Artemisinin Combination Therapies and Malaria Parasite Drug Resistance: The Game Is Afoot

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

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Comparative Efficacies of Artemisinin Combination Therapies in Plasmodium falciparum Malaria and Polymorphism ofpfATPase6,pfcrt,pfdhfr, andpfdhpsGenes in Tea Gardens of Jalpaiguri District, India

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05388-11 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2511-2517 ◽

Cited By ~ 25

Author(s):

Pabitra Saha ◽

Subhasish K. Guha ◽

Sonali Das ◽

Shrabanee Mullick ◽

Swagata Ganguly ◽

...

Keyword(s):

Plasmodium Falciparum Malaria ◽

Study Groups ◽

Combination Therapies ◽

Antimalarial Drug Resistance ◽

Content Type ◽

Private Practitioners ◽

Mutational Pattern ◽

Sequencing Method ◽

Periodic Monitoring ◽

Artemisinin Combination Therapies

ABSTRACTIn India, chloroquine has been replaced by a combination of artesunate and sulfadoxine-pyrimethamine (AS-SP) for uncomplicatedP. falciparummalaria. Other available combinations, artemether-lumefantrine (AM-LF) and artesunate-mefloquine (AS-MQ), not included in the national program, are widely used by private practitioners. Little is known about the therapeutic efficacy of these artemisinin combinations and the prevalence of molecular markers associated with antimalarial drug resistance. A total of 157 patients withP. falciparummonoinfection were recruited and randomized into three study groups (AS-SP, AM-LF, and AS-MQ). All patients were followed up for 42 days to study the clinical and parasitological responses according to the WHO protocol (2009). We assessed the polymorphism of thepfATPase6,pfcrt,pfdhfr, andpfdhpsgenes by the DNA-sequencing method. The PCR-corrected therapeutic efficacies of AS-SP, AM-LF, and AS-MQ were 90.6% (95% confidence interval [CI], 0.793 to 0.969), 95.9% (95% CI, 0.860 to 0.995), and 100% (95% CI, 0.927 to 1.00), respectively. No specific mutational pattern was observed in thepfATPase6gene. All isolates had a K76T mutation in thepfcrtgene. In thepfdhfr-pfdhpsgenotype, quadruple mutation was frequent, and quintuple mutation was documented in 6.3% ofP. falciparumisolates. The significant failure rate of AS-SP (9.5%), although within the limit (10%) for drug policy change, was due to SP failure because of prevailing mutations inpfdhfr, I51R59N108, withpfdhps, G437and/or E540. The efficacy of this ACT needs periodic monitoring. Artemether-lumefantrine and artesunate-mefloquine are effective alternatives to the artesunate-sulfadoxine-pyrimethamine combination.

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Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination

F1000Research ◽

10.12688/f1000research.14874.1 ◽

2018 ◽

Vol 7 ◽

pp. 1170 ◽

Cited By ~ 9

Author(s):

Emily S. Mathews ◽

Audrey R. Odom John

Keyword(s):

Drug Resistance ◽

Malaria Elimination ◽

Large Scale ◽

Therapeutic Targets ◽

Control Measures ◽

Multi Drug Resistance ◽

Development Projects ◽

Combination Therapies ◽

The Past ◽

Antimalarial Compounds

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination.

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Combined Transcriptome and Proteome Profiling for Role of pfEMP1 in Antimalarial Mechanism of Action of Dihydroartemisinin

Microbiology Spectrum ◽

10.1128/spectrum.01278-21 ◽

2021 ◽

Author(s):

Lina Chen ◽

Zhongyuan Zheng ◽

Hui Liu ◽

Xi Wang ◽

Shuiqing Qu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Mechanism Of Action ◽

Blood Cells ◽

Artemisinin Derivative ◽

Combination Therapies ◽

Proteomic Profiling ◽

First Line ◽

Content Type ◽

Artemisinin Combination Therapies

Malaria parasites induce morphological and biochemical changes in the membranes of parasite-infected red blood cells (iRBCs) for propagation, with artemisinin combination therapies as the first-line treatments. To understand whether artemisinin targets or interacts with iRBC membrane proteins, this study investigated the molecular changes caused by dihydroartemisinin (DHA), an artemisinin derivative, in Plasmodium falciparum 3D7 using a combined transcriptomic and membrane proteomic profiling approach.

