Di Prospero Nicholas A, Baker Angela, Jeffries Neal, Fischbeck Kenneth H
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3705, USA.
Lancet Neurol. 2007 Oct;6(10):878-86. doi: 10.1016/S1474-4422(07)70220-X.
Friedreich's ataxia (FA) 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.
48 genetically confirmed FA 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 FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632.
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, FARS, 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, FARS, and ADL scores.
Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. 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.
弗里德赖希共济失调（FA）是一种由frataxin减少引起的进行性多系统退行性疾病。在患者和模型系统中，frataxin的缺失会导致线粒体功能障碍和氧化损伤。先前的研究表明，抗氧化剂艾地苯醌（每日5mg/kg）可减轻心脏肥大，但尚未显示出神经功能有明显改善。
48名经基因确诊的9至17岁FA患者参与了一项为期6个月的随机双盲安慰剂对照研究。患者按体重分层后接受安慰剂或三种剂量艾地苯醌（约5mg/kg、15mg/kg和45mg/kg）之一的治疗。主要终点是尿8-羟基-2'-脱氧鸟苷（8OH2'dG）（氧化DNA损伤的标志物）相对于基线的变化。次要终点包括国际合作共济失调评定量表（ICARS）、FA评定量表（FARS）的变化以及日常生活活动（ADL）调查。本研究已在ClinicalTrials.gov注册，编号为NCT00229632。
艾地苯醌总体耐受性良好，各组不良事件数量相似。一名接受高剂量艾地苯醌治疗的儿童在6个月后出现中性粒细胞减少，停药后缓解。8OH2'dG浓度未升高，且艾地苯醌治疗后无显著变化。虽然总体分析未显示ICARS、FARS或ADL总分有显著差异，但有迹象表明ICARS评分存在剂量依赖性反应。第二项预先指定的分析排除了需要轮椅辅助的患者，结果显示ICARS有显著改善（Bonferroni p = 0.03），并提示ICARS、FARS和ADL评分存在剂量相关反应。
高剂量艾地苯醌治疗总体耐受性良好，与FA患者神经功能和ADL的改善相关。改善程度与艾地苯醌剂量相关，提示可能需要更高剂量才能对神经功能产生有益影响。
