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Received September 12, 2002; revised November 19, 2002; accepted November 20, 2002. From the Departments of Neurology and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA. Address correspondence to Jeffrey L. Cummings, M.D., Reed Neurological Research Center, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095-1769. e-mail: cummings{at}ucla.edu
ABSTRACT
Cholinesterase inhibitors (ChE-Is) are the standard of therapy for treatment of patients with Alzheimer disease (AD) and are the only class of drugs approved by the Food and Drug Administration (FDA) for treatment of this condition. This review provides evidenced-based recommendations for use of ChE-Is in clinical practice. The author searched computerized literature databases of the approved ChE-Is widely used in clinical practice (donepezil, rivastigmine, and galantamine), and extended the review with bibliographies from identified articles and package inserts of information reviewed by the FDA. Double-blind, placebo-controlled trials providing Class I evidence were used as data sources whenever possible. Articles with Class II and Class III data were used when Class I data were unavailable. In general, ChE-Is exert modest reproducible effects in patients with mild-to-moderate AD. Drug–placebo differences are evident on global and cognitive measures. Secondary outcomes, including measures of activities of daily living and behavior, also typically demonstrate drug–placebo differences in favor of the active agent. Head-to-head trials of ChE-Is are limited; existing trials suggest no major differences in efficacy. Observations from clinical trials imply that early initiation of therapy is associated with greater long-term benefits. Clinical trials with withdrawal periods indicate that withdrawal and re-initiation of treatment may result in loss of benefit. Open-label extensions of double-blind trials show that differences in level of functioning between treated populations and extrapolated for untreated populations continue for several years. Side effects of ChE-Is include nausea, vomiting, diarrhea, and anorexia, and are more frequent during dose escalation than maintenance therapy. Clinical-trial populations differ substantially from unselected populations of AD patients, and these selection biases demand that efficacy data from clinical trials be generalized with caution.
Key Words: Cholinesterase Inhibitors • Alzheimer's Disease
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