Pharmacology of ORF 17578, a new histamine H2-receptor antagonist: comparison with cimetidine and ranitidine

This paper describes the pharmacology of ORF 17578, a new histamine H2-receptor antagonist, in comparison to the standard H2-blockers cimetidine and ranitidine. ORF 17578 inhibited betazole-stimulated gastric acid output in gastric fistula dogs and gastric acid secretion in pylorus-ligated rats. When administered enterally (p.o. or i.d.) ORF 17578 (ED50 = 0.21 mg/kg in dogs and 2.5 mg/kg in rats) was 10 to 11 times more potent than cimetidine and 1.8 to 2.1 time more potent than ranitidine in dogs and rats. In both species, duration of p.o. antisecretory activity was longer than with ranitidine. When administered parenterally ORF 17578 (ED50 = 0.15 mg/kg i.v. in dogs and 1.1 mg/kg i.p. in rats) was more potent than cimetidine and ranitidine in rats and similar in potency to ranitidine in dogs. Comparison of parenteral to enteral potencies suggests that ORF 17578 was well absorbed from the gastrointestinal tract of both species with a bioavailability profile similar to that of ranitidine. In rabbit isolated parietal cells (pA2 = 7.53) and guinea-pig isolated atria (pA2 = 7.26), ORF 17578 competitively antagonized the effects of histamine with a potency greater than cimetidine and similar to ranitidine. Results from several additional test systems indicated that ORF 17578 was specific for the histamine H2-receptor and did not exhibit the additional pharmacology often associated with cimetidine.