In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates of<i>Plasmodium falciparum</i>in Cameroon

Basco, Léonardo K.; Ringwald, Pascal

doi:10.1128/aac.47.4.1391-1394.2003

Cited by 80 publications

(71 citation statements)

References 8 publications

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“…PQ is active against Kilifi isolates, with IC 50 s falling between 2 and 132 nM, and IC 50 s of Ͼ100 nM were found for only two of the isolates tested. Similar results were obtained for isolates from other areas of malaria endemicity (2,3,6). We also demonstrate that polymorphism in pfcrt-76 and pfmdr1-86 is not associated with decreased susceptibility to PQ.…”

Section: Discussionsupporting

confidence: 82%

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Mwai

Kiara

Abdi

et al. 2009

Antimicrob Agents Chemother

150

156

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We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr1 at codon 86, as well as with variations of the copy number of pfmdr1. The median drug concentrations that inhibit 50% of parasite growth (IC 50 s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM (r 2 ‫؍‬ ؊0.26; P ‫؍‬ 0.02). Interestingly, parasites for which LM IC 50 s were higher were wild type for pfcrt-76 and pfmdr1-86. All isolates had one pfmdr1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt-76 and pfmdr1-86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.Chemotherapy is still the main approach for the control of malaria, and current strategies for malaria treatment rely on the use of combinations of drugs that include artemisinin compounds. Although this strategy is designed to reduce the chance of resistance emerging, there is considerable concern that this will inevitably occur.For instance, the combination of lumefantrine (LM) and artemether (ATM), known as Coartem, has become the firstline treatment for malaria in many African countries, including Kenya (19). ATM is converted in vivo to dihydroartemisinin (DHA). Emerging reports indicate that the use of LM (in Coartem) selects for parasites that show increased tolerance to Coartem, and these parasites select for a wild-type pfmdr1 genotype or show increased copy numbers of pfmdr1, a gene associated with chloroquine (CQ) and mefloquine (MFQ) resistance (7,13,15,20,36,38). Thus, there is concern that resistance to LM could emerge rapidly. On the other hand, recent reports from Southeast Asia indicate that resistance to artemisinin derivatives is increasing, threatening the concept of artemisinin-based combinations (8).Another combination, piperaquine (PQ) and DHA, known as Artekin, is undergoing clinical evaluation (17,39,42). This drug is efficacious, safe, and affordable and thus is likely to become an alternative to Coartem. PQ is a bisquinoline derivative consisting of two linked CQ molecules. Although reports indicate that PQ retains potency against CQ-resistant parasites (3), there is concern that PQ could become less susceptible against a backdrop of high CQ resistance (17,22).In this paper, we sought to analyze the in vitro activities of the antimalarials LM, DHA, and PQ in relation to polymorphisms in pfcrt at codon 76 (pfcrt-76) and in pfmdr1 at codon 86 (pfmdr1-86) and in relation to pfmdr1 copy number variations in Kenyan isolates. We used CQ as a reference drug. MATERIALS AND METHODSCQ was purchased from Sigma Chemical Co. (Poole, Dorset, United...

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Section: Discussionsupporting

confidence: 82%

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Mwai

Kiara

Abdi

et al. 2009

Antimicrob Agents Chemother

150

156

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“…Also, rescue treatment with dihydroartemisininpiperaquine resulted in 3/8 patients at Pailin and 2/4 patients at Pursat failing therapy within 42 days. These consecutive failures suggest possible cross-resistance between piperaquine and pyronaridine, as was reported in 2003 for African P. falciparum strains in vitro (25). If piperaquine resistance also confers resistance to pyronaridine, this might explain why pyronaridine-artesunate has insufficient efficacy at specific locations in Cambodia, despite its very limited use in this region.…”

Section: Discussionmentioning

confidence: 64%

Efficacy and Safety of Pyronaridine-Artesunate for Treatment of Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Leang

Canavati

Khim

et al. 2016

Antimicrob Agents Chemother

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“…Stock solutions of chloroquine diphosphate (CQ), mefloquine hydrochloride (MQ), quinine sulfate (QN), ATS, and DHA (Sigma, Steinheim, Germany) were prepared in 70% ethanol. Stock solutions of piperaquine tetraphosphate (PPQ) were prepared in 0.5% lactic acid (Sigma) in culture water (Lonza, Walkersville, MD) to enhance its solubility (18). Twofold serial dilutions of stock solutions were prepared in culture water.…”

Section: Methodsmentioning

confidence: 99%

Ex Vivo Susceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers

Lim

Dek

Try

et al. 2013

Antimicrob Agents Chemother

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iIn 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated Plasmodium falciparum malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the ex vivo 50% inhibitory concentrations (IC 50 s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC 50 s (GMIC 50 s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (P < 0.001). An increased copy number of P. falciparum mdr1 (pfmdr1), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC 50 s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The ex vivo IC 50 and pfmdr1 copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR P. falciparum is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance.

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In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates ofPlasmodium falciparumin Cameroon

Cited by 80 publications

References 8 publications

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Efficacy and Safety of Pyronaridine-Artesunate for Treatment of Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Ex Vivo Susceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers

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