RESUMO
INTRODUCTION: This study evaluates the activity of SDZ ENA 713, a centrally-selective acetylcholinesterase (AChE) inhibitor, in the cerebral spinal fluid (CSF) of patients with Alzheimer's disease (AD), and its relationship to central and peripheral pharmacokinetic parameters. METHODS: Eighteen AD patients were enrolled in this open-label, multiple-dose study. Patients were titrated in 1 mg bid/week increments to target doses of 1, 2, 3, 4, 5, or 6 mg bid SDZ ENA 713. After patients had been maintained at their target dose for at least 3 days, continuous CSF samples were obtained via a lumbar catheter for 12.5 h, beginning 0.5 h prior to the final dose of SDZ ENA 713. RESULTS: Dose-dependent inhibition of CSF AChE was significantly correlated (P < 0.05) with plasma drug and metabolite concentrations. The 6 mg bid treatment group showed a maximum mean inhibition of 62% at 5.6 h post-dose. CONCLUSION: Rapid, sustained, dose-dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Carbamatos/administração & dosagem , Líquido Cefalorraquidiano/efeitos dos fármacos , Líquido Cefalorraquidiano/enzimologia , Inibidores da Colinesterase/administração & dosagem , Fenilcarbamatos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Área Sob a Curva , Carbamatos/efeitos adversos , Carbamatos/sangue , Carbamatos/líquido cefalorraquidiano , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/sangue , Inibidores da Colinesterase/líquido cefalorraquidiano , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RivastigminaRESUMO
We report a case of hypervagotonia manifested by idioventricular rhythm in a healthy, athletic man who participated in a Phase I study of an investigational calcium-channel blocker. Upon breaking the study's double-blind study code, it was discovered that the subject had received placebo. We discuss this unusual finding and the implications of including athletic subjects in safety/tolerance studies.