76 children and 30 adults) with uncomplicated Plasmodium falciparum malaria in Cambodia (12C ). The respective doses of dihydroartemisinin and piperaquine, which were given at 0, 8, 24, and 32 hours, were 9.1 mg/kg and 74 mg/kg in children and 6.6 and 53 mg/kg in adults. All the patients became aparasitemic within 72 hours. Excluding the results in one child who died on day 4, there was a 97% 28-day cure rate (99% in children and 92% in adults). Patients who had recrudescent infections used low doses of Artekin. Adverse effects, most commonly gastrointestinal complaints, were reported by 22 patients (21%) but did not necessitate premature withdrawal.

QUININE AND CONGENERS (SED-14, 962; SEDA-24, 333; SEDA-26, 318)

Quinine Quinine is effective against all forms of Plasmodium species and is the drug of choice for severe malaria in most parts of the world. It is also often used to prevent leg cramps. Frequently documented adverse effects are nausea, dizziness, hypoglycemia, and tinnitus.

Antiprotozoal drugs

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Respiratory Quinine has not so far been implicated in pulmonary toxicity. • A 45-year-old woman with long-standing rheumatoid arthritis developed wheeze, severe anxiety, breathlessness, cough, orthopnea, mild fever, chills, and pleuritic chest discomfort after taking a single dose of quinine for nocturnal leg cramps (13A ). A chest X-ray showed diffuse, bilateral pulmonary inﬁltrates suggestive of pulmonary edema. No cause other than acute quinine ingestion was identiﬁed despite thorough cardiac and infectious disease evaluation.

Sensory systems Ocular toxicity with vasospasm has been described after poisoning with 4.5 g of quinine 24–36 hours before (14A ). Therapy for vasospasm using nimodipine, hemodilution, and hypervolemia was instituted, with subsequent resolution of the symptoms. Blindness has also been attributed to quinine (15A ). • A 43-year-old Ghanaian man with a mild attack of malaria due to Plasmodium falciparum received quinine 750 mg intravenously over 5 hours and another identical infusion 3.5 hours after the end of the ﬁrst infusion. Half an hour after the start of the second infusion he wakened and reported complete blindness. The infusion was immediately stopped, and ocular examination showed ﬁxed, dilated pupils, complete blindness, and normal fundi. A CT scan of the brain, electroencephalography, and retinal ﬂuorescein angiography were all normal. Serum quinine concentrations continued to rise after the end of the infusion, but this effect was mitigated by an increase in the serum concentration of alpha1 -acid glycoprotein, to which quinine binds. Six hours after the end of the infusion of quinine his sight began to improve.

Hematologic Isolated thrombocytopenia after the use of quinine for malaria or leg cramps has previously been described in isolated cases. The FDA’s Center for Drug Evaluation and Research received 141 reports of isolated thrombocytopenia in association with quinine from 1974 to December 2000 (16c ). After elimination of cases that were confounded by acute or chronic disease or concomitant drug therapy, 64 reports of quinine-associated thrombocytopenia were analysed. Thrombocytopenia occurred soon after the start of therapy (median 7 days) and was often severe (hospitalization reported in 55 of the 64 cases). Since 1972, the Australian Adverse Drug Reactions Advisory Committee has received 198 reports of thrombocytopenia associated

with quinine, four of which had a fatal outcome (17C ). In 17 of the 20 reports received since the beginning of 2000, patients had platelet counts of 0–14 × 109 /l; most of them required hospitalization and treatment with platelet transfusions, corticosteroids, or immunoglobulin. In most cases the platelet count normalized within 1 week of quinine withdrawal. As quinineinduced thrombocytopenia has an immunebased mechanism, the Committee suggested that patients who develop this reaction should subsequently avoid all products that contain quinine, including drinks such as tonic water. They also reminded prescribers that quinine is no longer recommended for the treatment of nocturnal cramps; the FDA withdrew nocturnal cramps as an indication for all quinine products in 1995 because of lack of evidence of efﬁcacy, and the Australian Medicines Handbook advises against its use for this indication. Urinary tract Quinine-induced disseminated intravascular coagulation and hemolytic–uremic syndrome occurred in a 78-year-old woman who took quinine 150 mg for leg cramps; this is the ﬁrst report of the two diseases occurring simultaneously after quinine (18A ). Concomitant acral necrosis and hemolytic– uremic syndrome have been attributed to quinine (19A ). • A 65-year-old man, who had taken a single dose of quinine 300 mg for leg cramps, developed both acral necrosis and hemolytic–uremic syndrome, which resolved promptly after treatment with corticosteroids.

8-AMINOQUINOLINES (PRIMAQUINE AND CONGENERS) (SED-14, 958; SEDA-24, 332; SEDA-25, 345; SEDA-26, 318)

Chlorproguanil + dapsone Hematologic Since chlorproguanil + dapsone exerts lower resistance pressure on Plasmodium falciparum than does pyrimethamine + sulfadoxine, a randomized trial in out-patients with

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uncomplicated falciparum malaria was conducted in Africa in 910 children (20C ). Treatment failure was more common with pyrimethamine + sulfadoxine. Despite the rapid elimination of chlorproguanil + dapsone, children treated with this combination did not have more episodes of malaria than those who were treated with pyrimethamine + sulfadoxine. However, there was a higher incidence of anemia.

dose 400 mg/day for 3 days followed by 400 mg/month in 5 consecutive months) age and weight affected the apparent volume of distribution and subjects who contracted malaria had higher clearance rates (23C ). The population estimate of the ﬁrst-order absorption half-life was 1.0 hour, clearance was 3.20 l/hour, volume of distribution was 1820 l, and half-life was 16.4 days.

Proguanil + atovaquone (Malarone™ )

ENDOPEROXIDES

Psychiatric In a double-blind, randomized, placebo-controlled study in 119 healthy volunteers (mean age 35 years) who took either atovaquone 250 mg/day + chloroguanide 100 mg/day or meﬂoquine 250 mg/week, depression, anger, and fatigue occurred during the use of meﬂoquine but not atovaquone + chloroguanide (11C ).

Sitamaquine (WR-6026) Sitamaquine is an orally active 8-aminoquinoline for the potential treatment of visceral leishmaniasis in Phase III trials and for the treatment of Pneumocystis infection in HIV-infected individuals in phase I trials (21R ). In a phase II, open, dose-escalating safety and efﬁcacy study in 22 Brazilian patients with kala-azar, ﬁve groups were given different oral regimens, containing 1.0–3.25 mg of sitamaquine, for 28 days (22c ). There was nephrotoxicity with 2.5 mg/kg/day in two patients and in the single patient who took 3.25 mg/kg/day. Interstitial nephritis with acute tubular necrosis was proven by biopsy in two patients. Headache and gastrointestinal adverse effects occurred in under 5%. Methemoglobinemia of less than 6% after 7 days was common.

Tafenoquine (WR 238605) Susceptibility factors In 104 healthy men (mean age 29 years, weight 60 kg) who took tafenoquine for malaria prophylaxis (loading

Artemisia derivatives

(SED-14, 966; SEDA-24, 331; SEDA-25, 346; SEDA-26, 319)

Arteether The ethyl ether derivative of artemisinin, Artemotil™ (previously called beta-arteether) has been developed as an artemisinin derivative with the advantages that it is more stable than artesunate and that methanol would not be a breakdown product as it is with artemether. In 25 patients with acute uncomplicated Plasmodium falciparum malaria treated with arteether (3.2 mg/kg followed by either 1.6 mg/kg or 0.8 mg/kg), the most frequent adverse events were headache, dizziness, nausea, vomiting, and abdominal pain; two patients complained of mild pain at the site of injection (24c ). In a post-marketing surveillance study of arteether in 300 patients, 294 (98%) were cured, ﬁve improved, and one did not show any change (25c ). The adverse effects were mild headache, nausea, vomiting, and giddiness. Drug formulations When the sesame oil vehicle in beta-arteether was replaced by Cremophor (polyethoxylated castor oil) the total exposure in rats was 2.7-fold higher, owing to increased systemic availability (26E ). Anorexia and gastrointestinal toxicity from beta-arteether in sesame oil were signiﬁcantly more severe than with beta-arteether in Cremophor. However, histological examination of the brain showed neurotoxic changes, which were worse with the castor oil formulation.

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Artemether Recently the effects of artemether against human schistosomiasis japonica, mansoni, and hematobia have been investigated in rabbits (27E ). Artemether has greatest activity against juvenile stages of the parasites, while adult worms are signiﬁcantly less susceptible. There was no evidence of neurotoxicity after repeated high doses of artemether given fortnightly for up to 5 months. Combined treatment with artemether and praziquantel, given to rabbits harboring juvenile and adult schistosome worms, resulted in signiﬁcantly higher worm burden reductions than with either drug alone.

modest increased risk of QTc prolongation, but this is far outweighed by the potential therapeutic beneﬁt. The effects on the QTc interval of single oral doses of halofantrine 500 mg and artemether 80 mg + lumefantrine 480 mg have been studied in 13 healthy men in a double-blind, randomized, crossover study (30c ). The length of the QTc interval correlated positively with halofantrine exposure but was unchanged by coartemether (i.e. artemether + lumefantrine).

Artesunate

Nervous system Neurotoxicity from artemether is related to drug accumulation due to slow and prolonged absorption from intramuscular injection sites. In mice high doses of intramuscular artemether (50–100 mg/kg/day for 28 days) resulted in an unusual pattern of selective damage to certain brain stem nuclei, especially those implicated in hearing and balance (28E ).

Fluid balance Sodium artesunate inhibits sodium chloride transport in the thick ascending limb of the loop of Henle and therefore has a diuretic effect. In two men, aged 16 and 32 years, with falciparum malaria who were given four intravenous doses of sodium artesunate 60 mg, neither of whom had received diuretics or vasoactive drugs, there was a diuresis (6 l/day) accompanied by a natriuresis (31A ).

Artemether + lumefantrine (benﬂumetol) (Riamet™ )

Pyrimethamine

Cardiovascular A combination of artemether + lumefantrine (six doses over 3 days) followed by quinine (a 2-hour intravenous infusion of 10 mg/kg, not exceeding 600 mg in total, 2 hour after the last dose of artemether + lumefantrine) was given to 42 healthy volunteers in a double-blind, parallel, three-group study (14 subjects per group) to examine the electrocardiographic effects of these drugs (29c ). Artemether + lumefantrine had no effect on the QTc interval. The infusion of quinine alone caused transient prolongation of the QTc interval, and this effect was slightly but signiﬁcantly greater when quinine was infused after artemether + lumefantrine. Thus, the inherent risk of QTc prolongation by intravenous quinine was enhanced by prior administration of artemether + lumefantrine. Overlapping therapy with artemether + lumefantrine and intravenous quinine in the treatment of patients with complicated or multidrug-resistant Plasmodium falciparum malaria may result in a

(SED-13, 811;

SEDA-26, 320) Pyrimethamine is used for the treatment of toxoplasmosis and the prophylaxis of malaria. Among its well-documented adverse effects are megaloblastic anemia, leukopenia, thrombocytopenia, rash, vomiting, and diarrhea. Skin Hyperpigmentation is a very rare adverse effect of pyrimethamine. • A 29-year-old woman (HIV negative) developed hyperpigmentation after taking pyrimethamine 25 mg bd for 40 days (32A ). The hyperpigmentation regressed 15 days after withdrawal of pyrimethamine.

Pyrimethamine + dapsone Immunologic Three patients developed a hypersensitivity syndrome after taking pyrimethamine 12.5 mg + dapsone 100 mg weekly as malaria prophylaxis (33A ). The diagnosis was

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based on the presence of fever, lymphadenopathy, a maculopapular rash, and hepatitis. A mild Coombs’ positive hemolytic anemia was also observed in one of the patients. All the clinical, hematological, and biochemical abnormalities normalized within 3 months of tapering regimens of moderate-dose prednisolone.

Pyrimethamine + sulfadoxine Intermittent iron supplementation with pyrimethamine + sulfadoxine has been investigated in 328 anemic but symptom-free Kenyan children, who were randomly given either iron (ferrous fumarate suspension 6.25 g/l twice a week) or placebo and pyrimethamine + sulfadoxine (25 mg and 1.25 mg/kg once every 4 weeks) or placebo (82 in each group) (34C ). After 12 weeks, those who took iron and pyrimethamine + sulfadoxine, iron alone, or pyrimethamine + sulfadoxine alone had higher hemoglobin concentrations than those who took the double placebo. No adverse effects were reported. Immunologic The safety and efﬁcacy of a ﬁxed combination of pyrimethamine 25 mg + sulfadoxine 500 mg, supplemented with folinic acid 15 mg, both twice a week, as primary prophylaxis of Pneumocystis pneumonia and Toxoplasma encephalitis has been evaluated in 106 patients infected with HIV in a single-arm, open, prospective study (35C ). There were allergic reactions in 18 patients and permanent withdrawal was required in seven. One patient who took continued prophylaxis despite progressive hypersensitivity reactions developed a serious adverse reaction (Stevens–Johnson syndrome).

Malaria vaccine For many years attempts have been made to develop a malaria vaccine. The results of different ﬁeld studies are continually being reported, as well as concomitant adverse effects.

Annelies S. Zinkernagel and Markus Schneemann

Immunologic Immediate-type hypersensitivity reactions (acute, systemic urticaria after the third immunization) occurred in two of 39 volunteers immunized with a synthetic multiantigen peptide vaccine (PfCS-MAP1NYU) against Plasmodium falciparum sporozoites, with detection of serum IgE MAP antibody (36c ). Immediate pain at the injection site was associated with the adjuvant QS-21, and delayed local inﬂammatory reactions were associated with high titers of circulating IgG anti-MAP antibody. Skin tests using intradermal injections of diluted MAP vaccine, to identify those who were sensitized to the vaccine, were negative in seven volunteers tested 27 days after the ﬁrst vaccination, but six of these developed positive wheal and ﬂare reactions when tested 14 or 83 days after the second vaccination; IgE MAP antibody was detected in only one of them. Skin tests may help in identifying individuals who have been sensitized to malaria peptides and who are at risk of developing systemic allergic reactions after revaccination. On the other hand, delayed-type hypersensitivity testing has been used to test T cell functional activity in 27 volunteers immunized with a synthetic multi-antigen peptide vaccine (MAP) (PfCS-MAP1NYU) against Plasmodium falciparum sporozoites (37c ). Intradermal inoculations (0.02 ml) of several concentrations of the MAP vaccine and adjuvant control solutions were applied and induration measured 2 days after. Nine of 14 vaccinees with high serum titers of anti-MAP antibody developed positive skin tests (at least 5 mm induration), which ﬁrst appeared by 29 days after immunization and persisted for at least 3–6 months after one or two more immunizations. In contrast, skin tests were negative in all of eight vaccinees with no or low antibody titers, and in all of ﬁve non-immunized volunteers. Biopsies of positive skin test sites were histologically compatible with a delayed hypersensitivity reaction. The authors concluded that the presence of T cell functional activity is reﬂected by a positive skin test response to the MAP antigen and may serve as another marker for vaccine immunogenicity.

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DRUGS USED IN THE TREATMENT OF PNEUMOCYSTIS JIROVECI INFECTIONS (SED-14, 970; SEDA-24, 334; SEDA-25, 347; SEDA-26, 320) The organism that causes human Pneumocystis pneumonia is now called Pneumocystis jiroveci, instead of Pneumocystis carinii (38r ). Changing the organism’s name does not preclude the use of the abbreviation PCP, because it can be read as “Pneumocystis pneumonia”. Since 1988 it has also been known to be a fungus and not a protozoon.

Co-trimoxazole (trimethoprim + sulfamethoxazole) Nervous system Aseptic meningitis is a rare adverse effect of co-trimoxazole. The pathogenic mechanism is still uncertain. A 15-yearold man developed aseptic meningitis while taking trimethoprim 200 mg in the morning and 100 mg in the evening (39A ). Hematologic Hemophagocytosis in the setting of severe drug hypersensitivity syndrome due to co-trimoxazole has been reported (40A ). • A 53-year-old woman with congenital dyskeratosis took trimethoprim 960 mg/day and sulfamethoxazole 4800 mg/day in the form of six doublestrength tablets of co-trimoxazole per day, plus folic acid, for Pneumocystis pneumonia. After 9 days she suddenly developed a fever (39◦ C), a morbilliform rash, and painful cervical lymphadenopathy. Her white blood cell count was 17 × 109 /l, hemoglobin, 7.3 g/dl, platelet count 170 × 109 /l, and there was evidence of cytolysis. The bone marrow showed extensive hemophagocytosis. Polyvalent intravenous immunoglobulin (1 g/kg/day) was given for 2 days. She became apyrexial within 48 hours and improved over the next month.

Urinary tract In rats indinavir nephrotoxicity was potentiated by co-trimoxazole, but nelﬁnavir alone or in combination with cotrimoxazole was not nephrotoxic (41E ).

295 Immunologic The hydroxylamine metabolites of sulfamethoxazole bind covalently to proteins, resulting in induction of speciﬁc adverse immune responses. Changes in the activity of metabolic and detoxiﬁcation pathways are therefore associated with a greater risk of allergic reactions to sulfonamides. Allergies to sulfonamides, particularly sulfamethoxazole, are more frequent in patients with AIDS, but the reason for this increased risk is not fully understood. No valid tools are available to predict which patients have a greater risk of sulfonamide-induced allergies. The lymphocyte toxicity assay has been used as a diagnostic tool in a small study in 35 HIV-positive patients with hypersensitivity reactions (42C ). In patients who absolutely require further treatment, successful desensitization may be achieved (43R ). Susceptibility factors Susceptibility factors for drug eruptions have been assessed in 136 patients who were hospitalized for Pneumocystis infection or toxoplasmosis; 48 patients had a drug eruption and 88 did not (44C ). A high CD8(+) cell count and age under 36 years were associated with a risk of drug eruption. Despite current concepts, the risk was not increased by glutathione deﬁciency, slow acetylation, or active viral infections, and corticosteroids were not preventive. Drug interactions Co-trimoxazole greatly increased the risk of overanticoagulation in patients taking long-term acenocoumarol and phenprocoumon (45R ). The adjusted relative risk was 20 (95% CI = 11, 38). The authors proposed different mechanisms for this interaction: • displacement of the coumarins from protein plasma binding sites by sulfamethoxazole, which would have transiently increased the unbound concentrations of the coumarins; however, this is an unlikely mechanism, since the clearance of these coumarins, which are low-clearance drugs, depends on the unbound fraction, and any reduction in binding is soon compensated for by increased total clearance; • reduced vitamin K availability from the gut by elimination of bacterial ﬂora in the gut; this is also unlikely, since two-thirds of daily vitamin K intake is derived from the diet, not from gut bacteria;

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• inhibition of the action of vitamin-K dependent coagulation factors.

DRUGS USED IN THE TREATMENT OF TOXOPLASMA INFECTIONS Atovaquone Gastrointestinal Atovaquone suspension (1500 mg orally bd) plus either pyrimethamine (75 mg/day after a 200 mg loading dose) or sulfadiazine (1500 mg qds), as treatment for acute Toxoplasma encephalitis (for 6 weeks) and as maintenance therapy (for 42 weeks), has been studied in a randomized phase II trial in HIV-positive patients (46C ). There were good responses in 21 of 28 patients who received pyrimethamine and 9 of 11 who received sulfadiazine. Of 20 patients in the maintenance phase, only one relapsed. Of 40 eligible patients 11 discontinued treatment as a result of adverse events, nine because of nausea and vomiting or intolerance of the taste of the atovaquone suspension.

Clindamycin Immunologic An allergic reaction to clindamycin has been reported (47A ). • A 57-year-old Caucasian woman with a history of ocular toxoplasmosis, treated with intravitreal clindamycin (10 mg/ml) and dexamethasone (4 mg/ml), developed a generalized erythematous macular rash over the scalp, face, arms, thighs, and trunk 2 days after the start of treatment.

Co-trimoxazole Skin In a prospective randomized open trial of the effect of long-term intermittent cotrimoxazole on recurrences of Toxoplasma choroidoretinitis, four of 54 patients, who took a single tablet of a co-trimoxazole (trimethoprim 160 mg + sulfamethoxazole 800 mg), developed mild allergic reactions (cutaneous erythema), which subsequently resolved (48C ).

Annelies S. Zinkernagel and Markus Schneemann

Pyrimethamine + azithromycin In a prospective, randomized, open, multicenter trial of pyrimethamine + azithromycin vs pyrimethamine + sulfadiazine for the treatment of ocular toxoplasmosis in 46 patients with sight-threatening ocular toxoplasmosis, the two regimens had similar efﬁcacy; however, the adverse effects were signiﬁcantly less common and severe with pyrimethamine + azithromycin (49C ).

DRUGS USED FOR LEISHMANIASIS Miltefosine Miltefosine is an alkylphospholipid that affects cell-signalling pathways and membrane synthesis; it was originally developed as an oral antineoplastic agent but is now licensed for use in visceral leishmaniasis in India (50r , 51R ). In an open, multicenter trial in 120 patients, aged 12–50 years, who received 50, 100, or 150 mg/day of miltefosine for 4 or 6 weeks, there was an initial parasitological cure in all cases (52C ). Six patients had clinical and parasitological relapses by 6 months after initial treatment. There was a 97% cure rate with miltefosine 100 mg/day. Gastrointestinal adverse effects were frequent (in 62%) but mild to moderate in intensity, and no patient discontinued therapy as a result. In one patient, treatment was withdrawn because of raised AsT activity, and in 12 others the AsT activity increased to 100–150 U/l during treatment. In one patient treatment was withdrawn because of a raised creatinine concentration. Miltefosine has been compared with the most effective standard treatment, amphotericin, in a randomized, open comparison in India, in which 299 patients, aged 12 years or over, received oral miltefosine (50 or 100 mg) and 99 patients received intravenous amphotericin B deoxycholate (1 mg/kg every other day to a total of 15 injections) (53EC ). Vomiting and diarrhea were more common with miltefosine. However, the effects were mild in almost all cases, and only 3–4% of patients needed antiemetic drugs in both groups. One patient

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who took miltefosine withdrew because of gastrointestinal intolerance and one developed Stevens–Johnson syndrome. Fertility Miltefosine caused infertility in male rats, but not in 211 men (53EC ).

Pentamidine

(SED-13, 823;

SEDA-26, 323) Pentamidine is the drug of choice for the treatment of cutaneous leishmaniasis in Surinam. Pentamidine mesylate in 235 patients and pentamidine isethionate in 80 patients have been compared in a retrospective study; the cure rate (healing without relapse) was nearly 90% in both groups (54C ). Relapses occurred in about 10% of patients in both groups. Minor adverse effects, such as pain at the injection site, bitter taste, and nausea, occurred with both drugs in about 65% of patients. Respiratory tract problems occurred in under 10% of patients who took pentamidine isethionate but were uncommon in those who took pentamidine mesylate. Cardiovascular Torsade de pointes has been reported in a 48-year-old HIV-positive woman treated with intravenous pentamidine (55A ). Hematologic Intravenous pentamidine caused megaloblastic anemia in a 38-year-old woman with Pneumocystis pneumonia (56A ). Musculoskeletal Two patients (aged 31 and 38 years) with cutaneous leishmaniasis given intramuscular pentamidine 600 mg twice in 48 hours developed rhabdomyolysis (57A ). They recovered with ﬂuid replacement and alkaline diuresis.

Pentavalent antimonials (SED-14, 984; SEDA-23, 310; SEDA-24, 336; SEDA-25, 349) Allopurinol and meglumine antimoniate (Glucantime™ ) have been evaluated in a randomized controlled trial in 150 patients with cutaneous

297 leishmaniasis (58C ). They received oral allopurinol (15 mg/kg/day) for 3 weeks, or intramuscular meglumine antimoniate (30 mg/kg/day, corresponding to 8 mg/kg/day of pentavalent antimony, for 2 weeks), or combined therapy. There were a few adverse effects in those who used allopurinol: nausea, heartburn (n = 3), and mild increases in AsT and AlT (n = 2). These symptoms subsided on drug withdrawal. In an open study 72 patients each received meglumine antimoniate (60 mg/kg/day) or allopurinol (20 mg/kg/day) plus low-dose meglumine antimoniate (30 mg/kg/day) for 20 days, and each was followed for 30 days after the end of treatment (59C ). Only six patients in the combined treatment group complained of mild abdominal pain and nausea; however, one patient who received meglumine antimoniate developed a skin eruption. Generalized muscle pain and weakness occurred in four patients. The characteristics of 111 consecutive patients with visceral leishmaniasis in Sicily have been described (60C ). They were given intramuscular meglumine antimoniate (560 mg/m2 of pentavalent antimony) generally for 21 days. There were adverse effects in 16 patients, including rash (n = 3) and dry cough (n = 13). All the adverse effects bar one (a severe urticarial rash) were transient and self-limiting and did not require drug withdrawal. A randomized, double-blind, placebo-controlled study of sodium stibogluconate for 10 and 20 days has been conducted in 38 US military personnel with cutaneous leishmaniasis; 19 received sodium stibogluconate for 10 days (and placebo for 10 days), and 19 received sodium stibogluconate for 20 days (61C ). Treatment withdrawal was necessary as a result of pancreatitis in seven patients (four in the 10-day treatment group and three in the 20day group), and this occurred during the ﬁrst 10 days of therapy in all seven patients. Myalgia occurred in eight patients in the 10-day group and in 13 patients in the 20-day group. Patients in the 20-day group had myalgia on signiﬁcantly more days than those in the 10day group. Increases in amylase, lipase, AsT, and AlT and falls in white blood cell count, hematocrit, and platelet count also differed signiﬁcantly between the two groups. Even the normal dose of sodium stibogluconate can lead to both cardiotoxicity and hemotoxicity, because of its cumulative effects.

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Annelies S. Zinkernagel and Markus Schneemann

• Fatal accumulation of sodium stibogluconate occurred in a 4-year-old boy with visceral leishmaniasis treated with intravenous sodium stibogluconate 20 mg/kg (1200 mg/day) and oral allopurinol 16 mg/kg/day (100 mg tds) (62A ). On day 3 he reported chest pain and persistent cough, and the drugs were withdrawn. Three days later he developed a petechial rash on the legs and died with ventricular ﬁbrillation.

maculopapular rash 3.2%, severe pruritus 3.2% (64C ). Milder reactions were fever, headache, and diarrhea.

DRUGS USED FOR HUMAN AFRICAN TRYPANOSOMIASIS

OTHER ANTIPROTOZOAL DRUGS

(SED-14, 981; SEDA-24, 335; SEDA-25, 350; SEDA-26, 323)

Benznidazole

Eﬂornithine

The adverse effects of benznidazole can be classiﬁed into three groups (66R , 67C ):

In 42 patients with late-stage Trypanosoma brucei gambiense trypanosomiasis, who relapsed after initial treatment with melarsoprol, a sequential combination of intravenous eﬂornithine (100 mg/kg every 6 hours for 4 days) followed by three daily injections of melarsoprol (3.6 mg/kg, up to 180 mg) was used (63A ). They were followed for 24 months. In one case the administration of eﬂornithine had to be interrupted for 48 hours because of convulsions, but treatment was then resumed without recurrence. Other adverse effects during treatment were abdominal pain or vomiting (n = 4 each), diarrhea (n = 1), and loss of hearing (n = 1). Two patients died during treatment: • a 37-year-old man died of an acute cholera-like syndrome, with severe diarrhea, vomiting, and dehydration, after the last dose of eﬂornithine but before receiving his ﬁrst dose of melarsoprol; • a 34-year-old man died of an unknown cause after having received all 16 doses of eﬂornithine as well as the ﬁrst injection of melarsoprol.

Nervous system In 56 patients with African trypanosomiasis, one treated with melarsoprol (total dose 26 mg/kg) developed a reactive arsenical encephalopathy (65C ).

• symptoms of hypersensitivity—dermatitis with skin eruptions (usually occurring at 7– 10 days of treatment), generalized edema, fever, lymphadenopathy, and joint and muscle pains; • bone-marrow suppression, thrombocytopenia and agranulocytosis being the most severe manifestations; • peripheral polyneuropathy, paresthesia, and polyneuritis. In a systematic Cochrane review the incidence of adverse effects was less than 20% (68M ). In one study, under 5% of participants complained of a variety of minor symptoms, but rash and pruritus were reported more commonly. In children the drug was well tolerated and there were no severe adverse effects. The only study in adults reported a non-quantiﬁed variety of mild adverse effects (skin reactions, peripheral neuropathy, digestive disturbances), but it was said that they were less intense than those seen with nifurtimox.

Melarsoprol In a randomized trial in 500 patients infected with Trypanosoma brucei gambiense treated with ten daily consecutive doses of melarsoprol 2.2 mg/kg, the adverse effects were: encephalopathic syndrome 5.6%, death from encephalopathy 2.4%, polyneuropathy less than 1%, severe bullous dermatitis 1.2%, severe

Metronidazole

(SED-14, 977; SEDA-25, 350; SEDA-26, 323; see also Chapter 26)

Nervous system Ataxia and dysarthria can occur during treatment with metronidazole (69A ).

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• A 62-year-old man with multiple epidural abscesses treated with oral metronidazole (500 mg qds) and intravenous cefepime (2 g bd) developed ataxia and dysarthria about 1 month after the start of therapy. • A 74-year-old man who had taken oral metronidazole (500 mg tds) and oral levoﬂoxacin (500 mg/day) for intra-abdominal abscesses developed ataxia and dysarthria 4 weeks after the start of therapy.

Both patients recovered from the subacute cerebellar syndrome, but resolution of their symptoms took a number of weeks.

reaction when it is taken with alcohol, due to inhibition of hepatic aldehyde dehydrogenase. In a double-blind study in 12 healthy men from Finland, six took metronidazole for 5 days and the other six took placebo (74C ). All took ethanol 0.4 g/kg at the beginning of the study. Metronidazole neither increased blood acetaldehyde concentrations nor had any objective or subjective adverse effects when used together with ethanol. However, it is possible that a disulﬁram-like reaction can occur in some subgroups and by mechanisms other than inhibition of hepatic aldehyde dehydrogenase.

Pancreas Metronidazole can rarely cause acute pancreatitis (70A ). • A 49-year-old woman took a single oral dose of metronidazole 2 g for recurrent vaginal trichomoniasis and less than 12 hours later developed dyspnea and epigastric pain. Acute pancreatitis was diagnosed, with an amylase of 1397 (reference range 25–125) U/l and a lipase of 6916 (8–57) U/l. She made a full recovery and experienced no further symptoms of pancreatitis. She had previously had acute pancreatitis after taking metronidazole for 3–5 days for an episode of trichomoniasis 3 years before.

Skin Two cases of ﬁxed drug eruption have been reported, without details of dosages or duration of therapy (71A , 72A ). • A 41-year-old woman developed a ﬁxed drug eruption after taking oral metronidazole for recurrent trichomonal vaginitis (73A ). She had received the drug on four separate occasions and each time had developed “sores” on the arms, legs, and axillae within hours of exposure.

Drug interactions Metronidazole has previously been reported to cause a disulﬁram-like

Nifurtimox For treatment of the acute phase of Chagas’ disease and in congenital cases the recommended dosage of nifurtimox is 8–10 mg/kg/day, divided into two or three daily doses, for 30– 60 consecutive days. The more frequent adverse effects are anorexia, loss of weight, psychic alterations, excitability or sleepiness, and digestive manifestations, such as nausea, vomiting, and occasionally intestinal colic and diarrhea (66R ).

Ornidazole Nervous system Recently, the ﬁrst case of a meningeal syndrome with fever has been reported in a 65-year-old man on the fourth day of administration of ornidazole (500 mg tds) (75A ). Spontaneous recovery occurred within a few days and without sequelae.

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5. Pelle MT, Callen JP. Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus. Arch Dermatol 2002; 138: 1231–3. 6. Ball DE, Tagwireyi D, Nhachi CF. Chloroquine poisoning in Zimbabwe: a toxicoepidemiological study. J Appl Toxicol 2002; 22: 311–15. 7. Ajayi AA, Adigun AQ. Syncope following oral chloroquine administration in a hypertensive patient controlled on amlodipine. Br J Clin Pharmacol 2002; 53: 404–5. 8. Charbit B, Becquemont L, Lepere B, Peytavin G, Funck-Brentano C. Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine. Clin Pharmacol Ther 2002; 72: 514– 23. 9. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of meﬂoquine in healthy adults. Acta Trop 2002; 81: 167–73. 10. Van Riemsdijk MM, Ditters JM, Sturkenboom MC, Tulen JH, Ligthelm RJ, Overbosch D, Stricker BH. Neuropsychiatric events during prophylactic use of meﬂoquine before travelling. Eur J Clin Pharmacol 2002; 58: 441–5. 11. Van Riemsdijk MM, Sturkenboom MC, Ditters JM, Ligthelm RJ, Overbosch D, Stricker BH. Atovaquone plus chloroguanide versus meﬂoquine for malaria prophylaxis: a focus on neuropsychiatric adverse events. Clin Pharmacol Ther 2002; 72: 294–301. 12. Denis MB, Davis TM, Hewitt S, Incardona S, Nimol K, Fandeur T, Poravuth Y, Lim C, Socheat D. Efﬁcacy and safety of dihydroartemisinin–piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria. Clin Infect Dis 2002; 35: 1469–76. 13. Krantz MJ, Dart RC, Mehler PS. Transient pulmonary inﬁltrates possibly induced by quinine sulfate. Pharmacotherapy 2002; 22: 775–8. 14. Barrett NA, Solano T. Quinine ocular toxicity: treatment of blindness using therapy for vasospasm. Anaesth Intensive Care 2002; 30: 234–5. 15. Di Perri G, Allegranzi B, Bonora S. Quinineinduced blindness reversed by an increase in alpha1 -acid glycoprotein level. Ann Intern Med 2002; 136: 339. 16. Brinker AD, Beitz J. Spontaneous reports of thrombocytopenia in association with quinine: clinical attributes and timing related to regulatory action. Am J Hematol 2002; 70: 313–17. 17. Anonymous. Quinine. Reports of thrombocytopenia. WHO Pharmaceuticals Newslett 2000; 4: 10. 18. Morton AP. Quinine-induced disseminated intravascular coagulation and haemolytic–uraemic syndrome. Med J Aust 2002; 176: 351. 19. Agarwal N, Cherascu B. Concomitant acral necrosis and haemolytic uraemic syndrome following ingestion of quinine. J Postgrad Med 2002; 48: 197–8. 20. Sulo J, Chimpeni P, Hatcher J, Kublin JG, Plowe CV, Molyneux ME, Marsh K, Taylor TE,

Annelies S. Zinkernagel and Markus Schneemann Watkins WM, Winstanley PA. Chlorproguanil– dapsone versus sulfadoxine–pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial. Lancet 2002; 360: 1136–43. 21. Yeates C. Sitamaquine (GlaxoSmithKline/Walter Reed Army Institute). Curr Opin Investig Drugs 2002; 3: 1446–52. 22. Dietze R, Carvalho SF, Valli LC, Berman J, Brewer T, Milhous W, Sanchez J, Schuster B, Grogl M. Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi. Am J Trop Med Hyg 2001; 65: 685–9. 23. Edstein MD, Kocisko DA, Brewer TG, Walsh DS, Eamsila C, Charles BG. Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers. Br J Clin Pharmacol 2001; 52: 663–70. 24. Looareesuwan S, Oosterhuis B, Schilizzi BM, Sollie FA, Wilairatana P, Krudsood S, Lugt ChB, Peeters PA, Peggins JO. Dose-ﬁnding and efﬁcacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria. Br J Clin Pharmacol 2002; 53: 492–500. 25. Asthana OP, Srivastava JS, Das Gupta P. Postmarketing surveillance of arteether in malaria. J Assoc Phys India 2002; 50: 539–45. 26. Li QG, Mog SR, Si YZ, Kyle DE, Gettayacamin M, Milhous WK. Neurotoxicity and efﬁcacy of arteether related to its exposure times and exposure levels in rodents. Am J Trop Med Hyg 2002; 66: 516–25. 27. Xiao S, Tanner M, N’Goran EK, Utzinger J, Chollet J, Bergquist R, Chen M, Zheng J. Recent investigations of artemether, a novel agent for the prevention of schistosomiasis japonica, mansoni and haematobia. Acta Trop 2002; 82: 175–81. 28. Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R, Looareesuwan S, White NJ. Neuropathologic toxicity of artemisinin derivatives in a mouse model. Am J Trop Med Hyg 2002; 67: 423– 9. 29. Lefevre G, Carpenter P, Souppart C, Schmidli H, Martin JM, Lane A, Ward C, Amakye D. Interaction trial between artemether–lumefantrine (Riamet) and quinine in healthy subjects. J Clin Pharmacol 2002; 42: 1147–58. 30. Bindschedler M, Lefevre G, Degen P, Siouﬁ A. Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants. Am J Trop Med Hyg 2002; 66: 293–8. 31. Seguro AC, Campos SB. Diuretic effect of sodium artesunate in patients with malaria. Am J Trop Med Hyg 2002; 67: 473–4. 32. Ozturk R, Engin A, Ozaras R, Mert A, Tabak F, Aktuglu Y. Hyperpigmentation due to pyrimethamine use. J Dermatol 2002; 29: 443–5. 33. Thong BY, Leong KP, Chng HH. Hypersensitivity syndrome associated with dapsone/pyrimethamine (Maloprim) antimalaria chemoprophylaxis. Ann Allergy Asthma Immunol 2002; 88: 527–9. 34. Verhoef H, West CE, Nzyuko SM, De Vogel S, Van der Valk R, Wanga MA, Kuijsten A, Veene-

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mans J, Kok FJ. Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial. Lancet 2002; 360: 908–14. 35. Schurmann D, Bergmann F, Albrecht H, Padberg J, Wunsche T, Grunewald T, Schurmann M, Grobusch M, Vallee M, Ruf B, Suttorp N. Effectiveness of twice-weekly pyrimethamine–sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection. Eur J Clin Microbiol Infect Dis 2002; 21: 353–61. 36. Edelman R, Wasserman SS, Kublin JG, Bodison SA, Nardin EH, Oliveira GA, Ansari S, Diggs CL, Kashala OL, Schmeckpeper BJ, Hamilton RG. Immediate-type hypersensitivity and other clinical reactions in volunteers immunized with a synthetic multi-antigen peptide vaccine (PfCS-MAP1NYU) against Plasmodium falciparum sporozoites. Vaccine 2002; 21: 269–80. 37. Kublin JG, Lowitt MH, Hamilton RG, Oliveira GA, Nardin EH, Nussenzweig RS, Schmeckpeper BJ, Diggs CL, Bodison SA, Edelman R. Delayed-type hypersensitivity in volunteers immunized with a synthetic multi-antigen peptide vaccine (PfCS-MAP1NYU) against Plasmodium falciparum sporozoites. Vaccine 2002; 20: 1853–61. 38. Stringer JR, Beard CB, Miller RF, Wakeﬁeld AE. A new name (Pneumocystis jiroveci) for Pneumocystis from humans. Emerg Infect Dis 2002; 8: 891–6. 39. Redman RC, Miller JB, Hood M, DeMaio J. Trimethoprim-induced aseptic meningitis in an adolescent male. Pediatrics 2002; 110: e26. 40. Lambotte O, Costedoat-Chalumeau N, Amoura Z, Piette JC, Cacoub P. Drug-induced hemophagocytosis. Am J Med 2002; 112: 592–3. 41. De Araujo M, Seguro AC. Trimethoprim– sulfamethoxazole (TMP/SMX) potentiates indinavir nephrotoxicity. Antivir Ther 2002; 7: 181–4. 42. Neuman MG, Malkiewicz IM, Phillips EJ, Rachlis AR, Ong D, Yeung E, Shear NH. Monitoring adverse drug reactions to sulfonamide antibiotics in human immunodeﬁciency virus-infected individuals. Ther Drug Monit 2002; 24: 728–36. 43. Choquet-Kastylevsky G, Vial T, Descotes J. Allergic adverse reactions to sulfonamides. Curr Allergy Asthma Rep 2002; 2: 16–25. 44. Eliaszewicz M, Flahault A, Roujeau JC, Fillet AM, Challine D, Mansouri S, Wolkenstein P, Aractingi S, Penso-Assathiany D, Maslo C, Bourgault-Villada I, Chosidow O, Caumes E. Prospective evaluation of risk factors of cutaneous drug reactions to sulfonamides in patients with AIDS. J Am Acad Dermatol 2002; 47: 406. 45. Visser LE, Penning-Van Bees FJ, Kasbergen AA, De Smet PA, Vulto AG, Hofman A, Stricker BH. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 2002; 88: 705–10. 46. Chirgwin K, Hafner R, Leport C, Remington J, Andersen J, Bosler EM, Roque C, Rajicic N, McAuliffe V, Morlat P, Jayaweera DT, Vilde JL,

301 Luft BJ. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeﬁciency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039. Clin Infect Dis 2002; 34: 1243–50. 47. Kim P, Younan N, Coroneo MT. Hypersensitivity reaction to intravitreal clindamycin therapy. Clin Exp Ophthalmol 2002; 30: 147–8. 48. Silveira C, Belfort R Jr, Muccioli C, Holland GN, Victora CG, Horta BL, Yu F, Nussenblatt RB. The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis. Am J Ophthalmol 2002; 134: 41–6. 49. Bosch-Driessen LH, Verbraak FD, SuttorpSchulten MS, Van Ruyven RL, Klok AM, Hoyng CB, Rothova A. A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis. Am J Ophthalmol 2002; 134: 34–40. 50. Murray HW. Kala-azar—progress against a neglected disease. New Engl J Med 2002; 347: 1793– 4. 51. Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, Wasunna MK, Bryceson AD. Visceral leishmaniasis: current status of control, diagnosis, treatment, a proposed research and development agenda. Lancet Infect Dis 2002; 2: 494– 501. 52. Jha TK, Sundar S, Thakur CP, Bachmann P, Karbwang J, Fischer C, Voss A, Berman J. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. New Engl J Med 1999; 341: 1795–800. 53. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J. Oral miltefosine for Indian visceral leishmaniasis. New Engl J Med 2002; 347: 1739–46. 54. Lai A, Fat EJ, Vrede MA, Soetosenojo RM, Lai A, Fat RF. Pentamidine, the drug of choice for the treatment of cutaneous leishmaniasis in Surinam. Int J Dermatol 2002; 41: 796–800. 55. Kroll CR, Gettes LS. T wave alternans and torsades de pointes after the use of intravenous pentamidine. J Cardiovasc Electrophysiol 2002; 13: 936–8. 56. Au WY, Ma ES, Kwong YL. Intravenous pentamidine induced megaloblastic anaemia. Haematologica 2002; 87: ECR06. 57. Lieber-Mbomeyo A, Lipsker D, Milea M, Heid E. Rhabdomyolyse induite par l’iséthionate de pentamidine (Pentacarinat) lors du traitement d’une leishmaniose cutanée: 2 cas. Ann Dermatol Venereol 2002; 129: 50–2. 58. Esfandiarpour I, Alavi A. Evaluating the efﬁcacy of allopurinol and meglumine antimoniate (Glucantime) in the treatment of cutaneous leishmaniasis. Int J Dermatol 2002; 41: 521–4. 59. Momeni AZ, Reiszadae MR, Aminjavaheri M. Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate. Int J Dermatol 2002; 41: 441–3.

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60. Cascio A, Colomba C, Antinori S, Orobello M, Paterson D, Titone L. Pediatric visceral leishmaniasis in Western Sicily, Italy: a retrospective analysis of 111 cases. Eur J Clin Microbiol Infect Dis 2002; 21: 277–82. 61. Wortmann G, Miller RS, Oster C, Jackson J, Aronson N. A randomized, double-blind study of the efﬁcacy of a 10- or 20-day course of sodium stibogluconate for treatment of cutaneous leishmaniasis in United States military personnel. Clin Infect Dis 2002; 35: 261–7. 62. Cesur S, Bahar K, Erekul S. Death from cumulative sodium stibogluconate toxicity on kala-azar. Clin Microbiol Infect 2002; 8: 606. 63. Mpia B, Pepin J. Combination of eﬂornithine and melarsoprol for melarsoprol-resistant Gambian trypanosomiasis. Trop Med Int Health 2002; 7: 775–9. 64. Blum J, Burri C. Treatment of late stage sleeping sickness caused by T.b. gambiense: a new approach to the use of an old drug. Swiss Med Wkly 2002; 132: 51–6. 65. Ruiz JA, Simarro PP, Josenando T. Control of human African trypanosomiasis in the Quicama focus, Angola. Bull WHO 2002; 80: 738–45. 66. Rodriques Coura J, De Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 2002; 97: 3–24. 67. Cancado JR. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop Sao Paolo 2002; 44: 29–37.

Annelies S. Zinkernagel and Markus Schneemann 68. Villar JC, Marin-Neto JA, Ebrahim S, Yusuf S. Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection. Cochrane Database Syst Rev, CD003463, 2002. 69. Woodruff BK, Wijdicks EF, Marshall WF. Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. New Engl J Med 2002; 346: 68–9. 70. Feola DJ, Thornton AC. Metronidazole-induced pancreatitis in a patient with recurrent vaginal trichomoniasis. Pharmacotherapy 2002; 22: 1508– 10. 71. Walﬁsh AE, Sapadin AN. Fixed drug eruption due to doxycycline and metronidazole. Cutis 2002; 69: 207–8. 72. Vila JB, Bernier MA, Gutierrez JV, Gomez MT, Polo AM, Harrison JM, Miranda-Romero A, Munoz CM. Fixed drug eruption caused by metronidazole. Contact Dermatitis 2002; 46: 122. 73. Short KA, Fuller LC, Salisbury JR. Fixed drug eruption following metronidazole therapy and the use of topical provocation testing in diagnosis. Clin Exp Dermatol 2002; 27: 464–6. 74. Visapaa JP, Tillonen JS, Kaihovaara PS, Salaspuro MP. Lack of disulﬁram-like reaction with metronidazole and ethanol. Ann Pharmacother 2002; 36: 971–4. 75. Mondon M, Ollivier L, Daumont A. Méningite aseptique rapportée a l’ornidazole au cours d’une endocardite infectieuse. Rev Med Interne 2002; 23: 784–7.

J.K. Aronson

29 DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS Cidofovir

(SED-14, 989; SEDA-24, 340; SEDA-25, 353; SEDA-26, 328) Cidofovir has been used to treat 14 patients with cytomegalovirus infection after stem-cell transplantation; no adverse effects were reported in this small study (1c ). In a open study of the use of intralesional cidofovir in treating laryngeal papilloma, 14 adults received monthly injections of cidofovir (maximum dose 37.5 mg per injection in 6 ml of saline; mean 22.5 mg) (2c ). Remission was achieved in all cases with an average of six injections and without additional laryngeal scarring, vocal cord damage, or systemic adverse effects.

Special senses In a placebo-controlled study of the efﬁcacy of cidofovir 1% eye-drops with and without ciclosporin 1% eye-drops four or ten times a day for acute adenovirus keratoconjunctivitis in 34 patients, the frequency of severe corneal opacities was lower with cidofovir (3C ). However, cidofovir caused conjunctival pseudomembranes, conjunctivitis, and erythematous inﬂammation of the skin of the eyelids, and the trial was stopped as a result. Urinary tract Nephrotoxicity is the main adverse effect that limits the use of cidofovir (SEDA-26, 328), although it is usually mild. However, cases of acute renal insufﬁciency leading to end-stage disease have been reported (4A , 5A ). Acute renal insufﬁciency has also been attributed to topical cidofovir (6A ). © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Antiviral drugs • A 28-year-old bone-marrow transplant recipient with chronic renal insufﬁciency developed genital condylomata resistant to standard therapy. After application of topical cidofovir (1% daily for 5 days, then 4% for 12 days) the lesions improved but local erosions appeared. He developed acute renal insufﬁciency with features of tubular acidosis on day 19. He recovered after cidofovir withdrawal.

It was not clear whether this effect was due to the cidofovir or to its vehicle, propylene glycol. The authors suggested that topical cidofovir should be avoided on abraded skin and should be carefully monitored.

Fomivirsen (SEDA-24, 341; SEDA-25, 354; SEDA-26, 328) Special senses In 150 patients who were given intravitreous fomivirsen 165 μg/injection (35 eyes, 30 patients) or two different regimens of 330 μg/injection (142 eyes, 110 patients) anterior chamber inﬂammation and increased intraocular pressure were dose-dependent and schedule-dependent: 165 μg/injection, 4.1 events/patient–year; 330 μg/injection, 6.6 events/patient–year (less intense regimen) and 8.4 events/patient–year (more intense regimen) (7c ). A large number of other ocular adverse events may not have been related to the drug.

Ganciclovir

(SED-14, 990; SEDA-24, 341; SEDA-25, 354 SEDA-26, 329) In 261 patients with cytomegalovirus retinitis given oral ganciclovir 3–6 g/day or intravenous ganciclovir 5 mg/kg/day the most common adverse effects were on the gastrointestinal tract (nausea in 29–43%, vomiting in 17–23%, diarrhea in 33–52%, and ﬂatulence in 2–18%)

303

304 (8c ). There were rashes in 9–32%, a low neutrophil count (below 0.5 × 109 /l) in 12–16%, a low hemoglobin concentration (below 8 g/dl) in 8–15%, a low platelet count (below 25 × 109 /l) in 0–3%, and a raised serum creatinine in 17– 27%. Special senses Endophthalmitis with scleral damage has been associated with a ganciclovir implant (9A ). • A 39-year-old woman complained of increasing pain and complete loss of vision in the left eye 1 month after insertion of a ganciclovir implant. The eye was enucleated and pathological examination showed a vitreous abscess; the implant suture tab was intrasclerally located.

The authors concluded that intraocular infection had resulted from a foreign body (the surgical implant) in the scleral gap. Metabolism Six infants with cholestasis (aged 3–16 weeks) and signs of cytomegalovirus infection were given intravenous ganciclovir for 3–7 weeks (10c ). One patient with septo-optic dysplasia and hypothyroidism had episodes of symptomatic hypoglycemia during treatment, which was withdrawn. Hematologic Of 40 patients who had achieved engraftment after allogeneic hemopoietic stem cell transplantation, 23 of whom had high-risk features, including transplant from an HLA-mismatched or unrelated donor, or associated acute graft–versus–host disease, 19 had pre-emptive therapy with ganciclovir in an initial dose of 5 mg/kg/day (8c ). There were no signiﬁcant adverse effects attributed to ganciclovir, except low total leukocyte counts (below 0.5× 109 /l) in three patients, lasting 3, 4, and 14 days, while they were treated with granulocyte colony-stimulating factor.

DRUGS ACTIVE AGAINST HEPATITIS C VIRUS Ribavirin (tribavirin) (SED-14, 992; SEDA-24, 341; SEDA-25, 355; SEDA-26, 329) Ribavirin 15 mg/kg/day plus interferon alpha in 12 teenagers has been compared with interferon

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alone in ten (11c ). There was no difference in dropout rate, but viral clearance was achieved in 50% of the patients who took the combination treatment versus 30% of those who took monotherapy. Adverse events were similar in the two groups. There was mild hemolytic anemia at the end of the ﬁrst month in most of the children who took ribavirin, but four had moderate to severe hemolysis and two had to stop taking ribavirin. Severe hemolysis in a patient with thalassemia warranted withdrawal of ribavirin within 3 months. Hematologic Ribavirin can cause a hemolytic anemia by an unknown mechanism, perhaps related to oxidative damage to the erythrocyte membrane. In patients taking ribavirin plus interferon alpha-2b the average fall in hemoglobin is 2–3 g/dl. Of 57 patients taking ribavirin 800 mg/day 28 were randomized to a high dose of peginterferon alpha-2b once a week (3 μg/kg for 1 week, 1.5 μg/kg for 3 weeks, and 1.0 μg/kg for 44 weeks) and 27 patients were randomized to receive a low dose (0.5 μg/kg) for 48 weeks, three patients required reduced doses of ribavirin because of anemia (12c ). Treatment of ribavirin-induced hemolytic anemia with recombinant human erythropoietin has been described in 13 patients (13c ). The hemoglobin concentration increased from a nadir of 10.2 g/dl to a median of 11.5 g/dl and ribavirin treatment did not have to be withdrawn. Drug interactions An interaction of warfarin with ribavirin has been reported (14A ). • In a 61-year-old white man with chronic hepatitis C, who took interferon plus ribavirin, the dosage of warfarin had to be increased by about 40% (from 45 to 63 mg/week) in order to maintain the desired degree of anticoagulation. This effect was reproduced on rechallenge with ribavirin.

The mechanism of this supposed interaction is not known. For example, ribavirin is cleared by intracellular phosphorylation and its metabolites by the kidneys, warfarin by cytochrome P450 isozymes in the liver; warfarin is highly protein bound, ribavirin is not. However, an effect on warfarin absorption or its action on clotting factor synthesis is possible.

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DRUGS ACTIVE AGAINST HERPESVIRUSES (SED-14, 990; SEDA-25, 353; SEDA-26, 329) The effects of aciclovir and valaciclovir for anogenital herpes have been studied in HIVinfected individuals in two controlled trials (15C ). In the ﬁrst study, 1062 patients with CD4+ counts over 100 × 106 /l received valaciclovir or aciclovir for 1 year and were assessed monthly. In the second study, 467 patients were treated episodically for at least 5 days with valaciclovir or aciclovir and were assessed daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpesvirus infections. Hazard ratios for the time to recurrence with valaciclovir 500 mg bd and 1000 mg od compared with aciclovir were 0.73 (95% CI = 0.50, 1.06) and 1.31 (0.94, 1.82). Valaciclovir 1000 mg bd and aciclovir had similar effects on the duration of infective episodes (HR = 0.92; CI = 0.75, 1.14). The most common adverse events, which occurred at similar rates with all regimens, were diarrhea, headache, infections, rashes, nausea, rhinitis, pharyngitis, abdominal pain, fever, depression, and cough.

Aciclovir

(SED-14, 990; SEDA-23, 314; SEDA-25, 353; SEDA-26, 329) Urinary tract There has been another report of crystalluria due to aciclovir, within 24 hours of the start of therapy with 500 mg 8-hourly in a 4-year-old African–American boy (16A ). Slow intravenous infusion over 1–2 hours and volume repletion avoids the problem.

Valaciclovir

(SEDA-26, 330)

In a double-blind comparison of two regimens of valaciclovir 500 mg bd for recurrent genital herpes, a 5-day course (n = 398) and a 3day course (n = 402) there were no signiﬁcant differences in therapeutic outcome or adverse events between the two regimens (17C ). The most common adverse events were headache (10%), nausea (4%), diarrhea (3%), and fatigue (1.5%).

305 Nervous system Elderly patients and people with chronic renal insufﬁciency are most susceptible to the neurotoxic effects of aciclovir— confusion, hallucinations, dizziness, irritability, ataxia, tremor, myoclonus, and seizures. The symptoms usually occur within 3 days of the start of therapy and resolve within 5 days after withdrawal. Plasma aciclovir concentrations do not correlate with symptoms. Lumbar puncture and CT scans of the head are essentially unremarkable. The most common electroencephalographic abnormality is diffuse generalized slowing of brain wave activity. Valaciclovir is a prodrug of aciclovir and can therefore cause similar effects, as two cases have demonstrated (18Ar ). • A 65-year-old man was given valaciclovir 1 g bd for 36 hours and had reduced concentration and was incoherent. All investigations were normal or negative. He improved rapidly on withdrawal of valaciclovir. • A 44-year-old man was given valaciclovir 1 g tds for 5 days and developed a fever, disorientation, confusion, ataxia, dysarthria, and photophobia. All investigations were normal or negative. He was given antimicrobial drugs, including aciclovir, but his symptoms did not improve until the aciclovir was withdrawn.

Drug interactions In an open single-dose study of the effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite aciclovir in 12 healthy men, valaciclovir 1 g, valaciclovir plus probenecid 1 g, valaciclovir plus cimetidine 800 mg, and valaciclovir with a combination of probenecid and cimetidine were studied (19c ). At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine respectively increased the mean Cmax of valaciclovir by 23 and 53% and its AUC by 22 and 73%. Probenecid and cimetidine also respectively increased the mean aciclovir Cmax by 22 and 8% and its AUC by 48 and 27%. The combination had a greater effect than either drug alone. Neither cimetidine nor probenecid affected the absorption of valaciclovir.

306

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS Reproductive system Gynecomastia, previously attributed to efavirenz (SEDA-26, 331), has been reported in 15 patients taking a variety of antiretroviral drugs (20c ). The authors suggested that it was due to increased cytokine concentrations following immune restoration. Infection risk A man developed several erythematous plaques on his face due to borderline tuberculoid leprosy with a reversal reaction (21A ). He had severe CD4 T cell lymphocytopenia due to HIV infection and had been given highly active antiretroviral therapy (HAART). A fall in viral load and an increase in CD4 count preceded the development of the skin lesions, suggesting immune reconstitution as the underlying mechanism for the reversal reaction. Paradoxical reactions are often observed in patients with pulmonary and extra-pulmonary tuberculosis being treated with HAART. Clinicians need to distinguish these from other adverse reactions related to drug therapy. Reversal reactions in leprosy are increasingly likely as more patients with HIV infection are treated with HAART in developing countries.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) (SED-14, 993; SEDA-23, 319; SEDA-24, 342; SEDA-25, 356; SEDA-26, 330) In a 24-week open, single-arm trial, 108 antiretroviral therapy-naive, HIV-infected prisoners were given a combination tablet of lamivudine + zidovudine (150 mg/300 mg) and a tablet of abacavir 300 mg bd (22c ). The plasma HIV-1 RNA concentration remained at 400 copies/ml or less in 85% of the patients and at less than 50 copies/ml in 75%. Nausea was the most common adverse effect (n = 40). Four patients withdrew prematurely because of one or

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J.K. Aronson

more of the following: abdominal discomfort and pain; abdominal distension; neutropenia; malaise or fatigue; nausea and vomiting. Two patients had a suspected hypersensitivity reaction to abacavir and were withdrawn. A combination of nucleosides analogues, stavudine 2 mg/kg/day plus didanosine 180 mg/ m2 /day for 48 weeks, has been assessed in 16 asymptomatic children, median age 6.5 years, with HIV infection (23c ). They had plasma HIV RNA concentrations below 50 000 copies/ml and CD4 counts above 15%. Plasma HIV RNA was reduced to 400 copies/ml or less in 43% and 44% of cases at 24 and 48 weeks respectively. There were minor adverse effects in two-thirds of the children; none led to drug withdrawal. There were no cases of lipoatrophy. There were no resistance mutations linked to didanosine (L74V or M184V) or stavudine (V75T) nor multinucleoside resistant genotypes (151 complex or 69 inserts). However, four children developed zidovudine-like mutations, T215Y and/or M41L. Metabolism The prevalence of lipodystrophy has been studied during follow-up for 30 months of previously untreated patients who had been randomized to receive different nucleoside analogue combinations for 6 months in the ALBI–ANRS 070 trial (24C ). After 30 months 37 of 120 patients who had used nucleoside analogues with or without other antiretroviral drugs had at least one morphological change, and 21 of those had isolated peripheral lipoatrophy; the corresponding values for the patients who used only nucleoside analogues during follow-up were 20 of 66 and 14 of 21 respectively. The factors associated with lipodystrophy were initial assignment to stavudine plus didanosine compared with zidovudine plus lamivudine (OR = 6.7), age below 10 years (OR = 3.6), and HIV RNA concentration at month 30 (OR = 0.4). There were no differences in cholesterol and glucose concentrations. Thus, exposure to stavudine and didanosine was associated with lipodystrophy (predominantly lipoatrophy). Pregnancy Two HIV-1-positive women, both of whom had taken regimens containing stavudine and didanosine for at least 2 years, presented in the third trimester of pregnancy, one with acute lactic acidosis and one with acute

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Chapter 29

pancreatitis and lactic acidosis (25A ). In the ﬁrst case both mother and baby died. It is not known whether pregnancy is a risk factor for NRTIinduced lactic acidosis, perhaps in combination with riboﬂavin deﬁciency or a metabolic defect in the fetus, or whether NRTIs independently cause lactic acidosis through mitochondrial toxicity.

Abacavir

(SED-14, 995; SEDA-24, 342; SEDA-26, 330)

The effects of abacavir have been evaluated in a study in over 13 000 adults who no longer responded to commercially available treatment regimens. By month 2 of treatment with abacavir, plasma HIV-1 RNA concentrations fell by at least half a log unit in 31% of patients, and in 5.6% of the patients HIV-1 RNA concentrations fell to under 400 copies/ml (26c ). Serious drugrelated adverse events were reported by 7.7% of patients. The most common were nausea, skin rash, diarrhea, malaise or fatigue, and fever. About 4.6% of patients had a hypersensitivity reaction that was possibly drug related. Nervous system Vertigo has been attributed to abacavir (27A ). • A 44-year-old African–American developed vertigo, tinnitus in both ears, headache behind the eyes, and left ear pain and hearing loss soon after starting to take abacavir, lamivudine, and stavudine. There was left-sided nystagmus and vestibular tests showed evidence of vestibular impairment. An MRI scan was normal. All the antiretroviral drugs were withdrawn and he improved. When lamivudine and stavudine were restarted, with nevirapine, the vertigo did not recur.

Immunologic Hypersensitivity reactions to abacavir occur in about 4% of patients. The risk factors associated with hypersensitivity reactions have been sought in an analysis of all protocols conducted by GlaxoSmithKline that involved abacavir exposure for at least 24 weeks with a quality-assured or validated clinical database by June 30, 2000 (n = 5332) (28c ). There were 197 hypersensitivity reactions (3.7%). The risks of hypersensitivity reactions were lower in black people (OR = 0.59; 95% CI = 0.38, 0.91) than in other ethnic groups, and in patients who had received previous therapy for

HIV-1 infection with other antiretroviral agents (OR = 0.58; 95% CI = 0.44, 0.78) compared with those receiving therapy for the ﬁrst time. Genetic factors affecting the immune response to abacavir have also been sought in patients who had taken abacavir for more than 6 weeks, 18 with hypersensitivity reactions and 167 without (29c ). HLA-B*5701 was present in 14 of the 18 patients with abacavir hypersensitivity, and in four of the 167 others (OR = 117; 95% CI = 29, 481). The combination of HLA-DR7 and HLA-DQ3 was found in 13 of the 18 and ﬁve of the 167 (OR = 73; CI = 20, 268). HLA-B*5701, HLA-DR7, and HLADQ3 were present in combination in 13 of the 18 and none of the 167 (OR = 822; CI = 43, 15 675). Other MHC markers also present on the 57.1 ancestral haplotype to which these three markers belong conﬁrmed the presence of haplotype-speciﬁc linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. The authors concluded that susceptibility to abacavir hypersensitivity is carried on the 57.1 ancestral haplotype and that withholding abacavir from those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient. In a retrospective case–control study of patients with hypersensitivity reactions, HLAB57 was present in 39 of 84 patients compared with four of 113 controls (30c ). However, there were few women and other ethnic groups in the study, and so these ﬁndings relate largely to white men. In a multicenter trial, 128 children were randomly assigned to zidovudine + lamivudine (n = 36), to zidovudine + abacavir (n = 45), or to lamivudine + abacavir (n = 47) (31C ). One child had a hypersensitivity reaction to abacavir and stopped taking it, as did three with possible reactions.

Didanosine

(SED-14, 995;

SEDA-24, 343) The use of didanosine 125–200 mg bd plus interferon alpha-2b in AIDS-associated Kaposi’s

308

Chapter 29

sarcoma has been studied in 68 patients (32c ). Withdrawal of didanosine was required in cases of peripheral neuropathy, rises in serum amylase activity, and hypertriglyceridemia.

patients, but emergence of drug resistance is associated with a rapid fall in serum albumin.

Zidovudine Lamivudine

(SED-14, 995;

J.K. Aronson

(SED-14, 994;

SEDA-24, 343)

SEDA-24, 343) Gastrointestinal In a 1-year trial of lamivudine in ten children with vertically-acquired chronic hepatitis B, lamivudine made serum hepatitis B viral DNA undetectable in all the patients within 24 weeks (33c ). Serum AlT returned to the reference range within 36 weeks. Although nausea and vomiting were reported in one child, it was not necessary to withhold treatment. Liver Lamivudine is used orally to treat chronic hepatitis B in adults and children (34R ). It increases the rate of loss of hepatitis B e antigen and seroconversion in compensated chronic carriers, with improvement of histology at a similar rate to interferon alpha. However, the tyrosine– methionine–aspartate–aspartate (YMDD) mutation prevents efﬁcacy and can cause ﬂares of hepatitis. The indications for treatment must therefore be established with care and only by those who have expert knowledge of the disease, the drug, and the YMDD mutation. Drug tolerance (resistance) In patients with chronic hepatitis B taking lamivudine, the incidence of drug resistance increases with the duration of therapy (35c ). However, the effect of drug resistance on hepatic synthetic function has not been well deﬁned. In 38 patients (26 with cirrhosis) in an open study there was an initial antiviral response in all patients (hepatitis B virus DNA became undetectable by a hybridization assay), and nine of 22 (41%) hepatitis B e antigen-positive patients underwent hepatitis B e antigen seroconversion. In 29 patients with undetectable serum hepatitis B viral DNA at the end of the study, the mean serum albumin concentration rose from 40 to 43 g/l, corresponding to a yearly increase of 1.85 g/l; this was largely attributable to an increase in the cirrhotic patients. Resistance to lamivudine developed in nine patients. Suppression of viral replication by lamivudine improves hepatic synthetic function in chronic hepatitis B

Metabolism Lipodystrophy is a common adverse effect of antiretroviral drugs, particularly the NRTIs and has been reported again with zidovudine (36A ). • A 42-year-old woman developed abdominal and dorsocervical fat enlargement after having taken zidovudine for over 10 years. Zidovudine was withdrawn and the lesions improved considerably over the next 26 months.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) (SED-14, 996; SEDA-23, 320; SEDA-24, 344; SEDA-25, 357) The pharmaceutical chemistry and uses of the ﬁrst- and second-generation NNRTIs have been reviewed (37R ). In a non-randomized study of 694 patients taking two NRTIs, who were also given either nevirapine or efavirenz the reasons for discontinuation were as shown in Table 1 (38c ). In passing, it should be noted that although this paper contains details of adverse events, there is no way of knowing that from a perusal of the title or abstract. Thus, anyone searching on-line for data for a systematic review of the adverse effects of these drugs might miss this information. When adverse events data are included in accounts of trials, the fact should be mentioned in the title and/or abstract. Liver In 13 patients, studied retrospectively, who were given a combination of two NNRTIs, nevirapine + efavirenz, the most common adverse event was a change in liver function tests, to almost three times the upper end of the reference range in three cases; however, it was

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309

Chapter 29 Table 1. Numbers (%) of patients who discontinued therapy in a follow-up study of two NRTIs plus either nevirapine or efavirenz (38c ) Reason for discontinuation

Nevirapine (n = 460)

Efavirenz (n = 234)

47 (6.7) 31 (10.2)

16 (6.8) 5 (2.1)

1 (0.2) 3 (0.7) 12 (2.6) 56 (12.2)

12 (5.1) 0 1 (0.4) 5 (2.1)

3 (0.7) 9 (2.0)

1 (0.4) 1 (0.4)

Patient-related reasons∗ Failure of therapy Clinical adverse events Nervous system Metabolic (lipodystrophy) Gastrointestinal Immunologic Laboratory adverse events Hematologic Liver

∗ Poor adherence, patient’s decision, or therapy simpliﬁcation.

directly attributable to the antiretroviral drugs in only one case (39c ). The incidence of NNRTI-induced hepatotoxicity in HIV-infected patients and the effect of co-infection with hepatitis B or hepatitis C virus has been studied in 272 patients (40c ). The NNRTIs used were delavirdine (n = 40), efavirenz (n = 91), and nevirapine (n = 141). There were mild to moderate rises in serum AsT or AlT in 81 patients and large rises in three patients, one of whom was taking efavirenz and two nevirapine. Hepatitis B or hepatitis C virus infection did not signiﬁcantly increase the risk of hepatotoxicity. The authors concluded that NNRTIs cause little hepatotoxicity, despite the presence of co-infection with hepatitis B or hepatitis C viruses.

Delavirdine

(SED-14, 996;

SEDA-24, 344) Drug interactions Rhabdomyolysis with acute renal insufﬁciency has been reported in a 63-year-old man who was taking atorvastatin 20 mg/day and delavirdine 400 mg 8-hourly (41A ). The authors suggested that delavirdine had inhibited the metabolism of atorvastatin by inhibiting CYP3A4.

Efavirenz

(SED-14, 996; SEDA-24, 344; SEDA-25, 357; SEDA-26, 331) In 77 HIV-positive subjects randomized to switch from protease inhibitors to nevirapine

or efavirenz or to continue taking protease inhibitors, quality of life signiﬁcantly improved among those who switched (42c ). In those who took efavirenz there was an increase in gammaglutamyltransferase activity and three patients interrupted treatment because of central nervous system symptoms. Eight patients withdrew because of adverse events: rashes (n = 3), dizziness (n = 2), irritability and depression (n = 1), depression (n = 1), and hepatotoxicity (n = 1). Nervous system In a randomized comparison of an efavirenz-containing regimen and a protease inhibitor-containing regimen, nervous system adverse effects were speciﬁcally sought (43C ). Patients were randomized to two NRTIs plus efavirenz (n = 51) or two NRTIs plus one or more protease inhibitors (n = 49). The patients who took efavirenz reported the following at week 4: dizziness (66%), abnormal dreaming (48%), light-headedness (37%), and difﬁculty in sleeping (35%). At week 24, dizziness (13%), abnormal dreaming (18%), lightheadedness (13%), difﬁculty in sleeping (7%), and nervousness (13%) were signiﬁcantly less common. Irritability, abnormal dreaming, and nervousness persisted at week 48 in 13%, 10%, and 8% respectively. Psychiatric Efavirenz has been associated with psychiatric problems, such as anxiety, depression, and confusion (44c , 45c ). In a retrospective study of 1897 patients dementia and depression were signiﬁcantly associated with efavirenz compared with other drugs; the respective odds ratios were 4.0 (95% CI = 1.2,

310 14) and 1.7 (1.0, 3.0) (46c ). However, those who were given efavirenz were perhaps more ill than those who were not, judging by CD4 counts and opportunistic infections. Liver In a prospective study of the incidence of severe hepatotoxicity among 312 patients taking efavirenz, hepatitis C and hepatitis B viruses were detected in 7.7% of the patients (47c ). There was severe hepatotoxicity in 8.0%, but only 50% of the episodes were detected during the ﬁrst 12 weeks of therapy. The risk was signiﬁcantly greater among those with chronic viral hepatitis (69% of cases) and those taking concurrent protease inhibitors (82% of cases). However, 84% of patients with chronic hepatitis C or hepatitis B did not have severe hepatotoxicity. Immunologic The incidence of hypersensitivity to efavirenz is 10–34%. It usually causes an erythematous maculopapular rash, with or without fever, 1–3 weeks after the start of therapy. Desensitization has been reported (48A ). • A 37-year-old HIV-positive white man was given efavirenz, amprenavir, stavudine, lamivudine, and didanosine after failure of a previous regimen. After 8 days he developed a generalized pruritic rash and all the drugs were withdrawn. Two weeks later he was given efavirenz, stavudine, didanosine, lamivudine, and lopinavir, but developed red itchy skin within a day. All the drugs were withdrawn. He was then successfully restarted on stavudine, didanosine, lamivudine, lopinavir, and amprenavir. Desensitization to efavirenz was undertaken, but on day 12 he again developed a rash on the trunk and limbs, which was treated with a topical steroid and diphenhydramine 45 minutes before each dose of efavirenz. The desensitization protocol was continued for another 4 days, and 16 months later he was taking full-dose efavirenz in combination with the other antiretroviral drugs.

Chapter 29

J.K. Aronson

Teratogenicity A full-term boy, born to a woman who had taken efavirenz, stavudine, and zidovudine before pregnancy and for the ﬁrst 24 weeks, had a myelomeningocele (50A ). The baby was HIV-positive. The authors suggested that the efavirenz had been responsible, based on previous studies in monkeys. Drug interactions Efavirenz induces the activity of CYP3A4, causing increased requirements of other drugs that are metabolized by CYP3A4, such as ciclosporin and methadone. • A 39-year-old man took ciclosporin 200 mg bd after a kidney transplant (51A ). The blood ciclosporin concentration was 307 μg/l. The coadministration of prednisone caused the blood ciclosporin concentration to rise to 372 μg/l, but it fell to 203 μg/l when the dose was reduced to 175 mg bd. Efavirenz 600 mg/day, zidovudine 300 mg bd, and lamivudine 150 mg bd were added, and 7 days later the blood ciclosporin concentration fell to 80 μg/l and later to 50 μg/l.

Three patients taking methadone were given efavirenz-containing regimens and started to complain of opioid withdrawal symptoms 3– 7 days later (52c ). In one case the plasma methadone concentration fell from about 170 ng/ml to about 50 ng/ml over 6 days. The effect of multiple-dose efavirenz 600 mg/day on the steady-state pharmacokinetics of the combination of indinavir (800 mg) + lowdose ritonavir (100 mg) bd, in which ritonavir is used to increase indinavir plasma concentrations, has been investigated in 14 healthy men (53c ). Efavirenz signiﬁcantly reduced indinavir AUC (25%), Cmax (17%), and Cmin (50%). Ritonavir AUC, Cmax , and Cmin were reduced by 36%, 34%, and 39% respectively. The authors proposed that efavirenz had induced the activity of CYP3A and concluded that the dose of indinavir or ritonavir may need to be increased to maintain similar indinavir drug concentrations after the addition of efavirenz.

A leukocytoclastic vasculitis has been attributed to efavirenz (49A ). • A 44-year-old man, having taken various antiretroviral drugs, started to take efavirenz; 5 days later he developed palpable purpura on both legs, with pruritus. His white cell count was 14.4 × 109 /l and a skin biopsy showed a leukocytoclastic vasculitis. Efavirenz was withdrawn and he was given prednisolone for 3 days; the lesions disappeared, leaving only minimal hyperpigmentation.

Nevirapine

(SED-14, 997; SEDA-24, 345; SEDA-25, 357; SEDA-26, 332) Concerns about the adverse effects of nevirapine have delayed its implementation in preventing perinatal HIV. Decision analysis has been used to compare three strategies: a single dose

Antiviral drugs

Chapter 29

of nevirapine, a short course of zidovudine, and no intervention (54M ). The authors concluded that nevirapine would prevent more deaths than either zidovudine and no intervention, as long as the rate of nevirapine toxicity did not respectively exceed nine and 42 times that observed in an earlier nevirapine clinical trial (HIVNET). Nevirapine would be economically preferable to zidovudine as long as the rate of toxicity did not exceed 22 times that observed in the clinical trial. They thought that implementation of nevirapine should not be delayed by concerns about its adverse effects. Psychiatric Various psychiatric abnormalities (delirium, an affective state, and a psychosis) have been described in three patients who took nevirapine for 10–14 days (55A ): • cognitive impairment, clouding of consciousness, and a paranoid episode in a 35-year-old man; • delusions of persecutory and depressive thoughts in a 42-year-old woman; • delusions of persecution and infestation and hallucinations in a 36-year-old woman.

All three responded to withdrawal of nevirapine. Liver In 77 HIV-positive subjects randomized to switch from protease inhibitors to nevirapine or efavirenz or to continue taking protease inhibitors, quality of life signiﬁcantly improved among those who switched (42c ). Lipid proﬁles improved in those who took nevirapine but there were signiﬁcant increases in gammaglutamyltransferase and alanine aminotransferase activities and one patient interrupted treatment because of hepatotoxicity. In a prospective study of the incidence of severe hepatotoxicity 312 patients taking nevirapine, hepatitis C and hepatitis B viruses were detected in 43% (47c ). There was severe hepatotoxicity in 16%, but only 32% of episodes were detected during the ﬁrst 12 weeks of therapy. The risk was signiﬁcantly greater among those with chronic viral hepatitis (69% of cases) and those taking concurrent protease inhibitors (82% of cases). However, 84% of patients with chronic hepatitis C or hepatitis B did not have severe hepatotoxicity. Of 70 HIV-infected patients taking nevirapine 33 developed rises in transaminase activities (56c ). Higher nevirapine concentrations

311 and hepatitis C virus infection were independent predictors of liver toxicity. In those with chronic hepatitis C, nevirapine concentrations over 6 μg/ml were associated with a 92% risk of liver toxicity. The authors concluded that monitoring nevirapine concentrations, especially in individuals with chronic hepatitis C, may be warranted. Urinary tract Although indinavir can cause urinary stones, nelﬁnavir has not previously been implicated. • A 37-year-old woman stopped taking indinavir and other antiretroviral drugs because of skin reactions and started to take nelﬁnavir and delavirdine (57A ). An unspeciﬁed time later she presented with right ﬂank pain, due to nephrolithiasis with hydronephrosis. She was treated with lithotripsy, but 6 months later had another episode of ﬂank pain with microscopic hematuria and crystalluria. There was a large urinary stone in the right renal pelvis and a smaller stone obstructing the ureter. The stone fragments contained nelﬁnavir 99% and indinavir 1%.

The authors pointed out that nelﬁnavir is normally only 1–2% excreted in the urine, and they postulated that the indinavir may have started a nidus on which the nelﬁnavir was subsequently deposited. Drug interactions The mutual pharmacokinetic interaction of nevirapine with ethinylestradiol + norethindrone have been studied in ten women (58c ). After a single dose of ethinylestradiol + norethindrone, they took oral nevirapine 200 mg/day (days 2–15), followed by 200 mg bd (days 16–29); on day 30 they took another dose of ethinylestradiol + norethindrone. Steady-state nevirapine reduced the AUC of ethinylestradiol by 29% and signiﬁcantly reduced its mean residence time and half-life. The AUC of norethindrone was signiﬁcantly reduced by 18%, but there was no change in Cmax , mean residence time, or half-life. The kinetics of nevirapine were not affected by the oral contraceptive. The authors attributed this interaction to increased clearance of ethinylestradiol and concluded that oral contraceptives should not be the primary method of birth control in women of child-bearing potential who are taking nevirapine.

312

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: PROTEASE INHIBITORS (SED-14, 997; SEDA-24, 345; SEDA-25, 358; SEDA-26, 332) Nervous system In a randomized comparison of a protease inhibitor-containing regimen and an efavirenz-containing regimen, nervous system adverse effects were speciﬁcally sought (43C ). Patients were randomized to two NRTIs plus one or more protease inhibitors (n = 49) or two NRTIs plus efavirenz (n = 51). The patients who took the protease inhibitors reported the following at week 4: light-headedness (8%), dizziness (5%), difﬁculty in sleeping (4%), nervousness (4%), and headaches (3%). They reported the following at week 48: difﬁculty in sleeping (4%), nervousness (3%), headaches (3%), and light-headedness (2%). Three patients withdrew because of adverse events: diarrhea (n = 2) and nephrolithiasis (n = 1). Liver In a retrospective study of patients taking one protease inhibitor (n = 39) or two (n = 27) who discontinued protease inhibitor therapy as a result of hepatotoxicity, the proportions of patients with raised AlT activity to at least ﬁve times the upper limit of the reference range (26% vs 19%) and hyperbilirubinemia (38% vs 30%) were similar (59c ). Rates of withdrawal due to hepatotoxicity were also similar. Urinary tract In a randomized comparison of a protease inhibitor-containing regimen and an efavirenz-containing regimen in 100 patients, six patients taking protease inhibitors developed nephrolithiasis; one withdrew as a result (43C ). Musculoskeletal The results of a questionnaire survey of 878 people with HIV infection treated with antiretroviral drugs also suggested that other protease inhibitors can cause arthralgia; indinavir and the combination of ritonavir + saquinavir were particularly implicated (60Ac ). Drug interactions In nine patients who received amprenavir 750 mg bd for at least 3 weeks plus one of two doses of lopinavir/ritonavir, the trough concentration of amprenavir

Chapter 29

J.K. Aronson

was 0.35–2.54 with lopinavir/ritonavir 400/100 mg bd (n = 5) and 1.92–2.83 with lopinavir/ritonavir 532/133 mg bd (n = 4); the corresponding trough concentrations of lopinavir were 0.35–2.54 and 4.74–6.71 (61c ). These data suggest that these protease inhibitors inhibit the metabolism of each other, conﬁrming previous observations with amprenavir (SEDA-26, 332). A pharmacokinetic model has been developed to describe the interaction of amprenavir with ritonavir (62C ). A two-compartment linear model with ﬁrst-order absorption ﬁtted the amprenavir data best, while a one-compartment model best described the ritonavir data. Inhibition of the elimination of amprenavir by ritonavir was modeled with an Emax inhibition model. Simulation of drug regimens based on the model suggested that in patients who fail to respond to a traditional amprenavir regimen, amprenavir 600 mg plus ritonavir 100 mg bd would produce similar Cmin : IC50 ratios to amprenavir 1200 mg bd alone. There has been a study of the effects of ritonavir 400 mg bd plus saquinavir soft-gel capsules 400 mg bd on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin (40 mg/day each), and of the effect of pravastatin on the pharmacokinetics of nelﬁnavir in a randomized, open study in 56 healthy HIVnegative adults (63c ). Ritonavir + saquinavir reduced the steady-state AUC of pravastatin, markedly increased the AUC of simvastatin, and slightly increased the AUC of total active atorvastatin. The AUCs of nelﬁnavir and its active M8 metabolite were not altered by pravastatin. The authors concluded that simvastatin (and by implication lovastatin, which in common with simvastatin inhibits CYP3A4) should be avoided and atorvastatin should be used with caution in people taking ritonavir and saquinavir, that dosage adjustment of pravastatin may be necessary with concomitant use of ritonavir + saquinavir, and that concomitant use of pravastatin with nelﬁnavir appears to be safe.

Amprenavir

(SED-14, 998; SEDA-25, 358; SEDA-26, 332)

The clinical pharmacology of amprenavir has been reviewed (64R ). Amprenavir is an HIV protease inhibitor with an enzyme inhibitory

Antiviral drugs

Chapter 29

constant of 0.6 nmol/l, similar to the inhibitory constants of other protease inhibitors. Its in vitro IC50 against wild-type clinical HIV isolates is 115 ng/ml. It has a long half-life (7–10 hours). The recommended doses are 1200 mg bd for adults and 20 mg/kg bd or 15 mg/kg tds for children under 13 years of age or adolescents under 50 kg. Capsules and solution do not have equal systemic availability, and the recommended dose for amprenavir oral solution is 1.5 ml/kg bd or 1.1 ml/kg tds. The systemic availability increases with increasing doses. It is about 90% bound to alpha1 acid glycoprotein and 40% to albumin. It does not penetrate the brain well, because it is exported by P glycoprotein. It is mainly metabolized by CYP3A4 and its clearance is reduced in liver disease. Nervous system Neurotoxicity has been attributed to amprenavir (65A ). • A 61-year-old man, who had taken various antiretroviral drugs, took amprenavir 750 mg bd and after the ﬁrst dose had hallucinations, disorientation, tinnitus, and vertigo. The symptoms abated within 2 hours and recurred after the next dose.

Drug interactions In 12 healthy volunteers, coadministration of a single dose of amprenavir 1200 mg with grapefruit juice slightly reduced the Cmax compared with water (7.11 vs 9.10 μg/ml) and slightly increased the tmax (1.13 versus 0.75 hours), but did not affect the AUC (66A ). Thus, grapefruit juice has no clinically important effect on amprenavir pharmacokinetics.

Indinavir

(SED-14, 998; SEDA-24, 346; SEDA-25, 359; SEDA-26, 332) Adverse effects have been retrospectively evaluated and correlated with indinavir trough concentration in 63 patients taking indinavir + ritonavir 800/100 mg bd (67c ). The median indinavir trough concentration of 1446 ng/ml was associated with 60% of measured toxicity. Of 49 patients with an indinavir trough concentration over 500 ng/ml, 46 had at least one dosage adjustment; the main reason for dosage adjustment was toxicity (n = 43). The common adverse effects affected the skin (vitamin

313 A-like reactions; n = 39), kidneys (renal colic, nephrolithiasis, renal insufﬁciency; n = 35), gastrointestinal tract (nausea, vomiting, and diarrhea; n = 32), and liver (n = 14). After dosage adjustment, the median indinavir trough concentration was 459 ng/ml, which was associated with 8% of toxicity. Trough concentrations over 500 ng/ml correlated with increased toxicity. The authors concluded that indinavir trough concentrations below 500 ng/ml are safe, and that an optimal concentration range for indinavir trough concentration could be 150–500 ng/ml in patients taking twice daily indinavir + ritonavir. In an multicenter, open, uncontrolled trial of protease inhibitors in conjunction with NRTIs for at least 96 weeks in 32 children, the pharmacokinetics of indinavir and nelﬁnavir showed large interindividual differences (68c ). In all, 17 children suffered adverse events. The most common adverse events in those taking indinavir were diarrhea (n = 6), vomiting (n = 6), anorexia (n = 5), hematuria (n = 5), abdominal pain (n = 4), headache (n = 3); most were mild and occurred early in treatment. The rates of drug-related adverse effects were 0.4 per patient–year in those taking indinavir and 0.16 per patient–year in those taking nelﬁnavir. Cardiovascular A hypertensive crisis caused a secondary reversible posterior leukoencephalopathy in a patient taking indinavir-containing antiretroviral therapy (69A ). • A 40-year-old man, who had taken stavudine 30 mg bd, lamivudine 150 mg bd, and indinavir 800 mg qds, developed an occipital headache, nausea, and vomiting. His blood pressure was 220//140 mmHg and he had bilateral papilledema. His blood pressure was controlled and his symptoms disappeared. An MRI scan of the brain showed lesions in the periventricular white matter; the nuclei semiovale and occipital asta were most severely affected. Indinavir was withdrawn and replaced by nelﬁnavir; his blood pressure returned to normal and the MRI white matter lesions disappeared.

Nervous system Paraparesis due to epidural lipomatosis has been attributed to indinavir (70A ). • A 35-year-old man, who had taken indinavir 2400 mg/day, lamivudine 300 mg/day, and stavudine 80 mg/day for 10 months, developed a slowly progressive paraparesis, with sensory disturbances

314 in the legs. An MRI scan was consistent with epidural lipomatosis. On withdrawal of indinavir, the symptoms gradually resolved.

Although indinavir can cause abnormal fat accumulation, this is thought to have been the ﬁrst report of epidural lipomatosis. Urinary tract Of 23 indinavir-treated patients with persistent pyuria, four had interstitial nephritis, seven had urothelial inﬂammation, ten had both interstitial nephritis and urothelial inﬂammation, and two had nonspeciﬁc urinary tract inﬂammation (34c ). In all, 21 patients had multinucleated histiocytes identiﬁed by cytological testing of urine specimens. Urine abnormalities resolved in all 20 patients who stopped taking indinavir, and pyuria persisted in the other three. Six patients had raised serum creatinine concentrations, which returned to baseline when indinavir was withdrawn. Musculoskeletal Widespread osteosclerosis, accompanied by increased serum concentrations of osteocalcin and C telopeptide, developed in a 56-year-old man who took indinavir 800 mg tds for 27 months (71A ). A previous report has documented increased bone mineral density in patients taking indinavir (72c ), although in another study protease inhibitorcontaining regimens caused accelerated loss of bone density (73c ). This patient had been taking vitamin A 1 mg/day for 20 years and the authors proposed that the indinavir had also had a vitamin A-like effect. Frozen shoulder has previously been attributed to indinavir (SEDA-24, 347), and another two cases have been reported, one with Dupuytren’s contracture, and one case each with arthralgias and tendinitis (59Ac ). The results of a questionnaire survey of 878 people with HIV infection treated with antiretroviral drugs conﬁrmed the risk of arthralgias in patients taking indinavir. The authors suggested that crystal deposition in joints, analogous to the crystalluria with nephrolithiasis that indinavir and other protease inhibitors can cause, might be responsible. Susceptibility factors Sex The pharmacokinetics of indinavir in 220 women and 94 men have been compared; there was no difference (74c ).

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Gilbert’s syndrome It has been postulated that indinavir-induced hyperbilirubinemia is due to inhibition of bilirubin UDP glucuronyl transferase activity, since it is more common in individuals with Gilbert’s syndrome (75r ). Drug interactions The absorption of indinavir was not affected by co-administration of didanosine in an encapsulated enteric bead formulation in 24 patients (76c ). Cannabinoids The effects of smoked marijuana (3.95% tetrahydrocannabinol; up to three cigarettes per day) and oral dronabinol (2.5 mg tds) on the pharmacokinetics of indinavir 800 mg 8-hourly (n = 28) have been evaluated in a randomized placebo-controlled study in HIVinfected patients (77C ). At day 14, marijuana reduced the 8-hour AUC of indinavir by 15%, the Cmax by 14%, and the Cmin by 34%. However, only the change in Cmax was signiﬁcant. Dronabinol had no effects. Inhibition of glucuronyl transferase activity by indinavir has been blamed for an interaction of indinavir with levothyroxine, causing hyperthyroidism (78A ). • A 36-year-old woman, who had taken levothyroxine for several years, took stavudine, lamivudine, and indinavir for 1 month and developed nervousness, palpitation, restlessness, weakness, and weight loss. She had an undetectable serum TSH concentration and raised unbound serum T4 and T3. The dose of levothyroxine was reduced to onethird and then to one-sixth of the previous dose, and the thyroid function tests returned to normal.

The pharmacokinetics of indinavir 800 mg 8-hourly have been studied in the presence and absence of milk thistle 175 mg (containing silymarin 153 mg) tds for 3 weeks in an open study in ten healthy volunteers; milk thistle had no signiﬁcant effect except a small reduction in Cmin.ss (79c ).

Lopinavir/ritonavir

(SEDA-26, 333)

The pharmacology, clinical pharmacology, uses, and adverse effects and interactions of lopinavir + ritonavir have been reviewed (80R ). In a randomized, double-blind study in 70 patients taking a regimen containing protease inhibitors, lopinavir + ritonavir 400/100 mg

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Chapter 29

or 400/200 mg bd was substituted (81C ). On day 15 nevirapine (200 mg bd) was added and NRTIs were changed to include at least one NRTI not previously taken. Despite a more than four-fold reduction in phenotypic susceptibility to the pre-entry protease inhibitor in 63% of the patients, mean plasma HIV-1 RNA concentrations fell by 1.14 log copies/ml after 2 weeks. At week 48, 86% had plasma HIV1 RNA concentrations of under 400 copies/ml, and 76% under 50 HIV-1 RNA copies/ml. Mean CD4 cell counts increased by 125 cells/μl. The most common clinical adverse events were diarrhea (n = 16) and weakness (n = 4). There were rises in gamma-glutamyltransferase activity (n = 18), total cholesterol (n = 17), and triglycerides (n = 17), and transient rises in AsT or AlT activity (n = 11). Three patients discontinued therapy because of drug-related adverse events. Immunologic So-called inﬂammatory edema (SEDA-26, 333) has again been observed, this time in three of eight patients 1–4 weeks after beginning regimens that contained lopinavir + ritonavir (82A ). The edema affected the feet, ankles, and calves and was associated in one case with fever and in another with a transient rash; in one case the left shoulder and groin were also affected. All three recovered completely within 1–4 weeks despite continued drug treatment, but 7 months later one had a relapse that required withdrawal of lopinavir + ritonavir.

Nelﬁnavir

(SED-14, 998; SEDA-24, 347; SEDA-25, 359; SEDA-26, 333) In an multicenter, open, uncontrolled trial of protease inhibitors in conjunction with NRTIs for at least 96 weeks in 32 children, the pharmacokinetics of nelﬁnavir showed large interindividual differences (68c ). In all, 17 children suffered adverse events, most of which were mild and occurred early in treatment. The rate of drug-related adverse effects was 0.16 per patient–year in those taking nelﬁnavir.

Susceptibility factors Children The pharmacokinetics of three doses of nelﬁnavir, 15, 30, and 45 mg/kg bd, have been studied in 22 neonates, who were also given stavudine and

315 didanosine for 4 weeks after birth (83c ). Median values of Cmin (mg/l) at 1, 7, 14, and 28 days of age were respectively: 0.19, 1.21, 0.51, and 0.33 (15 mg/kg); 1.02, 3.18, 0.73, and 0.55 (30 mg/kg); and 0.67, 3.21, 0.70, and 0.73 (45 mg/kg). The median values of steadystate AUC (h.mg/l) at 14 and 28 days were respectively: 14 and 8.7 (15 mg/kg); 19 and 16 (30 mg/kg); and 23 and 19 (45 mg/kg). There were no serious adverse events. Thus, systemic exposure to nelﬁnavir fell after 7 days of age, perhaps because of hepatic enzyme maturation, autoinduction of nelﬁnavir metabolism, and/or changes in nelﬁnavir absorption. Because of the highly variable kinetics the authors suggested that plasma concentration monitoring was warranted to ensure adequate nelﬁnavir dosing in neonates. In a multicenter trial, 128 children were randomly assigned to zidovudine + lamivudine (n = 36), to zidovudine + abacavir (n = 45), or to lamivudine + abacavir (n = 47) (31C ). The children who were free of symptoms (n = 55) were also randomized to nelﬁnavir or placebo, while those with more advanced disease received open-label nelﬁnavir (n=73). All 13 episodes of diarrhea occurred in those taking nelﬁnavir. Nelﬁnavir did not affect serum cholesterol or triglyceride concentrations and there were no cases of lipodystrophy. There were 24 serious adverse events; six were in the symptom-free children (all taking nelﬁnavir), but all were attributed to the NRTIs. Drug interactions Cannabinoids The effects of smoked marijuana (3.95% tetrahydrocannabinol; up to three cigarettes per day) and oral dronabinol (2.5 mg tds) on the pharmacokinetics of nelﬁnavir 750 mg tds (n = 34) have been evaluated in a randomized placebocontrolled study in HIV-infected patients (76C ). At day 14, marijuana reduced the 8-hour AUC of nelﬁnavir by 10%, the Cmax by 17%, and the Cmin by 12%. However, none of these changes was signiﬁcant. Dronabinol had no effects.

Ritonavir (SED-14, 998; SEDA-24, 347; SEDA-25, 360; SEDA-26, 333) Immunologic Subcutaneous non-tuberculous granulomatous lesions developed in a 48-year-

316 old HIV-positive man when he was given ritonavir (84A ). Drug interactions Ritonavir inhibits CYP3A4 and CYP2D6 and has been used to enhance the actions of other protease inhibitors, by inhibiting their clearance (85R ). However, ritonavir and acenocoumarol have been reported to interact in the opposite way (86A ). • A 46-year-old man with prosthetic cardiac valves took acenocoumarol and later started to take stavudine, lamivudine, and ritonavir 600 mg bd. His INR fell markedly. Although the dose of acenocoumarol was progressively increased to three times the original dose, it was impossible to achieve the previous INR, and ritonavir was withdrawn.

An interaction of ritonavir with simvastatin reportedly resulted in rhabdomyolysis (87A ). • A 51-year-old woman taking zidovudine, lamivudine, indinavir, and simvastatin started to take ritonavir and after 1 week developed diffuse muscle weakness and body aches. Creatine kinase (total and MB isozyme), lactate dehydrogenase, AsT, and AlT were all raised. There were crystals and hemoglobin in the urine.

Presumably this interaction occurred through inhibition of CYP3A4 by ritonavir.

Saquinavir

(SED-14, 998; SEDA-24, 348; SEDA-26, 334)

Benign tumors Eruptive angiolipomata occurred in a 49-year-old woman after she had taken stavudine 30 mg bd, lamivudine 150 mg bd, and saquinavir 600 mg 8-hourly for 3 months (88A ). This has previously been reported with other protease inhibitors (89A , 90A ) and the mechanism is not known. In one case lipomata regressed after the introduction of indinavir (91A ).

COMBINATIONS OF DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS NRTIs + NNRTIs The efﬁcacy and safety of abacavir and efavirenz plus background therapy have been ret-

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J.K. Aronson

rospectively evaluated in 50 patients, who had previously been treated with HAART (92c ). There was some immunological beneﬁt, albeit limited, in most of the patients. Adverse effects were not mentioned in detail, but the drop-out rate during the ﬁrst 4 weeks of treatment was high, owing to skin rashes and hypersensitivity reactions. Of 80 injecting drug users who took two NRTIs + nevirapine, 20 discontinued treatment and 20 had treatment failures (93c ). Adverse events led to withdrawal of therapy in ten: eight had rashes (in one case Stevens–Johnson syndrome), one had liver failure thought to be unrelated to the drugs; and one had “general intolerance”. Two patients taking methadone had opioid withdrawal symptoms, presumably due to induction of methadone metabolism by nevirapine. Special senses In a report of ototoxicity in a patient taking three antiretroviral drugs, the authors suggested that nucleoside analogues can cause mitochondrial damage and that they should be avoided in patients with known neurotoxicity. • A 23-year-old woman who took stavudine, lamivudine, and nevirapine had nausea and diarrhea during the ﬁrst few days and within 2 weeks developed sudden bilateral hearing loss, dizziness, and tinnitus (94A ). The hearing defect was sensorineural. CT and MRI scans were normal. Prednisolone was ineffective.

NRTIs + protease inhibitors A variable-dose plasma concentration-controlled approach to combination antiretroviral therapy (zidovudine, lamivudine, and indinavir) has been compared with conventional ﬁxeddose therapy in 40 patients in a randomized, 52-week, open trial (95c ). Signiﬁcantly more concentration-controlled recipients achieved the desired concentrations for all three drugs: there was a good response in 15 of 16 concentration-controlled recipients compared with nine of 17 conventional regimen recipients. However, there was no difference in the occurrence of drug-related clinical events or laboratory abnormalities between the two regimens. Three patients withdrew because of gastrointestinal

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Table 2. Numbers (%) of infants and children with moderate or severe adverse events in a study of one or two NRTIs plus an NNRTI and/or a protease inhibitor (99c ) Adverse event

Respiratory Hematologic (neutropenia) Gastrointestinal Nausea/vomiting Other Liver Skin Body temperature (fever)

Stavudine + nevirapine + ritonavir (n = 41)

Regimen Stavudine + Stavudine + nevirapine + lamivudine + nelﬁnavir nevirapine + (n = 44) nelﬁnavir (n = 44)

Stavudine + lamivudine + nelﬁnavir (n = 52)

12 (29) 17 (41)

18 (41) 9 (20)

23 (52) 14 (32)

50 (96) 23 (44)

29 (71) 10 (24) 12 (29) 27 (66) 24 (59)

32 (73) 25 (57) 14 (32) 41 (93)∗ 30 (68)∗

18 (41) 18 (41) 18 (41) 32 (73) 20 (45)

15 (29) 19 (37) 23 (44) 17 (33)∗ 10 (19)∗

∗ Signiﬁcantly different from the other groups.

adverse effects, one because of a peripheral neuropathy, and one with headache and anemia. There was nephrolithiasis in four cases. The combination of indinavir + ritonavir 400/400 mg bd plus two NRTIs has been studied in 93 patients in an open, uncontrolled, multicenter trial (96c ). Raised triglycerides (n = 78) and raised cholesterol (n = 63) were the commonest adverse effects, followed by nausea (n = 22) and circumoral paresthesia (n = 9). Withdrawal was required in four cases of nausea, four of lipodystrophy, one of diarrhea, and one of osteonecrosis. Drug interactions By inhibiting their metabolism, ritonavir potentiates the actions of other protease inhibitors. The addition of delavirdine instead of another NNRTI in three patients taking protease inhibitors plus ritonavir further increased the exposure to the protease inhibitors (97c ).

NRTIs + NNRTIs + protease inhibitors In an open 48-week, single-arm, multicenter phase II study in 99 patients abacavir 300 mg bd, amprenavir 1200 mg bd, and efavirenz 600 mg/day were associated with rashes in 50 patients, possibly because of abacavir hypersensitivity; 17 permanently discontinued one or more drugs as a result (98c ). Other

adverse effects included nausea (n = 41), diarrhea (n = 27), sleep disorders (n = 27), dizziness (n = 25), fatigue (n = 23), hypertriglyceridemia (n = 18), neutropenia (n = 8), hyperamylasemia (n = 4), leukopenia (n = 3), hypercholesterolemia (n = 2), raised alkaline phosphatase (n = 1), and raised AsT (n = 1). In infants and children assigned to different combinations of one or two NRTIs plus an NNRTI and/or a protease inhibitor, the numbers of patients with moderate or severe adverse events were as shown in Table 2 (99c ). In cases of rash, the rash was worse in those who were taking nevirapine-containing regimens.

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS (SED-14, 999; SEDA-24, 348; SEDA-25, 360; SEDA-26, 334) Gastrointestinal It is not yet clear whether the beneﬁt of the neuraminidase inhibitors in patients with inﬂuenza or ﬂu-like illnesses outweighs the risk of their adverse effects. In a meta-analysis of trials, there was a reduction in the duration of symptoms of about 1 day (100M ). Oseltamivir caused signiﬁcantly more gastrointestinal symptoms (dyspepsia or nausea) than placebo; the effect increased with dose. Similarly, zanamivir caused signiﬁcantly more gastrointestinal symptoms than placebo (OR = 2.6; 95% CI = 1.6, 4.2).

318

Oseltamivir

(SED-14, 999; SEDA-25, 360; SEDA-26, 334)

Drug interactions Oseltamivir is an ester prodrug, whose active metabolite is a potent selective inhibitor of inﬂuenza virus neuraminidase, to which it is rapidly hydrolysed by hepatic carboxylesterases. The metabolite is then completely excreted by the kidneys by ﬁltration and secretion. In healthy subjects who took oral oseltamivir alone and with probenecid, cimetidine, or amoxicillin, probenecid completely blocked the renal secretion of the metabolite, increasing its AUC 2.5 times; cimetidine and amoxicillin had no effect (101cE ). In vitro studies of the metabolite on the human renal organic anionic transporter I (hOAT1) were investigated in Chinese hamster ovary cells stably transfected with the transporter. The metabolite was a low-efﬁciency substrate for hOAT1 and a very weak inhibitor of hOATl-mediated transport of para-aminohippuric acid. It did not inhibit the hOAT1-mediated transport of amoxicillin, but probenecid inhibited the transport

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J.K. Aronson

of the metabolite, para-aminohippuric acid, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data. In 730 residents of nursing homes who took oseltamivir prophylaxis for a median of 9 days (range 5–12), adverse effects were identiﬁed in 30 (4.1%), of whom 20 had one adverse effect and 10 had two (102c ). The most common adverse effects were diarrhea (n = 12), nausea or vomiting (n = 7), cough (n = 5), and confusion (n = 4).

Zanamivir

(SED-14, 999; SEDA-24, 348; SEDA-25, 360; SEDA-26, 334) In seven patients with inﬂuenza (three type A and four type B) after allografting inhaled zanamivir (10 mg bd) was used until excretion of virus ceased (median duration 15, range 5–44, days); there was rapid resolution of the inﬂuenza and no adverse effects attributable to zanamivir (103c ).

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320 Non-nucleoside HIV-1 reverse transciptase (RT) inhibitors: past, present, and future perspectives. Curr Pharm Des 2002; 8: 615–57. 38. Cozzi-Lepri A, Phillips AN, D’Arminio Monforte A, Piersantelli N, Orani A, Petrosillo N, Leoncini F, Scerbo A, Tundo P, Abrescia N, Moroni M. Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals (I.Co.N.A.) study. J Infect Dis 2002; 185: 1062–9. 39. Olivieri J. Nevirapine + efavirenz based salvage therapy in heavily pretreated HIV infected patients. Sex Transm Infect 2002; 78: 72–3. 40. Palmon R, Koo BCA, Shoultz DA, Dieterich DT. Lack of hepatotoxicity associated with nonnucleoside reverse transcriptase inhibitors. J Acquired Immune Deﬁc Syndr 2002; 29: 340–5. 41. Castro JG, Gutierrez L. Rhabdomyolysis with acute renal failure probably related to the interaction of atorvastatin and delavirdine. Am J Med 2002; 112: 505. 42. Negredo E, Cruz L, Paredes R, Ruiz L, Fumaz CR, Bonjoch A, Gel S, Tuldra A, Balague M, Johnston S, Arno A, Jou A, Tural C, Sirera G, Romeu J, Clotet B. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeﬁciency virus infection and long-lasting viral suppression. Clin Infect Dis 2002; 34: 504–10. 43. Fumaz CR, Tuldra A, Ferrer MaJ, Paredes R, Bonjoch A, Jou T, Negredo E, Romeu J, Sirera G, Tural C, Clotet B. Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens. J Acquired Immune Deﬁc Syndr 2002; 29: 244–53. 44. Morales-Ramirez J, Tashima K, Hardy D, et al. A phase III, multicenter randomized open-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus EFV + zidovudine (ZDV) + lamivudine (3TC), versus IDV + ZDV + 3TC at 36 weeks (DMP 266-006). 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Diego). Washington DC: American Society for Microbiology, 1998: I–103. 45. Mayers D, Jemesk J, Eyster E, et al. A doubleblind, placebo-controlled study to assess the safety, tolerability and antiretroviral activity of efavirenz (EFV DMP 266) in combination with openlabel zidovudine (ZDV) and lamivudine (3TC) in HIV infected patients (DMP 266-004). 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Diego). Washington DC: American Society for Microbiology, 1998: 22340. 46. Welch KJ, Morse A. Association between efavirenz and selected psychiatric and neurological conditions. J Infect Dis 2002; 185: 268–9. 47. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002; 35: 182–9.

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48. Phillips EJ, Kuriakose B, Knowles SR. Efavirenz-induced skin eruption and successful desensitization. Ann Pharmacother 2002; 36: 430–2. 49. Domingo P, Barcelo M. Efavirenz-induced leukocytoclastic vasculitis. Arch Intern Med 2002; 162: 355–6. 50. Fundaro C, Genovese O, Rendeli C, Tamburrini E, Salvaggio E. Myelomeningocele in a child with intrauterine exposure to efavirenz. AIDS 2002; 16: 299–300. 51. Tseng A, Nguyen ME, Cardella C, Humar A, Conly J. Probable interaction between efavirenz and cyclosporine. AIDS 2002; 16: 505–6. 52. Bofﬁto M, Rossati A, Reynolds HE, Hoggard PG, Back DJ, Di Perri G. Undeﬁned duration of opiate withdrawal induced by efavirenz in drug users with HIV infection and undergoing chronic methadone treatment. AIDS Res Hum Retroviruses 2002; 18: 341–2. 53. Aarnoutse RE, Grintjes KJT, Telgt DSC, Stek M Jr, Hugen PWH, Reiss P, Koopmans PP, Hekster YA, Burger DM. The inﬂuence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers. Clin Pharmacol Ther 2002; 71: 57–67. 54. Stringer JSA, Sinkala M, Rouse DJ, Goldenberg RL, Vermund SH. Effect of nevirapine toxicity on choice of perinatal HIV prevention strategies. Am J Public Health 2002; 92: 365–6. 55. Wise MEJ, Mistry K, Reid S. Neuropsychiatric complications of nevirapine treatment. Br Med J 2002; 324: 879. 56. Gonzalez de Requena D, Nunez M, JimenezNacher I, Soriano V. Liver toxicity caused by nevirapine. AIDS 2002; 16: 290–1. 57. Engeler DS, John H, Rentsch KM, Ruef C, Oertle D, Suter S. Nelﬁnavir urinary stones. J Urol 2002; 167: 1384–5. 58. Mildvan D, Yarrish R, Marshak A, Hutman HW, McDonough M, Lamson M, Robinson P. Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-infected women. J Acquired Immune Deﬁc Syndr 2002; 29: 471–7. 59. Cooper CL, Parbhakar MA, Angel JB. Hepatotoxicity associated with antiretroviral therapy containing dual versus single protease inhibitors in individuals coinfected with hepatitis C virus and human immunodeﬁciency virus. Clin Infect Dis 2002; 34: 1259–63. 60. Florence E, Schrooten W, Verdonck K, Dreezen C, Colebunders R. Rheumatological complications associated with the use of indinavir and other protease inhibitors. Ann Rheum Dis 2002; 61: 82–4. 61. Khanlou H, Graham E, Brill M, Farthing C. Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy. AIDS 2002; 16: 797–8. 62. Sale M, Sadler BM, Stein DS. Pharmacokinetic modeling and simulations of interaction of amprenavir and ritonavir. Antimicrob Agents Chemother 2002; 46: 746–54. 63. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA, Blaschke T, Alston B, Fang

Antiviral drugs

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F, Kosel B, Aweeka F. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG study A5047. AIDS 2002; 16: 569–77. 64. Sadler BM, Stein DS. Clinical pharmacology and pharmacokinetics of amprenavir. Ann Pharmacother 2002; 36: 102–18. 65. James CW, McNelis KC, Matalia MD, Cohen DM, Szabo S. Central nervous system toxicity and amprenavir oral solution. Ann Pharmacother 2002; 36: 174. 66. Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, Taburet AM. Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice. Antimicrob Agents Chemother 2002; 46: 1589–90. 67. Solas C, Basso S, Poizot-Martin I, Ravaux I, Gallais H, Gastaut J-A, Durand A, Lacarelle B. High indinavir Cmin is associated with higher toxicity in patients on indinavir-ritonavir 800/100 mg twice-daily regimen. J Acquired Immune Deﬁc Syndr 2002; 29: 374–7. 68. Van Rossum AMC, Geelen SPM, Hartwig NG, Wolfs TFW, Weemaes CMR, Scherpbier HJ, Van Lochem EG, Hop WCJ, Schutten M, Osterhaus ADME, Burger DM, De Groot R. Results of 2 years of treatment with protease-inhibitor-containing antiretroviral therapy in Dutch children infected with human immunodeﬁciency virus type 1. Clin Infect Dis 2002; 34: 1008–16. 69. Giner V, Fernandez C, Esteban MJ, Galindo MJ, Forner MJ, Guix J, Redon J. Reversible posterior leukoencephalopathy secondary to indinavirinduced hypertensive crisis: a case report. Am J Hypertens 2002; 15: 465–7. 70. Cersósimo MG, Lasala B, Folgar S, Micheli F. Epidural lipomatosis secondary to indinavir in an HIV-positive patient. Clin Neuropharmacol 2002; 25: 51–4. 71. Begovac J, Bayer K, Krpan D, Kusec V. Osteosclerosis and periostal new bone formation during indinavir therapy. AIDS 2002; 16: 803–4. 72. Nolan D, Upton R, McKinnon E, John M, James I, Adler B, Roff G, Vasikaran S, Mallal S. Stable or increasing bone mineral density in HIVinfected patients treated with nelﬁnavir or indinavir. AIDS 2001; 15: 1275–80. 73. Tebas P, Powderly WG, Claxton S, Marin D, Tantisiriwat W, Teitelbaum SL, Yarasheski KE. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14: F63–7. 74. Burger DM, Siebers MC, Hugen PWH, Aarnoutse RE, Hekster YA, Koopmans PP. Pharmacokinetic variability caused by gender: do women have higher indinavir exposure than men? J Acquired Immune Deﬁc Syndr 2002; 29: 101–2. 75. Sen S, Jalan R. Is “Gilbert’s” the culprit in indinavir-induced hyperbilirubinemia? Hepatology 2002; 35: 1269–70. 76. Damle BD, Mummaneni V, Kaul S, Knupp C. Lack of effect of simultaneously administered didanosine encapsulated enteric bead formulation (Videx EC) on oral absorption of indinavir, ke-

321 toconazole, or ciproﬂoxacin. Antimicrob Agents Chemother 2002; 46: 385–91. 77. Kosel BW, Aweeka FT, Benowitz NL, Shade SB, Hilton JF, Lizak PS, Abrams DI. The effects of cannabinoids on the pharmacokinetics of indinavir and nelﬁnavir. AIDS 2002; 16: 543–50. 78. Lanzafame M, Trevenzoli M, Faggian F, Marcati P, Gatti F, Carolo G, Concia E. Interaction between levothyroxine and indinavir in a patient with HIV infection. Infection 2002; 30: 54–5. 79. Piscitelli SC, Formentini E, Burstein AH, Alfaro R, Jagannatha S, Falloon J. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002; 22: 551–6. 80. Qazi NA, Morlese JF, Pozniak AL. Lopinavir/ritonavir (ABT-378/r). Expert Opin Pharmacother 2002; 3: 315–27. 81. Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, Murphy RL, Hicks C, King M, Wheeler D, Feinberg J, Stryker R, Sax PE, Riddler S, Thompson M, Real K, Hsu A, Kempf D, Japour AJ, Sun E. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeﬁciency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 2002; 185: 599–607. 82. Eyer-Silva WA, Neves-Motta R, Pinto JFC, Morais De Sa CA. Inﬂammatory oedema associated with lopinavir-including HAART regimens in advanced HIV-1 infection: report of 3 cases. AIDS 2002; 16: 673–4. 83. Rongkavilit C, Van Heeswijk RPG, Limpongsanurak S, Thaithumyanon P, Boonrod C, Hassink EAM, Srigritsanapol A, Chuenyam T, Ubolyam S, Hoetelmans RMW, Ruxrungtham K, Lange JMA, Cooper DA, Phanuphak P. Dose-escalating study of the safety and pharmacokinetics of nelﬁnavir in HIV-exposed neonates. J Acquired Immune Deﬁc Syndr 2002; 29: 455–63. 84. Kawsar M, El-Gadi S. Subcutaneous granulomatous lesions related to ritonavir therapy in a HIV infected patient. Int J STD AIDS 2002; 13: 273–4. 85. Rathbun RC, Rossi DR, Nazario M, Edouard B. Low-dose ritonavir for protease inhibitor pharmacokinetic enhancement. Ann Pharmacother 2002; 36: 702–6. 86. Llibre JM, Romeu J, Lopez E, Sirera G, Larouche M. Severe interaction between ritonavir and acenocoumarol. Ann Pharmacother 2002; 36: 621–3. 87. Cheng CH, Miller C, Lowe C, Pearson VE. Rhabdomyolysis due to probable interaction between simvastatin and ritonavir. Am J Health-Syst Pharm 2002; 59: 728–30. 88. Dauden E, Alvarez S, Garcia-Diez A. Eruptive angiolipomas associated with antiretroviral therapy. AIDS 2002; 16: 805. 89. Dank JP, Colven R. Protease inhibitor-associated angiolipomatosis. J Am Acad Dermatol 2000; 42: 129–31. 90. Bornhšvd E, Sakrauski AK, Brÿhl H, Walli R, Plewig G, Ršcken M. Multiple circumscribed subcutaneous lipomas associated with use of hu-

322 man immunodeﬁciency virus protease inhibitors. Br J Dermatol 2000; 143: 1097–131. 91. Bates D. Valacyclovir neurotoxicity: two case reports and a review of the literature. Can J Hosp Pharm 2002; 55: 123–7. 92. Wasmuth J-C, Herhaus C, Romer K, Salzberger B, Kaiser R, Schliefer K, Voigt E, Rockstroh JK. Efﬁcacy and safety of abacavir plus efavirenz as a salvage regimen in HIV-infected individuals after 48 weeks. AIDS 2002; 16: 1077–8. 93. Zaccarelli M, Barracchini A, De Longis P, Perno CF, Soldani F, Liuzzi G, Serraino D, Ippolito G, Antinori A. Factors related to virologic failure among HIV-positive injecting drug users treated with combination antiretroviral therapy including two nucleoside reverse transcriptase inhibitors and nevirapine. AIDS Patient Care STDs 2002; 16: 67– 73. 94. Rey D, L’Heritier A, Lang JM. Severe ototoxicity in a health care worker who received postexposure prophylaxis with stavudine, lamivudine, and nevirapine after occupational exposure to HIV. Clin Infect Dis 2002; 34: 418–19. 95. Fletcher CV, Anderson PL, Kakuda TN, Schacker TW, Henry K, Gross CR, Brundage RC. Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS 2002; 16: 551–60. 96. Lichterfeld M, Nischalke HD, Bergmann F, Wiesel W, Rieke A, Theisen A, Fatkenheuer G, Oette M, Carls H, Fenske S, Nadler M, Knechten H, Wasmuth J-C, Rockstroh JK. Long-term efﬁcacy and safety of ritonavir/indinavir at 400/400 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors as ﬁrst line antiretroviral therapy. HIV Med 2002; 3: 37–43. 97. Harris M, Alexander C, O’Shaughnessy M, Montaner JSG. Delavirdine increases drug exposure of ritonavir-boosted protease inhibitors. AIDS 2002; 16: 798–9. 98. Falloon J, Ait-Khaled M, Thomas DA, Brosgart CL, Eron JJ Jr, Feinberg J, Flanigan TP, Hammer

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SM, Kraus PW, Murphy R, Torres R, Masur H, Manion DJ, Rogers M, Wolfram J, Amphlett GE, Rakik A, Tisdale M. HIV-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients. AIDS 2002; 16: 387–96. 99. Krogstad PA, Lee S, Johnson G, Stanley K, McNamara J, Moye J, Jackson JB, Aguayo R, Dieudonne A, Khoury M, Mendez H, Nachman S, Wiznia A, Ballow A, Aweeka F, Rosenblatt HM, Perdue L, Frasia A, Jeremy R, Anderson M, Japour A, Fields C, Farnsworth A, Lewis R, Schnittman S, Gigliotti M, Maldonaldo S, Lane B, Hernandez JE, et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelﬁnavir, or ritonavir for pretreated children infected with human immunodeﬁciency virus type 1. Clin Infect Dis 2002; 34: 991–1001. 100. Pitts SR. Use of the neuraminidase inhibitor class of antiviral drugs for treatment of healthy adults with an acute inﬂuenza-like illness. Ann Emerg Med 2002; 39: 552–4. 101. Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The antiinﬂuenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion–correlation of in vivo and in vitro studies. Drug Metab Dispos 2002; 30: 13–19. 102. Bowles SK, Lee W, Simor AE, Vearncombe M, Loeb M, Tamblyn S, Fearon M, Li Y, McGeer A, Marguerite V, Baker D, Collins V, VanHorne E, Louie MA, Friedman P, Kam A, Goette M, Lam J, LaRue M, MacDonald M, McArthur MA, Mazzulli T, McDougall R, Satchell S, Simpson M, Stanton S, Warshawsky B, Wier H. Use of oseltamivir during inﬂuenza outbreaks in Ontario nursing homes, 1999–2000. J Am Geriatr Soc 2002; 50: 608–16. 103. Johny AA, Clark A, Price N, Carrington D, Oakhill A, Marks DI. The use of zanamivir to treat inﬂuenza A and B infection after allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 29: 113–15.

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Drugs used in tuberculosis and leprosy

Antituberculosis drug regimens containing pyrazinamide in the treatment of latent pulmonary tuberculosis infection Pyrazinamide plus rifampicin There is continuing concern about the hepatotoxicity of the combination of pyrazinamide with rifampicin for the treatment of latent pulmonary tuberculosis. Among 148 who were given the combination for 2 months, grade 3 hepatotoxicity (AsT or AlT more than 5–20 times the upper limit of the reference range) and grade 4 hepatotoxicity (AsT or AlT more than 20 times the upper limit of the reference range) were reported in ten and four patients respectively (1c ). The risk of hepatotoxicity was associated with female sex (OR = 4.1 95% CI = 1.2, 14) and presumed recent infection (OR = 14.3 95% CI = 1.8, 115). The investigators recommended caution in using the combination of pyrazinamide with rifampicin in populations in whom its safety has not been established. Others consider that this combination is useful for high-risk, traditionally non-adherent patients, such as alcoholics and the homeless, but have also emphasized the need for careful monitoring for toxicity (2c ). This suggestion is based on the presumption that the combination regimen, although toxic, is more likely to be completed by high-risk patients than 6 months of isoniazid alone. However, others observed similar completion rates for the two regimens in a multicenter study (61% and 57%) (3c ), and the safety and cost-effectiveness of this combination in the treatment of latent tuberculosis has been questioned (4r ). © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Revised CDC guidelines for the treatment of latent tuberculosis with pyrazinamide plus rifampicin were summarized in SEDA-26 (p. 339). Only two non-fatal cases of severe liver injury have been reported to the CDC since the publication of revised guidelines as of November 2002 (5c ). Hepatotoxicity is generally considered to be rare among children who receive antituberculosis drugs. However, a report from Japan has suggested that this might not be the case, at least in Asia (6c ). The authors noted high activities of AsT and AlT, more than ﬁve times the upper end of the reference range, in eight of 99 children aged 0–16 years who received various combinations of drugs, including rifampicin and isoniazid; 18 children were excluded because of baseline abnormalities in liver function. Age under 5 years and pyrazinamide in the drug regimen were risk factors for hepatotoxicity. There have been few other reports of the risk of hepatotoxicity in children. Pyrazinamide plus levoﬂoxacin This combination is the ﬁrst-line treatment for multidrugresistant latent tuberculosis. In 17 Canadian patients there were important adverse reactions affecting the musculoskeletal and central nervous systems; hyperuricemia, gastrointestinal effects, and dermatological effects were also common (7c ). This combination may be used with careful monitoring for adverse effects. Management of drug-induced liver damage with herbal products Several herbal products have been claimed to mitigate druginduced hepatitis caused by antituberculosis agents. However, few of them have undergone rigorous randomized controlled trials. Glycyrrhizin is widely used in Japan for the treatment of chronic hepatitis, but in a nonrandomized trial in 24 patients who developed

323

324 drug-induced hepatitis while undergoing antituberculosis chemotherapy, there was no difference in the time required for recovery between the patients who were treated with or without intravenous glycyrrhizin 40 ml/day (8c ). Moringa oleifera, commonly known as “drumstick”, has been mentioned in the treatment of various illnesses in Indian folk medicine, and an ethanolic extract of the leaves had a hepatoprotective effect in a rat model of antituberculosis drug-induced liver injury (9E ). Russian investigators have reported a hepatoprotective effect of a plant product “Galstena” in a rat model and have extended their observations to a clinical trial, with favorable results; however, few data were given in this report (10Ec ). It cannot be denied that there is a need for continuing research in this area, but it is necessary to undertake well-conducted scientiﬁc studies before claims of hepatoprotective effects of herbal products can be accepted.

Rifampicin

(SED-14, 1014; SEDA-24, 353; SEDA-25, 364; SEDA-26, 341)

Respiratory Only one case of rifampicininduced pneumonitis has been reported before, but now another case has been attributed to rifampicin (11A ). • An 81-year-old man with smear- and culturepositive pulmonary tuberculosis developed clinical and radiological features of localized interstitial pneumonitis 1 week after starting to take rifampicin, isoniazid, and ethambutol. The bronchoalveolar lavage ﬂuid contained 83% lymphocytes with a CD4/CD8 ratio of 10.5. Antituberculosis treatment was withheld and he was treated with methylprednisolone for 3 days because of progressive respiratory failure. A drug lymphocyte stimulation test showed a high stimulation index with rifampicin (370%). He was subsequently treated with streptomycin instead of rifampicin. Re-challenge with rifampicin was not undertaken.

Sudden clinical and radiological worsening during treatment for pulmonary tuberculosis may be due to bronchogenic spread of infection, immune reconstitution producing a paradoxical reaction, drug-induced hypersensitivity pneumonitis, or other unrelated causes, such as pulmonary embolism. Hypersensitivity pneumonitis with rifampicin is most unusual, as is

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the high CD4/CD8 ratio observed in the brochoalveolar lavage ﬂuid. Liver Severe itching is often a distressing symptom in patients with primary biliary cirrhosis and in cholestatic jaundice due to other causes. Rifampicin has been recommended for controlling this symptom, even though it is known to be hepatotoxic. Rifampicin-induced hepatitis has been reported in three of 41 patients with primary biliary cirrhosis (7.3%, 95% CI = 2.5, 19) (12c ). This risk is greater than the risk of hepatitis during rifampicin monotherapy for latent tuberculosis. Pre-existing liver disease is a recognized risk factor for drug-induced hepatitis, and these patients need to be monitored carefully during rifampicin therapy. Urinary tract Acute renal insufﬁciency on restarting antituberculosis treatment with regimens containing rifampicin is well known. There have been two retrospective Romanian case series of patients who developed acute renal insufﬁciency on re-treatment after variable periods of interruption. One was a study in 60 patients from the Iasi Dialysis Center during 1987–95 (13c ) and the other was a study in 92 patients from a county hospital during 1974–2000 (14c ). In most cases symptoms appeared within 48 hours of restarting treatment. The most frequent symptoms were abdominal pain, particularly in the lumbar region, nausea and vomiting, ﬂu-like symptoms (fever, chills, and myalgia), and occasionally jaundice. Abnormal liver function tests and autoimmune hemolytic anemia with a positive Coombs’ test were frequent associated complications. Antirifampicin antibodies were detected in 55% of the patients. One-third had sterile leukocytouria, suggesting interstitial nephritis. There was thrombocytopenia in a quarter. The outcome was favorable in most cases, despite these complications. Similar ﬁndings have been reported in 11 patients in India (15c ) and in 25 patients seen at Chennai over the 10 years from 1990 to 2000 (16c ). Most of the patients had taken a single capsule of rifampicin after having taken a daily regimen in the past. All had oliguric renal insufﬁciency. Anemia and thrombocytopenia were frequent (60%). Acute hepatitis was present in one-third. Of 12 patients who underwent kidney biopsy, seven had histological features of

Drugs used in tuberculosis and leprosy

Chapter 30

acute interstitial nephritis. There was crescentic glomerulonephritis in one patient, and mesangial proliferation in three. There were no deaths, and all patients had complete recovery of renal function. Although interstitial nephritis and acute tubular necrosis are the most common causes of rifampicin-associated acute renal insufﬁ-

325 ciency, rapidly progressive glomerulonephritis with characteristic crescentic lesions on renal histology has been reported occasionally. • A 60-year-old Japanese man developed rapidly progressive glomerulonephrits 1 month after the reintroduction of rifampicin (17A ). There was cresentic glomerulonephritis in a renal biopsy. The patient responded well to methylprednisolone.

