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.
Aloi
J A
JA
Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908.
Gertz
B J
BJ
Hartman
M L
ML
Huhn
W C
WC
Pezzoli
S S
SS
Wittreich
J M
JM
Krupa
D A
DA
Thorner
M O
MO
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