ヒスタミンH[2]受容体拮抗薬ファモチジンの薬理学的特性 : 特にシメチジンとの比較 Pharmacological profile of famotidine, a histamine H2-receptor antagonist : With special reference to the comparison with cimetidine.

博士論文

In order to examine the pharmacological properties of famotidine， the potencyand selectivity of famotidine on H2－antagonizing activity， and the mechanismsfor the gastric mucosal protection by famotidine were investigated and mainlycompared with those of cimetidine． ln addition， the effects of famotidine andcimetidine on cardiovascular and bronchial functions， and pharmacokinetic druginteractions with muscle relaxant and narcotics were also examined．1． Famotidine inhibited the depressor response to dimaprit in anesthetized dogsand the hypersecretory response to histamine in stomach－perfused， anesthetizedrats． Famotidine was 166 times more potent than cimetidine in the former test and 108 times more so in the latter one．2． The development of gastric lesions produced by taurocholate－histamine andhemorrhage－histamine was dose－dependently inhibited by famotidine at doses ofwhich suppressed histamine－induced acid secretion in pylorus－ligated rats．3． Famotidine also prevented gastric mucosal lesions induced by taurocholateserotonin， HCI－aspirin， HCI-ethanol and iodoacetamide all of which concern the damage of the mucosal defensive factors in rats． Cimetidine， pirenzepine and cetraxate showed the inhibitory effects on almost all types of the gastric lesions but their inhibitory effects were much less potent than those of famotidine． The inhibitory effects of famotidine and cimetidine on HCI－ethanol-evoked mucosal lesion were not influenced by pretreatment with indomethacin．4． Famotidine and cimetidine inhibited the decreases in gastric mucosal blood flow caused by hemorrhage and by HCI-ethanol and the reduction of the mucosal contents of glycoprotein induced by water immersion restraint stress． These H2-antagonists also increased the transfer of bicarbonate into the gastric lumen． Furthermore， famotidine， but not cimetidine， was effective in increasing the transgastric potential difference(PD) and promoted the recovery of decreased transgastric PD induced by HCI-ethanol in rats．5． Famotidine did not affect cardiovascular and bronchial functions in dogs anesthetized with pentobarbital or the mixture of a combination of halothane，nitrous oxide and oxygen， and did not produce any pharmacokinetic drug interactions with hexobarbital and muscle relaxants． On the contrary， cimetidine significantly prolonged the sleeping times induced by hexobarbital in mice in addition to causing the decreases in heart rate， blood pressure， cardiac contractility and coronary blood flow in dogs． No hemodynamic changes wereobserved after famotidine in dogs whose cardiac function was depressed by propranolol. 6． These results indicate that famotidine is a competitive and selective H2－receptor antagonist． The preventive effects of famotidine on gastric lesions in rats is thought to be attributable not only to suppress acid secretion but also to activate the gastric rnucosal defensive mechanisms． lt is， furthermore，suggested that famotidine is far superior to cimetidine because of its potent H2-antagonizing， antisecretory and antiulcer activities besides its negligible effects on cardiovascular and bronchial functions, and pharmacokinetic drug interactions．