The gastrin-receptor antagonist L-365,260 inhibits stimulated acid secretion in humans.
We investigated the effect of a novel gastrin-cholecystokinin-B receptor antagonist, L-365,260 [(3R)-3(N'-3-methylphenyl)ureido)-1,3-dihydro-5-phenyl- 2H-1,4-benzodiazepin-2-one], on gastric acid secretion in humans. In a double-blind, four-period crossover study, eight subjects received single oral doses of placebo or of 2.5, 10, or 50 mg L-365,260, followed by an intravenous infusion of pentagastrin at doses of 0.05, 0.4, and 2 micrograms/kg/hr for successive 30-minute periods. L-365,260 caused a dose-dependent inhibition of pentagastrin-stimulated gastric acid secretion. A single oral dose of 50 mg L-365,260 produced 50% inhibition of the gastric acid output response to pentagastrin (0.4 micrograms/kg/hr) when the mean (+/- SD) plasma L-365,260 concentration was 502 +/- 108 ng/ml. Plasma L-365,260 concentrations (all doses combined) and the inhibition of gastric acid output were correlated with a correlation coefficient of r = 0.45 (p < 0.05). Single oral doses of L-365,260 up to 50 mg did not inhibit basal gastric acid output or alter plasma gastrin concentrations. L-365,260 was well tolerated at oral doses up to 50 mg. These findings show that L-365,260 is an orally active antagonist at gastrin-cholecystokinin-B receptors in humans.
Murphy
M G
MG
Center for Ulcer Research and Education (CURE), Veterans Affairs Medical Center, University of California at Los Angeles School of Medicine.
Sytnik
B
B
Kovacs
T O
TO
Mertz
H
H
Ewanik
D
D
Shingo
S
S
Lin
J H
JH
Gertz
B J
BJ
Walsh
J H
JH
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001570:Benzodiazepinones / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D010418:Pentagastrin / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012016:Reference Values
D001570:Benzodiazepinones; D005755:Gastrins; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; D010418:Pentagastrin