Effects of acute and repeated intravenous administration of L-692,585, a novel non-peptidyl growth hormone secretagogue, on plasma growth hormone, IGF-1, ACTH, cortisol, prolactin, insulin, and thyroxine levels in beagles

Abstract

Abstract L-692,585 is a 2-hydroxypropyl derivative of L-692,429, both novel non-peptidyl growth hormone (GH) secretagogues. The effects of single and repeated intravenous administration of L-692,585 on serum or plasma GH and other hormones in beagles were evaluated. In a balanced 8-dog dose-ranging study, compared to the saline control with a mean (± s.e.m.) after-dose serum GH peak of 6·1 ± 1·3 ng/ml, L-692,585 significantly increased (P<0·05) peak GH concentrations 4·3-fold (32·5 ± 7·0 ng/ml) at a dose of 0·005 mg/kg, 7-fold (49·4±10·6 ng/ml) at a dose of 0·02 mg/kg, and 21-fold (134·3±29·0 ng/ml) at a dose of 0·10 mg/kg. Total GH release, expressed as area under the curve, showed a similar dose-dependent increase. Peak GH levels were recorded at 5 or 15 min after dosing with the levels returning to near baseline by 90 min. Serum cortisol levels were increased above saline control levels in a dose-dependent manner; however, the increases were modest compared to the GH increases. Based on peak responses and total GH release, L-692,585 was 10- to 20-fold and 2- to 2·5-fold more potent than L-692,429 and the growth hormone releasing peptide, GHRP-6, respectively. When L-692,585 was administered once daily for 14 consecutive days at 0, 0·01 or 0·10 mg/kg to each of 6 dogs, peak plasma GH levels and total GH release on days 1, 8 and 15 significantly increased in a dose-dependent manner, and no desensitization was evident. Mean peak levels ranged from 42 to 50 ng/ml and from 64 to 100 ng/ml for the 0·01 and 0·10 mg/kg doses, respectively. Six hours after dosing, IGF-1 levels were increased on each of the sampling days. Mean adrenocorticotrophic hormone and cortisol levels were modestly elevated transiently on each of the sampling days, while prolactin, insulin and thyroxine levels were unaltered over the course of the study. These studies demonstrated that L-692,585 is a potent GH secretagogue that induces an acute, transient increase in GH levels. The magnitude of the response is not down-regulated following repeated daily administration for 14 days. IGF-1 levels are increased for an extended period following each treatment. Journal of Endocrinology (1994) 143, 399–406