RESUMO
The antiemetic activity of DAU 6215, a novel antagonist of 5-HT3 receptors, was investigated in animal models of cytotoxic treatment-evoked emesis and compared with the antiemetic activity of ondansetron and metoclopramide. In dogs, vomiting was induced by i.v. cisplatin; in ferrets, the emetic response was elicited by i.v. doxorubicin or X-ray exposure. Pretreatment with 0.1-1 mg/kg DAU 6215 given i.v. or p.o. prevented the vomiting response to the different emetic agents. In the dog, the antiemetic potency of metoclopramide was 30 times lower than that of DAU 6215. Ondansetron was less potent than DAU 6215 against cisplatin and doxorubicin but was equally effective in the radiotherapy protocol. In this model, lengthening of the pretreatment time to 2 h did not affect the antiemetic efficacy of DAU 6215, whereas it decreased that of ondansetron. The results demonstrate that DAU 6215 is a highly effective and long-lasting inhibitor of cytotoxic treatment-induced emesis in different animal species.
Assuntos
Antieméticos/uso terapêutico , Benzimidazóis/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Antagonistas da Serotonina/uso terapêutico , Animais , Cisplatino/efeitos adversos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Feminino , Furões , Imidazóis/uso terapêutico , Masculino , Metoclopramida/uso terapêutico , Neoplasias Experimentais/complicações , Ondansetron , Fatores de Tempo , Vômito/etiologia , Vômito/prevenção & controleRESUMO
This study investigated the ability of NBQX, an AMPA receptor antagonist, and cerestat, a NMDA receptor antagonist, to counteract neurological deficits and morphological damage induced by permanent occlusion of the left middle cerebral artery (MCAO model) in the rat. NBQX (3, 10, and 30 mg/kg, ip) injected at 10, 60, and 120 min postocclusion did not reduce the volume of infarct in the MCAO model of cerebral ischemia and had marginal effects on sensory dysfunctions (vibrissae stimulation and body proprioception) and no effects on motor dysfunctions (forelimb flexion and footfault test). Conversely, cerestat (0.3, 1, and 3 mg/kg, sc) injected at 10 and 120 min postocclusion significantly reduced the ischemic volume at the dose of 1 mg/kg, and, at the same dose, significantly attenuated behavioural deficits in the body proprioception and in the forelimb flexion tests.