Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial.

Di Prospero NA, Baker A, Jeffries N, Fischbeck KH.

Lancet Neurol. 2007 Oct;6(10):878-86.
Neurogenetics Branch,
National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD 20892-3705. diprospern@ninds.nih.gov

Abstract

BACKGROUND: Friedreich's ataxia is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown.

METHODS: 48 genetically confirmed Friedreich's ataxia patients, aged 9-17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone (approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the Friedreich's ataxia rating scale (Friedreich's ataxiaRS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632.

FINDINGS: Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2'dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, Friedreich's ataxiaRS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0.03) and suggested a dose-related response in ICARS, Friedreich's ataxiaRS, and ADL scores.

INTERPRETATION: Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with Friedreich's ataxia. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.

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MELAS
Idebenone  improves cerebral mitochondrial oxidative metabolism in MELAS
Idebenone  in young patients with mitochondrial encephalomyopathy (MELAS)
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Idebenone  functions as a potent protective hepatocyte antioxidant

Idebenone  neuroprotective effects of idebenone can be attributed to its antioxidant ability

Idebenone  inhibition of brain mitochondrial swelling

Idebenone  suppression of cold ischemia/reperfusion injury of liver endothelium

Idebenone  ability to eliminate a nitroxide radical in the rat

Idebenone  interaction with respiratory complexes of heart mitochondria

Idebenone  effect on serotonin release and seroton receptors in rats

Idebenone  protects hepatic microsomes against damage in organ preservation solutions

Idebenone  protects against toxicity induced by low density lipoprotein

Idebenone  protects against disorders due to cerebral hypoxia or ischemia

Idebenone  protects against toxicity induced by low density lipoprotein

Idebenone  attenuates neuronal degeneration induced by excitotoxins

Idebenone  augments long-term potentiation in hippocampal slices in the guinea pig

Idebenoneeffects on lipid peroxidation in erythrocytes of stroke-prone, hypertensive rats

Idebenone  brain distribution and its effect on local cerebral glucose utilization in rats

Idebenone  effects on acetylcholine levels in the brains of rats with cerebral ischemia

Idebenone  protective effect of idebenone against hypoxia in mice

Idebenone  improves learning and memory impairment induced in rats

Idebenone  effects of idebenone on neurological deficits in stroke-prone rats

Idebenone  effects on memory induced impairment in rats

Idebenone  effects of idebenone on cerebral blood flow in rats with cerebral ischemia

Idebenone  inhibition of brain mitochondrial swelling by idebenone

Idebenone  inhibition of platelet aggregation by idebenone

Idebenone  effects of idebenone on monoamine metabolites of patients with dementia

Idebenone  effects of idebenone on metabolism of monoamines and cyclic AMP formation

Idebenone  effects on impairment of radial maze learning in cerebral embolized rats

Idebenone  effect of idebenone on lipid peroxidation in rat brain homogenate

Idebenone  effects on muricidal behavior in rats with raphe lesions

Idebenone  inhibitory effect of idebenone on vascular lesions in hypertensive rats

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