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

开发避免胃肠道损伤的 NSAID。-COX-2 选择性和 NO 释放 NSAID-

• 批准号: 10557246
• 负责人: TAKEUCHI Koji
• 金额: $ 8.64万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557246/
• 关键词: USAIDs; indomethacin; gastric lesion; small intestinal lesion; nitric oxide; 一酸化窒素; NO遊離型アスピリン; 胃粘膜傷害性; 損傷治癒; 粘膜血流

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

非甾体类抗炎药（NSAID）的使用与胃肠道完整性和功能的一系列改变有关。人们已经采取了各种方法来开发降低胃肠道毒性的非甾体抗炎药，但很少能成功降低不良反应的发生率。这些包括环氧合酶-2 (COX-2) 选择性抑制剂和释放一氧化氮 (NO) 的非甾体抗炎药。本研究探讨了COX和NO在不同情况下对胃肠黏膜管家功能的作用，以及胃肠道保护类NSAIDs（NO-阿司匹林和NO-吲哚美辛）对实验动物胃肠黏膜溃疡发生和愈合反应的影响，得到以下结果：1.吲哚美辛和阿司匹林均 其本身会引起溃疡，也会损害原有胃溃疡的愈合。前一种作用是由于 COX-1 的抑制，而后一种作用可能是由于 COX-2 的抑制，并由 COX-2 选择性 NSAID NS-398 模仿。释放 NO 的 NSAID，如 NCX-4016（阿司匹林衍生物）或 NCX-530（吲哚美辛衍生物），尽管会抑制 COX-1 和 COX-2，但仍能保护胃免受损伤并保持胃溃疡的愈合反应，这可能是因为 NO.2 的有益作用。吲哚美辛引起的小肠病变的致病机制涉及超氧自由基以及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造成的，过氧亚硝酸盐是在超氧自由基存在下由 NO 产生的。肠杆菌在粘膜中的第一步移位需要激活iNOS/NO和中性粒细胞等多种因子，它们都参与了吲哚美辛引起的肠道病变的发病机制。此外，NO在吲哚美辛引起的肠道溃疡的发病机制中发挥双重作用； cNOS 产生的 NO 通过维持肠粘膜的完整性来对抗吲哚美辛，而 iNOS 产生的 NO 在溃疡形成过程中发挥着关键的致病作用。较少的

项目成果

Takeuchi K. et al.: "Gastrointestinal sparing anti-inflammatory drugs - Effects on ulcerogenic and healing responses-"Current Pharmaceutical Design (in press).

Takeuchi K. 等人：“胃肠道保护抗炎药物 - 对溃疡发生和愈合反应的影响 -”当前药物设计（正在印刷中）。

Shinichi Kato, Akiko Tanaka, Akira Konaka, Tomonori Kunikata and Koji Takeuchi: "Changes in gastric mucosal ulcerogenic responses in rats with adjuvant arthritis : Role of nitric oxide."Alimentary Pharmacology and Therapeutics. Vol. 13. 833-840 (1999)

Shinichi Kato、Akiko Tanaka、Akira Konaka、Tomonori Kunikata 和 Koji Takeuchi：“佐剂关节炎大鼠胃粘膜溃疡反应的变化：一氧化氮的作用。”消化药理学和治疗学。

Takeuchi K.et al.: "Role of nitric oxide in pathogenesis of aspirin-induced gastric mucosal damage in rats." Digestion. 59. 298-307 (1998)

Takeuchi K.等人：“一氧化氮在阿司匹林引起的大鼠胃粘膜损伤发病机制中的作用。”

Takeuchi K.et al.: "Effects of COX-2 selective and NO-releasing NSAIDs on gastric ulcerogenic responses." Journal of Pharmacology and Physiology. 49. 501-513 (1998)

Takeuchi K.等人：“COX-2 选择性和 NO 释放型 NSAID 对胃溃疡反应的影响。”

Takeuchi K. et al.: "Effects of COX-2 selective and NO-releasing NSAIDs on gastric ulcerogenic responses"Journal of Physiology and Pharmacology. 49. 501-513 (1998)

Takeuchi K.等人：“COX-2选择性和NO释放NSAIDs对胃溃疡反应的影响”生理学和药理学杂志。