Growth hormone (GH) and insulin-like growth factor I responses after treatments with an orally active GH secretagogue L-163,255 in swine.
L-163,255 is a potent orally active spiropiperidine GH secretagogue. When administered iv or orally, L-163,255 caused GH to be increased in a dose-related manner, with a return to baseline by 90 min. After iv administrations of saline and L-163,255 at 1, 3, and 10 micrograms/kg, GH areas under the curves (GH AUCs) over 120 min were 377 +/- 136, 1151 +/- 413 (P < 0.05), 795 +/- 413 (P = NS), and 1770 +/- 416 ng.min/ml (P < 0.01), and peak GH concentrations were 8 +/- 3, 16 +/- 7 (P = NS), 17 +/- 5 (P = NS), and 43 +/- 12 ng/ml (P < 0.01), respectively. No changes in plasma cortisol concentrations were noted. After oral administrations at 3, 10, and 30 micrograms/kg, GH AUCs over 180 min were 1133 +/- 154, 1246 +/- 129 (P = NS), and 1551 +/- 210 ng.min/ml (P = NS), and peak GH concentrations were 7 +/- 2, 11 +/- 3 (P = NS), and 23 +/- 6 ng/ml (P < 0.01), respectively. After administration in feed, L-163,255 caused a dose-related increase in GH, with an initial peak observed at 60 min for both 30 and 300 micrograms/kg dose groups, and remained elevated above baseline through 180 min for the high dose group only. GH AUCS for 180 min posttreatment were 929 +/- 134 and 1897 +/- 244 ng.min/ml, and peak GH concentrations were 9 +/- 2 and 22 +/- 4 ng/ml for the 30 and 300 micrograms/kg doses prepared in 150 g feed, respectively. When provided in feed ad libitum over the 72-h period, mean plasma insulin-like growth factor I levels increased 15%, 62% (P < 0.01), and 109% (P < 0.01) in the untreated, treated with L-163,255 at 360 ppm, or treated with porcine somatotropin groups, respectively. Repeated iv administration of L-163,255 at 1 mg/kg once daily over 14 days resulted in an initial marked GH response, followed by a much reduced, but significantly elevated, GH response over the saline control values on subsequent treatment days. Repeated iv treatments with L-163,255 also resulted in an elevated insulin-like growth factor I level (approximately 60%) over that in saline controls. Compared to those in saline controls, plasma cortisol concentrations tended to be increased after the initial dose of L-163,255, but no significant increases were noted on days 7 and 14 in the L-163,255 group. The results of these studies indicate that L-163,255 is an orally active GH secretagogue suitable for long term efficacy studies in swine.
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA. robert_chang@Merck.Com
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Chang
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Rickes
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McGuire
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Frazier
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Chen
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Barakat
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Nargund
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Patchett
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Smith
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Hickey
D000284:Administration, Oral; D000821:Animal Feed; D000818:Animals; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007275:Injections, Intravenous; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D009919:Orchiectomy; D010880:Piperidines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors
D010880:Piperidines; D013141:Spiro Compounds; C102119:L 163255; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D006854:Hydrocortisone