Open Access Research

Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum

Aurélie Pascual12, Philippe Parola3, Françoise Benoit-Vical4, Fabrice Simon5, Denis Malvy6, Stéphane Picot7, Pascal Delaunay8, Didier Basset9, Danièle Maubon10, Bernard Faugère11, Guillaume Ménard12, Nathalie Bourgeois13, Claude Oeuvray14, Eric Didillon15, Christophe Rogier1 and Bruno Pradines12*

Author Affiliations

1 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

2 Centre National de Référence du Paludisme, Marseille, France

3 Institut Hospitalo-Universitaire en Maladies Infectieuses et Tropicales, Hôpital Nord, Marseille, France

4 Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Rangueil, Toulouse, France

5 Service de Pathologie Infectieuse et Tropicale, Hôpital d'Instruction des Armées Laveran, Marseille, Frnace

6 Travel Clinics and Division of Tropical Medicine and Imported Diseases, Centre Hospitalier Universitaire, Bordeaux, France

7 Malaria Research Unit, UMR 5246, CNRS Lyon, France

8 Laboratoire de Parasitologie-Mycologie, Hopital de 1'Archet, Nice, France

9 Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire Lapeyronnie, Montpellier, France

10 Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire et Université de Grenoble 1, Grenoble, France

11 Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire La Timone, Marseille, France

12 Fédération des Laboratoires, Hôpital d'Instruction des Armées Sainte Anne, Toulon, France

13 Service de Bactériologie-Virologie-Parasitologie, Centre Hospitalier Universitaire Caremeau, Nimes, France

14 Medicines for Malaria Venture, Geneva, Switzerland

15 Fulcrum Pharma (Europe) Ltd, Hemel Hempstead, UK

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Malaria Journal 2012, 11:45  doi:10.1186/1475-2875-11-45

Published: 14 February 2012

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.

Keywords:
Malaria; Plasmodium falciparum; Anti-malarial; In vitro; Resistance; Pyronaridine; Piperaquine