Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.

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.

Liquid chromatography-tandem mass spectrometry method for the simultaneous determination of delta-ALA, tyrosine and creatinine in biological fluids.

BACKGROUND: Several acquired and congenital human disorders perturb the concentrations of delta-aminolevulinate (delta-ALA), creatinine and tyrosine in biological fluids. There is currently no facile, sensitive and specific method to measure these analytes simultaneously. METHOD: We developed an LC-MS/MS method to quantify delta-ALA, creatinine and tyrosine in urine that requires minimal sample preparation and no derivatization. The method is also applicable to the analysis of tyrosine in plasma. RESULTS: All calibration plots were linear, with R(2)>or=0.996. Intra- and interday CVs were <10%. The limit of quantitation for delta-ALA was approximately 0.1 micromol/l, and for creatinine and tyrosine it was well below the lowest measured physiological concentrations. The method was applied to analyze urine from 75 healthy volunteers and 43 patients with hereditary tyrosinemia type I (HT I). The mean urinary concentration of delta-ALA in patients (38+/-35 micromol/l, 53+/-30 mg/g creatinine) was higher than that measured in healthy subjects (5.5+/-2.6 micromol/l, 0.9+/-0.2 mg/g creatinine; p<0.001). Treatment with 2-(2-nitro-4-trifluoromethylbenzyl)-1,3-cyclohexanedione (NTBC), an inhibitor of an early step in tyrosine catabolism, decreased urinary delta-ALA (6.4+/-4.8 micromol/l, 13+/-24 mg/g creatinine; p<0.001). The average plasma tyrosine concentration in healthy volunteers (56+/-14 micromol/l) was within normal reference interval used in clinical practice. CONCLUSIONS: The method is simple, specific and precise and allows simultaneous quantitation of delta-ALA, creatinine and tyrosine at concentrations present under physiological or pathophysiological conditions.