Plasma Concentration and CNS Effects of Ca Antagonists Darodipine and Nimodipine after Single-Dose Oral Administration to Healthy Volunteers

Abstract

The dynamics at the brain level (quantitative EEG), plasma kinetics and effects on blood pressure and heart rate of the Ca antagonists, darodipine (slow-release, 50– 200 mg) and nimodipine (30 mg), were compared in a double-blind cross-over study on healthy volunteers during a 9-hour period following single drug/placebo administration. Increased EEG total power was observed after 100 and 200 mg daropidine; a concomitant decrease of 14.5–32.0 Hz relative power was observed at 100 mg. The 50-mg dose proved ineffective. These effects were correlated with the darodipine plasma concentration only at the 100-mg dose, with indications of an active concentration interval at approximately 5–10 ng/ml; a reduction in diastolic blood pressure and increased heart rate proved to be linearly correlated with the drug plasma concentration throughout the entire concentration range. Comparable EEG effects were observed after nimodipine, but they did not correlate with the plasma concentration. Implications of the predictability of the brain effect from the drug plasma concentration and differential thresholds for the brain action and effects on (peripheral) circulation are suggested.

Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

“…For the 20 Hz range, clinical studies have shown no change under treatment with Ca ++ channel blocker nimodipine [69], [70], or modest decreases in the relative power of this band [71]. For other frequency bands, general increases in resting EEG power [71] with treatment have been seen. Thus, simulation results are consistent with the clinical EEG literature.…”