REFERENCES 1. Lee AM, Mennone JZ, Jones RC, Paul WS. Risk factors for hepatotoxicity associated with rifampicin and pyrazinamide for the treatment of latent tuberculosis infection: experience from three public health tuberculosis clinics. Int J Tuberc Lung Dis 2002; 11: 995–100. 2. Stout JE, Engemann JJ, Cheng AC, Fortenberry ER, Hamilton CD. Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis. Am J Respir Crit Care Med 2003; 167: 824–7. 3. Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, King MD, Kawamura LM, Hopewell PC. Short course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002; 137: 640–7. 4. Jasmer RM, Daley CL. Rifampin and pyrazinamide for treatment of latent tuberculosis: is it safe? Am J Respir Crit Care Med 2003; 167: 809– 10. 5. Anonymous. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 2002 51: 998–9. 6. Ohkawa K, Hashiguchi M, Ohno K, Kiuchi C, Takahashi S, Kondo S, Echizen H, Ogata H. Risk factors for antituberculous chemotherapy-induced hepatotoxicity in Japanese pediatric patients. Clin Pharmacol Ther 2002; 72: 220–6. 7. Papastavros T, Dolovich LR, Holbrook A, Whitehead L, Loeb M. Adverse events associated with pyrazinamide and levoﬂoxacin in the treatment of latent multidrug-resistant tuberculosis. Can Med Assoc J 2002; 167: 131–6. 8. Miyazawa N, Takahashi H, Yoshiike Y, Ogura T, Watanuki Y, Sato M, Kakemizu N, Yamakawa Y, Ch U, Goto H, Odagiri S. Effect of glycyrrhizin

on anti-tuberculosis drug-induced hepatitis [in Japanese]. Kekkaku 2003; 78: 15–19. 9. Pari L, Kumar NA. Hepatoprotective activity of Moringa oleifera on anti-tubercular drug-induced liver damage in rats. J Med Food 2002; 5: 171–7. 10. Katikova O, Asanov BM, Vize-Khripunova MA, Burba EN, Ruzov VI. Use of the plant hepatoprotector Galstena in tuberculostatics-induced hepatic lesions: experimental and clinical study [in Russian]. Probl Tuberk 2002; 4: 32–6. 11. Kunichika N, Miyahara N, Kotani K, Takeyama H, Harada M, Tanimoto M. Pneumonitis induced by rifampicin. Thorax 2002; 57: 1000–1. 12. Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut 2002; 50: 436–9. 13. Covic A, Gusbeth-Tatomir P, Tarevici Z, Mihaescu T, Covic M. Post-rifampicin acute renal failure—serious, but seldom recognized complication of the anti-tuberculosis treatment [in Romanian]. Pneumologia 2001; 50: 225–31. 14. Munteanu L, Golea O, Nicolicioiu M, Tudorache V. Speciﬁc features of acute renal failure in patients treated with rifampicin [in Romanian]. Pneumologia 2002; 51: 15–20. 15. Prakash J, Kumar NS, Saxena RK, Verma U. Acute renal failure complicating rifampicin therapy. J Assoc Phys India 2001; 49: 877–80. 16. Muthukumar T, Jayakumar M, Fernando EM, Muthusethupathi MA. Acute renal failure due to rifampicin: a study of 25 patients. Am J Kidney Dis 2002; 40: 690–6. 17. Yoshioka K, Satake N, Kasamatsu Y, Nakamura Y, Shikata N. Rapidly progressive glomerulonephritis due to rifampicin therapy. Nephron 2002; 90: 116–18.

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Antihelminthic drugs

BENZIMIDAZOLES

(SED-14, 1030; SEDA-24, 356; SEDA-25, 367; SEDA-26, 344)

Albendazole, mebendazole, and thiabendazole Drug interactions The poor intestinal absorption of albendazole, which may be enhanced by a fatty meal, contributes to difﬁculties in predicting its therapeutic response in echinococcosis. The effect of grapefruit juice or cimetidine co-administration on the systemic availability of albendazole has been studied in six healthy men (1c ). After an overnight fast, a single oral dose of albendazole (10 mg/kg) was administered on an empty stomach with water, a fatty meal, grapefruit juice, or grapefruit juice plus cimetidine. The systemic availability of albendazole was increased by grapefruit juice and reduced by cimetidine. There were no adverse events. These results are consistent with presystemic metabolism of albendazole by CYP3A4. Susceptibility factors Children Children aged under 2 years who are infected with helminths are currently excluded from treatment with mebendazole and other antihelminthic drugs on the basis of the manufacturer’s instructions. In a double-blind, randomized trial in Tanzania 212 children aged under 2 years were given a total of 653 antihelminthic treatments (317 mebendazole 500 mg; 336 placebo) (2c ). There were no signiﬁcant differences in adverse events in the two groups. In the light of the potential nutritional beneﬁt achieved by regular deworming in this age group, the policy that excludes children aged under 2 years from treatment should probably be reconsidered. © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

326

Benzimidazoles and echinococcosis Hydatid disease is a common zoonosis caused by the larval cysts of Echinococcus granulosus. Hydatid cysts most commonly form in the liver, but can occur in any organ. The management and operative complications in 70 patients with hydatid disease aged 10–78 years have been studied retrospectively to assess the impact of albendazole and praziquantel compared with surgery (3c ). In all, 39 patients received albendazole and praziquantel in combination and 19 received albendazole alone; none was treated with praziquantel alone. The combined use of albendazole and praziquantel pre-operatively signiﬁcantly reduced the number of cysts that contained viable protoscolices. During the 12-year followup period an initial 3 months of drug treatment (albendazole throughout and praziquantel for 2 weeks), re-assessment, followed by either surgery or continuation with chemotherapy was found to be a rational treatment algorithm. In 11 patients albendazole, given for a median of 3 months at a dose of 400 mg bd, had adverse effects: ﬁve patients developed nausea and six had abnormal liver function tests. Therapy was withdrawn in two patients owing to altered liver function. The efﬁcacy of albendazole emulsion has been studied In 212 patients with hydatid disease of the liver, aged 4–82 years (4c ). Two regimens of albendazole were given for a variable period (3 months to more than 1 year); 67 adults received albendazole 10 mg/kg/day and 145 adults received 12.5 mg/kg/day. The overall cure rate was 75%. In the follow-up study the recurrence rate was 10%. The highest cure rate was observed in those who received albendazole 12.5 mg/kg/day for 9 months. At the start of therapy about 15% of the patients had mild pruritus, rash, and transient gastric pain, which resolved without speciﬁc therapy. Two patients had alopecia. There were frequent rises in serum aminotransferase activities in both groups but not to above 30–50 IU/l, except in six patients, who had values above

Antihelminthic drugs

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200 IU/l. In two patients albendazole was withdrawn because of vomiting. In one patient who took 12.5 mg/kg/day severe adverse effects, such as anorexia, jaundice, anemia, edema, and hypoproteinemia, developed, necessitating withdrawal. Reintroduction of albendazole 10 mg/kg/day was uneventful. In 78 patients with hydatid disease there was a low recurrence rate of hydatid disease (below 3%) after a postoperative prophylactic course of mebendazole 20 mg/kg/day in three divided doses for 3 months (5c ). The only adverse effect of mebendazole was excessive loss of hair in two women. The unusual low recurrence rate of hydatid disease after treatment with mebendazole in this study was subsequently questioned and attributed to meticulously careful surgical procedures, with avoidance of spillage of hydatid ﬂuid and complete removal of parasitic components (6r ). Benzimidazoles and ﬁlariasis Treatment of patients with high Loa loa microﬁlaraemia is sometimes complicated by an encephalopathy, suggested to be related to a rapid killing of large number of Loa loa microﬁlariae. If the Loa loa microﬁlarial count could be reduced more slowly, before ivermectin is distributed, ivermectin-related encephalopathy might be prevented. In 125 patients with Loa loa microﬁlariasis the effect of albendazole (800 mg/day for three consecutive days) or multivitamin tablets on Loa loa microﬁlarial load and the occurrence of encephalopathy was studied (7c ). Loa loa microﬁlarial loads were followed for 9 months. There was no signiﬁcant change in the overall microﬁlarial loads among those treated with albendazole, although the loads in patients with more than 8000 microﬁlariae/ml tended to fall more progressively during the ﬁrst 3 months of follow-up. There were no cases of encephalopathy. The main adverse effects reported were itching (in eight patients taking

albendazole and seven taking multivitamins), abdominal pain (two taking albendazole), and diarrhea (one taking albendazole, two taking multivitamins); overall analysis showed no signiﬁcant difference in these events between the groups. Albendazole was associated with modest but signiﬁcantly raised plasma aminotransferase activities. Benzimidazoles and neurocysticercosis The pharmacological interactions of the antiepileptic drugs phenytoin, carbamazepine, and phenobarbital with albendazole have studied in 32 adults with active intraparenchymatous neurocysticercosis (8c ): • nine patients took phenytoin 3–4 mg/kg/day; • nine patients took carbamazepine 10–20 mg/kg/day; • ﬁve patients took phenobarbital 1.5–4.5 mg/ kg/day; • nine patients took no antiepileptic drugs. All were treated with albendazole 7.5 mg/kg every 12 hours on 8 consecutive days. Phenytoin, carbamazepine, and phenobarbital all induced the oxidative metabolism of albendazole to a similar extent in a non-enantioselective manner. In consequence, there was a signiﬁcant reduction in the plasma concentration of the active metabolite of albendazole, albendazole sulfoxide. Benzimidazoles and roundworms The efﬁcacy of 2 years of mass chemotherapy against ascariasis has been evaluated in Iran (9c ). A single dose of albendazole 400 mg was given at 3-month intervals for 2 years to every person, except children under 2 years of age and pregnant woman. After 2 years of treatment the prevalences, based on 2667 post-treatment samples, had fallen (Table 1). There were no adverse effects of mass treatment with albendazole.

Table 1. Changes in prevalences of helminthic infections in patients treated with albendazole (9c ) Helminth

Number (%) positive before treatment (3098 samples)

Number (%) positive after treatment (2667 samples)

Ascaris lumbricoides Trichuris trichiura Hymenolepis nana

1198 (39%) 22 (0.7%) 63 (2.0%)

196 (7.4%) 5 (0.2%) 49 (1.8%)

328 In 110 children with ascariasis or trichuriasis the efﬁcacy of a single dose of albendazole 400 mg has been compared with that of nitazoxanide 100 mg bd for 3 days aged 1–3 years and 200 mg bd for 3 days in children aged 4–11 years (10c ). Nitazoxanide cured 89% and 89% of the cases of ascariasis and trichuriasis respectively. Albendazole cured 91% and 58% of the cases of ascariasis and trichuriasis respectively. Abdominal pain (n = 9), nausea (n = 1), diarrhea (n = 2), and headache (n = 1) were reported as mild adverse effects in 105 patients who took nitazoxanide, and abdominal pain (n = 1), nausea (n = 1), and vomiting (n = 1) were reported as adverse effects in 54 patients who took albendazole. All the adverse events were mild and transient and drug withdrawal was not necessary. Benzimidazoles and protozoal infections The efﬁcacy of albendazole 800 mg bd for 14 days for persistent diarrhea due to cryptosporidiosis (n = 10), isosporiasis (n = 54), or microsporidiosis (n = 23) has been studied in 153 HIV-positive patients (11c ). Albendazole reduced the burden of protozoal infection and promoted mucosal recovery in 87 patients who had a complete clinical response. Two patients reported nausea and vomiting. One patient developed leukopenia (1.9 × 109 /l) after treatment and four patients developed thrombocytopenia (51–98 × 109 /l). A 38-year-old woman with cough, eosinophilia, and pulmonary inﬁltrates due to visceral larva migrans from Toxocara canis infection took albendazole 600 mg for 8 weeks and developed slight transient skin eruptions (12A ).

Diethylcarbamazine

(SED-14, 1034; SEDA-24, 357; SEDA-25, 368; SEDA-26, 345) The adverse effects of diethylcarbamazine are generally proportional to the microﬁlarial burden and include fever, headache, dizziness, and transient exacerbation of lymphangitis. The efﬁcacy of control programmes for lymphatic ﬁlariasis using diethylcarbamazine has been limited by the long duration of treatment, which eventually leads to reduced compliance.

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Diethylcarbamazine and lymphatic ﬁlariasis The efﬁcacy of new treatment strategies for lymphatic ﬁlariasis using a single dose of diethylcarbamazine or a combination of diethylcarbamazine plus albendazole has been studied in 30 people (aged 11–52 years, weighing 25–63 kg) infected with Brugia timori and compared with the results of 27 people (aged 13–52 years, weighing 27–73 kg) infected with Wuchereria bancrofti (13c ). All were allocated at random to diethylcarbamazine (100 mg on day 1 and up to a total dose of 6 mg/kg on day 3) or diethylcarbamazine plus albendazole group (placebo on day 1 and diethylcarbamazine 6 mg/kg plus albendazole 400 mg on day 3). There was no difference in adverse reactions between diethylcarbamazine alone and diethylcarbamazine plus albendazole. Headache (n = 15), myalgia (n = 13), itching (n = 8), and adenolymphangitis (n = 8) were the most common adverse effects; none was severe or life-threatening. The microﬁlaricidal effect of the drugs was achieved more rapidly for B. timori, which is associated with more adverse reactions than W. bancrofti ﬁlariasis. As previously shown, there was a strong correlation of microﬁlarial density with the frequency and severity of adverse reactions. The addition of albendazole resulted in no additional adverse reactions compared with diethylcarbamazine alone. The pharmacokinetics, safety, and tolerability of co-administered diethylcarbamazine and albendazole has been investigated in a double-blind, randomized, placebo-controlled trial in 42 subjects (aged 18–52 years, weighing 46–67 kg) living in a lymphatic ﬁlariasis endemic region but without detectable microﬁlariae (14c ). Three groups of 14 patients received diethylcarbamazine 6 mg/kg alone, albendazole 400 mg alone, or diethylcarbamazine 6 mg/kg plus albendazole 400 mg. Both diethylcarbamazine and albendazole were well tolerated alone and in combination. In contrast to the study in patients with lymphatic ﬁlariasis (13c ), there were no adverse events in amicroﬁlaremic individuals. In all three treatment groups the drugs were rapidly absorbed from the gastrointestinal tract, although there was marked interindividual variation. The pharmacokinetics of diethylcarbamazine, albendazole, and albendazole sulfoxide were similar.

Antihelminthic drugs

Ivermectin (SED-14, 1035; SEDA-24, 357; SEDA-25, 370; SEDA-26, 346) Emesis, ataxia and mydriasis, are cardinal signs of ivermectin toxicity. The safety, tolerability, and pharmacokinetics of escalating high-dose ivermectin have been studied in 68 healthy subjects in a randomized, double-blind, placebocontrolled study (15C ) in the following doses: • • • • •

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30 mg fasted (n = 15); 60 mg fasted (n = 12); 90 mg fasted (n = 12); 120 mg fasted (n = 12); 30 mg fed (n = 11).

Ivermectin was generally well tolerated. Quantitative pupillometry ruled out any mydriatic effect of ivermectin. There was no CNS toxicity associated with oral ivermectin at any of the doses. There were no serious clinical or laboratory adverse events. Three of the 51 subjects who took ivermectin fasted reported minor adverse gastrointestinal events—fecal abnormality (n = 1), nausea (n = 1), and vomiting (n = 1); six reported minor neurological adverse events—headache (n = 4), anxiety (n = 1), and dizziness (n = 1). There were no adverse events in the subjects who took ivermectin 120 mg. The absorption of ivermectin was about 2.5 times higher when it was given after a high-fat meal. Ivermectin and onchocerciasis The Mazzotti reaction, which is often seen after treatment of Onchocerca volvulus with diethylcarbamazine or ivermectin, is characterized by fever, tachycardia, hypotension, adenitis, pruritus, and arthralgia. It is commonly believed that these adverse effects of diethylcarbamazine and ivermectin result from proinﬂammatory responses to antigens released from killed microﬁlariae, rather than by direct drug or metabolite toxicity. Previous studies have suggested a role for the release of Wolbachia bacterial endosymbionts in the pathogenesis of the Mazzotti reaction (SEDA-26, 345). In a recent study (16c ) there was a good correlation between Wolbachia DNA, serum TNF-alpha, and the antibacterial peptides calprotectin and calgranulin after treatment with ivermectin or diethylcarbamazine, supporting a role for Wolbachia

products in mediating these inﬂammatory responses. It is generally accepted that annual mass treatment with ivermectin will eventually reduce the prevalence of onchocerciasis in a community. However, there are still questions about the ideal frequency and length of community treatment and the expected beneﬁts from different regimens. Sound evidence that ivermectin reduces the prevalence of blindness or impaired vision attributable to onchocerciasis is currently lacking. The impact of 5 years of annual community treatment with ivermectin on the prevalence of onchocerciasis and onchocerciasis-associated morbidity in the village of Gami (Central African Republic) has therefore been assessed (17c ). Pruritus, onchocercal nodules, and impaired vision were all signiﬁcantly reduced by annual treatment with ivermectin. In a study of the effect of ivermectin on adult Onchocerca worms (18c ) the following regimens were compared: • • • •

150 μg/kg yearly (reference group; n = 166); 400 μg/kg then 800 μg/kg yearly (n = 172); 150 μg/kg 3-monthly (n = 161); 400 μg/kg then 800 μg/kg 3-monthly (n = 158).

After 3 years of treatment more female worms had died in those who were treated every 3 months than in the reference group; female worms were also less fertile. There was no difference between the two groups of patients who were treated yearly. There were no serious adverse events, even at high doses. However, subjective complaints of visual disturbances, such as blurred vision, ocular pain, or dyschromatopsia were more frequent in those who were given 800 μg/kg than in those who were given 150 μg/kg; the effects lasted less than 1 week. Detailed ocular examination showed no differences between patients from the reference group and the three other groups. Ivermectin and scabies In 80 children aged 6 months to 14 years a single dose of ivermectin 200 μg/kg was compared with topical benzyl benzoate for the treatment of pediatric scabies in a randomized, controlled trial (19c ). Ivermectin cured 24 of 43 patients and topical benzyl benzoate cured 19 of 37 patients at

330 3 weeks after treatment. There were no serious adverse effects with either treatment, although benzyl benzoate was more likely to produce local skin reactions. These results are in line with those of another study, in which 18 children aged 14 months to 17 years with either scabies (n = 11) or cutaneous larva migrans (n = 7) were treated with a single dose of ivermectin 150–200 μg/kg (20c ). A single oral dose cured 15 patients, and three patients with crusted scabies required a second dose. None had signiﬁcant adverse reactions. Ivermectin and strongyloidiasis The efﬁcacy and adverse effects of ivermectin 200 μg/ kg, repeated 2 weeks later, have been studied in 50 patients with chronic strongyloidiasis, aged 30–79 years (21c ). The eradication rate was 96% at 2 weeks after the ﬁrst dose and 98% after the second dose. There was no recurrence after follow-up of 4 months. One patient had nausea and vomiting 3 hours after the ﬁrst dose and again after the second dose, but they were transient and required no therapy. In four patients there were mild laboratory abnormalities (slight increases in liver function tests in two, microscopic hematuria in one, and mild leukopenia and lymphocytosis in one). Of the 50 patients 12 were positive for human T lymphotropic virus type-I.

Levamisole

(SED-14, 1037; SEDA-24, 358; SEDA-25, 372; SEDA-26, 347) Levamisole and refractory oral candidiasis In two patients with thymoma associated with myasthenia gravis, who both had recurrent oral candidiasis after thymectomy, radiotherapy, and chemotherapy levamisole was added as adjunctive therapy in combination with oral nystatin (22c ). Oral candidiasis responded favorably and substantial relief was obtained, with a concurrent increase in T cells and CD4/CD8 ratio, suggesting restoration of T cell immunity. Adverse effects were not mentioned. Levamisole and nephrotic syndrome In a detailed review of the management of nephrotic syndrome in childhood levamisole was advocated as a weak but effective steroid-sparing agent (23R ). In general, after induction of

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remission of nephrotic syndrome with prednisolone, levamisole may be given in a dose of 2.5 mg/kg on alternate days. This may allow tapering and possible withdrawal of alternateday maintenance prednisolone. In a prospective study in 20 children (aged 3–15 years; 16 boys, 4 girls) with steroid-dependent minimal-change nephrotic syndrome, adjunctive therapy with levamisole led to successful withdrawal of corticosteroids after 2 months in 11 children (24c ). At the end of 6 months (i.e. after 4 months of steroid withdrawal) 10 patients were in remission with levamisole alone. After 12 months (i.e. after 6 months of levamisole withdrawal) ﬁve were still in remission without any treatment. There were no signiﬁcant adverse effects during levamisole treatment. Levamisole and colorectal cancer The Gastrointestinal Intergroup has studied postoperative adjuvant chemotherapy and radiation therapy in 1659 patients with T3/4 and lymph-nodepositive rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure (25c ). There was no advantage to regimens containing leucovorin or levamisole over bolus 5-ﬂuorouracil alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates were still high, especially in T3 and T4 lymph node positive patients, even with full adjuvant chemoradiation therapy.

Nitazoxanide Nitazoxanide is a nitrothiazole benzamide compound, which is effective against a wide variety of parasites and bacteria that infect animals and humans. In vitro it has a documented efﬁcacy against protozoa such as Trichomonas vaginalis and Entamoeba histolytica, and in vivo in particular against Cryptosporidium parvum in patients with AIDS, as well as against nematodes such as Syphacia obvelata, Uncinaria stenocephala, and Trichuris vulpis, and cestodes such as Dipylidium canimum, Taenia pisiformis, and Hymenolepis nana (26c , 27c ).

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Nitazoxanide in healthy individuals Although nitazoxanide has been given to many patients, its tolerability and pharmacokinetics have not been adequately assessed (26c , 27c ). To study this, 32 men were randomly assigned to one of four treatment groups, in each of which two took a placebo and six took a single oral dose of nitazoxanide 1, 2, 3, or 4 g, ﬁrst fasted and a week later with a standardized breakfast (26c ). There were no signiﬁcant changes in electrocardiograms, vital signs, or laboratory tests. Plasma concentrations increased linearly with dose, although there was a trend to increased systemic availability at a dose of 4 g. Food approximately doubled the concentrations of the metabolites of nitazoxanide, deacetylnitazoxanide (or tizoxanide) and tizoxanide glucuronide, irrespective of dose. Tizoxanide glucuronide was eliminated more slowly than tizoxanide. Tolerability was good up to the maximum dose of 4 g. There were 89 adverse events; all were mild and none required treatment. Minor adverse events were dizziness, fatigue, discolored urine, malaise, and postural hypotension. However, the most frequent adverse events were gastrointestinal— diarrhea (n = 13), abdominal pain (n = 8), ﬂatulence and nausea (n = 5), and vomiting (n = 3). Their frequency increased signiﬁcantly with dose under fed conditions but not fasted. In a second study nitazoxanide 0.5 g bd and 1 g bd was given to 16 healthy volunteers for 7 days with food to study its pharmacokinetics and tolerability (27c ). The pharmacokinetics of both tizoxanide and tizoxanide glucuronide were only slightly inﬂuenced by repeated administration of nitazoxanide 0.5 g bd; the treatment group had no more adverse events than the placebo group and there was no accumulation. In contrast, repeated administration of nitazoxanide 1 g bd resulted in a signiﬁcant increase in adverse events—diarrhea (n = 9), abdominal pain (n = 9), ﬂatulence (n = 5), nausea (n = 4), and dyspepsia (n = 1). All reported discolored urine. Four subjects in the highdose group reported headaches. Vital signs, electrocardiograms, and laboratory tests were normal. There was accumulation of nitazoxanide metabolites, because of solubility-limited or transport-limited elimination at the higher dose of nitazoxanide.

Piperazine (SED-14, 1034; SEDA-24, 357; SEDA-25, 368; SEDA-26, 345) Nervous system Piperazine is relatively nontoxic vermicidal agent that has been used for over 50 years in children. Neurotoxicity from piperazine, although rare, includes headache, confusion, irritability, incoordination, and generalized tonic–clonic, atonic, and myotonic seizures, and even status epilepticus. • A previously well 23-month-old girl was given piperazine 65 mg/kg/day for 7 days for a suspected worm infestation and developed cerebellar ataxia after 8 days (28A ). Over the next 48 hours her symptoms gradually settled. She made a complete recovery 5 days later.

Praziquantel

(SED-14, 1041; SEDA-24, 360; SEDA-25, 372; SEDA-26, 349)

Praziquantel and paragonimiasis Traditionally biothionol was used to treat paragonimiasis, a food-borne zoonosis that is endemic in limited areas of the world. However, owing to the need for long-term administration and moderate to severe adverse effects, such as nausea and diarrhea, biothionol has been replaced by praziquantel. At a dose of 75 mg/kg/day for only 2–3 days, praziquantel has the advantage of an easier dosing schedule in combination with excellent therapeutic efﬁcacy. Adverse effects, if any, are mild and transient (29R ). In patients with pleural effusion, pleural ﬂuid must be drained before starting chemotherapy; insufﬁcient drainage often causes complications, such as chronic empyema or insufﬁcient inﬂation of the lungs. Praziquantel is also effective for cutaneous, cerebral, or any form of extrapulmonary paragonimiasis.

Suramin

(SED-14, 1042; SEDA-24, 361; SEDA-25, 373; SEDA-26, 350) Suramin and hormone-refractory metastatic prostate cancer In a randomized study in 390 patients suramin has been given in a ﬁxed low dose (3.192 g/m2 ), intermediate

332 dose (5.320 g/m2 ), or high dose (7.661 g/m2 ) to determine whether its efﬁcacy and toxicity in the treatment of patients with hormonerefractory prostate cancer is dose-dependent (30c ). There was no clear dose-response relation for survival or progression-free survival, but toxicity increased especially with the higher dose. There were neurological adverse effects in 40% of the patients and cardiac adverse effects in 15%. This raises questions about the usefulness of suramin, particularly in high

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doses, in advanced prostate cancer. However, in another phase I study of suramin with once- or twice-monthly dosing in patients with advanced cancer, suramin was relatively safely administered without using plasma concentrations to guide dosing (31c ). Dose-limiting toxic effects included fatigue, neuropathy, anorexia, and renal toxicity. Diffuse colitis, erythema multiforme, and hemolytic anemia were reported as unusual effects.

REFERENCES 1. Nagy J, Schipper HG, Koopmans RP, Butter JJ, Van Boxtel CJ, Kager PA. Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability. Am J Trop Med Hyg 2002; 66: 260– 3. 2. Montresor A, Stoltzfus RJ, Albonico M, Tielsch JM, Rice AL, Chwaya HM, Savioli L. Is the exclusion of children under 24 months from anthelmintic treatment justiﬁable? Trans R Soc Trop Med Hyg 2002; 96: 197–9. 3. Ayles HM, Corbett EL, Taylor I, Cowie AGA, Bligh J, Walmsley K, Bryceson ADM. A combined medical and surgical approach to hydatid disease: 12 years’ experience at the Hospital for Tropical Diseases, London. Ann R Coll Surg Engl 2002; 84: 100–5. 4. Chai J, Menghebat A, Jiao W, Sun D, Liang B, Shi J, Fu C, Li X, Mao Y, Wang X, Dolikun A, Guliber A, Wang Y, Gao F, Xiao S. Clinical efﬁcacy of albendazole emulsion in treatment of 212 cases of liver cystic hydatidosis. Chin Med J 2002; 115: 1809–13. 5. Ammari FF, Omari AK. Surgery and postoperative mebendazole in the treatment of hydatid disease. Saudi Med J 2002; 23: 568-71. 6. Meshikhes AN. Surgery and postoperative mebendazole in the treatment of hydatid disease. Saudi Med J 2002; 23: 1425. 7. Tsague-Dongmo L, Kamgno J, Pion SDS, Moyou-Somo R, Boussinesq M. Effects of a 3-day regimen of albendazole (800 mg daily) on Loa loa microﬁlaraemia. Ann Trop Med Parasitol 2002; 96: 707–15. 8. Lanchote VL, Garcia FS, Dreossi SAC, Takayanagui OM. Pharmacokinetic interaction between albendazole sulfoxide enantiomers and antiepileptic drugs in patients with neurocysticercosis. Ther Drug Monit 2002; 24: 338–45. 9. Fallah M, Mirarab A, Jamalian F, Ghaderi A. Evaluation of two years of mass chemotherapy against ascariasis in Hamadan, Islamic Republic of Iran. Bull WHO 2002; 80: 399–402.

10. Ortiz JJ, Lopez Chegne N, Gargala G, Favennec L. Comparative clinical studies of nitazoxanide, albendazole and praziquantel in the treatment of ascariasis, trichuriasis and hymenolepiasis in children from Peru. Trans R Soc Trop Med Hyg 2002; 96: 193–6. 11. Zulu I, Veitch A, Sianongo S, McPhail G, Feakins R, Farthing MJG, Kelly P. Albendazole chemotherapy for AIDS-related diarrhoea in Zambia—clinical, parasitological and mucosal responses. Aliment Pharmacol Ther 2002; 16: 595– 601. 12. Inoue K, Inoue Y, Arai T, Nawa Y, Kashiwa Y, Yamamoto S, Sakatani M. Chronic eosinophilic pneumonia due to visceral larva migrans. Intern Med 2002; 41: 478–82. 13. Supali T, Ismid IS, Ruckert P, Fischer P. Treatment of Brugia timori and Wuchereria bancrofti infections in Indonesia using DEC or a combination of DEC and albendazole: adverse reactions and short-term effects on microﬁlariae. Trop Med Int Health 2002; 7: 894–901. 14. Shenoy RK, Suma TK, John A, Arun SR, Kumaraswami V, Fleckenstein LL, Na-Bangchang K. The pharmacokinetics, safety and tolerability of the co-administration of diethylcarbamazine and albendazole. Ann Trop Med Parasitol 2002; 96: 603–14. 15. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY-K, Lasseter KC. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol 2002; 42: 1122–33. 16. Keiser PB, Reynolds SM, Awadzi K, Ottesen EA, Taylor MJ, Nutman TB. Bacterial endosymbionts of Onchocerca volvulus in the pathogenesis of posttreatment reactions. J Infect Dis 2002; 185: 805–11. 17. Kennedy MH, Bertocchi I, Hopkins AD, Meredith SE. The effect of 5 years of annual treatment with ivermectin (Mectizan) on the prevalence and morbidity of onchocerciasis in the village of Gami in the Central African Republic. Ann Trop Med Parasitol 2002; 96: 297–307.

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18. Gardon J, Boussinesq M, Kamgno J, GardonWendel N, Ngangue D, Duke BOL. Effects of standard and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomised controlled trial. Lancet 2002; 360: 203–10. 19. Brooks PA, Grace RF. Ivermectin is better than benzyl benzoate for childhood scabies in developing countries. J Paediatr Child Health 2002; 38: 401–4. 20. Del Mar Saez-de-Ocariz M, Duran McKinster C, Orozco-Covarrubias L, Tamayo-Sanchez L, Ruiz-Maldonado R. Treatment of 18 children with scabies or cutaneous larva migrans using ivermectin. Clin Exp Dermatol 2002; 27: 264–7. 21. Zaha O, Hirata T, Kinjo F, Saito A, Fukuhara H. Efﬁcacy of ivermectin for chronic strongyloidiasis: two single doses given 2 weeks apart. J Infect Chemother 2002; 8: 94–8. 22. Lai W-H, Lu S-Y, Eng H-L. Levamisole aids in treatment of refractory oral candidiasis in two patients with thymoma associated with myasthenia gravis: report of two cases. Chang Gung Med J 2002; 25: 606–11. 23. Holt RCL, Webb NJA. Management of nephrotic syndrome in childhood. Curr Paediatr 2002; 12: 551–60. 24. Donia AF, Amer GM, Ahmed HA, Gazareen SH, Moustafa FE, Shoeib AA, Ismail AM, Khamis S, Sobh MA. Levamisole: adjunctive therapy in steroid dependent minimal change nephrotic children. Pediatr Nephrol 2002; 17: 355–8. 25. Tepper JE, O’Connell M, Niedzwiecki D, Hollis DR, Benson III AB, Cummings B, Gunderson

333 LL, Macdonald JS, Martenson JA, Mayer RJ. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control—ﬁnal report of Intergroup 0114. J Clin Oncol 2002; 20: 1744–50. 26. Stockis A, Allemon A-M, De Bruyn S, Gengler C. Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses. Int J Clin Pharmacol Ther 2002; 40: 213–20. 27. Stockis A, De Bruyn S, Gengler C, Rosillon D. Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d. Int J Clin Pharmacol Ther 2002; 40: 221–7. 28. Shroff R, Houston B. Unusual cerebellar ataxia: “worm wobble” revisited. Arch Dis Child 2002; 87: 333–4. 29. Nakamura-Uchiyama F, Mukae H, Nawa Y. Paragonimiasis: a Japanese perspective. Clin Chest Med 2002; 23: 409–20. 30. Small EJ, Halabi S, Ratain MJ, Rosner G, Stadler W, Palchak D, Marshall E, Rago R, Hars V, Wilding G, Petrylak D, Vogelzang NJ. Randomized study of three different doses of suramin administered with a ﬁxed dosing schedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukemia group B 9480. J Clin Oncol 2002; 20: 3369–75. 31. Ryan CW, Vokes EE, Vogelzang NJ, Janisch L, Kobayashi K, Ratain MJ. A phase I study of suramin with once- or twice-monthly dosing in patients with advanced cancer. Cancer Chemother Pharmacol 2002; 50: 1–5.

S. Dittmann

32 Surveillance of adverse events following immunization Adverse events reported to the Vaccine Adverse Event Reporting System (VAERS) during the period 1991–2001 have been summarized and evaluated (1R ). VAERS is a passive surveillance system, which was established in 1990 under the joint administration of the Centers for Disease Prevention and Control (CDC) and the Food and Drug Administration (FDA) to accept reports of suspected adverse events after the administration of any vaccine licensed in the USA. Like other passive surveillance systems that accept voluntarily submitted reports from caregivers, VAERS is subject to multiple limitations, such as under-reporting, reporting of temporal associations or unconﬁrmed diagnoses, lack of denominator data, and unbiased comparison groups. However, passive surveillance data can be used as a signal to initiate careful follow-up studies. The main results were as follows: • during 1991–2001, annual reports of deaths constituted 1.4–2.3% of all reports, and reports of life-threatening illness constituted 1.4–2.8% of all reports; • a clinical research team followed up all deaths reported to VAERS; most of these deaths were ultimately classiﬁed as sudden infant death syndrome (SIDS); analysis of the age distribution and seasonality of infant deaths reported to VAERS showed that they matched the age distribution and seasonality of SIDS: both peaked at 2–4 months and during the winter; the reduction in the number of deaths reported to VAERS since 1992–3 parallels the overall reduction in the incidence of SIDS in the US population since the © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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Vaccines implementation of the “back to sleep” campaign; the FDA and the Institute of Medicine reviewed 206 deaths reported to VAERS during 1990–1: only one death was believed to have resulted from a vaccine; • intussusception after rotavirus vaccine was described as an example to underline the value of passive surveillance systems as an indicator for carefully designed follow-up studies (intussusception was discussed at length in SEDA-23, p. 354); • an increase in the number of reports of Guillain–Barré syndrome after the receipt of inﬂuenza vaccine was noted in VAERS data by week 29 of the 1993–4 inﬂuenza season; the numbers of reports of Guillain–Barré syndrome increased from 23 during 1991– 2 to 40 during 1992–3 and to 80 during 1993–4; a study of the VAERS signal showed that slightly more than one additional case of Guillain–Barré syndrome occurred per 1 million people immunized against inﬂuenza, a risk that is less than the risk from severe inﬂuenza, which can be prevented by the vaccine; • a detailed review of VAERS reports received during the ﬁrst 3 years after the licensure of the varicella vaccine documented that the majority of reported adverse events were minor and serious adverse events were rare.

Multiple immunizations General risks of multiple immunizations Some parents, particularly in industrialized countries, believe that infants get more vaccines than are good for them, and they fear that too many immunizations could overwhelm the infant’s immune system. However, the actual number of antigens that children receive in the USA (the schedule includes 11 vaccines) or in some Western European countries (on aver-

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age 9 vaccines) has declined when compared with immunization programs used during the 1960s or 1980s. Whereas smallpox vaccine contained about 200 proteins, the current routinely recommended vaccines for children in countries in which whole-cell pertussis vaccine was replaced by acellular pertussis vaccine (e.g. Austria, Germany, Japan, the Scandinavian countries, the USA) contain a total of 50 to 125 proteins and polysaccharides. The replacement of whole cell pertussis vaccine by acellular pertussis vaccine reduced the content of immunogenic proteins and polysaccharides from about 3000 to 2–5 (Table 1) (2R ). If vaccines overwhelmed the immune system, smaller immune responses would be expected. However, the authors of many carefully designed studies have concluded that there is no evidence that adding vaccines to combination products increases the burden on the immune system. Young infants have a large capacity to respond to multiple vaccines, as well as to many other environmental challenges. Increased reactogenicity after the receipt of combination vaccines has not been a major issue. Combining antigens usually does not increase the risk of adverse effects, and can actually lead to an overall reduction in the numbers of adverse events (3R , 4R ). The Safety Review Committee of the Institute of Medicine (IOM) has reviewed the evidence regarding multiple immunizations and immune dysfunction (5M ). The review did not support

the hypothesis that an infant’s immune system is inherently incapable of handling the number of antigens to which children in the USA are exposed during routine immunizations. The committee rejected a causal relation between multiple immunizations and increased risks of infections or type 1 diabetes mellitus. The evidence was inadequate to accept or reject a causal relation between multiple immunizations and allergic disease, particularly asthma. Sudden infant death syndrome (SIDS) and multiple immunizations Current recommendations call for infants and very young children to receive multiple doses of vaccines during their ﬁrst year of life, and since sudden infant death syndrome (SIDS) is the most frequent cause of death in highly developed countries during that early period of life, it is important to take into account concerns that multiple immunization might play a role in SIDS. SIDS is the diagnosis most commonly used to explain unexpected sudden death of uncertain cause occurring mainly in infancy at 2–7 months of life, sometimes later. By deﬁnition, the cause or causes of SIDS are unknown, but risk factors (e.g. maternal characteristics, prenatal factors, and postnatal conditions, including the infant’s sleeping position) have been identiﬁed. Recently, the results of the most comprehensive analysis “Vaccinations and sudden unexpected death in infancy” have been provided by the Immunization Safety Review Committee of the

Table 1. Number of immunogenic pathogens/polysaccharides in vaccines over the past 100 years (adapted from (2R ))

Vaccine

1900 Proteins

1960s Vaccine

1980s Proteins

Vaccine

Proteins

Smallpox

∼200

Smallpox ∼200 Diphtheria 1 Tetanus 1 WC-pertussiis∗ ∼3000 Poliomyelitis 15

Diphtheria 1 Tetanus 1 WC-pertussis∗ ∼3000 Poliomyelitis 15 Measles 10 Mumps 9 Rubella 5

total

∼200

total

∼3200

∼3040

Vaccine

2000 Proteins/ Polysaccharides

Diphtheria Tetanus AC-pertussis∗ Poliomyelitis Measles Mumps Rubella H. inﬂuenzae Hepatitis B total Germany Varicella Pneumococcus∗∗ total US

∗ WC-pertussis: whole-cell pertussis vaccine; AC-pertussis: acellular pertussis vaccine. ∗∗ Pneumococcus: conjugated pneumococcal vaccine.

1 1 2–5 15 10 9 5 2 1 46–49 69 8 123–126

336 Institute of Medicine (IOM) (6M ). The committee reviewed an extensive collection of material, primarily from published peer-reviewed scientiﬁc and medical literature. The causality conclusions of the committee were as follows: • the evidence favors rejection of a causal relation between exposure to multiple vaccines and SIDS; • the evidence favors acceptance of a causal relation between diphtheria toxoid and whole cell pertussis vaccine and death due to anaphylaxis in infants; however, anaphylaxis of infants following vaccination is very rare, and a fatal outcome is extremely rare; • the committee has not recommended a policy review of the recommended (US) childhood immunization schedule on the basis of concerns about SIDS. The committee also noted that there are studies that show that vaccinated infants are at a reduced risk of SIDS (6M , 7C ).

Immunization and autoimmune disease Autoimmunity is characterized by the development of one or several immune responses, directed against antigenic components of the host. The detection of antibodies against host antigens (autoantibodies) or autoreactive T cells does not indicate current or future disease, and autoimmunity does not always result in autoimmune disease. An autoimmune disease results from autoimmunity when autoantibodies or autoreactive T cells reach the corresponding antigen in a target organ and become pathogenic, or when autoantibodies form pathogenic immune complexes with antigens released from host cells. An autoimmune disease can be clinically silent for months or years before the destruction of the tissues involved leads to clinical symptoms, e.g. the appearance of type 1 diabetes following the autoimmune destruction of pancreatic islets. As many as 5% of individuals in Europe and North America have some form of autoimmune disease. There is clear evidence that genetic predisposition is necessary for the development of some autoimmune diseases. In

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genetically predisposed individuals an infection can induce or trigger an autoimmune disease. Of the many potential environmental factors, infections are the most likely cause. The causal linkage between some infections and autoimmune diseases has raised the question as to whether autoimmune diseases might also be triggered by vaccines (8M ). Autoimmune diseases include autoimmune thrombocytopenia, Graves’ disease, hemolytic anemia, Hashimoto’s thyroiditis, insulin-dependent diabetes mellitus (diabetes type 1), multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus; dermatomyositis, and Reiter’s syndrome (8M , 9R , 10R ). The number of publications that include claims and counterclaims about the risk of autoimmune diseases after immunization is increasing. However, only in rare instances has evidence established a causal relation or favored acceptance of a causal relation: • rabies vaccine produced in rabbit CNS tissue caused acute disseminated encephalomyelitis in some immunized individuals (11C ); • during the US swine ﬂu immunization campaign (1976–7) immunized individuals had a much higher risk of Guillain–Barré syndrome than non-immunized individuals (relative risk 7.60); currently, the risk of Guillain– Barré syndrome after immunization (one additional case per million people immunized) is estimated to be substantially lower than the risk of severe inﬂuenza and its complications (12R ); • idiopathic thrombocytopenia can occur after measles–mumps–rubella immunization (about one case in 30 000 immunized children); however, the risks of thrombocytopenia after natural measles or rubella are respectively 5 and 10 times higher (8R , 13R ). For other potential association between vaccines and autoimmune diseases, the evidence favors rejection of a causal relation: • hepatitis B vaccine and multiple sclerosis (SEDA-24, 374; SEDA-25, 386; and see below); • vaccines and diabetes mellitus (14R , 15R ); • Lyme disease vaccine and a treatment-resistant form of autoimmune arthritis; however, owing to public misperception and

Vaccines

the promotion of false concerns about its safety, the demand for Lyme disease vaccine did not reach a sustainable level and the manufacturer withdrew it (SEDA-24, 366; SEDA-26, 357). How to assess a potential link between a vaccine and an autoimmune condition Careful epidemiological studies should be the basis of conclusions about an association between a speciﬁc vaccine and a particular autoimmune disease. Recently, Wraith and colleagues took into account WHO recommendations for the assessment of adverse events after immunization and established the following four basic principles that apply to autoimmune diseases: • • • •

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consistency of ﬁndings in various studies; strength (in an epidemiological sense); speciﬁcity; temporal relation (8R ).

Immunization and multiple sclerosis Studies of the role of inﬂuenza or inﬂuenza immunization in multiple sclerosis have been reviewed by Jeffery (16R ). He considers that in patients with multiple sclerosis and advanced disability inﬂuenza can constitute a life-threatening illness. Even in patients who have minimal disability, severe inﬂuenza can be followed by secondary bacterial infection. The risk of relapse after inﬂuenza may be as high as 33%, whereas the risk of relapse after inﬂuenza immunization appears to be negligible. The only exception to the general rule that inﬂuenza immunization is beneﬁcial for patients with multiple sclerosis is in patients with rapidly evolving neurological deﬁcits due to active disease, in whom immunization should be withheld pending treatment with high-dose corticosteroids to suppress inﬂammation or stabilization through immunomodulatory treatment. In the absence of active disease, Jeffery strongly recommends inﬂuenza immunization for patients with multiple sclerosis. Regarding hepatitis B immunization and multiple sclerosis, Jeffery recommends hepatitis B immunization only for patients with multiple sclerosis at high risk of hepatitis B infection. If a high-risk patient has active multiple sclerosis, immunization should be withheld until the disease activity has been adequately treated. With regard to other immunizations,

Jeffery has made similar recommendations: immunization should be postponed if a patient with multiple sclerosis shows disease activity.

BACTERIAL VACCINES Bacille Calmette-Guérin (BCG) vaccine (SED-14, 1056; SEDA-25, 380; SEDA-26, 355) Infection risk The Global Advisory Committee on Vaccine Safety has noted that there has been repeated reference to local or disseminated BCG infection several years after BCG immunization in HIV-infected persons (17S ). However, the committee has not recommended a change in immunization policy (BCG immunization recommended in asymptomatic HIV-infected persons; not recommended in symptomatic HIV-infected persons), but surveillance for BCG-immunized HIV-infected persons should be continued for 5–7 years.

Meningococcal vaccine (SED-14, 1080; SEDA-24, 368; SEDA-25, 389) Worldwide, the most important serogroups of Neisseria meningitidis that cause meningococcal disease are serogroups A, B, C, W135 , and Y. For many years, combination polysaccharide vaccines against Neisseria meningitidis serogroups A, C, W135 , and Y have been commercially available. Since 1999, conjugated meningococcal vaccines of serogroup C have been licensed and commercially available. Different from meningococcal polysaccharide vaccines, they are also immunogenic in infants and young children. Universal immunization programs for infants, children, and adolescents in the UK and the Netherlands have shown excellent effectiveness. Except for local and systemic adverse effects, no severe adverse events have hitherto been reported. Considering the serogroup distribution mentioned above, conjugated vaccines covering the other serogroups are urgently needed. The development of a meningococcal serogroup B vaccine (either as

338 a polysaccharide or conjugated vaccine) is difﬁcult and will take some years. Clinical trials of combination meningococcal conjugate vaccines continue. The results of a phase 1 study in 30 children aged 12– 23 months, who received two doses of tetravalent A-C-W135 -Y conjugated meningococcal vaccines (conjugated to diphtheria toxoid), have been reported (18C ). Three different doses were used: 1, 4, and 10 μg/ml polysaccharide of each serogroup. The 4 μg/ml dose appeared to be immunologically optimal. No children had a temperature of over 39.9◦ C. Local reactions were reported in 40–60% of children after each injection, with no apparent relation to dose. None of these local reactions was severe. The investigators considered the results as being sufﬁciently promising for further evaluation of this vaccine in a larger trial in toddlers and infants. Urinary tract Recently, the possible risk of relapse of nephrotic syndrome after administration of meningococcal serogroup C conjugate vaccine to children has been discussed (19C ). In 106 children with nephrotic syndrome, there were 63 relapses during the 12-month period before immunization and 96 relapses during the equivalent 12-month period after meningococcal immunization. The increase was statistically signiﬁcant and the risk was especially higher in the ﬁrst 6 months after immunization. Regarding the possible pathogenesis of the increased rate of relapses the authors discussed the hypothesis that disturbance of cytokines by the conjugated vaccine might mediate the onset of proteinuria. This is the ﬁrst report of possible serious advesre effects of conjugated meningococcal immunization; further studies are needed before a real risk can be conﬁrmed.

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genital cancer. Various HPV vaccines are currently under development or undergoing clinical trials. In a double-blind study in 2392 young women (aged 16–23 years) randomly assigned to either three doses of placebo or HPV-16 vaccine at day 0, month 2, and month 6, the vaccine reduced the incidence of both HPV-16 infection (3.8 per 100 women-years at risk in the placebo group versus 0 per 100 women-years at risk in the vaccine group) and HPV-16-related cervical intraepithelial neoplasia (all nine cases of neoplasia occurred among the placebo recipients) (20C ).

Mumps vaccine

(SED-14, 1080; SEDA-21, 336; SEDA-22, 352) Nervous system The Global Advisory Committee on Vaccine Safety has considered a comprehensive review of the world literature on the safety of mumps immunization, with special attention to vaccine-associated meningitis. They found no cases of virologically proven aseptic meningitis after mumps immunization based on the Jeryl Lynn vaccine strain. If mumps vaccines based on vaccine strains such as Urabe Am9, Leningrad-3, or Leningrad–Zagreb are being used in mass immunization campaigns, the committee recommends that the potential for clustering of aseptic meningitis cases after the campaign should be taken into consideration. The available data are insufﬁcient to distinguish between the safety proﬁles of the Urabe Am9, Leningrad-3, and Leningrad– Zagreb strains with regard to vaccine-associated meningitis (17S ).

Rotavirus vaccine (SED-14, 1091; SEDA-24, 379; SEDA-25, 390; SEDA-26, 360) VIRAL VACCINES Human papilloma virus vaccine (SEDA-26, 358) A vaccine that reduces the incidence of infection caused by human papilloma virus type 16 (HPV-16) may provide important health beneﬁts, because some HPV infections progress to

The safety and immunogenicity of two human– bovine reassortant rotavirus candidate vaccines have been evaluated in infants, children, and adults (21C ). One candidate vaccine contained a single human rotavirus gene, while the other candidate vaccine contained two human rotavirus genes. The remaining genes for both vaccines were derived from bovine rotavirus strain UK. Each of these vaccines was well

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tolerated and immunogenic. This was also the case in the important group of infants under 6 months of age after a single dose of vaccine. Gastrointestinal Based on the results of an expedited review of scientiﬁc data that suggested a strong association between Rotashield (a tetravalent rhesus-based rotavirus vaccine) and intussusception (SEDA-23, 354), the US licensing authorities, along with the manufacturer, recommended in October 1999 that Rotashield should no longer be used. However, various research groups and manufacturers continue to develop different rotavirus vaccines. Rotavirus is the single most important cause of dehydrating diarrhea in infants and young children worldwide.

Smallpox vaccination

(SEDA-25, 378;

SEDA-26, 354) Recently, the threat of bioterrorism has made it necessary to consider again prevention and control strategies through vaccination and the potential hazards associated with the administration of smallpox vaccine. Guidelines for prevention and control of smallpox have been elaborated in many countries. The guidelines distinguish between pre-event vaccination programs (worldwide no re-emergence of smallpox) and post-event vaccination programs (reemergence of smallpox conﬁrmed). Taking into account the risk of smallpox vaccine, most countries have elaborated plans for post-event vaccination programs. During the US preevent vaccination program, in 1 per 20 000 members of the military who received primary smallpox vaccination, cardiac inﬂammation (myocarditis and/or pericarditis), including one death (myocardial infarction), has been reported. Compared with the rate reported in an unvaccinated military population during 1998–2000, the rate of myo/pericarditis was substantially increased. There were no cases after revaccination. In 2003, among 38 257 civilian health-care and public health workers vaccinated against smallpox, 17 suspected and ﬁve probable cases of myo/pericarditis were reported. The other adverse events include one

case of suspected encephalitis, three of generalized vaccinia, three of ocular vaccinia, and 21 of inadvertent inoculation. • A 57-year-old woman with a history of hypertension, a transient ischemic attack, and carotid endarterectomy died 22 days after smallpox vaccination. Histopathologic evaluation showed no evidence of heart inﬂammation.

All case reports of myo/pericarditis have been carefully evaluated. It was concluded that the data are consistent with a causal relation between myo/pericarditis and smallpox vaccination; however, no causal association between ischemic cardiac events and smallpox has been identiﬁed (22R , 23R ). Considering the adverse effects of cardiac inﬂammation, the Advisory Committee on Immunization Practices (ACIP) has recommended that people who have underlying heart disease, with or without symptoms, or who have three or more known major cardiac risk factors (i.e. hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years in a ﬁrst-degree relative, and smoking) should be excluded from the pre-event smallpox vaccination program (24S ). During the period of routine smallpox vaccination, only rare reports of cardiac inﬂammation (pericarditis, fatal myocarditis, and electrocardiographic evidence of myocarditis) have been published in the world literature (SED8, 709). To determine the risk of cardiac death after smallpox vaccination, death certiﬁcates from a period in 1947 when 6 million New York City residents were vaccinated after a smallpox outbreak were analysed; the incidence of cardiac deaths did not increase after the vaccination campaign (25R ). During the US pre-event smallpox vaccination program, there were no reports of eczema vaccinatum, progressive vaccinia, or fetal vaccinia (22R , 23R ). During a meeting in June 2003, the Global Advisory Committee on Vaccine Safety considered two expert reports on the safety of smallpox vaccine in detail. They concluded that there is a real risk of serious adverse events after smallpox vaccination, including safety issues that have not previously been recognized. Therefore, if the vaccine is being used in mass campaigns, it would be very important to include adverse events monitoring. The committee found that the available data were insufﬁcient to deﬁne the risk after primary vaccination

340 compared with the risk of revaccination after a long interval (17S ). Accidental needlestick inoculation with vaccinia virus has been reported (26A ). • A 26-year-old laboratory worker, who had been vaccinated against smallpox in childhood, developed a pustule and erythema on his left thumb 3 days after an accidental needlestick while working with vaccinia virus. Further pustules occurred on the fourth and ﬁfth ﬁngers of the same hand, accompanied by a large erythematous lesion on the left forearm, secondary bacterial infection, and axillary lymphadenopathy. After surgical excision of the necrotic tissue, he improved slowly and the lesions healed in about 3 weeks.

For a full account of the complications that can follow smallpox immunization, see previous editions (SED-8, 709; SED-11, 685); for additional reports see the Annuals (SEDA-1, 247;

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SEDA-3, 262; SEDA-4, 227; SEDA-6, 289; SEDA-13, 289; SEDA-15, 357).

Tickborne encephalitis vaccine (SED-14, 1095; SEDA-24, 380) Nervous system During the period 1987– 2000, the Swiss Center for Adverse Events Drug Monitoring (Schweizerische Arzneimittel–Nebenwirkungszentrale) received 33 reports, including 39 neurological adverse events, following the receipt of tickborne encephalitis vaccine: headache (36% of reports), neuropathy (18%), and meningeal signs (13%); 12 of 33 patients were hospitalized and all recovered (27R ).

REFERENCES 1. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)— United States, 1991–2001. MMWR Morbid Mortal Wkly Rep 2003; 52: 1–24. No SS-1. 2. Ofﬁt PA, Quarles J, Gerber MA, Hackett ChJ, Marcuse EK, Kollman TR, Gellin BG, Landry S. Addressing parents’ concerns: do multiple vaccines overwhelm or weaken the infant’s immune system? Pediatrics 2002; 109: 124–9. 3. Dittmann S. Vaccines. In: Dukes MNG, Aronson JK, editors. Meylers Side Effects of Drugs. Amsterdam: Elsevier, 2000: 1047–110. 4. Halsey NA. Safety of combination vaccines: perception versus reality. Pediatr Infect Dis J 2001; 20 Suppl 1: S40–4. 5. Institute of Medicine (IOM) Report. Immunizations Safety Review. Multiple immunizations and immune dysfunction. http://www.cdc.gov/nip// vacsafe/concerns/gen/multiplevac_iom.htm (accessed Oct 28, 2002). 6. Institute of Medicine (IOM) Report. Immunizations Safety Review. Vaccinations and sudden unexpected death in infancy. The National Academies Press, 2003. http://www.nap.edu/nap-cgi (accessed June 20, 2003). 7. Fleming PJ, Blair PS, Platt MW, Tripp J, Smith IJ, Golding J. The UK accelerated immunization programme and sudden unexpected death in infancy: case-control study. Br Med J 2001; 322: 822–5. 8. Wraith DC, Goldman M, Lambert P-H. Vaccination and autoimmune disease: what is the evidence? http://image.thelancet.com/extras/02art9340web. pdf.

9. Ofﬁt PA, Hackett CJ. Addressing parents’ concerns: do vaccines cause allergic or autoimmune diseases. Pediatrics 2003; 111: 653–9. 10. Shoenfeld Y, Aron-Maor A. Vaccination and autoimmunity—“Vaccinosis”: a dangerous liaison? J Autoimmun 2000; 14: 1–10. 11. Stuart G, Krikorian KS. The neuroparalytic accidents of anti-rabies treatment. Ann Trop Med Parasitol 1928; 22: 327–77. 12. Kilbourne ED, Arden NH. Inactivated inﬂuenza vaccines. In: Plotkin SA, Orenstein WA, editors. Vaccines. 3rd edition. Philadelphia: Saunders, 1999: 542. 13. Miller E, Waight P, Farrington P, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine. Arch Dis Child 2001; 84: 221–9. 14. CDC. National Immunization program. Diabetes and vaccines. Questions and answers. http:// www.cdc.gov/nip/vacsafe/concerns/diabetes/q&a. htm (accessed October 5, 2003). 15. World Health Organization. Vaccines and Biologicals. Diabetes. htpp://www.who.int/vaccinesdiseases/safety/infobank/diabetes/shtml (accessed November 29, 2003). 16. Jeffery DR. The use of vaccinations in patients with multiple sclerosis. Infect Med 2002; 19: 73–9. 17. Global Advisory Committee on Vaccine Safety, 11–12 June, 2003. Wkly Epidemiol Rec 2003; 78: 282–3. 18. Rennels M, King J, Ryall R, Manoff S, Papa T, Weddle A, Froeschle J. Dose escalation, safety and immunogenicity study of a tetravalent meningococcal polysaccharide diphtheria conjugate vaccine in toddlers. Pediatr Infect Dis J 2002; 21: 978–9.

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19. Abeyagunawardena AS, Goldblatt D, Andrews N, Trompeter RS. Risk of relapse after meningococcal conjugate vaccine in nephritic syndrome. Lancet 2003; 362: 449–50. 20. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM, Jansen KU. A controlled trial of a human papillomavirus Type 16 vaccine. New Engl J Med 2002; 347: 1645–51. 21. Eichelberger MC, Sperber E, Wagner M, Hoshino Y, Dudas R, Hodgins V, Marron J, Nehring P. Casey R, Burns B, Karron R, Clements-Mann ML, Kapikian AZ. Clinical evaluation of a single oral dose of human bovine (UK) reassortant rotavirus vaccines Wa x UK (P1A[8]G6) and Wa x (DS-1 x UK) (P1A[8],G2). J Med Virol 2002; 66: 407–16. 22. Update: Adverse events following smallpox vaccination—United States 2003. MMWR Morbid Mortal Wkly Rep 2003; 52: 819–20. 23. Update: Adverse events following smallpox vaccination—United States 2003. MMWR Morbid Mortal Wkly Rep 2003; 52: 278–82.

341 24. Supplemental recommendations on adverse events following smallpox vaccine in the preevent vaccination program. Recommendations of the Advisory Committee on Immunization Practices. MMWR Morbid Mortal Wkly Rep 2003; 52: 282–4. 25. Cardiac deaths after a mass smallpox vaccination campaign—New York City, 1947. MMWR Morbid Mortal Wkly Rep 2003; 52: 933–6. 26. Moussatché N, Tuyama M, Kato SEM, Castro APV, Njaine B, Peralta RH, Peralta JM, Damaso CRS, Barroso PF. Accidental infection of laboratory worker with vaccinia virus. Emerg Infect Dis 2003; 9: 724-6. 27. Koller Doser A, Hartmann K, Fleisch F, Kuhn M. Vermutete neurologische Nebenwirkungen der FSME–Impfung: Erfahrung Schweizerischen Arzneimittel–Nebenwirkungs–Zentrale (SANZ). Praxis 2002; 91: 159–62.

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Blood, blood components, plasma, and plasma products

ALBUMIN Immunologic A meta-analysis of 193 albumin-treated women versus 185 controls showed a signiﬁcant reduction of severe ovarian hyperstimulation syndrome after administration of human albumin; two cases of urticaria and one case of an anaphylactic reaction were reported (1M ). Death A Cochrane meta-analysis of human albumin, published in 1998, suggested that infusion of human albumin might cause increased mortality in patients with hypovolemia, burns, and hypoalbuminemia (SEDA-23, 359). The validity of these ﬁndings has been questioned, because some papers chosen for meta-analysis were suggested to have been incorrectly included (2r , 3R ). The results obtained by the Cochrane meta-analysis have also been challenged by a recent meta-analysis of albumin administration in critically ill patients, which showed no increased risk in mortality (4M ). This illustrates the need for high-quality randomized controlled trials to generate deﬁnitive evidence.

Cardiovascular In a phase III trial using drotrecogin alpha, hypertension (2.6% versus 0.6% with placebo) was one of the most frequent adverse events (5R ). Nervous system In a phase III trial hallucinations occurred in 1.1% of patients treated with drotrecogin alpha versus 0.1% in the placebo group (5R ). Hematologic As can be expected, the predominant adverse effect of activated protein C is bleeding. In a phase III trial, in which 1690 patients with severe sepsis were treated with drotrecogin alpha or placebo, serious bleeding episodes occurred in 3.5% of patients treated with drotrecogin alpha, compared with 2.0% of those treated with placebo (6R , 7R , 8r ). It has been suggested that the risk of bleeding can be minimized by withholding drotrecogin alpha immediately after major surgery; when surgery must be performed during the treatment period, drotrecogin alpha should be temporarily withdrawn (9R , 10R ).

ANTICOAGULANT PROTEINS

Immunologic In two of 370 patients treated with drotrecogin alpha during a phase III trial, antibodies to activated protein C were found, but these were not inhibitory; no cases of neutralizing antibodies have been found (6R ).

The protein C pathway serves as a natural defence mechanism against thrombosis. Patients with severe sepsis have a very low concentration of activated protein C compared with healthy individuals. Recombinant human activated protein C (drotrecogin alpha) markedly lowers mortality in patients with severe sepsis.

Infection risk Because activated drotrecogin alpha reduces inﬂammation, it is theoretically possible that there is an increased risk of infection. However, a phase III trial did not show an increased rate of infection in the drotrecogin alpha-treated patients compared with placebo (5R ).

© 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Drug interactions Contraindications to drotrecogin alpha are conditions with an increased risk of bleeding. Drotrecogin alpha should

342

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therefore be used with care in patients using heparin, thrombolytic drugs, oral anticoagulants, glycoprotein IIb–IIIa inhibitors, and aspirin or other antiplatelet drugs (5R ).

BLOOD SUBSTITUTES Two types of oxygen-carrying blood substitutes are under development—hemoglobin-based oxygen carriers and perﬂuorocarbon emulsions. The advantages of such agents, which could eventually replace red cell concentrates, are longer storage times, no need for cross-typing, lower risks of pathogen transmission, and lower costs.

Hemoglobin-based oxygen carriers Of various hemoglobin-based oxygen carriers under development, two (Polyheme® and Hemopure® ) have been tested in phase III studies. One product, Hemopure, polymerized hemoglobin of bovine origin, has been licensed for human use in South Africa. The tetrameric hemoglobin easily dissociates in vivo into dimers and monomers that are quickly eliminated by the kidneys. As the administration of tetrameric hemoglobin is associated with renal insufﬁciency, intermolecular crosslinking of hemoglobin has been performed using different agents to polymerize hemoglobin. Newly developed hemoglobin-based oxygen carriers are conjugated hemoglobin or packed hemoglobin in nanocapsules or lipid vesicles (11R –14R ). Cardiovascular It has been suggested that cell-free hemoglobin, particularly low molecular weight hemoglobin, such as tetrameric hemoglobin, has the ability to come more closely to the endothelial cell lining of blood vessels than red cells and to extravasate into the subendothelial space. There, hemoglobin might scavenge nitrous oxide and so induce vasoconstriction and hypertension (11R , 13R , 15R ). A randomized controlled phase II study has suggested that hemoglobin rafﬁmer (Hemolink® ) is safe and effective in patients undergoing coronary artery bypass surgery. The

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incidence of hypertension was higher in the treated group, but blood pressure management prevented serious hypertension-related events (16C ). Hematologic Administration of red blood cells can cause neutrophil priming, which leads to a dysfunctional inﬂammatory response. This neutrophil priming, which has been associated with the occurrence of multiple organ failure after trauma, was not observed after administration of Polyheme® , a glutaraldehyde-crosslinked hemoglobin product (11R ). Gastrointestinal Occasionally, gastrointestinal disorders have been related to the use of hemoglobin-based oxygen carriers, possibly through binding of nitrous oxide, causing gastrointestinal smooth muscle spasm (15R , 17r ). Liver In a single-blind, randomized study, four of 55 surgical patients who were treated with Hemopure® developed jaundice without an increase in serum bilirubin (18c ). Similarly, in a double-blind, randomized study of 98 patients undergoing cardiac surgery, Hemopure® was related to some cases of jaundice (19C ). Skin In a single-blind, randomized study, two of 55 surgical patients who were treated with Hemopure® had ecchymotic rashes (18c ).

Perﬂuorocarbons Perﬂuorocarbons are synthetic ﬂuorinated hydrocarbons that increase the amount of oxygen dissolved in the ﬂuid phase of the blood. Oxygent® is a perﬂubron-based emulsion with lecithin as an emulsiﬁer, which eliminates the adverse effect of complement activation observed in earlier studies (13R ). Flu-like symptoms can occur during infusion of perﬂuorocarbons (15R ). In a phase II study in 25 patients undergoing cardiac surgery another perﬂubron emulsion (AF0144) was well tolerated (20c ).

BLOOD TRANSFUSION Misidentiﬁcation errors in blood transfusion remain an important cause of death and injury (21R ).

344 Respiratory Transfusion-related acute lung injury includes symptoms such as dyspnea, hypoxemia, hypotension, bilateral pulmonary edema, and fever within a few hours after transfusion (22C ). These symptoms can vary from mild to severe and they lead to death in 5–10% of cases. Transfusion-related acute lung injury has been associated with the presence of granulocyte antibodies, HLA antibodies, or biologically active lipids in the plasma. These agents activate granulocytes and endothelial cells and cause release of inﬂammatory mediators, which cause increased vascular permeability, fever, and hypotension (22C ). HLA class II antibodies can provoke transfusion-related acute lung injury, as observed in a 19-year-old woman, who developed transfusion-related acute lung injury after treatment with fresh-frozen plasma (23r ). Probably, monocytes are then involved in the pathogenesis of the acute lung injury (24A ). Most of the fatal cases of transfusion-related acute lung injury have involved transfusions of fresh frozen plasma; whole blood, packed red cells, cryoprecipitate, platelet concentrates, apheresis platelets, and occasionally intravenous immunoglobulin have also been implicated. The donors most often involved in fatal injury have been multiparous women who were antihuman lymphocyte antigen-positive or antigranulocyte antibody-positive; one or both of these antibody types have been found in 89% of reported cases. The factors that predispose to transfusion-related acute lung injury include surgery, active infection, massive transfusion, and cytokine therapy, which activates pulmonary endothelium and primes the patient’s leukocytes. It has been hypothesized that transfusion-related acute lung injury results from a combination of two independent insults, the patient’s clinical state and the presence of antileukocyte antibodies. The FDA has issued a Dear Colleague letter, outlining the risk of transfusion-related acute lung injury with the use of blood products, particularly those that contain plasma (25A ). The agency has noted that since the ﬁrst report of fatal transfusion-related acute lung injury in 1992, 45 more reports have been received by the Center for Biologics Evaluation and Research. Transfusion-related acute lung injury is now believed to be the third commonest cause of infusion-related deaths. The number of

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non-fatal cases of transfusion-related acute lung injury associated with blood products is also on the increase, but this may be due to better recognition and reporting. A patient with acute myeloid leukemia developed pulmonary alveolar proteinosis during the period of leukopenia following an unrelated umbilical cord blood transplantation (26A ). Infection risk The emergence of variant Creutzfeldt–Jakob disease (vCJD) in the UK and France has raised concern about a new “theoretical” risk of infection in patients treated with blood and blood products (27C ). Although there is still no human report of variant Creutzfeldt–Jakob disease from transmission of prions by blood transfusion, animal experiments in which blood from sheep infected with bovine spongiform encephalopathy and natural scrapie-infected sheep into scrapiefree recipient animals have suggested disease transmission by the blood transfusion route in two of 24 sheep with bovine spongiform encephalopathy and in four of 21 sheep with scrapie (28E ). Many European countries have incorporated leukodepletion of all blood products, as leukocytes are believed to play a key role in the pathogenesis of variant Creutzfeldt– Jakob disease (27R ). In some countries, people who have lived in the UK for a period longer than 6 months between 1980 and 1996 are excluded from blood donation (29R ). Furthermore, it has been shown that various steps used in the manufacture of plasma-derived products also contribute to reduced infectivity by bovine spongiform encephalopathy (27R ). A Georgia woman who died after an automobile crash was given multiple blood transfusions before she died (30A ). Blood samples taken at arrival in the emergency department were negative for West Nile virus, while blood samples that were taken after she had received several transfusions were positive. This ﬁnding raised concerns about transmission of West Nile virus via blood. One out of ﬁve people infected with West Nile virus will develop a mild febrile illness, lasting 3–6 days; one out of 150 people will develop meningitis or encephalitis. The West Nile virus circulates in the blood of an infected person for only a few days or weeks. Therefore, the risk of transmission of West Nile virus from transfusion of blood components is low (31C ).

Blood, blood components, plasma, and plasma products

INTRAVENOUS IMMUNOGLOBULINS Intravenous immunoglobulin has been effective and safe in patients with primary and secondary immunodeﬁciencies, as well as a number of autoimmune diseases, such as idiopathic thrombocytopenic purpura. It has also been used successfully in different neurological diseases, such as Guillain–Barré syndrome, Kawasaki disease, chronic inﬂammatory demyelinating polyneuropathy, multifocal neuropathy, multiple sclerosis, and myasthenia gravis. Intravenous immunoglobulin, especially products with a relatively high IgM content, can be used to avoid graft–versus–host disease in the case of hemopoietic stem cell transplantation. Common adverse reactions include headache, backache, nausea, vomiting, diarrhea, ﬂushing, fever, chills, shaking, shortness of breath, tightness in the chest, changes in blood pressure, and rashes (32R ). These adverse events, which start at 30–60 minutes after the start of infusion, are usually transient, and can usually be avoided by reducing the infusion rate. Sometimes patients require antihistamines or antipyretic drugs as prophylaxis before starting treatment with intravenous immunoglobulin. Intravenous immunoglobulin can cause malaise and fever in patients with infections, probably through a temporarily increased titer of antibodies against different pathogenic microorganisms (33R ). The current high dosage of 0.8–1.0 g/kg intravenous immunoglobulin for 1–2 days (instead of the original dosage regimen of 0.4 g/kg for 5 days) for patients with idiopathic thrombocytopenic purpura is probably associated with an increased risk of adverse effects (34R ). Cardiovascular Several cases of thrombosis have been reported after administration of intravenous immunoglobulin (32R ). Platelet activation and increased plasma viscosity have been implicated in these thrombotic events. • A 75-year-old man with idiopathic thrombocytopenia purpura who was treated with intravenous immunoglobulin developed recurrent myocardial ischemia (35A ). • A 54-year-old woman with idiopathic thrombocytopenic purpura received intravenous immunoglobulin 1 g/kg/day for 2 days and had an ischemic stroke with hemiparesis; 3 days later she had a deep vein thrombosis (36A ).

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• A 33-year-old woman with Evan’s syndrome received intravenous immunoglobulin 400 mg/kg/ day and developed a deep vein thrombosis after 1 week (36A ). She was treated with warfarin, and 6 months later received an additional course of intravenous immunoglobulin for recurrent hemolytic anemia; 1 day later she died of pulmonary thromboembolism. • A 70-year-old woman with polycythemia vera and Guillain–Barré syndrome, but no known risk factors for thrombosis, had a cerebral infarction 10 days after receiving intravenous immunoglobulin; the authors wondered whether there was a relation to the polycythemia vera (37A ).

In a randomized controlled study in 56 patients with untreated autoimmune thrombocytopenic purpura, who were treated with intravenous immunoglobulin 0.7 g/kg/day for 3 days, one had a deep vein thrombosis complicated by pulmonary embolism (38C ). One of 10 children with toxic epidermal necrolysis, for which they were given intravenous immunoglobulin 0.5 g/kg/day, developed a deep vein thrombosis requiring heparin (39A ). Only this of the 10 children received intravenous immunoglobulin for 7 days instead of the standard 4-day course. Nervous system Patients with a history of migraine seem to be at higher risk of aseptic meningitis, which occurs rarely after intravenous immunoglobulin administration. The mechanism is unknown, but it is suggested that the release of histamine, serotonin, and prostaglandins affects the meningeal microvasculature (32R ). Two children with idiopathic thrombocytopenic purpura developed aseptic meningitis after receiving intravenous immunoglobulin 1 g/kg/day, with unusual large numbers of leukocytes in the cerebrospinal ﬂuid (40A ). Severe headache has also been reported in children with idiopathic thrombocytopenic purpura using intravenous immunoglobulins (34R ). In a randomized, controlled study of patients with myasthenia gravis, two of six patients who received intravenous immunoglobulin developed severe headache after the initial dose of 2 g/kg (41c ). In 14 patients with primary immunodeﬁciency disease progressive neurodegeneration occurred and a possible relation to immunoglobulin therapy could not be ruled out (42c ).

346 Hematologic Both leukopenia and neutropenia have been reported after treatment with intravenous immunoglobulin (32R ). Urinary tract Acute renal insufﬁciency, a rare complication of immunoglobulin therapy, occurs mostly in patients who have received an intravenous immunoglobulin product containing sucrose as a stabilizing agent. The suggested mechanism is extensive vacuolization of the proximal tubules, due to osmosis by sucrose exposure. Therefore, sucrose-containing intravenous immunoglobulin products should be avoided in patients with known renal insufﬁciency (32R , 43R ). Acute renal insufﬁciency was also observed in a kidney allograft recipient treated with intravenous immunoglobulin. The authors suggested that sucrose, in combination with underlying renal disease and drugs that affect renal function, appears to be an important risk factor (44A ). Skin In a patient with type II mixed cryoglobulinemia, intravenous immunoglobulin caused severe cutaneous vasculitis accompanied by an increased cryocrit (45A ). A simple method of mixing the patient’s serum in vitro with intravenous immunoglobulin could probably predict this. Skin diseases such as eczema, erythema multiforme, purpuric erythema, and alopecia are rare, but have been reported (32R ). Immunologic Anaphylactic reactions are rare, but can occur in patients who are deﬁcient in IgA and who have developed antibodies against IgA (32R ). Infection risk A life-threatening infection, fulminant hepatitis, due to transmission of human parvovirus B19 by intravenous immunoglobulin has been reported (46A ). The manufacturing process of this intravenous immunoglobulin product includes pasteurization (60◦ C for 10 hours), treatment with polyethylene glycol, ethanol fractionation, and nanoﬁltration. Removal of the small, non-lipidenveloped parvovirus B19, which is highly resistant to different virus reducing and inactivating steps, requires 15 nm nanoﬁltration.

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CLOTTING FACTORS Cardiovascular Prothrombin complex concentrate has been associated with thromboembolic complications, such as disseminated intravascular coagulation, pulmonary embolism, and acute myocardial infarction (SEDA-25, 396). In 42 patients who required immediate reversal of oral anticoagulant therapy by prothrombin complex concentrate, no laboratory and clinical evidence for coagulation activation was found (47C ). The authors suggested that the concentration of protein C within the prothrombin complex concentrate is an important factor for preventing thrombosis. The activated form of protein C is an important natural anticoagulant. Thromboembolic complications developed in two of 81 patients with von Willebrand disease treated with a high-purity factor VIII/von Willebrand factor (VWF) concentrate (48c ). Four cases of venous thrombosis were reported in patients with von Willebrand disease treated with an intermediate-purity factor VIII/VWF concentrate. Use of pure VWF concentrate without increased FVIII:C is preferable (49A ). Recombinant factor VIIa (rFVIIa) is a hemostatic agent that was initially developed for patients with hemophilia and inhibitors (antibodies against factor VIII). It is also potentially effective for patients with liver disease and bleeding. The mode of action of recombinant factor VIIa is tissue factor-dependent activation of factors Xa and IXa on the surfaces of activated platelets. Factor Xa leads to thrombin generation and hemostasis, by converting ﬁbrinogen to ﬁbrin. This process is limited to the site of injury, since exposure of tissue factor from the subendothelial matrix has a role in the action of recombinant factor VIIa, thereby reducing the risk of thromboembolic events (50A ). • A 38-year-old patient with hemophilia A with factor VIII inhibitors was treated with recombinant factor VIIa for about 1 month and 18 days after the last infusion developed a distal deep venous thrombosis. An effect of the factor VIIa could not be ruled out, but long-term immobilization and severe infection could have contributed (51A ). • A 71-year-old man with acquired hemophilia and high titers of antibodies to factor VIII developed a fatal thrombosis while receiving porcine factor VIII concentrate (52A ).

Blood, blood components, plasma, and plasma products

Skin Recombinant factor IX gave rise to an episode of urticaria in patients with hemophilia B undergoing surgery (53C ). Immunologic One of the main complications of factor VIII replacement therapy is the development of inhibitor antibodies. Gene deletions, truncations, and inversions of the factor VIII gene give rise to abnormal forms of the factor VIII protein, resulting in failure to induce tolerance against the normal form of factor VIII (54A ). Starting with factor VIII treatment at an early age is associated with an increased risk of developing inhibitors (55C ). Inhibitor bypassing agents currently used include prothrombin complex concentrates, activated prothrombin complex concentrates (such as FEIBA), porcine factor VIII, and recombinant factor VIIa. During 10 years usage of FEIBA (3.95 × 105 FEIBA units infused) a total of 16 thrombotic events were reported, corresponding to an incidence of 4.05 per 105 infusions. In 13 of these 16 events, known risk factors, such as FEIBA overdose, obesity, and serum lipid abnormalities, were present (56C ). Antibody reactivity against factor VIIa, which was detected in patients with hemophilia with high titer antibodies, was a response to treatment with blood products or by-passing agents or due to cross-reactivity. This reactivity might hamper the hemostatic effect (57A ). The production process of porcine factor VIII does not incorporate virus-eliminating steps. However, each batch is extensively screened to conﬁrm the absence of viruses. In a pharmacovigilance study of 81 hemophiliacs treated with porcine factor VIII, there were no cases of transmission of porcine viruses (porcine parvovirus, encephalomyocarditis virus, porcine respiratory, and reproductive syndrome virus) (58C ). A study of 31 previously untreated and minimally treated children with severe hemophilia A, who received full-length recombinant factor VIII (formulated with sucrose) for home therapy and surgery, showed no difference in the incidence of inhibitor formation compared with other recombinant products or plasmaderived products (59C ). Six cases of factor VIII inhibitor development within the postoperative period have been described (60A ). Some patients have a greater tendency to develop inhibitors, such as patients

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with severe hemophilia who were sparingly treated, patients with moderate hemophilia and a family history of inhibitor development, patients who had transient inhibitors in the past, and patients with high-risk mutations in their factor VIII gene (60A ). It has been suggested that alteration of the immune system, by operative stress or the use of antibiotics, increases the risk of inhibitor development (60A ). Of 81 patients with von Willebrand disease, who were treated with high-purity factor VIII/von Willebrand factor concentrate, two had reduced in vivo recovery, suggesting antibody formation (48c ). One case of low-titer and transient factor VII antibody formation has been reported in a patient with factor VII deﬁciency (61A ). Infection risk One of 81 patients with von Willebrand disease treated with a high-purity factor VIII/von Willebrand factor concentrate was infected with parvovirus B19 after infusion of a solvent/detergent-treated formulation. Parvovirus B19 is not lipid-enveloped and is resistant to treatment by solvent detergent (48c ). Parvovirus B19 transmission occurred in a child who had received vapor heat-treated prothrombin complex concentrate (60◦ C for 10 hours and 80◦ C for 1 hour) and in another child who received dry-heated factor VIII concentrate (80◦ C for 72 hours). Both children had severe hemophilia A and were treated for factor VIII inhibitors (62A ). Second-generation recombinant factor VIII products, which contain lower amounts of human albumin, and third-generation products, which are free of human proteins and thereby carry a lower risk of pathogen transmission, are currently being tested.

Coagulation factor gene therapy Gene therapy for hemophiliacs has been associated with three theoretical risks: the development of inhibitors, as observed in substitution therapy, insertional mutagenesis (e.g. through disruption of a regulatory gene such as a tumor suppressor gene), and transmission of genes to germ cells (63R ). In the various phase I trials performed in hemophiliacs such adverse events have not been observed (63R ).

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ERYTHROPOIETIN (EPOETIN) AND DERIVATIVES Erythropoietin is indicated for the treatment of anemia in patients with chronic kidney disease and for cancer-related anemia. It has also been used to reduce allogenic transfusion by increasing the efﬁcacy of autologous transfusion for elective surgery (64A ). There are four different forms of human recombinant erythropoietin: epoetin alpha, epoetin beta, epoetin omega, and darbepoetin alpha. Darbepoetin alpha is a supersialylated form of erythropoietin with a prolonged half-life. Both epoetin alpha and beta and darbepoetin alpha are quite well tolerated (65C ). Common adverse effects are infection, hypertension, hypotension, shunt thrombosis, myalgia, nausea, headache, and chest pain (66R ). Subcutaneous administration can cause pain, mostly mild and transient, at the injection site. Cardiovascular As erythropoietin can cause hypertension, many patients require antihypertensive therapy during erythropoietin treatment (66R ). The several mechanisms that are suggested to be responsible for this include increased vascular resistance, impaired vasodilatory tone (by diminishing the effect of nitrous oxide), and modulation of vasoconstrictor factors, such as an increased cytoplasmic calcium concentration, increased endothelin and prostaglandin production, and increased activity of the renin–angiotensin system. A 14-yearold child developed hypertensive encephalopathy, a known rare adverse effect of erythropoietin, after 2 months (67A ). During an open, uncontrolled study in 22 patients with end-stage renal disease treated with epoetin omega there was one case of hypertensive encephalopathy (68c ). In a placebo-controlled study of severely anemic patients with low-grade non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, or multiple myeloma, a fatal case of pulmonary embolism was thought to have been related to treatment with epoetin beta (69C ). Thrombotic events, such as vascular access thrombosis, venous thrombosis, and pulmonary embolism, have occurred after treatment with epoetin or darbepoetin alpha (70R ). It is therefore recommended that a rapid rise in the hemoglobin concentration be avoided and that care should

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be taken that the hemoglobin concentration does not exceed 12.1 g/dl (7.5 mmol/l) (71R ). In 173 renal patients with anemia, in which once-weekly administration of subcutaneous epoetin beta was compared with thrice-weekly administration, there were seven serious adverse events, possible related to epoetin beta (72C ). There were two cases of arteriovenous ﬁstula thrombosis in the once-weekly group and three in the thrice-weekly group. A transient ischemic attack and a hypertensive crisis occurred in one patient in the once-weekly group.

Erythropoietin and pure red cell aplasia World wide, 112 cases of pure red cell aplasia have been reported after subcutaneous administration of epoetin alpha (especially Eprex® ) in patients with chronic renal insufﬁciency. In these patients, neutralizing anti-erythropoietin antibodies were detected (73A , 74r , 75A ); these antibodies cross-react with all other erythropoietin products. This adverse effect was probably restricted to patients with renal insufﬁciency because these patients had used subcutaneous erythropoietin for many years. The incidence was calculated as one in 10 000 patients after 1 year of use of erythropoietin. In other reports from Canada and the UK, patients typically developed sudden worsening of anemia unresponsive to increasing doses of epoetin alpha or any other form of erythropoietin and became transfusion dependent (76C ). In patients who develop sudden lack of efﬁcacy or worsening of anemia, typical causes of nonresponse (e.g. deﬁciencies of iron, folate, and vitamin B12 , infection or inﬂammation, blood loss, hemolysis, and aluminium intoxication) should be investigated. If pure red cell aplasia is suspected and no cause can be identiﬁed, erythropoietin antibodies should be sought. The Australian Adverse Drug Reactions Advisory Committee has also received 12 reports of pure red cell aplasia associated with the use of epoetin alpha (Eprex® ) in patients with renal insufﬁciency (77R ). The patients were aged 28– 76 years and the duration of epoetin alpha use, when known, was 4–13 months. Janssen–Ortho Inc, in association with Health Canada, have issued a “Dear Health

Blood, blood components, plasma, and plasma products

Professional” letter about the addition of a boxed section to the product monograph of epoetin-alpha (Eprex® ). The addition recommends that epoetin alpha should be administered intravenously rather than subcutaneously in patients with chronic renal insufﬁciency. This advice is based on the fact that most of the worldwide reports of pure red cell aplasia in patients treated with epoetin-alpha have been associated with subcutaneous administration. The suggested mechanism for these cases of pure red cell aplasia is an immune reaction that is probably induced by repeated, subcutaneous administration of a foreign protein, a biotechnologically processed erythropoietin. However, no antibodies towards darbepoetin alpha were detected in over 1534 patients treated for 2 years (78r ). • A 70-year-old woman with a history of diabetes mellitus and renal insufﬁciency rapidly developed a severe anemia (with a hemoglobin concentration of 3.5 mmol/l). She had been treated with recombinant erythropoietin (4000 IU/week) for 6 months with an initial favorable response (hemoglobin concentration between 6.8 and 7.5 mmol/l) (73A ). Her bone marrow showed pure red cell aplasia with early termination of maturation. The dose of recombinant erythropoietin was increased to 8000 IU/week. She required 3 units of packed red cells per month. This patient had developed

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antibodies against recombinant erythropoietin. After recombinant erythropoietin was withdrawn, the concentration of antibodies fell slightly. Because of persistent transfusion requirements, she received prednisone (1 mg/kg/day) for 6 months. At that time, antibodies against erythropoietin could not be detected anymore and the hemoglobin concentration was around 5.6 mmol/l.

Urinary tract The use of darbepoetin alpha is associated with an increase in red blood cells and a reduction in plasma volume, which can lead to reduced efﬁcacy of dialysis (66R ). Skin Urticaria and other skin rashes have been reported after treatment with erythropoietin (66R , 79C ). Susceptibility factors Age The adverse effects of erythropoietin in neonates are minimal compared with adults. There were no hypertensive effects reported and no effect on development and growth measured at 18–22 months (80r ). Drug interactions Possible synergy between erythropoietin and moxiﬂoxacin was observed in a patient with myelodysplastic syndrome who did not respond to erythropoietin alone (81A ).

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32. Wiles CM, Brown P, Chapel H, Guerrini R, Hughes RA, Martin TD, McCrone P, Newsom Davis J, Palace J, Rees JH, Rose MR, Scolding N, Webster ADB. Intravenous immunoglobulin in neurological disease: a specialist review. J Neurol Neurosurg Psychiatry 2002; 72: 440–8. 33. Teeling JL, Bleeker WK, Hack CE, Kuijpers TW. Nieuwe inzichten in het ontstaan van bijwerkingen van intraveneuze immunoglobuline (IVIG)-preparaten. Ned Tijdschr Allergie 2001; 1: 20–5. 34. Bolton-Maggs PH. The management of immune thrombocytopenic purpura. Curr Paediatr 2002; 12: 298–303. 35. Crouch ED, Watson LE. Intravenous immunoglobulin-related acute coronary syndrome and coronary angiography in idiopathic thrombocytopenic purpura—a case report and literature review. Angiology 2002; 53: 113–17. 36. Emerson GG, Herndon CN, Sreih AG. Thrombotic complications after intravenous immunoglobulin therapy in two patients. Pharmacotherapy 2002; 22: 1638–41. 37. Byrne NP, Henry JC, Herrmann DN, Abdelhalim AN, Shrier DA, Francis CW, Powers JM. Neuropathologic ﬁndings in a Guillain–Barré patient with strokes after IVIg therapy. Neurology 2002; 59: 458–61. 38. Godeau B, Chevret S, Varet B, Lefrere F, Zini JM, Bassompierre F, Cheze S, Legouffe E, Hulin C, Grange MJ, Fain O, Bierling P. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359: 23–9. 39. Tristani-Firouzi P, Petersen MJ, Safﬂe JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 2002; 47: 548–52. 40. Obando I, Duran I, Martin-Rosa L, Cano JM, Garcia-Martin FJ. Aseptic meningitis due to administration of intravenous immunoglobulin with an unusually high number of leukocytes in cerebrospinal ﬂuid. Pediatr Emerg Care 2002; 18: 429– 32. 41. Wolfe GI, Barohn RJ, Foster BM, Jackson CE, Kissel JT, Day JW, Thornton CA, Nations SP, Bryan WW, Amato AA, Freimer ML, Parry GJ, Mendell JR. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 2002; 26: 549–52. 42. Ziegner UHM, Kobayashi RH, CunninghamRundles C, Espanol T, Fasth A, Huttenlocher A, Krogstad P, Marthinsen L, Notarangelo LD, Pasic S, Rieger CHL, Rudge P, Sankar R, Shigeoka AO, Stiehm ER, Sullivan KE, Webster AD, Ochs HD. Progressive neurodegeneration in patients with primary immunodeﬁciency disease on IVIG treatment. Clin Immunol 2002; 102: 19–24. 43. Sokos DR, Berger M, Lazarus HM. Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 117–30.

Blood, blood components, plasma, and plasma products 44. Tsinalis D, Dickenmann M, Brunner F, Gurke L, Mihatsch M, Nickeleit V. Acute renal failure in a renal allograft recipient treated with intravenous immunoglobulin. Am J Kidney Dis 2002; 40: 667–70. 45. Yebra M, Barrios Y, Rincon J, Sanjuan I, DiazEspada F. Severe cutaneous vasculitis following intravenous infusion of gammaglobulin in a patient with type II mixed cryoglobulinemia. Clin Exp Rheumatol 2002; 20: 225–7. 46. Hayakawa F, Imada K, Towatari M, Saito H. Life-threatening human parvovirus B19 infection transmitted by intravenous immune globulin. Br J Haematol 2002; 118: 1187–9. 47. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efﬁcacy and safety in 42 patients. Br J Haematol 2002; 116: 619–24. 48. Mannucci PM, Chediak J, Hanna W, Byrnes J, Ledford M, Ewenstein BM, Retzios AD, Kapelan BA, Schwartz RS, Kessler C, et al. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood 2002; 99: 450–6. 49. Makris M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost 2002; 88: 387–8. 50. Veldman A, Fischer D, Voigt B, Beyer PA, Schlosser R, Allendorf A, Kreuz W. Life-threatening hemorrhage in neonates: management with recombinant activated factor VII. Intensive Care Med 2002; 28: 1635–7. 51. Van der Planken MG, Schroyens W, Vertessen F, Michiels JJ, Berneman ZN. Distal deep venous thrombosis in a hemophilia A patient with inhibitor and severe infectious disease, 18 days after recombinant activated factor VII transfusion. Blood Coagul Fibrinolysis 2002; 13: 367–70. 52. Ashrani AA, Reding MT, Greeno EW, Shet A, Key NS. Thrombotic stroke associated with the use of porcine factor VIII in a patient with acquired haemophilia. Haemophilia 2002; 8: 56–8. 53. Ragni MV, Pasi KJ, White GC, Giangrande PL, Courter SG, Tubridy KL. Use of recombinant factor IX in subjects with haemophilia B undergoing surgery. Haemophilia 2002; 8: 91–7. 54. Spiegel PC Jr, Stoddard BL. Optimization of factor VIII replacement therapy: can structural studies help in evading antibody inhibitors? Br J Haematol 2002; 119: 310–22. 55. Van der Bom JG, Mauser-Bunschoten EP, Fischer K, Marijke VDB. Age at ﬁrst treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003; 89: 475–9. 56. Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA(R)): 10-year compilation of thrombotic adverse events. Haemophilia 2002; 8: 83–90. 57. Astermark J, Ekman M, Berntorp E. Antibodies to factor VIIa in patients with haemophilia and

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high-responding inhibitors. Br J Haematol 2002; 119: 342–7. 58. Giangrande PL, Kessler CM, Jenkins CE, Weatherill PJ, Webb PD. Viral pharmacovigilance study of haemophiliacs receiving porcine factor VIII. Haemophilia 2002; 8: 798–801. 59. Giangrande PL. Safety and efﬁcacy of KOGENATE® Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs). Haemophilia 2002; 8 Suppl 2: 19–22. 60. Ghosh K, Jijina F, Shetty S, Madkaikar M, Mohanty D. First-time development of FVIII inhibitor in haemophilia patients during the postoperative period. Haemophilia 2002; 8: 776–80. 61. Scharrer I. Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deﬁciency. Haemophilia 1999; 5: 253–9. 62. Blumel J, Schmidt I, Effenberger W, Seitz H, Willkommen H, Brackmann HH, Lower J, Eis Hubinger AM. Parvovirus B19 transmission by heat-treated clotting factor concentrates. Transfusion 2002; 42: 1473–81. 63. Manno CS. Gene therapy for bleeding disorders. Curr Opin Hematol 2002; 9: 511–15. 64. Shapiro GS, Boachie-Adjei O, Dhawlikar SH, Maier LS. The use of epoetin alpha in complex spine deformity surgery. Spine 2002; 27: 2067–71. 65. Nissenson AR, Swan SK, Lindberg JS, Soroka SD, Beatey R, Wang C, Picarello N, McDermott Vitak A, Maroni BJ. Randomized, controlled trial of darbepoetin alpha for the treatment of anemia in hemodialysis patients. Am J Kidney Dis 2002; 40: 110–18. 66. Cada DJ, Levien T, Baker DE. Darbepoetin alpha. Hosp Pharm 2002; 37: 46–57. 67. Taylor J, Pahl M, Rajpoot D. Erythropoietininduced hypertensive encephalopathy in a child: possible mechanisms. Dial Transplant 2002; 31: 170–88. 68. Sikole A, Spasovski G, Zaﬁrov D, Polenakovic M. Epoetin omega for treatment of anemia in maintenance hemodialysis patients. Clin Nephrol 2002; 57: 237–45. 69. Osterborg A, Brandberg Y, Molostova V, Iosava G, Abdulkadyrov K, Hedenus M, Messinger D. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin beta, in hematologic malignancies. J Clin Oncol 2002; 20: 2486–94. 70. Hudson JQ, Sameri RM. Darbepoetin alpha, a new therapy for the management of anemia of chronic kidney disease. Pharmacotherapy 2002; 22: 141S–149S. 71. Overbay DK, Manley HJ. Darbepoetin-alpha: a review of the literature. Pharmacotherapy 2002; 22: 889–97. 72. Locatelli F, Baldamus CA, Villa G, Ganea A, Martin de Francisco AL. Once-weekly compared with three-times-weekly subcutaneous epoetin beta: results from a randomized, multicenter, therapeutic-equivalence study. Am J Kidney Dis 2002; 40: 119–25. 73. Mercadal L, Sutton L, Casadevall N, Bagnis C, Jacobs C. Immunological reaction against ery-

352 thropoietin causing red-cell aplasia. Nephrol Dial Transplant 2002; 17: 943. 74. Gershon SK, Luksenburg H, Cote TR, Braun MM. Pure red-cell aplasia and recombinant erythropoietin. New Engl J Med 2002; 346: 1584–6. 75. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. New Engl J Med 2002; 346: 469–75. 76. Anonymous. Epoetin alpha. Reports of pure red blood cell aplasia. WHO Pharmaceuticals Newslett 2002; 1: 7. 77. Anonymous. Epoetin alpha. Pure red cell aplasia. WHO Pharmaceuticals Newslett 2002; 4: 7. 78. Anonymous. Darbepoetin alpha: proﬁle report. Drugs Ther Perspect 2002; 18: 4–5. 79. Terpos E, Mougiou A, Kouraklis A, Chatzivassili A, Michalis E, Giannakoulas N, Manioudaki E,

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Lazaridou A, Bakaloudi V, Protopappa M, Liapi D, Grouzi E, Parharidou A, Symeonidis A, Kokkini G, Laoutaris NP, Vaipoulos G, Anagnostopoulos NI, Christakis JI, Meletis J, Bourantas KL, Zoumbos NC, Yataganas X, Viniou N-A. Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients. Br J Haematol 2002; 118: 174–80. 80. Ohls RK. Erythropoietin treatment in extremely low birth weight infants: blood in versus blood out. J Pediatr 2002; 141: 3–6. 81. Fragasso A, Mannarella C, Sacco A. Response to erythropoietin and moxiﬂoxacin in a patient with myelodysplastic syndrome non-respondent to erythropoietin alone. Eur J Intern Med 2002; 13: 521–3.

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34

Intravenous infusions— solutions and emulsions

PLASMA SUBSTITUTES (SED-14, 1145; SEDA-24, 393; SEDA-25, 406; SEDA-26, 374)

Dextrans Cardiovascular Severe pulmonary edema developed in a patient who underwent breast reconstruction in whom dextran was used to improve the deterioration of ﬂap perfusion during the postoperative period (1A ). • A 48-year-old white woman underwent right modiﬁed radical mastectomy for inﬁltrative ductal carcinoma. She was given dextran 40, 10 ml/kg, on the second postoperative day because of partial ischemic changes in the ﬂap. She then had nausea, vomiting, and fever, and 10 hours later developed dyspnea and chest pain, which worsened on the following day. Chest radiography showed bilateral pleural effusions and bilateral reticulonodular opacities that were interpreted as pneumonic inﬁltration. She did not have hemoptysis or pleuritic chest pain, and there were no signs of heart failure. She had a leukocytosis (16.4×109 /l). Cultures of sputum and ﬂuid aspirate were negative. On postoperative day 4, her dyspnea worsened, her PO2 fell, and her pH rose to 7.53. Lymphangitic carcinomatosis was considered, but this was not supported by cytology of the effusion ﬂuid or tumor markers. Her history of allergic reactions suggested the possibility of dextran-induced severe pulmonary edema leading to respiratory distress syndrome. Dextran was withdrawn and she was given an intravenous bolus dose of prednisolone 250 mg. Her symptoms rapidly improved and she recovered gradually over the following week.

Severe pulmonary edema with respiratory failure is not a typical allergic reaction to dextrans, but this case illustrates that it cannot be discounted. In most cases the pulmonary complications are anaphylactic, occurring within © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

minutes of dextran administration and accompanied by bronchospasm and hypotension. Pulmonary edema is not observed and chest radiographs are typically normal. Severe pulmonary edema resulting from dextran infusion is rare; it has been reported to progress to respiratory distress syndrome and its progress is commonly protracted, ranging from several hours to a few days. Urinary tract Although acute renal insufﬁciency is a well recognized complication of dextran infusion, such reactions to its use in microsurgery are extremely rare. However, two more cases have been observed (2A ). • An 81-year-old woman underwent commando resection and supraomohyoidal lymphadenectomy for recurrent squamous cell carcinoma of the right inferior alveolar process. Preoperatively, she was given intravenous gentamicin 120 mg and clindamycin to be continued twice daily postoperatively. During surgery and the ﬁrst 5 postoperative days, she was given dextran 40, 1 l/day, as an antithrombotic and rheological agent. On the second postoperative day she became increasingly dyspneic. Despite furosemide her urine production fell and she became anuric on day 4. Gentamicin was stopped on day 3. On day 5, she was reintubated and artiﬁcially ventilated; thrice-weekly plasmapheresis was started. Three days later spontaneous diuresis recurred and she was extubated on postoperative day 10. On day 25, she refused further plasmapheresis and diuresis returned to normal. • A 69-year-old man underwent radical resection, supraomohyoidal lymphadenectomy, and radial forearm ﬂap reconstruction for squamous cell carcinoma of the oropharynx. Preoperatively, he was given intravenous gentamicin 320 mg/day and clindamycin 600 mg bd, to be continued for 5 days. He was given dextran 50, 500 ml/day. Despite extra intravenous hydration combined with dopamine and furosemide, his urine output fell to 40 ml/h on the ﬁrst postoperative day and he became anuric on day 2. Gentamicin and dextran were withdrawn, he was artiﬁcially ventilated, and thrice-weekly plasmapheresis was started. Renal biopsy showed hydropic swelling and vacuolation of the tubular epithelium and narrowing of the tubular lumen.

353

354 After 6 days, he was extubated and his renal function recovered only marginally. One month after surgery, he died of respiratory failure.

The authors suggested that acute renal insufﬁciency had been caused by dextran rather than gentamicin, because both patients developed anuria, which is commonly present in dextraninduced acute renal insufﬁciency, rather than the initial non-oliguric course characteristic of aminoglycosides. Further evidence for this conclusion was the renal biopsy in the second patient, while negative immunoﬂuorescence and the rapid return of kidney function in the ﬁrst patient suggested a non-structural effect of dextran on the kidney. The authors have stopped using dextran as an antithrombotic agent in microsurgery. Immunologic Two cases of severe dextraninduced anaphylactic reactions have been reported. The ﬁrst was fatal (3A ). • A 54-year-old man developed generalized pruritus, dyspnea, and sudden hemodynamic shock, with cardiac and respiratory arrest 8 h after the resection of a hepatic hydatid cyst, while being given dextran 40 infusion. He had no prior history of atopy or adverse drug reactions. Despite intensive resuscitation he remained unconscious and hemodynamically unstable. During the succeeding days he became septic with progressive renal function impairment and died on day 5. A range of serum tests for antibodies detected dextran-reactive antibodies. In addition, there was evidence of complement protein consumption within 6–24 hours of the clinical reaction.

The authors suggested that dextran-reactive antibodies had formed immune complexes with dextran, leading to complement activation and release of mediators of anaphylaxis. There was also evidence of mast cell degranulation. The authors therefore recommended that titration of dextran-reactive antibodies before administration of dextrans could provide a method of identifying those who are at risk of dextran-induced anaphylactic reactions. The administration of a monovalent hapten dextran before dextran infusion also reduces the risk of dextran-induced anaphylactic reactions. The second report concerns a healthy volunteer (4A ). • A 24-year-old healthy volunteer was given 10 ml of 6% dextran 60 during a preliminary examination. After about 5 min the ﬁrst clinical symptoms

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of anaphylactic shock were evident, with a reduction in systolic blood pressure to 90 mmHg and an increased heart rate to over 90. These returned to normal after therapy in the head-down position with clemastine 2 ml (2 mg), hydrocortisone 200 mg, and hydroxyethyl starch 500 ml over about 8 min. During this period, responsiveness was unsatisfactory although he complained of warming of the skin, paresthesia, and nausea.

The authors suggested that this reaction had been due to dextran-induced anaphylactic reaction, but were uncertain as to the cause of these observations, as they were not accompanied by immediate symptoms of shock. It is unclear if this case was caused by an antibody reaction.

Hydroxyethyl starch Hypervolemic hemodilution with agents such as hydroxyethyl starch or dextran increases cerebral blood ﬂow and may therefore reduce ischemic tissue damage in the penumbra zones when given within the therapeutic time window. However, the clinical beneﬁt of such therapy has yet to be proven. Since hydroxyethyl starch is considered to be the safer choice, in particular the recently developed lower molecular weight form (hydroxyethyl starch 130/0.4), an explorative randomized placebo-controlled safety trial of hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke has been undertaken (5C ). This was a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in 106 patients with acute ischemic stroke, who were recruited over 3 years. Treatment comprised high-dose hypervolemic hemodilution with either hydroxyethyl starch 130/0.4 or placebo within 6 h of the start of symptoms, with a randomization ratio of 2 : 1 in favor of hydroxyethyl starch. There were no signiﬁcant differences between the groups with regard to the incidence of speciﬁc adverse events (cardiovascular, bleeding complications, allergic reactions), assessed over days 1–30, or of deaths over days 1–8. The author, on behalf of the Hydroxyethyl Starch in Acute Stroke Study Group in Germany, noted that while the study was not designed to prove efﬁcacy, the global tests of efﬁcacy suggested a slight but insignificant trend towards better functional outcome with hydroxyethyl starch.

Intravenous infusions—solutions and emulsions

Chapter 34

Urinary tract The risk of acute renal insufﬁciency associated with the use of hydroxyethyl starch in volume replacement therapy has been critically reviewed (6R ). The author made the important point that not all hydroxyethyl starch formulations are the same—they differ widely in physicochemical characteristics. Such differences have consequences for adverse events, including impaired renal function. Furthermore, all volume replacement therapies have potential hazards. The author therefore concluded that hydroxyethyl starch, in particular products containing hydroxyethyl starch with a low or medium molecular weight (e.g. 70, 130, or 200 kD) and a low degree of substitution (0.4 or 0.5), can be considered for use in patients without pre-existing kidney dysfunction. It is recommended that all formulations of hydroxyethyl starch, including the latest (molecular weight 130, degree of substitution 0.4) should be used only very cautiously in patients with some degree of renal impairment (plasma creatinine concentration greater than 365 μmol/l, 3 mg/l) and are probably best avoided for alternative regimens.

Polygelines Immunologic Anaphylactic reactions associated with parenteral gelatin products are relatively common. The number of reports to the UK licensing authority now approaches 300, involving 127 patients, with seven deaths. Most of these reactions are associated with multiconstituent gelatin-containing products, such as Gelofusine. An anaphylactic reaction due solely to the use of Gelofusine in a patient with nonhemorrhagic hypovolemia has been reported (7A ). • A 57-year-old man presented with a 3-day history of lower abdominal pain and vomiting. He was hemodynamically stable but febrile, with tenderness and guarding in the lower abdomen. He was given intravenous ﬂuids and antibiotics and mini-laparotomy was performed. Although 6 l of crystalloids were given, his urine output was minimal, so 500 ml Gelofusine was prescribed. Within 10 minutes he developed an urticarial rash, with wheals on his face and chest and difﬁculty in breathing. The infusion was stopped and replaced with crystalloids via a new administration set. Intravenous chlorpheniramine and hydrocortisone improved his condition and the operation was completed without further complications.

355

Anaphylactic reactions to gelatins occur in about 0.1% of patients. Such reactions are more common in atopic patients and men and often occur within 10 minutes of starting the infusion. The authors recommended the use of allergy identiﬁcation jewellery in such individuals, to reduce the possibility of life-threatening reactions.

PARENTERAL NUTRITION (SED-14, 1150; SEDA-24, 395; SEDA-25, 407; SEDA-26, 377) Hematologic The major cause of megaloblastic anemia in children is folate deﬁciency. The following case indicates the importance of including regular supplementation of parenteral nutrition with folate (8A ). • A Japanese boy, born at 34 weeks with congenital microvillous atrophy, was given total parenteral nutrition 7 days after birth. The mixture included trace elements and most vitamins, but not folate. At 3 months he became lethargic, with facial pallor and hepatosplenomegaly. He had a hemoglobin of 6.9 g/dl with thrombocytopenia and a normal white blood cell count. Bone marrow showed typical megaloblasts. The serum folate concentration was 0.6 (reference range 2.4–9.8) ng/ml and vitamin B12 was 290 (249–938) pg/ml. These ﬁndings indicated megaloblastic anemia due to folate deﬁciency. Daily intramuscular folate 30 μg/kg and vitamin B12 40 μg/kg improved his anemia and thrombocytopenia and his serum folate concentration returned to normal after 14 days. Both vitamins were then added daily and there was no recurrence of anemia, but he died at 4 months because of sepsis.

It is estimated that the minimum daily requirement of folate is 5 μg/kg. Liver stores are about 160 μg in premature children, and 220 μg in full-term infants. Infants who require total parenteral nutrition will rapidly become folate deﬁcient unless folic acid is included in the regimen. Since many multivitamin supplements do not contain folic acid, its inclusion should be ensured by the addition of folic or folinic acid. Iron deﬁciency anemia can also be an important adverse effect of long-term parenteral nutrition. This is usually caused by partial or complete absence from the regimen, inadequate absorption if oral iron is substituted, or chronic iron loss from gastrointestinal lesions.

356 In a retrospective study, the records of 55 patients on long-term parenteral nutrition (more than 6 months) were examined for evidence of iron deﬁciency anemia (9c ). All had received home parenteral nutrition, comprising amino acids, glucose, and fat emulsion, with appropriate electrolytes, vitamins, and trace elements, but without iron. All had taken substantial amounts of food despite malabsorption. Iron deﬁciency anemia was identiﬁed in patients whose hemoglobin concentration was less than 12 g/dl and who had at least one of the following: serum iron less than 60 μg/dl and TIBC less than 350 μg/dl; iron to TIBC ratio (or transferrin saturation) 16% or less; or serum ferritin less than 15 ng/ml. Iron studies had been monitored at about 3-monthly intervals, reduced to yearly if no problems were found. In 30 patients there was evidence of iron deﬁciency anemia; ten of these were detected at the start of home parenteral nutrition, and the other 20 developed iron deﬁciency anemia during treatment. Many had evidence of acute blood loss, for example from the gastrointestinal or genitourinary tracts. The time between the start of parenteral nutrition and the development of anemia was 2–97 (mean 29) months. Mild iron loss from the gastrointestinal tract was identiﬁed as the predominant cause. Regular treatment with small amounts of iron (10–15 mg/day had been used in these patients) added to the parenteral nutrition regimen appeared to be safe and efﬁcacious, with no reported adverse effects. In contrast, total dose infusion of iron (for example, iron dextran infusion) had adverse effects in 25% of patients. Iron is an essential element in nutrition, and its inclusion in any long-term parenteral nutrition regimen should be mandatory. However, it is not included in all trace element formulations, although this varies from country to country; most European products include 20 μmol

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of iron in trace element formulations. While it might be considered unnecessary to include iron as a daily supplement, because of safety and pharmaceutical considerations, there is ample evidence that the use of iron-containing trace element formulations is both safe and efﬁcacious, with no associated adverse effects. Immunologic Anaphylactic reactions to total parenteral nutrition are rare. A case that links hypersensitivity to vitamin B complex in the parenteral nutrition regimen has been reported (10A ). • An 8-year-old girl had a diaphragmatic hernia repaired at 7 days of age and had two episodes of adhesion ileus at 8 months. After laparotomy she was given all-in-one total parenteral nutrition and after 21 days developed a reddish rash on her face and chest. The rash was pruritic and resolved quickly after intravenous diphenhydramine. She was readmitted 15 d after discharge because of malnutrition. Total parenteral nutrition was restarted and she rapidly became irritable and developed an itchy rash over her face and trunk and swelling of her lips and eyelids. Parenteral nutrition was discontinued, diphenhydramine was given, and her symptoms abated rapidly. The possibility of hypersensitivity to a component of the parenteral nutrition was considered, and by a process of elimination the cause of the reaction was identiﬁed as the vitamin product MVI No 1. This was further conﬁrmed by a skin test 1 year after the anaphylactic episode, but using a vitamin B complex solution.

Previous reports of anaphylactic reactions to total parenteral nutrition have been identiﬁed as being caused by fat emulsion, vitamin K, iron dextran, and in particular multivitamins. This appears to be the ﬁrst report of reaction to vitamin B complex injection. However, neither the source of the vitamin B complex test product nor its formulation was identiﬁed by the authors, and doubt remains regarding the speciﬁc allergens responsible for the observed allergic response.

REFERENCES 1. Demirkan F, Unal S, Arslan E, Calkoglu M, Kandemir O. Severe pulmonary edema related to dextran 40. Ann Plast Surg 2002; 49: 221–2. 2. Vos SCB, Hage JJ, Woerdeman LAE, Noornadus RP. Acute renal failure during dextran 40

antithrombotic prophylaxis: report of two microsurgical cases. Ann Plast Surg 2002; 48: 193–6. 3. Harnandez D, De Rojas F, Martinez-Escribano C, Arriago F, Cuellar J, Molins J, Barber L. Fatal dextran-induced allergic anaphylaxis. Allergy Eur J Allergy Clin Immunol 2002; 57: 862.

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4. Lehmann G, Asskali F, Forster H. Severe adverse event following iv administration of 10 ml 6% dextran 60 in a healthy volunteer. Anaesthetist 2002; 51: 820–4. 5. Rudolf J. Hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: a randomized, placebo-controlled phase II safety study. Cerebrovasc Dis 2002; 14: 33–41. 6. Boldt J. Hydroxyethylstarch as a risk factor for acute renal failure: is a change of clinical practice indicated? Drug Saf 2002; 25: 837–46. 7. Jenkins SC, Clifton MA. Gelofusine allergy— the need for identiﬁcation jewellery. Ann R Coll Surg Engl 2002; 84: 206–7.

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8. Kaneko K, Shimizu T, Nagaoka R, Fujiwara S, Igarashi J, Ohtomo Y, Yamashiro Y. Megaloblastic anemia in an infant receiving total parenteral nutrition. Pediatr Int 2002; 44: 101–2. 9. Khaodhiar L, Keane-Ellison M, Tawa NE, Thibault A, Burke PA, Bistrian BR. Iron-deﬁciency anemia in patients receiving home total parenteral nutrition. J Parenter Enter Nutr 2002; 26: 114–19. 10. Wu S-F, Chen W. Hypersensitivity to vitamin preparation in parenteral nutrition: report of one case. Acta Paediatr Taiwan 2002; 43: 285–7.

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35

Drugs affecting blood coagulation, ﬁbrinolysis, and hemostasis

COUMARIN CONGENERS (SED-14, 1184; SEDA-24, 398; SEDA-25, 411; SEDA-26, 379) Drug interactions Inhibition of the effect of different oral anticoagulants by different antiviral drugs has been described in two case reports. • A 46-year-old man with two prosthetic heart valves taking acenocoumarol started to take ritonavir 600 mg/day. Despite a progressive increase in the dose of acenocoumarol to three times the original dose, it was impossible to achieve a therapeutic INR, and the ritonavir was withdrawn (1A ). • In a 61-year-old man, who was taking long-term warfarin after a heart valve replacement, the dose of warfarin had to be increased by 40% after the introduction of ribavirin for chronic hepatitis C; the inhibition of the effect of warfarin was reproduced on rechallenge (2A ).

The authors proposed that ritonavir had induced CYP1A2, CYP1A4, and CYP2C9/19 activity, leading to increased metabolism, at least of acenocoumarol. However, this effect was the opposite of what was expected, since ritonavir is a potent inhibitor of most hepatic isoenzymes.

HEPARINS

(SED-14, 1177; SEDA-21, 358; SEDA-22, 386; SEDA-26, 379) Hematologic Heparin-induced thrombocytopenia is a well-characterized immunoglobulinmediated disorder that is often complicated by © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

358

life- and limb-threatening thrombotic complications. The platelet count generally begins to fall 5–8 days after the start of heparin therapy, followed soon after by thrombotic complications. Low-molecular-weight heparin is signiﬁcantly less likely to cause thrombocytopenia than unfractionated heparin (3R ). A newly recognized effect, so-called “delayed-onset heparin-induced thrombocytopenia” has been described in several recent reports. In 12 patients, recruited from secondary and tertiary care hospitals, thrombocytopenia and associated thrombosis occurred at a mean of 9.2 (range 5–19) days after the withdrawal of heparin; nine received additional heparin, with further falls in platelet counts (4c ). In a retrospective case series, 14 patients, seen over a 3-year period, developed thromboembolic complications a median of 14 days after treatment with heparin (5c ). The emboli were venous (n = 10), or arterial (n = 2), or both (n = 2); of the 12 patients with venous embolism seven had pulmonary embolism. Platelet counts were mildly reduced in all but two patients at the time of the second presentation. On readmission, 11 patients received therapeutic heparin, which worsened their clinical condition and further reduced the platelet count. • A 44-year-old woman developed delayed-onset thrombocytopenia and cerebral thrombosis 7 days after a single dose of unfractionated heparin 5000 units (6Ar ).

Drugs affecting blood coagulation, ﬁbrinolysis, and hemostasis

SHORT POLYSACCHARIDE INHIBITORS OF COAGULATING FACTORS Fondaparinux Fondaparinux is a synthetic pentasaccharide that mimics the site of heparin that binds to antithrombin III and inhibits factor Xa activity, which in turn inhibits thrombin generation. It does not release tissue factor pathway inhibitor. It is nearly completely absorbed after subcutaneous administration, has a rapid onset of action and a long half-life (14–20 hours), and is excreted by the kidneys. Its pharmacology, clinical pharmacology, and uses have been reviewed (7R –23R ). There have been two double-blind randomized comparisons of fondaparinux 2.5 mg/day or enoxaparin 40 mg/day after hip fracture surgery (24C ) or elective major knee surgery (25C ). Fondaparinux reduced the risk of thromboembolism by 56% in the ﬁrst study (n = 1250) and by 55% in the second (n = 724). There were no signiﬁcant differences between the two groups in the ﬁrst study in the incidence of death or clinically important bleeding. In the second study major bleeding occurred more often with fondaparinux, but there were no signiﬁcant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ. In a double-blind randomized study of 2309 consecutive patients undergoing elective hip replacement, postoperative subcutaneous fondaparinux 2.5 mg/day was compared with preoperative enoxaparin 40 mg/day (26C ). By day 11, venous thromboembolism had occurred in 85 (9%) of 919 patients assigned to enoxaparin and in 37 (4%) of 908 patients assigned to fondaparinux, a relative risk reduction of 56% (95% CI = 33, 73). In a similar comparison of postoperative fondaparinux 2.5 mg/day and enoxaparin 30 mg bd in 2275 consecutive patients undergoing elective hip replacement, by day 11 venous thromboembolism had occurred in 48 (6%) of 787 patients assigned to fondaparinux and in 66 (8%) of 797 patients assigned to enoxaparin, a relative risk reduction of 26% (95% C = 11, 53) (27C ). In a meta-analysis of these studies bleeding was slightly, but not signiﬁcantly, more frequent with fondaparinux than with enoxaparin (28M , 29M ).

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359

Drug interactions In a randomized, crossover study in 24 healthy volunteers the pharmacokinetics of fondaparinux sodium 10 mg/day subcutaneously for 7 days were unaffected by digoxin 0.25 mg/day orally for 7 days (30C ). In another study there was no pharmacodynamic interaction of subcutaneous fondaparinux 4 mg with warfarin in 12 healthy men (31C ). In healthy volunteers steady-state fondaparinux did not alter the pharmacodynamic effects of single doses of aspirin 975 mg or piroxicam 20 mg (32C ). Neither aspirin nor piroxicam altered the pharmacokinetics of fondaparinux.

DIRECT THROMBIN INHIBITORS The class of direct thrombin inhibitors includes the hirudins lepirudin and bivalirudin, and the tripeptide or peptidomimetic compounds argatroban, efegatran, inogatran, napsagatran, melagatran, and ximelagatran. They act by binding to the active site on thrombin and inhibiting its enzymatic activity. They thus inhibit ﬁbrin formation, activation of anticoagulant factors V, VIII, and XIII, and protein C, and platelet aggregation. The antithrombin action occurs rapidly and is quickly reversible. A meta-analysis has been performed of individual patients’ data from randomized comparisons of direct thrombin inhibitors (hirudin, bivalirudin, argatroban, efegatran, or inogatran) with heparin (33M ). In 11 trials, 35 970 patients were given treatment for up to 7 days and followed for at least 30 days. Compared with heparin, the direct thrombin inhibitors were associated with a lower risk of death or myocardial infarction at the end of treatment (OR = 0.85; 95% CI = 0.77, 0.94) and at 30 days (OR = 0.91; CI = 0.84, 0.99). There was no excess of intracranial hemorrhages with the direct thrombin inhibitors.

Argatroban Argatroban has been approved in the USA and Canada for prophylaxis and treatment of throm-

360 bosis in patients with heparin-induced thrombocytopenia, and in Japan and Korea for various thrombotic disorders. Its effects can be monitored using the activated partial thromboplastin time for low doses and the activated clotting time for high doses. Its pharmacology, clinical pharmacology, and uses have been reviewed (34R –41R ). Drug interactions Argatroban is metabolized by CYP3A4/5, and its pharmacokinetics might therefore be expected to be altered by inhibitors of CYP3A. However, in 14 healthy men erythromycin 500 mg qds had no effects on the pharmacokinetics of argatroban 1 μg/kg/minute infused over 5 hours (42c ). The pharmacokinetics of intravenous argatroban 1.5–2.0 μg/kg/minute were also unaffected by co-administration of oral paracetamol, oral digoxin, or intravenous lidocaine in healthy volunteers (43c ).

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DRUGS THAT ALTER PLATELET FUNCTION Abciximab

(SED-14, 1194;

SEDA-23, 377) Hematologic Thrombocytopenia, often severe, occurs in 1–2% of patients treated with the ﬁbrinogen receptor antagonist abciximab. The cause of this complication has yet to be deﬁned. Nine patients who developed profound thrombocytopenia after a second exposure to abciximab had an IgG antibody that recognized platelets sensitized with abciximab. In contrast, in 104 healthy subjects, in whom IgG antibodies reactive with abciximab-coated platelets were found in 77, the antibodies were speciﬁc for murine sequences in abciximab and were capable of causing life-threatening thrombocytopenia (44cE ). Immunologic In a 46-year-old woman anaphylactic shock occurred after abciximab readministration (45A ).

REFERENCES 1. Llibre JM, Romeu J, Lopez E, Sirera G. Severe interaction between ritonavir and acenocoumarol. Ann Pharmacother 2002; 36: 621–3. 2. Schulman S. Inhibition of warfarin activity by ribavirin. Ann Pharmacother 2002; 36: 72–4. 3. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79: 1–7. 4. Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135: 502–6. 5. Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med 2002; 136: 210–15. 6. Warkentin TE, Bernstein RA. Delayed-onset heparin-induced thrombocytopenia and cerebral thrombosis after a single administration of unfractionated heparin. New Engl J Med 2003; 348: 1067–9. 7. Keam SJ, Goa KL. Fondaparinux sodium. Drugs 2002; 62: 1673–85. 8. Walenga JM, Jeske WP, Samama MM, Frapaise FX, Bick RL, Fareed J. Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent. Expert Opin Investig Drugs 2002; 11: 397– 407. 9. Regazzoni S, De Moerloose P. Deux nouveaux agents antithrombotiques très prometteurs: le pen-

tasaccharide et le ximelagatran. Rev Med Suisse Romande 2002; 122: 29–33. 10. Bounameaux H, Perneger T. Fondaparinux: a new synthetic pentasaccharide for thrombosis prevention. Lancet 2002; 359: 1710–11. 11. Bauer KA, Hawkins DW, Peters PC, Petitou M, Herbert JM, Van Boeckel CA, Meuleman DG. Fondaparinux, a synthetic pentasaccharide: the ﬁrst in a new class of antithrombotic agents—the selective factor Xa inhibitors. Cardiovasc Drug Rev 2002; 20: 37–52. 12. Bauer KA. Selective inhibition of coagulation factors: advances in antithrombotic therapy. Semin Thromb Hemost 2002; 28 Suppl 2: 15–24. 13. Turpie AG. Optimizing prophylaxis of venous thromboembolism. Semin Thromb Hemost 2002; 28 Suppl 2: 25–32. 14. Buller HR. Treatment of symptomatic venous thromboembolism: improving outcomes. Semin Thromb Hemost 2002; 28 Suppl 2: 41–8. 15. Keam SJ, Goa KL. Fondaparinux sodium. Drugs 2002; 62: 1673–85. 16. Turpie AG. Pentasaccharides. Semin Hematol 2002; 39: 158–71. 17. Gallus AS, Coghlan DW. Heparin pentasaccharide. Curr Opin Hematol 2002; 9: 422–9. 18. Bauer KA, Eriksson BI, Lassen MR, Turpie AG. Factor Xa inhibition in the prevention of ve-

Drugs affecting blood coagulation, ﬁbrinolysis, and hemostasis nous thromboembolism and treatment of patients with venous thromboembolism. Curr Opin Pulm Med 2002; 8: 398–404. 19. Garces K. Fondaparinux for post-operative venous thrombosis prophylaxis. Issues Emerg Health Technol 2002; (37): 1–4. 20. Petitou M, Duchaussoy P, Herbert JM, Duc G, El Hajji M, Branellec JF, Donat F, Necciari J, Cariou R, Bouthier J, Garrigou E. The synthetic pentasaccharide fondaparinux: ﬁrst in the class of antithrombotic agents that selectively inhibit coagulation factor Xa. Semin Thromb Hemost 2002; 28: 393–402. 21. Cheng JW. Fondaparinux: a new antithrombotic agent. Clin Ther 2002; 24: 1757–69. 22. Reverter JC. Fondaparinux sodium. Drugs Today (Barc) 2002; 38: 185–94. 23. Samama MM, Gerotziafas GT, Elalamy I, Horellou MH, Conard J. Biochemistry and clinical pharmacology of new anticoagulant agents. Pathophysiol Haemost Thromb 2002; 32: 218–24. 24. Eriksson BI, Bauer KA, Lassen MR, Turpie AG, Steering Committee of the Pentasaccharide in Hip Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. New Engl J Med 2001; 345: 1298–304. 25. Bauer KA, Eriksson BI, Lassen MR, Turpie AG, Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. New Engl J Med 2001; 345: 1305–10. 26. Lassen MR; Bauer KA; Eriksson BI; Turpie AG. European Pentasaccharide Elective Surgery Study EPHESUS Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised doubleblind comparison. Lancet 2002; 359: 1715–20. 27. Turpie AG, Bauer KA, Eriksson BI, Lassen MR, PENTATHALON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721–6. 28. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized doubleblind studies. Arch Intern Med 2002; 162: 1833–40. 29. Turpie AG, Eriksson BI, Lassen MR, Bauer KA. A meta-analysis of fondaparinux versus enoxaparin in the prevention of venous thromboembolism after major orthopaedic surgery. J South Orthop Assoc 2002; 11: 182–8. 30. Mant T, Fournie P, Ollier C, Donat F, Necciari J. Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers. Clin Pharmacokinet 2002; 41 Suppl 2; 39–45.

