Interactions between tafenoquine and artemisinin-combination therapy partner drug in asexual and sexual stage Plasmodium falciparum

Kemirembe, Karen; Cabrera, Mynthia

doi:10.1016/j.ijpddr.2017.03.002

Cited by 21 publications

(20 citation statements)

References 49 publications

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“…The combination of PND with PG seemed to provide more synergistic effect than with ATQ, or TQ. Our results on TQ-PND combination were different from the previous report demonstrating TQ had synergistic interaction with PND [56]. The discrepancy may be accounted for by the drug concentration used to test the drug interactions.…”

Section: Discussioncontrasting

confidence: 99%

Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization

Boonyalai

Vesely

Thamnurak

et al. 2020

Preprint

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Background: High rates of dihydroartemisinin-piperaquine (DHA-PPQ) treatment failures have been documented for uncomplicated Plasmodium falciparum in Cambodia. It is essential to establish sensitive and reliable markers of PPQ resistance which can be adopted for monitoring the prevalence of drug resistance and guide drug policy change. Several genetic markers have been proposed such as copy numbers of P. falciparum multidrug resistance 1 ( pfmdr1 ) and plasmepsin 2 (PM2), and mutations in exonuclease (exo-E415G) and P. falciparum chloroquine resistance transporter (PfCRT) genes.Methods: To examine the relative contribution of each marker to PPQ resistance, in vitro culture and the PPQ survival assay were performed on seventeen P. falciparum isolates from northern Cambodia and the presence of exo-E415G and PfCRT mutations as well as PM2 copy number polymorphisms were determined. Parasites were then cloned by limiting dilution and the cloned parasites were tested for drug susceptibility. The efficacy of several drug combinations between standard clones and newly cloned P. falciparum Cambodian isolates was also measured.Results: The characterization of culture-adapted isolates revealed that exo-E415G and novel PfCRT mutations can confer PPQ-resistance, in the absence of PM2 amplification. In vitro testing of PPQ resistant parasites showed bimodal dose-response phenotype as previously reported in both Cambodian isolates and genome-edited Dd2 strains. Our finding is the first PPQ resistant clinical isolate with documented swollen digestive vacuole phenotype. From the field isolates, we were able to clone a new parasite line, 14-B5, which is sensitive to arteminsinin and piperaquine but resistant to chloroquine. Most of the drug combinations tested revealed antagonistic interaction against the 14-B5 line, indicating its different genetic background from other P. falciparum laboratory reference lines.Conclusions: Surveillance for PPQ resistance in regions that rely on DHA-PPQ as the first line treatment should depend on the monitoring of the reflective molecular markers. Bimodal dose response curves and swelling of the food vacuole can be used as PPQ resistant phenotype. The use of currently circulating parasite isolates is necessary for relevant drug combination development against current P. falciparum resistance profiles.

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Section: Discussioncontrasting

confidence: 99%

Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization

Boonyalai

Vesely

Thamnurak

et al. 2020

Preprint

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“…Other drugs, such as artemisinin and atovaquone, are known to be effective only against early gametocyte stages (54-56). Only a few compounds have shown effects against mature gametocytes in vivo in humans, including methylene blue (57), the 8-aminoquinoline primaquine (58), and tafenoquine (16). The mode of action of primaquine in gametocytes is unclear, but it has been suggested that it targets mitochondrial function (59).…”

Section: Discussionmentioning

confidence: 99%

“…ACTs appeared as a solution for drug-resistant P. falciparum malaria, with rapid elimination of asexual parasites and young gametocytes (14,15). However, ACTs are ineffective against mature gametocytes, allowing persistent parasite transmission after treatment (16). Besides using potent antimalarial drugs against the blood-stage parasites, blocking through vector control or utilizing transmissionblocking drugs is essential for the effective control of malaria transmission.…”

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confidence: 99%

Ivermectin Impairs the Development of Sexual and Asexual Stages of Plasmodium falciparumIn Vitro

