Pharmacokinetic–pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects

Abstract

Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK-PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t(1/2) k(eo) of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK-PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems.

An anti‐nicotinic cognitive challenge model using mecamylamine in comparison with the anti‐muscarinic cognitive challenge using scopolamine

“…All treatments administered were considered safe and well tolerated, as all adverse events were transient and mild to moderate in severity. Pharmacokinetics of scopolamine are in line with previously described results . The plasma concentrations of mecamylamine almost doubled with the doubling of the dose, which suggests dose proportionality, as has been described before .…”

“…The mean C max of scopolamine was 2549 pg ml À1 (range 1349-4835 pg ml À1 ) measured 15 min after the start of scopolamine infusion in all subjects. This is consistent with a previously published PK model of scopolamine [27].…”

“…Several previous studies attempted to do this, but none of these studies found significant cognitive effects of mecamylamine to compare with, probably due to low doses and few measurements . In this study, scopolamine had a significant effect on all cognitive domains measured, including inhibition and working memory, as has been described before . The increase in reaction time and decrease in saccadic peak velocity, which was not observed after mecamylamine administration, and the larger reduction of VAS alertness, suggest that scopolamine has a strong sedative effect.…”

Model‐based exposure‐response analysis to quantify age related differences in the response to scopolamine in healthy subjects

“…The developed structural model is in agreement with the two‐exponential equation describing bi‐phasic pharmacokinetics (central and peripheral volume of distribution) as reported in previous literature using nonlinear regression (noncompartmental analysis) and NLME methods . Also, the relatively large apparent volume of distribution, mainly of the peripheral compartment, is in agreement with the weak basic nonpolar alkaloid high lipophilicity physicochemical properties of scopolamine.…”

First‐in‐man study of ACT‐709478, a novel selective triple T‐type calcium channel blocker

“…This test has been applied previously to evaluate psychedelic drug effects . It consists of 13 VAS, which allow the subjects to rate their subjective feelings.…”