Artemisinin-resistant malaria: research challenges, opportunities, and public health implications

Rick M Fairhurst, Gaurvika M L Nayyar, Joel G Breman, Rachel Hallett, Jonathan L Vennerstrom, Socheat Duong, Pascal Ringwald, Thomas E Wellems, Christopher V Plowe, Arjen M Dondorp, Rick M Fairhurst, Gaurvika M L Nayyar, Joel G Breman, Rachel Hallett, Jonathan L Vennerstrom, Socheat Duong, Pascal Ringwald, Thomas E Wellems, Christopher V Plowe, Arjen M Dondorp

Abstract

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance.

Figures

Figure 1.
Figure 1.
Percentages of patients with Plasmodium falciparum parasitemia on Day 3 after treatment with an ACT (2006–2010).

References

    1. Johanson E, Cibulskis R, Steketee R. Malaria Funding & Resource Utilization: The First Decade of Roll Back Malaria. Geneva, Switzerland: Roll Back Malaria; 2010.
    1. WHO Learning to outwit malaria. WHO Bulletin. 2011;89:10–11.
    1. Tanner M, Savigny D. Malaria eradication back on the table. Bull World Health Organ. 2008;86:81–160.
    1. WHO . Global Report on Antimalarial Efficacy and Drug Resistance: 2000–2010. Geneva: World Health Organization; 2010.
    1. Trape J. The public health impact of chloroquine resistance in Africa. Am J Trop Med Hyg. 2001;64((1–2 Suppl)):12–17.
    1. Dondorp AM, Yeung S, White L, Nguon C, Day NP, Socheat D, von Seidlein L. Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol. 2010;8:272.
    1. Dondorp AM, Fanello CI, Hendriksen ICE, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ. AQUAMAT group Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomized trial. Lancet. 2010;376:1647–1657.
    1. SEAQUAMAT Artesunate versus quinine for treatment of severe falciparum malaria: a randomized trial. Lancet. 2005;366:717–725.
    1. WHO Marketing of Oral Artemisinin-Based Monotherapy Medicines at Country Level. 2010. Available at. Accessed February 15, 2011.
    1. WHO . Global Report on Antimalarial Drug Efficacy and Drug Resistance: 2000–2010. Geneva: World Health Organization; 2005.
    1. WHO . Marketing of Oral Artemisinin-Based Monotherapy Medicines. Geneva: WHO; 2010. Available at. Accessed February 15, 2011.
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–467.
    1. Anderson TJ, Nair S, Nkhoma S, Williams JT, Imwong M, Yi P, Socheat D, Das D, Chotivanich K, Day NP, White NJ, Dondorp AM. High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in Western Cambodia. J Infect Dis. 2010;201:1326–1330.
    1. WHO . Global Plan for Artemisinin Resistance Containment (GPARC) Geneva: World Health Organization; 2011.
    1. PATH . Staying the Course? Malaria Research and Development in a Time of Economic Uncertainty. Seattle, WA: PATH; 2011.
    1. Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, Binh TQ, D'Alessandro U, Day NP, de Vries PJ, Dorsey G, Guthmann JP, Mayxay M, Newton PN, Olliaro P, Osorio L, Price RN, Rowland M, Smithuis F, Taylor WR, Nosten F, White NJ. In vivo parasitological measures of artemisinin susceptibility. J Infect Dis. 2010;201:570–579.
    1. WHO . Update on Artemisinin Resistance. Geneva: World Health Organization; 2011.
    1. Price R, van Vugt M, Nosten F, Luxemburger C, Brockman A, Phaipun L, Chongsuphajaisiddhi T, White N. Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria. Am J Trop Med Hyg. 1998;59:883–888.
    1. White N. The parasite clearance curve. Malar J. 2011;10:278.
    1. Flegg J, Guerin P, White N, Stepniewska K. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J. 2011;10:339.
    1. Chotivanich K, Udomsangpetch R, McGready R, Proux S, Newton P, Pukrittayakamee S, Looareesuwan S, White NJ. Central role of the spleen in malaria parasite clearance. J Infect Dis. 2002;185:1538–1541.
    1. Seidlein VL, Drakeley C, Greenwood B, Walraven G, Targett G. Risk factors for gametocyte carriage in Gambian children. Am J Trop Med Hyg. 2001;65:523–527.
    1. Barnes KI, Little F, Mabuza A, Mngomezulu N, Govere J, Durrheim D, Roper C, Watkins B, White NJ. Increased gametocytemia after treatment: an early parasitological indicator of emerging sulfadoxine-pyrimethamine resistance in falciparum malaria. J Infect Dis. 2008;197:1605–1613.
