RESUMEN
Oncogenicity studies of ramosetron ((R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazol e hydrochloride, CAS 132907-72-3, YM060), a new compound having serotonin (5-HT)3 receptor antagonist activity, were carried out in male and female mice and rats. Six groups (two control and four treated) of B6C3F1 mice and F344 rats were given YM060, dissolved in distilled water, once daily by oral intubation at doses of 0, 1, 10, 30 and 100 mg/kg/d. Toxicokinetics indicated that sufficient exposure of the animals to the test material was achieved during the oncogenicity studies. Cmax and AUC of YM060 at 100 mg/kg/d were in the range of 3-5 micrograms/ml and 8 micrograms.h/ml in mice, 1-5 micrograms/ml and 7-16 micrograms.h/ml in rats, respectively. The administration of YM060 resulted in a slightly increased mortality rate among female rats treated with 30 or 100 mg/kg/d, particularly during the Weeks 38-87. Body weights of the high-dosed male and female rats during the Weeks 36 to 96 were significantly decreased when compared to controls. An approximately 30% suppression of body weight gain was recorded during Weeks 36-96 for both male and female rats, and 15% suppression of body weight gain was recorded during Weeks 0-104 for male mice. There was no evidence of a treatment-related effect on the incidence of any tumor or tumor type, and there were no non-neoplastic findings considered to be related to the administration of YM060. All microscopic changes seen in mice and rats were of the usual type commonly occurring in untreated aged B6C3F1 mice and F344 rats. In conclusion, there was no evidence of an oncogenic effect of YM060 in mice and rats.
Asunto(s)
Bencimidazoles/toxicidad , Carcinógenos/toxicidad , Antagonistas de la Serotonina/toxicidad , Animales , Bencimidazoles/farmacocinética , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344 , Antagonistas de la Serotonina/farmacocinética , Sobrevida , Aumento de Peso/efectos de los fármacosAsunto(s)
Envejecimiento , Disopiramida/sangre , Orosomucoide/metabolismo , Albúmina Sérica/metabolismo , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Unión Proteica , Factores SexualesRESUMEN
From 6 experiments in which 99 ferrets were infected with influenza virus A/Finland/74 and treated with various agents which suppress virus shedding and other parameters of infection, we assessed whether rectal temperature correlated with nasal virus shedding. A number of temperature and virus-shedding related parameters were determined for each experiment but statistical analysis showed little correlation between them, although an elevated temperature occurred at some time after infection. The pooled data also suggested that temperature and virus shedding parameters are not clearly related. The analysis indicates that intermittent rectal temperature measurements are unsatisfactory for determining the efficacy of anti-influenza agents in ferrets.