Wallace J L, Reuter B, Cicala C, McKnight W, Grisham M B, Cirino G
Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Alberta, Canada.
Gastroenterology. 1994 Jul;107(1):173-9. doi: 10.1016/0016-5085(94)90074-4.
BACKGROUND/AIMS: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is limited by their ability to induce gastrointestinal injury. Two NSAIDs were modified by incorporation of an nitroxybutyl moiety. The short-term ulcerogenic and anti-inflammatory properties of these derivatives were compared with the native NSAIDs.
Rats were given flurbiprofen, ketoprofen, or their respective derivatives, and the extent of gastric damage and effect on gastric prostaglandin E2 synthesis was assessed. The damage-promoting effects of these compounds were also compared following twice-daily administration for 1 week. Anti-inflammatory properties were examined using a carrageenan-induced paw edema model.
The derivatives of flurbiprofen and ketoprofen caused significantly less short-term gastric mucosal injury at all doses tested, despite producing comparable suppression of prostaglandin synthesis. The NSAID derivatives also showed comparable anti-inflammatory activity to the native compounds. The flurbiprofen derivative inhibited collagen-induced platelet aggregation significantly more than the native NSAID. Plasma nitrate/nitrite levels increased significantly following administration of the flurbiprofen derivative, consistent with release of a nitrogen oxide.
Addition of a nitroxybutyl moiety to two NSAIDs markedly reduced the ability of these agents to induce short-term gastric injury but did not interfere with their ability to suppress inflammatory processes, inhibit prostaglandin synthesis, or inhibit platelet aggregation. These NSAID derivatives may therefore represent a novel class of anti-inflammatory drugs with markedly less ulcerogenic effects on the stomach.
背景/目的：非甾体抗炎药（NSAIDs）的使用因其诱发胃肠道损伤的能力而受到限制。通过引入硝氧丁基部分对两种NSAIDs进行了修饰。将这些衍生物的短期致溃疡和抗炎特性与天然NSAIDs进行了比较。
给大鼠服用氟比洛芬、酮洛芬或它们各自的衍生物，并评估胃损伤程度以及对胃前列腺素E2合成的影响。在每日给药两次，持续1周后，还比较了这些化合物的促损伤作用。使用角叉菜胶诱导的爪肿胀模型检查抗炎特性。
尽管氟比洛芬和酮洛芬的衍生物对前列腺素合成的抑制作用相当，但在所有测试剂量下，它们引起的短期胃黏膜损伤明显较少。NSAID衍生物还显示出与天然化合物相当的抗炎活性。氟比洛芬衍生物对胶原诱导的血小板聚集的抑制作用明显强于天然NSAID。服用氟比洛芬衍生物后，血浆硝酸盐/亚硝酸盐水平显著升高，这与一氧化氮的释放一致。
在两种NSAIDs中添加硝氧丁基部分显著降低了这些药物诱发短期胃损伤的能力，但不影响它们抑制炎症过程、抑制前列腺素合成或抑制血小板聚集的能力。因此，这些NSAID衍生物可能代表一类对胃致溃疡作用明显较小的新型抗炎药。
