Angioedema Congress Book

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Angioedema Congress Book Edited by Murat Bas Thomas K. Hoffmann Georg Kojda

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19 figures 3 tables

Georg Thieme Verlag Stuttgart · New York

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Bibliographic Information published by die Deutsche Nationalbibliothek Die Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available on the internet at http://dnb.d-nb.de.

This publication has been sponsored by Jereni/Shire HGT.

© 2009 Georg Thieme Verlag KG Rüdigerstraße 14 70469 Stuttgart, Germany http://www.thieme.de Thieme New York, 333 Seventh Avenue New York, NY 10001, USA http://www.thieme.com Printed in Germany Cover design by Thieme Verlagsgruppe Figures by Ziegler + Müller, Kirchentellinsfurt Typesetting by Ziegler + Müller, Kirchentellinsfurt Printing and Bookbinding by Grafisches Centrum Cuno, Calbe ISBN 978-3-13-147421-6

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Important Note: Medicine is an ever-changing science undergoing continual development. Research and clinical experience are continually expanding our knowledge, in particular our knowledge of proper treatment and drug therapy. Insofar as this book mentions any dosage or application, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such references are in accordance with the state of knowledge at the time of production of the book. Nevertheless, this does not involve, imply, or express any guarantee or responsibility on the part of the publishers in respect to any dosage instructions and forms of applications stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompanying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturers differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or every form of application used is entirely at the user’s own risk and responsibility. The authors and publishers request every user to report to the publishers any discrepancies or inaccuracies noticed.

Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain. This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation, without the publisher’s consent, is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage.

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Preface

Hereditary angioedema and other forms of nonallergic angioedema are long known and were described first by Quincke in 1882 and by Ossler in 1888. Both describe swellings of the mucosa and/ or submucosa of the skin which may impair breathing and are potentially life-threatening. In particular, swellings of the pharynx and the larynx often require emergency treatment and several days of hospitalization. The differentiation of bradykinin-induced angioedema to allergic angioedema is crucial for successful therapy. Even today, many patients with hereditary angioedema are not correctly diagnosed in the first place. Furthermore, pharmacotherapy is often misdirected if patients are treated in hospitals where no or minor experience exists with such patients. For example, it still happens that physicians refuse to provide effective but expensive antibradykinin pharmacotherapy even for patients having a card identifying them as having hereditary angioedema. Thus, it is one important aim of this book to alert physicians and other health care providers to the course of this disease, its diagnosis and its pharmacotherapy.

Another important aim of this book is to draw attention to bradykinin-induced angioedema which is caused by certain drugs such as ACE-inhibitors and/or sartans. Some of these angioedema are present in the larynx and may cause death as well. Currently, there is no published algorithm for diagnosis and treatment. Likewise, there is no evidence-based treatment at all. In more severe cases, such patients are usually hospitalized and receive glucocorticoids and antihistamines. Fortunately, new drugs have been developed in recent years which are based on entirely new molecular mechanisms and which are subcutaneously applied. This appears to be a considerable advance. For the first time, these new drugs offer the possibility of on-demand self-administration even in children. Düsseldorf, September 2009

Georg Kojda

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Addresses

Prof. Dr. Volker Adams Herzzentrum Leipzig GmbH Strümpellstraße 39 04289 Leipzig e-mail: [email protected] Dr. Murat Bas Hals-Nasen-Ohrenklinik und Poliklinik Klinikum rechts der Isar der Technischen Universität München Ismaninger Straße 22 81675 München e-mail: [email protected] Prof. Dr. Konrad Bork Universitäts-Hautklinik Mainz Johannes-Gutenberg-Universität Langenbeckstraße 1 55101 Mainz e-mail: [email protected] Prof. Dr. Ingrid Fleming Klinikum J. Wolfgang Goethe-Universität Theodor-Stern-Kai 7 60596 Frankfurt e-mail: [email protected] Prof. Dr. Peter Gohlke Universitätsklinikum Schleswig-Holstein Institut für Pharmakologie Hospitalstraße 4 24105 Kiel e-mail: [email protected]

PD Dr. med. Karin Hartmann Klinikum der Universität zu Köln Klinik und Poliklinik für Dermatologie und Venerologie Kerpener Straße 62 50937 Köln e-mail: [email protected] PD Dr. med. Thomas K. Hoffmann Universitätsklinikum Düsseldorf Hals-Nasen-Ohren-Klinik Gebäude-Nr.: 13.76 Moorenstraße 5 40225 Düsseldorf e-mail: Thomas.Hoffmann@ med.uni-duesseldorf.de PD Dr. Wolfhart Kreuz Klinikum J. Wolfgang Goethe-Universität Zentrum für Kinderheilkunde III Hämostaseologie Theodor-Stern-Kai 7 60596 Frankfurt Dr. med. Jan Ramakers Universitätsklinikum Düsseldorf Moorenstraße 5 40225 Düsseldorf e-mail: [email protected] Prof. Dr. Bernd Rosenkranz Via Dr. med. Jens Zimmermann Jerini AG Invalidenstraße 130 10115 Berlin e-mail: [email protected]

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Table of Contents

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Treatment of Allergic Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 K. Hartmann

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Therapy for Acute Angioedema . . . . . . . . . . . . . 2

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Therapy for Chronic Angioedema . . . . . . . . . . . . 2

Emergency Therapy for Angioedema of the Upper Airway . . . . . . . . . . . . . . . . . . . . . . . 4 T. K. Hoffmann, H. Bier, G. Kojda, M. Bas

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

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Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Hereditary Angioedema: Clinical Manifestation and Therapy . . . . . . . . . . . . . . . . . . . . . 8 W. Kreuz, E. Aygören-Pürsün, I. Martinez Saguer, E. Rusicke

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Biological Characteristics of C1-INH. . . . . . . . . . 8 Diagnosis and Classification of C1-INH Deficiency . . . . . . . . . . . . . . . . . . . . . 8

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Epidemiology and Genetics of C1-INH Deficiency . . . . . . . . . . . . . . . . . . . Clinical Symptoms of Hereditary Angioedema Current Treatment of Hereditary Angioedema Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . .

. 9 . 10 . 12 . 13

Special Aspects of the Treatment of Hereditary Angioedema in Children . . . . . . . . . . 15 J. Ramakers, T. Niehues

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . . 15 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Differential Diagnoses . . . . . . . . . . . . . . . . . . . 16 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Patient Information and Psychosocial Aspects . 17

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Table of Contents

Acute Phase Proteins in Kinin-Induced Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 M. Bas, H. Bier, M. Oppermann, T. K. Hoffmann, G. Kojda

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 19 The Role of Bradykinin in Non-Allergic Angioedema . . . . . . . . . . . . . . . 20

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Acute Phase Proteins in Bradykinin-Induced Angioedema . . . . . . . . . . 21 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Bradykinin and the Kallikrein-Kinin System: Kallikreins, Bradykinin and Vascular Signal Transduction . . . . . . . . . . . . . . . . . . . . . . . 23 V. Adams

The Kallikrein-Kinin System. . . . . . . . . . . . . . 23

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Animal Models with Participation of the Kallikrein-Kinin Systems . . . . . . . . . . . 24

Drugs Affecting the Kallikrein-Kinin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 B. Rosenkranz, W. Fan, J. Zimmermann

The Kallikrein-Kinin System. . . . . . . . . . . . . . 28

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Antagonists of the Kallikrein-Kinin System . . . 28

RAAS Blocker and Bradykinin Metabolism: The Role of Bradykinin for Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 P. Gohlke

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 32 The Kallikrein-Kinin System. . . . . . . . . . . . . . 33 ACE Inhibitor and Kinins . . . . . . . . . . . . . . . . 34

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AT1 Receptor Antagonists and Bradykinin . . . . . . . . . . . . . . . . . . . . . . . 36 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . 36

A New Look at the Therapeutic Effects of ACE Inhibitors: ACE as Signal Transduction Molecule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 K. Kohlstedt, I. Fleming

Angiotensin Converting Enzyme (ACE) . . . . . . 38 ACE Inhibitors and ACE Signalling . . . . . . . . . 39

Perspective: New Viewpoint with Regard to RAS . . . . . . . . . . . . . . . . . . . . 40

10 Current and Future Treatment Options for Hereditary Angioedema . . . . . . . . . . . . . . 42 K. Bork

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

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Treatment of Allergic Angioedema K. Hartmann Department of Dermatology, University of Cologne, Cologne, Germany

Abstract Angioedemas are characterized by a sudden onset of swelling in the deep dermis and subcutis. For simplicity, angioedemas are classified into those with genetic causes and acquired forms. Causes of acquired angioedemas include allergic reactions, autoimmune mechanisms, infections and non-allergic/pseudo-allergic hypersensitivity reactions. Often, acquired angioedemas are accompanied by urticaria. As in the case of spontaneous urticaria, it is reasonable to distinguish between acute acquired angioedema with a course of less than six weeks and chronic acquired angioedema that exists for more than six weeks. For both forms, possible triggering factors such as drugs and infections should first be excluded. Acute angioedemas are treated with glucocorticoids and H1-antihistamines. For chronic angioedemas, non-sedative H1-antihistamines are recommended as first-line therapy. In some cases, higher dosages of antihistamines – up to four times the approved dose – are required. In severe forms, cyclosporin A can be considered, whereas glucocorticoids are not recommended for longer use. Some patients with autoimmune angioedema may also respond to dapsone or hydroxychloroquine.

Introduction Angioedemas (synonyms: angioneurotic edema, Quincke’s edema) are characterized by sudden onset of swelling in the deep dermis or subcutis. The various forms of angioedema include acquired angioedemas, angioedemas due to ACE inhibitors, hereditary angioedemas, angioedemas with eosinophilia (Gleich syndrome) and other rare angioedemas in association with, e.g., alpha-1-antitrypsin deficiency or carcinoid [1]. Therapy differs for the various forms. In this chapter, the therapy for acquired angioedemas of allergic and non-allergic origins will be discussed. Since many acquired angioedemas occur in combination with urticaria, the therapy recommendations are comparable to the guidelines for the treatment of spontaneous urticaria [2]. As in cases of spontaneous urticaria one should distinguish between acute angioedema that lasts for less than six weeks and chronic angioedema that lasts for more than six weeks and occur at least two times per week. Causes and pathomechanisms of acquired angioedemas are manifold. For example, allergic processes, pseudo-allergic hypersensitivity reactions, autoimmune mechanisms or infections can lead to activation of mast cells. Activated mast cells se-

crete histamine and many other mediators that, for example, lead to vasodilatation and edema of the tissues. Acute angioedemas are often triggered by IgE-mediated allergies, e.g., food allergies, viral infections and drugs. Chronic angioedemas, in contrast, are mostly caused by pseudo-allergic reactions, chronic bacterial infections, e.g., Helicobacter pylori, autoreactive processes and non-steroidal antirheumatic drugs [3]. More than half of all patients with acquired angioedema suffer concomitantly from urticaria. While isolated hives last for less than 24 hours, angioedemas exist for up to 72 hours. As a rule, angioedemas are not associated with pruritus but are accompanied by pain or burning sensations. They affect above all the eye lids, lips, tongue, oral and pharyngeal mucosa and the genital region (Figs. 1.1 and 1.2). Dangerous forms, especially of acute angioedemas, are laryngeal edema and anaphylactic reactions. Chronic angioedema often exist for many years or even decades and are associated with decreased quality of life and working ability [4]. For the diagnosis of acute angioedema, emphasis is placed on the case history and specific laboratory tests according to the history, e.g., allergy tests for angioedema after consumption of food or in-

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1 Treatment of Allergic Angioedema

Fig. 1.1 Allergic angioedema with pronounced swelling of the eye lids.

flammatory parameters for an infectious history. For chronic angioedema, in contrast, comprehensive, systemic diagnostics with detailed case history, differential blood count, BSG, CRP, antistreptolysin titer, Helicobacter serology, autologous serum test, antinuclear antibodies, thyroid antibodies and a three-week period on a low pseudoallergen diet are necessary [5].

Therapy for Acute Angioedema Acute angioedema should first be treated with corticosteroids and H1-antihistamines. After intravenous administration of, e.g., 250 mg methylprednisolone and 4 mg dimetinden (Fenistil® injection solution) angioedemas usually regress within a few minutes. It should be noted that intravenous antihistamines should be injected slowly (e.g., 4 mg Fenistil® injection solution over 2 minutes). In severe forms with respiratory distress and anaphylaxis, norepinephrine is also necessary. Since acute angioedemas often persist for several days one should expect that, after a short-term improvement following intravenous treatment, angioedema and hives may reappear. Thus, we administer additional oral glucocorticoids (starting with 1 mg/kg/BW prednisolone equivalents for 2 – 3 days, then stepwise reduction) that exhibit a longer half-life than intravenously administered glucocorticoids, and non-sedative H1-antihistamines for 5 – 10 days. Our experience shows that this ad-

Fig. 1.2 Allergic angioedema with swelling of the right half of the tongue.

ditional oral treatment with glucocorticoids and antihistamines markedly reduces the number of patients who present again at the emergency department and then – with even more pronounced angioedema – have to be admitted to the hospital.

Therapy for Chronic Angioedema Patients with chronic angioedemas should at first be informed in detail about possible triggering factors. These include non-steroidal antirheumatic drugs, especially acetylsalicylic acid, ACE inhibitors, angiotensin II antagonists, chronic infections, alcohol and stress. In every case, infections should be adequately treated. When all triggering factors have been excluded, treatment with non-sedative H1-antihistamines is recommended as first line option. As clearly shown in a recently published review on evidence-based therapy for chronic urticaria, the evidence level for a series of different H1-antihistamines (azelastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine and mizolastine) is

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Therapy for Chronic Angioedema very high whereas all other therapeutic alternatives show only a low evidence level [6]. Modern, non- or only mildly sedative antihistamines are just as clinically effective as the older sedative antihistamines and, in addition, exhibit a better side effect profile. Besides the sedative effects, for example, the undesired anticholinergic actions are reduced. In cases of a lack of response or an only low response, first of all the antihistamine should be changed. Although the activities of the various modern H1-antihistamines are highly comparable in the treatment of larger patient groups, quite considerable individual differences may occur. In cases in which a change of the antihistamine was unsuccessful the next step recommended by urticaria specialists is to increase the dosage up to 3or 4-fold although official approval is still lacking (off-label use) [2]. Even severe forms often respond well to higher dosages. One must consider, however, that the dose increase can be accompanied, even with the modern substances, by an increasing sedative effect, impairment of cognitive ability and accumulation of cytochrome P450-metabolized preparations [7]. If possible, glucocorticoids should be avoided in cases of chronic angioedema. Mostly, they offer only short-term help, must then be readministered, possibly in higher doses, and then give rise to increasing side effects. Exceptions are acute exacerbations accompanied with, e.g., swelling of the tongue or pharynx. Treatment in such cases should be similar to that for acute angioedemas: at first high doses for 2 – 3 days and then step-wise reduction for 5 – 10 days. Cyclosporin A in combination with antihistamines is recommended as alternative for the longterm treatment of a severely affected patient [8, 9]. In particular, patients with an autoimmune pathogenesis and positive autologous serum test can benefit from cyclosporin A. However, the side effects are not inconsiderable. Thus, blood pressure and kidney values should be monitored regularly. From our clinical experience, some patients with autoimmune angioedemas also respond well to dapsone or hydroxychloroquine [10]. Both substances can be administered in combination with H1-antihistamines. However, larger controlled studies on dapsone and hydroxychloroquine are still lacking. To date mainly individual case reports or uncontrolled studies are available on other alternatives such as montelukast, doxepin, ketotifen, sulfasalazine, tacrolimus, methotrexate, interfer-

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on, plasmapheresis and intravenous immunglobulins. In summary, for patients with chronic angioedemas and after exclusion of triggering factors, non-sedative H1-antihistamines, above all are recommended. A higher dose of the antihistamine may be necessary. Glucocorticoids should not be given for longer periods, for individual, severely affected patients, however, cyclosporin A may be beneficial. Some patients appear to respond well to dapsone or hydroxychloroquine.

References 1 Grabbe J. Angioödem. CME Dermatologie 2007; 1: 30 – 39 2 Zuberbier T, Bindslev-Jensen C, Canonica W, Grattan CEH, Greaves MW, Henz BM, Kapp A, Kozel MMA, Maurer M, Merk HF, Schäfer T, Simon D, Vena GA, Wedi B. EAACI/GA2LEN/EDF guideline: management of urticaria. Allergy 2006; 61: 321 – 231 3 Wedi B, Raap U, Kapp A. Chronic urticaria and infections. Curr Opin Allergy Clin Immunol 2004; 4: 387 – 396 4 Baiardini I, Giardini A, Pasquali M, Dignetti P, Guerra L, Specchia C, Braido F, Majani G, Canonica GW. Quality of life and patients’ satisfaction in chronic urticaria and respiratory allergy. Allergy 2003; 58: 621 – 623 5 Hartmann K. Urtikaria. Klassifikation und Diagnose. Hautarzt 2005; 55: 340 – 343 6 Wedi B, Kapp A. Evidence-based therapy of chronic urticaria. J Dtsch Dermatol Ges 2007; 5: 146 – 157 7 Ridout SM, Tariq SM. Cetirizine overdose in a young child. J Allergy Clin Immunol 1997; 99: 860 – 861 8 Grattan CE, O’Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, Kobza Black A, Greaves MW. Randomized double-blind study of cyclosporine in chronic “idiopathic” urticaria. Br J Dermatol 2000; 143: 365 – 372 9 Toubi E, Blant A, Kessel A, Golan TD. Low-dose cyclosporine A in the treatment of severe chronic idiopathic urticaria. Allergy 1997; 52: 312 – 316 10 Reeves GE, Boyle MJ, Bonfield J, Dobson P, Loewenthal M. Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and evaluation. Intern Med J 2004; 34: 182 – 186

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Emergency Therapy for Angioedema of the Upper Airway T. K. Hoffmann, H. Bier, G. Kojda, M. Bas HNO-Universitätsklinik, Universität Düsseldorf, Düsseldorf, Germany

Abstract Acute angioedemas (AA) of the upper airway are potentially life-threatening and require a rapid therapeutic intervention. Clinical symptoms include hoarseness, swallowing problems and, above all, respiratory distress characterized by an inspiratory stridor. Such cases should be immediately admitted to an ENT clinic for observation and treatment. Depending on the severity, emergency treatment includes oxygenation, an adequate pharmacotherapy and, if necessary, by-passing the upper airway by intubation or in fulminant cases by a coniotomy/tracheotomy. Pharmacotherapy for non-hereditary forms of AA currently involves the use of antihistamines, steroids as well as epinephrine inhalation and will in future probably be supplemented with specifically active drugs. The technically difficult intubation should be carried out with tracheotomy stand by. Tracheotomy may also be difficult when the cervical soft tissues are swollen making a coniotomy necessary. In the short term this must be converted to a tracheotomy in order to avoid laryngeal perichondritis and subglottic stenosis. In summary, AAs of the upper aerodigestive tract are potentially life-threatening and demand admission to a hospital facilitating intubation or tracheotomy in combination with the currently available drugs.

