Donepezil

Abstract

Donepezil is a specific and potent acetylcholinesterase inhibitor according to in vitro data. It displays primarily noncompetitive inhibitory activity. In vivo, donepezil inhibited acetylcholinesterase activity in human erythrocytes and increased extracellular acetylcholine levels in the cerebral cortex and hippocampus of the rat. Donepezil demonstrated efficacy in tests of reference memory in animals, but had less consistent activity in tests of working memory. Donepezil 5 or 10 mg/day was associated with significant improvements in cognitive function [assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)] after 14 and 30 weeks and patient global function (Clinician's Interview-based Impression of Change incorporating caregiver input score) after 30 weeks, compared with placebo, in patients with mild to moderate Alzheimer's disease. After 2 years, donepezil 5 or 10 mg/day was associated with an ADAS-cog score approximately 4 points better than would be expected in untreated patients with mild to moderate Alzheimer's disease. The most common adverse events reported in association with donepezil 5 mg/day were gastrointestinal events (nausea/vomiting, diarrhoea, gastric upset and constipation) and dizziness. No hepatotoxicity was reported after 12 weeks' treatment.

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

“…10,11 Although all ChE inhibitors share the same basic mode of action (inhibition of AChE), their pharmacokinetic characteristics differ substantially ( Table I). [12][13][14][15][16][17][18][19][20][21][22][23][24] …”

“…These differences occur as a direct result of the underlying pharmacodynamic and pharmacokinetic properties of ChE inhibitors, as outlined in Table I. [12][13][14][15][16][17][18][19][20][21][22][23][24] Safety Drug-Drug Interactions Donepezil and galantamine are both metabolized via the hepatic cytochrome P450 (CYP450) enzyme system. 12 Therefore, caution should be exercised when coprescribing other drugs metabolized via these pathways.…”

“…At present, only limited data 9 are available to examine this hypothesis. For example, delayed-start clinical trials in patients with mild to moderately severe AD (baseline MMSE scores, [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] indicate that any delay in the initiation of treatment with ChE inhibitors may result in irretrievable loss of benefit compared with patients receiving treatment earlier in the disease course. Two 52-week studies 9,93 were conducted, with an initial 26-week placebo-controlled phase followed by a 26-week, openlabel extension study during which all patients received rivastigmine.…”

Cognitive Enhancing Properties and Tolerability of Cholinergic Agents in Mice: A Comparative Study of Nicotine, Donepezil, and SIB-1553A, a Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

“…However, AChE inhibitors have been less promising therapeutically as they produce only modest improvements in cognitive function (Bryson and Benfield, 1997;Greenberg et al, 2000;Mohs et al, 2001;Winblad et al, 2001) along with undesirable side effects (Wilkinson, 1999;Dunn et al, 2000;Imbimbo, 2001). …”

Virtual Screening of Acetylcholinesterase Inhibitors

“…The major marketed drugs for the symptomatic treatment of AD are acetylcholinesterase (AChE) inhibitors, that is, tacrine (TC) (Davis & Powchik, 1995), donepezil (Bryson & Benfield, 1997), rivastigmine (Gabelli, 2003), and galantamine (Sramek et al, 2000) which inhibit AChE activity to promote an increase in the concentration and the duration of acetylcholine in the brain. However, they do not address the etiology of the disease.…”