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31. Faaij RA, Burggraaf J, Schoemaker RC, Van Amsterdam RG, Cohen AF. Absence of an interaction between the synthetic pentasaccharide fondaparinux and oral warfarin. Br J Clin Pharmacol 2002; 54: 304–8. 32. Ollier C, Faaij RA, Santoni A, Duvauchelle T, van Haard PM, Schoemaker RC, Cohen AF, De Greef R, Burggraaf J. Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers. Clin Pharmacokinet 2002; 41 Suppl 2: 31–7. 33. Direct Thrombin Inhibitor Trialists’ Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a metaanalysis based on individual patients’ data. Lancet 2002; 359: 294–302. 34. Hursting MJ, Alford KL, Becker JC, Brooks RL, Joffrion JL, Knappenberger GD, Kogan PW, Kogan TP, McKinney AA, Schwarz RP Jr. Novastan (brand of argatroban) a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost 1997; 23: 503–16. 35. Walenga JM. An overview of the direct thrombin inhibitor argatroban. Pathophysiol Haemost Thromb 2002; 32 Suppl 3: 9–14. 36. Ikoma H. Development of argatroban as an anticoagulant and antithrombin agent in Japan. Pathophysiol Haemost Thromb 2002; 32 Suppl 3: 23–8. 37. Fareed J, Hoppensteadt D, Iqbal O, Tobu M, Lewis BE. Practical issues in the development of argatroban: a perspective. Pathophysiol Haemost Thromb 2002; 32 Suppl 3: 56–65. 38. Hauptmann J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. A review of small-molecule thrombin inhibitors. Eur J Clin Pharmacol 2002; 57: 751–8. 39. Kathiresan S, Shiomura J, Jang IK. Argatroban. J Thromb Thrombolysis 2002; 13: 41–7. 40. Kaplan KL, Francis CW. Direct thrombin inhibitors. Semin Hematol 2002; 39: 187–96. 41. Breddin HK. Experimentelle und klinische Befunde mit dem Thrombinhemmer Argatroban. Hämostaseologie 2002; 22: 55–9. 42. Tran JQ, DiCicco RA, Sheth SB, Tucci M, Peng L, Jorkasky DK, Hursting MJ, Benincosa LJ. Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban. J Clin Pharmacol 1999; 39: 513–19. 43. Inglis AML, Sheth SB, Hursting MJ, Tenero DM, Graham AM, DiCicco RA. Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin. Am J Health-Syst Pharm 2002; 59: 1258–66. 44. Curtis BR, Swyers J, Divgi A, McFarland JG, Aster RH. Thrombocytopenia after second exposure to abciximab is caused by antibodies that recognize abciximab-coated platelets. Blood 2002; 99: 2054–9. 45. Pharand C, Palisaitis DA, Hamel D. Potential anaphylactic shock with abciximab readministration. Pharmacotherapy 2002; 22: 380–3.

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ANTIEMETICS In a randomized, double-blind study in 106 patients with non-ulcer dyspepsia, cinitapride 1 mg tds was as effective as cisapride 5 mg tds in relieving symptoms (1c ). Adverse events, mainly gastrointestinal, were transient and did not require drug withdrawal. In another randomized study in 28 children (aged 5–17 years) with diabetic gastroparesis, domperidone 0.9 mg/kg/day for 8 weeks was superior to cisapride 0.8 mg/kg/day in reversing gastric emptying delay and gastric electrical abnormalities, as well as in improving dyspeptic symptoms and diabetic control (2c ). No potentially drugrelated adverse effects were reported.

by gas distension of the stomach (4C ). Adverse effects were similar in the two treatment sequences, although there were a few more episodes of abdominal cramps, nausea, and headache with cisapride. Cardiovascular The effect of cisapride 0.8 mg/kg/day for 14 days on the QTc interval has been studied prospectively in 50 infants with feeding intolerance, apnea, and bradycardia episodes secondary to gastro-esophageal reﬂux and gastrointestinal dysmotility (5c ). In 15 infants there was prolongation of the QTc interval at some time during the 14 days. Infants with a QTc interval on day 3 at least two standard deviations above the mean baseline QTc interval were more likely to develop a prolonged QTc interval.

Cisapride

(SED-14, 1223; SEDA-24, 401; SEDA-25, 416; SEDA-26, 382)

The effect of cisapride 10 mg qds for 5 days on the frequency of nocturnal transient lower esophageal sphincter relaxation and esophageal acid exposure has been studied in a doubleblind, placebo-controlled, crossover study in 10 patients with gastro-esophageal reﬂux disease (3c ). Cisapride signiﬁcantly reduced the frequency of transient lower esophageal sphincter relaxation during sleep and increased lower esophageal sphincter pressure without changing gastric emptying. However, in a larger doubleblind, placebo-controlled, crossover study in 30 patients with gastro-esophageal reﬂux disease, cisapride 20 mg bd for 4 weeks (despite adequate plasma concentrations) had no signiﬁcant effects on swallow-induced esophageal peristaltic activity, the basal tone of the lower esophageal sphincter, or the number of transient lower esophageal sphincter relaxations induced © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

362

Metoclopramide

(SED-13, 1069;

SEDA-25, 417) In a four-way crossover study in 16 healthy men a modiﬁed-release formulation of metoclopramide (30 mg) administered fasting and after a high-fat meal, an immediate-release formulation (30 mg), and a short intravenous infusion of 30 mg have been compared (6c ). The absolute systemic availability of the modiﬁedrelease formulation was about 17% lower than that of the immediate-release formulation. Food had no signiﬁcant effect on absorption. Uniform absorption of the drug from modiﬁed-release formulations supports their use in long-term treatment. Nervous system Adverse reactions to metoclopramide in 52 children aged 2.5–4.5 years who were admitted to hospital over 6 years have been studied retrospectively (7c ). All had various dystonic symptoms that occurred several hours after taking the drug. The prominent clinical effect was an oculogyric crisis in all

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cases, while children who took higher doses also became drowsy. All extrapyramidal symptoms were treated successfully with a single intravenous dose of procyclidine hydrochloride 0.1 mg/kg. Severe parkinsonism has been reported in a 73-year-old woman with tuberculosis of the large intestine who had taken metoclopramide for nausea; she recovered on withdrawal of the drug and treatment with biperiden (8A ). Acute dystonia has been reported in three men with AIDS who had received metoclopramide; they recovered on withdrawal and treatment with biperiden or diazepam (9A ). Psychiatric Supersensitivity psychosis has been reported in two men, aged 74 and 65 years, who had taken metoclopramide 5 mg qds for 6 months and 3 months respectively (10A ). Hallucinations and delusions developed 12 hours after the drug was withdrawn in one patient and 3 days after withdrawal in the other. Both recovered after treatment with risperidone.

5-HT3 RECEPTOR ANTAGONISTS (SED-14, 1225; SEDA-24, 401; SEDA-25, 417; SEDA-26, 382) The antiemetic effects of intravenous metoclopramide 1 mg/kg tds and ondansetron 8 mg/kg tds, alone or in combination with dexamethasone or methylprednisolone, have been compared in an open study in 101 patients receiving several cycles of moderately emetogenic chemotherapy (11c ). The regimens had similar efﬁcacy in controlling emesis during the ﬁrst course of chemotherapy. However, ondansetron alone, ondansetron plus steroids, and metoclopramide plus steroids were more effective than metoclopramide alone during the next two cycles. All the antiemetic regimens were well tolerated and caused similar frequencies of adverse effects. The most common were headache, constipation, and diarrhea. In a randomized, double-blind trial in 179 patients undergoing thyroid or parathyroid surgery, premedication with oral tropisetron 5 mg was more effective in preventing postoperative nausea and vomiting in the initial postoperative period (0–2 hours) than either oral ondansetron 16 mg or oral metoclopramide 10 mg

when given 1 hour before the operation (12C ). When the entire 24-hour postoperative period was considered, the incidence of vomiting was lower with ondansetron and tropisetron than with metoclopramide. The adverse effects proﬁles were similar in the three groups. Common adverse effects were headache, dizziness, pruritus, and visual disturbances. In a randomized trial in 60 patients who underwent elective laparoscopic cholecystectomy the combination of intravenous granisetron 3 mg plus droperidol 1.25 mg was more effective in preventing postoperative nausea and vomiting than granisetron 3 mg alone (13c ). No signiﬁcant adverse effects were reported in either group. Oral ramosetron 0.1 mg without water has been compared with oral granisetron 2 mg with water given 1 hour before infusion of chemotherapy in a multicenter, randomized, single-blind, crossover study in 73 patients with cancer (14c ). The two regimens had similar efﬁcacy in the prevention of chemotherapyinduced anorexia, nausea, and vomiting. The incidence of adverse effects was similar in the two treatment groups. More patients given ramosetron (10%) complained of headache than those given granisetron (1.3%). The other important adverse effects were dry mouth, insomnia, heavy-headedness, and dizziness. In another multicenter, randomized, singleblind study in 194 patients receiving cisplastin chemotherapy for cancer, intravenous ramosetron 3 mg was as effective as intravenous granisetron 3 mg in preventing nausea and vomiting (15c ). Although the incidence of adverse effects was similar in the two groups, signiﬁcantly more patients who received granisetron than ramosetron complained of dull headache.

HISTAMINE H2 RECEPTOR ANTAGONISTS (SED-14, 1225; SEDA-24, 402; SEDA-25, 419; SEDA-26, 384) Nutrition Vitamin B12 deﬁciency has been reported in a 78-year-old non-vegetarian white woman with gastro-esophageal reﬂux who had taken H2 receptor antagonists and omeprazole for 4.5 years (16A ). H2 receptor antagonists and proton pump inhibitors impair the absorption

364 of protein-bound dietary vitamin B12 . This is thought to be due to impaired release of the vitamin from food protein, which requires gastric acid and pepsin as the initial step in the absorption process.

Famotidine The effects of famotidine 20 mg bd and omeprazole 20 mg/day for 8 weeks have been compared in the treatment of reﬂux esophagitis in a randomized trial in 56 patients (17c ). Omeprazole was more effective in healing esophagitis and providing symptom relief. Adverse events, which were rare, were similar in the two groups, and consisted of nausea, palpitation, abdominal pain, and mild abnormalities of liver function tests. Drug interactions Intragastric acid control by omeprazole 20 mg taken in the morning after variable dosing of over-the-counter famotidine 10 mg has been assessed in 12 healthy volunteers negative for Helicobacter pylori (18c ). Famotidine did not reduce the daytime efﬁcacy of the next-morning dose of omeprazole.

Nizatidine Drug interactions In a randomized, crossover, open study in 16 healthy volunteers a rise in gastric pH to above 6 by nizatidine did not result in clinically important changes in the rate or extent of absorption of oral dapsone (19c ).

Ranitidine Liver Cholestatic jaundice has been reported in a 73-year-old woman who had taken ranitidine 150 mg bd (20A ). She developed pruritus 4 days after starting to take the drug and jaundice after 3 weeks. Her liver function tests returned to normal 50 days after ranitidine was withdrawn.

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Susceptibility factors Children The pharmacokinetics and pharmacodynamics of a single dose of ranitidine 75 mg have been evaluated in a randomized, double-blind, placebocontrolled trial in 29 children aged 4–11 years with gastro-esophageal reﬂex disease (21c ). Ranitidine signiﬁcantly increased the intragastric pH in children, and the pharmacokinetics and pharmacodynamics were similar to those in adults. The drug was effective in the control of intragastric acidity for 5–6 hours. Adverse effects were reported only in children taking ranitidine, and included nausea, vomiting, abdominal pain, dizziness, intermittent headache, and light-headedness.

PROTON PUMP INHIBITORS (SED-14, 1230; SEDA-24, 402; SEDA-25, 420; SEDA-26, 384) The effects of omeprazole 40 mg/day and esomeprazole 40 mg/day for 5 days on intragastric acidity have been compared in an open, crossover study in 130 patients with symptoms of gastro-esophageal reﬂux (22c ). Esomeprazole provided more effective acid control than twice the standard dose of omeprazole. Adverse effects were similar with the two drugs, and the most commonly reported were headache, nausea, and abdominal pain. Omeprazole multiple unit pellet system (MUPS) 20 mg/day and pantoprazole 40 mg/ day for 8 weeks were more effective than lansoprazole 30 mg/day in relieving heartburn in a randomized, double-blind trial in 461 patients with symptomatic reﬂux esophagitis (23C ). Patient satisfaction and adverse effects were similar in the three groups. The most common adverse effects were diarrhea, headache, and nausea. In a multicenter, double-blind, crossover study in primary care in 240 patients with acidrelated disorders, omeprazole 20 mg/day and rabeprazole 40 mg/day for 4 weeks provided similar symptom control (24C ). The adverse effect proﬁles were also similar in the two groups. However, more patients preferred rabeprazole to omeprazole. Omeprazole 40 mg/day and rabeprazole 20 mg/day for 4 weeks have been compared

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in a randomized, double-blind trial in 251 patients with erosive esophagitis (25C ). The two treatments had similar efﬁcacy in relieving symptoms on day 4 and healing esophageal lesions, but rabeprazole had a faster onset of action in patients with severe heartburn. Both drugs were well tolerated and gave rise to similar frequencies of adverse effects, commonly involving the gastrointestinal tract (10%) and nervous system (4.4%).

Esomeprazole The pharmacology, pharmacokinetics, efﬁcacy, and safety of esomeprazole have been reviewed (26R ). Esomeprazole produces acid control comparable to that of currently available proton pump inhibitors. It undergoes less hepatic metabolism than omeprazole, has an oral availability of 89% at a dose of 40 mg, and a half-life of 1.5 hours. Esomeprazole is well tolerated; its common adverse effects are diarrhea, headache, nausea, abdominal pain, respiratory infection, and sinusitis.

Lansoprazole Lansoprazole 15 mg/day and 30 mg/day were more effective than placebo, but not misoprostol 200 μg qds, for the prevention of NSAIDinduced gastric ulcers in a multicenter, doubleblind, placebo-controlled trial in 537 patients without Helicobacter pylori infection who were long-term users of NSAIDs (27C ). However, adverse effects were signiﬁcantly more frequent (31% vs less than 20%) and treatment adherence signiﬁcantly less (71% vs more than 90%) in patients taking misoprostol. The most commonly reported adverse effects in all groups were diarrhea, abdominal pain, and nausea.

Omeprazole Gastrointestinal Omeprazole 20 mg/day and famotidine 20 mg bd for 4 weeks had equivalent ulcer healing rates in a randomized, endoscopist-blinded study in 16 patients who had undergone endoscopic mucosal resection for early

gastric cancer (28c ). Although concentrations of ﬁbroblast growth factor-2 in biopsy specimens were similar in the two treatment groups, ﬁbromuscular hyperplasia was signiﬁcantly greater in the omeprazole group on day 28. Hematologic Iron deﬁciency anemia has been reported in a 49-year-old man eating a normal diet who had taken omeprazole 40 mg/day for three years (29A ). Two months after withdrawal of omeprazole his anemia improved and his serum ferritin concentration normalized after 4 months. During this period he took his usual diet and was not given any iron supplements. Prolonged suppression of gastric acid, which plays an important role in the absorption of non-heme iron, was thought to have led to iron deﬁciency. Skin Cutaneous adverse reactions attributed to omeprazole are uncommon; they include rashes, urticaria, angio-edema, acute disseminated epidermal necrolysis, lichen spinulosus, and contact dermatitis. Cutaneous leukocytoclastic vasculitis has been reported for the ﬁrst time in a 71-year-old woman with epigastric pain who had taken omeprazole 20 mg/day for 4 weeks (30A ). She made a full recovery after omeprazole was withdrawn. Susceptibility factors The pharmacokinetics of omeprazole during intravenous infusion in patients with varying degrees of liver dysfunction have been examined in an open study in 13 patients with hepatic cirrhosis (31c ). Each patient received a bolus of omeprazole 80 mg over 30 minutes, followed by a continuous infusion of 8 mg/hour for 47.5 hours. Exposure to omeprazole after intravenous administration was higher in patients with liver dysfunction. However, even in patients with severely impaired liver function, the plasma concentration of omeprazole did not change by more than 100% and the drug was well tolerated. Adverse effects were infrequent and occurred in three patients—epigastric pain, arthralgia, and hepatic encephalopathy; the last was probably unrelated to the drug.

Pantoprazole Pantoprazole 40 mg/day and ranitidine 150 mg bd for 8 weeks have been compared in the treat-

366 ment of grades II and III reﬂux esophagitis in a randomized, double-blind trial in 256 patients (32C ). Symptom relief and healing rates were signiﬁcantly better with pantoprazole. The incidences of adverse effects were similar in the two groups; the most commonly reported were diarrhea and somnolence with pantoprazole (2–3%) and headache, diarrhea, dizziness, increases in liver enzymes, and pruritus (2–4%) with ranitidine. Pantoprazole 20 mg/day and 40 mg/day and nizatidine 150 mg bd for 8 weeks have been compared in the treatment of reﬂux esophagitis (grade II or worse) in a multicenter, randomized, double-blind trial in 221 patients (33C ). Both doses of pantoprazole were more effective in relieving symptoms and healing erosive esophagitis than nizatidine. The incidences of adverse effects were similar in the three groups; the most commonly reported were diarrhea and headache. Pantoprazole 20 mg/day and ranitidine 300 mg/day for 12 months have been compared in the relief of symptoms in a multicenter, randomized, double-blind trial in 307 patients with symptomatic gastro-esophageal reﬂux disease in primary care (34C ). Symptom control was signiﬁcantly more effective and faster with pantoprazole than ranitidine. Adverse effects were similar in the two groups; the most common adverse effects were headache, diarrhea, nausea, constipation, and vomiting.

Rabeprazole The safety and efﬁcacy of rabeprazole have been evaluated in 124 patients aged 65 years and over being treated for a variety of acidrelated disorders (35c ). Rabeprazole controlled symptoms and healed mucosal lesions. The incidence of adverse effects was 4.9%, and adverse effects were more common in the presence of hepatic dysfunction and with increasing duration of treatment. The efﬁcacy and tolerability of rabeprazole 10 mg/day for 8 weeks in the treatment of reﬂux esophagitis has been assessed in an open, postmarketing surveillance investigation in 61 patients (36c ). Rabeprazole was well tolerated and was effective in relieving symptoms and healing esophagitis. Two patients developed slight rises

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H.J. de Silva

in liver enzymes, which resolved after treatment. In an open, multicenter trial in 2579 patients with erosive gastro-esophageal reﬂux disease, rabeprazole 20 mg/day for 8 weeks relieved symptoms in most patients (in over 60% by day 1 and over 80% by day 7) (37C ). Rabeprazole was well tolerated, and the most common adverse effects were headache, diarrhea, abdominal pain, and nausea, each reported by under 2% of the patients. In another open multicenter study in 92 patients with erosive esophagitis, rabeprazole 20 mg/day was effective in healing esophageal lesions and relieving heartburn (38c ). Adverse effects (diarrhea, headache, and nausea) were attributed to the medication in four cases.

HELICOBACTER PYLORI ERADICATION REGIMENS (SEDA-24, 404; SEDA-25, 422; SEDA-26, 386) Regimens for Helicobacter pylori eradication continue to be based on proton pump inhibitors (newer ones such as rabeprazole being increasingly used) or H2 receptor antagonists, two or three antibiotics, and less commonly bismuth compounds or sucralfate. They last 1 or 2 weeks. Adverse effects are those of the individual drugs used. The effect of eradicating Helicobacter pylori in 20 patients with chronic idiopathic urticaria has been assessed in a randomized, placebocontrolled trial (39c ). After 7 days of treatment with omeprazole 20 mg bd, amoxicillin 500 mg bd, and clarithromycin 500 mg bd Helicobacter pylori was eradicated in nine of 10 patients (compared with three of 10 in the placebo group) and there was a signiﬁcant improvement in urticaria in four of these nine (compared with one of the seven in whom Helicobacter pylori was not eradicated). No serious adverse effects were reported in either treatment group. In an open trial, 7-day triple therapy with omeprazole 30 mg bd, amoxicillin 500 mg tds, and clarithromycin 400 mg bd was safe and effective in eradicating Helicobacter pylori in 12 of 13 patients undergoing hemodialysis (40c ). There were adverse effects in two patients (compared with three of 27 patients not

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undergoing hemodialysis). and treatment had to be discontinued in one, owing to severe nausea and vomiting.

ANTIDIARRHEAL AGENTS (SED-14, 1233; SEDA-25, 423)

Racecadotril Racecadotril is an orally active potent inhibitor of enkephalinase, which has an antihypersecretory effect without increasing intestinal transit time. Racecadotril 100 mg tds has been compared with loperamide 2 mg tds in a singleblind study in 945 out-patients with acute diarrhea in 21 centers in 14 countries (41C ). Racecadotril resolved acute diarrhea as rapidly and as effectively as loperamide and produced more rapid resolution of abdominal symptoms and less constipation. The incidence of adverse effects attributable to medication was less in the racecadotril group (9% vs 18%). Common adverse effects were constipation, abdominal distension, anorexia, headache, and abdominal pain.

tolerated and safe and provided bowel cleansing similar to polyethylene glycol. Five patients who received polyethylene glycol and four who received sodium phosphate reported nausea, and eight patients who received polyethylene glycol and one who received sodium phosphate complained of abdominal fullness. The standard regimen of sodium phosphate used for bowel cleansing before colonoscopy is 40 tablets (60 g). In a randomized, multicenter, endoscopist-blinded trial in 98 patients undergoing colonoscopy, two smaller doses of sodium phosphate, 28 tablets (42 g) and 32 tablets (48 g), were effective (quality of colon cleansing excellent or good in over 80%) and well tolerated (44c ). The incidences of adverse effects were similar in the two groups. The reported adverse effects were nausea, vomiting, dizziness, and headache. Nervous system Tonic–clonic seizures have been reported in four adults who took oral sodium phosphate as Visicol (InKline Pharmaceutical; total 40 tablets) for bowel cleansing before colonoscopy (45A ). None of the patients had a history of seizures or electrolyte abnormalities. In all cases the seizures were associated with electrolyte abnormalities, mainly hyponatremia, after administration of Visicol.

LAXATIVES

(SED-14, 1235; SEDA-24, 406; SEDA-25, 423; SEDA-26, 387)

Lactulose In a double-blind, placebo-controlled study in 10 healthy volunteers, 10 g of lactulose powder daily for 26–33 days was an effective foodgrade prebiotic (42c ). Fecal biﬁdobacteria increased signiﬁcantly during lactulose intake, with a concomitant decrease in Clostridia.

Sodium phosphate Oral sodium phosphate 90 ml mixed with 300 ml of clear liquid has been compared with 2 liters of polyethylene glycol solution in a colonoscopist-blinded, randomized trial in 100 patients undergoing colonoscopy as a day-care procedure (43c ). Sodium phosphate was well

AMINOSALICYLATES (SED-14, 1237; SEDA-24, 406; SEDA-25, 423; SEDA-26, 387) An analysis of suspected serious adverse reactions reported to the Committee on Safety of Medicines in the UK in 1991–8 has failed to show a safety advantage for mesalazine over sulfasalazine in the treatment of inﬂammatory bowel disease (46R ). Pancreatitis and interstitial nephritis were signiﬁcantly more common with mesalazine. To assess the effects of 9 months of treatment with oral mesalazine 1.2 g/day and olsalazine 1 g/day on renal function, a randomized trial has been performed in 40 patients with ulcerative colitis in complete remission (47c ). Neither drug had a signiﬁcant effect on glomerular ﬁltration rate. Adverse effects (all mild to moderate) were more common in the

368 mesalazine group; they included abdominal pain and distension, dyspepsia, nausea, and diarrhea. Drug interactions The in vivo interaction between azathioprine and aminosalicylates has been investigated in 16 patients with quiescent Crohn’s disease taking a stable dose of azathioprine plus sulfasalazine or mesalazine (48c ). After aminosalicylate withdrawal mean 6-thioguanine nucleotide concentrations fell signiﬁcantly without signiﬁcant changes in thiopurine methyltransferase activity. This suggests an interaction between azathioprine and aminosalicylates, although the mechanism is unclear.

Mesalazine (5-aminosalicylic acid, mesalamine) The role of mesalazine in the acute and longterm treatment of ulcerative colitis has been reviewed (49R ). Mesalazine is equivalent to or better than sulfasalazine and better than placebo in inducing remission of acute disease, and comparable to sulfasalazine and better than placebo for long-term maintenance of remission. Adverse effects are uncommon, but include idiosyncratic worsening of colitis and renal toxicity. Mesalazine is safe during pregnancy and breast feeding. In maintenance therapy, it may reduce the risk of developing colorectal carcinoma. In an open, randomized trial in 266 patients with active distal ulcerative colitis, mesalazine foam enema 24 g/day was as effective as mesalazine standard liquid enema 4 g/day (50c ). The number of adverse effects attributable to medication was higher in the foam group than in the liquid enema group (14 vs 4). The most commonly reported adverse effect was ﬂatulence. Cardiovascular Constrictive pericarditis has been reported in a 37-year-old woman with chronic ulcerative colitis who had taken mesalazine 2 g/day for 2 weeks (51A ). She recovered after radical pericardiectomy. Respiratory A limited form of Wegener’s granulomatosis with a bronchiolitis obliterans

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organizing pneumonia-like variant has been reported in a 19-year-old man, a non-smoker, with ulcerative colitis, 6 months after the introduction of mesalazine 2.25 g tds orally (52A ). He recovered after mesalazine withdrawal and treatment with corticosteroids. Gastrointestinal Reports of exacerbation of colitic symptoms caused by intolerance of mesalazine are infrequent. Diarrhea, rectal bleeding, and weight loss have been described in three patients (aged 13, 14, and 17 years) with ulcerative colitis who were taking mesalazine 2–4 g/day (53A ). Their symptoms resolved dramatically after mesalazine withdrawal. Urinary tract There have been three reports of interstitial nephritis associated with mesalazine in patients with inﬂammatory bowel disease, two with ulcerative colitis and one with Crohn’s disease (54A –56A ). One patient continued to be dialysis-dependent and in two patients withdrawal of the drug and treatment with corticosteroids resulted in partial improvement in renal function. Acute tubular necrosis has been reported in a 49-year-old man with Crohn’s disease who had taken mesalazine 4 g/day for 1 month (57A ). Renal function normalized rapidly after withdrawal of mesalazine. Immunologic Angio-edema has been reported in a 23-year-old man with inﬂammatory bowel disease 48 hours after he was given mesalazine 4 g/day (58A ).

Sulfasalazine Respiratory Hypersensitivity lung disease has been attributed to sulfasalazine. The typical presentation is with new-onset dyspnea and inﬁltrates on the chest X-ray. Common symptoms are cough and fever and there are usually crackles on auscultation and peripheral eosinophilia. Sputum production, a history of allergy, rash, chest pain, and weight loss are inconsistent ﬁndings. The lung pathology is variable, the commonest change being an eosinophilic pneumonia with peripheral eosinophilia and interstitial inﬂammation with or without ﬁbrosis. In case reports, the majority of patients with suspected sulfasalazine-induced lung disease improved within weeks of drug withdrawal (59R ).

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Hematologic In a randomized, double-blind, placebo-controlled trial, 70 patients with established ankylosing spondylitis and a mean disease duration of 17 years were investigated in two centers for 26 weeks, comparing sulfasalazine 3 g/day with placebo. In the treatment group there were signiﬁcantly more cases of anemia, leukopenia, eosinophilia, and thrombocytopenia (60C ). Gastrointestinal The most common adverse effects of sulfasalazine are nausea, vomiting, and ﬂatulence (61R ). Liver Sulfasalazine can cause a fulminant hepatitis (62R ).

CHOLELITHOLYTIC AGENTS Bile acids (SED-14, 1240; SEDA-24, 408; SEDA-25, 426; SEDA-26, 389) In a retrospective review of medical records over 12 months, ursodeoxycholic acid (20 mg/ kg/day) reduced serum bilirubin concentrations in four of ﬁve children in intensive care with cholestasis and hyperbilirubinemia (65A ). No adverse effects were reported. Skin Lichenoid skin eruptions have been reported in a 1-month-old infant with neonatal hepatitis 3 weeks after the administration of ursodeoxycholic acid (66A ). There was complete resolution after withdrawal of ursodeoxycholic acid and treatment with corticosteroids.

ANTISPASMODIC AGENTS (SED-13, 1084; SEDA-25, 426; SEDA-26, 389)

Cimetropium In a randomized, double-blind, placebo-controlled trial in 97 infants with colic, cimetropium bromide 1.2 mg/kg/day for 3 days was more effective than placebo in reducing crying time (63C ). Adverse effects did not differ significantly between the two groups, except for sleepiness, which was more common with cimetropium. The reduced crying time may have been due to increased sleepiness, and the authors suggested that increased sleepiness with cimetropium bromide may relate to relief of pain and not a central nervous system effect.

Spasmocanulase® In an open study in 29 patients with irritable bowel syndrome refractory to other treatments, Spasmocanulase (active ingredients metixene hydrochloride, dimethyl polysiloxane, pepsin, and glutamic acid hydrochloride) 1 tablet tds for 6 months resulted in symptom relief in more than half the patients (64c ). No adverse effects were reported.

OTHER GASTROINTESTINAL AGENTS Sclerosant injections

(SED-13, 1086;

SEDA-25, 387) In an open trial, percutaneous ethanol injections into the liver improved prognosis compared with conservative treatment in 63 patients with cirrhosis and hepatocellular carcinoma who were not suitable for surgery or transcatheter arterial chemoembolization (67c ). Most of the patients had mild to moderate local pain during or immediately after injection and 29% developed fever. Electrolyte balance Hypernatremia and death have been reported in a 36-year-old patient with a hydatid cyst that was treated by injection of hypertonic sodium chloride and resulting in cyst rupture into the peritoneal cavity (68A ). Acknowledgement I thank Dr Mindu Weerasinghe for help with the references.

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14. Feng FY, Zhang P, He YJ, Li YH, Zhou MZ, Cheng G, Chen Y, Kikkawa T, Yamamoto M. Oral formulations of the selective serotonin 3 antagonists ramosetron (intraoral disintegrator formulation) and granisetron hydrochloride (standard tablet) in treating acute chemotherapyinduced emesis, nausea and anorexia: a multicenter, randomized, single-blind, crossover, comparison study. Curr Ther Res Clin Exp 2002; 63: 725–35. 15. Kang YK, Park YH, Rayoo BY, Bang YJ, Cho KS, Shin DB, Kim HC, Lee KH, Park YS, Lee KS, Heo DS, Kim SY, Cho EK, Lim HY, Kim WK, Lee JA, Kim TY, Lee JC, Yoon HJ, Kim NK. Ramosetron for the prevention of cisplatin-induced acute emesis: a prospective randomized comparison with granisetron. J Int Med Res 2002; 30: 220–9. 16. Ruscin JM, Page RL II, Valuck RJ. Vitamin B12 deﬁciency associated with histamine 2-receptor antagonists and a proton pump inhibitor. Ann Pharmacother 2002; 36: 812–16. 17. Kawano S, Murata H, Tsuji S, Kubo M, Tatsuta M, Iishi H, Kanda T, Sato T, Yoshihara H, Masuda E, Noguchi M, Kashio S, Ikeda M, Kaneko A. Randomized comparative study of omeprazole and famotidine in reﬂux esophagitis. J Gastroenterol Hepatol 2002; 17: 955–9. 18. Tutuian R, Katz PO, Ahmed F, Korn S, Castell DO. Over-the-counter H2-receptor antagonists do not compromise intragastric pH control with proton pump inhibitors. Aliment Pharmacol Ther 2002; 16: 473–7. 19. Itokazu GS, Fischer JH, Manitpisitkul P, Hariharan R, Danziger LH. Lack of effect of nizatidineinduced elevation of gastric pH on the oral bioavailability of dapsone in healthy volunteers. Pharmacotherapy 2002; 22: 1420–5. 20. Liberopoulos EN, Nonni AB, Tsianos EV, Elisaf MS. Possible ranitidine induced jaundice. Ann Pharmacother 2002; 36: 172. 21. Orenstein SR, Blumer JL, Faessel HM, McGuire JA, Fung K, Li Buk, Lavine JE, Grunow JE, Treem WR, Ciociola AA. Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reﬂux. Aliment Pharmacol Ther 2002; 16: 899–907. 22. Rohss K, Hasselgren G, Hedenstrom H. Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reﬂux disease. Dig Dis Sci 2002; 47: 954–8. 23. Mulder CJJ, Westerveld BD, Smit JM, Oudkerk Pool M, Otten MH, Tan TG, Van Milligen de Wit AWM, De Groot GH. A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reﬂux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicenter trial. Eur J Gastroenterol Hepatol 2002; 14: 649–56.

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24. Johnson M, Guilford S, Libretto SE. Patients have treatment preferences: a multicenter, doubleblind, crossover study comparing rabeprazole and omeprazole. Curr Med Res Opin 2002; 18: 303–10. 25. Holtmann G, Bytzer P, Metz M, Loefﬂer V, Blum AL. A randomized, double-blind, comparative study of standard-dose rabeprazole and highdose omeprazole in gastro-oesophageal reﬂux disease. Aliment Pharmacol Ther 2002; 16: 479–85. 26. Kale-Pradhan PB, Landry HK, Sypula WT, Mena R, Perreault MM. Esomeprazole for acid peptic disorders. Ann Pharmacother 2002; 36: 655–63. 27. Graham DY, Agrawal NM, Campbell DR, Haber MM, Collis C, Lukasik N, Huang B. Ulcer prevention in long-term users of nonsteroidal anti-inﬂammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162: 169–75. 28. Esaki M, Aoyagi K, Matsumoto T, Kuwano Y, Shimizu M, Fujishima M. Effects of omeprazole and famotidine on ﬁbroblast growth factor-2 during artiﬁcial gastric ulcer healing in humans. Eur J Gastroenterol Hepatol 2002; 14: 365–9. 29. Khatib MA, Rahim O, Kania R, Molloy P. Iron deﬁciency anemia-induced by long term ingestion of omeprazole. Dig Dis Sci 2002; 47: 2596–7. 30. Odeh M, Lurie M, Oliven A. Cutaneous leucocytoclastic vasculitis associated with omeprazole. Postgrad Med J 2002; 78: 114–15. 31. Pique JM, Feu F, De Prada G, Rohss K, Hasselgren G. Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction. Clin Pharmacokinet 2002; 41: 999–1004. 32. Meneghelli UG, Boaventura S, Morraes-Filho JPP, Leitao O, Ferrari AP Jr, Almeida JR, Magalhaes AFN, Castro LP, Haddad MT, Tolentino M, Jorge JL, Silva E, Maguilnik I, Fischer R. Efﬁcacy and tolerability of pantoprazole versus ranitidine in the treatment of reﬂux esophagitis and the inﬂuence of Helicobacter pylori infection on healing rate. Dis Esophagus 2002; 15: 50–6. 33. Kovacs TOG, Wilcox CM, Devault K, Miska D, Bochenek W, Avner D. Comparison of the efﬁcacy of pantoprazole vs nizatidine in the treatment of erosive oesophagitis: a randomized, activecontrolled, double-blind study. Aliment Pharmacol Ther 2002; 16: 2043–52. 34. Talley NJ, Moore MG, Sprogis A, Katelaris P. Randomized controlled trial of pantoprazole vs ranitidine for the treatment of uninvestigated heartburn in primary care. Med J Aust 2002; 177: 423–7. 35. Fujita R, Takahashi H, Iwashige M, Kamiyama T, Hara H, Koyoma T. Clinical evaluation of proton pump inhibitor, rabeprazole—special surveillance in patients of advanced age with peptic ulcer diseases. Jpn Pharmacol Ther 2002; 30: 539–49. 36. Kinoshita Y, Hirayama M, Hamada S, Yoshida T, Ishii N, Nakata R, Chishima J, Handa Y, Saito K, TakayamaT, Tatsumi S, Iishi H, Kohll Y, Fujita S, Tanaka H, Ookuchi S, Suzuki S, Koyama T, Yoshida Y, Kabemura T, Matsumoto K. Efﬁcacy of rabeprazole in patients with reﬂux esophagitis: a

371 single-center, open-label, practice-based, postmarketing surveillance investigation. Curr Ther Res Clin Exp 2002; 63: 810–20. 37. Robinson M, Fitzgerald S, Hegedus R, Murthy A, Jokubaitis L. Onset of symptom relief with rabeprazole: a community-based, open-label assessment of patients with erosive oesophagitis. Aliment Pharmacol Ther 2002; 16: 445–54. 38. De Freitas JA. Effectiveness and tolerability of rabeprazole 20 mg as once-daily monotherapy in treatment of erosive or ulcerative gastrooesophageal disease. Clin Drug Invest 2002; 22: 279–89. 39. Gaig P, Garcia-Ortega P, Enrique E, Papo M, Quer JC, Richard C. Efﬁcacy of the eradication of Helicobacter pylori infection in patients with chronic urticaria. A placebo-controlled double blind study. Allergol Immunopathol 2002; 30: 255– 8. 40. Tsukada K, Miyazaki T, Katoh H, Masuda N, Ojima H, Fukai Y, Nakajima M, Manda R, Fukuchi M, Kawano H, Tsukada O. Seven day triple therapy with omeprazole, amoxycillin and clarithromycin for Helicobacter pylori infection in haemodialysis patients. Scand J Gastroenterol 2002; 37: 1265–8. 41. Prado D. A multinational comparison of racecadotril and loperamide in the treatment of acute watery diarrhoea in adults. Scand J Gastroenterol 2002; 37: 656–61. 42. Tuohy KM, Ziemer CJ, Klinder A, Knobel Y, Pool-Zobel BL, Gibson GR. A human volunteer study to determine the prebiotic effects of lactulose powder on human colonic microbiota. Microb Ecol Health Dis 2002; 14: 165–73. 43. Reddy DN, Rao GV, Sriram PVJ. Efﬁcacy and safety of oral sodium phosphate versus polyethylene glycol solution for bowel preparation for colonoscopy. Indian J Gastroenterol 2002; 21: 219– 21. 44. Rex DK, Chasen R, Pochapin MB. Safety and efﬁcacy of two reduced dosing regimens of sodium phosphate tablets for preparation prior to colonoscopy. Aliment Pharmacol Ther 2002; 16: 937–44. 45. Mackey AC, Shaffer D, Prizant R. Seizure associated with the use of Visicol for colonoscopy. New Engl J Med 2002; 346: 2095. 46. Ransford RAJ, Langman MJS. Sulphasalazine and mesalazine: serious adverse reactions reevaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002; 51: 536–9. 47. Mahmud N, O’Toole D, O’Hare N, Freyne PJ, Weir DG, Keileher D. Evaluation of renal function following treatment with 5-aminosalicylic acid derivatives in patients with ulcerative colitis. Aliment Pharmacol Ther 2002; 16: 207–15. 48. Dewit O, Vanheuverzwyn R, Desager JP, Horsmans Y. Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn‘s disease. Aliment Pharmacol Ther 2002; 16: 79–85. 49. Schroeder KW. Role of mesalazine in acute and long term treatment of ulcerative colitis and its

372 complications. Scand J Gastroenterol Suppl 2002; 37: 42–7. 50. Malchow H, Gertz B. A new mesalazine foam enema (Claversal Foam) compared with a standard liquid enema in patients with active distal ulcerative colitis. Aliment Pharmacol Ther 2002; 16: 415–23. 51. Oxentenko AS, Loftus EV, Oh JK, Danielson GK, Mangan TF. Constrictive pericarditis in chronic ulcerative colitis. J Clin Gastroenterol 2002; 34: 247–51. 52. Yano S, Kobayashi K, Kato K, Nishimura K. A limited form of Wegener‘s granulomatosis with bronchiolitis obliterans organizing pneumonitislike variant in an ulcerative colitis patient. Intern Med 2002; 41: 1013–15. 53. Iofel E, Chawla A, Daum F, Markowitz J. Mesalamine intolerance mimics symptoms of active inﬂammatory bowel disease. J Pediatr Gastroenterol Nutr 2002; 34: 73–6. 54. Frandsen NE, Saugmann S, Marcussen N. Acute interstitial nephritis associated with the use of mesalazine in inﬂammatory bowel disease. Nephron 2002; 92: 200–2. 55. Ohya M, Otani H, Kimura K, Kodama N, Minami Y, Liang X-M, Maeshima, Yamada Y, Mune M, Yakawa S. Interstitial nephritis induced by mesalazine. Jpn J Nephrol 2002; 44: 414–19. 56. Laboudi A, Makdassi R, Cordonnier C, Fournier A, Choukroun G. Chronic interstitial nephritis induced by mesalazine. [French] Nephrologie 2002; 23: 343–7. 57. Beaulieu S, Rocher P, Hillion D, Tennenbaum R, Vitte R-L, Eugene C. Acute tubular necrosis with acute renal failure during the ﬁrst month of treatment with 5-amino-salicylate (Pentasa). Gastroenterol Clin Biol 2002; 26: 412–14. 58. Nguyen-Khac E, Le Baron F, Thevenot T, TiryLescut C, Tiry F. Angioedema in Crohn’s disease possibly due to mesalazine. Gastroenterol Clin Biol 2002; 26: 535–6.

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59. Parry SD, Barbatzas C, Peel ET, Barton JR. Sulphasalazine and lung toxicity. Eur Respir J 2002; 19: 756–64. 60. Schmidt WA, Wierth S, Milleck D, Droste U, Gromnica-Ihle E. Sulfasalazine in ankylosing spondylitis: a prospective, randomized, doubleblind placebo-controlled study and comparison with other controlled studies. [German] Z Rheumatol 2002; 61: 159–67. 61. Jiang L, Zhao N, Ni L. Retrospective study of adverse events in patients with rheumatoid arthritis treated with second-line drugs. Zhonghua Liu Xing Bing Xue Za Zhi 2002; 23: 213–17. 62. Schiemann U, Kellner H. Gastrointestinal side effects in the therapy of rheumatologic diseases. [German] Z Gastroenterol 2002; 40: 937–43. 63. Savino F, Brondello C, Cresi F, Oggero R, Silvestro L. Cimetropium bromide in the treatment of crisis in infantile colic. J Pediatr Gastroenterol Nutr 2002; 34: 417–19. 64. Mohamed AE, Ghandour ZM, Al-Karawi MA. Spasmocanulase in irritable bowel syndrome. Saudi Med J 2002; 23: 1074–7. 65. George R, Stevens A, Berkenbosch JW, Turpin J, Tobias J. Ursodeoxycholic acid in the treatment of cholestasis and hyperbilirubinemia in pediatric intensive care unit patients. South Med J 2002; 95: 1276–9. 66. Buyukgebiz B, Arslan N, Ozturk Y, Soyal C, Lebe B. Drug reaction to ursodeoxycholic acid: lichenoid drug eruption in an infant using ursodeoxycolic acid for neonatal hepatitis. J Pediatr Gastroenterol Nutr 2002; 35: 384–6. 67. Huo T-L, Huang Y-H. Wu J-C, Lee P-C, Chang F-Y, Lee S-D. Survival beneﬁt of cirrhotic patients with hepatocellular carcinoma treated by percutaneous ethanol injection as a salvage therapy. Scand J Gastroenterol 2002; 37: 350–5. 68. Memis D, Tukenmez B, Pamukcu Z. Hypernatremia due to hypertonic solution usage during cyst hydatid surgery. [Turkish] Turk Anesteziyol Reanim 2002; 30: 330–3.

Thierry Vial, Jacques Descotes, Corinna Ludwig, and Matthias Behrend

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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 and Drs Ludwig and Behrend the sections on monoclonal antibodies, immunosuppressive drugs, and immunoenhancing drugs.

IMMUNOSUPPRESSIVE DRUGS Azathioprine

(SED-14, 1280; SEDA-24, 422; SEDA-25, 440; SEDA-26, 404) Hematologic Leukopenia is the most serious adverse effect of azathioprine in patients with inﬂammatory bowel disease (1R ). It is variable and unpredictable and occurs 2 weeks to 11 years after the start of treatment (median 9 months); most cases recover 1 month after withdrawal. Azathioprine is withdrawn in one-third of patients with inﬂammatory bowel disease because of toxicity or lack of response. In a retrospective analysis of 106 patients with inﬂammatory bowel disease, to evaluate the importance of thiopurine methyl transferase (TPMT) activity in the management of azathioprine therapy in inﬂammatory bowel disease, the relation between inherited variations in TPMT enzyme activity and azathioprine toxicity was conﬁrmed (2c ). In 3291 patients receiving azathioprine 10% had a low TPMT activity and 15 (1 in 220 or 0.46%) had no detectable enzymatic activity at all (3R ), slightly more common than has been reported in other studies (1 in 300). This makes © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

the economics of screening, to avoid myelosuppression in patients receiving azathioprine, attractive. Aplastic anemia due to azathioprine therapy after corneal transplantation has reportedly caused bilateral macular haemorrhage (4A ). • A 38-year-old man underwent therapeutic penetrating keratoplasty for non-healing fungal keratitis in his left eye. Although the infection was controlled he underwent a second corneal transplantation after 2 years. Since there was corneal vascularization in three quadrants, he was given oral azathioprine postoperatively. Four months later he developed gastrointestinal bleeding and a sudden reduction in vision in both eyes. His platelet count was less than 30 × 109 /l, his hemoglobin 4.1 g/dl, and a bone-marrow aspirate was hypocellular. There were macular hemorrhages in both eyes. The haemorrhages resolved within 2 months.

Carcinogenicity Data from patients with rheumatoid arthritis and after renal transplantation suggest that azathioprine causes an increased risk of malignancy, particularly colorectal cancer. In 626 patients with inﬂammatory bowel disease who had taken azathioprine for a mean duration of 27 months (mean followup 6.9 years), there was no increased risk of cancer (colorectal or other) (5C ). Long-term treatment with azathioprine has been associated with transitional carcinoma of the bladder and non-Hodgkin’s lymphoma in a single case (6A ). • A 59-year-old man who had had a testicular non-Hodgkin’s lymphoma for 9 years developed

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374 diplopia and ptosis due to myasthenia gravis with antibodies to the acetylcholine receptor. He was given pyridostigmine and prednisolone. After 6 months he developed pernicious anemia, and he was given vitamin B12 injections. An attempt to reduce the dose of prednisolone failed, and he was therefore given azathioprine and the dose of prednisone was progressively reduced. Two years later he developed a transitional carcinoma of the bladder (pTa G1), which was removed by transurethral resection. Seven years later he developed a swollen tender right testis due to a B-cell lymphoma. He tolerated chemotherapy (CHOP) poorly and died 2 months later.

Teratogenicity Maternal azathioprine treatment during pregnancy is clearly teratogenic in animals, but the mechanisms are not known. In 27 clinical series the frequency of congenital anomalies among infants of patients who took azathioprine after renal transplantation ranged from 0 to 11% (7M ). Drug interactions Inhibition of TPMT by aminosalicylates has been described in vitro. In 16 patients with Crohn’s disease taking a stable dose of azathioprine, plus sulfasalazine or mesalazine, mean 6-thioguanine nucleotide concentrations fell signiﬁcantly over 3 months; withdrawal of the aminosalicylates had no effect on the clinical and biological evolution of Crohn’s disease in these patients (8c ).

Ciclosporin (SED-14, 1286; SEDA-24, 424; SEDA-25, 441; SEDA-26, 404) Nervous system Neurological adverse effects of ciclosporin have been reported in up to 39% of all transplant patients. Most are mild. The most frequent is a ﬁne tremor, the mechanism of which is not known. Endogenous ligands for ciclosporin and tacrolimus, known as immunophilins, are found in very high concentrations in the basal ganglia, and ciclosporin may alter dopamine phosphorylation in the mediumsized neurons in the striatum. Changes in basal ganglia glucose metabolism have been studied in a patient with severe ciclosporin-related tremor (9A ). • A 37-year-old man received ciclosporin after bone marrow transplantation for chronic myelogenous leukemia. Soon after he developed a severe tremor, which persisted despite dosage reduction. A brain

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MRI scan was normal. After 22 months he developed a personality change. A high resolution PET scan showed symmetrical increases in 18Fdeoxyglucose uptake in both caudate and putamen.

These results conﬁrm that ciclosporin can modulate dopaminergic transmission in the striatum, presumably by inhibition of calcineurin. • A 16-year-old girl with end-stage renal insufﬁciency underwent successful renal transplantation and was given ciclosporin on day 1 (10A ). On day 10 she complained of tinnitus and tremor and had a right facial nerve palsy. An MRI scan showed areas of increased signal in the white matter of the periventricular region. The dose of ciclosporin was reduced, since no other cause could be determined. Her tremor and tinnitus resolved, but the facial nerve palsy persisted. She was given tacrolimus, but the tremor and tinnitus recurred. She was then given mycophenolate mofetil and prednisone, and the tremor and tinnitus disappeared, although the facial nerve palsy persisted. The MRI scan 3 months later was normal.

The serum magnesium concentration was below the reference range in this case, which may have favored the development of neurotoxicity. Liver Ciclosporin can cause cholestasis and cellular necrosis by an inhibitory effect on hepatocyte membrane transport proteins at both sinusoidal and canalicular levels. It induces oxidative stress by accumulation of various free radicals. Ademethionine (s-adenosylmethionine) is a naturally occurring substance that is involved in liver detoxiﬁcation processes. The efﬁcacy of ademethionine in the treatment and prevention of ciclosporin-induced cholestasis has been studied in 72 men with psoriasis (11c ). The patients who were given ciclosporin plus admethionine had low plasma and erythrocyte concentrations of oxidants and high concentration of antioxidants. The authors concluded that admethionine may protect the liver against hepatotoxic substances such as ciclosporin. Urinary tract Ciclosporin is effective in treating children with steroid-dependent nephrotic syndrome, to replace corticosteroids and alkylating agents in those with adverse effects. Ciclosporin can cause tubulointerstitial lesions, whose pathogenesis remains unclear. In 37 patients the duration of ciclosporin treatment and

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of heavy proteinuria were independent risk factors for ciclosporin-induced tubulointerstitial disease (12c ). Skin Juxtaclavicular beaded lines are unique malformation of sebaceous glands or a variant of sebaceous hyperplasia. • A 63-year-old man developed small, asymptomatic, linear papules over the neck and clavicles. He had taken prednisone and ciclosporin for 30 months after kidney transplantation (13A ). A skin biopsy showed sebaceous hyperplasia.

The pathogenesis of juxtaclavicular beaded lines is unclear. Some authors have reported a prevalence of 16% in heart transplant patients, but only in men. Because ciclosporin is highly lipophilic it has many adverse effects associated with alterations of pilosebaceous follicles, such as hypertrichosis and acne. In this case the authors postulated that the combined effect of prednisone and ciclosporin may have induced sebaceous gland hyperplasia. Carcinogenicity In patients with transplanted organs ciclosporin is associated with a small but signiﬁcant risk of Epstein–Barr virus-associated lymphoproliferative disorders. • A 39-year-old man with atopic eczema was given ciclosporin for an exacerbation, which responded well (14A ). After 2 years he developed a large ulcerated erythematous nodule, a CD30+ lymphoma of the skin. Ciclosporin was withdrawn and the lesion resolved within 2 months.

Of all transplant-related lymphomas 15% are of T cell origin and are unrelated to Epstein– Barr virus infection. Cutaneous T cell lymphomas are rare and carry a good prognosis, with a 90% 4-year survival rate. Regression is often observed when immunosuppression is withdrawn or reduced. Drug monitoring Inadequate exposure to ciclosporin is a key factor in acute rejection and contributes to the development of chronic rejection and graft failure. Recent data have suggested that monitoring of ciclosporin concentrations is now widely adopted as an accurate and practical measure of drug exposure (15R ). In an open, randomized, parallel-group study in 307 patients ciclosporin blood concentrations measured 2 hours after a dose were compared

with conventional trough ciclosporin blood concentrations (16C ). The traditional pre-dose blood concentration did not correlate well with drug exposure and the 2-hour concentration was superior in preventing acute rejection. This is important, because data derived from the database of the United Network for Organ Sharing Scientiﬁc Liver Transplant Registry has shown that moderate and more severe grades of rejection are associated with poor graft function and outcome in liver transplant recipients. Drug interactions In a double-blind, randomized, placebo-controlled study in renal transplant patients receiving ciclosporin, voriconazole increased the mean ciclosporin AUC 1.7-fold (17C ). The authors therefore recommend halving the dose of ciclosporin in these patients and carefully monitoring ciclosporin blood concentrations. Obesity is a problem in transplant patients. Orlistat has been reported to reduce plasma ciclosporin concentrations (18A ). • A 29-year-old woman with increased body weight after renal transplantation was unable to adhere to a low-fat diet and took orlistat, which gave her severe diarrhea. Her plasma ciclosporin concentrations fell to subtherapeutic, even though she took the orlistat 2 hours before the ciclosporin and even though the daily dose of orlistat was reduced to 240 mg/day.

Orlistat reduced the plasma ciclosporin concentration by reducing absorption of fats rather than by a direct drug–drug interaction.

Cyclophosphamide

(SED-14, 1283; SEDA-24, 427; SEDA-25, 443; SEDA-26, 406) Immunologic Cyclophosphamide reportedly caused a type I hypersensitivity reaction in a patient with systemic lupus erythematosus (19A ).

• A 17-year-old Chinese girl with systemic lupus erythematous developed acute angio-edema over the neck, chest, and larynx and required mechanical ventilation. She had received two previous courses of cyclophosphamde without incident. She developed urticaria 30 min after an infusion of cyclophosphamide, without angio-edema, stridor, wheezing, or hypotension. Skin prick testing with cyclophosphamide was negative. Four weeks later, 15 minutes after the start of an

376 infusion of cyclophosphamide, she developed generalized urticaria. Further infusions were given with diphenhydramine premedication.

In the absence of drug-induced angio-edema or anaphylaxis, monthly therapy can be continued with antihistamine premedication. Fertility The risk of ovarian failure and infertility has been studied in 84 women with an underlying inﬂammatory disease receiving intravenous cyclophosphamide (20c ). The incidence of sustained amenorrhea was 22% and was independent of the underlying inﬂammatory disease. Cyclophosphamide crosses the placenta and reaches an amniotic ﬂuid concentration of 25%. Six pregnancies occurred in women taking cyclophosphamide; three had induced abortions, one had a spontaneous abortion, and two had normal pregnancies. After withdrawal of cyclophosphamide 16 women became pregnant; three had induced abortions for severe morphological anomalies, three had spontaneous miscarriages, and 10 delivered healthy infants. Contraception during intravenous cyclophosphamide therapy is recommended, and after withdrawal pregnancy is possible, with a favourable outcome in twothirds of cases.

Methotrexate

(SED-14, 1297; SEDA-24, 427; SEDA-25, 444; SEDA-26, 406) Liver The main concern over long-term treatment with methotrexate is hepatic ﬁbrosis and cirrhosis. Liver biopsy is the most reliable way of detecting hepatoxicity, as liver function tests may be unchanged. The incidence of liver cirrhosis after a mean dose of 2 g is 7–10%. Therefore once 1.5 g has been administered, or 2 years after starting long-term treatment, biopsy should be discussed (1R ).

Carcinogenicity Sarcoidosis is a chronic disorder associated with immune dysfunction of unknown cause. The association of sarcoidosis with lymphoma is controversial. Lymphoproliferative disorders have recently been observed during treatment of connective tissue diseases with low-dose methotrexate.

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• A 51-year-old man with systemic sarcoidosis took methotrexate for 36 months and developed a large anal ﬁssure with a diffuse polymorphic inﬁltrate containing large Ebstein–Barr virus-positive lymphoid cells, similar to the classical B cell lymphoproliferative disorders that occur in immunosuppressed transplant recipients of solid organs (21A ).

This case supports the hypothesis that immunosuppression therapy may contribute to an increased risk of Epstein–Barr virus-associated lymphoproliferative disorders.

Mycophenolate mofetil (SED-14, 1303; SEDA-24, 429; SEDA-25, 445; SEDA-26, 407) Gastrointestinal Patients with inﬂammatory bowel disease unresponsive to azathioprine or intolerant of it may beneﬁt from mycophenolate mofetil. Of 12 patients so treated, three had minor adverse effects (headache, nausea, arthralgia). Three with ulcerative colitis developed rectal bleeding while taking mycophenolate mofetil. Histological features of the mucosa were highly suggestive of drug-induced bleeding. Enterohepatic recycling results in high colonic concentrations of mycophenolic acids, which may have a direct toxic effect on the epithelium (22c ). Infection risk Mycobacterium hemophilum is a recently described pathogen that is found in immunosuppressed patients, such as those with malignancy, AIDS, and organ transplants. Systemic lupus erythematosus may make patients more susceptible to infection. • A 25-year-old Chinese woman with systemic lupus erythematosus had a disease course characterized by multiple ﬂares involving the kidneys, central nervous system, and gastrointestinal tract (23A ). She was given mycophenolate mofetil and multiple courses of antibiotics, with a poor response. After about 9 months she developed a recurrent right leg cellulitis. Two initial skin biopsies yielded negative bacterial and mycobacterial cultures, but histopathology of the muscle of her right thigh showed acid-fast bacilli and culture subsequently grew Mycobacterium hemophilum.

The authors concluded that this complication had been due to late diagnosis, multiple antibiotics, and immunocompromise. These points must be taken into consideration when treating a patient with mycophenolate mofetil.

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Sirolimus (rapamycin) (SED-14, 1304; SEDA-24, 430; SEDA-25, 446; SEDA-26, 408) Metabolism Hyperlipidemia is a signiﬁcant adverse effect of sirolimus, and often leads to cardiovascular disease. In six patients with renal transplants treated with sirolimus mean total plasma cholesterol, triglyceride, and apolipoprotein concentrations increased (24c ). The authors suggested that sirolimus increases lipase activity in adipose tissue and reduces lipoprotein lipase activity, resulting in increased hepatic synthesis of trigylcerides, increased secretion of VLDL, and increased hypertriglyceridemia. Drug interactions Combination of sirolimus with ciclosporin or tacrolimus virtually eliminates acute rejection. However, the adverse effects of both drugs are potentiated, increasing the nephrotoxicity of ciclosporin and tacrolimus (25A ).

Tacrolimus

(SED-14, 1304; SEDA-24, 431; SEDA-25, 446; SEDA-26, 408) Nervous system A polymorphism of the ABCB1 gene may be associated with a risk of tacrolimus-induced neurotoxicity after liver transplantation. In six patients with neurotoxicity and 11 without neurotoxicity, high tacrolimus concentration, liver dysfunction, and a mutation in position 2677 in exon 21 were positive predictive factors for tacrolimusinduced neurotoxicity (26c ).

Metabolism Diabetes mellitus after transplantation is a common complication of immunosuppression. Hepatitis C virus has been associated with diabetes and is a signiﬁcant renal transplant co-morbidity. In 427 patients with renal transplants and no previous diabetes mellitus, diabetes after transplantation occurred more often in hepatitis C virus-positive than hepatitis C virus-negative patients (39% vs. 9.8%) (27C ). Diabetes mellitus after transplantation occurred more often in hepatitis C virus-positive patients taking tacrolimus than in those taking ciclosporin (58% vs. 7.7%). In

hepatitis C virus-negative patients the rates of diabetes mellitus were similar. The authors concluded that hepatitis C is strongly associated with diabetes mellitus after renal transplantation because of the greater diabetogenicity of tacrolimus. In 17 patients, in whom fasting blood samples were taken immediately before transplantation and at 1 and 3 months after transplantation for measurement of HbA, insulin, C-peptide, free fatty aids, lipids, urea and creatinine, the incidence of diabetes mellitus was high (47%) (28c ). Diabetes was more common in black patients, but owing to the small number of patients the difference was not statistically signiﬁcant. Insulin resistance seems to be the main pathogenic mechanism involved. Drug interactions In a non-randomized pharmacokinectic study four patients taking tacrolimus after kidney and liver transplantation were given diltiazem in seven incremental dosages of 0–180 mg at 2-week intervals (29c ). The mean tacrolimus-sparing effect was similar to the ciclosporin-sparing effect previously reported. This effect occurred at a lower dose of diltiazem in renal transplant patients than in liver transplant patients. Tacrolimus is metabolized by CYP3A4 and is also a substrate for P glycoprotein, and this interaction could have occurred by inhibition of these mechanisms. In a patient who took tacrolimus after liver transplant, co-administration of voriconazole resulted in raised trough tacrolimus concentrations (nearly 10-fold); there were no changes in another patient, who took a placebo (30c ). Voriconazole inhibits the metabolism of tacrolimus in liver microsomes by 50% in vitro.

Thalidomide Metabolism A 70-year-old man with no family history of diabetes or known diabetes took thalidomide 400 mg/day for refractory multiple myeloma. He developed hyperglycemia, which had to be treated with insulin and later with glipizide GITS 5 mg/day (31A ).

378

MONOCLONAL ANTIBODIES (SED-14, 1308; SEDA-24, 419; SEDA-25, 438; SEDA-26, 402)

Abciximab Abciximab is a Fab fragment of the chimeric human–murine monoclonal antibody 7E3, which binds to the platelet glycoprotein GP IIb/IIIa receptor and inhibits platelet aggregation. It is used for prevention of cardiac ischemic events in patients undergoing percutaneous coronary intervention. Nervous system Seven patients undergoing neurointerventional procedures who received abciximab developed fatal intracerebral hemorrhages (32A ). The procedures included angioplasty and stent placement in the cervical internal carotid artery (n = 4), angioplasty of the intracranial carotid artery (n = 1), and angioplasty of the middle cerebral artery (n = 2). Aggressive antithrombotic treatment is used as adjuvant to angioplasty and/or stent placement to reduce the rate of ischemic and thrombotic complications associated with these procedures. Intravenous abciximab has a short life (10 min), but its inhibitory effect on platelets lasts for 48 hours. The exact cause of abciximab-associated intracerebral hemorrhage remains unclear. Hematologic Thrombocytopenia (below 100 × 109 /l) occurs in 2.4–4.2% of patients receiving abciximab and severe thrombocytopenia (below 50 × 109 /l) in 1%. It usually occurs within 12–96 hours, but there has been a report of acute profound thrombocytopenia 7 days after the use of abciximab (33A ). • A 65-year-old woman with type 2 diabetes mellitus and coronary artery disease received a 0.25 mg/kg bolus of abciximab at the time of intervention followed by an infusion of 10 μg/min for 12 hours. Her baseline platelet counts were 286 × 109 /l before use, 385 × 109 /l at 2 hours, and 296 × 109 /l at 18 hours. On day 7 she developed petechiae over her legs and her platelet count was 1 × 109 /l. Coagulation tests were normal and there was no evidence of heparin-induced thrombocytopenia. She received 10 units of single-donor platelets and recovered slowly over the next 4 days. The platelet count was 114 × 109 /l on day 12.

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The mechanism of severe thrombocytopenia associated with abciximab is unclear. Further administration should be avoided, but other GP IIb/IIIa inhibitors (eptiﬁbatide and tiroﬁban) have been successfully used in patients with history of abciximab-induced thrombocytopenia. Thrombocytopenia after a second exposure to abciximab in nine patients showed that each had a strong immunoglobulin IgG antibody that recognized platelets sensitized with abciximab (34c ). Five patients also had IgM antibodies. Thrombocytopenia occurred four times as often as after the ﬁrst exposure. The mechanism is not understood, but these ﬁndings suggest the it may be antibody mediated. These antibodies were also found in 77 of 104 healthy patients, but in the patients the antibodies were speciﬁc for murine sequences in abciximab, causing the life-threatening thrombocytopenia. Ethylenediaminetetraacetate can cause pseudothrombocytopenia by activating platelet agglutination, resulting in a spuriously low platelet count (SEDA-21, 250). Of 66 patients receiving abciximab after coronary revascularization, 17 developed thrombocytopenia and nine severe thrombocytopenia (35c ). However, of these 26 patients, 18 had pseudothrombocytopenia. True thrombocytopenia occurred at 4 hours after infusion whereas pseudothrombocytopenia occurred within the ﬁrst 24 hours. The mechanism of pseudothrombocytopenia may be the effect of EDTA on the calcium-dependant glycoprotein IIb–IIIa complex, which frees the antigenic binding site on GPIIb available to IgM antibody. This increased antibody binding may cause platelet clumping and lead to false thrombocytopenia. True thrombocytopenia did not lead to hemorrhagic complications, but the patients required platelet transfusion. In 7800 patients with chest pain and either ST segment depression or a positive troponin test, the addition of abciximab to unfractionated heparin or low molecular-weight heparin in the treatment of acute coronary syndrome is not associated with any signiﬁcant reduction in cardiac events, but a doubled risk of bleeding (36C ). Without early coronary intervention there is no indication for abciximab. Immunologic An anaphylactic reaction to abciximab has been reported (37A ).

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• An obese 46-year-old woman with prolonged angina pectoris underwent coronary angiography. She had no known drug allergies, but on administration of an iodinated contrast media she developed anaphylactic shock. After successful resuscitation angiography was completed and she was given aspirin, ticlopdine for a month, and metoprolol. Five months later she developed chest pain again, and angiography was repeated after pretreatment with prednisone and diphenhydramine and she was given abciximab. Within 5 minutes she had an anaphylactic reaction, requiring resuscitation.

owing to progressive multifocal leukoencephalophathy; papovavirus was isolated from the cerebrospinal ﬂuid (39c ).

This case shows that anaphylactic reactions to abciximab can occur even after pretreatment with prednisone and diphenhydramine for a known allergy to iodine.

Skin In a placebo-controlled study in 48 patients with active rheumatoid arthritis CD4 blockade produced clinical beneﬁt (40C ). Adverse events were reported in 97% of the patients, compared with 73% of those given placebo. In both groups most of the events were mild to moderate. Serious adverse events were reported in ﬁve patients who received antiCD4; syncope/vasovagal attacks (n = 3), back pain (n = 1), abdominal pain/rectal bleeding (n = 1). Skin rashes occurred in 62% of the patients who received the antibody. In ﬁve cases a skin biopsy was performed, and showed a cellular inﬁltration centered on the blood vessels, suggesting a drug-induced vasculitis.

Alemtuzumab Infection risk Alemtuzumab is a humanized monoclonal antibody used to treat refractory B cell chronic lymphocytic leukemia. It binds to CD52, which is intensively expressed on the surface of malignant B and T lymphocytes. From previous experience the risk of infection is known; for instance, reactivation of cytomegalovirus is a frequent complication during treatment with alemtuzumab, but other organisms are occasionally described. • A 52-year-old man with B cell chronic lymphocytic leukemia had weight loss and a steadily rising blood lymphocyte count. He received alemtuzumab as ﬁrst-line treatment as part of a clinical trial. After 12 weeks the leukemia completely remitted. Three years later he received chlorambucil for progressive disease and had a partial remission. After another 2 years his chemotherapy regimen was change to ﬂudarabine and cyclophosphamide. After a further year his disease became rapidly progressive, with anemia, splenomegaly, and lymphadenopathy. Alemtuzumab was reintroduced and standard prophylaxis treatment was started with co-trimoxazole, valaciclovir, and ﬂuconazole. After 8 weeks he developed fever up to 39.0◦ C. There was no evidence of bacterial or viral infection. His general condition worsened rapidly and he showed signs of acute hepatitis, renal insufﬁciency, disseminated intravascular coagulation, and ﬁnally respiratory failure. He died 14 days after the start of the fever. Adenovirus 5 was recovered from the lung, spleen, liver, and blood (38A ).

Among 18 patients with chronic lymphocytic leukemia, one with a long-lasting lymphocytopenia died 3 months after treatment,

Anti-CD4 Anti-CD4 is a monoclonal antibody that induces a more than 80% down-regulation of CD4 molecules in the surface of T lymphocytes.

Basiliximab Basiliximab in a chimeric monoclonal antibody used in immunosuppressive induction therapy in transplantation. It acts by binding the alpha chain of IL-2 receptors on activated T lymphocytes. Immunologic Basiliximab is composed of murine sequences (30%), which can cause IgEmediated hypersensitivity reactions. • A 42-year-old Hispanic woman, with end-stage renal disease, anemia, hypertension, and a history of an anaphylactic reaction to basiliximab, was scheduled to receive a living donor transplant and received basiliximab uneventfully (41A ). However, owing to donor infection the procedure was canceled and rescheduled for 2 weeks later. Within 10 min after basiliximab reinduction she developed an anaphylactic reaction. In an attempt to ﬁnd another induction therapy for this patient skin testing was performed for daclizumab without response. She therefore received full-dose induction with daclizumab before her organ transplant without adverse effect.

380 Daclizumab, a humanized monoclonal antibody, is composed of only 10% murine antibody sequences and therefore is less immunogenic. These ﬁndings suggest that despite the similar compositions of human and mouse antibody protein sequences the IgE responsiveness is signiﬁcantly different.

Gemtuzumab Gemtuzumab (Mylotarg) is a humanized antiCD33 antibody linked to an antitumor antibiotic. It has been approved for treatment of patients with relapsed acute myeloid leukemia in association with topotecan + cytarabine. As expected, the most common adverse effects are leukopenia and thrombocytopenia. Liver Hepatotoxicity, with raised bilirubin and liver enzymes, is common with gemtuzumab (30–50%) and is mostly reversible. A more severe complication, hepatic veno-occlusive disease, is rare and is mostly seen in patients previously undergoing bone marrow transplantation (4–5%). Close monitoring of patients receiving gemzutumab is necessary, even if they have not had previous bone marrow transplantation (42M ). Hepatic veno-occlusive disease is a clinical syndrome consisting of hyperbilirubinemia, painful hepatomegaly, and ﬂuid retention or ascites. It occurs most commonly after highdose chemotherapy and hematopoietic stem cell transplantation. Patients with severe venoocclusive disease die from progressive multiorgan failure. Of eight patients who were given an infusion of gemtuzumab 9 months after hemopoietic stem cell transplantation, seven had normal serum bilirubin concentrations, and all eight had transaminase and alkaline phosphatse activities that were less than 1.5 times the upper limit of the reference range (43c ). Six had no evidence of hepatotoxicity. One developed abdominal pain, ascites, and mildly raised transaminases. A CT scan showed no evidence of hepatic disease. This patient did not meet the criteria of veno-occlusive disease. Patient 8 did meet the criteria of veno-occlusive disease 3 days after infusion with gemzutumab. She developed multi-organ failure and died.

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Of 17 patients who were given gemtuzumab, three developed grade 3 hyperbilirubinemia, and ﬁve developed grade 3–4 hepatic transaminitis after a median of 13 days, including one who developed veno-occlusive disease (43c ). This patient had abrupt onset of weight gain, associated with ascites, abdominal distension, acute hepatic failure, and right upper quadrant pain, and died. As a possible mechanism gemtuzumab may selectively target CD33-expressing cells in hepatic sinusoids, activate stellated cells, damage sinusoidal endothelial cells, and cause sinusoidal vasoconstriction or ischemic hepatocyte necrosis. Liver histology showed sinusoidal injury with extensive sinusoidal ﬁbrosis, centrilobular congestion, and hepatocyte necrosis (44c ).

Ibritumomab Ibritumomab is a murine IgG1 anti-CD20 antibody, the parent of the engineered chimeric antibody rituximab, a monoclonal antibody with mouse variable and human constant regions. It induces apoptosis and has antiproliferative effects. Ibritumomab tiuxetan (Zevalin) is composed of the monoclonal antibody ibritumomab, the linking chelator tiuxetan, and the radioisotope 90 yttrium. Carcinogenicity Acute myelogenous leukemia has been attributed to ibritumomab (45A ). • An 80-year-old woman with a small B cell extranodal lymphoma was initially given chorambucil for 10 months, with complete remission for 2 years. When she developed recurrent lymph node swelling she was given ibritumomab tiuxetan, with near-complete remission. When she developed progressive disease 14 months later, she received cyclophosphamide, vincristine, and prednisone for one cycle. She had persistent pancytopenia, and a bone marrow biopsy showed extensive inﬁltration by acute myelogenous leukemia.

This seems to be the ﬁrst case of drug-related acute myelogenous leukemia. Fluorescent in situ hybridization studies on the bone marrow showed a signal consistent with rearrangement of the mixed myeloid leukemia (MLL) gene on chromosome 11. This abnormality was not present before treatment.

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Chapter 37

Inﬂiximab See Tumor Necrosis Factor antagonists.

Muromonab-CD3 Liver The introduction of muromonab-CD3 (OKT3) revolutionized the management of steroid-resistant rejection in transplant patients. Hepatitis has been attributed to cytokine release (46A ). • A 31-year-old man underwent renal transplantation for end-stage renal disease secondary to hypertension. He was given basiliximab for induction immunosuppression. At 13 months after transplantation he had a bout of transplant rejection. His creatinine concentration rose acutely from 83 to 165 μmol/l over 1 week. This was his ﬁrst rejection episode (Banff IIa). There was no evidence of viral infection. He received muromonab with conventional prophylaxis (antihistamines, paracetamol, and corticosteroids) to reduce the severity of cytokine release. This was his ﬁrst exposure to muromonab. Initially he complained of fever and nausea, and the following day he was somnolent and had right upper quadrant tenderness. Liver function tests, which had been normal on the day of admission, were abnormal (alkaline phosphatase 136 U/l, AsT 1238 U/l, AlT 1125 U/l, LDH 1551 U/l, γ GT 332 U/l, and total bilirubin 66 μmol/l). Hepatitis serology showed positive hepatitis B core antibody (IgM and IgG), positive hepatitis A antibody, negative hepatitis surface antigen, and negative hepatitis C antibody. The hepatitis B core antibody (IgM and IgG) had been positive before transplantation 16 months before. Muromonab was withdrawn and he showed signs of clinical and chemical improvement. Rejection was successfully treated with steroids and antithymocyte globulin.

Rituximab Rituximab is a chimeric mouse human antigen anti-CD20 antibody licensed for the treatment of low-grade-non-Hodgkin’s lymphoma. Recently it has also been used in the treatment of diffuse large B cell lymphoma. Hematologic The factors associated with toxicity in patients with B cell lymphoma receiving rituximab have been studied in Japan (47C ). By univariate analysis overall non-hematological

381 toxic effects (grade 2 or greater) were more frequent in patients with extranodal disease and especially in those with bone marrow involvement. Fever was more frequent in patients with raised LDH activity, whereas chills/rigors and vomiting were more frequent in patients with extranodal disease. Patients with raised LDH activity or extranodal disease may therefore require closer monitoring. Hematological toxic effects of grade 3 or worse were more common in women. • A 26-year-old woman with a diffuse large B cell lymphoma received CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin® , and prednisone), rituximab, and radiotherapy (48A ). She developed a transfusion-dependent anemia. Bone marrow biopsy conﬁrmed pure red cell aplasia and parvovirus infection. She had no antibodies to parvovirus, suggesting that she never had a previous exposure. Intravenous immunoglobulin resulted in a reticulocytosis and recovery of her hemoglobin.

The authors suggested that rituximab had depleted her primary B cells, resulting in an inability to mount a primary immune response to parvovirus infection. Parvovirus is pathogenic to red cell precursors, causing their destruction before release from the bone marrow. Skin Stevens–Johnson syndrome has been attributed to rituximab (49A ). • A 33-year-old man with a follicular non-Hodgkin lymphoma entered a phase II trial of rituximab. The ﬁrst two cycles were given without infusionrelated toxicity, but during the second cycle mucositis was noticed. Before the third cycle he developed a pruritic rash on the trunk, grade 2 mucositis, and weight loss. He was given oral ﬂuconazole, aciclovir, and antihistamines, which led to improvement. One week after the third infusion of rituximab he had grade 3 orogenital mucositis and the maculopapular rash on the trunk worsened, with areas of ulceration. Rituximab was withdrawn. Stevens–Johnson syndrome was conﬁrmed by biopsy.

Immunologic Infusion reactions with rituximab are generally well tolerated, as with most monoclonal antibodies. Most reactions are limited to the ﬁrst infusion, including nausea, chills, and fever. They are encountered in over 90% of patients. More serious is the cytokine release syndrome, which occurs within 60–90 minutes and is characterized by fever, chills, rigors, bronchospasm, hypoxia, hypotension,

382 urticaria, and angio-edema. Infusion must be discontinued and the patient carefully monitored with chest radiography and ﬂuid and electrolyte assessment and treated with oxygen and bronchodilators. A rapid tumor clearance syndrome can also occur within 30–60 minutes, with similar symptoms. Lymphocytes rapidly disappear from the peripheral blood and uric acid and LDH increase markedly. Treatment includes interruption of the infusion, hydration, allopurinol, oxygen, and bronchdilators. It mainly occurs in patients with high white blood cell counts, such as those with chronic lymphatic leukemia. Carcinogenicity A second cancer is possible when treating a tumor by mutagenicity or immunosuppression. There may be a link between the therapy given and the development of Merkel cell carcinoma (50A ). • A 54-year-old man with stage I follicular lymphocytic lymphoma with cervical lymph nodes underwent splenectomy followed by chemotherapy with chlorambucil and had a partial response. Five months later, when he developed generalized lymphadenopathy and bone marrow involvement, he received ﬂudarabine, cyclophosphamide, and rituximab, with complete remission. Ten months later he developed a Merkel cell carcinoma involving the liver and lymph nodes. The disseminated tumor was chemoresistent and he died. His lymphoma remained in complete clinical remission throughout this time.

Two patients developed a peripheral T cell non-Hodgkin’s lymphoma after rituximab therapy, one after 15 months and the other after 18 months (51R ).

Trastuzumab Trastuzumab (Herceptin® ) is a recombinant DANN-derived humanized monoclonal antibody against the proto-oncogene, HER-2/neu gene product. It inhibits tumor growth in breast cell cancer cells that overexpress the human epidermal growth factor receptor (HER2). This growth factor is ampliﬁed in 25–30% of breast cancers and is associated with an aggressive form of disease. Serious adverse events, including death, have occurred in 0.25% of patients treated with trastuzumab. They fall into three

Chapter 37

Thierry Vial et al.

categories: infusion reactions; hypersensitivity reactions, including fatal anaphylaxis; and pulmonary events, including ARDS. Cardiovascular The most signiﬁcant adverse event of trastuzumab is cardiac dysfunction, which occurs in 5% of patients given trastuzumab alone, in 13% of patients given trastuzumab with paclitaxel, and in 27% of patients given trastuzumab in combination with anthracylines and cyclophosphamide (52A ). Seven phase II and III clinical trials of trastuzumab in patients with metastatic breast cancer have been reviewed (53M ). The physiopathology of trastuzumab-associated cardiac disease is poorly understood, and baseline MUGA scanning is recommended to identify cardiac disease. The rates of cardiac disease were highest when trastuzumab was given in combination with anthracyclines or when there had been previous exposure to anthracyclines. Given the 25% improvement in overall survival in these patients with metastatic disease, the use of trastuzumab is justiﬁed. • A 60-year-old woman with coronary heart disease and hypertension developed breast cancer and a core biopsy showed ER+/PR+/HER2–3+ (52A ). She enrolled in an institutional study with neoadjuvant trastuzumab with docetaxel. A pretreatment blood pool radionuclide angiography (MUGA) scan revealed a left ventricular ejection fraction of 56%. She had a good clinical response to treatment at 3 months. Before surgery a repeat MUGA showed a dilated left ventricle and a reduced ejection fraction (35%). She underwent surgery and 2 months later her ejection fraction was 44%. • An overweight 59-year-old woman with hypertension and asthma developed breast cancer (ER+ /PR+/HER2–2+) (52A ). Her MUGA scan showed a left ventricular ejection fraction of 57%. She was given trastuzumab with doxotaxel and had a good response after 4 months. Before surgery she became dyspneic, and a MUGA scan showed an ejection fraction of 24%; even 7 months after surgery her MUGA scan showed no improvement.

The efﬁcacy and tolerability of trastuzumab in clinical trials has been reviewed (54AR ). Of the ﬁrst 48 patients treated in Sweden with or without chemotherapy, two had serious cardiac events and both had previously been treated with an anthracycline. As not all patients who received trastuzumab had echocardiography, the number of cardiac events was probably underestimated. It has been postulated that HER2 pathways may be involved in myocyte

Drugs acting on the immune system

Chapter 37

repair, and that concomitant administration of trastuzumab may interfere with the repair of anthracyline-damaged myocytes (55R ). Recent evidence from 20 patients has shown that cardiotoxicity is related to trastuzumab uptake in the myocardium, suggesting that the extent of HER2 receptor expression, or a related crossreactive antigen in the myocardium, may be the underlying mechanism. Respiratory The toxicity of ﬁve escalating doses of trastuzumab (1–8 mg/kg) when combined with a ﬁxed dose of IL2 has been determined in 45 patients with non-hematological malignancies that overexpressed HER2 (56c ). There was no evidence of increasing toxicity related to the dose of trastuzumab. Five patients had pulmonary toxicity of grade 3 or higher; these were primarily attributed to IL2, as the patients improved on reduction of the dose of IL2. Drug interactions In primates, trastuzumab clearance was reduced when it was administered with paclitaxel (57M ).

INTERFERONS

(SED-14, 1246; SEDA-24, 411; SEDA-25, 431; SEDA-26, 393)

Interferon-alpha Both natural and recombinant interferon-alpha are commercially available, but there have been few direct comparisons of different forms of interferons. In a randomized comparison of recombinant interferon-alpha-2b and interferonalpha-n-3 (9 million units/week for 1 year) in 168 naive patients with chronic hepatitis C, there was no signiﬁcant difference in clinical outcomes and the incidence or type of adverse effects between the groups (58C ). There was a non-signiﬁcant trend toward more severe leukopenia and a higher incidence of severe thyroid disorders in patients who received recombinant interferon-alpha-2b. Interferon-alpha, in combination with ribavirin, is currently ﬁrst-line therapy for patients with chronic hepatitis C and compensated liver disease, and its use has been extensively reviewed (59R ). A meta-analysis of trials in patients who were previously non-responsive

383 to interferon-alpha alone showed that treatment withdrawal for an adverse event was more frequent in patients who received combination therapy (8.8%) compared with interferon-alpha monotherapy (4%) (60M ). However, treatment withdrawal is more frequent in practice. In a retrospective analysis of 441 consecutive patients treated with interferon-alpha and ribavirin, 25% of patients discontinued treatment because of adverse effects (61C ). The study identiﬁed female sex, a dose of interferon-alpha above 15 MU/week, and naive patients as independent susceptibility factors for premature withdrawal. Cardiovascular Severe interferon-alpha-induced cardiovascular complications have mostly been described in patients with malignancies. The following report suggested that myocardial dysfunction can completely reverse after withdrawal and does not exclude further treatment with lower doses of interferon-alpha (62A ). • A 47-year-old man with renal cancer and no previous history of cardiovascular disease developed gradually worsening exertional dyspnea after he had received interferon-alpha in a total dose of 990 MU over 5 years. Echocardiography and a myocardial CT scan conﬁrmed a dilated cardiomyopathy, with left ventricle dilatation and diffuse heterogeneous perfusion at rest. He improved after interferon-alpha withdrawal and treatment with furosemide, quinapril, and digoxin. Myocardial scintigraphy conﬁrmed normal perfusion. He restarted low-dose interferon-alpha (6 MU/week) 1 year later and had no recurrence of congestive heart failure after a 1-year follow-up period.

Raynaud’s syndrome is a rare adverse effect of interferon. In 24 cases, interferon-alpha was the causative agent in 14, interferon beta in three, and interferon gamma in ﬁve (63AR ). There was no consistent delay in onset and the duration of treatment before the occurrence of symptoms ranged from 2 weeks to more than 4 years. The most severe cases were complicated by digital artery occlusion and necrosis requiring amputation. Few patients had other ischemic symptoms, such as myocardial, ophthalmic, central nervous system, or muscular manifestations. Severe Raynaud’s phenomenon was also reported in a 5-year-old girl with hepatitis C (64A ). Respiratory Although it is seldom reported, pulmonary toxicity of interferon alpha should be promptly recognized, in order to avoid

384 further complications. In four patients with hematological malignancies who developed symptoms suggestive of pneumonitis (i.e. a dry cough and dyspnea) after 1 week to 38 months of interferon alpha treatment, there was a marked reduction in carbon monoxide diffusion capacity in all cases, whereas there were pathological ﬁndings in ordinary chest X-rays in only two (65A ). What the authors called ultracardiography and high-resolution CT scanning were suggested to have higher sensitivity in evaluating pulmonary symptoms. In three patients, complete reversal was obtained after interferonalpha withdrawal, either spontaneously or after corticosteroid treatment, although one patient required long-term corticosteroid treatment. In a retrospective review of 70 patients with hepatitis C enrolled in four clinical trials, there were four cases of signiﬁcant pulmonary toxicity (two of bronchiolitis obliterans and two of interstitial pneumonitis) (66A ). Three recovered completely, but one still required corticosteroids for exertional dyspnea that persisted 17 months after interferon-alpha withdrawal. The authors suggested that there was an increased risk with high-dose interferon, because three of these patients received high doses (5 MU/day) or pegylated interferon-alpha. In contrast, they were unaware of any signiﬁcant pulmonary toxicity in any of their approximately 500 patients with hepatitis C. Nervous system The ﬁrst report of multiple sclerosis attributed to interferon-alpha has been described (67A ). • A 29-year-old woman received interferon-alpha2b (6–10 MU/day) for chronic myeloid leukemia, and about 3 years later developed headaches, back pain, progressive visual disturbance, and a sensory deﬁcit in the legs. MRI scans of the brain and spinal cord suggested a ﬁrst episode of multiple sclerosis. In addition, the myelin basic protein concentration was slightly raised, and perimetry showed bilateral optic neuritis. Most of her neurological symptoms, except central vision impairment, improved after interferon-alpha withdrawal and treatment with high-dose methylprednisolone. As a major partial cytogenetic response had been obtained with interferon, she was given natural interferon-alpha (3 MU/day) 2 months later. After 2 days of treatment, she complained of transient but severe pain in the back and the legs, and developed acute paraplegia and loss of micturition desire. Again, interferon was withdrawn and she was given high-dose methylprednisolone. There was no further neurological deterioration at followup.

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This account is reminiscent of the various autoimmune diseases that may be unmasked or exacerbated by interferon-alpha. The new onset or worsening of neuropathy has rarely been described in patients with hepatitis C. In 17 reports, sensorimotor polyneuropathy was the most frequent presentation (68AR ). Other neurological manifestations included mononeuropathy multiplex, cranial neuropathy, and chronic inﬂammatory demyelinating polyneuropathy. The symptoms developed after 2–28 weeks of treatment (up to 12 weeks in 13/16), and there was no obvious relation to cumulative dose. Nerve biopsy showed necrotizing vasculitis or axonal degeneration. Most patients stabilized or improved slowly over several months after interferon-alpha withdrawal and/or treatment with corticosteroids. Four patients also required plasmapheresis or cyclophosphamide. Although several authors suggested an autoimmune process, the underlying pathogenic mechanism is unclear. Two further cases of Bell’s palsy, which reversed after interferon-alpha withdrawal, have been reported (69A ). Although the delay in onset (7.5 and 8 weeks) suggested that interferonalpha might be the cause, one patient had no recurrence after rechallenge. A coincidental adverse event cannot therefore be completely ruled out. The use of intraspinal interferon-alpha (1 MU three times a week for 4 weeks) in 22 patients with neoplastic meningitis was associated with frequent adverse effects that mostly manifested as chronic fatigue syndrome in 91% of patients (severe in 45%) and arachnoiditis in 73% (severe in 9%) (70c ). Sensory systems Although most patients with interferon-alpha retinopathy remain asymptomatic, ocular complications, such as sudden loss of vision due to occlusive vasculitis or central retinal artery occlusion (71A ) and anterior ischemic optic neuropathy (72A ), continue to be reported. Regular ophthalmological monitoring to detect retinal changes, even though the patient is still asymptomatic, is therefore strongly recommended in patients receiving interferonalpha. Psychiatric Interferon-alpha-induced psychiatric adverse effects have been extensively studied, and recent reviews have provided comprehensive analysis of the large amount of experimental and clinical data that have accumulated

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since 1979 (73R , 74R ). In four recent clinical studies in a total of 210 patients with chronic hepatitis C, the rate of major depressive disorders during interferon-alpha treatment was 23– 41%. Most patients developed severe depressive symptoms within the ﬁrst 3 months of treatment (75c –78c ). Various possible risk factors have been analysed in several studies (76c –79c ). Sex, the dose or type of interferon-alpha (natural or recombinant), a prior personal history of psychiatric disease, substance abuse, the extent of education, the duration and severity of the underlying chronic hepatitis, and scores of depression before interferon alpha treatment were not signiﬁcantly different between patients with and without interferon-alpha-induced depression. Advanced age was suggested to be a risk factor in only one study (78c ). Although a worsening of psychiatric symptoms was noted during treatment in 11 patients receiving psychiatric treatment before starting interferon, only one was unable to complete the expected 6month course of interferon-alpha and ribavirin therapy (76c ). This suggests that pre-existing psychiatric disorders should not be systematically regarded as an absolute contraindication to interferon treatment. A study in 18 patients treated with interferon-alpha for chronic hepatitis C has given insights into the possible pathophysiological mechanism of depression (80c ). Depression rating scales, plasma tryptophan concentrations, and serum kynurenine and serotonin concentrations were measured at baseline and after 2, 4, 16, and 24 weeks of treatment with interferonalpha 3–6 MU 3–6 times weekly. During treatment, tryptophan and serotonin concentrations fell signiﬁcantly, while kynurenine concentrations rose signiﬁcantly. Depression rating scales also rose from baseline after the ﬁrst month of treatment, with continued increases thereafter. In addition, there was a relation between increased scores of depression and changes in serum kynurenine and serotonin concentrations. These changes suggested a predominant role of the serotonergic system in the pathophysiological mechanisms of interferon-alpha-associated depression. Accordingly, 35 of 42 patients included in three open trials of antidepressant treatment responded to a selective serotonin reuptake inhibitor drug, such as citalopram or paroxetine, and were able to complete interferon treatment (77c , 81c , 82c ).

385 Endocrine In a prospective study, the overall incidence of biochemical thyroid disorders was 11.8% in 254 patients with chronic hepatitis C randomized to receive ribavirin plus high-dose interferon alpha (6 MU/day for 4 weeks then 9 MU/week for 22 weeks) or conventional treatment (9 MU/week for 26 weeks) (83C ). There was no difference in the incidence or the time to occurrence of thyroid disorders between the groups. Of the 30 affected patients, 11 (37%) had positive thyroid peroxidase autoantibodies (compared with 1% of patients without thyroid dysfunction), nine developed symptomatic thyroid dysfunction, and only three had to discontinue treatment. There was no correlation between the viral response and the occurrence of thyroid disorders, and only female sex and Asian origin were independent predictors of thyroid disorders. The occurrence of thyroid dysfunction in 72 patients treated with interferon-alpha plus ribavirin (1–1.2 g/day) has been compared with that of 75 age- and sex-matched patients treated with interferon-alpha alone for chronic hepatitis C (84C ). Of the former, 42 patients, and of the latter, 40 patients had received previous treatment with interferon-alpha alone. There was no difference in the rate of thyroid autoimmunity (antithyroglobulin, antithyroid peroxidase, and thyroid stimulating hormone receptor antibodies) between the two groups, but the patients who received interferon-alpha plus ribavirin developed subclinical or overt hypothyroidism more often (15% versus 4%). Similarly, the incidence of hypothyroidism increased to 19% in patients who underwent a second treatment with interferon-alpha plus ribavirin compared with 4.8% after the ﬁrst treatment with interferon-alpha alone, while the incidence remained essentially the same in patients who had two consecutive treatments with interferonalpha alone (4.7% and 7.1% respectively). Furthermore, there was no higher incidence of thyroid autoimmunity or clinical disorders after a second course of interferon-alpha whether alone or combined with ribavirin in patients who had no thyroid autoantibodies at the end of a ﬁrst course of interferon-alpha alone, suggesting that these patients are relatively protected against the development of thyroid autoimmunity. The clinical, biochemical, and thyroid imaging characteristics of thyrotoxicosis resulting

386 from interferon-alpha treatment have been retrospectively analysed from data on 10 of 321 patients with chronic hepatitis (75 with chronic hepatitis B and 246 with chronic hepatitis C) who developed biochemical thyrotoxicosis (85c ). Seven patients had symptomatic disorders, but none had ocular symptoms or a palpable goiter. Six had features of Graves’ disease that required interferon-alpha withdrawal in four and prolonged treatment with antithyroid drugs in all six. Three presented with transient thyrotoxicosis that subsequently progressed to hypothyroidism and required interferon withdrawal in one and thyroxine treatment in all three. Although thyroid disorders in patients treated with interferon-alpha generally follows a benign course after interferon-alpha withdrawal or speciﬁc treatment, severe long-lasting ophthalmopathy resulting from Graves’ disease has been described in a 49-year-old woman (86A ). Metabolism Insulin-dependent diabetes mellitus has been reported after 2 weeks to 6 months of treatment with interferon-alpha in four patients with chronic hepatitis C (87A ). All discontinued interferon-alpha, and one woman who restarted treatment had a subsequent increase in insulin requirements. A severe acute ﬂare of porphyria cutanea tarda has been reported in a 61-year-old man after 4 months of treatment with interferon-alpha2b plus ribavirin for chronic hepatitis C (88A ). No further relapse was observed after chloroquine treatment, despite continuation of the antiviral drugs. This patient had previously had episodes of small blisters that spontaneously resolved, and hereditary porphyria cutanea tarda was demonstrated by chromatographic and mutation analysis. Hematologic Although neutropenia induced by interferon-alpha is common, little is known about the exact risk of bacterial infections in patients with pre-existing neutropenia before treatment or in whom the dosage is not adjusted when neutropenia develops during treatment. In one study in 119 patients treated with interferon-alpha and ribavirin for chronic hepatitis C, in whom neutropenia was not considered as a cause for exclusion or dosage modiﬁcation, the neutrophil count fell by an average of 34% (31–74%) (89C ). During the course of

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treatment, 32 patients had at least one neutrophil count below 1 × 109 /l, 11 had a neutrophil count below 0.75 × 109 /l, and two had a neutrophil count below 0.5 × 109 /l; however, none of these patients required dosage modiﬁcation because of neutropenia. None of the 22 patients who developed documented or suspected bacterial infections during or immediately after treatment withdrawal had concomitant neutropenia. The three black patients with constitutional neutropenia (pre-treatment neutrophil counts below 1.5 × 109 /l) had only minimal changes in their neutrophil counts during treatment and no infection, suggesting that these patients can be safely treated. The effects of interferon-alpha-2b on platelet aggregation have been studied in 29 patients with melanoma who received a low-dose regimen (9 MU/week in ﬁve patients) or a highdose regimen (100 MU/m2 /week intravenously for 4 weeks then 30 MU/m2 /week subcutaneously for 48 weeks in 24 patients) (90c ). Compared with pretreatment values and healthy controls, there was signiﬁcant inhibition of platelet aggregation in the high-dose group, while the effects were minimal in the low-dose group. In the high-dose group, the inhibition was more prominent during the subcutaneous maintenance dose and was still detectable 8 weeks after interferon-alpha withdrawal in 60% of the tested samples. An increased risk of bleeding should therefore be anticipated in patients who receive high-dose interferon-alpha. Urinary tract Reports of acute nephrotic syndrome during interferon-alpha treatment for chronic hepatitis C are infrequent, but two further cases have been reported. • A 57-year-old woman developed severe nephrotic syndrome after 3 months of interferon-alpha retreatment, and renal biopsy showed minimal change nephrotic syndrome with T-cell-predominant interstitial nephritis (91A ). Proteinuria persisted despite interferon-alpha withdrawal and resolved only after corticosteroid treatment. • A 55-year-old woman was treated with interferonalpha and ribavirin for 1 year and developed asymptomatic nephrotic syndrome with focal segmental glomerulosclerosis on renal biopsy (92AR ). Proteinuria slowly improved over the next 21 months.

Possible exacerbation of an underlying glomerulopathy was not ruled out in either case.

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The author who reported the second case reviewed 17 other cases of interferon-induced nephrotoxicity and found a wide variety of histological changes; most of the cases were reported in patients with malignancies. Hemolytic–uremic syndrome is a possible complication of interferon-alpha treatment. To determine the characteristics of thrombotic microangiopathy associated with interferon-alpha, data from eight patients were carefully examined (93CR ). All had chronic myeloid leukemia and had received high-dose interferon-alpha (mean 39 MU/week) for a long time (mean 32 months) before diagnosis. Severe arterial hypertension was the most common sign before diagnosis. Five patients had distal ischemic lesions that required amputation in one, and all had typical lesions of renal thrombotic microangiopathy involving both glomeruli and small arterioles. After interferon-alpha withdrawal, two recovered normal renal function, three had persistent renal insufﬁciency, one relapsed 17 months after treatment withdrawal, and two required chronic dialysis. One patient had already had reversible renal insufﬁciency during a previous course of interferon-alpha. From a review of 21 other previously published similar cases, the authors conﬁrmed that interferon-alpha-induced thrombotic microangiopathy mostly occurred in patients with chronic myeloid leukemia, whereas only two cases were reported in patients with chronic hepatitis C and one in a patient with hairy cell leukemia. The delayed occurrence of renal toxicity was also suggested to be highly predictive of histological thrombotic microangiopathy. Skin As with interferon-alpha, pegylated interferon-alpha has been associated with injection site skin necrosis (94A ). Severe local reactions after subcutaneous injections mostly consist of ulceration and skin necrosis, but a variety of reactions have been described. Prominent suppuration and granulomatous dermatitis at the injection sites of interferon-alpha have been reported in two patients (95A ). A spectrum of cutaneous lesions has been described distant from sites of interferon-alpha injection. The clinical and histological characteristics of inﬂammatory skin lesions that occurred away from injection sites have been investigated in 20 patients treated with interferon-alpha-2a or 2b plus ribavirin for chronic

387 hepatitis C (96C ). Cutaneous lesions developed between 2 weeks and 4 months and consisted of pruritic papular erythematous eruptions with occasional vesicles. These eczema-like skin lesions predominated on the distal limbs, the head, and the neck. Photosensitivity was also noted in four patients and mucous lesions in two. Skin biopsy mostly showed non-speciﬁc mononuclear inﬁltrates. The skin lesions were promptly reversible in 10 patients who required treatment withdrawal, while others improved after symptomatic treatment. Two of the three patients who again received the same or another type of interferon-alpha had recurrence of their lesions. Skin tests performed in six patients were negative, including the two patients who relapsed after interferon-alpha rechallenge, and were therefore considered unhelpful. In contrast, three patients who had severe rashes while receiving pegylated interferon-alpha-2a or 2b had positive intracutaneous tests to both pegylated forms of interferon-alpha but not to standard interferon-alpha-2a or 2b (97A ). One of these patients subsequently tolerated standard interferon-alpha. • A 46-year-old woman developed transient facial erythema with telangiectasia after each injection of interferon-alpha, resolving within 1–2 days, and completely disappearing after deﬁnitive withdrawal of treatment 7 months later (98A ).

There has been one report of cutaneous thrombotic microangiopathy in two patients treated with pegylated interferon-alpha-2b and ribavirin (99A ). • A 54-year-old woman had small bullous lesions mainly on the backs of her hands and feet after 6 months of treatment with pegylated interferonalpha-2b plus ribavirin for chronic hepatitis C. The lesions lasted 48 hours and healed rapidly after bullae rupture. • A 62-year-old woman developed generalized pruritus and excoriated lesions after 5 months of treatment with pegylated interferon-alpha-2b plus ribavirin. The lesions were maximal on the backs of her hands and feet after 8 months of treatment, but there were no bullae.

Skin biopsies in both patients showed microthrombi of the dermal capillaries and a necrotic epidermis. Immunoﬂuorescence showed only ﬁbrinogen. Some bullous lesions were still present 1 month after withdrawal in the ﬁrst patient, while the second patient responded to

388 local corticosteroids and a reduced dose of pegylated interferon-alpha but continued to have episodes of severe pruritus. Hair Telogen efﬂuvium is the most common type of alopecia reported with interferon-alpha. Alopecia areata has been very occasionally described, and a further case has been reported in a 48-year-old woman (100A ). In two patients with previously natural curly hairs, the combination of interferon-alpha plus ribavirin was suggested to have triggered a rapid change in hair texture, with diffuse straightening hairs, eyelashes, and eyebrow hypertrichosis (101A ). In one patient, a causal role of treatment was supported by the spontaneous recovery of hair abnormalities after withdrawal and the recurrence of similar abnormalities on rechallenge. Immunologic The occurrence of autoantibodies and the development or exacerbation of autoimmune diseases are well-recognized adverse effects of interferon-alpha. Two recent studies have provided insights into the incidence and risk factors of the immunemediated complications of interferon-alpha in patients with chronic myeloid leukemia. In the ﬁrst study, 13 of 46 patients had autoimmune manifestations consisting of a combination of autoimmune thyroiditis in four, a direct antiglobulin test without hemolysis in eight, cryoagglutinins in one, Raynaud’s phenomenon in two, and chronic autoimmune hepatitis in one (102C ). Overall, six patients had clinically symptomatic manifestations after a median of 15 months of treatment. In the second study there were autoimmune diseases in seven of 76 patients after a median of 19 months of treatment, including hypothyroidism in one, immune-mediated hemolysis in two, systemic lupus erythematosus in two, Raynaud’s phenomenon in one, and mixed connective tissue disease in one (103C ). In both studies there was a strong association with female sex and it was conﬁrmed that patients who developed clinical autoimmune complications had relatively long exposures to interferon-alpha. What seems to be the ﬁrst case of systemic sclerosis attributed to interferon-alpha-2a has been reported (104A ). • A 52-year-old woman received interferon-alpha2a for chronic myeloid leukemia and after about

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2 years developed fever, dyspnea, and limb edema. The erythrocyte sedimentation rate was 50 mm/ hour and pulmonary imaging showed pulmonary vascular congestion. She improved after interferonalpha withdrawal and administration of diuretics, but similar symptoms recurred 3 months later. She also had progressive thickening of the skin on the hands and wrists. There was diffuse parenchymal and interstitial ﬁbrosis of the lungs, absence of peristalsis on esophago-gastroduodenoscopy, renal impairment, and positive antisclero-70 antibodies. Capillaroscopy showed typical features of scleroderma. Based on these ﬁndings, a diagnosis of systemic sclerosis was suggested and she slowly improved over the next months with cyclophosphamide, prednisone, iloprost, and hydroxyurea.

This patient had the HLA-DR11 haplotype, which is associated with systemic sclerosis, and this suggests that interferon-alpha may have triggered the autoimmune phenomenon. Cutaneous or systemic sarcoidosis is being increasingly often described in patients treated with interferon-alpha alone or combined with ribavirin for chronic hepatitis C, and further cases have been reported, including de novo sarcoidosis in six patients (105A –108A , 109AR ) and reactivation of pre-existing disease in one (110AR ). One of these patients had chronic hepatitis B, suggesting that interferon-alpha treatment rather than the underlying disease was the most probable triggering factor. Remission was observed in all patients after withdrawal, either spontaneously or after corticosteroid treatment. Infection risk Two patients aged 38 and 54 years with hemodialysis dependent end-stage renal insufﬁciency developed severe bacterial infections, osteomyelitis and prostatitis, within 3 months of interferon-alpha-2b treatment for hepatitis C virus infection (111A ). These cases are reminiscent of the few reports of opportunistic infections that have previously been attributed to interferon-alpha (SED-14, 1255). Susceptibility factors Children There is little information on the use of interferon-alpha in children with chronic hepatitis C. In a review of 19 studies published between 1990 and 2000, there were data on only 366 treated children (105 untreated) and they suggested a higher rate of sustained response than in adults (112M ). Besides ﬂu-like symptoms, reversible weight loss, neutropenia, and alopecia were the most commonly reported adverse events, but adverse events were not systematically recorded in these studies.

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Interferon-beta The efﬁcacy and safety of different regimens of interferon beta have been investigated in two large randomized trials in patients with relapsing–remitting multiple sclerosis. In 188 patients assigned to receive interferon beta-1a 30 μg intramuscularly once a week or interferon beta-1b 44 μg subcutaneously three times a week, only injection site reactions and neutralizing antibodies to interferon-beta were signiﬁcantly more frequent in the interferon beta-1b group (113C ). These differences were probably related to the subcutaneous route of administration of interferon beta-1b. In contrast, there were signiﬁcant differences in favor of interferon beta-1b for clinical outcomes after 2 years of treatment. In a comparison of two regimens of interferon beta-1a (44 μg Rebif® subcutaneously three times a week versus 30 μg Avonex® intramuscularly once a week) in 677 patients, Rebif® was more effective on primary clinical outcomes (patients remaining relapse-free at 24 weeks), but produced signiﬁcantly more frequent injection site reactions (88% versus 28%), asymptomatic and mild liver enzyme abnormalities (18% versus 9%), mild white cell abnormalities (11% versus 5%), and neutralizing antibodies to interferon-beta (25% versus 2%) (114C ). However, the severity of adverse events and withdrawal due to an adverse event were similar in both groups. A ﬂu-like illness is the most common adverse effect of interferon-beta. In an open randomized study of the effects of paracetamol 1 g or ibuprofen 400 mg before and 6 hours after interferon-beta injection on interferon-betainduced ﬂu-like symptoms in 104 patients, the two drugs were equally effective (115C ). Nervous system Although headache was not speciﬁcally identiﬁed as an adverse effect of interferon beta in pivotal trials, the frequency, duration, and intensity of headache increased during the ﬁrst 6 months of treatment in 65 patients (116c ). There was a 35% probability of aggravated headaches in patients with preexisting headaches. Psychiatric The lifetime risk of depression in patients with multiple sclerosis is high, and there has been a lively debate about whether

389 interferon-beta causes or exacerbates depression in such patients. A critical review of the methodological limitations in studies that assessed mood disorders in patients on disease modifying drugs for multiple sclerosis may help explain the widely divergent results from one study to another (117R ). Recent results have argued against a speciﬁc role of interferon-beta in the risk of depressive disorders. A multicenter comparison of 44 μg and 22 μg of interferon beta-1a and placebo in 365 patients showed no signiﬁcant differences in depression scores between the groups over a 3-year period of follow-up (118c ). In 106 patients with relapsing–remitting multiple sclerosis, depression status was evaluated before and after 12 months of interferon beta-1a treatment (119C ). According to the Beck Depression Inventory II scale, most of the patients had minimum (53%) or mild (32%) depression at baseline, and depression scores were not signiﬁcantly increased after 1 year of treatment. There were no cases of suicidal ideation. In another study of 42 patients treated with interferon beta-1b, major depression at baseline was found in 21% of patients and was associated with a past history of psychiatric illness in most cases (120c ). Major depression was not considered as an exclusion criterion for interferon-beta treatment when patients were on antidepressant therapy. There was a three-fold reduction in the prevalence of depression over the 1-year course of interferon treatment, suggesting a possible beneﬁcial effect of treatment on mood. Finally, a single subcutaneous injection of interferon beta-1b did not alter cognitive performance and mood states in eight healthy volunteers (121c ). One debatable case of visual pseudo-hallucinations occurred only, but not reproducibly, within 30–60 minutes after interferon beta-1a injection in a 37-year-old woman with disseminated encephalomyelitis (122A ). Hematologic A 42-year-old woman developed aplastic anemia after using interferon beta-1a for 1 year (123A ). There was hematological improvement after withdrawal and immunosuppressive therapy. Urinary tract Proteinuria with minimalchange nephrotic syndrome on renal biopsy has

390 been attributed to interferon-beta in a 64-yearold man with malignant melanoma (124A ). Although the proteinuria abated after withdrawal, the potential role of previous chemotherapy cannot be excluded. Skin Erythromelalgia has been attributed to interferon beta-1a in a 38-year-old woman (125A ). Complete recovery was obtained only after interferon withdrawal. Injection site reactions to interferon beta1b are common. In one patient, there was cutaneous mucinosis on skin biopsy, and skin lesions persisted for several months before healing spontaneously (126A ). Musculoskeletal A 39-year-old man developed monoarthritis in his right elbow after receiving interferon-beta for 16 days for chronic hepatitis C (127A ). Although the arthritis resolved after withdrawal, this report casts doubt on the causal relation, as there was no recurrence on readministration. Immunologic Neutralizing antibodies to interferon beta can reduce the therapeutic response and are found in about a quarter of patients treated with subcutaneous interferon beta-1b. A randomized study has been conducted in 161 patients to evaluate whether a monthly intravenous pulse of methylprednisolone reduces the frequency of neutralizing antibodies to interferon beta-1b (128C ). The patients who received both interferon-beta and methylprednisolone had a 55% relative reduction in the development of neutralizing antibody and were signiﬁcantly more likely to remain negative for neutralizing antibodies after 6 months of treatment compared with those who received interferon-beta alone. The overall frequency of adverse effects and the number of withdrawals were similar between the groups, but headaches, fatigue, and myalgia were less frequent in the combination therapy group. A limitation of this study was that there was no difference in clinical outcome between the two groups.

Interferon-gamma Respiratory Of 10 patients treated with interferon-gamma-1b 200 μg three times a week for

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advanced idiopathic pulmonary ﬁbrosis, four developed irreversible acute respiratory failure (129A ). All four patients had increasing dyspnea, fever, and rapidly progressive hypoxemia, and had new alveolar opacities on lung imaging. The symptoms occurred shortly after interferon-gamma had been started in three patients, and after 35 injections in the fourth. Three patients died from refractory hypoxemia and the fourth underwent lung transplantation, but died a few weeks later. Pathological examination in two patients showed diffuse alveolar damage with pre-existing interstitial pneumonitis. Interferon-gamma was suspected, as no other cause of abrupt pulmonary deterioration was found. Although the number of patients was small, the authors noted that before interferon-beta pulmonary function tended to be worse in the four patients who developed acute respiratory failure than in the other six.

INTERLEUKINS

(SED-14, 1260; SEDA-24, 416; SEDA-25, 436; SEDA-26, 397)

Interleukin-1 receptor antagonist (anakinra) Drug interactions Regulatory agencies have recently issued an important post-marketing warning of an increased risk of serious infections and neutropenia in patients who receive concomitant anakinra and etanercept (130S ). This warning was based on an analysis of a randomized clinical trial in 242 patients with rheumatoid arthritis, in which 7% of patients receiving concomitant treatment had serious infections, compared with none in those treated with etanercept alone. Concurrent administration of these two drugs was therefore not recommended.

Interleukin-2 (IL-2) Nervous system Severe pain resulting from a previously asymptomatic thoracic spine metastasis has been attributed to IL-2 in a 64-yearold man with metastatic renal cell carcinoma (131A ).

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Psychiatric In 10 patients with advanced tumors, low-dose subcutaneous IL-2 produced signiﬁcant psychological changes; increased depression scores, psychasthenia, and conversion hysteria were the most common ﬁndings (132c ). Hematologic In a phase III trial in 190 patients with metastatic melanoma, sequential chemotherapy with dacarbazine, cisplatin, and vinblastine plus interferon-alpha and IL-2 modestly increased the response rates and produced considerably more frequent and severe toxic effects than chemotherapy alone (133C ). In particular, severe episodes of anemia and thrombocytopenia that required blood or platelet transfusions were 2–6 times more frequent in the chemotherapy group. Skin There has been one report of fatal toxic epidermal necrolysis with pancytopenia that developed after 5 days of IL-2 therapy in a 67year-old woman with renal carcinoma (134A ). The potential role of localized vertebral palliative radiotherapy before IL-2 treatment was denied, since the area of cutaneous toxicity was broader than the irradiated ﬁeld. Immunologic IL-2 sometimes causes acute exacerbation of latent autoimmune disease, as has been further exempliﬁed by the following description, which that also included the ﬁrst report of IL-2-induced myasthenia gravis (135A ).

gravis) in a single patient, a retrospective analysis of the patient’s serum before IL-2 therapy showed the presence of antibodies against glutamic acid decarboxylase, insulin, islet cell antigen, and striated muscle, but was negative for acetylcholine receptor antibodies. Immune stimulation by IL-2 was therefore thought to have caused broken tolerance to self-antigens and enhanced latent autoimmunity.

Interleukin-4 (IL-4) Of 49 patients with advanced renal cell carcinoma treated with subcutaneous IL-4 (4 μg/kg/ day for 28 days followed by a 7-day rest), nine had 13 episodes of grade 4 toxicity (136c ). Severe unexpected toxic effects included three cases of Bell’s palsy and one episode of severe hypoglycemia in a previously well-controlled patient with diabetes mellitus.

Interleukin-11 (IL-11, oprelvekin) Severe ﬂuid retention resistant to furosemide and ﬂuid restriction was observed in 10 patients randomized to receive subcutaneous IL11 50 μg/kg/day to prevent mucositis and acute graft–versus–host disease after allogeneic stem cell transplantation (137c ). One patient also had a large but reversible increase in serum transaminases.

• A 64-year-old man with non-insulin-dependent diabetes was given 14 large doses of IL-2 (600 000 IU/kg every 8 hours) for metastatic renal cell carcinoma. One week after the completion of the ﬁrst cycle he had a reversible episode of hyperosomolar, non-ketotic hyperglycemia, and insulin was started. A second cycle 3 months later was associated with hypotension, mild weakness of the right shoulder, and increased activity of creatine kinase (CK)-MB fraction. After four doses of the third cycle he again had hypotension and a raised CK-MB fraction. Two weeks later, he developed typical features of myasthenia gravis and required mechanical ventilation. Acetylcholine receptor antibodies were found and there was an inﬂammatory primary myositis on muscle biopsy. He gradually recovered with prednisone, pyridostigmine, and daily insulin.

SEDA-24, 417; SEDA-25, 437; SEDA-26, 398)

In this case, which was marked by three autoimmune complications (insulin-dependent diabetes mellitus, myositis, and myasthenia

The safety of ﬁlgrastim in healthy donors for mobilization and collection of allogeneic blood progenitor cells is being evaluated in a

COLONY-STIMULATING FACTORS (SED-14, 1270; Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)

392 large prospective multicenter study (138C ). The interim results, obtained from the ﬁrst 150 enrolled donors aged 18–64 years who received either 10 μg/kg/day or 16 μg/kg/day, have shown that 99 patients had at least one adverse effect graded as mild (grade I) in 35% of cases, moderate (grade II) in 62%, and severe (grade III) in 3%. Bone pain and headaches were the most common acute adverse events, and all the patients completely recovered after withdrawal of ﬁlgrastim. There were no apparent differences in the proportion, the severity, or the type of adverse effects according to the administered regimen. In a retrospective comparison in 90 healthy donors of 10 and 16 μg/kg/day of ﬁlgrastim for stem cell mobilization, severe adverse effects were found only in patients who had been given the highest ﬁlgrastim dose (139c ). However, one obese patient (body weight 170 kg) who received 10 μg/kg/day had a non-traumatic spleen rupture that resolved spontaneously. Data on the long-term safety of brief exposure to G-CSF in healthy donors are limited. No cases of acute or chronic leukemia were detected in a telephone interview study performed after a median of 39 months after peripheral blood progenitor cell donation in 281 donors (140c ). Although these ﬁndings are reassuring, more data are needed. Respiratory Acute adult respiratory distress syndrome (ARDS) has been described in ﬁve of 310 patients who received G-CSF after allogeneic bone-marrow transplantation or conventional chemotherapy (141C ). All had also been exposed to drugs or procedures with signiﬁcant pulmonary toxicity. Respiratory symptoms developed suddenly in conjunction with rapid recovery of the white blood cell count. Retrospective investigations showed that all ﬁve patients had the HLA-B51 or HLA-B52 antigens. In addition, tumor necrosis factor-alpha and IL-8 plasma concentrations were high at the onset of the ARDS. These effects did not occur in 45 patients who did not develop ARDS. The authors suggested that the risk of G-CSFinduced ARDS increases when the white blood cell count rises rapidly in patients who have the following conditions: HLA-B51 or HLA-B52 antigens, treatment with drugs with pulmonary toxicity, and a concomitant infection before recovery from granulocytopenia.

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Sensory systems A 61-year-old healthy donor developed marginal keratitis with associated mild uveitis after being given injections of ﬁlgrastim and sargramostim for 3 days (142A ). Topical prednisolone and withdrawal of sargramostim produced improvement within 24 hours, while ﬁlgrastim injections were continued. Musculoskeletal A 69-year-old man with a non-small-cell lung cancer treated with paclitaxel and nedaplatine developed polyarthralgia and myalgia with rising fever after receiving G-CSF for 5 days (143A ). Similar symptoms recurred after the second cycle of chemotherapy and on retreatment with G-CSF. Synovial biopsy showed acute synovitis with a foreign body-type giant cell reaction. Carcinogenicity Whether G-CSF increases the risk of myelodysplastic syndrome in patients with aplastic anemia is an important issue, particularly in children. In a randomized study in 102 patients of the safety and efﬁcacy of lenograstim (5 μg/kg/day for 14 weeks) combined with standard immunosuppressants, there were no differences between the groups in survival, hematological response, or the occurrence of secondary leukemia (one case of myelodysplastic syndrome in each group) at a median follow-up of 5 years (144C ). In a prospective, multicenter, cohort study of 113 patients under 18 years of age, 12 developed myelodysplastic syndrome after a median of 37 months after the diagnosis of aplastic anemia and four others developed other cytogenetic clonal changes, of which the most common abnormality was monosomy 7 (145C ). From a multivariate analysis, G-CSF treatment duration and non-response to immunosuppressive therapy at 6 months were statistically signiﬁcant risk factors for the development of myelodysplastic syndrome. The risk increased in proportion to the duration of G-CSF treatment, and the relative risks for myelodysplastic syndrome were respectively 4.4 and 8.7 times higher in patients who received G-CSF for more than 120 and 180 days, compared with those who received it for less. Although the last study added further evidence that G-CSF can increase the risk of myeloid leukemia, large randomized trials with long-term follow-up are still awaited to clarify these ﬁndings, because the underlying

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predisposition of patients with aplastic anemia to develop myeloid malignancy usually confounded attempts to determine whether growth factors are contributing factors. The risk of secondary cancer has been assessed in 412 children treated with etoposide and anthracyclines for acute lymphoblastic leukemia, 99 of whom also received GCSF and 58 cranial irradiation (146C ). Overall, 20 children developed myeloid leukemia and myelodysplastic syndrome at a median of 2.3 years after treatment. The 6-year cumulative incidence of these secondary cancers was 11% among patients who received G-CSF, close to that observed in those who received cranial irradiation (12%), but signiﬁcantly higher than in those who received neither irradiation nor GCSF (2.7%). Drug formulations Pegﬁlgrastim was developed by adding a polyethylene glycol molecule to the N-terminus of ﬁlgrastim. In a phase III study in 301 patients with advanced breast cancer who underwent myelosuppressive chemotherapy a single injection of pegﬁlgrastim had similar efﬁcacy and safety proﬁle to repeated injections of ﬁlgrastim (147C ). Further investigations are awaited to establish the safety proﬁle of pegﬁlgrastim. Interference with diagnostic tests A single dose of G-CSF in a healthy donor produced a false positive test for hepatitis B surface antigen using an enzyme immunoassay (148A ).

TUMOR NECROSIS FACTOR ANTAGONISTS (SEDA-24, 420; SEDA-25, 440; SEDA-26, 399) Carcinogenicity There is great concern about the potential development of malignancy after TNF-alpha blockade, and it is biologically plausible. The FDA received reports of 26 cases of lymphoproliferative disorders in patients treated with etanercept (18 cases) or inﬂiximab (8 cases) over 20 months (149c ). Although this reporting rate does not exceed the ageadjusted incidence of lymphomas in the USA, spontaneous reporting underestimates the true incidence. In addition, several ﬁndings were

similar to those reported in patients taking immunosuppressive drugs after transplantation. For example, 81% of the reported cases were non-Hodgkin’s lymphomas. Also, the median time to occurrence after the start of anti-TNFalpha treatment was only 8 weeks. Finally, lymphoma regressed in two patients after withdrawal and without speciﬁc cytotoxic therapy. Although the actual incidence of neoplasia was low, additional long-term data that take into account concomitant or previous immunosuppressive treatment are needed before ﬁrm conclusions can be reached.

Etanercept The clinical pharmacology and adverse effects of etanercept in patients with rheumatoid disorders have been reviewed (150R ). Respiratory The typical histological morphology of pulmonary rheumatoid nodules that developed during etanercept treatment has been reported (151A , 152A ). Pulmonary granulomas during etanercept treatment may be coincidental and difﬁcult to distinguish from other pulmonary complications, such as relapse of tuberculosis. In two patients with rheumatoid arthritis who underwent lung biopsy for etanercept-associated pulmonary granulomas, there were non-caseating granulomas containing birefringent particulate in one (153A ) and caseating necrosis in the other (154A ). Infectious causes were ruled out. After etanercept withdrawal, the lesions resolved completely with steroid treatment in the ﬁrst patient but persisted over 1 year despite antituberculosis treatment in the other. Nervous system Central nervous system demyelinating disorders have previously been reported (SEDA-26, 399) and transverse myelitis of abrupt onset has also been attributed to etanercept (155A ). • A 45-year-old woman with resistant rheumatoid arthritis was given etanercept 25 mg twice weekly. Nine days later she developed total acute sensory loss, with ﬂaccid paraplegia, fecal incontinence, and urinary retention. MRI imaging and cerebrospinal ﬂuid analysis were consistent with a diagnosis of transverse myelitis. She also had

394 positive antinuclear and anticardiolipin antibodies. After etanercept withdrawal and treatment with dexamethasone and cyclophosphamide, her motor function improved with no change in sensory function.

Skin There have been several descriptions of new cutaneous or pulmonary nodulosis in patients with rheumatoid arthritis treated with etanercept (152A , 156A ); concomitant cutaneous vasculitis was also reported in two patients (156A ). Although this may have been due to the natural history of rheumatoid arthritis or a lack of response to treatment, the short time to the occurrence of cutaneous nodulosis after the start of therapy in some patients implicated the etanercept. Cutaneous vasculitis can also be the sole cutaneous manifestation of etanercept treatment (157A ). • A 13-year-old girl developed a slowly reversible purpuric rash after 6 weeks of etanercept treatment, and the lesions recurred on readministration (158A ). However, further administration of a gradually increasing dose of etanercept, with concomitant high-dose steroids, and antihistamines, was well tolerated, suggesting that tolerance can be obtained.

Musculoskeletal A single case of painless orbital myositis has been reported in a 42year-old woman taking etanercept, but a causal relation was not established (159A ).

Inﬂiximab Respiratory A 32-year-old man with Crohn’s disease developed an eosinophilic pleural effusion soon after a second infusion of inﬂiximab (160A ). He recovered within 8 weeks, but the effusion recurred after inﬂiximab re-treatment 1 year later. Allergic granulomatosis of the lung was also brieﬂy reported in one of 35 patients with active ankylosing spondylitis (161c ). Sensory systems Optic neuropathy has recently been described in patients with rheumatoid arthritis taking inﬂiximab. In three patients aged 54–62 years, blurred vision or visual ﬁeld loss in one or both eyes occurred after the third dose (162A ). Ophthalmic examination showed anterior optic neuropathy in all three patients and MRI scanning ruled out demyelinating optic neuritis. In one patient an additional infusion

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of inﬂiximab produced similar symptoms in the previously unaffected eye; vision failed to improve despite inﬂiximab withdrawal and steroid treatment. Retrobulbar optic neuritis was diagnosed after the ninth dose of inﬂiximab in a 55-year-old woman (163A ). MRI scanning showed demyelination of the left optic nerve and the visual ﬁeld defect improved after treatment with prednisone. Hematologic There have been several cases of lymphoproliferative disease (B cell nonHodgkin’s lymphoma and nodular sclerosing Hodgkin’s disease) in the 9 months after inﬂiximab infusion in patients with Crohn’s disease. It is unclear whether this was a drug-related or a disease-related phenomenon (164M ). Skin Skin reactions, including erythema multiforme in three patients and a lichenoid eruption in one, were attributed to inﬂiximab (165A ). One patient had similar lesions after etanercept. Patch tests with inﬂiximab in three patients were negative, but produced a ﬂare-up of lesions in one patient and recurrence of malaise and nausea in another patient, suggesting that inﬂiximab is well absorbed percutaneously. • A 72-year-old man developed bullous skin lesions the day after receiving his fourth dose of inﬂiximab for rheumatoid arthritis (166A ). Human antichimeric antibodies were positive, as were antinuclear antibodies, and he completely recovered after treatment with prednisone.