Introduction

Symptoms

Acute angioedemas (AA; syn.: angioneurotic edema, Quincke’s edema) occur suddenly as firm elastic swelling in the subcutis or submucosa and can, in principle, appear at any site of the body. Although edema in the facial region gives rise to a deformed appearance they generally do not cause any problems. Manifestations in tongue base or throat may quickly escalate into a life-threatening situation due to upper airway obstruction [1]. Typical causes of AA include such widely differing mechanisms as histamine-mediated reactions (urticaria, allergy) and the hereditary C1 inhibitor deficiency [1, 2]. Furthermore, AA have been observed after consumption of certain drugs, for example, this side effect is characteristic particularly for the group of angiotensin-converting enzyme inhibitors, even after year-long consumption [3, 4, 5].

The symptoms of patients with AAs of the upper aerodigestive tract (tongue, tongue base, pharynx, larynx) include a foreign body sensation, slurred speech, difficulties in articulation, swallowing problems (dysphagia) or pain during swallowing (odynophagia), possibly also dry cough, hypersalivation, hoarseness and inhalation problems (inspiratory stridor).

Diagnostics The above-mentioned symptoms are the first indications of the respective problem in the upper aerodigestive tract. Further examinations are necessary to exclude other causes such as foreign body, tumor, or inflammation. The oral cavity can be inspected using a light source and a tongue depressor. The larynx and pharynx should be examined by an ENT specialist. Extended manipulations in this region should be avoided to prevent a possible exacerbation of the AA. We favor the atraumatic, flexible endoscopy by a transnasal approach. Dis-

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Therapy advantages are the high costs of the optics and the necessity for special training. If the suspicion of the presence of an AA persists, the examination should proceed only when facilities for intubation and tracheotomy are close by (see below). In addition, further treatment in the intermediate or intensive care unit or even in the operating room with oxygen, ECG and blood pressure monitoring is recommended.

Therapy If the cause of the AA is known a specific therapy can be initiated. Thus, in the case of hereditary AA, substitution with virus-inactivated C1 concentrate (Berinert® HS) is the first choice. However, such cases represent the exception in clinical practice. In general we are usually faced with a patient with a first swelling episode of which the origin is unknown. Often the patient is not able to name the consumed drugs or does not possess a drug passport from which a potential causative drug can be extracted.

Eliminate Trigger When the triggering factor of AA can be identified (e.g., drugs or food) this is to be discontinued or replaced by an alternative agent. For the frequent case of unknown AA genesis we need to apply a broad spectrum therapy [6].

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this group of drugs finds use in clinical routine because there are no specific alternatives. First line drugs as prednisolone (e.g. Solu-Decortin H®) or methylprednisolone (e.g. Urbason®) are administered intravenously in doses of 250 – 1000 mg. In contrast to other steroids, the advantage of the above-mentioned drugs is the approval of their oral (but unfortunately not intravenous) forms for Quincke’s edema. The use of other steroids remains in the “off-label” status. Administration of 100 mg of dexamethasone (Fortecortin®) could be considered as an alternative because, in contrast to prednisolone/methylprednisolone, the mineral corticoid, sodium-retaining and thus edema-forming activity is completely absent.

Antihistamines Antihistamines belong to the standard therapy for chronic histaminergic, mucosal swelling caused by allergies. In case of acute urticaria H2 blockers are effective within 15 – 30 min. The use of antihistamines for acute, non-urticarial mucosal swelling has not yet been sufficiently studied in clinical studies [9]. In order to fulfill the widest possible therapeutic requirements for a patient with AA of the upper aerodigestive tract, we also administer 1 – 2 amp. (2 – 4 mg in 5 – 10 mL) of clemastin (Tavegil®) intravenously.

C1 Inhibitor Concentrates Intravenous Access An intravenous access for the pharmacotherapy must be placed. This allows administration of three medication groups: 1) corticosteroids, 2) antihistamines, 3) C1-esterase inhibitors.

Corticosteroids Because of their anti-inflammatory “sealing” action corticosteroids are not only used for allergies but also for laryngeal edemas of inflammatory origin and those resulting from surgery or radiotherapy [7]. Bradykinin-induced AA (hereditary and drug-induced angioedema) represent an important limitation. In these cases corticosteroids exhibit no or only very low activities [8]. Even so,

The use of human C1 inhibitor concentrate is, as described above, highly efficient for the treatment of hereditary angioedemas (HAE) with C1 esterase deficiency. Efficacy has also been described for the treatment of laryngeal angioedemas within the clinical picture of HAE [10]. C1 inhibitor concentrates are isolated from the plasma of human donors and, in the case of an AA episode, must be administered intravenously. The dose for children amounts to 500 – 1000 IU and for adults 1000 – 2000 IU (Berinert® HS). A case report and our own observations suggest successful therapy with C1 inhibitor concentrate for ACE-inhibitor-induced AA [11]. However, further systematic clinical studies are needed before the indication for C1 inhibitor concentrate can be extended to other forms of AA.

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2 Emergency Therapy for Angioedema of the Upper Airway

It should be noted that the use of these human blood products necessitates informed patient consent according to current transfusion regulations even when, so far, no single case of HIV or HCV transfer has been reported in an over 2 decades period of use of the virus-inactivated product.

Inhalation with Epinephrine The inhalative administration of a-mimetic sympathomimetics (epinephrine, 4 – 8 mg during 15 min, InfectoKrupp Inhal®) in the treatment of laryngeal edema is frequently used but is classified as an off-label use. It is approved only for the treatment of pseudocroup. In low doses (2 – 3 mg) the b-mimetic components predominate, whereas upon increasing the dose (> 10 mg) stimulation of the alpha receptors is dominant. Arrhythmias and an increase in systolic blood pressure can be expected as side effects at excessively high doses, thus administration of the drug is recommended only under monitoring of vital signs (pulse, blood pressure, oxygen saturation). The time to onset of action of inhalative epinephrine is reported to be 10 min and its duration of action as 30 min so that repeated administrations are necessary in cases of persisting edema.

Bypassing the Upper Aerodigestive Tract During an episode of AA of the upper aerodigestive tract it is recommended to apply oxygen, for example, via a nasal tube. For patients with advanced angioedema and increasing stridor with exhaustion or significant oxygen desaturation, it may be necessary to temporarily bypass the upper aerodigestive tract. In cases of AA with tongue manifestation the placement of a nasopharyngeal tube is helpful. This so-called Wendel tube is coated with a lubricant and introduced through a nostril (prior use of decongestant nasal drops) to just above the level of the larynx.

Intubation Intubation is possible either transnasally under fiber optic guidance (Fig. 2.1) or by a direct transoral route. Both interventions should only be performed by experienced medical personnel. Be-

Fig. 2.1 A patient with acute, ACE inhibitor-induced angioedema of the lips, tongue and tongue base. Because of rapidly progressing dyspnea a fiberoptic-controlled, transnasal intubation was performed.

cause of the fact that the AA can be aggravated by intubation (mechanical trigger), these procedures should only be done when facilities for a conio- or tracheotomy are at hand.

Coniotomy and Tracheotomy If the intubation attempt was unsuccessful, the swollen upper aerodigestive tract can be quickly bypassed by a coniotomy. In this process the membrane between the cricoid cartilage and the thyroid cartilage is opened. In a surgical coniotomy, the membrane is cut horizontally with a scalpel and a small caliber endotracheal tube (e.g., size 5) is placed. Instead of opening with a scalpel, puncture with a trocar and subsequent introduction of the breathing tube is also possible. Coniotomy, however, is only a provisional procedure. In order to avoid complications (laryngeal perichondritis, stenosis), the patient should be intubated or subjected to a tracheotomy as soon as possible. The tracheotomy is placed clearly below the cricoid cartilage, between the 2nd and 3rd tracheal ring (Fig. 2.2). The skin, subcutis, infrahyoid muscles and the isthmus of the thyroid are cut in order to open the exposed trachea. The opened trachea can be sutured to the skin (mucocutaneous anastomosis). In emergency cases in the course of an “uncontrolled” tracheotomy, heavy bleeding can be expected due to injury to the anterior jugular vein and, especially, vessels of the thyroid gland. A large caliber suction system with collateral holes (to

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Conclusion

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References

Fig. 2.2 A patient with acute ACE inhibitor-induced angioedema of the larynx. The laryngeal edema progressed under standard pharmacotherapy with the necessity for an emergency tracheotomy.

prevent blockage) should be used to prevent blood entering the opened trachea. Complications of the two mentioned surgical interventions are, besides bleeding and infection, also a “via falsa” with possible injury to the pleura, esophagus and vocal cord nerves and tracheal constriction.

Conclusion In summary, AA of the upper aerodigestive tract are potentially life-threatening emergency situations requiring inpatient treatment with the currently available drugs (steroids, antihistamines, C1 inhibitors) and eventually intubation and tracheostomy. At present various pharmacological substances are in the test phase that may in future play a role for the treatment of AA of the upper aerodigestive tract.

1 Bas M, Hoffmann TK, Kojda G. Evaluation and management of angioedema of the head and neck. Curr Opin Otolaryngol Head Neck Surg 2006; 14: 170 – 175 2 Bork K. Rezidivierende Angioödeme durch C1-Inhibitor-Mangel: Erstickungsrisiko. Dtsch Ärztebl 1997: 94: A-726 – 737 3 Brown NJ, Snowden M, Griffin MR. Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. JAMA 1997; 278: 232 – 233 4 Waldfahrer F, Leuwer A, Krause J, Iro H. Schweres oropharyngeales Angioödem durch ACE-Hemmer. Eine Fallbeobachtung. HNO 1995; 43: 35 – 38 5 Bas M, Kojda G, Bier H, Hoffmann TK. ACE inhibitorinduced angioedema in the head and neck region: A matter of time? HNO 2004; 52: 886 – 890 6 Bowen T, Cicardi M, Farkas H et al. Canadian 2003 International Consensus Algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004; 114: 629 – 637 7 Shiber JR. Angioedema of the arytenoids. N Engl J Med 2005; 353: e15 8 Agostoni A, Cicardi M, Cugno M, Zingale LC, Gioffre D, Nussberger J. Angioedema due to angiotensinconverting enzyme inhibitors. Immunopharmacology 1999; 44: 21 – 25 9 Agostoni A, Cicardi M. Drug-induced angioedema without urticaria. Drug Saf 2001; 24: 599 – 606 10 Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Inter Med 2001; 161: 714 – 718 11 Nielsen EW, Gramstad S. Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate. Acta Anaesthesiol Scand 2006; 50: 120 – 122

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Hereditary Angioedema: Clinical Manifestation and Therapy W. Kreuz, E. Aygören-Pürsün, I. Martinez Saguer, E. Rusicke Klinikum der Johann-Wolfgang-Goethe Universität Frankfurt, Zentrum für Kinder- und Jugendmedizin, Klinik III, Pädiatrische Hämatologie, Onkologie und Hämostaseologie, Ambulanz für Gerinnungs- und Immundefekte, Frankfurt am Main, Germany

Abstract Hereditary angioedema is a frequently missed, rare disease of the complement system due to a deficiency of C1-inhibitor (C1-INH). Manifestation of the disease occurs in the form of episodic angioedema of the skin or mucous membranes. A laryngeal localization of the edema may potentially be life-threatening, however, also gastrointestinal edema, which may present as acute abdomen, and skin edema may lead to considerable distress in affected patients. Frequently recurrent and/or severe angioedema may significantly reduce the quality of life and ability to work. Hence, an effective therapy for acute angioedema is crucial. At present, replacement therapy with plasma-derived C1-INH concentrate is licensed in Germany. Several alternative therapeutic agents are currently undergoing clinical testing.

Introduction Hereditary angioedema (HAE) is a rare disease resulting from a defect of the C1 inhibitor (C1-INH) due to mutations within the C1-INH gene. Typically, the disease manifests as recurrent angioedema characterized by edema of the skin or mucous membranes. Whereas cutaneous edema may localize in any part of the body, mucous membrane edema mostly affect the bowel or the larynx. Depending on the localization and extent of the edema, different symptom profiles may arise. Frequently, patients are correctly diagnosed as HAE only after considerable delays, the patients being frequently misdiagnosed as allergic edema, acute abdomen and other conditions.

tions. C1-INH has been detected in endothelial cells, monocytes, chondrocytes and fibroblasts [1]. However, the liver may be considered as the main site of synthesis [2]. The main functions of C1-INH comprise the regulation of activation of the classical pathway of complement, the inhibition of autoactivation of C1, and the regulation of the contact system [3]. C1-INH belongs to the family of serine protease inhibitors (serpins), it forms a stable 1 : 1 complex with the target protease and is thus regarded as a suicide substrate [4]. C1-INH is the sole inhibitor of the proteases C1r and C1s, two serine proteases that together with C1q form the C1 complex of the classical pathway of complement. A deficiency of C1-INH results in uncontrolled complement activation and an increased formation of bradykinin through elevated activation of the kinin system.

Biological Characteristics of C1-INH C1-INH plays a central part in the control of the complement system and is furthermore involved in the regulation of the contact phase of blood coagulation, of the fibrinolytic system and the kininkininogen system. In human plasma C1-INH is found in a concentration of 240 – 270 mg/L or, by definition 1 unit/mL plasma. It is an acute phase protein, which increases up to 2-fold during infec-

Diagnosis and Classification of C1-INH Deficiency In the differential diagnosis of angioedema further possible etiologies, such as urticaria-associated angioedema, drug-induced angioedema, estrogendependent angioedema and the like, should be considered. With regard to the appreciable thera-

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Epidemiology and Genetics of C1-INH Deficiency peutic consequences, a proper diagnosis of angioedema is essential.

Hereditary Angioedema (HAE) Generally, patients with C1-INH deficiency present with the typical laboratory pattern during symptom-free intervals as well. Two types of hereditary angioedema can be distinguished. Most of the afflicted patients (ca. 85 %) exhibit a quantitative defect (HAE type I) due to reduced synthesis of C1INH and resulting reduction of C1-INH activity and C1-INH antigen level. Qualitative defects (HAE type II) are characterized by low C1-INH activity with normal or elevated C1-INH antigen. There is no difference between HAE type I and type II with regard to clinical symptoms. The residual activity of C1-INH does not correlate with the frequency or severity of the symptoms. Additionally, in virtually all HAE patients C4 complement is markedly reduced, so this may be used as a confirmation assay. In about 60 % of patients total complement (CH 50) also shows decreased serum levels. In the laboratory evaluation of a patient, a concomitant or recent administration of C1-INH concentrate or attenuated androgens must be taken into account. The diagnosis of HAE can be finally confirmed by C1-INH gene analysis, which is informative in the majority of cases.

Acquired Angioedema (AAE) While hereditary C1-INH deficiency already is considered a rare disease, acquired C1-INH deficiency (acquired angioedema, AAE) is detected even more rarely. In our patient population of at present 389 patients with C1-INH deficiency, the proportion of AAE amounts to about 4%. AAE frequently occurs in association with the formation of autoantibodies against C1-INH, lymphoproliferative diseases, rarely also with solid tumors and other diseases, and may also arise without a detectable underlying disease. Clinical angioedema may occasionally even precede the diagnosis of an underlying disease by many years. In suspected AAE cases determination of C1q serum levels can be helpful for differentiation from HAE since, in patients with hereditary angioedema, C1q is persistently found in the normal range [5]. C1-INH activity and antigen, C4 and C1q usually exhibit nearly undetect-

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able serum levels in AAE, but these parameters can fluctuate widely and may even be temporarily normalized. Their pronounced decrease has been attributed to increased consumption of C1-INH, vast activation of the classical pathway of complement, and also to the effect of inactivation by C1INH by autoantibodies.

Hereditary Angioedema without C1-INH Deficiency Hereditary angioedema without C1-INH deficiency, which has also been referred to as “HAE type III” in the past, has been described by several groups [6 – 8]. Characteristically, in the families concerned, women are affected almost exclusively and a predisposition for angioedema has been reported in association with exposure to estrogens [6 – 8]. In some of these patients a novel “gain of function” mutation of the factor XII gene, which leads to an increased amidolytic activity of the coagulation factor XII, has been detected [9,10].

Epidemiology and Genetics of C1-INH Deficiency The prevalence of hereditary angioedema cannot be exactly stated due to the presumably large number of unknown or misdiagnosed cases. It is estimated to be about 1 : 50 000 [11]. Hereditary transmission of C1-INH deficiency is autosomal dominant with incomplete penetrance. The C1INH gene, which includes 8 exons and 7 introns, is located on chromosome 11 and encompasses 17159 kb [12]. A large number of different mutations of the C1-INH gene are currently known in HAE patients, a high proportion of them being point mutations, which are distributed over the entire length of the gene. Small deletions or duplications occur in about 20 % of the cases [13]. Mutations that affect the reactive center of C1-INH lead to a functional deficiency of the protein [14]. The rate of de novo mutations amounts to ca. 20 %, whereas in ca. 80 % further family members are concerned. After confirmation of C1-INH deficiency in a patient, first degree family members should be examined in order to achieve an early diagnosis for asymptomatic family members, especially children.

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3 Hereditary Angioedema: Clinical Manifestation and Therapy

Fig. 3.1 a, b Facial angioedema in a patient with acquired C1-INH deficiency (AAE) during the maximum swelling (a) and after therapy (b). The edema is clini-

cally indistinguishable from that in hereditary C1-INH deficiency (HAE).

Clinical Symptoms of Hereditary Angioedema

the fact that it becomes obvious only during attacks and patients usually appear in perfect health between attacks. Many patients describe typical prodromal symptoms: a local sensation of tension and tingling as well as general symptoms like thirst, fatigue and aggressive behavior. Sometimes, located mostly on the upper body, a non-itching skin rash can be observed before the manifestation of angioedema.

The age at first manifestation of hereditary angioedema is under 10 years for about 50 % of the patients, however, at this time only about 13% have a correct diagnosis [11]. The clinical severity of HAE in terms of localization, frequency and extent of angioedema shows evidence of a broad interand intraindividual variability. Accordingly, the restrictions experienced by the patients due to the disease are also highly variable. Occasionally patients, mostly males, may even remain practically asymptomatic through to a very old age. There are many patients, however, who experience the most severe symptoms 2 – 3 times a week. These patients represent about 10 – 15% of our patient population. On the other hand, it has to be considered that even mild episodes of peripheral angioedema, that may prevent certain activities like writing, wearing shoes etc., may lead to major restrictions in daily life and at work and school. The patients’ impairment is often underestimated, also due to

Clinical Pattern According to Localization of Angioedema Cutaneous Edema 91% of patients with hereditary angioedema suffer from edema of the skin [11]. Frequently affected body parts are the face (Fig. 3.1 a, b), hands, feet, genitalia, neck. Less frequently entire limbs, buttocks or the back are affected. Purely periorbital or perioral edema occur only rarely in HAE. Angioedema of the skin may migrate into various parts

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Clinical Symptoms of Hereditary Angioedema of the body, at times involving several sites of swelling simultaneously. A concomitant or consecutive gastrointestinal or laryngeal involvement may be observed. Edema of the skin usually shows a slow development over several hours and lasts for ca. 2 – 5 days [11]. In cases of large skin edema, tension pain may also occur. Cutaneous angioedema in HAE is characteristically non-itching and non-erythematous. The affected skin parts are located in the region of the subcutis and deep skin layers, in contrast to urticaria, where edema affects the upper cutaneous layer.

