title: Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum.
abstract: BACKGROUND
  The aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) and piperaquine (PPQ), as new components of artemisinin-based combination therapy (ACT), to define susceptibility baseline, ii) their activities compared to other partner drugs, namely monodesethylamodiaquine (MDAQ), lumefantrine (LMF), mefloquine (MQ), artesunate (AS) and dihydroartemisinin (DHA) against 181 Plasmodium falciparum isolates from African countries, India and Thailand, and iii) in vitro cross-resistance with other quinoline drugs, chloroquine (CQ) or quinine (QN).
  
  
  METHODS
  The susceptibility of the 181 P. falciparum isolates to the nine anti-malarial drugs was assessed using the standard 42-hours 3H-hypoxanthine uptake inhibition method.
  
  
  RESULTS
  The IC50 values for PND ranged from 0.55 to 80.0 nM (geometric mean = 19.9 nM) and from 11.8 to 217.3 nM for PPQ (geometric mean = 66.8 nM). A significant positive correlation was shown between responses to PPQ and PND responses (rho = 0.46) and between PPQ and MDAQ (rho = 0.30). No significant correlation was shown between PPQ IC50 and responses to other anti-malarial drugs. A significant positive correlation was shown between responses to PND and MDAQ (rho = 0.37), PND and LMF (rho = 0.28), PND and QN (rho = 0.24), PND and AS (rho = 0.19), PND and DHA (rho = 0.18) and PND and CQ (rho = 0.16). All these coefficients of correlation are too low to suggest cross-resistance between PPQ or PND and the other drugs.
  
  
  CONCLUSIONS
  In this study, the excellent anti-malarial activity of PPQ and PND was confirmed. The absence of cross-resistance with quinolines and artemisinin derivatives is consistent with the efficacy of the combinations of PPQ and DHA or PND and AS in areas where parasites are resistant to conventional anti-malarial drugs.
authors.affiliation: Unité de Recherche en Biologie et Epidémiologie Parasitaires Unité de Recherche pour les Maladies Infectieuses et Tropicales Emergentes UMR-6236, Institut de Recherche Biomédicale des Armées, Allée du Médecin-colonel Jamot,-BP 60109, 13262 Marseille Cedex, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pascual
authors.forename: Philippe
authors.initials: P
authors.lastname: Parola
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
authors.forename: Fabrice
authors.initials: F
authors.lastname: Simon
authors.forename: Denis
authors.initials: D
authors.lastname: Malvy
authors.forename: Stéphane
authors.initials: S
authors.lastname: Picot
authors.forename: Pascal
authors.initials: P
authors.lastname: Delaunay
authors.forename: Didier
authors.initials: D
authors.lastname: Basset
authors.forename: Danièle
authors.initials: D
authors.lastname: Maubon
authors.forename: Bernard
authors.initials: B
authors.lastname: Faugère
authors.forename: Guillaume
authors.initials: G
authors.lastname: Ménard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bourgeois
authors.forename: Claude
authors.initials: C
authors.lastname: Oeuvray
authors.forename: Eric
authors.initials: E
authors.lastname: Didillon
authors.forename: Christophe
authors.initials: C
authors.lastname: Rogier
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
mesh_terms: D000349:Africa; D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D007194:India; D020128:Inhibitory Concentration 50; D009287:Naphthyridines / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D011804:Quinolines / Q000494:pharmacology*; D013785:Thailand; D014316:Tritium / Q000378:metabolism; D010879:Piperazines
chemical_list: D000962:Antimalarials; D019271:Hypoxanthine; D009287:Naphthyridines; D011804:Quinolines; D014316:Tritium; C034759:piperaquine; D010879:Piperazines; C027871:pyronaridine