Biological and Neuropsychological Characterization of Physostigmine Responders and Nonresponders in Alzheimer's Disease

Abstract

To assess the efficacy of oral physostigmine for the treatment of Alzheimer's disease, 20 patients were entered into a clinical trial. All patients underwent a dose-finding phase (two weeks), followed by an open trial (two weeks), and a double-blind crossover phase (two weeks drug, two weeks placebo). Extensive neuropsychological testing (Buschke Selective Reminding procedure, category generation, picture recognition, finger tapping) and measurement of systemic cholinergic parameters were measured during each of these phases. Patients were classified as physostigmine responders and nonresponders based on a priori established criteria. Using these, nine patients were found to respond to physostigmine, while 11 were classified as nonresponders. During baseline conditions, responders when compared to nonresponders were found to have higher concentrations of red blood cell (RBC) choline (Ch) and higher ratios of RBC Ch to plasma Ch. Neuropsychological tests were found to fall into one of three categories. The first group of tests were sensitive to drug effects and differentiated physostigmine responders from nonresponders; the second group was found to predict responsiveness; and the third group was neither predictive nor sensitive to drug effects.

A Strategy of “Combination Chemotherapy” in Alzheimer's Disease: Rationale and Preliminary Results with Physostigmine plus Deprenyl

“…The finding of modest but statistically significant improvement during the initial dose-finding phase of our study with oral physostigmine is consistent with previous work (Harrell et al, 1990;Mohs et al, 1985;Stem et al, 1987). The lack of significant improvement during the subacute phases of this study, when subjects were treated for weeks at a time with physostigmine alone or physostigmine plus deprenyl, is more difficult to understand.…”

“…Our intent was to study the combination of deprenyl and physostigmine, two medications that have eachbeen shown to have some beneficial effects in Alzheimer's disease, in order to test the possible synergistic therapeutic results of "combination chemotherapy" in Alzheimer's disease (Agnoli et al, 1990Harrell et al, 1990Mangoni et al, 1991;Mohs et al, 1985;Piccinin et al, 1990;Stern et al, 1987;Tariot et al, 1987). Several lines of research data regarding the biology of Alzheimer's disease converge to suggest that a combination of these pharmacological agents may be of use in DAT (Decker & McGaugh, 1987).…”

Donepezil Improves Cognition and Global Function in Alzheimer Disease<subtitle>A 15-Week, Double-blind, Placebo-Controlled Study</subtitle>

“…The rate of patient withdrawal from treatment was much lower with the use of donepezil than with the rates reported for other cholinesterase inhibitors, such as physostigmine, rivastigmine (ENA-713), velnacrine maleate, and tacrine. 12,[36][37][38] All these cholinesterase inhibitors are associated with a higher incidence of peripheral cholinergic adverse effects than the use of donepezil, with some (tacrine and velnacrine) being associated with hepatotoxic effects. 12,[36][37][38] One of several factors contributing to this low rate of patient withdrawal is that the long halflife of donepezil (approximately 70 hours) combined with the once-daily administration produced AChE inhibition with little diurnal variation and a slow and gradual rise to steady state levels of activity.…”

Extraneuronal Manifestations of Alzheimer's Disease

“…Biochemical Studies There have been several reports 10–12 showing an increase in choline in red blood cells in AD. These support the theory that abnormalities in choline metabolism might be related to the cholinergic neuron deficits in the brain.…”