Ex vivo susceptibility and genotyping of Plasmodium falciparum isolates from Pikine, Senegal

Mbaye, Aminata; Gaye, Amy; Dièye, Baba; Ndiaye, Yaye Dié; Bei, Amy K.; Affara, Muna; Déme, Awa B.; Yade, Mamadou Samb; Diongue, Khadim; Ndiaye, Ibrahima; Ndiaye, Tolla; Sy, Mouhamed Habib; Sy, Ngayo; Koïta, Ousmane; Krogstad, Donald J.; Volkman, Sarah K.; Nwakanma, Davis; Ndiaye, Daouda

doi:10.1186/s12936-017-1897-6

Cited by 10 publications

(11 citation statements)

References 27 publications

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“…One way of assessing the in vitro drug susceptibility of parasite species lacking representative culture-adapted lines is through using an ex vivo platform, where infected erythrocytes are removed from the patient and exposed to serial dilutions of drugs in a 96-well plate. These parasites are then allowed to grow for a period of time (up to one complete life cycle usually, as they do not re-invade if not culture-adapted) and the survivors can be quantified using either microscopy or measuring [ 3 H]hypoxanthine incorporation ( Chaorattanakawee et al, 2017 ; Fatih et al, 2013 ; Kaewpongsri et al, 2011 ; Mbaye et al, 2017 ; Rangel et al, 2018 ). Obtaining ex vivo non-falciparum parasites is a challenge, especially in a non-endemic setting such as the UK.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo susceptibility to new antimalarial agents differs among human-infecting Plasmodium species

Schalkwyk¹,

Moon²,

Duffey³

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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Several promising antimalarial drugs are currently being tested in human trials, such as artefenomel, cipargamin, ferroquine and ganaplacide. Many of these compounds were identified using high throughput screens against a single species of human malaria, Plasmodium falciparum , under the assumption that effectiveness against all malaria species will be similar, as has been observed for other antimalarial drugs. However, using our in vitro adapted line, we demonstrated recently that P. knowlesi is significantly less susceptible than P. falciparum to some new antimalarial drugs (e.g., cipargamin and DSM265), and more susceptible to others (e.g., ganaplacide). There is, therefore, an urgent need to determine the susceptibility profile of all human malaria species to the current generation of antimalarial compounds. We obtained ex vivo malaria samples from travellers returning to the United Kingdom and, using the [ 3 H]hypoxanthine incorporation method, compared susceptibility to select established and experimental antimalarial agents among all major human infective Plasmodium species. We demonstrate that P. malariae and P. ovale spp. are significantly less susceptible than P. falciparum to cipargamin, DSM265 and AN13762, but are more susceptible to ganaplacide. Preliminary ex vivo data from single isolates of P. knowlesi and P. vivax demonstrate a similar profile. Our findings highlight the need to ensure cross species susceptibility profiles are determined early in the drug development pipeline. Our data can also be used to inform further drug development, and illustrate the utility of the P. knowlesi in vitro model as a scalable approach for predicting the drug susceptibility of non-falciparum malaria species in general.

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Section: Discussionmentioning

confidence: 99%

Ex vivo susceptibility to new antimalarial agents differs among human-infecting Plasmodium species

Schalkwyk¹,

Moon²,

Duffey³

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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“…However, with widespread discontinued use, numerous molecular-epidemiological studies showed that there was return of chloroquine susceptibility in P. falciparum field isolates [4]. This is supported by ex vivo [5][6][7][8][9][10][11][12][13][14][15][16] and in vivo drug-susceptibility studies [5,17,18]. Findings suggest that chloroquine might be reused in the future as an option for the treatment and/or chemoprophylaxis on the condition that chloroquine sensitivity is maintained in the area.…”

Section: Introductionmentioning

confidence: 99%

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda.

Balikagala

Yatsushiro²,

Tachibana

et al. 2020

Preprint

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Background Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum parasites, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods Methods Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed. Results Chloroquine resistance (100 nM) was observed in only 3 (1.3%) samples. Average IC 50 values for chloroquine were persistently low throughout the study period (17.4–24.9 nM). Parasites harboring p fcrt K76 alleles showed significantly lower IC 50 s to chloroquine than the parasites harboring K76T alleles (21.4 nM vs 43.1 nM, p-value= 3.9×10 -8 ). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. Conclusion This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.

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“…However, with widespread discontinued use, numerous molecular-epidemiological studies showed that there was return of chloroquine susceptibility in P. falciparum field isolates [4]. This is supported by ex vivo [5][6][7][8][9][10][11][12][13][14][15][16] and in vivo drug-susceptibility studies [5,17,18]. Findings suggest that chloroquine might be re-used in the future as an option for the treatment and/or chemoprophylaxis on the condition that chloroquine sensitivity is maintained in the area.…”

mentioning

confidence: 94%

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda

Balikagala

Sakurai-Yatsushiro

Tachibana

et al. 2020

Malar J

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Background: Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods.Methods: Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda, where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed.Results: Chloroquine resistance (≥ 100 nM) was observed in only 3 (1.3%) samples. Average IC 50 values for chloroquine were persistently low throughout the study period (17.4-24.9 nM). Parasites harbouring pfcrt K76 alleles showed significantly lower IC 50 s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 × 10 −8 ). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. Conclusion:This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.

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Ex vivo susceptibility and genotyping of Plasmodium falciparum isolates from Pikine, Senegal

Cited by 10 publications

References 27 publications

Ex vivo susceptibility to new antimalarial agents differs among human-infecting Plasmodium species

Ex vivo susceptibility to new antimalarial agents differs among human-infecting Plasmodium species

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda.

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda

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