Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment.
Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P > .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P < .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria.
Krishna
S
S
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Supanaranond
W
W
Pukrittayakamee
S
S
Karter
D
D
Supputamongkol
Y
Y
Davis
T M
TM
Holloway
P A
PA
White
N J
NJ
D000140:Acidosis, Lactic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D003999:Dichloroacetic Acid / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016778:Malaria, Falciparum / Q000150:complications* / Q000378:metabolism; D008875:Middle Aged
D003999:Dichloroacetic Acid