MK-677, AN ORALLY-ACTIVE GROWTH-HORMONE SECRETAGOGUE, REVERSES DIET-INDUCED CATABOLISM

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 s tudy was designed to investigate whether MK-677, an orally active nonp eptide 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 al-day washout interval betw een periods. During the first week of caloric restriction (i.e. diet a lone), daily nitrogen losses were similar for both treatment groups (m ean +/- 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 da ily nitrogen balance was 0.31 +/- 0.21 g/day in the MK-677 treatment g roup 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 trea tment; 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 apeak GH response of 55.9 +/- 31.7 mu g/L after single dose (day 1 of treatment) and 22.6 +/- 9.3 mu g/L after a week of dosing compared with placebo treatment peak GH values of approxima tely 9 (treatment day 1) and approximately 7 mu g/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 M K-677 group and from 236 +/- 19 to 174 +/- 23 ng/mL in the placebo gro up. 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 i n IGF binding protein-2 was found between the MK-677 and placebo treat ments. However, the mean in IGF binding protein-3 for the last 5 days of MK-677 treatment was also significantly increased to 3273 +/- 330 n g/mL (mean +/- SE) compared with placebo 2604 +/- 253 ng/mL (P < 0.01) . Neither the serum cortisol nor the PRL response was significantly gr eater after 7 days of MK-677 dosing compared with 7 days of placebo. M K-677 (25 mg) was generally well tolerated and without clinically sign ificant adverse experiences. In conclusion, MK-677 reverses diet-induc ed nitrogen wasting, suggesting that if these short-term anabolic effe cts are maintained in patients who are catabolic because of certain ac ute or chronic disease states, it may be useful in treating catabolic conditions.