Development of NSAIDs that spare gastrointestinal tract injury.-COX-2 selective and NO-releasing NSAIDs-

非类固醇抗炎药(NSAIDs)的使用与胃肠道完整性和功能的一系列侧面改变有关。已经采取了各种方法来开发降低胃肠道毒性的非类固醇抗炎药，但很少有人成功地降低了不良反应的发生率。这些药物包括环氧合酶-2(COX-2)选择性抑制剂和释放一氧化氮(NO)的非甾体抗炎药。在本研究中，我们研究了不同环境下COX和NO在胃肠黏膜管家功能中的作用，以及胃肠非甾体抗炎药(非阿司匹林和非吲哚美辛)对实验动物胃肠黏膜的溃疡形成和愈合反应的影响，得到了以下结果：1.消炎痛和阿司匹林本身都是溃烂的，也都会损害先前存在的胃溃疡的愈合。前者通过抑制COX-1发挥作用，后者可能通过抑制…发挥作用。COX-2表达增加，并被COX-2选择性非甾体抗炎药NS-398模拟。释放NO的非甾体抗炎药，如NCX-4016(阿司匹林衍生物)或NCX-530(吲哚美辛衍生物)，尽管同时抑制COX-1和COX-2，但保护胃免受损伤，并保留胃溃疡的愈合反应，可能是因为2号的有益作用。吲哚美辛致小肠损伤的发病机制涉及超氧阴离子自由基和iNOS产生的NO。NO的有害作用可能是通过过氧亚硝酸盐的细胞毒性作用来解释的，过氧亚硝酸盐是在超氧阴离子自由基存在下由NO产生的。肠道细菌在粘膜的第一步移位需要iNOS/NO和中性粒细胞等多种因子的激活，它们都参与了消炎痛诱导的肠道损伤的发病机制。此外，NO在消炎痛诱导的肠溃疡发病机制中具有双重作用，cNOS产生的NO通过维持肠粘膜的完整性对消炎痛具有保护作用，而iNOS产生的NO在溃疡形成过程中起着关键的致病作用。较少

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 … More 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. Less