Histamine H2-receptor antagonist action of ebrotidine. Effects on gastric acid secretion, gastrin levels and NSAID-induced gastrotoxicity in the rat
Palop, D.; Agut, J.; Márquez, M.; Conejo, L.; Sacristán, A.; Ortiz, J.A.
Arzneimittel-Forschung 47(4a): 439-446
1997
ISSN/ISBN: 0004-4172 PMID: 9205740 Document Number: 476652
The antagonism of histamine H-2-receptors by ebrotidine (N-((E)-((2-(((2-((diaminomethylene)amino)-4-thiazolyl)methyl)thiolethyl)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 pA-2 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 H-2-receptor antagonist. Following intravenous administration to rats, ebrotidine inhibited histamine- and pentagastrin-stimulated acid secretion in a dose-dependent manner, ED-50 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, ED-50 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. ED-50 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, indomethacin and naproxen, respectively. ED-50 values of ranitidine were of the same order: 20.6, 13.9, gt 50 and 15.1 mg/kg.