Plasmodium falciparum: Microaerophilic requirements in human red blood cells

Scheibel, L. W.; Ashton, Sarah; Trager, William

doi:10.1016/0014-4894(79)90094-8

Cited by 107 publications

(48 citation statements)

References 20 publications

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“…The cultures were incubated at 37°C in an airtight desiccator cabinet flushed with a gas mixture of 1% O 2 and 5% CO 2 in N 2 balance (BOC Gases, Australia) for 60 to 90 s daily or when opened. The oxygen concentration within the chamber ranged between 3 and 9% over 24 h. This provided a controlled microaerophilic atmosphere for the culture of P. falciparum as described previously (21,27).…”

Section: Methodsmentioning

confidence: 99%

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Wong

Salman

Ilett

et al. 2011

Antimicrob Agents Chemother

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Desbutyl-lumefantrine (DBL) is a metabolite of lumefantrine. Preliminary data from Plasmodium falciparum field isolates show greater antimalarial potency than, and synergy with, the parent compound and synergy with artemisinin. In the present study, the in vitro activity and interactions of DBL were assessed from tritiumlabeled hypoxanthine uptake in cultures of the laboratory-adapted strains 3D7 (chloroquine sensitive) and W2mef (chloroquine resistant). The geometric mean 50% inhibitory concentrations (IC 50 s) for DBL against 3D7 and W2mef were 9.0 nM (95% confidence interval, 5.7 to 14.4 nM) and 9.5 nM (95% confidence interval, 7.5 to 11.9 nM), respectively, and those for lumefantrine were 65.2 nM (95% confidence interval, 42.3 to 100.8 nM) and 55.5 nM (95% confidence interval, 40.6 to 75.7 nM), respectively. An isobolographic analysis of DBL and lumefantrine combinations showed no interaction in either laboratory-adapted strain but mild synergy between DBL and dihydroartemisinin (sums of the fractional inhibitory concentrations of 0.92 [95% confidence interval, 0.87 to 0.98] and 0.94 [95% confidence interval, 0.90 to 0.99] for 3D7 and W2mef, respectively). Using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay and 94 day 7 samples from a previously reported intervention trial, the mean plasma DBL was 31.9 nM (range, 1.3 to 123.1 nM). Mean plasma DBL concentrations were lower in children who failed artemether-lumefantrine treatment than in those with an adequate clinical and parasitological response (ACPR) (P ‫؍‬ 0.053 versus P > 0.22 for plasma lumefantrine and the plasma lumefantrine-to-DBL ratio, respectively). DBL is more potent than the parent compound and mildly synergistic with dihydroartemisinin. These properties and the relationship between day 7 plasma concentrations and the ACPR suggest that it could be a useful alternative to lumefantrine as a part of artemisinin combination therapy.Desbutyl-lumefantrine (DBL) or desbutyl-benflumetol is a 2,3-benzindene compound with antimalarial activity. Although previously considered only a putative metabolite of lumefantrine because of a lack of supportive pharmacokinetic data (20,24), recent analytical developments have enabled the reliable detection of relatively low concentrations of DBL in samples of plasma from small numbers of patients treated with conventional doses of artemether-lumefantrine combination therapy (11,15,18). The ratio of the maximum plasma concentration (C max ) of the parent compound to that of the metabolite in this situation has varied substantially, from 6 (18) to Ͼ270 (11).DBL is more potent in vitro against chloroquine (CQ)-resistant Plasmodium falciparum and Plasmodium vivax field isolates than lumefantrine (13, 17, 23). There is evidence of in vitro synergy between lumefantrine and DBL against P. falciparum but at ratios (999:1 and 995:5) that were presumably selected at a time when plasma concentrations of DBL were assumed to be very much lower than those of the parent compound (23,24). Int...

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Section: Methodsmentioning

confidence: 99%

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Wong

Salman

Ilett

et al. 2011

Antimicrob Agents Chemother

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“…Experiments were conducted in a tissue culture chamber (Billups-Rothenburg, Inc.) gassed with a mixture of 1% 22 DIVO, GEARY, AND JENSEN 02-3% C02-96% N2 (low oxygen) or in candle jars; the gas mixture in these containers was reported to be approximately 15% 02, 2% C02, and 84% N2 (43). Gas phases were changed daily.…”

Section: Methodsmentioning

confidence: 99%

Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture

Divo¹,

Geary²,

Jensen³

1985

Antimicrob Agents Chemother

123

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Several antibiotics which inhibit protein synthesis on 70S ribosomes, including clindamycin, pirlimycin, 4'-pentyl-N-demethyl clindamycin, four tetracyclines, chloramphenicol, thiamphenicol, and erythromycin, had antimalarial effects against Plasmodium falciparum in culture which were greatly influenced by the duration of drug exposure and by oxygen tension. In 96-h incubations, potency was increased by a factor of up to 106 over the first 48-h period and by a factor of up to 104 in 15% 02 versus 1% 02. Two aminoglycosides, kanamycin and tobramycin, had no antimalarial activity. Rifampin and nalidixic acid, which inhibit nucleic acid synthesis, were not similar to the 70S inhibitors. The mitochondrial inhibitors Janus Green, rhodamine 123, antimycin Al, and 8-methylamino-8-desmethyl riboflavin had activities which were influenced by the duration of exposure and oxygen tension. Quinoline-containing antimalarial agents, ionophores, and other antimalarial drugs were influenced to a minor extent by the duration of exposure but were not affected by oxygen tension. These data can best be explained by the hypothesis that antimalarial 70S ribosome-specific protein synthesis inhibitors are toxic to the parasites by acting on the mitochondrion.

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“…Semiautomated devices reduce the amount of time spent on maintenance of stock cultures of the parasite. Although the malarial parasite is found in red blood cells, it is microaerophilic in its oxygen preference (74). Taylor-Robinson (78) used a commercial system designed for growth of Campylobacter spp.…”

Section: Erythrocytic Stagesmentioning

confidence: 99%

Cultivation of Plasmodium spp

Schuster

2002

Clin Microbiol Rev

102

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Cultivation of both human and non-human species of Plasmodium spp., the causal agent of malaria, has been a major research success, leading to a greater understanding of the parasite. Efforts at cultivating the organisms in vitro are complicated by the parasites' alternating between a human host and an arthropod vector, each having its own set of physiological, metabolic, and nutritional parameters. Life cycle stages of the four species that infect humans have been established in vitro. Of these four, P. falciparum remains the only species for which all stages have been cultured in vitro; different degrees of success have been achieved with the other human Plasmodium spp. The life cycle includes the exoerythrocytic stage (within liver cells), the erythrocytic stage (within erythrocytes or precursor reticulocytes), and the sporogonic stage (within the vector). Culture media generally consist of a basic tissue culture medium (e.g., minimal essential medium or RPMI 1640) to which serum and erythrocytes are added. Most of the efforts have been directed toward the stage found in the erythrocyte. This stage has been cultivated in petri plates or other growth vessels in a candle jar to generate elevated CO2 levels or in a more controlled CO2 atmosphere. Later developments have employed continuous-flow systems to reduce the labor-intensive nature of medium changing. The exoerythrocytic and sporogonic life cycle stages have also been cultivated in vitro. A number of avian, rodent, and simian malarial parasites have also been established in vitro. Although cultivation is of great help in understanding the biology of Plasmodium, it does not lend itself to use for diagnostic purposes

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Plasmodium falciparum: Microaerophilic requirements in human red blood cells

Cited by 107 publications

References 20 publications

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture

Cultivation of Plasmodium spp

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