Nimesulide - Actions and Uses (eBook)

Contents 5
List of contributors 12
Preface 14
The discovery, development and novel actions of nimesulide 16
Introduction 16
Discovery of R-805 – nimesulide 19
Chemical synthesis 22
Development of nimesulide 22
Physical and chemical properties 26
Chemical analysis 29
Chemical reactions of nimesulide 30
Versatile formulations 35
Novel ‘non-pain’ uses of nimesulide 39
Miscellaneous uses 45
Conclusions 47
References 47
APPENDIX A: Trademark names for nimesulide 63
APPENDIX B: Summary of Product Characteristics for nimesulide as approved by the European Medicines Agency ( formerly the European Medicines Evaluation Agency) in 2003 64
Pharmacokinetics of nimesulide 77
Introduction 77
Physicochemical factors governing the oral bioavailability of nimesulide 77
Animal pharmacokinetics 80
Pharmacokinetics in humans 85
Conclusions 128
References 129
Pharmaceutical formulations of nimesulide 135
Introduction 135
Formulations for topical application 135
Formulations for systemic administration 136
Oral cyclodextrin formulations 137
Oral modified-release formulations 137
Generic formulations 138
References 144
Pharmacological properties of nimesulide 147
Introduction 147
In vivo pharmacological actions 147
Mechanisms of action of nimesulide on pathways of inflammation 159
Effects of nimesulide on arachidonic acid metabolism in vitro, ex vivo and in vivo 163
Structural aspects of cyclooxygenase (COX) activity and COX-2 inhibition by nimesulide 176
Nimesulide and neutrophil functional responses 187
Analgesic actions of nimesulide in animals and humans 201
Actions on joint destruction in arthritis 211
Regulation by eicosanoids of cartilage–synovial–leucocyte interactions 212
In vivo effects of nimesulide on cartilage and bone in experimental model systems 216
Actions of nimesulide on cartilage degradation in vitro 217
Smooth muscle and related pharmacological properties 228
Conclusions 229
References 229
Clinical applications of nimesulide in pain, arthritic conditions and fever 259
NSAIDs: The survivors from the laboratory 259
Osteoarthritis: A leading target for NSAIDs 261
Nimesulide in the treatment of osteoarthritis 265
Miscellaneous rheumatic conditions 273
The analgesic properties of nimesulide in inflammatory pain 274
Nimesulide in the treatment of primary dysmenorrhoea and other gynaecological conditions 280
NSAIDs in sports medicine 287
Acute pain models and conditions 297
Adverse events encountered in clinical trials 313
Conclusions 313
References 313
Adverse reactions and their mechanisms from nimesulide 328
Introduction 328
Nimesulide safety profile from spontaneous reporting 330
Nimesulide safety from epidemiological and population studies 339
Meta-analysis and systematic reviews of adverse reactions from clinical trials 347
Gastrointestinal tolerance of nimesulide compared with other NSAIDs: Clinical studies 348
Clinical aspects of nimesulide-related hepatic reactions from published case reports 356
Mechanisms of toxic reactions 370
Discussion and conclusions 396
Summary 398
References 402
Index 429