title: Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo.
abstract: Pyronaridine is a Mannich base anti-malarial with demonstrated efficacy against drug resistant Plasmodium falciparum, P. vivax, P. ovale and P. malariae. However, resistance to pyronaridine can develop quickly when it is used alone but can be considerably delayed when it is administered with artesunate in rodent malaria models. The aim of this study was to evaluate the efficacy of pyronaridine in combination with artesunate against P. falciparum in vitro and in rodent malaria models in vivo to support its clinical application. Pyronaridine showed consistently high levels of in vitro activity against a panel of six P. falciparum drug-sensitive and resistant strains (Geometric Mean IC50=2.24 nM, 95% CI=1.20-3.27). In vitro interactions between pyronaridine and artesunate showed a slight antagonistic trend, but in vivo compared to pyronaridine and artesunate administered alone, the 3:1 ratio of the combination, reduced the ED90 of artesunate by approximately 15.6-fold in a pyronaridine-resistant P. berghei line and by approximately 200-fold in an artesunate-resistant line of P. berghei. Complete cure rates were achieved with doses of the combination above or equal to 8 mg/kg per day against P. chabaudi AS. These results indicate that the combination had an enhanced effect over monotherapy and lower daily doses of artesunate could be used to obtain a curative effect. The data suggest that the combination of pyronaridine and artesunate should have potential in areas of multi-drug resistant malaria.
authors.affiliation: London School of Hygiene and Tropical Medicine, Department of Infectious and Tropical Diseases, London WC1E 7HT, United Kingdom. livia.vivas@lshtm.ac.uk <livia.vivas@lshtm.ac.uk>
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Lauren
authors.initials: L
authors.lastname: Rattray
authors.forename: Lindsay
authors.initials: L
authors.lastname: Stewart
authors.forename: Emily
authors.initials: E
authors.lastname: Bongard
authors.forename: Brian L
authors.initials: BL
authors.lastname: Robinson
authors.forename: Wallace
authors.initials: W
authors.lastname: Peters
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use; D010961:Plasmodium / Q000187:drug effects*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D009287:Naphthyridines; D012717:Sesquiterpenes; D000077332:Artesunate; C027871:pyronaridine