Stegmeier K, Pill J, Müller-Beckmann B, Schmidt F H, Witte E C, Wolff H P, Patscheke H
Thromb Res. 1984 Aug 15;35(4):379-95. doi: 10.1016/0049-3848(84)90230-5.
BM 13.177 (4-[2-(benzenesulfonamido)-ethyl]-phenoxyacetic acid) is a representative of a new class of sulfonamidophenylcarboxylic acids which possess platelet-inhibitory and anti-thrombotic activity and inhibits the contraction of rabbit aorta stimulated by PG endoperoxides and TXA2. BM 13.177 5 mg/kg body weight p.o. protected rabbits from arachidonate-induced sudden death and greater than or equal to 10 mg/kg dose-dependently reduced the experimental thrombus formation induced in the rabbit aorta by perivascular administration of silver nitrate. In guinea-pigs, the collagen-induced bronchoconstriction was inhibited in a dose- and time-dependent fashion. The formation of TXA2 and the TXA2-induced platelet aggregation and smooth muscle contraction are probably crucial events in these experimental models. The protective effect of BM 13.177 may, therefore, be due to the TXA2-antagonizing effect of BM 13.177, which has been conclusively demonstrated in human platelets (PATSCHEKE and STEGMEIER, Thrombosis Res., 33, 277-288 (1984). The antagonism of TXA2 is supported by the observation that BM 13.177 also specifically inhibits the contraction of isolated arterial strips from rabbits which were stimulated with the thromboxane A2 mimetic U 46619. Schild-plot with a slope close to unity suggests a competitive type of antagonism. BM 13.177 exhibited neither anti-inflammatory nor ulcer-inducing activity of cyclooxygenase inhibitors. Furthermore it did not block the TXB2 formation in spontaneously clotting blood from rabbits and did not inhibit the release of prostacyclin-like activity from rabbit aortas. The lack of toxicological effects in long-term toxicity studies in rat and dog, together with the absence of objective and subjective side effects in the first human studies have encouraged us to initiate clinical trials in order to evaluate the therapeutic benefit of this new approach in humans.
BM 13.177（4-[2-(苯磺酰胺基)-乙基]-苯氧基乙酸）是一类新型磺酰胺基苯基羧酸的代表，这类酸具有血小板抑制和抗血栓形成活性，可抑制前列腺素内过氧化物和血栓素A2刺激引起的兔主动脉收缩。口服给予体重5mg/kg的BM 13.177可保护兔子免于花生四烯酸诱导的猝死，剂量大于或等于10mg/kg时，可剂量依赖性地减少通过硝酸银血管周围给药诱导的兔主动脉实验性血栓形成。在豚鼠中，胶原诱导的支气管收缩以剂量和时间依赖性方式受到抑制。血栓素A2的形成以及血栓素A2诱导的血小板聚集和平滑肌收缩可能是这些实验模型中的关键事件。因此，BM 13.177的保护作用可能归因于其对血栓素A2的拮抗作用，这已在人血小板中得到确凿证明（帕施克和施特格迈尔，《血栓形成研究》，33，277 - 288（1984年））。血栓素A2的拮抗作用得到以下观察结果的支持：BM 13.177还特异性抑制用血栓素A2模拟物U 46619刺激的兔离体动脉条的收缩。斜率接近1的施尔德图表明是竞争性拮抗类型。BM 13.177既不表现出环氧合酶抑制剂的抗炎活性，也不具有致溃疡活性。此外，它不会阻止兔自发凝血血液中血栓素B2的形成，也不会抑制兔主动脉中前列环素样活性的释放。大鼠和犬的长期毒性研究中缺乏毒理学效应，以及首次人体研究中没有客观和主观副作用，促使我们开展临床试验，以评估这种新方法对人类的治疗益处。
