Cholinesterase inhibitors: A therapeutic strategy for Alzheimer disease

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 pertinen t 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,mec hanism of inhibition, substrate specificity, pharmacokinetics/pharmacodynam ics, safety/tolerability, and efficacy. DATA SYNTHESIS: Cholinergic deficits, leading to cognitive impairment, are a significant aspect of neurodegeneration in AD. AChEIs reduce the degradat ion 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 gala ntamine are under investigation as potential therapy for AD. These compound s are structurally diverse, possess unique patterns of specificities for th e various forms of cholinesterase enzymes, use distinct mechanisms of enzym e inhibition, present unique adverse event profiles, and offer relatively s imilar 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 impro ved tolerability profiles and more convenient dosing relative to tacrine. T he 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.