Neuroendocrine responses to a novel growth hormone secretagogue, L-692,429, in healthy older subjects.

Abstract

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.

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

“…In addition, the GHRP-6-and GHRH-induced release of GH was lower in the old versus the young dogs, although this difference was not statistically significant. These observations are compatible with findings in humans, showing that not only the GH-releasing effect of ghrelin (Broglio et al, 2003) but also that of GHRH and peptidyl or non-peptidyl synthetic GHSs undergoes an age-related decrease (Aloi et al, 1994;Bowers et al, 1992;Broglio et al, 2003;Chapman et al, 1996;Muccioli et al, 2002). In old rats, the GH response to synthetic GHSs is impaired as well (Ceda et al, 1986;Walker et al, 1990).…”

METABOLISM, PHARMACOKINETICS, TISSUE DISTRIBUTION, AND EXCRETION OF [14C]CP-424391 IN RATS

“…Although recombinant GH therapy represents the current standard of care for GH-deficient patients, it is not ideal due to adverse effects associated with long-term therapies (Gibney et al, 1999). On the other hand, GH secretagogue has shown marked improvements over the traditional remedies by enhancing pulse amplitudes and integrated hormone production in elderly subjects (Huhn et al, 1993;Aloi et al, 1994;Chapman et al, 1997).…”

“…Although recombinant GH therapy represents the current standard of care for GH-deficient patients, it is not ideal due to adverse effects associated with long-term therapies (Gibney et al, 1999). On the other hand, GH secretagogue has shown marked improvements over the traditional remedies by enhancing pulse amplitudes and integrated hormone production in elderly subjects (Huhn et al, 1993;Aloi et al, 1994;Chapman et al, 1997).CP-424391 belongs to the pyrazolidine-piperidine class of compounds currently being developed as an orally active GH secretagogue for the treatment of growth hormone-compromised states. Its pharmacological mechanism of action is the elevation of circulating GH levels by stimulation of GH release from the pituitary gland (Pan, 2000).…”

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

“…Furthermore, the nonpeptide L-692,429 (MK-0751) ( Fig. 1) has been shown to elevate GH in young male volunteers (9) and in healthy older subjects (10) with only small transient increases in cortisol and prolactin. Thus, the effectiveness of the GHRP-6 mechanism has been established in the clinic with peptides as well as a nonpeptide.…”