Administration of an antagonist of neurokinin receptors 1, 2, and 3 results in reproductive tract changes in beagle dogs, but not rats.
SCH 206272, an antagonist of neurokinin receptors 1, 2, and 3, was administered orally by gavage for 1 month to 8- to 10-month-old dogs at doses of 0, 15, 30, or 60 mg/kg, and to 6-week-old rats at doses of 0, 30, 100, or 300 mg/kg. The most important changes occurred in the reproductive tract of the dogs at all doses. Absolute and relative group mean organ weights for the testes, prostate gland, epididymides, ovaries, and uterus were 33-86% lower than concurrent controls in groups receiving SCH 206272. Organ weight changes were not dose-related. Microscopic changes that correlated with the organ weight changes occurred in all groups receiving SCH 206272. For males, they included minimal to severe atrophy of the testes, epididymides, and prostate gland. In addition, the epididymides exhibited severe oligospermia or aspermia, minimal epithelial apoptosis and mild epithelial vacuolation. In female dogs, the ovaries and uteri appeared immature. Microscopic changes were similar in incidence and severity in dogs receiving 30 or 60 mg/kg, but were slightly less in dogs receiving 15 mg/kg. In contrast, similar findings were not observed in the reproductive tract of male or female rats, despite overlapping systemic, hypothalamic, and pituitary gland concentrations of SCH 206272.
Losco
Patricia E
PE
Schering-Plough Research Institute, Lafayette, NJ 07848, USA. pat.losco@spcorp.com
Leach
Michael W
MW
Sinha
Dineshwar
D
Davis
Preston
P
Schmahai
Theodore J
TJ
Nomier
Amin
A
Kakkar
Tarundeep
T
Reyderman
Larisa
L
Lynch
Mary Ellen
ME
D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects / Q000473:pathology*; D005837:Genitalia, Male / Q000187:drug effects / Q000473:pathology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D012737:Sex Factors; D013045:Species Specificity
D000081:Acetamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C472346:SCH 206272; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone