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Pharmacokinetic and ‐dynamic studies in elderlies with a potential antihypoxidotic/nootropic drug tenilsetam utilizing pharmaco‐EEG and psychometry

In a double‐blind, placebo‐controlled study, the pharmacokinetic, encephalotropic, and psychotropic properties of a new metabolically active thienyl‐piperazine derivative were studied in ten elderly subjects in their sixties by means of quantitative EEG and psychometric analyses. At weekly intervals, they received randomized single oral doses of placebo; 75 mg, 150 mg, and 300 mg tenilsetam (CAS 997); and 3.2 g piracetam as reference drug. Blood sampling EEG recordings, psychometric and psychophysiological tests, as well as the monitoring of blood pressure, heart rate, and side effects were carried out at 0, 2, 4, 6, 8, and 24 hr. Pharmacokinetic investigations showed that CAS 997 was rather well absorbed, as peak concentrations were observed consistently at 2 hr and were clearly dose‐dependent. The terminal half‐life was between 18 and 22 hr, as compared with 6 hr for the reference drug piracetam, which also exhibited plasma peaks at 2 hr. Computer‐assisted spectral analyses of the EEG showed a significant CNS effect of CAS 997 as compared with placebo, characterized by an increase of alpha activity, decrease of delta activity, and fast beta activity, as well as by tendency towards an augmentation of total power and decrease of the centroid and centroid deviation of the total beta activity. Partly similar though less pronounced alterations were exhibited by 3.2 g piracetam. Such changes were described previously by us after several other antihypoxidotics/nootropics and are indicative of improvement in vigilance. Dose/treatment–efficacy calculations demonstrated 75 and 150 mg CAS 997 superior both to placebo and the reference compound but also to the highest given dosis (300 mg CAS 997). Time–efficacy calculations showed two pharrnacodynamic peaks: one in the 4th and another one in the 8th to 24th hour. The time lag between pharmacokinetic and ‐dynamic changes may be due to the penetration of the drug through the blood brain barrier to a deep compartment receptor as well as to the formation of active metabolites. Psychometric investigations showed only small and inconsistent psychotropic effects after single doses of CAS 997 in elderlies. Evaluation of pulse rate, blood pressure, and side effects showed a good tolerability of both drugs.