Immunologic Infusion reactions Immediate infusion reactions to inﬂiximab are usually deﬁned by any signiﬁcant adverse effect that occurs during or within 1–2 hours after the infusion. The symptoms mostly consist of ﬂushing, shortness of breath, hotness, and anaphylactoid reactions, and occur in 7–19% of adults. In a retrospective evaluation of 165 patients (479 inﬂiximab infusions) with Crohn’s disease, the overall incidence of infusion reactions was 6.1% (29 episodes) (167C ). Acute infusion reactions within 24 hours of infusion were the most frequent (26 episodes) and delayed infusion reactions from 1 to 14 days after treatment were noted in three instances only. Prophylaxis with diphenydramine and paracetamol and the use of a test dose of inﬂiximab allowed additional infusions without consequences in patients with mild or moderate previous acute

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infusion reactions. Three of the four patients who had acute severe reactions received the same prophylaxis plus corticosteroids before re-treatment: one had a similar severe acute reaction, while the other two had no recurrences. This study also suggested that acute infusion reactions are probably not IgE-mediated, as tryptase and IgE serum concentrations were not raised. In a retrospective review of 361 inﬂiximab infusions in 57 children with inﬂammatory bowel disease there was a similar incidence of infusion reactions (35 episodes) (168c ). Further analysis suggested that female sex, previous episodes of infusion reactions, and the use of immunosuppressive therapy for less than 4 months were signiﬁcant predictors of subsequent infusion reactions. Of 86 patients with Crohn’s disease receiving inﬂiximab 14% of patients experienced severe systemic reactions, with a signiﬁcant difference between adults (21%) and children (3%), the reason for which was unclear (169c ). Antibody formation Antibodies to inﬂiximab occur commonly. Of patients who receive inﬂiximab about 13% produce human antichimeric antibodies, and high concentrations are more common in those who have infusion reactions than in those who do not. In a randomized, placebo-controlled trial in 573 patients with Crohn’s disease who responded to an initial infusion of inﬂiximab and were then given repeated infusions, antibodies to inﬂiximab were found in 14%; there was a trend toward a lower incidence of antibodies in patients taking concurrent corticosteroids and immunosuppressive drugs (170C ). The incidence of infusion reactions was also higher in patients positive for antibodies to inﬂiximab compared with patients without antibodies (16% versus 8%) and lower in patients who were taking both corticosteroids and immunosuppressants compared with patients who were receiving neither (8% versus 32%). The clinical signiﬁcance of antibodies to inﬂiximab has also been explored in 125 patients with Crohn’s disease who were given inﬂiximab, of whom 61% had antibodies after the ﬁfth infusion; however, there was no further increase in incidence after subsequent treatment (171C ). The presence of antibodies was associated with a 2.4-fold increase in the

395 risk of infusion reactions, lower serum inﬂiximab concentrations, and a shorter duration of clinical response, compared with patients with no inﬂiximab antibodies. Patients who received concomitant immunosuppressive therapy had a lower incidence of inﬂiximab antibodies, higher inﬂiximab serum concentrations, and a longer duration of clinical response. Pretreatment with corticosteroids may reduce the risk of antibody formation, but whether a pretreatment test for human antichimeric antibodies has a predictive value for adverse reactions is not known (172c ). Hypersensitivity reactions Inﬂiximab has been reported to cause delayed hypersensitivity (SEDA-26, 401) and now an acute anaphylactic reaction, suggestive of type I hypersensitivity, has been reported (173A ). • A 36-year-old man with Crohn’s disease became refractory to standard anti-inﬂammatory treatment (corticosteroids, mercaptopurine, methotrexate, ciclosporin, tacrolimus). Remission over 8 months was achieved with a single infusion of inﬂiximab. With the onset of relapse he was given another infusion of inﬂiximab and had an anaphylactic-like reaction within 1 minute.

Autoimmunity Inﬂiximab may increase the risk of autoimmunity. In trials, the incidence of inﬂiximab-induced anti-double-stranded DNA antibodies ranged from 5 to 34% of patients, depending on the assay method used and the duration of exposure (170C , 174C , 175R ). However, these abnormalities were rarely associated with clinical manifestations. In two large randomized trials in more than 900 inﬂiximab-treated patients, only three developed a lupus-like syndrome, with no evidence of systemic organ involvement (170C , 175R ). However, since then, several reports have detailed inﬂiximabinduced lupus-like syndrome in patients with Crohn’s colitis or rheumatoid arthritis, with improvement on withdrawal of inﬂiximab (176A – 179A ). Inﬂiximab binds to TNF-alpha on cell surfaces and produces apoptotic cell death, releasing the nucleosomal autoantigens that induce autoantibody formation (178A ). • A 69-year-old woman with a 5-year history of rheumatoid arthritis developed drug-induced lupus after receiving inﬂiximab for 23 weeks. She had initially been given methotrexate and prednisone for 4 years. Then, because of lack of efﬁcacy, inﬂiximab was introduced. After three infusions of inﬂiximab and only partial remission the dose

396 was increased to 5 mg/kg, with success. However, before the sixth infusion she developed fever, polyarthralgia, myalgia, and general malaise. Serology excluded viral infection. Autoantibody assessment was positive, conﬁrming the diagnosis of drug-induced lupus.

Infection risk Inﬂiximab can increase the susceptibility of patients to severe infections, and in particular opportunistic infections (SEDA-26, 402). In patients who received repeated infusions of inﬂiximab, infections requiring antimicrobial treatment occurred in about 30% of patients and severe infections in 4% (170C ). Bacterial infections TNF-alpha blockade impairs resistance to infections with intracellular pathogens such as mycobacteria, Pneumocystis carinii, Listeria monocytogenes, and Legionella pneumophila (180R ). Recent case reports with fatal outcomes have included: • necrotizing fasciitis due to streptococcal infection (181A ); • septicemia due to Staphylococcus aureus (182A ); • Listeria monocytogenes infection (183A ); • disseminated tuberculosis (184A ). There has also been a detailed report of extensive pulmonary coccidioidomycosis (185A ). Most of these patients were taking concomitant immunosuppressive drugs at the time of diagnosis. • An 11-year-old boy with Crohn’s disease received inﬂiximab and 3 days later developed fever, signs of cardiac failure, and Staphylococcus aureus sepsis (186A ). At surgery an intramyocardial paraaortic abscess with destruction of the aortic valve was found, suggesting chronic infection, possibly activated by the use of inﬂiximab.

Crohn’s disease can lead to vasculitic changes of the aorta, which may have favored the development of the intramyocardial abscess in this case. The size of the abscess suggested persistence for several weeks. Severe necrotizing fasciitis has been reported in a patient who was given inﬂiximab (181A ). • A 54-year-old man with rheumatoid arthritis for 12 years was given inﬂiximab, with remission. He then developed a painful, conﬂuent, erythematous,

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pustular rash over his trunk and limbs. Skin biopsy showed an acute pustular dermatitis. Five hours later he collapsed with a tachycardia (140/min) and a blood pressure of 120/70 mmHg. He was apyrexial. His left leg was very tense, painful, and swollen, and he had a disseminated intravascular coagulopathy. There was marked necrosis of his adductor compartment and fascia of his left thigh and necrotic muscles were debrided. Blood cultures and skin swabs grew group A hemolytic streptococci. He then became unstable and died, despite efforts at resuscitation.

Tuberculosis Reactivation of latent tuberculosis is a major concern with inﬂiximab (SEDA26, 402), and accounts for 39% of infections in these patients. The risk of tuberculosis in the ﬁrst year of inﬂiximab treatment has been estimated at 0.035 in US citizens and 0.2% in non-US citizens. Further investigations, such as a chest X-ray and a Mantoux test, and prophylactic treatment with isoniazid, will show whether the incidence can be reduced in patients taking anti-TNF treatment (187M ). In a multicenter trial in 70 patients with ankylosing spondylitis given inﬂiximab, treatment had to be withdrawn in three patients because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leukopenia; after withdrawal all three recovered (161C ). However, the allergic granulomatosis of the lung was probably due to a hypersensitivity reaction. The safety and efﬁcacy of inﬂiximab have been assessed in 40 patients with severe active spondylarthropathy in a double-blind, randomized, placebo-controlled trial (188CA ). One 65-year-old patient improved but 3 weeks after the third infusion developed a systemic illness. He had enlarged mediastinal lymph nodes and nodular lesion of the liver and spleen. Biopsy of the mediastinal lymph nodes showed tuberculosis, which was conﬁrmed by culture. He was treated and recovered slowly. Patients with evidence of active infection should not receive inﬂiximab until the infection is under control; all should be screened for tuberculosis before starting inﬂiximab (189R ). Viral infections Inﬂiximab can also compromise antiviral defence mechanisms. There have been detailed reports of cytomegalovirus retinitis (190A ) and life-threatening disseminated cytomegalovirus infection (191A ). Most of these patients were taking concomitant immunosuppressive drugs at the time of diagnosis.

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• A 67-year-old woman with a 5-year history of rheumatoid arthritis, who had taken prednisone and methotrexate, was given inﬂiximab (192A ). Her rheumatoid arthritis improved, but she developed multiple bilateral lesions of molluscum contagiosum on the upper and lower eyelids, despite normal CD4 and CD8 counts. She had similar lesions during a previous course of inﬂiximab. Excisional biopsy conﬁrmed the diagnosis.

Protozoal infections There has been a detailed report of Pneumocystis carinii pneumonia (193A ). Most of these patients were taking concomitant immunosuppressive drugs at the time of diagnosis. Fungal infections In 41 patients with rheumatic disease who received a total of 300 infusions of inﬂiximab over 9 months there were severe adverse effects in 15% (anaphylaxis, vasculitis, gastrointestinal bleeding, infection, histoplasmosis) (194c ). One patient, a 28-yearold woman with unresponsive rheumatic disease, developed histoplasmosis after a second infusion of inﬂiximab. She had pet birds, and

397 the authors thought that she had reactivation of an infection rather than a new infection. Similar results were found in a review of all cases of histoplasmosis in patients treated with inﬂiximab (n = 9) or etanercept (n = 1) (195c ). The infection occurred within 1 week to 6 months after the ﬁrst dose. Of these ten patients, nine required treatment in an intensive care unit and one died. All lived in regions in which histoplasmosis was endemic. It was not possible to determine which patients had new infections or reactivation of previous infections. Death Death due to worsening of cardiac insufﬁciency in patients with congestive heart failure has previously been mentioned (SEDA26, 401). • A 64-year-old man without heart failure was found dead 18 hours after a single infusion of inﬂiximab for rheumatoid arthritis (196A ). No obvious cause was found at autopsy, except that the patient was known to have had frequent intervention by a pacemaker that had been implanted for several years.

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403 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. 162. ten Tusscher MP, Jacobs PJ, Busch MJ, de Graaf L, Diemont WL. Bilateral anterior toxic optic neuropathy and the use of inﬂiximab. Br Med J 2003; 326: 579. 163. Foroozan R, Buono LM, Sergott RC, Savino PJ. Retrobulbar optic neuritis associated with inﬂiximab. Arch Ophthalmol 2002; 120: 985–7. 164. Drewe E, Powell RJ. Clinically useful monoclonal antibodies in treatment. J Clin Pathol 2002; 55: 81–5. 165. Vergara G, Silvestre JF, Betlloch I, Vela P, Albares MP, Pascual JC. Cutaneous drug eruption to inﬂiximab: report of 4 cases with an interface dermatitis pattern. Arch Dermatol 2002; 138: 1258–9. 166. Kent PD, Davis JM III, Davis MD, Matteson EL. Bullous skin lesions following inﬂiximab infusion in a patient with rheumatoid arthritis. Arthritis Rheum 2002; 46: 2257–8. 167. Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, Plevy S. The incidence and management of infusion reactions to inﬂiximab: a large center experience. Am J Gastroenterol 2003; 98: 1315–24. 168. Crandall WV, Mackner LM. Infusion reactions to inﬂiximab in children and adolescents: frequency, outcome and a predictive model. Aliment Pharmacol Ther 2003; 17: 75–84. 169. 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. 170. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P. Maintenance inﬂiximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–9. 171. Baert F, Noman M, Vermeire S, Van Assche G, D’ Haens G, Carbonez A, Rutgeerts P. Inﬂuence of immunogenicity on the long-term efﬁcacy of inﬂiximab in Crohn’s disease. N Engl J Med 2003; 348: 601–8. 172. 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. 173. 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. 174. Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with inﬂiximab, a monoclonal antibody to tumor necrosis factor alpha: ﬁndings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000; 43: 2383–90.

404 175. Mikuls TR, Moreland LW. Beneﬁt-risk assessment of inﬂiximab in the treatment of rheumatoid arthritis. Drug Saf 2003; 26: 23–32. 176. Ali Y, Shah S. Inﬂiximab-induced systemic lupus erythematosus. Ann Intern Med 2002; 137: 625–6. 177. Debandt M, Vittecoq O, Descamps V, Le Loet X, Meyer O. Anti-TNF-alpha-induced systemic lupus syndrome. Clin Rheumatol 2003; 22: 56–61. 178. Favalli EG, Sinigaglia L, Varenna M, Arnoldi C. Drug-induced lupus following treatment with inﬂiximab in rheumatoid arthritis. Lupus 2002; 11: 753–5. 179. Klapman JB, Ene-Stroescu D, Becker MA, Hanauer SB. A lupus-like syndrome associated with inﬂiximab therapy. Inﬂammatory Bowel Dis 2003; 9: 176–8. 180. Shanahan JC, St Clair W. Tumor necrosis factor-alpha blockade: a novel therapy for rheumatic disease. Clin Immunol 2002; 103: 231–42. 181. Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving inﬂiximab for rheumatoid arthritis. Postgrad Med J 2002; 78: 47– 8. 182. Matzkies FG, Manger B, Schmitt-Haendle M, Nagel T, Kraetsch HG, Kalden JR, Schulze-Koops H. Severe septicaemia in a patient with polychondritis and Sweet’s syndrome after initiation of treatment with inﬂiximab. Ann Rheum Dis 2003; 62: 81–2. 183. Gluck T, Linde HJ, Scholmerich J, MullerLadner U, Fiehn C, Bohland P. Anti-tumor necrosis factor therapy and Listeria monocytogenes infection: report of two cases. Arthritis Rheum 2002; 46: 2255–7. 184. Liberopoulos EN, Drosos AA, Elisaf MS. Exacerbation of tuberculosis enteritis after treatment with inﬂiximab. Am J Med 2002; 113: 615. 185. Ramzan NN, Shapiro MS, Robinson E, Smilack JD. Use of inﬂiximab leading to extensive pulmonary coccidioidomycosis. Am J Gastroenterol 2002; 97 Suppl: 157. 186. Reichardt P, Dahnert I, Tiller G, Hausler H-J. Possible activation of an intramyocardial inﬂammatory process (Staphylococcus aureus) after treatment with inﬂiximab in a boy with Crohn disease. Eur J Pediatr 2002; 161: 281–3.

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187. Antoni C, Braun J. Side effects of anti-TNF therapy: current knowledge. Clin Exp Rheumatol 2002; 20 Suppl 28: S152–7. 188. Van Den Bosch F, Kruithof E, Baeten D, Herssens A, De Keyser F, Mielants H, Veys EM. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (inﬂiximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002; 46: 755–65. 189. Sandborn WJ, Hanauer SB. Inﬂiximab in the treatment of Crohn’s disease: a user’s guide for clinicians. Am J Gastroenterol 2002; 97: 2962–72. 190. Haerter G, Manfras B, Schmitt M, Wendland T, Moch B. Severe CMV retinitis in a patient with HLA-B27 associated spondylarthropathy following immunosuppressive therapy with anti-TNF alpha (inﬂiximab). Infection 2003; 31 Suppl 1: 150. 191. Helbling D, Breitbach TH, Krause M. Disseminated cytomegalovirus infection in Crohn’s disease following anti-tumour necrosis factor therapy. Eur J Gastroenterol Hepatol 2002; 14: 1393–5. 192. Cursiefen C, Grunke M, Dechant C, Antoni C, Junemann A, Holbach LM. Multiple bilateral eyelid molluscum contagiosum lesions associated with TNFalpha-antibody and methotrexate therapy. Am J Ophthalmol 2002; 134: 270–1. 193. Tai TL, O’Rourke KP, McWeeney M, Burke CM, Sheehan K, Barry M. Pneumocystis carinii pneumonia following a second infusion of inﬂiximab. Rheumatology 2002; 41: 951–2. 194. Fitzcharles M-A, Clayton D, Menard HA. The use of inﬂiximab in academic rheumatology practice: an audit of early clinical experience. J Rheumatol 2002; 29: 2525–30. 195. Lee J-H, Slifman NR, Gershon SK, Edwards ET, Schwieterman WD, Siegel JN, Wise RP, Brown SL, Udall Jr JN, Braun MM. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists inﬂiximab and etanercept. Arthritis Rheum 2002; 46: 2565–70. 196. De’Clari F, Salani I, Safwan E, Giannacco A. Sudden death in a patient without heart failure after a single infusion of 200 mg inﬂiximab: does TNFalpha have protective effects on the failing heart, or does inﬂiximab have direct harmful cardiovascular effects? Circulation 2002; 105: 183.

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38 VITAMIN A (RETINOL) (SED-14, 134; SEDA-24, 443; SEDA-25, 454; SEDA-26, 416) The adverse effects of all-trans-retinoic acid 50 mg/m2 /day for 3 months have been studied in 20 patients with emphysema in a randomized, double-blind, placebo-controlled trial (1C ). The treatment was well tolerated and associated with only mild adverse effects, including skin changes, such as dry skin and cracking lips in 15 (1 placebo), transient headache in 13 (1), hyperlipidemia in 11 (5), pruritus in 6 (2), muscle/bone pain in 6 (0), generalized fatigue in 6 (2), raised transaminases in 5 (1), a sensation of clogged ears in 3 (2), nausea in 2 (0), hair loss in 2 (0), and blurred vision in 1 (1). Retinoic acid syndrome The treatment of acute promyelocytic leukemia with all-transretinoic acid sometimes results in a retinoic acid syndrome, characterized by fever, respiratory distress, weight gain, pleural and pericardial effusions, and pulmonary inﬁltrates. Of 69 patients with acute promyelocytic leukemia treated with all-trans-retinoic acid for 5 years, 15 developed retinoic acid syndrome (2R ). The following features were found on chest radiographs: an increased cardiothoracic ratio, an increased pedicle width, pulmonary congestion in 13, pleural effusion in 11, groundglass opacities, septal lines, and peribronchial cufﬁng in nine, consolidation and nodules in seven, and an air bronchogram in ﬁve. Three patients had pulmonary hemorrhages and bilateral, diffuse, poorly delineated nodules and ground-glass opacities on radiography. Lung inﬁltrates cleared completely within 8 days after administration of prednisolone. © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Vitamins Nervous system A 15-year-old girl developed pseudotumor cerebri due to prolonged consumption of vitamin A for acne (3A ). • A 15-year-old girl developed headache, vertigo, nausea, and epistaxis, diplopia, and reduced visual acuity. She had taken Arovit® corresponding to vitamin A 200 000 IU/day for 6 months for acne. Ophthalmoscopy showed bilateral papilledema and minor bilateral abducens paresis. She had hypercalcaemia (3.24 mmol/l) and a reduced parathyroid hormone concentration, a mild anemia (10.5 g/dl) and thrombocytopenia (112 × 109 /l). Lumbar puncture showed a pressure of 62 cm H2 O with otherwise normal liquor. Her serum vitamin A concentration was 1.5 mg/l (reference range 0.3–0.7 mg/l).

Pseudotumor cerebri due to hypervitaminosis A is a serious complication, which can cause permanent visual impairment. Patients who take retinoids require proper surveillance. Raised serum concentrations of retinoids can persist for weeks after withdrawal. Hematologic Vitamin A toxicity appears to occur only when the amount of vitamin A exceeds the binding capability of the retinol binding protein. Hypervitaminosis A can cause severe anemia and thrombocytopenia, resulting from retinol-dependent bone marrow cell growth inhibition (4A ). • A 3-month-old boy who was given Arovit (an aqueous solution of vitamin A palmitate, Roche, Italy), corresponding to vitamin A 62 000 IU/day for 80 days, developed signs of retinol intoxication (severe normochromic normocytic anemia, hemoglobin 5.9 g/dl, leukocyte count 6.2 × 109 /l with lymphocytes 74%, neutrophils 17%, eosinophils 3 %, and monocytes 6%, platelet count 20×109 /l). The blood ﬁlm showed anisopoikilocytosis. He had increased concentrations of unbound retinol, with high concentrations of retinyl esters and a raised retinol : retinol binding protein ratio. Vitamin A was withdrawn and 15 days later his hemoglobin rose to 7.5 g/dl and the platelet count to 105 × 109 /l. The reticulocyte count increased from 8 to 300 × 109 /l. The bone marrow showed normal populations of erythroid and myeloid cells and megakaryocytes. The retinyl esters fell by about 80% after 3 months.

405

406 These are the ﬁrst ﬁndings to suggest that infant hypervitaminosis A can cause severe anemia and thrombocytopenia, probably due to the direct effect of vitamin A on the growth of all bone marrow cells. Investigation of the effect of retinol on the growth of the pluripotent hemopoietic cell line K-562 and on bone marrow mesenchymal stem cells showed strong inhibition of cell proliferation at concentrations similar to those found in vivo. Subsequent biochemical analysis of the cell cycle suggested that the effect was mediated by up-regulation of the cyclin-dependent kinase-inhibitors p21Cip1 and p27Kip1 . Skin Only 11 cases of Sweet’s syndrome associated with all-trans-retinoic acid have been previously reported, involving only the skin in eight cases, the skin and muscles in two cases, and the lung, kidney, fascia, and muscles in one case. In one case Sweet’s syndrome was followed by retinoic acid syndrome. Sweet’s syndrome has now been reported in a patient with acute promyelocytic leukemia treated with all-trans-retinoic acid (5A ). • A 46-year-old man with promyelocytic leukemia was given all-trans-retinoic acid 45 mg/m2 plus daunorubicin 60 mg/m2 /day for 3 days and cytarabine 200 mg/m2 /day by continuous infusion for 7 days. He became febrile on day 3 and was given cefotaxime and vancomycin. On day 6 he developed non-pruritic, erythematous, violaceous vesicles on the limbs and upper trunk. His temperature rose to 40◦ C and he gained 4.5 kg, which was attributed to a mild retinoic acid syndrome. Skin biopsy showed inﬁltration by neutrophilic granulocytes and marked edema in the dermis, without vasculitis or evidence of leukemic cells, fungi, or herpesvirus. Hepatic enzymes were moderately increased. The clinical presentation and histopathological ﬁndings were consistent with Sweet’s syndrome. All-trans-retinoic acid was withdrawn and he was given dexamethasone 40 mg/day for 10 days and then tapering doses of prednisone. He improved, and all-trans-retinoic acid was reintroduced without recurrence.

Liver Clinical presentations, changes in liver function tests, and liver morphology have previously been examined in 41 consecutive patients with vitamin A hepatotoxicity (6C ). The cause of liver disease was suspected at initial interview in only 13 instances, and there was histological evidence of fat-storage hyperplasia with ﬂuorescent vacuoles in the other cases. Cirrhosis was found in 17 cases, mild

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chronic hepatitis in 10, non-cirrhotic portal hypertension in ﬁve, and “increased storage” alone in nine. During a mean follow-up period of 4.6 years, six patients died of causes related to the liver disease. Precise appraisal of drug consumption was obtained in 29 cases. Among them the total cumulative intake was the highest in patients with cirrhosis (423 MIU) and signiﬁcantly lower in those with non-cirrhotic liver disease (89 MIU). The smallest continuous daily consumption leading to cirrhosis was 25 000 IU for 6 years, whereas higher doses (greater than or equal to 100 000 IU/day) taken for 2.5 years resulted in similar histological changes. Liver ﬁbrosis induced by beta-carotene therapy for pigmentary retinopathy has now also been reported (7A ). • A 66-year-old woman with a pigmentary retinopathy that had been treated for 30 years with antocyanosides combined with beta-carotene (total dose 165 g) developed anicteric cholestasis. Liver biopsy showed pronounced portal ﬁbrosis with normal bile ducts and no evidence of portal inﬂammation. The usual causes of chronic hepatic diseases were excluded. The serum concentration of vitamin A was 0.43 (reference range: 0.5–0.8) g/l. After withdrawal of beta-carotene and administration of ursodesoxycholic acid for 6 months the cholestasis resolved.

Another feature of vitamin A hepatotoxicity, namely respiratory symptoms caused by hepatic hydrothorax, associated with excessive vitamin A consumption has been reported (8A ). • A 52-year-old woman who had taken multivitamin supplements daily for 17 years and vitamin A whenever she had a cold, became progressively breathless, with 18 kg weight loss, increasing abdominal girth, increasing fatigue, leg weakness and pain, worsening chronic diarrhea, and intermittent nose bleeds. Her total vitamin A intake over 17 years had been at least 63 MIU (average 10 273 IU/day) and in the previous year she had taken at least 98 MIU (270 000 IU/day). When she noted pruritus, epistaxis, hair loss, and nail degeneration, she reduced her vitamin A intake to 66 000–150 000 IU/day. She was thin with alopecia, dry skin, and dystrophic nails, and was in mild respiratory distress with reduced breath sounds throughout the right lung and mild expiratory wheezes at the apices. There was no hepatomegaly or splenomegaly, but her liver was tender. Her serum vitamin A concentration was within the reference range. She had marked ascites, a pleural effusion, and partial collapse of the right lung. Liver biopsy showed changes consistent

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with vitamin A hepatotoxicity, namely prominent aggregates of hypertrophied perisinusoidal hepatic stellate cells, focal pericellular ﬁbrosis, and mild perivenular ﬁbrosis.

Susceptibility factors Children The National Prophylaxis Program for Prevention of Blindness due to Vitamin A Deﬁciency has been implemented in India since the 1970s and covers all children aged 9 months to 3 years (9S ). Children aged 9–12 months received a single dose of 100 000 IU and those aged 1–3 years received 200 000 IU every 6 months. According to the Assam State Government, 700 children of 3.2 million who were given vitamin A became ill and more than 15 children died. Whether all these cases were a direct consequence of highdose vitamin A is being investigated. One of the possible reasons is overdose of vitamin A, because of use of a new 5 ml measuring cup, which was used instead of the traditional 2 ml spoon.

VITAMINS OF THE B GROUP (SED-14, 1344; SEDA-24, 446; SEDA-25, 462; SEDA-26, 419)

Safety aspects of folic acid Negative effects resulting from dietary intake of high concentrations of folic acid have only rarely been documented in some older case reports and uncontrolled intervention studies. Some of these negative effects were not conﬁrmed in subsequent randomized controlled intervention studies (10R ). General toxicity of folic acid In humans the toxicity of folic acid is low, even after longterm use (11S , 12R , 13R ). Only in one trial in 14 volunteers (six women, eight men, aged 22–57 years) were there adverse effects, such as gastrointestinal disturbances, insomnia, irritability, or depressive states (14C ). As a possible cause the authors suggested a high folic acid concentration in the cerebrospinal ﬂuid (5–10 times higher than that in serum). However, these ﬁndings were not conﬁrmed in subsequent trials with high-dose folic acid supplementation.

407 Does folic acid mask vitamin B12 deﬁciency? Most frequently vitamin B12 deﬁciency is seen in people over 60 years of age (15R ). Deﬁciency of vitamin B12 in younger adults is rare, but can occur as a result of reduced absorption of vitamin B12 , for example in pernicious anemia, atrophic gastritis type B, long-term use of blockers of acid secretion, or short bowel syndrome after resection of the terminal ileum (16M , 17M ). Vitamin B12 deﬁciency in children usually depends on inborn defects of vitamin B12 metabolism or on insufﬁcient support during pregnancy and breast feeding. Vitamin B12 deﬁciency can present as hematological, gastrointestinal, and neurological disturbances. The anemia of B12 deﬁciency is actually due to functional deﬁciency of folic acid, and results from accumulation of folic acid derivatives in the form of 5-methyltetrahydrofolate, which prevents regeneration of tetrahydrofolic acid and consequently, by interfering with the synthesis of purines and DNA, reduces cell proliferation. Therefore, giving folic acid to patients with vitamin B12 deﬁciency can abolish the hematological effects but will not affect the neurological symptoms. Normalization of the blood count requires high doses of folic acid in the absence of B12 replacement therapy. Treatment with folic acid 0.3–1 mg/day normalizes the blood count in 50% of patients with B12 deﬁciency, while at doses over 5 mg/day the hematological changes are normalized in most patients (18R ). However, the hematological effects can recur, even after treatment with high doses of folic acid (5–500 mg/day), if the vitamin B12 deﬁciency is not treated. Concerning possible masking of vitamin B12 deﬁciency by folic acid, blood counts in 11– 33% of the patients with neurological symptoms of vitamin B12 deﬁciency are in the reference range. That means that in patients with severe funicular myelosis, a vitamin B12 deﬁciency psychosis, changes in the blood count may not occur, while on the other hand in patients with severe pernicious anemia neurological symptoms are not inevitably present. Nervous system Does folic acid enhance the neurological symptoms of vitamin B12 deﬁciency? The results of some animal experiments and case reports have suggested that high doses of folic acid can enhance or worsen

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the neurological effects of vitamin B12 deﬁciency. Thus, in animals with vitamin B12 deﬁciency being treated with folic acid, neurotoxicity developed more rapidly than in the untreated controls (19E –21E ). Some unproven hypotheses about how folic acid could enhance the neurological symptoms of vitamin B12 deﬁciency have been discussed, for example redistribution of B12 from the nervous system into the bone marrow, accompanied by a fall in serum concentration and reticulocytosis (18R ). There have also been some reports that in patients with vitamin B12 deﬁciency neurological complications occurred for the ﬁrst time or increased in severity when folic acid was given, the severity and onset of the complications correlating with the dose of folic acid. Whether folic acid is responsible for these observations or whether the neuropathy depends on progressive vitamin B12 deﬁciency and simply coincides with the administration of high doses of folic acid cannot be determined from these reports. In patients who were treated beforehand with liver extracts the neurological changes were weaker and occurred later than in patients who were treated with folic acid exclusively. This suggests that progressive reduction in cobalamin pools is as important for the development of the neurological complications as the supply of folic acid. Furthermore, rapid worsening of neurological changes in patients with cobalamin deﬁciency has also been seen in patients who have not received folic acid. Because there have been no double-blind placebo-controlled intervention studies of the effect of folic acid, the question of whether folic acid in patients with vitamin B12 deﬁciency aggravates the neurological complications cannot be answered deﬁnitively. From the data to hand we cannot exclude the possibility that folic acid may exacerbate the effects of vitamin B12 deﬁciency. For that reason an upper limit of 1 mg/day folic acid (in supplements or a vitamin-enriched diet) has been set in the recently published “Dietary Reference Intakes” (11S ).

Besides its effect on antiepileptic drugs, folic acid in animal experiments was neurotoxic and epileptogenic (24E ). However, when the neurotoxicity of folic acid was investigated in two groups of patients, the newborns of mothers who had taken folic acid during pregnancy and patients with parkinsonian syndromes, neurotoxicity was not found in either group (12R ).

Folic acid and epilepsy Antiepileptic drugs reduce serum folate concentrations. Conversely, the use of folic acid can reduce the effects of antiepileptic drugs such as phenytoin and can reduce their serum concentrations (22R , 23C ).

Carcinogenesis In a large US cohort study folic acid was associated with an increased risk of cancer in general and of cancers of the oropharynx and hypopharynx (28C ). However, the authors pointed to the possibility that the

Mineral balance Does folic acid inﬂuence zinc supply? The authors of the “Dietary Reference Intakes” (11S ) have concluded that reports of the effect of folic acid supplementation on the intestinal absorption of zinc are controversial, but that the recent literature shows that folic acid supplementation has either no effect or an extremely weak effect on zinc supply. Immunologic There have been some reports of hypersensitivity after oral, parenteral, and intradermal administration of folic acid, and a case has recently been reported with folinic acid (25A ). • An 80-year-old woman had a colonic resection for Duke’s C stage adenocarcinoma and was then given ﬂuorouracil 400 mg/m2 /day and folinic acid 200 mg/m2 /day for 5 days every 4 weeks. She later developed metastases and a second course of chemotherapy included irinotecan (180 mg/m2 ), ﬂuorouracil 400 mg/m2 , followed by a continuous infusion of 2400 mg/m2 over 2 days, folinic acid 200 mg/m2 , ondansetron, and atropine. During the ﬁrst course of chemotherapy she developed urticaria following the administration of ondansetron and folinic acid. The ondansetron was withdrawn and replaced by metoclopramide and prednisone. During the next course, just after the administration of folinic acid, metoclopramide, and prednisone, she had more urticaria and profound hypotension and required intravenous adrenaline. Folinic acid was withdrawn and subsequent courses were uneventful.

Using a published method (26R ) the reaction in this case was considered to be very probably due to folinic acid. IgE-antibodies to folic acid have been demonstrated in a woman with anaphylactic reactions to two multivitamin formulations containing folic acid (27A ).

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observed association could have depended on confounding by alcohol and smoking. Pregnancy Folic acid and twin-births In a recent non-randomized Swedish study in 2569 women the number of twin births in those who took folic acid supplements during early pregnancy was increased (29C ). In those who took folic acid the rate of twin births was 2.8% compared with 1.5% overall. However, in the large, randomized, multicenter MRC study with high doses of folic acid (4 mg/day) there was no increase in the frequency of twin births (30C ). Because of the higher rate of complications in twin pregnancies and twin births, the authors suggested that folic acid prophylaxis in countries with low frequencies of spina biﬁda might be harmful rather than useful. Similar results have also been seen in other studies (31C , 32C ). Drug interactions Folic acid and folinic acid with methotrexate Methotrexate is an antagonist of folic acid and is used for treating neoplastic diseases and non-neoplastic diseases such as rheumatoid arthritis and psoriasis. As methotrexate reduces the activity of dihydrofolate reductase, supplementation with folic acid and especially with folinic acid could reduce the beneﬁcial effects of methotrexate. This assumption has been supported by the results of an intervention study (33c ). Patients with rheumatoid arthritis treated with methotrexate (15 g/week) had an increase in symptoms. An open intervention trial of folinic acid 45 mg/week also showed an increase in arthritis symptoms (34C ). However, other trials showed no effects of this sort, and administration of folic acid or folinic acid is important in preventing methotrexate-induced blood dyscrasias. Conclusions Conclusions have only been drawn with respect to synthetic folic acid formulations, because there is little information about excessive intake of folate or folic acid in food. Assessment of the risk of folic acid is made more difﬁcult by the poor quality of the available data, which neither allow deﬁnite conﬁrmation nor exclusion of effects of folic acid supplementation. From the results of the trials reported here it can be concluded that the general toxicity of folic acid is low, and that zinc supply is hardly inﬂuenced. Interactions of folic acid with antiepileptic drugs or a direct

epileptogenic effect of folic acid has not been conﬁrmed in intervention studies. Hypersensitivity reactions have been described, but seem to occur only rarely. The main argument against an increase of folic acid supply in the total population is the possible masking of vitamin B12 deﬁciency by normalization of the blood count. By masking vitamin B12 deﬁciency the neurological symptoms could be reinforced. However, the case reports that suggest worsening of the neurological effects of vitamin B12 deﬁciency by treatment with folic acid are not sufﬁcient for proof of a causal relation. Nevertheless, because the available data do not exclude such an effect, in the recently published US–Canadian “Dietary Reference Intakes” an upper limit for adults of 1 mg/day folic acid in supplements or enriched food preparations and for children (1–18 years of age) of 300–800 μg have been set. At doses of 5 mg/day in more than 100 patients there was progression of neurological complications, but there have only been eight case reports of the effect of lower doses of folic acid. Because there is no NOAEL (no observed adverse effect level), a LOAEL (lowest observed adverse effect level) of 5 mg/day had to be used for the upper limit. In contrast, in 1996 the FDA ﬁxed an upper limit of 1 mg/day folic acid (natural and synthetic preparations) (35M ). It was also argued that in children of vegetarians natural folate had masked vitamin B12 deﬁciency. These previous values have now been re-evaluated by the FDA. Dietary supplementation with both folic acid and vitamin B12 offers a solution to this problem. No risks of increasing the supply of vitamin B12 are expected, but the dosage that would repair vitamin B12 deﬁciency remains to be deﬁned (12R , 35M ).

Hydroxocobalamin, cyanocobalamin Immunologic Hydroxocobalamin and cyanocobalamin are synthetically derived versions of vitamin B12 . Allergy to vitamin B12 injection is infrequent, but can be serious. Positive results of basophil histamine release assay and skin testing suggest an IgE-mediated mechanism (36r ). A patient with allergy to hydroxocobalamin without cross-reaction to cyanocobalamin has been reported (37A ).

410 • A 45-year-old woman with pernicious anemia was given intramuscular hydroxocobalamin and developed mild generalized pruritus. Subsequent monthly injections of hydroxocobalamin 1 mg were followed by incrementally worsening pruritus and then frank urticaria. The last of nine injections was followed by urticaria, bronchospasm, and oropharyngeal angio-edema, which responded to adrenaline. She underwent skin prick and intradermal testing with hydroxocobalamin and cyanocobalamin. Wheal-and-ﬂare reactions occurred after injection of hydroxocobalamin, suggesting an IgE-mediated response. There was no reaction to cyanocobalamin. She subsequently had a reaction to subcutaneous cyanocobalamin 0.1 ml (100 μg) and then intramuscular cyanocobalamin 0.5 ml (500 μg). Her macrocytic anemia resolved with monthly cyanocobalamin. After 1 year she had an episode of delayed urticaria after a routine injection of cyanocobalamin. Skin prick and intradermal tests were again negative with cyanocobalamin, but there were wheal-and-ﬂarereactions to hydroxocobalamin. She then tolerated monthly intramuscular cyanocobalamin for over 12 months.

One way of dealing with vitamin B12 allergy is to use the alternative compound after skin testing to exclude cross-reactivity. If crossreactivity occurs, desensitization may be considered. Alternatively, oral B12 can be used.

VITAMIN D (CALCIFEROL) AND ANALOGUES (SED-14, 1351; SEDA-24, 446; SEDA-25, 464; SEDA 26, 421) Mineral metabolism Two cases of hypercalcemia following the administration of vitamin D analogues in end-stage renal insufﬁciency have been reported (38A ). • A 10-year-old boy with terminal renal insufﬁciency and secondary hyperparathyroidism was treated with calcitriol (0.5 mg/day; 0.02 mg/kg). His serum calcium rose to 3.05 mmol/l with a parathormone concentration of 51 pg/ml (reference range 15–65 pg/ml; the target range is 2–4 times higher). Calcitriol was withdrawn, hemodialysis was performed, and oral calcium acetate 2 g/day was administered as a phosphate binder. His calcium returned to normal after 4 months. • A 12-year-old girl with terminal renal insufﬁciency was given alfacalcidol (0.5 mg/day; 0.02 μg/kg) and calcium carbonate (1 g/day) and developed calciﬁcation of the papillary muscles, of the ventricular septum, and of the atrioventricular valves, with sinus bradycardia and heart block that required a cardiac pacemaker. Her serum calcium

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was 2.7 mmol/l, phosphate 3.14 mmol/l, and parathormone 23 pg/ml. Calcidiol and calcium carbonate were withdrawn and hemodialysis was continued. She was given Sevelamer hydrochloride 4 g/day as a phosphate-binder and then several months later calcium acetate 5.2 g/day. After a further 4 months her laboratory values were near the upper limit of the reference ranges.

Because of its potent effects on parathyroid hormone, intestinal calcium absorption, and bone calcium mobilization, calcitriol can cause hypercalcaemia, often precluding its use in therapeutic doses (39R ). Hyperphosphatemia is also a persistent problem in patients on chronic hemodialysis and can be aggravated by therapeutic doses of calcitriol. The use of large doses of calcium carbonate or acetate to control phosphate absorption can increase the risk of hypercalcemia from calcitriol (40R ). Therefore, an analog of calcitriol that has the same therapeutic effects but minor effects on calcium and phosphorus metabolism would be better for the treatment of secondary hyperparathyroidism. In the past decade, several vitamin D analogs have been developed. These retain the action of vitamin D on the parathyroid gland but have smaller effects on calcium and phosphorus metabolism. In the USA two vitamin D analogs 19-nor-1,25-dihydroxycolecalciferol and 1α-hydroxycolecalciferol are currently used for the treatment of secondary hyperparathyroidism. Studies in animals have shown that 19-nor-1,25-dihydroxycolecalciferol is less calcemic and phosphatemic than 1α-hydroxycolecalciferol. The lower calcium x phosphate product in rats treated with 19-nor1,25-dihydroxycolecalciferol may be important, but further studies in patients are necessary to deﬁne these differences.

VITAMIN K (PHYTOMENADIONE) (SED-14, 1356; SEDA-24, 448; SEDA-25, 461; SEDA-26, 424) Study of the literature suggests that intravenous administration of vitamin K is associated with signiﬁcant adverse effects, but systematic studies and documentation are lacking. The results of intravenous administration of 100 sequential doses of vitamin K in 45 patients (34

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men, 11 women) have been retrospectively reviewed (41R ). Vitamin K1 was administered as Aquamephyton® . The dose averaged 9.7 (range 1–20) mg. The mean age was 44 (range 18– 66) years. Many of the patients were seriously ill and had signiﬁcant underlying surgical and medical problems, as evidenced by the fact that 16 died. However, none of the deaths was attributable to vitamin K. In the 11 instances in which the duration of administration was noted, the mean time was 49 (range 12.5–60) min. Only one patient had an episode of transient hypotension. • A 37-year-old man with a history of ethanol abuse presented with hepatic failure and non-cardiogenic pulmonary edema after an overdose of paracetamol, codeine, ibuprofen, and diazepam. He received two doses of Aquamephyton® over 2 days and 10 minutes after the second dose his blood pressure fell to 79/40 mmHg.

In this study the incidence of adverse effects was 1%, contrasting with the impression that one obtains from reading the medical literature on vitamin K, which suggests an overall incidence of less than 1%. Previously reported adverse effects in several cases may have been caused by diluents (e.g. polyethoxylated castor oil). Immunologic An unusual case of allergy to vitamin K, with a relapsing and remitting eczematous reaction, has been described after an intramuscular injection of vitamin K1 (42A ). • A 27-year-old woman with cystic ﬁbrosis and pancreatic insufﬁciency was given intramuscular vitamin K1 into her thigh. The next day transient erythema occurred over the injection site and 6 weeks later there was localized pain, erythema, and edema. She was given intravenous cefuroxime for presumed cellulitis, but over the next few days the features became more consistent with localized eczema; she was given oral prednisolone 30 mg/day, super-potent topical corticosteroids, corticosteroid injections, and corticosteroids under occlusion with Duoderm® , all of which failed to result in improvement. She then also developed an eczematous reaction to the Duoderm dressing. Patch tests were positive to vitamin K1 and crossreacted with vitamin K4 . She was also positive to colophonium and ester gum rosin, the dressing adhesive. Recurrent angio-edema persisted for several months and 2 years later she still had symptoms at the injection sites.

In all reported cases, only the whole formulation of vitamin K1 (in its vehicle) or vitamin K1 alone elicited positive patch tests. When individual additives were tested the results were negative. No previous exposure to vitamin K1 was required for the development of type IV hypersensitivity, and primary sensitization occurred within 1–2 weeks or after a longer time period, as in the patient described here.

OTHER VITAMINS AND VITAMIN-LIKE SUBSTANCES Pantothenic acid, pantothenyl alcohol, dexpanthenol (Bepanthen® , CAS 81-13-0) Skin Contact allergy to dexpanthenol is rare, but it occurs more often in some patients (e.g. those with eczema of the lower leg). Between 1992 and 1999, only 163 of 13 216 patients tested in the Information Network of Departments of Dermatology had a positive reaction to dexpanthenol. There have been no previous cases of occupational dexpanthenol sensitization caused by occupational exposure, but one has now been reported in a junior nurse (43AR ). • Six weeks after starting training a 29-year-old nurse developed ﬂushing and pruritus on the backs of both hands and ﬁngers, spreading to the forearms. Because of increased skin sensitivity she had been recommended to use skin protection measures; however, she did not use the skin protection cream that was available at the hospital but used a “Hand- und Hautsalbe” that had been designed for use especially in hairdressing salons. In addition to the lesions on her hands and arms she had periorbital shadowing, angular cheilitis, palmar hyperlinearity, and slightly generalized xerosis of the skin. She also reported seasonal rhinoconjunctivitis, intolerability of metals, and rhagades on the ears. After withdrawal of all supposed allergenic substances and local antieczematous therapy the hand and arm lesions healed within a few days. Skin tests were positive for nickel-II-sulfate, imidazolidinyl urea, phenyl mercury acetate, and the hand cream, in which pantothenol (5% in vaseline) was identiﬁed as the allergen. She avoided the cream and the eczema did not recur.

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REFERENCES 1. Mao JT, Goldin JG, Dermand J, Ibrahim G, Brown MS, Emerick A, McNitt-Gray MF, Gjertson DW, Estrada F, Tashkin DF, Roth MD. A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am J Respir Crit Care Med 2002; 165: 718–23. 2. Jung JI, Choi JE, Hahn ST, Min CK, Park SH. Radiologic features of all-trans-retinoic acid syndrome. Am J Roentgenol 2002; 178: 475–80. 3. Meyer-Heim A, Landau K, Boltshauser E. Aknetherapie mit Folgen—Pseudotumor cerebri durch Hypervitaminose A. Schweiz Rundsch Med Prax 2002; 91: 23–6. 4. Perrotta S, Nobili B, Rossi F, Criscolo M, Iolascon A, Di Pinto D, Passarro I, Cennamo L, Oliva A, Della Ragione F. Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition. Blood 2002; 99: 2017–22. 5. Astudillo L, Loche F, Reynisch W, Rigal-Hugnet F, Lamant L, Pris J. Sweet’s syndrome associated with retinoic acid syndrome in a patient with promyelocytic leukaemia. Ann Hematol 2002; 81: 111–14. 6. Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 1991; 100: 1701–9. 7. Grafﬁn B, Genty I, Crétel E, Jean R, Durand JM. Beta-carotene-induced hepatic ﬁbrosis. Dig Dis Sci 2002; 47: 793. 8. Miksad R, De Lédinghen V, McDougall CM, Fiel I, Rosenberg H. Hepatic hydrothorax associated with vitamin A toxicity. J Clin Gastroenterol 2002; 34: 275–9. 9. Kapil U. Deaths in Assam during vitamin A pulse distribution: The needle of suspicion is in the new measuring cup. Indian Pediatr 2002; 19: 114– 15. 10. Eichholzer M, Luthy J, Moser U, Stahelin HB, Gutzwiller F. Safety aspects of folic acid for the general population. [German] Schweiz Rundsch Med Prax 2002; 91: 7–16. 11. Standing Committee on the Scientiﬁc Evaluation of Dietary Reference Intakes and its Panel on Folate, other B vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Dietary reference intakes for thiamin, riboﬂavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington DC: National Academy Press, 1998. 12. Campbell NRC. How safe are folic acid supplements? Arch Intern Med 1996; 156: 1638–44. 13. Bässler KH, Golly I, Loew D, Pietrzik K. Vitamin-Lexikon. Stuttgart, Jena, Lübeck, Ulm: Fischer Verlag, 1999. 14. Hunter R, Barnes J, Oakley HF, Matthews DM. Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1971; 1: 61–3.

15. Rothenberg SP. Increasing the dietary intake of folate: pros and cons. Sem Hematol 1999; 36: 65– 74. 16. Bayer W, Schmidt K. Vitamine in Prävention und Therapie. Stuttgart: Hippokrates, 1991. 17. Bächli E, Fehr J. Diagnose eines Vitamin-B12 – Mangels nur scheinbar ein Kinderspiel. Schweiz Med Wochenschr 1999; 129: 861–72. 18. Savage DG, Lindenbaum J. Folate–cobalamin interactions. In: Bailey LB, editor. Folate in Health and Disease. New York: Marcel Dekker Inc, 1994: 237–85. 19. Agamanolis DP, Chester EM, Victor M, Kark JA, Hines JD, Harris JW. Neuropathology of experimental vitamin B12 deﬁciency in monkeys. Neurology 1976; 26: 905–14. 20. Van der Wesdthuyzen J, Metz J. Tissue S-adenosylmethionine levels in fruit bats with nitrous oxide-induced neuropathy. Br J Nutr 1983; 50: 325–30. 21. Van der Westhuyzen J, Fernandes-Costa F, Metz J. Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: protection by methionine and aggravation by folates. Life Sci 1982; 31: 2001–10. 22. Seligmann H, Potasman I, Weller B, Schwartz M, Prokocimer M. Phenytoin–folic acid interaction: a lesson to be learned. Clin Neuropharmacol 1999; 22: 268–72. 23. Furlanut M, Benetello P, Avogaro, A, Dainese R. Effects of folic acid on phenytoin kinetics in healthy subjects. Clin Pharmacol Ther 1978; 24: 294–7. 24. Weller M, Marini M, Martin B, Paul SM. The reduced unsubstituted pteroate moiety is required for folate toxicity of cultured cerebellar granule neurons. J Pharmacol Exp Ther 1994; 269: 393– 401. 25. Benchalal M, Yahchouchy-Chouillard E, Fouere S, Fingerhut A. Anaphylactic shock secondary to intravenous administration of folinic acid: a ﬁrst report. Oncology 2002; 13: 480–1. 26. Moore N, Biour M, Paux G, Loupi E, Begaud B, Boismare F, Royer RJ. Adverse drug reaction monitoring: doing it the French way. Lancet 1985; 2: 1056–8. 27. Dykewicz MS, Orfan NA, Sonne W. In vitro demonstration of IgE antibody to folate-albumin in anaphylaxis from folic acid. J Allergy Clin Immunol 2000; 106: 386–9. 28. Selby JV, Friedman GD, Fireman BH. Screening prescription drugs for possible carcinogenicity: eleven to ﬁfteen years of follow-up. Cancer Res 1989; 49: 5736–47. 29. Ericson A, Källen B, Aber A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001; 4: 63–6. 30. Mathews F, Murphy M, Wald N, Hackshaw A. Twinning and folic acid use. Lancet 1999; 353: 291–2.

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31. Czeizel AE, Métneki J, Dudas I. Higher rate of multiple births after periconceptional vitamin supplementation. New Engl J Med 1994; 330: 1687–8. 32. Werler M, Cragan J, Wasserman C, Shaw G, Erickson J. Multivitamin supplementation and multiple births. Am J Med Genet 1997; 71: 93–6. 33. Joyce DA, Will RK, Hofmann DM, Laing B, Blackbourn SJ. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis 1991; 50: 913–14. 34. Tishler M, Caspi D, Fishel B, Yaron M. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 1988; 31: 906–8. 35. FDA (Food and Drug Administration). Food additives permitted for direct addition to food for human consumption; folic acid (folacin). Federal Register, Rules and Regulations 1996; 61: 8797– 807. Internet release: http://vm.cfsan.fda.gov/~Ird/ fr96305c.html. 36. De Blay F, Sager MF, Hirth C, Alt M, Chamouard P, Baumann R, Pauli G. IGE-mediated reaction to hydroxocobalamin injection in patient with pernicious anaemia. Lancet 1992; 20: 1535–6. 37. Heyworth-Smith D, Hogan PG. Allergy to hydroxycobalamin, with tolerance of cyanocobalamin. Med J Aust 2002; 177: 162–3.

413 38. Bosch B, Plank C, Rascher W, Dötsch J. Hyperkalzämie als Folge einer hoch dosierten Vitamin-D-Therapie bei terminaler Niereninsufﬁzienz. Monatsschr Kinderheilk 2002; 150: 1508– 12. 39. Slatopolsky E, Brown AJ. Vitamin D analogs for the treatment of secondary hyperparathyroidism. Blood Purif 2002; 20: 109–12. 40. Meyrier A, Marsac J, Richet G. The inﬂuence of a high calcium carbonate intake on bone disease in patients undergoing hemodialysis. Kidney Int 1973; 4: 146–53. 41. Bosse GM, Mallory MNS, Malone GJ. The safety of intravenously administered vitamin K. Vet Hum Toxicol 2002; 44: 174–6. 42. Sommer S, Wilkinson SM, Peckham D, Wilson K. Type IV hypersensitivity to vitamin K. Contact Dermatitis 2002; 46; 94–6. 43. Scudlik C, Schnuch A, Uter W, Schwanitz HJ. Berufsbedingtes Kontaktekzem nach Anwenung einer Dexpanthenol-haltigen Salbe und Überblick über die IVDK-Daten zu Dexpanthenol (IVDK = Informationsverbund Dermatologischer Kliniken). Aktuel Dermatol 2002; 28: 398–401.

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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.

CORTICOTROPHINS

(SED-14, 1365;

SEDA-24, 450; SEDA-25, 465) Nervous system In 138 Japanese patients with West syndrome treated with low-dose synthetic adrenocorticotropic hormone (ACTH) the initial effects of ACTH on seizures and longterm outcome were not related to dose (daily dose 0.005–0.032 mg/kg, 0.2–1.28 IU/kg; total dose 0.1–0.87 mg/kg, 4–35 IU/kg) (1C ). There were moderate or severe adverse effects in 30 percent of the patients. There was slight loss of brain volume on CT/MRI scans in 64% of the patients, moderate loss in 23%, and severe loss in 4%. The severity of adverse effects correlated with the total dose of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily and total doses of ACTH. The authors recommended a reduction in the dose of ACTH in order to avoid serious adverse effects.

© 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

414

SYSTEMIC GLUCOCORTICOSTEROIDS (SED-14, 1369; SEDA-24, 450; SEDA-25, 465; SEDA-26, 427) Cardiovascular Hemangioma is the most common tumor of infancy, with a natural history of spontaneous involution. Some hemangiomas, however, as a result of their proximity to vital structures, destruction of facial anatomy, or excessive bleeding, can be successfully treated with systemic corticosteroids between other therapies. The risk of hypertension is poorly documented in this setting. In one prospective study of 37 infants (7 boys, 17 girls; mean age 3.5 months, range 1.5–10) with rapidly growing complicated hemangiomas treated with oral prednisone 1– 5 mg/kg/day, blood pressure increased in seven cases (2A ). Cardiac ultrasound examination in ﬁve showed two cases of myocardial hypertrophy, which was unrelated to the hypertension and which regressed after withdrawal of the prednisone. Transient hypertrophic cardiomyopathy has been attributed to systemic corticosteroid administration for a craniofacial hemangioma (3A ). • A 69-day-old white child presented with a rapidly growing 2.5 × 1.5 cm hemangioma of the external left nasal side wall. He was normotensive and there

Corticotrophins, corticosteroids, and prostaglandins was no family history of cardiomyopathy or maternal gestational diabetes. Because of nasal obstruction and possible visual obstruction, he was given prednisolone 3 mg/kg/day. After 10 weeks his weight had fallen from 7.6 to 7.1 kg and 2 weeks later he became tachypneic with a respiratory rate of 40/min. A chest X-ray showed cardiomegaly and pulmonary venous congestion. An echocardiogram showed hypertrophic cardiomyopathy. The left ventricular posterior wall thickness was 10 mm (normal under 4 mm), and the peak left ventricular outﬂow gradient was 64 mmHg. He was given a beta-blocker and a diuretic and the steroid dose was tapered. The cardiomyopathy eventually resolved.

Sensory systems Bacterial keratitis is one of the most frequent ophthalmic infections. In a meta-analysis of publications from 1950 to 2000 the use of a topical corticosteroid before the diagnosis of bacterial keratitis signiﬁcantly predisposed to ulcerative keratitis in eyes with pre-existing corneal disease (OR = 2.63; 95% CI = 1.41, 4.91) (4M ). Previous corticosteroid use signiﬁcantly increased the risk of antibiotic failure or other infectious complications (OR = 3.75; 95% CI = 2.52, 5.58). The use of corticosteroids with an antibiotic for the treatment of bacterial keratitis did not increase the risk of complications, but neither did it improve the outcome of treatment. Psychiatric Glucocorticoids can cause neuropsychiatric adverse effects that dictate a reduction in dose and sometimes withdrawal of treatment. Of 32 patients with asthma (mean age 47 years) who took prednisone in a mean dosage of 42 mg/day for a mean duration of 5 days, those with past or current symptoms of depression had a signiﬁcant reduction in depressive symptoms during prednisone therapy compared with those without depression (5c ). After 3–7 days of therapy there was a signiﬁcant increase in the risk of mania, with return to baseline after withdrawal. Obsessive–compulsive behavior after oral cortisone has been described (6A ). • A 75-year-old white man, without a history of psychiatric disorders, took cortisone 50 mg/day for 6 weeks for pulmonary ﬁbrosis and developed severe obsessive–compulsive behavior without affective or psychotic symptoms. He was given risperidone without any beneﬁcial effect. The dose of cortisone was tapered over 18 days. An MRI scan showed no signs of organic brain disease and an electroencephalogram was normal. His symptoms

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improved 16 days after withdrawal and resolved completely after 24 days. Risperidone was withdrawn without recurrence.

Metabolism Acute tumor lysis syndrome is a life-threatening metabolic emergency that results from rapid massive necrosis of tumor cells. Corticosteroid-induced acute tumor lysis syndrome has been reported (7Ar ). • A 60-year-old woman took dexamethasone 4 mg 8-hourly for dyspnea due to a precursor T lymphoblastic lymphoma–leukemia with bilateral pleural effusions and a large mass in the anterior mediastinum. She developed acute renal insufﬁciency and laboratory evidence of the metabolic effects of massive cytolysis. She received vigorous hydration, a diuretic, allopurinol, and hemodialysis. She recovered within 2 weeks and then underwent six courses of CHOP chemotherapy. The mediastinal mass regressed completely. She remained asymptomatic until she developed full-blown acute lymphoblastic leukemia, which was resistant to treatment.

Liver Although liver steatosis is a potential adverse effect of long-term prednisolone therapy, liver damage is rarely severe. Fatal acute liver failure caused by prednisolone has been described (8A ). • A 67-year-old teetotaler was given intravenous prednisolone 25 mg tds for primary dermatomyositis and 8 days later developed painless icteric hepatitis, with daily progressive marked deterioration of liver biochemistry. She had not taken any other hepatotoxic drugs, and serological tests for hepatitis and hepatotropic viruses were all negative. Antinuclear, antimitochondrial, and smooth muscle autoantibodies were negative. Ultrasound and CT scan of the upper abdomen showed liver fatty inﬁltration. Prednisolone was tapered gradually, and she gradually improved. However, on day 26 she developed pneumonia and died 6 days later.

Skin Prednicarbate is a topical glucocorticoid that seems to have an improved beneﬁt–harm balance, as has been shown in 24 healthy volunteers (7 men, 17 women, aged 25–49 years) in a double-blind, randomized, placebo-controlled study of the effects of prednicarbate, mometasone furoate, and betamethasone 17-valerate on total skin thickness over 6 weeks (9C ). On day 36, total skin thickness was reduced by a mean of 1% in test ﬁelds treated with vehicle; the relative reductions were 13, 17, and 24% for prednicarbate, mometasone furoate, and betamethasone 17-valerate respectively. There

416 were visible signs of atrophy or telangiectasia in two subjects each with betamethasone 17valerate and mometasone furoate, but not with prednicarbate or its vehicle. Musculoskeletal Oral and inhaled glucocorticoid therapy is associated with bone loss resulting in glucocorticoid-induced osteoporosis and an increase in fracture risk. Guidelines for the prevention and treatment of glucocorticoidinduced osteoporosis have been published (10S ). Although there are several consensus statements and recommendations for prophylactic measures against steroid-induced osteoporosis in patients with rheumatoid arthritis, prophylaxis is commonly underprescribed. In two recent studies of 191 and 92 patients taking long-term corticosteroids, relatively few were taking primary prevention, although some were taking vitamin D and calcium tablets. Around 65–68% of all those who qualiﬁed for prophylaxis for steroid-induced osteoporosis did not receive therapy, and only 9% of those in one study and 21% in the other were taking bisphosphonates (11c , 12c ). Systemic glucocorticoids are often prescribed for rheumatoid arthritis. Even in low doses they can have clinical beneﬁts and can inhibit joint damage, but they can cause osteoporotic fractures. In a 2-year double-blind, randomized, placebo-controlled trial in 81 patients (29 men, mean age 62 years) with early active rheumatoid arthritis who had not been treated with disease-modifying antirheumatic drugs, 41 were assigned to oral prednisone 10 mg/day and 40 to placebo. NSAIDs were allowed in both groups and after 6 months sulfasalazine (2 g/day) could be prescribed as rescue medication. Those who took prednisone had more clinical improvement with less use of concomitant drugs. After month 6, radiological scores had progressed signiﬁcantly less in those who took prednisone. After 24 months, seven patients had new vertebral fractures, ﬁve in the prednisone group and two in the placebo group (13c ). Budesonide, a corticosteroid with little systemic activity after oral administration has been approved in some countries for the treatment of ileocecal Crohn’s disease. Bone loss in patients taking oral budesonide has been evaluated in a longitudinal study in which bone mineral density was measured annually for 2 years in

Chapter 39

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138 patients (67 men, mean age 36 years old) with quiescent Crohn’s disease (14c ). They took budesonide (8.5 mg/day; n = 48), prednisone (10.5 mg/day, n = 45), or non-steroidal drugs (n = 45). After 1 year, the bone mineral density in the lumbar spine fell by 2.36% in those who took budesonide, by 0.61% in those who took prednisone, and by 0.09% in those who took non-steroidal drugs. In the second year, the largest fall occurred in those who took budesonide (1.97%), but the differences between the groups were not signiﬁcant. After 2 years, bone mineral density in the femoral neck fell by 2.94% with budesonide, 0.36% with prednisone, and 1.05% with the non-steroidal drugs. These results suggest that budesonide can cause bone loss, but the non-randomized design of the study limits conclusions about the comparison between budesonide and prednisone. Immunologic Urticaria with angio-edema has been described in a patient taking deﬂazacort (15A ). • A 64-year-old woman with allergic alveolitis caused by parakeet feathers improved with intravenous methylprednisolone, and was given oral deﬂazacort 60 mg/day, to be reduced progressively. After 30 days she developed generalized itchy blotches and lip edema. At that time she was mistakenly taking deﬂazacort in a dose of 120 mg/day. She was given an antihistamine, without any improvement. Deﬂazacort was then replaced by prednisolone and her symptoms disappeared immediately. Skin tests (a prick test and an epicutaneous test) were positive with deﬂazacort. Oral provocation with deﬂazacort 30 mg was positive, with the immediate appearance of the same symptoms as in the initial episode.

Infection risk Patients taking corticosteroids have an increased risk of infections, including those produced by opportunistic and rare pathogens. Mycobacterium avium septic arthritis has been reported in two patients with preexisting rheumatic disease (scleroderma and polymyositis) who were taking prednisolone and azathioprine; the infection was in the left shoulder in one patient and in the knee in the other (16A ). The effect of dexamethasone has been assessed in a retrospective chart review study in neonates weighing less than 1200 g, both with (n = 65) and without (n = 269) Candida sepsis; dexamethasone therapy and prolonged

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Chapter 39

antibiotic therapy were associated with Candida infection (17c ). Fatal Aspergillus myocarditis, probably related to short-term administration of corticosteroids, has been described.

over 5% of pre-pregnant weight treated with steroids (n = 30) or without (n = 25), gestational evolution and singleton birth weights were not different in the two groups (23c ). The effects of exposure to topical corticosteroids during pregnancy have been evaluated in a population-based follow-up study in 363 primigravida exposed to topical corticosteroids during pregnancy and 9263 controls who received no prescriptions at all (24C ). The prevalence of malformations was 2.9% among 170 infants exposed to corticosteroids during the ﬁrst trimester and 3.6% among the controls. There were no increases in the risks of low birth weight, malformations, or preterm delivery in the offspring of women who were exposed to topical corticosteroids during pregnancy.

• A 58-year-old man had an acute exacerbation of his chronic obstructive pulmonary disease and received oxygen, bronchodilators, omeprazole, coamoxiclav, and intravenous methylprednisolone 40 mg 8-hourly; he died 5 days later and postmortem examination showed a fungal myocarditis (18A ).

Carcinogenicity A possible relation between systemic corticosteroid use and a risk of esophageal cancer has been described in a population-based study in Denmark, in which the prescriptions database and the Danish cancer registry were linked (19c ). There was an increase in the number of cases observed (36) compared with the number expected (19), with a standardized incidence ratio of 1.92 (95% CI = 1.34, 2.65). Pregnancy In a recent statement the American Academy of Pediatrics and the Canadian Paediatric Society did not recommend the routine use of systemic dexamethasone for the prevention or treatment of chronic lung disease in infants with very low birth weights, because it does not reduce overall mortality and is associated with impaired growth and neurodevelopment delay (20S , 21S ). In an analysis of 595 preterm infants born at 26–32 weeks gestation during a randomized controlled trial for the prevention of lung disease, corticosteroids given to women at risk of preterm delivery promoted fetal lung maturation, reduced the incidence of respiratory distress syndrome, and reduced neonatal morbidity and mortality (22C ). Dexamethasone was given as either two doses of 12 mg 24 hours apart or four doses of 6 mg every 6 hours. Mortality was 9.2% after three or more courses, compared with 4.8% after one or two courses. This association was not explained by other factors (maternal or other common preterm morbidities). Teratogenicity Corticosteroids have been used in cases of hyperemesis gravidarum when standard antiemetics are ineffective. In an observational comparison of women with complicated hyperemesis gravidarum and weight loss

PROSTAGLANDINS

(SED-14, 1396; SEDA-24, 459; SEDA-25, 472; SEDA-26, 430)

Alprostadil (prostaglandin E1 ) Musculoskeletal Continuous chronic infusion of alprostadil via a portable pump and neuromuscular electrical stimulation help to improve the quality of life in patients with severe chronic heart failure waiting for a donor heart, as both treatments can be performed at home. Hypertrophic osteoarthropathy has been reported in a woman with severe chronic heart failure who was referred for cardiac rehabilitation (25A ). • A 56-year-old woman with muscle weakness and severe chronic heart failure (NYHA Class III) caused by aortic coarctation received an intravenous infusion of alprostadil 5 ng/kg/min. Although her hemodynamics improved, her muscle weakness and exercise intolerance persisted. Neuromuscular electrical stimulation of both thigh muscles was begun. However, during simultaneous continuous intravenous infusion of alprostadil she developed pain in her knees and elbows. The overlying skin was warm and dusky red and the subcutaneous tissues were swollen. The discomfort was aggravated by motion. There were signs of non-inﬂammatory synovial effusions and Xrays showed symmetric bilateral periosteal bone deposition in the distal humerus and synovial effusions in both knees. The bone scintigram showed increased bilateral symmetrical tracer uptake in both knees, ankles, wrists, and carpal bones, and

418 increased radionuclide uptake in periarticular regions. Secondary hypertrophic osteoarthropathy caused by continuous intravenous infusion of alprostadil was diagnosed. The dosage of alprostadil was reduced to 2.5 ng/kg/min, and the signs of osteoarthropathy disappeared within 5 days.

Immunologic Allergic contact dermatitis has been attributed to latanoprost (26A ). • An 85-year-old man with glaucoma developed tearing, red eyes, and pruritic, edematous, eczematous eyelids. Treatment for presumed ocular rosacea and seborrhea with oral tetracyclines, topical corticosteroids, and metronidazole gel was unhelpful. He was using topical carboxymethylcellulose sodium 1%, propylmethyl cellulose 0.3%, polyvinyl alcohol 1.4%, latanoprost, and levobunolol. Patch testing with a standard 64-antigen patch elicited a strong reaction only to balsam of Peru. However, repeated open application of levobunolol and latanoprost for 4 days elicited a strong positive reaction to latanoprost.

When latanoprost was applied for 4 months to the eyes in 14 patients, there was an increase in HLA-DR expression (27c ). Since HLA-DR is a marker of ocular surface inﬂammation, these results suggested a subclinical inﬂammatory re-

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J. Costa and M. Farré

action to latanoprost. However, the clinical signiﬁcance of HLA-DR expression is not clear.

Misoprostol The efﬁcacy and tolerability of sublingual misoprostol has been evaluated in an uncontrolled trial in China in 50 women who requested medical abortions at up to 12 weeks of gestation (28c ). All received three doses of misoprostol 600 micrograms sublingually 3-hourly, and two more doses of 600 micrograms sublingually if an abortion did not occur. The overall complete abortion rate was 86% and the mean number of doses of misoprostol required was four. There was no signiﬁcant change in hemoglobin concentration and the median duration of vaginal bleeding was 15 days. Lower abdominal pain, fatigue, diarrhea, fever, and chills were the most common adverse effects, and they occurred more often (from 70 to 100%) than in studies in which repeated doses of vaginal misoprostol were used.

REFERENCES 1. Ito M, Aiba H, Hashimoto K, Kuroki S, Tomiwa K, Okuno T, Hattori H, Go T, Sejima H, Dejima S, Ikeda H, Yoshioka M, Kanazawa O, Kawamitsu T, Ochi J, MikiN, Noma H, Oguro K, Ozaki N, Tamamoto A, Matsubara T, Miyajima T, Fujii T, Konishi Y, Okuno T, Hojo H. Low-dose ACTH therapy for West syndrome: initial effects and longterm outcome. Neurology 2002; 58: 110–14. 2. Thedenat B, Leaute-Labreze C, Boralevi F, Roul S, Labbe L, Marliere V, Taieb A. Blood pressure monitoring in infants with hemangiomas treated with corticosteroids. Ann Dermatol Venereol 2002; 129: 183–5. 3. Pokorny JJ, Roth F, Balfour I, Rinehart G. An unusual complication of the treatment of a hemangioma. Ann Plast Surg 2002; 48: 83–7. 4. Wilhelmus KR. Indecision about corticosteroids for bacterial keratitis: an evidence-based update. Ophthalmology 2002; 109: 835–42. 5. Brown ES, Suppes T, Khan DA, Carmody TJ 3rd. Mood changes during prednisone bursts in outpatients with asthma. J Clin Psychopharmacol 2002; 22: 55-61. 6. Scheschonka A, Bleich S, Buchwald AB, Ruther E, Wiltfang J. Development of obsessive–

compulsive behaviour following cortisone treatment. Pharmacopsychiatry 2002; 35: 72–4. 7. Lerza R, Botta M, Barsotti B, Schenone E, Mencoboni M, Bogliolo G, Pannacciulli I, Arboscello E. Dexamethasone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma. Leuk Lymphoma 2002; 43: 1129–32. 8. Dourakis SP, Sevastianos VA, Kaliopi P. Acute severe steatohepatitis related to prednisolone therapy. Am J Gastroenterol 2002; 97: 1074–5. 9. Korting HC, Unholzer A, Schafer-Korting M, Tausch I, Gassmueller J, Nietsch K-H. Different skin thinning potential of equipotent mediumstrength glucocorticoids. Skin Pharmacol Appl Skin Physiol 2002; 15: 85–91. 10. Bone and Tooth Society, National Osteoporosis Society, Royal College of Physicians. Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment. London: Royal College of Physicians, 2002. 11. Hart SR, Green B. Osteoporosis prophylaxis during corticosteroid treatment: failure to prescribe. Postgrad Med J 2002; 78: 242–3. 12. Gudbjornsson B, Juliusson UI, Gudjonsson FV. Prevalence of long term steroid treatment and the frequency of decision making to prevent steroid in-

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duced osteoporosis in daily clinical practice. Ann Rheum Dis 2002; 61: 32–6. 13. Van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efﬁcacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 2002; 136: 1–12. 14. Cino M, Greenberg GR. Bone mineral density in Crohn’s disease: a longitudinal study of budesonide, prednisone, and nonsteroid therapy. Am J Gastroenterol 2002; 97: 915–21. 15. Gomez CM, Higuero NC, Moral de Gregorio A, Quiles MH, Nunez Aceves AB, Lara MJ, Sanchez CS. Urticaria–angioedema by deﬂazacort. Allergy Eur J Allergy Clin Immunol 2002; 57: 370–1. 16. Bridges MJ, McGarry F. Two cases of Mycobacterium avium septic arthritis. Ann Rheum Dis 2002; 61: 186–7. 17. Pera A, Byun A, Gribar S, Schwartz R, Kumar D, Parimi P. Dexamethasone therapy and Candida sepsis in neonates less than 1250 grams. J Perinatol 2002; 22: 204–8. 18. Carrascosa Porras M, Herreras Martinez R, Corral Mones J, Ares Ares M, Zabaleta Murguiondo M, Ruchel R. Fatal Aspergillus myocarditis following short-term corticosteroid therapy for chronic obstructive pulmonary disease. Scand J Infect Dis 2002; 34: 224–7. 19. Sorensen HT, Mellemkjaer L, Friis S, Olsen JH. Use of systemic corticosteroids and risk of esophageal cancer. Epidemiology 2002; 13: 240–1. 20. American Academy of Pediatrics and Canadian Paediatric Society. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002; 109: 330–8.

21. Canadian Paediatric Society and American Academy of Pediatrics. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatr Child Health 2002; 7: 20–8. 22. Banks BA, Macones G, Cnaan A, Merrill JD, Ballard PL, Ballard RA, North American TRH Study Group. Multiple courses of antenatal corticosteroids are associated with early severe lung disease in preterm neonates. J Perinatol 2002; 22: 101–7. 23. Moran P, Taylor R. Management of hyperemesis gravidarum: the importance of weight loss as a criterion for steroid therapy. Q J Med Mon J Assoc Phys 2002; 95: 153–8. 24. Mygind H, Thulstrup AM, Pedersen L, Larsen H. Risk of intrauterine growth retardation, malformations and other birth outcomes in children after topical use of corticosteroid in pregnancy. Acta Obstet Gynecol Scand 2002; 81: 234–9. 25. Crevenna R, Quittan M, Hulsmann M, Wiesinger GF, Keilan MY, Kainberger F, Leitha T, FialkaMoser V, Pacher R. Hypertrophic osteoarthropathy caused by PGE1 in a patient with congestive heart failure during cardiac rehabilitation. Wien Klin Wochenschr 2002; 114: 115–18. 26. Jerstad KM, Warshaw E. Allergic contact dermatitis to latanoprost. Am J Contact Dermatitis 2002; 13: 39–41. 27. Guglielminetti E, Barabino S, Monaco M, Mantero S, Rolando M. HLA-DR expression in conjunctival cells after latanoprost. J Ocul Pharmacol Ther 2002; 18: 1–9. 28. Tang OS, Miao BY, Lee SW, Ho PC. Pilot study on the use of repeated doses of sublingual misoprostol in termination of pregnancy up to 12 weeks gestation: efﬁcacy and acceptability. Hum Reprod 2002; 17: 654–8.

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40

Sex hormones and related compounds, including hormonal contraceptives

More than any other area of clinical pharmacology and drug safety, that relating to the sex hormones and the hormonal contraceptives confronts the periodic reviewer with formidable problems in seeking to deﬁne current knowledge. It is an area in which commercial interests are vast, public fascination unbounded, and the mass media likely to run riot. Many products— and minor variations on them—are hurried on to the market, only to be succeeded by others well before their long-term effects have been fully deﬁned. It is an area in which strong views and ﬁrm conclusions are sometimes more likely to be advanced by courts of law, politicians, journalists, and even ecclesiastical leaders than by the scientists who are best qualiﬁed to formulate them. As to the published literature, it is characterized by a constant ﬂow of papers, some of them apparently prepared in haste for commercial or academic reasons, too many of them based on inadequate material, and some betraying elements of frank bias. Any attempt at overall analysis soon encounters outright contradictions in the published evidence. All this has been the case for more than 30 years with hormonal contraception and estrogen replacement therapy, while in such ﬁelds as post-coital contraception, abortifacients, and even the use of androgens in the hope of maintaining sexual function in elderly people, the debate has been confounded by arguments which, while selectively citing the evidence, in fact reﬂect ethical, social, sectarian, or religious convictions. It is not therefore surprising that, in the 27 years since these Annuals began, their initial conclusions in these matters have so often © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

420

been fundamentally modiﬁed later; the ability of certain hormones or their antagonists to induce cancers of various organ systems is a case in point. Much of the current ﬂow of evidence has to be noted, insofar as it seems credible; sometimes a clear trend can be discerned, often not. The only beacons that point the way with a fair degree of reliability are provided by the few massive population studies that have been conducted, some of which are still proceeding. The Women’s Health Initiative in the USA and the Million Women Study in the UK, both of which reported as this Annual was being prepared, are examples. Yet even such studies are open to challenge, and it is rare for two such investigations to be so compatible in materials and methods as to be mutually supportive. In the legal case regarding the third-generation oral contraceptives, the statisticians and epidemiologists associated with several such large-scale studies found themselves pitted aggressively against one another in court, leaving a patient civil judge to draw whatever conclusions he could from the conﬂicting materials (SEDA-26, 442).

GONADOTROPHINS AND OVULATION-INDUCING DRUGS (SED-14, 1464; SEDA-24, 473; SEDA-25, 478; SEDA-26, 434) Endocrine Ovarian hyperstimulation is a well-recognized risk of controlled ovarian stimulation in patients with polycystic ovary syndrome. Just how dangerous and even lifethreatening such hyperstimulation can be is illustrated by a recent case (1A ).

Sex hormones and related compounds, including hormonal contraceptives • A 28-year-old woman who had undergone attempted hormonal induction of ovulation presented some days later with ascites, oliguria, and vomiting. Over 2 weeks she developed severe hypoalbuminemia, due to a combination of intractable vomiting, intravenous rehydration, paracentesis, hypercatabolism, and proteinuria, with gross edema and progressively worsening liver function. Her serum albumin dropped to 9 g/l with liver function abnormalities: AsT 462 IU/l, alkaline phosphatase 706 IU/l, bilirubin 26 μmol/l, prothrombin time 19 seconds. Paracentesis and total parenteral nutrition coincided with rapid clinical improvement.

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• a conventional human menopausal gonadotropin/human chorionic gonadotropin (hMG– hCG) program; • the hMG step-down method, in which the daily dose of hMG was reduced from 150 IU to 75 IU when the follicle diameter reached 11–13 mm; • the sequential hMG/gonadotropin-releasing hormone (GnRH) method, in which hMG injection was switched to pulsatile GnRH administration (20 μg/120 min subcutaneously) when the follicle diameter reached 11–13 mm; • a new, modiﬁed hMG–GnRH method, in which pulsatile GnRH was injected together with hMG; daily hMG was stopped and the GnRH dosage was changed from 10 to 20 μg when the follicle diameter reached 11–13 mm.

was only 50% with the sequential hMG–GnRH method. By contrast, with the new method fewer than three growing follicles occurred in 82% of patients, there was a 100% rate of ovulation, and there were no multiple pregnancies or ovarian hyperstimulation syndrome. Moreover, the new method induced pregnancy in three out of ﬁve patients. The authors considered their modiﬁed method suitable for the treatment of severe hypogonadotrophic amenorrhea. In view of the risks attached to ovarian hyperstimulation, this type of program certainly merits further evaluation. In vitro maturation of immature oocytes represents a potential alternative for fertility treatment in patients who are likely to suffer hyperstimulation. In two patients considered to be at risk of hyperstimulation, because of polycystic ovaries, priming with HCG 10 000 IU (speciﬁed only as the IVF-C brand) was followed by removal of the oocytes 36 hours later (4c ). Oocytes considered to be mature at the time of collection were inseminated using in vitro fertilization or intracytoplasmic sperm injection (ICSI), and the resulting embryos were cultured to the blastocyst stage. Transfer of these blastocysts resulted in pregnancy in both patients. Immature oocytes were matured in a culture medium containing 30% human follicular ﬂuid, recombinant follicle stimulating hormone 1 IU/ml, hCG 10 IU/ml, and recombinant epidermal growth factor (rhEGF) 10 ng/ml. ICSI was then carried out. Two and ﬁve expanded blastocysts were obtained after 5 days of culture and were cryopreserved. The ﬁndings suggested that one can avoid the risk of ovarian hyperstimulation when using hCG in women with polycystic ovaries and that (at least when using mature oocytes) pregnancy can be established.

Initially, the established methods were used randomly to treat 34 cycles in 20 women; subsequently, ﬁve patients who failed to conceive after treatment with sequential hMG–GnRH were then treated by the new method. More than eight growing follicles and multiple pregnancies were observed during treatment by the conventional method. The incidence of ovarian hyperstimulation syndrome was 26% with the conventional method, 20% with the step-down method, and 0% with the sequential hMG– GnRH method; however, the rate of ovulation

Drug formulations The composition of different formulations of hCG is not entirely consistent, and could account for some discrepancies in clinical studies, as well as introducing risks. For example, previously formulations of hCG have been shown to be toxic to Kaposi’s sarcoma (KS) cells. However, clinical studies using commercial hCG formulations in the human sarcoma are highly contradictory (5cR ). The apparent discrepancies between different studies may be because both pro- and anti-KS components are present in varying proportions

Other presenting signs of ovarian hyperstimulation include ascites, hydrothorax, thrombophlebitis and, as in one recently reported case, acute dyspnea (2A ). The incidence of ovarian hyperstimulation is highly dependent on the therapeutic regimen. In one study (3c ) the following methods were compared:

422 in different hCG formulations. As certain hCG formulations may not only lack the ability to control Kaposi’s sarcoma, but also contain contaminant KS growth factor(s), the authors suggested caution when using crude hCG for the treatment of Kaposi’s sarcoma. These ﬁndings point to the need to reconsider the international standards applicable to the standardization, formulation, and marketing of hCG products, whether of natural or recombinant origin.

ESTROGENS

(SED-14, 1448; SEDA-24, 467; SEDA-25, 478; SEDA-26, 436)

The safety of using estrogens in adolescent girls to arrest excessive growth in height has never been properly documented. This use of estrogens was widely advocated in the 1950s for cosmetic and social rather than medical purposes and still remains popular among American pediatric endocrinologists when a family requests treatment. A questionnaire survey among this group has shown that the most common adverse effects were weight gain, nausea or vomiting, areolar or nipple pigmentation, headache, and irregular menses (6cR ). However, there seems to have been no methodical follow up to determine the long-term consequences. Immunologic There are periodic reports that provide a reminder that allergic reactions to estrogens and other steroids, while unusual, do occur, and that they are not limited to topical use. • A 47-year-old postmenopausal woman developed eczematous lesions at the sites of application of an estradiol transdermal system and subsequently at the sites of application of an estradiol gel (7A ). She was therefore given oral estrogen instead, but this promptly elicited a systemic pruritic rash. The causal link was in all instances conﬁrmed by patch testing.

It is clear that when a patient has a hypersensitivity reaction to transdermal estrogen one must be cautious about subsequently giving oral estrogen.

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Diethylstilbestrol (stilbestrol) The long and troubled history of the use of stilbestrol in pregnancy, reviewed in earlier volumes in this series, has been the subject of a new and thoughtful discussion (8R ), pointing in particular to some of the lessons that can be distilled for the safe use of drugs in general. Musculoskeletal Since therapeutic androgen deprivation as a form of treatment of prostatic disease brings with it a considerable risk of osteoporosis, it is important to determine which type of treatment is associated with the least risk. Various relevant parameters were evaluated over 18 months in 54 men with prostatic cancer and 24 with benign prostatic hyperplasia who were being treated in different ways (9c ). All the men with prostate cancer received either external beam radiotherapy without androgen deprivation or androgen deprivation therapy; diethylstilbestrol was used either alone or in conjunction with luteinizing hormone releasing hormone agonists or orchidectomy. There was a signiﬁcantly higher concentration of urinary telopeptides in patients on androgen deprivation therapy who were not taking diethylstilbestrol; in other words, the estrogenic effect of diethylstilbestrol provided protection from bone resorption. The men who took diethylstilbestrol did not have higher degrees of bone breakdown than those with benign prostatic hyperplasia or those who never underwent any form of androgen deprivation. The authors concluded that rapid bone turnover and resorption can be adequately prevented with diethylstilbestrol 1 mg/day, irrespective of whether it is given alone or in conjunction with other modes of androgen deprivation. This seems to show that in men who require long-term antiandrogen therapy diethylstilbestrol should be used alone. Drug formulations The parenteral formulation diethylstilbestrol diphosphate is less commonly used than the oral formulation. In Japan 24 elderly patients with advanced relapsed prostatic cancer were treated with high doses supplemented with ethinylestradiol (doses unclear); there was some slight therapeutic effect, but there were gastrointestinal symptoms and ﬂuid retention (10c ). Also in Japan, a few patients with advanced disease were treated using intravenous diethylstilbestrol diphosphate

Sex hormones and related compounds, including hormonal contraceptives

500 mg/day for 20 consecutive days to a total dose of 10 g; the authors’ conclusion was more positive but adverse events were not speciﬁed (11c ).

Hormone replacement therapy (HRT) (SED-14, 1457; SEDA-24, 468; SEDA-25, 479; SEDA-26, 436) With increasing concern over the long-term safety of HRT, the beneﬁt–harm balance has to be continually reassessed and conclusions as to its prophylactic or therapeutic value need to be adjusted as experience accumulates. Not all the promises held out for the beneﬁts of this therapy have been conﬁrmed. For example, while estrogens prevent peripheral bone loss they do not prevent vertebral fractures (12C ). And in a 2-year placebo-controlled, crossover study in 34 healthy postmenopausal women, treatment with transdermal estrogen alone (Menorest® 50 μg/day) did not improve lipid proﬁles or any indices of arterial function (13C ). It is remarkable that, despite decades of accumulated observational evidence, the balance of beneﬁts and harms for hormone use in healthy postmenopausal women remains uncertain (14CR ). Quite apart from the constantly changing spectrum of the available data, one explanation for the confusion is the relatively high proportion of poor quality clinical work, particularly studies that are designed to promote particular commercialized forms of treatment from among the many alternatives available. A study that cannot be faulted on that score is the Women’s Health Initiative, a randomized controlled primary prevention trial (planned to last for 8.5 years), in which 16 608 postmenopausal women aged 50–79 years with an intact uterus at baseline were recruited at 40 US clinical centers over the period 1993–8 (15CR ). In one part of this study, 8506 participants received conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day; 8102 were given placebo. The primary desired outcome was reduction of coronary heart disease (non-fatal myocardial infarction and death), with invasive breast cancer as the primary anticipated adverse outcome. After a mean of 5.2 years, the data and safety

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monitoring board recommended stopping the trial of estrogen plus progestagen vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported harms exceeding beneﬁts. The estimated hazard ratios (and 95% conﬁdence intervals) were: • • • • • • • •

coronary disease 1.29 (1.02, 1.63; n = 286); breast cancer 1.26 (1.00, 1.59; n = 290); stroke 1.41 (1.07, 1.85; n = 212); pulmonary embolism 2.13 (1.39, 3.25; n = 101); colorectal cancer 0.63 (0.43, 0.92; n = 112); endometrial cancer 0.83 (0.47, 1.47; n = 47); hip fracture 0.66 (0.45, 0.98; n = 106); death due to other causes 0.92 (0.74, 1.14; n = 331).

What the above amounts to is that the absolute excess risks per 10 000 woman–years attributable to the use of an estrogen plus a progestagen were seven more coronary heart disease events, eight more strokes, eight more pulmonary embolisms, and eight more invasive breast cancers, while the risk reductions per 10 000 woman– years were six fewer colorectal cancers and ﬁve fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 woman–years. The overall harms in this study thus clearly exceeded the beneﬁts. Allcause mortality was not affected. Other published studies, many of which are of limited scope, do not run closely parallel to the above ﬁndings from the Women’s Health Initiative, and the data on cardiovascular effects remain particularly confusing. However, Beral et al have pointed out optimistically that “substantial new data should soon be available from randomized trials of estrogen-alone hormonal replacement therapy versus placebo”, although they added that “few additional trial data on combined hormone replacement therapy are expected for about a decade” (16R ). They also pointed out that existing randomized trials are too small to provide reliable evidence on some basic matters, including the relative risks of the various compounds in use. Special senses The possibility that estrogen replacement therapy might cause dryness of the eyes has been reviewed in the light of data from

424 the large Women’s Health Study in the USA (17C ), and this work has been further reviewed (18r ). Questionnaires were sent to 25 665 participants. For every 3-year increase in the duration of replacement therapy there was a 15% increase in the incidence of dry eye syndrome. The risk was greater in women who used estrogen alone than in those who used combined estrogen/progestagen regimens. The evidence was not statistically strong, but it suggests that there is some correlation and that users and prescribers should be aware of it. Metabolism If it is indeed true that transdermal estrogens have certain advantages over oral estrogens in terms of safety, this needs to be better documented than hitherto; as in so many instances, the evidence is confusing, because of the multiplicity of products and doses. In 35 postmenopausal women who had been amenorrheic for at least 1 year, two consecutive 2-month courses of transdermal estrogen (estradiol patches 25 μg and 50 μg) were randomly followed by a 2-month course of treatment with either an estradiol patch 100 μg/day or an estradiol patch 50 μg/day combined with either progesterone 300 mg/day or medroxyprogesterone acetate 5 mg/day during the last 14 days (19c ). Neither transdermal estradiol alone nor transdermal estradiol plus progestagen altered the lipoprotein proﬁle, LDL resistance to oxidation, or LDL particle size. However, all treatments similarly reduced myeloperoxidase protein concentrations. Hematologic Although the thrombogenic potential of oral estrogen in postmenopausal women is well documented, it has been argued that direct studies of the effect of estrogen replacement on hemostasis are largely lacking and not well known (20R ). A review of a series of randomized trials has shown that the treatment has no signiﬁcant effect on concentrations of ﬁbrinogen and factor VII. Plasma concentrations of antithrombin and protein S fell with oral estrogen but not with transdermal estrogen. No form of replacement affected protein C concentrations, but there was activation of coagulation in the presence of oral estrogen, as reﬂected by a rise in the concentration of prothrombin fragment 1 + 2. As far as ﬁbrinolysis is concerned, oral estrogen reduces plasma PAI-1 and tPA, leading to an increase in ﬁbrinolytic potential. The absence of an effect of transdermal

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estrogen on coagulation and ﬁbrinolysis suggests that the route of estrogen administration is important, but it has not to date been convincingly shown that transdermal estrogen in equieffective doses is less thrombogenic than the oral form. In a case–control study 155 postmenopausal women who had had venous thromboembolism were compared with 381 matched controls (21C ). In all, 32 cases and 27 controls were current users of oral replacement therapy, whereas 30 cases and 93 controls were current users of transdermal products. After adjustment for potential confounding variables, the estimated risk ratio for venous thromboembolism in current users of the oral products compared with the transdermal users was 4.0 (1.9–8.3). This is strong evidence that the transdermal route was considerably safer. However, the conclusions of different studies continue to conﬂict with one another, no doubt in part because of variations in the formulations and patterns of use of the products. Reproductive system Various companies and investigational groups continue to examine the relative efﬁcacy and safety of different forms of combined postmenopausal treatment. In a randomized, placebo-controlled trial 579 women were treated for 26 cycles with sequential combinations of 17-beta-estradiol 1 mg plus dydrogesterone 5 or 10 mg or 17-beta-estradiol 2 mg with dydrogesterone 10 or 20 mg (22C ). The effects of these treatments in the 442 women who underwent biopsy were considered satisfactory in terms of cycle control and endometrial response, but the 1 mg dose of 17-beta-estradiol was associated with more intermittent uterine bleeding than the 2 mg dose. Higher doses of dydrogesterone were associated with a higher incidence of cyclical bleeds and a later time of onset. Two doses of transdermal estrogen, 50 and 100 μg/day, have been compared with placebo in preventing bone loss in postmenopausal women over 24 months (23c ). Bone mineral density in the lumbar spine was only marginally better with the higher dose; the slightly better effect was largely offset by a higher incidence of breast pain, reported by 8% of women on placebo, by 6% of the who took 50 μg/day, and by 17% of women who took 100 μg/day.

Sex hormones and related compounds, including hormonal contraceptives

Carcinogenicity Breast cancer By far the largest piece of evidence to emerge on the risk of breast cancer is that from the Million Women Study (24C ). In all, more than a million women aged 50–64 were recruited into this study between 1996 and 2001 and are being followed up with respect to cancer incidence and deaths. Current users of HRT at the time of recruitment were signiﬁcantly more likely than neverusers to develop breast cancer (adjusted RR = 1.66; 95% CI = 1.58, 1.75) and to die from it. The signiﬁcance of the increase was substantially greater for current users of estrogen plus progesterone than for those who took estrogen only or tibolone. This major study, and the reactions to it from other workers, will require fuller discussion in a future volume. Although the conclusion is roughly similar to that of the Women’s Health Initiative, it has already been challenged on methodological and statistical grounds as presenting an unjustiﬁed threat to the continued use of HRT in women who need it (25r ). When breast cancers occur in women taking estrogen replacement therapy they are sometimes claimed to be less aggressive than in other women. The effect of the duration or type of replacement therapy on the aggressiveness of such tumors has been studied in 1105 consecutive postmenopausal patients treated for operable breast cancer at the European Institute of Oncology (26C ). Tumors in women who had been exposed to estrogen replacement therapy were characterized by better stage distribution, a smaller diameter, and less extensive involvement of the axillary lymph nodes; histological grade III tumors were less common. The prognosis was generally better in women who took estrogen replacement therapy for more than 5 years. Tumors with estrogen-positive receptors were more common in the controls, but this tendency was reversed when the comparison was limited to those who had had particularly long exposure. Overall these ﬁndings seem to conﬁrm that prolonged use of estrogen replacement therapy does reduce the degree of aggressiveness of breast cancer, but they still have to be set against the evidence that the incidence of such cancers is increased. A new approach to the study of the effects of hormone replacement therapy on the breast is to examine breast density, using mammography and the Wolfe classiﬁcation. In a

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randomized study of 166 menopausal women, using this technique, there was increased breast density after 6 months of treatment eight times more commonly in those who took estradiol and norethisterone acetate than in those who took tibolone (27CR ). The signiﬁcance of this increased density is not clear, but it should for the present be regarded as undesirable, perhaps representing the prodromal phase of more serious complications. Endometrial cancer The possibility that the risk of endometrial complications might have been incorrectly estimated and commonly underestimated has been examined with the hypothesis that the method of endometrial examination or sampling is crucial (28c ). Hysteroscopy was performed in 98 menopausal women with endometrial thickening, and the ﬁndings were matched with those of histopathology based on various means of tissue collection, including suction curettage, oriented-streak curettage, hysteroscopically targeted biopsies, or polypectomy and hysterectomy. There was an abnormal endometrium in 35 patients (65% in symptomatic and 22% in asymptomatic women) and there were six carcinomas, 18 polyps, and 11 cases of hyperplasia. Hysteroscopy had a sensitivity of 89% and a speciﬁcity of 98%. With blind sampling, tissue collection was too scant to make diagnosis possible in 29% of patients, while in 81% of patients in whom hysteroscopy showed cystic atrophy the pathologist failed to conﬁrm this condition. Moreover, eight endometrial polyps (36%) detected by hysteroscopy were missed when samples were studied in the laboratory. Hysteroscopy with targeted sampling thus appears to be the most effective method for assessing the endometrial lining and detecting unwanted changes. The endometrial effects of transdermal sequential combination therapy with estradiol and levonorgestrel in various doses has been examined over 1 year in 468 postmenopausal women, who each month used patches that released estradiol for 1 week followed later in the month by combined patches that released both estradiol and levonorgestrel, again for 1 week (29C ). The dose of estradiol was 50–100 μg/day and that of levonorgestrel 15–20 μg/day. Endometrial biopsies, obtained from 399 subjects, generally showed good tolerance for all the various combinations tested. However, there were two

426 cases of endometrial hyperplasia at the highest doses, while the lowest dose was associated with less bleeding than the two higher doses and a somewhat different histological pattern. Ovarian cancer The risk of ovarian cancer with various hormonal replacement regimens has been examined in a nationwide study in Sweden in relation to plain estrogen regimens as well as estrogen plus sequentially added progestagens or continuously added progestagens (30c ). Between 1993 and 1995, the investigators enrolled 655 women with histologically veriﬁed ovarian cancers and 3899 randomly selected population controls, all aged 50–74. Data on the use of estrogen replacement therapy were collected by postal questionnaires. The risk of ovarian cancer was higher among ever users than never users as regards both plain estrogen supplementation (OR = 1.43, 95% CI = 1.02, 2.00) and estrogens with sequentially added progestagens (OR = 1.54, 95% CI = 1.15, 2.05); the increase in risk applied to the serous, mucinous, and endometrioid subtypes. For all cancer types combined, the greatest increases in risk were seen when hormone use exceeded 10 years. The odds ratios after ever use of lowpotency estrogens were 1.18 (95% CI = 0.89, 1.55) for oral and 1.33 (95% CI = 1.03, 1.72) for vaginal use. There was no increase in risk among users of continuously added progestagens. In other words, the continuous addition of progestagens appeared to reduce or eliminate the risk. Drug administration route Transdermal In a open non-comparative study, the efﬁcacy of a low dose transdermal estrogen (Oesclim 25® transdermal patches, releasing 17-beta-estradiol 25 μg/day) was tested in 60 women with postmenopausal symptoms over 8 weeks (31c ). The dosage could be doubled if required and sequential treatment with an oral progestagen was also given for 12 days or more each month in all non-hysterectomized women. Of the 60 patients, 53 reacted satisfactorily to the basic dose and all the various treatments were said to be well tolerated. One could cite a dozen similar papers from the recent past in which the ﬁndings were so amorphous that they have not made a serious contribution to the evolution of knowledge. In two multicenter, double-blind, randomized, controlled trials of three once-a-week

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transdermal systems delivering continuous combined 17-beta-estradiol/levonorgestrel (estrogen 0.045 mg/day plus progestagen 0.015, 0.030, or 0.040 mg/day) to treat vasomotor symptoms and prevent estrogen-induced endometrial hyperplasia in 1138 women, all were highly effective (32C ). Reactions at the site of application, vaginal hemorrhage, and breast pain were the most common adverse events, and the proportion of women with amenorrhea increased over time in all the treatment groups. Drug interactions With growing interest in the use of statins in women, the question naturally arises whether hormonal replacement could have any effect on their efﬁcacy or safety. Data from the Heart and Estrogen/Progestagen Replacement Study (conducted in women with cardiac disorders) seem to have shown that there is no interaction (33C ). Estrogen replacement itself resulted in a signiﬁcant increase in the early risk of primary events in women who did not use statins but not in statin users. Adjustment for statin use after randomization showed no adverse effect of estrogen on the efﬁcacy of statins, in terms of either cardiovascular events or mortality.

HORMONAL CONTRACEPTIVES (SED-14, 1405; SEDA-24, 471; SEDA-25, 484; SEDA-26, 442) Hematologic No clear evidence has undermined the conclusion presented in earlier volumes in this series (SEDA-26, 442) that the third-generation contraceptives introduce a higher risk of thromboembolism than their predecessors, but the fact remains that the actual incidence of thromboembolic episodes is not high. The coarse measure represented by overall mortality ﬁgures is not greatly affected by oral contraceptives alone, although very recent work from the Oxford Family Planning Association’s continuing study has shown convincingly that death from all causes is more than doubled in oral contraceptive users who smoke 15 or more cigarettes daily (34C ). Those who advance the view that the increase in risk with the newer products is not sufﬁcient to condemn them (35r ) generally fail

Sex hormones and related compounds, including hormonal contraceptives

to consider the fact that these newer products have to date shown no advantage whatsoever over their predecessors, such as might outweigh the further increase in risk. However, methodological debate will clearly continue, and some points of detail are likely to be thrashed out in the process. For example, a German group, stressing the inﬂuence of study design on ﬁndings related to thromboembolic risks, has provided evidence that the overall risk is likely to be overestimated if the analysis is based purely on cases in which the complication led to hospitalization (36Cr ). Case reports of various events secondary to thromboembolism, including both myocardial infarction (37A ) and cerebral infarction (38c ), continue to appear, without adding substantially to the broad picture. Larger current studies in various centers seem at all events likely to conﬁrm approximately the conclusions that have been advanced earlier. A 5-year case–control study involving all Danish hospitals has once more quantiﬁed the thromboembolic risks associated with oral contraceptives as a whole; the risk with thirdgeneration products was some 30% higher than with second-generation products (RR = 1.3; CI = 1.0, 1.8) (39C ). However, data on cerebral thrombosis from the same study showed that with third-generation products the mean risk was some 40% lower than with second generation products (RR = 0.6, CI = 0.4, 0.9) (40C ). For current or potential users of oral contraceptives the question arises whether it is not wise to examine the individual’s possible predisposition to thromboembolism (“thrombophilia”) before deciding for or against this form of birth control. It has been suggested that in teenage users who might prove to be carriers of the Factor V Leiden mutation, routine screening would not be economically justiﬁed (41R ). It was instead the author’s view that clinicians can use thoughtful screening questions to identify potentially high-risk patients for thrombophilia and consider testing for inherited risk factors case by case. Skin Sweet’s syndrome (acute febrile neutrophilic dermatosis) is characterized by fever, neutrophilia, and rash. A case has recently been attributed to an oral contraceptive (42A ). However, bearing in mind that the syndrome has a variable presentation and is thought to represent a form of hypersensitivity reaction, it is not

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at all clear that there was a true cause-and-effect relation. Carcinogenicity Cervical cancer The Chief Medical Ofﬁcer of the UK Department of Health has issued an urgent communication to all Health Professionals that oral contraceptives may contribute to the development of cervical cancer in women with high-risk type human papilloma virus, because of an association between an increased risk of cervical cancer and increasing duration of use of oral contraceptives (43S ). There was a three-fold increase in risk after 5–9 years of oral contraceptive use versus a four-fold increase after 10 or more years in women with human papilloma virus, which is sexually transmitted. There are more than 80 human papilloma viruses, only a few of which are associated with an increased risk of cervical cancer. With the current evidence it is difﬁcult to state what the main precipitating factors for cervical cancer are—the use of oral contraceptives, sexual activity, the type of human papilloma virus, or the duration of infection. While cervical screening is not perfect, 80–90% of cervical abnormalities can be detected and treated in women who attend regular screening programmes. The Chief Medical Ofﬁcer has therefore advised that all sexually active women, especially those taking longterm oral contraceptives, should be encouraged to have regular cervical smears. The beneﬁt of using oral contraceptives outweighs the risks in the vast majority of women who use them. Pregnancy In pregnancies that occur after failure of progestagen-only emergency oral contraception, the possibility of ectopic pregnancy should be considered, according to a Prescriber Update article recently posted on the New Zealand Medsafe website (44S ). This may occur by the same mechanism by which pregnancies in women using daily progestagen-only oral contraceptives are more likely to be ectopic than pregnancies in users of other contraceptive methods. The Centre for Adverse Reaction Monitoring has received three reports of ectopic pregnancies after the use of progestagen-only emergency oral contraceptives, and prescribers are reminded to advise women about the possibility of ectopic pregnancy after failure of progestagen-only emergency oral contraceptives. Women should seek prompt medical

428 attention if, after using a progestagen-only emergency oral contraceptive, amenorrhea or any other symptoms suggestive of pregnancy occur. Drug formulations Chlormadinone acetate combinations In 19 650 women who had received six cycles of treatment with chlormadinone acetate 2 mg and ethinylestradiol 30 μg, cycle control was good, with beneﬁcial reductions in intracyclic bleeding, severe withdrawal bleeding, dysmenorrhea, and amenorrhea (45c ). At baseline, 70% of the women had androgenrelated skin disorders. After six cycles of chlormadinone acetate 2 mg/ethinylestradiol 30 μg, these disorders were improved in 87% of patients, including 29% who had complete resolution. The incidence of greasy or very greasy hair fell from 47 to 17%. There were two cases of venous thromboembolism. Breast pain (3.6%) and migraine or headache (2.6%) were the most frequently reported adverse events, but these symptoms disappeared in most women (85 and 80%) who had had them before treatment. Cyproterone acetate combinations There has been a single report of autoimmune hepatitis with the combination of cyproterone acetate and progestagen (46A ). Similar events have been described very occasionally with other oral contraceptives and with diethylstilbestrol; they are not unique to cyproterone. Drospirenone combinations The effects of a monophasic oral contraceptive containing drospirenone 3 mg and ethinylestradiol 30 μg on pre-existing premenstrual symptoms has been studied in 326 women during 13 menstrual cycles (47c ). There were beneﬁcial effects on water retention and appetite. Concentration was not signiﬁcantly affected, and assessments of undesired hair changes and feelings of wellbeing did not change appreciably. There were no adverse effects of note. Implantable contraceptives Patient acceptability of the Norplant® or Implanon® type of implantable progestagen-based contraceptive continues to be the subject of conﬂicting clinical evidence. Acute rejection of the method by some users, because of discomfort and local complications (e.g. because of breakage or migration of the device, or less than expert

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placement and removal), has attracted much attention in past reviews; there is also a fairly high incidence of breakthrough bleeding or amenorrhea (48R ). The cause of the irregular bleeding is not fully understood, but recent evidence suggests that an increase in endometrial vascular fragility might precipitate vessel breakdown and hence breakthrough bleeding (49R ). While such menstrual disturbance is by far the most common reason for discontinuation, headache, acne, and weight gain account for other cases. Fertility returns rapidly after withdrawal of the implant. The evidence suggests that the use of implants does not increase the risks of pelvic inﬂammatory disease, reduced bone mineral density, anemia, thrombocytopenia, or death. The evidence is probably too limited to draw useful conclusions about any effect on the incidence of neoplastic disease or cardiovascular complications (50R ). Whatever difﬁculties have been reported in the past, the method has now become widely used, especially in some developing countries, without major problems (51R ). In certain Western populations too, it seems to be well accepted, provided that it is expertly supervised; indeed, there is now a ﬂow of papers from those with experience in using the method, who have concluded that Norplant, Norplant II, and Implanon are all well accepted by patients (51R ). The motivation of the users, their willingness to accept minor discomfort, and the provision of special training for physicians in the insertion and removal of the devices appear to be important elements in acceptance. In a recent study in Greece the method was well accepted by adolescents, although the study was small (13 subjects) (52c ). No signiﬁcant problems arose during the 24-month follow-up period. One particular advantage of progestagenonly contraception is its suitability for use during breastfeeding, since there are no estrogens to impede lactation. The infant’s intake of steroids is low and appears to be acceptable; its daily intake of steroids (estimated from concentrations in maternal milk during the ﬁrst month of use) has been estimated to be 90–100 ng of levonorgestrel (Norplant), 75–120 ng of etonogestrel (Implanon), and 50 ng and 110 ng of nestorone (Nestorone and Elcometrine implants respectively) (53c ). However, it is still considered advisable to defer the implantation of these devices until 6 weeks after delivery, in view of

Sex hormones and related compounds, including hormonal contraceptives

the theoretical possibility of an adverse inﬂuence on the newborn.

Post-coital contraception While post-coital administration of hormones to prevent pregnancy (“emergency contraception”) is probably now widespread, undesirable effects either on the women or (in the case of failure of the method) on the pregnancy are not well documented. It is particularly difﬁcult to recruit and retain a suitable study population, in view of the common lack of openness on the part of physicians, patients, or both, about using the method. A review of the English language literature for such evidence as is available on the matter has shown that in the USA, the source of most of the material, the two most commonly used forms of post-coital contraception are the Yuzpe regimen (high-dose ethinylestradiol with highdose levonorgestrel) and “Plan B” (high-dose levonorgestrel alone) (54R ). Although both methods sometimes stop ovulation, they may also act by reducing the probability of implantation, through an effect on the endometrium (the “post-fertilization effect”). The available evidence for the latter mechanism is moderately strong. If this is the manner in which development of a zygote is prevented one would anticipate a certain proportion of failures, with the possibility of second-generation injury. This ﬁnding also has potential implications in such areas as informed consent, emergency department protocols, and conscience clauses, since it is more in the character of abortion than true contraception.

ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) (SEDA-14, 1466; SEDA-24, 475; SEDA-25, 489; SEDA-26, 445) Experience over more than 30 years with postmenopausal estrogens has underlined the need for great caution in embarking on long-term

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programmes of prophylactic antiestrogen treatment in healthy women; one could do more harm than good by deranging the physiological balance. This sombre prospect has not deterred attempts to prevent future development of breast cancer by prolonged administration of antiestrogens. Several large placebo-controlled studies in over 20 000 women in which tamoxifen has been used for this purpose have been reviewed (55R ). The clinical similarity of various antiestrogens has tended to foster the view that their efﬁcacy/safety ratios are likely to prove similarly comparable. In fact there is no reason why this should be the case, since they are not chemically homogeneous: droloxifene, idoxifene, tamoxifen, and toremifene are polyphenylethylene antiestrogens, whereas raloxifene and the pure antiestrogen ICI 182,780 (faslodex) have different structures. In an extensive review of the choice of medicinal therapy for invasive breast cancer, it has been emphasized that the risks of treatment must be carefully weighed against the beneﬁts, particularly in women who already have a good overall prognosis (56R ). Adjuvant polychemotherapy is recommended in women considered at high risk of relapse and death. In addition, women with hormone-sensitive breast cancer should be offered adjuvant tamoxifen. Nevertheless, there are some patients with lowrisk disease or with signiﬁcant co-morbidities who are unlikely to beneﬁt from adjuvant therapies and are likely to suffer disproportionate toxicity. In women with metastases, treatment is focused on palliation of symptoms, as under 10% of such patients achieve 5-year survival. Several novel SERMs have reached the stage of clinical development, including arzoxifene, droloxifene, idoxifene, lasofoxifene, MDL 103,323, and ospemifene; no conclusions about their safety can yet be drawn (57R ).

Genotoxicity and carcinogenicity of antiestrogens In vitro studies Tamoxifen has been shown to be genotoxic in several studies (58Er ). It induces unscheduled DNA synthesis in rat hepatocytes and micronuclei in MCL-5a cells in

430 vitro; it also induces aneuploidy in rat liver in vivo and chromosome aberrations and micronuclei in mouse bone marrow. Toremifene is also genotoxic, but to a far lesser extent, by inducing micronuclei in MCL-5a cells in vitro and by inducing aneuploidy in rat liver in vivo (59ER ). In vivo animal studies Tamoxifen was hepatocarcinogenic in rats in at least four independent long-term studies. The initiation of tumors in rats is the result of metabolic activation by cytochrome P450 isoenzymes to electrophilic species that bind irreversibly to DNA. The other antiestrogens have not been shown to be carcinogenic in rodents. The effects of bazedoxifene and raloxifene on the uterus are strikingly different; when they are administered together in rodents bazedoxifene inhibits the stimulation of the rodent uterus attributable to raloxifene. Human studies Breast cancer When raloxifene was used in a trial primarily concerned with the prevention of osteoporotic fractures in women with low bone mineral density, routine annual mammography showed an approximately 80% reduction in the early incidence of breast cancer; further follow-up of this trial continues (55R ). In the meantime, new trials in chemoprevention of breast cancer have been started or proposed, variously using other selective anti-estrogens, luteinizing-hormonereleasing hormone analogues, or aromatase inhibitors. Endometrial cancer The adverse effects of tamoxifen and other antiestrogens on the uterine endometrium—essentially involving proliferation with angiogenesis, which may proceed to hyperplasia, polyp formation, and even carcinoma—are now being studied in depth, while cases continue to be reported, including a mixed Mullerian tumor of the endometrium in a woman of 67 (60A , 61Ar ). Several independent clinical studies have shown an increase in the risk of endometrial cancer among tamoxifen-treated women. After reviewing the available data, the International Agency for Research on Cancer concluded that there was sufﬁcient evidence to show that tamoxifen is a class I human carcinogen. The increased risk of endometrial cancer occurs predominantly among women aged 50 years

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or more and who have been treated with tamoxifen. It is not yet clear whether uterine tumor formation results from genetic mechanisms, analogous to those seen in the rat liver, or the estrogen agonist action of tamoxifen. However, the other antiestrogens with a more or less similar intrinsic estrogenic potential have not been shown to be carcinogenic in humans. The only substantial reservation about the above conclusions is that tamoxifen is older than all other antiestrogens and has been more widely tested and used in practice; it is not impossible that certain of the problems associated with it will in due course emerge with other members of the group. The apparently favorable proﬁle of raloxifene on the endometrium and uterus has now been studied in two investigations using transvaginal color Doppler sonography (62c , 63c ). The larger of these studies involved 34 asymptomatic postmenopausal women who had taken raloxifene 60 mg/day for 6 months (63c ). The mean endometrial thickness and uterine volume were not signiﬁcantly different before and after treatment, nor was there any effect on blood ﬂow in the uterine arteries. The effects of tamoxifen on a series of angiogenic factors (acidic and basic ﬁbroblast growth factors, thymidine phosphorylase, vascular endothelial growth factor, and adrenomedullin) in normal and tamoxifen-exposed premenopausal and postmenopausal endometrium have been studied (64c ). There was increased expression of acidic and basic ﬁbroblast growth factors and adrenomedullin after treatment with tamoxifen, mainly in premenopausal tissue. Vascular density was signiﬁcantly increased in premenopausal but not postmenopausal endometrium. Such results support the notion that angiogenesis is integral to the endometrial response to tamoxifen exposure, and is a potential target for blocking these adverse effects. When tamoxifen is used for breast cancer, the advisability of prophylactic hysterectomy needs to be considered. An attempt has been made to identify patients treated with tamoxifen for breast cancer in whom hysteroscopy with biopsy should be considered mandatory (65c ). Of 414 breast cancer patients already selected for hysterectomy with biopsy, some 80% had already been treated with tamoxifen for periods of up to 8 years. Among those who had never used tamoxifen there were no

Sex hormones and related compounds, including hormonal contraceptives

instances of endometrial hyperplasia or malignancy. In contrast, the incidence of endometrial pathology was 33% in postmenopausal women who had taken the drug. Analysis of other subgroups showed that the incidence of abnormalities was higher with longer durations of treatment, in postmenopausal than in premenopausal women, and particularly in women with uterine bleeding. The investigators concluded that hysteroscopy with biopsy should be the ﬁrst diagnostic procedure to perform in tamoxifen-treated postmenopausal women with uterine bleeding and in postmenopausal women treated for longer than 3 years. In premenopausal women, hysteroscopy should be considered for those with ultrasonographic abnormalities and/or uterine bleeding and for those at high risk of endometrial cancer. The authors of a study of endometrial complications attributable to tamoxifen in more than 400 users, with data from 823 controls, concluded that while careful surveillance is needed, it may sometimes have been unnecessarily intensive (66CR ). In their view, an acceptable screening scheme might include a baseline assessment before the start of treatment followed, if normal, by yearly screening (with transvaginal ultrasonography) after 3 years of tamoxifen therapy; yearly surveillance from the outset is advisable for women with an abnormal baseline assessment. Women who develop symptoms suggestive of endometrial complications should be examined immediately. Transvaginal sonography is a dependable method for monitoring the effects of treatment on the uterus, and particularly for detecting an early increase in endometrial thickness, which could herald more serious changes. A thorough review of the literature on the use of tamoxifen or raloxifene for the prevention of breast cancer, and the risks of such treatment, has shown that while both drugs were effective in the doses generally recommended for this purpose, they both increased the risk of venous thromboembolic disease and hot ﬂashes, while tamoxifen also increased the risk of endometrial cancer and stroke (67R ). Ovarian cancer When data from seven randomized, placebo-controlled trials, in a total of 9837 women, were analysed to examine the incidence of ovarian cancer in postmenopausal women treated with raloxifene

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compared with placebo no correlation was found (68M ). The apparent incidence of ovarian cancer was lower in the raloxifene group than in the remainder, but no signiﬁcance can be attached to that.

Bazedoxifene acetate From the available data on the relatively new compound bazedoxifene acetate, evidence has been adduced that it may be a promising and particularly “tissue selective” member of the group of SERM compounds (59cR ). In vitro and in vivo animal models have shown that not all SERMs are equivalent. This was especially evident when assessing hepatic lipase promoter activation: bazedoxifene was a relatively potent agonist whereas raloxifene was inactive. The effects of bazedoxifene and raloxifene on the uterus are strikingly different; when they are administered together in rodents bazedoxifene inhibits the stimulation of the rodent uterus attributable to raloxifene. The preclinical data suggest that it is now possible to develop more selective molecules that could achieve the optimal therapeutic target proﬁle for a SERM with less effect on organs other than the breast, and bazedoxifene acetate could prove to be an important step in this direction. Clinical ﬁndings will be awaited with interest; however, as noted above, prior experience with this series of compounds shows how cautious one must be in drawing early conclusions as to their selectivity and safety.

Raloxifene Cardiovascular There is evidence that raloxifene favorably affects cardiovascular risk factors, but it has been uncertain whether in practice it truly reduces the incidence of cardiovascular events. The issue has been brieﬂy reviewed (69r ). An attempt to throw light on the question has involved secondary analysis of data from the well-controlled Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter trial that was conducted between 1994 and 1999 in 7705 osteoporotic women studied at 180 sites in 25 countries, who took

432 raloxifene 60 or 120 mg/day or placebo (70C ). In the overall cohort there were no signiﬁcant differences between treatment or placebo in the incidence of coronary and/or cerebrovascular events. However, among a subset of 1035 women who already had increased cardiovascular risk at baseline, those assigned to raloxifene had a signiﬁcantly lower incidence of cardiovascular events after 4 years compared with placebo.

Tamoxifen Prevention of breast cancer The ability of tamoxifen to reduce the risk of breast cancer remains in dispute, with contradictory ﬁndings from the two sides of the Atlantic (53R ). The largest study of the use of tamoxifen in this connection is the American National Surgical Adjuvant Breast and Bowel P-1 Project, in which over 13 000 women took tamoxifen or placebo and had a 49% reduction in the early incidence of breast cancer (55R , 71C ). Treatment was associated with a reduction in osteoporotic fractures, but the risks of endometrial cancer, cataract, and thromboembolism were increased. In the Royal Marsden Tamoxifen Trial in the UK, 2500 women were similarly randomized to tamoxifen or placebo (55R , 72C ) while in an Italian national trial 5000 women were randomized (55R , 73C ). Interim analyses from these two European trials showed no effect on the early incidence of breast cancer. Thus, these studies have not clearly shown overall beneﬁt of tamoxifen in healthy women; nor is it clear whether there is a particular subgroup of women who are likely to beneﬁt. The discrepancy between the European and US ﬁndings is for the moment unexplained. The difﬁculty in assessing the efﬁcacy/safety balance of this type of treatment fairly is well illustrated by a randomized interview study in 98 breast cancer patients over 5 years (74R ). The participants had received adjuvant highdose or standard-dose chemotherapy, followed by radiotherapy and tamoxifen. With tamoxifen the most frequent complaints were hot ﬂushes (85%), disturbed sleep (55%), vaginal dryness and/or dyspareunia (47%), reduced sexual desire (44%), and musculoskeletal symptoms (43%). Disturbed sleep correlated signiﬁcantly

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with hot ﬂushes and problems in concentrating. Reduced sexual interest correlated with vaginal dryness and/or dyspareunia. In the high-dose group signiﬁcantly more women became postmenopausal (95% vs 33%) and more reported symptoms than in the standarddose group. After withdrawal of tamoxifen, the symptoms abated signiﬁcantly. However, hot ﬂushes, disturbed sleep, and vaginal dryness persisted more often in those who remained postmenopausal after high-dose chemotherapy. In a thorough retrospective study of the relative frequency of adverse effects as experienced in a single practice, 264 women who had been treated for early breast cancer with tamoxifen, raloxifene, or both were compared (75c ). The patients in the three subgroups were similar, although the women taking raloxifene had a shorter average duration of therapy. Vaginal discharge, severe hot ﬂushes, and weight gain of 10 pounds or more were signiﬁcantly more frequent with tamoxifen than with raloxifene; however, weight gain was also related to the duration of therapy with either drug, and raloxifene may have been assessed too favorably, although earlier studies suggested that in this respect raloxifene is safer than tamoxifen. Nervous system There have been conﬂicting reports about whether tamoxifen might adversely affect brain metabolism and function or cause cognitive impairment. The effects of tamoxifen and estrogen on brain chemistry have been studied in 76 elderly women, of whom 16 had used tamoxifen, 27 had used estrogen as hormone replacement therapy, and 33 had used neither (controls) (76c ). Proton magnetic resonance spectroscopy was used to measure the concentrations of N-acetyl-containing compounds, myoinositol, total creatine (creatine plus phosphocreatine), and choline-containing compounds in the frontal white matter, basal ganglia, and hippocampus. The women who had used tamoxifen and HRT had signiﬁcantly lower concentrations of myoinositol than the controls in all areas of the brain. Those who had used tamoxifen and HRT had lower concentrations of myoinositol in their basal ganglia, where the concentration of myoinositol was inversely correlated with the duration of tamoxifen treatment. The fact that the effect of tamoxifen on myoinositol was essentially the same as that of estrogen replacement therapy

Sex hormones and related compounds, including hormonal contraceptives

suggested that there is no particular risk to brain function from tamoxifen. Metabolism Porphyria cutanea tarda has been described in a patient with breast cancer following adjuvant tamoxifen; withdrawal of tamoxifen resulted in a prompt fall in urinary porphyrins, suggesting a causative role (77A ). Although tamoxifen is known to be hepatotoxic, its association with porphyria is unclear.

PROGESTAGENS

(SED-14, 1468;

SEDA-26, 447) The bulk of progestagen use continues to be in combination with other agents. Recent ﬁndings are reviewed in the above sections on hormonal contraceptives and hormonal replacement therapy.

PROGESTERONE ANTAGONISTS (SEDA-14, 1471; SEDA-25, 492; SEDA-26, 448)

Mifepristone With well over 15 years of experience in the licensed use of mifepristone for termination of pregnancy, its adverse reactions pattern has been well documented, and it can be useful to examine the preferences currently expressed by women for or against its use compared with surgical termination. In a comparison of attitudes in 368 women who required abortion at 10–13 weeks, 15 opted in advance for medical termination and 62 chose surgery; the other 291 expressed no preference and were randomized to one method or the other (78c ). Mifepristone was used in 188 women in a dose of 200 mg followed by up to three doses of misoprostol 200 μg. Surgery (vacuum aspiration under general anesthesia) was used in 180 women. Among those who underwent medical abortion, 5.4% required a second procedure, compared with 2.1% who had surgery, but this difference was not statistically signiﬁcant. The incidence of familiar adverse effects was higher in those who received mifepristone, but there was no

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signiﬁcant difference in the rates of major complications up to 8 weeks. Following abortion, 70% of those who underwent medical termination and 79% who had undergone surgery stated that they would opt for the same method in the future. It therefore seems that medical termination offers a fully acceptable option for women who want to avoid surgery. Do-it-yourself abortion? Following the worldwide debate on the liberalization of postcoital contraception, it was only to be expected that there would be a move to bring medicinal abortion similarly within the scope of self-medication. The use of mifepristone plus misoprostol to terminate pregnancy has been surveyed in 17 US medical centers and clinics (79MR ). The authors’ view was that most women can effectively and safely handle most steps of the medical abortion process themselves, and that the value of clinic supervision is questionable. For many women, they thought, even the follow-up visit could perhaps be replaced by telephone follow-up, combined with home pregnancy tests. Experience with selfmedication in other ﬁelds has rarely conﬁrmed the dire forebodings advanced by physicians about the risks of self-treatment. At least from the literature one has the impression that programmes for medicinal termination of pregnancy are now simple, well developed, and widely documented, and that problems rarely arise. Reproductive system The predominant use of mifepristone for the termination of pregnancy has overshadowed the emergence of knowledge about its possible usefulness as a female contraceptive (80R ). The steady-state plasma concentration of mifepristone ranges from 65 nmol/l at a dose of 1 mg/day to 1 μmol/l at 10 mg/day, and inhibition of ovulation can be achieved at a serum mifepristone concentration as low as 233 nmol/l. Mifepristone antagonizes the effect of progesterone in the pituitary, suppressing gonadotropin and steroid hormone secretion, rather than acting primarily in the hypothalamus to delay or inhibit ovulation. The endometrium is most sensitive to the effects of mifepristone. Low-dose mifepristone impairs luteal phase endometrial development and receptivity by altering endometrial parakine and cytokine concentrations

434 and enzyme activity. Low doses of mifepristone can signiﬁcantly reduce the rate of conception without inhibiting ovulation. However, further research is needed to determine whether a dosage schedule can be developed that will prevent pregnancy without inducing serious endometrial adverse effects, either in the short term or in the long term. In particular, attention will need to be paid to the ability of endometrial function to recover promptly and fully when pregnancy is desired, and to the development of endometrial disorders, including endometriosis and malignancies. The effects of mifepristone on the Fallopian tube have been compared with those of levonorgestrel in 24 women who were due to undergo voluntary sterilization via laparoscopy (81c ). They took one dose of mifepristone 200 mg or levonorgestrel 0.75 mg in two doses 12 hours apart 2–4 days before surgery. In the 12 control women in the same group there was a higher concentration of progesterone receptors in the stromal cells in the isthmus compared with the ampulla. Mifepristone increased the progesterone receptor concentration in epithelial and stromal cells and increased the estrogen receptor concentration in epithelial cells. Levonorgestrel had no effect on steroid receptor concentration. The contraceptive effect of postovulatory mifepristone has previously been considered to be due purely to its effect on the endometrium, but these ﬁndings suggest that an effect on the Fallopian tube could also be relevant. What this could mean in terms of adverse effects is not clear, but the risk of extrauterine pregnancies might be increased through derangement of transport of the ovum.

