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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Journal ArticleDOI
Current status of artemisinin-resistant falciparum malaria in South Asia: a randomized controlled artesunate monotherapy trial in Bangladesh.
Peter Starzengruber,Paul Swoboda,Hans-Peter Fuehrer,Wasif A. Khan,Verena Hofecker,Anja Siedl,Markus A. Fally,Oliver Graf,Paktiya Teja-Isavadharm,Rashidul Haque,Pascal Ringwald,Harald Noedl +11 more
TL;DR: There is currently no indication that artemisinin resistance has reached Bangladesh, however, the fact that resistance has recently been reported from nearby Myanmar indicates an urgent need for close monitoring of artemis inin resistance in the region.
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Aminoindoles, a Novel Scaffold with Potent Activity against Plasmodium falciparum
Robert H. Barker,Sameer Urgaonkar,Ralph Mazitschek,Ralph Mazitschek,Cassandra Celatka,Renato Skerlj,Joseph F. Cortese,Erin Tyndall,Hanlan Liu,Mandy Cromwell,Amar Bir Singh Sidhu,Jose E. Guerrero-Bravo,Keila N. Crespo-Llado,Adelfa E. Serrano,Jing-wen Lin,Chris J. Janse,Shahid M. Khan,Manoj T. Duraisingh,Bradley I. Coleman,Iñigo Angulo-Barturen,María Belén Jiménez-Díaz,Noemi Magan,Vanesa Gomez,Santiago Ferrer,María Santos Martínez,Sergio Wittlin,Sergio Wittlin,Petros Papastogiannidis,Petros Papastogiannidis,Thomas O'Shea,Jeffrey D. Klinger,Mark Bree,Edward R. Lee,Mikaela Levine,Roger C. Wiegand,Benito Munoz,Dyann F. Wirth,Jon Clardy,Ian Bathurst,Edmund Sybertz +39 more
TL;DR: Characterizes aminoindole molecules that are analogs of Genz-644442, a potent inhibitor of Plasmodium falciparum in vitro and in vitro absorption, distribution, metabolism, and excretion properties that are a good candidate for preclinical development.
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Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium.
Matthew Cross,David L. Flanigan,Andrii Monastyrskyi,Alexis N. LaCrue,Fabián E. Sáenz,Jordany R. Maignan,Tina S. Mutka,Karen L. White,David M. Shackleford,Ian Bathurst,Frank R. Fronczek,Lukasz Wojtas,Wayne C. Guida,Susan A. Charman,Jeremy N. Burrows,Dennis E. Kyle,Roman Manetsch +16 more
TL;DR: Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability.
Journal ArticleDOI
Polymorphisms of the artemisinin resistant marker (K13) in Plasmodium falciparum parasite populations of Grande Comore Island 10 years after artemisinin combination therapy.
Bo Huang,Changsheng Deng,Tao Yang,Linlu Xue,Wang Qi,Shiguang Huang,Xin-zhuan Su,Xin-zhuan Su,Yajun Liu,Shaoqin Zheng,Guan Yezhi,Qin Xu,Jiuyao Zhou,Yuan Jie,Afane Bacar,Kamal Said Abdallah,Rachad Attoumane,Ahamada M. S. A. Mliva,Yanchun Zhong,Fangli Lu,Jianping Song +20 more
TL;DR: This study showed increased K13-propeller gene diversity among P. falciparum populations on the Island over the course of 8 years (2006–2014), which will be useful for developing and updating anti-malarial guidance in Comoros.
Journal ArticleDOI
Predictors of antimalarial self-medication in illegal gold miners in French Guiana: a pathway towards artemisinin resistance.
Maylis Douine,Yassamine Lazrek,D. Blanchet,Stéphane Pelleau,R Chanlin,Florine Corlin,Louise Hureau,Béatrice Volney,Helene Hiwat,S. Vreden,Félix Djossou,Magalie Demar,Mathieu Nacher,Lise Musset +13 more
TL;DR: The risk factors for the selection of resistance are well known and this study showed that they are present in FG with persons who self-medicated with poor adherence, and interventions should be implemented among this specific population to avoid the emergence of artemisinin resistance.
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
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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).
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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.
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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.
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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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