Antisecretory effects of a novel and long-lasting histamine H2-receptor antagonist, YM-14471, in rats and dogs.
We investigated some properties of YM-14471 (2-2(-[2-(diaminomethyleneamino)thiazol-4-yl]methylthio)ethy l-5-[3- (diethylamino)propyl]-6-methyl-pyrimidine-4-one trihydrochloride), a new H2-receptor antagonist, in comparison with those of famotidine, cimetidine and omeprazole. In guinea pig atria, famotidine and cimetidine produced a competitive dose-dependent displacement of histamine-induced tachycardia. In contrast, low concentrations of YM-14471 showed competitive inhibition of tachycardia, whereas high concentrations were irreversible or slowly dissociable. In pylorus-ligated rats, intravenous YM-14471, famotidine and cimetidine dose-dependently inhibited basal gastric secretion with ED50 values of 0.04, 0.43 and 31.2 mg/kg, respectively. ED50 values for oral YM-14471, famotidine, cimetidine and omeprazole were 0.81, 0.42, 28.9 and 7.7 mg/kg when given at 1 hr before ligation, and 5.7, 26.7, 1639.5 and 18.6 mg/kg at 5 hr before ligation. In anesthetized dogs, intravenous YM-14471, famotidine, cimetidine and omeprazole also dose-dependently inhibited histamine (160 micrograms/kg.hr)-induced acid secretion with ED50 values of 13.7, 8.7, 333.3 and 65.3 micrograms/kg, respectively. In Heidenhain pouch dogs, YM-14471 inhibited histamine (40 micrograms/kg.hr)-induced acid secretion by both intravenous (0.02 mg/kg) and oral administration (0.3 mg/kg). Moreover, the inhibitory effect of YM-14471 was more prolonged than those of famotidine and cimetidine by either route, and it was as long as that of omeprazole dosed orally. These results suggest that YM-14471 is an irreversible or slowly dissociable H2-receptor antagonist, and has long antisecretory effect.
Yuki
H
H
Neuroscience & Gastrointestinal Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Kamato
T
T
Nishida
A
A
Fujihara
A
A
Takeda
M
M
Miyata
K
K
D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015738:Famotidine / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D006635:Histamine H2 Antagonists; D011744:Pyrimidinones; D013844:Thiazoles; D015738:Famotidine; D002927:Cimetidine; D006632:Histamine; C085921:YM 14471; D009853:Omeprazole