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Professor K.D Rainsford, Professor Emeritus of Biomedical Sciences, Sheffield Hallam University.
List of Contributors xiii
Preface xv
1 History and Development of Ibuprofen 1Kim D. Rainsford
Summary 1
1.1 Introduction 1
1.2 Historical Background 5
1.3 Initial Stages 7
1.4 Compounds in Development 10
1.5 Ibufenac - Almost There, but for Liver Toxicity 12
1.6 More Setbacks 12
1.7 More Learning 12
1.8 Ibuprofen 12
1.8.1 First Clinical Trials 12
1.8.2 Gastrointestinal Safety 14
1.9 Achievements and Rewards at Last 15
1.10 Ultimate Recognition of Safety - OTC Status 17
1.11 Worldwide Developments 19
1.11.1 Evolving Applications of Ibuprofen 19
Acknowledgements 20
References 20
2 The Medicinal Chemistry of Ibuprofen 22Kenneth J. Nichol and David W. Allen
2.1 Introduction 22
2.2 The Discovery of Ibuprofen 22
2.3 Synthetic Routes to Ibuprofen 27
2.4 Biological Activities of Ibuprofen Analogues 31
2.5 Metabolites of Ibuprofen 36
2.5.1 Metabolites and Enantiomer Inversion 36
2.5.2 Synthesis of Metabolites 37
2.6 Ibuprofen Enantiomers 38
2.7 Physicochemical Aspects 42
Acknowledgements 43
References 43
3 The Pharmaceutics of Ibuprofen 50Fred Higton
Summary 50
3.1 Physical and Chemical Characteristics of Ibuprofen 50
3.2 Products Available Worldwide 54
3.3 Solid Dose Presentations 54
3.3.1 Conventional Ibuprofen Tablets 56
3.3.2 In vitro/in vivo Testing 58
3.3.3 Sustained Release Preparations 60
3.3.4 Ibuprofen Fast Acting: Ibuprofen Salts and Derivatives 64
3.4 Liquids 67
3.5 Taste-Masking of Ibuprofen 67
3.6 Suppositories 69
3.7 Topical Presentations 70
3.8 Conclusion 72
References 72
4 The Pharmacokinetics of Ibuprofen in Humans and Animals 81Fakhreddin Jamali and Dion R. Brocks
Summary 81
4.1 Absorption 82
4.2 Distribution 83
4.2.1 Protein Binding 83
4.2.2 Tissue Distribution 88
4.3 Clearance 92
4.3.1 Metabolism of Ibuprofen 93
4.3.2 Excretion of Ibuprofen 104
4.4 Interspecies Differences in Pharmacokinetics of (R)- and (S)-Ibuprofen 105
4.5 Relationship between Effect and Plasma Concentrations 106
4.5.1 Therapeutic Effects 106
4.5.2 Toxic Effects 107
4.6 Pharmacokinetics in Special Populations 108
4.6.1 Pharmacokinetics and Analgesic Effects in Patients in Pain 108
4.6.2 Febrile Children and Infants 114
4.6.3 Postoperative Paediatric Patients 115
4.6.4 Premature Infants 115
4.6.5 Juvenile Arthritis 116
4.6.6 Children with Cystic Fibrosis 116
4.6.7 Elderly Adults 117
4.6.8 Rheumatic Disease 117
4.6.9 Renal Insufficiency 118
4.6.10 Hepatic Disease 119
4.6.11 Burn Patients 119
4.6.12 Effect of Gender and Race 119
4.6.13 Effect of Operational Stessors 120
4.7 Drug Interactions 120
4.7.1 Anti-ulcer Medications 120
4.7.2 Zidovudine 121
4.7.3 Codeine and Oxycodone 121
4.7.4 Anti-hyperlipidemic Drugs 121
4.7.5 Oral Contraceptive Steroids 122
4.7.6 Self-interaction; Enantiomer-Enantiomer Interaction 123
4.7.7 Effect of Ibuprofen on the Pharmacokinetics of Other Drugs 123
4.7.8 Other Drugs 123
References 124
5 Pharmacology and Toxicology of Ibuprofen 132Kim D. Rainsford
Summary 132
5.1 Introduction 133
5.2 Basic Pharmacology and Toxicology 134
5.2.1 The Relevance of Data from Animal Models to the Clinical Situation in Humans 134
5.2.2 Acute Anti-inflammatory Activity 136
5.2.3 Chronic Anti-inflammatory Activity 141
