Clinical-pharmacological study with the two isomers (d-, l-) of fenfluramine and its comparison with chlorpromazine and d-amphetamine: blood levels, EEG mapping and safety evaluation.

In a double-blind, placebo-controlled, crossover study, the blood levels and pharmacodynamic properties of single oral doses of 15 and 30 mg d-fenfluramine (d-FEN) and 30 mg l-fenfluramine (l-FEN) were investigated as compared with 50 mg chlorpromazine (CPZ) and 20 mg d-amphetamine (AMPH) utilizing pharmaco-electroencephalogram (EEG) mapping as well as prolactin and safety assessments. Eighteen healthy young volunteers randomly (Latin square) received at weekly intervals the different treatments. Blood sampling to determine AMPH, FEN and its main metabolite norFEN, as well as plasma prolactic levels, EEG recordings and evaluation of hemodynamics and spontaneous side effects were carried out at 0, 2, 4, 6 and 8 h after drug administration. Before and 24 h after drug intake morning subjective sleep quality was also assessed. Blood level investigations after d-FEN demonstrated dose-dependent blood concentrations peaking after 2-4 h and slowly declining thereafter. NorFEN, the main metabolite, exhibited a steady increase in plasma concentrations up to the 8th h. After l-FEN a similar time course was obtained but the concentrations of the parent compound were higher and those of the metabolite lower in comparison with the d-isomer, suggesting stereoselective kinetics. d-FEN induced significant and dose-dependent pharmaco-EEG changes characterized by a decrease in total power and combined delta/theta activity and by an increase in beta activity and an acceleration of the centroid of the total activity with no changes in alpha power, which were quite different from those of the reference drugs. l-FEN produced only minimal changes (of the same type as d-FEN). 50 mg CPZ and 20 mg d-AMPH produced significant changes as compared to placebo but with quite opposite patterns, the former exhibiting the typical sedative-neuroleptic profile and the latter that typical of psychostimulants. Dose/treatment- and time-efficacy calculations based on all variables showed in the V-EEG that only 30 mg d-FEN and 50 mg CPZ were different from placebo (with peak effects in the 8th and 4th h, respectively), while in the resting condition (R-EEG) all drugs/dosages but 30 mg l-FEN differed from placebo (with the peak effect occurring in the 4th-6th h after d-FEN and l-FEN, in the 2nd h after CPZ and in the 4th-6th h after AMPH). Plasma prolactin levels were only modified by CPZ (maximal increase in the 2nd h).(ABSTRACT TRUNCATED AT 400 WORDS)