Gastrointestinal Edema Involvement of the gastrointestinal tract in the form of bowel wall edema is an acute, mostly severe clinical situation, with which ca. 73% of the patients are affected [11]. The symptoms correspond to those of an ileus or subileus. The majority of abdominal attacks show a severe course with intense, typically colic-like pain [15]. Vomiting accompanies 73% of the abdominal attacks, diarrhea 41% [15]. Hypovolemia due to acute ascites is common in association with gastrointestinal edema and can lead to collapse in up to 4% of episodes [15]. The diagnosis of an intestinal edema can by confirmed by ultrasound, which can visualize the bowel wall edema and an accompanying ascites. Up to 34 % of the patients undergo unnecessary surgical procedures such as appendectomy or explorative laparotomy, because of a lack of knowledge about the clinical symptoms of HAE [11].

Laryngeal Edema The most severe complication of hereditary angioedema is laryngeal edema, a life-threatening condition with a high fatality rate, if untreated. 48 – 50 % of HAE patients are affected by one or more episodes of laryngeal edema in the course of their lives [11,16,17]. The mean time interval between onset and maximum extent of laryngeal edema in patients with HAE is ca. 8 hours, with a range of 3 to 48 hours [17]. So usually there should be sufficient time for therapeutic interventions, although treatment should nevertheless be initiated as soon as possible. The patients should be informed about the symptoms of laryngeal edema, such as a lump in the throat, swallowing difficulties, hoarseness and breathing difficulties, in order to be able to take timely action.

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Further Manifestations of Angioedema Rare manifestations of hereditary angioedema may involve the palate, tongue, muscle, joints, kidneys and esophagus. Thoracic angioedema is still disputed, but there are indications that some patients may suffer from transient pleuritic symptoms. Mucous membrane edema of the urinary bladder may mimic symptoms of an acute infection. Angioedema of the central nervous system, which may present as transient aphasia, drowsiness and other neurological symptoms, has only recently been accepted as a possible manifestation of HAE.

Triggering Factors Frequently, angioedema in patients with HAE occur spontaneously, without any recognizable triggering factors. Typically infections, exhaustion, as well as negative and positive emotional stress can predispose to more frequent and more severe angioedema. Accompanying diseases such as a Helicobacter pylori infection may also lead to enhanced manifestation of angioedema [18]. Trauma and operations, dental procedures and especially intubation can trigger angioedema. In many patients even slight mechanical irritations are sufficient to cause a local swelling. In women, the manifestation tendency may be increased by physiological hormone fluctuations such as ovulation, menstruation and pregnancy, as well as by administration of estrogens, as contained in oral contraceptives and hormone replacement therapy [19]. ACE inhibitors can lower the manifestation threshold for edema formation, presumably caused by the associated elevated serum bradykinin concentration. Also angiotensin II receptor antagonists can, in our experience, lead to more pronounced angioedema symptoms in HAE patients. Factors that can positively influence the clinical course of the disease include a reliable diagnosis, comprehensive patient information, as well as support from the social environment and the physician. Avoiding well-known triggering factors can also affect the manifestation tendency. Furthermore, therapy for accompanying diseases can cause a reduction of the episode frequency [18].

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3 Hereditary Angioedema: Clinical Manifestation and Therapy

Current Treatment of Hereditary Angioedema In the treatment of hereditary angioedema 3 therapeutic principles are distinguished: the management of acute attacks, long-term prophylaxis, and periprocedural short-term prophylaxis.

Therapy for Acute Angioedema Corticosteroids and antihistamines are not effective for angioedema due to C1-INH deficiency. Therapy for acute edema consists of the intravenous administration of a C1-INH concentrate at a dose of 10 – 30 IU/kg BW [20]. At present, in Germany the pasteurized, plasma-derived (pd) C1INH concentrate Berinert P (CSL Behring) is licensed for the treatment of acute angioedema episodes in patients with C1-INH deficiency. The preparation has been in use for more than 20 years and is well tolerated. Since its introduction to the market about 100 million units of the concentrate have been sold and no viral transmission has been reported as yet [21, 22]. In view of the potentially life-threatening nature of the disease, all patients should be provided with an individually appropriate home supply of C1-INH concentrate or, respectively, immediate access to C1-INH concentrate in emergency situations should be assured [23].

Treatment of Cutaneous Edema Therapy for solitary edema of the skin will usually not be indicated, except in cases of particularly severe edema with tension.

Treatment of Laryngeal Edema In HAE patients presenting with laryngeal edema the intravenous injection of 500 – 1000 units of pd C1-INH concentrate leads to rapid symptom regression. The time to onset of relief is usually 20 – 60 minutes [24, 25].

Treatment of Gastrointestinal Edema In abdominal attacks the use of pd C1-INH concentrate results in a significant decrease of the maximal pain score, compared to untreated patients [26]. The mean duration of the attacks after administration of pdC1-INH concentrate is signifi-

cantly decreased [26], the time to onset of relief being only 10 minutes in some cases [16, 26]. In case of hypovolemia, volume substitution is indicated [23].

Home Therapy with pd C1-INH Concentrate In suitable patients self-treatment at home with pdC1-INH concentrate can be initiated after an appropriate training program. Patients qualify for home treatment in our center when an angioedema attack demanding treatment occurs at least once a month and patients are mentally and physically able to perform the treatment. The goals of home therapy are a reduction of hospitalization periods and of absence from work or school. The major advantage of self-treatment is the reduction of the time between onset of symptoms and start of therapy. An early treatment leads to a shorter interval between administration of pdC1-INH concentrate and improvement of symptoms [26]. Early therapy of an angioedema attack can lead to lower effective doses of pdC1-INH concentrate [16]. Moreover, home treatment can ensure the access to immediate treatment in emergency situations.

Individual Replacement Therapy (IRT) In our center, patients who suffer from clinically severe HAE with 1 – 3 angioedema attacks per week receive an individual replacement therapy (IRT) with pd C1-INH concentrate. This regime is constituted by the immediate injection of pd C1INH concentrate on the first signs of an angioedema attack and is performed as home therapy. At present 55 (51 adults, 4 children) of a total of 375 patients with HAE (290 adults, 85 children) at our center are on IRT. A significant reduction of attack frequency and a significant improvement in the quality of life for these patients could be demonstrated [27].

Long-Term Prophylaxis for Hereditary Angioedema Patients with frequent attacks (> 1 severe attack/ month) may receive angioedema prophylaxis with attenuated androgens (e.g., danazol) and antifibrinolytics, according to International Guidelines [28]. In Germany danazol is not licensed for treatment of “hereditary angioedema” and is no longer available. However, it does find widespread use in

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Conclusion many countries, especially those in which C1-INH concentrate is not available. The objective of danazol prophylaxis is to reduce the tendency for manifestation of HAE. However, non-responders to danazol are not uncommon, i.e., even with doses as high as 800 – 1200 mg/d these patients do not show a sufficient improvement of the clinical symptoms [29]. Where necessary, pdC1-INH concentrate is administered additionally. The use of danazol is limited by a number of side effects. Known side effects include arterial hypertension, weight gain, acne, and menstrual irregularities [30]. Only 10 % of the involved patients in our patient population did not exhibit any side effect [29]. The most frequent symptoms are virilization and amenorrhea in 79 % or, respectively, 78 % of the involved women. In the entire danazol population we found elevated transaminases (68%) and hepatic adenoma (3%), depression (47%), irritability (28 %) and panic attacks (10 %). In addition, arterial hypertension (25 %), headache (40 %), migraine (9%) and frequently a considerable gain in weight were also observed [29]. In our experience antifibrinolytics are less effective for the hereditary form of C1-INH deficiency but can achieve good results in patients with an acquired C1-INH deficiency.

Short-Term, Periprocedural Prophylaxis In the course of invasive or surgical interventions, angioedema can also arise not only in the operated region but also in every other part of the body including the gastrointestinal tract and the larynx. Thus, prior to intubation and surgical or invasive procedures, replacement therapy with 500 – 1000 units C1-INH is indicated. This also holds for dental procedures as these can also lead to fatal laryngeal edema. Sufficient pd C1-INH concentrate should also be at hand for possible further doses [23, 28].

New Therapeutic Approaches A series of novel therapeutics for the treatment of acute angioedema in HAE are at present undergoing clinical testing. In Germany the licensing of the bradykinin 2 receptor antagonist Icatibant, which achieves a rapid response in acute attacks, is awaited. Further promising new therapeutics are the kallikrein inhibitor DX-88 and recombinant C1-INH concentrate.

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Conclusion Hereditary angioedema due to C1-INH deficiency is a condition which may lead to temporarily disabling and even life-threatening episodes of angioedema. Although it is a rare disease, much knowledge about the pathophysiology, genetic causes and clinical pattern of HAE has accumulated in the past decades. Also treatment modalities have significantly improved and are undergoing constant reevaluation. Because of these developments patients can be provided with qualified care, which is the prerequisite for many patients for full integration into social and work life.

References 1 Gulati P, Lemercier C, Guc D, Lappin D. Whaley K. Regulation of the synthesis of C1 subcomponents and C1-Inhibitor. Behring Institute Mitteilungen 1993; 93: 196 – 203 2 Zuraw BL, Lotz M. Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma. J Biol Chem 1990; 265: 12664 – 12670 3 Rosen FS, Davis AE III. Deficiencies of C1 inhibitor. Best Practice and Research Clinical Gastroenterology 2005; 19: 251 – 261 4 Patson PA, Gettings P, Beechem M, Shapira M. Mechanisms of serpin action: evidence that C1 inhibitor functions as a suicide substrate. Biochemistry 1991; 8876 – 8882 5 Cicardi M, Zingale L, Pappalardo E, Folcioni A, Agostoni A. Autoantibodies and lymphoproliferative diseases in acquired C1-Inhibitor deficiencies. Medicine 2003; 82: 274 – 281 6 Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-Inhibitor activity in women. Lancet 2000; 356: 213 – 217 7 Binkley KE, Davis A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000; 106: 546 – 550 8 Martin L, Degenne D, Toutain A, Ponard D, Watier H. Hereditary angioedema type 3: an additional French pedigree with autosomal dominant transmission. J Allergy Clin Immunol 2001; 107: 747 9 Dewald G, Bork K. Missense mutation in the coagulation factor XII (Hagemann factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006; 343: 1286 – 1289 10 Cichon S, Martin L, Hennies HC, Müller F, Van Driesche K, Karpushova A et al. Increased activity of coagulation factor XII (Hagemann factor) causes hereditary angioedema type III. Am J Hum Genet 2006; 79: 1098 – 1104

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11 Agostoni, A., Cicardi M. Hereditary and acquired C1Inhibitor deficiency: Biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992; 71: 205 – 219 12 Carter PE, Duponchel C, Tosi M, Fothergill GE. Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements. Eur J Biochem 1991; 197: 301 – 308 13 Tosi M. Molecular genetics of C1 inhibitor. Immunology 1998; 199: 358 – 365 14 Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC. CpG mutations in the reactive site of human C1 inhibitor, J Biol Chem 1989; 264: 3066 – 3071 15 Bork K, Staubach P, Eckhardt AJ, Hardt J. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol 2006; 101: 1 – 9 16 Unpublished observations of our group 17 Bork K, Ressel N. Sudden upper airway obstructions in patients with hereditary angioedema. Transfus Apher Sci 2003; 29: 235 – 238 18 Farkas H, Fust G, Fekete B, Karadi I, Varga L. Eradication of Helicobacter pylori and improvement of hereditary angioneurotic oedema. Lancet 2001; 358: 1695 – 1696 19 Bork K, Fischer B, Dewald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003; 114: 294 – 298 20 Bundesärztekammer – Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten. 3. Auflage. Hrsg.: Vorstand und Wissenschaftlicher Beirat der Bundesärztekammer. Köln: Deutscher Ärzte-Verlag; 2003: 201 – 210 21 Jürs M, Gröner A. In: Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, Bucher C et al. Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004; 114 (Suppl. 3): S51 – S131 22 Longhurst HJ. Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence? Int J Clin Pract 2005; 59: 594 – 599

23 Kreuz W, Fischer D, Heller C, Martinez Saguer I, Klarmann D. Substitution des C1-Esterase-Inhibitors bei Hereditärem Angioödem. Die gelben Hefte 1998; Jg. XXXVIII, Heft 4: 109 – 119 24 Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 Inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 2001; 161: 714 – 718 25 Bork K, Kreuz W, Witzke G. Hereditäres angioneurotisches Ödem. Klinik, Diagnostik, Patientenführung und medikamentöse Therapie. DMW 1984; 109: 1331 – 1335 26 Bork K, Meng G, Staubach P, Hardt J. Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Transfusion 2005; 45: 1774 – 1784 27 Kreuz W, Martinez Saguer I, Aygören-Pürsün E, Rusicke E, Klingebiel T. Individual replacement therapy (IRT) with C1-Inhibitor concentrate in patients with severe hereditary angioedema increases significantly quality of life parameters compared to danazol prophylaxis. J Thromb Haemostas 2005; 3 (Suppl. 1): abstract no. P0602 28 Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L, Varga L, Martinez Saguer I, Aygören-Pürsün E et al. Canadian 2003 International consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004; 114: 629 – 637 29 Kreuz W, Aygören-Pürsün E, Martinez Saguer I, Rusicke E, Klingebiel T. Adverse effects of danazol in the treatment of hereditary or acquired C1-Inhibitor deficiency. J Allergy Clin Immunol 2007; 119 (Suppl. 1): abstract no. 165 30 Cicardi C, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol 1997; 99: 194 – 196

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Special Aspects of the Treatment of Hereditary Angioedema in Children J. Ramakers, T. Niehues Klinik für Kinder-Onkologie, Hämatologie und Klinische Immunologie, Jeffrey Modell Foundation, Immundefekt-Zentrum, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany

Abstract The first attacks occur in 75% of all patients before the age of 15 years. The symptoms of hereditary angioedema (HAE) in childhood are convulsive abdominal pain, swellings of the limbs, swallowing problems, hoarseness and acute respiratory distress. The attacks are, as a rule, milder and less frequent than in adults. Only 35% of all diagnoses are made in childhood. In the absence of a positive family history the diagnosis is often delayed. The therapy for an acute attack and short-term prophylaxis can be managed safely and reliably with C1-INH concentrate. Long-term prophylaxis of HAE in childhood differs from the therapy in adults. A regular substitution of C1-INH concentrate is recommended. The use of attenuated androgens in childhood is reserved for isolated cases and requires strict monitoring due to the possible complications with regard to growth and development. The use of antifibrinolytic substances is an alternative to androgens in the severely afflicted patient due to its better safety profile but on the whole they show a poorer response. It is of decisive importance to inform the parents, patients and general practitioner about the disease. Patients should be provided with an emergency supply of C1-INH concentrate for home use. Only in this way can unnecessary invasive procedures be avoided and potentially life-threatening complications such as laryngeal edema be managed.

Introduction Hereditary angioedema (HAE) was considered for a long time to be a disease of adulthood. However, longitudinal studies over more than 20 years on more than 340 patients from 120 families have documented that almost 40 % of all patients experience their first attack before the age of 5 years and 75 % before the age of 15 years [1 – 3]. The earliest manifestations were even described in infant age. On the other hand, only 35% of all diagnoses are made in childhood.

Clinical Picture The symptoms of HAE in childhood resemble those in adult patients and include subcutaneous swelling, convulsive abdominal pain, vomiting, swallowing difficulties, hoarseness and acute respiratory distress (see Fig. 4.1). Two-thirds of the child patients experience subcutaneous swellings on the limbs and face, 50 – 75% of the patients suffer from gastrointesti-

nal symptoms, and in about 10 – 25 % potentially life-threatening laryngeal edemas can occur [4, 5]. The subcutaneous swellings last for 2 – 5 days and then spontaneously disappear. The swellings are often associated with an unpleasant feeling of tension. Itching is not typical and represents an important symptom for differentiation from urticarial angioedema. In about 20 – 30 % of the children a generalized, non-itching exanthema before and during the attacks has been described [4]. Except for the convulsive abdominal pain, in children the attacks are usually milder and less frequent than in adults [6 – 9]. Triggering factors for attacks include mechanical trauma, psychosocial stress, drugs (e.g., ACE inhibitors) and, especially in children, also infections of the upper airways. Patients with Helicobacter pylori infection seem to be more susceptible to symptoms and eradication can lead to a reduction in the frequency and severity of the attacks, especially of the bowels [10]. On reaching puberty, the severity and frequency of the attacks can increase; in girls, menstruation can trigger attacks.

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4 Special Aspects of the Treatment of Hereditary Angioedema in Children

Differential Diagnoses The above-described symptoms are generally very frequent in childhood. Some examples of differential diagnoses are urticaria, insect bites, pseudocroup, aspiration, gastroenteritis, appendicitis and invagination. The abdominal complaints can be very pronounced and present like an acute abdomen, leading to the performance of an appendectomy. In such cases of frequent abdominal symptoms, sonography of the abdomen can provide useful diagnostic information. In this way ascites can be detected, 80 % of the scans exhibit edema of the gastrointestinal tract [14].

Therapy

Fig. 4.1 face.

A 5-year-old girl with angioedema in her

Diagnosis In clinically suspicious cases the diagnosis is based on determination of the C1-INH concentration and function in plasma and measurement of the C4 concentration. The adult normal range for C1-INH is almost reached at about 3 months of age [11]. In umbilical cord blood the C1-INH function amounts to ca. 70% of the normal adult value [12]. The values for C4 in childhood seem to undergo larger fluctuations so that their diagnostic value is questionable [13]. In general, the diagnosis of HAE can be made when the C1-INH concentration and/or function in two determinations with an interval of at least one month amount to less than 50 % of the normal value. Examinations before the age of one year should be repeated for confirmation after the age of one year. In the absence of a positive family history, the diagnosis is often delayed, sometimes to the second or third decade.

There are only very few publications on drug therapy for HAE in childhood and no controlled studies have been carried out [5, 15 – 17]. C1-INH concentrate and antifibrinolytics are mainly administered. Androgens should be used cautiously in childhood and must be closely monitored on account of the possible complications with regard to growth and development. C1-INH concentrate is obtained from pooled, steam-heated or pasteurized donor plasma. Since it is a blood product there is still a residual risk of transmission of viral diseases in spite of the virusinactivating production process. C1-INH concentrate is available in Europe but not in USA. The costs are high. The use of antifibrinolytic substances is an alternative to androgens for the severely afflicted patient on account of a better safety profile but on the whole they elicit a poorer response. e-Aminocapronic acid and tranexamic acid are also used. Tranexamic acid is generally better tolerated, possible side effects are abdominal pain, with transient mild diarrhea, nausea and itching. Danazol is a synthetic analogue of ethinyltestosterone (17-a-alkylated androgen). Attenuated androgen prevents attacks more effectively than other androgens [5]. Degradation takes place in the liver. Possible side effects are hepatotoxicity, induction of hepatocellular carcinoma [18], weight gain, myalgias, headache, tremor, disturbed libido, menstrual complaints and hirsutism.

