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Treatment of Alzheimer's disease (AD) is one of the great challenges to neuroscience for the 21st century. Despite intense investigation since the late 1970s, AD research has not provided a cure or therapy that permanently arrests the disease. Yet, over the past 10 years, there has been a considerable effort directed toward finding palliative therapies for AD that act through enhancement of cholinergic neuro-transmission. Therapy with cholinesterase inhibitors (CEIs) clearly affects the symptomatic expression of AD, but the practical benefits have been unclear.
Two articles1,2 in this issue of Neurology present data from clinical trials with the CEI metrifonate for the treatment of AD. Metrifonate has been available for many years as a treatment for schistosomaisis. In the late 1980s, it was suspected that as a CEI, metrifonate might have activity against AD.3 Recognition of its potential led to the current studies of metrifonate. The results provide additional confirmation of the CEI effect. Unfortunately, metrifonate's benefits are no greater than those of other CEIs.
Metrifonate's pharmacology is unique among the CEIs being used or considered for AD. It has a short half-life in plasma (2 hours) but a very long action in the brain because it is an irreversible CEI. It lacks specificity for central versus peripheral cholinesterases. Metrifonate is largely unbound to plasma proteins (<15%) and is not metabolized through the hepatic P450 system. Donepezil,4,5 tacrine,6 and rivastigmine,7 another CEI currently awaiting FDA approval, have different pharmacologic profiles. Which is the best profile? The clinical efficacy would suggest that none of these features make a difference across the CEIs. Patient tolerability differs, however.
The current studies used accepted diagnostic criteria and disease severity assessments. Both were placebo-controlled, randomized trials. Dropout rates were low, and as a consequence, an intent-to-treat analytic strategy adequately reflected the …
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