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A Double-Blind, Placebo-Controlled Multicenter Study of Tacrine for Alzheimer's Disease

  • Author(s): Davis, KL
  • Thal, LJ
  • Gamzu, ER
  • Davis, CS
  • Woolson, RF
  • Gracon, SI
  • Drachman, DA
  • Schneider, LS
  • Whitehouse, PJ
  • Hoover, TM
  • Morris, JC
  • Kawas, CH
  • Knopman, DS
  • Earl, NL
  • Kumar, V
  • Doody, RS
  • et al.
Abstract

In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease. Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living. At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P<0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment. In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients. (N Engl J Med 1992;327: 1253–9.), IN Alzheimer's disease the brain has a variety of neurotransmitter deficits, and the most striking and consistent change is a marked decrease in the activity of choline acetyltransferase, a marker for cholinergic neurons. Although there are other changes in neurotransmitters, the reduction in choline acetyltransferase activity correlates best with the degree of memory impairment.1 Drugs that inhibit central cholinergic function also induce memory deficits2 — a finding further supporting the role of the cholinergic System in normal cognitive function. A possible therapeutic approach to Alzheimer's disease may be to compensate for the loss of central cholinergic neurons by potentiating the… © 1992, Massachusetts Medical Society. All rights reserved.

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