Abstract

Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether alpha-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS. Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment. After 12 months of treatment, alpha-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B (P=0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma (P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species (P = 0.0055) in the group of patients given alpha-tocopherol in combination with riluzole. Although alpha-tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints.

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