Wallace J L, Reuter B, Cicala C, McKnight W, Grisham M, Cirino G
Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Alberta, Canada.
Eur J Pharmacol. 1994 May 23;257(3):249-55. doi: 10.1016/0014-2999(94)90136-8.
In this study, we assessed the effects of addition of a nitroxybutyl moiety to diclofenac on its ulcerogenic properties. The diclofenac derivative, 'nitrofenac', was examined in terms of its ability to induce acute gastric erosions and chronic-type gastric ulcers in rats and rabbits, respectively. The effects of these compounds on prostaglandin synthesis in the stomach and at a site of peripheral inflammation were also assessed, as were their anti-inflammatory properties in a model of acute inflammation. Diclofenac dose-dependently caused acute gastric mucosal injury in the rat at all doses tested (10-40 mg/kg), that was significantly greater in severity than that observed with the same doses of nitrofenac. In rabbits, twice-daily administration of diclofenac induced penetrating antral ulcers and small intestinal damage. No damage was observed in the stomach or small intestine of rabbits receiving nitrofenac. Diclofenac and nitrofenac exerted similar inhibitory effects on prostaglandin E2 synthesis in the stomach and in a carrageenan-sponge model of peripheral inflammation. These compounds exerted similar inhibitory effects on carrageenan-induced paw edema. Nitrofenac, but not diclofenac, caused a significant increase in plasma levels of nitrate/nitrite. These results suggest that the addition of a nitroxybutyl moiety to diclofenac markedly reduces the ulcerogenic properties of this compound without interfering with its ability to inhibit cyclo-oxygenase activity or to reduce acute inflammation.
在本研究中，我们评估了在双氯芬酸上添加硝氧丁基部分对其致溃疡特性的影响。分别在大鼠和兔子中检测了双氯芬酸衍生物“硝芬酸”诱导急性胃糜烂和慢性胃溃疡的能力。还评估了这些化合物对胃和外周炎症部位前列腺素合成的影响，以及它们在急性炎症模型中的抗炎特性。在所有测试剂量（10 - 40 mg/kg）下，双氯芬酸均剂量依赖性地导致大鼠急性胃黏膜损伤，其严重程度显著高于相同剂量的硝芬酸。在兔子中，每日两次给予双氯芬酸会诱发穿透性胃窦溃疡和小肠损伤。接受硝芬酸的兔子的胃或小肠未观察到损伤。双氯芬酸和硝芬酸对胃以及角叉菜胶海绵外周炎症模型中的前列腺素E2合成具有相似的抑制作用。这些化合物对角叉菜胶诱导的爪肿胀具有相似的抑制作用。硝芬酸而非双氯芬酸会导致血浆硝酸盐/亚硝酸盐水平显著升高。这些结果表明，在双氯芬酸上添加硝氧丁基部分可显著降低该化合物的致溃疡特性，而不影响其抑制环氧化酶活性或减轻急性炎症的能力。