    1. Price R, Nosten F, Simpson JA, Luxemburger C, Phaipun L, ter Kuile F, van Vugt M, Chongsuphajaisiddhi T, White NJ. Risk factors for gametocyte carriage in uncomplicated falciparum malaria. Am J Trop Med Hyg. 1999;60:1019–1023.
    1. Sutherland CJ, Alloueche A, Curtis J, Drakeley CJ, Ord R, Duraisingh M, Greenwood BM, Pinder M, Warhurst D, Targett GA. Gambian children successfully treated with chloroquine can harbor and transmit Plasmodium falciparum gametocytes carrying resistance genes. Am J Trop Med Hyg. 2002;67:578–585.
    1. Méndez F, Herrera S, Murrain B, Gutiérrez A, Moreno LA, Manzano M, Muñoz A, Plowe CV. Selection of antifolate-resistant Plasmodium falciparum by sulfadoxine-pyrimethamine treatment and infectivity to Anopheles mosquitoes. Am J Trop Med Hyg. 2007;77:438–443.
    1. Carrara VI, Zwang J, Ashley EA, Price RN, Stepniewska K, Barends M, Brockman A, Anderson T, McGready R, Phaiphun L, Proux S, van Vugt M, Hutagalung R, Lwin KM, Phyo AP, Preechapornkul P, Imwong M, Pukrittayakamee S, Singhasivanon P, White NJ, Nosten F. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS ONE. 2009;4:e4551.
    1. Wernsdorfer WH. Field evaluation of drug resistance in malaria. In vitro micro-test. Acta Trop. 1980;37:222–227.
    1. Noedl H, Attlymar B, Wernsdorfer W, Kollaritsch H, Miller RS. A histidine-rich protein 2-based malaria drug sensitivity assay for field use. Am J Trop Med Hyg. 2004;71:711–714.
    1. WHO . In vitro Micro Test for the Assessment of the Response to Plasmodium to Chloroquine, Mefloquine, Amodiaquine, Sulfadoxine/Pyrimethamine and Artemisinin. Geneva: World Health Organization; 2001.
    1. Saralamba S, Pan-Ngum W, Maude RJ, Lee SJ, Tarning J, Lindegårdh N, Chotivanich K, Nosten F, Day NP, Socheat D, White NJ, Dondorp AM, White LJ. Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc Natl Acad Sci USA. 2011;108:397–402.
    1. Witkowski B, Lelièvre J, Barragán MJ, Laurent V, Su XZ, Berry A, Benoit-Vical F. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob Agents Chemother. 2010;54:1872–1877.
    1. Codd A, Teuscher F, Kyle DE, Cheng Q, Gatton ML. Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure. Malar J. 2011;10:56.
    1. Teuscher F, Gatton ML, Chen N, Peters J, Kyle DE, Cheng Q. Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J Infect Dis. 2010;202:1362–1368.
    1. Plowe CV, Roper C, Barnwell JW, Happi CT, Joshi HH, Mbacham W, Meshnick SR, Mugittu K, Naidoo I, Price RN, Shafer RW, Sibley CH, Sutherland CJ, Zimmerman PA, Rosenthal PJ. World Antimalarial Resistance Network (WARN) III: molecular markers for drug resistant malaria. Malar J. 2007;6:121.
    1. Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte Y, Coulibaly D, Dicko A, Su XZ, Nomura T, Fidock DA, Wellems TE, Plowe CV. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med. 2001;344:257–263.
    1. Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science. 2002;298:210–213.
    1. Johnson DJ, Fidock DA, Mungthin M, Lakshmanan V, Sidhu AB, Bray PG, Ward SA. Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol Cell. 2004;15:867–877.
    1. Holmgren G, Gil JP, Ferreira PM, Veiga MI, Obonyo CO, Björkman A. Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infect Genet Evol. 2006;6:309–314.
    1. Sisowath C, Petersen I, Veiga MI, Martensson A, Premji Z, Björkman A, Fidock DA, Gil JP. In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa. J Infect Dis. 2009;199:750–757.
    1. Valderramos SG, Valderramos JC, Musset L, Purcell LA, Mercereau-Puijalon O, Legrand E, Fidock DA. Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum. PLoS Pathog. 2010;6:e1000887.
    1. Duraisingh MT, von Seidlein LV, Jepson A, Jones P, Sambou I, Pinder M, Warhurst DC. Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum. Parasitology. 2000;121((Pt 1)):1–7.
    1. Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, Patel R, Laing K, Looareesuwan S, White NJ, Nosten F, Krishna S. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004;364:438–447.
    1. Sidhu AB, Valderramos SG, Fidock DA. pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Mol Microbiol. 2005;57:913–926.
