Objective measures in determining the central effectiveness of a new antihypoxidotic SL-76188: pharmaco-EEG, psychometric and pharmacokinetic analyses in the elderly.

In a double-blind, placebo-controlled, cross-over study, the blood levels as well as the encephalotropic and psychotropic properties of SL-76188 - a new molecule of the hexahydrocanthinone series - were studied in 10 elderly subjects by means of quantitative EEG and psychometric analysis. They received randomized and in weekly intervals single oral doses of 100, 175 and 250 mg SL-76188, placebo and 20 mg D-amphetamine as the reference substance. Blood sampling, EEG recordings and the monitoring of blood pressure, heart rate and side effects were done at 0, 1, 2, 4, 6 and 8 h. Psychometric tests were performed at 0, 2, 4, 6 and 8 h. HPLC demonstrated that the drug was rapidly absorbed as the peak plasma levels were found within the first 2 h. A dose-dependent kinetic profile was observed based on exponential correlations between dose and peak plasma levels and AUC. Computer-assisted spectral analysis of the EEG showed a significant CNS effect as compared with placebo. The attenuation of delta and theta activity, increase of alpha and certain beta activities and the acceleration of dominant frequency suggested an improvement in vigilance. This was reflected behaviorally by an improvement in concentration, attention variability, complex reaction and mood, especially in the higher dosage range. The reference substance 20 mg D-amphetamine exhibited more psychostimulatory properties, which were also observed in regard to the side effects. Blood pressure and heart rate increased only with D-amphetamine as compared to placebo. Finally, the relationship between kinetic and dynamic data was explored. An increase in pharmacodynamic changes on the descending slope of the kinetic curve resulted in a so-called 'hysteresis loop', the implication of which is discussed.