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Cholinesterase inhibitors: a therapeutic strategy for Alzheimer disease.

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By Krall WJ, Sramek JJ, Cutler NR • • April 1, 1999

OBJECTIVE: To provide a review of acetylcholinesterase inhibitors (AChEIs) tested as therapeutic agents for Alzheimer disease (AD).

DATA SOURCES: MEDLINE searches (January 1986-July 1998) identified pertinent literature. Selected references from these articles, as well as abstracts from recent meetings and package insert literature from approved compounds, were also used as source material.

DATA EXTRACTION: AChEIs were reviewed with regard to chemical structure, mechanism of inhibition, substrate specificity, pharmacokinetics/pharmacodynamics, safety/tolerability, and efficacy. DATA

SYNTHESIS: Cholinergic deficits, leading to cognitive impairment, are a significant aspect of neurodegeneration in AD. AChEIs reduce the degradation of acetylcholine, thus enhancing cholinergic transmission. In addition to the two agents approved by the Food and Drug Administration, tacrine and donepezil, six other compounds of diverse chemical structure and mechanism of inhibition including physostigmine, metrifonate, rivastigmine, and galantamine are under investigation as potential therapy for AD. These compounds are structurally diverse, possess unique patterns of specificities for the various forms of cholinesterase enzymes, use distinct mechanisms of enzyme inhibition, present unique adverse event profiles, and offer relatively similar mean gains in cognitive abilities to patients with AD in controlled clinical trials.

CONCLUSIONS: Relative to placebo, new AChEIs in development provide modest improvements in cognition for patients with mild to moderate AD, with improved tolerability profiles and more convenient dosing relative to tacrine. The availability of a wide array of AChEIs soon to be accessible to patients with AD will provide additional options to those who cannot tolerate or do not respond to drugs currently used for AD.

Source: Ann Pharmacother 1999 Apr;33(4):441-50 4940
PMID: 10332536, UI: 9926

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