Dichloroacetate causes toxic neuropathy in MELAS - A randomized, controlled clinical trial
Dichloroacetate causes toxic neuropathy in MELAS - A randomized, controlled clinical trial
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DOI：
10.1212/01.wnl.0000196641.05913.27
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发表时间：
2006-02-14
期刊：
影响因子：
9.9
通讯作者：
De Vivo, DC
中科院分区：
文献类型：
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作者：
Kaufmann, P;Engelstad, K;De Vivo, DC
目的：评价二氯醋酸盐（DCA）治疗线粒体肌病、脑病、乳酸酸中毒和卒中样发作（MELAS）的疗效。背景：高水平的心室乳酸，MELAS的脑光谱特征，与更严重的神经功能缺损相关。作者假设慢性脑乳酸酸中毒加重MELAS中的神经元损伤，因此研究了DCA（一种强效乳酸盐降低剂）作为MELAS的潜在治疗。研究方法：作者在30例MELAS和A3243 G突变患者（年龄10 - 60岁）中进行了一项为期3年的DCA（25 mg/kg/天）双盲、安慰剂对照、随机、交叉试验。主要结局指标是基于健康相关事件清单以及神经学、神经心理学和日常生活功能的治疗疗效总体评估（GATE）评分。生物学结局指标包括静脉、CSF和H-1 MRI估计的脑乳酸。进行血液检查和神经传导研究以监测安全性。结果如下：在最初的24个月治疗期间，随机分配至DCA组的15例患者中有15例停用了研究药物，而随机分配至安慰剂组的15例患者中有4例停用了研究药物。19例患者中有17例因周围神经病变发作或恶化而停用研究药物。由于周围神经毒性，临床试验提前终止。治疗组之间的平均GATE评分无显著差异。结论：25 mg/kg/天DCA与周围神经毒性相关，导致停药和提前终止研究的发生率较高。在这些实验条件下，作者无法检测到任何有益效果。研究结果表明，DCA相关的神经病变掩盖了MELAS的任何潜在益处的评估。
Objective: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes ( MELAS). Background: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. Methods: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients ( aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy ( GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and H-1 MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety. Results: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. Conclusion: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.