New Developments in Antirheumatic Therapy

New Developments in Antirheumatic Therapy

INFLAMMATION AND DRUG THERAPY SERIES VOLUME III New Developments in Antirheumatic Therapy Edited by KD Rainsford Department of Biomedical Sciences McMaster University Faculty of Health Sciences Hamilton, Ontario Canada GPVelo Institute of Pharmacology University of Verona... " KLUWER ACADEMIC PUBLISHERS KLUWER ACADEMIC PUBLISHERS DORDRECHT/BOSTON/LONDON

Distributors For the United States and Canada: Kluwer Academic Publishers, PO Box 358, Accord Station, Hingham, MA 02018-0358, For all other countries: Kluwer Academic Publishers Group, Distribution Center, PO Box 322, 3300 AH Dordrecht, The Netherlands British Library Cataloguing in Publication Data New developments in antirheumatic therapy. 1. Man. Joints. Arthritis & rheumatic diseases. Therapy I. Rainsford, K.D. (Kim D.), 1941- II. Velo, G.P. (Giampaolo) 1943- III. Series 616.7'206 ISBN -13: 978-94-010-7056-0 DOl: 10.1007/978-94-009-1253-3 Copyright e-isbn-13: 978-94-009-1253-3 1989 by Kluwer Academic Publishers Softcover reprint of the hardcover 1st edition 1989 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior permission from the publishers, Kluwer Academic Publishers BV, PO Box 17, 3300 AA Dordrecht, The Netherlands. Published in the United Kingdom by Kluwer Academic Publishers, PO Box 55, Lancaster,. Kluwer Academic Publishers BV incorporates the publishing programmes of D. Reidel, Martinus Nijhoft, Dr W. Junk and MTP Press. iv

Contents Preface vi List of Contributors vii Recent developments in antirheumatic therapy P Nash and BL Hazleman 2 Osteoarthritis: a metabolic disorder CWDenko 29 3 Concepts of mode of action and toxicity of anti-inflammatory drugs. A basis for safer and more selective therapy, and for future drug developments KD Rainsford 37 4 Animal models of arthritic disease: influence of novel, compared with classical, antirheumatic agents 1M Hunneyball, MEJ Billingham and KD Rainsford 93 5 Novel eicosanoid inhibitors LA Marshall and J Chang 133 6 New steroidal anti-inflammatory drugs HJ Lee, AS Heiman and IB Taraporewala 153 7 Oxyradicals, inflammation and drugs acting on oxyradical production DV Parke, AM Symons and AL Parke 187 8 Gold(l) thiolates: slow-acting anti-arthritic drugs DR Haynes and MW Whitehouse 207 9 Do platelet activating factor antagonists have a potential role in the therapy of rheumatoid arthritis? CP Page and AJ Coyle 235 10 Interleukin 1: past, present, future MC Powanda and ED Moyer 255 11 The T cell as a therapeutic target IG Otterness and ML Bliven 277 12 Superoxide dismutase modifications for anti-inflammatory therapy FM Veronese, A Conforti and GP Velo 305 Index 315 v

