title: Effect of high-dose or split-dose artesunate on parasite clearance in artemisinin-resistant falciparum malaria.
abstract: BACKGROUND
  The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves parasite clearance in falciparum malaria in the 2 regions.
  
  
  METHODS
  In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009-2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a once-daily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence for up to 63 days of follow-up were assessed.
  
  
  RESULTS
  A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) parasitemia half-life (half-life) was 6.03 (4.89-7.28) hours in Pailin versus 3.42 (2.20-4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68).
  
  
  CONCLUSIONS
  Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum. Clinical Trials Registration. ISRCTN15351875.
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Debashish
authors.initials: D
authors.lastname: Das
authors.forename: Rupam
authors.initials: R
authors.lastname: Tripura
authors.forename: Aung Pyae
authors.initials: AP
authors.lastname: Phyo
authors.forename: Khin Maung
authors.initials: KM
authors.lastname: Lwin
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpong
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
authors.forename: Didier
authors.initials: D
authors.lastname: Menard
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.forename: Kamolrat
authors.initials: K
authors.lastname: Silamut
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.forename: Poravuth
authors.initials: P
authors.lastname: Yi
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Duong
authors.initials: D
authors.lastname: Socheat
authors.forename: Chea
authors.initials: C
authors.lastname: Nguon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics; D037621:Artemisinins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077332:Artesunate; D002160:Cambodia; D002648:Child; D004351:Drug Resistance; D005260:Female; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D059208:Parasite Load; D018512:Parasitemia / Q000188:drug therapy*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000276:immunology; D013785:Thailand; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D000962:Antimalarials; D037621:Artemisinins; D007074:Immunoglobulin G; D000077332:Artesunate; C031327:artemisinin