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MK-677, an Orally Active Growth Hormone Secretagogue, Reverses Diet-Induced Catabolism¹

Merck Research Laboratories (M.G.M., B.J.G., W.H., J.W., W.M.P.), Rahway, New Jersey 07065; and Department of Medicine, University of North Carolina at Chapel Hill (L.M.P., D.R.C.), Chapel Hill, North Carolina 27514

Address all correspondence and requests for reprints to: M. Gail Murphy, Merck Research Laboratories, Building 10, Sentry Parkway, Bluebell, Pennsylvania 19422.

The reversal of diet-induced negative nitrogen balance by GH suggests a possible therapeutic role for GH treatment in catabolic patients. A double-blind, randomized, placebo-controlled, two-period, cross-over study was designed to investigate whether MK-677, an orally active nonpeptide mimic of GH-releasing peptide, can reverse diet-induced protein catabolism. Eight healthy volunteers (ages 24–39 yr) were calorically restricted (18 kcal/kg·day) for two 14-day periods. During the last 7 days of each diet period, subjects received either oral MK-677 25 mg or placebo once daily. There was a 14- to 21-day washout interval between periods. During the first week of caloric restriction (i.e. diet alone), daily nitrogen losses were similar for both treatment groups (mean ± SE; MK-677 group -2.67 ± 0.40 g/day vs. placebo group -2.83 ± 0.26 g/day). During the second week (diet and study drug), mean daily nitrogen balance was 0.31 ± 0.21 g/day in the MK-677 treatment group compared with -1.48 ± 0.21 g/day in the placebo group (P < 0.01). MK-677 improved nitrogen balance integrated over the 7 days of treatment; area under the curve day 8–14 nitrogen balance response was +2.69 ± 5.0 (SE) for MK-677 and -8.97 ± 5.26 g·day for placebo (P < 0.001). MK-677 produced a peak GH response of 55.9 ± 31.7 µg/L after single dose (day 1 of treatment) and 22.6 ± 9.3 µg/L after a week of dosing compared with placebo treatment peak GH values of approximately 9 (treatment day 1) and approximately 7 µg/L (treatment day 7). Following the initial 7-day caloric restriction, insulin-like growth factor-I (IGF-I) declined from 232 ± 25 to 186 ± 19 ng/mL in the MK-677 group and from 236 ± 19 to 174 ± 23 ng/mL in the placebo group. Mean IGF-I concentration increased significantly during MK-677 to 264 ± 31 ng/mL (mean for the last 5 days of treatment) compared with 188 ± 19 ng/mL with placebo (P < 0.01). No significant difference in IGF binding protein-2 was found between the MK-677 and placebo treatments. However, the mean in IGF binding protein-3 for the last 5 days of MK-677 treatment was also significantly increased to 3273 ± 330 ng/mL (mean ± SE) compared with placebo 2604 ± 253 ng/mL (P < 0.01). Neither the serum cortisol nor the PRL response was significantly greater after 7 days of MK-677 dosing compared with 7 days of placebo. MK-677 (25 mg) was generally well tolerated and without clinically significant adverse experiences. In conclusion, MK-677 reverses diet-induced nitrogen wasting, suggesting that if these short-term anabolic effects are maintained in patients who are catabolic because of certain acute or chronic disease states, it may be useful in treating catabolic conditions.

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