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.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Jacks
T
T
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065.
Hickey
G
G
Judith
F
F
Taylor
J
J
Chen
H
H
Krupa
D
D
Feeney
W
W
Schoen
W
W
Ok
D
D
Fisher
M
M
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D006854:Hydrocortisone / Q000097:blood*; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D011388:Prolactin / Q000097:blood; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013974:Thyroxine / Q000097:blood; D013997:Time Factors
D001552:Benzazepines; D007328:Insulin; C091588:L 692585; D013777:Tetrazoles; D007334:Insulin-Like Growth Factor I; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013006:Growth Hormone; D013974:Thyroxine; D006854:Hydrocortisone