title: Repeat administration of the GH secretagogue MK-0677 increases and maintains elevated IGF-I levels in beagles.
abstract: We have reported that MK-0677 is a novel, orally active GH secretagogue that stimulates an immediate and long-lasting increase in serum GH levels in dogs. Significant elevations in IGF-I levels were associated with 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 cortisol levels; we also investigated if the GH and cortisol responses to MK-0677 are influenced by circulating IGF-I concentrations. Following the initial oral administration of MK-0677, GH secretion (area under the time-response curve (AUC) 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 mg/kg and 1.0 mg/kg groups. Individual beagle GH profiles indicated that the increased GH concentration was associated with an amplified GH pulsatile 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 longest treatment period evaluated. While daily MK-0677 administration appeared to increase IGF-I levels over 24 h, as evidenced by significant increases in the pretreatment IGF-I levels on days 4-14, no such increase was noted with alternate day MK-0677 administration; thus the dosage regimen modulated circulating IGF-I levels. MK-0677 stimulated increases in cortisol secretion (AUC microgram/dl per h) on the first day of treatment. A decreased cortisol response was observed following repeated daily treatment with MK-0677; in contrast, with alternate day treatment, no decrease in cortisol response to MK-0677 occurred. A marked increase in circulating IGF-I concentrations following administration of exogenous GH resulted in a significant decrease in both the GH and cortisol response to MK-0677 compared with control animals. Our findings suggested, therefore, that circulating IGF-I concentrations regulate GH and cortisol response to MK-0677. In summary, chronic oral administration 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 increases above control. Compared with day 1, repeated daily treatment with MK-0677 resulted in an attenuated GH response that was associated with an increase in circulating IGF-I levels. The cortisol response was similarly reduced during chronic MK-0677 treatment, suggesting that IGF-I mediated negative feedback on both the GH and cortisol axes. The fact that similar attenuation of the GH and cortisol responses to MK-0677 on day 1 was observed if IGF-I levels were increased by treating animals with exogenous GH suggested that the attenuated response to MK-0677 that occurred during chronic treatment was mediated by increases in IGF-I rather than desensitization to MK-0677. Thus, a regulatory feedback loop apparently prevents hyperstimulation of the GH axis by MK-0677. We conclude that MK-0677 offers the potential of an orally active GH secretagogue that can maintain elevated IGF-I levels when administered chronically.
authors.affiliation: Department of Physiology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Hickey
authors.forename: T M
authors.initials: TM
authors.lastname: Jacks
authors.forename: K D
authors.initials: KD
authors.lastname: Schleim
authors.forename: E
authors.initials: E
authors.lastname: Frazier
authors.forename: H Y
authors.initials: HY
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Krupa
authors.forename: W
authors.initials: W
authors.lastname: Feeney
authors.forename: R P
authors.initials: RP
authors.lastname: Nargund
authors.forename: A A
authors.initials: AA
authors.lastname: Patchett
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D004285:Dogs; D005246:Feedback; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism*; D008297:Male; D013141:Spiro Compounds / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013997:Time Factors
chemical_list: D007211:Indoles; D013141:Spiro Compounds; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C094817:ibutamoren mesylate; D006854:Hydrocortisone