Carvalho

Sandri

Melo

et al. 2019

Antimicrob Agents Chemother

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Ivermectin is the drug of choice for many parasitic infections, with more than one billion doses being distributed in onchocerciasis programs. The drug has been put into focus recently by the malaria community because of its potential to kill blood-sucking mosquitoes, thereby reducing malaria transmission. However, the activity of ivermectin against the malaria parasite itself has been only partly investigated. This study aimed to investigate the in vitro activity of ivermectin against asexual and sexual stages of Plasmodium falciparum. Both asexual and late-stage gametocytes were incubated with ivermectin and control drugs in vitro. The growthinhibiting effects were assessed for asexual stages of different Plasmodium falciparum laboratory strains and culture-adapted clinical isolates using the histidine-rich protein 2 enzyme-linked immunosorbent assay technique. The effect against stage IV/V gametocytes was evaluated based on ATP quantification. Ivermectin showed activities at nanomolar concentrations against asexual stages (50% inhibitory concentration of ϳ100 nM) and stage IV/V gametocytes (500 nM) of P. falciparum. Stagespecific assays suggested that ivermectin arrests the parasite cycle at the trophozoite stage. Ivermectin might add a feature to its "wonder drug" properties with activity against asexual stages of the malaria parasite Plasmodium falciparum. The observed activities might be difficult to reach with current regimens but will be more relevant with future high-dose regimens under investigation. Further studies should be performed to confirm these results in vitro and in vivo.

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“…The major advantage of tafenoquine over primaquine is its considerably longer plasma elimination half-life (approximately 15 days) (12,13) which allows for single dose (radical cure) or weekly administration for prophylaxis, thus reducing adherence issues commonly associated with primaquine dosing regimens (14). Although not currently approved for transmission blocking, the potential utility of tafenoquine for such is evident given its gametocytocidal activity in vitro (15) and transmission blocking activity in murine models (16). Like primaquine, tafenoquine can cause severe hemolytic anemia in G6PD-deficient individuals at currently recommended doses (17); however, as with primaquine, it is possible that a sufficient safety margin may be present for its therapeutic use in G6PD-deficient individuals (18).…”

Section: Introductionmentioning

confidence: 99%

“…Tafenoquine is a long acting analogue of primaquine that has been recently approved for malaria prophylaxis and for radical cure of P. vivax malaria (11). The major advantage of tafenoquine over primaquine is its considerably longer plasma elimination half-life (approximately 15 days) (12, 13) which allows for single dose (radical cure) or weekly administration for prophylaxis, thus reducing adherence issues commonly associated with primaquine dosing regimens (14). Although not currently approved for transmission blocking, the potential utility of tafenoquine for such is evident given its gametocytocidal activity in vitro (15) and transmission blocking activity in murine models (16).…”

Section: Introductionmentioning

confidence: 99%

Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum

Webster

Mitchell

Peters

et al. 2022

Preprint

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Background Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low dose tafenoquine. Methods Healthy adults were inoculated with P. falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50 mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays pre-dose and at 1, 4 and 7 days post-dose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia post-tafenoquine, and safety parameters. Results Six participants were enrolled, and all were infective to mosquitoes pre-tafenoquine, with a median 86% (range: 22-98) of mosquitoes positive for oocysts and 57% (range: 4-92) positive for sporozoites. By day 4 post-tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (IQR: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density post-tafenoquine was not significant. No significant participant safety concerns were identified. Conclusion Low dose tafenoquine reduces P. falciparum transmission to mosquitoes, with a delay in effect. Trial registration Australian New Zealand Clinical Trials Registry (ACTRN12620000995976). Funding QIMR Berghofer Medical Research Institute.

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Interactions between tafenoquine and artemisinin-combination therapy partner drug in asexual and sexual stage Plasmodium falciparum

Cited by 21 publications

References 49 publications

Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization

Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization

Ivermectin Impairs the Development of Sexual and Asexual Stages of Plasmodium falciparumIn Vitro

Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum

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