Safety Pharmacology of Antiinflammatory Drugs
- PDF / 190,162 Bytes
- 10 Pages / 547.087 x 762.52 pts Page_size
- 3 Downloads / 255 Views
I.K.1 I.K.2 I.K.3
I.K.4 I.K.5
General Considerations . . . . . . . . Ulcerogenic Effect in Rats . . . . . . Measurement of Gastric Mucosal Damage by Intragastric Inulin . . . . . . . . . . . . . . . . . . . . . . . . . . Determination of Blood Loss . . . Determination of Specific COX-1 and COX-2 Inhibition . .
233 233
et al. 2000, Weir et al. 2003, Clark et al. 2004, Spektor & Fuster 2005, Mitchell & Warner 2006). REFERENCES
235 235 236
I.K.1 General Considerations Gastrointestinal side effects are among the most frequent of the untoward or adverse reactions associated with orally ingested anti-inflammatory or anti-arthritic agents. Nonsteroidal anti-inflammatory agents, like indomethacin and acetyl-salicylic acid, induce gastric lesions in man and in experimental animals by inhibition of gastric cyclo-oxygenase resulting in less formation of prostacyclin, the predominant prostanoid produced in the gastric mucosa. The risk of gastrointestinal ulceration, bleeding and even perforation with non-steroidal anti-inflammatory drug therapy is well known (Hawkey 1994; Lanas et al. 2003). The mechanisms by which these drugs cause gastro-intestinal irritation are complex (Rainsford 1989). Deleterious effects may result from local actions, which cause injuries to the submucosal capillaries with subsequent necrosis and bleeding, or from inhibition of the formation of protective prostaglandins. Unfortunately, methods in safety pharmacology and safety toxicology were not able to predict the risk of serious cardiovascular events (myocardial infarction and stroke), which became apparent after treatment of patients for more than 18 months with a selective COX-2 antagonist (VIGOR study group, Bombardier et al. 2000, FDA Drug Information September 30, 2004). The mechanism of action of these effects remains to be clarified, since other long-term studies did not show an increased cardiovascular risk (Silverstein
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davies B, Day R, Ferraz MB, Schnitzer TJ for the VIGOR study group (2000) Comparison of upper gastrointestinal toxicty of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 343:1520–1528 Clark DWJ, Layron D, Shakir SAW (2004) Do some inhibitors of COX-2 increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology. Drug Safety 27:427–456 Hawkey CJ (1994) Review article: Aspirin and gastrointestinal bleeding. Aliment Pharmacol Ther 8:141–146 Lanas A, Panes J, Pique JM (2003) Clinical implication of COX-1 and/or COX-2 inhibition for the distal gastrointestinal tract. Curr Pharm Des 9:2253–2266 Mitchell JA, Warner TD (2006) COX isoforms in the cardiovascular system. Understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov 5:75–86 Rainsford KD (1989) Gastrointestinal side effects. In: Pharmacological Methods in the Control of Inflammation. Alan R Liss Inc, pp 343–362 Silverstein FE, Faich G, Goldstein JL, Simon SL, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, B
Data Loading...
