Okabe S, Takagi K, Igata H, Kato S, Shimosako K, Yamaji Y, Seiki M
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Japan.
Jpn J Pharmacol. 1992 Jul;59(3):275-89. doi: 10.1254/jjp.59.275.
We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl.ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.
我们研究了一种新化合物N-[3-[3-(哌啶甲基)苯氧基]-丙基]-2-(2-羟乙基-1-硫代)乙酰胺.2-(4-羟基苯甲酰基)苯甲酸酯(Z-300)对组胺H2受体、大鼠和犬胃酸分泌以及大鼠急性胃十二指肠损伤或慢性胃溃疡的影响。已知的组胺H2受体拮抗剂盐酸罗沙替丁用作参考化合物。Z-300和罗沙替丁对分离的豚鼠心房的pA2值分别为6.8和7.0。这些药物在浓度低于10(-5)M时不影响豚鼠回肠对卡巴胆碱的收缩反应。口服或胃肠外给予Z-300均能显著抑制大鼠基础胃酸分泌和组胺刺激的胃酸分泌。组胺、五肽胃泌素或卡巴胆碱刺激海登海因小胃犬的胃酸分泌也被该化合物显著抑制。组胺刺激情况下，该作用持续超过7小时。口服Z-300能显著保护胃黏膜免受水浸应激、吲哚美辛、阿司匹林和盐酸乙醇诱导的损伤，并保护十二指肠黏膜免受甲吡唑和半胱胺诱导的溃疡。总体而言，这些对胃酸分泌和损伤形成的作用比罗沙替丁观察到的作用更强。Z-300能显著加速大鼠乙酸溃疡的自然愈合，并预防吲哚美辛导致的溃疡愈合延迟，而罗沙替丁则无此作用。Z-300对急性损伤和慢性溃疡的作用机制似乎主要与其强大的抗分泌和黏膜保护活性有关。
