EFFECTS OF ACUTE AND REPEATED INTRAVENOUS ADMINISTRATION OF L-692,585, A NOVEL NON-PEPTIDYL GROWTH-HORMONE SECRETAGOGUE, ON PLASMA GROWTH-HORMONE, ICF-1, ACTH, CORTISOL, PROLACTIN, INSULIN, AND THYROXINE LEVELS IN BEAGLES

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 G H and other hormones in beagles were evaluated. In a balanced 8-dog do se-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 significa ntly increased (P < 0.05) peak GH concentrations 4.3-fold (3.25 +/- 7. 0 ng/ml) at a dose of 0.005 mg/kg, 7-fold (49.4 +/- 10.6 ng/ml) at a d ose of 0.02 mg/kg, and 21-fold (134.3 +/- 29.0 ng/ml) at a dose of 0.1 0 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 compare d 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. Wh en 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-depe ndent manner, and no desensitization was evident. Mean peak levels ran ged 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 horm one 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 tha t L-692,585 is a potent GH secretagogue that induces an acute, transie nt increase in GH levels. The magnitude of the response is not down-re gulated following repeated daily administration for 14 days. IGF-1 lev els are increased for an extended period following each treatment.