Propantheline Attenuates the Peripheral Side Effects of Donepezil without Affecting Its Antiamnestic Properties in Cerebral Ischemic Mice

Abstract

Cholinergic deficits are found in both vascular dementia and Alzheimer's disease (AD). Cholinesterase inhibition (CHI) is the only strategy that has been proven to have beneficial effects in patients, but may cause a broad spectrum of adverse events such as nausea, vomiting, and diarrhea, etc. To investigate how to attenuate the peripheral side effects of CHI agents without affecting their efficacy, the effects of propantheline bromide (PB) co-administered with donepezil on the gastric emptying (GE), gastrointestinal transit (GIT), brain cholinesterase (ChE) activities, and maze tasks of mice with memory impairment induced by transient ischemia were observed. The results indicated that PB decreased the increase in GE and GIT, but did not change brain acetylcholinesterase (AChE) activity or the latency of escape in cerebral ischemic mice treated with donepezil. These findings suggest that PB is nearly unable to penetrate the blood-brain barrier and could attenuate the peripheral side effects of CHI agents in the peripheral nervous system and without affecting their therapeutic effects in the central nervous system.

A Randomized, Crossover, Single-Dose Bioequivalence Study of Two Extended Release Tablets of Donepezil 23 mg in Healthy Human Volunteers under Fasting and Fed State

“…It is a centrally-active anticholinergic drug that exerts its effect through competitive antagonism of acetylcholine (or other direct cholinomimetics) at the muscarinic receptor, and thus blocks the vestibular input to the emetic center. This means that a high dose of a cholinomimetic agent is required to abolish its effect [20]. …”