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Adaptive Drug Resistance in Malaria Parasite: A Threat to Malaria Elimination Agenda?

10.5772/intechopen.98323 ◽

2021 ◽

Author(s):

Moses Okpeku

Keyword(s):

Drug Resistance ◽

Malaria Elimination ◽

Malaria Parasite ◽

Disease Burden ◽

Drug Application ◽

African Region ◽

Malaria Parasites ◽

Sub Saharan ◽

Host Development

Malaria is a global disease of importance, especially in the sub-Saharan African region, where malaria accounts for great losses economically and to life. Fight to eliminate this disease has resulted in reduced disease burden in many places where the diseases is endemic. Elimination strategies in most places is focus on the use of treated nets and drug application. Exposure of malaria parasites to anti-malaria drugs have led to the evolution of drug resistance in both parasites and host. Development of drug resistance vary but, studies on adaptive drug resistance has implications and consequences. Our knowledge of this consequences are limited but important for the pursuit of an uninterrupted malaria elimination agenda. This chapter draws our attention to this risks and recommends interventions.

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Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites

Life Science Alliance ◽

10.26508/lsa.202101237 ◽

2021 ◽

Vol 5 (3) ◽

pp. e202101237

Author(s):

Kutub Ashraf ◽

Shahin Tajeri ◽

Christophe-Sébastien Arnold ◽

Nadia Amanzougaghene ◽

Jean-François Franetich ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Inhibitory Activity ◽

Parasite Species ◽

Artemisia Annua ◽

Combination Therapies ◽

Lead Compounds ◽

Low Concentrations ◽

Inhibitory Activities

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or Artemisia afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of Plasmodium falciparum and the pre-erythrocytic (i.e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for Plasmodium vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

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In Silico Investigation of the Decline in Clinical Efficacy of Artemisinin Combination Therapies Due to Increasing Artemisinin and Partner Drug Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01292-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 1

Author(s):

Sophie G. Zaloumis ◽

Pengxing Cao ◽

Saber Dini ◽

Miles P. Davenport ◽

Deborah Cromer ◽

...

Keyword(s):

Drug Resistance ◽

Treatment Failure ◽

In Silico ◽

Artemisinin Resistance ◽

Exact Nature ◽

Artemisinin Derivative ◽

Combination Therapies ◽

Content Type ◽

Artemisinin Derivatives ◽

The Impact

ABSTRACT Antimalarial treatment currently relies on an artemisinin derivative and a longer-acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated. An in silico exploration of dihydroartemisinin-piperaquine and mefloquine-artesunate, two artemisinin-based combination therapies that are commonly used in Southeast Asia, was performed. The percentage of treatment failures was simulated from a within-host pharmacokinetic-pharmacodynamic (PKPD) model, assuming that parasites developed increasing levels of (i) artemisinin derivative resistance or (ii) concomitant resistance to both the artemisinin derivative and the partner drug. Because the exact nature of how resistant Plasmodium falciparum parasites respond to treatment is unknown, we examined the impact on treatment failure rates of artemisinin resistance that (i) reduced the maximal killing rate, (ii) increased the concentration of drug required for 50% killing, or (iii) shortened the window of parasite stages that were susceptible to artemisinin derivatives until the drugs had no effect on the ring stages. The loss of the ring-stage activity of the artemisinin derivative caused the greatest increase in the treatment failure rate, and this result held irrespective of whether partner drug resistance was assumed to be present or not. To capture the uncertainty regarding how artemisinin derivative and partner drug resistance affects the assumed concentration-killing effect relationship, a variety of changes to this relationship should be considered when using within-host PKPD models to simulate clinical outcomes to guide treatment strategies for resistant infections.

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