Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children
Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children
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DOI：
10.1542/peds.2005-1226
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发表时间：
2006-05-01
期刊：
影响因子：
8
通讯作者：
Valenstein, E
中科院分区：
文献类型：
--
作者：
Stacpoole, PW;Kerr, DS;Valenstein, E
目标。开放标签研究表明，口服二氯乙酸酯(DCA)可能对先天性乳酸酸中毒患者有效。我们通过对DCA进行首次双盲、随机、对照试验来检验这一假设。方法：43名年龄从0.9岁到19岁的患者入选。所有患者均有持续性或间歇性高血症，多数患者有严重的精神运动障碍。11例患者存在丙酮酸脱氢酶缺陷，25例患者存在1种或1种以上呼吸链酶缺陷，7例患者存在线粒体DNA突变。患者接受6个月的安慰剂预适应，然后被随机分配到另外6个月的安慰剂或DCA，剂量为12.5 mg/kg，每12小时。主要结果是(1)治疗效果的全球评估，其中包括神经肌肉和行为功能以及生活质量的测试；(2)线性增长；(3)禁食状态和碳水化合物餐后的血乳酸浓度；(4)并发疾病和住院的频率和严重程度；以及(5)安全性，包括肝脏和周围神经功能的测试。DCA能显著降低碳水化合物喂养引起的血乳酸升高。长期服用DCA与药物的血浆清除率下降以及尿中酪氨酸分解代谢产物马来基丙酮和血红素前体β-氨基乙酰丙酸的排泄增加有关。结论在这一高度异质性的先天性乳酸血症儿童群体中，口服DCA 6个月可以很好地耐受性，并抑制餐后循环乳酸的增加。然而，它并没有改善神经学或其他临床结果的指标。
OBJECTIVE. Open-label studies indicate that oral dichloroacetate ( DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease.METHODS. Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were ( 1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; ( 2) linear growth; ( 3) blood lactate concentration in the fasted state and after a carbohydrate meal; ( 4) frequency and severity of intercurrent illnesses and hospitalizations; and ( 5) safety, including tests of liver and peripheral nerve function.OUTCOME. There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor delta-aminolevulinate.CONCLUSIONS. In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.