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.