EC6 HUMAN PHARMACOLOGY (PHASE I) RANDOMIZED, CROSSOVER CLINICAL TRIAL WITH A BUTYRYLCHOLINESTERASE AND SELECTIVE MONOAMINE OXIDASE-A INHIBITOR IN HEALTHY VOLUNTEERS. MULTIPLE DOSE STUDY

摘要

Background: Desoxypeganine (DOP) is a natural alkaloid with selective inhibitory activity towards butyrylcholinesterase and monoamine oxidase-A.Objectives: 1) To evaluate the oral bioavailabiiity and pharmaco-kinetic profile in healthy volunteers of two oral doses of DOP given in multiple dose twice daily for three successive days; 2) To evaluate safety and tolerability.Setting: Following the approval from Txagorritxu Hospital Ethics Committee and Spanish Medicines Agency, this study was carried out in the Clinical Trial Unit at Txagorritxu Hospital. Good Clinical Practice guidelines were strictly followed. The pharmacokinetics analysis was performed at CIDASAL (Barcelona).Method: Design was a single blind, crossover, randomized, placebo-controlled and multipie oral doses clinical trial. Eighteen (9 males and 9 females) healthy subjects according with usual inclusion/exclusion criteria, 18-38 years-old, were enrolled in this study. At a randomized sequence the volunteers received: DOP 50 mg bid X3 days, DOP 100 mg bid X3 days and placebo b.i.d. x3 days with at least one week of washout period. Subjects remained hospitalised under continuous monitoring. Serial blood samples were collected up to 72 h post-dose. One female dropped out due to family problems.Result: Main pharmacokinetics parameters of the two doses of DOP were: 1.5 h, (+-)285 h ng/ml, tl/2 (0-12 h)=49(+-)235, AUCt (60-72 h)=I067(+-)AUCt (0-12 h)=848 0.31 h ng/ml with DOP (+-)1.4 h, ratio AUCt (60-72)/AUCt (0-12 h)=1.29(+-)tl/2 (60-72 h)= 4.7 894 h ng/ml (+-)658, AUCt (60-72 h)=2409(+-)50 mg and AUCt (0-12 h)=1782 0.9, ratio(+-)1.4 h, t,/2(60-72 h)=5.6(+-)t1/2 (0-12 h)= 5.2 0.31 h-ng/ml with DOP 100 mg. No serious adverse(+-)AUCt (60-72 h)/AUCt (0-12 h)=1.39 events or electrocardiograph alterations occurred. The most common side effects were faintness and gastrointestinal disturbances.Conclusions: In general, desoxypeganine was well tolerated. Pharmacokinetic parameters were described. The steady state was not attained at day three but some accumulation was observed.