ANABOLIC STEROIDS, ANDROGENS, AND RELATED COMPOUNDS (SED-14, 1471; SEDA-24, 476; SEDA-25-493; SEDA-26, 449) There is continuing controversy about the merits and risks of androgen supplementation in postmenopausal women. It is still uncertain whether physiological testosterone replacement can improve health-related outcomes in older women without causing virilizing adverse effects (82R ). Although it is often asserted that

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the dose-response curve for testosterone effects is different in women and men, and that in women clinically useful effects can therefore be achieved at lower doses of testosterone, these assumptions have not been tested rigorously. Androgen deﬁciency in women has no clear-cut deﬁnition. The features can include impaired sexual function, low energy, depression, and a total testosterone concentration of less than 150 pg/ml, the lower end of the reference range. Unbound testosterone concentration provides a better estimate of the biologically relevant fraction; however, it is difﬁcult to measure and is not widely used in clinical practice. In marked contrast to the abrupt fall in estrogen and progesterone production at the time of the menopause, serum testosterone begins to fall a decade before the menopause. It is still not known which drug might most safely be used for androgen replacement in women. Drug abuse It is unclear how, when the legitimate use of anabolic steroids has all but disappeared, a liberal supply of various agents of this type apparently remains accessible to those sports practitioners who ill-advisedly use them in the hope of enhancing performance. In one recent check of hair and urine samples from seven French bodybuilders, the compounds identiﬁed included ephedrine, norandrosterone, noretiocholanolone, stanozolol, methenolone, testosterone (including its enanthate and cypionate esters), and epitestosterone (83C ). Some of the agents used are not even in normal production for medicinal purposes. One of the few remaining supposed indications for anabolic steroids in medical practice—treatment of alcohol-induced liver disease—now seems to have been ﬁrmly discredited by an extensive Cochrane review (84R ). Not surprisingly, in view of the known hepatic effects of these compounds, the only noticeable effects were adverse ones. Particular attention has been devoted to the potential of the anabolic steroids to damage the liver, but the dominant occurrence of effects on the cardiovascular system and mental health and the increased incidence of neoplasms have been stressed (85cR ). There is an increased incidence of premature death among power lifters. Since power training itself does not present health risks, the early mortality is probably due to the various complications of the use of anabolic steroids and other drugs.

Sex hormones and related compounds, including hormonal contraceptives

Dihydrotestosterone Reproductive system It has sometimes been argued that the non-aromatizable androgen dihydrotestosterone should be seriously considered as a better alternative to testosterone for elderly men. The case for dihydrotestosterone has been reviewed in an authoritative editorial (86R ). A major argument is that since dihydrotestosterone (unlike testosterone) is not metabolized to estrogen, it will not cause gynecomastia. There have been three studies in which dihydrotestosterone was given as a percutaneous gel and was an effective androgen (87C – 89C ). Gynecomastia was not seen, but the studies were of short duration. There is also theoretical reason to believe that dihydrotestosterone might be much less likely than testosterone to cause prostatic enlargement. On the other hand, concern has been raised that if taken over long periods it might compromise bone calciﬁcation by reducing tissue estrogen concentrations. The perspectives and possible risks can only be assessed if much more extensive studies are conducted than those available to date.

Testosterone Despite the progressive fall in serum testosterone concentrations in men with advancing age (a process that is accentuated variously by age-associated disease, some medications, and malnutrition) and the fact that there is a parallel fall in various physiological functions, it has never been convincingly shown that the two processes are linked and that the widespread use of testosterone replacement therapy is justiﬁed. However, after some 60 years of argument it still has its champions. It has been pointed out that short-term controlled studies of testosterone in small numbers of healthy older men suggest beneﬁcial effects on body composition, bone mineral density, LDL cholesterol, angina, and exercise-induced cardiac ischemia, and possibly muscle strength, libido, general well-being, and certain aspects of cognitive function (90R ). In these studies, there have been no signiﬁcant adverse effects, except for a degree of erythrocytosis requiring dosage reduction in some men. Testosterone replacement may be justiﬁed in older men with

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evidence of androgen deﬁciency and with consistently low serum unbound testosterone concentrations, in whom the potential beneﬁts of therapy outweigh the potential risks. However, neither these potential beneﬁts nor the risks have been adequately documented as yet. Metabolism Although there is much evidence about the effects of sex hormones on cholesterol concentrations and vascular tone in women, there is rather less on the corresponding effects of testosterone in men. Low testosterone concentrations have been associated with higher cholesterol concentrations in epidemiological studies, but it is not clear how these are affected by testosterone replacement. Of 67 men aged 65–87 who used transdermal testosterone 2–2.5 μg/day or placebo for 1 year, 44 completed the study (91C ). There were no changes in concentrations of total cholesterol, LDL cholesterol, or triglycerides, but HDL cholesterol fell signiﬁcantly in those who took active treatment. There was no effect on vascular tone as measured in the brachial artery. This work is helpful, but there is still a need for a proper study of the relation, if any, between testosterone replacement and the incidence of cardiovascular events. Immunologic In three men who had had cardiac transplantation, the donor heart was rejected after leuprorelin acetate was used for prostate cancer and testosterone for symptoms of ageing (92A ). It seems hardly possible to conclude on the basis of these individual cases whether or not the drugs played any role in rejection of the graft.

ANTIANDROGENS (SED-14, 1475; SEDA-24, 479; SEDA-25, 494; SEDA-26, 451) Bicalutamide Endocrine Hot ﬂushes resulting from antiandrogens or gonadotrophin-releasing hormone analogues are often difﬁcult to treat and leave many patients disabled. Gabapentin has been successfully used for this purpose (93A ).

436 • A 70-year-old man had very severe hot ﬂushes from therapy with the antiandrogen bicalutamide and the GnRH analogue goserelin acetate. The symptoms failed to respond to clonidine 0.1 mg bd, megestrol acetate 40 mg/day, diethylstilbestrol 1 mg/day, and venlafaxine 25 mg bd. He was then given gabapentin 600 mg/day and had nearcomplete resolution of the symptoms.

Controlled trials are clearly necessary to evaluate the role of gabapentin compared with other treatments for this purpose.

Finasteride Using a hormonal or antihormonal treatment for cosmetic purposes always raises the issue of the beneﬁt–harm balance. In an unusual study, ﬁnasteride 1 mg/day was used for 1 year to treat male pattern baldness in nine subjects; each had an identical twin who received placebo (94c ). Finasteride signiﬁcantly improved hair growth. There were no drug-related adverse events, either clinical or biochemical. In a much longer study from the same center, 1553 men with male pattern baldness took ﬁnasteride 1 mg/day (95C ). All had initially taken part in one of two 1-year placebo-controlled studies, but 1215 of them continued into further controlled studies over another 4 years. There was durable improvement in scalp hair over 5 years and no new safety concerns were identiﬁed. Breasts Four young men developed unilateral gynecomastia when they took ﬁnasteride 1 mg/day (96Ar ). The complication occurred at 2–12 months after the start of treatment. There has been one similar earlier report from Australia (97A ), and in an earlier case the same complication was seen in a patient taking 5 mg/day (98A ). There have been similar reports to national adverse reaction monitoring centers (96Ar ).

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The suggested mechanism was that ﬁnasteride inhibited the hepatic metabolism of sibutramine, which then displaced ﬁnasteride from its plasma protein binding sites; inhibition of serotonin and noradrenaline reuptake by sibutramine then triggering the psychotic event.

Flutamide Liver The possibility that the use of ursodeoxycholic acid plus ﬂutamide in treating prostatic cancer might inhibit the development of ﬂutamide-induced liver damage has been examined in a multicenter retrospective study of 181 Japanese patients (100c ). After eliminating confounding variables, there was liver damage in eight of 70 patients who took ursodeoxycholic acid and in 36 of 111 who did not. The difference was signiﬁcant and further study is justiﬁed. There is now evidence that the so-called caffeine test is of use in predicting the risk of hepatic injury due to ﬂutamide. This test measures the activity of CYP1A2, the major enzyme involved in the activation of ﬂutamide and the metabolism of caffeine. The method involves giving a standard caffeine-containing drink and measuring the subsequent excretion of caffeine metabolites. The ratio between the total excretion of paraxanthine and 1,7-dimethyluric acid and the excretion of unchanged caffeine is a reliable indicator of CYP1A2 activity, and in one study in nine patients correlated with measures of ﬂutamide-induced hepatic impairment (101c ). Urinary tract Acute renal insufﬁciency has been attributed to ﬂutamide (102A ).

Drug interactions An interaction of ﬁnasteride with sibutramine has been described (99A ).

• A 54-year-old man with metastatic prostate cancer developed non-oliguric acute renal insufﬁciency while taking ﬂutamide (250 mg tds). After withdrawal his renal function returned to normal within 4 weeks. On rechallenge his serum concentrations of blood urea nitrogen and creatinine again rose. His renal function again recovered completely after withdrawal.

• A 30-year-old man who was being successfully treated for obesity with sibutramine added ﬁnasteride to treat alopecia. Soon after he developed paranoid psychotic behavior. The reaction abated and disappeared when ﬁnasteride was withdrawn.

Although it is very rare, ﬂutamide-induced renal insufﬁciency should be considered an established risk, in the light of this and earlier reports.

Sex hormones and related compounds, including hormonal contraceptives

Drug interactions It has long been known that in cases of congenital adrenal hyperplasia there is a defect in the secretion of cortisol, and often of aldosterone as well, accompanying the hyperandrogenic state. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution, to prevent adrenal crises, and to suppress excess adrenocortical androgen secretion. In recent years, antiandrogen therapy with ﬂutamide has provided an alternative approach that allows control of hyperandrogenism without recourse to supraphysiological doses of glucocorticoid. There is now evidence that ﬂutamide reduces the clearance of cortisol (103A ). • In a 17-year-old woman with classic congenital adrenal hyperplasia taking ﬂutamide, the clearance of a simultaneously administered bolus dose of hydrocortisone was reduced by some 27% and its volume of distribution was reduced by 13%; the half-life increased markedly.

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These ﬁndings suggest that a reduction in the daily replacement dose of glucocorticoid may need to be considered when ﬂutamide is added in patients taking hydrocortisone.

MISCELLANEOUS COMPOUNDS Tibolone Drug interactions In a randomized, open, placebo-controlled trial in 65 women about to undergo laparoscopic myomectomy there was no interaction of tibolone with gonadotropinreleasing hormone, which was equally effective when tibolone had been given (104c ).

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62. Christodoulacos G, Panoulis C, Botsis D, Rizos D, Kassanos D, Creatsas G. Transvaginal sonographic monitoring of the uterine effects of raloxifene and a continuous combined replacement therapy in postmenopausal women. Maturitas 2002; 42: 77–84. 63. Chittacharoen A, Theppisai U, Manonai J. Transvaginal color Doppler sonographic evaluation of the uterus in postmenopausal women on daily raloxifene therapy. Climacteric 2002; 5: 156–9. 64. Hague S, Manek S, Oehler MK, MacKenzie IZ, Bicknell R, Rees MCP. Tamoxifen induction of angiogenic factor expression in endometrium. Br J Cancer 2002; 86: 761–7. 65. Taponeco F, Curcio C, Fasciani A, Giuntini A, Artini PG, Fonaciari G, Petraglia F, Genazzani AR. Indication of hysteroscopy in tamoxifen treated breast cancer patients. J Exp Clin Cancer Res 2002; 21: 37–43. 66. Vosse M, Renard F, Coibion M, Neven P, Nogaret JM, Hertens D. Endometrial disorders in 406 breast cancer patients on tamoxifen: the case for less intensive monitoring. Eur J Obstet Gynecol Reprod Biol 2002; 101: 58–63. 67. Kinsinger LS, Harris R, Woolf SH, Sox HC, Lohr KN. Chemoprevention of breast cancer: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002; 137: 59–67. 68. Neven P, Goldstein SR, Ciaccia AV, Zhou L, Silfen SL, Muram D. The effect of raloxifene on the incidence of ovarian cancer in postmenopausal women. Gynecol Oncol 2002; 85: 388–90. 69. Ireland B. Does raloxifene affect risk of cardiovascular events in osteoporotic postmenopausal women? J Fam Pract 2002; 51: 481. 70. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: Four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. J Am Med Assoc 2002; 287: 847–57. 71. Fisher B, Costantino JP, Wickerham DL. Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand SM, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer. Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371–88. 72. Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, Tidy A, Viggers J, Davey J. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital Tamoxifen Randomised Chemoprevention Trial. Lancet 1998; 352: 98–101. 73. Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, Boyle P. Prevention of breast cancer with tamoxifen: preliminary ﬁndings from the Italian randomised trial among hysterectomised women. Lancet 1998; 352: 93–7. 74. Mourits MJ, Bockermann I, De Vries EG, Van der Zee AG, Ten Hoor KA, Van der Graaf WT, Sluiter WJ, Willemse PH. Tamoxifen effects on subjective and psychosexual well-being, in a

440 randomised breast cancer study comparing highdose and standard-dose chemotherapy. Br J Cancer 2002; 86: 1546–50. 75. Rohatgi N, Blau R, Lower EE. Raloxifene is associated with less side effects than tamoxifen in women with early breast cancer: a questionnaire study from one physician’s practice. J Women’s Health Gender Med 2002; 11: 291–7. 76. Ernst T, Chang L, Cooray D, Salvador C, Jovicich J, Walot I, Boone K, Chlebowski R. The effects of tamoxifen and estrogen on brain metabolism in elderly women. J Natl Cancer Inst 2002; 94: 592–7. 77. Agarwal R, Peters TJ, Coombes RC, Vigushin DM. Tamoxifen-related porphyria cutanea tarda. Med Oncol 2002; 19: 121–3. 78. Ashok PW, Kidd A, Flett GMM, Fitzmaurice A, Graham W, Templeton A. A randomized comparison of medical abortion and surgical vacuum aspiration at 10–13 weeks gestation. Hum Reprod 2002; 17: 92–8. 79. Harper C, Ellertson C, Winikoff B. Could American women use mifepristone–misoprostol pills safely with less medical supervision? Contraception 2002; 65: 133–42. 80. Sarkar NN. The potential of mifepristone (RU486) as a female contraceptive drug. Int J Clin Pract 2002; 56: 140–4. 81. Christow A, Sun X, Gemzell-Danielsson K. Effect of mifepristone and levonorgestrel on expression of steroid receptors in the human Fallopian tube. Mol Hum Reprod 2002; 8: 333–40. 82. Padero MCM, Bhasin S, Friedman TC. Androgen supplementation in older women: too much hype, not enough data. J Am Geriatric Soc 2002; 50: 1131–40. 83. Dumestre-Toulet V, Cirimele V, Ludes B, Gromb S, Kintz P. Hair analysis of seven bodybuilders for anabolic steroids, ephedrine, and clenbuterol. J Forensic Sci 2002; 47: 211–14. 84. Rambaldi A, Iaquinto G, Gluud C. Anabolicandrogenic steroids for alcoholic liver disease: a Cochrane review. Am J Gastroenterol 2002; 97: 1674–81. 85. Parssinen M, Seppala T. Steroid use and longterm health risks in former athletes. Sports Med 2002; 32: 83–94. 86. Wang C. Editorial: Should the nonaromatizable androgen dihydrotestosterone be considered as an alternative to testosterone in the treatment of the andropause? J Clin Endocrinol Metab 2002; 87: 1462–6. 87. De Lignieres B. Transdermal dihydrotestosterone treatment of “andropause”. Ann Med 1993; 25: 235–41. 88. Ly LP, Jiminez M, Zhuang TN, Celermajer DS, Conway AJ, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility and quality of life in older men with partial androgen deﬁciency. J Clin Endocrinol Metab 2001; 86: 4078–88. 89. Kunelius P, Lukkarinen O, Hannuksela ML, Itkonen P, Tapanainen JS. The effects of transdermal dihydrotestosterone in the aging male: a

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prospective, randomized, double-blind study. J Clin Endrocrinol Metab 2002; 87: 1467–72. 90. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol Ser A Biol Sci Med Sci 2002; 57: M76–99. 91. Kenny AM, Prestwood KM, Gruman CA, Fabregas G, Biskup B, Mansoor G. Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels. J Gerontol Ser A Biol Sci Med Sci 2002; 57: M460–5. 92. Schoﬁeld RS, Hill JA, McGinn CJ, Aranda JM. Hormone therapy in men and risk of cardiac allograft rejection. J Heart Lung Transplant 2002; 21: 493–5. 93. Jeffery SM, Pepe JJ, Popovich LM, Vitagliano G. Gabapentin for hot ﬂashes in prostate cancer. Ann Pharmacother 2002; 36: 433–6. 94. Stough DB, Rao NA, Kaufman KD, Mitchell C. Finasteride improves male pattern hair loss in a randomized study in identical twins. Eur J Dermatol 2003; 12: 32–7. 95. Kaufman KD. Long-term (5-year) multinational experience with ﬁnasteride 1 mg in the treatment of men with androgenetic alopecia. Eur J Dermatol 2002; 12: 38–49. 96. Ferrando J, Grimalt R, Alsina M, Bulla F, Manasievska E. Unilateral gynecomastia induced by treatment with 1 mg of oral ﬁnasteride. Arch Dermatol 2002; 138: 543–4. 97. Wade MS, Sinclair RD. Reversible painful gynaecomastia induced by low dose ﬁnasteride. Aust J Dermatol 2000; 41: 55. 98. Marberger MJ. Long-term effects of ﬁnasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. Urology 1998; 51: 677–86. 99. Dogol Sucar D, Botelho Sougey E, Brandao Neto J. Psychotic episode induced by potential drug interaction of sibutramine and ﬁnasteride. Rev Bras Psiquiatr 2002; 24: 30–3. 100. Kojima M, Kamoi K, Ukimura O, Fujito A, Nakao M, Tanaka S, Miyashita H, Iwamoto N, Ohe H, Kitamori T, Date S, Kitamura K, Araki H, Aoki T, Imada N, Takada H, Imaide Y, Mikami K, Uchida M, Saitoh M, Miki T. Clinical utility of ursodeoxycholic acid in preventing ﬂutamideinduced hepatopathy in patients with prostate cancer: a preliminary study. Int J Urol 2002; 9: 42–6. 101. Ozono S, Yamaguchi A, Mochizuki H, Kawakami T, Fujimoto K, Otani T, Yoshida K, Ichinei M, Yamashita T, Hirao Y. Caffeine test in predicting ﬂutamide-induced hepatic injury in patients with prostate cancer. Prostate Cancer Prostatic Dis 2003; 5: 128–31. 102. Altiparmak MR, Bilici A, Kisacik B, Ozguroglu M. Flutamide-induced acute renal failure in a patient with metastatic prostate cancer. Med Oncol 2002; 19: 117–19. 103. Charmandari E, Johnston A, Honour JW, Brook CGD, Hindmarsh PC. Treatment with ﬂutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 2002; 15: 435–9.

Sex hormones and related compounds, including hormonal contraceptives 104. Palomba S, Morelli M, Noia R, Santagata M, Oliverio A, Sena T, Zullo F, Mastrantonio P. Shortterm administration of tibolone plus GnRH analog

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before laparoscopic myomectomy. J Am Assoc Gynecol Laparoscopists 2002; 9: 170–4.

J.A. Franklyn

41

Thyroid hormones and antithyroid drugs

THYROID HORMONES (SED-14, 1485; SEDA-24, 484; SEDA-25, 503; SEDA-26, 457) Ingestion of excessive amounts of thyroid hormones can cause symptoms and signs similar to those that result from endogenous overproduction. However, the symptoms and signs are generally relatively trivial in those who take standard doses of thyroxine (T4) replacement therapy, although abnormalities have been evident in detailed studies of those who take T4 in doses sufﬁcient to suppress serum TSH (1c ). Since thyroxine is occasionally used in supraphysiological doses to treat euthyroid people with refractory depression, adverse effects in healthy controls (n = 13) and patients with refractory depression also taking antidepressants (n = 13) have been studied in an 8-week nonblind study (2c ). There was a higher rate of discontinuation of thyroxine in the control subjects than in the patients, because of perceived adverse effects (38% versus 0%), together with a more marked rise in serum free thyroxine and free triiodothyronine (T3) in the controls. This suggests that the inﬂuence of supraphysiological doses of thyroxine is greater in healthy subjects than in those with psychiatric illness, perhaps reﬂecting the inﬂuence of the illness, or its therapy, on thyroid hormone metabolism in the latter. Drug interactions Thyroxine is one of the most frequently prescribed medications. Despite this, the incidence of important drug interactions appears to be relatively low, especially interactions that augment the effects of thyroxine. Thyroxine is metabolized in part through © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

442

the action of glucuronyl transferase, which can be inhibited by some antiretroviral drugs, such as indinavir. • Clinical and biochemical hyperthyroidism occurred in a 36-year-old woman, after previously stable thyroxine replacement therapy, when antiretroviral drugs for HIV infection were introduced (3A ). She was reported to be taking a very large dose of thyroxine (750 micrograms/day) after partial thyroidectomy for Graves’ hyperthyroidism some 6 years before. One month after starting antiretroviral treatment she developed symptoms and signs suggestive of thyroid hormone excess and had markedly raised serum free thyroxine and free T3 concentrations, with suppression of TSH. The dose of thyroxine was reduced progressively to 120 micrograms/day, and after about 2 months her thyroid function tests returned to normal.

While this pattern of biochemistry does not exclude transient relapse of Graves’ hyperthyroidism (despite the ﬁnding of negative TSH receptor antibodies), or a transient thyroiditis, the authors speculated that indinavir (prescribed in this patient together with stavudine and lamivudine) inhibited the glucuronidation of thyroxine and hence caused a rise in serum thyroid hormone concentrations.

ANTITHYROID DRUGS (SED-14, 1489; SEDA-24, 484; SEDA-25, 503; SEDA-26, 458) Hematologic The most feared complication of thionamide drugs is bone-marrow suppression. The reported incidence of agranulocytosis varies from 0.1 to 0.3%; pancytopenia occurs less often. In a series of 18 cases of antithyroid drug-induced agranulocytosis in China, previous evidence that most cases occur early in treatment (2–12 weeks in 17 of 18 cases) and in those taking high doses was conﬁrmed (4A ).

Thyroid hormones and antithyroid drugs

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This series also conﬁrmed that agranulocytosis develops abruptly, arguing against routine monitoring of white cell count, and that fever and sore throat are the earliest symptoms. In a retrospective cohort study of 90 cases of drug-induced agranulocytosis in Strasbourg antithyroid drugs were implicated in 23% of cases, second only to antibiotics in terms of frequency of prescription in the affected cohort (5c ). The clinical presentation was often severe and included isolated fever (41% of cases), septicemia or septic shock (31%), and pneumonia (10%). The outcome was favorable in 98% of cases. All the patients were treated with broad-spectrum antibiotics and 42 received hemopoietic growth factors; in those given growth factors the mean durations for hematological recovery, antibiotic therapy, and hospitalization were signiﬁcantly reduced. While patient selection may have contributed to these ﬁndings, they do suggest a useful role for such growth factors in supporting patients with this potentially life-threatening complication of thionamide therapy. Liver Both carbimazole and propylthiouracil can cause liver damage, sometimes as part of a hypersensitivity reaction associated with pruritus, rash, fever, and arthralgia. Fatal hepatitis and hepatic necrosis have been described, but severe liver injury is believed to be rare. Of 14 cases of suspected drug-induced liver disease presenting to a gastroenterology department over a 3-year period, one was thought to be related to methimazole, with a hepatitic pattern of liver function tests in a 39-year-old woman 6 days after the start of therapy; recovery was swift and complete (6A ). Pancreas There has previously been only one report of pancreatitis attributed to methimazole (7A ). • A 33-year-old woman developed acute pancreatitis together with mild cholestatic hepatitis and erythema nodosum 1 month after starting carbimazole for Graves’ disease; rechallenge with a single dose of carbimazole (10 mg) 7 days after initial recovery led to a further episode of acute pancreatitis, from which she recovered (8A ).

The temporal association with carbimazole therapy, the response to rechallenge, and the absence of other causes of acute pancreatitis suggested that the drug had been causative.

443 Immunologic Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a well described complication of the thionamides, particularly propylthiouracil and to a lesser extent carbimazole, and has been most often described in patients with Graves’ disease. In 61 patients with Graves’ hyperthyroidism, 32 of whom were taking propylthiouracil and 29 methimazole, there was a higher prevalence of antimyeloperoxidase ANCAs in those taking propylthiouracil than in those taking methimazole (25% versus 3.4%) (9c ). There were no signiﬁcant differences in age, drug duration, or drug dosage in those who developed antimyeloperoxidase ANCAs compared with those who did not. Two ANCA-positive patients in this study developed rheumatoid arthritis or membranous glomerulonephritis, but none developed classical ANCA-associated vasculitis. However, there have been three further case reports of antimyeloperoxidase ANCAs associated with diffuse pulmonary alveolar hemorrhage (10A ), IgA nephropathy (11A ), and druginduced neutropenia (12AE ) in patients who had Graves’ hyperthyroidism taking propylthiouracil. Investigation using serum from the last of these patients implicated a complementmediated mechanism. In another case ANCAs developed in two of three monozygotic triplets, both of whom had Graves’ disease treated with propylthiouracil, supporting a genetic role in the development of this drug complication (13A ). In a study in Japan long-term outcomes in a series of seven children who developed myeloperoxidase-speciﬁc ANCA-positive necrotizing crescentic glomerulonephritis associated with propylthiouracil were studied (14A ). Three had nephritis alone and four had extrarenal vasculitis. All had received glucocorticoids, some with additional drugs, and all had achieved remission. None had progressed to end-stage renal insufﬁciency or death during a mean period of follow-up of 58 months. This apparently benign course, albeit with a relatively short period of follow-up, is similar to that seen in adult patients with this drug complication and implies a better prognosis than in subjects with non-drug-induced ANCApositive vasculitic disease. Teratogenicity Aplasia cutis congenita has been attributed to the administration of carbimazole, or its active metabolite methimazole,

444 during early pregnancy. Scalp atresia has now been described in an infant whose mother had taken carbimazole in a high dose (60 mg/day) during the ﬁrst 12 weeks of pregnancy and thereafter propylthiouracil (15A ). The infant had other dysmorphic features (a ﬂat face, lowset ears, upper lip retraction, and a low-set ﬁfth ﬁnger) in addition to transient hypothyroidism. This is the 25th reported case of aplasia cutis congenita in association with carbimazole or methimazole. Choanal atresia has also been described in an infant whose mother presented in early pregnancy with Graves’ hyperthyroidism and who took carbimazole in doses up to 60 mg/day in the ﬁrst trimester (16A ). She was also clinically and biochemically severely

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J.A. Franklyn

hyperthyroid at this time. This is the fourth case of choanal atresia associated with carbimazole; the other infants had additional congenital abnormalities. These case reports do not conﬁrm causation, either for aplasia cutis congenita or choanal atresia. However, the rare congenital abnormality of aplasia cutis congenita has not been described in association with propylthiouracil therapy, which therefore appears to be a more appropriate drug for use in early pregnancy. Choanal atresia has been reported even less often, and its occurrence in the offspring of patients treated for hyperthyroidism may likewise reﬂect the inﬂuence of severe or partially treated hyperthyroidism itself.

REFERENCES 1. Biondi B, Fazio S, Cuocolo A, Sabatini D, Nicolai E, Lombardi G, Salvatore M, Sacca L. Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1996; 81: 4224–8. 2. Bauer M, Baur H, Berghofer A, Strohle A, Hellweg R, Muller-Oerlinghausen B, Baumgartner A. Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders. J Affect Disord 2002; 68: 285–94. 3. Lanzafame M, Trevenzoli M, Faggian F, Marcati P, Gatti F, Carolo G, Concia E. Interaction between levothyroxine and indinavir in a patient with HIV infection. Infection 2002; 30: 54–5. 4. Dai WX, Zhang JD, Zhan SW, Xu BZ, Jin H, Yao Y, Xin WC, Bai Y. Retrospective analysis of 18 cases of antithyroid drug (ATD)-induced agranulocytosis. Endocr J 2002; 49: 29–33. 5. Andres E, Maloisel F, Kurtz JE, Kaltenbach G, Alt M, Weber JC, Sibilia J, Schlienger JL, Blickle JF, Brogard JM, Dufour P. Modern management of non-chemotherapy drug-induced agranulocytosis: a monocentric cohort study of 90 cases and review of the literature. Eur J Intern Med 2002; 13: 324–8. 6. Hartleb M, Biernat L, Kochel A. Drug-induced liver damage – a three-year study of patients from one gastroenterological department. Med Sci Monit 2002; 8: CR292–6. 7. Taguchi M, Yokota M, Koyano H, Endo Y, Ozawa Y. Acute pancreatitis and parotitis induced by methimazole in a patient with Graves’ disease. Clin Endocrinol (Oxf) 1999; 51: 667–70. 8. Marazuela M, Sanchez de Paco G, Jimenez I, Carraro R, Fernandez-Herrera J, Pajares JM, Gomez-Pan A. Acute pancreatitis, hepatic cholestasis, and erythema nodosum induced by carbimazole

treatment for Graves’ disease. Endocr J 2002; 49: 315–18. 9. Wada N, Mukai M, Kohno M, Notoya A, Ito T, Yoshioka N. Prevalence of serum antimyeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves’ disease treated with propylthiouracil and thiamazole. Endocr J 2002; 49: 329–34. 10. Katayama K, Hata C, Kagawa K, Noda M, Nakamura K, Shimizu H, Fujimoto M. Diffuse alveolar hemorrhage associated with myeloperoxidase-antineutrophil cytoplasmic antibody induced by propylthiouracil therapy. Respiration 2002; 69: 473. 11. Winters MJ, Hurley RM, Lirenman DS. ANCApositive glomerulonephritis and IgA nephropathy in a patient on propylthiouracil. Pediatr Nephrol 2002; 17: 257–60. 12. Akamizu T, Ozaki S, Hiratani H, Uesugi H, Sobajima J, Hataya Y, Kanamoto N, Saijo M, Hattori Y, Moriyama K, Ohmori K, Nakao K. Drug-induced neutropenia associated with antineutrophil cytoplasmic antibodies (ANCA): possible involvement of complement in granulocyte cytotoxicity. Clin Exp Immunol 2002; 127: 92–8. 13. Herlin T, Birkebaek NH, Wolthers OD, Heegaard NH, Wiik A. Anti-neutrophil cytoplasmic autoantibody (ANCA) proﬁles in propylthiouracilinduced lupus-like manifestations in monozygotic triplets with hyperthyroidism. Scand J Rheumatol 2002; 31: 46–9. 14. Fujieda M, Hattori M, Kurayama H, Koitabashi Y, for the Members and Coworkers of the Japanese Society for Pediatric Nephrology. Clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody-positive glomerulonephritis associated with propylthiouracil treatment. J Am Soc Nephrol 2002; 13: 437–45.

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15. Bihan H, Vazquez MP, Krivitzky A, Cohen R. Aplasia cutis congenita and dysmorphic syndrome after antithyroid therapy during pregnancy. Endocrinologist 2002; 12: 87–91.

445 16. Barwell J, Fox GF, Round J, Berg J. Choanal atresia: the result of maternal thyrotoxicosis or fetal carbimazole? Am J Med Genet 2002; 111: 55–6.

H.M.J. Krans

42

Insulin, glucagon, and hypoglycemic drugs

BLOOD GLUCOSE MONITORING The site of blood withdrawal can give different values during acute monitoring of glucose (SEDA-26, 461). Blood was tested before and 60, 90, 120, 150, and 180 minutes after a meal from the ﬁnger tips, the arms, and the thighs with the One-Touch Ultra Blood Glucose Monitoring System (LifeScan) and an extra ﬁnger prick using a blood monitoring system. When the blood glucose concentration was rising, only the ﬁnger prick gave accurate results; the readings from the other sites were lower (even after extensive rubbing) (1C ). In patients with diabetes given a 75 g oral glucose load followed by a rapid-acting insulin, producing a wide range of blood glucose concentrations, of three different devices for blood glucose estimation, only ﬁnger-prick estimations followed the changes in blood glucose (2C ), although patients preferred other sites for testing (3c ). A subcutaneous continuous glucose monitoring system was used for 24 hours in seven strictly regulated adolescents and young adults. For comparison blood was drawn from an intravenous cannula and determined in the laboratory, and capillary samples were measured on a glucose meter. During the night-time the readings on the continuous glucose monitoring system were on average 38% lower than the other measurements, indicating a high number of false (asymptomatic) attacks of hypoglycemia (4C ). Infection risk Finger sepsis aggressive enough to cause osteomyelitis has been reported in two women, one aged 61 years with Staphylococcus aureus, S. agalactiae, and E. faeca© 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

446

lis, and another aged 57 years with a beta-hemolytic staphylococcus, Candida non-albicans, and unidentiﬁed anerobic bacteria. Antibiotic treatment and local drainage were unsuccessful and the third phalanx had to be amputated. Both patients had poorly controlled diabetes (HbA1c 14% and 12% respectively); they had estimated their blood glucose six times a week using an automatic lancet without changing their disposable needle (5A ). Drug interactions Icodextrin in the dialysis ﬂuid in continuous ambulatory peritoneal dialysis can contribute to overestimation of blood glucose (SEDA 26, 461). Comparing a meter using the glucose oxidation method and a meter using the glucose dehydrogenase method, only the former gave results that were comparable with the laboratory method (6c ). The authors concluded that meters must be cross-checked with the laboratory before they can be used to measure blood glucose in patients in contact with icodextrin.

INSULIN

(SED-14, 1501; SEDA-24, 487; SEDA-25, 507; SEDA-26, 461) Mortality was reduced from 8.0% to 4.6% in 1548 patients (of whom only 13% had a history of diabetes) by intensive insulin therapy, with frequent monitoring to keep blood glucose concentrations of 4.4–6.1 mmol/l, for 12 months in an intensive care unit (7C ). The greatest reduction was in patients with multiple-organ failure with a proven septic focus. The incidence of hypoglycemia was not reported; however, in these circumstances, with careful intravenous administration of insulin serious hypoglycemia would be unlikely.

Insulin, glucagon, and hypoglycemic drugs

Chapter 42

Nervous system Cerebral edema has been described during therapy of diabetic ketoacidosis with a large volume of ﬂuid, resulting in rapid changes in plasma osmolality, mostly in young patients (SEDA-26, 462). However, in ten adults with ketoacidosis no signs of cerebral edema (supported by CT scans) were found (8c ). Psychiatric The effect of hypoglycemia on cognitive function has been investigated for 18 months in 142 intensively treated children aged 6–15 years with type 1 diabetes; 58 had 111 periods of treatment. There were no effects on cognitive functions (9C ). Metabolic Hypoglycemia has recently been reviewed, with emphasis on autonomic failure, since antecedent hypoglycemia causes both defective glucose counter-regulation and lack of awareness of hypoglycemia, with extensive discussion of the role of the brain in lack of awareness of hypoglycemia and the question of whether the brain is the primary site for sensing hypoglycemia (10R ). In older people markedly fewer autonomic symptoms are reported and there is greater slowing of psychomotor performance. In young children hypoglycemia can lead to more mood and behavioral disturbances than in adults, although they also occur in the latter. It may be that the cortical responses to recurrent hypoglycemia are less plastic and reversible than the hypothalamic and glucosesensing functions (11R ). A questionnaire about the prevalence of severe hypoglycemia in relation to risk factors was answered by 387 patients in 1984 and by 641 patients in 1998; 178 patients answered both questionnaires (12C ). The following changed signiﬁcantly from 1984 to 1998: multiple injection therapy increased from 71% to 98%, daily self monitoring from 17% to 48%, episodes of nocturnal hypoglycemia from 76% to 83%, and lack of awareness from 40% to 55%; HbA1c fell from 7.6% to 7.4%. In 28 children aged 3.1–8.3 years using twice- or thrice-daily insulin, blood glucose was measured with a subcutaneous continuous glucose monitoring system on 3 consecutive days and nights (13C ). Hypoglycemia was deﬁned as a blood glucose concentration below 3.3 mmol/l for longer than 15 minutes. The prevalence of hypoglycemia was 10% and it

447

was more common at night than during the day (19% vs 4.4%). Hypoglycemia at night had a longer duration (median 3.3 hours) and was asymptomatic in 91% of the episodes. The highest prevalence occurred at between 04.00 and 07.30. On a thrice-daily insulin injection regimen, nightly hypoglycemia was less frequent, but the frequency was higher on the following morning. With increasing age there was less hypoglycemia. In 86 intensively treated patients with type 1 diabetes aged 7–18 years the incidence of severe hypoglycemia correlated with the serum activity of acetylcholine esterase. Patients with acetylcholine esterase activity at the median or above reported 3.0 events/year and those with acetylcholine esterase activity below the median reported 0.5 events/year, suggesting that a genetic factor may play a role in the emergence of severe hypoglycemia (14C ). During 12 months 244 episodes of severe hypoglycemia in 166 patients were recorded in a district with a population of 367 051 people (8655 with diabetes); there were 69 (7.1%) episodes in people with type 1 diabetes, 66 (7.3%) in people with type 2 diabetes using insulin, and 23 (0.8%) in those taking a sulfonylurea. Age, duration of diabetes, and lower social class were risk factors. The total cost of emergency treatment was estimated to be no more than $92 078/year (15C ). In a German study in a comparable group of 200 000 people, there were 92 cases in those with type 1 diabetes and 146 cases in those with type 2 diabetes during 3 years (16r ). The estimated costs were lower: $88 676/year for type 2 diabetes and $16 258 for type 1 diabetes. Skin Amyloid-like deposition in the skin has been reported in a patient using porcine insulin (17A ). • A 34-year-old man with a 17-year history of type 1 diabetes developed a 7 cm ﬁrm mass, distinct from adjacent areas of lipohypertrophy, and numerous smaller lesions of the same consistency. The lump consisted of acellular waxy material that appeared to be amyloid, formed by insulin. He had used porcine insulin for a long time.

This complication has been described before (SEDA-14, 373).

448 Pregnancy A 37-year-old nurse with type 1 diabetes was adequately treated with lispro and NPH insulin during her ﬁrst pregnancy (18A ). In her second pregnancy, 3 years later, she had frequent episodes of hypoglycemia with the same regimen, for which she sometimes needed an injection of glucagon during the night. When the NPH in the evening was changed to glargine she had no more serious episodes of hypoglycemia. Drug administration route Insulin pumps Insulin pumps have been in regular use for 15 years, and reviews of their long-term effects in large populations have been published. In a meta-analysis of the metabolic and psychosocial impact of pumps, 52 studies were found; 22 were published before 1987 and 13 after 1993, the year in which the results of the DCCT were published (19M ). The authors stated that therefore conclusions about efﬁcacy are not deﬁnitive. All pump malfunctions were reported before 1988. All types of changes were reported when the frequency and severity of hypoglycemia were compared with prepump times. Infection and skin irritation were expressed in different ways in the various studies. The risk of diabetic ketoacidosis fell after 1993. Most users preferred to continue pump treatment mainly because of more ﬂexibility, greater freedom, and improved glycemic control. In 103 patients who used continuous subcutaneous insulin infusion for 2 years, the incidence of severe hypoglycemia fell from 0.70 cases/patient/year before treatment to 0.06 cases/patient/year during treatment, and HbA1c improved from 7.7 to 7.2% (20C ). The incidence of abscesses was 0.1 cases/patient/year and of ketoacidosis 0.01 cases/patient/year. The patients with HbA1c concentrations above 8.5% had a higher incidence of serious hypoglycemia and abscesses. Quality of life assessments showed great improvements. The reasons for continuous subcutaneous insulin infusion were optimization of metabolic control, greater ﬂexibility, or prevention of severe hypoglycemia. In 138 patients treated with continuous subcutaneous insulin infusion for 7 years there was a fall in the incidence of episodes of serious hypoglycemia (from 0.31 to 0.09 cases/patient/ year) and ketoacidosis (from 0.41 to 0.11 cases/ patient/year); the number of infections was unchanged (0.2 infections/patient/year) (21C ).

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When continuous subcutaneous insulin infusion was instituted in patients with longstanding poor glycemic control during a crossover study in 79 patients for 32 weeks, 17 dropped out after the ﬁrst crossover, making it impossible to use the second arm. HbA1c and quality of life both improved. There were more episodes of mild hypoglycemia with continuous subcutaneous insulin infusion (22C ). The authors of an editorial concluded that continuous subcutaneous insulin infusion can anticipate changes in insulin need, which is important for diabetics with a variable lifestyle or an exaggerated dawn phenomenon (23r ). For a large group the increase in cost and the hassle of continuous subcutaneous insulin infusion do not offset that, and multiple daily injections with glargine as basal insulin (see below) can be equally effective. Continuous intraperitoneal insulin infusion with implantable pumps has been assessed in 34 patients with poorly controlled diabetes (24C ). In two patients the pump was explanted: in one patient with Werner’s syndrome (no subcutaneous fat) the pump was explanted because of infection in the pocket, and one pump was explanted because the patient had local complaints and psychological problems. One patient refused to be included. Patients were followed for 58 months. HbA1c fell from 10.0 to 9.0% in the ﬁrst year and remained there. Median days in hospital fell from 45 to 13 after 1 year. The quality of life was relatively low and many had psychiatric problems. Although longterm glycemic control improved and lengths of hospital stay were reduced, normal glucose control and normal quality of life could not be achieved. Pumps in children In 95 patients aged 4– 18 years with a median follow-up of 28 months continuous subcutaneous insulin infusion produced no change in medical complications (diabetic ketoacidosis, visit to the emergency department), but there was a reduction in the number of episodes of hypoglycemia (25C ). HbA1c was signiﬁcantly lower than prepump values, but gradually increased in the ﬁrst year and then remained stable. In 118 children aged 1.5–18 years treated with continuous subcutaneous insulin infusion, HbA1c in preschool children fell from 7.1 to 6.5%, in school children from 7.8 to 7.3%, and

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in adolescents from 8.1 to 7.4% (26C ). Daily insulin consumption did not increase and the frequency of severe episodes of hypoglycemia fell.

NEW ULTRASHORT-ACTING INSULINS (SED-14, 1506; SEDA-24, 489; SEDA-25, 509; SEDA-26, 463) Aspart insulin and biphasic insulin aspart (30% soluble rapid-acting insulin and 70% protamine-bound aspart insulin) have been reviewed (27M ). Both lispro and aspart (Novorapid) were equally effective in 24 patients with type 1 diabetes (28C ). Frequent addition of NPH to an aspart regimen is unnecessary, as has been shown in a multicenter, multinational, randomized, open study in 368 patients followed for 64 weeks (29C ). Frequent addition of NPH up to four times daily to aspart did not improve HbA1c or change the number of episodes of hypoglycemia compared with regular insulin combined with NPH. Only postprandial blood glucose concentrations were reduced. In an open, randomized, multicenter study, 33 women with type 1 diabetes for at least 2 years were randomized to preprandial lispro or regular insulin in week 15 of their pregnancy; both groups used NPH insulin as well (30C ). HbA1c concentrations fell at the same rate. One patient in the regular group had one episode of severe hypoglycemia and one had three episodes. Biochemical hypoglycemia (under 3.0 mmol/l) was signiﬁcantly more frequent in the lispro group (5.5% vs 3.9%). Retinopathy progressed during pregnancy in three of the 16 who used lispro and six of the 17 who used regular insulin; retinal aneurysms were seen at the beginning of the study in 10/16 and 5/17 patients respectively. There were no differences in the neonates. Skin Lispro can cause lipoatrophy, but it was less extensive in a case in which it had occurred with regular insulin, perhaps because of lispro’s greater solubility. • Several combinations of regular and NPH insulin reduced the risk of hypoglycemia and optimized

449 blood glucose in a 29-year-old woman who had type 1 diabetes for 6 years (31A ). Continuous subcutaneous insulin infusion with regular insulin reduced the risk of hypoglycemia, but after 7 months she developed lipoatrophy. Changing the site of the cannula did not help. She was given lispro instead and after 11 months a new, less extensive area of lipoatrophy emerged, which did not disappear.

Immunologic The long-term antigenicity of lispro insulin and cross-reactivity with human insulin antibodies over 4 years has been investigated in 1221 patients with both type 1 and type 2 diabetes, either insulin-naïve or with prior insulin treatment, in a multicenter combination of controlled and non-controlled open studies (32C ). Like recombinant human insulin, lispro elicited a low immunogenic response. The reversal of aminoacids in B28 and B29 is in a relatively non-immunogenic area. Moreover, antigenicity often correlates with residence of insulin in subcutaneous tissues, and lispro insulin has a short residence time. The patients did not develop increased dosage requirements. Intermittent treatment did not increase speciﬁc or cross-reactive responses. The antibody responses were slightly higher in type 1 than in type 2 diabetes. A few patients treated with aspartate insulin developed antibodies, which cross-reacted with antibodies against human insulin and fell after 3 months (33C ). In lipodystrophy with lipoatrophic diabetes high insulin resistance is often found, for which leptin deﬁciency is one contributory factor. Allergic reactions have been described with lispro and now also with aspart insulin. • A 53-year-old woman had type 2 diabetes that was not well controlled with diet and oral hypoglycemic drugs (34A ). She took intermediateacting insulins, and after 2 months noticed redness and itching at injection sites. When she used aspart and lispro insulin successively, the local reactions continued. She had a high serum concentration of total IgE (748 IU/ml; reference range below 400) and insulin speciﬁc IgE (20 IU/ml; reference range below 0.34), positive insulin antibodies, and positive prick tests for lispro, aspart, human insulin, porcine insulin, and protamine. With intensive nutrition therapy and oral drugs her HbA1c fell to 5.5%. • A 29-year-old woman with raised insulin concentrations during therapy had lipodystrophy and high insulin antibodies titers with high binding capacity and high afﬁnity (35A ). Insulin antibodies are rarely determined in patients with lipodystrophy.

450 Drug contamination A skin reaction to latex in rubber associated with an insulin formulation has been reported (36A ). • In a 35-year-old woman pruritic, erythematous, urticated plaques occurred at insulin injection sites, and persisted for 48 hours, after the use of a preﬁlled cartridge pen containing Humulin (Lilly) and Human Monotard (Novo Nordisk) aspirated from a punctured vial, but not when the insulin was taken directly from the vial. She had positive skin prick tests to latex solutions. Both the cartridge bungs and the vial bungs contain butyl rubber with added natural rubber latex. Switching to latex-free vials alleviated the problem.

Drug administration route Continuous subcutaneous insulin infusion with lispro has been reported to give variable control (37A ). • A 12-year-old boy with type 1 diabetes had problems with lispro insulin in his pump. After multiple daily injections he started continuous subcutaneous insulin infusion with lispro and could freely adjust his eating schedule and had fewer episodes of hypoglycemia and a HbA1c of 5.4%. Later he developed a pattern of variable responsiveness to insulin, starting with increased responsiveness on the day on which he changed his subcutaneous needle, followed by reduced sensitivity and hyperglycemia on the third day. The infusion site was changed and Velosulin was added to lispro, making it possible for him to use his injection site for 3 days consistently; the HbA1c was 7.2%. After 2.5 years he started using aspart insulin. It then became possible to change the infusion site every 4–5 days, when the cartridge was empty. The HbA1c fell to 6.2%.

NEW LONG-ACTING INSULINS (SEDA-26, 463) Glargine has been reviewed (38M , 39R ). The general conclusion was that it is an effective long-acting insulin with no pronounced peaks of action. Patients using glargine have a reduced risk of hypoglycemia. Glargine, which is metabolically active for at least 24 hours, could have an overlapping effect after a second injection. However, there was no evidence of accumulation when glargine, mean dose 24 units/day, was used in combination with lispro for 11 days (40C ). In reaction to comments, and discussing whether ﬂuctuations in insulin concentrations still occur during

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glargine administration, the authors agreed that the dose of glargine insulin should be constant for at least 2 days before a change in dose is made. It is also not clear whether higher doses of glargine could accumulate because of slower inactivation (41r ). In speciﬁc cases one injection of long-acting insulin can be a good alternative therapy. • A 60-year-old man with type 2 diabetes received radiation therapy for a carcinoma of the esophagus and needed continuous enteric tube feeding (42A ). One daily injection of glargine controlled his diabetes well, with an HbA1c concentration of 6.1% and no episodes of hypoglycemia for almost 4 months. This made continuous infusion of a short-acting insulin unnecessary.

However, control can be inadequate with a once-daily injection. • A 53-year-old man with type 1 diabetes needed tube feeding after a stroke and received glargine insulin once daily (43A ). He had marked hyperglycemia after 22 hours and when the dose was divided into two equal doses every 12 hours the hyperglycemia was reduced.

Immunologic An unspeciﬁed allergic reaction to insulin detemir has been reported (44C ). Drug formulations Mistakes in administration Glargine is a clear solution, in contrast to NPH. There have been two previous cases in which patients gave themselves rapid-acting insulin instead of glargine (SEDA-26, 464). Now four more mistakes have been reported (45A , 46A ). The authors advised the use of pens for injection of short-acting insulins, as all the mistakes were made by patients who used vials and syringes to administer both types of insulin.

COMBINATIONS OF NEW LONG-ACTING AND SHORT-ACTING INSULINS Metabolic The combinations lispro/glargine and regular/NPH have been compared in a randomized crossover study for 32 weeks in 25 patients (47C ). HbA1c was not different, but the total insulin dose was lower with lispro/glargine and there were fewer episodes of nocturnal hypoglycemia.

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The new short-acting insulins can be bound to protamine, allowing the preparation of mixed formulations. In a randomized, open, crossover study for 24 weeks, a 50% mixture of lispro and protamine lispro injected immediately before each meal plus NPH in the evening gave a comparable proﬁle to regular insulin injected 30 minutes before each meal plus NPH in the evening (48C ). There were no differences in HbA1c or episodes of hypoglycemia. When Mix 25™ (25% lispro plus 75% protamine lispro) was compared with 30/70 human insulin in an open, randomized, crossover study during Ramadan, the daily average blood glucose concentration was better with the lispro combination. The number of hypoglycemic episodes was the same with both formulations (49C ). In an open, randomized, single-dose, threeway, crossover trial biphasic insulin aspart 30 (30% aspart plus 70% protaminated aspart, BIAsp 30), biphasic insulin lispro 25 (25% lispro plus 75% protaminated lispro, Mix 25) and biphasic human insulin 30 (30% regular plus 70% NPH insulin, BHI 30) were compared in 45 patients (50C ). Biphasic insulin aspart improved postprandial control better. There were 23 episodes of hypoglycemia with BIAsp 30, 19 with Mix 25, and 11 with BHI 30; two episodes with BIAsp 30, ﬁve with Mix 25, and two with BHI 30 required third-party intervention. When 30% aspart insulin plus 70% protamine aspart was compared with the same mixture of regular plus NPH insulins, both injected twice daily for 12 weeks, in 294 patients with type 1 and type 2 diabetes, control was better with the aspart mixture (51C ). There were fewer episodes of major hypoglycemia (20 vs 42) but the same number of minor episodes (362) with aspart. In a multinational study for 6 months in 448 patients with type 1 diabetes, two-thirds were given the long-acting insulin detemir and onethird received NPH, both in addition to premeal rapid-acting insulin aspart (44C ). HbA1c concentrations were comparable, but in the detemir group the risk of hypoglycemia was 22% less and the risk of nocturnal hypoglycemia was 34% lower. There were two cases of severe hypoglycemia with detemir and one with NPH. Three patients who used detemir developed reactions at the injection site (pain, myalgia, redness, or lipodystrophy) compared with one who used NPH (itching). One potentially allergic reaction was possibly related to detemir.

451

Drug administration route Continuous subcutaneous insulin infusion has been compared with short-acting insulins plus glargine or NPH as long-acting insulins for 1 year in 32 patients with poor control (52c ). Four of them had serious attacks of hypoglycemia. There were no differences in HbA1c or other metabolic parameters (including lipids). In those treated with continuous subcutaneous insulin infusion the reduction in the amount of insulin required was larger. Insulin delivery by a pump may be superior to glargine insulin. Continuous subcutaneous insulin infusion was compared with intensive therapy with glargine plus lispro in 19 patients (53C ). The patients who received glargine were exposed to glucose concentrations under 3.9 mmol/l overnight for three times as long as those who used continuous subcutaneous insulin infusion. Inhaled insulin Inhalation of insulin is still experimental. The dose of inhaled insulin is about ten times higher than the subcutaneous dose that produces the same hypoglycemic effect. In an open, randomized, crossover study subcutaneous insulin was compared with a ten times higher dose of inhaled insulin in 15 nonsmoking patients with type 2 diabetes (54C ). The peak action of inhaled insulin was earlier. Apart from that, the effects were similar. There were no differences in FEV1 at baseline or at 4 or 8 hours after treatment. Absorption of inhaled insulin is signiﬁcantly higher in smokers (55C ). In non-diabetics absorption is reduced in asthma (56C ). Inhaled insulin may increase the titer of insulin antibodies (57R ).

GLUCAGON AND GLUCAGON-LIKE PEPTIDE-1 (SED-14, 1508; SEDA-25, 510; SEDA-26, 466)

Glucagon Skin Glucagon, used to treat persistent hyperinsulinemic hypoglycemia of infancy, caused erythema necrolyticum migrans in two neonates (58A ).

452 • In the ﬁrst child, a monozygotic twin girl, delivered at 30 weeks, diazoxide, chlorothiazide, and nifedipine did not alter glucose requirements, but octreotide halved the need, and intravenous glucagon lowered it further. However, the child then developed a maculopapular rash on the face and trunk. After 4 weeks the lesions worsened, increased in size, and became superﬁcially necrosed with thick caked scales. The rash also involved the limbs and mucous membranes, making feeding almost impossible. When glucagon was withdrawn the skin lesions resolved from the center within 2 days and disappeared without scarring in 10 days. • The second child, who was delivered at term, had a blood glucose of 0.8 mmol/l 6 hours after birth and suffered a seizure that was treated with subcutaneous glucagon, octreotide, and other drugs. It was impossible to give sufﬁcient feeding, and notwithstanding subcutaneous glucagon 11 μg/kg/hour and octreotide 4.3 μg/kg/hour, she had a generalized seizure when the blood glucose was 1.4 mmol/l. At 6 months subtotal pancreatectomy was performed. During glucagon therapy she had seborrheic skin with silvery scales and on the thoracic skin an area of pale licheniﬁcation with mild hyperkeratosis. Within 2 weeks after surgery (and withdrawal of glucagon) the skin became totally normal.

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ORAL HYPOGLYCEMIC DRUGS (SED-14, 1508; SEDA-24, 491; SEDA-25, 510; SEDA-26, 466) Adherence to therapy has been studied in patients taking oral drugs, using a database of dispensed drugs and a diabetes information system (63C ). Adherence to therapy was poor in 2537 patients who took sulfonylureas: 88% among the 262 who also took insulin and 87% among the 2275 who used a sulfonylurea without insulin. Adherence was even worse in 1519 patients who took metformin: 80% among the 169 who also took insulin and 83% among the other 1350, who used metformin without insulin. Suboptimal adherence was not associated with subsequent insulin requirements. In a retrospective study in 1305 patients with type 2 diabetes, 11% of those who initially took a sulfonylurea and 6% of those who initially took metformin switched to insulin. Switching to insulin was more frequent in younger patients, in men, and in those with a higher HbA1c and lower body mass index (64C ).

Glucagon-like peptide-1 Glucagon-like peptide-1 increases insulin secretion and biosynthesis, has a trophic effect on beta-cells, increases satiety, and reduces food intake. This could make it an important candidate for the treatment of type 2 diabetes. However, it has to be injected and is extremely rapidly degraded by dipeptidyl peptidase IV. Analogs resistant to degradation and inhibitors of the degrading enzyme are being investigated. Glucagon-like peptide-1 has recently been reviewed (59R ). In healthy volunteers a fatty acid derivative (NN2211), which binds to albumin and has a half-life of about 12 hours, caused more dizziness, headache, nausea, and vomiting than placebo (60C , 61C ). In a crossover study 20 patients with type 2 diabetes were treated for 6 weeks with glucagon-like peptide-1 or saline added to continuous subcutaneous insulin infusion; glucagonlike peptide-1 reduced appetite and caused nausea and reduced well-being (62C ).

ALPHA-GLUCOSIDASE INHIBITORS (SED-14, 1513; SEDA-24, 495; SEDA-25, 513; SEDA-26, 466)

Acarbose Acarbose has recently been reviewed (65R ). It binds reversibly in a dose-dependent manner to the oligosaccharide binding site of alphaglucosidase enzymes in the brush border of the mucosa, mainly in the upper half of the small intestine. It delays the degradation of polysaccharides and starch to glucose and thus reduces the absorption of glucose. When carbohydrates appear in the colon, bacterial fermentation can occur, leading to gastrointestinal adverse effects, of which ﬂatulence and loose stools are the most frequent. During long-term treatment the colonic bacterial mass can increase. Acarbose may reduce the incidence of colon cancer, the risk of which is 30% higher in people with diabetes than in the non-diabetic population. Reversible increases in liver enzymes

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Chapter 42

sometimes occur and reversible hepatotoxicity has been reported. Acarbose should not be given in progressive renal insufﬁciency. Acarbose reduces insulin resistance, as has been reported in 192 patients over 65 years of age (mean age 70) in a double-blind placebocontrolled study (66C ). HbA1c was signiﬁcantly but modestly reduced. The most frequent adverse effect was ﬂatulence, which caused 12 patients (nine taking acarbose and three taking placebo) to withdraw. In a multicenter, double-blind, placebo-controlled study, 81 patients, in whom treatment with metformin was inadequate, received extra acarbose or placebo during 24 weeks after a 4-week run-in period to establish the optimal dose of acarbose (67C ). HbA1c was reduced by 1.02% and fasting blood glucose by 1.13 mmol/l. Gastrointestinal adverse effects were more common in the acarbose group. Gastrointestinal Acarbose may have caused pneumatosis cystoides intestinalis in a 55-yearold woman with pemphigus vulgaris (68A ).

AMYLIN ANALOGUES Amylin is a hormone produced in the beta-cells of the islet of Langerhans and is co-secreted with insulin. It has glucoregulatory effects that may complement the actions of insulin. Pramlintide is a non-aggregating analogue of amylin. It has been studied in a double-blind, placebocontrolled, multicenter study in 480 patients with type 1 diabetes for 1 year, followed by an 1-year open extension (69C ). Glucose control improved with pramlintide. Hypoglycemia was less frequent with pramlintide, but nausea and anorexia doubled in frequency and was the most often caused reason for withdrawal. In a comparable study 656 patients with type 2 diabetes took preprandial pramlintide 60 μg tds, 90 μg bd, or 120 μg bd (70C ). Only 120 μg bd gave a sustained reduction in HbA1c . In the ﬁrst 4 weeks there was an increase in the risk of hypoglycemia, but not thereafter. Mild to moderate nausea and headache were the most frequent adverse effects; nausea abated during treatment. In none of the studies was there evidence of cardiac, hepatic, or renal toxicity or hypersensitivity reactions. The reduction in postprandial

453

glucose excursions is probably due to reduced stomach emptying and not stimulation of GLP1 release (71E ).

BIGUANIDES

(SED-14, 1512; SEDA-24, 495; SEDA-25, 513; SEDA-26, 467)

Metformin In a large American study in 3234 non-diabetic people with a raised fasting blood glucose and a raised blood glucose 2 hours after a glucose load, diabetes occurred in 7.8 cases per 100 participants per year after a mean treatment period of 2.8 years with metformin 850 mg bd; there were 11 cases per 100 participants per year after placebo and 4.8 cases per 100 participants per year after a life-style intervention program (72C ). Gastrointestinal symptoms were most frequent in those who took metformin. In a later study, glucose tolerance tests were performed after a 14-day washout period of metformin and placebo in the patients who had not developed diabetes (73c ). Diabetes was more frequently diagnosed in the metformin group, but when the diabetes conversions during treatment and washout were combined, diabetes was still signiﬁcantly less common in the metformin group. Metabolic Lactic acidosis is a dangerous complication of biguanide therapy. All patients admitted to a hospital during 6 months who had taken at least one dose of metformin were retrospectively evaluated for risk factors for metformin-associated lactic acidosis (74c ). There were 263 hospitalizations in 204 patients. In 71 admissions there was at least one contraindication, such as renal or liver disease, renal dysfunction, congestive cardiac failure, metabolic acidosis, or an intravenous iodinated contrast medium given within 48 hours of metformin. In 29 (41%) metformin was continued despite the contraindication. The most frequent contraindication was a raised serum creatinine, but in only eight of the 32 admissions was metformin withdrawn. Of nine patients using metformin who died (not necessarily directly related to metformin), six had an absolute contraindication. In two patients who died and in one who survived, blood lactate was increased

454 and this was temporally related to the use of metformin. Five patients with metformin-associated severe lactic acidosis, seen between 1 September 1998 and 31 May 2001, have been reported (75A ). Two had attempted suicide (details below under “Drug overdose”). All had severe metabolic acidosis with a high anion gap and raised blood lactate concentrations. Four developed profound hypotension and three had acute respiratory failure. Three had normal preceding renal function. Three required conventional hemodialysis and two continuous renal replacement therapy. Lactic acidosis has also been reported in an 83-year-old woman with mild renal insufﬁciency (76c ). The various risk factors for lactic acidosis include reduced renal function in older patients and the use of ACE inhibitors, thiazide diuretics, NSAIDs, and drugs such as furosemide, nifedipine, cimetidine, amiloride, triamterene, trimethoprim, and digoxin, which are all secreted in the renal tubules, compete with metformin, and may contribute to increased plasma metformin concentrations (77r ). The best therapy is immediate hemodialysis. Metformin in the tissues continues to produce lactate, while the drug is removed during dialysis. Sodium bicarbonate is not very effective and can paradoxically lower the pH and cause hypernatremia and ﬂuid overload. Tracheal intubation and mechanical ventilation may be necessary. Hematologic Metformin can occasionally cause a hemolytic anemia. • A 68-year-old woman of North African Jewish descent with a raised HbA1c was given metformin 850 mg tds and repaglinide 1 mg tds, and 14 days later developed extreme weakness and anemia, her hemoglobin having fallen from 12 g/dl to 8 g/dl within 1 week (78A ). Her reticulocyte count was 11%, with polychromasia. The bilirubin rose to 35 μmol/l (27 μmol/l direct). The haptoglobin concentration was low and a direct Coombs’ test negative. Metformin was withdrawn. Two units of erythrocytes were transfused and the hemoglobin rose to 11 g/dl and remained stable. Glucose-6-phosphate dehydrogenase (G6PD) activity was signiﬁcantly reduced. There were no other precipitating factors for hemolysis due to G6PD deﬁciency.

It is unclear whether metformin caused hemolysis directly in this case or via G6PD deﬁciency. Two other patients have been reported

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with normal G6PD activity (79A , 80A ); one had a positive Coombs’ test (80A ). Nutrition Vitamin B12 deﬁciency can be caused by metformin. • A 63-year-old man with type 2 diabetes, who had taken metformin for at least 5 years, had a low serum vitamin B12 concentration (110 pg/ml; reference range 200–230) and a normal serum folate (81A ). There were no autoantibodies. A Schilling test showed malabsorption of vitamin B12 . Metformin was withdrawn and 2 months later a Schilling test showed no malabsorption.

This case prompted a report of 10 metformin-associated patients with cobalamin deﬁciency among 162 patients with vitamin B12 concentrations below 200 pg/ml (82C ). They had taken a mean dose of metformin of 2015 mg/day for an average of 8.9 years. The mean vitamin B12 concentration was 140 pg/ml. All had normal serum folate and creatinine concentrations and no antibodies to intrinsic factor. In one patient there was malabsorption. Lactation Metformin is increasingly being used in the polycystic ovarian syndrome and therefore in lactating women. In seven breastfeeding mothers taking a median dose of 1500 mg/day, the mean relative infant dose transferred in the milk was 0.28% (83c ). Serum metformin concentrations were very low or undetectable in infants and they appeared to be healthy. A speciﬁc warning was given for children with impaired renal function (prematurity, renal insufﬁciency). Drug overdose Three cases of metformin overdose have been reported. • A healthy 21-year-old woman took metformin 45 g (53 × 850 mg) in a suicide attempt and developed acute pancreatitis with metabolic acidosis (pH 6.96), hypoglycemia (1.3 mmol/l), and an anion gap of 37 mmol/l (84A ). She was given 290 g of dextrose, and her blood glucose rose to 25 mmol/l. Other laboratory tests were normal. When later measured, serum amylase was 121 U/l, urinary amylase 97 U/l (both twice the upper limit of the reference range), and serum lipase 724 U/l (5–6 times raised). A CT scan with contrast showed stage B acute pancreatitis. Serum amylase and serum lipase rose to 368 and 1900 U/l respectively. She recovered after 8 days. A CT scan 1 month later was normal. Lactic acid and metformin were not determined. The use of alcohol or other drugs that can cause pancreatitis could not be

Insulin, glucagon, and hypoglycemic drugs

Chapter 42

established. Gallstones and hyperlipidemia were not present. The initial hypoglycemia could have been a direct effect of metformin; hyperglycemia is more often seen during lactic acidosis. • A non-diabetic 25-year-old woman died after 2 days of lactic acidosis and multiple organ failure, having taken an unknown amount of her father’s metformin (75A , 85A ). • A 58-year-old woman with type 2 diabetes took an overdose of metformin 55 g plus 100 mg of glibenclamide and 3.1 g of acarbose (75A ) (85A ). She developed lactic acidosis and survived with hemodialysis.

The authors of the second paper warned that when a patient in coma has an unexplained anion gap, a suicide attempt with metformin should be considered.

455

that the efﬁcacy in lowering HbA1c is almost equivalent for sulfonylureas and repaglinide and is slightly lower for nateglinide. When a lunch-time meal was omitted (SEDA-23, 462) patients taking glibenclamide had the lowest blood glucose concentrations, often within the hypoglycemic range, in contrast to patients taking repaglinide. Both drugs can cause hypoglycemia.

Repaglinide

MEGLITINIDES

Metabolic The effects of repaglinide and glibenclamide have been compared in 235 patients during Ramadan, when people eat two meals a day (90C ). Before Ramadan they were adjusted to optimal treatment with thrice-daily repaglinide or once- or twice-daily glibenclamide. During Ramadan they took twicedaily repaglinide or glibenclamide. After Ramadan they continued to take the pre-Ramadan regimen for 4 weeks. Mid-day hypoglycemia (blood glucose below 4.5 mmol/l) occurred in 2.8% of those who took repaglinide and 7.9% of those who took glibenclamide. There were 19 events reported by 15 patients in the repaglinide group and 35 by 19 patients in the glibenclamide group. During Ramadan the numbers were nine events in seven patients and 12 events in nine patients respectively. Mean serum fructosamine concentrations fell by 17 μmol/l and 7 μmol/l during Ramadan in those taking repaglinide and glibenclamide respectively.

The meglitinides bind to the same type of receptor as the sulfonylureas in beta-cells in the pancreas, but in a different way. After binding, the ATP-dependent potassium channels are closed, reducing potassium efﬂux and depolarizing the cell membrane. The meglitinides do not have to be internalized in the membrane, in contrast to the sulfonylureas. This may explain their rapid onset of the action and the end of that action when glucose concentrations are falling. Nateglinide acts more quickly than repaglinide, and both act more quickly than sulfonylureas, which stimulate insulin secretion independent of blood glucose concentrations (87R ). It has been stated (88r ) that earlier studies (SEDA-22, 478; SEDA-23, 462; 89C ) showed

Skin A 62-year-old woman with type 2 diabetes, hypertension, and chronic hepatitis C virus infection developed palpable purpura over her legs and buttocks 3 weeks after starting to take repaglinide 500 mg qds (91A ). The purpura ulcerated and became infected. Repaglinide was withdrawn and the purpura resolved. A biopsy showed leukocytoclastic vasculitis. Repaglinide, which is metabolized in the liver, is cleared more slowly in people with liver disease, and hepatitis C may have played a part in this case. Although hepatitis C can cause a leukocytoclastic vasculitis, the clinical correlation and the rapid disappearance of the purpura after the withdrawal of repaglinide makes it likely that this was an adverse effect of the drug. Caution with repaglinide in liver disease is important.

Drug interactions A 79-year-old woman was admitted to hospital stuporose and unresponsive (86c ). She had taken metformin 850 mg bd for 14 days, during which time she complained of loss of appetite and consumed little starch. On that morning she had nausea and dizziness. Her blood glucose was 2.0 mmol/l and her serum potassium 3.3 mmol/l. A CT scan of the head was normal. The combination of metformin, which itself does not cause hypoglycemia, with an ACE inhibitor, nitrofurantoin, and an NSAID, which all have glucoselowering effects, and poor food intake may have led to hypoglycemia.

(SEDA-24, 494; SEDA-25, 512; SEDA-26, 468)

456 Susceptibility factors In 235 patients with normal renal function or moderate to severe renal impairment switched from their original therapy to repaglinide (titrated to 0.5–4 mg tds within 4 weeks and continued for 3 months), the number of episodes of hypoglycemia increased with increasing severity of renal impairment during the run-in period but not during treatment (92C ). The ﬁnal dose tended to be lower in patients with severe renal impairment. Although the concentrations of repaglinide in the patients with renal impairment were higher, they did not exceed the effective concentrations in people without renal impairment. However, patients with renal impairment have other problems, and it is wise not to use repaglinide in patients with severe renal disease. Patients with severe renal impairment (creatinine clearance 20–40 ml/min) had excess accumulation of the drug after taking multiple doses for 5 days (93C ). Drug interactions Gemﬁbrozil raised the AUC of repaglinide 8-fold and itraconazole only 1.4-fold; however, the combination increased it nearly 20-fold in 12 healthy subjects (94C ).

SULFONYLUREAS

(SED-14, 1508; SEDA-24, 492; SEDA-25, 511; SEDA-26, 469)

Metabolic In a retrospective study in Hong Kong, drug-induced hypoglycemia accounted for 0.5% of admissions; 50% of the episodes were related to sulfonylureas (95c ). These patients were older, predominantly female, in poorer general health, and needing assistance in daily activities, including feeding. Co-morbidities, such as macrovascular complications, renal insufﬁciency, and concurrent infections, were common. Low plasma albumin concentrations probably reﬂected poor nutritional status. Of those who had recurrent admissions, 67% lived in old peoples’ homes, compared with 22% in those without previous admissions. The prognosis in this group was poor: 23% died within 1 year. Patients taking gliclazide (n = 13) or glipizide (n = 10) accounted for 37% of the episodes. They had more vascular complications than patients who used glibenclamide or chlorpropamide. They had a higher frequency

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of previous admissions (47% vs 19%) and a higher mortality rate (1 year, 47% vs 10%; 5 years, 72% vs 34%). In a period of 12 months 23 episodes of severe hypoglycemia were recorded in those taking a sulfonylurea in a district with a population of 367 051 (8655 with diabetes) (15C ). The total cost of emergency treatment was estimated to be up to $92 078/year (see also above, under insulin). Three patients became comatose due to hypoglycemia (96A ): • an 83-year-old woman who took 2 times 5 mg glibenclamide bd; • a 61-year-old man who took 2 mg glimepiride bd and 500 mg metformin bd; • a 79-year-old woman who took 5 mg glibenclamide tds and metformin 850 mg bd.

All of these patients had general malaise, reduced food intake, and vomiting; glucose had to be given for a long time and one patient died with pneumonia. Factitious hypoglycemia occurred in a 33year-old nurse, with only small increases in insulin and C-peptide (97A ). Glibenclamide was found in her serum. However, she denied using it and did not want psychiatric therapy. Liver Two cases of liver damage have been attributed to gliclazide. • A 64-year-old man who took gliclazide 160 mg bd for 3 months developed hepatitis (98A ). No other cause could be detected. Gliclazide was withdrawn. A liver biopsy after 2 weeks showed resolving acute hepatitis, consistent with a drug reaction, and 3 months later the liver proﬁle was normal. • A 42-year-old woman with newly diagnosed diabetes and no other known diseases developed a slightly abnormal liver proﬁle (99A ). Good glycemic control was obtained with metformin 850 mg bd and gliclazide 80 mg bd. After 4 weeks she developed a pruritic skin rash, which resolved after 4 days of treatment with fexofenadine. A liver proﬁle 2 weeks later was abnormal. Metformin was withdrawn, but 3 days later she was icteric and gliclazide was withdrawn. A liver biopsy was consistent with cirrhosis and there were moderate inﬂammatory inﬁltrates. The liver function tests improved and after 3 weeks she was rechallenged with metformin without exacerbation. Cirrhosis may have contributed to the adverse effect of gliclazide in this case.

Immunologic Glibenclamide contains a sulfa moiety and can cause allergic reactions in someone who is allergic to sulfonamides.

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Chapter 42

• A 57-year-old man with a previously undocumented sulfa allergy used atenolol 100 mg/day, hydrochlorothiazide 25 mg/day, docusate sodium 100 mg/day, and ranitidine 300 mg bd for several months (100A ). He started to take celecoxib 200 mg/day, and 1 month later developed erythema multiforme and difﬁculty in breathing caused by swelling of the throat. He improved after withdrawal of his drugs and further treatment. He was then instructed to reintroduce his previous drugs one a day. One day later, after taking glibenclamide 5 mg, he developed new lesions and dyspnea. After 3 weeks he had another relapse when he reintroduced hydrochlorothiazide. He omitted glibenclamide, celecoxib, and hydrochlorothiazide, but continued to use insulin, metformin, ranitidine, and psyllium. The urticarial lesions disappeared.

Celecoxib and hydrochlorothiazide also have sulfa moieties and could have contributed in this case. Drug formulations New formulations of some sulfonylureas offer the possibility of oncedaily therapy. They include gliclazide MR (SEDA-25, 511) and glipizide GITS (SEDA-22, 444; SEDA-23, 475). Gliclazide MR has recently been reviewed (101R ). In a small study 30–120 mg/day had similar efﬁcacy to 80– 320 mg/day of the immediate-release formulation. The most commonly observed adverse events were arthralgia, arthritis, back pain, and bronchitis, which may not all have been directly related to the drug, as they also occurred with placebo. There was symptomatic hypoglycemia in about 5%. Glipizide GITS was also studied in 19 patients with type 2 diabetes in an open, randomized, two-way, crossover study for 5 days, comparing 20 mg/day and 10 mg bd (102CR ). Despite lower serum concentrations with glipizide GITS, the effects on serum concentrations of glucose, insulin, and C-peptide were the same. This may explain the low overall rate of hypoglycemia and lack of weight gain with glipizide GITS. Drug interactions Two men aged 82 and 72 years with impaired renal function and respectively taking glibenclamide 5 mg/day and glipizide 15 mg/day, became comatose due to hypoglycemia within 48 hours of starting to take clarithromycin (103A ). Clarithromycin inhibits cytochrome CYP3A4. It should be used carefully in patients with diabetes and reduced renal function taking oral drugs.

457

THAZOLIDINEDIONES (GLITAZONES) (SEDA-14, 1514; SEDA-24, 496; SEDA-25, 515; SEDA-26, 471) Rosiglitazone and pioglitazone are the main representatives of these so-called insulin sensitizers, which act by reducing insulin resistance, speciﬁcally in fat. They are metabolized in the liver. The nuclear PPAR-gamma receptor is an important molecular target. However, they may also intervene directly in the fuel metabolism of skeletal muscle and liver, as suggested by in vitro experiments (104E ). They can reduce HbA1c , the glucose AUC after a glucose tolerance test, and the glucose AUC after a meal in glucocorticoid-induced diabetes, as has been shown in seven patients taking troglitazone (105c ). Weight gain and reduced hemoglobin were adverse effects.

Pioglitazone Liver There have been two more reports of hepatotoxicity of pioglitazone (SEDA-26, 471). There were asymptomatic rises in serum aminotransferase activities after the start of pioglitazone therapy, with normalization after drug withdrawal. • A 49-year-old man developed scleral icterus with raised bilirubin and aminotransferases after using pioglitazone 15–30 mg for 6 months and 45 mg for 1 week (106A ). No other cause for hepatitis was found. After withdrawal his liver function improved substantially within 14 days. • A 49-year-old woman developed jaundice after taking pioglitazone 30 mg/day for 6 weeks, and after 3 weeks the AlT was 131 U/l and AsT 79 U/l (107A ). Tests for viral hepatitis were negative. A liver biopsy showed marked portal edema, patchy chronic inﬂammation, a cellular inﬁltrate, and marked bile duct proliferation. There was no ﬁbrosis. The laboratory results worsened after pioglitazone was withdrawn, and 1 month after withdrawal the bilirubin reached a peak of 585 μmol/l. Over the next 8 weeks the symptoms and laboratory tests improved, and after 6 months her condition was the same as when she had started to take pioglitazone.

Rosiglitazone Rosiglitazone has recently been reviewed (108R ). Its main adverse effects are ﬂuid reten-

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tion, with falls in hemoglobin and hematocrit and increased body weight. Other adverse effects are rare. It has a half-life of about 4 hours and is metabolized in the liver. Its half-life, Cmax , and AUC were similar in 10 patients on hemodialysis and 10 healthy subjects. Dosage adjustment is not necessary when renal function is reduced (109C ). In 203 patients, randomly assigned for 1 year to rosiglitazone 4 mg bd or glibenclamide to achieve optimal control, there was signiﬁcant and sustained reduction in hyperglycemia and a signiﬁcant reduction in diastolic blood pressure with rosiglitazone (110C ). There were no differences in adverse effects or in left ventricular mass index.

A liver biopsy showed a periportal mixed cellular inﬁltrate and granulomas within the portal triad and the parenchyma. There was no evidence of sarcoidosis. After withdrawal of rosiglitazone he improved and the liver enzymes became normal within 2 months. • A 49-year-old man with pre-existing hepatic pathology took rosiglitazone 4 mg/day for 2 months and 8 mg/day for 5 months (114A ). He developed a “bull” face and then edema of the eyelids and neck. He had anorexia and nausea. His serum sodium was 110 mmol/l, potassium 3.3 mmol/l, chloride 81 mmol/l, cholesterol 21 mmol/l, triglycerides 33 mmol/l, and his liver enzymes were raised. Rosiglitazone was withdrawn and he was given saline and potassium, acarbose for his diabetes, spironolactone 200 mg/day for edema, and atorvastatin 10 mg/day for hyperlipidemia. He improved over 3 weeks.

Metabolic In 38 patients taking metformin 2550 mg/day and glimiperide 6 mg/day, rosiglitazone 4 or 8 mg/day was added for 20 weeks (111C ). HbA1c and fasting blood glucose fell signiﬁcantly. There was hypoglycemia in 19% of those who took 4 mg/day and 28% of those who took 8 mg/day, and body weight increased by 4.2 and 4.6 kg respectively. There were no signs or symptoms of liver disease and no changes in liver function tests.

Combinations of hypoglycemic drugs

Liver Liver function was monitored in patients aged 30–80 years with type 2 diabetes taking rosiglitazone (112R ). When a patient had aminotransferase or alkaline phosphatase activities higher than 2.5 times the upper limit of the reference range they were not included in the studies. In 5006 patients taking rosiglitazone as monotherapy or combined therapy there were no hepatotoxic effects. At entry to the studies 5.6% of the patients had values between 1.0 and 2.5 times the upper limit. Of the placebo-treated patients, 39% had a fall to normal values and 39% had an increase, but not over three times the upper limit. In 66% of the patients treated with a hypoglycemic drug the values fell (often with a fall in HbA1c ); in 13% they increased to below three times the upper limit and in 2.0% to over three times (four patients). • An obese 37-year-old man with type 2 diabetes, who used rosiglitazone for 15 months, at ﬁrst 4 mg/day then 8 mg/day for 6 months, developed granulomatous hepatitis (113A ). His liver enzymes were normal at 6 and 8 months. After 14 months he developed fatigue, abdominal discomfort, and weight loss and 3 weeks later chills, nausea, vomiting, and diarrhea. No hepatic viruses were found.

The different mechanisms of action of the various classes of hypoglycemic drugs makes combined therapy feasible. Large studies of the effects of lifestyle changes, the effects of drugs in preventing or postponing the complications of diabetes, or the usefulness of various combinations are regularly published. The different mechanisms of action of the various classes give different metabolic effects and different adverse effects proﬁles (115M ). Comparative costs of the various therapies in the USA have been presented (116c ). This subject was recently reviewed in relation to combined oral therapy. In a systematic review of 63 studies with a duration of at least 3 months and involving at least 10 patients at the end of the study, and in which HbA1c was reported, ﬁve different classes of oral drugs were almost equally effective in lowering blood glucose concentrations (117M ). HbA1c was reduced by about 1–2% in all cases. Combination therapy gave additive effects. However, longterm vascular risk reduction was demonstrated only with sulfonylureas and metformin. Glitazones plus biguanides In a placebocontrolled study in 116 patients who responded insufﬁciently to metformin 2.5 g/day, rosiglitazone 2 or 4 mg bd was added for 26 weeks

Insulin, glucagon, and hypoglycemic drugs

Chapter 42

(118C ). HbA1c and fasting plasma glucose improved and hemoglobin fell. Edema was reported in 5.2% of the patients who took rosiglitazone and two patients withdrew because of headache. Glitazones plus meglitinides In 585 patients in a double-blind, randomized, placebo-controlled, multicenter study lasting 16 weeks nateglinide 40 mg tds alone, troglitazone 200 mg/day alone, and the combination were compared (119C ). The combination was most effective in lowering HbA1c . The most frequent adverse effects were mild hypoglycemia, most often in the combination group. Three patients (two in the combination group and one in the troglitazone alone group) withdrew because of hypoglycemia. Most of the withdrawals were related to increased liver enzymes and weight gain, known adverse effects of troglitazone. Twelve patients withdrew because of predeﬁned changes from baseline (AsT and AlT more than 200% and alkaline phosphatase and bilirubin more than 100% over baseline); seven were taking troglitazone alone, four combined therapy, and one placebo. Sulfonylureas plus meglitinides Glipizide, nateglinide, and their combination have been compared in a double-blind, randomized, placebo-controlled study in 20 patients with type 2 diabetes not requiring insulin (120C ). Before a standardized breakfast they took glipizide 10 mg, nateglinide 120 mg, both, or placebo; 4 hours after the meal blood glucose concentrations were signiﬁcantly higher after nateglinide, but peak and integrated glucose concentrations did not differ. Integrated insulin concentrations were higher with glipizide. There were three episodes of hypoglycemia in the glipizide alone group and three in the combined group; three required treatment with glucose. Insulin plus oral hypoglycemic drugs Metformin was given as an adjunct to insulin in a double-blind, placebo-controlled study in 28 adolescents needing more than 1 unit/kg/day (121C ). The dose of metformin was 1000 mg/day when body weight was under 50 kg, 1500 mg/ day when it was 50–75 kg, and 2000 mg/day when it was over 75 kg. Metformin lowered insulin requirements. The number of episodes of hypoglycemia increased compared with placebo. There was gastrointestinal discomfort in

459

six patients taking metformin and ﬁve taking placebo. A comparable placebo-controlled study was reported in 353 patients with type 2 diabetes for 48 weeks. All were taking insulin, and HbA1c fell in those who also took metformin. Body weight was reduced by 0.4 kg by metformin and increased by 1.2 kg by placebo. Symptomatic episodes of hypoglycemia were more common with metformin. There were mild transient gastrointestinal complaints in 56% and 13% respectively (122C ). Insulin plus metformin (27 patients, 2000 mg/day) or troglitazone (30 patients, 600 mg/ day) in patients with type 2 diabetes using at least 30 units/day was compared with insulin alone (30 patients) for 4 months (123C ). Body weight increased in the insulin and the insulin plus triglitazone groups. In the insulin plus metformin group there were signiﬁcantly more gastrointestinal adverse effects but less hypoglycemia than the other groups. In 80 patients taking metformin 850 or 1000 mg tds plus NPH insulin at bedtime, metformin was withdrawn and repaglinide 4 mg tds added in half of the patients for 16 weeks (124C ). In the repaglinide group the dose of insulin increased slightly and weight gain was 1.8 kg more. Mild hypoglycemia occurred more often in the metformin group; nightly episodes of hypoglycemia occurred only with repaglinide. One patient taking repaglinide had a myocardial infarction, and one had three separate hospitalizations for chest pain (myocardial infarction was excluded). No speciﬁc data were presented about gastrointestinal adverse effects or infections. The amylin analogue pramlintide 30 μg was given to 16 patients using insulin pumps as an injection at meal times (125C ). Meal time insulin was reduced by 17%. Serum fructosamine improved. Nausea was the most common adverse effect. There was no hypoglycemia. Conclusions Combinations of drugs are being more frequently used in the treatment of diabetes. In some countries the thiazolidinediones are licensed to be used only in combination with other drugs. The various classes of oral drugs have different mechanisms of action: the sulfonylureas and meglitinides stimulate insulin production, the biguanides reduce glucose production by the liver and excretion from the

460 liver, acarbose reduces the absorption of glucose from the gut, and the thiazolidinediones reduce insulin resistance in fat. This makes combinations of drugs feasible, both combinations of oral drugs and combinations of oral drugs with insulin, and it is not necessary to wait until the maximal dose of one drug has been reached before starting another. Sulfonylureas and meglitinides should no longer be used when endogenous insulin production is

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minimal. Combinations of insulin with sulfonylureas or meglitinides should only be used while the patient is changing to insulin, except when long-acting insulin is given at night in order to give the islets a rest and to stimulate daytime insulin secretion. The adverse effects of combined drug therapy are attributable to the adverse effects of the single drugs. Increased adverse effects or new adverse effects in patients taking combinations have not been reported.

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36. Roest MAB, Shaw S, Orton DI. Insulininjection-site reactions associated with type I latex allergy. New Engl J Med 2003 348: 265–6. 37. Becker DI. Pediatric use of insulin pumps: longer infusion site life time with Novolog. Diabetes Care 2002; 25: 1663–4. 38. Campbell RK, White JR, Levien T, Baker D. Insulin glargine. Clin Ther 2001; 23: 1938–57. 39. Home PD, Ashwell SG. An overview of insulin glargine. Diabetes Metab Res Rev 2002; 18 Suppl 3: S57–63. 40. Heise T, Bott S, Rave K, Dressler A, Rosskamp R, Heinemann L. No evidence for accumulation of insulin glargine (LANTUS® ): a multiple injection study in patients with type 1 diabetes. Diabetic Med 2002; 19: 490–5. 41. Biermann E. No evidence for accumulation of insulin glargine (LANTUS). Diabetic Med 2003; 20: 333–5. 42. Putz D, Kabadi UM. Insulin glargine in continuous enteric tube feeding. Diabetes Care 2002; 25: 1889–90. 43. Clement S, Bowen-Wright H. Twenty-four hour action of insulin glargine (Lantus) may be too short for once-daily dosing: a case report. Diabetes Care 2002; 25: 1479–80. 44. Vague P, Selam J-L, Skei S, De Leeuw I, Elte JWF, Haahr H, Kristensen A, Draeger E. Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 2003; 26: 590–6. 45. Schutta MH. Reducing mistakes in patient administration of glargine and lispro. Diabetes Care 2002; 25: 1098–9. 46. Phillips W, Lando H. Insulin confusion: an observation. Diabetes Care 2002; 25: 1103–4. 47. Murphy NP, Keane SM, Ong KK, Ford-Adams M, Edge JA, Acerini CL, Dunger DB. Randomized cross-over trial of insulin glargine plus lispro or NPH insulin plus regular insulin in adolescents with type 1 diabetes on intensive insulin regimens. Diabetes Care 2003; 26: 799–804. 48. Herz M, Arora V, Sun B, Ferguson SC, Bolli GB, Frier BM. Basal-bolus insulin therapy in type 1 diabetes: A comparative study of pre-meal administration of a ﬁxed mixture of insulin lispro (50%) and neutral protamin lispro (50%) with human soluble insulin. Diabetic Med 2002; 19: 917–23. 49. Mattoo V, Milicevic Z, Malone JK, Schwarzenhofer M, Ekangaki A, Levitt LK, Liong LHC, Rais N, Tounsi H. A comparison of insulin lispro Mix 25™ and human insulin 30/70 in the treatment of type 2 diabetes during Ramadan. Diabetes Res Clin Pract 2003; 59: 137–43. 50. Hermansen K, Colombo M, Storgaard H, Østergaard A, Kølendorf K, Madsbad S. Improved postprandial glycemic control with biphasic insulin aspart relative to biphasic insulin lispro and biphasic human insulin in patients with type 2 diabetes. Diabetes Care 2002; 25: 883–8. 51. Boehm BO, Home PD, Behrend C, Kamp NM, Lindholm A. Premixed insulin aspart 30 vs. Pre-

462 mixed human insulin 30/70 twice daily: a randomized trial in type 1 and type 2 diabetic patients. Diabetic Med 2002; 19: 393–9. 52. Lepore G, Dodesini AR, Nosari I, Trevisan R. Both continuous subcutaneous insulin infusion and a multiple daily insulin injection regimen with glargine as basal insulin are equally better than traditional multiple daily insulin injection treatment. Diabetes Care 2003; 26: 1321–2. 53. King AB, Armstrong D. A comparison of basal insulin delivery. Diabetes Care 2003; 26: 1322. 54. Perera AD, Kapitza C, Nosek L, Fishman RS, Shapiro DA, Heise T, Heinemann L. Absorption and metabolic effect of inhaled insulin. Diabetes Care 2002; 25: 2276–81. 55. Himmelmann A, Jendle J, Mellén A, Petersen AH, Dahl UL, Wollmer P. The impact of smoking on inhaled insulin. Diabetes Care 2003; 26: 677–82. 56. Henry RR, Mudaliar SRD, Howland WC III, Chu N, Kim D, An B, Reinhardt RR. Inhaled insulin using the AERx Insulin diabetes management system in healthy and asthmatic subjects. Diabetes Care 2003; 26: 764–9. 57. Stoever JA, Palmer JP. Inhaled insulin and insulin antibodies: a new twist to an old debate. Diabetes Technol Ther 2002; 4: 157–61. 58. Wald M, Lawrenz K, Luckner D, Seimann R, Mohnike K, Schober E. Glucagon therapy as a possible cause of erythema necrolyticum migrans in two neonates with persistent hyperinsulinaemic hypoglycaemia. Eur J Pediatr 2002; 161: 600–3. 59. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev 2002; 18: 430–41. 60. Jakobsen G, Larsen S, AgersøH, Jensen LB, Rolan P, Sturis J, Hatorp V, Zdravkovic M. Pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care 2002; 25: 1398–402. 61. Agersø H, Jensen LB, Elbrønd B, Rolan P, Zdravkovic M. Pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 2002; 45: 195–202. 62. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of a 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and betacell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359: 824–30. 63. Evans JMM, Donnan PT, Morris AD. Adherence to oral hypoglycaemic agents prior to insulin therapy in type 2 diabetes. Diabetic Med 2002; 19: 685–8. 64. Donnan PT, Steinke DT, Newton RJ, Morris AD. Changes in treatment after the start of oral hypoglycaemic therapy in type 2 diabetes: a population-based study. Diabetic Med 2002; 19: 606–10. 65. Laube H. Acarbose: an update of its therapeutic use in diabetes treatment. Clin Drug Invest 2002; 22: 141–56. 66. Josse RG, Chiasson J-L, Ryan EA, Lau DCW, Ross SA, Yale J-F, Leiter LA, Maheux P, Tessier

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D, Wolever TMS, Gerstein H, Rodger NW, Dornan JM, Murphy LJ, Rabasa-Lhoret R, Meneilly GS. Acarbose in the treatment of elderly patients with type 2 diabetes. Diabetes Res Clin Pract 2003; 59: 37–43. 67. Phillips P, Karrasch J, Scott R, Wilson D, Moses R. Acarbose improves glycemic control in overweight type 2 diabetic patients insufﬁciently treated with metformin. Diabetes Care 2003; 26: 269–73. 68. Maeda A, Yokoi S, Kunou T, Murata T. A case of pneumatosis cystoides intestinale assumed to be induced by acarbose administration for diabetes mellitus and pemphigus vulgaris. Jpn J Gastroenterol 2002; 99: 1345–9. 69. Whitehouse F, Kruger DF, Fineman R, Shen L, Ruggles JA, Maggs DG, Weyer C, Kolterman OG. A randomized study and open-label extension evaluating the long-term efﬁcacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 2002; 25: 724–30. 70. Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer C, Kolterman OG. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes. Diabetes Care 2003; 26: 784–90. 71. Ahrén B, Adner N, Svartberg J, Petrella E, Holst JJ, Gutniak MK. Anti-diabetogenic effect of the human amylin analogue, pramlintide, in type 1 diabetes is not mediated by GLP-1. Diabetic Med 2002; 19: 790–2. 72. Diabetes Prevention Research Program. Reduction in the incidence of type 2 diabetes with life style intervention. New Engl J Med 2002; 346: 393–403. 73. Diabetes Prevention Research Program. Effect of withdrawal from metformin on the development of diabetes in the Diabetes Prevention Program. Diabetes Care 2003; 26: 977–80. 74. Calabrese AT, Coley KC, DaPos SV, Swanson D, Rao RH, Evaluation of prescribing practice; risk of lactic acidosis with metformin therapy. Arch Intern Med 2002; 162: 434–7. 75. Chang C-T, Chen Y-C, Fang J-T, Huang C-C. Metformin-associated lactic acidosis: case reports and literature review. J Nephrol 2002; 15: 398–402. 76. Berner B, Hummel KM, Strutz F, Ritzel U, Ramadori G, Hagenlocher S, Kleine P, Müller GA. Metformin-assoziierte Lactatazidose mit akutem Nierenversagen bei Diabetes mellitus Typ 2. Med Klin 2002; 97: 99–103. 77. Lothholz H, Rahn A, Thurman P. Metforminassoziierte Lactatazidose mit akutem Nierenversagen bei Diabetes mellitus Typ 2. Med Klin 2002; 97: 434–6. 78. Meir A, Kleinman Y, Rund D, Da’as N. Metformin-induced hemolytic anemia in a patient with glucose-6-phosphate dehydrogenase deﬁciency. Diabetes Care 2003; 26: 956–7. 79. Lin KD, Lin JD, Huang JH. Metformin induced hemolysis. New Engl J Med 1989; 339: 1860–1. 80. Kashyap AS, Kashyap S. Hemolytic anemia due to metformin. Postgrad Med J 2000; 76: 125–6. 81. Gilligan MA. Metformin and vitamin B12 deﬁciency. Arch Intern Med 2002; 162: 484–5.

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82. Andres E, Noel E, Goichot B. Metforminassociated vitamin B12 deﬁciency. Arch Intern Med 2002; 162: 2251–2. 83. Hale TW, Kristensen JH, Hackett LP, Kohan R, Hett KF. Transfer of metformin in human milk. Diabetologia 2002; 45: 1509–14. 84. Ben MH, Thabet H, Zaghdoudi I, Amamou M. Metformin associated pancreatitis. Vet Hum Toxicol 2002; 44: 47–8. 85. Chang C-T, Chen Y-C, Fang J-T, Huang C-C. High anion gap metabolic acidosis in suicide: don’t forget metformin intoxication—two patients’ experiences. Renal Fail 2002; 24: 671–5. 86. Zitzmann S, Reiman IR, Schmechel, H. Severe hypoglycemia in an elderly patient treated with metformin. Int J Clin Pharmacol Ther 2002; 40: 108–10. 87. Hu S, Boettcher BR, Dunning BE. The mechanisms underlying the unique pharmacodynamics of nateglinide. Diabetologia 2002; 46 Suppl 1: M37– 43. 88. Cohen RM, Ramlo-Halsted BA. How do the new secretagogues compare? Diabetes Care 2002; 25: 1472–3. 89. Kahn SE, Montgomery B, Howell W, LiguerosSaylan M, Hsu CH, Devineni D, McLeod JF, Horowitz A, Foley JE. Importance of early phase insulin secretion to intravenous glucose tolerance in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2001; 86: 5824–9. 90. Mafauzy M. Repaglinide versus glibenclamide treatment of type 2 diabetes during Ramadan fasting. Diabetes Res Clin Pract 2002; 58: 45–53. 91. Margolin N. Severe leucocytoclastic vasculitis induced by repaglinide in a patient with chronic hepatitis C. Clin Drug Invest 2002; 22: 795–6. 92. Hasslacher C. Safety and efﬁcacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care 2003; 26: 886–91. 93. Schumacher S, Abassi I, Weise D, Hatorp V, Sattler K, Sieber J, Hasslacher C. Single- and multidose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment. Eur J Clin Pharmacol 2001; 57: 147–52. 94. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemﬁbrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemﬁbrozil and repaglinide. Diabetologia 2003; 46: 347–51. 95. So WY, Chan JCN, Yeung VTF, Chow CC, Ko GTC, Li JKY, Cockram CS. Sulfonylurea-induced hypoglycaemia in institutionalized elderly in Hong Kong. Diabetic Med 2002; 19: 966–8. 96. Van Vonderen AG, Thijs A. Hypoglycaemia caused by oral hypoglycaemic agents: risk of relapse after normalisation of blood glucose. Ned Tijdschr Geneeskd 2002; 146: 289–92. 97. Meier JJ, Hücking K, Grüneklee D, Schmiegel W, Nauck MA. Unterschiede im InsulinSekretionsverhalten erleichtern die Differentialdiagnose von Insulinom und Hypoglycaemia factitia. Dtsch Med Wochenschr 2002: 127: 375–8.

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98. Subramanian G, Walmsley D, Blewitt RW. Gliclazide-induced hepatitis. Pract Diabetes Int 2003; 20: 18–20. 99. Chitturi S, Le V, Kench J, Loh C, George J. Gliclazide-induced acute hepatitis with hypersensitivity features. Dig Dis Sci 2002; 47: 1107–10. 100. Ernst EJ, Egge JA. Celcoxib-induced erythema multiforme with glyburide cross-reactivity. Pharmacotherapy 2002; 26: 637–40. 101. McGavin JK, Perry CM, Goa KL. Gliclazide modiﬁed release. Drugs 2002; 62: 1357–64. 102. Chung M, Kourides I, Canovatchel W, Sutﬁn T, Messig M, Chaiken RL. Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediate-release glipizide in patients with type II diabetes mellitus. J Clin Pharmacol 2002; 42: 651–7. 103. Bussing R, Gende A. Severe hypoglycemia from clarithromycin–sulfonylurea drug interaction. Diabetes Care 2002; 25: 1659–60. 104. Fürnsinn C, Waldhäusl W. Thiazolidinediones: metabolic actions in vitro. Diabetologia 2002; 45: 1211–23. 105. Willi SM, Kennedy A, Brant BP, Wallace P, Rogers NL, Garvey WT. Effective use of thiazolidinediones for the treatment of glucocorticoidinduced diabetes. Diabetes Res Clin Pract 2002; 58: 87–96. 106. May LD, Lefkowitch JH, Kram MT, Rubin DE. Mixed hepatocellular–cholestatic liver injury after pioglitazone therapy. Ann Intern Med 2002; 136: 449–52. 107. Pinto AG, Cummings OW, Chalasani N. Severe but reversible cholestatic liver injury after pioglitazone therapy. Ann Intern Med 2002; 137: 857. 108. Wagstaff AJ, Goa KL. Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 2002; 62: 1805–37. 109. Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res 2002; 30: 391–9. 110. St John Sutton M, Rendell M, Dandona P, Dole JF, Murphy K, Patwardhan R, Patel J, Freed M. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 2002; 25: 2058–64. 111. Kiayias JA, Vlachou ED, Theodosopoulou E, Lakka-Papadodima E. Rosiglitazone in combination with glimiperide plus metformin in type 2 diabetic patients. Diabetes Care 2002; 25: 1995–6. 112. Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials; evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care 2002; 25: 815–21. 113. Dhawan M, Agrawal R, Ravi J, Gulati S, Silverman J, Nathan G, Raab S, Brodmerkel G Jr. Rosiglitazone-induced granalomatous hepatitis. J Clin Gastroenterol 2002; 34: 582–4. 114. Kuschel U, Hesselbarth N, Herrmann A, Hippius M, Hoffmann A. Schwere Elektrolytstorung

464 und Odeme unter Therapie mit Rosiglitazon. Med Klin 2002; 97: 553–5. 115. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes; scientiﬁc review. J Am Med Assoc 2002; 87: 360–72. 116. Holmboe ES. Oral antihyperglycemic therapy for type 2 diabetes: clinical applications. J Am Med Assoc 2002; 87: 373–6. 117. Van Gaal LF, De Leeuw JH. Rationale and options for combination therapy in the treatment of type 2 diabetes. Diabetologia 2003; 46 Suppl 1: M44–50. 118. Gómez-Perez FJ, Fanghänel-Salomon G, Barbosa JA, Montes-Villarreal J, Berry RA, Warsi G, Gould EM. Efﬁcacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Diabetes Metab Res Rev 2002; 18: 127–34. 119. Rosenstock J, Shen SG, Gatlin MR, Foley JE. Combination therapy with nateglinide and a thiazolidinedione improves glycemic control in type 2 diabetes. Diabetes Care 2002; 25: 1529–33. 120. Carroll MF, Izard A, Riboni K, Burge MR, Schade DS. Control of postprandial hyperglycemia. Diabetes Care 2002; 25: 2147–52. 121. Hamilton J, Cummings E, Zdravkovic V, Finegood D, Danemen D. Metformin as an adjunct

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therapy in adolescents with type 1 diabetes and insulin resistance. Diabetes Care 2003; 26: 138–43. 122. Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger Van Den Burg B, Donker AJM, Stehouwer CDA. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002; 25: 2133–40. 123. Strowig SM, Avilés-Santa ML, Raskin P. Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes Care 2002; 25: 1691–8. 124. Furlong NJ, Hulme SA, O’Brien SV, Hardy KJ. Repaglinide versus metformin in combination with bedtime NPH insulin in patients with type 2 diabetes established on insulin/metformin combination therapy. Diabetes Care 2002; 25: 1685–90. 125. Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, Maggs DG, Kolterman OG, Chandran M, Mudaliar SR, Henry RR. Impact of pramlintide on glucose ﬂuctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 2003; 26: 1–8.

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43

Miscellaneous hormones

Calcitonin

(SED-14, 1520; SEDA-24, 503; SEDA-25, 520; SEDA-26, 477) Drug formulations Intranasal calcitonin is associated with fewer adverse effects than parenteral formulations, probably because of low systemic availability. However, a meta-analysis has conﬁrmed that adverse events are poorly reported in clinical trials (1M ). The pooled relative risk for rhinitis from four trials (n = 1663) was 1.72, but this did not reach statistical signiﬁcance.

Gonadotrophin-releasing hormone (GnRH, gonadorelin) and analogues (SED-14, 1523; SEDA-24, 503; SEDA-25, 520; SEDA-26, 477) Psychological During a 6-month randomized trial, men randomized to gonadorelin agonists had reduced attention and memory test scores, compared with men who were not given gonadorelin agonists but were closely monitored, in whom there was no change (2C ). Endocrine In the third reported case of an association between autoimmune thyroid disease and gonadorelin agonists, a 47-year-old woman developed symptoms of thyrotoxicosis (palpitation, tremor, tachycardia, and goiter) due to Graves’ disease, after using goserelin acetate for 13 months (3A ). Musculoskeletal Osteoporosis is common in adults treated with gonadorelin agonists (SEDA-26, 478). In 47 children treated with depot leuprolide acetate for precocious puberty for 2 years, bone mineral density decreased © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

signiﬁcantly and markers of bone turnover increased signiﬁcantly during treatment but were normal for age 2 years after treatment was withdrawn (4C ). • An 87-year-old man developed progressive proximal limb weakness 1 year after starting leuprolide therapy for prostate cancer (5A ). Electromyography showed a moderately severe non-inﬂammatory myopathy without evidence of ﬁber necrosis or associated biochemical changes. Within 6 months after stopping leuprolide he was able to resume his usual activities.

Three men developed rheumatoid arthritis 1–9 months after starting antiandrogen therapy with either cyproterone acetate or leuprolide acetate (6A ). Reproductive system Ovarian hyperstimulation syndrome (cystic ovarian enlargement, increased capillary permeability, and ﬂuid accumulation in the bowel lumen, subcutaneous tissues, or pleural or peritoneal spaces) has been described in up to 33% of patients treated with gonadorelin, and the severe form affects 1–10% of patients (SEDA-26, 477). • A 35-year-old obese woman with a previously undiagnosed pituitary gonadotroph adenoma developed multiple ovarian cysts and abdominal distension after 1 month of leuprolide therapy (7A ).

This is the only such case report, but spontaneous ovarian hyperstimulation has previously been described with this type of tumor. Immunologic Altered immune function has been reported in several cases associated with gonadorelin agonist therapy. This is possibly related to the initial surge in sex steroids that occurs with these agents, but there is no evidence that this is the mechanism. Cardiac allograft rejection occurred in three men within months of starting gonadorelin therapy for prostate cancer. One died of heart failure, but the other two recovered cardiac function after the gonadorelin agonist was withdrawn (8A ).

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Gonadotrophin-releasing hormone antagonists (SED-14, 1523; SEDA-24, 504; SEDA-25, 521; SEDA-26, 478) Cetrorelix and ganirelix do not share the lipophilic and histamine-releasing properties of earlier generation gonadorelin antagonists and neither do they lead to depot formation. There appears to be a narrow therapeutic margin in ovarian stimulation protocols. Ganirelix concentrations correlate with body weight, and it has been suggested that the dose should be adjusted to weight to maximize pregnancy rates (9R ). Skin Five of 168 men with prostate cancer treated with abarelix had urticaria and pruritus, which resolved without treatment (10C ).

Growth hormone (human growth hormone, hGH, somatotropin) (SED-14, 1520; SEDA-24, 504; SEDA-25, 521; SEDA-26, 479) Most of the information about the long-term safety of growth hormone in children has been derived from databases voluntarily maintained by two pharmaceutical companies; thus, there may be under-reporting. Other trials have generally been of short duration, with few participants, and may thus have been subject to type II error. The clinical effectiveness and safety of human growth hormone treatment in children has been the subject of a recent systematic review (11M ). Nervous system Of 267 cases of iatrogenic Creutzfeldt–Jakob disease, a fatal neurodegenerative condition, 139 were caused by human cadaver-derived human growth hormone (SEDA-25, 479). A further case has been reported in Brazil, 28 years after human growth hormone therapy (12A ). Metabolism Increased fasting insulin is consistently reported with human growth hormone therapy, especially at high doses, with associated increased glycated hemoglobin within the reference range (13R ). Plasma glucose is inconsistently described as showing a sustained

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increase within the reference range, a transient increase, or no change. This reﬂects both the small non-controlled populations reported and possible selection bias, with exclusion of some patients because of hyperglycemia before the start of a cohort study (13R ). To date there have been no large long-term controlled studies to explore this issue. In a 6-month randomized study of 74 men and 57 women aged over 65 years, diabetes or glucose intolerance developed in 18 men treated with human growth hormone compared with seven controls (14C ). Of 21 children, 15 developed hyperglycemia in a study of high-dose human growth hormone (0.2 mg/kg/day) for burns (15c ). In another study of 29 children with renal insufﬁciency (a group known to have insulin resistance), integrated insulin concentrations increased signiﬁcantly in the ﬁrst year of human growth hormone treatment, with no associated change in plasma glucose or glycated hemoglobin (16c ). In a retrospective study, the fasting glucose:insulin ratio, a marker of insulin resistance, decreased more in girls with Turner syndrome than in children with idiopathic short stature during human growth hormone therapy. The lower glucose:insulin ratio was due to increased fasting insulin and correlated with increased body mass index (17c ). In 25 patients a depot formulation of human growth hormone was associated with a non-sustained increase in glucose and insulin concentrations, more pronounced in men (18c ). Gastrointestinal Nausea, which did not require speciﬁc treatment, occurred within 72 hours after an injection of long-acting human growth hormone in six of 25 patients (18c ). Skin A 51-year-old woman with both panhypopituitarism and liver disease developed localized abdominal lipohypertrophy during human growth hormone therapy (19A ). This adverse effect has been reported only rarely. The authors speculated that hepatic IGF-1 secretion was compromised and that peripheral growth hormone reached supraphysiological concentrations. In a 2-year study of once- or twice-monthly injections of a modiﬁed-release formulation of human growth hormone in 56 prepubertal

Miscellaneous hormones

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children, injection site reactions were common, especially in the ﬁrst year of treatment. These included skin nodules in 56% of injections, erythema in 49%, and lipoatrophy in 12% (20C ). Musculoskeletal A boy with osteogenesis imperfecta, with no previous fractures, who received human growth hormone from age 5 to 14, had four fractures during his pubertal growth spurt, similar to two previous case reports (21A ). Immunologic Patients treated with recombinant human growth hormone commonly develop antibodies against growth hormone; the incidence is 22–88% (22Ar ). This almost never has clinical signiﬁcance, but the fourth case of reduced growth due to neutralizing antibodies against growth hormone has been reported in a 9-year-old boy; growth resumed after he was changed to a methionyl-free human formulation of growth hormone (22Ar ). Carcinogenicity Long-term surveillance of recipients of human growth hormone continues, because of increased cancer rates (particularly colorectal cancer) in patients with acromegaly. In a cohort study in 1848 British patients who received human pituitary-derived growth hormone from 1959 to 1985 (30 000 patient-years), there were two cases of colorectal cancer (0.25 expected) and two cases of Hodgkin’s disease (0.85 expected); the standardized mortality ratios were 10.8 and 11.4 respectively (23C ). However, the number of cancers was small and the doses used were higher than typical today, and these results should be interpreted with caution. Pregnancy Only a few pregnancies have been reported in women treated with human growth hormone. Eight women with hypopituitarism were followed prospectively during 12 pregnancies at a mean daily pre-gestation dose of 0.5 mg/day. The dose of human growth hormone was gradually reduced during the second trimester and withdrawn at the start of the third trimester. No congenital abnormalities were observed and weight and length at birth were normal (24c ).

Susceptibility factors Sex Growth hormone is being increasingly prescribed for growth hormone-deﬁcient adults. Men have more adverse effects than women, probably because of a greater IGF-1 response (25C ). This was also seen in 74 elderly men and 57 elderly women in a controlled trial, and was not inﬂuenced by concomitant sex steroid therapy (14C ). Drug dosage regimens Early studies using doses of human growth hormone that have been derived from pediatric experience had a high rate of adverse effects, and doses have been progressively reduced. In a 6-month multicenter randomized study 302 adults were given human growth hormone 3 μg/kg/day, increasing to 6 μg/kg/day after 3 months, and 293 were given 6 μg/kg/day, increasing to 12 μg/kg/day (26C ). The lower dose was associated with signiﬁcantly fewer adverse events (in particular, arthralgia in 12% vs. 20%). However, 78% of women or patients with childhood-onset growth hormone deﬁciency had subnormal IGF-1 concentrations, suggesting that treatment should be titrated to IGF-1 concentrations and adverse effects.

Growth hormone release-inhibiting hormone (somatostatin) and analogues (SED-14, 1522; SEDA-24, 505; SEDA-25, 522; SEDA-26, 480) Nervous system Dizziness occurred in 7.4% of 68 patients randomized to somatostatin and 8.2% of 73 randomized to octreotide, both by rapid infusion, to control variceal bleeding, in which the effectiveness of somatostatin and its analogues is probably via a transient reduction in heart rate and cardiac output (27C ). Metabolism Hyperglycemia is common but usually mild after acute administration of somatostatin. In a meta-analysis of trials for variceal bleeding, hyperglycemia occurred in 41 of 310 patients who received somatostatin, octreotide, or vapreotide, compared with 26 of 318 patients who received placebo (28M ). Reports of the effects of octreotide on glucose metabolism in acromegaly are inconsistent

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and are complicated by the high prevalence of insulin resistance and overt diabetes in acromegaly. In 10 patients with acromegaly who used modiﬁed-release lanreotide for 19 months followed by modiﬁed-release octreotide for 21 months after a 3-month washout period, mean fasting glucose, the glucose response to oral glucose tolerance testing, and glycated hemoglobin all increased after octreotide but not lanreotide (29c ). However, the study was small and the order of the two medications was not randomized. Gastrointestinal Nausea and vomiting, usually mild and transient, occur in up to 25% of patients after somatostatin and are also common after octreotide (30R ). Two of 15 patients in a phase I trial of malignant gastrinoma had to stop using long-acting octreotide because of severe nausea (31c ). Diarrhea is common soon after starting octreotide but usually resolves within 2 weeks without speciﬁc treatment. In a randomized, double-blind, placebo-controlled trial in 203 mostly postmenopausal women with locally recurrent or metastatic breast carcinoma, all of whom were also taking tamoxifen, and who had estrogen-receptor positive and/or progesteronereceptor positive tumors, octreotide was added to the basic treatment in 99 cases (32C ). The adverse events experienced by 10% or more of the patients and attributed to octreotide were gastrointestinal: diarrhea (53%), nausea (16%), and abdominal pain (11%); diarrhea occurred in only 11% of the controls. Drug interactions Pre-treatment with octreotide enhanced the gastric prokinetic effects of erythromycin in eight healthy subjects, suggesting that octreotide may be clinically useful in patients with tachyphylaxis to this effect of erythromycin (33c ).

Oxytocin

(SED-14, 1523; SEDA-26, 481)

Cardiovascular Tachycardia and a fall in blood pressure are common and usually shortlived after oxytocin administration during labor. There has been one reported maternal death after a hypovolemic woman was given a bolus dose of oxytocin 10 units (34S ).

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In 34 women undergoing cesarean section at full term under spinal anesthesia, heart rate and cardiac output increased signiﬁcantly within 2 minutes of the rapid administration of either 5 or 10 units of oxytocin, with an associated 10 mmHg fall in mean arterial pressure in those who received 10 units (35c ). There were significant ST segment changes in 11 of 26 women undergoing cesarean section, with raised concentrations of troponin I in two; however, the relationship to oxytocin administration was not clear in this report (36c ). In another report, a previously ﬁt 19-yearold woman had severe ST segment depression and increased troponin concentrations after a bolus dose of oxytocin 5 units (37A ).

Parathyroid hormone (PTH) (SED-14, 1520; SEDA-25, 525; SEDA-26, 481) Mineral balance Mild asymptomatic hypercalcemia is common during treatment with parathyroid hormone (38C ). The hypercalcemia is persistent, and requires dosage reduction in 3% of patients using 20 μg/day and in 11% using 40 μg/day (39R ). Carcinogenicity The rate of osteosarcoma in animal and human trials of parathyroid hormone has been reviewed (40ER ). Rats treated with parathyroid hormone for 2 years had a high dose-dependent rate of osteosarcoma, up to 48% in animals given 75 μg/kg; human trials were therefore interrupted (41E ). However, the anabolic effect of parathyroid hormone is much greater and occurs much earlier in rats than in humans, possibly because of fundamental differences in bone biology: moreover, osteosarcoma has never been associated with primary, secondary, or tertiary hyperparathyroidism in humans (40R ). There has been no evidence of osteosarcoma in several hundred patients involved in parathyroid hormone clinical trials lasting up to 3 years, after 5 years minimum follow-up (40R ). Drug interactions Alendronate signiﬁcantly reduced the anabolic effect of parathyroid hormone when the two were used in combination, both in postmenopausal women (42C ) and in

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men (43C ). It seems likely that this interaction will also apply to other bisphosphonates, although the mechanism has not been determined.

VASOPRESSIN AND ANALOGUES (SED-14, 1522;

Desmopressin (N-deamino-8-D-arginine vasopressin, DDAVP) Cardiovascular Facial ﬂushing occurred in two of 25 children with either hemophilia or von Willebrand disease given high-dose intranasal desmopressin (150 μg) in a single-dose open study (48c ).

SEDA-24, 506; SEDA-25, 525; SEDA-26, 482) Cardiovascular Cardiac dysrhythmias are common after vasopressin treatment; 10 of 86 cirrhotic patients treated with terlipressin developed a tachycardia, four developed atrial ﬁbrillation, and one developed ventricular tachycardia. Four patients in the same study developed hypertension (44C ). In another study, tachycardia occurred in 23% of patients randomized to pitressin for acute variceal bleeding and 8% developed transient hypertension (27C ). One of 21 patients with hepatorenal syndrome developed ﬁnger ischemia on the fourth day of intermittent intravenous terlipressin and recovered after terlipressin was stopped (45c ). Respiratory An elderly patient (over 70 years old) with cirrhosis and hepatorenal syndrome developed severe bronchospasm and died after intravenous terlipressin administration; the mechanism was not determined (46c ). Electrolyte balance High-dose terlipressin (1 mg intravenously every 4 hours for 5 days) was associated with severe hyponatremia and loss of consciousness in one of 45 cirrhotic patients in a randomized trial (44C ). Although cirrhosis is itself associated with hyponatremia, high-dose vasopressin and its analogs also have an antidiuretic effect. Skin Skin necrosis is often reported after vasopressin therapy. In a retrospective study, two of ﬁve patients treated with a continuous infusion of terlipressin developed skin necrosis at the infusion site and a third developed scrotal necrosis (46c ). • A 46-year-old woman with septic shock had a peripheral venous infusion of vasopressin 0.04 units/min, in addition to dobutamine, via the subclavian vein; extravasation of vasopressin to local soft tissue resulted in ischemic skin necrosis (47A ).

Electrolyte balance Hyponatremia has often been reported with desmopressin, because of its potent antidiuretic effect, particularly in patients with a high water intake (SEDA-24, 506). Several further cases have been reported. In a double-blind study of desmopressin, 10 of 224 adult men had serum sodium concentrations below 130 mmol/l during a 3-week, open, dose-titration period. Men aged 65 years and over were more likely to develop hyponatremia (49C ). In another open study of elderly men and women, one of 30 subjects developed generalized weakness in association with a serum sodium concentration of 125 mmol/l and a serum potassium concentration of 3.1 mmol/l (50c ). • An 80-year-old woman with a high baseline ﬂuid intake developed severe hyponatremia, with loss of consciousness and seizures, after a single dose of desmopressin 0.2 mg (51A ). • An 89-year-old woman, who had previously been stable on desmopressin, developed severe hyponatremia and became confused and unresponsive after an increase in ﬂuid intake (51A ). • A 47-year-old woman with von Willebrand disease, who was given desmopressin and intravenous ﬂuids perioperatively, developed hyponatremia and seizures, which resolved after water restriction (52A ).

Hematologic Transient thrombocytopenia has previously been reported after high-dose desmopressin was given to patients with von Willebrand disease (SEDA-24, 507). In 224 adult men, mean age 65 (range 37–88) years thrombocytopenia developed in one man during a 1-week washout period after dose titration to up to 0.4 mg of oral desmopressin daily over the preceding 3 weeks; thrombocytopenia did not recur on rechallenge (49C ). In another case, a 38-year-old man with von Willebrand disease type 2B developed severe thrombocytopenia after a single dose of desmopressin (53A ).

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database. J Clin Endocrinol Metab 2002; 87: 1600– 6. 26. Kehely A, Bates PC, Frewer P, Birkett M, Blum WF, Mamessier P, Ezzat S, Ho KKY, Lombardi G, Luger A, Marek J, Russell-Jones D, Sönksen P, Attanasio AF. Short-term safety and efﬁcacy of human GH replacement therapy in 595 adults with GH deﬁciency: a comparison of two dosage algorithms. J Clin Endocrinol Metab 2002; 87: 1974–9. 27. Zhang HB, Wong BCY, Zhou XM, Guo XG, Zhao SJ, Wang JH, Wu KC, Ding J, Lam SK, Fan DM. Effects of somatostatin, octreotide and pitressin plus nitroglycerine on systemic and portal haemodynamics in the control of acute variceal bleeding. Int J Clin Pract 2002; 56: 447–51. 28. Banares R, Albillos A, Rincon D, Alonso S, Gonzalez M, Ruiz-del-Arbol L, Salcedo M, Molinero L-M. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology 2002; 35: 609–15. 29. Ronchi C, Epaminoonda P, Cappiello V, BeckPeccoz P, Arosio M. Effects of two different somatostatin analogs on glucose tolerance in acromegaly. J Endocrinol Invest 2002; 25: 502–7. 30. Abraldes JG, Bosch J. Somatostatin and analogues in portal hypertension. Hepatology 2002; 35: 1305–12. 31. Shojamanesh H, Gibril F, Louie A, Ojeaburu JV, Bashir S, Abou-Saif A, Jensen RT. Prospective study of the antitumor efﬁcacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma. Cancer 2002; 94: 331–43. 32. Bajetta E, Procopio G, Ferrari L, Martinetti A, Zilembo N, Catena L, Alu M, Della Torre S, Alberti D, Buzzoni R. A randomized, multicenter prospective trial assessing long-acting release octreotide pamoate plus tamoxifen as a ﬁrst line therapy for advanced breast carcinoma. Cancer 2002; 94: 299– 304. 33. Athanasakis E, Chrysos E, Zoras OJ, Tsiaoussis J, Karkavitsas N, Xynos E. Octreotide enhances the accelerating effect of erythromycin on gastric emptying in healthy subjects. Aliment Pharmacol Ther 2002; 16: 1563–70. 34. Why mothers die 1997–1999. The conﬁdential enquiries into maternal deaths in the United Kingdom. London: RCOG Press, 2001. 35. Pinder AJ, Dresner M, Calow C, O’Riordan J, Johnson R. Haemodynamic changes caused by oxytocin during caesarean section under spinal anaesthesia. Int J Obstet Anesthesia 2002; 11: 156–9. 36. Moran C, Bhuinneain MN, Geary M, Cunningham S, McKenna P, Gardiner J. Myocardial ischaemia in normal patients undergoing elective Caesarean section: a peripartum assessment. Anaesthesia 2001; 56: 1051–8. 37. Spence A. Oxytocin during Caesarean section. Anaesthesia 2002; 57: 710–11. 38. Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz A, Dore RK, Correa-Rotter R, Papaioannou A, Cumming DC, Hodsman AB. A randomized double-blind trial to compare the efﬁcacy of teriparatide [recombinant human parathyroid hormone (1–34)] with alendronate in post-

471 menopausal women with osteoporosis. J Clin Endocrinol Metab 2002; 87: 4528–35. 39. Rubin MR, Bilezikian JP. The potential of parathyroid hormone as a therapy for osteoporosis. Int J Fertil 2002; 47: 103–15. 40. Tashjian AH Jr, Chabner BA. Commentary on clinical safety of recombinant human parathyroid hormone 1–34 in the treatment of osteoporosis in men and postmenopausal women. J Bone Miner Res 2002; 17: 1151–61. 41. Vahle JL, Sato M, Long GG, Young JK, Francis PC. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety. Toxicol Pathol 2002; 30: 312–21. 42. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. New Engl J Med 2003; 349: 1207–15. 43. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. New Engl J Med 2003; 349: 1216–26. 44. Bruha R, Marecek Z, Spicak J, Hulek P, Lata J, Petrtyl J, Urbanek P, Taimr P, Volfova M, Dite P. Double-blind randomized, comparative multicenter study of the effect of terlipressin in the treatment of acute esophageal variceal and/or hypertensive gastropathy bleeding. Hepato-Gastroenterology 2002; 49: 1161–6. 45. Ortega R, Ginès P, Uriz J, Cárdenas A, Calahorra B, De las Heras D, Guevera M, Bataller R, Jiménez W, Arroyo V, Rodés J. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 2002; 36: 941–8. 46. Halimi C, Bonnard P, Bernard B, Mathurin P, Mofredj A, Di Martino V, Demontis R, HenryBiabaud E, Fievet P, Opolon P, Poynard T, Cadranel JF. Effect of terlipressin (Glypressin® ) on hepatorenal syndrome in cirrhotic patients: results of a multicentre pilot study. Eur J Gastroenterol Hepatol 2002; 14: 153–8. 47. Kahn JM, Kress JP, Hall JB. Skin necrosis after extravasation of low-dose vasopressin administered for septic shock. Crit Care Med 2002; 30: 1899– 901. 48. Gill JC, Ottum M, Schwartz B. Evaluation of high concentration intranasal and intravenous desmopressin in pediatric patients with mild hemophilia A or mild-to-moderate type I von Willebrand disease. J Pediatr 2002; 140: 595–9. 49. Mattiasson A, Abrams P, Van Kerrebroek P, Walter S, Weiss J. Efﬁcacy of desmopressin in the treatment of nocturia: a double-blind placebocontrolled study in men. BJU Int 2002; 89: 855–62. 50. Kuo H-C. Efﬁcacy of desmopressin in treatment of refractory nocturia in patients older than 65 years. Urology 2002; 59: 485–9. 51. Shindel A, Tobin G, Klutke C. Hyponatremia associated with desmopressin for the treatment of nocturnal polyuria. Urology 2002; 60: 344i–iii.

