|Budget Amount *help
¥13,500,000 (Direct Cost : ¥13,500,000)
Fiscal Year 1999 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 1998 : ¥12,500,000 (Direct Cost : ¥12,500,000)
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a side array of alterations in gastrointestinal integrity and function. Various approaches have been taken to developing NSAIDs with reduced gastrointestinal toxicity, and few have been successfully reduced the incidence of adverse reactions. These include cyclooxygenase-2(COX-2) selective inhibitors and nitric oxide (NO)-releasing NSAIDs. In this study, we investigated the roles of COX and NO in housekeeping functions of the gastrointestinal mucosa in various circumstances, and the effects of gastrointestinal sparing NSAIDs(NO-aspirin and NO-indoemthacin), on the ulcerogenic and healing responses in the gastrointestinal mucosa of experimental animals, and obtained the following results;
1.Both indomethacin and aspirin are ulcerogenic by themselves and impair the healing of pre-existing gastric ulcers as well. The former action is due to inhibition of COX-1, while the latter effect may be acoounted for by inhibi
tion of COX-2 and mimicked by NS-398, the COX-2 selective NSAID. NO-releasing NSAIDs such as NCX-4016 (aspirin derivative) or NCX-530 (indomethacin derivative), despite inhibiting both COX-1 and COX-2, protects the stomach against demage and preserves the healing response of gastric ulcers, probably because of the beneficial action of NO.
2. The pathogenic mechanism of indomethacin-induced small intestinal lesions involves superoxide radicals as well as NO produced by iNOS. The deleterious effect of NO may be accounted for by the cytotoxic action of peroxynitrite, produced from NO in the presence of superoxide radicals. The enterobacterial translocation in the mucosa in the first step required for activation of various factors such as iNOS/NO and neutrophils, and they are all involved in the pathogenesis of indomethacin-induced intestinal lesions. In addition, NO exerts a dual action in the pathogenesis of indomethacin-induced intestinal ulceration ; NO generated by cNOS is protective against indomethacin, by maintaining the integrity of intestinal mucosa, while NO derived by iNOS play a key pathogenic role in the ulcerogenic process.