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

Abstract

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 ED_50s were 2.3, 12.2 and 92.8 mg·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 ED_50s 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·kg^-1 intravenously) and cysteamine (250 mg· kg^-1 subcutaneously), respectively. As far as gastric ulcer is concerned, the ED_50s (the effective dose which protected 50% of the animals from lesions) were 0.23, 4.40 and 9.70 mg·kg^-1 for mifentidine, ranitidine and cimetidine, respectively. As regards duodenal ulcer, the ED₅₀ was 4.48 for mifentidine and 150.00 mg·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.

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

“…One hour after intravenous administration, dimaprit induced gastric damage in almost all the treated animals. As previously described (Scarpignato et al, 1986), this damage consisted of single prepyloric antral erosions. Both H2-antagonists were able to reduce ulcer incidence in a dose-dependent manner ( Figure 5).…”

“…Since vagal stimulation following pylorus ligation in the rat causes mobilization of histamine (Code, 1982), this model appears to be suitable for the evaluation of antisecretory properties of H2-receptor antagonists and has been successfully employed in our laboratory to study new compounds of this type (Scarpignato et al, 1986 Gastric emptying was measured by a method previously described and validated (Scarpignato, 1983;Scarpignato et al, 1984;. The test meal consisted of 1.5 ml per rat of a prewarmed (350C) solution of phenol red (50mg dissolved in 100 ml of aqueous methylcellulose; 1.5% w/v).…”

“…In this paper we compared famotidine and ranitidine in two different models of gastric and duodenal ulcer reported to be suitable for the evaluation of H2-receptor antagonists (Scarpignato et al, 1986). The dimaprit-induced gastric damage results from H2-receptor stimulation (Del Soldato et al, 1982), whereas the pathogenesis of cysteamine-induced duodenal ulcer is complex.…”

Pharmacokinetics of mifentidine after single and multiple oral administration to healthy volunteers.

“…In vivo and in vitro studies mifentidine Pagani et al, have shown the compound is a competitive H2-1985). Evidence suggests that mifentidine is at receptor antagonist (Bertaccini etal., 1984; Pagani least three times more potent than ranitidine in etal., 1985;Poli etal., 1984Poli etal., , 1985Giachetti etal., inhibiting gastric acid secretion Micheletti et al, 1985Micheletti et al, ) without significant 1985Scarpignato et al, 1985) and longer acting activity at H,-receptors (Montagna et al, 1982) than either cimetidine or ranitidine (Scarpignato or at cholinergic receptors (Bertaccini et al, et al, , 1986. In addition, the antiulcer activity against a variety of experimentallyinduced gastric and duodenal ulcers was found to be very high (Scarpignato et al, 1986;Del Soldato et al, 1985).…”

Cimetidine Inhibition of Dimaprit-Induced Writhing in the Rat

“…In an attempt to set up a model of Hireceptor mediated gastric damage [4] to be used in the evaluation of antiulcer properties of Hi-receptor antagonists [11], we observed that ulcerogenic doses ofdimaprit (a selective H2-receptor agonist), administered intraperitoneally in rats, invariably cause signs of ab dominal discomfort, such as twisting, exten sion of hind limbs, turning and flexion of the trunk. These features are characteristic of the 'writhing phenomenon' that follows intraper itoneal injection of phenylquinone and other pain-causing substances commonly em ployed in analgesic tests [9].…”