Preventing Donepezil-Induced Adverse Effects Through N-acetylcysteine Co-Administration.

BACKGROUND

Drug-induced adverse symptoms affect patients' quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer's disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL.

OBJECTIVE

Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and investigate the underlying mechanisms.

METHODS

Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes.

RESULTS

High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+]i levels in muscle cells.

CONCLUSIONS

Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients.