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

Abstract

AIMSubjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure. METHODSWe applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. RESULTSA two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min À1 . Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. CONCLUSIONSMost of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels.

Annona atemoya Leaf Extract Improves Scopolamine-Induced Memory Impairment by Preventing Hippocampal Cholinergic Dysfunction and Neuronal Cell Death

“…The cholinergic function is reduced in the forebrain, especially in the hippocampus, and a change in AChE activity in the hippocampus is usually a biomarker for diagnosing AD [29]. SCO impairs memory in rodents and humans, which interferes with the cholinergic system, including ACh, and causes oxidative stress, leading to cognitive dysfunction [30,31,32]. Thus, SCO-induced cognitive impairment is a valid model to investigate the anti-AD effects of novel drugs.…”

No synergistic effect of subtherapeutic doses of donepezil and EVP‐6124 in healthy elderly subjects in a scopolamine challenge model

“…Evidence also suggests that low concentrations of scopolamine (0.3 mg subcutaneous) can already induce a measurable significant decline in visuomotor speed and spatial working memory in healthy older people [15] . Altogether, the scopolamine challenge model has the potential to show the expected synergistic effect in the elderly, but dose selection and dosage form require careful reconsideration [49] .…”

Anticholinesterase and Antioxidant Potential of Hydromethanolic Extract ofZiziphus mucronata(Rhamnaceae) Leaves on Scopolamine-Induced Memory and Cognitive Dysfunctions in Mice

“…Additionally, scopolamine triggers reactive oxygen species (ROS) production, thereby inducing an oxidative stress materialised by an increased lipid peroxidation and deterioration in antioxidant defence mechanisms [9]. Thus, scopolamine has been used as a model in screening antiamnestic drugs [10]. Since ROS mediates neurotoxicity in AD, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy [11].…”