ORAL-ADMINISTRATION OF GROWTH-HORMONE (GH) RELEASING PEPTIDE-MIMETIC MK-677 STIMULATES THE GH INSULIN-LIKE GROWTH-FACTOR-I AXIS IN SELECTEDGH-DEFICIENT ADULTS/

To determine the effect of the GH releasing peptide (GHRP)-mimetic, MK -677, on the OH/insulin-like growth factor-I (IGF-I) axis in selected GH-deficient adults, we studied nine severely GH-deficient men [peak s erum GH concentration in response to insulin-induced hypoglycemia of 1 .2 +/- 1.5 mu g/L, mean +/- so (range 0.02-4.79)], age 17-34 yr, heigh t 168 +/- 1.5 cm, body mass index 22.6 +/- 3.3 kg/m(2), who had been t reated for GH deficiency with GH during childhood. In a double-blind r ising-dose design, subjects received once daily oral doses of 10 or 50 mg MK-677 or placebo for 4 days over two treatment periods separated by at least 28 days. Four subjects received placebo and 10 mg/day MK-6 77 in a cross-over fashion in periods 1 and 2. Five subjects received 10 mg and then 50 mg/day MK-677 in a sequential, rising-dose fashion i n periods 1 and 2, respectively. Blood was collected every 20 min for 24 h before treatment and at the end of each period for GH measurement using an ultrasensitive assay. The drug was generally well tolerated, with no significant changes from baseline in circulating concentratio ns of cortisol, PRL, and thyroid hormones. Serum IGF-I and 24-h mean G H concentrations increased in all subjects after treatment with both 1 0 and 50 mg/day MK-677 vs. baseline. After treatment with 10 mg MK-677 , IGF-I concentrations increased 52 +/- 20% (65 +/- 6 to 99 +/- 9 mu g /L, geometric mean +/- intrasubject SE, P less than or equal to 0.05 u s. baseline), and 24 h mean GH concentrations increased 79 +/- 19% (0. 14 +/- 0.01 to 0.26 +/- 0.02 mu g/L, P less than or equal to 0.05 vs. baseline). Following treatment with 50 mg MK-677, IGF-I concentrations increased 79 +/- 9% (84 +/- 3 to 150 +/- 6 mu g/L, P less than or equ al to 0.05 vs. baseline) and 24-h mean GH concentrations increased 82 +/- 29% (0.21 +/- 0.02 to 0.39 +/- 0.04 mu g/L, P less than or equal t o 0.05 us. baseline), respectively. Serum IGF binding protein-3 concen trations increased with both 10 mg(1.2 +/- 0.1 to 1.7 +/- 0.1 mu g/L, P less than or equal to 0.05) and 50 mg MK-677 (1.7 +/- 0.1 to 2.2 +/- 0.2 mu g/L, P less than or equal to 0.05). The GH response to MK-677 was greater in subjects who were the least GH/IGF-I deficient at basel ine; by linear regression analysis the increase in 24-h mean GH concen tration was positively related to both baseline 24-h mean GH concentra tion (r = 0.81, P = 0.009) and baseline IGF-I (r = 0.79, P = 0.01) for 10 mg MK-677. IGF-I responses were not significantly related to any b aseline measurement. Fasting and postprandial insulin and postprandial glucose increased significantly after MK-677 treatment, and the clini cal significance of these changes will need to be assessed in longer t erm studies. Oral administration of such GHRP-mimetic compounds may ha ve a role in the treatment of GH deficiency of childhood onset.