Nimesulide - Actions and Uses

by Rainsford, K.D.

• ISBN13: 9783764370688
• ISBN10: 3764370688
• eBook ISBN(s): 9783764374105
• Edition: 1st
• Format: Hardcover
• Copyright: 2006-03-01
• Publisher: SPRINGER

Summary

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) which acts as a cyclooxygenase- 2 inhibitor but also has other novel pharmacological features which account for its effect in the control of pain and inflammation. It has become a leading NSAID in over 50 countries worldwide. This book provides a comprehensive and fully up-to-date critical review of the published literature on nimesulide, including comparisons with anti-inflammatory, analgesic and antipyretic agents. The emphasis is on the action of nimesulide in relation to its therapeutic and side effects in comparison with other established NSAIDs, including the new class of Coxibs. The chapters are written by leading experts and cover development of nimesulide, including synthesis and production, introduction, and approved uses and applications, followed by pharmacokinetics and toxicological properties, adverse reactions and their mechanisms.

Table of Contents

List of contributors	xiii
Preface	xv
The discovery, development and novel actions of nimesulide
K. D. Rainsford
Introduction	1	(3)
Discovery of R-805 - nimesulide	4	(3)
Chemical synthesis	7	(1)
Development of nimesulide	7	(4)
Physical and chemical properties	11	(3)
Chemical analysis	14	(1)
Chemical reactions of nimesulide	15	(5)
Versatile formulations	20	(4)
Novel ``non-pain'' uses of nimesulide	24	(6)
Nimesulide in cancer	25	(2)
Alzheimer's disease and neurodegenerative disorders	27	(3)
Miscellaneous uses	30	(2)
Conclusions	32	(1)
References	32	(16)
Appendix A	48	(1)
Appendix B	49	(14)
Pharmacokinetics of nimesulide
A. Bernareggi
K. D. Rainsford
Introduction	63	(1)
Physicochemical factors governing the oral bioavailability of nimesulide	63	(3)
Animal pharmacokinetics	66	(5)
Pharmacokinetics in humans	71	(43)
Absorption	71	(4)
Regional absorption	75	(2)
Effect of food on oral absorption	77	(2)
Distribution	79	(1)
Binding to blood components	80	(1)
Elimination	80	(1)
Excretion	81	(1)
Metabolism	82	(5)
Plasma pharmacokinetics of 4'-hydroxynimesulide (M1)	87	(1)
Linearity	88	(1)
Rectal administration	89	(1)
Multiple dose administration	90	(1)
Topical administration	91	(2)
Influence of gender	93	(3)
Effect of age	96	(1)
Children	97	(1)
The elderly	97	(9)
Effect of moderate renal insufficiency	106	(1)
Effect of severe hepatic failure	107	(1)
Drug interaction studies	108	(1)
Glibenclamide	108	(1)
Cimetidine	108	(1)
Antacids	108	(4)
Furosemide	112	(1)
Theophylline	112	(1)
Warfarin	113	(1)
Digoxin	113	(1)
Alteration of protein binding	114	(1)
Conclusions	114	(1)
References	115	(6)
Pharmaceutical formulations of nimesulide
A. Maroni
A. Gazzaniga
Introduction	121	(1)
Formulations for topical application	121	(1)
Formulations for systemic administration	122	(1)
Oral cyclodextrin formulations	123	(1)
Oral modified-release formulations	123	(1)
Generic formulations	124	(6)
References	130	(3)
Pharmacological properties of nimesulide
K. D. Rainsford
M. Bevilacqua
F. Dallegri
F. Gago
L. Ottonello
G. Sandrini
C. Tassorelli
I. G. Tavares
Introduction	133	(1)
In vivo pharmacological actions	133	(12)
Models of acute inflammation	133	(6)
Relationship of acute anti-inflammatory effects to prostaglandin production	139	(1)
Models of chronic inflammation	140	(2)
Analgesic activities	142	(2)
Antipyretic effects	144	(1)
Mechanisms of action of nimesulide on pathways of inflammation	145	(4)
Effects of nimesulide on arachidonic acid metabolism in vitro, ex vivo and in vivo	149	(13)
COX-2 selectivity	154	(6)
Inhibition of the synthesis of COX-2	160	(1)
Leukotriene production and lipoxygenase activity	161	(1)
Anandamide production	161	(1)
Structural aspects of cyclooxygenase (COX) activity and COX-2 inhibition by nimesulide	162	(11)
Introduction	162	(2)
Structural overview of PGHS	164	(3)
Structural studies on nimesulide	167	(3)
Experimental support for the proposed binding mode	170	(3)
Conclusions	173	(1)
Nimesulide and neutrophil functional responses	173	(14)
Introduction	173	(1)
Hallmarks of neutrophil-mediated inflammation	174	(2)
In vitro effects of nimesulide on neutrophil functions	176	(3)
Relevance of in vitro findings and ex vivo studies	179	(2)
Apoptosis and superoxide release	181	(1)
Regulation of NADH oxidase	182	(1)
Time-dependent effects	183	(1)
Phagosome and lysosome accumulation and protease inhibition	184	(1)
Other biochemical effects on leucocytes	185	(1)
Complement activation	185	(1)
Endothelial reactions and angiogenesis	186	(1)
Summary and conclusions	186	(1)
Analgesic actions of nimesulide in animals and humans	187	(10)
Molecular biology and neural mechanisms of pain	187	(3)
Central sensitisation, the wind-up phenomenon and the role of nitric oxide	190	(1)
Experimental studies in laboratory animal models	190	(5)
