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pfmdr1 amplification is related to increased Plasmodium falciparum In Vitro sensitivity to the Bisquinoline Piperaquine

2012-07Journal article Open access
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dc.contributor.authorVeiga, M. I.
dc.contributor.authorFerreira, P. E.
dc.contributor.authorMalmberg, M.
dc.contributor.authorJornhagen, L.
dc.contributor.authorBjorkman, A.
dc.contributor.authorNosten, F.
dc.contributor.authorGil, J. P.
dc.date.accessioned2018-12-07T14:53:21Z
dc.date.available2018-12-07T14:53:21Z
dc.date.issued2012-07
dc.description.abstractThe 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC(50)s) and IC(90)s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P = 0.005 for IC50 and P = 0.002 for IC90) and chloroquine, reaching statistical significance at IC(90)s (P = 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.
dc.description.sponsorshipSwedish Development Cooperation Agency-Department for Research Cooperation [SWE 2005-0017, SWE 2005-4596, SWE-2007-174, SWE-2005-4027]; Fundacao para a Ciencia e Tecnologia (FCT)/Ministerio da Ciencia e Ensino Superior, Portugal-MCES [SFRH/BPD/76614/2011]; Wellcome Trust of Great Britain
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1128/AAC.06350-11
dc.identifier.issn0066-4804
dc.identifier.issn1098-6596
dc.identifier.urihttp://hdl.handle.net/10400.1/11468
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmerican Society for Microbiology
dc.relationCONTRIBUTION OF DRUG TRANSPORTER GENES TO THE EMERGENCE OF MULTI- AND EXTREMELY-DRUG RESISTANT PATHOGENS
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectMultidrug-resistance gene
dc.subjectArtemether-Lumefantrine
dc.subjectDihydroartemisinin-Piperaquine
dc.subjectMalaria parasites
dc.subjectCopy number
dc.subjectArtemisinin resistance
dc.subjectMefloquine resistance
dc.subjectUncomplicated malaria
dc.subjectNorthwestern border
dc.subjectSelection
dc.titlepfmdr1 amplification is related to increased Plasmodium falciparum In Vitro sensitivity to the Bisquinoline Piperaquine
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCONTRIBUTION OF DRUG TRANSPORTER GENES TO THE EMERGENCE OF MULTI- AND EXTREMELY-DRUG RESISTANT PATHOGENS
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F76614%2F2011/PT
oaire.citation.endPage3619
oaire.citation.issue7
oaire.citation.startPage3615
oaire.citation.titleAntimicrobial Agents and Chemotherapy
oaire.citation.volume56
person.familyNameGil
person.givenNameJosé Pedro
person.identifier.ciencia-idD01A-B30E-BCD5
person.identifier.orcid0000-0002-6107-9379
person.identifier.scopus-author-id7201625436
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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relation.isAuthorOfPublication.latestForDiscoverycb728715-0e4c-4ae5-9e21-b6a8f35a8313
relation.isProjectOfPublication5ffca221-7894-4a82-82d7-d0c852d8727c
relation.isProjectOfPublication.latestForDiscovery5ffca221-7894-4a82-82d7-d0c852d8727c

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