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

Mount Sinai Medical Center, New York, NY 10029-6574.
New England Journal of Medicine (Impact Factor: 55.87). 10/1992; 327(18):1253-9. DOI: 10.1056/NEJM199210293271801
Source: PubMed


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.

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    • "Findings of reduced cholinergic activity and loss of cholinergic neurons in the brains of individuals with Alzheimer's disease (AD) formed the rationale for the development of acetylcholinesterase inhibitors as drugs to ameliorate the dementia associated with AD (Davis et al., 1992; Rogers et al., 1998; Francis et al., 1999; Tariot et al., 2000; Csernansky et al., 2002). Donepezil, an acetylcholinesterase inhibitor, is one of the most popular approved therapies for AD. "
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    • "The mAChRs are G protein-coupled receptors (GPCRs) with five subtypes termed M 1 through M 5 that respond to the endogenous neurotransmitter acetylcholine (ACh); M 1 , M 3 , and M 5 couple to G q , whereas M 2 and M 4 couple via G i/o to downstream signaling pathways and associated effector systems (Wess, 1996; Langmead et al., 2008). It is interesting that mAChR agonists and acetylcholinesterase inhibitors have established efficacy in improving cognitive performance in patients with AD (Davis et al., 1992; Bodick et al., 1997; Rogers et al., 1998; Raskind et al., 1999). In addition, the mAChR agonist xanomeline has robust efficacy in reducing delusions, hallucinations, and other psychotic symptoms in patients with AD (Bodick et al., 1997) and schizophrenia (Shekhar et al., 2008). "
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    • "Perhaps, if more attention were focused on the issues underlying the sub-populations of responders and the wide individual variations of the most effective dose, we might gain the required insight to improve treatment responses in this treatment-resistant patient population. While some in the AD field might argue that this concept was indeed tested in one of the earliest tacrine trials (Davis et al. 1992), in fact, this trial only tested two different doses per subject (and a very limited dose range) and thus hardly tested the concept identified in aged monkeys (Bartus 1979c; Bartus and Dean 1988c) for a wide variation exists (i.e., an order of magnitude ) in peak effective doses between individual subjects. "
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