The disposition and effects of two doses of dichloroacetate in adults with severe falciparum malaria

Abstract

1. Dichloroacetate (DCA) is a promising treatment for lactic acidosis complicating severe malaria. The pharmacokinetics, pharmacodynamics and toxicity of dichloroacetate were evaluated in 11 patients with severe malaria, and their lactate responses compared with nine control patients in an open-label prospective study. 2. Intravenous DCA (46 mg kg-1 infused in 30 min) or saline placebo was given on admission to the study, and 12 h later, as an adjunct to standard quinine treatment. 3. An open one-compartment model with the following parameters described the pharmacokinetics of DCA after one dose (mean [s.d.]): V = 0.44(0.2) 1 kg-1; CL = 0.13[0.027] 1. h-1 kg-1; C(max) = 106[28] mg l-1; t( 1/2 ) = 3.4(2.2) h. After two doses of DCA (n = 9) the pharmacokinetic parameters were similar to those after the first dose. 4. DCA decreased venous plasma lactate concentrations by 42% of baseline values 8 h after admission, normalized arterial pH from a mean(s.d.) of 7.367(0.063) to 7.39(0.1), and decreased the calculated base deficit from 9.2(7.3) mEq l-1 to 6.4(10.4) mEq l-1. In control patients lactate concentrations fell by ~ 14% of baseline concentrations (P < 0.02 compared with DCA recipients). Venous lactate concentrations fell, a further 16% from baseline values after the second dose of DCA but this change was not significantly different from controls. There was no electrocardiographic or other evidence of toxicity associated with DCA. 5. These data suggest that a single intravenous infusion of DCA rapidly reduces hyperlactataemia in patients severely ill with malaria, and that DCA should be evaluated further as an adjunct to conventional antimalarial and supportive measures for such patients with lactic acidosis.