RESUMO
NPS 1506 is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2-hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1-1.0 mg/kg, with peak plasma concentrations ranging from 8-80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK-801-like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5-100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100-mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP-like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half-life of NPS 1506 (approximately 60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.
Assuntos
Fluorbenzenos/farmacologia , Aprendizagem/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Adolescente , Adulto , Animais , Isquemia Encefálica/tratamento farmacológico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Fluorbenzenos/sangue , Fluorbenzenos/uso terapêutico , Humanos , Masculino , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/uso terapêutico , Propilaminas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
NPS Pharmaceuticals, Inc. (NPS) has synthesized a series of open-channel blockers with varying potencies at the NMDA receptor. NPS 1506 (Fig. 1) is a moderate affinity antagonist that inhibits NMDA/glycine-induced increases in cytosolic calcium in cultured rat cerebellar granule cells (IC50 = 476nM) and displaces the binding of [3H]MK-801 to rat cortical membranes (IC50 = 664nM).