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Patient Information and Psychosocial Aspects Therapy for HAE is divided into acute therapy, especially for the life-threatening laryngeal edema and the highly painful gastrointestinal edema, short-term prophylaxis prior to interventions that could trigger attacks, and long-term prophylaxis for patients with a high frequency of attacks.

Acute Therapy Acute therapy for laryngeal or gastrointestinal edema consists of 500 – 1000 IU or, respectively, 10 to 30 IU/kg BW C1-INH concentrate. As a rule, infusion leads to a marked improvement of the complaints within 30 – 60 min. In the case of an unsatisfactory clinical response after 1 hour, the dose can be repeated. Complete disappearance of all symptoms and clinical signs may take up to 24 – 48 hours [5,19].

Short-Term Prophylaxis Short-term prophylaxis should be performed prior to invasive medical interventions (dental procedures) that are accompanied by an increased risk for triggering a laryngeal or gastrointestinal edema or, respectively, prior to such interventions on patients with a history of potentially life-threatening attacks. In principle, C1-INH concentrate is preferred for prophylaxis in children. In case of its unavailability, androgens are the substances of second choice. Androgens are more effective substances for long-term prophylaxis and are only accompanied by minor side effects on short-term use. Thus they are to be preferred over antifibrinolytics. Finally, tranexamic acid can be given when the use of androgens is contraindicated. C1-INH concentrate for prophylaxis is generally given as an infusion of 500 – 1000 IU 1 hour before the planned intervention. For adolescents who have developed laryngeal or facial edema after similar interventions in the past, danazol at 300 mg/day for 4 days before and after a dental procedure can prevent a renewed attack [4]. Tranexamic acid at a dose of 500 mg 4 ×/day for 5 days before and after the intervention has also been used as an effective short-term prophylaxis for children [20].

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Long-Term Prophylaxis In general, patients with a history of severe, lifethreatening attacks or patients experiencing more than 1 attack per month receive long-term prophylaxis [15]. In childhood, C1-INH concentrate is again recommended at doses of 500 IU once or twice per week on account of the good tolerability and efficacy [19, 21]. Limitations are the high costs and the necessity for regular infusions. Because of its better safety profile, tranexamic acid is preferred over danazol in long-term prophylaxis. The recommended dosage of tranexamic acid is 50 mg/kg per day in 3 – 4 individual doses (max. 1.5 g/dose) [16]. Investigations on a limited number of cases have demonstrated the successful and safe use also of attenuated androgens in children over a period of up to 11 years [17, 22, 23]. In 8 of 8 children, therapy with danazol at 100 – 200 mg/day successfully prevented attacks. One female patient exhibited delayed menarche and irregular menstruation. Regular laboratory controls and abdominal ultrasound did not reveal any suspicious findings [4]. With antifibrinolytics and androgens the dose should slowly be titrated down to the lowest effective level. New therapeutic options such as the use of recombinant C1-INH, kallikrein inhibitor (DX-88) or bradykinin antagonists (icatibant) are currently being tested in adults but have not yet been applied in the therapy for children.

Patient Information and Psychosocial Aspects Of decisive importance is comprehensive information and clarification for the parents, patients, general practitioners and hospital staff about the disease. The patients are given emergency identification cards. Patients with frequent or severe attacks should have an emergency supply of C1-INH concentrate at home and, if necessary, parents should be instructed in self-treatment. Possible patient-specific triggering factors should be taken into account in activities of daily life. In this way unnecessary invasive procedures can be avoided and potentially life-threatening complications such as laryngeal edema can be managed.

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4 Special Aspects of the Treatment of Hereditary Angioedema in Children

Contact with self-help groups (e.g., www.angiooedem.de, www.hae.org) can decisively improve knowledge about the disease, access to specialist centers and quality of life.

References 1 Agostoni A, Cicardi M. Hereditary and acquired C1inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992; 71: 206 – 215 2 Cicardi M, Bergamaschini L, Marasini B, Boccassini G, Tucci A, Agostoni A. Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci 1982; 284: 2 – 9 3 Cicardi M, Bergamaschini L, Cugno M, Beretta A, Zingale LC, Colombo M et al. Pathogenetic and clinical aspects of C1 inhibitor deficiency. Immunobiology 1998; 199: 366 – 376 4 Farkas H, Harmat G, Fust G, Varga L, Visy B. Clinical management of hereditary angio-oedema in children. Pediatr Allergy Immunol 2002; 13: 153 – 161 5 Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004; 114 (Suppl. 3): 51 – 131 6 Abinun M. Diagnosis and treatment of hereditary angioedema, a genetically determined deficiency of C1 inhibitor. MSc Thesis, Medical School, University of Belgrade; 1988 7 Bork K, Hardt J, Schicketanz KH, Ressel N. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med 2003; 163: 1229 – 1235 8 Donaldson VH, Rosen FS. Hereditary angioneurotic edema: a clinical survey. Pediatrics 1966; 37: 1017 – 1027 9 Gwynn CM. Therapy in hereditary angioneurotic oedema. Arch Dis Child 1974; 49: 636 – 640 10 Farkas H, Fust G, Fekete B, Karadi I, Varga L. Eradication of Helicobacter pylori and improvement of hereditary angioneurotic oedema. Lancet 2001; 358: 1695 – 1696

11 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165 – 172 12 Nielsen EW, Johansen HT, Holt J, Mollnes TE. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatr Res 1994; 35: 184 – 187 13 Norman ME, Gall EP, Taylor A, Laster L, Nilsson UR. Serum complement profiles in infants and children. J Pediatr 1975; 87 (6 Pt 1): 912 – 916 14 Farkas H, Harmat G, Kaposi PN, Karadi I, Fekete B, Fust G et al. Ultrasonography in the diagnosis and monitoring of ascites in acute abdominal attacks of hereditary angioneurotic oedema. Eur J Gastroenterol Hepatol 2001; 13: 1225 – 1230 15 Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L et al. Canadian 2003 international consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004; 114: 629 – 637 16 Boyle RJ, Nikpour M, Tang ML. Hereditary angiooedema in children: a management guideline. Pediatr Allergy Immunol 2005; 16: 288 – 294 17 Farkas H, Harmat G, Gyeney L, Fust G, Varga L. Danazol therapy for hereditary angio-oedema in children. Lancet 1999; 354: 1031 – 1032 18 Bork K, Pitton M, Harten P, Koch P. Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema. Lancet 1999; 353: 1066 – 1067 19 Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996; 334: 1630 – 1634 20 Abinun M. Hereditary angio-oedema in children. Lancet 1999; 353: 2242 21 Bork K, Witzke G. Long-term prophylaxis with C1inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency. J Allergy Clin Immunol 1989; 83: 677 – 682. 22 Barakat A, Castaldo AJ. Hereditary angioedema: danazol therapy in a 5-year-old child. Am J Dis Child 1993; 147: 931 – 932 23 Church JA. Oxandrolone treatment of childhood hereditary angioedema. Ann Allergy Asthma Immunol 2004; 92: 377 – 378

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5

Acute Phase Proteins in Kinin-Induced Angioedema M. Bas1, H. Bier1, M. Oppermann2, T. K. Hoffmann3, G. Kojda2 1

2

3

Hals-Nasen-Ohrenklinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität, München, Germany Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Germany Hals-, Nasen- und Ohrenklinik, Heinrich-Heine-Universität Düsseldorf, Germany

Abstract Introduction: Patients under ACE inhibitor (ACEI) therapy as well as those with congenital C1 inhibitor (C-INH) deficiencies exhibit elevated bradykinin (BK) plasma concentrations. The vascular highly active peptide BK is able to dilate blood vessels through the intracellular NO signalling pathway and to increase the permeability of vessel walls. Clinical observations have revealed that not all patients with high BK plasma concentrations also develop edema. Only 0.5% of the ACEI patients suffer from angioedema. The findings clearly demonstrate that other factors must also play a role in the development of angioedema. In this context it is remarkable that patients with elevated BK plasma concentrations frequently develop angioedemas during and directly after an operation or in cases of inflammation. As the reason for this we can consider an interaction between acute phase proteins and chronically elevated BK. Just recently it was found that, in plasma, the acute phases proteins CRP and fibrinogen were elevated up to 4-fold during an acute angioedema. Methods: We have now performed experimental studies on the role of acute phase proteins in the pathophysiology of angioedema. Results: In organ bath experiments with human and porcine vascular explants, we have found that acute phase proteins, on the one hand, act themselves as mediators for the development of angioedema and, on the other hand, can strengthen BK action by up to 10-fold. NO activation occurs thereby in a receptor-dependent manner both in endothelial cells and in smooth muscle cells. Conclusions: These observations show the necessity for appropriate precautions both pre- and postoperatively as well as in episodes of inflammation.

Introduction Angioedema develops through different pathomechanisms. An exact knowledge of the various forms is essential for their classification and clinical management. According to our current state of knowledge, three proteins in particular seem to play a decisive role in the development of angioedema: histamine, bradykinin and substance P. While the histaminergic angioedema is associated above all with allergic reactions, angioedema promoted by bradykinin and substance P are non-allergic forms. For the non-allergic angioedema we distinguish between two idiopathic forms (IAE), pseudoallergies in which substance C is assumed to play a role (PAE) and the bradykinin-induced angioede-

ma (Table 5.1). The function of substance P in angioedema has not yet been clarified. An elevated plasma bradykinin level can arise as the result of a bradykinin degradation disorder due to inhibition of the renin-angiotensin-aldosterone system, e.g., by ACE inhibitors. A pathologically increased formation exists in cases of hereditary angioedema (HAE) due to a C1 esterase inhibitor defect or in the rare cases of an acquired angioedema with formation of antibodies against C1-INH (AAE) (Table 5.2). Bradykinin plays a key role in most non-allergic angioedemas. In clinical routine bradykinin-dependent angioedemas occur most frequently upon consumption of ACEI. With around seven million users in Germany alone, an incidence of about 0.5 % or several ten thousand angioedemas per year is to be expected. Since, in contrast to HAE an-

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5 Acute Phase Proteins in Kinin-Induced Angioedema

Table 5.1

Classification of non-allergic angioedema.

Non-allergic angioedema IAE (idiopathic)

PAE (pseudoallergic)

RAE (RAAS blocker)

HAE (hereditary)

AAE (acquired)

?

Drugs

Drugs

C1-INH defect

lymphoma

– Aspirin

– ACE inhibitors

Bradykinin

Bradykinin

– AT-1 blocker ?

Leukotriene

Bradykinin

Table 5.2 Classification of bradykinin-dependent angioedema. Kinin-induced angioedema

Table 5.3 Estimated ratio of manifestation of ACE inhibitor-induced angioedema. ACE inhibitor-induced angioedema

No allergy RAE

HAE

AAE

Estimated ratio on the basis of literature data

Drugs

C1 INH defect

Lymphoma

– ACE inhibitor

100

:1

:?

Upper airway/ throat

abdominal

skin (trunk/ extremities)

– AT-1 blocker Bradykinin degradation disorder

Bradykinin synthesis disorder

gioedema, ACEI angioedemas occur almost exclusively in the head and neck region, a life-threatening danger due to attack on the upper airway must be taken into consideration (Table 5.3 and Fig. 5.1).

The Role of Bradykinin in Non-Allergic Angioedema The major vascular action of bradykinin occurs through the bradykinin B2 receptors of endothelial cells. In this process, bradykinin induces vasodilatation by way of the NO signalling pathway and is able to change the permeability of capillaries (capillary leakage). Thus, bradykinin appears to play a decisive role in the development of many angioedemas [1, 2]. However, it remains unclear why the increases of the bradykinin plasma level – that affect the estimated 7 million patients (in Germany alone) under ACE inhibitor therapy – lead only to few angioedemas. Also in the cases of HAE patients the concentration of functional C1-INH does not determine the frequency and severity of angioedemas. These observations show that further factors besides bradykinin must be present for the development of kinin-induced angioedemas, and that they must at least have a triggering function. In particu-

lar in the case of ACEI angioedemas the fundamental pathomechanisms have not yet been clarified. ACEI angioedemas can occur as the early onset form directly in the first two weeks after initiation of the drug or, in part, after many years of inconspicuous consumption of the drug (late onset). According to our evaluations angioedemas occur on average three years after initiation of the drug therapy with one patient developing an angioedema after 11 years of consumption of the drug. The ACE inhibitor must be discontinued and replaced by another antihypertensive agent otherwise recurrences can occur [3]. Our own observations and clinical case reports indicate that the angiotensin I receptor blocker (AT-I receptor blocker = sartan) cannot be automatically considered as the first choice substitute antihypertensive agent. Patients who have suffered from an angioedema after taking an ACE inhibitor are at risk for developing a sartan-induced angioedema [4, 5]. Larger case control studies with ACE inhibitors and sartans have revealed that sartans also exhibit a not inconsiderable angioedema rate (0.3 %) [6]. The exact mechanisms are still unexplored but first findings are indicative of a possible connection with bradykinin [7]. According to a study by Campbell et al. losartan also causes an increase in the plasma bradykinin level. Conclusive, clarifying investigations are,

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Acute Phase Proteins in Bradykinin-Induced Angioedema

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Fig. 5.1 a, b a Female patient with an ACE inhibitor-induced angioedema of the tongue. b Angioedema in the region of the base of the tongue and larynx.

however, necessary to determine finally the pathomechanisms. Out-patients were given amlodipin as substitute antihypertensive agent and no recurrence has developed in an observation period of up to five years.

Acute Phase Proteins in Bradykinin-Induced Angioedema Our studies revealed that patients (n = 24) with an acute ACE inhibitor-induced angioedema had markedly higher plasma concentrations of the acute phase proteins – C-reactive protein (CRP 4.4 mg/dL) and fibrinogen (476 mg/dL) – during the edema [8]. Control investigations after disappearance of the edema showed a return of both proteins to normal levels. These observations let us assume that acute phase proteins participate in the development of kinin-induced angioedema and are not merely unspecific markers. It is also known from clinical routine that heavy physical work, operations, infections and even some endoscopic investigations (esophagogastroduodenoscopy) can provoke an episode of angioedema. In all of the above-mentioned, accompanying conditions one can observe an elevation of inflammatory factors. In part, some patients with a predisposition for angioedema such as, e.g., HAE patients, are given prophylactic C1-INH concentrate prior to the planned operation.

We have performed experimental studies for clarification of the role of acute phase proteins in the pathophysiology of kinin-induced angioedema. For this purpose we checked the functional properties of the two acute phase proteins on porcine coronary vessels and human arteries (internal mammary artery) and veins (great saphenous vein) in organ bath experiments. Our major results as yet are, firstly, that both active phase proteins are themselves functionally active and induced vasodilatations in a concentration-dependent manner. The vasodilatative properties of fibrinogens were strongest at, in particular, 450 mg/dL, just the plasma concentration that our angioedema patients exhibited during the acute angioedema. Secondly, we have found that both proteins are able to significantly (10-fold) reinforce the vascular properties of bradykinins [9]. The complete clarification of the signaling pathways involved in this process has not yet been achieved and is still the subject of ongoing experimental work. Further inflammatory factors such as thrombin and tumor necrosis factor a also appear to be able to influence endothelial permeability [10,11] and, in part, even have a synergistic effect. The vascular permeability-increasing effects of thrombin are assumed to proceed via proteinase-activating receptors (PAR) and lead to an intracellular calcium increase [11]. These experimental results in combination with clinical observations are suggestive of a tight relationship between inflammation and angioedema. Inflammatory factors can, on the one hand, them-

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5 Acute Phase Proteins in Kinin-Induced Angioedema

selves change the endothelial permeability and, on the other hand as we have observed, reinforce the vascular action of bradykinin. Accordingly, the development of an angioedema is presumably a multicausal phenomenon in which a series of factors must act together. An elevated plasma bradykinin concentration alone is not sufficient to trigger an angioedema. However, when further factors such as acute phase proteins and presumably cytokines [12,13] are present, several conditions for the development are simultaneously at hand. A much more comprehensive review on the topic non-allergic angioedema has been published recently [14].

Conclusion The development of an angioedema is a multifactorial process. Inflammatory factors act normally as a trigger in the development of an angioedema. New results on the close relationship between inflammation and angioedema may find use as a foundation for new therapeutic concepts.

References 1 Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angiooedema. Lancet 1998; 351: 1693 – 1697 2 Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med 2002; 347: 621 – 622 3 Bas M, Kojda G, Bier H, Hoffmann TK. Durch ACEHemmer induziertes Angioödem des Kopf-Hals-Bereichs. Eine Frage der Zeit? HNO 2004; 52: 886 – 890. 4 Bas M, Kojda G. Angioödem nach Einnahme von Irbesartan [Angioedema induced by irbesartan]. Apothekenmagazin 2005; 23: 254 – 255 5 Hellebrand MC, Kojda G, Hoffmann TK, Bas M. [Angioedema due to ACE inhibitors and AT(1) receptor antagonists]. Hautarzt 2006; 57: 808 – 810 6 Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de WF, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349: 1893 – 1906 7 Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation 2005; 111: 315 – 320 8 Bas M, Hoffmann TK, Bier H, Kojda G. Increased C-reactive protein in ACE-inhibitor-induced angioedema. Br J Clin Pharmacol 2005; 59: 233 – 238 9 Bas M, Kirchhartz N, Hochfeld J, Tüllmann C, Kumpf S, Suvorava T, Oppermann M, Hafner D, Bier H, Hoffmann TK, Balz V, Kojda G. Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema. J Allergy Clin Immunol 2008; 121: 969 – 972 10 Seybold J, Thomas D, Witzenrath M, Boral S, Hocke AC, Burger A, Hatzelmann A, Tenor H, Schudt C, Krull M, Schutte H, Hippenstiel S, Suttorp N. Tumor necrosis factor-{alpha}-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability. Blood 2005; 105: 3569 – 3576 11 Tiruppathi C, Naqvi T, Sandoval R, Mehta D, Malik AB. Synergistic effects of tumor necrosis factor-{alpha} and thrombin in increasing endothelial permeability. Am J Physiol Lung Cell Mol Physiol 2001; 281: L958 – L968 12 Banerji A, Weller PF, Sheikh J. Cytokine-associated angioedema syndromes including episodic angioedema with eosinophilia (Gleich’s Syndrome). Immunol Allergy Clin North Am 2006; 26: 769 – 781 13 Mizukawa Y, Shiohara T: The cytokine profile in a transient variant of angioedema with eosinophilia. Br J Dermatol 2001; 144: 169 – 174 14 Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G. Nonallergic angioedema: role of bradykinin. Allergy 2007; 62: 842 – 856

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6

Bradykinin and the Kallikrein-Kinin System: Kallikreins, Bradykinin and Vascular Signal Transduction V. Adams Universität Leipzig, Herzzentrum Leipzig, Leipzig, Germany

Abstract Bradykinin is a protein belonging to the group of kinins. It is a vasoactive oligopeptide composed of nine amino acids with an activity similar to that of histamine. As a result of its specific binding to receptors in the vascular endothelium, it causes a change in tone of the smooth musculature and increases the permeability of the vessels. Kinin receptors are cell surface receptors and belong to the family of the G-protein-coupled “seven-transmembrane” receptors. Two receptor subtypes (BKR-1 and BKR-2) have been described on the basis of their pharmacological properties as well as by expression cloning. The human gene for BKR-2 is found on chromosome 14q32 whereas theBKR-1 gene has been mapped to chromosome 14q32.1-q32.2. The BK1 receptor is synthesized de novo in many organs after tissue damage whereas, in contrast, BKR-2 exists constitutively in numerous tissues. Bradykinin is one of the most potent vasodilators and is able to liberate the most important vasodilators from the endothelium – NO, prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor (EDHF). At the level of endothelial cells it is generally accepted that the binding of bradykinin to BKR-2 activates intracellularly phospholipase C, resulting in the increased formation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). As a consequence of the elevated IP3 formation, calcium is liberated from intracellular stores, leading to an elevated intracellular calcium concentration which, in turn, activates endothelial NO syn+ + thase. The elevated Ca2 concentration also leads to an activation of Ca2 -sensitive phospholipase A2 which, in turn, hydrolyzes membrane phospholipids, thereby liberating arachidonic acid which is the rate-determining step in the biosynthesis of prostacyclin.

The Kallikrein-Kinin System The discovery of the kallikrein-kinin system dates back to work done in 1909 when Abelous and Bardier were able to determine a hypotensive effect of urine [1]. Kinins are pharmacologically active peptides formed from kininogenes by an enzymatic reaction of kallikreins [2]. The prototype of the kinins is bradykinin (BK), an oligopeptide composed of nine amino acids. In addition, there are amino terminal-lengthened forms of bradykinin such as kallidin (Lys-BK) or T-kinin (Ile-Ser-BK), that also occur physiologically (Fig. 6.1). Kinins are typically liberated locally, either by tissue kallikreins that are expressed in specific tissues [3, 4, 5, 6] or by plasma kallikreins which occur, above all, in the blood vessels. Tissue kallikrein (EC 3.4.21.35) is coded by the gene KLK1 which is localized in the human system on chromosome 19q13.2-13-4 and in the mouse on chromosome 7 [7]. From the evolutionary point of view, kinins exhibit extraordi-

narily conserved sequences and are found with only minor modification in all the large classes of vertebrates. This system is of eminent importance in the cardiovascular region since it is known from numerous investigations that there is an interaction between the renin-angiotensin-aldosterone system (RAAS) and the kallikrein-kinin system. The functional interaction between the systems is based on the ability of angiotensin-converting enzyme (ACE) to generate angiotensin II from the precursor angiotensin I as well as to degrade kinins, especially bradykinin, into inactive peptides [8].

Kinin Receptors The effects of many biologically important substances such as, e.g., peptide hormones are typically mediated by binding to specific surface receptors. This is also true for the kinins which bind to

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6 Bradykinin and the Kallikrein-Kinin System

Kallikreins (tissue and plasma kallikreins) Kininogens (HMW/LMW)

Signal Transduction Kinases

Kinins

Peptides (inactive)

Kinin receptors

Psychological action

Fig. 6.1 Schematic summary of the kallikrein-kinin system.

specific kinin receptors that are expressed on numerous types of cell in various organs [9]. Kinin receptors are G-protein-coupled receptors and belong to the family of “seven-transmembrane” receptors. Pharmacological investigations [10,11, 12,13] as well as expression cloning studies [14,15,16] have now led to the identification of two different receptors for the most important kinin, bradykinin. Chromosomal mapping identified the localization of bradykinin receptor 1 (BKR-1) on chromosome 14q32 [17] and of bradykinin receptor 2 (BKR-2) on chromosome 14q32.1-q32.2 [18]. The human BKR-2 gene consists of 3 exons whereby the gene product consisting of 391 amino acids is only coded by exon 3 [19, 20]. Furthermore, the two bradykinin receptors also differ in their level of expression on the cell surface. BKR-1 is normally not constitutively expressed on cells, but is rather first synthesized in a sufficient amount after tissue damage [21, 22]. In contrast, BKR-2 is constitutively expressed in numerous types of tissue [23] but occurs mainly on endothelial cells, smooth musculature, fibroblasts, mesangial cells, some neurons, astrocytes and multinuclear neutrophils [24]. The homology at the amino acid level between the two receptor types amounts to 36% [16]. In addition to the pharmacological differences between BKR-1 and BKR-2, the receptors also differ with regard to a desensitization. After binding of an agonist to BKR-2 it is very rapidly desensitized through Ser and Tyr phosphorylation steps [25]. This holds for BKR-1 only to a very limited extent and agonist-mediated phosphorylation has not yet been detected [26].

As described above, the bradykinin receptors belong to the class of G-protein-coupled receptors. When bradykinin binds to BKR-2, phospholipase C (PLC) is activated through a coupling with various G-proteins (Ga, Gi). The activated PLC, in turn, cleaves diacylglycerol (DAG) and inositol triphosphate (IP3) from phospholipids. IP3 acts as a second messenger for, on the one hand, the liberation of Ca2+ from the endoplasmatic reticulum and, on the other hand, the activation of phospholipase A2 (PLA2) through a protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathway. The activated PLA2 finally releases arachidonic acid. This represents the rate-limiting step of prostacyclin synthesis. On the other side, the elevated liberation from internal stores leads to an activation of the Ca2+-sensitive, endothelial NO synthase (ecNOS) and elevated amounts of NO are produced. These two mechanisms (prostaglandin synthesis and elevated amounts of NO) finally lead to the relaxation of the vessels (Fig. 6.2). Besides the above-described signal transduction via IP3 activation, other pathways that lead to a bradykinin-induced increase of eNOS activity have been described in the literature. In endothelial cells bradykinin also activates the components of the JAK/STAT signalling pathway localized in caveolae [27]. Here, tyrosine kinases phosphorylate the STAT proteins of the JAK family which, in turn, specifically regulate the transcription of certain genes. In addition, Bae and co-workers have detected, in cell culture experiments on bovine aortic endothelial cells, a protein kinase A-dependent, bradykinin-induced phosphorylation and activation of endothelial NO synthase [28].

Animal Models with Participation of the Kallikrein-Kinin Systems In the current literature three different mouse models have been described by means of which the physiological significance of bradykinin and the kallikrein-kinin system can be investigated (Fig. 6.3). The first model was described by Chao and coworkers in 1996; which involves a transgenic mouse that expresses tissue kallikrein either under the influence of an albumin or a metallothionin promotor [22]. These animals secrete kallikrein in

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Animal Models with Participation of the Kallikrein-Kinin Systems

25

Fig. 6.2 Schematic summary of the signal transduction of bradykinin in endothelial cells.

Bradykinin Arg Prol Pro Gly Phe Ser Pro Phe Arg Ca2+ Endothelial cells

JAK P STAT3

Ga PLC

BKR-2

ER

Ga Ca2+

DAG IP3

EDHF

Hyperpolarization

Smooth muscle cells

PLA2

eNOS

PGI2

NO·

NO·

AC ATP cAMP ­

sGC GTP cGMP ­

Animal model in which the BK system is altered Overexpression of kallikrein

C1-INH knock-out

Unspecific overexpression B2

Reduced blood pressure treatable with Hoe-140

Capillary hyperpermeability no information on blood pressure

Reduced blood pressure, uterine contractility

Fig. 6.3 Summary of the animal models that display an attack on the kallikreinkinin system.

No spontaneous or iatrogenic angioedema!

the plasma and exhibit a 10- to 40-fold elevated concentration. These mice were chronically hypotensive, but this could be eliminated by treating the animals either with aprotinin, a specific inhibitor of tissue kallikrein, or with Hoe-140, a specific BKR-2 blocker. This was the first indication in vivo that an increased production of bradykinin and its action via BKR-2 led to reduced blood pressure. Another animal model was described in 1997 by Wang and co-workers [28]. In this model BKR2 was overexpressed unspecifically in all tissues under the control of an RSV promotor. As expected,

these animals also exhibited a significant reduction in blood pressures as compared to healthy, wild-type animals. As in the previous animal model, the reduced blood pressure could be treated by administration of Hoe-140. This model also supports the finding that the overexpression of BKR-2 and its signal transduction participate in the regulation of blood pressure. The third model to be described in the current literature makes use of the observation that the deletion of C1-INH is associated with the development of hereditary angioedema. From a phenotyp-

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6 Bradykinin and the Kallikrein-Kinin System

ical point of view, the C1-INH knock-out animals do not exhibit any conspicuous abnormalities [29]. However, after injection of Evans’ blue, a technique by which the permeability of vessels can be examined, the authors detected that the knock-out animals exhibited an elevated vascular permeability. This increase in permeability could be eliminated by administration of the kallikrein inhibitor DX-88 or the BKR-2 antagonist Hoe-140. When mice deficient for both C1-INH and BKR-2 were generated the elevated vascular permeability could no longer be detected. In summary, this C1INH KO model shows that bradykinin can probably participate in the development of angioedema via BKR-2. Common to all three animal models is that they all attack the kallikrein-kinin system and all lead to an elevated signal transduction via BKR-2 by widely differing mechanisms. Furthermore, all animals did not exhibit, as would actually be expected, a phenotypically visible angioedema. Thus, the question as to the reason for the non-occurrence of angioedema must be addressed. One possible explanation would be, for example, that the elevated bradykinin activity in these animal models is essential but not sufficient for the development of an angioedema. However, there are no current data to support this hypothesis. A further possible explanation would be that all animals generated to date exhibit a ubiquitous elevation of the kallikrein-kinin system. Thus, it is possible that the local concentration at the vessel wall is not high enough to favor the development of angioedema. To address this question one would have to generate a transgenic animal model in which bradykinin or also BKR-2 would be expressed under the control of an endothelium-specific promotor. In this way we would be able to confirm that the factors are highly and locally overexpressed in the endothelium, the target organ. However, such animals are not yet available. The establishment of an animal model that develops an isolated angioedema would be of major importance for research since one would then be able to demonstrate the pathophysiology and establish therapeutic concepts with such a model.

References 1 Abelous J, Bardier E. Les substances hypotensives de l’urine humaine normale. CR Soc Biol 1909; 66: 511 – 512 2 Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F, Adam A. The kallikrein-kinin system: Current and future pharmacological target. J Pharmacol Sci 2005; 99: 6 – 38 3 Britos J, Nolly H. Kinin-forming enzyme of rat cardiac tissue. Subcellular distribution and biochemical properties. Hypertension 1981; 3: II-5 4 Sharma JN, Kesavarao U. Cardiac kallikrein in hypertensive and normotensive rats with and without diabetes. Immunopharmacology 1996; 33: 341 – 333 5 Sharma JN, Uma K, Yusof AP. Left ventricular hypertrophy and its relation to the cardiac kinin-forming system in hypertensive and diabetic rats. Int J Cardiol 1998; 63: 229 – 235 6 Nustad K, Vaaje K, Pierce JV. Synthesis of kallikreins by rat kidney slices. Br J Pharmacol 1975; 53: 229 – 234 7 Clements J, Hooper J, Dong Y, Harvey T. The expanded human kallikrein (KLK) gene family: genomic organisation, tissue-specific expression and potential functions. Biol Chem 2001; 382: 5 – 14 8 Fleming I. Signaling by the angiotensin-converting enzyme. Circ Res. 2006; 98: 887 – 896 9 Howl J, Payne SJ. Bradykinin receptors as a therapeutic target. Expert Opin Ther Targets. 2003; 7: 277 – 285 10 Regoli D, Barabe J. Pharmacology of bradykinin and related kinins. Pharmacol Rev 1980; 32: 1 – 46 11 Regoli D, Rhaleb NE, Drapeau G, Dion S. Kinin receptor subtypes. J Cardiovasc Pharmacol 1990; 15 (Suppl. 6): S30 – S38 12 Vavrek RJ, Stewart JM. Competitive antagonists of bradykinin. Peptides 1985; 6: 161 – 164 13 McEachern AE, Shelton ER, Bhakta S, Obernolte R, Bach C, Zuppan P et al. Expression cloning of a rat B2 bradykinin receptor. Proc Natl Acad Sci USA 1991; 88: 7724 – 7728 14 Roberts RA. Bradykinin receptors: characterization, distribution and mechanisms of signal transduction. Prog Growth Factor Res 1989; 1: 237 – 252 15 Hess JF, Borkowski JA, Young GS, Strader CD, Ransom RW. Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor. Biochem Biophys Res Commun 1992; 184: 260 – 268 16 Menke JG, Borkowski JA, Bierilo KK, MacNeil T, Derrick AW, Schneck KA et al. Expression cloning of a human B1 bradykinin receptor. J Biol Chem 1994; 269: 21583 – 21586 17 Ma JX, Wang DZ, Ward DC, Chen L, Dessai T, Chao J et al. Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor. Genomics 1994; 23: 362 – 369

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References 18 Chai KX, Ni A, Wang D, Ward DC, Chao J, Chao L. Genomic DNA sequence, expression, and chromosomal localization of the human B1 bradykinin receptor gene BDKRB1. Genomics 1996; 31: 51 – 57 19 Bachvarov DR, Hess JF, Menke JG, Larrivee JF, Marceau F. Structure and genomic organization of the human B1 receptor gene from kinins (BDKRB1). Genomics 1996; 33: 374 – 381 20 Yang X, Polgar P. Genomic structure of the bradykinin B1 receptor gene and preliminary characterization of ist regulatory regions. Bicochem Biophys Res Commun 1996; 222: 718 – 725 21 Regoli DC, Marceau F, Lavigne J. Induction of beta 1receptors for kinins in the rabbit by a bacterial lipopolysaccharide. Eur J Pharmacol 1981; 71: 105 – 115 22 Chao J, Chao L. Functional analysis of human tissue kallikrein in transgenic mouse models. Hypertension 1996; 27: 491 – 494 23 Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992; 44: 1 – 80 24 Couture R, Harrison M, Vianna RM, Cloutier F. Kinin receptors in pain and inflammation. Eur J Pharmacol 2001; 429: 161 – 176 25 Faussner A, Proud D, Town M, Bathon JM. Influence of the cytosolic carboxyl termini of human B1 and B2 kinin receptors on receptor sequestration, ligand internalisation, and signal transduction. J Biol Chem 1998; 273: 2617 – 2623 26 Blaukat A, Pizard A, Rajerison RM, Alhenc-Gelas F, Müller-Esterl W, Dickie I. Activation of mitogen activated protein kinase by bradykinin B2 receptor is independent of receptor phosphorylation and phosphorylation-triggered internalisation. FEBS Lett 1999; 451: 337 – 341

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27 Ju H, Venema VJ, Liang H, Harris MB, Zou R, Venema RC. Bradykinin activates the Janus-activated kinase/ signal transducers and activators of transcription (JAK/STAT) pathway in vascular endothelial cells: localization of JAK/STAT signalling proteins in plasmalemmal caveolae. Biochem J 2000; 351: 257 – 264 28 Bae SW, Kim HS, Cha YN, Park YS, Jo SA, Jo I. Rapid increase in endothelial nitric oxide production by bradykinin is mediated by protein kinase A signaling pathway. Biochem Biophys Res Commun 2003; 306: 981 – 987 29 Wang DZ, Chao L, Chao J. Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. Hypertension 1997; 29: 488 – 493 30 Han ED, MacFarlane RC, Mulligan AN, Scafidi J, Davis AE, III. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002; 109: 1057 – 1063 31 Yang HY, Erdos EG, Levin Y. A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta 1970; 214: 374 – 376 32 Yang HY, Erdos EG, Levin Y. Characterization of a dipeptide hydrolase (kininase II: angiotensin I converting enzyme). J Pharmacol Exp Ther 1971; 177: 291 – 300

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7

Drugs Affecting the Kallikrein-Kinin System B. Rosenkranz1, W. Fan2, J. Zimmermann2 1

2

corresponding author: Department of Medicine, Division of Pharmacology, University of Stellenbosch, Cape Town, South Africa Jerini AG, Berlin, Germany

Abstract The kallikrein-kinin system is an endogenous metabolic cascade responsible for the production of vasoactive kinins such as bradykinin. Pharmacologically active kinins are implicated in many physiological and pathological processes, such as vasodilation, vascular permeability, inflammation, pain perception and cardioprotection. Bradykinin is the end product of the plasma kallikrein-kinin cascade. Bradykinin is efficiently metabolized by endogenous metalloproteases, namely angiotensin converting enzyme (ACE), carboxypeptidase N (CPN) and aminopeptidase P (APP). The rate of metabolism is rapid, and bradykinin in vivo has a plasma half-life of less than 1 minute. Bradykinin is cleaved by CPN at the C-terminal peptide bond to form des-Arg9-bradykinin, an agonist of the bradykinin type 1 receptor. In contrast, native bradykinin is an agonist of both the bradykinin type 1 and type 2 receptors. Drugs that affect the kallikrein-kinin system may do so either by affecting the production or metabolism of bradykinin, or by interfering with the binding of bradykinin to the bradykinin type 2 receptor. The (clinical) pharmacology of 4 drugs which act as antagonists of the kallikrein-kinin system is discussed. Two of these, aprotinin and DX-88/ecallantide, inhibit the production of bradykinin by functioning as kallikrein antagonists. In contrast, ACE inhibitors increase bradykinin concentrations by blocking its metabolism. Finally, icatibant, a potent, selective and specific bradykinin type 2 receptor antagonist, has found a role in the treatment of bradykinin-mediated hereditary angioedema by blocking the pathophysiological responses arising from an elevation in bradykinin levels in these patients.

The Kallikrein-Kinin System The existence of the kallikrein-kinin system was first described by Abelous and Bardier in 1909, when they showed the hypotensive effect of urine [1]. In the 1920s and 1930s, Frey, Kraut and Werle isolated the hypotensive substance in urine, and found a similar substance in saliva, plasma and a variety of tissues [2]. Since then, the kallikrein-kinin system has been the subject of intensive research, and has subsequently been shown to play an important role in both physiological and pathological processes, including: bronchoconstriction [3], pain perception [4], inflammation [5], and vascular permeability [6]. The kallikrein-kinin system is activated by a number of stimuli such as tissue damage, allergic reactions, viral infections, and other inflammatory events. These events trigger the activation of a proteolytic cascade whose end result is the production

of kinins. Components of the kallikrein-kinin system include factor XII (Hageman factor) of the contact system, high and low molecular weight kininogens (HMWK and LMWK, respectively), kallikrein and its precursor prekallikrein, and kinins, consisting of bradykinin, kallidin and methionyl-lysylbradykinin. The initiation of bradykinin production has been reported to begin with contact of plasma with a negatively charged surface, resulting in the binding and autoactivation of factor XII to factor XII a [7]. However, it should be noted that the relevance of this mechanism in vivo remains unclear, since no such surface could be identified. Kallikrein, a serine protease, circulates in the plasma in its inactive form prekallikrein, which is 80 – 90 % complexed to HMWK [8]. Factor XII a cleaves prekallikrein, thereby forming active kallikrein which, in turn, cleaves HMWK to liberate the nonapeptide hormone bradykinin [9]. Indeed, many of the physiological effects associated with

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Antagonists of the Kallikrein-Kinin System

Toxins, injury, inflammation, ischemia, viral infections, etc. Prekallikrein Factor XIIa

Aprotinin DX-88 ACE

Kallikrein

C1-INH HMW-Kininogen

Bradykinin

ACE Inhibitors des8,9-Bradykinin inactive

Icatibant

29

Fig. 7.1 Antagonists of the kallikrein-kinin system. Endogenous C1-INH inhibits the serine proteases factor XII a and kallikrein; ACE inhibitors block the bradykinin-metabolizing activity of ACE; kallikrein function is inhibited by aprotinin and DX-88; icatibant inhibits bradykinin activity by displacing the native peptide at the B2 receptors.

