Degrees of chloroquine resistance in Plasmodium – Is the redox system involved?

Lehane, Adele M.; McDevitt, Christopher A.; Kirk, Kiaran; Fidock, David A.

doi:10.1016/j.ijpddr.2011.11.001

Cited by 40 publications

(34 citation statements)

References 105 publications

(185 reference statements)

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“…2) 5 . Malaria parasites avoid heme toxicity by converting dimers of hematin into inert crystals (called hemozoin) and perhaps also by heme degradation through peroxidative or glutathione-mediated pathways 6 . Drugs that interfere with crystal formation have been some of the most successful in malaria therapy.…”

Section: The Digestive Vacuole and Continuing Drug Discoverymentioning

confidence: 99%

Malaria biology and disease pathogenesis: insights for new treatments

Miller

Ackerman

et al. 2013

Nat Med

502

493

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Plasmodium falciparum malaria, an infectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each year in Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisinin derivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeast Asia. Renewed initiatives to eliminate malaria will benefit from an expanded repertoire of antimalarials, including new drugs that kill circulating P. falciparum gametocytes, thereby preventing transmission. Our current understanding of the biology of asexual blood-stage parasites and gametocytes and the ability to culture them in vitro lends optimism that high-throughput screenings of large chemical libraries will produce a new generation of antimalarial drugs. There is also a need for new therapies to reduce the high mortality of severe malaria. An understanding of the pathophysiology of severe disease may identify rational targets for drugs that improve survival.

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Section: The Digestive Vacuole and Continuing Drug Discoverymentioning

confidence: 99%

Malaria biology and disease pathogenesis: insights for new treatments

Miller

Ackerman

et al. 2013

Nat Med

502

493

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“…For vivax malaria, chloroquine, a drug that also induces oxidative stress (18), was abandoned in 2012 and replaced by dihydroartemisinin plus piperaquine. This change was based on data from clinical therapeutic efficacy studies (day 28 follow-up, PCR-uncorrected WHO protocol) that showed proportions of treatment failure ranging from 0% to 17.4% (in Ratanak Kiri province, 2010) following a chloroquine regimen, while in the same areas, dihydroartemisinin plus piperaquine was 100% effective (19).…”

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confidence: 99%

Reduced Polymorphism in the Kelch Propeller Domain in Plasmodium vivax Isolates from Cambodia

Popovici

Kao

Eal

et al. 2015

Antimicrob Agents Chemother

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Polymorphism in the ortholog gene of the Plasmodium falciparum K13 gene was investigated in Plasmodium vivax isolates collected in Cambodia. All of them were Sal-1 wild-type alleles except two (2/284, 0.7%), and P. vivax K12 polymorphism was reduced compared to that of the P. falciparum K13 gene. Both mutant allele isolates had the same nonsynonymous mutation at codon 552 (V552I) and were from Ratanak Kiri province. These preliminary data should encourage additional studies for associating artemisinin or chloroquine resistance and K12 polymorphism. In areas in which malaria is endemic and Plasmodium falciparum and Plasmodium vivax are present, such as in Southeast Asia and Pacific Oceania, both species share the same vectors and human hosts, either successively or concomitantly (mixed infections) (1, 2). These two species, in this context, often undergo similar mutation-driven evolution and natural selection. This includes nucleotide substitution, gene duplication/deletion, chromosomal change, and genome duplication (3). In terms of drug resistance, regardless of the fundamental biological differences between the two Plasmodium species, it is well known that antimalarial drug pressure induces a strong selection of resistant parasites for both of these parasite populations. For instance, sequencing of the dhfr gene in P. vivax isolates collected in areas where sulfadoxine-pyrimethamine was used to treat falciparum malaria and the alignment of these alleles with the P. falciparum dhfr gene have clearly demonstrated that mutations in codons 57, 58, 61, 117, and 173 were involved in pyrimethamine resistance and corresponded to the codons 51, 59, 108, and 164 found in P. falciparum pyrimethamine-resistant strains (4). More recently, we observed high frequencies of P. falciparum and P. vivax isolates with increased mdr-1 copy numbers in areas where mefloquine has been extensively used as the first-line treatment in falciparum-uncomplicated malaria, while in areas where mefloquine has never been used, P. falciparum and P. vivax isolates with increased mdr-1 copy numbers are rare (5). These studies clearly show that antimalarial drugs used to treat falciparum malaria have a significant impact on sympatric Plasmodium species, such as P. vivax.Since 2001, artemisinin combination therapies (ACTs) have been recommended as first-line treatment in the national treatment guidelines of most countries in which malaria is endemic. In 2008, the emergence of artemisinin-resistant P. falciparum parasites was observed in Southeast Asia (6-15). Recent molecular and biological studies showed that artemisinin resistance was associated with P. falciparum early ring stages and mutations in the PF3D7_1343700 kelch propeller domain (K13-propeller) (8,14,15). To date, although the role of the P. falciparum K13 protein remains unknown, two pieces of evidence suggest that it is involved in the cellular response to oxidative stress (8): (i) its homology to the KEAP1 human protein, which is involved in cell adaptation to oxidative stress (16), a...

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“…Plasmodia manage this toxicity by converting hematin into hemozoin and heme degradation through peroxide or glutathione-mediated pathways [12]. CQ prevents the detoxification of heme in the parasite's food vacuole.…”

Section: Mode Of Action/resistancementioning

confidence: 99%

Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance

Seidlein

Dondorp

2015

Expert Review of Anti-infective Therapy

102

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The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured.

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Degrees of chloroquine resistance in Plasmodium – Is the redox system involved?

Cited by 40 publications

References 105 publications

Malaria biology and disease pathogenesis: insights for new treatments

Malaria biology and disease pathogenesis: insights for new treatments

Reduced Polymorphism in the Kelch Propeller Domain in Plasmodium vivax Isolates from Cambodia

Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance

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