RESUMO
The effects of treatment with a soluble IL-4 receptor (sIL-4R) on reproduction and neonatal development were assessed in pregnant cynomolgus monkeys and mice. When pregnant cynomolgus monkeys were administered a human sIL-4R intravenously twice a week during organogenesis (GD 20-51) at 0, 0.2 or 2.0mg/kg, there was an increase in abortion/embryo-fetal death in the 0.2 (42.9%) and 2.0 (26.3%) mg/kg groups compared to controls (17.6%). All fetuses removed at cesarean sectioning on GD 100-102 were alive and no abnormalities were noted. There were three stillborn neonates (2.0mg/kg group), which were determined to have died before birth. No neonates died after birth and no abnormalities were noted. Due to the unanticipated results in the monkey study, a mouse developmental study with a murine surrogate molecule was conducted. When pregnant Crl:CD-1((R))(ICR)BR mice were administered murine sIL-4R intravenously once daily during the organogenesis period (GD 6-15) at 0, 25, 75, 250, or 625microg/mouse ( approximately 20mg/kg), there were no test-article-related abnormalities in any parameters. Antibody development to the drug did not influence toxicity in the monkey or mouse. In conclusion, evaluation of reproductive effects in mice administered murine soluble IL-4R was not predictive of reproductive effects noted in cynomolgus monkeys administered human soluble IL-4R.
Assuntos
Exposição Materna/efeitos adversos , Receptores de Interleucina-4 , Proteínas Recombinantes , Reprodução/efeitos dos fármacos , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/patologia , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Organogênese/efeitos dos fármacos , Gravidez , Receptores de Interleucina-4/administração & dosagem , Receptores de Interleucina-4/química , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/toxicidade , Solubilidade , Especificidade da EspécieAssuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Animais , Quimerismo , Cães , Modelos Animais , Polietilenoglicóis/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/farmacologia , Análise de Sobrevida , Transplante Homólogo/efeitos adversosRESUMO
Bald thigh syndrome (BTS) is a disease limited to Greyhound dogs. It is characterized clinically and grossly by bilateral hair loss on the lateral and caudal thighs. The cause of BTS is unknown but may be associated with hypothyroidism or hyperadrenocorticism. Samples of skin, thyroid glands, and adrenal glands from 43 Greyhound dogs with BTS were examined microscopically. Microscopic changes were characterized by dilatation of follicular infundibula, presence of catagen follicles and epidermal hyperplasia. Changes in the skin from these Greyhound dogs suggest an endocrinopathy as the cause; however, we were unable to confirm which one.