Microvascular leakage, vasodilatation, pain

the kallikrein-kinin system are achieved through the action of bradykinin at one of its two receptors, the bradykinin type 1 and type 2 receptors (BK1 and BK2 receptors, respectively) [10].

Antagonists of the Kallikrein-Kinin System The multiplicity of pharmacological activities and physiological functions of the kallikrein-kinin system make it a complex, but nonetheless promising target for the development of therapeutic agents. Here we discuss the clinical applications of four agents that target various components of this system: angiotensin-converting enzyme (ACE) inhibitors; the kallikrein inhibitors, aprotinin and DX-88 (ecallantide); and the BK2 receptor antagonist, icatibant (Firazyr®). ACE inhibitors have emerged as first-line therapy in a wide range of cardiovascular and renal disorders. By inhibiting the activity of ACE, ACE inhibitors block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and growth promoter. More recently, however, the role of ACE in the metabolism of bradykinin has been examined. Studies using the specific BK2 receptor inhibitor, icatibant, demonstrate that bradykinin antagonism attenuates the antihypertensive effects of ACE inhibitors under acute administration [11], but not when both drugs are given concurrently under chronic ACE inhibitor administration [12]. Furthermore, the observation that 0.1 – 0.7 % of patients treated with ACE inhibitors experience a bradykinin-mediated form of angioedema supports a

presumptive role for bradykinin in mediating this clinically relevant side effect of ACE inhibitors [13]. Aprotinin is a 58 amino acid serpin isolated from bovine lung that inhibits several mediators of the inflammatory response, fibrinolysis, and thrombin generation. While aprotinin shows a particularly high affinity for kallikrein [14], the inhibition of plasmin and other coagulation factors is likely responsible for its effectiveness in the prevention of excessive bleeding. As such, aprotinin is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft (CABG) surgery. Aprotinin administration has been associated with some serious risks, namely fatal anaphylactic/anaphylactoid reactions and renal dysfunction. In October 2007, the BART study (Blood Conservation using Antifibrinolytics: A Randomized Trial in High-Risk Cardiac Surgery Patients), an independent, multi-institutional, blinded, randomized, controlled trial comparing the efficacy and safety of aprotinin, aminocaproic acid and tranexamic acid in approximately 3000 highrisk patients undergoing cardiac surgery, was stopped after preliminary analysis suggested a trend toward an increase in all-cause 30-day mortality associated with aprotinin [15]. Hereditary angioedema (HAE) is a genetic disorder characterized by a reduction in C1-esterase inhibitor (C1-INH) activity, an important negative regulator of the kallikrein-kinin system. C1-INH deficiency results in an elevation in factor XII and kallikrein activity, ultimately leading to the overproduction of bradykinin. There is now sufficient

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7 Drugs Affecting the Kallikrein-Kinin System

evidence that bradykinin is the key mediator of symptoms of HAE [6, 22]. HAE patients exhibit a two- to twelve-fold increase in bradykinin levels during attacks [20, 21, 23]. Since bradykinin is an important mediator of microvascular leakage, this can explain the edema formation during HAE attacks. Key symptoms of acute HAE attacks are cutaneous swelling, submucosal swelling in the gastrointestinal tract leading to abdominal pain, nausea and vomiting, and laryngeal edema which potentially may be life-threatening. Two new compounds, DX-88 and icatibant, were designed for the treatment of HAE. The kallikrein inhibitor, DX-88, is a 60 amino acid recombinant peptide based on the first Kunitz domain of human lipoprotein-associated coagulation inhibitor, representing the reactive site of aprotinin [16]. In three phase II clinical trials (EDEMA0, EDEMA1 and EDEMA2), all types of HAE attacks were successfully treated with either intravenous or subcutaneous administration of DX-88 [17,18]. DX-88 has completed two phase III clinical trials (EDEMA3 & 4). which have shown DX-88 to be superior to placebo. Although DX-88 has thus far shown promising results in the treatment of HAE attacks, reports of serious drug-related adverse events have raised concerns about its safety and tolerability [19]. Icatibant is a synthetic decapeptide with a similar structure to bradykinin. It contains five nonproteinogenic amino acids, which stabilize the compound by conferring it resistance to degradation by the two main bradykinin-cleaving enzymes, carboxypeptidase and ACE. It is a selective and specific antagonist of the BK2 receptors, and does not interact with BK1 receptors or with receptors of other peptides (e. g., angiotensin II, substance P and neurokinin A). Several lines of evidence support bradykinin as the key mediator for HAE-associated vasodilation and increased vascular permeability. Namely, increased vascular permeability characteristic of C1-INH knockout mice can be reversed by icatibant [6]. Furthermore, icatibant is able to inhibit bradykinin-induced vasodilation in humans. Hence, blocking BK2 receptors on endothelial cells represents a logical approach to the treatment of HAE. Icatibant was assessed in phase II and phase III trials for the treatment of acute attacks of HAE (type I & II) where it proved to be safe and effective (see Chapter 10).

References 1 Abelous J, Bardier E. Les substances hypotensives de l’urine humaine normale. Comptes rendus des séances de la Société de Biologie et de ses filiales/ Centre National de la Recherche Scientifique 1909; 66: 511 – 512 2 Werle E. Discovery of the most important kallikreins and kallikrein inhibitors. In: Bradykinin, Kallidin and Kallikrein. [Handbuch der Experimentellen Pharmakologie], Vol. 25, Erdos EG, ed. Berlin: Springer Verlag; 1970: 1 – 6 3 Fuller RW, Dixon CM, Cuss FM, Barnes PJ. Bradykinin-induced bronchoconstriction in humans. Mode of action. Am Rev Respir Dis 1987; 135: 176 – 180 4 Geppetti P. 1993. Sensory neuropeptide release by bradykinin: mechanisms and pathophysiological implications. Regul Pept 1993; 47: 1 – 23 5 Dray A, Perkins M. 1993. Bradykinin and inflammatory pain. Trends Neurosci 1993; 16: 99 – 104 6 Han ED, MacFarlane RC, Mulligan AN, Scafidi J, Davis AE, 3rd. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002; 109: 1057 – 1063 7 Kaplan AP, Joseph K, Shibayama Y, Reddigari S, Ghebrehiwet B, Silverberg M. The intrinsic coagulation/ kinin-forming cascade: assembly in plasma and cell surfaces in inflammation. Adv Immunol 1997; 66: 225 – 272 8 Mandle RJ, Colman RW, Kaplan AP. Identification of prekallikrein and high-molecular-weight kininogen as a complex in human plasma. Proc Natl Acad Sci USA 1976; 73: 4179 – 4183 9 Mori K, Sakamoto W, Nagasawa S. Studies on human high molecular weight (HMW) kininogen. III. Cleavage of HMW kininogen by the action of human salivary kallikrein. J Biochem 1981; 90: 503 – 509 10 Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL. International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2005; 57: 27 – 77 11 Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998; 339: 1285 – 1292 12 Witherow FN, Helmy A, Webb DJ, Fox KA, Newby DE. Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure. Circulation 2001; 104: 2177 – 2181 13 Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am 2006; 26: 725 – 737 14 Alston TA. Aprotinin. Int Anesthesiol Clin 2004; 42: 81 – 91 15 Kristeller JL, Roslund BP, Stahl RF. Benefits and risks of aprotinin use during cardiac surgery. Pharmacotherapy 2008; 28: 112 – 124

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References 16 Williams A, Baird LG. DX-88 and HAE: a developmental perspective. Transfus Apher Sci 2003; 29: 255 – 258 17 Gonzales-Quevedo T, Caballero T, Cicardi M, Bork K, XXX WA. The synthetic Kunitz domain protein DX88 to treat angioedema in patients with hereditary angioedema. In XIX International Complement Workshop (ICW). Vol. 2. International Complement Society (ICS), Palermo, Italy, 2002, p 1318 18 Lumry W, Ritchie B, Beck T, Morrison J. Interim Results of EDEMA2, a multicenter, open-label, repeatdosing study of intravenous and subcutaneous administration of ecallantide (DX-88) in hereditary angioedema. In AAAAI 62nd Annual Meeting. Vol. 117. American Academy of Allergy, Asthma and Immunology, Miami Beach, Florida, 2006: S179 19 Caballero T, C. Lopez-Serrano C. 2006. Anaphylactic reaction and antibodies to DX-88 (kallikrein inhibitor) in a patient with hereditary angioedema. J Allergy Clin Immunol 2006; 117: 476 – 477; discussion 477

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20 Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. 1998. Plasma bradykinin in angio-oedema. Lancet 1998; 351: 1693 – 1697 21 Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol 2007; 119(6): 1497 – 1503 22 Cugno M, Nussberger J, Cicardi M, Agostoni A. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003; 3: 311 – 317 23 Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med 2002; 347: 621 – 622

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8

RAAS Blocker and Bradykinin Metabolism: The Role of Bradykinin for Clinical Efficacy P. Gohlke Institut für Pharmakologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany

Abstract Various peptide systems control blood pressure and cardiovascular functions. The kallikrein-kinin system with its effector peptide bradykinin functionally antagonizes the action of the renin-angiotensin system. This functional coupling of the two peptide systems is illustrated by the action of angiotensin-converting enzyme (ACE), that is responsible for the formation of angiotensin II (ANG II) and simultaneously also for the degradation of bradykinin. Accordingly, the formation of ANG II and the degradation of bradykinin are reduced after blockade of ACE by ACE inhibitors. On the basis of clinical studies it is very difficult to distinguish which effects of ACE inhibitors are mediated via ANG II blockade and which by bradykinin potentiation. In contrast, a participation of bradykinin in the cardiovascular actions of ACE inhibitors has been well established by animal experiments. Bradykinin is a potent vasodilatator, inhibits the growth of smooth muscle cells and takes part in anti-thrombotic, pro-fibrinolytic and anti-atherosclerotic processes. These effects of bradykinin are predominately mediated via the B2 receptor. Activation of the B2 receptors by bradykinin leads, among others, to the liberation of nitric oxide and prostacyclin from vascular endothelium. AT1 receptor antagonists inhibit highly selectively the AT1 receptor and almost complete eliminate the action of ANG II on AT1 receptors. As an indirect consequence of AT1 receptor blockade, ANG II, that is elevated by a negative feed-back mechanism, has an increased stimulatory effect on AT2 receptors. In contrast to ACE inhibitors, AT1 receptor antagonists do not directly have an effect on the metabolism of bradykinin. Even so, manifold bradykinin-dependent effects of AT1 receptor antagonists have been described experimentally. A local new synthesis of bradykinin as a result of AT2 receptor activation has been discussed as a mechanism. In conclusion, numerous animal experiments and clinical studies have given support for the participation of bradykinin in the cardioprotective actions of ACE inhibitors and AT1 receptor antagonists.

Introduction In the past two decades angiotensin-converting enzyme (ACE) inhibitors have repeatedly demonstrated their clinical relevance in the treatment of hypertension, cardiac insufficiency, post-infarct status and diabetic nephropathy. Even so, the exact mechanism of action is still not clear. The inhibition of ACE is at the center of discussion (reviewed in [1]). ACE symbolizes the close physiological and pathophysiological relationships between the renin-angiotensin system (RAS) and the kallikreinkinin system (KKS) since it is, on the one hand, essential for the formation of angiotensin II (ANG II) from angiotensin I (ANG I) and, on the other hand, mainly responsible for the inactivation of bradykinin. The physiological activities that ANG II mediates via the AT1 receptor and that bradykinin medi-

ates via the B2 receptor are often antagonistic and the KKS can rightly be considered as the physiological opposite of the RAS (Figs. 8.1 and 8.2). Accordingly, ACE is by no means specific for the formation of ANG II from ANG I but also has a high affinity for a large number of other, biologically active peptides. These include, especially, bradykinin and substance P, which are both inactivated. Thus, ACE simultaneously attacks several hormone systems. This has consequences not only for the therapeutic actions of ACE inhibitors but also for their side effects. Badykinin is at the center of discussion and frequently is held to be responsible for the side effects of ACE inhibitors such as dry cough and angioedema. In the following paragraphs the significance of bradykinin for the clinical action of ACE inhibitors in comparison to the AT1 receptor antagonists will be discussed.

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The Kallikrein-Kinin System

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AT1 receptor-mediated action of angiotensin II

Fig. 8.1

­ Vasoconstriction ­ Sympathic activation ­ Vasopressin ­ Endothelin

­ Growth factors (TGFb, PDGF) ­ Extracellular matrix ­ Myocyte growth

Increased vascular tone

Remodelling (heart & vessels)

­ Aldosterone

­ Na+ retention ­ Vasopressin

Na+ and water retention

­ Superoxide production ­ Plasminogen activator inhibitor-1

Thrombosis Arteriosclerosis

Action of angiotensin II on AT1 receptors.

B2 receptor-mediated actions of bradykinin ­ Nitric oxide ­ Prostacyclin ­ EDHF (Endothelial-derived hyperpolarizing factor) ¯ Endothelin

Reduced vascular tone

Fig. 8.2 Action of bradykinin on B2 receptors.

¯ ¯ ¯ ­

Superoxide production Myocyte growth Thrombocyte aggregation t-PA (Tissueplasminogen activator) ¯ Extracellular matrix

Anti-thrombotic Anti-arteriosclerotic Growth inhibiting

The Kallikrein-Kinin System The peptide family of the kinins includes bradykinin, which is liberated from the high-molecular kininogen by the action of plasma kallikrein, and kallidin (Lys-bradykinin) which is formed from lowmolecular kininogen by tissue kallikrein (review in [2]). Kallidin can be further metabolized to bradykinin (Fig. 8.3). The actions of kinins are mediated by two receptors, the B1 and the B2 receptor. While bradykinin and kallidin are potent agonists at the B2 receptor, des-Arg9-bradykinin and, in particular, des-Arg10-kallidin stimulate the B1 receptor. The B2 receptor, that is constitutively synthesized in various types of cells, including vascular

endothelial cells, mediates the major pharmacological actions of the kinins. One of the most important hemodynamic effects of bradykinin is vasodilatation, caused by stimulation of endothelial B2 receptors in arteries and arterioles, with subsequent endothelial liberation of nitric oxide (NO) or prostacyclin (PGI2) (Fig. 8.2) (review in [3]). Kinins can be considered as local, paracrine/autocrine-acting tissue hormones, i.e., the activity occurs at or in the immediate vicinity of the site of formation. Transport in blood vessels to other sites of action is of little relevance due to the rapid metabolism by kininases. In the vascular system the enzymes localized on the endothelial membrane, ACE (kininase II), carboxypeptidase M (kininase I), aminopeptidase P and the neutral endopeptidase,

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8 RAAS Blocker and Bradykinin Metabolism

Synthesis and degradation of kinins in blood vessels B2 receptor

Normal endothelial cells

Damaged endothelial cells

CPM APP

NEP

ACE

Bradykinin

Inactive peptide fragments

Inactive peptide fragments

APP ACE

Blood plasma Bradykinin

Plasma Kallikrein

APP

Kallidin CPN

CPN des-Arg9-BK

Tissue Kallikrein

des-Arg10-KD CPM Kallidin

HMW Kininogen

LMW Kininogen

B1 receptor

Fig. 8.3 Synthesis and degradation of kinins in blood vessels. B2 receptors are constitutively formed in normal endothelial cells whereas the formation of B1 receptors is initiated after injuries. Bradykinin is formed from high-molecular kininogen (HMW kininogen) out of plasma kallikrein. Tissue kallikrein releases kallidin from the low-molecular kininogen (LMW kininogen), which can be further metabolized via an aminopeptidase to bradykinin. Bradykinin and kallidin can be me-

tabolized by the carboxypeptidases N and M (= kininase II) to the B1 receptor agonists, des-Arg9bradykinin and des-Arg10-kallidin. In blood plasma the kinins are mainly degraded by angiotensin-converting enzyme (ACE) and the aminopeptidase P (APP) to inactive peptide fragments. The major part of kinin inactivation occurs at vascular endothelium by APP, the neutral endopeptidase (NEP) and, especially, ACE.

are responsible for the degradation of bradykinin (Fig. 8.3). In this process ACE plays a decisive role and is responsible for up to 75 % of the bradykinin metabolism in plasma [2].

periments. This was possible through the development of specific B2 receptor antagonists for systematic administration, the breeding of kinindeficient rats as well as the generation of B2 receptor knock-out mice.

ACE Inhibitor and Kinins Besides inhibition of the synthesis of ANG II, the action of bradykinin is reinforced by inhibition of bradykinin degradation and this is considered to be a major element for the activity of ACE inhibitors (Fig. 8.4). In addition, possible direct interactions between ACE inhibitors and the B2 receptor have been discussed [4]. The participation of bradykinin in the mechanism of action of ACE inhibitors has been well documented in animal ex-

Animal Experimental Studies Pharmacological Blockade of B2 Receptors and Studies on B2 Receptor Knock-out Mice Numerous experimental studies have provided indications for the participation of kinins in the organ-protecting activities of ACE inhibitors (review in [2, 3, 5]). The development of the B2 receptor antagonist icatibant represented a breakthrough in kinin research. Earlier studies on rats with renin-

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ACE Inhibitor and Kinins

AT1 Antagonist

ANG I

?

