MK-0677, A POTENT, NOVEL, ORALLY-ACTIVE GROWTH-HORMONE (GH) SECRETAGOGUE - GH, INSULIN-LIKE GROWTH-FACTOR-I, AND OTHER HORMONAL RESPONSES IN BEAGLES

MK-0677, a spiroindoline sulfonamide, is a novel, orally active GH sec retagogue. The effects of MK-0677 on serum GH and other hormones after oral and iv single dose administrations in beagles were evaluated. Af ter oral administration in a balanced eight-dog crossover study, treat ment with MK-0677 significantly increased peak GH concentrations, with a 5.3-fold increase (mean +/- SEM, 10.5 +/- 1.9 ng/ml) at the 0.25 mg /kg dose, a 9.0-foLd increase (18.0 +/- 3.3 ng/ml) at the 0.50 mg/kg d ose, and a 15.8-fold increase (31.6 +/- 5.8 ng/ml) at the 1.0 mg/kg do se. Total GH release, expressed as the area under the curve, showed si milar significant increases over the effect of the water placebo. A si ngle oral 1 mg/kg dose in three dogs induced a mean GH peak of 27.6 +/ - 1.5 ng/ml at 120 min, and GH levels remained elevated up to 360 min after treatment. Insulin-like growth factor I (IGF-I) levels were sign ificantly increased by 30% at 480 min after treatment. Cortisol levels were increased 2.4-fold over pretreatment levels. After iv administra tion, compared to the saline control group which had a mean (+/-SEM) s erum GH peak of 3.8 +/- 0.7 ng/ml, MK-0677 at 0.25 mg/kg significantly increased (P < 0.05) peak GH concentrations 20.4-fold (77.4 +/- 13.7 ng/ml). Total GH release, expressed as the area under the curve, showe d a similar increase. The mean peak GH level was recorded 10 min after treatment, with GH levels elevated up to 180 min after treatment. IGF -I levels were significantly elevated by 25% 360 min after the adminis tration of MK-0677. Cortisol levels were increased 2.3-fold over pretr eatment levels. Insulin and glucose levels were higher, LH and PRL lev els were unaltered, and T-4 levels were marginally lower; the levels o f each of these hormones remained within the normal ranges for dogs th roughout the experiment. In summary, MK-0677 is a potent GH secretagog ue that induces an immediate, large, long lasting increase in GH level s when administered orally or iv. In contrast to GH-releasing peptide- 6 and benzolactam secretagogues, GH levels were elevated up to 360 min after treatment, and this was associated with a significant increase in IGF-I levels. Cortisol levels were increased; however, the increase s were modest compared to those in GH.