5.2.4 Analgesic Activity 143
5.2.5 Antipyretic Activity 149
5.2.6 General Toxicology 149
5.2.7 Effects on Prostaglandin Production Related to Pharmacological Activities 164
5.2.8 Effects on Leukotriene Production 180
5.2.9 Smooth Muscle Contractility 181
5.2.10 Effects on Nitric Oxide Production 181
5.2.11 Leucocytes and Vascular Permeability 182
5.2.12 Leukocyte Functions 188
5.2.13 Immune Functions 191
5.2.14 Effects on Articular Joint Integrity 192
5.2.15 Miscellaneous Biochemical and Cellular Actions 194
5.3 Experimental Therapeutics 196
5.3.1 Endotoxin Shock 196
5.3.2 Acute Lung Injury Induced by Exposure to Chemicals 198
5.3.3 Acute Myocardial Injury and Coronary Functions 199
5.3.4 Cerebral Injury 201
5.3.5 Tourniquet Shock Ischemia 202
5.3.6 Transcutaneous Hypoxia 202
5.3.7 Cytokines and Surgical Stress 203
5.3.8 Pleurisy from Delayed Hypersensitivity Reaction 203
5.3.9 Abdominal Adhesions 203
5.3.10 Uveitis 204
5.4 Clinical Pharmacology and Toxicology 204
5.4.1 Experimental Inflammation 204
5.4.2 Experimental Pain 205
5.4.3 Effects on Platelet Aggregation and Thrombosis 206
5.4.4 Gastrointestinal Injury and Bleeding 208
5.4.5 Hypersensitivity and Other Immunological Reactions 210
5.4.6 Gynaecological and Obstetric Uses 211
5.4.7 Effects on Lung Inflammation in Cystic Fibrosis 212
5.4.8 Malignant Conditions 212
5.4.9 Prevention of Cataract 213
5.5 Conclusions 214
References 214
6 Therapeutics of Ibuprofen in Rheumatic and Other Chronic and Painful Diseases 237Walter F. Kean, Kim D. Rainsford and the late William W. Buchanan
Summary 237
6.1 Introduction 238
6.2 Overview of Clinical Pharmacology 239
6.2.1 Pharmacokinetics Relevant to Therapy of Inflammatory Diseases and Pain 240
6.2.2 Anti-inflammatory and Analgesic Activities 245
6.2.3 Criteria for Determining Therapeutic Responses 247
6.3 NSAID-Related Adverse Drug Reactions and Toxicity 248
6.3.1 Gastrointestinal Side-Effects 248
6.3.2 Cardiovascular Reactions 251
6.3.3 Hepatic Reactions 251
6.3.4 Renal Adverse Reactions 251
6.3.5 Miscellaneous Reactions 253
6.4 Rheumatoid Arthritis 254
6.4.1 Early Studies at Low Doses 255
6.4.2 Later Higher?]Dose Studies 257
6.5 Juvenile Idiopathic (Rheumatoid) Arthritis 261
6.6 Primary and Secondary Osteoarthritis 262
6.6.1 Acceleration of Cartilage and Bone Destruction 272
6.6.2 Therapeutic Aspects 273
6.6.3 Comparisons with Coxibs 274
6.7 Formulations 276
6.8 Variability in Response 276
6.9 Relation of Drug Kinetics to Clinical Response 277
6.10 Low Back Pain 278
6.11 Shoulder Pain 279
6.12 Reactive Arthritis (Reiter's Syndrome) 280
6.13 Psoriatic Arthritis 280
6.14 Ankylosing Spondylitis 280
6.15 Gout 280
6.16 Fibromyalgia 281
6.17 Haemophiliac Arthritis 281
6.18 Postoperative Pain 281
6.19 Sports Injuries 282
6.20 Other Painful States 283
6.21 Cancer 284
6.22 Potential Non?]analgesic Usage 285
6.23 The Elderly 285
6.24 Dexibuprofen 286
6.25 Conclusions 286
References 287
7 Safety and Efficacy of Non-prescription, Over-the?]Counter (OTC) Ibuprofen 313Kim D. Rainsford
Summary 313
7.1 Introduction 313
7.2 Analysis of Clinical Trials 315
7.2.1 Studies in Prospective Clinical Trials 317
7.3 Epidemiological Studies and Case Reports 327
7.4 Considerations for Special Groups 330
7.4.1 Use of Drugs in the Elderly 330
7.4.2 Safety in Pregnancy and Lactation 331
