title: High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria.
abstract: BACKGROUND
  Due to development of multidrug-resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard-dose chloroquine remained effective for decades despite the existence of "chloroquine-resistant" P. falciparum. This study aimed to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance-conferring genotypes.
  
  
  METHODS
  Standard or double-dose chloroquine was given to 892 children aged <15 years with uncomplicated malaria during 3 clinical trials (2001-2008) with ≥ 35 days follow-up. The P. falciparum resistance-conferring genotype (pfcrt 76T) and day 7 chloroquine concentrations were determined. Data were divided into age groups (<5, 5-9, and 10-14 years) because concentrations increase with age when chloroquine is prescribed according to body weight.
  
  
  RESULTS
  Adequate clinical and parasitological responses were 14%, 38%, and 39% after standard-dose and 66%, 84%, and 91% after double-dose chloroquine in children aged <5, 5-9, and 10-14 years, respectively, and infected with P. falciparum genotypes conferring chloroquine resistance (n = 195, P < .001). In parallel, median chloroquine concentrations were 471, 688, and 809 nmol/L for standard-dose and 1040, 1494, and 1585 nmol/L for double-dose chloroquine.
  
  
  CONCLUSIONS
  Chloroquine resistance is dose dependent and can be overcome by higher, still well-tolerated doses.
authors.affiliation: Projecto de Saúde de Bandim, Indepth Network, Bissau, Guinea-Bissau Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Department of Infectious Diseases, Danderyds Hospital, Stockholm.
authors.forename: Johan
authors.initials: J
authors.lastname: Ursing
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Centre for Clinical Research, Sörmland County Council, Eskilstuna, and Uppsala University.
authors.forename: Lars
authors.initials: L
authors.lastname: Rombo
authors.affiliation: Dalarna University College, Borlänge, Sweden.
authors.forename: Yngve
authors.initials: Y
authors.lastname: Bergqvist
authors.affiliation: Projecto de Saúde de Bandim, Indepth Network, Bissau, Guinea-Bissau.
authors.forename: Amabelia
authors.initials: A
authors.lastname: Rodrigues
authors.affiliation: Projecto de Saúde de Bandim, Indepth Network, Bissau, Guinea-Bissau Department of Paediatrics, Kolding Hospital, Denmark.
authors.forename: Poul-Erik
authors.initials: PE
authors.lastname: Kofoed
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D059208:Parasite Load; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine
keywords: Plasmodium falciparum; chloroquine; efficacy; pfcrt; resistance