artelinic-acid has been researched along with Malaria--Falciparum* in 4 studies
4 other study(ies) available for artelinic-acid and Malaria--Falciparum
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Phenotypic changes in artemisinin-resistant Plasmodium falciparum lines in vitro: evidence for decreased sensitivity to dormancy and growth inhibition.
The appearance of Plasmodium falciparum parasites with decreased in vivo sensitivity but no measurable in vitro resistance to artemisinin has raised the urgent need to characterize the artemisinin resistance phenotype. Changes in the temporary growth arrest (dormancy) profile of parasites may be one aspect of this phenotype. In this study, we investigated the link between dormancy and resistance, using artelinic acid (AL)-resistant parasites. Our results demonstrate that the AL resistance phenotype has (i) decreased sensitivity of mature-stage parasites, (ii) decreased sensitivity of the ring stage to the induction of dormancy, and (iii) a faster recovery from dormancy. Topics: Animals; Antimalarials; Artemisinins; Cell Culture Techniques; Drug Resistance; Erythrocytes; Genotype; Humans; Inhibitory Concentration 50; Life Cycle Stages; Malaria, Falciparum; Microscopy; Parasitic Sensitivity Tests; Phenotype; Plasmodium falciparum; Recurrence | 2012 |
Phenotypic and genotypic analysis of in vitro-selected artemisinin-resistant progeny of Plasmodium falciparum.
Emergence of artemisinin resistance in Cambodia highlights the importance of characterizing resistance to this class of drugs. Previously, intermediate levels of resistance in Plasmodium falciparum were generated in vitro for artelinic acid (AL) and artemisinin (QHS). Here we expanded on earlier selection efforts to produce levels of clinically relevant concentrations, and the resulting lines were characterized genotypically and phenotypically. Recrudescence assays determined the ability of resistant and parent lines to recover following exposure to clinically relevant levels of drugs. Interestingly, the parent clone (D6) tolerated up to 1,500 ng/ml QHS, but the resistant parasite, D6.QHS340×3, recovered following exposure to 2,400 ng/ml QHS. Resistant D6, W2, and TM91c235 parasites all exhibited elevated 50% inhibitory concentrations (IC(50)s) to multiple artemisinin drugs, with >3-fold resistance to QHS and AL; however, the degree of resistance obtained with standard methods was remarkably less than expected for parasite lines that recovered from 2,400-ng/ml drug pressure. A novel assay format with radiolabeled hypoxanthine demonstrated a greater degree of resistance in vitro than the standard SYBR green method. Analysis of merozoite number in resistant parasites found D6 and TM91c235 resistant progeny had significantly fewer merozoites than parent strains, whereas W2 resistant progeny had significantly more. Amplification of pfmdr1 increased proportionately to the increased drug levels tolerated by W2 and TM91c235, but not in resistant D6. In summary, we define the artemisinin resistance phenotype as a decrease in susceptibility to artemisinins along with the ability to recover from drug-induced dormancy following supraclinical concentrations of the drug. Topics: Antimalarials; Artemisinins; Benzothiazoles; Cell Culture Techniques; Diamines; Dose-Response Relationship, Drug; Drug Resistance; Erythrocytes; Gene Dosage; Genotype; Humans; Hypoxanthine; Inhibitory Concentration 50; Malaria, Falciparum; Merozoites; Microscopy; Multidrug Resistance-Associated Proteins; Organic Chemicals; Parasitic Sensitivity Tests; Phenotype; Plasmodium falciparum; Quinolines; Recurrence | 2012 |
Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum.
Artemisinin and its derivatives are the most rapidly acting and efficacious antimalarial drugs currently available. Although resistance to these drugs has not been documented, there is growing concern about the potential for resistance to develop. In this paper we report the selection of parasite resistance to artelinic acid (AL) and artemisinin (QHS) in vitro and the molecular changes that occurred during the selection. Exposure of three Plasmodium falciparum lines (W2, D6, and TM91C235) to AL resulted in decreases in parasite susceptibilities to AL and QHS, as well as to mefloquine, quinine, halofantrine, and lumefantrine. The changes in parasite susceptibility were accompanied by increases in the copy number, mRNA expression, and protein expression of the pfmdr1 gene in the resistant progenies of W2 and TM91C235 parasites but not in those of D6 parasites. No changes were detected in the coding sequences of the pfmdr1, pfcrt, pfatp6, pftctp, and pfubcth genes or in the expression levels of pfatp6 and pftctp. Our data demonstrate that P. falciparum lines have the capacity to develop resistance to artemisinin derivatives in vitro and that this resistance is achieved by multiple mechanisms, to include amplification and increased expression of pfmdr1, a mechanism that also confers resistance to mefloquine. This observation is of practical importance, because artemisinin drugs are often used in combination with mefloquine for the treatment of malaria. Topics: Alleles; Animals; Antimalarials; Artemisinins; Drug Resistance; Gene Amplification; Gene Dosage; Gene Expression; Genes, Protozoan; Humans; In Vitro Techniques; Malaria, Falciparum; Mefloquine; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; RNA, Messenger; RNA, Protozoan | 2010 |
Deamplification of pfmdr1-containing amplicon on chromosome 5 in Plasmodium falciparum is associated with reduced resistance to artelinic acid in vitro.
Amplification of the Plasmodium falciparum multidrug resistance 1 gene (pfmdr1) has been implicated in multidrug resistance, including in vitro resistance to artelinic acid (AL). The stability and fitness of having multiple copies of pfmdr1 are important factors due to their potential effects on the resistance phenotype of parasites. These factors were investigated by using an AL-resistant line of P. falciparum (W2AL80) and clones originating from W2AL80. A rapid reduction in pfmdr1 copy number (CN) was observed in the uncloned W2AL80 line; 63% of this population reverted to a CN of <3 without exposure to the drug. Deamplification of the pfmdr1 amplicon was then determined in three clones, each initially containing three copies of pfmdr1. Interestingly, two outcomes were observed during 3 months without drug pressure. In one clone, parasites with fewer than 3 copies of pfmdr1 emerged rapidly. In two other clones, the reversion was significantly delayed. In all subclones, the reduction in pfmdr1 CN involved the deamplification of the entire amplicon (19 genes). Importantly, deamplification of the pfmdr1 amplicon resulted in partial reversal of resistance to AL and increased susceptibility to mefloquine. These results demonstrate that multiple copies of the pfmdr1-containing amplicon in AL-resistant parasites are unstable when drug pressure is withdrawn and have practical implications for the maintenance and spread of parasites resistant to artemisinin derivatives. Topics: Animals; Antimalarials; Artemisinins; Chromosomes; Drug Resistance; Gene Amplification; Gene Dosage; Humans; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Plasmodium falciparum | 2010 |