Donepezil: A Review of Pharmacological Characteristics and Role in the Management of Alzheimer Disease

Abstract

Donepezil is a potent, selective, noncompetitive, and rapidly reversible inhibitor of acetylcholinesterase (AChEI) licensed for the treatment of Alzheimer disease (AD); and is the first and only AChEI licensed for the treatment of severe AD. Its efficacy as monotherapy, or in combination with the NMDA-agonist, memantine, has been documented in several randomised double-blind, placebo-controlled, short-term clinical trials, as well as long-term extension trials and observational studies. Donepezil is a well tolerated drug that is generally safe as demonstrated even in patients with multiple co-morbidities receiving polypharmacy. It has been shown that donepezil improves cognition and global function in patients with mild-to-moderate AD; and long-term efficacy is maintained for up to 50 weeks. There is a dose-response relationship, with higher doses more likely to produce symptomatic benefit. Furthermore, donepeziltreated patients may improve cognitively and show global clinical improvement in all disease stages, including severe AD. Less consistent results in all disease stages were obtained on measures of function and behavior, and observations of mood. No effect on transition to AD has been found in long-term, randomized clinical trials in mild cognitive impairment (MCI). Cost-effectiveness of the treatment has been questioned by one long-term open-label societal study of 2-years duration. This study reported modest improvement of cognition but no statistically significant benefits during donepezil treatment as compared to placebo, in terms of rates of institutionalization and progression toward greater disability. However, there is a need for further research on clinically meaningful outcomes and treatment benefits favored by patients and caregivers, which are traditionally not defined as outcomes in clinical trials. Likewise, we need to know how to select responders, what is an optimal AChE inhibition particularly during the long-term treatment, in which patients the dosage should be increased for a sustained benefit, what is the optimal duration of treatment and when is meaningful to stop the treatment. After almost two decades of donepezil use in everyday clinical practice these issues are still unresolved.

Pharmacological evaluation of Salvadora persica on scopolamine-induced memory disorder

“…Donepezil is powerful, discriminating, noncompetitive & reversible antagonist of AChE used especially in the treatment of AD. Donepezil improve cognition of patient with mild to moderate AD and its effectiveness can be maintained up to 50 weeks (Jelic V. et al 2010). In present study estimation of AChE enzyme activity in rat hippocampus and cerebral cortex were performed.…”

Concentration of Donepezil in the Cerebrospinal Fluid of AD Patients: Evaluation of Dosage Sufficiency in Standard Treatment Strategy

“…Hence, we focused here on the long-term 3-month steady-state concentration profile of donepezil in the plasma and CSF of AD patients, and its fluctuations between 12 and 24 h post dosing. This study contributed to broaden our information on plasma and CSF donepezil concentrations, particularly with respect to donepezil concentration fluctuation after 12 and 24 h post morning dosage which was rare and limited until this time (Tiseo et al 1998; Darreh-Shori et al 2006; Jelic and Darreh-Shori 2010). The plasma concentrations of donepezil were 30 ng/ml in patients receiving 5 mg/day and 60 ng/ml in patients receiving 10 mg/day of the drug.…”

Concentration of donepezil in the cerebrospinal fluid of AD patients: Evaluation of dosage sufficiency in standard treatment strategy

“…Hence, we focused here on the long-term 3-month steady-state concentration profile of donepezil in the plasma and CSF of AD patients, and its fluctuations between 12 and 24 h post dosing. This study contributed to broaden our information on plasma and CSF donepezil concentrations, particularly with respect to donepezil concentration fluctuation after 12 and 24 h post morning dosage which was rare and limited until this time (Tiseo et al 1998;Darreh-Shori et al 2006;Jelic and Darreh-Shori 2010). The plasma concentrations of donepezil were 30 ng/ml in patients receiving 5 mg/day and 60 ng/ml in patients receiving 10 mg/day of the drug.…”