7.4.3 Uses and Safety in Sport and Exercise 334
7.5 Conclusions 336
References 336
8 Use of Ibuprofen in Dentistry 346Raymond A. Dionne, Sharon M. Gordon and Stephen A. Cooper
Summary 346
8.1 Introduction 346
8.2 Analgesia 347
8.2.1 Preventive Analgesia 348
8.2.2 Analgesic Activity of Ibuprofen Isomers 349
8.2.3 Ibuprofen-Containing Combinations 350
8.2.4 Ibuprofen Formulations 354
8.3 Effects on Oedema 355
8.4 Interactions with Plasma ß-Endorphin 356
8.5 Use for Chronic Temporomandibular Pain 356
8.6 Recommendations for the Use of Ibuprofen in Dentistry 358
References 359
9 Gastrointestinal Adverse Reactions from Ibuprofen 363Kim D. Rainsford and Ingvar Bjarnason
Summary 363
9.1 Background and Introduction 364
9.2 Current Status Concerning NSAID Ulceration 365
9.2.1 Morbidity and Mortality 366
9.3 Occurrence of Ulcers and Complications 369
9.3.1 Epidemiological Studies 369
9.3.2 Large-Scale Mega Trials 376
9.4 Clinical Investigations on Comparative GI Effects of Ibuprofen 378
9.4.1 Early Symptom-Based Studies in GI?]Intolerant Subjects 378
9.4.2 Procedures for Assessing GI Injury 379
9.4.3 Upper GI Endoscopy 380
9.4.4 NSAID-Enteropathy: Capsule and Device Assisted Intestinal Endoscopy and Other Techniques 381
9.4.5 Radiochromium [51Cr]-Labelled Red Cell GI Blood Loss 389
9.4.6 Intragastric and Occult Blood Loss and Reduced Haemoglobin 394
9.5 Clinically-Relevant Pathogenesis of NSAID-Associated GI Injury 395
9.5.1 Factors Affecting NSAID-Induced Gastroduodenal Injury 395
9.5.2 Influence of Gastric Acidity 397
9.5.3 Physicochemical Associations, Topical versus Systemic Actions of NSAIDs, Cyclo?]oxygenases and Reduced Prostanoids 399
9.5.4 Effects of NSAIDs on Gastric pH and Acid Secretion 402
9.6 Procedures for Reducing GI Symptoms 404
9.6.1 Ibuprofen Formulations 404
9.6.2 Effects of Food or Drinks 406
9.6.3 Mucus Protection Strategies 409
9.6.4 Anti-ulcer Agents 410
9.7 Overall Assessment of GI Safety of Ibuprofen 412
References 412
10 Hepatorenal Effects of Ibuprofen Compared with other NSAIDs and Paracetamol 432Kim D. Rainsford
10.1 Introduction 432
10.2 Hepatorenal Syndromes 433
10.3 NSAID, Analgesic and DMARD-Induced Liver Injury 433
10.3.1 Historical Associations of NSAIDs with Liver Toxicity 433
10.3.2 Awareness of Liver Reactions with Modern NSAIDs 434
10.3.3 Simultaneous Use of Potentially Hepatotoxic Medications 439
10.4 Renal Adverse Reactions Form NSAIDs and Analgesics 442
10.4.1 Renal Adverse Reactions from Ibuprofen 444
10.5 Conclusions 446
References 446
11 Adverse Drug Reactions Attributed to Ibuprofen: Effects Other Than Gastrointestinal 452L.J. Miwa, M. Manenos and Judith K. Jones
11.1 Introduction 452
11.2 Allergy and Hypersensitivity 453
11.2.1 Points to Consider when Evaluating Allergy-Type Reactions to NSAIDs 453
11.2.2 Epidemiology of Allergy or Hypersensitivity with NSAIDs 454
11.3 Adverse Dermatological Effects 457
11.4 Hepatotoxicity 458
11.5 Haematological Adverse Effects 465
11.5.1 Neutropenia, agranulocytosis and aplastic anaemia 465
11.5.2 Other Blood Disorders 466
11.6 Renal Adverse Effects 466
11.7 Cardiovascular Adverse Effects 470
11.8 Adverse Effects on Reproduction 477
11.8.1 Animal Studies of Teratogenic and Reproductive Effects 477
11.8.2 Reports of Teratogenic Effects in Humans 478
11.8.3 Perinatal Adverse Effects Associated with Therapeutic Use 479
11.8.4 Other Reproductive Effects 480
11.9 Endocrine and Metabolic Adverse Effects 480
11.10 Central Nervous System Effects 480
11.10.1 General CNS Effects 480
11.10.2 Aseptic Meningitis 481
11.10.3 Cognitive Dysfunction 481
11.10.4 Psychiatric Adverse Effects 481
11.11 Ocular Adverse Effects 481
11.12 Infection-Related Adverse Event 482
11.13 Drug Interactions 482
11.13.1 NSAID-Anti-hypertensive Interactions 483
11.13.2 NSAID-Diuretic Interactions 484
11.13.3 NSAID-ß-Adrenergic Blocker Interactions 484
11.13.4 NSAID-Angiotensin-Converting Enzyme Inhibitor Interactions 484
11.13.5 NSAID-Oral Anti-coagulant Interactions 484
11.13.6 NSAID-Aminoglycoside Interactions 485
11.13.7 NSAID-Oral Hypoglycemic Interactions 485
11.13.8 NSAID-Cyclosporin Interactions 485
11.13.9 NSAID-Lithium Interactions 485
11.13.10 NSAID-Methotrexate Interactions 485
11.13.11 Ibuprofen-Aspirin Interactions 486
11.14 Future Needs 486
References 487
12 Human Toxicity of Ibuprofen 500Glyn Volans
Summary 500
12.1 Introduction 500
12.2 Mechanism of Toxicity in Overdosage 501
12.3 Epidemiological Reviews of the Effects of Ibuprofen in Overdosage 501
12.4 Reports of Deaths after Ibuprofen Overdose 502
12.5 Dose-Response and Toxicokinetics 502
12.6 Gastrointestinal Effects 508
12.7 Renal Effects 509
12.7.1 Cases of Massive Overdose 509
12.7.2 Cases Affected by Additional Factors 509
12.8 Metabolic Effects 510
12.9 Central Nervous System (CNS) Effects 511
12.10 Cardiovascular Effects 511
12.11 Respiratory Effects 512
12.12 Haematological Effects 512
12.13 Skin Reactions 512
12.14 Ibuprofen Toxicity in Children 512
12.15 Ibuprofen in Pregnancy and Breast Feeding 513
12.16 Chronic Abuse of Ibuprofen 513
12.17 Conclusion 514
12.17.1 Management of Ibuprofen Overdosage 514
12.17.2 Continuing Surveillance 515
12.17.3 Comparative Human Toxicity - Ibuprofen versus Other NSAIDs and Non?]opioid Analgesics 516
References 516
13 Ibuprofen in the Prevention and Therapy of Cancer 520Randall E. Harris
Summary 520
13.1 Introduction and Background 521
13.2 Ibuprofen, COX-1 and COX-2 522
13.3 COX-2 and the Inflammogenesis of Cancer 522
13.4 Preclinical Efficacy Studies of Ibuprofen and Cancer 523
13.4.1 Preclinical Efficacy Study of Ibuprofen Therapy for Breast Cancer 523
13.4.2 Preclinical Efficacy Study of Ibuprofen versus Retinoic Acid for the Prevention of Breast Cancer 523
13.4.3 Preclinical Efficacy Study of Celecoxib versus Ibuprofen for the Prevention of Breast Cancer 524
13.4.4 Other Animal Studies of NSAIDs and Cancer 524
13.5 Human Epidemiologic Studies of Ibuprofen for the Prevention of Cancers of the Breast, Colon, Prostate and Lung 525
13.5.1 Methods of Analysis 526
13.5.2 Comparative Results for Ibuprofen and Aspirin from Eepidemiologic Studies of Cancers of the Breast, Colon, Prostate and Lung 526
13.5.3 Comparison of Ibuprofen, Aspirin and Selective COX?]2 Inhibitors in Cancer Prevention 527
13.5.4 Meta-analyses of Epidemiologic Studies of NSAIDs for Cancer Prevention 528
13.5.5 Discussion of Meta-analyses of NSAIDs and Cancer 530
13.6 Therapeutic Studies of Non-selective COX-2 Inhibitors for Human Cancer 531
13.7 COX-2 and the Inflammogenesis of Cancer 533
13.7.1 COX-2 Blockade of Molecular Carcinogenesis 533
13.7.2 Role of COX-1 in Carcinogenesis 534
