title: Pharmacological comparison of ORF 17910, a potent, long-acting histamine H2-receptor antagonist, to cimetidine and ranitidine.
abstract: This paper describes the pharmacology of ORF 17910, a specific, long-acting histamine H2-receptor antagonist. ORF 17910 (ED50 = 0.26 mg/kg) is 26 and 2.7 times more potent p.o. than cimetidine and ranitidine, respectively, at inhibiting acid output in betazole-stimulated total gastric fistula dogs. When given i.v., ORF 17910 (ED50 = 0.06 mg/kg) is 3.6 times more potent than ranitidine. Qualitatively similar antisecretory potency differences are seen in rats (ED50 = 3.7 mg/kg intraduodenal). ORF 17910 retains 43 and 37% of its antisecretory potency 16 hr after dosing in dogs and rats, respectively, suggesting a long duration of action, whereas ranitidine is either inactive (rats) or loses 97% of its potency (dogs) at this time. When the parenteral and enteral (p.o. or intraduodenal) potencies of ORF 17910 and ranitidine are compared, ORF 17910 appears less bioavailable than ranitidine, although this difference is greater in the rat than in the dog and diminishes with time. In rabbit isolated parietal cell (pA2 = 7.96) and guinea pig isolated atria preparations (pA2 = 7.51), ORF 17910 is more potent than both cimetidine and ranitidine at inhibiting the effects of histamine. At high concentrations, the inhibitory effect of ORF 17910 in atria can not be overcome completely, a property which may contribute to its long duration of action in vivo. In several additional test systems, ORF 17910 does not exhibit any biologically significant pharmacology and appears to be specific for the histamine H2-receptor.
mesh_terms: D000726:Androgen Antagonists; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010295:Parietal Cells, Gastric / Q000187:drug effects; D010434:Pepsin A / Q000378:metabolism; D011817:Rabbits; D011899:Ranitidine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D000726:Androgen Antagonists; D006635:Histamine H2 Antagonists; D013830:Thiadiazoles; D002927:Cimetidine; C048885:ORF 17910; D011899:Ranitidine; D010434:Pepsin A