World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria

Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF1-480, Baltimore, Maryland 21201, USA.
Malaria Journal (Impact Factor: 3.49). 02/2007; 6:121. DOI: 10.1186/1475-2875-6-121
Source: PubMed

ABSTRACT Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs.

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    Malaria Journal 12/2015; 14(1). DOI:10.1186/s12936-015-0588-4 · 3.49 Impact Factor
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    ABSTRACT: The involvement of Pfmdr1 polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ) and dihydroartemisinin (DHA) in174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N or 1246Y mutations were detected. The Pfmdr1 86Y mutation was significantly associated with increased susceptibility to MDAQ (p-value = 0.0023), LMF (p-value = 0.0001), DHA (p-value = 0.0387) and MQ (p-value = 0.00002). The N86Y mutation was not associated with CQ (p-value = 0.214) or QN (p-value = 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (p-values = 0.168 for CQ; 0.778 for MDAQ; 0.324 for LMF; 0.961 for DHA; 0.084 for QN and 0.298 for MQ). The Pfmdr1 86Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ p-value = 0.0136), LMF (p-value = 0.0019) and MQ (p-value = 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (p-value < 00001), LMF (p-value < 00001), MQ (p-value < 00001) and QN (p-value = 0.0026) in wild type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to CQ (p-value = 0.0179) in Pfcrt 76T CQ-resistant parasites.
    Antimicrobial Agents and Chemotherapy 09/2014; DOI:10.1128/AAC.03494-14 · 4.45 Impact Factor
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    ABSTRACT: In 2002, the World Health Organization recommended that artemisinin-based combination therapy (ACT) be used to treat uncomplicated malaria. Dihydroartemisinin-piperaquine and artesunate-pyronaridine are two of these new combinations. The aim of the present work was to assess the distribution of the in vitro values of pyronaridine (PND) and piperaquine (PPQ) and to define a cut-off for reduced susceptibility for the two anti-malarial drugs. The distribution and range of the 50% inhibitory concentration values (IC50) of PND and PPQ were determined for 313 isolates obtained between 2008 and 2012 from patients hospitalized in France for imported malaria. The statistical Bayesian analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to PND and PPQ. The PND IC50 values ranged from 0.6 to 84.6 nM, with a geometric mean of 21.1 ± 16.0 nM (standard deviation). These values were classified into three components. The PPQ IC50 values ranged from 9.8 to 217.3 nM, and the geometric mean was 58.0 ± 34.5 nM. All 313 PPQ values were classified into four components. Isolates with IC50 values greater than 60 nM or four-fold greater than 3D7 IC50 are considered isolates that have reduced susceptibility to PND and those with IC50 values greater than 135 nM or 2.3-fold greater than 3D7 IC50 are considered isolates that have reduced susceptibility to PPQ. The existence of at least three phenotypes for PND and four phenotypes for PPQ was demonstrated. Based on the cut-off values, 18 isolates (5.8%) and 13 isolates (4.2%) demonstrated reduced susceptibility to PND and PPQ, respectively.
    Malaria Journal 12/2015; 14(1). DOI:10.1186/s12936-015-0586-6 · 3.49 Impact Factor

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