13.7.3 Other Molecular Targets of NSAIDs 535
13.8 Safety Profile of Ibuprofen 535
13.8.1 COX-1 and COX-2 Isoforms 535
13.8.2 Gastrointestinal and Renal Effects of Ibuprofen 535
13.8.3 Ibuprofen and Cardiovascular Disease 536
13.9 Future Perspectives for Cyclooxygenase Inhibitors in Cancer Chemoprevention 536
References 537
14 Ibuprofen in Prevention of Neurodegenerative Diseases 549Kim D. Rainsford
Summary 549
14.1 Introduction 550
14.2 Pathogenesis of AD 550
14.3 Early Clinical Observations of Effects of NSAIDs in AD 551
14.4 Cellular and Molecular Effects of Ibuprofen in AD 555
14.4.1 Actions of Ibuprofen in Rodent AD Models 556
14.4.2 In Vitro Effects and Molecular Actions of Ibuprofen in AD 558
14.4.3 Conclusions 559
14.5 Ibuprofen in Parkinson's Disease 559
14.5.1 Effects of Ibuprofen in Models of PD 561
14.6 Other Neuroprotective Effects of Ibuprofen 561
14.7 Conclusions 562
References 562
Appendix A Some Proprietary Brands and Preparations of Ibuprofen Available Worldwide 573Kim D. Rainsford
Appendix B References to Analytical Methods for Determination ofIbuprofen in Biological Fluids, Principally Plasma 583Kim D. Rainsford
Index 000
K.D. Rainsford
Biomedical Research Centre, Sheffield Hallam University, UK
Ibuprofen was discovered over half a century ago following pioneering approaches by Professor Stuart Adams OBE for the identification of anti-inflammatory properties of drugs related to aspirin and later screening of a range of acidic compounds that were synthesized by the late Dr John Nicholson. The subsequent clinical assessments of the anti-rheumatic activities of ibuprofen were initially as a prescription-only medication for treating rheumatoid arthritis. With extensive trials in various other rheumatic and painful states the drug consistently proved to be effective and relatively safe. By the early 1980s the data amassed on the safety of ibuprofen set the basis for granting by the health authorities in the United Kingdom and United States of America as a non-prescription drug for over-the-counter (OTC) sale by pharmacies at the half-prescription (1200 mg/day) dose for short-term use by the lay public. Later OTC sale was approved by a large number of drug regulatory agencies worldwide and this has since been extended to it being available in stores under the general sales list (GSL) regulations in a large number of countries. Ibuprofen has become amongst the most widely used pain-relieving medication worldwide with its proven safety and efficacy. The drug has also been widely investigated for application in a variety of painful and non-pain inflammatory states including cancer, Parkinson's disease and dementias, reflecting the unique and novel properties of the drug that would never have been foreseen from knowledge of the properties when it was initially discovered.
The history of ibuprofen began over 50 years ago and has been inextricably linked to understanding of the concepts of the pathogenesis of inflammatory diseases and the actions of therapeutic agents used at that time (Rainsford, 2011). 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, United Kingdom. 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.
Figure 1.1 A photograph of Dr Stewart Adams taken in 1987 (a) and a recent photograph taken in 2012 (b).
