RESUMO
BACKGROUND: SCH 486757 is a nociceptin-1 receptor agonist that was in development as an antitussive. Studies were conducted to characterize its effects on female fertility and to examine its potential modes of action. METHODS: Female rats were administered up to 20 mg/kg SCH 486757 before/during mating through gestation day (GD) 7; female fertility and embryonic development were assessed on GD 14. In a subsequent study, pregnant rats were dosed up to 50 mg/kg SCH 486757 from GD 0 to 7. Reproductive hormones were assessed on GD 1, 3, 5, and 7, and embryonic development was assessed on GD 14. A subset of dosed dams were allowed to deliver, were subsequently re-mated, and reproductive hormones and fertility were assessed on GD 7 and 14, respectively. To determine the effects of SCH 486757 on nonpregnant rats, doses of up to 50 mg/kg SCH 486757 were administered for 4 days beginning on the day of estrus; reproductive hormones were assessed after the final dose. RESULTS: Female rats administered ≥20 mg/kg SCH 486757 exhibited abnormal estrous cycles; decreased fertility, number of corpora lutea, and implantation sites; and increased pre- and postimplantation loss. In general, administration of SCH486757 was associated with lower luteinizing hormone (LH) progesterone (P4), and estradiol (E2) levels in pregnant rats. These effects on fertility/embryonic development and reproductive hormones exhibited reversibility post dosing. Nonpregnant rats in the 50-mg/kg group exhibited apparent decreases in P4 and E2 levels, with no apparent effects on LH values. CONCLUSIONS: The SCH 486757-related effects on fertility and embryonic development were likely the result of decreases in P4, E2, and/or LH, rather than being due to decreased prolactin levels.
Assuntos
Compostos Azabicíclicos/toxicidade , Fertilidade/efeitos dos fármacos , Hormônios/sangue , Pirimidinas/toxicidade , Receptores Opioides/agonistas , Reprodução/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Cesárea , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Gravidez , Ratos , Receptores Opioides/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Análise de Sobrevida , Receptor de NociceptinaRESUMO
Monkey studies were conducted for the preclinical safety assessment of SCH 412499, an adenovirus encoding p21, administered by subconjunctival injection prior to trabeculectomy for postoperative maintenance of the surgical opening. Biodistribution of SCH 412499 was minimal and there was no systemic toxicity. Findings included swollen, partially closed or shut eye(s) and transient congestion in the conjunctiva. A mononuclear cell infiltrate was present in the conjunctiva, choroid and other ocular tissues, but completely or partially resolved over time. Electroretinograms and visual evoked potentials revealed no adverse findings. Thus, the findings are not expected to preclude the clinical investigation of SCH 412499.