thiourea and mifentidine

The H2-receptor antagonists mifentidine and cimetidine were compared for their ability to antagonize the activation of H2-receptors in the conscious dog. Dose-response curves to dimaprit in stimulating gastric secretion were displaced to the right in a dose-related fashion by both drugs. Schild and Eadie-Hofstee analysis of these data indicated that mifentidine and cimetidine inhibited in vivo activation of H2-receptors in a manner compatible with competitive surmountable antagonism. Mifentidine displayed a 24fold greater potency than cimetidine as H2 antagonist in the conscious dog.

Topics: Animals; Cimetidine; Dimaprit; Dogs; Dose-Response Relationship, Drug; Female; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Imidazoles; Random Allocation; Receptors, Histamine H2; Thiourea

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.

Topics: Animals; Bethanechol; Bethanechol Compounds; Cimetidine; Cysteamine; Dimaprit; Duodenal Ulcer; Female; Gastric Juice; Gastrointestinal Motility; Histamine H2 Antagonists; Imidazoles; Male; Ranitidine; Rats; Stomach Ulcer; Thiourea

The protective effect of cimetidine, ranitidine and a newer H2-receptor antagonist, mifentidine (proposed INN), on models of gastric and duodenal damage, caused by activation of H2 receptors, was studied. Gastric erosions were induced in rats by intravenous dimaprit (100 mg/kg) while duodenal damage was investigated in guinea pigs following subcutaneous administration of dimaprit (2 mg/kg, 6 doses). All the compounds reduced or abolished gastric and duodenal damage in rats and guinea pigs, mifentidine being more potent than both cimetidine and ranitidine. The antiulcer effect of the H2-receptor antagonists was related to the dose and to their ability to inhibit dimaprit-induced gastric acid secretion. The duration of action proved to be different for the three compounds. According to the two dosing schedules adopted to evaluate the duration of action, mifentidine, compared to cimetidine and ranitidine, required considerably lower oral dosages to display its protective effect.

Topics: Animals; Cimetidine; Dimaprit; Disease Models, Animal; Duodenal Ulcer; Female; Guinea Pigs; Histamine H2 Antagonists; Imidazoles; Ranitidine; Rats; Rats, Inbred Strains; Receptors, Histamine H2; Stomach Ulcer; Thiourea

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.

Topics: Animals; Cats; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Gastric Acid; Half-Life; Histamine H2 Antagonists; Imidazoles; Ranitidine; Thiourea; Time Factors

The generation of secondary cytotoxic T-lymphocyte (CTL) responses in vitro toward allogeneic P815 mastocytoma cells were suppressed 60-80% when 10(-4) mol/l histamine, 10(-5) mol/l dimaprit (S-[3-(N,N-dimethylamino) propyl]isothiourea dihydrochloride) or 10(-5) mol/l impromidine were present in the culture. Three lines of evidence suggest this observation was a result of an active suppression mechanism and not a result of drug toxicity: Control level activity was obtained when Interleukin-2/T-cell growth factor (IL-2) containing supernatants were added to suppressed cultures. Removal of drug after incubation resulted in control level responses upon reculture. The addition of these H2 agonists to spleen cells from nonimmune animals did not affect the primary CTL response to P815. The effects of H1 and H2 antagonists were also tested in this model. The observed suppression was abrogated by the H2 antagonists cimetidine and mifentidine but not by the H2 antagonist ranitidine nor H1 antagonists, chlorpheniramine, pyrilamine or diphenhydramine. These results suggest regulation of CTL differentiation to alloantigens can be modulated by H2 reactive entities.

Topics: Animals; Cell Line; Cell Survival; Chlorpheniramine; Chromium Radioisotopes; Cimetidine; Dimaprit; Diphenhydramine; Histamine; Histamine Antagonists; Imidazoles; Immunity, Cellular; Impromidine; Kinetics; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Ranitidine; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Thiourea