THE DISPOSITION AND EFFECTS OF 2 DOSES OF DICHLOROACETATE IN ADULTS WITH SEVERE FALCIPARUM-MALARIA

1 Dichloroacetate (DCA) is a promising treatment for lactic acidosis c omplicating 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 patie nts 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 s tudy, and 12 h later, as an adjunct to standard quinine treatment. 3 A n open one-compartment model with the following parameters described t he 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 1(-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 af ter 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 1(-1) to 6.4(10.4) mEq 1(-1). In control patients lactate concen trations fell by similar to 14% of baseline concentrations (P<0.02 com pared with DCA recipients). Venous lactate concentrations fell a furth er 16% from baseline values after the second dose of DCA but this chan ge was not significantly different from controls. There was no electro cardiographic or other evidence of toxicity associated with DCA. 5 The se data suggest that a single intravenous infusion of DCA rapidly redu ces hyperlactataemia in patients severely ill with malaria, and that D CA should be evaluated further as an adjunct to conventional antimalar ial and supportive measures for such patients with lactic acidosis.