Table Of ContentIbuprofen
Ibuprofen
A critical bibliographic review
Edited by
K D Rainsford
Sheffield Hallam University, Sheffield, UK
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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.
