ALZHEIMERS-DISEASE - TACRINE AND TACRINE METABOLITE CONCENTRATIONS INPLASMA AND COGNITIVE CHANGE

In a clinical trial of tacrine in patients with Alzheimer's disease, i mprovement, measured by changes on both total (ADAST) and the cognitiv e sub-component (ADASC) of the Alzheimer's Disease Assessment Scale (A DAS) over a 6-week period, correlated significantly with plasma levels of tacrine. Change on the ADAS (both total and the cognitive subcompo nent) also correlated significantly with three monohydroxylated metabo lites of tacrine 1,hydroxy-tacrine (1-OH-THA), 2,hydroxy-tacrine (2-OH -THA), and 4,hydroxy-tacrine (4-OH-THA). However, changes of the relat ively small non-cognitive component of the ADAS were not significantly correlated with plasma levels of tacrine. Multiple correlational anal ysis revealed that the combined influences of these metabolites were n o greater than the effects of tacrine alone in ameliorating the sympto ms of Alzheimer's disease. An alternative measure of cognitive perform ance, the Mini Mental State Exam (MMSE) did not correlate significantl y with plasma concentrations of tacrine or its metabolites. Tacrine an d these metabolites are bound to plasma proteins. In 10 patients with Alzheimer's disease receiving tacrine, the percentage of tacrine, 1-OH -THA, 2-OH-THA, and 4-OH-THA, that was free in plasma was found to be 19.7 +/- 3.3, 51.3 +/- 7.7, 40.7 +/- 6.9, and 42.4 +/- 6.3 (mean +/- S D), respectively. (C) 1995 Wiley-Liss, Inc.