4-Aminopyridine in the treatment of Alzheimer's disease.

The cognitive and behavioral effect of 4-aminopyridine (4-AP) was examined in Alzheimer's disease (AD) using a dose finding/replication study design. Fourteen inpatients, aged 54-89 years (mean 66.1 +/- 10.6 SD), meeting NINCDS criteria for probable AD, were studied. Three doses of 4-AP--2.5 mg b.i.d., 5 mg b.i.d., and 10 mg b.i.d.--or placebo were administered for 4 consecutive days in random order. Symptomatic assessment was performed on the fourth day of each condition using the Alzheimer Disease Assessment Scale (ADAS). Thereafter, the dose on which the best performance occurred was readministered, as was placebo. Of the 13 patients who completed the dose-finding phase, 7 patients had at least one dose of 4-AP that was associated with less severe symptoms than was placebo, and those patients were included in the replication phase. Results indicated no significant difference in total ADAS scores (p greater than 0.05). Examination of the ADAS subscales revealed no significant 4-AP effect on any particular symptom. Possible explanations of the lack of a drug effect in this study include the unselective release of neurotransmitters by 4-AP, poor penetration into the central nervous system (CNS), and the presenile onset of the disease in these patients.