Stewart Adams has written a detailed account of the pharmacological aspects of the discovery of the propionic acids (Adams, 1992). It is worth noting that the discovery of ibuprofen occurred in the period before the discovery by Vane and colleagues in 1971-1973 of prostaglandins as targets for the anti-inflammatory actions of non-steroidal anti-inflationary drugs NSAIDs (Vane, 1971; Flower et al., 1972; Ferreira, Moncada and Vane, 1973; Moncada, Ferreira and Vane, 1973). Thus there was no biochemical or cellular target established that could have been employed in the identification of anti-inflammatory actions of ibuprofen and its precursors. The animal models that were employed in the discovery of propionic acids and other NSAIDs were the only means then available for identifying their anti-inflammatory activity. The late Dr John Nicholson (Figure 1.2), 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 shortcomings 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 begun research programmes into aspirin-type drugs, notably Dr T.Y. Shen at Merck and Company (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. This assay was similar to that in use at Boots and they had, moreover, obtained similar results with standard drugs (e.g. aspirin). The Parke Davis group eventually produced mefenamic acid, flufenamic acid and other fenamates as a result of the initial testing of compounds in this assay.
Boots, however, started with a distinct disadvantage with their meagre resources as their Pharmacology Department was housed in a group of old rambling buildings attached to a Victorian house located in the outskirts of Nottingham (Figures 1.3 to 1.5). It was moved there at the beginning of the Second World War from the centre of Nottingham as a precaution against bombing - a wise move since part of the Research Department was destroyed in an air raid in 1941. The first six years of the research on new aspirin-type drugs was thus carried out under most unsatisfactory conditions. Adams' laboratory (Figure 1.3) was in one of the 'front rooms' of the house and later he was able to acquire the kitchen and larder (Figure 1.4) as additional accommodation.
Figure 1.2 The 'ibuprofen team' comprising Stewart Adams (centre) with his technician, Colin Burrows (right) and John Nicholson (left).
Figure 1.3 Stewart Adams with John Nicholson, Colin Burrows (right) in the mid-1960s.
Figure 1.4 Part of the laboratory ('kitchen') in 1957 showing the Kromayer ultraviolet lamp in the background and guinea-pig holding cages on either side.
Figure 1.5 The house where Stewart Adams had his laboratory in Rutland Road, West Bridgford, Nottingham and where the early pharmacological studies leading to the discovery of ibuprofen were performed.
It has been said that the road to drug development is a minefield, the path through which is both tortuous and dangerous. One of the leading medicinal chemists in the field of inflammatory drug research, T.Y. Shen, who developed the NSAIDs indomethacin, sulindac and diflunisal at Merck and Company (USA), described the period, 1955-1970, during which the earlier NSAIDs such as ibuprofen and indomethacin were developed as the 'golden era' of Edisonian empiricism (Shen, 1984). Without doubt this era set the stage for the later proliferation of NSAIDs in the 1970s and 1980s, many of which were discovered serendipitously (Shen, 1984) and are considered by some to represent little advance over those drugs developed previously. The mechanisms underlying the development of the rheumatic diseases for which these drugs were intended were little understood. The drugs available for treating pain and inflammation in rheumatic diseases in the 1950s to 1960s included aspirin, the other salicylates, aminophenols (phenacetin) and pyrazolones, which dated from the beginning of the century; phenylbutazone (which was originally used to solubilize aminopyrine and accidently discovered as an effective anti-inflammatory drug); and the corticosteroids discovered in the 1950s (Shen, 1984). Gold salts had also been found in the 1930s to have disease-modifying activity in rheumatoid and related arthropathies, though in the 1950s they were regarded as very toxic.
Thus, with the current remedies for rheumatic diseases being aspirin, corticosteroids, phenylbutazone and, to a lesser extent, gold salts, the need was readily identified in the 1950s for a more potent drug than aspirin, one that would not produce the potentially fatal side-effect of agranulocytosis seen with phenylbutazone or the serious side-effects with corticosteroids. Indeed a report (No. 848 entitled 'The Testing of Non-hormonal Anti-rheumatic Compounds' by Adams from the Pharmacology and Physiology Division of...
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