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

非甾体类抗炎药（NSAIDs）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胃肠道毒性的非甾体抗炎药，但很少有方法成功地降低了不良反应的发生率。其中包括环氧化酶-2（COX-2）选择性抑制剂和一氧化氮（NO）释放非甾体抗炎药。在本研究中，我们研究了COX和NO在不同情况下对胃肠道黏膜的清洁功能的作用，以及胃肠保护非甾体抗炎药（NO-阿司匹林和NO-吲哚美辛）对实验动物胃肠道粘膜溃疡和愈合反应的影响，得到以下结果：1。吲哚美辛和阿司匹林本身都是溃疡源性的，也会损害原有胃溃疡的愈合。前者的作用是由于对COX-1的抑制，而后者的作用可能是由于对COX-2的抑制，并由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），尽管抑制COX-1和COX-2，但保护胃免受损伤并保持胃溃疡的愈合反应，可能是因为2的有益作用。吲哚美辛致小肠病变的致病机制涉及超氧自由基和iNOS产生的NO。一氧化氮的有害作用可能是由一氧化氮在超氧自由基存在下产生的过氧亚硝酸盐的细胞毒性作用造成的。肠杆菌在粘膜中的易位首先需要激活iNOS/NO、中性粒细胞等多种因子，它们都参与了吲哚美辛诱发的肠道病变的发病机制。此外，NO在消炎痛致肠道溃疡的发病机制中发挥双重作用；cNOS产生的NO通过维持肠黏膜的完整性对吲哚美辛具有保护作用，而iNOS产生的NO在溃疡形成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