Parkinson's disease (PD) is a common neurological disorder, characterized clinically by progressive disability and pathologically by advancing nigral loss. A variety of dopaminergic therapies, aimed at rectifying the consequences of nigral degeneration, have been developed in the past two decades for symptomatic treatment of PD. Unfortunately, these therapies provide only transient benefit and are attended by a variety of adverse effects. Experimental therapeutics is gradually shifting to preventative strategies aimed at the pathogenesis of PD as we gain a better understanding of the process underlying nigral degeneration. Recent studies in animals and humans implicate toxicity from endogenous and exogenous oxidative mechanisms in the pathogenesis of PD. Preliminary observations from pilot studies suggest that deprenyl, a relatively selective inhibitor of monoamine oxidase type B, and alpha-tocopherol (vitamin E), an antioxidant with free-radical quenching capacities, may ameliorate disability and slow the clinical decline of PD. Our proposal for our clinical trial of deprenyl and tocopherol antioxidative therapies in PD is prompted by the need for preventive therapies, a rationale based on emerging knowledge of pathogenesis, the encouraging results of pilot studies, and the applicability of a feasible design. We hypothesize that chronic deprenyl and/or alpha-tocopherol antioxidative therapies will slow the progressive nigral degeneration and resulting clinical decline of PD. Our preliminary aim is to determine whether or not chronic deprenyl and/or tocopherol administration to early, otherwise untreated PD patients will prolong the time until levodopa therapy is required to treat supervening disability. To this end, we propose a double- blind, multi-institutional, prospective evaluation of PD patients who are in the earliest stages of illness and who are not receiving any symptomatic anti-PD therapies. Subjects will be assigned by randomization using a 2 x 2 factorial design to one of four treatments: 1) deprenyl, 2) tocopherol 3) deprenyl plus tocopherol, or 4) placebo. The primary response variable of interest is the time until levodopa therapy is required to treat disability, up to a maximum of two years of observation. Secondary response variables include clinical and CSF neurochemical measures relevant to the progression of PD.
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