title: In vitro piperaquine susceptibility is not associated with the Plasmodium falciparum chloroquine resistance transporter gene.
abstract: BACKGROUND
  Dihydroartemisinin-piperaquine is a new ACT that is administered as single daily dose for three days and has been demonstrated to be tolerated and highly effective for the treatment of uncomplicated Plasmodium falciparum malaria. Piperaquine was used alone to replace chloroquine as the first-line treatment for uncomplicated malaria in China in response to increasing chloroquine resistance in the 1970s. However, the rapid emergence of piperaquine-resistant strains that resulted in the cessation of its use in China in the 1980s, suggests that there is cross-resistance between piperaquine and chloroquine. Very few data are available on cross-resistance between piperaquine and chloroquine, and the data that do exist are often contradictory.
  
  
  METHODS
  In total, 280 P. falciparum isolates, collected between April 2008 and June 2012 from patients hospitalized in France with imported malaria from a malaria-endemic country, were assessed ex vivo for piperaquine and chloroquine susceptibilities by using the standard 42-hour 3H-hypoxanthine uptake inhibition method. The chloroquine resistance-associated mutation K76T in pfcrt was also investigated for the 280 isolates.
  
  
  RESULTS
  The IC50 for piperaquine ranged from 9.8 nM to 217.3 nM (mean = 81.3 nM. The IC50 for chloroquine ranged from 5.0 nM to 1,918 nM (mean = 83.6 nM. A significant but low correlation was observed between the Log IC50 values for piperaquine and chloroquine (r = 0.145, p < 0.001). However, the coefficient of determination of 0.021 indicates that only 2.1% of the variation in the response to piperaquine is explained by the variation in the response to chloroquine. The mean value for piperaquine was 74.0 nM in the Pfcrt K76 wild-type group (no = 125) and 87.7 nM in the 76 T mutant group (no = 155). This difference was not significant (p = 0.875, Mann Whitney U test).
  
  
  CONCLUSIONS
  The present work demonstrates that there was no cross-resistance between piperaquine and chloroquine among 280 P. falciparum isolates and that piperaquine susceptibility is not associated with pfcrt, the gene involved in chloroquine resistance. These results confirm the efficacy of piperaquine in association with dihydroartemisinin and support its use in areas in which parasites are resistant to chloroquine.
authors.affiliation: Département d'Infectiologie de Terrain, Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille, France. bruno.pradines@free.fr.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pascual
authors.forename: Marilyn
authors.initials: M
authors.lastname: Madamet
authors.forename: Lionel
authors.initials: L
authors.lastname: Bertaux
authors.forename: Rémy
authors.initials: R
authors.lastname: Amalvict
authors.forename: Nicolas
authors.initials: N
authors.lastname: Benoit
authors.forename: Dominique
authors.initials: D
authors.lastname: Travers
authors.forename: Julien
authors.initials: J
authors.lastname: Cren
authors.forename: Nicolas
authors.initials: N
authors.lastname: Taudon
authors.forename: Christophe
authors.initials: C
authors.lastname: Rogier
authors.forename: Daniel
authors.initials: D
authors.lastname: Parzy
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D005602:France; D006801:Humans; D020128:Inhibitory Concentration 50; D026901:Membrane Transport Proteins / Q000235:genetics*; D015233:Models, Statistical; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D011804:Quinolines / Q000494:pharmacology*; D010879:Piperazines
chemical_list: D000962:Antimalarials; D002738:Chloroquine; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D011804:Quinolines; C416369:PfCRT protein, Plasmodium falciparum; C034759:piperaquine; D010879:Piperazines