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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/12923
Title: Intrahost modeling of artemisinin resistance in Plasmodium falciparum
Authors: Sompob Saralamba
Wirichada Pan-Ngum
Richard J. Maude
Sue J. Lee
Joel Tarning
Niklas Lindegårdh
Kesinee Chotivanich
François Nosten
Nicholas P J Day
Duong Socheat
Nicholas J. White
Arjen M. Dondorp
Lisa J. White
Mahidol University
Nuffield Department of Clinical Medicine
Shoklo Malaria Research Unit
National Center for Parasitology, Entomology and Malaria Control
Keywords: Multidisciplinary
Issue Date: 4-Jan-2011
Citation: Proceedings of the National Academy of Sciences of the United States of America. Vol.108, No.1 (2011), 397-402
Abstract: Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic-pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log 10 scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=78651077288&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/12923
ISSN: 10916490
00278424
Appears in Collections:Scopus 2011-2015

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