ACE

35

Fragments ACE

+ Bradykinin ­

Angiotensin II ­

+ AT1 receptor AT1 receptormediated AT1 receptor

AT2 receptor

Effects

B2 receptor B2 receptormediated

AT2 receptor

B2 receptor

+ Angiotensin II ¯

ANG I

Bradykinin ­

ACE

ACE ACE Inhibitor

Fragments

Fig. 8.4 Mechanisms of action of AT1 receptor antagonist (top) and ACE inhibitors (bottom). AT1 receptor antagonists inhibit very selectively the AT1 receptor and completely prevent activities mediated via this receptor. Through prevention of the angiotensin IImediated inhibition of renin liberation, the formation of angiotensin II is increased which, via a stimulation of AT2-receptors, can lead to de novo synthesis of

bradykinin and a stimulation of B2 receptor. An intervention in the bradykinin metabolism, e.g., by inhibition of ACE is, in contrast, the subject of dispute. ACE inhibitors inhibit the formation of angiotensin II and suppress AT1 and AT2 receptor-mediated activities. Inhibition of bradykinin degradation leads to a local accumulation of bradykinin and reinforcement of B2mediated effects.

dependent high blood pressure confirmed that the antihypertensive action of ACE inhibitors can be influenced by chronic blockade of the B2 receptors (review in [3]). However, the B2 receptor antagonist did not have any effect on the hypertensive activity of ramipril in kinin-deficient rats. This result supports the hypothesis that a potentiation of the action of bradykinin is involved in the antihypertensive action of ACE inhibitors. Studies with spontaneously hypertensive rats (SHR and SHRSP) have shown that, in genetic high blood pressure, endogenous kinins are of less importance for blood pressure regulation but have a decisive role in the organ-protecting activity of ACE inhibitors. Thus, by chronic treatment of SHRSP with ACE inhibitors it is possible to improve the function and metabolism of the heart and vessels and to increase the capillarization of the heart [6, 7, 8]. The cardiac and vascular protective effects of ACE inhibitors are completely prevented by

chronic blockade of the B2 receptors. Also in rats with myocardial infarction and chronic cardiac insufficiency the protective effects of an ACE inhibitor could be reduced by icatibant [9]. A further indication for the relevance of bradykinin for the cardioprotective actions of ACE inhibitors is the limited cardioprotective response to ACE inhibition in bradykinin B2-knock-out mice [10].

Clinical Studies Changes in the bradykinin concentration in the plasma and urine of patients under ACE inhibitor treatment have not been demonstrated unambiguously. Elevated plasma concentrations of bradykinin after acute and chronic ACE inhibitor treatment were determined, among others, by Nussberger et al. [11] in normal subjects. Through pharmacological blockade of the B2 receptors in

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8 RAAS Blocker and Bradykinin Metabolism

the patients the therapeutic effects of ACE inhibitors could, in part, be prevented. Thus, icatibant reduces the hypotensive effect of captopril [12] and reduces the ACE inhibitor-induced increase of flow-dependent and endothelium-mediated vascular dilatation [13]. These results show that also in humans the accumulation of endogenous kinins in vascular endothelium plays an important role for the therapeutic effects of ACE inhibitors.

AT1 Receptor Antagonists and Bradykinin The mechanism of action of AT1 receptor antagonists can mainly be explained by the specific blockade of the AT1 receptors (review in [14,15]). However, it must be considered that blockade of the AT1 receptors in the kidneys abolishes the feedback mechanism of renin liberation by ANG II. The thus resulting elevation of plasma renin activity leads to an increased formation of ANG II and a potential stimulation of not blocked AT2 receptors (Fig. 8.4). The physiological relevance of the AT2 receptors is still a topic of further research. The fact that these receptors occur in high concentrations in embryonal tissue is indicative of a possible role for cell growth and cell differentiation. Numerous studies in the past few years have suggested that the effects mediated by AT2 receptor act against those of the AT1-receptors (review in [15,16,17]).

Animal Experimental Studies Pharmacological Blockade of B2 Receptors and Studies on AT2 and B2 Receptor Knock-out Mice A relationship between the stimulation of AT2 receptors and the bradykinin-NO system has frequently been demonstrated in experimental studies. Our investigations have confirmed that ANG II increases the NO production in vessel walls and that this effect can be abolished by blockade of the B2 receptors as well as of NO synthase [18]. Similar findings were obtained after overexpression of AT2 receptors in vascular muscle cells [19]. The AT2 receptor-mediated activation of enzymes similar to kallikrein with subsequent formation of bradykinin was postulated as a mechanism [19, 20]. The therapeutic relevance of the AT2 receptor-mediated synthesis of bradykinin in the

treatment of chronic cardiac insufficiency and in acute myocardial ischemia has frequently been established in animal models [9,10, 21]. Besides the formation of NO, the synthesis of PGI2 also plays a particular role in this process. Thus, in pigs with myocardial ischemia a reduction of the infarct size could by achieved by AT1 receptor blockade as well as by blockade of AT2 and B2 receptors and it could also be suppressed by inhibition of cyclooxygenase [21]. In the case of B2 and AT2 receptor knock-out mice with chronic cardiac insufficiency, the absence of bradykinin B2 receptors or, respectively, AT2 receptors prevented the favorable therapeutic effect of an AT1 receptor blockade [22].

Clinical Investigations In patients with hypertension Campbell et al. [23] demonstrated elevated plasma levels of bradykinin after four weeks of treatment with losartan but not after eprosartan. The results of other studies, however, did not support these findings [11, 24]. Similar to the results of an animal model, it appears that the action of bradykinin mediated via AT2 receptor activation is less responsible for the blood pressure-lowering effect of AT1 receptor antagonists and more for the cardiac and vesselprotecting activities. Thus, B2 receptor blockade in patients with coronary heart disease prevents the increase of flow-dependent vessel dilatation by candesartan [25]. In human coronary microarteries vascular constriction by ANG II is further increased by blockade of the AT2 receptors. This is clear evidence for an AT2 receptor-mediated vascular dilatation also in humans [26].

Conclusions Numerous animal experiments as well as an increasing number of clinical studies have shown that the inhibition of bradykinin degradation has a high relevance for the organ-protecting action of ACE inhibitors. Also AT1 receptor antagonists interact indirectly via an activation of AT2 receptors with the bradykinin-NO system. Since AT2 receptors are up-regulated under pathophysiological conditions, this mechanism could contribute to the organ-protecting activities of AT1 receptor antagonist (Fig. 8.4).

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References

References 1 Gohlke P, Schoelkens BA. ACE inhibitors: Pharmacology. In: Unger T, Schoelkens BA, eds. Handbook of Experimental Pharmacology. Heidelberg, Berlin: Springer Verlag; 2004: 375 – 413 2 Blais C, Marceau F, Rouleau JL, Adam A. The kallikrein-kininogen system: lessons from quantification of endogenous kinins. Peptides 2000; 21: 1903 – 1940 3 Linz W, Wiemer G, Gohlke P, Unger T, Schölkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995; 47: 25 – 49 4 Benzing T, Fleming I, Blaukat A, Müller-Esterl W, Busse R. Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells. Circulation 1999; 99: 2034 – 2040 5 Leeb-Lundberg LMF, Marceau F, Müller-Esterl W, Pettibone DJ, Zuraw BL. International Union of Pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmcol Rev 2005; 57: 27 – 77 6 Gohlke P, Lamberty V, Kuwer I, Bartenbach S, Schnell A, Linz W, Schölkens BA, Wiemer G, Unger T. Longterm low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3¢,5¢-monophosphate. Hypertension 1993; 22: 682 – 687 7 Gohlke P, Linz W, Schölkens BA, Kuwer I, Bartenbach S, Schnell A, Unger T. Angiotensin converting enzyme inhibition improves cardiac function: role of bradykinin. Hypertension 1994; 23: 411 – 418 8 Gohlke P, Kuwer I, Schnell A, Amann K, Mall G, Unger T. Bradykinin B2-receptor blockade prevents the increase in capillary growth density induced by chronic ACE inhibitor treatment in SHRSP. Hypertension 1997; 29: 478 – 482 9 Liu YH, Yand XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. J Clin Invest 1997; 99: 1926 – 1935 10 Yang XP, Liu YH, Metha D, Cavasin MA, Shesely E, Xu J, Liu F, Carretero OA. Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B2 kinin receptor gene knockout mice. Circ Res 2001; 88: 1072 – 1079 11 Nussberger J, Koike H. Antagonizing the angiotensin II subtype 1 receptor: a focus on olmesartan medoxomil. Clin Ther 2004; 26 (Suppl. A): A12 – A20 12 Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998; 339: 1285 – 1292 13 Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting

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20

21

22

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enzyme inhibitors in humans. Circulation 1997; 95: 1115 – 1118 Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993; 45: 205 – 251 Unger T, Chung O, Csikós T, Culman J, Gallinat S, Gohlke P, Höhle S, Meffert S, Stoll M, Stroth U, Zhu Y-Z. Angiotensin receptors. J Hypertens 1996; 14 (Suppl. 5): S95 – S103 Griendling KK, Lassègue B, Alexander RW. Angiotensin receptors and their therapeutic implications. Annu Rev Pharmacol Toxicol 1997; 36: 281 – 306 De Gasparo M., Catt KJ, Inagami T, Wright JW, Unger TH. International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000; 52: 415 – 472 Gohlke P, Pees C, Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension 1998; 31: 349 – 355 Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation, J Clin Invest 1999; 104: 925 – 935 Katada J, Majima M. AT2 receptor-dependent vasodilation is mediated by activation of vascular kinin generation under flow conditions. Br J Pharmacol 2002; 136: 484 – 491 Jalowy A, Schulz R, Dörge H, Behrends M, Heusch G. Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs. J Am Coll Cardiol 1998; 32: 1787 – 1796 Xu J, Carretero OA, Liu YH, Shesely EG, Yang F, Kapke A, Yang XP. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension 2002; 40: 244 – 250 Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation 2005; 111: 315 – 320 LeFebvre J, Shintani A, Gebretsadik T, Petro JR, Murphey LJ, Brown NJ. Bradykinin B2 receptor does not contribute to blood pressure lowering during AT1 receptor blockade. J Pharmacol Exp Ther 2007; 320: 1261 – 1267 Hornig B, Kohler C, Schlink D, Tatge H, Drexler H. AT1-receptor antagonism improves endothelial function in coronary artery disease by a bradykinin/ B2-receptor-dependent mechanism. Hypertension 2003; 41: 1092 – 1095 Batenburg WW, Garrelds IM, Chapuis Bernasconi C, Juilerat-Jeanneret L, van Kats JP, Saxena PR, Danser AHJ. Angiotensin II type 2 receptor-mediated vasodilation in human coronary microarteries. Circulation 2004; 109: 2296 – 2301

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9

A New Look at the Therapeutic Effects of ACE Inhibitors: ACE as Signal Transduction Molecule K. Kohlstedt, I. Fleming Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Abstract ACE inhibitors exert a series of positive effects on cardiovascular homeostasis that cannot be attributed solely to the inhibition of bradykinin degradation or angiotensin II formation. We have demonstrated that ACE in endothelial cells acts as a signal transduction molecule which, in response to the binding of an ACE inhibitor triggers the activation of CK2 which phosphorylates the cytoplasmic tail of ACE on Ser1270, which in turn activates the JNK/cJun signal transduction pathway. The incubation of cultured endothelial cells with an ACE inhibitor leads to the nuclear translocation of phosphorylated c-Jun as well as to the activation of the transcription factor AP-1. The latter responses were not observed in endothelial cells that express a non-phosphorylatable ACE mutant (S1270A) or that were deficient in ACE. The activation of AP-1 in response to ACE signalling results in the enhanced expression of ACE and cyclooxygenase 2 (COX2) in vitro as well as in vivo in the lungs of mice treated with ramipril for 5 days. The ramiprilat-induced increase in COX2 protein expression was linked to a JNK- and AP1-dependent increase in COX2 promoter activity as well as the increased production of prostacyclin and prostaglandin E2 in endothelial cells. These effects could be prevented by the simultaneous administration of the COX2 inhibitor celecoxib. In addition, using native gel electrophoresis and chemical cross-linking ACE has been shown to exist as a dimer in endothelial cells and that ACE inhibitors elicit protein dimerization. Preventing ACE dimerization by mutation of essential amino acid residues in the C-terminal active site of the enzyme resulted in a complete blockade of ACE signal transduction. Our findings demonstrate that the ACE inhibitorinduced ACE signalling pathway is initiated via dimerization and phosphorylation of ACE and elicits an increase in the expression of endothelial COX2 and prostacyclin production. This mechanism provides an explanation for the positive cardiovascular effects observed in patients under ACE inhibitor therapy, independent of the inhibition of bradykinin degradation and angiotensin II synthesis.

Angiotensin Converting Enzyme (ACE) ACE is a zinc metallopeptidase which is a central component of the renin-angiotensin system (RAS) and thus plays a key role in the regulation of blood pressure as well as fluid and electrolyte homeostasis. ACE is involved in the metabolism of two important vasoactive peptides; on the one hand it generates the vasoconstrictor angiotensin II (AngII) from angiotensin I and on the other hand, it cleaves the vasodilator bradykinin (BK). In mammals, two different isoforms of the enzyme exist: a somatic isoform with a molecular mass of 150 – 180 kDa as well as a germinal isoform of 90 – 110 kDa. Both isoforms are integral membrane proteins, whereby the somatic form of the enzyme is expressed on the luminal surface of endothelial cells as well as

on monocytes and T lymphocytes. In contrast, the germinal ACE isoform is only expressed in the testes [1]. Somatic and germinal ACE mRNA are transcribed by the same gene with use of alternative, specific promoters. Both isoforms have similar enzymatic activities but differ with regard to their immunological properties. Somatic ACE is composed of two highly homologous domains, the amino/N-terminal and the carboxy/C-terminal domain. The two homologous domains of the enzyme each possess a catalytically active center with a zinc binding site, within which the binding of the zinc atom is coordinated through the amino acid sequence HEMGH [2]. Germinal ACE possesses only the C-terminal domain and therefore only one active center. The two active centers of somatic ACE act independently of each other and, in spite

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ACE Inhibitors and ACE Signalling of the high homology, differ with regard to their substrate specificity, their ability to be activated by metal ions and their sensitivity to various ACE inhibitors. In addition to the membrane-bound form of somatic ACE an active, soluble form of the enzyme is also found in plasma, amniotic fluid and other body fluids. Soluble ACE is a posttranslationally modified form of the membrane-bound enzyme and is generated via proteolytical cleavage of the ACE C-terminus. The proteolytic cleavage occurs extracellularly in the juxtamembrane “stalk” region of ACE [3]. However, the secretase responsible for the protoeolysis has not yet been identified. Plasma analysis has revealed that in various diseases such as sarcoidosis, diabetes mellitus, Gaucher’s disease, leprosy and hyperthyreosis, the level of soluble ACE changes. Whether this is a cause or a result of the diseases and whether or not it has any effect on the course of the disease remains unclear.

ACE Inhibitors and ACE Signalling The inhibition of ACE as an antihypertensive therapy has found widespread clinical applications. ACE inhibitors influence the activity of the enzyme by complexing the central zinc atom of the active ACE centers. The effectiveness of these inhibitors for the treatment of hypertension and cardiac insufficiency has been demonstrated in numerous clinical studies, and beneficial effects on the maintenance of endothelial function, vascular “remodelling”, the progression of atherosclerosis and the frequency of cardiovascular incidents have also been reported. In addition, therapy with ACE inhibitors apparently delays the onset (self-reported) of type II diabetes mellitus in populations with a high risk of cardiovascular events. Over the last decade it has, however, become clear that the positive properties of ACE inhibitors cannot solely be attributed to an inhibition of AngII formation and BK degradation. For example, the level of circulating AngII is clearly reduced at the start of therapy with an ACE inhibitor, but increases in the course of treatment. Furthermore, ACE has been reported to interact with the B2-kinin receptor and to elicit a so-called “cross-talk” [4]. In order to reveal the molecular mechanisms underlying such a “cross-talk”, it is important to analyze whether ACE is intracellularly associated with signal transduction molecules that can be

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modified by the binding of an ACE inhibitor or whether ACE itself can be modified by ACE inhibitors. Since numerous putative phosphorylation sites are found within the ACE protein sequence, five serine residues in series exist in the short cytoplasmic sequence of the enzyme, the phosphorylation of ACE has been examined via 32P labelling of endothelial cells. Indeed, ACE exists in a phosphorylated form in these cells and phosphorylation is increased following stimulation with an ACE inhibitor. Mutation of the individual serine residues within the cytoplasmic sequence of human ACE and overexpression of the mutated proteins in endothelial cells revealed that the intracellular serine residue Ser1270 was phosphorylated and located within a consensus sequence for protein kinase CK2. CK2 could be confirmed as the ACE kinase in as much as it was associated with the cytoplasmic tail of the enzyme and inhibition of CK2 prevented the phosphorylation of Ser1270. The latter finding provided the first indication that ACE possesses properties similar to those of a signal transduction molecule, especially since the investigated endothelial cells did not express either an AngII receptor or a BK receptor. Subsequent experiments confirmed that the CK2-mediated phosphorylation of ACE not only regulates the intracellular localization and secretion of the enzyme but also triggers an ACE-mediated “outsidein signalling” [1] which is followed by an effect on additional ACE-associated proteins, i.e., non-muscle myosin heavy chain (NMMHC/MHY9) and the MAPK kinase MKK7. Indeed, upon treatment with an ACE inhibitor the phosphorylation of NMMHC/ MHY9 and the activation of JNK are initiated within a few minutes. Neither processes occurred in endothelial cells expressing the non-phosphorylatable ACE mutant ACE (S1270A), demonstrating that the phosphorylation is a decisive step in the signalling events initiated by ACE inhibitors binding to ACE. Only in wild-type ACE-expressing endothelial cells was the stimulation with an ACE inhibitor able to result in JNK activation and the nuclear translocation of the phosphorylated and activated c-Jun, an increased DNA binding activity of the transcription factor AP-1 and thus an elevated expression of AP1-regulating genes, e.g., ACE itself and cyclooxygenase 2 (COX2) [5]. Furthermore, in vivo in the lungs of ramipril-treated mice an enhanced expression of ACE and COX2 was detected. Even when an increase of ACE expression by ACE inhibitors may at first seem contradictory

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9 A New Look at the Therapeutic Effects of ACE Inhibitors: ACE as Signal Transduction Molecule

since a higher ACE expression would also be expected to result in the increased formation of AngII, an elevated plasma ACE level has been frequently described in patients under ACE therapy. Moreover, the increase in ACE expression could have positive effects, since in the presence of ACE inhibitors more ACE would then be available for signalling. The positive effects of this signalling were reflected by an increase in COX2 expression and the increased formation of prostacyclin which possesses well-documented vasodilator and antiaggregatory actions. Furthermore, an elevated prostacyclin production has been reported in patients undergoing ACE inhibitor therapy and selective COX2 inhibition in these patients reverses the blood pressure-lowering effects of ACE inhibitors. The increase in the COX2 protein expression via ACE signalling after administration of an ACE inhibitor has been confirmed by the measurement of COX2 promoter activity using a luciferase reporter gene assay, showing that not only the increase of COX2 protein but also the increase of the COX2 promoter activity no longer occurs after inhibition of the ACE signalling by JNK or AP1 blockade. Since the extracellular binding of an ACE inhibitor to ACE must mediate a signal through the plasma membrane in order to modify intracellular processes, we determined whether ACE, in analogy to other membrane-bound proteins, can dimerize and thus lead to transduction of a signal. Experiments with native gel electrophoresis demonstrated that ACE exists as the dimer in endothelial cells, a finding confirmed using the split ubiquitin assay in yeast and via chemical cross-linking in endothelial cells. In parallel to phosphorylation of ACE at Ser1270, treatment with an ACE inhibitor also concentration-dependently promotes the dimerization of ACE. The analysis of different ACE mutants demonstrated that the mutation of the two zinccomplexing histidine residues in the C-terminal active center of ACE led not only to the complete loss of ACE dimerization but also of ACE phosphorylation and JNK activation. The same mutation in the N-terminal active ACE center was without any effect on ACE signal transduction, confirming that dimerization of the enzyme through the C-terminal active centers of ACE is decisive for the ACEmediated “outside-in signalling” (Fig. 9.1).

