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Plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and Its association With pfmdr1 polymorphisms

2013-03Journal article Open access
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dc.contributor.authorMalmberg, Maja
dc.contributor.authorFerreira, Pedro
dc.contributor.authorTarning, Joel
dc.contributor.authorUrsing, Johan
dc.contributor.authorNgasala, Billy
dc.contributor.authorBjorkman, Anders
dc.contributor.authorMartensson, Andreas
dc.contributor.authorGil, José Pedro
dc.date.accessioned2018-12-07T14:53:43Z
dc.date.available2018-12-07T14:53:43Z
dc.date.issued2013-03
dc.description.abstractBackground. Multidrug-resistant Plasmodium falciparum is a major threat to global malaria control. Parasites develop resistance by gradually acquiring genetic polymorphisms that decrease drug susceptibility. The aim of this study was to investigate the extent to which parasites with different genetic characteristics are able to withstand individual drug blood concentrations. Methods. We analyzed 2 clinical trials that assessed the efficacy and effectiveness of artemether-lumefantrine. As a proof of concept, we used measured day 7 lumefantrine concentrations to estimate the concentrations at which reinfections multiplied. P. falciparum multidrug resistance gene 1 (pfmdr1) genotypes of these parasites were then correlated to drug susceptibility. Results. Reinfecting parasites with the pfmdr1 N86/184F/D1246 haplotype were able to withstand lumefantrine blood concentrations 15-fold higher than those with the 86Y/Y184/1246Y haplotype. Conclusions. By estimating drug concentrations, we were able to quantify the contribution of pfmdr1 single-nucleotide polymorphisms to reduced lumefantrine susceptibility. The method can be applied to all long-half-life antimalarial drugs, enables early detection of P. falciparum with reduced drug susceptibility in vivo, and represents a novel way for unveiling molecular markers of antimalarial drug resistance.
dc.description.sponsorshipSwedish Development Cooperation Agency-Department for Research Cooperation (SIDA-SAREC) [SWE 2004-3850, Bil-Tz 16/9875007059, SWE-2009-165]; World Health Organization MIM-TDR [[A60100] MAL IRM 06 03]; Goljes Foundation; Swedish medical research council [K2010-56X-21457-01-3]; Wellcome Trust of Great Britain
dc.identifier.doi10.1093/infdis/jis747
dc.identifier.issn0022-1899
dc.identifier.urihttp://hdl.handle.net/10400.1/11656
dc.language.isoeng
dc.peerreviewedyes
dc.publisherOxford Univ Press Inc
dc.subjectIn-Vivo Selection
dc.subjectArtemether-Lumefantrine
dc.subjectUncomplicated Malaria
dc.subjectTanzanian Children
dc.subjectRural Tanzania
dc.subjectAfrica
dc.subjectAmodiaquine
dc.subjectAlleles
dc.subjectCoartem
dc.subjectBlood
dc.titlePlasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and Its association With pfmdr1 polymorphisms
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage847
oaire.citation.issue5
oaire.citation.startPage842
oaire.citation.titleJournal of Infectious Diseases
oaire.citation.volume207
person.familyNameFerreira
person.familyNameGil
person.givenNamePedro
person.givenNameJosé Pedro
person.identifier332675
person.identifier.ciencia-id5E15-DD6D-50E6
person.identifier.ciencia-idD01A-B30E-BCD5
person.identifier.orcid0000-0002-2682-7722
person.identifier.orcid0000-0002-6107-9379
person.identifier.ridQ-6748-2016
person.identifier.scopus-author-id55427200100
person.identifier.scopus-author-id7201625436
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicatione0a51049-1676-475b-a9e8-1d911386238d
relation.isAuthorOfPublicationcb728715-0e4c-4ae5-9e21-b6a8f35a8313
relation.isAuthorOfPublication.latestForDiscoverye0a51049-1676-475b-a9e8-1d911386238d

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