    1. Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Björkman A, Gil JP. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem) J Infect Dis. 2005;191:1014–1017.
    1. Humphreys GS, Merinopoulos I, Ahmed J, Whitty CJ, Mutabingwa TK, Sutherland CJ, Hallett RL. Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrob Agents Chemother. 2007;51:991–997.
    1. Veiga MI, Ferreira PE, Jornhagen L, Malmberg M, Kone A, Schmidt BA, Petzold M, Björkman A, Nosten F, Gil JP. Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance. PloS One. 2011;6:e20212.
    1. Mu J, Ferdig MT, Feng X, Joy DA, Duan J, Furuya T, Subramanian G, Aravind L, Cooper RA, Wooton JC, Xiong M, Su XZ. Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol Microbiol. 2003;49:977–989.
    1. Anderson TJ, Nair S, Qin H, Singlam S, Brockman A, Paiphun L, Nosten F. Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance? Antimicrob Agents Chemother. 2005;49:2180–2188.
    1. Dahlstrom S, Ferreira PE, Veiga MI, Sedighi N, Wiklund L, Martensson A, Färnert A, Sisowath C, Osório L, Darhan H, Andersson B, Kaneko A, Conseil G, Björkman A, Gil P. Plasmodium falciparum multidrug resistance protein 1 and artemisinin-based combination therapy in Africa. J Infect Dis. 2009;200:1456–1464.
    1. Hunt P, Afonso A, Creasey A, Culleton R, Sidhu AB, Logan J, Valderramos SG, McNae I, Cheesman S, do Rosario V, Carter R, Fidock DA, Cravo P. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Mol Microbiol. 2007;65:27–40.
    1. Deplaine G, Lavazec C, Bischoff E, Natalang O, Perrot S, Guillotte-Blisnick M, Coppée JY, Pradines B, Mercereau-Puijalon O, David PH. Artesunate tolerance in transgenic Plasmodium falciparum parasites over-expressing a tryptophan rich protein. Antimicrob Agents Chemother. 2011;55:2576–2584.
    1. Mok S, Imwong M, Mackinnon M, Sim J, Ramadoss R, Yi P, Mayxay M, Chotivanich K, Liong KY, Russell B, Socheat D, Newton PN, Day NP, White NJ, Preiser PR, Nosten F, Dondorp AM, Bozdech Z. Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription. BMC Genomics. 2011;12:391.
    1. Imwong M, Dondorp AM, Nosten F, Yi P, Mungthin M, Hanchana S, Das D, Phyo AP, Lwin KM, Pukrittayakamee S, Lee SJ, Saisung S, Koecharoen K, Nguon C, Day NP, Socheat D, White NJ. Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum. Antimicrob Agents Chemother. 2010;54:2886–2892.
    1. Mu J, Myers RA, Jiang H, Liu S, Ricklefs S, Waisberg M, Chotivanich K, Wilairatana P, Krudsood S, White NJ, Udomsangpetch R, Cui L, Ho M, Ou F, Li H, Song J, Li G, Wang X, Seila S, Sokunthea S, Socheat D, Sturdevant DE, Porcella SF, Fairhurst RM, Wellems TE, Awadalla P, Su XZ. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nat Med. 2010;42:268–271.
    1. Beez D, Sanchez CP, Stein WD, Lanzer M. Genetic predisposition favors the acquisition of stable artemisinin resistance in malaria parasites. Antimicrob Agents Chemother. 2010;55:50–55.
    1. Yuan J, Cheng KC-C, Johnson RL, Huang R, Pattaradilokrat S, Liu A, Guha R, Fidock DA, Inglese J, Wellems TE, Austin CP, Su XZ. Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets. Science. 2011;333:724–729.
    1. Jefford CW, Vicente MGH, Jacquier Y, Favarger F, Mareda J, Millasson-Schmidt P, Brunner G, Burger U. The deoxygenation and isomerization of artemisinin and artemether and their relevance to antimalarial action. Helv Chim Acta. 1996;79:1475–1487.
    1. Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol. 2002;32:1655–1660.
    1. O'Neill PM, Posner GH. A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem. 2004;47:2945–2964.
    1. Robert A, Cazelles J, Meunier B. Characterization of the alkylation product of heme by the antimalarial drug artemisinin. Angew Chem Int Ed. 2001;40:1954–1957.
    1. Hartwig CL, Rosenthal AS, D'Angelo J, Griffin CE, Posner GH, Cooper RA. Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent. Biochem Pharmacol. 2009;77:322–336.
    1. Klonis N, Crespo-Ortiz MP, Bottova I, Abu-Bakar N, Kenny S, Rosenthal PJ, Tilley L. Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci USA. 2011;108:11405–11410.
    1. Kaiser M, Wittlin S, Nehrbass-Stuedli A, Dong Y, Wang X, Hemphill A, Matile H, Brun R, Vennerstrom JL. Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160) Antimicrob Agents Chemother. 2007;51:2991–2993.
