Antisecretory and antiulcer effect of the H2-receptor antagonist famotidine in the rat: comparison with ranitidine.

1 The effects of the new H2-receptor antagonist famotidine, administered orally, on gastric secretion and emptying as well as on experimentally-induced gastric and duodenal ulcers were studied in the rat. Ranitidine was used as a reference compound. 2 Both compounds inhibited acid secretion in a dose-dependent manner. Calculated ED50 values were 0.80 and 6.84 mg kg-1 for famotidine and ranitidine, respectively. However, the duration of the antisecretory action was the same for both drugs. 3 The effect of the two drugs, administered at equiactive antisecretory doses, on gastric emptying was different. Ranitidine significantly accelerated the emptying rate whereas famotidine had no effect. 4 Famotidine reduced, in a dose-dependent manner, ulcer incidence in stomachs of dimaprit-treated rats and in duodena of cysteamine-treated animals with a potency respectively 2 and 7 times higher than that of ranitidine. 5 Famotidine is therefore an effective antisecretory and untiulcer compound. Its potency, but not its efficacy, is higher than that of ranitidine. Moreover, the duration of the antisecretory action is virtually the same for both drugs.

Inhibition of gastric acid secretion by adenosine receptor stimulation in the rat.

The effects of adenosine and its metabolically stable derivative L-phenylisopropyladenosine (L-PIA), acting mainly on A1 receptors, on gastric acid secretion were studied in the rat. Although inactive by intraduodenal route, subcutaneous adenosine significantly inhibited acid secretion. This inhibition, however, was not dose-dependent. On the contrary, L-PIA was able to decrease dose-dependently acid output by both subcutaneous and intraduodenal route, its ED50 being 0.11 mg/kg subcutaneously and 0.24 mg/kg intraduodenally. The inhibitory effect of L-PIA was reduced by prior administration of theophylline. These results suggest that activation of A1-receptors inhibits acid secretion in the rat.

The effect of the new H2-receptor antagonist mifentidine on gastric secretion, gastric emptying and experimental gastric and duodenal ulcers in the rat: comparison with cimetidine and ranitidine.

The new H2-receptor antagonist mifentidine (DA 4577) was tested for its antisecretory and gastric motor effects in comparison with cimetidine and ranitidine. The Shay rat preparation (5 h) was used for studying gastric secretion; the gastric emptying of a liquid meal was chosen for studying gastric motility. All the three compounds inhibited acid secretion in a dose-dependent fashion. Calculated ED50s were 2.3, 12.2 and 92.8 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. Therefore, in this animal model, mifentidine was about 40 times more potent than cimetidine and 5 times more potent than ranitidine. As far as gastric emptying is concerned, the effect of equiactive antisecretory doses (i.e. the respective ED50s calculated from the previously established dose-response curves) of all the three antagonists was completely different. Cimetidine delayed emptying rate, whereas ranitidine accelerated it and mifentidine was completely ineffective. However, at higher doses, also this compound affected emptying rate by reducing it dose-dependently. Gastric and duodenal ulcers were induced in the rat by dimaprit (100 mg X kg-1 intravenously) and cysteamine (250 mg X kg-1 subcutaneously), respectively. As far as gastric ulcer is concerned, the ED50s (the effective dose which protected 50% of the animals from lesions) were 0.23, 4.40 and 9.70 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. As regards duodenal ulcer, the ED50 was 4.48 for mifentidine and 150.00 mg X kg-1 for ranitidine. In this animal model, the efficacy of cimetidine was very low. Therefore an ED50 could not be determined. In conclusion, results of the present investigation demonstrated that mifentidine is a potent antisecretory compound and an effective anti-ulcer agent in the rat.

Effect of the new H2-receptor antagonist mifentidine on gastric acid secretion in the cat: comparison with cimetidine and ranitidine.

The effect of the H2-receptor antagonist mifentidine (DA 4577) was studied in conscious fistula cats in comparison with cimetidine and ranitidine. Two series of experiments were carried out. In the first, submaximal gastric secretion was induced by continuous intravenous infusion of dimaprit (a selective H2-agonist). Once a plateau of gastric secretion had been reached, antagonists were infused intravenously at increasing doses for 3 hr. Mifentidine, ranitidine, cimetidine or saline were administered in different days at random order. In the second set of experiments, equiactive doses (that is the respective ED50s calculated from the previously established dose-response curves) of all the compounds were infused during dimaprit-induced acid hypersecretion, in order to evaluate their duration of action. All the compounds inhibited acid secretion in a dose-dependent fashion. Calculated ED50s were 0.39 +/- 0.05, 0.49 +/- 0.04 and 10.13 +/- 0.33 mumol.kg-1.hr-1 for mifentidine, ranitidine and cimetidine respectively. After the infusion of the equiactives doses, the half-life (that is the time taken to return to 50% inhibition) was 76.4 +/- 14.7 min for mifentidine, 38.3 +/- 10.1 min for ranitidine and 33.6 +/- 2.9 min for cimetidine. These data demonstrate that mifentidine is a potent antisecretory compound with a duration of action longer than that of cimetidine and ranitidine.