Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum

Malaria Journal

Research

Eric Didillon¹  Claude Oeuvray²  Rémy Amalvict³  Eric Baret³  Bruno Pradines³  Sébastien Briolant³  Maud Henry³  Christophe Rogier³ 

[1] Fulcrum Pharma (Europe) Ltd, Hemel Hempstead, UK;Medicines for Malaria Venture, Geneva, Switzerland;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 - antenne de Marseille, Marseille, France;

关键词: Quinoline;    Chloroquine;    Quinine;    Mefloquine;    Artesunate;   

DOI  :  10.1186/1475-2875-9-339

 received in 2010-08-09, accepted in 2010-11-25,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundThe aim of the present work was to assess the in vitro cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as pfcrt, pfmdr1, pfmrp and pfnhe.MethodsThe in vitro chemosusceptibility profiles of 23 strains of Plasmodium falciparum were analysed by the standard 42-hour 3H-hypoxanthine uptake inhibition method for pyronaridine, artesunate, chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine and doxycycline. Genotypes were assessed for pfcrt, pfmdr1, pfnhe-1 and pfmrp genes.ResultsThe IC50 values for pyronaridine ranged from 15 to 49 nM (geometric mean = 23.1 nM). A significant positive correlation was found between responses to pyronaridine and responses to artesunate (r2 = 0.20; P = 0.0317) but too low to suggest cross-resistance. No significant correlation was found between pyronaridine IC50 and responses to other anti-malarials. Significant associations were not found between pyronaridine IC50 and polymorphisms in pfcrt, pfmdr1, pfmrp or pfnhe-1.ConclusionThere was an absence of cross-resistance between pyronaridine and quinolines, and the IC50 values for pyronaridine were found to be unrelated to mutations in the transport protein genes pfcrt, pfmdr1, pfmrp or pfnhe-1, known to be involved in quinoline resistance. These results confirm the interest and the efficacy of the use of a combination of pyronaridine and artesunate in areas in which parasites are resistant to quinolines.

【 授权许可】

CC BY   
© Pradines et al; licensee BioMed Central Ltd. 2010