The potential role for corticosterone in the induction of cleft palate in mice after treatment with a selective NK-1 receptor antagonist, casopitant (GW679769B).

Autor: Ziejewski MK; Department of Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania 19406, USA. mary.k.ziejewski@gsk.com, Solomon HM, Stanislaus D, Clark RL, White TE, Apostoli AR
Jazyk: angličtina
Zdroj: Birth defects research. Part B, Developmental and reproductive toxicology [Birth Defects Res B Dev Reprod Toxicol] 2012 Feb; Vol. 95 (1), pp. 54-62. Date of Electronic Publication: 2011 Nov 29.
DOI: 10.1002/bdrb.20341
Abstrakt: Background: Casopitant is a potent and selective NK-1 receptor antagonist that has shown clinical efficacy in the prevention of chemotherapy-induced and postoperative-induced nausea and vomiting.
Methods: In an embryo-fetal development study, pregnant mice were given vehicle (sterile water) or doses of 30, 100, or 300 mg/kg/day casopitant on Gestation Day (GD) 6 to 15. Fetuses were evaluated for external, visceral, and skeletal abnormalities on GD 18. In a follow-on study to investigate casopitant-induced hormonal changes during the developmental period for palate formation, pregnant mice were given vehicle (sterile water) or 300 mg/kg/day casopitant once daily on GD 6 to 13. Blood was collected on GD 13 at various time-points for measurement of plasma adrenocorticotropic hormone and corticosterone (CRT) concentrations.
Results: There was no evidence of developmental toxicity in mice at 30 or 100 mg/kg/day but 9% of fetuses at 300 mg/kg/day had cleft palate. Mice are sensitive to glucocorticoid-induced cleft palates, and NK-1 antagonists are known to modulate the hypothalamic-pituitary-adrenal axis leading to increases in corticosterone. On GD 13, mean plasma adrenocorticotropic hormone levels at 300 mg/kg/day were elevated by approximately twofold from vehicle-treated levels at 1 hr post-dose and mean plasma CRT levels were elevated by 3, 5, and 10-fold at 0.5, 1, and 2 hr post-dose, respectively.
Conclusions: The increased level of CRT was in the range previously shown in the literature to cause cleft palates in mice and was likely the underlying mechanism behind casopitant-induced cleft palate in mice.
(© 2011 Wiley-Liss, Inc.)
Databáze: MEDLINE
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