    1. Haynes RK, Chan W-C, Wong H-N, Li K-Y, Wu W-K, Fan K-M, Sung HH, Williams ID, Prosperi D, Melato S, Coghi P, Monti D. Facile oxidation of leucomethylene blue and dihydroflavins by artemisinins: relationship with flavoenzyme function and antimalarial mechanism of action. ChemMedChem. 2010;5:1282–1299.
    1. Wang J, Huang L, Li J, Fan Q, Long Y, Li Y, Zhou B. Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS ONE. 2010;5:e9582.
    1. Eckstein-Ludwig U, Webb RJ, van Goethem IDA, East JM, Lee AG, Kimura M, O'Neill PM, Bray PG, Ward SA, Krishna S. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424:957–961.
    1. Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, Ekala MT, Bouchier C, Esterre P, Fandeur T, Mercereau-Puijalon O. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet. 2005;366:1960–1963.
    1. Bhisutthibhan J, Pan X-Q, Hossler PA, Walker DJ, Yowell CA, Carlton J, Dame JB, Meshnick SR. The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J Biol Chem. 1998;273:16192–16198.
    1. Bakar NA, Klonis N, Hanssen E, Chan C, Tilley L. Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum. J Cell Sci. 2010;123:441–450.
    1. Dluzewski AR, Ling IT, Hopkins JM, Grainger M, Margos G, Mitchell GH, Holder AA, Bannister LH. Formation of the food vacuole in Plasmodium falciparum: a potential role for the 19 kDa fragment of merozoite surface protein 1 (MSP1(19)) PLoS ONE. 2008;3:e3085.
    1. Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K, Ruttvisutinunt W, Lin J, Kuntawungin W, Gosi P, Timmermans A, Smith B, Socheat D, Fukuda MM. Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial. PLoS ONE. 2011;6:e19283.
    1. MMV . Medicines for Malaria Venture Concept Note—May 2009. Geneva: Medicines for Malaria Venture; 2009.
    1. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of Artemisinin-Resistant Malaria in Western Cambodia. N Engl J Med. 2008;359:2619–2620.
    1. WWARN Asia Regional Center Activities: Tracking Resistance to Artemisinin Collaboration (TRAC) 2011. Available at. Accessed August 1, 2011.
    1. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379:1960–1966.
    1. Naidoo I, Roper C. Following the path of most resistance: dhps K540E dispersal in African Plasmodium falciparum. Trends Parasitol. 2010;26:447–456.
    1. Mita T, Venkatesan M, Ohashi J, Culleton R, Takahashi N, Tsukahara T, Ndounga M, Dysoley L, Endo H, Hombhanje F, Ferreira MU, Plowe CV, Tanabe K. Limited geographical origin and global spread of sulfadoxine-resistant dhps alleles in Plasmodium falciparum populations. J Infect Dis. 2011;204:1980–1988.
    1. WHO Battling Malaria Drug Resistance Along the Thai-Cambodian Border. Available at. Accessed May 28, 2011.
    1. Meankaew P, Kaewkungwal J, Khamsiriwatchara A, Khunthong P, Singhasivanon P, Satimai W. Application of mobile-technology for disease and treatment monitoring of malaria in the “Better Border Healthcare Programme”. Malar J. 2010;9:237.
    1. WHO . Battling Malaria Drug Resistance Along the Thai-Cambodian Border. Geneva: World Health Organization; Available at. Accessed May 30, 2011.
    1. Maude R, Pontavornpinyo W, Saralamba S, Aguas R, Yeung S, Dondorp A, Day NP, White NJ, White LJ. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J. 2009;8:31.
    1. MalEra Consultative Group on Drugs A research agenda for malaria eradication: drugs. PLoS Med. 2011;8:e1000402.
    1. Song J, Socheat D, Tan B, Dara P, Deng C, Sokunthea S, Seila S, Ou F, Jian H, Li G. Rapid and effective malaria control in Cambodia through mass administration of artemisinin-piperaquine. Malar J. 2010;9:57.
    1. Nayyar GML, Breman JG, Newton PN, Herrington J. Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa. The Lancet Infectious Diseases. 2012;12:488–496.
    1. White NJ. Qinghaosu (artemisinin): the price of success. Science. 2008;320:330–334.
    1. WHO . Essential medicines: regulatory action needed to stop the sale of oral artemisinin-based monotherapy. WHO Drug Information Bulletin. Volume 24. Geneva: World Health Organization; 2010.

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