Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum

Simple item page
dc.contributor.authorLe Manach, Claireen_ZA
dc.contributor.authorScheurer, Christianen_ZA
dc.contributor.authorSax, Sibylleen_ZA
dc.contributor.authorSchleiferbock, Sarahen_ZA
dc.contributor.authorCabrera, Diegoen_ZA
dc.contributor.authorYounis, Yassiren_ZA
dc.contributor.authorPaquet, Tanyaen_ZA
dc.contributor.authorStreet, Leslieen_ZA
dc.contributor.authorSmith, Peteren_ZA
dc.contributor.authorDing, Xavieren_ZA
dc.contributor.authorWaterson, Daviden_ZA
dc.contributor.authorWitty, Michaelen_ZA
dc.contributor.authorLeroy, Didieren_ZA
dc.contributor.authorChibale, Kellyen_ZA
dc.contributor.authorWittlin, Sergioen_ZA
dc.date.accessioned2015-11-23T12:08:38Z
dc.date.available2015-11-23T12:08:38Z
dc.date.issued2013en_ZA
dc.description.abstractBACKGROUND: Recent whole cell in vitro screening campaigns identified thousands of compounds that are active against asexual blood stages of Plasmodium falciparum at submicromolar concentrations. These hits have been made available to the public, providing many novel chemical starting points for anti-malarial drug discovery programmes. Knowing which of these hits are fast-acting compounds is of great interest. Firstly, a fast action will ensure rapid relief of symptoms for the patient. Secondly, by rapidly reducing the parasitaemia, this could minimize the occurrence of mutations leading to new drug resistance mechanisms.An in vitro assay that provides information about the speed of action of test compounds has been developed by researchers at GlaxoSmithKline (GSK) in Spain. This assay also provides an in vitro measure for the ratio between parasitaemia at the onset of drug treatment and after one intra-erythrocytic cycle (parasite reduction ratio, PRR). Both parameters are needed to determine in vitro killing rates of anti-malarial compounds. A drawback of the killing rate assay is that it takes a month to obtain first results. METHODS: The approach described in the present study is focused only on the speed of action of anti-malarials. This has the advantage that initial results can be achieved within 4-7 working days, which helps to distinguish between fast and slow-acting compounds relatively quickly. It is expected that this new assay can be used as a filter in the early drug discovery phase, which will reduce the number of compounds progressing to secondary, more time-consuming assays like the killing rate assay. RESULTS: The speed of action of a selection of seven anti-malarial compounds was measured with two independent experimental procedures using modifications of the standard [3H]hypoxanthine incorporation assay. Depending on the outcome of both assays, the tested compounds were classified as either fast or non-fast-acting. CONCLUSION: The results obtained for the anti-malarials chloroquine, artesunate, atovaquone, and pyrimethamine are consistent with previous observations, suggesting the methodology is a valid way to rapidly identify fast-acting anti-malarial compounds. Another advantage of the approach is its ability to discriminate between static or cidal compound effects.en_ZA
dc.identifier.apacitationLe Manach, C., Scheurer, C., Sax, S., Schleiferbock, S., Cabrera, D., Younis, Y., ... Wittlin, S. (2013). Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. <i>Malaria Journal</i>, http://hdl.handle.net/11427/15250en_ZA
dc.identifier.chicagocitationLe Manach, Claire, Christian Scheurer, Sibylle Sax, Sarah Schleiferbock, Diego Cabrera, Yassir Younis, Tanya Paquet, et al "Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum." <i>Malaria Journal</i> (2013) http://hdl.handle.net/11427/15250en_ZA
dc.identifier.citationLe Manach, C., Scheurer, C., Sax, S., Schleiferböck, S., Cabrera, D. G., Younis, Y., ... & Wittlin, S. (2013). Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. Malar. J, 16, 424-430.en_ZA
dc.identifier.ris TY - Journal Article AU - Le Manach, Claire AU - Scheurer, Christian AU - Sax, Sibylle AU - Schleiferbock, Sarah AU - Cabrera, Diego AU - Younis, Yassir AU - Paquet, Tanya AU - Street, Leslie AU - Smith, Peter AU - Ding, Xavier AU - Waterson, David AU - Witty, Michael AU - Leroy, Didier AU - Chibale, Kelly AU - Wittlin, Sergio AB - BACKGROUND: Recent whole cell in vitro screening campaigns identified thousands of compounds that are active against asexual blood stages of Plasmodium falciparum at submicromolar concentrations. These hits have been made available to the public, providing many novel chemical starting points for anti-malarial drug discovery programmes. Knowing which of these hits are fast-acting compounds is of great interest. Firstly, a fast action will ensure rapid relief of symptoms for the patient. Secondly, by rapidly reducing the parasitaemia, this could minimize the occurrence of mutations leading to new drug resistance mechanisms.An in vitro assay that provides information about the speed of action of test compounds has been developed by researchers at GlaxoSmithKline (GSK) in Spain. This assay also provides an in vitro measure for the ratio between parasitaemia at the onset of drug treatment and after one intra-erythrocytic cycle (parasite reduction ratio, PRR). Both parameters are needed to determine in vitro killing rates of anti-malarial compounds. A drawback of the killing rate assay is that it takes a month to obtain first results. METHODS: The approach described in the present study is focused only on the speed of action of anti-malarials. This has the advantage that initial results can be achieved within 4-7 working days, which helps to distinguish between fast and slow-acting compounds relatively quickly. It is expected that this new assay can be used as a filter in the early drug discovery phase, which will reduce the number of compounds progressing to secondary, more time-consuming assays like the killing rate assay. RESULTS: The speed of action of a selection of seven anti-malarial compounds was measured with two independent experimental procedures using modifications of the standard [3H]hypoxanthine incorporation assay. Depending on the outcome of both assays, the tested compounds were classified as either fast or non-fast-acting. CONCLUSION: The results obtained for the anti-malarials chloroquine, artesunate, atovaquone, and pyrimethamine are consistent with previous observations, suggesting the methodology is a valid way to rapidly identify fast-acting anti-malarial compounds. Another advantage of the approach is its ability to discriminate between static or cidal compound effects. DA - 2013 DB - OpenUCT DO - 10.1186/1475-2875-12-424 DP - University of Cape Town J1 - Malaria Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum TI - Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum UR - http://hdl.handle.net/11427/15250 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15250
dc.identifier.urihttp://dx.doi.org/10.1186/1475-2875-12-424
dc.identifier.vancouvercitationLe Manach C, Scheurer C, Sax S, Schleiferbock S, Cabrera D, Younis Y, et al. Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. Malaria Journal. 2013; http://hdl.handle.net/11427/15250.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2013 Le Manach et al.; licensee BioMed Central Ltd.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceMalaria Journalen_ZA
dc.source.urihttp://www.malariajournal.com/en_ZA
dc.subject.otherPlasmodium falciparumen_ZA
dc.subject.otherSpeed of actionen_ZA
dc.subject.otherStage-specificityen_ZA
dc.titleFast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparumen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Le_Manach_Fast_in_vitro_methods_2013.pdf
Size:
391.4 KB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Journal Articles