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Effect of growth hormone secretagogue LY444711 on IGF‐1, growth hormone, and cortisol levels in beagle dogs after one and seven daily oral doses
Author(s) -
Seyler David E.,
Dodge Jeffrey A.,
Osborne John J.,
Cox Karen L.,
Viswanath Devanarayan,
Wilmot Anita F.,
Keaton M. Joni,
Heiman Mark L.,
Bryant Henry U.,
Cutler Gordon B.
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/1098-2299(200004)49:4<260::aid-ddr5>3.0.co;2-6
Subject(s) - medicine , endocrinology , beagle , secretagogue , somatostatin , hormone , hydrocortisone , receptor
Growth hormone (GH) release involves interaction of somatostatin and an endogenous GH secretagogue (GHS) on the hypothalamus. GH causes release of IGF‐1, which acts by negative feedback to restrain subsequent GH release. GH secretagogues produce increases in cortisol. In this study, we determined if compound LY444711 produces sustained elevation of GH and IGF‐1 in beagle dogs without sustained alteration of baseline cortisol secretions after one and seven daily doses. Adult male beagle dogs received oral doses of LY444711 at 1 mg/kg/day, or vehicle (10% hydroxypropyl beta‐cyclodextrin). Jugular vein blood was collected periodically after one and seven doses, and plasma levels of IGF‐1, GH, and cortisol were determined. LY444711 increased IGF‐1 levels by approximately 60% over controls after one and seven daily doses. IGF‐1 was elevated within 6 h of dosing on Day 1 and remained elevated 24 h postdose. GH levels (AUC) increased approximately 50‐fold above controls following a single dose of LY444711. With repeated dosing, GH levels rose to approximately 8‐fold over controls. Regardless of the reduction in GH AUC with repeat dosing, sufficient GH was produced to cause sustained IGF‐1 elevation after seven doses. LY444711 produced little or no effect on cortisol AUC level after one or seven doses. These data demonstrate that LY444711 functions as a GH secretagogue in dogs, with associated increases in IGF‐1 levels and an absence of meaningful increases in cortisol levels. Drug Dev. Res. 49:260–265, 2000. © 2000 Wiley‐Liss, Inc.