Yamaguchi T, Mukaiyama O, Itoh K, Satoh Y, Terada A, Iizuka Y
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Eur J Pharmacol. 1993 May 12;236(1):43-50. doi: 10.1016/0014-2999(93)90225-7.
The anti-asthmatic effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a specific thromboxane A2 (TXA2) synthase inhibitor, were investigated in the ovalbumin-sensitized guinea pig asthmatic model. Although CS-518 slightly inhibited (about 25%) whole bronchoconstriction, it significantly inhibited the antigen-induced bronchoconstriction mediated by slow-reacting substance of anaphylaxis (SRS-A), which was not reduced by chlorpheniramine, a histamine H1 antagonist. On the other hand, indomethacin, a cyclooxygenase inhibitor, potentiated the SRS-A-mediated constriction. CS-518 strongly, and indomethacin slightly, suppressed the leukotriene D4-induced bronchoconstriction. CS-518 clearly inhibited the antigen-induced airway hyperresponsiveness, but this compound had no effect on the airway hyperresponsiveness induced by U-46619, a TXA2-mimetic agent, and propranolol. These results suggest that CS-518 suppresses the development of bronchoconstriction and airway hyperresponsiveness in asthmatic models by inhibition of TXA2 synthesis with the concomitant increase in bronchodilating prostaglandins such as prostaglandin E2 and prostaglandin I2.
在卵清蛋白致敏的豚鼠哮喘模型中，研究了特异性血栓素A2（TXA2）合酶抑制剂CS - 518（2 -（1 - 咪唑基甲基）- 4,5 - 二氢苯并[b]噻吩 - 6 - 羧酸钠）的抗哮喘作用。尽管CS - 518对整体支气管收缩有轻微抑制作用（约25%），但它能显著抑制由过敏反应慢反应物质（SRS - A）介导的抗原诱导的支气管收缩，而组胺H1拮抗剂氯苯那敏对此并无作用。另一方面，环氧化酶抑制剂吲哚美辛可增强SRS - A介导的收缩。CS - 518能强烈抑制，而吲哚美辛则轻微抑制白三烯D4诱导的支气管收缩。CS - 518能明显抑制抗原诱导的气道高反应性，但该化合物对TXA2模拟剂U - 46619和普萘洛尔诱导的气道高反应性无影响。这些结果表明，CS - 518通过抑制TXA2合成并伴随支气管扩张性前列腺素如前列腺素E2和前列腺素I2的增加，来抑制哮喘模型中支气管收缩和气道高反应性的发展。
