Histamine H2-receptor antagonist action of ebrotidine. Effects on gastric acid secretion, gastrin levels and NSAID-induced gastrotoxicity in the rat.

The antagonism of histamine H2-receptors by ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl ] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) was assessed on isolated guinea-pig right atrium. The dose-response curves obtained by histamine on the positive chronotropic effect in guinea-pig atrium were displaced to the right in parallel depending on the concentration of ebrotidine and ranitidine without change in the maximum response with pA2 values of 7.12 and 7.26, respectively. The slope of the regression line of log (DR-1) against log ebrotidine concentration was not significantly different from unity: 0.96 (95% confidence limits: 0.89-1.03). These results indicate that ebrotidine is a competitive H2-receptor antagonist. Following intravenous administration to rats, ebrotidine inhibited histamine- and pentagastrin-stimulated acid secretion in a dose-dependent manner, ED50 being 0.21 and 0.44 mg/kg, respectively. After oral administration to fasting rats 3 h before their sacrifice, ebrotidine decreased the total acid contents of the stomach in a dose-dependent manner, ED50 being 7.5 mg/kg. After a single dose of 100 mg/kg in fasting rats, ebrotidine increased significantly serum gastrin levels within 2 and 5 h after administration, but 8 h after administration serum gastrin levels returned to normal values. In contrast, ranitidine at a single oral dose of 100 mg/kg increased serum gastrin levels more markedly within 2 and 5 h after administration, while after 8 h, this increase still persisted although without significant differences with respect to control, and after 24 h levels returned to normal values. Both ebrotidine and ranitidine were administered orally at a dose of 100 mg/kg for 26 days showing significant increments in plasma gastrin levels 5 h after administration. Such increments were not so marked after ebrotidine and normal values were attained at 24 h after administration. The results obtained after repeated oral administration for 15 days of ebrotidine and ranitidine at the doses of 15 and 50 mg/kg demonstrated that ebrotidine did not increase significantly serum gastrin levels with respect to control 2 h after administration, and no dose-related effect was observed. In contrast, ranitidine increased serum gastrin levels significantly and in a dose-dependent manner with respect to control group. ED50 values of ebrotidine obtained in the experiments on the prevention of NSAID-induced gastrotoxicity in the rat were 12.2, 12.5, 11.5 and 9.8 mg/kg against diclofenac, ketoprofen, indometacin and naproxen, respectively. ED50 values of ranitidine were of the same order: 20.6, 13.9, > 50 and 15.1 mg/kg.