472 52. Pruthi RS, Kang J, Vick R. Desmopressin induced hyponatremia and seizures after laparoscopic radical nephrectomy. J Urol 2002; 168: 187. 53. Gomez Garcia EB, Brouwers GJ, KappersKlunne MC, Leebeek FWG, Van Vliet HHDM. In-

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termittent thrombocytopenia as a manifestation of Von Willebrand’s disease. Ned Tijdschr Geneeskd 2002; 146: 1192–5.

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Drugs that affect lipid metabolism

Ezetimibe Ezetimibe is a selective potent inhibitor of the intestinal absorption of dietary and biliary cholesterol. A total of 432 patients were included a pooled analysis of two phase II studies both lasting for 12 weeks; ezetimibe was well tolerated, with an adverse events proﬁle similar to that of placebo (1c ). In 668 patients ezetimibe was given with simvastatin; adverse effects were similar to those with simvastatin alone (2C ).

FIBRATES

(SED-14, 1527; SEDA-24, 510; SEDA-25, 533; SEDA-26, 486) Metabolic There were recurrent episodes of hypoglycemia in a 76-year-old woman with type 2 diabetes taking gemﬁbrozil for pronounced hypertriglyceridemia; her insulin requirements fell by 65% and her HbA1c concentration fell from 9% to 6.5% over 5 months (3A ). Drug interactions Rhabdomyolysis due to the combination of colchicine with gemﬁbrozil has not previously been reported. A suspected case in a 40-year-old man with amyloidosis and chronic liver disease has suggested that monitoring for rhabdomyolysis should be performed when this combination is used (4A ).

HMG-COA REDUCTASE INHIBITORS (SED-14, 1530; SEDA-24, 510; SEDA-25, 533; SEDA-26, 487) Nervous system Peripheral neuropathy has occasionally been reported in patients taking statins (SEDA-24, 510). This has now been supported by a case–control study of 166 cases of idiopathic polyneuropathy, of which 35 had a deﬁnite diagnosis; in the latter the odds ratio for neuropathy was 14 for statin users compared with non-users (5c ). Liver HMG-CoA reductase inhibitors can be associated with small rises in alanine aminotransferase (AlT) activity, but have not been deﬁnitely associated with severe morbidity involving altered hepatic function. All cases of acute liver failure related to the use of lovastatin have now been reviewed, and probably the frequency is similar to the background rate. This suggests that periodic monitoring of AlT in these patients would be burdensome and expensive (6R ). The term “transaminitis” has been coined to describe a rise in the activities of serum transaminases (AlT and AsT) without clinical symptoms. One author has suggested that in such cases one should switch from one statin to another, thereby preventing unnecessary withdrawal of statin treatment in dyslipidemic patients at high cardiovascular risk (7r ). Special senses A 67-year-old woman had ocular myasthenia while taking various statins and also bezaﬁbrate (8A ). Atorvastatin had the smallest effect. The authors suggested that this was a variant of a generalized myopathy and due to a low co-enzyme Q10 concentration.

© 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Musculoskeletal The main musculoskeletal adverse effects of the statins are muscle pain

473

474 and weakness (SED-14, 1530), usually accompanied by raised creatine kinase activity. In four patients with muscle symptoms while taking statins, creatine kinase activity was normal, but they were subsequently able to distinguish from their symptoms whether they were taking drug or placebo; muscle biopsies showed evidence of mitochondrial dysfunction (9c ). Drug interactions Healthy volunteers were given protease inhibitors and statins and the authors concluded that simvastatin should be avoided and that atorvastatin could be used with caution in people taking ritonavir and saquinavir (10c ). Dosage adjustment of pravastatin may be necessary with co-administration of ritonavir and saquinavir. Pravastatin does not alter the pharmacokinetics of nelﬁnavir, and thus appears to be safe for co-administration. Rhabdomyolysis in a stable renal transplant recipient was attributed to the presence of red yeast rice (Monascus purpureus) in a herbal mixture (11A ). The condition resolved when he stopped taking the product. Rice fermented with red yeast contains several types of mevinic acids, including monacolin-K, which is identical to lovastatin. The authors postulated that the interaction of ciclosporin with these compounds through cytochrome P450 had resulted in the adverse effect. Transplant recipients must be cautioned against using herbal products to lower their lipid concentrations, in order to prevent such complications.

Atorvastatin Skin Various skin reactions have been described in patients using statins (SEDA-26, 487). • A 59-year-old man developed urticaria while taking atorvastatin for hypercholesterolemia (12A ). Scratch tests with his medications gave a strong positive reaction only with atorvastatin. Atorvastatin was withdrawn and his urticaria resolved over the next 10 days.

Immunologic Hypersensitivity reactions have been seen with statins (SED-14, 1531). • Antinuclear and antihistone antibodies developed in a 26-year-old man who was taking atorvastatin (13A ). He had constitutional symptoms and slight

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headaches but no deﬁnite symptoms of lupus. After some months without medication he became seronegative and asymptomatic.

This case was similar to other previous reports with other statins.

Fluvastatin Musculoskeletal In a pooled analysis of a large population of patients with hypercholesterolemia taking ﬂuvastatin 20 mg/day, 40 mg/ day, and ﬂuvastatin modiﬁed-release 80 mg/day, the frequency of signiﬁcant rises in creatine kinase activity was low and not different from placebo (14M ). This applied to men and women both above and below the age of 65 years. There were no increases in the frequency of rises in creatine kinase activity with higher doses of ﬂuvastatin. Pancreas Acute pancreatitis has been attributed to ﬂuvastatin (15A ). • A 36-year-old man took ﬂuvastatin 40 mg/day for 3 months and developed mild acute pancreatitis, which settled with medical treatment. Other causes were ruled out. Some months later, he started taking ﬂuvastatin again and had a recurrence of pancreatitis within a few days.

According to the authors, statin-induced acute pancreatitis can occur on the ﬁrst day of therapy or after several months. It is generally mild and runs a benign course; no deaths have been reported. Its frequency is unknown but it is probably rare.

Lovastatin Drug interactions Lovastatin caused prolongation of the QT interval in a patient taking quetiapine. • A 46-year-old African–American woman with schizophrenia, taking quetiapine 800 mg/day and sertraline 100 mg/day, was given lovastatin 10 mg/ day for dyslipidemia (16A ). Although 2 months later her lipid concentrations had improved, a routine electrocardiogram showed prolongation of the QTc interval to 569 msec; it had been 416 msec

Drugs that affect lipid metabolism

6 months before. There were no electrolyte abnormalities and no history of cardiac conduction abnormalities. The dose of lovastatin was reduced to 5 mg/day and an electrocardiogram the next day showed a normal QTc interval (424 msec). Later she switched from lovastatin to niacin and subsequent electrocardiograms were all normal.

Probably lovastatin caused an increase in plasma quetiapine concentrations through competitive inhibition of CYP3A4.

Pravastatin Liver A 64-year-old woman who was twice treated with pravastatin had cholestasis on both occasions with minimal hepatocellular injury (17A ). A similar case has been connected with lovastatin (SED-14, 1530).

Simvastatin Endocrine Simvastatin up to 40 mg/day was given to 98 boys and 75 girls, aged 10–17 years, for 48 weeks without any adverse effects beyond a small fall in dehydroepiandrosterone (18c ). Of special note was the observation that simvastatin had no adverse effects on growth or pubertal development. Metabolic A 53-year-old man taking simvastatin 40 mg/day developed rhabdomyolysis and hepatitis and had a raised serum lactate concentration (8.3 mmol/l; reference range 0.5–2.2) (19A ). Everything resolved 7 days after drug withdrawal. Lactic acidosis in this patient supports the view that interference with the mitochondrial respiratory chain may play a role in the toxicity of the statins.

ION-EXCHANGE RESINS Colestyramine

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Lorenzo’s oil Lorenzo’s oil is a 4 : 1 mixture of glyceryl trioleate and glyceryl trierucate. It is used in patients with adrenoleukodystrophy. Owing to lack of controlled trials, it is not known whether it works. The dyslipidemia in patients with adrenoleukodystrophy consists of increased blood concentrations of very-long-chain saturated fatty acids, particularly hexacosanoic acid (C26:0). Treatment with Lorenzo’s oil has tended to normalize the abnormality in the blood while the patient deteriorates. Neurological changes are unrelated to the fatty acid changes in the blood, and moreover erucic acid does not seem to enter the brain. Registration of adverse effects with Lorenzo’s oil has been hampered by the absence of controlled trials. In 22 patients treated for at least 12 months, although Lorenzo’s oil did not seem to be beneﬁcial, there were possible adverse effects, such as mild increases in liver enzymes (55%), thrombocytopenia (55%), gastrointestinal complaints (14%), and gingivitis (14%). Furthermore, there were falls in hemoglobin concentration and leukocyte count, and an increase in the plasma alkaline phosphatase concentration; the reduction in platelet count did not result in hemorrhage (21c ). It was thought that the thrombocytopenia might be due to platelet activation, resulting from an increase in the concentration of erucic acid in the platelet membrane. Low platelet counts have often been found by others. For example, Lorenzo’s oil affected blood platelet counts in 39 patients followed for 1 year (22c ). Blood platelet aggregation studies in those patients were normal and there were no plateletassociated immunoglobulins. Whether some of the adverse effects of Lorenzo’s oil are due to low concentrations of essential fatty acids or caused by reduced dietary fat intake is not known.

(SED-14, 1529)

Drug interactions The interaction of colestyramine with coumarins is due to the enterohepatic recirculation of coumarins, which is interrupted by colestyramine (SED-14, 1529). Now a fatal drug interaction between colestyramine and phenprocoumon has been described in a patient with a prosthetic aortic valve (20A ).

NICOTINIC ACID DERIVATIVES (SED-14, 1533; SEDA-25, 531)

Niacin Hematologic A 55-year-old man with localized prostate cancer was given pravastatin

476 (10 mg/day) and aspirin (325 mg/day) (23A ). He also took food supplements containing about 30 different ingredients, most notably niacin 2250 g/day. During preparation for prostate surgery it was discovered that his prothrombin time was slightly prolonged (17 sec,

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normal 11.4–14.4 sec). All prescribed medications were withheld, but his prothrombin time continued to be abnormal (24 sec). The authors thought that the high dose of niacin had caused this abnormality.

REFERENCES 1. Bays HE, Moore PB, Drehobl MA, Rosenblatt S, Toth PD, Dujovne CA, Knopp RH, Lipka LJ, LeBeaut AP, Yang B, Mellars LE, CufﬁeJackson C, Veltri EP. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 2001; 23h: 1209–30. 2. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S, Veltri EP. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40: 2125–34. 3. Klein J, Ott V, Schutt M, Klein HH. Recurrent hypoglycaemic episodes in a patient with type 2 diabetes under ﬁbrate therapy. J Diabetes Complications 2002; 16: 246–8. 4. Atmaca H, Sayarlioglu H, Kulah E, Demircan N, Akpolat T. Rhabdomyolysis associated with gemﬁbrozil–colchicine therapy. Ann Pharmacother 2002; 36: 1719–21. 5. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology 2002; 58: 1333–7. 6. Tolman KG. The liver and lovastatin. Am J Cardiol 2002: 89: 1374–80. 7. Dujovne CA. Side effects of statins: hepatitis versus “transaminitis”—myositis versus “CPKitis”. Am J Cardiol 2002; 89: 1411–13. 8. Parmar B, Francis PJ, Ragge NK. Statins, ﬁbrates, and ocular myasthenia. Lancet 2002; 360: 717. 9. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JDF. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002; 137: 581–5. 10. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA, Blaschke T, Alston B, Fang F, Kosel B, Aweeka F. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG study A5047. AIDS 2002; 16: 569–77. 11. Prasad GVR, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient. Transplantation 2002; 74: 1200–1. 12. Anliker MD, Wuthrich B. Chronic urticaria to atorvastatin. Allergy Eur J Allergy Clin Immunol 2002; 57: 366. 13. Jimenez-Alonso J, Jaimez L, Sabio JM, Hidalgo C, Leon L. Atorvastatin-induced reversible positive

antinuclear antibodies. Am J Med 2002; 112: 329– 30. 14. Benghozi R, Bortolini M, Jia Y, Isaacsohn JL, Troendle AJ, Gonasun L. Frequency of creatine kinase elevation during treatment with ﬂuvastatin. Am J Cardiol 2002; 89: 231–3. 15. Tysk C, Al-Eryani AY, Shawabkeh AA. Acute pancreatitis induced by ﬂuvastatin therapy. J Clin Gastroenterol 2002; 35: 406–8. 16. Furst BA, Champion KM, Pierre JM, Wirshing DA, Wirshing WC. Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin. Biol Psychiatry 2002; 51: 264–5. 17. Batey RG, Harvey M. Cholestasis associated with the use of pravastatin sodium. Med J Aust 2002; 176: 561. 18. De Jongh S, Ose L, Szamosi T, Gagne C, Lambert M, Scott R, Perron P, Dobbelaere D, Saborio M, Tuohy MB, Stepanavage M, Sapre A, Gumbiner B, Mercuri M, Van Trotsenburg ASP, Bakker HD, Kastelein JJP. Efﬁcacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebocontrolled trial with simvastatin. Circulation 2002; 106: 2231–7. 19. Goli AK, Goli SA, Byrd RP, Roy TM. Simvastatin-induced lactic acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002; 72: 461–4. 20. Balmelli N, Domine F, Pﬁsterer M, Krahenbuhl S, Marsch S. Fatal drug interaction between cholestyramine and phenprocoumon. Eur J Intern Med 2002; 13: 210–11. 21. Van Geel BM, Assies J, Haverkort EB, Koelman JHTM, Verbeeten B, Wanders RJA, Barth PG. Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with “Lorenzo’s oil”. J Neurol Neurosurg Psychiatry 1999; 67: 290–9. 22. Kickler TS, Zinkham WH, Moser A, Shankroff J, Borel J, Moser H. Effect of erucic acid on platelets in patients with adrenoleukodystrophy. Biochem Mol Med 1996; 57: 125–33. 23. D’Amico AV, Toupless G, Lopes L, Valentine KJ, Cormack RA, Tempany CM, Kumar S, Marks PJ. Self-administration of untested medical therapy for treatment of prostate cancer can lead to clinically signiﬁcant adverse events. Int J Radiation Oncol Biol Phys 2002; 54: 1311–13.

Hans-Peter Lipp, 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 topoisomerase inhibitors, by Drs Lipp 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.

Inhibitors of topoisomerase I and topoisomerase II Inhibitors of topoisomerase I and topoisomerase II are the most commonly used anticancer drugs. The camptothecins, topotecan and irinotecan (CPT-11), interact with the enzyme topoisomerase I; the podophyllotoxins, etoposide and teniposide, target topoisomerase II. They cause various forms of singleand double-strand breaks in DNA (1R –7R ). Drugs such as TAS-103 and others inhibit both enzymes simultaneously (8E ). Inhibitors of topoisomerase I Camptothecins were originally isolated from the wood, bark, and fruit of the oriental tree, Camptotheca acuminata (“tree of joy”). Why the tree produces these highly toxic alkaloids is not known, but the most likely reason is that the toxins are part of a survival strategy in combating herbivores. Among a lot of isolated plant constituents, the naturally occurring alkaloid camptothecin (CAM, NSC94600) was identiﬁed as a highly potent inhibitor of topoisomerase I, which is overexpressed in many cancers. The water-soluble salt CAM-sodium, which was introduced in early preclinical trials in the 1960s, was highly toxic in animals. Hemorrhagic cystitis, leukopenia, and thrombocytopenia were © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

its dose-limiting toxic effects. In addition, sterile hemorrhagic cystitis, myelosuppression, and gastrointestinal toxic effects were common in patients during phase I studies. Clinical testing of CAM-sodium was therefore discontinued in the 1970s. However, the semisynthetic derivatives irinotecan and topotecan are highly active in several malignancies and do not cause hemorrhagic cystitis, because of their greater physicochemical stability and solubility at lower pH values. However, the drugs differ from each other in approved therapeutic uses, recommended doses, toxicity proﬁles, and pharmacokinetics (1R –5R ). Several CPT analogues are currently being investigated. The water-soluble derivatives lurtotecan (GI147211) and exatecan (DX-8951-f) and the poorly water-soluble analogues 9aminocamptothecin and 9-nitrocamptothecin, which can be given orally, are in various stages of development (9R , 10R , 11c –13c ). Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, while irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN38 and topotecan respectively. Furthermore, it has a 2–10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in Pglycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are

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neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m2 /day or 0.3 mg/m2 /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14c , 15c ). Current clinical investigations with topoisomerase I inhibitors include the feasibility of oral administration of topotecan and irinotecan, the use of a liposomal lurtotecan formulation (NX211), and the use of a pegylated derivative of the naturally occurring camptothecin, which is soluble in aqueous solutions even at low pH values (9R , 10R ). Inhibitors of topoisomerase II Etoposide and teniposide are semisynthetic derivatives of podophyllin, which was originally isolated from the root of the Indian Podophyllum plant. After extensive isolation procedures the most effective “antileukemic” factor was identiﬁed as 4 -demethylepipodophyllin benzylidiene glucoside (DEPBG). Etoposide, its water-soluble derivative etoposide phosphate, and teniposide are semisynthetic analogues of DEPBG with increased antineoplastic activity. Etoposide is active in testicular tumors, non-Hodgkin’s lymphoma, Hodgkin’s disease, other lymphomas, ovarian carcinoma, gastric carcinoma, breast cancer, small-cell and non-small-cell lung cancers, and cancers of unknown origin. The major indications for teniposide include lymphoma, bladder cancer, acute lymphoblastic leukemia, and glioblastoma (6R , 7R ). Dual inhibitors of topoisomerases I and II Intoplicin is one of the ﬁrst congeners of the socalled dual inhibitors of topoisomerases I and II (16c ). These new antitumor drugs interact with both topoisomerase I and II simultaneously. This mechanism of action appears to be advantageous, because selective inhibition of topoisomerase I has been reported to increase topoisomerase II enzyme activity and vice versa, which may be important for the development of drug resistance (17E , 18c –20c ). Intoplicin may overcome this limitation. In phase I trials intoplicin has been reported to cause dose-limiting liver toxicity; other adverse effects were sporadic and mild (16c ). XR 5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamine) is another dual inhibitor of topoisomerase I and topoisomerase II. Its cytotoxicity was not affected by the presence of

P glycoprotein, and it seems to be a promising candidate, even in highly resistant tumor cells. However, neither complete nor partial remission was observed during a phase II trial in 20 patients with advanced or metastatic colorectal cancer (21c ). F11872 is a novel pentaﬂuorinated epipodophylloid characterized by marked antitumor activity in vivo. It is a dual inhibitor of the catalytic activity of both topoisomerases I and II, with markedly superior activity in vivo compared with other dual inhibitors, such as intoplicin, TAS-103, and others (22E ). Mechanisms of action Topoisomerase I is the target enzyme for the inhibitory effects of camptothecins. It modulates the topological structure of DNA by inducing transient DNA breaks. Single-strand breaks help to remove excessive positive and negative DNA supercoils, which arise during DNA replication and transcription. The interaction between the camptothecins and the enzyme results in the formation of a topoisomerase-I-DNA-complex (23R ). Etoposide and teniposide interact with topoisomerase II within the tumor cell. This nuclear enzyme catalyses the passage of DNA across adjacent strands during cell division and is most active during the late S and G2 phases of the cell cycle. If the tumor cell is exposed to etoposide during this stage, stabilization of the enzyme-DNA complex results in double- and single-strand breaks in DNA as well as cellcycle arrest. Several studies have shown that the activity of etoposide is schedule-dependent, which means that its antiproliferative effect on tumor cells is greater when it is given over several consecutive days rather than on a single day. At higher dosages, podophyllotoxins may also act as spindle poisons (24R ). In contrast to topoisomerase II, cellular concentrations of topoisomerase I are relatively independent of the cell cycle phase in normal tissues. Thus, topoisomerase I activity is only slightly increased in cells and tissues under conditions of proliferation. However, higher constitutive activities of this enzyme can be detected in several tumor tissues (e.g. adenocarcinoma of the colon and rectum) compared with healthy tissues (25E ). Pharmacokinetics of the camptothecins Both irinotecan and topotecan contain lactone structures, which can be hydrolysed non-enzymatically into the open-ring form. Under acidic

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conditions, the equilibrium between the biologically active lactone form and the less active carboxylate form is generally shifted to the lactone form, whereas at physiological or higher values of pH the lactone form is unstable, because hydrolysis to the open form is favored. In addition, owing to preferential binding of the salt form to serum albumin, the afﬁnity of the carboxylate form for human serum albumin is estimated to be 100 times higher than that of the lactone form. In consequence, when irinotecan is given intravenously, more than 95% of the dose is bound to serum albumin as inactive drug, and is therefore at least transiently unavailable to exert its antineoplastic activity (26R , 27R , 28r , 29c ). Novel camptothecin derivatives, such as exatecan or lurtotecan, are more resistant to rapid hydrolysis because of structural modiﬁcations, e.g. the removal of the 20-OH group (9R , 10R , 14c , 15c ). Topotecan Topotecan has been approved for the treatment of advanced pretreated ovarian and lung cancer in several countries. After intravenous administration of conventional dosages (e.g. 1.5 mg/m2 /day for 5 consecutive days) its half-life is 2–4 hours. Prolonged infusion for 3, 5, or 21 days increases drug exposure without affecting the disposition of topotecan (29c ). The ratio of the AUCs of the lactone and total topotecan appears to be relatively constant and averages about 0.3, which means that only 30% of the total drug concentration in the plasma represents the closed-ring lactone form. The distribution volume at steady-state is 25– 75 l/m2 , indicating extensive binding to tissues. Erythrocytes act as a depot for topotecan (lactone), with steady-state concentrations almost 1.7 times those obtained in plasma. Topotecan is primarily excreted unchanged in the urine. About 49% of the intravenous dose is recovered in the urine as parent drug and 18% in the feces (30c ). Despite high urinary concentrations, topotecan does not cause urinary toxicity, because of its high water solubility (30c , 31c ). Dosage modiﬁcation is warranted in patients with impaired renal function (32c ). Reduced doses of 0.75 mg/m2 /day and 0.5 mg/m2 /day have been recommended in untreated and extensively pretreated patients with reduced creatinine clearance (20–40 ml/min). It has also been suggested that dosage adjustment may even be required if the creatinine

479 clearance is 40–60 ml/min (33c ). The recommended starting dose should be 1.2 mg/m2 /day intravenously on 5 consecutive days, in order to reduce the risk of severe myelosuppression. Because there is no information, topotecan should not be given to patients with severe renal insufﬁciency (creatinine clearance below 20 ml/min) (32c ). There is also some evidence that topotecan is hemodialysable (34A ). Hepatic metabolism of topotecan, mediated by cytochrome P450 isozymes, is of minor quantitative importance (26R , 27R , 28r , 29c , 30c ). Metabolic pathways include N-dealkylation (producing N-demethyltopotecan) and glucuronidation. There is some evidence that potent inhibitors or inducers of CYP3A4 alter the clearance of topotecan (30c ). After conventional intravenous dosages of topotecan (e.g. 1.5 mg/m2 as a 30-minute infusion on days 1–5) the mean half-life, plasma clearance, and volume of distribution are respectively 2.7 hours, 1.1 ml/min, and 170 l. The plasma protein binding of topotecan is low (7–35%). In contrast to many other anticancer drugs, topotecan can penetrate the central nervous system. If the blood–brain barrier is intact, more than 30% of the plasma concentration can be recovered in the cerebrospinal ﬂuid (26R , 27R , 28r –30c ). Nevertheless, intrathecal drug administration has been suggested to be advantageous, in order to achieve higher drug concentrations in the cerebrospinal ﬂuid and to avoid systemic toxicity (35A , 36c ). The systemic availability of oral topotecan is about 30%. Dose-limiting toxicity was reached at a dose of 0.6 mg/m2 bd and consisted of diarrhea, which started from day 12 to day 20. Other toxic effects, including leukopenia and thrombocytopenia, were mild. The recommended dose for phase II trials was 0.5 mg/m2 bd for 21 days (37c –39c ). Irinotecan Irinotecan has been approved for ﬁrst-line and second-line treatment of advanced colorectal cancer. Conventional dosages range from 350 mg/m2 intravenously every 3 weeks to 100–125 mg/m2 intravenously weekly when it is given as a single agent, and 80–180 mg/m2 intravenously when it is given in combination with 5-ﬂuorouracil and folinic acid weekly (the AIO regimen) or every 14 days (the De Gramont regimen) (4R , 40c ). In contrast to the structurally related topotecan, irinotecan is a prodrug, which has to be

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converted to its active form, SN-38 (4R , 40c ). Cleavage of the side-chain, a bulky piperidino moiety, at the C10 position is rapidly catalysed by carboxyesterases after intravenous administration. SN-38 (7-ethyl-10-hydroxy-camptothecin) is 1000 times more potent than the parent compound. There is an equilibrium between the active lactone and the inactive carboxylated forms in a pH- and protein-dependent manner for both irinotecan and SN-38 (41E , 42E ). SN-38 is inactivated by conjugation, catalysed by a uridine diphosphate glucuronosyltransferase isoform, 1A1 (UGT 1A1) (43c , 44r , 45c ). This isozyme is also responsible for the glucuronidation of substrates such as bilirubin and valproic acid. Pharmacogenetic defects, such as Gilbert’s syndrome or Crigler– Najjar syndrome type I, result in impaired glucuronidation. The speciﬁc molecular defect in Gilbert’s syndrome is an AT(TA)7TAA fragment in the UGT 1A1 promoter region, instead of A(TA)6TAA. The incidence of Gilbert’s syndrome is 0.5–15% in different ethnic groups, and there is signiﬁcant variability of UGT 1A1 activity in human livers, with a 17-fold difference between minimum and maximum rates of SN-38 glucuronidation. Patients with Gilbert’s syndrome are at increased risk of irinotecaninduced gastrointestinal toxicity and leukopenia if conventional dosages are used (46r , 47r , 48R , 49A , 50E ). Paracetamol is a poor predictor of SN-38 glucuronidation capacity based on metabolism by another isozyme (UGT 1A6). However, genotype screening is increasingly becoming feasible. Thus, empirical irinotecan dosage modiﬁcation or the selection of another anticancer drug is appropriate in patients with poor glucuronidation capacity (46r , 47r , 48R , 49A , 50E ). Both irinotecan and SN-38 are primarily excreted into the bile by the canalicular multispeciﬁc organic anion transporter (cMOAT), a member of the ATP cassette of transporters. Therefore, inhibitors of cMOAT, such as ciclosporin, can reduce the clearance of irinotecan and SN-38 (51E , 52R ). SN-38 glucuronide can be deconjugated in the gut to active SN-38 by bacterial glucuronidases. This enterohepatic circulation of SN-38 results in a further plasma peak, and SN-38 released within the gut lumen has been suggested to be an important cause of delayed intestinal toxicity; in animal experiments constitutive bacterial beta-glucuronidase activity

correlated with irinotecan-induced cecal damage. In contrast, the prophylactic use of oral antibiotics (e.g. aminoglycosides or quinolones) resulted in attenuation of intestinal toxicity (53c ). Aminopentane-carboxylic acid (APC) is a second major metabolite of irinotecan; it is formed by oxidation of the terminal piperidine ring, catalysed by CYP3A4. APC itself is not hydrolysed to SN-38 and is only a weak inhibitor of topoisomerase I (54c –58c ). However, potent CYP3A4 inducers (e.g. St. John’s wort, carbamazepine, and phenytoin) or inhibitors (e.g. itraconazole) alter irinotecan pharmacokinetics (59r , 60c –64c ). Other identiﬁed metabolites include NPC (7-ethyl-10-(4-amino1-piperidono)carbonyloxycamptothecin), 5-hydroxyirinotecan, and RPR112526 (a decarboxylated product of the acid form of the irinotecan lactone). Further drug interactions occur if constitutive SN-38 glucuronidation capacity is modiﬁed. For example, phenobarbital and dexamethasone induce UGT 1A1 activity, whereas valproic acid inhibits it. Thus, co-administration can alter the clearance of irinotecan. A half-life of 5–14 hours has been reported after intravenous infusion of irinotecan over 30 and 90 minutes. The half-life of the active metabolite SN-38 (total) is 6–14 hours. However, continuous 5-day intravenous infusion schedules result in prolonged half-lives (about 27 h and 30 h for irinotecan and SN-38 respectively). In general, the Cmax of SN-38 is more than 100 times lower than the corresponding value for irinotecan. Plasma concentrations of SN-38 glucuronide were higher than the corresponding concentrations of SN-38: the AUC of SN-38 glucuronide was at least 10 times higher than that of SN-38 (54c –57c ). Because of the importance of hepatic metabolism in SN-38 elimination by glucuronidation, the biliary clearance of irinotecan and its metabolites is delayed in patients with impaired hepatic function (65c –67c ), and there is a negative correlation between serum bilirubin concentrations and the total body clearance of irinotecan. In a patient with moderately impaired liver function it was necessary to reduce the dose to 100 mg/m2 instead of 350 mg/m2 intravenously 3-weekly, in order to achieve halflives and Cmax values of irinotecan and SN-38 comparable to those observed in patients with

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normal liver function (65c ). However, the corresponding AUCs were signiﬁcantly increased, resulting in more severe leukopenia and delayed diarrhea. The authors concluded that to improve tolerance exposure to the drug in a patient of this kind should not exceed 30 mg/m2 intravenously. Detailed studies of irinotecan dose modiﬁcation in patients with liver dysfunction are warranted. According to the results of pharmacokinetic studies, thrice-weekly intravenous doses of irinotecan have been recommended: 350 mg/m2 in patients with bilirubin concentrations up to 1.5 times the upper limit of the reference range and 200 mg/m2 in patients with bilirubin concentrations 1.5–3.0 times the upper limit of the reference range (66c ). The systemic availability of oral irinotecan is low and variable (10–20%). Transintestinal transport of irinotecan and SN-38 by Pglycoprotein and cytochrome P450-mediated ﬁrst-pass removal in the intestine account for the low absolute availability of irinotecan. Etoposide At low doses of oral etoposide (e.g. 50–100 mg) the systemic availability averages 66% and at higher dosages (100 mg/m2 and over) 47%. If etoposide phosphate is used, the values are higher (range 66–84%). The higher availability of etoposide phosphate could be useful (68c –73c ). After intravenous administration of etoposide 150 mg/m2 the peak plasma concentration and half-life average 20 μg/ml and 7.1 hours respectively. Drug clearance and distribution volume are about 16 ml/min/m2 and 7.1 l/m2 (6R , 7R , 74R ). With respect to plasma concentrations of etoposide, intravenous etoposide phosphate is equivalent to intravenous etoposide with conventional or intensiﬁed dose schedules (75R , 76C , 77c –79c ). After intravenous administration, the prodrug etoposide phosphate undergoes rapid hydrolysis catalysed by alkaline phosphatase; this conversion is linear even at high intravenous doses of 1200 mg/m2 infused over 2 hours on days 1 and 2. About 96% of the dose of etoposide is bound to plasma proteins, the unbound fraction being 4% (80R , 81R , 82c , 83c ). There is a higher risk of myelotoxicity when the unbound fraction is increased by factors such as hyperbilirubinemia or hypoalbuminemia, which is common in

481 patients with hepatic dysfunction or cachexiainducing tumors (84c , 85c ). The variability in unbound drug concentrations has been suggested to be important in the setting of intravenous high-dose etoposide and reinfusion of autologous peripheral blood stem cells. If drug concentrations persist over a longer period of time the success of engraftment may be severely impaired. Thus, plasma concentration monitoring has been suggested, in order to identify patients at increased risk (86c , 87c ). The renal clearance of etoposide is about 30–40% of the total plasma clearance. Even in patients with nearly normal creatinine concentrations (100–130 μmol/l), there is a slight but signiﬁcant increase in the AUC, but without more pronounced hematological toxicity. Hepatic etoposide metabolism is mediated by CYP3A4, and results in the production of catechol metabolites. Further metabolic pathways include glucuronidation and hydroxyacid formation (88E ). Dosage reductions of 33% and 50% have been recommended for patients with creatinine clearances of 15–25 ml/min and under 15 ml/min respectively. In patients with obstructive jaundice and a reduced glomerular ﬁltration rate, a 50% dosage reduction has been recommended empirically (6R , 7R , 88E , 89c ). In patients with very severe forms of renal insufﬁciency, only moderate amounts of etoposide can be eliminated by hemodialysis (90c ). In patients with brain metastases, high intravenous dosages of etoposide may be needed in order to achieve adequate drug concentrations in the cerebrospinal ﬂuid. In such patients, intrathecal drug administration may be an alternative, in order to reduce systemic toxicity associated with dose intensive chemotherapy. However, this mode of etoposide administration has not been established (91c , 92c ). There is large interindividual variability in etoposide plasma concentrations with conventional dosages, and some authors have suggested that plasma concentration monitoring would reduce the pharmacokinetic variability and optimize outcomes (93r , 94c ). Plasma etoposide concentrations of 1–2 μg/ml are necessary for signiﬁcant antitumor activity, whereas concentrations of 2–3 μg/ml have been associated with increased hematological toxicity.

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Teniposide Teniposide undergoes more extensive metabolic degradation than etoposide, resulting in the catechol derivative 4 -demethyldeoxy-podophyllotoxin. The aglycone and the trans/cis-hydroxy acids appear to be formed by pH-dependent hydrolysis reactions (7R , 95c , 96c ). Plasma concentration monitoring has been proposed to be beneﬁcial in patients receiving teniposide. For example, in one study maintaining steady-state concentrations above 12 μg/ml appeared to be important for clinical responses in patients with recurrent leukemia, lymphoma, or neuroblastoma (95c ). In ten patients, whose steady-state concentrations were maintained above 12 mg/l, there was shrinkage of the tumor, whereas only ﬁve of 13 patients with lower steady-state concentrations had a response. Teniposide has been used as a continuous infusion over 72 hours in intravenous doses of 300–750 mg/m2 . The mean systemic availability of teniposide after oral administration is about 42% (range 20–71%). Teniposide capsules 50 mg have been suggested to be useful, but no oral formulation has been approved so far (96c ). Adverse effects proﬁle of topoisomerase I inhibitors—general aspects The dose-limiting adverse effects of irinotecan depend largely on the dosage schedule. Myelosuppression, particularly leukopenia and neutropenia and rarely thrombocytopenia and anemia, have been observed. Gastrointestinal toxicity (i.e. diarrhea) is also common and can be acute or subacute. The most dose-limiting adverse effect of topotecan is myelosuppression, which correlates with individual drug exposure. In contrast, gastrointestinal toxicity is generally mild (97c –99c ). Common adverse effects of etoposide and teniposide (100R ) include dose-limiting myelosuppression (causing neutropenia more often than thrombocytopenia), dose-dependent nausea or vomiting, and alopecia. Mucositis can be dose-limiting, particularly in patients receiving high doses of etoposide. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate, because the formulations of the former contain sensitizing solubilizers. Both drugs have been associated with acute myelogenous leukemia.

Cardiovascular There are reports of myocardial infarction in patients who have received combination chemotherapy containing etoposide. The mechanisms have not been clearly elucidated. • A 28-year-old man with a non-seminomatous retroperitoneal germ-cell cancer received etoposide (180 mg/day intravenously on days 1–5), bleomycin, and cisplatin (101A ). He had no cardiac risk factors and no history of cardiac symptoms. On day 3, during infusion of bleomycin, he developed chest pain and dyspnea. The infusion was discontinued and he was given glyceryl trinitrate and diazepam; his symptoms resolved. On day 4 he was given etoposide as scheduled, but 4 hours later developed severe angina. The electrocardiogram and raised cardiac enzymes were consistent with an acute posterolateral myocardial infarction. He was given heparin, aspirin, and nitrates, and the chemotherapy was discontinued. Within 20 hours his chest pain completely disappeared and his electrocardiogram became normal.

If hypotension occurs during drug administration, it usually subsides when the infusion ends and intravenous ﬂuids or other supportive agents are given. Elderly patients may be particularly susceptible to etoposide-induced hypotension. During a phase I trial of etoposide by continuous infusion, 17 patients were given 75 mg/m2 /day for 5 days and later courses of 100 mg/m2 /day and 150 mg/m2 /day (102c ). Two patients with pre-existing cardiovascular disease developed myocardial infarctions, one at the 100 mg/m2 /day dose and one at the 150 mg/m2 /day dose. Another patient developed congestive heart failure at the end of the 5-day infusion and died on day 8; however, this patient also received a saline load of 1500 ml/day for 5 days during etoposide administration and had previous episodes of congestive cardiac failure. The authors concluded that in patients with underlying cardiovascular disease etoposide must be administered cautiously and that extensive saline loading should be avoided in patients with a history of previous congestive heart failure. Nervous system Fatigue is a frequent adverse effect of topotecan and occurs in up to 70% of patients when they receive 1.5 mg/m2 /day (30minute infusions) for 5 days repeated at day 22; however, only 10% have severe symptoms (4R ). Topotecan causes headache in some patients.

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Rare cases of peripheral neuropathy have been reported after intravenous topotecan, but a causal relation is uncertain. Neurotoxicity occurs in under 1% of patients who receive teniposide or etoposide, and it is more common after high dosages. Adverse nervous system effects, including headache, transient mental confusion, and vertigo, may be related to the blood alcohol concentration, since teniposide and etoposide formulations contain alcohol (103A ). Peripheral neuropathy, mainly mild and infrequent, has been observed after conventional dosages of etoposide and teniposide. However, during combination therapy with etoposide and vinca alkaloids more serious forms of peripheral neuropathy have been reported. Of 142 patients with autologous bone marrow transplantation given high-dose etoposide (e.g. 60 mg/kg combined with melphalan) six developed grade 2–3 polyneuropathy starting 2–8 weeks after transplantation. About 76% of patients given irinotecan complain of weakness. Grade 3 and 4 weakness has been described in 12–15% with weekly or thrice-weekly administration and during the administration of combination regimens containing ﬂuorouracil. Hematologic Myelosuppression, neutropenia, and to a lesser extent thrombocytopenia, are dose-limiting toxic effects of topotecan. Reversible non-cumulative neutropenia usually occurs at between days 8 and 15 after an intravenous dosage of 1.5 mg/m2 on 5 consecutive days. The nadir of the neutrophil count occurs on day 11, with recovery on day 21. Neutropenia, with cell counts less than 1.5 × 109 /l (grade 2) and 0.5×109 /l (grade 4) are observed in 70–97% of patients. In addition, 4–33% of patients treated with conventional dosages of topotecan develop neutropenic fever (97c –99c ). Thrombocytopenia, with platelet counts under 50 × 109 /l (grade 3) and 25 × 109 /l (grade 4), occur in 25–77% of patients, with a nadir on day 15 and recovery on day 21. Platelet transfusions are needed in 4–27% of patients. Anemia, deﬁned as a fall in hemoglobin below 8 g/dl (grade 3) or 6.5 g/dl (grade 4), has been reported in 21–41% of patients; erythrocyte transfusions were required in about 25% of treatment courses. More extensive myelosuppression can occur in patients who have been

483 pretreated with cytotoxic drugs. The extent of myelosuppression correlates signiﬁcantly with both the total topotecan AUC and the topotecan lactone AUC. When prophylactic G-CSF is given, thrombocytopenia is the dose-limiting myelotoxic effect (97c –99c ). Leukopenia is a dose-limiting adverse effect of irinotecan. Weekly intravenous doses (e.g. 100–125 mg/m2 ) appear to produce a slightly greater incidence of grade 3–4 neutropenia compared with 3-weekly schedules (350 mg/m2 ) (16–28% versus 14–22%). The median leukocyte nadir occurs on day 21 (15– 27) and recovers 8 days later. Severe anemia (hemoglobin concentrations below 8 g/dl) and severe thrombocytopenia (platelet count below 50 × 109 /l) occur in 15% and 2% of patients respectively. There is eosinophilia in up to onethird of patients (2R , 3R ). Myelosuppression is a dose-limiting adverse effect of etoposide and teniposide. Leukopenia is the most common adverse effect associated with oral and intravenous etoposide. Nadirs in neutrophil counts generally occur within 7– 14 days. Severe forms following conventional etoposide doses can be expected in about 17% of patients. Thrombocytopenia occurs in 23% of etoposide-treated patients and about 9% are severe (counts below 50 × 109 /l). Leukopenia and thrombocytopenia occur respectively in 65% and 80% of patients after administration of teniposide (6R , 7R ). Gastrointestinal Anorexia, nausea and vomiting, and diarrhea, are generally mild after the administration of conventional doses of etoposide and teniposide. Stomatitis is uncommon and mucositis starts to be more severe in patients who receive intravenous doses of etoposide up to 1000 mg/m2 . Gastrointestinal toxicity after topotecan is generally mild to moderate. Under 10% of patients complain of grade 3/4 nausea and vomiting, diarrhea or constipation, abdominal pain, or stomatitis. Mucositis is uncommon and mild after intravenous topotecan. Besides leukopenia, diarrhea is the major dose-limiting adverse effect of irinotecan (104R , 105A ). There are two different forms. The acute form occurs very early and is due to inhibition of acetylcholinesterase. The delayedonset form occurs simultaneously with the leukocyte nadir and depends on the concentration of the active compound SN-38 in the plasma and bowel.

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The acute form of diarrhea is short-lasting and can be effectively prevented or rapidly suppressed by concomitant atropine. The cholinergic symptoms are accompanied by abdominal cramps (36%), sweating (57%), salivation (11%), visual disturbances (15%), lacrimation (12%), and piloerection (3%). The recommended dose of atropine is 0.25 mg intravenously for prevention or 0.25–1.0 mg for acute treatment of patients with early cholinergic symptoms. As cholinergic symptoms have not been observed with other camptothecin derivatives, it can be speculated that these adverse effects are restricted to irinotecan, whose piperidino group bears some structural similarity to the potent nicotine receptor stimulant dimethylphenylpiperazinium (105A ). Delayed-onset diarrhea of all grades of severity occurs in nearly 90% of patients during the ﬁrst three treatment cycles with irinotecan. It can resemble a cholera-like syndrome, which occurs several days after completion of the infusion. There is grade 3–4 diarrhea (grade 3 being at least 7–9 stools per day, incontinence, or severe cramps, and grade 4 being 10 stools or more per day, grossly bloody stools, or a need for total parenteral nutrition) in 31–37% of patients treated weekly and in 35–39% of patients treated with 3-weekly regimens. The median day of occurrence was day 6 (range days 2–12). Of the four major pathophysiological mechanisms of diarrhea (osmotic, secretory, altered motility, and exudative), irinotecan-induced watery diarrhea appears to be secretory, deﬁned by abnormal ion transport in intestinal epithelial cells (104R ). There is increasing evidence that the extent and severity of gastrointestinal toxicity correlates with concentrations of the active compound SN-38 in the plasma and bowel. The role of plasma pharmacokinetics in predicting the severity of irinotecan-induced diarrhea has been highlighted by the introduction of a biliary index, which is the product of the relative area ratio of SN-38 to SN-38 glucuronide and the total AUC. According to preliminary evidence, preventive measures should be considered when the biliary index exceeds 3.484 h.mg/l (106A , 107c ). Because SN-38 glucuronide undergoes deconjugation by bacteria-derived beta-glucuronidase in the bowel after biliary excretion, a strategy for reducing irinotecan-induced subacute diarrhea has been proposed: inhibition

of intestinal microﬂora by a broad-spectrum antibiotic. In one study this ameliorated subacute diarrhea in subsequent cycles; in six of seven patients the prophylactic use of neomycin resulted in less severe forms of diarrhea compared with controls (53c ). About 30% of irinotecan is excreted via the bile unchanged and may be directly converted to SN-38 in the bowel by intestinal carboxyesterases; however, speciﬁc non-absorbable inhibitors of intestinal carboxyesterases for oral use are not yet available. Because the equilibrium between the active lactone form and the ring-opened carboxylate form is pH dependent, oral alkalinization with a mixture consisting of sodium bicarbonate (2.0 g/day), magnesium oxide (2.0–4.0 g/day), water (pH over 7.2, 1.5–2 l/day), and ursodeoxycholic acid (300 mg/day), combined with “controlled” defecation was used in a phase II trial to reduce subacute gastrointestinal toxicity. Anticancer activity was maintained and the incidences of diarrhea and myelosuppression were signiﬁcantly reduced compared with a non-randomized control group (108c , 109c , 110E ). The efﬁcacy of symptomatic antidiarrheal treatment with several drugs, including loperamide, octreotide, racecadodril, and budesonide, has been assessed (104R , 111r , 112C ). Loperamide is recommended when the ﬁrst signs of subacute, late-onset diarrhea occur; the dose is 4 mg at the start, followed by 2 mg every 2 hours, continued until the diarrhea has stopped for at least 12 hours. Premedication with loperamide is not indicated. Some authors also recommend dosage modiﬁcation in subsequent cycles. If loperamide alone is insufﬁcient, racecadodril (acetorphane, Tiorfan) 100 mg tds can be added. Racecadodril belongs to a group of drugs that block cAMP-mediated hypersecretion in the gut by inhibiting the intestinal enzyme enkephalinase. Loperamide not only delays small intestinal and whole gut transit, but also has some antisecretory actions in human jejunum and colon. The somatostatin analogue octreotide is effective in loperamiderefractory patients with severe diarrhea despite loperamide and/or acetorphane. Subcutaneous doses of 100 μg tds up to 500 μg every 8 hours for 48–96 hours have produced improvement in diarrhea by one WHO toxicity grade or even more (104R ). Oral budesonide has also been proposed to be beneﬁcial in patients with subacute diarrhea.

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It has 90% ﬁrst-pass removal in the liver, and so its systemic activity is low. Budesonide controls symptoms of diarrhea in most patients with inﬂammatory bowel disease. Preliminary data have suggested that the use of budesonide in patients with irinotecan-induced diarrhea could reduce the severity of symptoms. In addition, in a phase III trial budesonide 3 mg tds prevented irinotecan-induced diarrhea. Budesonide is an option in patients who do not respond to highdose oral loperamide (112C ). The use of oral immunomodulators (e.g. interleukin-15 and Kampo medicines) has been suggested in order to reduce irinotecan-related diarrhea; however, randomized clinical trials are required, to assess efﬁcacy (113R ). Liver Etoposide has been associated with increased liver enzymes, but a causal relation has not been established (114A ). Urinary tract In contrast to parenteral camptothecin sodium, the structurally related semisynthetic derivatives do not cause hemorrhagic cystitis, because they are highly soluble in aqueous solutions even at low pH values. Skin Skin rashes involving the trunk, scalp, and limbs have been reported in 17–25% of patients receiving topotecan as a short-term infusion, whereas continuous drug infusion appears to be very rarely associated with rashes. These skin reactions typically appear on days 4–8 and resolve on day 15. Skin rashes due to podophyllotoxin derivatives may be hypersensitivity reactions and can be related to the drug itself or more commonly to the vehicles used. Hair Reversible alopecia is very common at standard doses of podophyllotoxin derivatives, starting at doses of 500 mg/m2 etoposide. It is also common even with low continuous oral doses of etoposide (e.g. 50 mg/m2 /day). Partial or complete alopecia occurs in 12–70% of patients taking topotecan or irinotecan (115R ). Immunologic The epipodophyllotoxins etoposide and teniposide can cause hypersensitivity reactions, which appear to be of type I (116R ). In a review of 93 cases the characteristic features of the hypersensitivity reactions that occurred after intravenous etoposide included bronchospasm, facial ﬂushing, rashes,

485 dyspnea, fever, chills, tachycardia, chest tightness, cyanosis, and changes in blood pressure (hypotension and hypertension) (117R ). Very severe forms of hypersensitivity reactions, such as Stevens–Johnson syndrome, are very rare (118A ). There has been a single report of etoposide-induced hand–foot syndrome (119A ). Anaphylactic-like reactions have occurred in 0.7–2% of patients after etoposide administration. Some data suggest that the overall frequency of hypersensitivity reactions to teniposide may be as high as 50% if all forms of hypersensitivity are considered. With very few exceptions, patients recover quickly when the drug infusion is stopped immediately (116R ). Hypersensitivity reactions to etoposide or teniposide usually occur within minutes after intravenous administration, and are probably related to release of vasoactive substances by basophils and/or mast cells. Several reports have suggested that premedication with an antihistamine and/or a corticosteroid may prevent further hypersensitivity reactions, even in patients with a history of previous reactions. However, this strategy should not be followed when patients have had severe hypersensitivity reactions, such as long-lasting bronchospasm or severe hypotension (120A , 121A ). Etoposide was successfully restarted in 78% of patients who had a hypersensitivity reaction, especially when the drug was infused at a slower rate after premedication with an antihistamine and/or a corticosteroid (122A ). Hypersensitivity reactions to etoposide and teniposide occur in 33–51% of patients (115R , 116R ) and are primarily related to adjuvants in the parenteral formulations rather than the drugs themselves. In the case of teniposide, the solubilizing adjuvant polyethoxylated castor oil (Cremophor EL) has been implicated. However, in nine children who had facial edema and ﬂushing after receiving teniposide, the drug alone degranulated basophils in vitro, causing histamine release, while Cremophor did not (123cE ). In addition, etoposide formulations for parenteral use contain several adjuvants, including polysorbate 80, benzyl alcohol, and polyethylene glycol, because it is sparingly soluble in aqueous solutions, and these may contribute to hypersensitivity reactions. Polysorbate 80 may also been implicated in rare cases of hypotension and metabolic acidosis, particularly with high dosages (124c ).

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In contrast, the structurally related etoposide phosphate is highly soluble in aqueous solutions and no solubilizing adjuvants are necessary. Preliminary data suggest that the incidence of hypersensitivity reactions is lower with etoposide phosphate than with etoposide, strengthening the hypothesis that adjuvants have a major role in the development of allergic reactions (115R , 116R ). In one case, a patient who had a type I hypersensitivity reaction to etoposide was successfully retreated with etoposide phosphate (125A ). On the other hand, cross-reactivity to etoposide has been observed in patients with hypersensitivity reactions to teniposide, suggesting that allergic reactions are not exclusively restricted to the use of the solvents. In addition, hypersensitivity reactions have also been reported after oral etoposide (115R , 116R ). • Hypotension, bronchospasm, and facial ﬂushing occurred in a 38-year-old man with advanced testicular cancer associated with an intravenous infusion of etoposide (126A ). The reaction began within 3 minutes after the start of the infusion and resolved with intravenous ﬂuids and diphenhydramine. Later he was given four doses of etoposide after pretreatment with diphenhydramine and dexamethasone, without incident.

Mutagenicity Etoposide and teniposide are mutagenic in various bacterial and mammalian genotoxicity tests (127E ). Carcinogenicity Based on animal experiments, etoposide and teniposide should be classiﬁed as potential carcinogens (128S ). Exposure to etoposide and teniposide has been reported to be an important risk factor for the development of secondary acute myelogenous leukemia (129M , 130M , 131R , 132C , 133C , 134c , 135c ). Etoposide has been suggested to have considerable leukemogenic activity. Of 119 patients with advanced non-small-cell lung cancers, 24 survived for more than 1 year after treatment with etoposide and cisplatin with or without vindesine (136C ). Of these 24 patients, four developed secondary acute myelogenous leukemia at 13, 19, 28, and 35 months from the start of treatment, having received a two-fold greater cumulative dose of etoposide (6.8 versus 3.0 g/m2 ). Podophyllotoxin-related secondary acute myelogenous leukemia has a rather short latent period (2–3 years), and differs from malignancies caused by other drugs

(e.g. alkylating agents) by its unique molecular marker, a balanced translocation involving the mixed-lineage leukemia (MLL) gene on chromosome 11 (“11q23 abnormalities”); Southern blot analysis of enzyme-digested DNA from etoposide-treated cell lines and from peripheral blood cells after treatment with etoposide showed frequent rearrangements of MLL, but not of other genes (137M ). • A 15-year-old white girl with stage II Hodgkin’s disease, who was treated with a combination of vincristine, doxorubicin, bleomycin, and etoposide (total dose 2000 mg/m2 ) over 4 months followed by radiotherapy, developed secondary acute myelogenous leukemia 16 months after the initial diagnosis (134c ). • An 11-year-old boy with virus-associated hemophagocytic syndrome was treated with intravenous and oral etoposide (0.3 g and 2.8 g/m2 respectively) and developed acute myelogenous leukemia 26 months after the diagnosis (134c ).

These reports and others conﬁrm that even conventional doses of etoposide can be associated with a risk of secondary acute myelogenous leukemia. Two of 21 adults with Hodgkin’s disease developed secondary acute myelogenous leukemia after receiving a regimen that included a cumulative dose of etoposide of 945–3640 mg/m2 given over 3–6 months (133C ). Both patients also received MOPP after primary treatment failure, and the disease itself is associated with a high risk of secondary malignancies; however, the short latency period before the development of acute myelogenous leukemia (17–32 months) was thought to be typical of podophyllotoxin-associated disease. Altogether the etoposide-related incidence of secondary acute myelogenous leukemia in three retrospective case series was 0.4–8.1%. Secondary leukemia developed 9–68 months after the diagnosis of the ﬁrst cancer. Teniposide is about 10 times more potent than etoposide in causing DNA damage in vitro and in vivo. In 21 of 733 children with acute lymphoblastic leukemia in remission, who received maintenance therapy with teniposide once or twice weekly in combination with other anticancer drugs, the risk of secondary acute myelogenous leukemia was about 12 times higher than in patients who had been treated with less intensive schedules (e.g. a short course of teniposide for induction chemotherapy) (138M ).

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In conclusion, podophyllotoxin-containing regimens carry a small but signiﬁcant risk of secondary acute myelogenous leukemia. The risk may be increased by higher total cumulative doses (e.g. etoposide over 2 g/m2 ), weekly or twice weekly schedules, the concomitant administration of drugs that inhibit DNA repair, concomitant radiotherapy, or the use of high doses of cisplatin. It has therefore been recommended that etoposide be used cautiously in low-risk diseases. Fertility The effects on fertility of inhibitors of topoisomerases I and II have not yet been fully elucidated. However, ovarian failure, amenorrhea, anovulatory cycles, and hypomenorrhea have been described in women receiving etoposide (139R ). Teratogenicity Anticancer drugs can be classiﬁed as potentially teratogenic and embryocidal and can cause embryonic resorption, spinal defects, decreased fetal weight, and fetal abnormalities. However, there are no controlled studies of the use of these drugs in pregnant women, and women of childbearing potential should be advised to avoid pregnancy while they are receiving chemotherapy and should be informed about the potential hazards to the fetus (140A ). Drug interactions Etoposide The coadministration of etoposide and high-dose ciclosporin resulted in increased etoposide serum concentrations (141c ). Lower doses of etoposide were therefore recommended when combined with high-dose ciclosporin. Valspodar signiﬁcantly increased the AUC and half-life of etoposide, and dosage reductions up to 66% are required to minimize toxicity when these drugs are used together. Etoposide and teniposide are substrates of CYP3A4, and their clearance rate is increased by inducers such as carbamazepine, phenobarbital, phenytoin, rifampicin, and St John’s wort (142c ). Irinotecan If irinotecan is combined with 5-ﬂuorouracil and calcium folinate, an infusion regimen of ﬂuorouracil rather than bolus administration is associated with a lower incidence of severe toxicity (leukopenia and lifethreatening sepsis) (143C ).

487 Irinotecan (80 mg/m2 intravenously) given as a 1-hour infusion immediately after oxaliplatin (85 mg/m2 intravenously) was associated with hypersalivation and abdominal pain (144A , 145C ). These symptoms disappeared after an injection of atropine but recurred when irinotecan was given as a single agent or when the two drugs were separated by 24 hours. However, restarting the original schedule once more resulted in extended cholinergic symptoms. It has been postulated that oxaliplatin potentiates the direct inhibitory effect of irinotecan on acetylcholinesterase. St John’s wort (300 mg tds, starting 14 days before administration) reduced the AUC of the active metabolite of irinotecan, SN-38, by 42% and the severity of expected myelosuppression. Leukocyte and neutrophil counts were reduced by 8.6% and 4.3% after St John’s wort coadministration in contrast to monotherapy (reductions of 56% and 63%). In addition, the AUC of aminopentane-carboxylic acid was reduced by 28%. Whether the concomitant use of dexamethasone had some effect on this interaction has not been elucidated. Potent inhibitors of CYP3A4, such as ketoconazole or itraconazole, reduce the formation of inactive aminopentane-carboxylic acid, resulting in higher concentrations of the active metabolite SN-38. Topotecan Co-administration of cisplatin before topotecan has a sequence-dependent effect on the disposition of topotecan. Cisplatinrelated acute changes in glomerular ﬁltration rate can temporarily alter topotecan clearance with more severe myelosuppression. Nevertheless, this sequence has been recommended in clinical trials, based on its maximal antineoplastic effect. Patients therefore have to be monitored closely when the two agents are given together (146c ). Topotecan reduced docetaxel clearance by 50% and increased the severity of neutropenia when given over 3 consecutive days before the combination (147c ). The underlying reason for this interaction has not been elucidated; however, when combination therapy is used, docetaxel should be scheduled on day 1 and topotecan on days 1–4.

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GENERAL Recent reviews have discussed potentially new adverse effects of local therapy, but owing to the limited evidence available to date, they have not been reported in detail. New adverse effects may not be entirely attributable to the drug, but are more likely to be due to the route of administration or a direct response of the tumor, especially if they are associated with local administration. However, because direct administration often allows the use of lower doses, many of the traditional adverse effects are reported with less frequency or intensity. Two recent papers, both dealing with cisplatin, support this (148c , 149c ). The use of different schedules of administration to alter the adverse effects proﬁle of a drug has always been a particularly interesting area of research. One group of authors has looked at sequential and alternating strategies with docetaxel plus FEC (ﬂuorouracil, epirubicin, cyclophosphamide) (150c ). Others have looked at the duration of infusion of paclitaxel and thus overall exposure (151c ). There has been a good review of the complete spectrum of late or long-term adverse effects in survivors of testicular cancer with cisplatin (152M ). This year the ﬁrst reviews of gene therapy have appeared. Users of these new agents will have to decide whether their adverse effects are caused by the drugs or arise from reactions to antibody responses (153ME ). A review of ONYX-15, a replication-selective adenovirus, has shown that the common adverse effects, in decreasing order of frequency, are: fever, rigors, and chills; ﬂu-like symptoms; pain/extravasation at the injection site; sepsis; altered liver function tests. Cardiovascular The cardiotoxicity of the anthracyclines is well documented and has been conﬁrmed in two recent papers. In the ﬁrst, women with metastatic breast cancer were randomized to receive either liposomal doxorubicin (Myocet® ) 75 mg/m2 (n = 108) or conventional doxorubicin 75 mg/m2 (n = 116) (154c ). The liposomal formulation was less cardiotoxic than the conventional one, and the cumulative doses before the onset of cardiotoxicity were 780 mg/m2 versus 570 mg/m2 respectively; the liposomal formulation provided comparable antitumor activity. In another

study the authors tried to deﬁne the cumulative toxic dose of daunorubicin (DaunoXome® ) and concluded that it is 750–900 mg/m2 (155c ). Respiratory Various authors have reported what they believe to be the ﬁrst four cases of interstitial pneumonitis related to docetaxel (156A ). None of the patients had lung disease and they all had normal liver function. Within 8–14 days of receiving a second cycle of docetaxel (75 mg/m2 in three cases and 60 mg/m2 in the other), all developed acute dyspnea and fever, which progressed until they needed ventilation; two died. In contrast, in a study of 33 patients treated with paclitaxel and carboplatin, only one had reduced diffusion capacity for carbon monoxide, with no accompanying clinical or radiological changes (157C ). Gemcitabine has previously been reported to cause pulmonary toxicity. In one recent study the incidence was as high as 15%, even with low-dose gemcitabine 600 mg/m2 on days 1, 8, and 15 and docetaxel 60 mg/m2 on day 1; all resolved after withdrawal of treatment and administration of steroids (158c ). Nervous system The platinum-containing anticancer drugs have well documented neurological toxicity (SEDA-26, 494) and the differences between the drugs are well documented. Various authors have described a very atypical presentation of oxaliplatin neurotoxicity in four patients (159A ). Two presented with Lhermitte’s sign (an electric-like sensation induced by ﬂexion of the neck), one had urinary retention, and one had both. All had received cumulative doses of 1248–2040 mg/m2 , which is more than the generally accepted neurotoxic threshold for oxaliplatin (1000 mg/m2 ). In children from multiple German centers, the late CNS effects in survivors, 7 years after treatment for childhood acute lymphoblastic leukemia, included impaired concentration, attention, and memory (160c ). Liver Severe hepatic insufﬁciency in a 69year-old man after two courses of dacarbazine, 250 mg/m2 daily for 5 days, was successfully treated with intravenous hydrocortisone 300 mg/m2 /day (161A ). Urinary tract The phosphate disturbance that leads to Fanconi syndrome is well documented with ifosfamide. Of 43 children who

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received ifosfamide 3.5 g/m2 /day for 5 days for metastatic osteosarcoma, three developed the syndrome (162c ). Skin There has been a report of six cases of a new variant of the palmar–plantar erythrodysesthesia syndrome, in which patients who have previously reported the syndrome develop it again when they are treated with completely different chemotherapeutic drugs (163A ). The recall syndrome was of mild to moderate intensity, less severe than the primary syndrome, and self-limiting in all cases. The authors concluded that this may be analogous to radiation recall reactions, but a ﬁrst for chemotherapy. Immunologic Hypersensitivity reactions have been described with many chemotherapeutic agents, but the exact mechanisms are unclear, as is the course to take if further chemotherapy is required. Two cases of reactions with rechallenge have been reported. • Successful rechallenge has been reported after a reaction to etoposide in a 19-year-old man, who was successfully retreated with etoposide phosphate with only antiemetic doses of corticosteroids as cover (125A ).

489 • Type I hypersensitivity to monthly intravenous pulses of cyclophosphamide occurred in a 17-yearold woman (164A ). The reaction occurred after an approximate exposure of 11 g over 2 years. When rechallenged 2 weeks latter, she reacted again, but was later successfully rechallenged using antihistamine premedication.

The second case tends to support the old assumption that etoposide hypersensitivity is due to excipients in the formulation. Infection risk Patients who are immunocompromised are at risk of infection with chemotherapy. In one series of 27 patients who received ﬂudarabine serious infections developed in 24 (165c ). • Infection with JC virus, a human polyoma virus, occurred in two patients after ﬂudarabine treatment of a low-grade lymphoma, which led to a progressive multifocal leukoencephalopathy (166A ).

Carcinogenicity A ﬂare phenomenon is a well documented effect of hormonal therapies and/or hormone-responsive tumors. A prostatespeciﬁc antigen ﬂare occurred in four of 28 patients who received liposomal doxorubicin (Caelyx® ) for symptomatic androgen-independent prostate cancer (167c ).

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131. Horibe K, Matsushita T, Numata S, Miyajima Y, Katayama I, Kitabayashi T, Yanai M, Sekiguchi N, Egi S. Acute promyelocytic leukemia with t(15,17) abnormality after chemotherapy containing etoposide for Langerhans cell histiocytosis. Cancer 1993; 72: 3723–6. 132. Relling MV, Yanishevski, Nemec J, Evans WE, Boyett JM, Behm FG, Pui C-H. Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia. Leukemia 1998; 12: 346–52. 133. Zulian GB, Selby P, Milan S, Nandi A, Gore M, Forgeson G, Perren TJ, McElwain TJ. Highdose melphalan, BCNU and etoposide with autologous bone marrow transplantation for Hodgkin’s disease. Br J Cancer 1989; 59: 631–5. 134. Stine KC, Saylors RL, Sawyer JR, Becton DL. Secondary acute myelogenous leukemia following safe exposure to etoposide. J Clin Oncol 1997; 15: 1583–6. 135. Houck W, Einhorn LH. Secondary leukemias in germ cell tumor patients undergoing autologous stem cell transplantation utilizing high-dose etoposide. Proc ASCO 2003; 22: A1566. 136. Ratain MJ, Kaminer LS, Bitran JD, Larson RA, Le Beau MM, Skosey C, Purl S, Hoffman PC, Wade J, Vardiman JW, et al. Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung. Blood 1987; 70: 1412–17. 137. Pui C-H, Relling MV. Topoisomerase II inhibitor-related acute myeloid leukaemia. Br J Haematol 2000; 109: 13–23. 138. Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Raimondi SC, Head DR, Behm FG, Mahmoud MH, Sandlund JT, Crist W. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphocytic leukemia. New Engl J Med 1991; 325: 1682–7. 139. Lamont EB, Schilsky RL. Gonadal toxicity and teratogenicity after cytotoxic chemotherapy. In: Lipp H-P, editor. Anticancer Drug Toxicity: Prevention, Management and Clinical Pharmacokinetics. New York–Basel: Marcel Dekker Inc 1999; 491– 523. 140. Matsui H, Iitsuka Y, Seki K, Sekiya S. Pregnancy outcome after treatment with etoposide (VP16) for low-risk gestational trophoblastic tumor. Int J Gynecol Cancer 1999; 9: 166–9. 141. Lum BL, Kaubisch S, Yahanda AM, Adler KM, Jew L, Ehsan MN, Brophy NA, Halsey J, Gosland MP, Sikic BI. Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J Clin Oncol 1992; 10: 1635–42. 142. Baker DK, Relling MV, Pui CH, Christensen ML, Evans WE, Rodman JH. Increased teniposide clearance with concomitant anticonvulsant therapy. J Clin Oncol 1992; 10: 311–15. 143. Kohne CH, Van Cutsem E, Wils JA, Bokemeyer C, El-Seraﬁ M, Lutz M, Lorenz M, Anak O, Genicot B, Nordlinger B, for the EORTC GI Group. Irinotecan improves the activity of the AIO regimen in metastatic colorectal cancer: results of EORTC

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GI-group study 40986. Proc Am Soc Clin Oncol 2003; 22: A1018. 144. Dodds HM, Bishop JF, Rivory LP. More about: irinotecan-related cholinergic syndrome induced by coadminstration of oxaliplatin. J Natl Cancer Inst 1999; 91: 91–2. 145. Wasserman E, Cuvier C, Lokiec F, Goldwasser G, Kalla S, Mery-Mignard D, Ouldkaci M, Besmaine A, Dupont-Andre G, Mahjoubi M, Marty M, Misset JL, Cvitkovic E. Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics. J Clin Oncol 1999; 17: 1751–9. 146. Rowinsky EK, Kaufmann SH, Baker SD, Grochow LB, Chen TL, Peereboom D, Bowling MK, Sartorius SE, Ettinger DS, Forastiere AA, Donehower RC. Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 1996; 14: 3074–84. 147. Zamboni WC, Egorin MJ, Van Echo DA, Day RS, Meisenberg BR, Brooks SE, Doyle LA, Nemieboka NN, Dobson JM, Tait NS, Tkaczuk KH. Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors. J Clin Oncol 2000; 18: 3288–94. 148. Vogl TJ, Engelmann K, Mack MG, Straub R, Zangos S, Eichler K, Orenberg E. CT-guided intratumoural administration of cisplatin/epinephrine gel for treatment of liver tumours. Br J Cancer 2002; 86: 524–9. 149. Kovacs AF, Obitz P, Wagner M. Monocomponent chemoembolization in oral and oropharyngeal cancer using an aqueous crystal suspension of cisplatin. Br J Cancer 2002; 86: 196–202. 150. Spielmann M, Tubiana-Hulin M, Namer M, Mansouri H, Bougnoux Ph, Tubiana-Mathiew N, Lotz V, Eymard JC. Sequential or alternating administration of docetaxel (Taxotere) combined with FEC in metastatic breast cancer: a randomised phase II trial. Br J Cancer 2002; 86: 692–7. 151. Gelderblam H, Mross K, ten Tije AJ, Behringer D, Mielke S, van Zomeren DM, Verweij J, Sparreboom A. Comparative pharmacokinetics of unbound paclitaxel during 1- and 3- hour infusions. J Clin Oncol 2002; 20: 574–81. 152. Vaughn DJ, Gignac GA, Meadows AT. Longterm medical care of testicular cancer survivors. Ann Intern Med 2002; 136: 463–70. 153. Ries S, Korn WM. ONYX-015: Mechanisms of action and clinical potential of a replicationselective adenovirus. Br J Cancer 2002; 86: 5–11. 154. Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E. Liposomeencapsulated doxorubicin compared with conventional doxorubicin in a randomized multicentre trial as ﬁrst-line therapy of metastatic breast carcinoma. Cancer 2002; 94: 25–36. 155. Fassas A, Buffels R, Anagnostopoulos A, Gacos E, Vadikolia C, Haloudis P, Kaloyannidis P.

495 Safety and early efﬁcacy assessment of liposomal daunorubicin (DaunoXome) in adults with refractory or relapsed acute myeloblastic leukaemia: a phase I-II study. Br J Haematol 2002; 116: 308–15. 156. Read WL, Mortimer JE, Picus J. Severe interstitial pneumonitis associated with docetaxel administration. Cancer 2002; 94: 847–53. 157. Dimopoulou I, Galani H, Dafni U, Samakovil A, Roussos C, Dimopoulos MA. A prospective study of pulmonary function in patients treated with paclitaxel and carboplatin. Cancer 2002; 94: 452–8. 158. Ryan DP, Kulke MH, Fuchs CS, Grossbard ML, Grossman SR, Morgan JA, Earle CC, Shivdasani R, Kim H, Mayer RJ, Clark JW. A phase III study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer 2002; 94: 97–103. 159. Taieb S, Trillet-Lenoir V, Rambaud L, Descos L, Freyer G. Lhermitte sign and urinary retention: atypical presentation of oxaliplatin neurotoxicity in four patients. Cancer 2002; 94: 2434–40. 160. Langer T, Martus P, Ottensmeier H, Hertzberg H, Beck JD, Meier W. CNS late-effects after ALL therapy in childhood. Part III: Neuropsychological performance in long-term surviviors of childhood ALL: impairments of concentration attention and memory. Med Pediatr Oncol 2002; 38: 320–8. 161. Herishanu Y, Lishner M, Kitay-Cohen Y. The role of glucocorticoids in the treatment of fulminant hepatitis induced by dacarbazine. Anti-Cancer Drugs 2002; 13: 177–9. 162. Goorin AM, Harris MB, Bernstein M, Ferguson W, Devidas M, Siegal MC, Gebhardt, Schwartz CL, Link M, Grier HE. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 2002; 20: 426–33. 163. Hui YF, Giles FJ, Cortes JE. Chemotherapyinduced planar-plantar erythrodysesthesia syndrome—recall following different chemotherapy agents. Invest New Drugs 2002; 20: 49–53. 164. Thong BYH, Leong KP, Thumbo J, Koh ET, Tang CY. Cyclosphosphamide type 1 hypersensitivity in systemic lupus erythematosus. Lupus 2002; 11: 127–9. 165. Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in ﬂudarabine-refractory B-cell chronic lymphocytic leukaemia and small lymphocytic lymphoma. Cancer 2002; 94: 2033–9. 166. Vidarsson B, Mosher DF, Salamat MS, Isaksson HJ, Onundarson PT. Progressive multifocal leukoencephalopathy after ﬂudarabine therapy for low-grade lymphoproliferative disease. Am J Hematol 2002; 70: 51–4. 167. Fossa SD, Vaage S, Letocha H, Iversen J, Risberg T, Johannessen DC, Paus E, Smedsrud T, on behalf of the Norwegian Urological Cancer Group. Liposomal doxorubicin (Caelyx® ) in symptomatic androgen-independent prostate cancer (AIPC): delayed response and ﬂare phenomenon should be considered. Scand J Urol Nephrol 2002; 36: 34–9.

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46

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TYPES OF CONTRAST AGENTS Iodinated water soluble contrast media are of four types: • high osmolar ionic monomers (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 dimers (e.g. iodixonal, iotrolan). They are mainly used intravascularly, but can also be injected into body cavities, particularly the low osmolar contrast agents. They are also suitable for oral or rectal administration. There are also contrast agents that enhance the diagnostic information provided by ultrasound scanning and magnetic resonance imaging. The latter are mainly gadolinium based, but new non-gadolinium paramagnetic contrast agents have recently become available. Ultrasound contrast agents are microbubbles that provide acoustic enhancement. Adverse reactions to contrast media are generally few, and serious reactions are uncommon. Ultrasound contrast agents are particularly safe.

INTRAVASCULAR IODINATED CONTRAST AGENTS Water-soluble intravascular iodinated contrast agents (SEDA-24, 519; SEDA-25, 557; SEDA-26, 512) Incidence Adverse reaction to intravascular iodinated contrast agents can be minor, interme© 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

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diate, or severe and life-threatening. All types of reactions to low osmolar contrast media are at least ﬁve times less common than reactions to high osmolar contrast agents. According to a survey conducted by the Royal Australian College of Radiologists in 1986, the incidence of severe reactions with high osmolar ionic contrast media was 0.36% in high-risk patients (patients with a strong history of allergy or bronchial asthma or a history of reactions to contrast media) and 0.09% in low-risk patients. The incidence of these reactions with low osmolar non-ionic media was 0.03% in high-risk patients, and 0% in low-risk patients (1CR ). In another survey the incidence of contrast media reactions after intravenous administration was evaluated over 14 years (2CR ). The incidence of all reactions to contrast media was 6–8% with high osmolar contrast media and only 0.2% with low osmolar non-ionic agents. Most of the reactions (over 90%) were allergiclike and severe reactions were rare (0.05%). One death was reported after the use of a low osmolar agent. These data are compatible with previous reports, which showed that low osmolar contrast media have a much better safety proﬁle than high osmolar media and that there is no signiﬁcant difference in the incidence of acute adverse reactions between non-ionic dimeric and monomeric contrast media. In another study there was no signiﬁcant difference in the incidence of adverse effects associated with the use of the non-ionic dimer iodixanol or the non-ionic monomer iopromide in femoral angiography (3C ). Psychiatric To reduce the incidence of generalized reactions to contrast media in highrisk patients some authors have advocated the prophylactic administration of corticosteroids (prednisolone 30 mg orally or methylprednisolone 32 mg orally, 12 and 2 hours before contrast injections). In one case an acute psychosis complicated corticosteroid premedication to reduce the risk of contrast reactions (4A ).

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Table 1. European Society of Urogenital Radiology (ESUR) Guidelines on Prevention of Generalised Contrast Medium Reactions in Adults (5S ) A. Susceptibility factors for reactions • Previous generalized reaction to a contrast medium, either moderate (e.g. urticaria, bronchospasm, moderate hypotension) or severe (e.g. convulsions, severe bronchospasm, pulmonary edema, cardiovascular collapse) • Asthma • Allergy requiring medical treatment B. To reduce the risk of generalized contrast medium reactions • Use non-ionic agents C. Premedication is recommended in high risk patients (deﬁned in A) • When ionic agents are used • When non-ionic agents are used, opinion is divided about the value of premedication D. Recommended premedication • Corticosteroids – Prednisolone 30 mg orally or methylprednisolone 32 mg orally 12 and 2 hours before contrast medium – Corticosteroids are not effective if given less than 6 hours before contrast medium • Histamine H1 and H2 receptor antagonists may be used in addition to corticosteroids, but opinion is divided E. Remember for all patients • Have a trolley with resuscitation drugs in the examination room • Observe patients for 20–30 minutes after contrast medium injection F. Extravascular administration • When absorption or leakage into the circulation is possible, take the same precautions as for intravascular administration

• A 13-year-old girl with bipolar disorder and a history of adverse reactions to contrast media was given methylprednisolone (32 mg/day) and ranitidine (300 mg/day) before a CT scan of the head with intravenous contrast enhancement. After 1 day she developed psychiatric symptoms, which were more severe than her initial symptoms, including extreme agitation and mental confusion. All medications were withdrawn and her symptoms resolved within 2 weeks.

how to reduce the risk of generalized reaction to intravascular use of contrast media (Table 1) (5S ).

Delayed reactions to iodinated-contrast media (SEDA-25, 558; SEDA-26, 513)

The authors suggested that the recurrence of the manic symptoms could have been due to premedication with prednisolone. Exacerbation of manic symptoms after the use of corticosteroids has been documented before, but never in a case of short-term premedication before contrast-enhanced radiographic examination. This report shows that even a short-term course of corticosteroids can have signiﬁcant adverse effects in patients with a history of mood disorders. The value of prophylactic use of corticosteroids to reduce the risk of contrast reactions is contentious. The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) considered this issue and produced guidelines on

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 illness, may not be caused by the contrast agents. However, the delayed allergic-like skin reactions are usually induced by the contrast media. The delayed skin reactions tend to be commoner with non-ionic dimers compared with other types of contrast media (SEDA-22, 499). Delayed reactions are generally benign, but not always. In a Japanese study the incidence of delayed reactions was investigated in 6764 patients who received the low osmolar non-ionic contrast medium iohexol intra-

498 venously (6CR ). Delayed reactions (rash, pruritus, nausea, vomiting, fever, headache, fever, and others) occurred in 192 patients (2.8%). There were no severe delayed reactions. A history of allergy and hay fever were risk factors for delayed adverse reactions. Cardiovascular It is now well recognized that low osmolar contrast media are in general better tolerated than high osmolar ionic agents in cardiac and coronary angiography, and it has recently been suggested that the nonionic iso-osmolar dimer iodixanol has minimal cardiotoxic effects (SEDA-25, 558). Iodixanol 320 (n = 307) has been compared with the low osmolar ionic dimer ioxaglate 320 (n = 311) in patients undergoing percutaneous coronary intervention (7C ). The two groups were well matched for basic demographic data and comparable in relation to cardiovascular state and other medical conditions. In the iodixanol group 15 patients (4.9%) and in the ioxaglate group 27 patients (8.7%) had reactions within 24 hours of the procedure; they were likely to be due to the contrast medium and included nausea, vomiting, ﬂushing, facial edema, urticaria, and wheezing. There was no signiﬁcant difference in the outcome of the procedure between the two groups. The authors suggested that in view of the higher incidence of adverse effects with ioxaglate, its automatic selection for percutaneous coronary intervention should be reviewed. The authors of a large review of the comparative tolerability of contrast media used for coronary intervention recommended the use of ionic or non-ionic dimers over non-ionic low osmolar monomeric agents, because of the antithrombotic advantage of the dimers (8C ). However, the recommendation to use ionic low osmolar contrast media in preference to nonionic contrast media is not widely endorsed, since the latter are less toxic than ionic media. In another study there was no difference in the incidence of contrast media reactions between the non-ionic monomeric contrast agents iopamidol and iopromide, and both agents were well tolerated following left ventricle and coronary angiography (9C ). The authors concluded that both agents are perfectly acceptable for cardiac angiography. The electrocardiographic effects of different types of non-ionic low osmolar contrast media

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have been investigated in 41 patients undergoing left ventricular angiography (10C ). There was transient prolongation of the QT interval in all of the patients. The effect did not cause important cardiac events and was less than 60 msec in most cases. The authors concluded that this effect was too brief to present any signiﬁcant risk. In spite of the safety of the non-ionic contrast media cardiac arrest can complicate the infusion of these agents. • A 47-year-old man with chest pain and a myeloproliferative disorder had a CT scan of the abdomen with contrast enhancement (the type of contrast medium was not stated) (11A ). He had no signiﬁcant past medical history or history of allergy. During a later CT scan of the abdomen infusion of 60 ml of the non-ionic monomer iohexol 300 mgI/ml caused a sudden cardiac arrest. Resuscitation was ineffective and post-mortem examination showed intramural acute and old organizing infarctions in the entire left ventricular wall.

Although the authors suggested that this event was an adverse effect of the contrast medium, it is possible that the cardiac arrest in this patient was secondary to an acute coronary event independent of the contrast agent. Nervous system Tremor and convulsions have been reported as unusual delayed reactions to contrast administration (12A ). • A 69-year-old man with idiopathic nasal bleeding underwent contrast-enhanced CT examination of the head with an intravenous non-ionic low osmolar contrast medium. Convulsions and tremor developed 1 hour after the examination and lasted for 50 minutes.

Neurotoxicity from contrast agents can occur during diagnostic and therapeutic procedures. Transient cortical blindness is a well recognized complication of vertebral angiography, due to extravascular leakage of the contrast medium into the occipital lobe (SEDA-23, 497; SEDA-24, 521; SEDA-25, 559; SEDA-26, 514). • A 63-year-old woman with a left-sided spastic hemiparesis underwent cardiac and coronary angiography with a large volume (300 ml) of the nonionic contrast medium iomeprole (350 mgI/ml) (13A ). After the procedure her hemiparesis dramatically worsened, prompting emergency CT scanning of the head, which showed a marked hyperdensity in the right cerebral hemisphere.

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The right hemisphere was more affected, because the contrast medium injected into the left ventricle or ascending aorta during angiography is likely to reach the right brachiocephalic artery ﬁrst. The hyperdensity of the affected cerebral hemisphere seen on CT scanning is due to leakage of the iodinated contrast medium into the extracellular space, because of an increase in the permeability of the blood–brain barrier. Fortunately this complication tends to be transient. The patient recovered from this acute event, and follow-up CT of the brain showed complete resolution of the hyperdensity. Electrolyte balance Iodinated contrast media can cause increased release of potassium from blood cells and vascular endothelial cells, as has been investigated in vitro using blood, collected from 52 patients, mixed with iodinated contrast media for 30 minutes (14C ). The following contrast media were used: iopamidol 370 mgI/ml, ioxaglate 320 mgI/ml and diatrizoate 370 mgI/ml. Potassium release increased after exposure to the contrast media and the high osmolar diatrizoate caused the greatest release, followed by iopamidol and then ioxaglate. The osmolality of contrast media may play an important role in the mechanism responsible for the release of potassium from blood cells. Chemotoxicity may also play a role. There are no data to suggest that the release of potassium is due to hemolysis, and it is most likely due to increased membrane permeability. Hematologic The hematological effects of ioxaglate (a low osmolar ionic dimer) 105 (range 95–114) ml (n = 15) and iopromide (a low osmolar non-ionic monomer) 102 (range 90–108) ml (n = 16) have been investigated in patients undergoing abdominal and femoral angiography (15C ). The aim was to investigate in vivo whether non-ionic contrast media are less anticoagulant or more prothrombotic than ionic agents. Activation of coagulation and platelets were found in almost 50% of patients before any contrast medium was given. Both iopromide and ioxaglate caused further increases in thrombin–antithrombin complex, prothrombin fragments 1 + 2, and beta-thromboglobulin; the degree of activation was similar with both agents. In contrast to the ﬁndings in in vitro studies, there were no signiﬁcant differences between the effects of the non-ionic agent opromide and the ionic agent ioxaglate. The results

499 supported the notion that the catheterization procedure per se may represent a source of hemostatic activation and that ionic contrast agents have insufﬁcient anticoagulant effect to prevent clotting activation being induced by the procedure. The study also yielded no support for the concept that non-ionic contrast media are less anticoagulant or more prothrombotic than ionic agents. However, it has been suggested that anticoagulant effects are high with ionic media and low with non-ionic media (16CR ). The authors also suggested that there is no direct activation of platelets with low osmolar ionic and nonionic dimeric contrast agents but a high degree of activation with non-ionic monomeric contrast media. They concluded that although the interaction between contrast media and coagulation has been widely studied in vitro and in vivo, this issue is contentious and further studies are required for better understanding. Gastrointestinal The use of low osmolar or iso-osmolar water-soluble contrast media for imaging the gastrointestinal tract is recommended in neonates and when aspiration is suspected or leakage of the contrast media outside of the lumen of the bowel is expected (SEDA26, 516). The use of low osmolar contrast media in pediatric gastrointestinal imaging has been investigated in children under 16 years. One group received the iso-osmolar dimer iodixanol (74 patients, mean age 5.8 years, range 0–15, mean volume of contrast medium 87 ml) and the other group received the low osmolar nonionic monomer iohexol (78 patients, mean age 6.4 years, range 0–15, mean volume of contrast medium 93 ml) (17C ). There was a lower frequency of adverse events with iodixanol than with iohexol. Diarrhea developed in 16% of the patients given iodixanol and in 36% of those given iohexol. The safety of the iso-osmolar dimer iotrolan in imaging the upper gastrointestinal tract has been investigated in neonates and young children (81 patients, age range 2 days to 14 years), 21 of whom were under 1 month old (18C ). The dose of contrast medium was 15–30 ml. There were no signiﬁcant adverse effects and the authors concluded that iotrolan is a safe contrast agent for imaging the gastrointestinal tract in children.

500 Skin Delayed skin reactions after intravascular administration of contrast media are well recognized (SEDA-24, 523; SEDA-25, 561; SEDA-26, 518). Delayed rashes have been reported in two patients (19A ). • A 54-year-old woman and a 68-year-old man developed rashes 24 hours after intravascular injection of iohexol (a non-ionic monomer). The woman developed widespread pruritic erythema and eyelid edema. The man developed a maculopapular rash involving the trunk and legs. Both patients were treated with antihistamines, which resulted in complete recovery within 1 week. The man had slight desquamation of the affected area after his rash resolved. Patch tests were positive to iohexol in both patients. The man also had a positive patch test to iodixanol and the woman was positive to the non-ionic monomer ioversol.

Immunologic Three cases of contrast media triggering cutaneous graft–versus–host disease have been reported (20A ). • A 49-year-old man with acute myeloid leukemia underwent allogeneic bone marrow transplantation from his brother. Pre-existing pulmonary aspergillosis was treated with intravenous amphotericin. A CT scan of the chest and abdomen using 120 ml of the non-ionic dimer iodixanol was performed and 6 hours after the injection he developed generalized erythema with a pruritic painful skin rash. Skin biopsies showed changes typical of chronic graft–versus–host disease. He received prednisolone 50 mg orally and the rash resolved within a few weeks. • A 30-year-old woman with acute myeloid leukemia received an allogeneic bone marrow transplant from her brother. A CT scan of the abdomen was performed a few weeks after transplantation using 150 ml of iodixanol. Two days later she developed acute cutaneous graft–versus–host disease, which was treated with intravenous methylprednisolone 1 g/day for 4 days. Four months later another CT was performed with 150 ml of iodixanol and 2 hours later she developed a generalized maculopapular rash over the whole body, which was diagnosed as grade 2 graft–versus–host disease. Intravenous methylprednisolone 1 g and clemastine 2 mg did not control the rash, which worsened. She was given daclizumab 50 mg/day for 2 days, prednisolone 100 mg/day, and mycophenolate mofetil 2 g/day. The rash resolved completely within 10 weeks. • A 38-year-old man with acute myeloid leukemia underwent allogeneic bone marrow transplantation from his brother. He received iopromide 120 ml during CT scanning of the chest 15 months after the transplantation and 6 hours later developed generalized erythroderma, which was treated with oral prednisolone 50 mg. The lesion persisted and cholestatic jaundice developed. Graft–versus–host

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disease of the skin and liver was diagnosed. The patient still required immunosuppressive therapy and prednisolone 18 months after the event.

The authors suggested that the skin manifestations had been due to graft–versus–host disease triggered by the contrast medium and not a type IV immunological reaction. Skin biopsy in one of the patients showed typical features of graft–versus–host disease. In addition, the reactions in these patients lasted for longer than one would expect in simple delayed reactions with skin manifestations, which usually resolve within 7–10 days.

Contrast medium-induced renal damage Contrast medium-induced renal damage is associated with impaired renal function (an increase in serum creatinine by more than 25% or 44 μmol/l) within 3 days after the intravascular administration of a contrast medium in the absence of an alternative cause. Incidence The incidence of contrast-induced renal damage has been investigated in 100 consecutive trauma patients (mean age 37 years) who underwent angiographic embolization (mean dose of contrast medium “non-ionic low osmolar” 248 ml) for bleeding in the abdomen or pelvis (21C ). None had diabetes or renal impairment before the injury (mean baseline serum creatinine 88 μmol/l). The serum creatinine increased by more than 25% of baseline in ﬁve patients, and returned to baseline within 5 days. The author concluded that contrast nephropathy was not a major clinical problem in relatively young patients with normal kidneys and no risk factors, who can tolerate large doses of contrast media without sustaining clinically important renal injury. Vigorous ﬂuid resuscitation and the prevention of hypotension also offered effective protection against contrast nephropathy in spite of a large contrast load. Susceptibility factors There are several risk factors for the development of contrast mediuminduced renal damage, including pre-existing

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renal insufﬁciency, particularly if it is secondary to diabetes mellitus, dehydration, multiple repeat exposure to contrast media within a short period of time (72 hours), congestive heart failure, or concurrent administration of nephrotoxic drugs, such as non-steroidal antiinﬂammatory drugs (22CR ). Hepatic cirrhosis is not a risk factor, according to the results of a study in 72 patients with hepatic cirrhosis and 72 controls, who received 100–150 ml of low osmolar contrast media intravenously for abdominal or chest CT scans (23C ). Serum creatinine was measured before and 48–72 hours after the administration of the contrast agent. The incidence of contrast nephrotoxicity was comparable in the two groups (two patients in the cirrhosis group and one control). The type and dose of contrast media are important factors in the development of contrast nephrotoxicity. It is now well recognized that in patients with pre-existing renal impairment low osmolar non-ionic contrast media are less nephrotoxic than high osmolar media. It has also recently been shown that the isoosmolar non-ionic dimers are less nephrotoxic than the low osmolar non-ionic monomers. In 129 diabetic patients (mean age 71 years), with renal impairment (baseline serum creatinine 133–309 μmol/l) requiring angiographic examinations, the iso-osmolar dimer iodixanol (n = 64) was signiﬁcantly less nephrotoxic than the low osmolar non-ionic monomer iohexol (n = 65) (24C ). The incidence of contrast nephrotoxicity was 3% in the iodixanol group and 26% in the iohexol group. The authors concluded that iodixanol has low nephrotoxicity and should be the contrast medium of choice in patients at high risk of this complication. Prevention Several strategies have been advocated to reduce the incidence of contrast media nephrotoxicity. The lowest possible dose of a low osmolar non-ionic contrast medium should be used in patients at high risk of this complication. High osmolar contrast media and large doses should be avoided. In addition, intravenous hydration with saline (1 ml/kg/hour for 4–6 hours before contrast injection to be continued for 12 hours afterwards) should be given. However, it was not clear whether half-strength or normal-strength saline should be used. This issue has been

501 investigated in 809 patients who received halfstrength saline and 811 patients who received isotonic saline (25R ). The two groups were matched in relation to baseline characteristics and the mean serum creatinine before contrast injection was 80 μmol/l. All underwent coronary angioplasty using the low osmolar non-ionic contrast medium iopromide (mean volume 234 ml). The incidence of contrast nephrotoxicity in those who received isotonic saline was 0.7% and in those who received half-isotonic saline it was 2%. The authors concluded that isotonic saline is superior to half-strength solution in reducing the incidence of contrast media nephrotoxicity. In addition to using a small dose of low osmolar non-ionic contrast medium and offering hydration, some authors have recommended the use of calcium channel blockers in patients at high risk of contrast nephrotoxicity. However, the effectiveness of this class of drugs in preventing contrast nephrotoxicity has not been consistently proven, particularly in patients with pre-existing advanced renal disease (26CR ). Theophylline, a non-selective adenosine receptor antagonist, has also been recommended, since adenosine has been suggested to be an important mediator of contrast-induced nephrotoxicity. Patients undergoing coronary angiography with the high osmolar contrast medium diatrizoate (370 mgI/ml) were randomized to receive either theophylline (200 mg bd orally 24 hours before and for 48 hours after coronary angiography, n = 35, mean age 54 years, mean dose of contrast medium 78 ml) or placebo (n = 35, mean age 52 years, mean dose of contrast medium 80 ml) (27C ). The glomerular ﬁltration rate at 48 hours was reduced by 36% (from a mean of 85 ml/min to a mean of 67 ml/min) in the placebo group and by 9% in the theophylline group. Contrast nephrotoxicity, deﬁned as a fall in glomerular ﬁltration rate by 25% or more from baseline at 48 hours developed in 11 patients in the control group and only in one patient in the theophylline group. The authors concluded that nephrotoxicity induced by high osmolar contrast media can be reduced by prophylactic administration of theophylline. The protective effect of theophylline against contrast media nephrotoxicity has also been shown in another study (28C ). Intravenous theophylline 100 mg 30 minutes before intravascular administration of 100 ml of low

502 osmolar contrast medium offered good protection against contrast nephrotoxicity in patients with chronic renal insufﬁciency (mean serum creatinine 183 μmol/l). The incidence of contrast nephrotoxicity was 4% in the theophylline group and 16% in the placebo group (base line serum creatinine 110 μmol/l). The authors concluded that theophylline offers good protection against contrast nephrotoxicity in patients with pre-existing renal impairment. However, the dose of contrast medium was relatively small (100 ml) and the pre-existing renal impairment was not advanced. The consistency of theophylline in offering good protection against contrast nephrotoxicity has not been conﬁrmed at higher doses of contrast media and in patients with more advanced renal disease. Fenoldopam, a selective dopamine-1 receptor agonist, has also been advocated to reduce the risk of contrast nephrotoxicity. It is a renal vasodilator and increases glomerular inﬁltration rate. The authors of a review of studies that used fenoldopam to prevent contrast nephrotoxicity concluded that it offers good protection (29CR ). In another study the incidence of contrast nephrotoxicity was 4.7% in patients who received intravenous fenoldopam 0.1 μg/kg/min starting 15–20 minutes before contrast injection and continued for 6 hours after and 19% in controls (30C ). However, fenoldopam has not been consistent in offering good protection against contrast nephrotoxicity, it has to be given by intravenous infusion, and it requires careful monitoring of blood pressure and dosage adjustment if hypotension develops. The antioxidant N-acetylcysteine has also been recommended to reduce the risk of contrast nephrotoxicity. N-acetylcysteine 600 mg bd for 2 days, starting the day before the examination, in addition to hydration, reduced the incidence of contrast nephrotoxicity in 41 patients (31C ). The incidence of contrast nephrotoxicity was 2% in patients who received acetylcysteine (baseline serum creatinine 220 μmol/l) following intravenous injection of 75 ml of low osmolar non-ionic contrast media, and 21% in controls (baseline serum creatinine 211 μmol/l). However, the dose of contrast medium used was rather small and the patients did not have advanced renal impairment before contrast injection. The protective effects of intravenous hydration alone (0.45% isotonic saline, 1 ml/kg/hour

Chapter 46

Sameh K. Morcos and G. Girish

for 12 hours before and 12 hours after contrast administration), fenoldopam (0.1 μg/kg/min for 4 hours before and 4 hours after the procedure), and acetylcysteine (600 mg bd 24 for hours before and 24 hours after the procedure) have been compared in preventing contrast nephrotoxicity after intravascular administration of low osmolar non-ionic contrast medium (32C ). The incidence of nephrotoxicity was 15% in the hydration group, 16% in the fenoldopam group, and 18% in the acetylcysteine group. All the groups were comparable and baseline creatinine clearance was about 60 ml/min in all the patients who received a similar dose of the contrast medium (1.5 ml/kg). The authors concluded that fenoldopam and acetylcysteine do not offer extra protection against contrast nephrotoxicity over hydration alone. Another strategy to prevent contrast nephrotoxicity is prophylactic hemodialysis after contrast medium injection in patients with pre-existing renal impairment. Although hemodialysis is effective in removing contrast media from the body, its ability to prevent contrast nephrotoxicity has been disappointing. Several studies have shown that prophylactic hemodialysis offered immediately after procedures that require intravascular contrast media did not protect against contrast nephrotoxicity. This is understandable, since the effect of contrast media on the kidney after intravascular administration is almost instant and hemodialysis is usually offered at best 30–60 minutes after the procedure, which is too late to prevent the effects of contrast media on the kidney. The Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR) has produced useful guidelines on dialysis and the intravascular use of contrast media (Table 2) and has reviewed the literature on this subject (33S ). In addition they have produced guidelines on the prevention of contrast medium-induced renal damage (Table 3) following a consensus of experts in this ﬁeld and of members and fellows of the society (34S ). Immunologic Prophylactic use of immunosuppression has been described to prevent delayed hypersensitivity reactions to contrast media (35A ). • A 19-year-old man developed delayed hypersensitivity skin reactions to iopamidol (a low osmolar contrast medium) after cerebral angiography

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Table 2. European Society of Urogenital Radiology (ESUR) simple guidelines on dialysis and contrast media administration (34S ) Patients on dialysis

Recommendations

Hemodialysis [all contrast media can be removed by hemodialysis]

• Avoid osmotic and ﬂuid overload • Correlation of the time of contrast media injection with the hemodialysis session is unnecessary • Extra hemodialysis session for removal of contrast media is unnecessary

Continuous ambulatory peritoneal dialysis (CAPD) [all contrast media can be removed by peritoneal dialysis]

X-ray examinations • To protect residual renal function refer to ESUR guidelines to avoid contrast medium-induced renal damage • Hydration should be considered only after careful evaluation of ﬂuid balance state of the patient. • Hemodialysis is unnecessary MRI scans • To protect residual renal function use doses under 0.3 mmol/kg of gadolinium-based contrast agents • Refer to ESUR guidelines to avoid contrast mediuminduced renal damage (hydration, use small doses of low osmolar contrast media) • Hemodialysis is unnecessary • In MRI avoid doses over 0.3 mmol/kg of gadoliniumbased contrast agents

Patients with severely reduced renal function

Table 3. European Society of Urogenital Radiology (ESUR) simple guidelines to avoid Contrast Medium Nephrotoxicity (35S ) Deﬁnition

Contrast medium nephrotoxicity is a condition in which an impairment in renal function (an increase in serum creatinine by more than 25% or 44 μmol/l) occurs within 3 days after the intravascular administration of a contrast medium in the absence of an alternative cause

Susceptibility factors

Look for

• Raised serum creatinine concentration, particularly secondary to diabetic nephropathy • Dehydration • Congestive heart failure • Age over 70 years • Concurrent administration of nephrotoxic drugs, e.g. non-steroidal anti-inﬂammatory drugs

In patients with susceptibility factor(s)

Do

• Make sure that the patient is well hydrated; give at least 100 ml/hour orally (e.g. soft drinks) or intravenously (isotonic saline) depending on the clinical situation, starting from 4 hours before to 24 hours after contrast administration; in hot climates increase the ﬂuid volume • Use low osmolar or iso-osmolar contrast media • Stop administration of nephrotoxic drugs for at least 24 hours • Consider alternative imaging techniques that do not require the administration of iodinated contrast media

Do not

• • • •

Give high osmolar contrast media Administer large doses of contrast media Administer mannitol or diuretics, particularly loop-diuretics Perform multiple studies with contrast media within a short space of time

for an arteriovenous malformation. Three months later he required embolization of the malformation. He was given prophylactic betamethasone (4 mg/day) for 2 days before the procedure in which iopamidole was used again. Three days after

the embolization he developed a generalized maculopapular rash with severe itching. The rash resolved completely after intramuscular chlorpheniramine 10 mg bd for 10 days and oral prednisone 25 mg bd. Skin tests conﬁrmed a delayed hyper-

504 sensitivity reaction to iopamidol and other types of contrast media. One month later he required further embolization and underwent immunosuppression with oral ciclosporin 100 mg bd and intramuscular methylprednisolone 40 mg/day for 1 week before and 2 weeks after the embolization. The contrast medium iobitridol, which gave negative results in skin tests, was used. The patient tolerated the procedure and did not develop further reactions.

MRI CONTRAST MEDIA Gadolinium

(SEDA-24, 256; SEDA-25, 562; SEDA-26, 20)

Gadobenate dimeglumine (Multihance, GdBOPTA) is a new gadolinium-based contrast agent that has been approved for MRI scanning. Multihance (intravenous bolus injection of 0.05 mmol/kg) was well tolerated by 103 patients (mean age 56 years) with acute myocardial infarction (36CR ). Minor adverse effects in 27 patients included injection site reactions (13%), paresthesia (6.8%), dry mouth (6.8%), taste disturbance (2.9%), and headache (1.9%). The authors concluded that the use of a bolus dose of Multihance 0.05 mmol/kg up to 6 days after acute myocardial infarction is safe. The safety of intravenous Multihance 0.025, 0.05, 0.1, and 0.2 mmol/kg in MR angiography has been assessed in 94 patients (mean age 58 years). Diagnostic accuracy was optimal at a dose of 0.1 mmol/kg (37CR ). All the doses were well tolerated and there were no signiﬁcant changes in safety parameters. Six patients reported mild adverse effects related to the contrast agent, including urticaria (n = 2), nausea (n = 2), and mild increases in liver enzymes (gamma-glutamyltranspeptidase, alanine aminotransferase, and asparate aminotransferase) (n = 2). All the adverse events resolved spontaneously. Similar observations were made in another study using similar doses of Multihance for MR angiography (38CR ). There were no important adverse effects, and the authors concluded that Multihance is safe for MR angiography and that the optimal diagnostic dose is 0.1 mmol/kg.

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Sameh K. Morcos and G. Girish

Drug administration route The safety of intrathecal gadopentetate dimeglumine (Magnevist) has been investigated in 95 patients (aged 1 month to 78 years) (39CR ). The contrast agent was injected into the subarachnoid space via a lumbar puncture needle; 3–5 ml of cerebral spinal ﬂuid were withdrawn and mixed with 0.5, 0.7, 0.8, or 1 ml of gadopentetate dimeglumine. There were no signiﬁcant behavioral changes, neurological changes, or seizure activity, but 19 patients had headache after lumbar puncture, six had nausea, and two had vomiting. All the adverse effects resolved within the ﬁrst 24 hours with bed rest. The safety of the new gadolinium based contrast agent OptiMARK (Gd–DTPA–BMEA) at doses of 0.1–0.7 mmol/kg has been evaluated in 18 clinical studies (40M ). Adverse events related to the contrast agent were reported in 31% of injections. There were no serious adverse events. Susceptibility factors The safety of Multihance in patients with impaired liver function has been evaluated in 16 subjects with liver impairment, 11 of whom (mean age 48 years) received Multihance (0.1 mmol/kg) intravenously and ﬁve of whom (mean age 42 years) received placebo (41CR ). There were no important adverse effects and no signiﬁcant changes in laboratory parameters. The pharmacokinetics of the contrast agent were not different from those with normal liver function. A study of 74 patients over the age of 18 years with possible metastatic brain disease found that a total cumulative dose of 0.2 mmol/kg of Multihance injected intravenously over a 20 minute period to be safe and enhance the assessment of brain secondaries (42CR ). The safety and dialysability of the MR intravenous contrast agent gadobutrol 0.1 or 0.3 mmol/kg have been investigated in 11 patients (median age 42 years) with end-stage renal insufﬁciency who required hemodialysis (43CR ). The patients were monitored for 120 hours. There were no important changes in hematology, clinical chemistry, or vital signs. Hemodialysis was effective in removing the gadolinium contrast agent from the body, and by the third session 98% of the injected dose had been eliminated. The use of gadolinium-based contrast media for radiographic examination as an alter-

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505

Chapter 46

Table 4. European Society of Urogenital Radiology (ESUR) position statement on the use of gadolinium-based contrast media for radiographic examinations (46CR ) Legal position

Gadolinium-based contrast media are not approved for X-ray examinations

Reported uses of gadolinium-based contrast media for X-ray examinations

• Signiﬁcant renal impairment • Prior severe generalized adverse reaction to iodinated contrast media • Imminent thyroid treatment with radioactive iodine

ESUR position

1. The use of gadolinium-based contrast media for radiographic examinations is not recommended to avoid nephrotoxicity in patients with renal impairment, since they are more nephrotoxic than iodinated contrast media in equivalent X-ray attenuating doses 2. The use of gadolinium-based contrast media in approved intravenous doses up to 0.3 mmol/kg will not give diagnostic radiographic information in most cases

native to iodinated contrast media in patients with impaired renal function has been erroneously endorsed by several authors. For example, in a German study gadopentetate dimeglumine (average dose 0.34 mmol/kg) was used in 29 patients (mean age 61 years) with renal impairment (mean baseline serum creatinine 318 μmol/l) as an alternative to an iodinated contrast agent for angiographic procedures (44CR ). Only one patient developed contrast medium-induce renal damage, deﬁned as an increase in serum creatinine by more than 88 μmol/l within 72 hours of injection of the contrast agent. The authors suggested that gadopentetate dimeglumine is a safe alternative to iodinated contrast agents for radiographic examinations in patients with renal impairment. In another study gadodiamide was used as an alternative for angiographic procedures in patients with contraindications to iodinated contrast media; 17 patients (mean age 74 years) received a mean volume of 136 ml of gadodiamide (range 60–200 ml) (45CR ). The contraindications to iodinated contrast injection were renal impairment (12 patients, serum creatinine 200–500 μmol/l), a history of iodinated contrast reaction (three patients), and hyperthyroidism (four patients). Several of the patients had renal artery stenosis, and renal function improved after successful angioplasty. There were no cases of nephrotoxicity. The authors concluded that patients with contraindications to iodinated contrast injection can safely receive gadolinium-based contrast media for radiographic examinations.

The authors of these reports have erroneously suggested that gadolinium-based contrast media are less nephrotoxic than iodinated contrast media. However, at equimolar concentrations gadolinium-based contrast media are more nephrotoxic than iodinated contrast media, and at equivalent X-ray attenuation gadolinium-based contrast media are actually more nephrotoxic. The Contrast Media Safety Committee of the European Society of Urogenital Radiology has recently produced a report on the use of gadolinium-based contrast media for radiographic examinations, and its position is summarized in Table 4 (46S ).

ULTRASOUND CONTRAST AGENTS (SEDA-24, 529; SEDA-25, 564; SEDA-26, 522)

Deﬁnity Deﬁnity (microspheres containing octaﬂuoropropane gas encapsulated in lipid shells) is a newly developed intravenous echocardiographic contrast agent. In a review of its diagnostic efﬁcacy and safety the authors concluded that it improves the diagnostic accuracy of echocardiographic examinations and has a good safety proﬁle (47CR ). Minor adverse effects were reported, such as headache, back pain, ﬂushing, and nausea. There were no serious adverse effects. However, Deﬁnity should not be used in patients with intracardiac shunts or in pregnant or lactating women. It should

506 also be used with caution in patients with severe liver or renal disease.

Levovist The safety of Levovist, which is a galactosebased ultrasound contrast agent, has been assessed in 5073 patients. In addition, spontaneous reporting of adverse events in 100 000 patients given injections of Levovist has been analysed (48CR ). The incidence of adverse events (12%) was similar in the Levovist group and in the controls, who were given isotonic saline. The adverse events included sensations of pain, cold, and warmth during injection, abnormal taste sensations, headache, nausea, and vomiting. There were no serious adverse events. The overall adverse event rate in spontaneous reports was 0.02%. One patient developed bronchospasm, another a generalized skin rash, and two other patients urticaria. The other reported adverse events were not serious and may not have been caused by the contrast agent. Intravesical Levovist has been used for voiding urosonography in 118 patients (aged 3 weeks to 16 years) (49CR ). The diagnostic accuracy of the examination was high and no adverse effects were reported.

Sono Vue Sono Vue is an ultrasound contrast media that consists of microbubbles containing sulfur

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Sameh K. Morcos and G. Girish

hexaﬂuoride gas stabilized by phospholipids. The safety of this contrast agent has been demonstrated in previous studies (SEDA-25, 565; SEDA-26; 522). The excellent safety and efﬁcacy of Sono Vue at doses of 0.7, 1, 2, and 4 ml has been demonstrated in 138 patients (mean age 57 years) (50CR ). There were mild adverse events, such as headache, nausea, paresthesia, and taste disturbance, but no severe adverse reactions.

Thorotrast

(SED-14, 1634;

SEDA-24, 530) Thorotrast was widely used between 1928 and 1955 as an X-ray contrast medium. It contains thorium dioxide with a radioactive half-life of about 400 years. After intravascular injection Thorotrast is retained mainly in the reticuloendothelial system especially the liver, spleen, and bone marrow. Thorotrast recipients often develop hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, or leukemia 20 years or more after the injection. Another case of Thorotrast-induced hepatic cholangiocarcinoma has been reported (51A ). • A 74-year-old developed nausea, night sweats, generalized fatigue, and weight loss. Thorotrast cerebral angiography had been performed 55 years before. Computed tomography of the abdomen showed areas of calciﬁcation within the liver, spleen, and peripancreatic lymph nodes, and there was a mass in the liver. Liver biopsy conﬁrmed cholangiocarcinoma.

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B.C.P. Polak

47

Drugs used in ocular treatment

Immunologic Allergic contact dermatitis is the most common dermatological condition that affects the eyelids. Allergic contact dermatitis was found in a retrospective study in 151 (74%) of 203 patients with persistent or recurrent eyelid dermatitis with or without dermatitis elsewhere (1C ): 46 (23%) had protein-contact dermatitis, but only 7% had protein-contact dermatitis without concurrent allergic contact dermatitis; 23 patients had atopic eczema, of whom 16 also had allergic contact dermatitis, protein-contact dermatitis, or both. Other conditions included seborrheic dermatitis, psoriasis, dry eyes, and dermatomyositis or overlapping connective tissue disease. Important sources of contact sensitivity were topical ocular medications, including corticosteroids, cosmetics, metals, dust mites, animal dander, and artiﬁcial nails; only ﬁve cases were caused by nail lacquer.

BETA-ADRENOCEPTOR AGONISTS Phenylephrine

(SED-14, 1643)

Cardiovascular Serious adverse systemic reactions have been reported after the use of phenylephrine eye-drops to effect pupillary dilatation. For example, a child developed cardiac dysrhythmias, severe hypertension, and pulmonary edema after intraoperative ocular phenylephrine administration (2A ). Topical ocular application of phenylephrine 10% in pledget form is used to produce hemostasis in laser-assisted in-situ keratomileusis © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

(LASIK) surgery and other ophthalmic surgical procedures. The FDA and the National Registry of Drug-induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon) have received 11 reports of adverse systemic reactions to a single dose of topical ocular phenylephrine 10% applied in pledget form (3S ). There were eight male and three female patients, aged 1– 76 years. Most of the patients noted systemic effects within minutes of applying phenylephrine, and the adverse systemic reactions included severe hypertension, pulmonary edema, cardiac dysrhythmias, cardiac arrest, and subarachnoid hemorrhage. Ophthalmologists should be warned not to apply phenylephrine in this way, which is believed to be contraindicated in ophthalmic surgery, especially when other medications may be used (SED-14, 1643). Skin There have been very few reports of allergic contact dermatitis caused by phenylephrine, and little is known about cross-reactivity between the phenylephrine, adrenaline, and ephedrine. Patch tests were performed on a man with allergic contact dermatitis to Neosynephrine POS eye-drops containing phenylephrine hydrochloride (4A ). Neosynephrine POS and aqueous phenylephrine hydrochloride 10% both gave positive reactions, whereas adrenaline and ephedrine tested negative, although phenylephrine is chemically related to them.

BETA-ADRENOCEPTOR ANTAGONISTS (SED-14, 1639; SEDA-26, 525) The systemic adverse effects of systemic or ophthalmic beta-blockers have been studied in a literature review of peer-reviewed journals and medical texts (5M ). Symptomatic bradycardia from systemic or ophthalmic use of

509

510 beta-blockers alone suggests underlying cardiac conduction disturbances. Beta2 -adrenoceptor blockade, regardless of route of administration, can exacerbate or trigger bronchospasm in patients with asthma or pulmonary disease associated with hyper-reactive airways. However, no studies have implicated ophthalmic beta-blockers in worsening of claudication, depression, hypoglycemic unawareness or prolonged hypoglycemia in non insulin-dependent diabetes, sexual dysfunction, or impaired neuromuscular transmission. Obtaining a careful medical history and checking pulse rate and rhythm should identify the vast majority of patients with potential cardiopulmonary contraindications.

Fluorescein dye Ocular complaints are common in primary care. Routine evaluation involves adequate inspection of the eye. Topical ﬂuoresein dye is often used during slit lamp or Wood’s lamp examination, because it helps in identifying corneal epithelial defects (6A ).

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B.C.P. Polak

that there is a predisposition to iris pigmentation in patients with eyes of hazel or heterochromic color. As latanoprost and travoprost are selective agonists at prostaglandin F2α receptors, it is likely that the phenomenon is mediated by these receptors. Latanoprost stimulates melanogenesis in iris melanocytes, and transcription of the tyrosinase gene is upregulated. No evidence of harmful consequences of this adverse effect has been found, and the only disadvantage appears to be potential heterochromia between the eyes in unilaterally treated patients: the heterochromia is likely to be permanent, or very slowly reversible. Cystoid macular edema, iritis, Herpes simplex keratitis, periocular skin darkening, and headaches have been described in patients treated with prostaglandin analogues. These adverse effects occur rarely, and cystoid macular edema, iritis and Herpes simplex keratitis occur in eyes with risk factors. Repeated rechallenge with masked controls is required to establish a causal relation. However, even without ﬁrm establishment of a causal relation, caution is advised with the use of prostaglandin analogues in eyes with risk factors for macular edema, iritis and Herpes simplex keratitis (9R ).

Skin The most common adverse effect of topical ﬂuorescein is local irritation (7A ). • A previously healthy 35-year-old man with conjunctival irritation had ﬂuorescein dye instilled using a ﬂuorescein-treated ophthalmic strip and isotonic saline. Within 30 minutes he began to notice a pruritic rash around his eye and on his arms, chest, and legs. His joints felt swollen. He had a diffuse erythematous macular rash with evidence of moderate excoriation over his arms and legs. His wrists and ankles were swollen. There were no oral lesions, and all laboratory studies, including the white blood cell count, were normal. Methylprednisolone succinate 125 mg plus diphenhydramine 50 mg produced rapid improvement.

PROSTAGLANDIN ANALOGUES (SEDA-26, 526) Sensory systems Latanoprost, travoprost, and bimatoprost cause increased pigmentation of the iris in some patients (8R ). Most data have been obtained with latanoprost, and it appears

Latanoprost Sensory systems In an observational cohort study of 43 patients, 30 had a deﬁnite acquired iris anisochromia (10c ). Latanoprost caused reduced intraocular pressure by 20–40% in adults with open-angle glaucoma or ocular hypertension, but its efﬁcacy and safety in children have not been widely reported. Most children reported so far gained little beneﬁt on intraocular pressure from latanoprost, but older children and those with juvenile-onset open-angle glaucoma do gain a signiﬁcant ocular hypotensive effect. Systemic and ocular adverse effects in children using latanoprost are infrequent (11R ). Hair Latanoprost causes growth of lashes and ancillary hairs around the eyelids, with greater thickness and length of lashes, additional rows of lashes, and conversion of vellus to terminal hairs in canthal areas and regions adjacent to lashes. As well as increased growth, there

Drugs used in ocular treatment

Chapter 47

is also increased pigmentation. Vellus hairs on the lower eyelids also undergo increased growth and pigmentation. Latanoprost therapy for 2–17 days can cause changes comparable to chronic therapy, and in one case it reversed alopecia of the eyelashes (12A ). The increased number and length of visible lashes are consistent with the ability of latanoprost to induce and prolong anagen growth in telogen (resting) follicles while pro-

511 ducing hypertrophic changes in the involved follicles. Laboratory studies suggest that the initiation and completion of the effects of latanoprost on hair growth occur very early in the anagen phase and that the likely target is the dermal papilla. Quantitative analysis of eyelash lengthening in 17 patients treated with latanoprost showed a signiﬁcant increase in eyelash length in the treated eyes (13c ).

REFERENCES 1. Guin JD. Eyelid dermatitis: experience in 203 cases. J Am Acad Dermatol 2002; 47: 755–65. 2. Baldwin FJ, Morley AP. Intraoperative pulmonary edema in a child following systemic absorption of phenylephrine eyedrops. Br J Anaesth 2002; 88: 440–2. 3. Fraunfelder FW, Fraunfelder FT, Jensvold B. Adverse systemic effects from pledgets of topical ocular phenylephrine 10%. Am J Ophthalmol 2002; 134: 624–5. 4. Erdmann SM, Sachs B, Merk HF. Allergic contact dermatitis from phenylephrine in eyedrops. Am J Contact Dermatitis 2002; 13: 37–8. 5. Lama PJ. Systemic adverse effects of betaadrenergic blockers: an evidence-based assessment. Am J Ophthalmol 2002; 134: 749–60. 6. Garcia GE. Management of ocular emergencies and urgent eye problems. Am Fam Phys 1996; 53: 565–74. 7. Lexi-Comp CRL Database: Fluorescein sodium. Available at www.emedline.com/lexicomp/ datasets/dihf/html-plain/chapter/mono/la055200. htm (accessed January 2002).

8. Stjernschantz JW, Albert DM, Hu DN, Drago F, Wistrand PJ. Mechanism and clinical signiﬁcance of prostaglandin-induced iris pigmentation. Surv Ophthalmol 2002; 47 Suppl 1: 162–75. 9. Schumer RA, Camras CB, Mandahl AK. Putative side effects of prostaglandin analogs. Surv Ophthalmol 2002; 47 Suppl 1: 219–30. 10. Teus MA, Arranz-Marquez E, Lucea-Suescun P. Incidence of iris colour change in latanoprost treated eyes. Br J Ophthalmol 2002; 86: 1085–8. 11. Enyedi LB, Freedman SF. Latanoprost for the treatment of pediatric glaucoma. Surv Ophthalmol 2002; 47 Suppl 1: 129–32. 12. Johnstone MA, Albert DM. Prostaglandininduced hair growth. Surv Ophthalmol 2002; 47 Suppl 1: 185–202. 13. Sugimoto M, Uji Y. Quantitative analysis of eyelash lengthening following topical latanoprost therapy. Can J Ophthalmol 2002; 37: 342–5.

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With increasing interest from both the public and the medical profession in complementary and alternative medicine, the literature on safety aspects in this area is steadily growing. Several general reviews have stressed the fact that “natural” must not be equated with “risk-free” (1R –4R ). Other articles have addressed more speciﬁc subjects, such as Ayurvedic medicines (5R ), Chinese medicines (6R ), pharmacovigilance of herbal medicines (7R ), the potential for herb–drug interactions (8R –10R ), and safety issues of herbal medicines for vulnerable populations: elderly patients (11R ), pregnant women (12R ), or surgical patients (13R , 14R ). Other reviews have focused on speciﬁc conditions or organ systems: cancer (15R ), hepatitis (16R ), cardiovascular system (17R ), or the skin (18R ). In all these reviews the emphasis was on herbal medicines.

HERBAL MEDICINES (SED-14, 1651; SEDA-24, 537; SEDA-25, 567; SEDA-26, 528) Despite the increased interest in herbal medicines, we still have far too few data on the risks of their adverse effects. A retrospective analysis of all adverse events related to herbal medicines and other dietary supplements reported to the California Poison Control System made a relevant contribution in this respect (19M ). Between January 1997 and June 1998, 918 calls relating to such supplements were received. Exposures resulting in adverse reactions occurred most © 2004 Elsevier B.V. All rights reserved. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

512

often at recommended doses. There were 233 adverse events, of which 29% occurred in children. The products most frequently implicated were zinc (38%), Echinacea (8%), chromium picolinate (6%), and witch hazel (6%). Most of the adverse events were not severe and required no treatment; hospitalization was required in only three cases. Death In a retrospective study of 2764 poisoning cases admitted to eight urban hospitals in Zimbabwe between 1998 and 1999, 7% of all cases and 13% of all deaths were related to traditional medicines (20C ). The authors noted that these ﬁgures are markedly lower than those from a similar survey 10 years earlier. Susceptibility factors Genetic Owing to extensive modiﬁcations of drug formulations and chemical extracts from an expanding range of natural products, herbal formulations may contain ingredients that are particularly harmful to individuals with G6PD deﬁciency. Extra vigilance is therefore required when herbal medicinal formulations, including topical applications, are used by patients with G6PD deﬁciency and even their carers (21S ). Drug contamination BotanicLab in the USA has manufactured the herbal medicines PC-SPES and SPES (22S ). These two products are marketed as “herbal dietary supplements” for “prostate health” and for “strengthening the immune system” respectively. They are sold through the internet, by mail and phone order, and through various distributors and healthcare professionals. An analytical report from the California Department of Health has shown that samples of PC-SPES and SPES have been contaminated with warfarin and

Treatments used in complementary and alternative medicine

alprazolam. The Canadian Medicines Regulatory Authority has also reported similar contaminations. In view of these reports Health Canada, the Irish Medicines Board and the State Health Director of California have all warned consumers to stop using these two products immediately and to consult their healthcare practitioners. Botanic Lab has also informed consumers of these laboratory ﬁndings and has issued a product recall of all lots of PC-SPES, pending further reports from additional testing of PC-SPES in both commercial and academic laboratories.

Asian herbal medicines “Ku shen” is a Chinese herbal remedy made from the root of Sophora ﬂavescens. A herbal monograph lists the following adverse effects: salivation, abnormal gait, dyspnea, tachycardia (23R ). In larger doses, CNS stimulation with muscle spasm and seizures can occur. There have been three reports of adverse reactions such as nausea, vomiting, dizziness, bradycardia, palpitation, ataxia, pallor, sweating, seizures, and dysphasia. A monograph about the Chinese herbal medicine “Xu Xin” was recently published (24R ). The remedy is made from the leaves and aerial parts of Asarum heterotropoides. Its volatile oil gives rise to the following adverse effects: vomiting, sweating, dyspnea, restlessness, fever, palpitation, and CNS depression. Death can result from respiratory paralysis at high doses. Nervous system A 73-year-old man developed a cholinergic syndrome, with dizziness, sweating, chills, lacrimation, salivation, rhinorrhea, nausea, and vomiting after taking the Chinese patent medicine “Ting Kung Teng” for arthritis (25A ). The herbal mixture contained tropane alkaloids with cholinergic activity. After withdrawal of the remedy he made a swift and complete recovery. Liver UK hepatologists have described two cases of severe liver damage, one fatal, attributed to Chinese herbal mixtures for minor complaints (26A ). The remedies implicated

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were “Jin bu huan” and “Dictamnus dasycarpus”. The authors pointed out that both have previously been associated with hepatotoxicity. All admission records of patients suspected of having liver problems related to Kampo medicines between 1979 and 1999 in a Japanese Department of Oriental Medicine were reviewed (27C ). There were 30 cases that were suspected of being caused by Kampo medicines. On closer examination, nine seemed to be deﬁnitely unrelated, six were probably unrelated, nine were possibly related, and six were deﬁnitely or probably related to Kampo medicines. There were no deaths on record. Drug contamination The export of herbal drugs has developed into an important business for China. The authors of a survey of German importers of Chinese herbs concluded that “only rarely” had herbal drugs to be returned because of contamination (28R ). The authors also stated that “a 100% check for all possible contaminants is not possible”. However, Chinese herbal remedies have repeatedly been reported to be contaminated with prescription drugs. A systematic review included 18 case reports, two case series, and four analytical studies showing contamination (29M ). The contaminants included aminopyrine, clobetasol propionate, corticosteroids (see below), diazepam, diclofenac, glibenclamide, hydrochlorothiazide, indometacin, mefenamic acid, methylsalicylate, phenacetin, phenylbutazone, and phenytoin. Corticosteroids Wau Wa cream is marketed in several countries as a herbal cream for eczema. After repeatedly observing surprising therapeutic successes, UK doctors analysed three samples of this cream given to them by three patients (30E ). The samples contained 0.013% clobetasol propionate, a powerful corticosteroid that does not occur naturally. Betamethasone, 0.1–0.3 mg per capsule, has been detected in Cheng Kum and Shen Loon, two herbal medicines that are popular for their beneﬁts in joint pain, skin problems, colds, menopausal symptoms, and dysmenorrhea (31r ). Over-exposure to betamethasone can result in typical signs of corticosteroid excess, such as moon face, hypertension, easy bruising, purple abdominal striae, truncal obesity, and hirsutism. The recommended

514 daily adult dose of Cheng Kum is 1–3 capsules per day, and there have been reports of corticosteroid-induced adverse effects in patients taking Cheng Kum and Shen Loon, even in the absence of other exogenous corticosteroid consumption. • Two patients, a 29-year-old woman and a 10year-old girl, developed Cushingoid features after taking Shen Loon for 4 and 5 months respectively (32A ). Their morning plasma cortisol concentrations were increased and adrenal suppression was conﬁrmed by a short Synacthen test. Both recovered after withdrawal of the remedy and treatment with prednisone.

