Absence of association between piperaquine in vitro responses and polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe genes in Plasmodium falciparum.
We have analyzed the profiles of 23 of Plasmodium falciparum strains for their in vitro chemosusceptibilities to piperaquine (PPQ), dihydroartemisinin (DHA), chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine, and doxycycline (DOX) in association with polymorphisms in genes involved in quinoline resistance (Plasmodium falciparum crt [pfcrt], pfmdr1, pfmrp, and pfnhe). The 50% inhibitory concentrations (IC(50)s) for PPQ ranged from 29 to 98 nM (geometric mean = 57.8 nM, 95% confidence interval [CI] = 51 to 65) and from 0.4 to 5.8 nM for DHA (geometric mean = 1.8 nM, 95% CI = 1.4 to 2.3). We found a significant positive correlation between the responses to PPQ and DHA (r(2) = 0.17; P = 0.0495) and between the responses to PPQ and DOX (r(2) = 0.41; P = 0.001). We did not find a significant association between the PPQ IC(50) (0.0525 < P < 0.9247) or the DHA IC(50) (0.0138 < P < 0.9018) and polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe-1 genes. There was an absence of cross-resistance with quinolines, and the IC(50)s for PPQ and DHA were found to be unrelated to mutations in the pfcrt, pfmdr1, pfmrp, and pfnhe-1 transport protein genes, which are involved in quinoline antimalarial drug resistance. These results confirm the interest in and the efficacy of the combination of PPQ and DHA for areas in which parasites are resistant to chloroquine or other quinolines.
Briolant
Sébastien
S
Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Recherche Biomédicale des Armées-Antenne de Marseille, Allée du Médecin-colonel Jamot, Parc le Pharo, BP 60109, 13262 Marseille Cedex 7, France.
Henry
Maud
M
Oeuvray
Claude
C
Amalvict
Rémy
R
Baret
Eric
E
Didillon
Eric
E
Rogier
Christophe
C
Pradines
Bruno
B
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D011804:Quinolines / Q000494:pharmacology*; D010879:Piperazines
D000962:Antimalarials; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011804:Quinolines; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C034759:piperaquine; D010879:Piperazines