PHARMACOKINETICS AND PHARMACODYNAMICS OF DICHLOROACETATE IN CHILDREN WITH LACTIC-ACIDOSIS DUE TO SEVERE MALARIA

Lactic acidosis frequently complicates severe malaria in African child ren, and is a strong independent predictor of mortality, We tested the hypothesis that sodium dichloroacetate (DCA), an activator of pyruvat e dehydrogenase, rapidly reduces hyperlactataemia in this patient popu lation. Eighteen children with severe malaria and capillary plasma lac tate greater than or equal to 5 mM were randomized to receive either i ntramuscular quinine plus a single 50 mg/kg intravenous infusion of DC A in saline, or quinine plus intravenous saline alone. Two patients in each treatment group died following randomization. Thirty minutes aft er treatment, the mean plasma lactate was 28% below pretreatment basel ine values in the DCA group, but was unchanged in the placebo group. T hroughout the first 4h after treatment, mean plasma lactate in the DCA -treated patients was significantly less than that in controls (p=0.00 3). Thereafter, mean plasma lactate declined in both groups and was <2 mM 10 h after treatment. DCA was well tolerated and did not alter qui nine pharmacokinetics. A single intravenous dose of DCA rapidly improv ed lactic acidosis in African children with severe malaria, suggesting that DCA may be a useful adjunct in the initial treatment of these pa tients, and may increase their chance of survival by improving a major complication of their illness.