Preface At present we may be at the cross-roads in the therapeutic approaches we have for the treatment of the 100 or more rheumatic conditions. This is because we now recognise that although some advances have been made with the development of a large range of non-steroidal and steroidal drugs during the past two decades or so, we now recognise that many, if not all, of these have rather limited effects on many of the disease processes which underlie the manifestations of the various rheumatic states. Advances in molecular bi- 010gy in the past 5-10 years have enabled these tools to be applied extensively for developing further our understanding of the rheumatic disease processes. In some cases these molecular tools (e.g.,),-interferon, interleukin- 2, T-cell antibodies) have been directly employed as therapies themselves. While the outcome from trials with such agents in rheumatoid arthritis in particular has not been as would have been hoped, these results as with cyclosporin A and low-dose methotrexate in the therapy of rheumatoid arthritis have given us important indications for the approach employing what are generally described as "immunomodulators" to control this disease. But this may not be the same type of approach which is desirable for all types of rheumatic conditions. Indeed, even the way which the present range of drugs and other therapies are applied may not be the most effective and safe means of treating different types of arthritic conditions. Thus, it was considered that the time is appropriate to review what we understand about the current range of therapies; what basic developments are occurring in the search for the newer, more specific and more effective agents; and what progress has been made in the understanding of the disease processes which can give clues or leads for future therapeutic approaches. While it may be considered that the coverage of some areas may be limited because of the size limitations necessary for such a book, it should be pointed out that further consideration is being given in some newly emerging approaches in the fields of, for example, neuro-inflammation, the broader range of cytokines other than interleukin-l, and the non-articular rheumatic conditions in companion volumes which are currently in preparation. Special thanks are given to the valued efforts of the contributors, Dr Peter Clarke (Publishing Director, Kluwer Academic Publishers) and Mrs Veronica Rainsford-Koechli for her help in proof-reading the manuscripts. K D Rains/ord Hamilton, Ontario, Canada February 1989 vi

List of Contributors M.E.J. BILLINGHAM Lilly Research Centre Eli Lilly and Co. Windlesham, Surrey GU20 6PH M.L. BLIVEN Department of Immunology and Infectious Diseases Pfizer Central Research Groton, CT 06340 J. CHANG Immunopharmacology Subdivision Wyeth-Ayerst Research Inc. CN 8000 Princeton, NY 08543-8000 A. CONFORTI Istituto di Farmacologia Universita di Verona Policlinico Borgo Roma 37134 Verona A.J. COYLE Department of Pharmacology King's College University of London Chelsea Campus, Manresa Road London SW3 C.W. DENKO Departments of Rheumatology and Medicine Case Western ReseNe University Cleveland, OH 44106 D.R. HAYNES Department of Pathology University of Adelaide GPO Box 498 South Australia 5001 Australia B.L. HAZLE MAN Rheumatology Research Unit Addenbrooke's Hospital Hills Road Cambridge CB2 2QQ A.S.HEIMAN Center for Anti-inflammatory Research College of Pharmacy Florida A&M University Tallahasee, FL 32307 I.M. HUNNEYBALL The Boots Company pic Nottingham NG2 3M H.J. LEE Center for Anti-inflammatory Research College of Pharmacy Florida A&M University Tallahasee, FL 32307 L.A. MARSHALL Immunopharmacology Subdivision Wyeth-Ayerst Research Inc. CN 8000 Princeton, NY 08543-8000 E.D. MOYER KabiVitrum Inc 1311 Harbor Bay Parkway Alameda, CA94501 vii

NEW DEVELOPMENTS IN ANTIRHEUMATIC THERAPY P. NASH Rheumatology Research Unit Addenbrooke's Hospital Hills Road Cambridge CB2 2QQ I.G.OTTERNESS Department of Immunology and Infectious Diseases Pfizer Central Research Groton, CT 06340 C.P. PAGE Department of Pharmacology King's College University of London Chelsea Campus, Manresa Road London SW3 A.L. PARKE Department of Biochemistry University of Surrey Guildford GU2 5XH Surrey D.V. PARKE Department of Biochemistry University of Surrey Guildford Surrey GU2 5XH M.e. POWANDA Letterman Army Institute of Research Presidio San Francisco, CA 94129 K.D. RAINSFORD Department of Biomedical Sciences McMaster University Faculty of Health Sciences Hamilton, Ontario Canada L8N 3Z5 A.M. SYMONS Department of Biochemistry University of Surrey Guildford Surrey GU2 5XH I.B. TARAPOREWALA Center for Anti-inflammatory Research College of Pharmacy Florida A&M University Tallahasee, FL 32307 F.M. VERONESE Dipartimento di Scienze Farmaceutiche Centro di Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR Universita di Pad ova Pad ova G.P. VELO Istituto di Farmacologia Universita di Verona Policlinico Borgo Roma 37134 Verona M.W. WHITEHOSE Department of Pathology University of Adelaide GPO Box 498 South Australia 5001 Australia viii