HUMAN STUDIES ON ABECARNIL A NEW BETA-CARBOLINE ANXIOLYTIC - SAFETY, TOLERABILITY AND PRELIMINARY PHARMACOLOGICAL PROFILE

1 Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a beta-carboline with high affinity for benzodiazepine receptors, was tested in healthy male subjects; single doses of abecarnil were given in five dosage levels (1 mg, 5 mg, 10 mg, 20 mg, 40 mg) and in a multiple dose study in four dosage levels (15 mg, 30 mg, 60 mg, 90 mg day-1) for 7 days. On two days following multiple dose treatment, placebo was given in single-blind conditions (follow-up). In each dosage level, in both studies drug was given to 10 subjects (7: verum, 3: placebo). 2 Safety and tolerability were evaluated by changes in vital signs, incidence and severity of adverse reactions and biochemical and haematological screening. Drug effects were estimated utilizing a bipolar visual analogue scale (poles: 'sleepy'-'alert') and a psychomotor task, the digit symbol substitution task. The pharmacokinetics of single and multiple doses were also determined in the multiple dose study. 3 Abecarnil was generally well tolerated. In the single dose study the most frequently reported side effects associated with abecarnil at high doses (20 and 40 mg) were dizziness, unsteady gait, and lack of concentration. A decrement in performance on the digit symbol substitution task was also observed in the two high dosage groups 20 mg and 40 mg. Evaluation of visual analogue scale ratings did not reveal a sedative effect even at higher doses. 4 In the multiple dose study the most frequently reported side effects during the treatment period were dizziness, unsteady gait, and lack of concentration. During the follow-up period the most frequently reported side effects were tiredness, headache and in the 90 mg day-1 group insomnia. A dose dependent decrement in performance on the digit symbol substitution task was observed during days 2-7. A dose-proportional increase in C(max) and in AUC values was also found. The terminal half-life of abecarnil was in the range from 5 to 7 h, and was not affected either by dose or by single vs multiple administrations.