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

非甾体抗炎药（NSAID）的使用与胃肠道完整性和功能的一系列改变有关。已经采取了各种方法来开发具有降低的胃肠道毒性的NSAID，并且很少成功地降低不良反应的发生率。这些包括环氧合酶-2（考克斯-2）选择性抑制剂和一氧化氮（NO）释放NSAID。在本研究中，我们研究了考克斯和NO在不同情况下胃肠道粘膜管家功能中的作用，以及胃肠道保护性NSAID的作用（NO-阿司匹林和NO-吲哚美辛）对实验动物胃肠道粘膜的溃疡形成和愈合反应的影响，并获得了以下结果; 1.消炎痛和阿司匹林本身都是致溃疡的，也会损害原有胃溃疡的愈合。前一种作用是由于抑制考克斯-1，而后一种作用可能是由于抑制COX-1， ...更多信息 考克斯-2的作用，并由NS-398模拟，考克斯-2选择性NSAID。释放NO的非甾体抗炎药，如NCX-4016（阿司匹林衍生物）或NCX-530（消炎痛衍生物），尽管同时抑制考克斯-1和考克斯-2，但可以保护胃免受损伤并保留胃溃疡的愈合反应，这可能是因为NO.2的有益作用。吲哚美辛诱导的小肠病变的致病机制涉及超氧自由基以及由iNOS产生的NO。NO的有害作用可能是由过氧亚硝酸盐的细胞毒性作用，产生NO在超氧自由基的存在下。肠道细菌在黏膜中的移位首先需要各种因子如iNOS/NO和中性粒细胞的激活，它们都参与了吲哚美辛诱导的肠道病变的发病机制。此外，NO在吲哚美辛诱导的肠溃疡的发病机制中发挥双重作用;由cNOS产生的NO通过维持肠粘膜的完整性而对吲哚美辛具有保护作用，而由iNOS产生的NO在溃疡发生过程中起关键的致病作用。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