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Ibuprofen: a Critical Bibliographical Review Ibuprofen Ibuprofen A critical bibliographic review Edited by K D Rainsford Sheffield Hallam University, Sheffield, UK TAYLOR AND FRANCIS LIMITED UK Taylor & Francis, 11 New Fetter Lane, London EC4P 4EE USA Taylor & Francis Inc., 325 Chestnut Street, Philadelphia PA 19106 Copyright © Taylor & Francis 1999 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, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without the prior permission of the copyright owner. Taylor & Francis is an imprint of the Taylor & Francis Group This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy copy of this or any of taylor & Francis or Routledge's collection of thousands of ebooks please go to www.eBookstore.tandf.co.uk.” British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library. ISBN 0-203-36258-6 Master e-book ISBN ISBN 0-203-37518-1 (Adobe eReader Format) ISBN 0-7484-0694-8 (cased) Library of Congress Cataloguing in Publication Data are available Cover design by Hyberts, Wattham St Lawrence, Berkshire Ibuprofen A critical bibliographic review PREFACE vii CHAPTER 1 History and Development of Ibuprofen 1 K D Rainsford CHAPTER 2 The Medicinal Chemistry of Ibuprofen 23 K J Nichol CHAPTER 3 The Pharmaceutics of Ibuprofen 48 F Higton CHAPTER 4 The Pharmacokinetics of Ibuprofen in Humans and Animals 79 D R Brocks and F Jamali CHAPTER 5 Pharmacology and Toxicology of Ibuprofen 132 K D Rainsford CHAPTER 6 Therapeutics of Ibuprofen in Rheumatic and Other Chronic and 254 Painful Diseases W F Kean, W W Buchanan and K D Rainsford CHAPTER 7 Safety and Efficacy of Non-prescription (OTC) Ibuprofen 324 K D Rainsford CHAPTER 8 Use of Ibuprofen in Dentistry 377 R A Dionne and S A Cooper CHAPTER 9 Gastrointestinal Adverse Drug Reactions Attributed to Ibuprofen 398 D A Henry, A Drew and S Beuzeville CHAPTER 10 Renal Effects of Ibuprofen 424 M D Murray and D C Brater CHAPTER 11 Adverse Drug Reactions Attributed to Ibuprofen: Effects Other 458 Than Gastrointestinal L J Miwa and J K Jones CHAPTER 12 Human Toxicity of Ibuprofen 497 G N Volans and R Fitzpatrick APPENDIX I 516 APPENDIX II 523 INDEX 528 Preface Ibuprofen is one of the safest drugs employed today for the treatment of pain, inflammation and fever. The development and extensive clinical use of this drug is one of the success stories of the pharmaceutical industry. In this day and age such successes are few since we tend to hear more of the negative or unsafe aspects attributed to the actions of many drugs. In respect of relative safety, this is really the success for ibuprofen since it has a wide range of tolerance while at the same time being often more effective on a dose-for-weight basis than aspirin and paracetamol in the treatment of many painful conditions. In rheumatic diseases it is probably the drug of first choice in many countries. Although it is certainly not the most potent among the NSAIDs, what is clear is that it represents a good balance of efficacy over a wide dosage range compared with safety. As the confidence over the safety of this drug developed following its introduction as one of the first of the newer NSAIDs introduced in the late 1960s, so the case developed for its switch from being a prescription-only drug to non-prescription (over-the-counter, or OTC) status worldwide. Now it is well recognized as probably being among the safer of the OTC analgesics available today. While not being without side-effects as noted in several chapters in this book, the worldwide incidence of reported adverse reactions, especially those in the gastrointestinal system, is relatively low at prescription and OTC dosages compared with others of its class. Ibuprofen has been studied extensively not only for its mechanisms and clinical application, but also with others of its class. In this respect, like aspirin, paracetamol or indomethacin, it has become a universal standard for comparison in many clinical conditions and experimental models. Bringing together the large amount of literature available on ibuprofen in what is the first published monograph has presented a major challenge. I am most indebted to the experts who assisted me in the preparation of chapters in this book, where we have attempted to give a balanced and comprehensive coverage of the extensive literature on the clinical studies and applications of ibuprofen; the historical aspects of its development, chemistry and pharmaceutical properties, pharmacological activity and toxicity; as well as its novel applications for treating non-pain states where ibuprofen has been of particular interest (e.g. in the prevention of colon, mammary or other cancers, Alzheimer’s disease, diabetic retinopathy, treatment of lung inflammation in cystic fibrosis, to name a few). As we discover more