The Impact of Pharmacokinetic Mismatched Antimalarial Drug Combinations on the Emergence and Spread of Drug Resistant Parasites

Li, Qigui; Hickman, Mark

doi:10.5772/59506

Cited by 4 publications

(1 citation statement)

References 61 publications

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“…Pyronaridine resistance has previously been selected in Plasmodium berghei and Plasmodium yoelii (Croft et al, 2012;Kimani et al, 2014;Peters and Robinson, 1992); however, the molecular organization of the phenotype was not investigated. Pyramax® (PRD/ASN), remains active against widespread Chloroquine (CQ) and Sufadoxine-Pyrimethamine (SP) drug-resistant P. falciparum clearance of malaria infection, studies indicate that use of drug combination with mismatched pharmacokinetics does not prevent selection of the resistance against longacting drug (Hastings and Hodel, 2014;Li and Hickman, 2015). Artesunate is a short-acting artemisinin derivative with half-life of less than 2 h, while PRD is long-acting with half-life of 16 to 17days (Park and Pradeep, 2010).…”

Section: Introductionmentioning

confidence: 99%

Antimalarial pyronaridine resistance may be associated with elevated MDR-1 gene expression profiles but not point mutation in Plasmodium berghei ANKA isolates

Kimani¹,

Shume²

2020

Afr. J. Biochem. Res.

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The selection of resistance is inevitable whenever chemotherapy is necessary for pathogen control. Notably, Plasmodium falciparum has developed multifaceted means to overcome the toxicity of nearly all antimalarial medicines. To bypass this challenge, not only should novel drugs be developed, but the resistance mechanisms to new and existing drugs need should be fully explored. Pyronaridine is a companion drug in Pyramax ® , a blend of artesunate (ASN)-pyronaridine (PRD) which is the WHO prequalified alternative for malaria treatment in the African setting. However, half-life mismatch predisposes the PRD to swift emergence of resistance especially in high malaria transmission settings. However, there are no well-characterized PRD-resistant parasite lines. Previously, stable PRD-resistant P. berghei ANKA lines were selected by in vivo drug pressure and preliminary results showed crossresistance with quinolines, therefore, hypothetically the activity of PRD and chloroquine or other quinolines may be comparable, hence, the resistance mechanisms may be parallel. Consequently, genetic polymorphisms and expression profiles of PbMDR-1 that could be associated with pyronaridine resistance were examined by PCR amplification, sequencing and transcript quantification by RT-qPCR. The transcripts level increased during resistance selection while translated PbMDR-1 sequence alignment of PRD-sensitive and PRD-resistant was the same, the expression may be linked to PRD resistance but not mutations.

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