The New Zealand Medicines and Medical Devices Safety Authority (Medsafe) has notiﬁed that the further importation of these herbal products into New Zealand will be stopped at Customs. However, because of the risk of adrenal suppression from corticosteroids, consumers have been sent a letter advising them against abruptly discontinuing these products. They should continue with the treatment and see their general practitioner as soon as possible for instructions on how they can be safely weaned off the product. Medsafe has issued a letter to doctors advising them to determine whether patients taking Cheng Kum or Shen Loon are at risk of adrenal suppression by estimating the potential total dose of corticosteroid (from Cheng Kum or Shen Loon plus any exogenous steroids) and the duration of use, by examining the patient for signs of corticosteroid excess, and by ascertaining if other risk factors for adrenal suppression are present (such as Addison’s disease, AIDS). Lead Lead contamination has been reported in Indian and Ayurvedic herbal medicines. • A 56-year-old woman developed the signs and symptoms of lead poisoning after taking an Indian herbal medicine for many years (33A ). Her blood and urine lead concentrations were 1530 μg/l and 4785 μg/day. She also had raised liver enzymes. After withdrawal of the remedy and treatment with penicillamine, she made a full recovery. • Czech doctors reported the case of a 26-year-old woman who had taken an Ayurvedic remedy (Astrum FE Femikalp) for sterility (34A ). It contained lead 113 mg/kg. Her blood lead concentration was raised and normalized 1 month after withdrawal of the remedy. Lead poisoning was also conﬁrmed by hair analysis.

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E. Ernst

Phenobarbital Phenobarbital has been reported as a contaminant in a Chinese patent medicine (35A ). • A 10-year-old boy developed respiratory depression and became comatose after taking the Chinese patent medicine “Diankexing” for 6 months. His urine phenobarbital concentration was 95 μg/ml (target range 20–40 μg/ml). The remedy was withdrawn and he was successfully treated with activated charcoal.

Other miscellaneous contaminants The Medicines Safety Authority of the Ministry of Health in New Zealand (Medsafe) has ordered the withdrawal of several traditional Chinese medicines sold as herbal remedies, since they have been found to contain scheduled medicines and toxic substances (36A ). The products that are to be withdrawn include: • Guan Xin Su He capsules, Long Dan Xie Gan Wan Pills, and Zhiyuan Xinqinkeli sachets, all of which contain aristolochic acid, which has been linked to severe kidney damage and urinary tract cancer; • Wei Ge Wang tablets, which contain sildenaﬁl; • Sang Ju Gan Mao Pian tablets, which contain diclofenac and chlorphenamine; • Yen Qiao Jie Du Pian capsules, which contain chlorphenamine, diclofenac, and paracetamol; • Niu Huang Jie Du Pian tablets, which contain 4% arsenic; • Xiaoke Wan pills, which contain glibenclamide; • Shuen Feng cream, which contains ketoconazole; • Dezhong Rhinitis drops, which contain ephedrine hydrochloride. The New Zealand Director General of Health has issued a Public Statement asking people to stop taking these products and to seek medical advice. Medsafe has asked all importers and distributors of traditional Chinese medicines to cease all distribution and sale of these products, to withdraw them from retail outlets, and to ensure that other products they sell do not contain scheduled medicines.

Treatments used in complementary and alternative medicine

Allium sativum

(SED-14, 1652;

SEDA-26, 529) Hematologic Bleeding due to impaired platelet function has been attributed to garlic (37A ). • A 54-year-old woman underwent strabismus surgery and had bilateral retrobulbar hemorrhages intraoperatively. In the absence of other possible causes, the authors thought that the bleeding had been due to garlic pills prescribed by a naturopath. On the day of surgery, she had taken ﬁve pills, equivalent to about 5 g of fresh garlic bulb. Garlic has well-documented effects on platelet aggregation. Platelet function, measured 2 weeks later, was normal.

Aloe capensis

(SED-14, 1652)

Urinary tract A 47-year-old South African man developed acute oliguric renal insufﬁciency and liver dysfunction after taking a herbal medicine prescribed by a traditional healer to “clean his stomach” (38A ). After withdrawal of the remedy and dialysis he recovered slowly, but his creatinine concentration did not fully normalize. Analysis of the remedy showed that it consisted of Aloe capensis (Aloe ferox Miller), which contains the nephrotoxic compounds aloesin and aloesin A. The authors also mentioned that 35% of all cases of acute renal insufﬁciency in Africa are due to traditional remedies.

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Animal experiments have shed more light on Chinese herb nephropathy (40E ). Salt-depleted male Wistar rats were regularly injected with two different doses of aristolochic acid or with vehicle only for 35 days. The histological signs of Chinese herb nephropathy were demonstrated only in animals that received the high dose of 10 mg/kg. The authors presented this as an animal model for studying the pathophysiology of Chinese herb nephropathy. • A 59-year-old man developed renal insufﬁciency after self-medication for 5 years with a Chinese herbal remedy to treat his hepatitis (41A ). Renal biopsy showed signs characteristic of Chinese herb nephropathy. Analysis of the remedy proved the presence of aristolochic acids I and II.

Drug contamination In Australia the product Longdan Qiegan Wan (“Wetness Heat” Pill) has been removed from the Australian Register of Therapeutic Goods following the detection of aristolochic acid by laboratory testing by the Therapeutic Goods Administration (42A ). In Canada, Health Canada has advised Canadians not to consume Longdan or Lung Tan Xi Gan products, since they may contain aristolochic acid. Health Canada is working with the manufacturers, distributers, and importers to recall these products in Canada. A customs alert has also been issued, to prevent importation of these products into Canada. Health Canada ﬁrst issued a warning on aristolochic acid in November 1999 that this ingredient posed a Class I Health Hazard with a potential to cause serious health effects or death (43A ).

Aristolochia species

(SED-14, 1654; SEDA-25, 568; SEDA-26, 529) Urinary tract The fact that Aristolochia species, which contain aristolochic acid, cause a characteristic type of renal insufﬁciency has been well established, and the clinical syndrome is now often referred to as “Chinese herb nephropathy”. Belgian nephrologists reinvestigated 71 patients who were originally affected by this syndrome (39c ). Using multiple regression analysis, they showed that the original dose of Aristolochia was the only signiﬁcant predictor of progression of renal insufﬁciency. The risk of end-stage renal insufﬁciency in these patients increased linearly with the dose of Aristolochia.

Breynia ofﬁcinalis Liver Taiwanese doctors have reported two cases of hepatocellular injury after oral administration of infusions of Breynia ofﬁcinalis (44A ). This herbal remedy is often used in Chinese herbal mixtures for a range of conditions. • One of the two patients had taken 1500 mg of the lower stem and root of Breynia ofﬁcinalis boiled in water in a suicide attempt. She was admitted with vomiting and headache and later developed gastritis, hematuria, and liver damage. Symptomatic treatment resulted in full recovery. • A 51-year-old woman consumed 20 pieces of the lower stem and root of Breynia ofﬁcinalis to treat dermatitis. She developed nausea, vomiting, and

516

Chapter 48

dizziness, and had raised liver enzymes. Her liver function recovered 1 month after withdrawal of Breynia ofﬁcinalis.

Chelidonium majus

(SED-14, 1656;

SEDA-24, 538) Liver Chelidonium majus (celandine) is traditionally used for dyspepsia and gall-bladder problems. It has been repeatedly associated with liver damage. Some 40 such cases have been reported to the German regulatory authorities and an additional published 15 cases can be found (45r ). The course of the hepatitis can be severe and can include cholestasis and ﬁbrosis. However, acute liver failure has not been observed. Based on these data, celandine has recently been banned for oral use in several countries.

Cimicifuga racemosa Liver A 47-year-old woman took an extract of Cimicifuga racemosa (black cohosh) for 1 week to treat menopausal symptoms; she developed jaundice and raised liver enzymes (46A ). No other causes of liver damage were found. She required liver transplantation. The authors pointed out that black cohosh contains diterpenoids, which cause liver damage in animals, either via reactive metabolites or by an autoimmune mechanism. Nevertheless, causality was not demonstrated beyond reasonable doubt in this report.

Coriandrum sativa Endocrine Adrenal insufﬁciency has been attributed to Coriandrum sativa (47A ). • A 28-year-old woman took an extract of Coriandrum sativa for 7 days to augment lactation while breastfeeding. She developed severe stomach pain and diarrhea and 15 days later presented with dark skin, depression, dehydration, and amenorrhea. A diagnosis of adrenal dysfunction was made, the herbal remedy was withdrawn, and she was treated with dexamethasone, prednisolone, and an oral contraceptive. Her symptoms resolved within 10 days.

E. Ernst

Echinacea (SED-14, 1658; SEDA-25, 569; SEDA-26, 531) Immunologic Five cases of adverse drug reactions have been attributed to oral Echinacea extracts (48ACr ). Two of the patients had anaphylaxis and one had an acute attack of asthma. The authors also mention 51 Australian adverse drug reports implicating Echinacea, of which 26 were suggestive of IgE-mediated hypersensitivity, including four cases of anaphylaxis, 12 acute attacks of asthma, and 10 cases of urticaria/angio-edema. The authors also tested 100 atopic subjects and found that 20 of them, who had never before taken Echinacea, had positive reactions to skin prick tests.

Ephedra

(SED-14, 1658; SEDA-24, 538; SEDA-25, 569) Cardiovascular The FDA’s Adverse Reaction Monitoring System was reviewed for all adverse events associated with Ephedra (Ma Huang) between 1995 and 1997 (49C ). There were 926 cases of possible Ephedra toxicity, including 16 strokes, 10 myocardial infarctions, and 11 sudden deaths. In 36 of these patients, the dose was reported to be within the manufacturer’s guidelines. The largest manufacturer of Ephedra-containing supplements is Metabolife. The ﬁrm repeatedly insisted that it was not aware of adverse events associated with its products, and claimed they were “absolutely safe” (50S ). An investigation by the US Justice Department into the truth of these statements showed that between 1997 and 2002 the company had received over 13 000 reports of suspected adverse drug reactions; they included nearly 2000 reports of signiﬁcant adverse reactions. • A 33-year-old man had a stroke while taking a herbal remedy (Thermadrene) containing Ephedra alkaloids and guaraná for “boosting his energy” (51A ). He was immediately treated with alteplase and was referred for rehabilitation 9 days later. At follow-up 5 months later he still had a minor neurological deﬁcit.

Overdose In a suicide attempt, a 32-year-old woman took 60 tablets of a weight-loss supplement containing Ephedra (52A ). She was

Treatments used in complementary and alternative medicine

delivered to hospital comatose. Her symptoms resolved over the next 5 days without treatment. At follow-up 5 months later she was euthymic, had no suicidal ideation, and was not taking any psychotropic medications. Based on increasing evidence of the risks of Ephedra selfmedication, various national regulatory authorities are currently considering recalling Ephedra products from over-the-counter sales.

Ginkgo biloba

(SED-14, 1658;

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Cardiovascular The WHO database contains seven cases from ﬁve countries of ginseng intake followed by arterial hypertension (57c ). In ﬁve of them no other medication was noted. In four cases the outcome was mentioned, which was invariably full recovery without sequelae after withdrawal of ginseng. Nervous system A 56-year-old woman with previous affective disorder had an episode of mania while taking ginseng (58A ). She was treated with neuroleptic drugs and benzodiazepines and ginseng was withdrawn. She made a full rapid recovery.

SEDA-26, 531) Hematologic Ginkgo biloba has well-documented antiplatelet effects, and bleeding complications can occur, including strokes. • A 59-year-old man developed bleeding complications after liver transplantation while taking Ginkgo biloba supplements (53A ). Postoperatively he developed large hematomas in the subphrenic space and near the porta hepatis. They were drained and his hematocrit fell to 21%. Three weeks later he complained of blurring in the right eye, and a vitreous hemorrhage was diagnosed. He then admitted to taking an unknown amount of Ginkgo biloba, which was withdrawn. Subsequently, no further bleeding episodes occurred. • A 78-year-old man developed progressive rightsided muscular weakness after a fall (54A ). A CT scan showed a subdural hematoma. He had taken 150 mg of Ginkgo biloba extract, and the authors believed that had caused or predisposed him to subdural hematoma.

Glycyrrhiza spp.

(SED-14, 1659; SEDA-24, 538; SEDA-25, 569; SEDA-26, 531) Electrolyte balance Glycyrrhizic acid has aldosterone-like effects and can cause hypokalemia (59A ).

• A 67-year-old Chinese man developed progressive muscular weakness. His medical history was unremarkable, but his urinary potassium excretion was high and he had hypokalemia and low plasma renin activity. He admitted taking a powdered Chinese herbal formulation for about 4 months, which was shown to contain large amounts of glycyrrhizic acid (336 mg/day). He was treated with spironolactone, and 2 weeks later his potassium values had normalized.

Hypericum perforatum (SED-14, 1660; SEDA-25, 570; SEDA-26, 532)

Ginseng

(SED-14, 1659)

The authors of a review of the adverse effects associated with Panax ginseng concluded that it is generally safe but at high doses can cause insomnia, headache, diarrhea, and cardiovascular and endocrine disorders (55R ). Inappropriate use and suboptimal formulations were deemed to be the most likely reason for adverse effects of ginseng. The authors of a systematic review reached similar conclusions and showed that serious adverse effects of ginseng seem to be true rarities (56M ).

Drug interactions In a systematic review of all reports of interactions of St John’s wort with ciclosporin, 11 case reports and two case series were found (60M ). In most cases there was little doubt about causality. Interactions of St John’s wort with prescribed drugs are due to the ability of hypericin to stimulate both CYP3A4 and the P glycoprotein transporter system (61E ). Other prescribed drugs that interact with St John’s wort include warfarin, oral contraceptives, theophylline, digoxin, HIV protease inhibitors, and serotonin re-uptake inhibitors (62R ). In a randomized, crossover study ﬁve patients with cancer taking irinotecan were given

518 St John’s wort (63c ). The plasma concentrations of irinotecan signiﬁcantly fell in the presence of the herbal remedy. The authors pointed out that this is likely to reduce the effectiveness of the anticancer drug. Cardiovascular A 41-year-old man had a hypertensive crisis after taking St John’s wort and enjoying cheese with red wine at the same time (64A ). St John’s wort is a monoamine oxidase inhibitor, and the authors believed that this explained how the concomitant use of a tyraminerich food with St John’s wort had caused this problem.

Illicium anisatum Drug contamination Japanese star anise, which contains the neurotoxin anisatin, was mixed into a commercially sold herbal tea, perhaps inadvertently (65c ). Consumption of this tea was associated with adverse events in 63 Dutch consumers. Their symptoms occurred 2–4 hours after they drank the tea and included general malaise, nausea, and vomiting. In 22 cases hospitalization was required, and 16 had generalized tonic–clonic seizures. All made a full recovery after withdrawal of the herbal tea. Anisatin is a non-competitive GABA-antagonist, which causes CNS hyperactivity, and the authors believed that this mechanism explained the high rate of seizures in these patients.

Paullinia cupana Cardiovascular The crushed seeds of Paullinia cupana are made into a dried paste called guaraná. All of its effects are directly related to its high caffeine content. US authors have reported two cases of ventricular extra beats associated with the intake of supplements containing guaraná (66A ). In both cases the supplements also contained multiple other ingredients, and causality was therefore not certain.

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E. Ernst

Piper methysticum

(SED-14, 1663; SEDA-25, 571; SEDA-26, 533) Nervous system Parkinsonism has been attributed to kava (67A ).

• A 45-year-old woman with a family history of essential tremor developed severe and persistent parkinsonism after taking kava extract for anxiety for 10 days. Her symptoms improved with anticholinergic drugs.

The authors concluded that kava derivatives can produce severe parkinsonism in individuals with a genetic susceptibility.

Liver damage from kava kava Kava kava (Piper methysticum) has been used for hundreds of years in the South Seas as a recreational drug and has been marketed in the West as a herbal pharmaceutical for use in the treatment of anxiety, for which it seems to be effective (68M ). However, the formulation used indigenously is an aqueous extract, while the pharmaceutical formulation is prepared from a lipid extract. There have been reports of liver damage with the latter (68M ), and it has therefore been banned in several countries. • A 34-year-old woman developed toxic hepatitis after taking kava-kava (69A ). Ultrasound showed an enlarged echogenic liver and histology showed centrolobular necrosis and periportal inﬂammation. After withdrawal of the kava the changes resolved completely. This case illustrates the high hepatotoxic potential of kava-kava.

Australia’s Therapeutic Goods Administration initiated a voluntary recall of all complementary medicines containing kava action after the death of a woman who used a medicine containing kava (70A ). Sponsors and retailers were asked to remove all products containing kava from the market immediately. Consumers were advised to discard kava-containing products in their possession. The Federal Institute of Germany has withdrawn all products that contain Kava kava and kavaine from the German market because of the risk of hepatotoxicity and insufﬁciently proven efﬁcacy. The regulation included homeopathic products with dilutions up to D4. The German

Treatments used in complementary and alternative medicine

regulation applies to all kava-containing pharmaceutical formulations. Moreover, following a provisional opinion from the UK Committee on Safety of Medicines (CSM), the Medicines and Healthcare products Regulatory Agency (MHRA) has consulted on a proposal to prohibit the sale, supply, or importation of unlicensed medicinal products containing kava in the UK. The CSM reviewed the issue of kavaassociated liver toxicity following the emergence of safety concerns in Europe. At that time, stocks of kava were voluntarily withdrawn by the herbal sector while the safety concerns were under investigation. Currently the MHRA is aware of 68 cases worldwide of suspected kava-associated liver problems, including six cases of liver failure that resulted in transplant, and three deaths. In the UK there have been three reports of kava-associated liver toxicity. The CSM has advised consumers to stop taking medicinal products containing kava, and to seek medical advice if they feel unwell or have concerns about possible liver problems. Finally, the FDA has advised consumers of the potential for liver injury by kava-containing dietary supplements. People who have liver disease or liver problems or who are taking medicines that can affect the liver have been advised to consult a physician before using kavacontaining supplements (71A ). Consumers who use kava-containing dietary supplements and who have signs of illness associated with liver disease should also consult a physician. The FDA has issued a letter to healthcare professionals informing them of the consumer advice and has urged consumers and healthcare professionals to report injuries that may be related to the use of kava. The incidence of liver damage with kava seems to be less than one case per million daily doses (72r ). The mechanism of the effect is currently unclear. It has been suggested that supervised, monitored, short-term medication with kava would still do more good than harm (73R ). However, the FDA will continue to investigate the relation, if any, between the use of dietary supplements containing kava and liver damage.

Spirulina

(SED-14, 1665)

Liver A 52-year-old Japanese man was admitted with signs and symptoms consistent with

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toxic liver damage (74A ). His medical history relevant to liver disease was unremarkable; in particular, his liver enzymes had been normal. It turned out that 5 weeks before admission he had started taking a remedy containing blue green algae (Spirulina). A lymphocyte stimulation test for Spirulina was positive and infectious hepatitis was excluded. Liver biopsy was consistent with toxic liver injury. After withdrawal of Spirulina all his liver enzymes quickly returned to normal.

Symphytum ofﬁcinale

(SED-14, 1665)

Liver Comfrey (Symphytum ofﬁcinale) contains pyrrolizidine alkaloids and has repeatedly been associated with hepatotoxicity. The author of a review of its toxicity pointed out that since 1990 no cases of adverse events have been reported and stated that comfrey has a history of effective therapeutic use in humans and that it “might not be as dangerous to humans as current restrictions indicate” (75R ).

Teucrium capitatum Liver A 62-year-old man had taken a tea made from Teucrium capitatum for 4 months when he developed anorexia, nausea, and malaise (76A ). He also noted dark urine and jaundice. He was admitted to hospital with acute icteric hepatitis. A liver biopsy showed bridging necrosis, inﬂammatory inﬁltration, and bile emboli. After withdrawal of the herbal tea he made a full recovery within 3 months.

Proprietary mixtures Liver The slimming aid “LipoKinetix” contains norephedrine hydrochloride, sodium usinate, 3,5-diiodothyronine, yohimbine hydrochloride, and caffeine. Seven patients all had the signs and symptoms of acute toxic hepatitis after taking this dietary supplement (77A ). Three patients had taken no other concomitant medications. All recovered spontaneously after “LipoKinetix” was withdrawn.

520 Copaltra is a herbal tea sold in France as an adjuvant therapy for diabetes. It contains Coutarea latiﬂora (50 g) and Centaurium erythreae (50 g). A 49-year-old black woman was admitted with jaundice and raised liver enzymes 4 months after starting to take Copaltra (78A ). She also took fenoﬁbrate, polyunsaturated fatty acids, metformin, benﬂuorex, and veralipride. Liver biopsy conﬁrmed the diagnosis of acute, severe, cytolytic hepatitis, most likely druginduced. She made a full recovery after withdrawal of Copaltra. The authors mentioned that ﬁve similar cases of Copaltra-induced hepatitis have been reported to the French authorities. Hematologic A 55-year-old man with localized prostate cancer was given pravastatin (10 mg/day) and aspirin (325 mg/day) (79A ). He also took food supplements containing about 30 different ingredients, most notably niacin 2250 g/day. During preparation for prostate surgery it was discovered that his prothrombin time was slightly prolonged (17 sec, normal 11.4–14.4 sec). All prescribed medications were withheld, but his prothrombin time continued to be abnormal (24.1 sec). The authors thought that the high dose of niacin had caused this abnormality.

ACUPUNCTURE

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No reason for this unusual phenomenon other than acupuncture could be found. The authors pointed out that in Chinese medicine, acupuncture at the points used in this patient promotes lactation. Infection risk Microbiologists from Hong Kong have reported four cases of mycobacterial infections within 2 years (83A ). All the patients had lesions at acupuncture points. Acid-fast bacilli were present in two cases. Gene sequencing identiﬁed the strain from two patients as Mycobacterium chelonae and from two patients as Mycobacterium nonchromogenium. • A 37-year-old man with diabetes had septicemia and compartment syndrome of the leg after acupuncture in the calf area (84A ). Decompression fasciotomy was performed and Gram-positive cocci were grown from the wound swab and group A streptococci from blood cultures. He required intensive care, including intravenous antibiotics, and eventually recovered.

Endophthalmitis occurred in a patient from Singapore (85A ). Group B streptococci were isolated from the blood. Despite aggressive intravitreal antibiotic therapy the affected eye lost its light perception.

AROMATHERAPY

(SED-14, 1668;

(SED-14, 1673; SEDA-24, 540; SEDA-25, 573; SEDA-26, 535)

SEDA-25, 573)

The authors of a review of the risks associated with acupuncture concluded that serious complications are rare (80R ). They included pneumothorax (more than 90 cases on record), cardiac tamponade (six cases), injuries of the spinal cord (10 cases), and infections (126 cases), particularly hepatitis.

Immunologic Aromatherapy is not associated with serious direct risks, with one exception: allergic contact dermatitis. In one report four cases of such events caused by essential oils used in aromatherapy were described (86A ). The authors pointed out that aromatherapists should be aware of the dangers of sensitization.

Respiratory A 30-year-old woman developed bilateral chest pain and dyspnea after paraspinal acupuncture resulted in bilateral pneumothorax; she recovered fully within 2 days (81A ).

SEDA-25, 573)

Endocrine A 41-year-old woman with breast cancer was treated with acupuncture for pain control (82A ). She had an episode of galactorrhea 6 days after the ﬁrst treatment and also during the second acupuncture treatment.

The author of a review of the safety of homeopathic products concluded that they are usually safe, but that continued vigilance is in order, not least because of the currently high popularity of homeopathy (87R ). In response, it was pointed

HOMEOPATHY

(SED-14, 1668;

Treatments used in complementary and alternative medicine

out that under-reporting is high, that homeopathic products are often mistaken for herbal medicines, and that the main risks of homeopathy relate to the prescriber rather than the medicine (88r ).

SPINAL MANIPULATION (SED-14, 1674; SEDA-24, 540; SEDA-25, 575; SEDA-26, 536) Cardiovascular Reports of arterial dissection after spinal manipulation have been published. • Two patients had oculosympathetic palsy after self-treatment with a “shiatsu-massager” (89A ). A thorough diagnostic work-up, including MRI and MRA scans, identiﬁed dissection of the carotid artery as the cause of the problem. In the absence of other causes, the authors believed that the selftreatment had caused dissection. • A 32-year-old woman who had seen a traditional American “bone-setter” for shoulder problems was subjected to a “sudden thrusting of the head upward and to the right” (90A ). She had neck discomfort immediately afterwards. The pain persisted for 6 days, when she noted vertigo and left-sided ataxia. An MRI scan showed acute infarction in the middle left cerebellar hemisphere and vermis. An MRA scan showed left vertebral artery dissection with a probable embolus.

Nervous system Spinal damage can occur after spinal manipulation. • A 46-year-old man consulted a traditional Chinese “bone setter” for persistent neck pain (91A ). The healer had “forcefully rotated his head to one side and then to the other side”. The patient immediately developed numbness of the whole body and dyspnea. An MRI scan showed incomplete cervical cord injury with mild cervical cord swelling. He was treated with high-dose methylprednisolone and made a good recovery with only minimal persistent deﬁcits. • A 67-year-old woman had spinal manipulation for neck pain and experienced severe pain (92A ). She subsequently noted weakness of her left side, which worsened rapidly and also affected bladder function. She had a left-sided ptosis, all sensation was impaired below C6, and she had urinary incontinence. An MRI scan showed an epidural hematoma in the left posterolateral aspect of the spinal cord at C3–C5. Laminectomy was performed and a large epidural hematoma was removed. She subsequently made a full recovery.

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Indirect risks of complementary/alternative therapies Even if complementary therapies were not associated with direct risks they could be linked with a range of indirect risks, i.e. risks that are not due to the treatment itself but arise from the context in which is used. When 1593 visitors to a “health fair” were surveyed on their use of complementary medicine, it emerged that elderly users were signiﬁcantly less likely to use inﬂuenza immunization (93C ). Students of a Canadian chiropractic college were questioned about whether they agreed with immunization in general. The longer they had attended college, the less favorable their attitude towards immunization became (94C ). An analysis of the contents of 22 leading antiimmunization websites showed that about 70% of these sites claimed that homeopathy represented an alternative to conventional vaccination (95R ). In a similar study it was found that 39% of the anti-immunization websites claimed that natural lifestyle conveys immunity to infections, thus allegedly rendering immunization unnecessary, and 45% claimed that “alternative health” is superior to immunization (96R ). In another study homeopaths and chiropractors were speciﬁcally asked about their advice regarding MMR immunization; 40% of the homeopaths and 19% of the chiropractors admitted advising mothers against it (97C ). More and more patients seek advice on complementary medicine via the internet. It is therefore important to monitor the validity of such advice. We identiﬁed the 13 most popular websites on complementary medicine for cancer (98C ). Most of them recommended cancer therapies for which there was no evidence of efﬁcacy. Three of the sites overtly discouraged cancer patients from using conventional therapies. When we repeated the study, this time focussing on HIV instead of cancer, the results were virtually identical (99C ). Our ﬁndings were similar to those of another study of 61 popular web sites on herbal medicines for cancer (100C ). Most of these sites were commercial by nature and claimed cancer cures through herbal medicines, with little regard for current regulations. We also sought the advice of medical herbalists regarding the administration of herbal medicines during pregnancy (101C ). We found that herbalists readily volunteer such advice,

522 but the nature of their advice is misleading at best and dangerous at worst. Others have studied the impact of herbal medicine on the use of conventional treatments (102C ). Their results

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showed that 32% of female patients in internal medicine delayed obtaining conventional care while waiting for a herbal medicine to work.

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19. Yang S, Dennehy CE, Tsourounis C. Characterizing adverse events reported to the California Poison Control System on herbal remedies and dietary supplements: a pilot study. J Herbal Pharmacother 2002; 2: 1–10. 20. Tagwireyi D, Ball DE, Nhachi CFB. Poisoning in Zimbabwe: a survey of eight major referral hospitals. J Appl Toxicol 2002; 22: 99–105. 21. Li AM, Hui J, Chik KW, Li CK, Fok TF. Topical herbal medicines causing haemolysis in glucose-6phosphate dehydrogenase deﬁciency. Acta Paediatr Int J Paediatr 2002; 91: 1012. 22. Anonymous. Herbal dietary supplements (PCSPES and SPES). Adulteration with prescription only medicines precipitates regulatory action. WHO Pharmaceuticals Newslett 2002; 2: 1–2. 23. Drew AK, Bensoussan A, Whyte IM, Dawson AH, Zhu X, Myers SP. Chinese herbal medicine toxicology database: monograph on Radix sophorae ﬂavescentis, “Ku shen”. Clin Toxicol 2002; 40: 173–6. 24. Drew AK, Whyte IM, Bensoussan A, Dawson AH, Zhu X, Myers SP. Chinese herbal medicine toxicology database: monograph on Herba asari, “Xu Xin”. Clin Toxicol 2002; 40: 169–72. 25. Lin C-C, Chen J-C. Medicinal herb Erycibe henri Prain (Ting Kung Teng) resulting in acute cholinergic syndrome. J Toxicol Clin Toxicol 2002; 40: 185–7. 26. McRae CA, Agarwal K, Mutimer D, Bassendine MF. Hepatitis associated with Chinese herbs. Eur J Gastroenterol Hepatol 2002; 14: 559– 62. 27. Mantani N, Kogure T, Sakai S, Goto H, Shibahara N, Kita T, Shimada Y, Terasawa K. Incidence and clinical features of liver injury related to Kampo (Japanese herbal) medicine in 2,496 cases between 1979 and 1999: problems of the lymphocyte transformation test as a diagnostic method. Phytomedicine 2002; 9: 280–7. 28. Wrobel A. Umfrage zu Kräutern und Kräuterprodukten bezüglich Pestizid- und Schadstoffbelastungen. Akupunktur 2002; 30: 38–40. 29. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Intern Med 2002; 252: 107–13. 30. Daniels J, Shaw D, Atherton D. Use of Wau Wa in dermatitis patients. Lancet 2002; 360: 1025. 31. Anonymous. Traditional medicines. Adulterants/undeclared ingredients pose safety concerns. WHO Pharmaceuticals Newslett 2002; 1: 11–12. 32. Florkowski CM, Elder PA, Lewis JG, Hunt PJ, Munns PL, Hunter W, Baldwin D. Two cases

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50. Durbin RJ, Waxman HA, Davis SA. Adverse event reports from Metabolife. House Committee on Government Reform, Oct 2002. http:// reform.house.gov/min/pdfs/pdf_inves/pdf_dietary_ ephedra_metabolife_rep.pdf.2002. 51. Kaberi-Otarod J, Conetta R, Kundo KK, Farkash A. Ischemic stroke in a user of Thermadrene: a case study in alternative medicine. Clin Pharmacol Ther 2002; 72: 343–6. 52. Traboulsi AS, Viswanathan R, Coplan J. Suicide attempt after use of herbal diet pill. Am J Psychiatry 2002; 159: 318–19. 53. Hauser D, Gayowski T, Singh N. Bleeding complications precipitated by unrecognized Ginkgo biloba use after liver transplantation. Transplant Int 2002; 15: 377–9. 54. Miller LG, Freeman B. Possible subdural hematoma associated with Ginkgo biloba. J Herbal Pharmacother 2002; 2: 57–63. 55. Xie J-T, Mehendale SR, Maleckar SA, Yuan CS. Is ginseng free from adverse effects? Oriental Pharm Exp Med 2002; 2: 80–6. 56. Coon JT, Ernst E. Panax ginseng. A systematic review of adverse effects and drug interactions. Drug Saf 2002; 25: 323–44. 57. Anonymous. Ginseng—hypertension. WHO SIGNAL 2002. 58. Vazquez I, Aguera-Ortiz LF. Herbal products and serious side effects: a case of ginseng-induced manic episode. Acta Psychiatr Scand 2002; 105: 76–8. 59. Lin S-H, Chau T. A puzzling cause of hypokalaemia. Lancet 2002; 360: 224. 60. Ernst E. St John’s wort supplements endanger the success of organ transplantation. Arch Surg 2002; 137: 316–19. 61. Karyekar CS, Eddington ND, Dowling TC. Effect of St John’s wort extract on intestinal expression of cytochrome P4501A2: studies in LS180 cells. J Postgrad Med 2002; 48: 97–100. 62. Henderson L, Yue QY, Bergquist C, Garden B, Arlett P. St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002; 54: 349–56. 63. Mathijssen RHJ, Verweij J, De Bruin P, Loos WJ, Sparreboom A. Effects of St John’s wort on irinotecan metabolism. J Natl Cancer Inst 2002; 94: 1247–9. 64. Patel S, Robinson R, Burk M. Hypertensive crisis associated with St John’s wort. Am J Med 2002; 112: 507–8. 65. Johanns ESD, Van Der Kolk LE, Van Gemert HMA, Sijben AEJ, Peters PWJ, De Vries I. Een epidemie van epileptische aanvallen na drinken van kruidenthee. Ned Tijdschr Geneeskd 2002; 146: 813–16. 66. Baghkhani L, Jafari M. Cardiovascular adverse reactions associated with guaraná: is there a causal effect? J Herbal Pharmacother 2002; 2: 57–61. 67. Meseguer E, Taboada R, Sanchez V, Mena, MA, Campos V, Garcia de Yebenes J. Life-threatening parkinsonism induced by kava-kava. Movement Disord 2002; 17: 195–6.

524 68. Stevinson C, Huntley A, Ernst E. A systematic review of the safety of kava extract in the treatment of anxiety. Drug Saf 2002; 25: 251–61. 69. Weise B, Wiese M, Plotner A, Ruf BR. Toxic hepatitis after intake of kava-kava. Vergauungskrankheiten 2002; 20: 166–9. 70. Anonymous. Kava-kava. More withdrawals due to hepatotoxic risks. WHO Pharmaceuticals Newslett 2002; 3: 4–5. 71. Anonymous. Kava-kava. Further investigations into Piper methysticum and liver injury. WHO Pharmaceuticals Newslett 2002; 2: 2–3. 72. Ernst E. Safety concerns about kava. Lancet 2002; 359: 1865. 73. Teschke R. Hepatotoxizität durch Kava–Kava. Deutsch Ärzteblatt 2002; 99: A3411–18. 74. Iwasa M, Yamamoto M, Tanaka Y, Kaito M, Adachi Y. Spirulina-associated hepatotoxicity. Am J Gastroenterol 2002; 97: 3212–13. 75. Rode D. Comfrey toxicity revisited. Trends Pharmacol Sci 2002; 23: 497–9. 76. Dourakis SP, Papanikolaou IS, Tzemanakis EN, Hadziyannis SJ. Acute hepatitis associated with herb (Teucrium capitanum L.) administration. Eur J Gastroenterol Hepatol 2002; 14: 693–5. 77. Favreau JT, Ryu ML, Braunstein G, Orshansky G, Park SS, Coody GL, Love LA, Fong T-L. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136: 590–5. 78. Wurtz A-S, Vial T, Isoard B, Saillard E. Possible hepatotoxicity from Copaltra, an herbal medicine. Ann Pharmacother 2002; 36: 941–2. 79. D’Amico AV, Toupless G, Lopes L, Valentine KJ, Cormack RA, Tempany CM, Kumar S, Marks PJ. Self-administration of untested medical therapy for treatment of prostate cancer can lead to clinically signiﬁcant adverse events. Int J Radiation Oncol Biol Phys 2002; 54: 1311–13. 80. White AR, Ernst E. Risks associated with acupuncture. Perfusion 2002; 15: 153-8. 81. Ramnarain D, Braams R. Bilateral pneumothorax in a young woman after acupuncture. Ned Tijdschr Geneeskd 2002; 146: 172–5. 82. Jenner C, Filshie J. Galactorrhoea following acupuncture. Acupunct Med 2002; 20: 107–8. 83. Woo PCY, Leung K-W, Wong SSY, Chong KTK, Cheung EYL, Yuen K-Y. Relatively alcoholresistant mycobacteria are emerging pathogens in patients receiving acupuncture treatment. J Clin Microbiol 2002; 40: 1219–24. 84. Shah N, Hing C, Tucker K, Crawford R. Infected compartment syndrome after acupuncture. Acupunct Med 2002; 20: 105–6. 85. Lee S-Y, Chee S-P. Group B Streptococcus endogenous endophthalmitis: case report and review of the literature. Opthalmology 2002; 109: 1879– 86.

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86. Bleasel N, Tate B, Rademaker M. Allergic contact dermatitis following exposure to essential oils. Australas J Dermatol 2002; 43: 211–13. 87. Kirby B. Safety of homeopathic products. J R Soc Med 2002; 95: 221–2. 88. Fisher P, Dantas F, Rampes H. The safety of homeopathic products. J R Soc Med 2002; 95: 474– 5. 89. Elliott MA, Taylor LP. “Shiatsu sympathectomy”: ICA dissection associated with a shiatsu massager. Neurology 2002; 58: 1302–4. 90. Quintana JG, Drew EC, Richtsmeier TE, Davis LE. Vertebral artery dissection and stroke following neck manipulation by native American healer. Neurology 2002; 58: 1434–5. 91. Chung OM. MRI conﬁrmed cervical cord injury caused by spinal manipulation in a Chinese patient. Spinal Cord 2002; 40: 196–9. 92. Tseng SH, Lin SM, Wang CH. Cervical epidural hematoma after spinal manipulation therapy. J Trauma Inj Infect Crit Care 2002; 52: 582–6. 93. Robinson AR, Crane LA, Davidson AJ, Steiner JF. Association between use of complementary/alternative medicine and health-related behaviors among health fair participants. Prev Med 2002; 34: 51–7. 94. Busse JW, Kulkarni AV, Campbell JB, Injeyan HS. Attitudes towards vaccination: a survey of Canadian chiropractic students. Can Med Assoc J 2002; 166: 1531–4. 95. Wolfe RM, Sharp LK, Lipsky MS. Content and design attributes of antivaccination web sites. J Am Med Assoc 2002; 287: 3245–8. 96. Davies P, Chapman S, Leask J. Antivaccination activists on the world wide web. Arch Dis Child 2002; 87: 22–5. 97. Schmidt K, Ernst E. Aspects of MMR. Br Med J 2002; 325: 597. 98. Ernst E, Schmidt K. “Alternative” cancer cures via the Internet? Br J Cancer 2002; 87: 479–80. 99. Schmidt K, Ernst E. “Alternative” therapies for HIV/AIDS: how safe is Internet advice? A pilot study. Int J STD AIDS 2002; 13: 433–5. 100. Bonakdar RA. Herbal cancer cures on the web: noncompliance with the Dietary Supplement Health and Education Act. Fam Med 2002; 34: 522–7. 101. Ernst E, Schmidt K. Health risks over the internet: advice offered by “medical herbalists” to a pregnant woman. Wien Med Wochenschr 2002; 152: 190–2. 102. Brienza RS, Stein MD, Fagan MJ. Delay in obtaining conventional healthcare by female internal medicine patients who use herbal therapies. J Women’s Health Gender Med 2002; 11: 79–87.

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49

Miscellaneous drugs, materials, and medical devices

Benzydamine Benzydamine is 1-benzyl-3-(3-dimethylaminopropoxy)-H-indazole, used for medical purposes as the hydrochloride. Benzydamine hydrochloride has analgesic, anti-inﬂammatory, and antipyretic effects. In the past it has been especially used in the symptomatic treatment of edematous postoperative or traumatic swelling, non-speciﬁc inﬂammation of the upper respiratory tract, and inﬂammation of connective tissues and joints. Nowadays, Tantum verde is the only such formulation listed in Germany; it is used for the treatment of oral and pharyngeal inﬂammation and can be administered as a spray, a gargle solution, or a rinsing solution. Skin Photocontact dermatitis has occurred after topical and systemic treatment (1c –3c ). • A 67-year-old woman with pharyngitis gargled with Tantum verde, and after 3 weeks, during a holiday, developed an erythematous rash on sunexposed skin, worsening within the next few days (4c ). She had not used a sunscreen. There were mainly well-demarcated areas of eczema on the face, neck, neckline, forearms, and lower legs. After oral and topical corticosteroids, the skin lesions improved within a few days.

There have only been two other case reports of photoallergic dermatitis after local pharyngeal treatment with formulations containing benzydamine (2c ). This presumably occurs because of oral or intestinal absorption.

Citric acid

(SEDA-26, 541)

Treatment of complex and large urinary calculi secondary to infection can be difﬁcult, © 2004 Published by Elsevier B.V. Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

and complete removal of the stone may not always be possible. Residual stone fragment rates are 37% (range 10–57%) after percutaneous nephrolithotomy and 20% after anatrophic nephrolithotomy (5R ). Technical advances in the management of urinary calculi have resulted in improved stone clearance rates in these cases. Owing to a combination of factors, such as large stone mass, associated infection, abnormal renal anatomy, and poor general health of the patient, infection stones can still pose a difﬁcult treatment problem. This has resulted in the use of alternative (and minimally invasive) treatment options. Dissolution treatment, either alone or as adjuvant therapy, has been used. Citric acid, in various concentrations, has been used in dissolution treatment (6S ). Citric acid, being a urinary acidiﬁer, inhibits the formation of precipitates of calcium phosphate, calcium carbonate, and magnesium ammonium phosphate and allows dissolution of stones. It may also help to reduce the size of calculi, allowing spontaneous elimination. Citric acid has been used to treat 22 patients (10 men and 12 women, mean age 45, range 15–60 years; 23 affected kidneys) with kidney stones (14 staghorn calculi, four partial staghorn calculi, and ﬁve large-burden calculi) (7C ). They underwent irrigation with solution R (citric acid monohydrate 6 g, magnesium carbonate 2.8 g, glucolactone 0.6 g, and water 100 ml) following debulking of the stone with percutaneous nephrolithotomy (n = 20), ureteroscopy, and shock wave lithotripsy (n = 2) combined with open procedures (n = 4). Irrigation was performed through a nephrostomy tube (n = 20) or in a retrograde fashion (n = 3) using a closed infusion pump system (40 ml/hour). The response to treatment was checked using a nephrostogram and/or plain X-ray. In six kidneys irrigation had to be abandoned because of loin pain, leak, or sepsis after

525

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an average duration of 2 (1–5) days. The average duration of irrigation was 6 (1–20) days. At the end of irrigation, four kidneys had complete radiographic clearance, and the stone was reduced to calyceal dust in three. There was a partial response in 11 and no response in ﬁve. Following alternative interventions in six cases (four with a partial response and two with no response) further clearance was achieved in three and calyceal dust in three. The response was better if the stone was reduced to less than 10 mm before irrigation. At the mean followup of 2.4 (1–4) years, of 13 kidneys with stone clearance or calyceal dust, nine suffered recurrence or re-growth, ﬁve of which required further interventions. Only four of the 23 kidneys remained stone free. In patients with complex stone disease, adjuvant solution R irrigation can reduce the stone burden, although the overall success rate is limited. However, there is a considerable potential for adverse effects, necessitating close monitoring for sepsis and electrolyte abnormalities.

Collagen

N.H. Choulis

• A 64-year-old woman with recurrent urinary leakage elected to undergo conservative therapy with collagen injection, had no reaction to a collagen skin test, and had an uneventful transurethral injection of collagen 30 days later (11c ). Her postoperative course was complicated by urethritis, trigonitis, severe urge, bilateral leg arthralgias, leg pain relieved by massage, and leg edema at 6 weeks. She had a total voided volume of 300 ml and a postvoid residual of 180 ml, and was started on intermittent self-catheterization for urinary retention. Induration at the skin injection test site was noticeable 9 weeks after the injection. Her severe urge, leg edema, and pain gradually resolved after 13 months, but her stress incontinence continued without relief. • A 50-year-old woman with stress urinary incontinence chose a trial of transurethral injection of collagen (12c ). A skin test showed no evidence of allergy at 1 month and collagen 2.5 ml was injected transurethrally without problems but with little improvement. A second injection of 2.5 ml 5 weeks later was again uneventful, but 2 weeks later she began to have difﬁculty in emptying her bladder, with a poor stream and a sense of incomplete emptying. At the same time she noticed redness and ﬁrmness at the initial skin test site on her arm, which had previously been benign.

Disulﬁram

(SED-14, 1683)

Collagen is a natural ﬁbrous protein found in human cartilage, connective tissue, and bone. Glutaraldehyde cross-linked bovine collagen is a sterile, biocompatible, biodegradable, puriﬁed bovine dermocollagen cross-linked with glutaraldehyde, mixed in a phosphate-buffered saline solution. It has been used for the treatment of stress urinary incontinence since the late 1980s (8c ). Transurethral injection of bovine collagen is considered safe and effective, with minimal complications (9r ). It is associated with a minimal inﬂammatory response and no foreign body reactions. Immunologic Delayed hypersensitivity reactions after bovine collagen injection for stress urinary incontinence have been reported. • A 50-year-old woman had a negative collagen skin test for 4 weeks (10A ). After an injection of transurethral collagen she developed a ﬂare-up at the skin test site and subsequently had recurrent ﬂares at 21–26 day intervals for six cycles, which corresponded to her menses and were thought to be hormone-related.

(SED-14, 1697; SEDA-25, 580; SEDA-26, 541) Disulﬁram, widely used in the treatment of chronic alcoholism, inhibits aldehyde dehydrogenase, resulting in aversive symptoms after the ingestion of ethanol (13R ). Several adverse effects of disulﬁram itself (as opposed to the aldehyde that it allows to accumulate) have been described. They include neurological reactions and skin reactions, but hepatotoxicity is the only previously reported life-threatening reaction, and it is rare (14C ). Disulﬁram also modiﬁes the metabolism of many drugs by inhibiting the cytochrome CYP2E1. Adverse reactions to disulﬁram occur with a frequency of 1 in 200 to 1 in 2000 per treatment year (15C ). The death rate is about 1 per 25 000 patients per year, and hepatic failure accounts for most of these. Psychiatric Psychotic reactions to disulﬁram are uncommon. • A 47-year-old man with alcohol abuse took disulﬁram (16c ). He developed a psychosis while taking it and for 2 weeks after. He stated that he had

Miscellaneous drugs, materials, and medical devices not taken alcohol. He was successfully treated with antipsychotic drugs. Afterwards it was discovered that his family history was positive for schizophrenia; it is therefore possible that he was more vulnerable to develop psychosis due to disulﬁram.

Skin A fatal rash has been attributed to disulﬁram. • A 47-year-old man developed a generalized rash and malaise (17c ). He had chronic alcoholism and had taken disulﬁram 250 mg/day for 1 month. He denied previous liver disease, blood transfusions, or having taken hepatotoxic drugs or alcohol. He was given clarithromycin 500 mg bd and paracetamol 500 mg tds and 1 week later noticed nonpruritic cutaneous maculopapular lesions on the legs, which spread to the rest of his body, excluding the palms and soles. His temperature was 41◦ C, his blood pressure 90/60 mmHg, and his heart rate 130/min. There were no signs of encephalopathy. His conjunctivae were yellow. There was furfuraceous desquamation on his face and conﬂuent erythematous annular lesions with a purpuric component on the groins, thighs, and the undersides of his arms. There was edema of the hands and feet. During the next several days the skin lesions worsened. He developed blisters, initially covering less than 10% of the body surface, but then extending all over the body. He developed septic shock and, despite supportive measures, died.

Fluorides

(SED-14, 1706)

Fluoride is the single most potent bone-forming agent currently available for therapeutic use (18A ). The active moiety is the ﬂuoride ion itself, and different ﬂuoride products have been used for the therapy of osteoporosis. The ﬁrst was sodium ﬂuoride (NaF), but that had several adverse effects, such as epigastric pain, gastric hemorrhage, leg pain, and so-called stress fractures (19R ). A 3-year, open study (20C ) has been performed with monoﬂuorophosphate in 60 patients under 75 years old (average age 62 years, body weight 42–84 kg, height 148–174 cm) with established postmenopausal vertebral osteoporosis and a lumbar t-score lower than −2.5 BDM (measured by dual-energy X-ray absorptiometry) and at least one vertebral fracture diagnosed according to WHO criteria (21S ). The patients had taken HRT for an average of 2 years. Patients with inﬂammatory

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527

rheumatic diseases and those who were taking other medications that can modify bone metabolism, such as calcitonins, bisphosphonates, vitamin D, or anabolic agents, were excluded. There were adverse events in 19 patients, 10 of which were probably due to the monoﬂuorophosphate or calcium components, three with gastrointestinal symptoms and seven with leg pain. The other nine adverse events were probably due to the HRT component: three with vaginal bleeding, four with breast tenderness, one with “heavy legs”, and one with increased body weight. All the adverse events were of mild or moderate intensity and resolved spontaneously; none required withdrawal of treatment.

Gelatin (SED-14, 1144; SEDA-24, 374; SEDA-26, 24) Immunologic Several reports have highlighted the importance of gelatin allergy in young children, with some deaths due to anaphylaxis. A 2-year-old and a 4-year-old boy developed anaphylactic symptoms after being given a chloral hydrate suppository, which contained gelatin, for sedation before electroencephalography (22A ). Chloral hydrate suppositories are often used to sedate children during various examinations and the authors suggested using gelatin-free formulations.

Glycerine Moisturizing creams have beneﬁcial effects in the treatment of dry, scaly skin, but they can cause adverse skin reactions. In a double-blind, randomized study, 197 patients with atopic dermatitis, none of whom had known allergy to ingredients in the test creams, were randomized to one of three creams: 20% glycerine (55 women and 13 men, mean age 35 years), 4% urea plus 4% sodium chloride (47 women and 16 men, mean age 32 years), and vehicle (49 women and 17 men, mean age 34 years); they were asked to apply the cream at least once daily for 30 days (23R ). After 2 weeks the patients were asked to score the degree of smarting sensation (a sharp, local, superﬁcial

528 effect), stinging, itching, and dryness/irritation on a ﬁve-point scale (0–4). They were also asked to note skin dryness at the beginning of the study and after 1 month on a visual analogue scale. A dermatologist assessed dry skin at the start and after 30 days using the product of the sum of severity scores and area affected in four body regions (24c ). Adverse skin reactions such as smarting were signiﬁcantly less common among patients who used the 20% glycerine cream (10%) compared with the urea–saline cream (24%). There were no differences in other skin reactions, such as stinging, itching and dryness/irritation.

Grapefruit juice Drug interactions By December 2002 the Australian Adverse Drug Reactions Advisory Committee had received 14 reports of possible drug interactions with grapefruit juice (25R ). Most of the reports involved interactions with dihydropyridine calcium channel blockers (ﬁve reports) and HMG-CoA reductase inhibitors (statins, ﬁve reports). The committee reminded prescribers that several drug classes can interact with grapefruit juice and that patients taking these drugs should be made aware of this. Health Canada has also advised the public not to take grapefruit or its juice (fresh or frozen) with certain drugs, since several substances in grapefruit can interfere with their metabolism, leading to higher blood concentrations with serious or even life-threatening adverse reactions (26A ). Affected products include (but are not limited to) drugs used in treating conditions such as angina, anxiety, cancer, convulsions, depression, erectile dysfunction, gastrointestinal reﬂux, high blood pressure, high lipid concentrations, HIV/AIDS, other infections, irregular heart rhythms, organ graft rejections, and psychotic problems. As little as one glass of grapefruit juice can cause an increased blood drug concentration and the effects can last for 3 days or more. Health Canada has issued several communication documents to remind health professionals of possible interactions of grapefruit with therapeutic drugs. In addition, Health Canada is working with drug manufacturers whose products are adversely

Chapter 49

N.H. Choulis

affected by grapefruit to ensure that the relevant information is printed on the product label.

Isosulfan blue

(SEDA-26, 543)

Isosulfan blue is a blue dye of the triphenylmethane family. Similar dyes have been used since the 1930s, primarily to visualize the lymph vessels before lymphangiography. Recently, isosulfan blue has been used during sentinel lymph node biopsy in patients with breast cancer as part of the staging process, since histopathological examination of sentinel lymph nodes can be used to predict the presence of metastases in the remainder of the lymphatics. This technique can spare many patients from radical lymph node dissection. Sentinel lymph node detection was ﬁrst described in 1977 in 80 patients with penile cancer, and this technique is currently being used or tested in patients with melanoma, breast cancer, colon cancer, certain types of thyroid and lung cancer, endometrial cancer, and various types of squamous cell cancers (27A ). Isosulfan blue is the only dye approved by the FDA for visualization of the lymphatic system (28S ). It is the best dye for this use, because of its rapid uptake into lymph tissues with little diffusion to other surrounding tissues. Immunologic There have been reports of isosulfan blue anaphylaxis in which evidence of an IgE mediated mechanism was provided by positive skin tests. • A 60-year-old woman with stage II carcinoma of the right breast underwent a sentinel lymph node biopsy (29c ). About 5 minutes after the subcutaneous administration of isosulfan blue 5 ml, she developed hypotension, hypoxemia (oxygen saturation 74%), wheezing, and diffuse urticaria. She required three intravenous doses of adrenaline 1 μg followed by two intravenous doses of 10 μg each. She was intubated and recovered without sequelae. • A 62-year-old woman with breast cancer underwent bilateral sentinel lymph node biopsy, and about 40 minutes after the start of the procedure developed hypotension and tachycardia (29c ). She did not have wheezing, desaturation, or urticaria. Despite treatment with phenylephrine (4 × 100 μg), her hypotension (70/40 mmHg) persisted for about 30 minutes. She recovered without sequelae.

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• A 54-year-old woman with an inﬁltrating breast carcinoma and no known drug allergies received isosulfan blue 5 ml into the left breast parenchyma, which was then massaged for 5 minutes (30c ). About 10 minutes later she developed hypotension and a red skin rash, which was not urticarial. She was given methylprednisolone and intravenous phenylephrine and recovered.

Polidocanol is a safe and effective sclerosing agent with an extremely low risk of local and systemic complications (33R ).

Phosphates

(SEDA-25, 581)

Sodium phosphates oral solution has been marketed in Canada since 1987 as a laxative for the relief of occasional constipation. It is also used as part of a bowel-cleansing regimen in preparing patients for surgery or colonoscopy. From 1987 to October 31, 2001 the Canadian Adverse Drug Reaction Monitoring Program received 10 reports of serious electrolyte disturbances (hypocalcemia, hyperphosphatemia, hypernatremia, and hypokalemia), acidosis, dehydration, renal insufﬁciency, and tetany in patients who had taken more than 45 ml of the solution, in patients at risk of these complications, and/or in patients using multiple purgatives for bowel preparation (31C ). In view of these reports, Johnson & Johnson, Merck Consumer Pharmaceuticals, and Pharmascience Inc, in consultation with Health Canada, have each issued a letter to all health professionals, giving information related to the safe use of sodium phosphates oral solution. The identiﬁcation, characterization, and management of drug-related adverse events depends on the active participation of health care professionals in adverse drug reaction reporting programs. Health care professionals are asked to report any suspected adverse reactions in patients who have taken sodium phosphates oral solution.

Polidocanol Sclerotherapy is well established for the treatment of esophageal varices, vascular malformations, recurrent pleural effusion, ganglions, hemorrhoids, and peripheral varicose veins. The common mechanism of action of all sclerosing agents is destruction of endothelial surfaces, with subsequent thrombosis, leading to intimal ﬁbrosis and obliteration of the vessel lumen (32A ).

Cardiovascular Cardiac arrest has been reported in a child who received polidocanol for the treatment of a symptomatic peripheral venous malformation (34C ). • A 5-year-old child with Klippel–Trenaunay syndrome, a cutaneous capillary malformation in the right leg, and a venous malformation of the lateral and posterior aspects of the right thigh and buttock had an injection of 1% polidocanol 4 ml into the malformation in the leg after oral premedication with midazolam 5 mg and atropine 0.5 mg and anesthesia with thiopental 80 mg and vecuronium bromide 2 mg for tracheal intubation. Shortly after the injection the patient developed rapidly progressive sinus bradycardia with eventual asystolic cardiac arrest. Anesthesia was discontinued and cardiopulmonary resuscitation, with 100% oxygen, external cardiac message, and intravenous orciprenaline 0.05 mg, was successful.

Silicone

(SED-14, 1686; SEDA-24, 548; SEDA-25, 583; SEDA-26, 544) Silicone granulomas are usually observed near silicone-injected areas (35S ). Facial granulomatous lesions and a connective tissue-like disorder have been attributed to silicone deposition following injection of silicone into the breasts (36c ). • A 56-year-old Japanese woman developed eyelid edema and erythema on her face and arms and 2 weeks later annular erythema on both arms, sicca syndrome, and progressive loss of sweating on her forehead. Laboratory studies, including muscle enzymes, antinuclear antibodies, and serum immunoelectrophoresis, were unremarkable. One month later, she developed skin lesions around the eyelids that resembled lupus miliaris disseminatus faciei. A biopsy showed non-caseating epithelioid granulomas in the mid-dermis, especially around the sweat glands. A CT scan of the chest showed ﬁbrous implant capsules in each breast, due to silicone injections 30 years before. Electron microscopy of a nodule from the lower eyelid showed particles of silicone within the granulomas. The silicone was thought to have been derived from the material that had been injected into her breasts. After subcutaneous mastectomy and axial lymphadenectomy the facial edema disappeared rapidly, but the nodules remained.

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Slim 10 Drug contamination “Slim 10”, an agent that was marketed in December 2001 as a Chinese Proprietary Medicine for slimming in Singapore, was withdrawn in April 2002 after it was found to contain undeclared substances (37R ). In March 2002 the ﬁrst report of acute hepatitis associated with “Slim 10” was received by Singapore’s Pharmacovigilance Unit, and three other reports, two of hyperthyroidism and one of menstrual irregularities, were subsequently received, prompting an investigation by the Singapore Health Sciences Authority. The investigation showed that “Slim 10” contained nicotinamide, fenﬂuramine, and thyroid gland components, and the Health Sciences Authority has initiated action against those who are involved in its sale and distribution.

Spermicides

(SED-14, 1687)

Modern spermicides are produced in a variety of formulations, including gels, foams, creams, suppositories, pessaries, capsules, foaming tablets, and melting ﬁlms. Spermicides are also used in conjunction with other methods, such as diaphragms, condoms, and sponges, but also with intrauterine contraceptive devices and methods based on fertility awareness (38A ). Contraceptive sponges are controversial: do they act by delivering spermicides or as barriers? However, it has been shown conclusively that the newest forms of sponges especially, which provide not one but a combination of three active spermicides, act much more like spermicides than as simple vaginal barriers. Spermicides are relatively inexpensive and, most importantly, widely available over the counter in most countries of the world. All of the currently used formulations contain the nonionic detergent nonoxynol-9, usually in a dose of 70–230 mg, but the newest formulations may contain octoxynol or benzalkonium chloride (39R ). All chemical agents used in spermicides disrupt the sperm cell membrane and ﬁnally rupture the cell. Spermicides, especially in certain communities, have important advantages over the more

N.H. Choulis

modern methods of contraception: they are immediately reversible, are available over the counter without prescription, can be used by breast-feeding women, and are under direct female control. However, spermicides also have adverse effects. They can cause local irritation in the woman or her partner, especially if they are used several times a day. Spermicides can cause local allergic reactions in the woman or her partner (very rarely). Infection risk Urinary tract infections are quite common although not very serious adverse effects of spermicides. For several years, the rate of urinary tract infections caused by the use of spermicides (in young sexually active women) has been uncertain and has not been thoroughly evaluated. Since this phenomenon was observed, special surveys have been carried out and several have conﬁrmed a higher risk of urinary tract infection among women who use a diaphragm with spermicides, compared with sexually active women who use other types of contraception (40S ). Finally, women who use spermicides are at higher risk of urinary tract infection than women who use other methods of contraception. Users of diaphragms and other barrier methods (including spermicide-coated male condoms) in conjunction with spermicides have increased degrees of introital and periurethral colonization with coliform organisms and Staphylococcus saproﬁticus, leading to urinary tract infection (41R ). Teratogenicity It has been suggested that the use of spermicides is related to congenital malformations in the children of mothers who have used this method of contraception. However, there is no evidence of an increased risk of fetal abnormalities in women who become pregnant while using spermicides, or in women who have used them before realizing that they were pregnant (42R ).

MISCELLANEOUS Reports on the adverse effects of other miscellaneous substances are listed in Table 1.

Miscellaneous drugs, materials, and medical devices

Chapter 49

531

Table 1. Miscellaneous reports Drug

Adverse effect(s)

Reference

Acamprosate Detergents FD and C Blue No 1 Food additives Gamolenic acid Lipokinetix Methylene blue injection Phenol Polyethylene glycol Polyvinylpyrrolidone Potassium salts Siliconized dressing Sodium metabisulﬁte

Diarrhea, mild abdominal pain Allergic contact dermatitis Intense green hyperpigmentation Urticaria Inadequate standards of efﬁcacy Liver injury Transient burning and blue discoloration Burns Fulminant pulmonary edema Allergic contact dermatitis Complex ventricular dysrhythmias Pigmentation abnormalities Bronchospasm, anaphylaxis and contact dermatitis Electrolyte disturbance, convulsions, syncope, metabolic alkalosis Empyema, dysrhythmia, respiratory failure Venous thromboembolism Risk of seizures

(43R ) (44c ) (45r ) (46c ) (47S ) (48A ) (49c ) (50c ) (51c ) (52c ) (53r ) (54r ) (55R )

Sodium picosulfate Talc Yasmin Visicol

(56R ) (57R ) (58R ) (59c )

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36. Suzuki K, Aoki M. Metastatic silicone granuloma: lupus miliaris disseminatus faciei-like facial nodules and sicca complex in a silicone breast implant recipient. Arch Dermatol 2002; 138: 537–8. 37. Anonymous. Slim 10. Withdrawal due to presence of undeclared substances. WHO Pharmaceuticals Newslett 2002; 4: 5. 38. Lech MM. Spermicides 2002: an overview. Eur J Contracept Reprod Health Care 2002; 7: 173–7. 39. Aubeny E, Colau JC, Nandeuil A. Local spermicidal contraception: a comparative study of the acceptability and safety of a new benzalkonium chloride, the vaginal capsule, with a reference formulation, the pessary. Eur J Contracept Reprod Health Care 2002; 5: 61–7. 40. Storm BL, Collins M, West SL, Kreisberg J, Weller S. Sexual activity, contraceptive use, and other risk factors for asymptomatic and symptomatic bacteriuria. A case-control study. Ann Intern Med 1987; 107: 816–23. 41. Fihn S, Boyko EJ, Chen C-L, Normand EH, Yarbro P, Scholes D. Use of spermicide-coated condoms and other risk factors for urinary tract infections caused by Staphylococcus saprophyticus. Arch Intern Med 1998; 158: 281–7. 42. Simpson JL, Philips OP. Spermicides, hormonal contraception and congenital malformations. Adv Contracept 1990; 6: 141–67. 43. Graham R, Wodak AD, Whelan G. New pharmacotherapies for alcohol dependence. Med J Aust 2002; 177: 103–7. 44. Balsito DV, Fransway AF, Fowler JF Jr, Sherertz EF, Maibach HI, Marks JG Jr, Mathias CGT, Rietschel RL, Storrs FJ, Nethercott JR. Allergic contact dermatitis to detergents. A multicenter study to assess prevalence. J Am Acad Dermatol 2002; 46: 200–6. 45. Czop M, Herr DL. Green skin discoloration associated with multiple organ failure. Crit Care Med 2002; 30: 598–601. 46. Kurek M, Grubska-Suchanek E. Challenge tests with food additives and aspirin in the diagnosis of chronic urticaria. J Allergy Clin Immunol 2001; 41: 463–9. 47. Anonymous. Gamolenic acid. Withdrawal of marketing authorizations. WHO Pharmaceuticals Newslett 2002; 4: 2. 48. Anonymous. Lipokinetix. Reports of liver injury. WHO Pharmaceuticals Newslett 2002; 1: 3. 49. Martinez Portillo FJ, Hoang-Boehm J, Weiss J, Alken P, Junemann KP. Methylene blue as a successful treatment alternative for pharmacologically induced priapism. Eur Urol 2001; 39: 20–3. 50. Sugden P, Levy M, Rao GS. Onychocryptosis– phenol burn ﬁasco. Burns 2001; 27: 289–92. 51. Argent A, Hatherill M, Reynolds L, Purves L. Fulminant pulmonary oedema after administration of a balanced electrolyte polyethylene glycol solution. Arch Dis Child 2002; 86: 209. 52. Stone N, Varma S, Hughes TM, Stone NM. Allergic contact dermatitis from polyvinylpyrrolidone (PVP)/1-triacontene copolymer in a sunscreen. Contact Dermatitis 2002; 47: 49.

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53. Parisi A, Alabiso A, Sacchetti M, Di Salvo V, Di Luigi L, Pigozzi FSO. Complex ventricular arrhythmia induced by overuse of potassium supplementation in a young male football player. J Sports Med Phys Fitness 2002; 42: 214–16. 54. Williams G, Withey S, Walker CC. Longstanding pigmentary changes in pediatric scalds dressed with a non-adherent siliconized dressing. Burns 2001; 27: 200–2. 55. Harrison DA, Smith AG. Concomitant sensitivity to sodium metabisulﬁte and clobetasone butyrate in Trimovate cream. Contact Dermatitis 2002; 46: 310.

56. Anonymous. Sodium picosulfate. Reports of severe electrolyte disturbances. WHO Pharmaceuticals Newslett 2002; 2: 9. 57. Sahn SA. Is talc indicated for pleurodesis? Pro: Talc should be used for pleurodesis. J Branchol 2002; 9: 223–7. 58. Anonymous. Yasmin and venous thromboembolism. WHO Pharmaceuticals Newslett 2002; 1: 14. 59. Mackey AC. Shaffer D, Prizant R. Seizure associated with the use of Visicol colonoscopy. New Engl J Med 2002; 346: 2095.

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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 Dra Mabel Teresa Foppiano Head Tel: +54-1-340 0866 Fax: +54-1-340 0866 E-mail: [email protected] Website: anmat.gov.ar

Administración Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT) Sistema Nacional de Farmacovigilancia Avenida de Mayo 869, piso 11o 1084 Buenos Aires Argentina

Armenia Dr Samvel Azatyan Deputy director Tel: +374-1-584 020, 584 120 Fax: +374-1-542 406 E-mail: [email protected] Website: pharm.am

Department of Pharmacovigilance and Rational Use of Drugs Armenian Drug and Medical Technology Agency 15 Moskowian Street Yerevan 375001 Armenia

Australia Dr John McEwen Principal Medical Advisor Tel: +61-2-6232 8113 Fax: +61-2-6232 8392 E-mail: [email protected] Website: tga.gov.au/adr Austria Eugen Obermayr Head Tel: +43-1-711 00, ext 4638 Fax: +43-1-712 0823 E-mail: [email protected] Website: bmsg.gv.at

Therapeutics Goods Administration PO Box 100 Woden ACT 2606 Australia

Federal Ministry for Social Security and Generations Pharmacovigilance Unit VI/A/7 Radetzkystrasse 2 A-1031 Vienna Austria

535

536 Bahrain Ms Layla Abdur-Rahman Director Tel: +973-25 86 68 Fax: +973-25 93 57 E-mail: [email protected] Belarus Mr Godovalnikov Tel: +7-017-289 55 14 Fax: +7-017-289 53 48

Belgium Johan Van Calster Director-General Tel: +32-2-227 5500 Fax: +32-2-227 5528 E-mail: johan.vancalster@aﬁgp.fgov.be Website: aﬁgp.fgov.be

Brazil Dr Anthony Wong Medical Director Tel: +55-11-3088 9431 Fax: +55-11-3088 9431 E-mail: [email protected] Website: ceatox.com.br

Address list of national centres

Ministry of Health Pharmacy and Drug Control PO Box 28136 Riffa Bahrain

Ministry of Health Center for Examinations and Test Health Service Republican Unitary Enterprise 2-a Tovarishcheskij Per 22 0037 Minsk Belarus

Federal Public Service Public Health Protection Directorate—General Medicinal Products National Centre for Pharmacovigilance Boulevard Bischoffsheim 33, 1st ﬂoor B-1000 Brussels Belgium

CEATOX Sao Paulo Regional Poison and Pharmacovigilance Centre Inst. Crianca Reference Centre Av. Dr Enéas de Carvalho Aguiar 647 05403-903 Sao Paulo SP Brazil

Brazil Mr Murilo Freitas Dias Head Tel: +55-61-448 1219 Fax: +55-61-448 1275 E-mail: [email protected] Website: anvisa.gov.br/farmacovigilancia

Pharmacovigilance Unit—UFARM Agencia Nacional de Vigilância Sanitárita ANVISA SEPN 515 Bl.B Ed. Omega 2 Andar, Sala 2 CEP 70770-502 Brasilia DF Brazil

Bulgaria Ms Daniela Encheva Head Tel: +359-2-9446 99 - 356, 944 2368 Fax: +359-2-9434 487 E-mail: [email protected] Website: bda.bg

Bulgarian Drug Agency Department of Pharmacovigilance Eurointegration and Pharmacopoeia 26 Yanko Sakazov Boulevard BG-1504 Soﬁa Bulgaria

537

Address list of national centres

Canada 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 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/hpb-dgps/therapeut/

Chile Dra Q F Cecilia Morgado-Cadiz Head Tel: +56-2-239 8769 Fax: +56-2-239 8760 E-mail: [email protected]

China Dr Yixin Chen Division Acting Director Tel: +86-10-6716 4979 Fax: +86-10-6718 4951 E-mail: [email protected] Website: cdr.gov.cn and adr.gov.cn

Congo, the Democratic Republic of the Mr Franck Biayi Kanumpepa Tel: +243-81-8125 838 +243-81E-mail: [email protected]

Costa Rica Dra Jetty Murillo Ocampo Farmacéutica responsable Tel: +506-222 1878 Fax: +506-295 2905 E-mail: [email protected]

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 Building, 1st Floor Tunney’s Pasture A/L 0201 C2 Ottawa, Ontario K1A 1B9 Canada

Instituto de Salud Publica de Chile CENIMEF – National Drug Information and Pharmacovigilance Centre Avenida Marathon 1000, 3 piso, Nuñoa-Casilla 48 Santiago Chile

Division of ADR Monitoring Center for Drug Reevaluation, SFDA Building 11, Fa-Hua-Nan-Li Chongwen District Beijing 100061 China

Ministère de la Santé Boulevard dy 30 Juin no 4310 BP 3088 Kinshasa Gombe The Democratic Republic of the Congo

Caja Costarricense de Seguro Social Centro Nacional de Farmacovigilancia Avda. Segunda San José Costa Rica

538 Croatia Dr Igor Francetic Head Tel: +385-1-2421 875 Fax: +385-1-2388 279 E-mail: [email protected]

Cyprus Dr Athos Tsinontides Clinical Pharmacist Tel: +357-2-240 7101 Fax: +357-2-233 9623 E-mail: [email protected]

Czech Republic Dr Ivana Koblihova Head Tel: +42-2-7218 5848, 7218 5111 Fax: +42-2-7143 2377, 7218 5816 E-mail: [email protected]

Denmark Ms Margit Handlos Head of Pharmacovigilance Tel: +45-44-88 92 87 Fax: +45-44-88 95 99 E-mail: [email protected] Website: dkma.dk

Egypt Prof Abdulla Molokhia Chairman, NODCAR Tel: +20-2-7484 989 Fax: +20-2-3379 445 E-mail: [email protected]

Eritrea Embaye Andom Tel: +291-1-122 429 Fax: +291-1-122 899 E-mail: [email protected]

Address list of national centres

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

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

Danish Medicines Agency Medicines Control Division Axel Heides gade 1 DK-2300 Kobenhavn Denmark

Ministry of Health National Organization for Drug Control and Research PO Box 29 51 Wezaret Al-Ziraa, Agouza Cairo Egypt

Ministry of Health Drug Information Unit PO Box 212 Asmara Eritrea

539

Address list of national centres

Estonia Dr Maia Uusküla Head Tel: +372-7-374 140 Fax: +372-7-374 142 E-mail: [email protected] Website: sam.ee

Ethiopia Mr Abraham Geberegiorgis Tel: +251-1-52 41 22 Fax: +251-1-52 13 92 E-mail: [email protected]

Fiji Mr Peter Zinck Chief Pharmacist Tel: +679-3-315 022 Fax: +679-3-304 199 E-mail: pzinck@healthﬁji.gov.fj

Ravimiamet State Agency of Medicines 19 Ravila Str. 50411 Tartu Estonia

Drug Administration and Control Authority of Ethiopia ADR Monitoring & Promotion Control Division PO Box 5681 Addis Ababa Ethiopia

Business and Essential Drugs (BED) Fiji Pharmaceutical Services Ministry of Health Box 106 Suva Fiji

Finland Prof Erkki Palva Research Director Tel: +358-9-4733 4288 Fax: +358-9-4733 4297 E-mail: erkki.palva@nam.ﬁ Website: nam.ﬁ

National Agency for Medicines—Lääkelaitos Drug Information Centre PO Box 55 Mannerheimintie 166 SF-00301 Helsinki Finland

France Dr Carmen Kreft Jaïs Head Tel: +33-1-5587 3533 Fax: +33-1-5587 3532 E-mail: [email protected] Website: afssaps.sante.fr

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 Dr Jürgen Beckmann Head Tel: +49-228-207 3311 Fax: +49-228-207 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

540 Ghana Dr Alex Dodoo Tel: +233-21-675 885 Fax: +233-21-666 8219 E-mail: [email protected]

Greece 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 Licda. Leticia Vargas de Ponce Tel: +502-471 9842 Fax: +502-440 8267 E-mail: [email protected]

Hungary Dr Mariann Virányi Head Tel: +36-1-266 6073 Fax: +36-1-266 6073 E-mail: [email protected]

Iceland Prof. Magnús Jóhannsson Tel: +354-5-20 2114 Fax: +354-5-61 2170 E-mail: [email protected] Website: lyfjastofnun.is

India Prof Suresh K. Gupta Chief Tel: +91-11-2659 3633 Fax: +91-11-6286 2663 or 652 10 41 E-mail: [email protected]

Address list of national centres

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 Av GR-155 62 Athens-Holargos Greece

Coordinadora del Programa Nacional de Farmacovigilancia MSPAS 11 Ave. “A” 11-57 zona 7 Finca La Verbena Guatemala

National Institute of Pharmacy Adverse 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

541

Address list of national centres

Indonesia Dra Engko Sosialine M. Head Tel: +62-21-4245 459 Fax: +62-21-4243 605 E-mail: [email protected] Website: pom.go.id

Iran, Islamic Republic of Dr Kheirollah Gholami Tel: +98-21-640 4223 Fax: +98-21-641 7252 E-mail: [email protected]

Ireland Ms Niamh Arthur Pharmacovigilance Co-ordinator Tel: +353-1-676 4971 Fax: +353-1-676 7836 E-mail: [email protected] Website: imb.ie Israel Dr Dina Hemo Head Tel: +972-2-568 1219 Fax: +972-2-672 58 20 E-mail: [email protected]

Italy Dr Roberto Raschetti Tel: +39-06-599 41 Fax: +39-06-5994 3554 E-mail: [email protected] Website: ministerosalute.it/medicinali /farmacovigilanza/farmaco Jordan Ms Nancy Ghabboun Tel: +962-6-5660 028 Fax: +962-6-5660 028 E-mail: [email protected]

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

Ministry of Health and Medical Education Research and Development Ofﬁce Iranian ADR Centre Under-secretary for Food and Drug Affairs Building no. 3, Fakhr-e-Razi Street, Enghlab Ave 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 Str. PO Box 1176 Jerusalem 91010 Israel

Ministry of Health Centro Nazionale di Epidemiologia Istituto Superiore di Sanita Viale Regina Elena 299 I-00161 Rome Italy

Drug Directorate Ministry of Health PO Box 86 Amman Jordan

542 Korea, Republic of Dr Joon-Shik Chang Tel: +82-2-382 0185, 380 1636 Fax: +82-2-386-0843 E-mail: [email protected] Website: kfda.go.kr Kyrgyzstan Saliya Karimbaeva Tel: +996-312-54 29 40 Fax: +996-312-54 29 10 E-mail: [email protected]

Latvia Dr Inese Studere Head of ADR Monitoring Dpt. Tel: +371-2-707 8442 Fax: +371-2-707 8442 E-mail: [email protected] Website: vza.gov.lv/index.html Lithuania Donatas Stakisaitis Tel: +370-5-2614 552 Fax: +370-5-2614 552 E-mail: [email protected]

Macedonia, the Former Yugoslav Republic of Ms Vesna Nasteska-Nedanovska Tel: +389-2-322 71 95, 323 76 69 Fax: +389-2-323 08 57

Malaysia Ms Abida Haq Bt Syed M. Haq Tel: +60-3-7957 3611 Fax: +60-3-7956 7151 E-mail: [email protected]

Malta Ms Lilian Wismayer Tel: +356-23-43 91 10 Fax: +356-23-43 91 61 E-mail: [email protected]

Address list of national centres

Korea Food and Drug Administration Pharmaceutical Safety Bureau 5 Nokbun-dong, Eunpyong-ku Seoul 135-793 Republic of Korea

Drug Information Centre Ministry of Health 3rd Liniya Street 720044 Bishkek Kyrgyzstan

State Agency of Medicine of Latvia (SAM) ADR Monitoring Department Jersikas St. 15 LV-1003 Riga Latvia

Division for Preclinical and Clinical Trials State Medicines Control Agency Traku 14 2001 Vilnius Lithuania

Ministry of Health ul. 50 Divizija b.b. 1000 Skopje The Former Yugoslav Republic of Macedonia

National Pharmaceutical Control Bureau Ministry of Health Jalan University PO Box 319 MA-46730 Petaling Jaya Malaysia

Medicines Regulatory Unit 198 Rue D’Argens Gzira Gzr 03 Malta

543

Address list of national centres

Mexico Dra Carmen Becerril Martinez Head Tel: +52-5203 4378 Fax: +52-5203 4378 E-mail: [email protected]

Moldavia, Republic of Dr Lucia Tsurcan Head Tel: +373-2-73 70 02, 73 87 86 Fax: +373-2-73 70 45 E-mail: [email protected]

Morocco Dr Rachida Soulaymani-Bencheikh Head Tel: +212-37-6110 47 45 (gsm) Fax: +212-37-77 71 79 E-mail: [email protected]

Mozambique Dr Esperanca Julia Sevene Tel: +258-1-32 52 27 / 32 42 10 Fax: +258-1-32 52 55 E-mail: [email protected] Netherlands Dr A.C. van Grootheest Director Tel: +31-73-646 9700 Fax: +31-73-642 6136 E-mail: [email protected] Website: lareb.nl

Ministry of Health Monterrey 33 piso 10 Col. Roma Del Cuauthémoc Mexico City DF CP 06700 Mexico

National Centre for Adverse Reaction Monitoring of the Republic of Moldova National Institute of Pharmacy Str. Korolenko 2/1 Chisinau 2028 Republic of Moldavia

Centre Anti Poisons et de Pharmacovigilance Rue Lamfedel Cherkaoui Al Irfane Rabat Institute BP 769 Rabat Morocco

Drug Information Center (CIMed) Av. Salvador Allende n. 702 Maputo Mozambique

Netherlands Pharmacovigilance Centre LAREB Goudsbloemvallei 7 NL-5237 MH’s-Hertogenbosch Netherlands

Netherlands Antilles 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

New Zealand 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

544 Nigeria Mrs Ijeoma P.C. Nnani Tel: +234-9-670 28 23 Fax: +234-9-6706 576 E-mail: [email protected]

Norway Ms Ingebjorg Buajordet Head Tel: +47-22-89 77 00 Fax: +47-22-89 77 99 E-mail: [email protected] Website: legemiddelverket.no Oman Dr Sawsan Ahmad Jaffar Head Tel: +968-600 016 Fax: +968-602 287 E-mail: [email protected]

Pakistan Prof Akhlaque Un-Nabi Khan Tel: +92-21-588 2997, 589 2801 Fax: +92-21-588 1444, 589 3062 E-mail: [email protected]

Peru 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

Philippines Mrs Nazarita Lanusa E-mail: [email protected]

Address list of national centres

National Agency for Food & Drug Administration and Control (NAFDAC) 2023 Olusegun Obasanjo way Zone 7, Wuse Abuja 7 Nigeria

Norwegian Medicines Agency Statens Legemiddelverk Adverse Drug Reaction Section Sven Oftedals vei 8 N-0950 Oslo Norway

Ministry of Health Directorate General of Pharmaceutical Affairs and Drug Control PO Box 393 Muscat, Sultanate of Oman 113 Oman

College of Physicians & Surgeons Pakistan (CPSP) Department of Clinical Pharmacology 7th Central Street Phase II, Defence Housing Authority Karachi 75500 Pakistan

Presidenta del Comite Tecnico Nacional de Farmacovigilancia CENAFIM, DIGEMID Ministerio de Salud Av. Arenales # 1302 - Of. 318-319 Lima, Ministerio de Salud 11 Peru

OIC, Product Service Division Bureau of Food and Drugs Department of Health Filinvest Corporate City, Alabang Muntinlipa City 1770 Philippines

545

Address list of national centres

Poland Dr Agata Maciejczyk Head Tel: +48-22-4520 645 Fax: +48-22-4520 634 E-mail: [email protected] Website: urpl.gov.pl

Pharmacovigilance Unit Ofﬁce for Medicinal Products Medical Devices and Biocides 30/34 Chelmska Street PL-00725 Warsaw Poland

Portugal 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 Dr Juliana Daniela Stanciu Head Tel: +40-1-224 1102, 224 1710 Fax: +40-1-2243 497 E-mail: [email protected]

National Medicines Agency Str Aviator Sanatescu no 48, Sector 1 R-71 324 Bucuresti Romania

Russian Federation Prof Victor Cheltsov Head Tel: +7-095-1905 427 or 1903 490 Fax: +7-095-434 02 92 E-mail: [email protected]

Department of Clinical Pharmacology Miklukho-Maklay Street 8 117198 Moscow Russian Federation

Serbia and Montenegro Prof Vaso Antunovic Head Tel: +381-11-361 5531 Fax: +381-11-361 56 30

Singapore Ms Chan Cheng Leng Head of Pharmacovigilance Tel: +65-6-325 5604, 325 5610 Fax: +65-6-325 5448 E-mail: [email protected] Website: hsa.gov.sg/hsa/cpa/CPA_pharma_about.htm Slovakia Dr Pavol Gibala Head Tel: +421-2-5293 1735, 5293 1732 Fax: +421-2-5293 1734 E-mail: [email protected] Website: sukl.sk

Clinical Centre of Serbia National Centre for Adverse Drug Reactions Visegradska 26 YU-11000 Belgrade Serbia and Montenegro

Pharmacovigilance, Communications & Research Division Health Sciences Authority No. 2 Jalan Bukit Merah Singapore 169547 Singapore

National Centre for Monitoring Adverse Reactions to Drugs State Institute for Drug Control Kvetná 11 825 08 Bratislava 26 Slovakia

546 South Africa Mrs Nanette O’Connor Tel: +27-21-447 1618 Fax: +27-21-448 6181 E-mail: [email protected]

Spain 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 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]

Address list of national centres

National Adverse Drug Event Monitoring Centre Division of Pharmacology, Medical School University of Cape Town Medical School K45 Old Main Building Groote Schuur Hospital Observatory 7925 South Africa

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

Sweden Dr Gunilla Sjölin-Forsberg Tel: +46-18-17 46 00 Fax: +46-18-54 85 66 E-mail: [email protected] Website: mpa.se

Medical Products Agency Husargatan 8 Box 26 S-751 03 Uppsala Sweden

Switzerland Dr Ruedi Stoller Head Tel: +41-31-322 0348 Fax: +41-31-322 0418 E-mail: [email protected] Website: swissmedic.ch

Swissmedic Schweizerisches Heilmittelinstitut Pharmacovigilance Zentrum Erlachstrasse 8 CH-3000 Bern 9 Switzerland

Tanzania, United Republic of Ms Mary Masanja Head, Drug Information Department Tel: +255-22-245 0512 / 245 07 51 Fax: +255-22-245 0793 E-mail: [email protected]

Tanzania Drug and Toxicology Information Service (TADATIS) Pharmacy Board PO Box 77150 Dar Es Salaam United Republic of Tanzania

547

Address list of national centres

Thailand Mr Chanchai Uerchakul Director Tel: +66-590 72 81 Fax: +66-591 84 57 E-mail: [email protected]

Tunisia Prof Chalbi Belkahia Head Tel: +216-1-562 098 Fax: +216-1-571 390 or 57 81 96 E-mail: [email protected]

Turkey Dr Seyfullah Dagistanli Head of Department Tel: +90-312-230 2769 Fax: +90-312-230 1610 E-mail: [email protected]

Ukraine Dr Marina Sharayeva Head Tel: +7-380-44268 2500 Fax: +7-380-44268 2500 E-mail: [email protected]

United Kingdom Dr June Raine Head Tel: +44-20-7084 2400 Fax: +44-20-7084 2675 E-mail: [email protected] Website: mhra.gov.uk

United States Dr M. Miles Braun Director Tel: +1-301-827 3974 Fax: +1-301-827 3529 E-mail: [email protected]

Thai National ADRM Centre Food and Drug Administration Ministry of Public Health Ti-wa-nondh Road Nonthaburi 11000 Thailand

Centre National de Pharmacovigilance Sis Hôpital Ch Nicolle Bd du 9 Avril Tunis 1006 Tunisia

TADMER Saglik Bakanlikgi Ilac ve Eczacilik Genel Mürdürlügü Ilkiz Sok, No. 4 06410 Sihhiye Ankara Turkey

Pharmacovigilance Department State Pharmacological Center Ministry of Health of Ukraine 18 Chygorina Str. 01042 Kiev Ukraine

Post-licensing Division Medicines and Healthcare Products Regulatory 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 United States of America

548 United States Dr Paul Seligman Tel: +1-301-827 6276 Fax: +1-301-827 6276 E-mail: [email protected]

Uruguay Dra Carolina Seade Fournie Tel: +598-2-487 27 02 Fax: +598-2-6226 969 E-mail: [email protected]

Uruguay Dra Mabel Burger Tel: +598-2-480 4000 Fax: +598-2-487 0300, hänvis (31/10-01): 487 5682/AK E-mail: [email protected] Website: ciat.hc.edu.uy Venezuela Dr Jesús Querales Castillo Head Tel: +58-212-6624 797 Fax: +58-212-6624 797, 693 1455

Vietnam Prof Hoang Tich Huy_n Head Tel: +84-4-245 292 Fax: +84-4-823 1253 E-mail: [email protected]

Zimbabwe Mrs Sakhile Dube-Mwedzi Regulatory Ofﬁcer Tel: +263-4-736981-5 Fax: +263-4-736980 E-mail: [email protected]

Address list of national centres

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 United States

Depto de Farmacologia Hospital de Clinicas Avda Italia s/n, piso 1 11600 Montevideo Uruguay

Depto de Toxicologia Hospital de Clínicas Avda Italia s/n, piso 7 11600 Montevideo Uruguay

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

Medicines Control Authority of Zimbabwe 106 Baines Ave Bulawayo Zimbabwe

Index of drugs Notes: For any therapy, see under speciﬁc item and the class; for example lisinopril and ACE inhibitors. Boldface page numbers refer to main discussions. abacavir efﬁcacy, 307 general effects, 306 hypersensitivity, 317 hypersensitivity reaction, 307 vertigo, 307 abarelix, 466 ABCD. see amphotericin B colloidal dispersion abciximab anaphylactic reactions, 378–379 nervous system, 378 thrombocytopenia, 360, 378 ABLC. see amphotericin B lipid complex acamprosate, 531 acarbose digoxin absorption, 186 general effects, 452–453 ACE inhibitors, 219 acenocoumarol bleeding gums, +citalopram, 14 concentration, +ritonavir, 316, 358 acetaminophen. see paracetamol acetazolamide, 220 acetylsalicylic acid (aspirin) bleeding, +drotrecogin alfa, 343 concomitant enoxaparin, 359 heart attack prevention, 109–110 heart protection, +ibuprofen, 111 aciclovir, 305 ACTH. see adrenocorticotrophic hormone acupuncture, 520 adenosine cardiac dysrhythmias, 189 cardiovascular system, 189 nervous system, 189 adrenaline cardiovascular system, 145 concomitant sufentanil, 96 uvular deviation, +lidocaine, 127 beta-adrenoceptor antagonists (blockers) effectiveness, +NSAIDs, 103 general effects, 509–510

adrenocorticotrophic hormone (ACTH), 414 aerosol delivery, 172–173 alatroﬂoxacin. see trovaﬂoxacin albendazole concentration, +antiepileptics, 327 concentration, +cimetidine, 326 concentration, +grapefruit juice, 326 efﬁcacy, 326–327, 328 albumin, 342 alemtuzumab, 379 alendronate, 468–469 alfacalcidol. see vitamin D (calciferol) and analogues alfentanil, 88 alimemazine, 54 ALLHAT trial, 219–220 Allium sativum (garlic), 515 Aloe capensis, 515 alprazolam, 44 alprostadil (prostaglandin E1 ), 417–418 alternative therapies, 521–522 aluminium, 222 aluminium hydroxide gel, 259 amfebutamone, 15 amikacin concomitant sevoﬂurane, 119 hearing loss, 251 macular toxicity, 252 retinal toxicity, 251–252 amiloride, 222 aminoglycosides, 251 aminosalicylates concomitant azathioprine, 368 efﬁcacy, 367 TPMT inhibition, azathioprine, 374 5-aminosalicylic acid. see mesalazine amiodarone bone marrow granulomata, 193 cardiovascular system, 190 concentration, warfarin, 194 concomitant mexiletine, 194 deaths, 193 efﬁcacy, 189–190 formulations, 194 hematologic effects, 193 immunologic system, 193–194 lupus-like syndrome, 193–194

nervous system, 191 pneumonia, 190–191 respiratory system, 190–191 skin, 193 special senses, 191 thyroid disease, 192–193 toxic epidermal necrolysis, 193 amisulpride, 49, 54–55 amlodipine granuloma annulare-like eruption, 205 hepatitis, 205 potentiation, +chloroquine, 205 syncope, +chloroquine, 289 amoxicillin, 244 amphetamines, 2–3 amphotericin B colloidal dispersion (ABCD), 277 amphotericin B deoxycholate (DAMB), 276 amphotericin B lipid complex (ABLC), 277 amprenavir, 312–313 amtolmetin, 111 anabolic steroids, 434 anakinra. see interleukin-1 receptor antagonists anesthesia. see speciﬁc agents, such as benzocaine; ropivacaine anti-cancer drugs, 488 anti-CD4, 379 antibiotics. see also speciﬁc drugs and classes, such as minocycline; macrolides anticholinergic drugs cardiovascular system, 152 concomitant diamorphine, 39 antidepressants, 24 antiemetics, 362 antiepileptic drugs bone mineral density, 74–75 concentration, +folic acid, 408 endocrine systems, 73 hematologic effects, 73–74 nervous system, 72 psychosis, 72–73 antiestrogens carcinogenicity, 430–431 genotoxicity, 429–430 antihistamines (H1 receptor antagonists), 165–166. see also speciﬁc drugs

549

550 antimicrobial drugs blood dyscrasias, 243–244 drug resistance, 242–243 antimony, 224 antiplatelet drugs, 343 antipsychotic drugs cardiovascular system, 52 comparison trials, 50–53 endocrine systems, 53 metabolism, 53–54 nervous system, 52 off-label uses, 49–50 psychiatric effects, 52–53 sexual dysfunction, 54 antiretroviral drugs, 306 antithyroid drugs, 442–443 appetite suppressants, 4–7 arbekacin, 252 argatroban concomitant digoxin, 186 concomitant lidocaine, 197 efﬁcacy, 359–360 interactions, 360 aristolochic acid, 515 aromatherapy, 520 arsenic, 225 arteether, 292 artemether, 293 artesunate, 293 articaine, 127 ASA. see acetylsalicylic acid Asian herbal medicines, 513–514 aspart insulin, 449 aspirin. see acetylsalicylic acid atorvastatin concentration, +erythromycin, 263 hypersensitive reactions, 474 rhabdomyolysis, +delavirdine, 309 rhabdomyolysis, +diltiazem, 206 urticaria, 474 atovaquone efﬁcacy, 296 safety, +proguanil, 292 atropine, 152 avoparcin, 243 azathioprine carcinogenicity, 373–374 concomitant aminosalicylates, 368 hematologic system, 373 teratogenicity, 374 TPMT inhibition, aminosalicylates, 374 azithromycin cholestasis, 261 delirium, 261 efﬁcacy, +pyrimethamine, 296 gastrointestinal system, 261 maculopapular nonpruritic rash, 261 QT interval prolongation, 261

Index of drugs azole derivatives, 278 aztreonam, 247 Bacille Calmette-Guérin vaccine, 337 baclofen, 141, 142 basiliximab, 379–380 bazedoxifene acetate, 431 BCG. see Bacille Calmette-Guérin vaccine beclomethasone dipropionate, 172 benzimidazoles for echinococcosis, 326–327 for ﬁlariasis, 327 for neurocysticercosis, 327 for protozoal infections, 328 for roundworms, 327–328 benznidazole, 298 benzocaine, 131 benzodiazepines concomitant levodopa, 44 death, 43–44 drug overdose, 43–44 +methadone, 91–92 neonates, 76 psychiatric effects, 75 psychological effects, 43 suicide, 43–44 teratogenicity, 76 benzophenone-3, 158 benzydamine, 159, 525 bepridil, 194 17-beta-estradiol, 424 betamethasone 17-valerate, 416 bicalutamide, 435–436 biguanides, 458–459 bismuth, 225–226 black cohosh, 516 beta-blockers. see beta-adrenoceptor antagonists blood glucose monitoring, 446 blood transfusion, 344 bosentan biliary tract, 215 cardiovascular system, 215 efﬁcacy, 214–215 susceptibility factors, 215 tolerance, 215 botulinum toxin A effecticacy for hyperhidrosis, 161–162 nervous system, 162 neuromuscular system, 162 bovine collagen, 526 brachial plexus anesthesia cardiovascular system, 124 nervous system, 124 respiratory system, 124 Breynia ofﬁcinalis, 515–516 bromazepam, 44, 279 bronopol, 157 bucillamine, 235 budesonide

adrenal insufﬁciency, +itraconazole, 280–281 bone loss, 416 concentration, +itraconazole, 177 contact allergies, 177 delivery method, 173 bupivacaine cardiovascular system, 131–132 intrathecal effectiveness, 126–127 nervous system, 132 spread, +fentanyl, 126 buprenorphine, 97 bupropion. see amfebutamone buspirone, 43 calciferol. see vitamin D (calciferol) and analogues calcipotriol, 157 calcitonin, 465 calcium channel blockers bleeding time prolongation, 204–205 concentration, +grapefruit juice, 528 overdose, 205 camptothecins. see topoisomerase I inhibitors cannabinoids indinavir concentration, 314 myocardial infarction, +sildenaﬁl, 33 nelﬁnavir concentration, 315 nervous system, 32 psychological effects, 32 respiratory system, 32 sensory systems, 32 cannabis, 30 caprylic/capric triglyceride, 157 captopril, 213 carbamazepine cardiovascular system, 76 central nervous system effects, +levetiracetam, 79 concentration, +ﬂuconazole, 279 concentration, +risperidone, 64, 76 concentration, +troleandomycin, 264 drug administration route, 76 interactions, 76 musculoskeletal system, 76 olanzapine concentration, 62 risperidone concentration, 64 teratogenesis, 76 teratogenicity, 443–444 carbimazole, 443 cardiac glycosides cardiovascular system, 185 death, 186 diagnosis of adverse drug reactions, 187

551

Index of drugs efﬁcacy, 185 interference with diagnostic tests, 187 management of poisoning, 187 special senses, 185–186 carvedilol, 203 carvone, 157 caspofungin, 285–286 catechol-O-methyl transferase inhibitors, 151 caudal anesthesia, 125 cefepime, 245 ceftriaxone, 245–246 celandine, 516 celecoxib, 111–112 Centaurium erythreae, 520 cetirizine, 166–167 chelation therapy. see ethylenediaminetetraacetic acid Chelidonium majus, 516 Cheng Kum, 513–514 chloral hydrate, 46 chloramphenicol, 254 chlorhexidine, 239–240 chlormadinone acetate, 428 chloroquine overdose, 289 potentiation, +amlodipine, 205 sensorineural hearing loss, 289 syncope, +amlodipine, 289 chlorproguanil, 292 chlorpromazine, 57 chlortalidone, 219–220 cholesterol, 435 cholinesterase inhibitors, 139–140 chromium picolinate general effects, 512 liver damage, 226 cibenzoline, 195 ciclosporin carcinogenicity, 375 concentration, +efavirenz, 310 concentration, +orlistat, 375 concentration, +St. John’s wort, 517 concentration, +voriconazole, 283, 375 etoposide concentration, 487 irinotecan toxicity, 480 juxtaclavicular beaded lines, 375 liver, 374 monitoring, 375 nephrotoxicity, amphotericin B deoxycholate (DAMB), 276 nervous system, 374 rhabdomyolysis, +itraconazole, 281 rhabdomyolysis, +red yeast rice, 474 urinary tract, 374–375 cidofovir, 303 cilostazol, 209

cimetidine, 305 cimetropium, 369 Cimicifuga racemosa, 516 cinnarizine, 209 ciproﬂoxacin acute psychotic reaction, 254 angioimmunoblastic lymphadenopathy, 255 diarrhea, 255 hematologic effects, 254 microprecipitates in the corneal epithelium, 254 musculoskeletal system, 255 QT interval prolongation, 254 cisapride, 362 cisatracurium, 138 cisplatin, 487 citalopram bleeding gums, +acenocoumarol, 14 drug overdose, 13 hypomania, +sibutramine, 7 serotonin disorder, +dexamphetamine, 3 serotonin toxicity, +sibutramine, 14 citric acid, 525–526 clarithromycin cardiovascular system, 262 hematologic effects, 261 interactions, 262 liver, 262 ototoxicity, 262 phototoxicity, 262 psychiatric effects, 262 sulfonylureas concentration, 457 thrombotic thrombocytopenic purpura, 262 clinaﬂoxacin, 255 clindamycin allergic reaction, 296 hypersensitivity, 261 skin, 260 clobetasone butyrate, 157 clomethiazole, 46 clonidine apnea, caudal administration, 125 cardiovascular system, 216 overdose, 216 sevoﬂurane agitation, 119 skin, 216 clotting factors cardiovascular system, 346 human parvovirus B19 transmission, 347 inhibitor antibodies, 347 recombinant factor IX, 347 clozapine cardiovascular system, 55–56 drug overdose, 57 endocrine systems, 57 gastrointestinal system, 57

hematologic system, 57 mania treatment, 49 metabolism, 56–57 nervous system, 56 seizures, 50 co-proxamol, 110 co-trimoxazole (trimethoprim + sulfamethoxazole) allergic reactions, 295, 296 aseptic meningitis, 295 concomitant indinavir, 267 hematologic system, 266 hemophagocytosis, 295 indinavir nephrotoxicity, 295 interactions, 295 nephrotoxicity, 295 nimesulide cross-sensitivity, 267 skin, 266–267 susceptibility factors, 295 coagulation factor gene therapy, 347 cocaethylene, 157 cocaine body temperature, 36 cardiovascular system, 33 death, 36 ear, nose, throat, 34 gastrointestinal system, 35–36 interactions, 37–38 myocardial infarction, 1 nervous system, 34 neuromuscular system, 34–35 pregnancy, 36 prenatal exposure and perinatal effects, 1–2 psychological effects, 35 respiratory system, 34 sensory systems, 35 teratogenicity, 36–37 cocaine + diamorphine, 37 colchicine, 473 colestyramine, 475 colistin, 265 collagen, 526 comfrey, 519 complementary therapies, 521–522 contraception. see mifepristone; oral contraceptives; post-coital contraception contrast agents, iodinated anticoagulant effects, 499 cardiovascular system, 498 delayed allergic-like skin reactions, 497–498 delayed hypersensitivity reactions, 502–504 gastrointestinal system, 499 graft-vs.-host disease, 500 nervous system, 498–499 potassium release, 499 skin, 500

552 contrast agents, water-soluble iodinated, intravascular, 496–497 contrast media, 500–503 Copaltra, 519 copper, 227 Coriandrum sativa, 516 corticosteroids. see glucocorticoids cortisone, 415 Coutarea latiﬂora, 520 COX-2 inhibitors lithium concentration, 25 urinary tract, 111 “crack”. see cocaine cyanocobalamin. see vitamin B12 cyclophosphamide fertility, 376 hypersensitivity reaction, 489 cyproterone acetate autoimmune hepatitis, 428 rheumatoid arthritis, 465 cytostatic drugs, 488 dacarbazine, 488 dairy products ciproﬂoxacin concentration, 255 norﬂoxacin concentration, 258 dalfopristin. see quinupristin/dalfopristin DAMB. see amphotericin B deoxycholate dapsone anemia, +chlorproguanil, 292 Coombs’ positive hemolytic anemia, +pyrimethamine, 294 hypersensitivity syndrome, +pyrimethamine, 292–293 nizatidine concentration, 364 daptomycin, 267 darbepoetin alpha. see erythropoietin daunorubicin, 488 DDAVP. see desmopressin deferiprone, 233 deferoxamine bone dysplasia, 234 efﬁcacy, 233 ocular toxicity, 234 ototoxicity, 234 Deﬁnity, 505 deﬂazacort, 416 delavirdine, 309 deletion of thymidine at position 961, 253 dental anesthesia immunologic system, 128 nervous system, 127 desloratadine cardiovascular system, 167 concomitant erythromycin, 263 concomitant grapefruit, 167

Index of drugs susceptibility factors, 167 desmopressin, 469 detergents, 531 dexamethasone acute tumor lysis syndrome, 415 Candida infection, 416–417 irinotecan concentration, 480 dexamphetamine concomitant modaﬁnil, 4 serotonin syndrome, +citalopram, 3 serotonin syndrome, +venlafaxine, 16–17 skin disorders, +ephedrine, 2 dexibuprofen, 111 dexketoprofen, 159 dexmedetomidine, 118 dexpanthenol, 411 dextrans acute renal insufﬁciency, 353 anaphylactic reactions, 354 pulmonary edema, 353 dextromethorphan, 88–89 dextropropoxyphene hepatic injury, +paracetamol, 89 suicide, 110 diamorphine (heroin) concomitant anticholinergic drugs, 39 death, 39 drug formulations, 38–39 drug overdose, 39 effectiveness, 89 endocrine systems, 38 interactions, 39 nervous system, 38, 89 overdose, 89 pregnancy, 38 respiratory system, 38 Diankexing, 514 diazepam apnea, 122 immunologic system, 44–45 dibucaine, 133 dibutyl phthalate, 157 dicaprylyl maleate, 157 diclofenac, 157 didanosine, 307–308 diethylcarbamazine, 328 diethylstilbestrol, 422–423 digoxin acarbose absorption, 186 concentration, +diltiazem, 187 concomitant argatroban, 186, 360 concomitant enoxaparin, 359 concomitant fondaparinux sodium, 186 concomitant macrolide antimicrobial drugs, 186 concomitant nitrates, 187 concomitant quinolone antimicrobial drugs, 187

concomitant statins, 187 concomitant tamsulosin, 187 efﬁcacy, 185 false assay, +spironolactone, 222 false test readings, 187 inappropriate prescribing, 187 poisoning management, 188 dihydropyridine calcium channel blockers, 528 dihydrotestosterone, 435 diltiazem digoxin concentration, 187 paralytic ileus, +nifedipine, 205–206 rhabdomyolysis, +atorvastatin, 206 tacrolimus concentration, 377 dimercaptopropane sulfonate (DMPS), 234 diphenhydramine hallucinations, +prolintane, 4 nervous system, 167 psychiatric effects, 168 tolerance, 168 dipryrone, 111 direct thrombin inhibitors, 359 disopyramide, 195 disulﬁram psychotic reactions, 526–527 toxic epidermal necrolysis, +clarithromycin, 262 diuretics. see also speciﬁc drugs and classes, such as furosemide; loop diuretics acute renal insufﬁciency, 221 bone marrow reaction, 221 electrolyte abnormalities, 219–220 skin reaction, 221 urinary tract, 221 divalproex formulations, 83 nausea, 49 DMPS. see dimercaptopropane sulfonate (DMPS) dobutamine, 147 docetaxel clearance, +topotecan, 487 interstitial pneumonitis, 488 dofetilide, 195 donepezil vs. rivastigmine, 7 succinylcholine duration, 140–141 dopamine receptor agonists. see also levodopa delirium, 149–150 hair, 150 pregnancy, 150 serosae, 150 sexual function, 150 sleep disorders, 149 dorzolamide, 220 doxazosin, 217

553

Index of drugs doxorubicin ﬂare phenomenon, 489 formulations, 488 doxycycline, 247 droperidol, 58 drospirenone, 428 drotrecogin alfa antibodies to activated protein, 342 bleeding, 342 hallucinations, 342 hypertension, 342 interactions, 342–343 “drumstick”, 324 dydrogesterone, 424 ebastine, 168 Echinacea (coneﬂower) general effects, 512 immunologic system, 516 echinocandins, 285 ecstasy. see methylenedioxymethamphetamine edetate/EDTA. see ethylenediaminetetraacetic acid efavirenz change in liver function tests, +nevirapine, 308–309 ciclosporin concentration, 310 general effects, 309 immunologic system, 310 interactions, 310 liver, 310 methadone concentration, 310 nervous system, 309 psychiatric effects, 309–310 teratogenicity, 310 eﬂornithine, 298 emedastine, 168 EMLA cream, 131 encephalitis vaccine, 340 enoxaparin, 359 enoximone, 188 entacapone, 151 Ephedra. see ephedrine ephedrine cardiovascular system, 145–146, 516–517 hypersensitivity, 146 overdose, 146 psychiatric effects, 146 skin disorders, +dexamphetamine, 2 epidural anesthesia, 125 eplerenone, 221 epoetin. see erythropoietin ergotamine, 151–152 erythromycin atorvastatin concentration, 263 concomitant argatroban, 360 concomitant desloratadine, 263 concomitant octreotide, 468 gastrointestinal system, 262–263

interactions, 263 phlebitis, 263 skin, 263 erythropoietin cardiovascular system, 348 erythroid response, +moxiﬂoxacin, 257 general effects, 348 moxiﬂoxacin concentration, 349 pure red cell aplasia, 348–349 reduced efﬁcacy of dialysis, 349 susceptibility factors, 349 urticaria, 349 esomeprazole, 365 essential oils, 156 estazolam, 281 estradiol, 422 estrogens, 422 etanercept infection, +anakinra, 390 nervous system, 393–394 neutropenia, +anakinra, 390 orbital myositis, 394 respiratory system, 393 skin, 394 ethanol, 32 ethmozine. see moricizine ethylenediaminetetraacetic acid (EDTA; edetate) general effects, 234–235 pseudothrombocytopenia, 378 renal damage, 235 ethylhexylglycerin, 157 etomidate, 121 etoposide cardiovascular system, 482 concentration, +ciclosporin, 487 concentration, +valspodar, 487 hypersensitivity reaction, 485–486, 489 interactions, 487 liver enzyme increase, 485 nervous system, 482–483 pharmacokinetics, 481 exatecan, 477–478 ezetimibe, 473 famotidine, 364 FD and C Blue No. 1, 531 fenﬂuramine, 4–5 fentanyl bupivacaine spread, 126 concentration, +itraconazole, 281 effectiveness, 90 overdose, 91 pregnancy, 90 transdermal use, 90–91 transmucosal use, 91 fexofenadine, 168–169

ﬁlgrastim. see granulocyte colony-stimulating factor ﬁnasteride efﬁcacy, 436 gynecomastia, 436 psychosis, +sibutramine, 436 psychotic behavior, +sibutramine, 7 ﬂavoxate, 152 ﬂecainide cardiovascular system, 195–196 interstitial pneumonia, 196 pregnancy, 196 respiratory system, 196 ﬂuconazole children, 279 concentration, +carbamazepine, 279 concentration, +methadone, 279 concomitant bromazepam, 44, 279 concomitant estazolam, 281 concomitant rosuvastatin, 279 general effects, 278 interactions, 279 QT interval prolongation, 278 ﬂucytosine, 278 ﬂudarabine, 489 ﬂunisolide, 172–173 ﬂuorescein dye, 510 ﬂuoroquinolones, 254 5-ﬂuorouracil, 487 ﬂuoxetine concomitant amfebutamone, 15 concomitant SSRIs, 13 mania, +mirtazapine, 16 risperidone concentration, 64 serotonin syndrome, +pseudoephedrine, 146 ﬂutamide acute renal insufﬁciency, 436 cortisol concentration, 437 liver damage, 436 ﬂuticasone, 177 ﬂuvastatin, 474 ﬂuvoxamine clozapine concentration, 58 concomitant lithium, 24 neuroleptic malignant syndrome, +risperidone, 64 folic acid antiepileptic drugs concentration, 408 carcinogenicity, 408–409 concentration, +methotrexate, 409 and epilepsy, 408 and twin-births, 409 vitamin B12 deﬁciency, 407–408 folinic acid, 408 fomivirsen, 303

554 fondaparinux, 186, 359 food additives, 531 formoterol, 179 fosfomycin, 267 fosinopril, 213 fosmidomycin, 268 fosphenytoin, 80 fragrances, 156 fructosamine, 455 furosemide bone marrow reaction, 221 ototoxicity, +gentamicin, 221, 252 fusidic acid, 259 G-CSF. see granulocyte colony-stimulating factor G6PD deﬁciency, 512 gabapentin, 77 gadobenate dimeglumine, 504 gadodiamide, 505 gadolinium, 504–505 gallium, 227 Galstena, 324 gammahydroxybutyrate, 39–40 gamolenic acid, 531 ganciclovir endophthalmitis with scleral damage, 304 gastrointestinal system, 303 hypoglycemia, 304 low total leukocyte counts, 304 garenoxacin, 255 garlic, 515 gatiﬂoxacin bioavailability, 255 gastrointestinal system, 256 hepatitis, 256 hypoprothrombinemia, +warfarin, 256 nervous system, 256 QT interval prolongation, 256 Gd-BOPTA. see gadobenate dimeglumine gelatin allergy, 46 anaphylactic reaction, 355, 527 gemcitabine, 488 gemﬁbrozil hypoglycemia, 473 repaglinide concentration, 456 rhabdomyolysis, +colchicine, 473 gemiﬂoxacin, 256 gemtuzumab, 380 gentamicin contact dermatitis, 251 ototoxicity, +furosemide, 221, 252 sensory systems, 252 susceptibility factors, 252 urinary tract, 252 geraniol, 158

Index of drugs Gilbert’s syndrome, +irinotecan, 480 Ginkgo biloba (maidenhair tree) bleeding risk, 209 clonic seizures, 210 hematologic system, 517 ginseng, 517 glargine insulin, 450 glibenclamide, 456–457 gliclazide, 456 glitazones combination therapy, 458–459 general effects, 457 glucagon, 451–452 glucagon-like peptide-1, 452 glucocorticoids, inhaled bone mineral density, 176–177 diabetes mellitus, 177 growth inhibition, 175–176 overdose, 175 risks in children, 174–177 skin, 177 systemic availability, 173–174 glucocorticoids, systemic in Asian herbal medicines, 513–514 bone loss, 416 carcinogenicity, 417 concentration, +itraconazole, 280 infection risk, 416–417 pregnancy, 417 teratogenicity, 417 glucocorticoids, topical, 415 glyburide. see glibenclamide glycerine, 527–528 glyceryl stearate, 157 glyceryl trinitrate (nitroglycerin), 157, 204 glycoprotein IIb-IIIa inhibitors, 343 Glycyrrhiza (licorice) efﬁcacy, 323–324 hypokalemia, 517 GM-CSF. see granulocyte-macrophage colony-stimulating factor GnRH. see gonadrotrophin-releasing hormone gold, 227 gonadorelin, 465 gonadorelin agonists, 465 gonadotrophin-releasing hormone, 465 gonadotrophin-releasing hormone antagonists, 466 goserelin acetate, 465 granulocyte colony-stimulating factor (G-CSF) adult respiratory distress syndrome, 392 formulations, 393 general effects, 392

interference with diagnostic tests, 393 musculoskeletal system, 392 myelodysplastic syndrome, 392–393 granulocyte-macrophage colony-stimulating factor (GM-CSF), 392 grapefruit, 167 grapefruit juice albendazole concentration, 326 concentration, fexofenadine, 168–169 concomitant amprenavir, 313 halofantrine concentration, 290 interactions, 528 grepaﬂoxacin, 256 growth hormone (human growth hormone, hGH, somatotropin) antibodies against growth hormone, 467 carcinogenicity, 467 Creutzfeldt–Jakob disease, 466 dosage regimens, 467 fractures, 467 nausea, 466 pregnancy, 467 skin, 466–467 susceptibility factors, 467 growth hormone release-inhibiting hormone (somatostatin), 467–468 guaraná, 518 hair bonds, 158–159 hair dyes, 156, 158 halofantrine, 289 haloperidol ataxia, +valproate, 59 cardiovascular system, 58 comparison trials, 50–51 endocrine systems, 58 interactions, 58 nervous system, 58 skin, 58 hCG. see human chorionic gonadotropin Helicobacter pylori eradication regimens, 366–367 hemoglobin-based oxygen carriers cardiovascular system, 343 ecchymotic rash, 343 gastrointestinal smooth muscle spasm, 343 hematologic effects, 343 jaundice, 343 heparins, 343, 358 herbal products management of liver damage, 323–324 pharmaceutical contamination, 5 heroin. see diamorphine

555

Index of drugs hetastarch. see hydroxyethyl starch hGH. see growth hormone histamine H2 receptor agonists, 363–364 HMG coenzyme-A reductase inhibitors. see statins Höllensteinstift 10® , 230 homeopathy, 520–521 hormone replacement therapy carcinogenicity, 425–426 concomitant statins, 426 dry eye syndrome, 423–424 general effects, 423 hematologic system, 424 metabolism, 424 reproductive system, 424 transdermal application, 426 HRT. see hormone replacement therapy 5-HT3 receptor antagonists (blockers), 363 human chorionic gonadotropin, 421–422 human growth hormone. see growth hormone human papilloma virus vaccine, 338 hydralazine, 217 hydrocodone, 91 hydrophilized ceramide, 157 hydroxychloroquine skin reaction, 289 Stevens–Johnson syndrome, 289 susceptibility factors, 289 hydroxocobalamin. see vitamin B12 hydroxyethyl salicylate, 157 hydroxyethyl starch acute renal insufﬁciency, 355 trial, 354 hyoscyamine cardiovascular system, 152 nervous system, 152 pregnancy, 152 Hypericum perforatum (St. John’s wort), 517 hypoglycemic drugs, 452, 458–460 ibritumomab, 380 ibuprofen, 111 icodextrin, 446 idebenone, 7 ifosfamide, 488–489 IL-2. see interleukin-2 IL-4. see interleukin-4 IL-11. see interleukin-11 Illicium anisatum, 518 imipramine, 11 immunizations adverse events surveillance, 334

autoimmune disease, 336–337 multiple, risks, 334–337 multiple sclerosis, 337 implantable contraceptives, 428 indinavir, 314 concentration, +cannabinoids, 314 concomitant co-trimoxazole, 267 concomitant milk thistle, 314 general effects, 313 hypertensive crisis, 313 interactions, 314 levothyroxine concentration, 314 musculoskeletal system, 314 nephrotoxicity, +co-trimoxazole, 295 nervous system, 313–314 susceptibility factors, 314 thyroxine concentration, 442 urinary stones, 311 urinary tract, 314 indomethacin, 102 inﬁltration anesthesia, 128 inﬂiximab antibody formation, 395 autoimmunity, 395 bacterial infections, 396 death, 397 eosinophilic pleural effusion, 394 fungal infections, 397 hematologic effects, 394 hypersensitivity reaction, 395 immunologic effects, 394–395 infection risk, 396–397 optic neuropathy, 394 protozoal infections, 397 skin, 394 tuberculosis, 396 viral infection, 396–397 insulin. see also aspart insulin; glargine insulin; lispro insulin administration route, 451 amyloid-like deposition in the skin, 447 cognitive function, 447 combination therapy, 459 efﬁcacy, 447 efﬁcacy, inhalation, 451 hypoglycemia, 447 latex contamination, 450 pregnancy, 448 pump delivery, 448–449 insulin combinations, 450–451 insulin detemir, 450 interferon-alfa cardiovascular system, 383 children, 388 depression, 384–385 hair, 388 hematologic effects, 386 immunologic effects, 388

infection risk, 388 metabolism, 386 nervous system, 384 ocular toxicity, 384 respiratory system, 383–384 skin, 387–388 susceptibility factors, 383 thyroid disorders, 385–386 urinary tract, 386–387 interferon-beta aplastic anemia, 389 headaches, 389 minimal-change nephrotic syndrome, 389–390 monoarthritis, 390 neutralizing antibodies, 390 psychiatric effects, 389 skin, 390 interferon-gamma, 390 interleukin-1 receptor antagonist (anakinra), 390 interleukin-2 (IL-2) hematologic effects, 391 myasthenia gravis, 391 pain, 390 psychiatric effects, 391 toxic epidermal necrolysis, 391 interleukin-4 (IL-4), 391 interleukin-11 (IL-11, oprelvekin), 391 intrathecal (spinal) anesthesia cardiovascular system, 126 nervous system, 126–127 respiratory system, 126 intravenous immunoglobulin acute renal insufﬁciency, 346 anaphylactic reactions, 346 cardiovascular system, 345 fulminant hepatitis, 346 general effects, 345 hematologic system, 346 nervous system, 345 skin, 346 intravenous regional anesthesia, 128 iodine. see contrast agents, water-soluble iodinated iodoform, 157 iodopropynylbutylcarbamate, 158 iohexol, 497–498 irinotecan concentration, +St. John’s wort, 487, 517–518 formulation, +5-ﬂuorouracil, 487 interactions, 487 pharmacokinetics, 479–481 toxicity, +oxaliplatin, 487 iron, 227–228 isepamicin, 252 isoﬂurane, 120 isosorbide-5-mononitrate, 204 isosulfan blue, 528–529 isotretinoin, 159–160

556 isradipine concentration, +phenytoin, 206 phenytoin concentration, 81 itraconazole children, 281 fentanyl concentration, 281 general effects, 279–280 glucocorticosteroids concentration, 280 interactions, 280–281 liver function, 280 rhabdomyolysis, +ciclosporin, 281 rhabdomyolysis, +simvastatin, 281 ivermectin albendazole pretreatment, 327 general effects, 329 for onchocerciasis, 329 for scabies, 329–330 for strongyloidiasis, 330 jasmine absolute, 156 josamycin, 263 kampo medicines, 513 kanamycin, 251 kava (Piper methysticum), 518–519 ketamine chiral forms, 121 effectiveness, 120 psychological effects, 121 kissing, 244 ku shep, 513 L-AmB. see liposomal amphotericin (L-AmB) labetalol cardiovascular system, 203 electrolyte balance, 204 hepatitis, 203–204 hyperkalemia, 204 liver, 203–204 lactulose, 367 lamivudine gastrointestinal system, 308 general effects, 306 liver, 308 tolerance, 308 lamotrigine drug withdrawal, 78 hematologic system, 78 interactions, 78–79 nervous system, 77–78 pregnancy, 78 skin, 78 teratogenicity, 78 lansoprazole, 365 latanoprost allergic contact dermatitis, 418 growth of lashes, 510–511 pigmentation of the iris, 510

Index of drugs lead in Asian herbal medicines, 514 fetotoxicity, 228–229 leukotriene receptor antagonists, 177–179 leuprolide, 465 levamisole, 330 levetiracetam central nervous system effects, +carbamazepine, 79 overdose, 79 susceptibility factors, 79 levobupivacaine, 133 levocetirizine cardiovascular system, 169 psychological effects, 169 sedation, 169 levodopa concomitant benzodiazepines, 44 nervous system, 148 respiratory system, 148 levoﬂoxacin Achilles tendinitis, 257 convulsions, 256 gastrointestinal system, 256 general effects, +pyrazinamide, 323 hypoprothrombinemia, +warfarin, 257 QT interval prolongation, 256 toxic epidermal necrolysis, 257 tubulointerstitial nephritis, 256 levothyroxine, 314 levovist, 506 licorice, 517 lidocaine administration route, 197 concentration, +mexiletine, 197 concomitant argatroban, 197, 360 drug overdose, 197 hypersensitivity, 128 overdose, 134 pupillary mydriasis, 196 sensory systems, 131, 133–134, 196 topical, effectiveness, 131 uvular deviation, +adrenaline, 127 lignocaine. see lidocaine limonene, 156 linezolid hematologic effects, 265 neuropathy, 265 serotonin syndrome after paroxetine, 265 serotonin toxicity, +SSRIs, 14 susceptibility factors, 265 LipoKinetix acute toxic hepatitis, 519 liver injury, 531 liposomal amphotericin (L-AmB), 277

lisinopril, 213–214 lispro insulin antigenicity, 449 glycemic control, 450 lipoatrophy, 449 lithium administration route, 23 cardiovascular system, 20 concentration, +topiramate, 24 concomitant antidepressants, 24 concomitant ﬂuvoxamine, 24 concomitant quetiapine, 24 endocrine systems, 20–21 fetotoxicity, 23 formulations, 23 hematologic beneﬁts, 19 immunologic beneﬁts, 19–20 interactions, 24–25 intoxication, +rofecoxib, 113 lactation, 23 metabolic effects, 21 metabolism beneﬁts, 19 mouth and teeth, 22 nervous system beneﬁts, 19 nervous system effects, 20 neuroleptic malignant syndrome, +olanzapine, 24 nutrition, 21 overdose, 23–24 pregnancy, 22 psychological effects, 20 sensory systems beneﬁts, 19 sensory systems effects, 20 sexual function, 22 skin beneﬁts, 19 skin effects, 22 teratogenicity, 22–23 thyroid, 19 urinary tract, 22 withdrawal, 22 lomeﬂoxacin, 257 Longdan Qiegan Wan, 515 loop diuretics, 220 lopinavir amprenavir interaction, 312 inﬂammatory edema, +ritonavir, 315 lopinavir/ritonavir, 314–315 loratadine, 169 Lorenzo’s oil, 475 lormetazepam, 45 losartan conversion, +phenytoin, 80 hepatic injury, 214 loss of taste discrimination, 214 lovastatin concentration, +roxithromycin, 264 QT interval prolongation, +quetiapine, 474–475 lower limb block, 128–129 lumefantrine, 293 Lung Tan Xi Gan, 515 lupus-like syndrome, 247–248

557

Index of drugs ma huang. see ephedrine macrolides, 186, 261 magnesium oxide, 259 malaria vaccine, 294 mannitol, 222 maprotiline, 12, 65 marijuana. see cannabinoids; cannabis MDMA. see methylenedioxymethamphetamine mebendazole, 326 meﬂoquine, 290 meglitinides combination therapy, 459 fructosamine concentration, 455 mechanism of action, 455 meglumine antimoniate, 297 melarsoprol, 298 meningococcal vaccine, 337–338 meperidine. see pethidine mepivacaine, 129 mercury, 229 meropenem, 246–247 mesalamine. see mesalazine mesalazine (5-aminosalicylic acid, mesalamine) angio-edema, 368 constrictive pericarditis, 368 efﬁcacy, 368 gastrointestinal system, 368 urinary tract, 368 Wegener’s granulomatosis, 368 metformin concomitant glucose-lowering drugs, 455 hemolytic anemia, 454 lactation, 454 lactic acidosis, 453–454 overdose, 454–455 vitamin B12 deﬁciency, 454 methadone administration route, 92 +benzodiazepines, 91–92 cardiovascular system, 91 concentration, +efavirenz, 310 concentration, +ﬂuconazole, 279 concentration, +nevirapine, 316 concentration, +paroxetine, 92 concomitant paroxetine, 14 concomitant SSRIs, 14 dosage regimens, 92 fetotoxicity, 92 methamphetamine, 29 methotrexate concentration, +ciproﬂoxacin, 255 folic/folinic acid concentration, 409 liver, 376 lymphoproliferative disorders, 376 methylene blue injection, 531

methylenedioxymethamphetamine (MDMA, ecstasy) concomitant ethanol, 32 death, 31–32 electrolyte balance, 30–31 hematologic effects, 31 immunologic effects, 31 interactions, 32 liver, 31 psychological effects, 29–30 psychopathology, +cannabis, 30 respiratory system, 29 methylphenidate, 3 methylprednisolone, 417 methylxanthines, 1 metoclopramide, 362–363 metronidazole acute pancreatitis, 299 ﬁxed drug eruption, 299 interactions, 299 nervous system, 298–299 mexiletine concentration, +lidocaine, 197 concomitant amiodarone, 194 efﬁcacy, 197 midazolam, 118 mifepristone acceptability, 433 efﬁcacy, 433 reproductive system, 433–434 milk thistle, 314 milrinone, 188–189 miltefosine efﬁcacy, 296 fertility, 297 minocycline, 247 minoxidil caudal regression syndrome, 160–161 hypersensitivity, 160 pericardial effusion, 217 mirtazapine, 16 misoprostol, 418 modaﬁnil clozapine concentration, 58 concomitant dexamphetamine, 4 toxicity, +clozapine, 3 mometasone furoate, 416 monoamine re-uptake inhibitors, 14 monoﬂuorophosphate, 527 montelukast Churg–Strauss syndrome, 178 overdose, 179 Moringa oleifera, 324 morphine administration route, 93 death, 92 susceptibility factors, 92–93 moxiﬂoxacin anaphylactic reactions, 257 cholestasis, 257

concentration, +erythropoietin, 349 concentration, +sucralfate or multivalent cations, 257 concomitant theophylline, 257 concomitant warfarin, 257 erythroid response, +erythropoietin, 257 gastrointestinal system, 257 QT interval prolongation, 257 Multihance. see gadobenate dimeglumine mumps vaccine, 338 mupirocin, 265 muromonab-CD3, 381 muscle relaxants, 139–140 mycophenolate mofetil, 376 N-deamino-8-d-arginine vasopressin. see desmopressin naloxone, 97 naltrexone administration route, 98 effectiveness, 97 psychiatric effects, 98 narcissus absolute, 156 nefopam, 98 nelﬁnavir, 315 neomycin, 253 netilmicin, 253 neuraminase inhibitors, 317 nevirapine liver, 311 liver function tests, +efavirenz, 308–309 methadone concentration, 316 oral contraceptives concentration, 311 psychiatric effects, 311 urinary tract, 311 vertical transmission prevention, 310–311 niacin, 475–476, 520 nicardipine, 206 nickel, 229 nifedipine with food, 206–207 paralytic ileus, +diltiazem, 205–206 nifurtimox, 299 nimesulide, 267 nitazoxanide, 328, 330–331 nitrates, 187 nitrofurantoin gene toxicity, 264 liver necrosis, 264 pulmonary toxicity, 264 nitroglycerin. see glyceryl trinitrate nitrous oxide, 120 nizatidine, 364 non-nucleoside reverse transcriptase inhibitors (NNRTIs), 308–309

