Artemisinin Resistance in Plasmodium falciparum Malaria
Arjen M. Dondorp,François Nosten,Poravuth Yi,Debashish Das,Aung Phae Phyo,Joel Tarning,Khin Maung Lwin,Frédéric Ariey,Warunee Hanpithakpong,Sue J. Lee,Pascal Ringwald,Kamolrat Silamut,Mallika Imwong,Kesinee Chotivanich,Pharath Lim,Trent Herdman,Sen Sam An,Shunmay Yeung,Pratap Singhasivanon,Nicholas P. J. Day,Niklas Lindegardh,Duong Socheat,Nicholas J. White +22 more
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TLDR
The overall median clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours in Wang Pha (P<0.001) in each of the two locations as discussed by the authors.Abstract:
We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate–mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P = 0. 31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco–endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)read more
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Drug resistance in malaria.
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TL;DR: The identification of mutations in the propeller domains of Kelch 13 as the primary marker for artemisinin resistance in P. falciparum is described and two major mechanisms of resistance that have been independently proposed are explored: the activation of the unfolded protein response and proteostatic dysregulation of parasite phosphatidylinositol 3- kinase.
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Targeting the cell stress response of plasmodium falciparum to overcome artemisinin resistance
Con Dogovski,Stanley C. Xie,Gaetan Burgio,Jess Bridgford,Sachel Mok,James M. McCaw,Kesinee Chotivanich,Shannon Kenny,Nina F. Gnädig,Judith Straimer,Zbynek Bozdech,David A. Fidock,Julie A. Simpson,Arjen M. Dondorp,Simon J. Foote,Nectarios Klonis,Leann Tilley +16 more
TL;DR: In this article, a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin).
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Arjen M. Dondorp,Rick M. Fairhurst,Laurence Slutsker,John R. MacArthur,Joel G. Breman,Philippe J Guerin,Thomas E. Wellems,Pascal Ringwald,Robert D. Newman,Christopher V. Plowe +9 more
TL;DR: Reduced susceptibility of Plasmodium falciparum to artemisinin is now being seen in some places, indicating reduced susceptibility to malaria control.
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References
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Journal ArticleDOI
Evidence of Artemisinin-Resistant Malaria in Western Cambodia
TL;DR: Artemisinins are potent and rapidly acting antimalarial drugs, and their widespread use for treating patients with Plasmodium falciparum malaria raises the question of emerging drug resistance.
Journal ArticleDOI
Artemisinins target the SERCA of Plasmodium falciparum
Ursula Eckstein-Ludwig,Richard Webb,I. D. A. van Goethem,J M East,Anthony G. Lee,Masatsugu Kimura,Paul M. O'Neill,Patrick G. Bray,Stephen A. Ward,Sanjeev Krishna +9 more
TL;DR: It is shown that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor).
Journal ArticleDOI
Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
TL;DR: Artesunate should become the treatment of choice for severe falciparum malaria in adults because it is more rapidly acting than intravenous quinine in terms of parasite clearance and is simpler to administer.
Journal ArticleDOI
Qinghaosu (artemisinin): the price of success.
TL;DR: Artemisinin combination treatments are now first-line drugs for uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries and a global subsidy would make these drugs more affordable and available.
Journal ArticleDOI
Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number.
Ric N. Price,Ric N. Price,Anne-Catrin Uhlemann,Alan Brockman,Rose McGready,Elizabeth A. Ashley,L Phaipun,Rina Patel,Ken Laing,Sornchai Looareesuwan,Nicholas J. White,Nicholas J. White,François Nosten,Sanjeev Krishna +13 more
TL;DR: It is shown that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine.
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