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Efficacy and safety of eptastigmine for the treatment of patients with Alzheimer’s disease

From the Medical Department (Drs. Imbimbo and Martelli), Mediolanum Farmaceutici, Milan, Italy; Mediolanum Pharmaceuticals, Inc. (Dr. Troetel), Scarsdale, NY; Department of Neurology (Dr. Lucchelli), San Carlo Hospital, Milan, Italy; Istituto di Ricerche Farmacologiche "Mario Negri" (Dr. Lucca), Milan, Italy; and Department of Neuroscience (Dr. Thal), University of California San Diego, La Jolla, CA.

Address correspondence and reprint requests to Dr. Bruno P. Imbimbo, Medical Department, Mediolanum Farmaceutici, Via Cottolengo 15, 20143 Milan, Italy.

OBJECTIVE: To evaluate the efficacy and safety of eptastigmine in patients with moderate to moderately severe AD.

BACKGROUND: Eptastigmine is a centrally acting cholinesterase inhibitor.

METHODS: The study was carried out according a multicenter, randomized, double-blinded, placebo-controlled, parallel-group design. Patients received a 24-week treatment with placebo or eptastigmine 15 mg or 20 mg three times daily after a 4-week, stepwise dose escalation. The effects of treatment on cognition, global function, and activities of daily living were evaluated with the Alzheimer’s Disease Assessment Cognitive Subscale (ADAS-Cog), the Clinician’s Interview-Based Impression of Change Plus (CIBIC-Plus), and the Instrumental Activities of Daily Living scale (IADL), respectively.

RESULTS: Thirty-six centers recruited 491 patients: 164 on placebo, 166 on eptastigmine 15 mg three times daily, and 161 on eptastigmine 20 mg three times daily. Percentages of patients completing double-blinded treatment were 87% in the placebo group and 86% in both the eptastigmine-treated groups. At the end of treatment, the intent-to-treat analysis on 463 patients showed a dose-dependent effect of eptastigmine on all efficacy variables, with a statistically significant effect of the 20 mg three times daily dose compared with placebo on the ADAS-Cog, CIBIC-Plus, and IADL. Patients on eptastigmine 15 mg three times daily performed significantly better than placebo-treated patients only on the ADAS-Cog. Eleven patients on placebo (7%), 13 patients on eptastigmine 15 mg three times daily (8%), and 12 patients on eptastigmine 20 mg three times daily (8%) discontinued study treatment because of adverse events. Adverse events were recorded in 49% of patients on placebo compared with 54% on eptastigmine 15 mg three times daily and 48% on eptastigmine 20 mg three times daily. Cholinergic side effects (nausea, vomiting, diarrhea, and abdominal pain) were reported with similar frequency in the eptastigmine- and placebo-treated patients. There was a dose-dependent transient and mild neutropenic effect associated with eptastigmine treatment, and one patient on 20 mg three times daily had an asymptomatic pancytopenia.

CONCLUSIONS: Eptastigmine produces significant cognitive, clinical, and functional benefits in patients with probable AD. Although the cholinergic tolerability of eptastigmine was found to be favorable, its potential adverse hematologic effects limit its clinical utility.

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