Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children.
The authors conducted a randomized, double-blind, placebo-controlled trial of intravenous dichloroacetate (DCA) for the purpose of treating lactic acidosis in 124 West African children with severe Plasmodium falciparum malaria. Lactic acidosis independently predicts mortality in severe malaria, and DCA stimulates the oxidative removal of lactate in vivo. A single infusion of 50 mg/kg DCA was well tolerated. When administered at the same time as a dose of intravenous quinine, DCA significantly increased the initial rate and magnitude of fall in blood lactate levels and did not interfere with the plasma kinetics of quinine. The authors developed a novel population pharmacokinetic-pharmacodynamic indirect-response model for DCA that incorporated characteristics associated with disease reversal. The model describes the complex relationships among antimalarial treatment procedures, plasma DCA concentrations, and the drug's lactate-lowering effect. DCA significantly reduces the concentration of blood lactate, an independent predictor of mortality in malaria. Its prospective evaluation in affecting mortality in this disorder appears warranted.
Department of Physiology, University of Science and Technology, School of Medical Sciences, Departments of Child Health and Medicine, Komfo-Anokye Teaching Hospital, Kumasi, Ghana.
Tsiri
T
Agbenyega
Tim
T
Planche
George
G
Bedu-Addo
Daniel
D
Ansong
Alex
A
Owusu-Ofori
Venkatesh A
VA
Bhattaram
Nelamangala V
NV
Nagaraja
Albert L
AL
Shroads
George N
GN
Henderson
Alan D
AD
Hutson
Hartmut
H
Derendorf
Sanjeev
S
Krishna
Peter W
PW
Stacpoole
D000140:Acidosis, Lactic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000962:Antimalarials / Q000627:therapeutic use; D002675:Child, Preschool; D003999:Dichloroacetic Acid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D011803:Quinine / Q000097:blood / Q000627:therapeutic use; D013997:Time Factors
D000962:Antimalarials; D003999:Dichloroacetic Acid; D011803:Quinine