Neuroendocrine responses to a novel growth hormone secretagogue, L-692,429, in healthy older subjects.
L-692,429 (L), a novel nonpeptide mimic of GH-releasing peptide (GHRP), is a potent GH secretagogue in animals and young men. To assess the safety and efficacy of L in stimulating GH release in healthy older men and women, 16 subjects were admitted to a randomized, double blind, cross-over comparison of i.v. administered placebo, GH-releasing hormone [GHRH-(1-29)-NH2; 1 microgram/kg] and two doses of L (0.2 and 0.75 mg/kg). Blood samples were obtained at 5-min intervals for 60 min before and 240 min after each dose for measurement of GH; cortisol, PRL, and insulin-like growth factor-I (IGF-I) were measured less frequently. Peak and integrated GH concentrations increased significantly after L in a dose-dependent manner. Responses to L at either dose were significantly greater than the response to GHRH: peak GH responses in older men and women were (mean +/- SE; micrograms per L): after placebo, 1.2 +/- 0.2; L (0.2 mg/kg), 16.5 +/- 1.8; L (0.75 mg/kg), 32.2 +/- 3.9; and GHRH, 7.6 +/- 1.3 (P < 0.05, L vs. placebo or GHRH). Serum cortisol and PRL concentrations increased after both doses of L, but to values within the respective normal ranges. Serum IGF-I values did not change consistently in any group. The GH responses to GHRH and L (0.75 mg/kg) were highly correlated (r2 = 0.61; P < 0.0004). Deconvolution analysis demonstrated that the increase in serum GH concentrations stimulated by L and GHRH resulted from enhanced GH secretion rates, with no change in the half-life of GH disappearance. Amplitudes of GH secretory pulses were increased 11-, 18-, and 4-fold after L (0.2 mg/kg), L (0.75 mg/kg), and GHRH treatments, respectively. The number of GH secretory pulses was significantly increased by L (0.75 mg/kg; 4.6 +/- 0.4) and GHRH (4.4 +/- 0.3) compared to placebo (2.6 +/- 0.5), but the interval between pulses was shorter after L (0.75 mg/kg; 28.6 +/- 3.6 min) than after GHRH (50.7 +/- 7.7 min; P < 0.05). Adverse experiences were limited to brief episodes of flushing or a warm sensation about the upper body. L-692,429 is a potent GH secretagogue that is well tolerated in healthy older men and women. At the doses employed in this study, L elicited greater increases in GH secretion rates and serum GH concentrations than GHRH. L-692,429 may have therapeutic advantages over peptide GH secretagogues to restore endogenous GH secretion in GH deficiency states or the hyposomatotropism of aging.
Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908.
J A
JA
Aloi
B J
BJ
Gertz
M L
ML
Hartman
W C
WC
Huhn
S S
SS
Pezzoli
J M
JM
Wittreich
D A
DA
Krupa
M O
MO
Thorner
D000368:Aged; D000375:Aging / Q000502:physiology*; D001552:Benzazepines / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007275:Injections, Intravenous; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D009490:Neurosecretory Systems / Q000187:drug effects*; D009994:Osmolar Concentration; D011388:Prolactin / Q000097:blood; D012016:Reference Values; D013777:Tetrazoles / Q000009:adverse effects / Q000494:pharmacology*
D001552:Benzazepines; D013777:Tetrazoles; C081455:L 692429; D007334:Insulin-Like Growth Factor I; D011388:Prolactin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D006854:Hydrocortisone