HISTAMINE H-2-RECEPTOR ANTAGONIST ACTION OF EBROTIDINE - EFFECTS ON GASTRIC-ACID SECRETION, GASTRIN-LEVELS AND NSAID-INDUCED GASTROTOXICITYIN THE RAT

The antagonism of histamine H-2-receptors by ebrotidine [[[2-[(diamino methylene)amino]-4-thiazolyl]methyl] ethyl]amino]methylene]-4-bromo-be nzenesulfonamide, CAS 100981-43-9, FI-3542) was assessed on isolated g uinea-pig right atrium. The dose-response curves obtained by histamine on the positive chronotropic effect in guinea-pig atrium were displac ed to the right in parallel depending on the concentration of ebrotidi ne and ranitidine without change in the maximum response with pA(2) va lues of 7.12 and 7.26, respectively. The slope of the regression line of log (DR-I) against log ebrotidine concentration was not significant ly different from unity: 0.96 (95% confidence limits: 0.89-1.03). Thes e results indicate that ebrotidine is a competitive H-2-receptor antag onist. Following intravenous administration to rats, ebrotidine inhibi ted histamine- and pentagastrin-stimulated acid secretion in a dose-de pendent manner, ED50 being 0.21 and 0.44 mg/kg, respectively. After or al administration to fasting rats 3 h before their sacrifice, ebrotidi ne decreased the total acid contents of the stomach in a dose-dependen t manner, ED50 being 7.5 mg/kg. After a single dose of 100 mg/kg in fa sting rats, ebrotidine increased significantly serum gastrin levels wi thin 2 and 5 h after administration, but 8 h after administration seru m gastrin levels returned to normal values. In contrast, ranitidine at a single oral dose of 100 mg/kg increased serum gastrin levels more m arkedly within 2 and 5 h after administration, while after 8 h, this i ncrease still persisted although without significant differences with respect to control, and after 24 h levels returned to normal values. B oth ebrotidine and ranitidine were administered orally at a dose of 10 0 mg/kg for 26 days showing significant increments in plasma gastrin l evels 5 h after administration. Such increments were not so marked aft er ebrotidine and normal Values were attained at 24 h after administra tion. The results obtained after repeated oral administration for 15 d ays of ebrotidine and ranitidine at the doses of 15 and 50 mg/kg demon strated that ebrotidine did not increase significantly serum gastrin l evels with respect to control 2 h after administration, and no dose-re lated effect was observed. In contrast, ranitidine increased serum gas trin levels significantly and in a dose-dependent manner with respect to control group. ED50 Values of ebrotidine obtained in the experiment s 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, indometac in and naproxen, respectively. ED50 values of ranitidine were of the s ame order: 20.6, 13.9, > 50 and 15.1 mg/kg.