Relationship between pharmacodynamic activity and cognitive effects of eptastigmine in patients with Alzheimer's disease. Eptastigmine Study Group.

OBJECTIVE: To assess the safety, tolerability, pharmacodynamics, and preliminary efficacy of eptastigmine, a new long-acting cholinesterase inhibitor, in patients with probable Alzheimer's disease.

METHODS: This was a double-blind, randomized, placebo-controlled, unbalanced parallel-group study. One-hundred and three patients (83 in the eptastigmine group and 20 in the placebo group) were recruited by 10 centers. Patients received 20 mg eptastigmine or placebo for 4 weeks with twice-a-day or three-times-a-day regimens, depending on body weight (< or = 65 kg or > 65 kg, respectively). Patient performance on the Logical Memory Test, Semantic Word Fluency Test, Trail Making Test, Index of Independence in Activities of Daily Living, Instrumental Activities of Daily Living Scales (IADL), and the Physician and Caregiver Clinical Global Impression of Change (CGIC) was assessed at baseline and at the end of treatment.

RESULTS: Nine patients, all from the eptastigmine group, did not complete treatment because of uncooperativeness (n = 3), adverse events (n = 3), protocol violations (n = 2), and clinical decline (n = 1). Twenty-five patients receiving eptastigmine (34%) reported adverse events mainly of the cholinergic type. Cholinergic side effects were generally associated with peak red blood cell cholinesterase inhibition exceeding 50% after the first dose, or 70% at steady state. At steady state, average daily acetylcholinesterase inhibition ranged from 13% to 54%. Overall, 34% of patients receiving eptastigmine versus 0% receiving placebo (p = 0.006) improved on the Physician CGIC. This percentage increased to 46% in the subgroup of patients with average daily acetylcholinesterase inhibition ranging from 30% to 35%. Patient performance on the IADL also improved significantly compared with the placebo group (p = 0.019). In the eptastigmine group, performances on all tests and scales improved with an inverted U-shaped relation to average daily acetylcholinesterase inhibition.

CONCLUSIONS: This study shows that doses of 40 to 60 mg per day of eptastigmine are relatively safe and well tolerated and that moderate acetylcholinesterase inhibition is associated with maximal cognitive efficacy.