RESUMO
The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (18 min (P = 0.02)) and WASO (54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.
Assuntos
Acetamidas/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Isoquinolinas/uso terapêutico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Acetamidas/efeitos adversos , Adulto , Nível de Alerta/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Receptores de Orexina , Polissonografia , Estudos Prospectivos , Escalas de Graduação PsiquiátricaRESUMO
Because there are reports on cytotoxic and cytoprotective effects of antipsychotics, the aim of the present study was to evaluate the impacts of different concentrations (1.6-50 microg/mL) of atypical antipsychotics on the survival of human neuronal (neuroblastoma SH-SY5Y) and immune (monocytic U-937) cells and on energy metabolism (ATP level after the incubation with antipsychotics in the concentration of 25 microg/mL). Statistical analysis showed that incubation for 24 h with the antipsychotics quetiapine, risperidone, 9-hydroxyrisperidone and ziprasidone led to a significantly enhanced cell survival in both cell lines in the lower concentrations. Higher concentrations exerted in part cytotoxic effects with the exception of quetiapine, but therapeutically relevant concentrations of the drugs were not cytotoxic in our experiments. Measurement of ATP contents in the neuronal cell line showed significantly increased levels after a 24-h treatment with 25 microg/mL risperidone and 9-hydroxyrisperidone. The other substances produced no effects. Our results show that the antipsychotic substances under investigation exert concentration-dependent effects on cell survival in both cell lines examined.
