results show that 25 mg MK-677 given orally for 7 days in healthy male volunteers improved nitrogen balance during dietary caloric restriction, a model for the treatment of a catabolic state. The effect of MK-677 occurred promptly and persisted for the 7 days of treatment. Nitrogen balance was positive after 2 and 7 days of treatment. The magnitude of this increase relative to response after placebo treatment was clinically meaningful, because the subjects averaged a 1.8 g/day improvement in nitrogen balance. It is not known whether these short-term effects will be maintained beyond 7 days (a slight waning of effect can not be excluded (Fig. 1)). Whether the effect on nitrogen balance would persist beyond 7 days was not evaluated in this study because there was limited clinical experience with longer periods of administration. However, if this response were sustained for several weeks, it would likely diminish the loss of skeletal muscle and visceral protein seen during catabolic states. GH has previously been shown to nearly reverse nitrogen wasting to a mean of −0.2 * 0.5 g/day after 5 days (29). Using this model and a similar degree of caloric restriction, the magnitude of change in nitrogen balance after MK-677 is similar to that seen after GH treatment. We conclude that MK-677 increases endogenous GH secretion sufficient to reverse this degree of nitrogen loss in normal volunteers who are made catabolic by caloric restriction and is therefore anabolic.
The oral dose of 25 mg MK-677 was chosen for this study because it produced a substantial GH response (peak GH >10 μg/L; mean peak 22.1 μg/L) when administered after an overnight fast to a group of healthy young nonobese males (M. G. Murphy, Merck). The peak GH response to MK-677 was similar in the present study. GH increases were sustained after the last dose of MK-677, documenting persistent secretagogue activity for the duration of the study. This suggests that the catabolic response induced by caloric restriction does not prevent the GH response of the pituitary to this compound.
MK-677-treated subjects had a 36% increase in serum IGF-I levels compared with the placebo-treated subjects, and this was associated with positive changes in nitrogen balance. Because we did not evaluate 24-h GH secretion, it is difficult to determine how this degree of increase in IGF-I would compare with the increase that occurs in response to an equivalent amount of exogenously administered GH. Caloric deprivation can reduce IGF-I response to GH (21) and may have played a role in limiting the IGF-I response to 36%. It is unlikely that a 36% increase in IGF-I at day 14 attenuated the GH response to MK-677, because this is substantially below the serum levels of IGF-I that are required to suppress spontaneous GH release in normal volunteers (30).
Although a 36% increase in IGF-I is substantially below that noted previously in subjects who were undergoing a similar degree of caloric restriction and received exogenous GH (21, 31), it was nonetheless associated with a positive effect on nitrogen balance. Whether an even greater effect on IGF-I and nitrogen balance would be achieved by increasing the dose of MK-677 was not evaluated in the current protocol because there was limited clinical experience with higher doses. However, the GH response in healthy males does not plateau until 100 mg MK-677 is given (mean peak = 71.2 μg/L) (M. G. Murphy, Merck). This suggests that use of a higher dose of MK-677 in this study might have resulted in a greater increase in GH and possibly a greater change in nitrogen balance.
