REPEAT ADMINISTRATION OF THE GH SECRETAGOGUE MK-0677 INCREASES AND MAINTAINS ELEVATED IGF-I LEVELS IN BEAGLES

We have reported that MK-0677 is a novel, orally active GH secretagogu e that stimulates an immediate and longlasting increase in serum GH le vels in dogs. Significant elevations in IGF-I levels were associated w ith the increased GH secretion. Cortisol secretion was also increased following MK-0677 administration. In the current study, we determined the effect of repeat oral administration of MK-0677 on GH, IGF-I and c ortisol levels; we also investigated if the GH and cortisol responses to MK-0677 are influenced by circulating IGF-I concentrations. Followi ng the initial Oral administration of MK-0677, GH secretion (area unde r the time-response curve (AUG) ng/ml per h) was increased 7.9- to 9.8 -fold (1.0 mg/kg), 5.6-fold (0.5 mg/kg) or 3.9-fold (0.25 mg/kg). With repeat MK-0677 administration, the GH response was decreased by 41-77 %; GH concentrations remained significantly above control in the 0.5 m g/kg and 1.0 mg/kg groups. Individual beagle GH profiles indicated tha t the increased GH concentration was associated with an amplified GH p ulsatile profile. Serum IGF-I levels were significantly increased over control levels at all dosage levels by 480 min on the first day of MK -0677 administration. With repeated administration, IGF-I levels were increased up to 126% and remained elevated through 14 days, the longes t treatment period evaluated. While daily MK-0677 administration appea red to increase IGF-I levels over 24 h, as evidenced by significant in creases in the pretreatment IGF-I levels on days 4-14, no such increas e was noted with alternate day MK-0677 administration; thus the dosage regimen modulated circulating IGF-I levels. MK-0677 stimulated increa ses in cortisol secretion (AUC mu g/dl per h) on the first day of trea tment. A decreased cortisol response was observed following repeated d aily treatment with MK-0677; in contrast, with alternate day treatment , no decrease in cortisol response to MK-0677 occurred. A marked incre ase in circulating IGF-I concentrations following administration of ex ogenous GH resulted in a significant decrease in both the GH and corti sol response to MK-0677 compared with control animals. Our findings su ggested, therefore, that circulating IGF-I concentrations regulate GH and cortisol response to MK-0677. In summary, chronic oral administrat ion of MK-0677 was associated with significant increases in GH and IGF -I levels that were maintained for the duration of the treatment. The GH profile following MK-0677 administration consisted of episodic incr eases above control. Compared with day 1, repeated daily treatment wit h MK-0677 resulted in an attenuated GH response that was associated wi th an increase in circulating IGF-I levels. The cortisol response was similarly reduced during chronic MK-0677 treatment, suggesting that IG F-I mediated negative feedback on both the GH and cortisol axes. The f act that similar attenuation of the GH and cortisol responses to MK-06 77 on day 1 was observed ii IGF-I levels were increased by treating an imals with exogenous GH suggested that the attenuated response to MK-0 677 that occurred during chronic treatment was mediated by increases i n IGF-I rather than desensitization to MK-0677. Thus, a regulatory fee dback loop apparently prevents hyperstimulation of the GH axis by MK-0 677. We conclude that MK-0677 offers the potential of an orally active GH secretagogue that can maintain elevated IGF-I levels when administ ered chronically.