Villegas I, Alarcón de la Lastra C, La Casa C, Motilva V, Martín M J
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Profesor García González Street, 41012, Seville, Spain.
Eur J Pharmacol. 2001 Feb 23;414(1):79-86. doi: 10.1016/s0014-2999(00)00883-9.
Large intestinal ulcers, bleeding and perforation are occasionally due to non-steroidal anti-inflammatory drugs (NSAID). In addition to suppression of prostaglandins synthesis, a number of factors have been implicated, including enterohepatic recirculation, food intake and vascular injury with oxygen free-radical generation. The present study aimed to determine the effect of food intake and the role of oxidative stress in the pathogenesis of intestinal injury induced by oral administration of meloxicam (preferential cyclooxygenase-2 inhibitor) vs. piroxicam (preferential cyclooxygenase-1 inhibitor). Therefore, the activity of oxidative stress-related enzymes such as myeloperoxidase, xanthine oxidase and superoxide dismutase, as well as levels of lipid peroxides and glutathione homeostasis were studied in an experimental model using re-fed rats. The animals treated with piroxicam (10-20 mg/kg) had a dose-dependent increase in the severity of intestinal lesions, but only the highest dose of meloxicam (15 mg/kg) caused macroscopic damage. The severity of piroxicam and meloxicam-induced damage was correlated with a significant increase of xantine oxidase activity and a decrease of superoxide dismutase activity and glutathione levels (P<0.05 and P<0.001 vs. control). In contrast, there was no significant neutrophil infiltration of the intestine after dosing. Our results support the hypothesis that oxygen free radicals, probably derived via the action of xantine oxidase, the decrease in superoxide dismutase activity, and depletion of mucosal glutathione contribute to the pathogenesis of meloxicam and piroxicam-induced intestinal ulceration in re-fed rats.
大肠溃疡、出血和穿孔偶尔是由非甾体抗炎药（NSAID）引起的。除了抑制前列腺素合成外，还涉及许多因素，包括肠肝循环、食物摄入以及伴有氧自由基生成的血管损伤。本研究旨在确定食物摄入的影响以及氧化应激在口服美洛昔康（选择性环氧化酶-2抑制剂）与吡罗昔康（选择性环氧化酶-1抑制剂）所致肠道损伤发病机制中的作用。因此，在使用再喂养大鼠的实验模型中，研究了髓过氧化物酶、黄嘌呤氧化酶和超氧化物歧化酶等氧化应激相关酶的活性，以及脂质过氧化物水平和谷胱甘肽稳态。用吡罗昔康（10 - 20mg/kg）治疗的动物肠道损伤严重程度呈剂量依赖性增加，但只有最高剂量的美洛昔康（15mg/kg）导致肉眼可见的损伤。吡罗昔康和美洛昔康所致损伤的严重程度与黄嘌呤氧化酶活性显著增加、超氧化物歧化酶活性降低以及谷胱甘肽水平降低相关（与对照组相比，P<0.05和P<0.001）。相比之下，给药后肠道没有明显的中性粒细胞浸润。我们的结果支持这样的假设，即氧自由基可能通过黄嘌呤氧化酶的作用产生，超氧化物歧化酶活性降低以及黏膜谷胱甘肽耗竭促成了再喂养大鼠中美洛昔康和吡罗昔康所致肠道溃疡的发病机制。