about the molecular and cellular modes of action in relation to the actions as an anti-inflammatory agent, so insight will come regarding how this drug works in pain and inflammation but also in the above mentioned novel non-pain states where knowledge of its mechanism(s) of action(s) is particularly puzzling. This book is dedicated to the original discoverers of ibuprofen—Dr Stewart Adams, the late Dr John Nicholson, and their colleagues at the Boots Pure Drug Company in Nottingham (UK); and to the immense number of scientists and physicians worldwide who have undertaken investigations on this drug and without whose work we would not have so much knowledge as is available now in the public domain on this drug’s actions and uses. I would also like to pay special tribute to the many colleagues who have helped in my understanding of this drug, and who encouraged me to put together this monograph. I am mindful of the fact that there are probably some points which could or should have been included; it is difficult to be exhaustive in coverage of the literature. My special thanks go to Mrs Veronica Rainsford-Koechli and Mrs Marguerite Lyons who provided an immense amount of secretarial support in the preparation of this book. K D Rainsford Sheffield Hallam University Sheffield, UK CHAPTER 1 History and Development of Ibuprofen K D RAINSFORD Division of Biomedical Sciences and Biomedical Research Centre, Sheffield Hallam University, Pond Street, Sheffield S1 1WB, UK Contents 1.1 Introduction 1.2 Historical background 1.3 Initial stages 1.4 Compounds in development 1.5 Ibufenac—almost there, but for liver toxicity 1.6 More setbacks 1.7 More learning 1.8 Ibuprofen 1.9 Achievements and rewards at last 1.10 Ultimate recognition of safety—OTC status 1.11 Worldwide developments 1.1 INTRODUCTION The history of ibuprofen began over 40 years ago and is inextricably linked to understanding of the concepts of the pathogenesis of inflammatory diseases and the actions of therapeutic agents used at that time. The principal initiator of this research leading to the discovery of ibuprofen was Dr Stewart Adams (Figure 1.1), a pharmacologist in the Research Department of The Boots Pure Drug Company Ltd at Nottingham, UK. His aim was to find analgesic drugs with improved efficacy over aspirin. As with all major discoveries, there is an important personal element and what has been attempted here is to bring together information to show what were the most significant events and thoughts that were important for the discovery process. I am most indebted to Stewart Adams for a considerable amount of information and historical detail that enabled me to write this important chapter. I am also especially grateful to him for discussing what have been most interesting historical details and for giving me an insight into those earlier years and the thinking behind the discovery of ibuprofen. Ibuprofen 2 Figure 1.1: A photograph of Dr Stewart Adams taken in 1987. Stewart Adams has written a detailed account of the pharmacological aspects of the discovery of the propionic acids (Adams, 1992). The late Dr John Nicholson, who first synthesized ibuprofen, reviewed in depth the medicinal chemistry of the propionic acids and the chemical discovery process underlying the development of ibuprofen (Nicholson, 1982). It is not proposed to give a total account of what these expert authors have already reviewed in depth. I hope more to emphasize the main thinking at the time and key events involved in the discovery of what has been one of the most successful NSAIDs developed since aspirin. The standard drugs for treating rheumatoid arthritis and other painful arthritic diseases at the time when Stewart Adams started his research were aspirin and cortisone. The pioneering studies supported by the Empire Rheumatism Council (later to become the Arthritis and Rheumatism Council) and the Medical Research Council in the United Kingdom had established the efficacy of cortisone and aspirin in the relief of pain and soft-tissue swelling in rheumatoid arthritis. However, the shortcoming of both drugs were becoming strikingly evident even at the time of these reports. In the 1950s when Boots were beginning this research, only a few other companies had History and Development of Ibuprofen 3 begun research programmes into aspirin-type drugs, notably Dr T Y Shen at Merck and Co. (Rahway, NJ, USA) and Dr Steve Winder at Parke Davis (Ann Arbor, MI, USA). Before this Dr G Wilhelmi at J R Geigy AG (Basel, Switzerland) had worked on derivatives of amidopyrine and other pyrazoles. In 1958 Winder and his colleagues published an important paper indicating their thinking about the use of the ultraviolet (UV) erythema technique for determining the anti-inflammatory activity of novel compounds.
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