Stacpoole Peter W, Kerr Douglas S, Barnes Carie, Bunch S Terri, Carney Paul R, Fennell Eileen M, Felitsyn Natalia M, Gilmore Robin L, Greer Melvin, Henderson George N, Hutson Alan D, Neiberger Richard E, O'Brien Ralph G, Perkins Leigh Ann, Quisling Ronald G, Shroads Albert L, Shuster Jonathan J, Silverstein Janet H, Theriaque Douglas W, Valenstein Edward
Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, Florida, USA.
Pediatrics. 2006 May;117(5):1519-31. doi: 10.1542/peds.2005-1226.
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.
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.
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.
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.
开放标签研究表明，口服二氯乙酸（DCA）可能对治疗先天性乳酸性酸中毒患者有效。我们通过开展第一项针对该疾病的DCA双盲、随机对照试验来验证这一假设。
纳入了43名年龄在0.9至19岁之间的患者。所有患者均有持续性或间歇性高乳酸血症，且大多数有严重的精神运动发育迟缓。11名患者有丙酮酸脱氢酶缺乏症，25名患者在呼吸链酶中有1种或更多缺陷，7名患者线粒体DNA有突变。患者先接受6个月的安慰剂预处理，然后随机分配接受额外6个月的安慰剂或DCA治疗，剂量为每12小时12.5mg/kg。主要结局结果包括：（1）治疗效果综合评估，包括神经肌肉和行为功能测试及生活质量；（2）线性生长；（3）禁食状态和进碳水化合物餐后的血乳酸浓度；（4）并发疾病和住院的频率及严重程度；（5）安全性，包括肝功能和周围神经功能测试。
治疗效果综合评估得分、线性生长或并发疾病的频率及严重程度方面无显著差异。DCA显著降低了碳水化合物喂养引起的血乳酸升高。长期服用DCA与药物血浆清除率下降以及酪氨酸分解代谢产物马来酰丙酮和血红素前体δ-氨基乙酰丙酸尿排泄增加有关。
在这个高度异质性的先天性乳酸性酸中毒儿童群体中，口服DCA 6个月耐受性良好，且能减轻餐后循环乳酸的增加。然而，它并未改善神经功能或其他临床结局指标。
