Shinkawa R, Kiso T, Kataoka H, Isoi T, Kakita T, Shogaki T, Ohtsubo Y
Research Department, Sawai Pharmaceutical Co. Ltd., Osaka, Japan.
Yakugaku Zasshi. 1996 Oct;116(10):783-91. doi: 10.1248/yakushi1947.116.10_783.
The antagonism of histamine H2-receptor by SWR-104SA (1'-bromo-N-[3-[3-(1-piperidinylmethyl) phenoxy] propyl]-spiro [1,3-dioxolane-2,9'-pentacyclo-[4.3.0.0.(2,5)0.(3,8) 0.(4,7)]nonane]-4'-carboxamide monooxalate) was estimated using the isolated guinea-pig atrium and gastric acid secretion in rats. The concentration-response curves for the positive chronotropic effect of histamine on the atrium were displaced to the right in parallel without change in the maximum response by SWR-104SA and roxatidine acetate hydrochloride (roxatidine). The pA2 values of SWA-104SA and roxatidine acetate hydrochloride were 7.27 and 7.38, respectively. The slopes of the regression line of log (DR-1) against log SWR-104SA and roxatidine concentration were 1.00 and 0.92, respectively. There was no significant difference between the two compounds with respect to the histamine H2-receptor antagonism and/or binding manner in vitro. In the rat gastric fistula model stimulated by histamine, however, antisecretory potency of SWR-104SA was 3 times less than that of roxatidine. SWR-104SA given p.o. prevented the formation of gastric lesion induced by HCl-ethanol and indomethacin dose-dependently, roxatidine also prevented its formation by HCl-ethanol, but failed to prevent that by indomethacine. These antiulcer activities of SWR-104SA were shown at the lesser doses of antisecretory activity. On the other hand, roxatidine did not prevent the ulcer formation at the same dose level of antisecretory activity. These results indicate that the antiulcer effect of SWR-104SA is not caused by the antisecretory action alone. In addition, the mucosal protective activity of SWR-104SA for HCl-ethanol induced gastric lesion was independent of endogenous prostaglandins. Moreover SWR-104SA had inhibitory effects on indomethacin-induced gastric hypermotility in rats. These actions may partly explain the gastric protection of this compound and additional mechanisms such as mucosal blood flow could be involved in the antiulcer efficacy. Consequently, it appears that SWR-104SA is a new antiulcer drug that exerts a potent cytoprotective effect in addition to its gastric antisecretory activity.
利用离体豚鼠心房和大鼠胃酸分泌，评估了SWR - 104SA（1'-溴 - N - [3 - [3 - (1 - 哌啶基甲基)苯氧基]丙基] - 螺[1,3 - 二氧戊环 - 2,9'-五环 - [4.3.0.0.(2,5)0.(3,8)0.(4,7)]壬烷] - 4'-甲酰胺单草酸盐）对组胺H2受体的拮抗作用。组胺对心房的正性变时作用的浓度 - 反应曲线在SWR - 104SA和盐酸罗沙替丁（罗沙替丁）作用下平行右移，最大反应无变化。SWA - 104SA和盐酸罗沙替丁的pA2值分别为7.27和7.38。log(DR - 1)对SWR - 104SA和罗沙替丁浓度的回归线斜率分别为1.00和0.92。在组胺H2受体拮抗作用和/或体外结合方式方面，这两种化合物之间无显著差异。然而，在组胺刺激的大鼠胃瘘模型中，SWR - 104SA的抗分泌效力比罗沙替丁低3倍。口服给予SWR - 104SA可剂量依赖性地预防盐酸 - 乙醇和吲哚美辛诱导的胃损伤形成，罗沙替丁也可预防盐酸 - 乙醇诱导的胃损伤形成，但不能预防吲哚美辛诱导的胃损伤形成。SWR - 104SA的这些抗溃疡活性在较低剂量的抗分泌活性时即可表现出来。另一方面，罗沙替丁在相同剂量水平的抗分泌活性时不能预防溃疡形成。这些结果表明，SWR - 104SA的抗溃疡作用并非仅由抗分泌作用引起。此外，SWR - 104SA对盐酸 - 乙醇诱导的胃损伤的黏膜保护活性与内源性前列腺素无关。而且，SWR - 104SA对吲哚美辛诱导的大鼠胃动力亢进有抑制作用。这些作用可能部分解释了该化合物的胃保护作用，并且可能涉及诸如黏膜血流等其他机制参与其抗溃疡疗效。因此，SWR - 104SA似乎是一种新型抗溃疡药物，除了具有胃抗分泌活性外，还具有强大的细胞保护作用。
