Reversal of Mefloquine and Quinine Resistance in
            <i>Plasmodium falciparum</i>
            with NP30

Ciach, Michelle; Zong, Kathleen; Kain, Kevin C.; Crandall, Ian

doi:10.1128/aac.47.8.2393-2396.2003

Cited by 23 publications

(20 citation statements)

References 33 publications

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“…However, these agents have the disadvantage of being pharmacologically active, with systemic effects that may result in a variety of side effects. In addition, the minimum concentrations of these agents needed to chemosensitize parasites to CQ (usually more than 1 M of free drug) (1,4,(11)(12)(13) are not achievable in vivo when normal doses are used; therefore, high doses have to be used, with all of the attendant risks of toxicity. All of these limitations may explain why the reversal of CQ resistance has never attained widespread application.…”

mentioning

confidence: 99%

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

Masseno

Muriithi

Nzila

2009

Antimicrob Agents Chemother

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We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.The modulation of chloroquine (CQ) resistance with the calcium channel blocker verapamil (VPM), antipsychotic drugs, histamine receptor antagonists, and antidepressant agents among others was the first case of resistance modulation to be reported (reviewed in references 6, 8, and 28).Clinical evaluation of some of these agents has been carried out in areas where CQ resistance is moderate (22,(24)(25)(26). However, these agents have the disadvantage of being pharmacologically active, with systemic effects that may result in a variety of side effects. In addition, the minimum concentrations of these agents needed to chemosensitize parasites to CQ (usually more than 1 M of free drug) (1, 4, 11-13) are not achievable in vivo when normal doses are used; therefore, high doses have to be used, with all of the attendant risks of toxicity. All of these limitations may explain why the reversal of CQ resistance has never attained widespread application.We have demonstrated that the uricosuric drug probenecid (PBN) chemosensitizes parasites to antifolate and CQ (16,18).In this study, we tested the effect of PBN against the aminoquinolines CQ, piperaquine (PPRQ), primaquine (PMQ), desethylamodiaquin (DEAQ), and amodiaquin (AQ); the amino alcohols lumefantrine (LM), mefloquine (MFQ), halofantrine (HLF), and quinine (QN); the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), and methotrexate (MTX); the benzonaphthyridine pyronaridine (PRN); and the sesquiterpene dihydroartemisinin (DHA). We used the chemosensitizer VPM as a comparator.CQ, PMQ, AQ, MFQ, QN, MTX, PBN, and VPM were purchased from Sigma (Poole, Dorset, United Kingdom). PPRQ was a gift from Universal Corporation Limited, Kikuyu, Kenya. DEAQ, DHA, LM, PRN, and HLF were gifts from Steve Ward, Liverpool School of Tropical Medicine, Liverpool, United Kingdom. Drugs were dissolved as suggested by manufacturers. For PBN, after dilution in dimethyl sulfoxide (500 mg/ml), a subsequent serial dilution was carried out; this consisted of fivefold dilution in absolute ethanol followed by twofold dilution in 2% sodium bicarbonate and then dilution in RPMI 1640 medium (PBN crystallizes when diluted directly from dimethyl sulfoxide to RPMI 1640 medium).We employed two reference P. falciparum laboratory strains: V1S, a multidrug-resistant strain (resistant to CQ, PM, and QN) and 3D7, a strain fully sensitive to all tested antimalarials, except LM and PMQ. Cultures were carried out in RPMI 1640 (GIBCO BRL, United Kingdom), and antimalarial activities were expressed as the drug concentration required for 50% inhibition of [ 3 H]hypoxanthine incorporation (IC 50 ) during the 66-h assay (19).Chemosensit...

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confidence: 99%

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

Masseno

Muriithi

Nzila

2009

Antimicrob Agents Chemother

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“…NP30 has a general effect in combination with several quinolines including chloroquine, quinine and mefloquine [129]. Probenecid, a uricosuric drug used to treat gout, was shown to chemosensitize chloroquine-resistant clones of P. falciparum in vitro by increasing chloroquine accumulation levels [130].…”

Section: Drug Resistance Reversalmentioning

confidence: 99%

Malaria Combination Therapies: Advantages and Shortcomings

Martinelli¹,

Moreira

Cravo

2008

MRMC

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“…Nevertheless, there is a subset of P. falciparum isolates that display CQ resistance that is insensitive to a polyethoxylated nonylphenol (NP30) [306]. The difference between the NP30 activities against these isolates can not be explained by point mutations in Pfcrt and Pfmdr1, since these mutations are present in all the parasites used in the study.…”

Section: -Transporter Inhibitors and Modulators Of The Multidrug Resimentioning

confidence: 99%

Chemosensitizers in Drug Transport Mechanisms Involved in Protozoan Resistance

Pradines

Pages²,

Barbe³

2005

CDTID

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The emergence and spread of antiparasitic drug resistance pose a severe and increasing public health threat. Failures in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic lactones, antifolate drugs, arsenic and antimony containing drugs sulfamides induce reemergence of parasitic-related morbidity and mortality. Resistance is often associated with alteration of drug accumulation into parasites, which results from a reduced uptake of the drug, an increased efflux or, a combination of the two processes. Resistance to quinolines, artemisinin derivatives and arsenicals and expression of an active efflux mechanism are more or less correlated in protozoa like Plasmodium spp., Leishmania spp., and Trypanosoma spp. Various parasite candidate genes have been proposed to be involved in drug resistance, each concerned in membrane transport. Genes encoding membrane glycoproteins, orthologue to the P-glycoproteins identified in MDR human cancer cells, have been described in these resistant pathogens in addition to various membrane proteins involved in drug transport. Several compounds have demonstrated, in the past decade, promising capability to reverse the drug resistance in parasite isolates in vitro, in animal models and for human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic 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 derivatives, and anthracene derivatives. Here, are summarized the molecular bases of antiparasitic resistance emphasizing recent developments with compounds acting on trans-membrane proteins involved in drug efflux or uptake.

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Reversal of Mefloquine and Quinine Resistance in Plasmodium falciparum with NP30

Cited by 23 publications

References 33 publications

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

Malaria Combination Therapies: Advantages and Shortcomings

Chemosensitizers in Drug Transport Mechanisms Involved in Protozoan Resistance

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