Lack of Prediction of Mefloquine and Mefloquine-Artesunate Treatment Outcome by Mutations in the Plasmodium Falciparum Multidrug Resistance 1 (Pfmdr1) Gene for Plasmodium Falciparum Malaria in Peru

Pillai, Dylan R.; Híjar, Gisely; Montoya, Ysabel; Marquiño, Wilmer; Ruebush, Trenton K.; Wongsrichanalai, Chansuda; Kain, Kevin C.

doi:10.4269/ajtmh.2003.68.107

Cited by 30 publications

(20 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lack of association between 3′ mutations and mefloquine IC 50 observed in other studies in SE Asia probably reflects reduced statistical power to detect effects when these SNPs are at low prevalence [40,41]. In South American parasites shown to have CDY alleles at the 3′ end, mefloquine IC 50 s are indeed low [42] and mefloquine remains predictably efficacious in such areas [43]. Despite several attempts, it has not been possible to engineer allelic exchange at the 5′ end of pfmdr1 [21]; nor has a classical genetic study focussing on this locus been undertaken.…”

Section: Resistance To Mefloquine and Other Arylaminoalcoholsmentioning

confidence: 68%

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance

Woodrow

Krishna

2006

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Molecular determinants of antimalarial drug resistance are useful and informative tools that complement phenotypic assays for drug resistance. They also guide the design of strategies to circumvent such resistance once it has reached levels of clinical significance. Established resistance to arylaminoalcohols such as mefloquine and lumefantrine in SE Asia is mediated primarily by gene amplification of the P. falciparum drug transporter, pfmdr1. Single nucleotide polymorphisms in pfmdr1, whether assessed in field isolates or transfection experiments, are associated with changes in IC(50) values (to arylaminoalcohols and chloroquine), but not of such magnitude as to influence clinical treatment outcomes. Recently described emerging in vitro resistance to artemisinins in certain areas correlates with mutations in the SERCA-like sequence PfATP6 and supports PfATP6 as a key target for artemisinins.

show abstract

Section: Resistance To Mefloquine and Other Arylaminoalcoholsmentioning

confidence: 68%

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance

Woodrow

Krishna

2006

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Moreover, transfections with Pfmdr1 wild-type 1034, 1042 and 1246 codons confer mefloquine resistance to susceptible parasites [80]. However, mutations at codons 1034, 1042 and 1246 seem not to be sufficient to explain variation in mefloquine susceptibility levels in P. falciparum isolates [81][82][83]. Analysis of these isolates revealed a correlation between a mutation at codon 86 and an increase in the susceptibility to mefloquine, halofantrine or artemisinin derivatives [79,[84][85][86].…”

Section: Abc Transportersmentioning

confidence: 92%

Chloroquine Resistance Reversal Agents as Promising Antimalarial Drugs

Henry¹,

Alibert²,

Orlandi-Pradines³

et al. 2006

CDT

View full text Add to dashboard Cite

The development and spread of resistance to antimalarial drugs poses a severe and increasing public health threat. Failures of prophylaxis or treatment with quinolines, hydroxynaphthoquinones, sesquiterpene lactones, antifolate drugs and sulfamides are involved in a return malaria-related morbidity and mortality. Resistance is associated with a decrease in accumulation of drugs into the vacuole, which results from a reduced uptake of the drug, an increased efflux or a combination of both. A number of candidate genes in P. falciparum have been proposed to be involved in antimalarial resistance, each concerned in membrane transport. Weaker or stronger associations are seen in P. falciparum between the resistance to quinolines or artemisinin derivatives and codon changes in Pfmdr1, a gene which encodes Pgh-1, an ortholog of one of the P-glycoproteins expressed in multi-drug resistant human cancer cells (ABC transporter). Further analysis has revealed a new gene, Pfcrt, encoding a PfCRT protein, which resembles an anion channel. Codon changes found in the Pfcrt sequence in drug resistant isolates could facilitate the drug efflux through a putative channel. It has been proposed that the reversal of quinoline resistance by verapamil is due to hydrophobic binding to the mutated PfCRT protein. Several compounds have demonstrated in the past decade a promising capability to reverse the antimalarial drug resistance in vitro in parasite isolates, in animal models and in human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic and antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and anthracenic derivatives. Here we summarize the progress made in biochemical and genetic basis of antimalarial resistance, emphasizing the recent developments on drugs, which interfere with trans membrane proteins involved in drug efflux or uptake.

show abstract

“…Moreover, transfection with a wild-type Pfmdr1 allele at codons 1034, 1042, and 1246 confers MQ resistance to susceptible parasites (10). However, mutations at Pfmdr1 codons 1034, 1042, and 1246 in P. falciparum isolates are not sufficient to explain the variations in MQ susceptibility (11). Analyses of P. falciparum isolates show an association between mutation at codon 86 and an increase in susceptibility to MQ, halofantrine, or artemisinin derivatives (12)(13)(14).…”

mentioning

confidence: 99%

Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

Wurtz

Fall

Pascual

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) 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) in 174 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 ‫؍‬ 0.0023), LMF (P ‫؍‬ 0.0001), DHA (P ‫؍‬ 0.0387), and MQ (P ‫؍‬ 0.00002). The N86Y mutation was not associated with CQ (P ‫؍‬ 0.214) or QN (P ‫؍‬ 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P ‫؍‬ 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 ‫؍‬ 0.0136), LMF (P ‫؍‬ 0.0019), and MQ (P ‫؍‬ 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (P < 0.0001), LMF (P < 0.0001), MQ (P < 0.0001), and QN (P ‫؍‬ 0.0026) in wild-type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation significantly increased the in vitro susceptibility to CQ (P ‫؍‬ 0.0179) in Pfcrt 76T CQ-resistant parasites.

show abstract

Lack of Prediction of Mefloquine and Mefloquine-Artesunate Treatment Outcome by Mutations in the Plasmodium Falciparum Multidrug Resistance 1 (Pfmdr1) Gene for Plasmodium Falciparum Malaria in Peru

Cited by 30 publications

References 12 publications

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance

Chloroquine Resistance Reversal Agents as Promising Antimalarial Drugs

Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

Contact Info

Product

Resources

About