Perspective: New Viewpoint with Regard to RAS The components of an active RAS are found not only in endothelial cells but also in monocytes, T lymphocytes and adipose tissue. The modulation of intracellular signal cascades through ACE signalling might also occur in these cells and represent the foundation of the positive effects of ACE inhibitors with regard to inflammatory processes or the development of type II diabetes. The discovery of the ACE signalling pathway as well as that of ACEhomologous enzymes and intracellular AngII receptors suggests that the RAS, which was until recently considered as having been exhaustively investigated, still has some open and undiscovered facets and that the search for further effectors may provide new aspects for the understanding and development of antihypertensive therapies [6].

References 1 Fleming I, Kohlstedt K, Busse R. New fACEs to the renin-angiotensin system. Physiology 2005; 20: 91 – 95 2 Villard E, Soubrier F. Molecular biology and genetics of the angiotensin-I-converting enzyme: potential implications in cardiovascular diseases. Cardiovasc Res 1996; 32: 999 – 1007 3 Hooper NM, Karran EH, Turner AJ. Membrane protein secretases. Biochem J 1997; 321 (Pt. 2): 265 – 279 4 Erdos EG, Deddish PA, Marcic BM. Potentiation of bradykinin actions by ACE inhibitors. Trends Endocrinol Metab 1999; 10: 223 – 229 5 Fleming I, Kohlstedt K, Busse R. The tissue renin-angiotensin system and intracellular signalling. Curr Opin Nephrol Hypertens 2006; 15: 8 – 13 6 Fleming I. Signaling by the angiotensin-converting enzyme. Circ Res 2006; 98: 887 – 896

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Perspective: New Viewpoint with Regard to RAS

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ACE inhibitor

N-Domain

N-Domain NH2

NH2 C-Domain

C-Domain

MKK7

MYH9 P CK2

MKK7 JNK

CK2

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P

COOH

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cJun ACE expression ­

P

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+1

COX2 expression ­ Nucleus

Prostacyclin ­

Fig. 9.1 Schematic view of the ACE inhibitor-induced ACE signal transduction cascade. After binding of an ACE inhibitor to ACE, dimerization and phosphorylation of the enzyme occurs whereby the JNK/cJun/AP1

signal cascade is activated and, finally, ACE and COX2 expression as well as prostacyclin production are increased.

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Current and Future Treatment Options for Hereditary Angioedema K. Bork Johannes Gutenberg-Universität, Universitäts-Hautklinik Mainz, Mainz, Germany

Abstract Until recently, it was generally accepted that the genetic basis of hereditary angioedema (HAE) in all patients (type I and II) is exclusively a genetic defect in the C1-esterase inhibitor (C1-INH) gene. Since then, families with HAE have been identified who do not exhibit a C1-INH deficiency (HAE type III). In affected patients from 6 of these families, a mutation in the factor XII gene was recently identified, while patients from other families with normal C1-INH levels did not present with this mutation. This suggests that HAE represents a group of heterogenous illnesses that require different types of therapy. Therapeutic options for HAE are classified as treatments for acute attacks or long-term treatments for the prevention of edema attacks. C1-INH concentrate derived from human plasma is available for the treatment of acute attacks in patients with HAE due to a C1-INH deficiency. Over 30 years of experience with C1-INH have established its high level of efficacy in treating HAE. Attenuated androgens such as danazol, stanozolol or oxandrolone are used for the long-term prophylaxis of patients who suffer from many edema attacks. They are, for the most part, very effective. However, they are not suitable for all patients. Numerous minor and serious adverse effects are possible and necessitate careful observation. New treatments for acute attacks will soon be available. Icatibant, a bradykinin type II receptor antagonist, has proven to have good efficacy and can be administered subcutaneously. Icatibant has recently been approved for the acute symptomatic treatment of HAE. Promising clinical studies with a recombinant C1INH preparation as well as a kallikrein inhibitor are ongoing. It will be interesting to see how the introduction of these new medications will alter the diagnostic and treatment guidelines for a disease that has thus far remained largely under-recognized.

Hereditary angioedema (HAE) is a rare genetic autosomal dominant disorder characterized by spontaneous and recurrent episodes of edema affecting the skin and the mucous membranes. Cutaneous edema of the extremities, face and genitals, and edema of the gastrointestinal tract are the most common symptoms of HAE (Bork et al., 2006). Edema of the larynx, although less common, can develop rapidly into complete airway obstruction and is potentially life-threatening. Until recently, it was generally accepted that HAE was caused by a mutation in the C1 esterase inhibitor (C1-INH) gene. Phenotypic expression of this genetic defect produces a deficiency in C1INH, manifesting as either a reduction in C1-INH concentration or normal to elevated secretion of a dysfunctional protein. The identification of HAE as a disease of C1-INH deficiency is reinforced by the classification of HAE as type I (patients presenting with a low concentration of C1-INH 5 to 30 % of

normal) and type II (patients presenting with normal to high concentrations of a dysfunctional C1INH protein). Recently, the identification of a new, C1-INH-independent form of HAE (HAE type III) has cast doubt on the exclusivity of a C1-INH deficiency in defining the etiology of HAE (Bork et al., 2000). The general clinical presentation of HAE type III is similar to that of HAE types I and II, although differences in the age of onset, frequency of attacks and sites affected have been observed (Bork et al., 2007 b). The distinguishing feature of HAE type III is the presence of normal C1-INH protein concentrations and activities in patients. Genetic analysis has thus far revealed the presence of two distinct missense mutations in exactly the same position in exon 9 of the factor XII (fXII) gene (1032C fi A and 1032C fi G) in a subgroup of these patients (Dewald and Bork, 2006).

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Current and Future Treatment Options for Hereditary Angioedema Bradykinin is the end product of the kallikreinkinin cascade. As such, the absence of negative regulation in a C1-INH deficient state leads to the uncontrolled proteolytic activity of fXII and plasma kallikrein, and results in the over-production of bradykinin. Although patients with HAE type I and II present with a constant deficiency of C1INH, their bradykinin levels are elevated only during attacks (Nussberger et al., 1998), suggesting the requirement of a trigger in eliciting attacks and the direct role played by bradykinin in mediating HAE attacks. The identification of HAE type III suggests that HAE represents a group of heterogenous illnesses, which may necessitate a change in the approach to the treatment of HAE. Current therapeutic options of HAE type I and II focus on the treatment of acute attacks or long-term prophylaxis. Attenuated androgens such as danazol, stanozolol and oxandrolone are the drugs of choice for the long-term prophylaxis of symptoms in patients who suffer from frequent and/or severe attacks. Although effective for the most part, androgens are not suitable for all patients due to their wide array of adverse effects (e. g. weight gain, acne, menstrual irregularities, virilization of female fetus, hypertension, hyperlipidemia, hepatocellular adenoma) (Banerji et al., 2008; Bork et al., 2008). In some patients, the antifibrinolytic agent tranexamic acid is used as an alternative. However, it demonstrates limited efficacy in the treatment and prevention of HAE symptoms. Adverse effects are rare and include nausea, vomiting, diarrhea, visual impairment, and thrombosis (Gompels et al., 2005). In countries where it is available, replacement therapy with plasma-derived C1-INH concentrate is the current treatment of choice for acute attacks. Over 30 years of clinical experience with C1-INH concentrate has established its efficacy in alleviating the symptoms of HAE. C1-INH concentrate is highly effective in patients with a deficiency in C1-INH (i. e. types I and II). Two new formulations of C1-INH have recently completed phase III clinical trials. Rhucin® is a recombinant form of human C1-INH generated and harvested from rabbit breast milk. Cinryze®, a form of C1-INH concentrate that is purified from plasma by nanofiltration, has yielded promising results in clinical trials. Cinryze® has been recently approved in the United States for prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema.

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Two new drugs that target the kallikrein-kinin system have been developed for the treatment of HAE. The kallikrein inhibitor DX-88 counters the elevation of plasma bradykinin during attacks by inhibiting the enzyme responsible for bradykinin production. Firazyr® (icatibant) is a new drug used in the symptomatic treatment of acute HAE attacks in adults with C1-INH deficiency. It is a synthetic decapeptide with a similar structure to that of bradykinin. The presence of 5 nonproteinogenic amino acids confers it resistance to degradation by endogenous metalloproteases, thereby extending its elimination half-life. Icatibant reverses bradykinin-mediated edema by functioning as a bradykinin receptor antagonist. Icatibant targets the final step in edema formation by displacing native bradykinin from its receptor during attacks. As a potent and specific bradykinin B2 receptor blocker, icatibant represents a novel approach to the treatment of HAE. In a phase II proof-of-concept clinical trial, icatibant was used to treat 20 cutaneous and abdominal attacks in 15 HAE patients (Bork et al., 2007 a). Icatibant was administered in 5 different dosing regimens, as an intravenous (i. v.) infusion (0.4 mg/kg × 2 h; 0.4 mg/kg × 0:5 h; 0.8 mg/kg × 0:5 h) or by subcutaneous (s. c.) injection (30 mg; 45 mg). First symptom improvement as reported by patients occurred between 0:5 and 1:5 h for all 5 treatment groups, with the s. c. groups responding within 27 to 35 min. Significant improvement of symptoms as measured by a clinically validated visual analog scale (VAS) at 4 h after the administration of icatibant compared to baseline (VAS score recorded before treatment) was observed (Fig. 10.1). Icatibant also reduced the mean duration of attacks by 83% relative to untreated attacks according to patient histories. Two international, multicenter, randomized, double-blind, comparator-controlled, phase III clinical trials assessing the efficacy and safety of s. c. icatibant in patients have recently been completed (FAST-1 & 2). Designated as the FAST trials (For Angioedema Subcutaneous Treatment), patients with moderate to very severe HAE attacks type I and II were treated with s. c. icatibant 30 mg. FAST-1 was a placebo-controlled trial that was conducted in the United States, Canada, Argentina and Australia. FAST-2 was performed in Europe and Israel, where orally administered tranexamic acid was used as a comparator. The con-

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10 Current and Future Treatment Options for Hereditary Angioedema

VAS (cm)

8 6 4 2 0 Baseline

After 4 hrs

Fig. 10.1 Significant decrease in symptom severity (per VAS) at 4 h after treatment with icatibant injection relative to baseline (p < 0.01) [4].

trolled phase of the trials consisted of double-blind treatment of first attacks involving cutaneous and abdominal symptoms (total of 130 patients: 56 in FAST-1; 74 in FAST-2), and open-label treatment of all laryngeal attacks with s. c. icatibant 30 mg (total of 11 patients: 8 in FAST-1; 3 in FAST-2). All subsequent attacks were treated with s. c. icatibant 30 mg in the open-label extension phases of the two studies. Up to three injections per attack could be administered with 6 hours apart from each injection. Icatibant provided a rapid onset of symptom relief in both trials. The primary endpoint was defined as the time to onset of symptom relief, designating the time to clinically significant symptom improvement of at least 30 % (TOR30+). TOR30+ was determined as the earliest of three consecutive time points at which the patient recorded a VAS score indicating a ‡ 30 % improvement in symptoms relative to baseline (VAS score recorded before treatment). Results from the controlled phase revealed that TOR30+ was achieved within 2 and 2:5 h after icatibant administration in FAST2 and FAST-1 respectively, compared to 12 h with tranexamic acid and 4:6 h with placebo. The primary endpoint was achieved in FAST-2. However, statistical significance was not achieved in FAST-1. Patients enrolled in FAST-1 demonstrated a disproportionately high number of abdominal attacks that exhibited a marked placebo response. Results for the secondary endpoints further reinforced the clinical efficacy of icatibant. First

symptom improvement occurred within 0:8 h after icatibant treatment according to patients in both trials (vs. 16:9 h with placebo and 7:9 h with tranexamic acid; p < 0.001). The response rate TOR30+ at 4 h after treatment, determined as the proportion of patients who reached TOR30+ within 4 h, was 80 % with icatibant vs. 30.6 % with tranexamic acid in FAST-2 (p < 0.001), and 66.7 % with icatibant vs. 46.4 % with placebo in FAST-1 (n. s.). TOR90+ or the time point of almost complete symptom relief was used to designate the end of an attack. TOR90+ was determined as the earliest of three consecutive time points at which the patient recorded a VAS score between 0 and 10 mm. In FAST-2, TOR90+ was reached within 10 h after icatibant administration compared to 51 h with tranexamic acid (p < 0.001). In FAST-1, TOR90+ was reached within 8:5 h compared to 19:4 h with placebo (p = 0.079). Open-label treatment of laryngeal attacks with icatibant provided a rapid relief of symptoms according to both patients and physicians. Additionally, the treatment of subsequent attacks in the open-label extension phase demonstrated that 90 % of attacks were successfully treated with just one injection of icatibant; 99 % of attacks were successfully treated with £ 2 injections. Icatibant did not demonstrate any loss of efficacy in the treatment of subsequent attacks in the same patients: 340 attacks in 72 patients were treated in FAST-1; 374 attacks in 54 patients were treated in FAST-2. The use of icatibant in clinical trials has not been associated with any drug-related serious adverse events. Icatibant did not cause any anaphylactic reactions. No development of antibodies against icatibant was observed. The most commonly reported adverse events were related to local injection site reactions, consisting of erythema, swelling, warm sensation, burning, itching and pain. These reactions were mild and transient (lasting only a few hours), and resolved spontaneously, without the need for medical intervention. In conclusion, HAE remains a disease without a cure. However, the recent development of new treatments has broadened the selection of therapeutic options for patients with HAE attacks type l and ll. Amongst these, icatibant emerges as a further promising drug for the effective treatment of acute attacks in HAE. Clinical trials have demonstrated its efficacy in providing a rapid onset of relief for cutaneous, abdominal and laryngeal attacks, in

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References shortening the duration of attacks, and in maintaining its efficacy in the successful treatment of subsequent attacks. Furthermore, icatibant has a favourable safety and tolerability profile, as well as a convenient subcutaneous route of administration. Recently icatibant was approved in the EU for symptomatic treatment of acute HAE attacks in adults with C1-INH deficiency.

References 1 Banerji A, Sloane DE, Sheffer AL. Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2008; 100: S19 – 22 2 Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000; 356: 213 – 217 3 Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 2008; 100: 153 – 161 4 Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol 2007; 119: 1497 – 1503

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5 Bork K, Gul D, Hardt J, Dewald G. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med 2007b; 120: 987 – 992 6 Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006; 119: 267 – 274 7 Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006; 343: 1286 – 1289 8 Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, Fay AC, Longhurst HJ, Morrison L, Price A, Price M, Watters D. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005; 139: 379 – 394 9 Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. Lancet 1998; 351: 1693 – 1697 10 FAST-1 & 2: Clinical study Report: Randomised, Double Blind, Controlled, Parallel Group, Multicentre Study of a Subcutaneous Formulation of Icatibant Versus Oral Tranexamic Acid for the Treatment of Hereditary Angioedema. 2007. Data on file

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Index

A ACE dimerization, in signal transduction 40 elevated expression, via ACE signalling 39, 40 function 38 inhibitors bradykinin action 34 clinical use 32 kallikrein–kinin system antagonists 29 mechanism and effects 34, 35, 39 therapeutic effects 38–41 phosphorylation, role in signal transduction 39 role in signal transduction 39 signal transduction cascade, ACE inhibitor induced 40, 41 Aerodigestive tract, upper, bypassing for acute angioedema of upper airway 6 Androgens, hereditary angioedema treatment 42 Angioedema acquired, causes 1 acute causes and diagnosis 1 therapy 2 upper airway diagnosis 4 emergency therapy 4–7 symptoms 4 therapy 5 allergic, treatment 1–3 bradykinin dependent, classification 20 bradykinin induced, acute phase proteins 21 chronic causes and diagnosis 1 therapy 2 hereditary causes 42 children acute therapy 17 diagnosis 16 long-term prophylaxis 17 psychosocial aspects 17 short-term prophylaxis 17 symptoms 15

therapy 16, 17 treatment 15–18 clinical symptoms 10 drug treatment 29–31 localized 10 manifestation 8–13 therapy 8–13 treatment 12, 13, 42–44 triggering factors 11 kinin induced, acute phase proteins 19–22 non-allergic bradykinin role 20 classification 20 therapy 1 various forms 1 Angiotensin converting enzyme – see ACE Angiotensin II, action on AT1 receptors 32, 33 Animal studies experimental ACE inhibitors and kinins 34 AT1 receptor antagonists and bradykinin 36 Antagonists, kallikrein-kinin system 28–31 Antihistamines chronic angioedema treatment 2 therapy for acute angioedema of upper airway 5 Aprotinin, kallikrein-kinin system antagonist 29 AT1 receptors angiotensin II action 32, 33 antagonists bradykinin action 36 mechanism of action 34, 35

B B2 receptors, bradykinin action 32, 33 Bradykinin action on ACE inhibitors 34 action on AT1 receptor antagonists 36 action on B2 receptors 32, 33 angioedema promotion 19 hereditary angioedema mediation 42 kallikrein-kinin system 23–26 metabolism, renin-angiotensin system blocker 32–36

role for clinical efficacy role in non-allergic angioedema 20

32–36

C C1 inhibitor acute hereditary angioedema treatment 43 concentrates, therapy for acute angioedema of upper airway 5 deficiency epidemiology 9 genetics 9 hereditary angioedema biological characteristics 8 classification 8 diagnosis 8 Chloroquine, hydroxy-, autoimmune angioedema treatment 3 Clinical studies ACE inhibitors and kinins 35 AT1 receptor antagonists and bradykinin 36 Coniotomy, for acute angioedema of upper airway 6 Corticosteroids, therapy for acute angioedema of upper airway 5 Cyclooxygenase 2, elevated expression, via ACE signalling 39, 40 Cyclosporin A, chronic angioedema treatment 3

D Dapsone, autoimmune angioedema treatment 3 DX-88 hereditary angioedema treatment 30, 43 kallikrein–kinin system antagonist 30

E Endothelial cells, bradykinin signal transduction 25 Ephedrine inhalation, therapy for acute angioedema of upper airway 6

I Icatibant acute hereditary angioedema treatment 43, 44

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Index hereditary angioedema treatment 30 kallikrein-kinin system antagonist 30 Intubation, for acute angioedema of upper airway 6

K Kallikrein-kinin system 23, 24 activation 28 animal models 24–26 drugs affecting 28–31 function 33, 34 physiological and pathological role 28 relationship with reninangiotensin system 32 Kinins receptors 23 synthesis and degradation in blood vessels 34

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P

T

Prostacyclin, increased formation, via ACE signalling 40 Proteins, acute phase, bradykinininduced angioedema 21

Tracheotomy, for acute angioedema of upper airway 6 Triggering factors, chronic angioedema 2

R

U

Renin–angiotensin system blocker, bradykinin metabolism 32–36 relationship with kallikrein-kinin system 32

Urticaria, acquired angioedema 1

S Signal transduction ACE phosphorylation role 39 bradykinin endothelial cells 25 function 24