Experimental studies in humans	195	(1)
Conclusions	196	(1)
Actions on joint destruction in arthritis	197	(1)
Joint destruction and effects of NSAIDs	197	(1)
Regulation by eicosanoids of cartilage--synovial--leucocyte interactions	198	(4)
In vivo effects of nimesulide on cartilage and bone in experimental model systems	202	(1)
Actions of nimesulide on cartilage degradation in vitro	203	(11)
Uptake of nimesulide into synovial tissues, synovial tissues and cartilage	205	(1)
Production of PGE2, cytokines and proteoglycans in vitro	206	(1)
Ex vivo studies on regulation of metalloproteinases in patients with OA	207	(1)
Glucocorticoid receptor activation and other signalling pathways	208	(4)
Oxidant stress injury, peroxynitrite, cell injury and lipid peroxidation	212	(1)
Regulation of other cytokine or cellular reactions that might be significant in controlling inflammation	212	(2)
Smooth muscle and related pharmacological properties	214	(1)
Conclusions	215	(1)
References	215	(30)
Clinical applications of nimesulide in pain, arthritic conditions and fever
M. Bianchi
G.E. Ehrlich
F. Facchinetti
E. C. Huskisson
P. Jenoure
A. La Marca
K. D. Rainsford
NSAIDs: The survivors from the laboratory	245	(2)
Signalling from pain	245	(1)
Control of pain	246	(1)
Gastrointestinal and other untoward events	246	(1)
Efficacy or safety?	247	(1)
Purpose of this chapter	247	(1)
Osteoarthritis: A leading target for NSAIDs	247	(4)
Development of osteoarthritis	248	(1)
Should NSAIDs be used for osteoarthritis? -- efficacy	248	(1)
Should NSAIDs be used for osteoarthritis? -- tolerability	249	(1)
Choice	249	(2)
Nimesulide in the treatment of osteoarthritis	251	(8)
Nimesulide -- efficacy	251	(6)
Nimesulide -- tolerance and safety in OA patients	257	(1)
Conclusions	258	(1)
Miscellaneous rheumatic conditions	259	(1)
Rheumatoid arthritis	259	(1)
Psoriatic arthritis	259	(1)
Gout	260	(1)
The analgesic properties of nimesulide in inflammatory pain	260	(6)
Onset of analgesia	260	(1)
Comparison of analgesic properties of nimesulide with coxibs	261	(1)
Experimental studies	262	(1)
Clinical data	262	(4)
Nimesulide in the treatment of primary dysmenorrhoea and other gynaecological conditions	266	(7)
Pelvic pain and pain in dysmenorrhoea	266	(2)
Primary dysmenorrhoea	268	(1)
Definition, prevalence and diagnosis	268	(1)
Etiology	269	(1)
Nimesulide compared with other NSAIDs in the clinical management of primary dysmenorrhoea	270	(3)
Conclusions	273	(1)
NSAIDs in sports medicine	273	(10)
Introduction	273	(1)
Inflammation	274	(2)
The use of nimesulide in sports medicine	276	(2)
Topical nimesulide in acute musculoskeletal injuries	278	(5)
Acute pain models and conditions	283	(16)
Oral surgical model	283	(1)
Effects of postoperative nimesulide in oral surgery	283	(6)
Other acute surgical pain	289	(2)
Otorhinolaryngological and upper respiratory tract inflammation	291	(4)
Miscellaneous conditions	295	(1)
Antipyretic effects	295	(2)
Headache	297	(1)
Cancer pain	297	(2)
Adverse events encountered in clinical trials	299	(1)
Conclusions	299	(1)
References	299	(16)
Adverse reactions and their mechanisms from nimesulide
I. Bjarnason
F. Bissoli
A. Conforti
L. Maiden
N. Moore
U. Moretti
K. D. Rainsford
K. Takeuchi
G. P. Velo
Introduction	315	(2)
Nimesulide safety profile from spontaneous reporting	317	(9)
Overall pattern of adverse event reports	318	(2)
Characteristics of the adverse reactions	320	(6)
Causality assessment and quality of information	326	(1)
Nimesulide safety from epidemiological and population studies	326	(8)
Gastrointestinal adverse reactions	326	(4)
Hepatic reactions	330	(1)
Cutaneous and allergic reactions	331	(1)
Renal adverse events	332	(1)
Cardiovascular events	332	(1)
Cardiovascular events associated with nimesulide	333	(1)
Meta-analysis and systematic reviews of adverse reactions from clinical trials	334	(1)
Gastrointestinal tolerance of nimesulide compared with other NSAIDs: Clinical studies	335	(8)
Introduction	335	(1)
Types of gastrointestinal investigations	336	(5)
Gastrointestinal studies with nimesulide	341	(1)
Endoscopy studies	341	(1)
Small bowel studies	342	(1)
NSAIDs and inflammatory bowel disease	343	(1)
Clinical aspects of nimesulide-related hepatic reactions from published case reports	343	(14)
History	346	(1)
Clinical presentation	346	(1)
Liver function tests (LFTs)	347	(1)
Histology	347	(2)
Hepatic adverse events reported in Finland	349	(5)
Biopsy data	354	(2)
Benefit/risk assessments	356	(1)
Mechanisms of toxic reactions	357	(26)
Gastrointestinal injury and bleeding	357	(16)
Conclusions	373	(1)
Intestinal enteropathy	373	(2)
Hepatotoxicity	375	(5)
Renal toxicity	380	(2)
Cutaneous reactions	382	(1)
Discussion and conclusions	383	(2)
Summary	385	(4)
Summary of evidence in major organ systems	385	(1)
Gastrointestinal tract	385	(2)
Hepatic	387	(1)
Renal	388	(1)
Cutaneous and allergic reactions	388	(1)
Cardiovascular system	389	(1)
Overall	389	(1)
References	389	(28)
Index	417