Second and Third Generation Cholinesterase Inhibitors: Clinical Aspects

Abstract

Loss of cholinergic neurons in the basal forebrain occurs early in Alzheimer’s disease (AD). This loss and the memory deficit generated by administration of cholinergic antagonists, e.g. scopolamine, suggest a potential for the development of cholinergic therapy for AD. Unfortunately, studies of physostigmine and tacrine (THA) have shown encouraging, but only transient improvement in memory and other cognitive measures in AD patients (Becker and Giacobini, 1991). One of the major limitations to use of these cholinesterase inhibitors (ChEI) is the appearance of adverse effects, including nausea, vomiting, diarrhea, and abdominal cramps. We reviewed the status of early cholinergic studies and determined that the appearance of adverse effects and toxicity were not related to the level of cholinesterase (ChE) inhibition or the concentration of acetylcholine (ACh) in brain tissue (Becker and Giacobini, 1988). Rather, the appearance of toxicity seemed to be related to the individual compounds, which suggested to us the possibility that ChEIs could be identified which would be free of interfering adverse events. Other characteristics that we selected as important for the successful use of ChEIs were the ability to achieve a full range of ChE inhibition and a long duration of action. After animal studies, we selected metrifonate (MTF), an organophosphate ChEI, that spontaneously hydrolyses to the active ChEI dichlorvos (DDVP). In initial open studies in 20 AD patients, we found we could achieve up to 88% inhibition of red blood cell (RBC) acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) without interfering side effects. Using the Alzheimer’s Disease Assessment Scale (ADAS), we found an inverted “U” shaped dose-response curve comparing dose of MTF to percent of individuals responding (Becker et al., 1990). By plotting the dose-response relationship level of RBC AChE inhibition and ADAS response for 14 responders, we calculated an estimated optimal level of inhibition of 45%. This relationship was consistent with the report of Thal et al. (1986) who found ChE inhibition in the CSF of five patients had a “U” shaped relationship to improvement in memory. Based on these initial findings, we hypothesized that using MTF, a 40–60% level of RBC AChE inhibition was required to achieve an optimal cognitive response. This range of inhibition places each patient about three standard deviations from the mean level of AChE activity prior to the administration of MTF. To prepare for a double-blind, placebo-controlled evaluation of MTF, with ChE inhibition within the 40–60% range, we developed a dosing model to administer MTF.KeywordsAChE ActivityCholinesterase InhibitorEnzyme RecoveryCholinergic TherapyGeneration CholinesteraseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.