Kleine A, Kluge S, Peskar B M
Department of Experimental Clinical Medicine, Ruhr-University of Bochum, Germany.
Dig Dis Sci. 1993 Aug;38(8):1441-9. doi: 10.1007/BF01308601.
The concept that gastroprotection by agents such as mild irritants, antacids, or sucralfate is prostaglandin (PG)-mediated has been challenged recently. These agents do not reproducibly stimulate prostaglandin formation, and indomethacin does not effectively attenuate their protective potency. Rebamipide is a novel antiulcer compound. This study was designed to clarify whether eicosanoids contribute to the gastroprotective activity of the drug. In the rat stomach, rebamipide (100 and 500 mg/kg, intraperitoneally) slightly increased release of PGE2, 6-keto-PGF1 alpha, thromboxane B2, and the metabolite 15-keto-13,14-dihydro-PGE2 from mucosal fragments incubated ex vivo and significantly enhanced secretion of these products into the lumen, resulting in gastric juice eicosanoid levels exceeding those in controls several-fold. Mucosal formation of leukotriene (LT) C4 was not affected by rebamipide. Rebamipide caused substantial protection against gastric damage produced by ethanol, which was antagonized by pretreatment with indomethacin (0.1-5 mg/kg, subcutaneously). The dose-response relationship of indomethacin for inhibition of prostaglandin formation and rebamipide-induced protection correlated well and 5 mg/kg indomethacin completely prevented the protective effect of rebamipide. The results indicate that: (1) in contrast to most other protective agents, protection by rebamipide involves the endogenous prostaglandin system; (2) the increase in prostaglandin formation results from stimulation of biosynthesis, and not inhibition of degradation; (3) gastroprotection by rebamipide occurs despite increased thromboxane formation and is not associated with reduced generation of LTC4; and (4) determinations of gastric juice eicosanoids seem to be particularly useful to evaluate effects of agents increasing formation of cyclooxygenase products in the stomach.
诸如轻度刺激剂、抗酸剂或硫糖铝等药物的胃保护作用是由前列腺素（PG）介导的这一概念最近受到了挑战。这些药物并不能重复性地刺激前列腺素的形成，并且吲哚美辛也不能有效减弱它们的保护效力。瑞巴派特是一种新型抗溃疡化合物。本研究旨在阐明类二十烷酸是否有助于该药物的胃保护活性。在大鼠胃中，瑞巴派特（100和500毫克/千克，腹腔注射）可使离体培养的黏膜碎片中PGE2、6-酮-PGF1α、血栓素B2和代谢产物15-酮-13,14-二氢-PGE2的释放略有增加，并显著增强这些产物向管腔的分泌，导致胃液类二十烷酸水平比对照组高出数倍。白三烯（LT）C4的黏膜形成不受瑞巴派特影响。瑞巴派特对乙醇所致的胃损伤有显著保护作用，吲哚美辛（0.1 - 5毫克/千克，皮下注射）预处理可拮抗这种保护作用。吲哚美辛抑制前列腺素形成与瑞巴派特诱导的保护作用之间的剂量反应关系相关性良好，5毫克/千克吲哚美辛可完全消除瑞巴派特的保护作用。结果表明：（1）与大多数其他保护剂不同，瑞巴派特的保护作用涉及内源性前列腺素系统；（2）前列腺素形成的增加是由生物合成的刺激引起的，而非降解的抑制；（3）尽管血栓素形成增加，但瑞巴派特仍具有胃保护作用，且与LTC4生成减少无关；（4）测定胃液类二十烷酸似乎对评估增加胃中环氧化酶产物形成的药物的作用特别有用。