558 norﬂoxacin eosinophilia, 257 gastrointestinal system, 258 pancreatitis, 258 nortriptyline, 284–285 NRTIs. see nucleoside analogue reverse transcriptase inhibitors NSAIDs (nonsteroidal anti-inﬂammatory drugs) blood pressure, 102–104 gastrointestinal damage, +H. pylori, 105–109 photocontact dermatitis, 159 nucleoside analogue reverse transcriptase inhibitors (NRTIs) efﬁcacy, 306 gastrointestinal system, 309 hematologic effects, 309 immunologic effects, 309 liver, 309 metabolism, 306, 309 nervous system, 309 ototoxicity, 316 pregnancy, 306–307 octreotide, 468 ocular anesthesia cardiovascular system, 129 drug abuse, 130 infection risk, 130 sensory systems, 129–130 olanzapine cardiovascular system, 59 comparison trials, 50–51 drug overdose, 62 endocrine systems, 60 hematologic effects, 61 interactions, 62 mania treatment, 49–50 metabolism, 61 nervous system, 59–60 neuroleptic malignant syndrome, +lithium, 24 psychiatric effects, 60 seizures, +quetiapine, 60 olprinone, 189 omeprazole concentration, +famotidine, 364 concentration, +ﬂuconazole, 279 concurrent liver dysfunction, 365 efﬁcacy, 364 ﬁbromuscular hyperplasia, 365 gastric ulcer, +NSAIDs, 108 iron deﬁciency anemia, 365 skin, 365 ondansetron, 96 ONYX-15, 488 opiates, 38–39 opioids, 88 oprelvekin. see interleukin-11 oral contraceptives

Index of drugs bleeding, +drotrecogin alfa, 343 cervical cancer, 427 concentration, +nevirapine, 311 concentration, +norﬂoxacin, 258 concentration, +oﬂoxacin, 258 concentration, +roxithromycin, 264 concomitant ciproﬂoxacin, 255 concomitant levetiracetam, 79 concomitant rofecoxib, 113 ectopic pregnancy, 427 formulations, 428 mifepristone, 433–434 Sweet’s syndrome, 427 thromboembolism, 426–427 orlistat, 375 ornidazole, 299 oseltamivir concentration, +probenecid, 318 gastrointestinal symptoms, 317 ovulation-inducing drugs, 420–421 oxaliplatin irinotecan toxicity, 487 nervous system, 488 oxcarbazepine electrolyte balance, 79–80 phenytoin concentration, 80 susceptibility factors, 80 oxybutynin cardiovascular system, 152 formulations, 152–153 oxycodone concomitant gatiﬂoxacin, 256 formulation, 93–94 paclitaxel, 383 pantoprazole, 365–366 pantothenic acid. see dexpanthenol paracetamol concomitant argatroban, 110, 360 hepatic injury, +dextropropoxyphene, 89 overdose, 110 parathyroid hormone (PTH), 468–469 parecoxib, 113 parenteral nutrition anaphylactic reactions, 356 hematologic effects, 355 paroxetine concentration, +methadone, 92 concomitant amfebutamone, 15 concomitant methadone, 14 concomitant SSRIs, 13 passive surveillance, 334 Paullinia cupana, 518 pazuﬂoxacin mesilate, 1 PC-SPES, 512–513

peﬂoxacin, 258 pegﬁlgrastim, 393 pemoline, 4 penicillamine colonic perforation, 236–237 efﬁcacy, 236 gigantism of the breasts, 236 hematuria, 236 lupus-induced pleurisy, 236 lupus-like syndrome, 236 skin, 236 pentamidine efﬁcacy, 297 megaloblastic anemia, 297 rhabdomyolysis, 297 torsade de pointes, 297 pentoxifylline, 210 PeptoBismol, 226 perﬂuorocarbons, 343 perphenazine, 57 pethidine, 94 phenobarbital in Asian herbal medicines, 514 irinotecan concentration, 480 phenol, 531 2-phenoxyethanol, 158 phenprocoumon, 475 phentermine, 4–5 phenylephrine cardiovascular system, 509 contact dermatitis, 509 eye drops, 147 phenytoin concentration, +isradipine, 206 losartan conversion, 80 nervous system, 80 skin, 80 topiramate concentration, 82 phosphates, 529 phototherapy, 159 phthalic anhydride/trimellitic anhydride/glycols copolymer, 157 phytomenadione. see vitamin K pioglitazone, 457 piperacillin electrolyte balance, 244 neutropenia, 244–245 piperaquine, 290 piperazine, 331 piroxicam blood pressure, 103 concomitant enoxaparin, 359 podophyllotoxins. see topoisomerase II inhibitors polidocanol, 529 polyethylene glycol, 531 polygeline, 355 polyvinylpyrrolidone, 531 polyvinylpyrrolidone (PVP)/1-triacontene copolymer, 157 post-coital contraception, 429 potassium salts, 531 povidone iodine, 240

559

Index of drugs pramlintide, 453 pravastatin, 475 praziquantel, 331 prednicarbate, 415–416 prednisolone acute liver failure, 415 mania, +contrast agents, water-soluble iodinated, intravascular, 497 prednisone hypertension, 414 hypertrophic cardiomyopathy, 414–415 psychiatric effects, 415 preservatives, 158 prime yellow carnauba wax, 157 pristinamycin, 265 probenecid oseltamivir concentration, 318 valaciclovir concentration, 305 procainamide, 197–198 proguanil, 292 prolintane, 4 propafenone, 198 propellants, 172–173 propofol cardiovascular system, 121 concentration, +remifentanil, 95 concomitant midazolam, 118 concomitant parecoxib, 113 metabolism, 121 nervous system, 121 pancreas, 121 propofol infusion syndrome, 121 safety, 88 prostaglandin analogues, 510 prostaglandin E1 . see alprostadil protease inhibitors arthralgia, 312 concentration, +efavirenz, 310 interactions, 312 interactions with statins, 474 liver, 312 nervous system, 312 risperidone concentration, 65 statins concentration, 312 urinary tract, 312 proton pump inhibitors, 364–365 pruliﬂoxacin, 258 pseudoephedrine, 146. see also ephedrine PTH. see parathyroid hormone (PTH) pyrazinamide, 323 pyrimethamine allergic reactions, 293 Coombs’ positive hemolytic anemia, +dapsone, 294 efﬁcacy, +azithromycin, 296 efﬁcacy, +sulfadoxine, 293 hyperpigmentation, 293 hypersensitivity syndrome, +dapsone, 292–293

quazepam, 45 quetiapine concomitant lithium, 24 endocrine systems, 62 QT interval prolongation, +lovastatin, 474–475 seizures, +olanzapine, 60 quinidine cardiovascular system, 198 hydroxylation activity, 198 QT interval prolongation, 198 quinine efﬁcacy, 290 QT interval prolongation, 293 respiratory system, 291 thrombocytopenia, 291 urinary tract, 291 vision, 291 quinolone antimicrobial drugs, 187 quinupristin/dalfopristin antibacterial resistance, 266 general effects, 265–266 myalgia, 266 rash, 266 rabeprazole, 366 racecadotril, 367 raloxifene breast cancer, 430 cardiovascular safety, 431–432 ramipril, 214 ranitidine, 364 rapamycin. see sirolimus reboxetine, 16 red yeast rice, 474 remacemide, 81 remifentanil cardiovascular system, 95 concentration, +propofol, 95 death, 95 effectiveness, 118 pregnancy, 95 respiratory effects, 94–95 repaglinide concentration, +gemﬁbrozil, 456 palpable purpura, 455 susceptibility factors, 456 retinol. see vitamin A ribavirin, 304 rifampicin hepatitis, 324 hepatotoxicity, +pyrazinamide, 323 pneumonitis, 324 urinary tract, 324–325 risperidone autism treatment, 50 comparison trials, 51 concentration, +carbamazepine, 64, 76 concentration, +maprotiline, 12, 65

concentration, +SSRIs, 14 endocrine systems, 63 extrapyramidal disorders, +SSRIs, 14 ﬂuid balance, 63–64 metabolism, 63 nervous system, 62–63 neuroleptic malignant syndrome, +ﬂuvoxamine, 64 pregnancy, 64 prolactin concentration, 63 psychiatric effects, 63 sexual function, 64 ritonavir. see also lopinavir/ritonavir acenocoumarol concentration, 358 inﬂammatory edema, +lopinavir, 315 rhabdomyolysis, +simvastatin, 316 subcutaneous non-tuberculous granulomatous lesions, 315–316 warfarin concentration, 358 rituximab carcinogenicity, 382 hematologic effects, 381 immunologic effects, 381–382 skin, 381 rivastigmine cardiovascular system, 7–8 gastrointestinal system, 8 rocuronium, 140 rofecoxib gastrointestinal system, 112 immunologic system, 113 intoxication, +lithium, 113 nervous system, 112 skin, 113 rokitamycin, 178, 263 ropivacaine, 129, 134–135 rosiglitazone, 458 rosuvastatin, 279 rotavirus vaccine, 338–339 roxithromycin cardiovascular system, 263 eosinophilic pneumonia, 263 interactions, 264 liver, 263 lovastatin concentration, 264 oral contraceptives concentration, 264 skin, 264 RU 486. see mifepristone salbutamol, 179 diabetic ketoacidosis, 180 hyperactivity, 179 lactic acidosis, 180 metabolism, 180 musculoskeletal system, 180 myopathy, 180

560 nervous system, 179 propellant change, 173 salicylates, 11 sandalwood oil, 156 saquinavir, 316 sargramostim. see granulocyte-macrophage colony-stimulating factor sclerosant injections, 369 selective serotonin re-uptake inhibitors (SSRIs) concentration, +risperidone, 14 concomitant ﬂuoxetine, 13 concomitant methadone, 14 concomitant paroxetine, 13 concomitant sertraline, 13 drug overdose, 13 electrolyte balance, 12–13 extrapyramidal disorders, +risperidone, 14 fetotoxicity, 13 nervous system, 12 reproductive system, 13 serotonin toxicity, +linezolid, 14 serotonin toxicity, +monoamine re-uptake inhibitors, 14 selenium, 230 sertraline concomitant SSRIs, 13 serotonin syndrome, +tramadol, 96 sevoﬂurane concomitant amikacin, 119 musculoskeletal system, 119 nervous system, 119 renal insufﬁciency, 119 rhabdomyolysis, 119 urinary tract, 119 shellac, 157 Shen Loon, 513–514 sibutramine cardiovascular system, 6–7 hypomania, +citalopram, 7 metabolic effects, 6–7 psychosis, +ﬁnasteride, 436 psychotic behavior, +ﬁnasteride, 7 serotonin toxicity, +citalopram, 14 sildenaﬁl cardiovascular system, 210–211 epistaxis, 211 myocardial infarction, +cannabinoids, 33 nervous system, 211 overdose, 211 sensory systems, 211 tachyphylaxis, 211 silicone, 529 siliconized dressing, 531 silver, 230

Index of drugs simvastatin dehydroepiandrosterone, 475 rhabdomyolysis, +itraconazole, 281 rhabdomyolysis, +ritonavir, 316 serum lactate concentration, 475 sirolimus (rapamycin), 377 sitamaquine, 292 Slim 10, 530 smallpox vaccine, 339–340 SN-27, 480 sodium ferric gluconate, 228 sodium fusidate. see fusidic acid sodium metabisulﬁte contact allergy, 157 general effects, 531 sodium myristoyl sarcosinate, 157 sodium phosphate, 367 sodium picosulfate, 531 sodium polystyrene sulfonate, 237 sodium stibogluconate, 297 somatostatin. see also growth hormone release-inhibiting hormone somatotropin. see growth hormone Sono Vue (sulfur hexaﬂuoride), 506 sparﬂoxacin, 258 spasmocanulase, 369 spermicides, 530 spinal manipulation, 521 spironolactone agranulocytosis, 221 digoxin assay, 222 electrolyte balance, 221 spirulina, 519 SSRIs. see selective serotonin re-uptake inhibitors St. John’s wort concentration, fexofenadine, 169 interactions, 517 irinotecan concentration, 487 serotonin syndrome, +buspirone, 43 star anise, 518 statins alanine aminotransferase (ALT) activity, 473 concentration, +grapefruit juice, 528 concentration, +protease inhibitors, 312 concomitant digoxin, 187 interactions with protease inhibitors, 474 musculoskeletal system, 473–474 ocular myasthenia, 473

peripheral neuropathy, 473 stearic acid, 157 stellate ganglion block, 130 stilbestrol. see diethylstilbestrol stimulant drugs, 1–4 streptomycin anaphylaxis, 253 hearing loss, 251 susceptibility factors, 253 succinylcholine electrolyte balance, 140 extended function, +donepezil, 140–141 vs. rocuronium, 140 susceptibility factors, 140 sufentanil, 96 sulfadiazine, 266 sulfadoxine, 293 sulfamethoxazole. see co-trimoxazole sulfasalazine gastrointestinal system, 369 hematologic effects, 369 hepatitis, 369 respiratory system, 368 sulfonamides allergic reaction, 295 allergy potential, 267 sulfonylureas combination therapy, 459 concentration, +clarithromycin, 457 formulations, 457 hypoglycemia, 456 sunscreen, 159 suramin, 331–332 Symphytum ofﬁcinale, 519 tacrine, 7 tacrolimus concentration, +clarithromycin, 262 concentration, +diltiazem, 377 concentration, +voriconazole, 377 diabetes mellitus, 377 interactions, 377 nervous system, 377 tafenoquine, 292 talc, 531 tamoxifen cognitive function, 432–433 efﬁcacy, 432 endometrial cancer, 430 porphyria cutanea tarda, 433 tamsulosin, 187 teicoplanin hematologic system, 259 nephrotoxicity, +aminoglycosides, 259 pustular skin eruption, 259 susceptibility factors, 259 telithromycin, 260 temazepam, 45 teniposide

561

Index of drugs hypersensitivity reaction, 485–486 pharmacokinetics, 481 terbinaﬁne baboon syndrome, 284 children, 285 hematologic effects, 284 interactions, 284 liver, 284 nortriptyline concentration, 284–285 terbutaline, 180 terlipressin bronchospasm, 469 ﬁnger ischemia, 469 hyponatremia, 469 skin necrosis, 469 testosterone cholesterol concentration, 435 efﬁcacy, 435 safety, 434 Teucrium capitatum, 519 tezosentan, 215 thalidomide hyperglycemia, 377 neuropathy, 161 theophylline concentration, +pazuﬂoxacin, 1, 258 concomitant moxiﬂoxacin, 257 thiazide diuretics photosensitive lichenoid eruption, 221 potassium balance, 219–220 respiratory system, 220 thiazolidinediones. see glitazones thimerosal. see thiomersal thiomersal autism, 240–241 sensitization to, 229 thiopental, 120 thioridazine death, 65 sensory systems, 65 withdrawal, 65–66 thorotrast, 506 thrombolytic drugs, 343 thyroxine, 442 tiagabine, 81 tibolone, 437 tickborne encephalitis vaccine, 340 Ting Kung Teng, 513 tiotropium bromide, 180–181 titanium, 230 tobacco, 62 tobramycin nephrotoxicity, 253 ototoxicity, 253 rash, 253 respiratory system, 253 tolterodine, 153 topical anesthesia hematologic system, 131

sensory systems, 131 skin, 131 topiramate concentration, +lithium, 24 hyperammonemia, +valproate, 82 metabolism, 81 nervous system, 81 phenytoin concentration, 82 pregnancy/lactation, 81–82 psychiatric effects, 81 topoisomerase I inhibitors alopecia, 485 general effects, 482 mechanism of action, 478 pharmacokinetics, 478–479 review, 477–478 teratogenicity, 487 topoisomerase II inhibitors alopecia, 485 carcinogenicity, 486–487 mechanism of action, 478 mutagenicity, 486 review, 478 teratogenicity, 487 topotecan concentration, +cisplatin, 487 docetaxel clearance, 487 hematologic system, 483 interactions, 487 pharmacokinetics, 479 rash, 485 tosuﬂoxacin concentration, +aluminium hydroxide gel, 259 concentration, +magnesium oxide, 259 general effects, 258 tramadol effectiveness, 96 effectiveness, +ondansetron, 96 serotonin syndrome, +sertraline, 96 transdermal estrogen, 424 trastuzumab cardiac dysfunction, 382–383 concentration, +paclitaxel, 383 respiratory system, 383 triazolam death, 43 liver, 45 tribavirin. see ribavirin tricyclic antidepressants, 11 trideceth-2-carboxamide monoethanolamine, 157 trimethoprim, 267. see also co-trimoxazole triptans, 210 troleandomycin, 264 trovaﬂoxacin, 254 tumor necrosis factor antagonists, 393 ultrashort-acting insulins, 449

ursodeoxycholic acid, 369 Vaccine Adverse Event Reporting System (VAERS), 334 valaciclovir, 305 valproate anovulation, 73 ataxia, +haloperidol, 59 endocrine systems, 82 formulations, 82 hyperammonemia, +topiramate, 82 metabolism, 82 nutrition, 82 pancreas, 82 urinary tract, 82 valproic acid, 78–79 valspodar, 487 vancomycin anaphylaxis, 260 cardiovascular system, 259–260 cross-drug resistance, 243 nephrotoxicity, 260 pancytopenia, 260 pseudomembranous colitis, 260 skin, 260 vasopressin, 469 venlafaxine concomitant amfebutamone, 15 sensory systems, 16 serotonin syndrome, +dexamphetamine, 3, 16–17 verapamil, 207 vigabatrin, 83 virginiamycin, 268 visicol, 531 vitamin A children, 407 hematologic effects, 405–406 liver, 406–407 nervous system, 405 retinoic acid syndrome, 405 Sweet’s syndrome, 406 vitamin B12 allergy, 409–410 deﬁciency and folic acid, 407–408 vitamin D (calciferol) and analogues, 410 vitamin K, 410–411 voriconazole children, 283–284 ciclosporin concentration, 283, 375 efﬁcacy, 281–282 tacrolimus concentration, 377 visual effects, 282 warfarin concentration, +amiodarone, 194 concentration, +ritonavir, 358 concomitant enoxaparin, 359 concomitant moxiﬂoxacin, 257

562 efﬁcacy, +ribavirin, 304 hypoprothrombinemia, +gatiﬂoxacin, 256 hypoprothrombinemia, +levoﬂoxacin, 257 Wau Wa cream, 513 witch hazel, 512 xenon, 120 Xu Xin, 513 Yasmin, 531

Index of drugs ylang-ylang oil I, 156 ylang-ylang oil II, 156 zaﬁrlukast, 178 zaleplon, 46 zanamivir efﬁcacy, 318 gastrointestinal symptoms, 317 zidovudine general effects, 306 lipodystrophy, 308 zinc general effects, 512

hematologic effects, 230 lichen planus, 230 ziprasidone cardiovascular system, 66 comparison trials, 51 musculoskeletal system, 66 nervous system, 66 psychiatric effects, 66 zolpidem, 46–47 zonisamide, 83 zopiclone, 47 zuclopenthixol, 66

Index of adverse effects abdominal discomfort amiodarone, 190 lamivudine + zidovudine + abacavir, 306 losartan, 214 tosuﬂoxacin, 258 abdominal distension gemtuzumab, 380 lamivudine + zidovudine + abacavir, 306 mesalazine, 368 racecadotril, 367 abdominal fullness polyethylene glycol, 367 sodium phosphate, 367 abdominal pain acamprosate, 531 albendazole, 328 anti-CD4, 379 arteether, 292 azithromycin, 261 deferiprone, 233 eﬂornithine, 298 esomeprazole, 365 famotidine, 364 fosmidomycin, 268 indinavir, 313 irinotecan, 484 lamivudine + zidovudine + abacavir, 306 lansoprazole, 365 meglumine antimoniate, 297 mesalazine, 368 methylenedioxymethamphetamine, 31 moxiﬂoxacin, 257 naltrexone, 97 nitazoxanide, 328, 331 octreotide, 468 omeprazole, 364 procainamide, 197 proton pump inhibitors, 364 rabeprazole, 366 racecadotril, 367 ranitidine, 364 rifampicin, 324 topoisomerase I inhibitors, 483 abducens paresis vitamin A, 405 abnormal dreaming efavirenz, 309 abnormal fat accumulation indinavir, 314 abnormal gait ku shep, 513 abortion, spontaneous

cyclophosphamide, 376 abscesses insulin pumps, 448 acanthosis haloperidol, 59 acetylcholine receptor antibodies interleukin-2 (IL-2), 391 Achilles tendinitis ciproﬂoxacin, 255 levoﬂoxacin, 257 acidosis sodium phosphates oral solution, 529 acne implantable contraceptives, 427 acral necrosis quinine, 291 acute respiratory distress syndrome (ARDS) chlorhexidine, 239 rocuronium, 138 acyclic menstrual bleeding copper, 227 adenitis diethylcarbamazine, 329 ivermectin, 329 adenolymphangitis diethylcarbamazine, 328 adenomas lithium, 21 administration, mistakes in glargine insulin, 450 adrenal insufﬁciency budesonide, 174 Coriandrum sativa, 516 ﬂuticasone propionate, 174 inhaled corticosteroids, 174–175 itraconazole + budesonide, 280–281 adult respiratory distress syndrome ﬁlgrastim, 392 adverse effects in trial accounts NNRTIs, 308 adverse events surveillance programs, 334 affective state nevirapine, 311 aggressive behavior ergotamine, 151 agitation amisulpride, 54 dexamphetamine + venlafaxine, 3

ﬂuoxetine, 12 hyoscyamine, 152 paroxetine, 12 pemoline, 4 pethidine, 94 risperidone, 63 agranulocytosis antithyroid drugs, 442–443 clozapine, 57 deferiprone, 233 dipyrone, 111 lamotrigine, 78 olanzapine, 61 spironolactone, 221 air bronchogram vitamin A, 405 airway hyper-responsiveness salbutamol, 179 airway problems propofol, 118 akathisia clozapine, 56 haloperidol, 51 olanzapine, 60 alanine aminotransferase (ALT) activity albendazole, 326–327 caspofungin, 286 deferiprone, 233 fosmidomycin, 268 lopinavir + ritonavir, 315 nevirapine, 311 NNRTIs, 309 protease inhibitors, 312 sodium stibogluconate, 297 statins, 473 sulfadiazine, 266 albumin concentration caspofungin, 286 alkaline phosphatase activity caspofungin, 286 losartan, 214 quinupristin/dalfopristin, 265 stavudine + lamivudine + nevirapine, 317 allergic granulomatosis inﬂiximab, 394, 396 allergic reactions aminoglycosides, 251 aspart insulin, 449 clindamycin, 296 co-trimoxazole, 266, 296 dental anesthesia, 128 dexpanthenol, 411 estradiol, 422

563

564 fragrances and essential oils, 156 glibenclamide, 456–457 insulin detemir, 450 iodopropynylbutylcarbamate, 158 muscle relaxants, 138–139 nickel, 229 pyrimethamine, 294 spermicides, 530 sulfonamides, 295 vitamin B12 , 409–410 allergic vasculitis celecoxib, 112 alopecia albendazole, 326 hair bonds and hair extensions, 158 interferon-alfa, 388 pramipexole, 150 topoisomerase I inhibitors, 482, 485 topoisomerase II inhibitors, 485 alopecia areata interferon-alfa, 388 ALT activity see alanine aminotransferase (ALT) activity alveolar bone necrosis arsenic toxicity, 225 alveolar damage interferon-gamma, 390 alveolar opacities interferon-gamma, 390 amenorrhea cyclophosphamide, 376 etoposide, 487 implantable contraceptives, 427 transdermal estrogen, 426 amylase activity didanosine, 308 sodium stibogluconate, 297 amyloid-like deposition in the skin insulin, 447 anal ﬁssures methotrexate, 376 anaphylaxis/anaphylactic reactions abciximab, 378–379 albumin, 342 basiliximab, 379 bismuth, 226 ceftriaxone, 246 celecoxib, 112 chloral hydrate, 46 chlorhexidine, 239–240 cisatracurium, 138 dextrans, 354 Echinacea (coneﬂower), 516 etoposide, 485 gelatin, 527 inﬂiximab, 395, 397

Index of adverse effects intravenous immunoglobulin, 346 isosulfan blue, 528–529 moxiﬂoxacin, 257 parenteral nutrition, 356 polygeline, 355 pseudoephedrine, 146 rocuronium, 138 sodium metabisulﬁte, 531 streptomycin, 253 trastuzumab, 382 vancomycin, 260 ANCA-associated vasculitis antithyroid drugs, 443 anemia albendazole, 327 ceftriaxone, 245–246 chloramphenicol, 253 dapsone + chlorproguanil, 292 interleukin-2 (IL-2), 391 irinotecan, 482 metformin, 454 parenteral nutrition, 355–356 rifampicin, 324 rituximab, 381 stavudine + lamivudine + nevirapine, 317 sulfasalazine, 369 topotecan, 483 vitamin A, 405, 406 zinc, 230 anger meﬂoquine, 290, 292 angina pectoris ﬂecainide, 196 angio-edema cyclophosphamide, 375 Echinacea (coneﬂower), 516 hair bonds, 159 mesalazine, 368 omeprazole, 365 pseudoephedrine, 146 rituximab, 382 rofecoxib, 113 roxithromycin, 264 angioimmunoblastic lymphadenopathy ciproﬂoxacin, 255 angle closure glaucoma venlafaxine, 16 anicteric cholestasis vitamin A, 406 anorexia albendazole, 327 antimony, 224 beta-arteether, 292 entacapone, 151 indinavir, 313 levetiracetam, 79 nifurtimox, 299 pramlintide, 453 racecadotril, 367 suramin, 332 topoisomerase II inhibitors, 483

anorgasmia gabapentin, 77 anovulation valproate, 73 anovulatory cycles antiepileptic drugs, 73 etoposide, 487 antepartum bleeding diamorphine, 38 anterior chamber inﬂammation fomivirsen, 303 anterior ischemic optic neuropathy interferon-alfa, 384 anterior subcapsular lens opacities amiodarone, 191 antibodies against growth hormone growth hormone, 467 antibodies to activated protein drotrecogin alfa, 342 antibody formation inﬂiximab, 395 anticholinergic intoxication atropine, 152 antigenicity lispro insulin, 449 antinuclear antibodies captopril, 213 anuria dextrans, 353, 354 anxiety amisulpride, 54 dexamphetamine and venlafaxine, 3 efavirenz, 309 fenﬂuramine, 5 ivermectin, 329 modaﬁnil, 3 quinine, 291 aortic dissection cocaine, 33 aortic regurgitation fenﬂuramines and phentermine, 4 apathy diamorphine, 38 aplasia erythropoietin, 348–349 rituximab, 381 aplasia cutis congenita carbamazepine, 443–444 aplastic anemia azathioprine toxicity, 373 chloramphenicol, 254 interferon-beta, 389 apnea caudal anesthesia, 125 diazepam, 121 ocular anesthesia, 129 appetite, change in olanzapine, 49

565

Index of adverse effects appetite increase risperidone, 50 application site reaction transdermal estrogen, 426 arachnoiditis interferon-alfa, 384 ARDS see acute respiratory distress syndrome (ARDS) arterial dissection spinal manipulation, 521 arterial hypertension ginseng, 517 arteriovenous ﬁstula thrombosis erythropoietin, 348 arthralgia captopril, 213 deferiprone, 233 diethylcarbamazine, 329 growth hormone, 467 indinavir, 314 ivermectin, 329 mycophenolate mofetil, 376 protease inhibitors, 312 quinupristin/dalfopristin, 265 sibutramine, 5–6 arthropathy ﬂuoroquinolones, 254 ascites gemtuzumab, 380 aseptic meningitis co-trimoxazole, 295 intravenous immunoglobulin, 345 pentoxifylline, 210 rofecoxib, 112 trimethoprim, 267 aspartate aminotransferase (AST) activity caspofungin, 286 lopinavir + ritonavir, 315 miltefosine, 296 NNRTIs, 309 sodium stibogluconate, 297 stavudine + lamivudine + nevirapine, 317 sulfadiazine, 266 Aspergillus myocarditis methylprednisolone, 417 aspiration pneumonia naltrexone, 98 asystole epidural anesthesia, 125 remifentanil, 95 asystolic cardiac arrest epidural anesthesia, 125 asystolic cardiorespiratory arrest lidocaine, 134 ataxia gatiﬂoxacin, 256 gentamicin, 252 ivermectin, 329

ku shep, 513 metronidazole, 298–299 valaciclovir, 305 atonic seizures piperazine, 331 atrial ﬁbrillation adrenaline, 145 dobutamine, 147 atrial ﬂutter amiodarone, 190 atrial tachycardia with Wenckebach atrioventricular block digoxin, 185 atrium, heart see entries at heart— atrophy betamethasone 17-valerate, 416 mometasone furoate, 416 attention level gonadorelin, 465 oxaliplatin, 488 auditory disturbance see entries at hearing— auditory hallucinations ergotamine, 151 lormetazepam, 45 autism thiomersal, 240–241 autoantibodies interferon-alfa, 388 autoimmune disease and immunization, 336–337 autoimmune hepatitis cyproterone acetate, 427 interferon-alfa, 388 autoimmune thyroiditis interferon-alfa, 388 autoimmunity inﬂiximab, 395 AV conduction delay olanzapine, 59 axial dystonia risperidone, 62 axillary lymphadenopathy smallpox vaccine, 340 axillary vein thrombosis mexiletine, 197 axonal degeneration interferon-alfa, 384 B cell non-Hodgkin’s lymphoma inﬂiximab, 394 baboon syndrome roxithromycin, 264 terbinaﬁne, 284 back pain anti-CD4, 379 Deﬁnity, 505 interferon-alfa, 384 backache adenosine, 189

intravenous immunoglobulin, 345 bacterial infections inﬂiximab, 396 balance disturbances droperidol, 58 gentamicin, 252 behavioral adverse effects benzodiazepines, 75 Bell’s palsy interferon-alfa, 384 interleukin-4 (IL-4), 391 benign orgasmic headache amiodarone, 191 bile duct proliferation josamycin, 263 birth defects lamotrigine, 78 bitter taste pentamidine, 297 bladder cancer azathioprine toxicity, 373–374 bladder discomfort dobutamine, 147 bleeding abciximab, 378 drotrecogin alfa, 342 enoxaparin, 359 bleeding risk antiepileptic drugs, 73 Ginkgo biloba (maidenhair tree), 209, 517 bleeding time prolongation see INR blindness lithium, 20 nitrous oxide, 120 quinine, 291 blisters amphetamines, 2 blood dyscrasias antimicrobial drugs, 243–244 blood loss parenteral nutrition, 356 blood pressure changes intravenous immunoglobulin, 345 NSAIDs, 102–104 oxytocin, 468 blue color vision amiodarone, 191 blue discoloration methylene blue injection, 531 blurred vision inﬂiximab, 394 ivermectin, 329 vitamin A, 405 bone dysplasia deferoxamine, 234 bone loss budesonide, 416 glucocorticoids, 416 bone marrow granulomata amiodarone, 193

566 bone marrow suppression benznidazole, 298 chloramphenicol, 254 bone mass index topiramate, 81 bone mineral density epilepsy and antiepileptic drugs, 74–75 indinavir, 314 bone pain ﬁlgrastim, 392 vitamin A, 405 bone turnover carbamazepine, 76 bowel complaints cilostazol, 209 bradycardia amiodarone, 190 beta-adrenoceptor antagonists, 509–510 clonidine, 126, 215 ku shep, 513 nicardipine, 206 phenylephrine, 147 propafenone, 198 remifentanil, 95 bradyphrenia diamorphine, 38 brain damage baclofen, 142 brain volume, loss of adrenocorticotrophic hormone, 414 breakthrough bleeding, menstrual implantable contraceptives, 427 breast cancer hormone replacement therapy, 423, 425 raloxifene, 430 breast density hormone replacement therapy, 425 breast-feeding lithium, 23 breast pain transdermal estrogen, 424, 426 breathing difﬁculty polygeline, 355 breathlessness ocular anesthesia, 129 quinine, 291 bronchial obstructions tobramycin, 253 bronchiolitis obliterans interferon-alfa, 384 bronchospasm beta-adrenoceptor antagonists, 510 dextrans, 353 rituximab, 381 rocuronium, 138 sodium metabisulﬁte, 531 terlipressin, 469

Index of adverse effects Brown–Sequard syndrome cocaine, 35 bullae cannabinoids, 32 bullous dermatitis melarsoprol, 298 bundle branch block ﬂecainide, 196 burning eyes netilmicin, 253 burns phenol, 531 C4 spinal lesion clonidine, 215 cancer azathioprine toxicity, 373 cancer, breast hormone replacement therapy, 423, 425 raloxifene, 430 cancer, cervical oral contraceptives, 427 cancer, colorectal azathioprine toxicity, 373 growth hormone, 467 cancer, endometrial hormone replacement therapy, 425–426 tamoxifen, 430, 432 cancer, ovarian antiestrogens, 431 hormone replacement therapy, 426 Candida infection dexamethasone, 416–417 candy-cane esophagus cocaine, 35–36 carcinoma of the bladder azathioprine toxicity, 373–374 cardiac see also entries at coronary—; heart— cardiac adverse effects suramin, 332 cardiac allograft rejection gonadorelin agonists, 465 cardiac arrest see also myocardial infarction contrast agents, iodinated, 498 dextrans, 354 intravenous regional anesthesia, 128 olanzapine, 62 phenylephrine, 509 polidocanol, 529 sibutramine, 5–6 cardiac dysfunction trastuzumab, 382 cardiac dysrhythmia adenosine, 189 ﬂuoxetine, 13 olprinone, 189

phenylephrine, 509 vasopressin, 469 cardiac failure inﬂiximab, 396 cardiac index labetalol, 203 cardiac inﬂammation smallpox vaccine, 339 cardiac tamponade acupuncture, 520 cardiomegaly lithium, 23 cardiomyopathy chloroquine, 289 clozapine, 55 ephedrine, 146 lithium, 20 cardiopulmonary arrest ocular anesthesia, 129 cardiotoxicity bupivacaine, 131–132 sodium stibogluconate, 297 cardiovascular anomalies carbamazepine, 76 cardiovascular collapse bupivacaine, 132 cardiovascular complications sevoﬂurane, 119 cardiovascular disorders ginseng, 517 cardiovascular dysfunction and malformation cocaine, 36 cataracts tamoxifen, 432 cauda equina syndrome intrathecal (spinal) anesthesia, 127 caudal regression syndrome minoxidil, 160–161 cellular necrosis ciclosporin, 374 cellulitis mycophenolate mofetil, 376 central retinal artery occlusion cocaine, 35 interferon-alfa, 384 centrilobular congestion gemtuzumab, 380 cerebellar ataxia diamorphine, 38 piperazine, 331 cerebellar syndrome metronidazole, 299 cerebral edema ﬂuid replacement, 447 methylenedioxymethamphetamine, 30 cerebral infarction intravenous immunoglobulin, 345 cerebral outcome clomethiazole, 46

567

Index of adverse effects cerebral thrombosis heparins, 358 cervical cancer oral contraceptives, 427 cervical lymphadenopathy co-trimoxazole, 295 chest discomfort quinine, 291 chest pain amfebutamone, 15 brachial plexus anesthesia, 124 cocaine, 1 dextrans, 353 erythropoietin, 348 methylenedioxymethamphetamine, 29 sibutramine, 6 sodium stibogluconate, 298 sulfasalazine, 368 children contrast agents, iodinated, 499 ﬂuconazole, 279 insulin pumps, 448–449 interferon-alfa, 388 itraconazole, 281 latanoprost, 510 linezolid concentration, 265 mebendazole, 326 nelﬁnavir, 315 ranitidine, 364 terbinaﬁne, 285 vitamin A, 405, 407 voriconazole, 283–284 chills amphotericin B colloidal dispersion (ABCD), 277 captopril, 213 caspofungin, 286 intravenous immunoglobulin, 345 misoprostol, 418 ONYX-15, 488 quinine, 291 rifampicin, 324 rituximab, 381 chloride concentrations meﬂoquine, 290 choanal atresia carbamazepine, prenatal, 444 cholestasis azithromycin, 261 bosentan, 215 ciclosporin, 374 clarithromycin, 262 ﬂecainide, 196 gabapentin, 77 methylenedioxymethamphetamine, 31 moxiﬂoxacin, 257 pravastatin, 475 cholestatic jaundice fusidic acid, 259 ranitidine, 364 cholestatic liver damage

roxithromycin, 263 cholesterol concentrations indinavir + ritonavir, 317 lopinavir + ritonavir, 315 olanzapine, 53 cholinergic effects rivastigmine, 7 cholinergic syndrome Ting Kung Teng, 513 choreoathetoid movements pemoline, 4 chromosome aberrations nitrofurantoin, 264 chronic fatigue syndrome interferon-alfa, 384 Churg–Strauss syndrome leukotriene receptor antagonists, 177–179 rokitamycin, 263 circumoral paresthesia indinavir + ritonavir, 317 cirrhosis methotrexate, 376 vitamin A, 406 cleft palate carbamazepine, 76 clonic seizures Ginkgo biloba (maidenhair tree), 210 clouding of consciousness nevirapine, 311 CNS depression Xu Xin, 513 CNS symptoms efavirenz, 309 intravenous regional anesthesia, 128 CNS toxicity bupivacaine, 132 coagulation disorders methylenedioxymethamphetamine, 31 cognitive function antipsychotic drugs, 52 benzodiazepines, 43 cocaine, 35, 37 insulin, 447 lamotrigine, 77–78 methylenedioxymethamphetamine, 30 nevirapine, 311 phenytoin, 80 tamoxifen, 432–433 cold urticaria lisinopril, 213–214 colic nifurtimox, 299 colitis mesalazine, 368 colonic perforation penicillamine, 236–237 colonic ulceration sodium polystyrene sulfonate, 237

color vision, impairment digoxin, 185–186 colorectal cancer azathioprine toxicity, 373 growth hormone, 467 coma cefepime, 245 ephedrine, 146 methylenedioxymethamphetamine, 31 procainamide, 198 complex ventricular dysrhythmias potassium salts, 531 concentration (mental) oxaliplatin, 488 valaciclovir, 305 confusion efavirenz, 309 ergotamine, 151 oseltamivir, 318 piperazine, 331 valaciclovir, 305 congenital anomalies azathioprine toxicity, 374 conjunctival pseudomembranes cidofovir, 303 conjunctivitis cidofovir, 303 connective tissue disease interferon-alfa, 388 consolidation vitamin A, 405 consort urticaria amoxicillin, 244 constipation buprenorphine, 97 clozapine, 57 5-HT3 receptor antagonists, 363 linezolid, 264 oxycodone, 93 pantoprazole, 366 racecadotril, 367 ranitidine, 366 topoisomerase I inhibitors, 483 trovaﬂoxacin, 254 constrictive pericarditis mesalazine, 368 contact allergies budesonide, 177 dexpanthenol, 411 preservatives, 158 contact dermatitis arbekacin, 252 aromatherapy, 520 clonidine, 215 detergents, 531 EMLA cream, 131 gentamicin, 251 latanoprost, 418 mercury, 229 minoxidil, 160 omeprazole, 365

568 phenylephrine, 147, 509 polyvinylpyrrolidone, 531 preservatives, 158 sodium metabisulﬁte, 531 topical ocular medications, 509 contact urticaria amoxicillin, 244 cosmetics, 157 hair bonds, 158–159 sunscreen, 159 conversion hysteria interleukin-2 (IL-2), 391 convulsions contrast agents, iodinated, 498 diamorphine, 38 eﬂornithine, 298 levoﬂoxacin, 256 lidocaine, 134 ropivacaine, 134 sevoﬂurane, 119 sodium picosulfate, 531 stellate ganglion block, 130 Coombs’ positive hemolytic anemia dapsone + pyrimethamine, 294 corneal complications ocular anesthesia, 130 corneal drug deposits amiodarone, 191 corneal perforations tetracaine, 130 coronary see also entries at cardi—; heart— coronary artery disease ephedrine, 146 coronary artery spasm ephedrine, 146 coronary disease hormone replacement therapy, 423 cough meglumine antimoniate, 297 oseltamivir, 318 quinine, 291 sulfasalazine, 368 crack lung cocaine, 34 cracking lips vitamin A, 405 cramps formoterol, 179 irinotecan, 484 cranial neuropathy interferon-alfa, 384 creatine kinase activity ephedrine, 146 ﬂuvastatin, 474 interleukin-2 (IL-2), 391 statins, 474 creatinine concentration indinavir, 314 miltefosine, 296 creatinine kinase activity

Index of adverse effects levoﬂoxacin, 256 crescentic glomerulonephritis rifampicin, 325 Creutzfeldt–Jakob disease see also variant Creutzfeld–Jakob disease blood transfusion, 344 human growth hormone, 466 cryoagglutinins interferon-alfa, 388 cryocrit intravenous immunoglobulin, 346 crystalluria aciclovir, 305 indinavir, 314 nevirapine, 311 cutaneous leukocytoclastic vasculitis omeprazole, 365 cutaneous lupus erythematosus phenytoin, 80 cutaneous nodulosis etanercept, 394 cutaneous sarcoidosis interferon-alfa, 388 cutaneous thrombotic microangiopathy interferon-alfa, 387 cutaneous vasculitis etanercept, 394 intravenous immunoglobulin, 346 cyanosis benzocaine, 131 CYP1A2 inhibition ﬂutamide, 436 pazuﬂoxacin, 258 CYP2C19 inhibition ﬂuconazole, 279 topiramate, 82 CYP2D2 inhibition risperidone, 12 CYP2D6 inhibition ritonavir, 316 SSRIs, 14 terbinaﬁne, 284 CYP3A4 induction efavirenz, 310 St. John’s wort, 517 CYP3A4 inhibition cannabinoids, 33 clarithromycin, 457 delavirdine, 309 ﬂuconazole, 279 itraconazole, 280 lovastatin, 475 macrolides, 261 ritonavir, 316 troleandomycin, 264 cystoid macular edema prostaglandin analogues, 510 cytokine release syndrome rituximab, 381–382

cytolysis methylenedioxymethamphetamine, 31 cytolytic hepatitis Centaurium erythreae, 520 Copaltra, 520 Coutarea latiﬂora, 520 cytomegalovirus reaction alemtuzumab, 379 cytomegalovirus retinitis inﬂiximab, 396 cytoplasmic calcium concentration erythropoietin, 348 Darier’s disease lithium, 22 daytime neurological impairment diphenhydramine, 167 De Toni–Debré–Fanconi syndrome valproate, 83 death abciximab, 378 albumin, 342 alemtuzumab, 379 antimony, 224 baclofen, 142 benzodiazepines, 43–44 chloral hydrate, 46 cocaine, 36 colestyramine + phenprocoumon, 475 diamorphine, 38 digoxin, 186 ephedrine, 146 epidural anesthesia, 125 inﬂiximab, 396–397 interferon-gamma, 390 interleukin-2 (IL-2), 391 intravenous regional anesthesia, 128 lidocaine, 134 melarsoprol, 298 methylenedioxymethamphetamine, 30–31 naltrexone, 98 olanzapine, 61, 62 rituximab, 382 sclerosant injections, 369 smallpox vaccine, 339 sodium stibogluconate, 298 traditional medicines, 512 trastuzumab, 382 triazolam, 43 Xu Xin, 513 deep vein thrombosis clotting factors, 346 intravenous immunoglobulin, 345 dehydration eﬂornithine, 298

569

Index of adverse effects sodium phosphates oral solution, 529 dehydroepiandrosterone simvastatin, 475 delayed allergic-like skin reactions contrast agents, iodinated, 497–498 delayed hypersensitivity reactions bovine collagen, 526 contrast agents, iodinated, 502–504 delayed-onset heparin-induced thrombocytopenia heparins, 358 delayed skin reactions contrast agents, iodinated, 500 delirium azithromycin, 261 dopamine receptor agonists, 149–150 methylenedioxymethamphetamine, 30, 32 nevirapine, 311 sevoﬂurane, 119 zolpidem, 46 delusions nevirapine, 311 dementia efavirenz, 309 depigmentation clonidine, 215 depression efavirenz, 309 interferon-beta, 389 interleukin-2 (IL-2), 391 meﬂoquine, 290, 292 prednisone, 415 depressive disorders interferon-alfa, 385 dermal edema haloperidol, 59 dermatitis see also contact dermatitis clonidine, 215 haloperidol, 59 inﬂiximab, 396 melarsoprol, 298 roxithromycin, 264 dermatological effects levoﬂoxacin + pyrazinamide, 323 desaturation brachial plexus anesthesia, 124 diabetes mellitus chlorpromazine, 57 clozapine, 57 growth hormone, 466 inhaled corticosteroids, 177 interferon-alfa, 386 olanzapine, 61 perphenazine, 57 tacrolimus, 377

diabetic ketoacidosis salbutamol, 180 diarrhea abacavir, 307 acamprosate, 531 albendazole, 327 azithromycin, 261 biothionol, 331 ciproﬂoxacin, 255 contrast agents, iodinated, 499 eﬂornithine, 298 entacapone, 151 esomeprazole, 365 ﬂecainide, 196 ganciclovir, 303 gatiﬂoxacin, 256 gemiﬂoxacin, 256 ginseng, 517 5-HT3 receptor antagonists, 363 indinavir, 313 indinavir + ritonavir, 317 intravenous immunoglobulin, 345 irinotecan, 481, 482, 483–485 iron, 228 itraconazole, 279 ketolides, 260 lansoprazole, 365 linezolid, 264 lopinavir + ritonavir, 315 mesalazine, 368 miltefosine, 296 misoprostol, 418 moxiﬂoxacin, 257 nelﬁnavir, 315 nifurtimox, 299 nitazoxanide, 328, 331 nizatidine, 366 octreotide, 468 oseltamivir, 318 pantoprazole, 366 paroxetine, 12 proton pump inhibitors, 364 quinupristin/dalfopristin, 265 rabeprazole, 366 ramipril, 214 ranitidine, 366 SN-38, 484 sodium stibogluconate, 298 stavudine + lamivudine + nevirapine, 316–317 topoisomerase II inhibitors, 483 topotecan, 479 tosuﬂoxacin, 258 valaciclovir, 305 diffuse colitis suramin, 332 diffuse erythema haloperidol, 59 diffuse generalized slowing of brain wave activity valaciclovir, 305

diffuse urticaria hair bonds, 159 digestive disturbances benznidazole, 298 diplopia botulinum toxin A, 162 ocular anesthesia, 129 remacemide, 81 tramadol, 96 vitamin A, 405 disorientation amprenavir, 313 valaciclovir, 305 disseminated encephalomyelitis rabies vaccine, 336 disseminated epidermal necrolysis omeprazole, 365 disseminated intravascular coagulation alemtuzumab, 379 quinine, 291 dizziness arteether, 292 bupivacaine, 132 buprenorphine, 97 diethylcarbamazine, 328 dofetilide, 195 efavirenz, 309 fentanyl, 91 ﬂecainide, 196 gabapentin, 77 glucagon-like peptide-1, 452 5-HT3 receptor antagonists, 363 hyoscyamine, 152 ivermectin, 329 ketolides, 260 ku shep, 513 modaﬁnil, 3 naltrexone, 97 nitazoxanide, 331 protease inhibitors, 312 ranitidine, 364, 366 remacemide, 81 risperidone, 50 sodium phosphate, 367 somatostatin, 467 stavudine + lamivudine + nevirapine, 316–317 tosuﬂoxacin, 258 trovaﬂoxacin, 254 valaciclovir, 305 dopaminergic transmission ciclosporin, 374 double vision lidocaine, 131 drooling risperidone, 50 drowsiness gabapentin, 77 oxycodone, 93 risperidone, 50, 63 drug intoxication

570 cocaine, 36 drug resistance antimicrobial drugs, 242–243 dry cough interferon-alfa, 384 meglumine antimoniate, 297 dry eyes amiodarone, 191 hormone replacement therapy, 423–424 dry mouth ethylenediaminetetraacetic acid, 234 gadobenate dimeglumine, 504 5-HT3 receptor antagonists, 363 hyoscyamine, 152 imipramine, 11 olanzapine, 49 oxybutynin, 153 procainamide, 197 sibutramine, 5, 6 tiotropium bromide, 181 tolterodine, 153 tramadol, 96 dry skin clindamycin, 260 erythromycin, 263 vitamin A, 405 Dupuytren’s contracture indinavir, 314 dysarthria atropine, 152 metronidazole, 298–299 valaciclovir, 305 dyschromatopsia ivermectin, 329 dysgeusia lithium, 22 dyskinesia entacapone, 151 dyspareunia tamoxifen, 432 dyspepsia mesalazine, 368 methoxsalen, 159 nitazoxanide, 331 oseltamivir, 317 dysphagia hydrocodone, 91 dysphasia ku shep, 513 dysphoria naltrexone, 98 dyspnea blood transfusion, 344 colistin, 265 dextrans, 353, 354 ﬂecainide, 196 interferon-alfa, 383, 384, 388 interferon-gamma, 390 ku shep, 513 metronidazole, 299 Xu Xin, 513

Index of adverse effects dysrhythmia bupivacaine, 132 digoxin, 185 lower limb block, 129 sibutramine, 5, 6 talc, 531 dystonia amfebutamone, 15 metoclopramide, 363 dystonic movements propofol, 121 dysuria reboxetine, 16 ear pain abacavir, 307 ear tenderness botulinum toxin A, 162 eating disorders olanzapine, 60 Ebstein’s anomaly lithium, 22–23 ecchymotic rash hemoglobin-based oxygen carriers, 343 ectopic pregnancy mifepristone, 434 oral contraceptives, 427 eczema intravenous immunoglobulin, 346 eczema-like skin lesions interferon-alfa, 387 edema albendazole, 327 cetirizine, 166 haloperidol, 59 interferon-alfa, 388 loratadine, 169 methylenedioxymethamphetamine, 31 quinupristin/dalfopristin, 265 risperidone, 63 ritonavir + lopinavir, 315 rosiglitazone, 459 verapamil, 207 electrocardiographic changes see QT interval prolongation electrolyte disturbances diuretics, 219–220 piperacillin, 244 sodium picosulfate, 531 emesis see vomiting emphysema methylenedioxymethamphetamine, 29 empyema talc, 531 encephalitis smallpox vaccine, 339 encephalomyelitis rabies vaccine, 336

encephalopathic syndrome melarsoprol, 298 encephalopathy bismuth, 225–226 methylenedioxymethamphetamine, 31 sodium stibogluconate, 298 endocrine disorders ginseng, 517 endometrial cancer hormone replacement therapy, 425–426 tamoxifen, 430, 432 endometriosis mifepristone, 434 endophthalmitis acupuncture, 520 endophthalmitis with scleral damage ganciclovir, 304 endothelin erythropoietin, 348 enhanced brightness of light and color voriconazole, 282 eosinophilia irinotecan, 483 norﬂoxacin, 257 olanzapine, 61 sulfasalazine, 369 tolterodine, 153 eosinophilic pleural effusion inﬂiximab, 394 facial edema hair bonds, 159 facial erythema interferon-alfa, 387 facial ﬂushing desmopressin, 469 facial nerve palsy ciclosporin, 374 facial swelling lidocaine, 128 faintness hair bonds, 159 familial Mediterranean fever isotretinoin, 160 Fanconi syndrome ifosfamide, 488–489 fat deposits tamoxifen, 26446 fatigue abacavir, 307 buprenorphine, 97 interferon-beta, 390 lamivudine + zidovudine + abacavir, 306 meﬂoquine, 290, 292 methoxsalen, 159 misoprostol, 418 nitazoxanide, 331 remacemide, 81

571

Index of adverse effects stavudine + lamivudine + nevirapine, 317 suramin, 332 topotecan, 482 valaciclovir, 305 vitamin A, 405 febrile reactions baclofen, 141–142 fecal abnormality ivermectin, 329 fecal incontinence etanercept, 393 ferritin concentration deferiprone, 233 fetal heart rate pethidine, 94 fetotoxicity lead, 228–229 fever abacavir, 307 alemtuzumab, 379 amphotericin B colloidal dispersion (ABCD), 277 arsenic, 262 atropine, 152 baclofen, 142 blood transfusion, 344 captopril, 213 caspofungin, 286 diethylcarbamazine, 328–329 efavirenz, 310 ethylenediaminetetraacetic acid, 234 interferon-alfa, 388 interferon-gamma, 390 intravenous immunoglobulin, 345 iohexol, 498 ivermectin, 329 misoprostol, 418 muromonab-CD3, 381 ONYX-15, 488 pseudoephedrine, 146 quinine, 291 rifampicin, 324 ritonavir + lopinavir, 315 rituximab, 381 sclerosant injections, 369 sodium stibogluconate, 298 sulfasalazine, 368 tolterodine, 153 valaciclovir, 305 vitamin A, 405 Xu Xin, 513 ﬁbrinolysis hormone replacement therapy, 424 ﬁbromuscular hyperplasia omeprazole, 365 ﬁnger ischemia terlipressin, 469 ﬁrst-degree heart block olanzapine, 59 ﬁxed drug eruption

loratadine, 169 metronidazole, 299 vancomycin, 260 ﬂaccid paraplegia etanercept, 393 ﬂare phenomenon doxorubicin, 489 ﬂare reactions malaria vaccine, 294 ﬂatulence acarbose, 452 ganciclovir, 303 mesalazine, 368 nitazoxanide, 331 sulfasalazine, 369 ﬂu-like symptoms interferon-alfa, 388 interferon-beta, 389 ONYX-15, 488 perﬂuorocarbons, 343 psoralens, 159 rifampicin, 324 ﬂuid retention bosentan, 215 gemtuzumab, 380 interleukin-11, 391 rosiglitazone, 457–458 ﬂushing contrast agents, iodinated, 498 Deﬁnity, 505 intravenous immunoglobulin, 345 focal epidermal cell degeneration haloperidol, 59 focal segmental glomerulosclerosis interferon-alfa, 386 focal seizure lidocaine, 134 focusing (mental) difﬁculty lidocaine, 131 follicular keratosis lithium, 22 fracture risk glucocorticoids, 416 fractures growth hormone, 467 frozen shoulder indinavir, 314 fungal infections inﬂiximab, 397 galactorrhea acupuncture, 520 haloperidol, 58 olanzapine, 60 risperidone, 63 gamma-glutamyl transpeptidase activity meﬂoquine, 290 gamma-glutamyltransferase activity

efavirenz, 309 lopinavir + ritonavir, 315 nevirapine, 311 gastric pain albendazole, 326 pruliﬂoxacin, 258 gastrointestinal bleeding aspirin, 109 azathioprine toxicity, 373 inﬂiximab, 397 gastrointestinal effects (unspeciﬁed) acarbose, 452–453 digoxin, 185 levoﬂoxacin + pyrazinamide, 323 lomeﬂoxacin, 257 Lorenzo’s oil, 475 metformin, 453 miltefosine, 296 monoﬂuorophosphate, 527 NSAIDs + H. pylori, 105–109 oseltamivir, 317 propafenone, 198 rivastigmine, 7 sitamaquine, 292 stavudine + lamivudine + nevirapine, 316–317 zanamivir, 317 gastrointestinal intolerance levoﬂoxacin, 256 gastrointestinal smooth muscle spasm hemoglobin-based oxygen carriers, 343 gastrointestinal toxicity beta-arteether, 292 gelatin allergy chloral hydrate, 46 General Practice Research Database (GPRD) described, xxxi–xxxii genotoxicity antiestrogens, 429–430 giant diverticulum in the sigmoid colon sodium polystyrene sulfonate, 237 giddiness arteether, 292 gigantism of the breasts bucillamine, 235 penicillamine, 236 gingivitis Lorenzo’s oil, 475 glaucoma venlafaxine, 16 global amnesia sildenaﬁl, 211 glomerulonephritis rifampicin, 325 glucose concentration beta2 adrenoceptor agonists, 179

572 glucose metabolism antipsychotic drugs, 53 growth hormone, 466 octreotide, 467–468 olanzapine, 61 glycosuria lithium, 21 valproate, 83 goiter lithium, 20, 23 GPRD see General Practice Research Database (GPRD) graft-vs.-host disease contrast agents, iodinated, 500 granulocytopenia deferiprone, 233 olanzapine, 61 granuloma annulare-like eruption amlodipine, 205 granuloma gluteale adultorum benzocaine, 131 granulomas silicone, 529 granulomatosis inﬂiximab, 394 mesalazine, 368 granulomatous dermatitis interferon-alfa, 387 granulomatous hepatitis rosiglitazone, 458 Graves’ disease goserelin acetate, 465 green hyperpigmentation FD and C Blue No 1, 531 ground-glass opacities vitamin A, 405 growth of lashes latanoprost, 510–511 Guillain–Barré syndrome inﬂuenza immunization, 336 gynecomastia antiretroviral drugs, 306 ﬁnasteride, 435–436 spironolactone, 221 hair loss see also alopecia mebendazole, 327 vitamin A, 405 hair texture changes interferon-alfa, 388 hallucinations (auditory) ergotamine, 151 lormetazepam, 45 hallucinations (visual) diphenhydramine, 168 voriconazole, 282 hallucinations (unspeciﬁed) amprenavir, 313 clarithromycin, 262 diphenhydramine, 168

Index of adverse effects drotrecogin alfa, 342 ergotamine, 151 interferon-beta, 389 lormetazepam, 45 nevirapine, 311 pemoline, 4 pethidine, 94 valaciclovir, 305 hand-foot syndrome etoposide, 485 headache abacavir, 307 adenosine, 189 antimony, 224 arteether, 292 botulinum toxin A, 162 cilostazol, 209 Deﬁnity, 505 diethylcarbamazine, 328 erythropoietin, 348 esomeprazole, 365 ﬁlgrastim, 392 ﬂecainide, 196 formoterol, 179 fosmidomycin, 268 gabapentin, 77 gadobenate dimeglumine, 504 ginseng, 517 glucagon-like peptide-1, 452 glyceryl trinitrate, 204 5-HT3 receptor antagonists, 363 hydrocodone, 91 implantable contraceptives, 427 indinavir, 313 interferon-alfa, 384 interferon-beta, 390 intravenous immunoglobulin, 345 iohexol, 498 isosorbide-5-mononitrate, 204 ivermectin, 329 levetiracetam, 79 levovist, 506 linezolid, 264 meﬂoquine, 290 methoxsalen, 159 modaﬁnil, 3 mycophenolate mofetil, 376 naltrexone, 97 nitazoxanide, 328, 331 nizatidine, 366 pantoprazole, 366 piperazine, 331 prostaglandin analogues, 510 protease inhibitors, 312 proton pump inhibitors, 364 rabeprazole, 366 racecadotril, 367 ranitidine, 364, 366 remacemide, 81 risperidone, 63 sitamaquine, 292 sodium phosphate, 367

sodium stibogluconate, 298 Sono Vue (sulfur hexaﬂuoride), 506 stavudine + lamivudine + nevirapine, 317 tezosentan, 215 tickborne encephalitis vaccine, 340 tosuﬂoxacin, 258 valaciclovir, 305 vitamin A, 405 hearing loss abacavir, 307 aminoglycosides, 251 chloroquine, 289 deferoxamine, 234 eﬂornithine, 298 gentamicin, 252 stavudine + lamivudine + nevirapine, 316 vancomycin, 259 heart see also coronary—; entries at cardi— heart attack aspirin for prevention, 105–109 heart beat see speciﬁc conditions such as cardiac dysrhythmias; sinus node dysfunction; tachycardia heart failure bosentan, 215 dopamine receptor agonists, 150 ﬂecainide, 196 heart failure, congestive doxazosin, 217 heart rate changes dextrans, 354 imipramine, 11 sibutramine, 5, 6 heart rate variability cocaine, 36–37 heavy-headedness 5-HT3 receptor antagonists, 363 HELLP syndrome hyoscyamine, 152 hematocrit rosiglitazone, 458 sodium stibogluconate, 297 hematuria ethylenediaminetetraacetic acid, 235 indinavir, 313 nevirapine, 311 penicillamine, 236 hemiparesis doxazosin, 217 intravenous immunoglobulin, 345 psychotic episodes, 81 topiramate, 81

573

Index of adverse effects hemoglobin caspofungin, 286 ganciclovir, 304 glitazones, 457 Lorenzo’s oil, 475 rosiglitazone, 458 hemolysis ribavirin, 304 hemolytic anemia ceftriaxone, 245–246 metformin, 454 ribavirin, 304 suramin, 332 hemolytic–uremic syndrome ciproﬂoxacin, 255 interferon-alfa, 387 quinine, 291 hemophagocytosis co-trimoxazole, 266, 295 teicoplanin, 259 hemopoietic toxicity ﬂucytosine, 278 hemoptysis brachial plexus anesthesia, 124 hemorrhagic stroke aspirin, 109 hemotoxicity sodium stibogluconate, 297 hepat— see also entries at liver— hepatic cholangiocarcinoma thorotrast, 506 hepatic failure, fulminant clarithromycin, 262 hepatic ﬁbrosis methotrexate, 376 hepatic hydrothorax vitamin A, 406–407 hepatic necrosis antithyroid drugs, 443 hepatic transaminitis gemtuzumab, 380 hepatic veno-occlusive disease gemtuzumab, 380 hepatitis acupuncture, 520 alemtuzumab, 379 amlodipine, 205 antithyroid drugs, 443 cetirizine, 167 cyproterone acetate, 427 gatiﬂoxacin, 256 interferon-alfa, 388 isoﬂurane, 120 kava (Piper methysticum), 518 labetalol, 203–204 LipoKinetix, 519 losartan, 214 methylenedioxymethamphetamine, 31 muromonab-CD3, 381 rifampicin, 324 simvastatin, 475 sulfasalazine, 369

Teucrium capitatum, 519 vitamin A, 406 hepatitis, fulminant cocaine + alcohol, 37 intravenous immunoglobulin, 346 hepatobiliary reactions terbinaﬁne, 284 hepatocellular failure methylenedioxymethamphetamine, 31 hepatocellular injury Breynia ofﬁcinalis, 515–516 hepatocellular liver damage roxithromycin, 263 hepatocyte necrosis gemtuzumab, 380 hepatomegaly gemtuzumab, 380 hepatosplenomegaly parenteral nutrition, 355 hepatotoxicity acarbose, 453 comfrey, 519 Dictamnus dasycarpus, 513 disulﬁram, 526 efavirenz, 309–310 entacapone, 151 gemtuzumab, 380 Jin bu huan, 513 methotrexate, 376 nevirapine, 311 NNRTIs, 308–309 pioglitazone, 457 protease inhibitors, 312 pyrazinamide + rifampicin, 323 heroin lung described, 38 herpes simplex keratitis prostaglandin analogues, 510 hiccups levodopa, 148 high spinal block epidural anesthesia, 125 histoplasmosis etanercept, 397 inﬂiximab, 397 Hodgkin’s disease growth hormone, 467 Horner’s syndrome epidural anesthesia, 125 hot ﬂushes bicalutamide, 435–436 tamoxifen, 432 human antichimeric antibodies inﬂiximab, 395 human parvovirus B19 transmission clotting factors, 347 intravenous immunoglobulin, 346 hyaline casts ethylenediaminetetraacetic acid, 235

hydronephrosis nevirapine, 311 hydropic swelling dextrans, 353 hyperactivity pemoline, 4 salbutamol, 179 hyperammonemic encephalopathy valproate, 82 hyperamylasemia stavudine + lamivudine + nevirapine, 317 hyperbilirubinemia gemtuzumab, 380 indinavir, 314 lithium, 23 meﬂoquine, 290 protease inhibitors, 312 hypercalcemia meﬂoquine, 290 parathyroid hormone (PTH), 468 vitamin A, 405 vitamin D (calciferol) and analogues, 410 hypercholesterolemia isotretinoin, 160 stavudine + lamivudine + nevirapine, 317 hyperesthesia articaine, 127 hyperglycemia growth hormone, 466 interleukin-2 (IL-2), 391 olanzapine, 60–61 somatostatin, 467 thalidomide, 377 hyperinsulinemia isotretinoin, 160 olanzapine, 61 valproate, 82 hyperkalemia labetalol, 204 thiopental, 120 hyperkeratosis glucagon, 452 hyperkinesia amisulpride, 54 hyperleptinemia olanzapine, 61 hyperlipidemia isotretinoin, 159 sirolimus (rapamycin), 377 vitamin A, 405 hypernatremia sclerosant injections, 369 sodium phosphates oral solution, 529 hyperparathyroidism lithium, 21 hyperphosphatemia sodium phosphates oral solution, 529

574 hyperpigmentation clonidine, 215 efavirenz, 310 pyrimethamine, 292 thioridazine, 65 hyperprolactinemia olanzapine, 60 hypersalivation clozapine, 55 hypersensitivity lung disease sulfasalazine, 368 hypersensitivity reaction abacavir, 306–307, 317 abacavir + efavirenz, 316 atorvastatin, 474 basiliximab, 379 benznidazole, 298 bovine collagen, 526 clindamycin, 261 contrast agents, iodinated, 502–504 cyclophosphamide, 375–376, 489 diazepam, 44–45 efavirenz, 310 etoposide, 489 folinic acid, 408 inﬂiximab, 395–396 malaria vaccine, 294 minoxidil, 160 muscle relaxants, 138–139 parenteral nutrition, 356 tolterodine, 153 topoisomerase I inhibitors, 482 topoisomerase II inhibitors, 485–486 trastuzumab, 382 hypersensitivity syndrome dapsone + pyrimethamine, 292–293 hypersexuality risperidone, 63 hypertension adrenaline, 145 baclofen, 142 carbamazepine, 76 celecoxib, 112 clonidine, 215 drotrecogin alfa, 342 erythropoietin, 348 fenﬂuramine, 5 ginseng, 517 hemoglobin-based oxygen carriers, 343 methylenedioxymethamphetamine, 32 pemoline, 4 phenylephrine, 509 prednisone, 414 sibutramine, 5–6 vasopressin, 469 vitamin A, 406 hypertensive crisis erythropoietin, 348

Index of adverse effects indinavir, 313 St. John’s wort, 518 hypertensive encephalopathy erythropoietin, 348 hyperthermia baclofen, 142 cocaine, 36 methylenedioxymethamphetamine, 32 paroxetine, 12 pemoline, 4 hyperthyroidism amiodarone, 192–193 indinavir + levothyroxine, 314 lithium, 20–21 hypertriglyceridemia didanosine, 308 isotretinoin, 160 stavudine + lamivudine + nevirapine, 317 hypertrophic cardiomyopathy prednisone, 414–415 hypertrophic osteoarthropathy alprostadil, 417–418 hyperuricemia levoﬂoxacin + pyrazinamide, 323 hypesthesia intrathecal (spinal) anesthesia, 127 hypesthesia of dermatomes brachial plexus anesthesia, 124 hypocalcemia ethylenediaminetetraacetic acid, 235 sodium phosphates oral solution, 529 hypoglycemia ciproﬂoxacin + insulin, 255 clarithromycin + sulfonylureas, 262 ganciclovir, 304 gemﬁbrozil, 473 glucose-reducing combination therapy, 459 inhaled corticosteroids, 174 insulin, 447 insulin combinations, 450–451 insulin pumps, 448 interleukin-4 (IL-4), 391 lithium, 21, 23 meglitinides, 455 rosiglitazone, 458 sulfonylureas, 456 hypokalemia chlortalidone, 219–220 licorice, 517 sodium phosphates oral solution, 529 hypomania ziprasidone, 66 hypomenorrhea etoposide, 487 hyponatremia

desmopressin, 469 methylenedioxymethamphetamine, 30 oxcarbazepine, 79–80 risperidone, 63–64 SSRIs, 12–13 terlipressin, 469 hypoproteinemia albendazole, 327 hypoprothrombinemia gatiﬂoxacin + warfarin, 256 levoﬂoxacin + warfarin, 257 hypotension adrenaline, 145 amiodarone, 190 blood transfusion, 344 carvedilol, 203 clomipramine, 11 clonidine, 126, 215 dextrans, 353 diethylcarbamazine, 329 dobutamine, 147 doxazosin, 217 erythropoietin, 348 ethylenediaminetetraacetic acid, 234 etoposide, 482 ﬂecainide, 196 fosphenytoin, 80 interleukin-2 (IL-2), 391 iron, 228 ivermectin, 329 metformin, 454 nitazoxanide, 331 olanzapine, 51 procainamide, 198 rituximab, 381 rocuronium, 138 hypothalamic-pituitary-adrenal axis function inhaled corticosteroids, 173, 175 lithium, 21 hypothalamic-pituitarygonadal axis suppression opioids, 88 hypothermia diamorphine, 38 hypothyroidism amiodarone, 190 interferon-alfa, 385, 388 lithium, 23 hypoxemia blood transfusion, 344 interferon-gamma, 390 hypoxia amphotericin B colloidal dispersion (ABCD), 277 rituximab, 381 icteric hepatitis Teucrium capitatum, 519 idiopathic thrombocytopenia MMR immunization, 336

575

Index of adverse effects IgE-mediated hypersensitivity reaction basiliximab, 379 IL-8 plasma concentration granulocyte colony-stimulating factor (G-CSF), 392 immediate-type hypersensitivity reactions malaria vaccine, 294 immune dysfunction methylenedioxymethamphetamine, 31 immune-mediated hemolysis interferon-alfa, 388 impotence spironolactone, 221 incoherence valaciclovir, 305 incoordination piperazine, 331 induration clonidine, 215 infantile hypertrophic pyloric stenosis erythromycin, 262–263 infarction see cerebral infarction; myocardial infarction infection acupuncture, 520 anakinra + etanercept, 390 erythropoietin, 348 inﬂiximab, 397 levetiracetam, 79 infection risk ﬂudarabine, 489 infectious complication ocular anesthesia, 130 infertility cyclophosphamide, 376 inﬂammatory demyelinating polyneuropathy interferon-alfa, 384 inﬂammatory edema ritonavir + lopinavir, 315 inﬂammatory primary myositis interleukin-2 (IL-2), 391 inﬂammatory reactions malaria vaccine, 294 infusion reactions amphotericin, 283 inﬂiximab, 394–395 phenytoin, 80 rituximab, 381 trastuzumab, 382 inhibition of platelet aggregation interferon-alfa, 386 inhibitor antibodies clotting factors, 347 injection site pain arteether, 292 malaria vaccine, 294 pentamidine, 297

propofol, 121 injection site reactions gadobenate dimeglumine, 504 growth hormone, 467 interferon-beta, 389–390 latex allergy, 450 sclerosant injections, 369 injection site skin necrosis interferon-alfa, 387 INR antiviral drugs, 358 calcium channel blockers, 204–205 co-trimoxazole + acenocoumarol or phenprocoumon, 267, 295 contrast agents, iodinated, 499 ethylenediaminetetraacetic acid + warfarin, 235 niacin, 475–476, 520 ribavirin + warfarin, 304 ritonavir + acenocoumarol, 316 insomnia amisulpride, 54 ginseng, 517 5-HT3 receptor antagonists, 363 linezolid, 264 insulin-dependent diabetes mellitus interferon-alfa, 386 insulin growth hormone, 466 intermittent uterine bleeding 17-beta-estradiol, 424 interstitial ﬁbrosis interferon-alfa, 388 interstitial inﬂammation sulfasalazine, 368 interstitial nephritis aminosalicylates, 367 indinavir, 314 lithium, 22 mesalazine, 367–368 rifampicin, 325 sitamaquine, 292 interstitial pneumonitis docetaxel, 488 gold, 227 interferon-alfa, 384 interferon-gamma, 390 intestinal colic nifurtimox, 299 intestinal obstruction cocaine, 36 intoxication cocaine, 36 intracerebral hemorrhage abciximab, 378 hyoscyamine, 152 intracranial hemorrhage methylenedioxymethamphetamine, 32 intramyocardial para-aortic abscess

inﬂiximab, 396 intraocular pressure changes fomivirsen, 303 intrathoracic ﬁbrosis dopamine receptor agonists, 150 intravascular coagulation clotting factors, 346 intussusception rotavirus vaccine, 339 involuntary movements pemoline, 4 iritis prostaglandin analogues, 510 iron-deﬁciency anemia omeprazole, 365 parenteral nutrition, 355–356 irregular bradycardia lithium, 20 irritability efavirenz, 309 parenteral nutrition, 356 piperazine, 331 valaciclovir, 305 irritant contact dermatitis minoxidil, 160 irritation ﬂuorescein dye, 510 ischemia cocaine, 35 ergotamine, 151 ischemic attack erythropoietin, 348 ischemic colitis rofecoxib, 112 triptans, 210 ischemic damage intrathecal (spinal) anesthesia, 126 ischemic hepatocyte necrosis gemtuzumab, 380 ischemic lesions interferon-alfa, 387 ischemic stroke with hemiparesis intravenous immunoglobulin, 345 itching albendazole, 327 diethylcarbamazine, 328 mupirocin, 265 parenteral nutrition, 356 quinupristin/dalfopristin, 265 itching eyes netilmicin, 253 Jarisch–Herxheimer reaction ciproﬂoxacin, 255 jaundice albendazole, 327 black cohosh, 516 hemoglobin-based oxygen carriers, 343 losartan, 214

576 methylenedioxymethamphetamine, 31 ranitidine, 364 rifampicin, 324 jitteriness pethidine, 94 joint pain antimony, 224 juxtaclavicular beaded lines ciclosporin, 375 Kaposi’s sarcoma of the skin deferoxamine, 234 keratitis ﬁlgrastim + sargramostim, 392 ketoacidosis insulin pumps, 448 salbutamol, 180 ketonuria ethylenediaminetetraacetic acid, 235 kidney see entries at nephro—; renal— lacrimation irinotecan, 484 lactate concentration simvastatin, 475 lactate dehydrogenase activity meﬂoquine, 290 lactic acidemia NRTIs, 306–307 lactic acidosis metformin, 453–454 salbutamol, 180 lactic dehydrogenase activity losartan, 214 language function prenatal cocaine, 1 lassitude gabapentin, 77 latex allergy insulin cartridges, 450 leg pain monoﬂuorophosphate, 527 Legionella pneumophila infection inﬂiximab, 396 leprosy antiretroviral drugs, 306 leptin concentration lithium, 21 lesions inﬂiximab, 394 lethargy antimony, 224 parenteral nutrition, 355 risperidone, 63 leukemia ibritumomab, 380 leukocyte count

Index of adverse effects ganciclovir, 304 Lorenzo’s oil, 475 leukocytoclastic vasculitis efavirenz, 310 leukocytosis dextrans, 353 tolterodine, 153 leukoencephalopathy diamorphine, 38, 89 leukopenia albendazole, 328 azathioprine, 373 ethylenediaminetetraacetic acid, 234 etoposide, 483 ﬂucytosine, 278 gemtuzumab, 380 inﬂiximab, 396 interferon-alfa-2b, 383 intravenous immunoglobulin, 346 irinotecan, 481–483 ivermectin, 330 olanzapine, 61 stavudine + lamivudine + nevirapine, 317 sulfasalazine, 369 teniposide, 483 topotecan, 479 Lewin, Louis biography, xxv–xxix Lhermitte’s sign oxaliplatin, 488 libido decrease gabapentin, 77 lithium, 22 lichen planus zinc, 230 lichen spinulosus omeprazole, 365 licheniﬁcation glucagon, 452 lichenoid eruptions etanercept, 394 hydralazine, 217 inﬂiximab, 394 ursodeoxycholic acid, 369 light-headedness efavirenz, 309 olanzapine, 59 protease inhibitors, 312 ranitidine, 364 limb edema interferon-alfa, 388 linear immunoglobulin A bullous disease vancomycin, 260 lingual paresthesia articaine, 127 lip erosions amphetamines, 2 lipase activity sodium stibogluconate, 297 lipoatrophy

growth hormone, 467 lispro insulin, 449 lipodystrophy indinavir + ritonavir, 317 NRTIs, 306 zidovudine, 308 lips, cracking vitamin A, 405 Listeria monocytogenes infection inﬂiximab, 396 livedo reticularis captopril, 213 liver see also entries at hepat— liver damage Asian herbal medicines, 513 celandine, 516 chromium picolinate, 226 ﬂutamide, 436 gliclazide, 456 kava (Piper methysticum), 518–519 LipoKinetix, 531 methylenedioxymethamphetamine, 31 spirulina, 519 triazolam, 45 liver dysfunction exatecan, 476 liver enzyme activity albendazole, 326 black cohosh, 516 etoposide, 485 famotidine, 364 ﬂuconazole, 278 interferon-beta, 389 ivermectin, 330 levoﬂoxacin, 256 nevirapine + efavirenz, 308–309 omeprazole, 364 ONYX-15, 488 rabeprazole, 366 ranitidine, 366 terbinaﬁne, 284 voriconazole, 282 liver failure amfebutamone, 15 gemtuzumab, 380 prednisolone, 415 terbinaﬁne, 284 liver ﬁbrosis vitamin A, 406 liver function abnormalities voriconazole, 283 liver insufﬁciency dacarbazine, 488 liver necrosis nitrofurantoin, 264 local allergic reactions spermicides, 530 local irritation ﬂuorescein dye, 510

577

Index of adverse effects local pain sclerosant injections, 369 local skin reactions benzyl benzoate, 330 localized abdominal lipohypertrophy growth hormone, 466 localized scleroderma penicillamine, 236 loose stools acarbose, 452 fosmidomycin, 268 lower abdominal pain misoprostol, 418 lower back pain iron, 228 lower limb block, 129 lung damage iron, 227–228 lung inﬁltrates vitamin A, 405 lung injury blood transfusion, 344 lupus, drug-induced inﬂiximab, 395–396 lupus erythematosus interferon-alfa, 388 lupus-induced pleurisy penicillamine, 236 lupus-like syndrome amiodarone, 193 captopril, 213 inﬂiximab, 395–396 minocycline, 247–248 penicillamine, 236 lymphadenopathy smallpox vaccine, 340 lymphangitis diethylcarbamazine, 328 lymphocytopenia ethylenediaminetetraacetic acid, 234 lymphocytosis ivermectin, 330 lymphoproliferative disorders inﬂiximab, 394 methotrexate, 376 tumor necrosis factor antagonists, 393 macrophagic myofasciitis aluminium, 224 macular hemorrhage azathioprine toxicity, 373 macular toxicity amikacin, 252 maculopapular rash azithromycin, 261 celecoxib, 112 sodium stibogluconate, 298 malaise abacavir, 307 captopril, 213

entacapone, 151 gabapentin, 77 inﬂiximab, 396 intravenous immunoglobulin, 345 lamivudine + zidovudine + abacavir, 306 nitazoxanide, 331 star anise, 518 sulfadiazine, 266 sulfonylureas, 456 tolterodine, 153 mania clarithromycin, 262 ginseng, 517 prednisone, 415 risperidone, 63 mast cell degranulation dextrans, 354 Mazzotti reaction ivermectin, 329 megaloblastic anemia parenteral nutrition, 355 pentamidine, 297 membranous glomerulonephritis mercury, 229 memory impairment oxaliplatin, 488 memory test scores gonadorelin, 465 meningeal signs tickborne encephalitis vaccine, 340 meningeal syndrome with fever ornidazole, 299 meningoencephalitis dexibuprofen, 110 menorrhagia SSRIs, 13 menstrual abnormalities dydrogesterone, 424 risperidone, 63 spironolactone, 221 valproate, 82 Merkel cell carcinoma rituximab, 382 mesangial proliferation rifampicin, 325 mesenteric ischemia triptans, 210 metabolic acidosis dorzolamide, 220 topiramate, 81 metabolic alkalosis sodium picosulfate, 531 metabolic derangements baclofen, 142 metabolic syndrome isotretinoin, 159 metallic taste propafenone, 198 methemoglobinemia sitamaquine, 292

topical anesthetic, 131 microprecipitates in the corneal epithelium ciproﬂoxacin, 254 microscopic hematuria ivermectin, 330 microthrombi interferon-alfa, 387 migraine gabapentin, 77 minimal-change nephrotic syndrome interferon-beta, 389–390 miscarriage, spontaneous cyclophosphamide, 376 mistakes in administration glargine insulin, 450 modulation of vasoconstrictor factors erythropoietin, 348 molluscum contagiosum inﬂiximab, 397 monoarthritis interferon-beta, 390 mononeuritis multiplex montelukast, 178 mononeuropathy multiplex interferon-alfa, 384 mononuclear inﬁltrates interferon-alfa, 387 monosomy granulocyte colony-stimulating factor (G-CSF), 392 mood changes ephedrine, 146 morbilliform rash co-trimoxazole, 295 morphological anomalies cyclophosphamide, 376 motor restlessness diamorphine, 38 movement disorders haloperidol, 51 mucinosis interferon-beta, 390 mucopurulent exudate hydrocodone, 91 mucositis rituximab, 381 topoisomerase I inhibitors, 482, 483 topoisomerase II inhibitors, 483 mucous lesions interferon-alfa, 387 multifocal action myoclonus lithium, 20 multinucleated histiocytes indinavir, 314 multiple sclerosis interferon-alfa, 384 muscle aches antimony, 224 methoxsalen, 159

578 muscle pain meglumine antimoniate, 297 statins, 473–474 vitamin A, 405 muscle rigidity dibucaine, 133 muscle spasm baclofen, 142 ethylenediaminetetraacetic acid, 234 ku shep, 513 muscle twitches pethidine, 94 muscular hyperactivity baclofen, 142 musculoskeletal adverse effects levoﬂoxacin, 256 musculoskeletal symptoms tamoxifen, 432 myalgia diethylcarbamazine, 328 erythropoietin, 348 fosmidomycin, 268 granulocyte colony-stimulating factor (G-CSF), 392 inﬂiximab, 396 interferon-beta, 390 quinupristin/dalfopristin, 266 rifampicin, 324 myasthenia gravis interleukin-2 (IL-2), 391 mycobacterial infections acupuncture, 520 Mycobacterium avium septic arthritis corticosteroids, 416 mydriasis ivermectin, 329 myelodysplastic syndrome granulocyte colony-stimulating factor (G-CSF), 392–393 myelogenous leukemia ibritumomab, 380 topoisomerase I inhibitors, 482 myeloid leukemia granulocyte colony-stimulating factor (G-CSF), 392–393 myelomeningocele efavirenz, 310 myelosuppression irinotecan, 482 topoisomerase II inhibitors, 483 topotecan, 483 myocardial dysfunction interferon-alfa, 383 myocardial infarction see also cardiac arrest adrenaline, 145 amfebutamone, 15 aspirin, 109 clotting factors, 346 cocaine, 1 ephedrine, 146

Index of adverse effects etoposide, 482 sildenaﬁl, 210–211 smallpox vaccine, 339 triptans, 210 myocardial ischemia intravenous immunoglobulin, 345 myocarditis amfebutamone, 15 clozapine, 55 methylprednisolone, 417 smallpox vaccine, 339 myoclonus paroxetine, 12 valaciclovir, 305 myopathy roxithromycin + gemﬁbrozil + simvastatin, 264 salbutamol, 180 myositis interleukin-2 (IL-2), 391 myotonic seizures piperazine, 331 narrowing of the tubular lumen dextrans, 353 nasal congestion botulinum toxin A, 162 nasal obstruction hydrocodone, 91 nasal septal perforation cocaine, 34 nausea abacavir, 307 albendazole, 326, 328 amiodarone, 190 antimony, 224 arteether, 292 azithromycin, 261 biothionol, 331 buprenorphine, 97 caspofungin, 286 contrast agents, iodinated, 498 deferiprone, 233 Deﬁnity, 505 dextrans, 353–354 divalproex, 49 entacapone, 151 erythropoietin, 348 esomeprazole, 365 famotidine, 364 fentanyl, 91 ﬂecainide, 196 formoterol, 179 gabapentin, 77 gadobenate dimeglumine, 504 ganciclovir, 303 gatiﬂoxacin, 256 gemiﬂoxacin, 256 glucagon-like peptide-1, 452 growth hormone, 466 Helicobacter pylori eradication regimens, 367

indinavir, 313 indinavir + ritonavir, 317 intravenous immunoglobulin, 345 iohexol, 498 itraconazole, 279 ivermectin, 329–330 ketolides, 260 ku shep, 513 lamivudine, 308 lamivudine + zidovudine + abacavir, 306 lansoprazole, 365 levovist, 506 linezolid, 264 meﬂoquine, 290 meglumine antimoniate, 297 mesalazine, 368 methoxsalen, 159 methylenedioxymethamphetamine, 31 mexiletine, 197 modaﬁnil, 3 morphine, 93 moxiﬂoxacin, 257 muromonab-CD3, 381 mycophenolate mofetil, 376 naltrexone, 97 nifurtimox, 299 nitazoxanide, 328, 331 omeprazole, 364 oseltamivir, 317–318 oxycodone, 93 pantoprazole, 366 pentamidine, 297 pethidine, 94 polyethylene glycol, 367 pramlintide, 453 proton pump inhibitors, 364 rabeprazole, 366 ranitidine, 364, 366 remifentanil, 94, 118 rifampicin, 324 risperidone, 63 sevoﬂurane, 119 sodium phosphate, 367 somatostatin, 468 Sono Vue (sulfur hexaﬂuoride), 506 star anise, 518 stavudine + lamivudine + nevirapine, 316–317 sulfasalazine, 369 tolterodine, 153 topoisomerase I inhibitors, 483 topoisomerase II inhibitors, 483 tosuﬂoxacin, 258 tramadol, 96 trovaﬂoxacin, 254 valaciclovir, 305 vitamin A, 405 neck pain methylenedioxymethamphetamine, 29

579

Index of adverse effects necrosis triazolam, 45 necrotizing fasciitis inﬂiximab, 396 necrotizing vasculitis interferon-alfa, 384 nephr— see also entries at renal— nephrogenic diabetes insipidus lithium, 23 nephrolithiasis indinavir, 313–314 nevirapine, 311 protease inhibitors, 312 stavudine + lamivudine + nevirapine, 317 nephropathy propylthiouracil, 443 nephrotic syndrome interferon-alfa, 386–387 interferon-beta, 389–390 nephrotic syndrome with focal glomerulosclerosis lithium, 22 nephrotoxicity aminoglycosides, 251 amphotericin, 276 caspofungin, 286 co-trimoxazole, 295 colistin, 265 isepamicin, 252 sitamaquine, 292 tobramycin, 253 vancomycin, 259, 260 nervous system adverse effects levoﬂoxacin, 256 nervousness efavirenz, 309 protease inhibitors, 312 neural tube defects carbamazepine, 76 neuroleptic malignant syndrome alimemazine, 54 haloperidol, 58 olanzapine, 60 neurological disturbances propafenone, 198 suramin, 332 neuromuscular impairment muscle relaxants, 139 neuromyopathy amiodarone, 191 neuropathy disopyramide, 195 interferon-alfa, 384 suramin, 332 thalidomide, 161 tickborne encephalitis vaccine, 340 neurotoxicity amprenavir, 313 folic acid, 407–408 oxaliplatin, 488

topoisomerase I inhibitors, 483 neutralizing antibodies interferon-beta, 389, 390 neutropenia anakinra + etanercept, 390 deferiprone, 233 exatecan, 476 ﬂuconazole, 278 interferon-alfa, 386, 388 intravenous immunoglobulin, 346 irinotecan, 482 lamivudine + zidovudine + abacavir, 306 olanzapine, 61 piperacillin, 244–245 propylthiouracil, 443 stavudine + lamivudine + nevirapine, 317 terbinaﬁne, 284 topotecan, 483 zinc, 230 neutropenia, drug-induced propylthiouracil, 443 neutrophil count co-trimoxazole, 266 ganciclovir, 304 nodular sclerosing Hodgkin’s disease inﬂiximab, 394 nodules vitamin A, 405 non-arteritic ischemic optic neuropathy sildenaﬁl, 211 non-cirrhotic portal hypertension vitamin A, 406 non-convulsive status epilepticus lithium, 20 tiagabine, 81 non-Hodgkin’s lymphoma azathioprine toxicity, 373–374 inﬂiximab, 394 rituximab, 382 tumor necrosis factor antagonists, 393 non-speciﬁc urinary tract inﬂammation indinavir, 314 non-traumatic spleen rupture ﬁlgrastim, 392 normochromic normocytic anemia vitamin A, 405 numbness intrathecal (spinal) anesthesia, 126 NURRI gene expression cocaine, 34 obsessive-compulsive behavior

cortisone, 415 olanzapine, 60 occipital lobe seizure activity lidocaine, 133 occlusive vasculitis interferon-alfa, 384 ocular dyskinesias levodopa, 148 ocular myasthenia statins, 473 ocular pain ivermectin, 329 ocular perforation ocular anesthesia, 129 ocular toxicity deferoxamine, 234 quinine, 291 oculogyric crisis metoclopramide, 362–363 odynophagia hydrocodone, 91 OHSS see ovarian hyperstimulation syndrome oliguria procainamide, 198 oliguric renal insufﬁciency Aloe capensis, 515 rifampicin, 324 opioid withdrawal symptoms efavirenz + methadone, 310 optic neuritis interferon-alfa, 384 optic neuropathy inﬂiximab, 394 linezolid, 265 orbital cellulitis ocular anesthesia, 130 orbital infarction cocaine, 35 orbital myositis etanercept, 394 orthopnea quinine, 291 orthostatic hypertension clonidine, 215 orthostatic hypotension clomipramine, 11 nitazoxanide, 331 oscillating vision gentamicin, 252 osteomyelitis interferon-alfa, 388 osteonecrosis indinavir + ritonavir, 317 osteoporosis glucocorticoids, 416 gonadorelin agonists, 465 osteosarcoma parathyroid hormone (PTH), 468 osteosclerosis indinavir, 314 ototoxicity

580 clarithromycin, 262 deferoxamine, 234 NRTIs, 316 ovarian cancer antiestrogens, 431 hormone replacement therapy, 426 ovarian failure cyclophosphamide, 376 etoposide, 487 ovarian hyperstimulation gonadorelin, 465 ovulation-inducing drugs, 420–421 ovarian hyperstimulation syndrome albumin, 342 ovulatory failure antiepileptic drugs, 73 oxygen saturation brachial plexus anesthesia, 124 remifentanil, 95 P glycoprotein induction St. John’s wort, 517 P glycoprotein inhibition ﬂuconazole, 279 itraconazole, 280 pain interleukin-2 (IL-2), 390 ONYX-15, 488 sclerosant injections, 369 palatal perforation cocaine, 34 pallor ku shep, 513 parenteral nutrition, 355 palmar irritation hair bonds, 159 palmar-plantar erythrodysesthesia syndrome cytotoxic drugs, 489 palpable purpura efavirenz, 310 repaglinide, 455 palpitation bupivacaine, 132 cilostazol, 209 famotidine, 364 fenﬂuramine, 5 ﬂecainide, 196 formoterol, 179 ku shep, 513 omeprazole, 364 Xu Xin, 513 pancreatitis aminosalicylates, 367 carbimazole, 443 ﬂuvastatin, 474 liposomal amphotericin, 277 mesalazine, 367 metformin, 454 metronidazole, 299

Index of adverse effects norﬂoxacin, 258 NRTIs, 307 propofol, 121 rocuronium, 138 sodium stibogluconate, 297 valproate, 83 pancytopenia olanzapine, 61 silver, 230 terbinaﬁne, 284 vancomycin, 260 panic attacks alprazolam, 44 papilledema indinavir, 313 vitamin A, 405 papules amphetamines, 2 parakeratosis haloperidol, 59 paralysis cocaine, 34–35 muscle relaxants, 139–140 paralysis of the arm brachial plexus anesthesia, 124 paralytic ileus baclofen, 141 diltiazem + nifedipine, 205–206 paranoid episode nevirapine, 311 paranoid hallucinatory state methamphetamine, 29 paraparesis indinavir, 313 terbutaline, 180 parathyroid hormone lithium, 21 parenchymal ﬁbrosis interferon-alfa, 388 paresthesia benznidazole, 298 dextrans, 354 gadobenate dimeglumine, 504 phenytoin, 80 Sono Vue (sulfur hexaﬂuoride), 506 parkinsonism kava (Piper methysticum), 518 lithium, 20 metoclopramide, 363 partial seizures lidocaine, 133 parvovirus infection clotting factors, 347 intravenous immunoglobulin, 346 rituximab, 381 peeling skin clindamycin, 260 pemphigus vulgaris fosinopril, 213 peptic ulcer NSAIDs + H. pylori, 105–109

perforated septum hydrocodone, 91 peribronchial cufﬁng vitamin A, 405 pericardial effusion clozapine, 55 minoxidil, 217 vitamin A, 405 pericardial ﬁbrosis dopamine receptor agonists, 150 pericarditis clozapine, 55–56 mesalazine, 368 smallpox vaccine, 339 perinatal effects cocaine, 1–2, 36–37 diamorphine, 38 periocular skin darkening prostaglandin analogues, 510 periodic alternating nystagmus lithium, 20 periodic paralysis cocaine, 34–35 periorbital itching dibucaine, 133 peripheral edema celecoxib, 112 peripheral eosinophilia sulfasalazine, 368 peripheral neuropathy benznidazole, 298 didanosine, 308 doxycycline, 247 linezolid, 265 statins, 473 stavudine + lamivudine + nevirapine, 317 topotecan, 483 peripheral polyneuropathy benznidazole, 298 peritonitis cocaine, 36 personality changes ciclosporin, 374 petechial rash sodium stibogluconate, 298 pharyngeal dysfunction muscle relaxants, 139 pharyngitis tobramycin, 253 phlebitis amiodarone, 190 erythromycin, 263 vancomycin, 259 photocontact dermatitis benzydamine, 525 photophobia botulinum toxin A, 162 valaciclovir, 305 voriconazole, 283 photosensitive lichenoid eruption thiazide diuretics, 221

581

Index of adverse effects photosensitivity interferon-alfa, 387 phototoxicity clarithromycin, 262 clinaﬂoxacin, 255 tosuﬂoxacin, 258 pigment changes in the ocular fundus thioridazine, 65 pigmentation abnormalities siliconized dressing, 531 pigmentation of the iris latanoprost, 510 piloerection irinotecan, 484 Pisa syndrome risperidone, 62 plaques amphetamines, 2 platelet aggregation interferon-alfa, 386 platelet count ganciclovir, 304 sodium stibogluconate, 297 platelet function Allium sativum (garlic), 515 pleural effusion dextrans, 353 dopamine receptor agonists, 150 vitamin A, 405 pleural ﬁbrosis dopamine receptor agonists, 150 pleuritic chest discomfort quinine, 291 pleuropulmonary ﬁbrosis dopamine receptor agonists, 150 pneumatosis cystoides intestinalis acarbose, 453 Pneumocystis carinii (jiroveci) pneumonia inﬂiximab, 396, 397 pneumomediastinum methylenedioxymethamphetamine, 29 pneumonia amiodarone, 190–191 inﬂiximab, 397 pneumonic inﬁltration dextrans, 353 pneumonitis interferon-alfa, 384 interferon-gamma, 390 rifampicin, 324 pneumothorax acupuncture, 520 poisoning lidocaine, 134 polyarthralgia granulocyte colony-stimulating factor (G-CSF), 392

inﬂiximab, 396 polycystic ovaries valproate, 82 polydipsia olanzapine, 61 risperidone, 63–64 polyhydramnios lithium, 23 polyneuritis benznidazole, 298 polyneuropathy melarsoprol, 298 polyuria lithium, 23–24 olanzapine, 61 porphyria cutanea tarda interferon-alfa, 386 tamoxifen, 433 potassium concentration beta2 adrenoceptor agonists, 179 PR interval prolongation olanzapine, 59 premature delivery diamorphine, 38 premature labor diamorphine, 38 premature rupture of the membranes cocaine, 36 prenatal exposure antiepileptic drugs, 73 benzodiazepines, 76 carbamazepine, 76, 444 cocaine, 1–2, 36–37 dexamethasone, 417 efavirenz, 310 ﬂecainide, 196 ﬂuoxetine, 13 glyceryl trinitrate, 204 lamotrigine, 78 lead, 228–229 lithium, 23 methadone, 91 nevirapine, 310–311 risperidone, 64 preterm delivery cocaine, 36 priapism antipsychotic drugs, 54 risperidone, 64 zuclopenthixol, 66 progressive neurodegeneration intravenous immunoglobulin, 345 prolactin haloperidol, 58 olanzapine, 60 prolonged QT interval see QT interval prolongation propofol infusion syndrome propofol, 121 prostaglandin production erythropoietin, 348

prostatitis interferon-alfa, 388 proteinuria ethylenediaminetetraacetic acid, 235 interferon-alfa, 386 interferon-beta, 389 prothrombin time see INR protozoal infections inﬂiximab, 397 proximal limb weakness leuprolide, 465 pruritic papular erythomatous eruptions with occasional vesicles interferon-alfa, 387 pruritic rash efavirenz, 310 rituximab, 381 pruritus abarelix, 465 albendazole, 326 azithromycin, 261 benznidazole, 298 buprenorphine, 97 cetirizine, 166 dextrans, 354 diethylcarbamazine, 329 efavirenz, 310 fentanyl, 90 formoterol, 179 5-HT3 receptor antagonists, 363 interferon-alfa, 387 iohexol, 498 ivermectin, 329 lithium, 22 loratadine, 169 morphine, 93 parenteral nutrition, 356 phenytoin, 80 ranitidine, 366 sodium stibogluconate, 298 tosuﬂoxacin, 258 vancomycin, 259–260 vitamin A, 405 pseudomembranous colitis levoﬂoxacin, 256 vancomycin, 260 pseudothrombocytopenia ethylenediaminetetraacetate, 378 pseudotumor cerebri lithium, 20 vitamin A, 405 psoriasis lithium, 22 neomycin, 253 psychasthenia interleukin-2 (IL-2), 391 psychic alterations nifurtimox, 299 psychomotor agitation

582 risperidone, 63 psychomotor inhibition lamotrigine, 78 psychosis amphetamines, 2 antiepileptic drugs, 72–73 cannabinoids, 32 nevirapine, 311 psychotic episodes topiramate, 81 psychotic reactions ciproﬂoxacin, 254 disulﬁram, 526–527 ptosis botulinum toxin A, 162 pulmonary alveolar hemorrhage propylthiouracil, 443 pulmonary alveolar proteinosis blood transfusion, 344 pulmonary coccidioidomycosis inﬂiximab, 396 pulmonary complications baclofen, 142 pulmonary congestion vitamin A, 405 pulmonary deterioration interferon-gamma, 390 pulmonary edema blood transfusion, 344 dextrans, 353 diamorphine, 38 naltrexone, 98 phenylephrine, 147, 509 pulmonary edema, fulminant polyethylene glycol, 531 pulmonary embolism brachial plexus anesthesia, 124 clotting factors, 346 clozapine, 56 erythropoietin, 348 heparins, 358 hormone replacement therapy, 423 intravenous immunoglobulin, 345 pulmonary granulomas etanercept, 393 pulmonary hypertension fenﬂuramines and phentermine, 5 pulmonary inﬁltrates vitamin A, 405 pulmonary nodulosis etanercept, 394 pulmonary rheumatoid nodules etanercept, 393 pulmonary thromboembolism intravenous immunoglobulin, 345 pulmonary toxicity gemcitabine, 488 interferon-alfa, 383–384 nitrofurantoin, 264

Index of adverse effects trastuzumab, 382 pupillary mydriasis lidocaine, 196 pure red cell aplasia erythropoietin, 348–349 rituximab, 381 pure tone audiography tobramycin, 253 purpuric erythema intravenous immunoglobulin, 346 purpuric rash etanercept, 394 pustular dermatitis inﬂiximab, 396 pustular skin eruption teicoplanin, 259 pustule smallpox vaccine, 340 pyloric stenosis erythromycin, 262–263 QT interval prolongation antihistamines (H1 receptor antagonists), 165 antipsychotic drugs, 52 azithromycin, 261 bepridil, 194 cisapride, 362 cisapride + erythromycin, 263 clarithromycin, 262 contrast agents, iodinated, 498 ﬂuconazole, 278 ﬂuoroquinolones, 254 fosphenytoin, 80 gatiﬂoxacin, 256 haloperidol, 58 levoﬂoxacin, 256 lovastatin + quetiapine, 474–475 olanzapine, 59 propofol, 121 quinidine, 198 quinine, 292 roxithromycin, 263 sparﬂoxacin, 258 telithromycin, 260 ziprasidone, 66 rabbit syndrome risperidone, 63 rapidly progressive glomerulonephritis rifampicin, 325 rash abacavir, 307 abacavir + amprenavir + efavirenz, 317 abacavir + efavirenz, 316 anti-CD4, 379 benznidazole, 298 celecoxib, 112

clindamycin, 260 co-trimoxazole, 295 disulﬁram, 527 efavirenz, 309–310 etanercept, 394 gabapentin, 77 ganciclovir, 304 haloperidol, 58–59 hemoglobin-based oxygen carriers, 343 inﬂiximab, 396 interferon-alfa, 387 intravenous immunoglobulin, 345 iohexol, 498 lamotrigine, 78 linezolid, 264 meglumine antimoniate, 297 omeprazole, 365 parenteral nutrition, 356 quinupristin/dalfopristin, 266 ritonavir + lopinavir, 315 rituximab, 381 sodium stibogluconate, 298 sulfasalazine, 368 tobramycin, 253 topotecan, 485 tosuﬂoxacin, 258 Raynaud’s phenomenon interferon-alfa, 383, 388 recombinant factor IX clotting factors, 347 rectal bleeding anti-CD4, 379 mesalazine, 368 mycophenolate mofetil, 376 red eyes netilmicin, 253 red man syndrome vancomycin, 259 redness lithium, 22 reduced efﬁcacy of dialysis erythropoietin, 349 reduced well-being glucagon-like peptide-1, 452 refractory hypoxemia interferon-gamma, 390 relapse of nephrotic syndrome meningococcal vaccine, 338 relapsing and remitting eczematous reaction vitamin K, 411 renal see also entries at nephr— renal colic indinavir, 313 renal damage contrast media, overview, 500–503 renal impairment amphotericin, 283 carvedilol, 203 dextrans, 354

583

Index of adverse effects interferon-alfa, 388 renal insufﬁciency alemtuzumab, 379 Aloe capensis, 515 aristolochic acid, 515 bismuth, 226 celecoxib, 112 cidofovir, 303 cocaine + alcohol, 37 dextrans, 353 diuretics, 221 ﬂutamide, 436 fusidic acid, 259 gentamicin, 252 hydroxyethyl starch, 355 indinavir, 313 interferon-alfa, 387 intravenous immunoglobulin, 346 lithium, 22 mannitol, 221 methylenedioxymethamphetamine, 31 rifampicin, 324 rocuronium, 138 sevoﬂurane, 119 sodium phosphates oral solution, 529 teicoplanin, 259 renal toxicity mesalazine, 368 suramin, 332 renal tubular necrosis povidone iodine, 240 renin-angiotensin system activity erythropoietin, 348 residual paralysis muscle relaxants, 139–140 respiratory arrest clonidine, 126 dextrans, 354 methylenedioxymethamphetamine, 31 sufentanil, 95 respiratory compromise brachial plexus anesthesia, 124 respiratory depression levetiracetam, 79 remifentanil, 94, 118 respiratory distress lithium, 23 vitamin A, 405 respiratory distress syndrome chlorhexidine, 239 dextrans, 353 respiratory effects remifentanil, 94 respiratory failure alemtuzumab, 379 interferon-gamma, 390 metformin, 454 talc, 531 respiratory paralysis

Xu Xin, 513 respiratory tract infection esomeprazole, 365 restless legs syndrome levodopa, 148 risperidone, 63 restlessness Xu Xin, 513 reticulonodular opacities dextrans, 353 retinal toxicity amikacin, 251–252 retinoic acid syndrome vitamin A, 405 retinol intoxication vitamin A, 405 retinopathy interferon-alfa, 384 retroperitoneal ﬁbrosis dopamine receptor agonists, 150 reversal reactions antiretroviral drugs, 306 rhabdomyolysis atorvastatin + delavirdine, 309 baclofen, 142 ciclosporin + red yeast rice, 474 cocaine + diamorphine, 38 colchicine + gemﬁbrozil, 473 diltiazem + atorvastatin, 206 itraconazole, 281 pemoline, 4 pentamidine, 297 ritonavir +simvastatin, 316 sevoﬂurane, 119 simvastatin, 475 tosuﬂoxacin, 258 ziprasidone, 66 rheumatoid arthritis cyproterone acetate, 465 rhinoconjuntivitis hair bonds, 159 rhinorrhea mupirocin, 265 right upper quadrant pain gemtuzumab, 380 rigor ONYX-15, 488 rituximab, 381 saddle-nose deformity cocaine, 34 salivation irinotecan, 484 ku shep, 513 sarcoidosis interferon-alfa, 388 sarcomatous papules deferoxamine, 234 scaling haloperidol, 59 scalp atresia

carbamazepine, prenatal, 444 scleral perforation ocular anesthesia, 129 scleroderma interferon-alfa, 388 seborrheic dermatitis minoxidil, 160 seborrheic skin glucagon, 452 secondary acute myelogenous leukemia topoisomerase II inhibitors, 486–487 sedation antihistamines (H1 receptor antagonists), 165–166 clozapine, 55 gabapentin, 77 levocetirizine, 169 methadone, 91 seizure duration etomidate, 121 seizures amfebutamone, 15 antiepileptic drugs, 72 cefepime, 245 clozapine, 50, 56 gatiﬂoxacin, 256 intravenous regional anesthesia, 128 ku shep, 513 levobupivacaine, 133 lidocaine, 133–134 lower limb block, 129 methylenedioxymethamphetamine, 30 procainamide, 197 sildenaﬁl, 211 sodium phosphate, 367 star anise, 518 stellate ganglion block, 130 valaciclovir, 305 visicol, 531 sensation of clogged ears vitamin A, 405 sensitization lidocaine, 128 sensorimotor polyneuropathy interferon-alfa, 384 sensorineural hearing loss chloroquine, 289 sensory deﬁcit in the legs interferon-alfa, 384 sensory loss etanercept, 393–394 sepsis ONYX-15, 488 septal lines vitamin A, 405 septicemia inﬂiximab, 396 serotonin syndrome dexamphetamine, 3 linezolid, after paroxetine, 265

584 lithium, 24 paroxetine, 14 sertraline + tramadol, 96 SSRIs, 12 severe pulmonary edema dextrans, 353 severe vision loss nitrous oxide, 120 sexual desire tamoxifen, 432 sexual dysfunction risperidone, 63 sexual function opioids, 88 shaking ephedrine, 146 intravenous immunoglobulin, 345 shivering dexamphetamine and venlafaxine, 3 shock dextrans, 354 shortness of breath brachial plexus anesthesia, 124 intravenous immunoglobulin, 345 shunt thrombosis erythropoietin, 348 SIADH see syndrome of inappropriate antidiuretic hormone secretion (SIADH) sialadenitis lithium, 22 sick sinus syndrome lithium, 20 SIDS see sudden infant death syndrome sinus bradycardia ﬂecainide, 196 lithium, 20 sinus node dysfunction cibenzoline, 195 ﬂecainide, 196 lithium, 20 sinus rhythm bupivacaine, 132 sinus tachycardia methylenedioxymethamphetamine, 31 pemoline, 4 procainamide, 197 ropivacaine, 134 sinusitis esomeprazole, 365 sinusoidal ﬁbrosis gemtuzumab, 380 sinusoidal vasoconstriction gemtuzumab, 380 sister chromatid exchanges nitrofurantoin, 264 skin disorders

Index of adverse effects azole derivatives, 278 chlormadinone acetate, 427 skin eruptions albendazole, 328 cetirizine, 167 meglumine antimoniate, 297 teicoplanin, 259 skin lesions inﬂiximab, 394 interferon-beta, 390 skin necrosis interferon-alfa, 387 terlipressin, 469 skin nodules growth hormone, 467 skin reaction benznidazole, 298 clonidine, 215 contrast agents, iodinated, 500 hydroxychloroquine, 289 skin reactions that mimic graft-vs.-host disease penicillamine, 236 sleep apnea clozapine, 57 risperidone, 63 sleep attacks dopamine receptor agonists, 149 sleep disorders stavudine + lamivudine + nevirapine, 317 sleep disturbance ﬂuoxetine, 12 tamoxifen, 432 sleep-related eating disorders olanzapine, 60 sleepiness cimetropium, 369 cinnarizine, 209 fentanyl, 91 nifurtimox, 299 zolpidem, 46 sleeping difﬁculty efavirenz, 309 protease inhibitors, 312 sodium concentrations meﬂoquine, 290 soft palate erosion hydrocodone, 91 somnolence cetirizine, 166 levetiracetam, 79 muromonab-CD3, 381 olanzapine, 49 pantoprazole, 366 remacemide, 81 spasticity cannabinoids, 32 spinal damage spinal manipulation, 521 spleen rupture ﬁlgrastim, 392 splenic infarction

triptans, 210 spongiosis haloperidol, 59 spontaneous psychosis methamphetamine, 29 sputum production sulfasalazine, 368 ST segment changes cocaine, 1 oxytocin, 468 staining of permanent teeth minocycline, 247 Staphylococcus aureus infection inﬂiximab, 396 status epilepticus methylenedioxymethamphetamine, 32 piperazine, 331 Stevens–Johnson syndrome hydroxychloroquine, 289 lamotrigine, 78 NRTIs + nevirapine, 316 rituximab, 381 sulfadoxine + pyrimethamine, 294 stomatitis lithium, 22 topoisomerase I inhibitors, 483 topoisomerase II inhibitors, 483 streptococcal infection inﬂiximab, 396 stroke ephedrine, 145 Ginkgo biloba (maidenhair tree), 517 hormone replacement therapy, 423 intravenous immunoglobulin, 345 sibutramine, 6 sildenaﬁl, 210–211 stunting of growth methylphenidate, 3 stuttering clozapine, 56 subacute dermatitis haloperidol, 59 subarachnoid hemorrhage cocaine, 34 phenylephrine, 509 subcortical stimulation lidocaine, 133 sudden death ephedrine, 146 sudden hemodynamic shock dextrans, 354 sudden infant death syndrome (SIDS) multiple immunizations, 335–336 vs. vaccine reactions, 334 suicide co-proxamol, 110

585

Index of adverse effects dextropropoxyphene, 110 lithium, 23 temazepam, 44 supersensitivity psychosis metoclopramide, 363 suppuration interferon-alfa, 387 supraventricular tachycardia lithium, 23 surgical emphysema methylenedioxymethamphetamine, 29 swallowing difﬁculty remifentanil, 95 sweating buprenorphine, 97 ephedrine, 146 ethylenediaminetetraacetic acid, 234 imipramine, 11 irinotecan, 484 ku shep, 513 paroxetine, 12 tramadol, 96 Xu Xin, 513 Sweet’s syndrome oral contraceptives, 427 vitamin A, 406 swelling lidocaine, 128 lithium, 22 swelling and wrinkling of the palms rofecoxib, 113 swelling of the lips and eyelids parenteral nutrition, 356 sympathomimetic toxicity ephedrine, 146 syncope anti-CD4, 379 ﬂecainide, 196 sodium picosulfate, 531 syndrome of inappropriate antidiuretic hormone secretion (SIADH) amiodarone, 191–192 diamorphine, 38 methylenedioxymethamphetamine, 30 systemic cholinergic autonomic impairment botulinum toxin A, 162 systemic lupus erythematosus interferon-alfa, 388 systemic sarcoidosis interferon-alfa, 388 systemic sclerosis interferon-alfa, 388 systemic toxicity bupivacaine, 132 systolic hypertension dobutamine, 147

T cell non-Hodgkin’s lymphoma rituximab, 382 T wave alternans amiodarone, 190 tachycardia bupivacaine, 132 cocaine, 33 diethylcarbamazine, 329 ephedrine, 146 ethylenediaminetetraacetic acid, 234 hair bonds, 159 inﬂiximab, 396 ivermectin, 329 ku shep, 513 lidocaine, 133 modaﬁnil, 3 oxytocin, 468 rocuronium, 138 salbutamol, 179 sibutramine, 6 tachyphylaxis sildenaﬁl, 211 tardive dyskinesia clozapine, 56 olanzapine, 59 ziprasidone, 66 tardive dystonia lithium, 20 taste discrimination, loss of losartan, 214 taste disturbance gadobenate dimeglumine, 504 levovist, 506 Sono Vue (sulfur hexaﬂuoride), 506 telangiectasia betamethasone 17-valerate, 416 interferon-alfa, 387 mometasone furoate, 416 telogen efﬂuvium interferon-alfa, 388 tendinitis ciproﬂoxacin, 255 ﬂuoroquinolones, 254 indinavir, 314 tendon rupture ciproﬂoxacin, 255 ﬂuoroquinolones, 254 tension ﬂuoxetine, 12 teratogenicity cocaine, 2 testosterone suppression opioids, 88 tetany sodium phosphates oral solution, 529 thiamine deﬁciency arsenic toxicity, 225 thickening of the skin interferon-alfa, 388 thrombocytopenia

abciximab, 360, 378 albendazole, 328 co-trimoxazole, 266 desmopressin, 469 ethylenediaminetetraacetic acid, 234 etoposide, 483 ﬂuconazole, 278 ﬂucytosine, 278 gemtuzumab, 380 heparins, 358 interleukin-2 (IL-2), 391 irinotecan, 482 Lorenzo’s oil, 475 olprinone, 189 parenteral nutrition, 355 quinine, 291 rifampicin, 324 sulfasalazine, 369 teicoplanin, 259 teniposide, 483 topotecan, 479, 483 vitamin A, 405–406 thrombocytosis methadone, 91 thromboembolic complications clotting factors, 346 thromboembolism enoxaparin, 359 oral contraceptives, 426–427 tamoxifen, 432 thrombophlebitis at the infusion site quinupristin/dalfopristin, 265 thrombosis heparins, 358 intravenous immunoglobulin, 345 thrombotic microangiopathy interferon-alfa, 387 thrombotic thrombocytopenic purpura ciproﬂoxacin, 255 clarithromycin, 262 thyroid disorders interferon-alfa, 385–386 interferon-alfa-2b, 383 lithium, 20 thyroid hormones co-trimoxazole, 266 thyrotoxicosis interferon-alfa, 385–386 povidone iodine, 240 tightness in the chest intravenous immunoglobulin, 345 tinnitus abacavir, 307 amprenavir, 313 bupivacaine, 132 ciclosporin, 374 stavudine + lamivudine + nevirapine, 316 tiredness

586 buprenorphine, 97 tissue necrosis temazepam, 45 TNF-alfa secretion aztreonam, 247 tonic–clonic seizures amfebutamone, 15 benzodiazepines, 15 clozapine, 56 cocaine, 15 diamorphine, 38 levobupivacaine, 133 piperazine, 331 procainamide, 197 ropivacaine, 134 sildenaﬁl, 211 sodium phosphate, 367 star anise, 518 stellate ganglion block, 130 torsade de pointes bepridil, 194 celecoxib, 111–112 cisapride + erythromycin, 263 ﬂuconazole, 278 grepaﬂoxacin, 256 macrolides, 261 methadone, 91 pentamidine, 297 roxithromycin, 263 toxic epidermal necrolysis amiodarone, 193 amphetamines, 2 celecoxib, 112 clarithromycin + disulﬁram, 262 co-trimoxazole, 266–267 interleukin-2 (IL-2), 391 levoﬂoxacin, 257 meropenem, 246–247 rofecoxib, 113 toxic hepatitis kava (Piper methysticum), 518 LipoKinetix, 519 toxic keratitis tetracaine, 130 TPMT activity azathioprine toxicity, 373 transaminase activity losartan, 214 vitamin A, 405 transient color changes voriconazole, 282 transient cortical blindness contrast agents, iodinated, 498–499 transient ischemic attack erythropoietin, 348 transient pain intrathecal (spinal) anesthesia, 126 transient paralysis inﬁltration anesthesia, 128 transient radicular irritation clonidine, 126–127

Index of adverse effects transitional carcinoma of the bladder azathioprine toxicity, 373–374 transverse myelitis etanercept, 393–394 trembling ethylenediaminetetraacetic acid, 234 tremor baclofen, 142 contrast agents, iodinated, 498 dexamphetamine and venlafaxine, 3 formoterol, 179 lithium, 20 pemoline, 4 salbutamol, 179 valaciclovir, 305 triglycerides indinavir + ritonavir, 317 lopinavir + ritonavir, 315 olanzapine, 53 troponin I concentration ephedrine, 146 truncal obesity isotretinoin, 160 tuberculoid leprosy antiretroviral drugs, 306 tuberculosis inﬂiximab, 396 tubular acidosis cidofovir, 303 tubular necrosis gentamicin, 252 mesalazine, 368 rifampicin, 325 tubulointerstitial lesions ciclosporin, 374–375 tubulointerstitial nephritis levoﬂoxacin, 256 tumor clearance syndrome rituximab, 382 tumor lysis syndrome dexamethasone, 415 tumor necrosis factor-alfa granulocyte colony-stimulating factor (G-CSF), 392 twin-births folic acid, 409 type I hypersensitivity reaction cyclophosphamide, 375–376 ulceration interferon-alfa, 387 ulcerative keratitis chlorhexidine, 239 glucocorticoids, topical, 415 unilateral descemetocele tetracaine, 130 unsteady gait dexamphetamine and venlafaxine, 3 uric acid

levoﬂoxacin, 256 urinary hesitancy reboxetine, 16 urinary retention COX-2 inhibitors, 111 etanercept, 393 oxaliplatin, 488 urinary stones indinavir, 311 nevirapine, 311 urinary tract anomalies carbamazepine, 76 urinary tract infections spermicides, 530 urinary tract inﬂammation indinavir, 314 urine discoloration nitazoxanide, 331 urothelial inﬂammation indinavir, 314 urticaria abarelix, 465 albumin, 342 atorvastatin, 474 cetirizine, 166 contrast agents, iodinated, 498 cyclophosphamide, 375–376 Echinacea (coneﬂower), 516 erythropoietin, 349 food additives, 531 hair bonds, 158–159 omeprazole, 365 pseudoephedrine, 146 rituximab, 382 roxithromycin, 264 sunscreen, 159 urticaria with angioedema deﬂazacort, 416 urticarial rash polygeline, 355 uveitis ﬁlgrastim + sargramostim, 392 vacuolation of the tubular epithelium dextrans, 353 vagal tone cocaine, 36–37 vaginal bleeding sertraline, 13 SSRIs, 13 venlafaxine, 13 vaginal candidiasis norﬂoxacin, 258 vaginal discharge tamoxifen, 432 vaginal dryness tamoxifen, 432 vaginal hemorrhage transdermal estrogen, 426 valvulopathy fenﬂuramines and phentermine, 4

587

Index of adverse effects variant Creutzfeldt–Jakob disease see also Creutzfeld–Jakob disease blood transfusion, 344 vascular access thrombosis erythropoietin, 348 vascular permeability blood transfusion, 344 vascular resistance erythropoietin, 348 labetalol, 203 vasculitis anti-CD4, 379 antithyroid drugs, 443 inﬂiximab, 397 vasoconstriction hemoglobin-based oxygen carriers, 343 triptans, 210 vasodilatory tone erythropoietin, 348 vasovagal attacks anti-CD4, 379 vein disorders azithromycin, 261 veno-occlusive disease gemtuzumab, 380 venous embolism heparins, 358 venous thromboembolism clozapine, 56 enoxaparin, 359 hormone replacement therapy, 424 Yasmin, 531 venous thrombosis clotting factors, 346 erythropoietin, 348 ventricular dysrhythmia clarithromycin, 262 lidocaine, 134 ventricular ﬁbrillation adenosine, 189 cocaine + diamorphine, 38 epidural anesthesia, 125 sodium stibogluconate, 298 ventricular tachycardia antihistamines (H1 receptor antagonists), 165 cilostazol, 209 dobutamine, 147 lidocaine, 134 vertigo abacavir, 307 amprenavir, 313 ﬂecainide, 196 gammahydroxybutyrate, 38 gentamicin, 252 meﬂoquine, 290 vitamin A, 405 vestibular neuronitis sildenaﬁl, 211 viral infection

inﬂiximab, 396–397 vision impairment interferon-alfa, 384 vision loss thioridazine, 65 visual acuity deferoxamine, 234 vitamin A, 405 visual disturbance ﬂecainide, 196 5-HT3 receptor antagonists, 363 hyoscyamine, 152 interferon-alfa, 384 irinotecan, 484 lidocaine, 133 voriconazole, 282 visual ﬁeld deﬁcits vigabatrin, 83 visual ﬁeld loss inﬂiximab, 394 visual hallucinations diphenhydramine, 168 voriconazole, 282 visual impairment vitamin A, 405 visual pseudo-hallucinations interferon-beta, 389 visual vestibular mismatch gentamicin, 252 vitamin A-like reactions indinavir, 313 vitamin B12 deﬁciency histamine H2 receptor agonists, 363–364 metformin, 454 vomiting albendazole, 327–328 antimony, 224 arteether, 292 azithromycin, 261 buprenorphine, 97 caspofungin, 286 contrast agents, iodinated, 498 deferiprone, 233 eﬂornithine, 298 fentanyl, 91 formoterol, 179 gabapentin, 77 gadobenate dimeglumine, 504 ganciclovir, 303 glucagon-like peptide-1, 452 Helicobacter pylori eradication regimens, 367 indinavir, 313 intravenous immunoglobulin, 345 iohexol, 498 iron, 228 itraconazole, 279 ivermectin, 329–330 ketolides, 260 ku shep, 513 lamivudine, 308

lamivudine + zidovudine + abacavir, 306 levovist, 506 linezolid, 264 methoxsalen, 159 methylenedioxymethamphetamine, 30–31 mexiletine, 197 miltefosine, 296 morphine, 93 nifurtimox, 299 oseltamivir, 318 oxycodone, 93 pantoprazole, 366 pethidine, 94 quinupristin/dalfopristin, 265 ranitidine, 364, 366 remifentanil, 94, 118 rifampicin, 324 risperidone, 63 rituximab, 381 sevoﬂurane, 119 sodium phosphate, 367 somatostatin, 468 star anise, 518 sulfasalazine, 369 sulfonylureas, 456 tolterodine, 153 topoisomerase I inhibitors, 483 topoisomerase II inhibitors, 483 tosuﬂoxacin, 258 tramadol, 96 trovaﬂoxacin, 254 Xu Xin, 513 warming of the skin dextrans, 354 water retention risperidone, 63 weakness acetazolamide, 220 botulinum toxin A, 162 cocaine, 34–35 fosmidomycin, 268 interleukin-2 (IL-2), 391 irinotecan, 483 losartan, 214 meglumine antimoniate, 297 propafenone, 198 statins, 474 Wegener’s granulomatosis mesalazine, 368 weight gain amisulpride, 54 antipsychotic drugs, 53–54 clozapine, 56–57 gabapentin, 77 gemtuzumab, 380 glitazones, 457 imipramine, 11 implantable contraceptives, 427 olanzapine, 49, 53, 60

588 risperidone, 50, 63 rosiglitazone, 458 tamoxifen, 432 valproate, 82 vitamin A, 405 weight loss interferon-alfa, 388 mesalazine, 368 nifurtimox, 299 rituximab, 381 sulfasalazine, 368 topiramate, 81

Index of adverse effects West Nile virus infection blood transfusion, 344 wheal-and-ﬂare reactions malaria vaccine, 294 wheals polygeline, 355 wheezing contrast agents, iodinated, 498 quinine, 291 white cell abnormalities interferon-beta, 389 white cell count

caspofungin, 286 sodium stibogluconate, 297 wide-complex tachycardia procainamide, 198 wind see ﬂatulence withdrawal drug toxicity naltrexone, 98 xerostomia lithium, 22