title: The potential role for corticosterone in the induction of cleft palate in mice after treatment with a selective NK-1 receptor antagonist, casopitant (GW679769B).
abstract: 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.
authors: Department of Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania 19406, USA. mary.k.ziejewski@gsk.com
authors: Mary K
authors: MK
authors: Ziejewski
authors: Howard M
authors: HM
authors: Solomon
authors: Dinesh
authors: D
authors: Stanislaus
authors: Robert L
authors: RL
authors: Clark
authors: Tacey E
authors: TE
authors: White
authors: April R
authors: AR
authors: Apostoli
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002585:Cesarean Section; D002972:Cleft Palate / Q000097:blood / Q000139:chemically induced* / Q000196:embryology* / Q000473:pathology; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists / Q000633:toxicity*; D010879:Piperazines / Q000633:toxicity*; D010880:Piperidines / Q000633:toxicity*; D011247:Pregnancy; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects; D014508:Urea
chemical_list: D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C531951:casopitant; D014508:Urea