Nimesulide: Actions and Uses

Contents......Page 5
List of contributors......Page 12
Preface......Page 14
Introduction......Page 16
Discovery of R-805 – nimesulide......Page 19
Development of nimesulide......Page 22
Physical and chemical properties......Page 26
Chemical analysis......Page 29
Chemical reactions of nimesulide......Page 30
Versatile formulations......Page 35
Novel “non-pain” uses of nimesulide......Page 39
Nimesulide in cancer......Page 40
Alzheimer’s disease and neurodegenerative disorders......Page 42
Miscellaneous uses......Page 45
References......Page 47
Appendix A......Page 63
Appendix B......Page 64
Physicochemical factors governing the oral bioavailability of nimesulide......Page 77
Animal pharmacokinetics......Page 80
Absorption......Page 85
Distribution......Page 93
Elimination......Page 94
Metabolism......Page 96
Linearity......Page 102
Rectal administration......Page 103
Multiple dose administration......Page 104
Topical administration......Page 105
Influence of gender......Page 107
Effect of age......Page 110
Effect of moderate renal insufficiency......Page 120
Effect of severe hepatic failure......Page 121
Drug interaction studies......Page 122
Conclusions......Page 128
References......Page 129
Formulations for topical application......Page 135
Formulations for systemic administration......Page 136
Oral modified-release formulations......Page 137
Generic formulations......Page 138
References......Page 144
Models of acute inflammation......Page 147
Relationship of acute anti-inflammatory effects to prostaglandin production......Page 153
Models of chronic inflammation......Page 154
Analgesic activities......Page 156
Antipyretic effects......Page 158
Mechanisms of action of nimesulide on pathways of inflammation......Page 159
Effects of nimesulide on arachidonic acid metabolism in vitro, ex vivo and in vivo......Page 163
COX-2 selectivity......Page 168
Inhibition of the synthesis of COX-2......Page 174
Anandamide production......Page 175
Introduction......Page 176
Introduction......Page 187
Hallmarks of neutrophil-mediated inflammation......Page 188
In vitro effects of nimesulide on neutrophil functions......Page 190
Complement activation......Page 199
Summary and conclusions......Page 200
Molecular biology and neural mechanisms of pain......Page 201
Experimental studies in laboratory animal models......Page 204
Experimental studies in humans......Page 209
Conclusions......Page 210
Joint destruction and effects of NSAIDs......Page 211
Regulation by eicosanoids of cartilage–synovial–leucocyte interactions......Page 212
In vivo effects of nimesulide on cartilage and bone in experimental model systems......Page 216
Actions of nimesulide on cartilage degradation in vitro......Page 217
Uptake of nimesulide into synovial tissues, synovial tissues and cartilage......Page 219
Production of PGE[sub(2)], cytokines and proteoglycans in vitro......Page 220
Ex vivo studies on regulation of metalloproteinases in patients with OA......Page 221
Glucocorticoid receptor activation and other signalling pathways......Page 222
Regulation of other cytokine or cellular reactions that might be significant in controlling inflammation......Page 226
Smooth muscle and related pharmacological properties......Page 228
References......Page 229
Signalling from pain......Page 259
Gastrointestinal and other untoward events......Page 260
Osteoarthritis: A leading target for NSAIDs......Page 261
Should NSAIDs be used for osteoarthritis? – efficacy......Page 262
Choice......Page 263
Nimesulide – efficacy......Page 265
Nimesulide – tolerance and safety in OA patients......Page 271
Conclusions......Page 272
Psoriatic arthritis......Page 273
Onset of analgesia......Page 274
Comparison of analgesic properties of nimesulide with coxibs......Page 275
Clinical data......Page 276
Pelvic pain and pain in dysmenorrhoea......Page 280
Primary dysmenorrhoea......Page 282
Etiology......Page 283
Nimesulide compared with other NSAIDs in the clinical management of primary dysmenorrhoea......Page 284
Introduction......Page 287
Inflammation......Page 288
The use of nimesulide in sports medicine......Page 290
Topical nimesulide in acute musculoskeletal injuries......Page 292
Oral surgical model......Page 297
Otorhinolaryngological and upper respiratory tract inflammation......Page 305
Antipyretic effects......Page 309
Cancer pain......Page 311
References......Page 313
Introduction......Page 328
Nimesulide safety profile from spontaneous reporting......Page 330
Overall pattern of adverse event reports......Page 331
Characteristics of the adverse reactions......Page 333
Gastrointestinal adverse reactions......Page 339
Hepatic reactions......Page 343
Cutaneous and allergic reactions......Page 344
Cardiovascular events......Page 345
Cardiovascular events associated with nimesulide......Page 346
Meta-analysis and systematic reviews of adverse reactions from clinical trials......Page 347
Introduction......Page 348
Types of gastrointestinal investigations......Page 349
Endoscopy studies......Page 354
Small bowel studies......Page 355
Clinical aspects of nimesulide-related hepatic reactions from published case reports......Page 356
Hepatic adverse events reported in Finland......Page 362
Biopsy data......Page 367
Benefit/risk assessments......Page 369
Gastrointestinal injury and bleeding......Page 370
Intestinal enteropathy......Page 386
Hepatotoxicity......Page 388
Renal toxicity......Page 393
Cutaneous reactions......Page 395
Discussion and conclusions......Page 396
Summary of evidence in major organ systems......Page 398
References......Page 402
A......Page 429
B......Page 430
C......Page 431
E......Page 433
G......Page 434
H......Page 435
J......Page 436
M......Page 437
N......Page 438
P......Page 440
S......Page 442
T......Page 443
V......Page 444
Z......Page 445