Correspondence
Evidence of Artemisinin-Resistant Malaria in Western Cambodia
N Engl J Med 2008; 359:2619-2620December 11, 2008
- Article
To the Editor:
Although artemisinins are potent and rapidly acting antimalarial drugs, their widespread use for treating patients with Plasmodium falciparum malaria raises the question of emerging drug resistance.1,2 Artemisinin monotherapy should not be used in areas where malaria is endemic; it requires an extended administration period and may lead to treatment failure, most frequently because of problems with compliance. Recent reports of high failure rates associated with artemisinin-based combination therapy, as well as in vitro drug-susceptibility data, suggest the possibility of clinical artemisinin resistance along the Thai–Cambodian border.3,4 We studied the potential emergence of artemisinin resistance using in vivo, in vitro, molecular, and pharmacokinetic methods specifically designed to address the question of potential artemisinin resistance.
We randomly assigned, in a ratio of 2:1, 94 adults from Battambang Province presenting with uncomplicated P. falciparum malaria (100 to 100,000 parasites per microliter) to receive either high-dose artesunate therapy (4 mg per kilogram of body weight per day, orally, for 7 days) (60 patients) or quinine (30 mg per kilogram per day) plus tetracycline (25 mg per kilogram per day) in a split dose every 8 hours for 7 days (34 patients). The study was approved by ethics review committees in Cambodia and the United States and was conducted from October 2006 through March 2007. Written informed consent was obtained from all study participants.
Patients were admitted for 28 days to rule out reinfection. The clinical outcome was recorded, plasma drug concentrations and in vitro drug susceptibility were measured, and molecular assays were performed to investigate genetic resistance markers and to rule out reinfection. Only patients who met all the following criteria were classified as having artemisinin-resistant infection: persistence of parasites 7 days after the start of treatment or reemergence of parasites within 28 days after the start of treatment; adequate plasma concentrations of dihydroartemisinin, a major artemisinin metabolite; prolonged time to parasite clearance; and reduced in vitro susceptibility to dihydroartemisinin.5
Four of the 60 patients who received artesunate had reemergence of parasitemia between days 21 and 28 after the start of treatment (with a Kaplan–Meier probability estimate for cure at day 28 of 93.6%; 95% confidence interval [CI], 84.7 to 97.7); 2 of these patients (3.3%) were classified as having artemisinin-resistant infection, according to the criteria listed above (Figure 1AFigure 1
Parasite Density, Parasite-Clearance Time, and 50% Inhibitory Concentration (IC50) among Patients Receiving Artesunate, According to Clinical Outcome.). These two patients had parasite-clearance times that were prolonged (133 and 95 hours, as compared with a median of 52.2 hours for patients who were cured), and the plasma drug concentrations after the first dose were classified as adequate (greater than the mean for the cured patients minus 1 SD) (see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). For these subjects, the 50% inhibitory concentrations for dihydroartemisinin were up to 4 times the geometric mean for cured patients and almost 10 times that for the reference clone W2. In the artesunate group, 47.9% (95% CI, 36.1 to 60.0) of the patients still had parasitemia 48 hours after the start of treatment, as did 21.9% (95% CI, 13.1 to 33.1) 72 hours after the start of treatment. Clinical and in vitro data suggest that artemisinin resistance may be more accurately portrayed as the long tail of a single distribution than as the result of a sudden change in sensitivity (Figure 1B). Resistance did not appear to be mediated by the number of copies of the P. falciparum multidrug resistance gene pfmdr1 or selected PfATPase6 polymorphisms tested in this study.The high overall treatment efficacy seen in patients treated with artesunate indicates that relatively few parasite isolates have crossed the threshold of artemisinin resistance as defined in our study. Artemisinin resistance does not seem to be a widespread epidemiologic phenomenon at this time. The prolonged parasite-clearance times and the two cases meeting our definition of artesunate resistance are nonetheless a concern.
Harald Noedl, M.D., Ph.D.
Medical University of Vienna, A-1090 Vienna, Austria
harald.noedl@meduniwien. ac. at Youry Se, M.D.
Kurt Schaecher, Ph.D.
Bryan L. Smith, M.D.
Armed Forces Research Institute of Medical Sciences, Bangkok 10400, ThailandDuong Socheat, M.D.
National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, CambodiaMark M. Fukuda, M.D.
Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailandfor the Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium
Supported by the U.S. Department of Defense Global Emerging Infections System Program. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
5 References1
Duffy PE ,Sibley CH . Are we losing artemisinin combination therapy already? Lancet 2005;366:1908-1909
CrossRef | Web of Science | Medline2
Krishna S ,Bustamante L ,Haynes RK ,Staines HM . Artemisinins: their growing importance in medicine. Trends Pharmacol Sci 2008;29:520-527
CrossRef | Web of Science | Medline3
Jambou R ,Legrand E ,Niang M , et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 2005;366:1960-1963
CrossRef | Web of Science | Medline4
Vijaykadga S ,Rojanawatsirivej C ,Cholpol S ,Phoungmanee D ,Nakavej A ,Wongsrichanalai C . In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health 2006;11:211-219
CrossRef | Web of Science | Medline5
Noedl H . Artemisinin resistance: how can we find it? Trends Parasitol 2005;21:404-405
CrossRef | Web of Science | Medline
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CrossRef22
Samuel Jacob Inbaneson, Sundaram Ravikumar. (2011) In vitro antiplasmodial activity of marine sponge Hyattella intestinalis associated bacteria against Plasmodium falciparum. Asian Pacific Journal of Tropical Biomedicine 1:1, S100-S104
CrossRef23
J. Yuan, K. C.-C. Cheng, R. L. Johnson, R. Huang, S. Pattaradilokrat, A. Liu, R. Guha, D. A. Fidock, J. Inglese, T. E. Wellems, C. P. Austin, X.-z. Su. (2011) Chemical Genomic Profiling for Antimalarial Therapies, Response Signatures, and Molecular Targets. Science 333:6043, 724-729
CrossRef24
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CrossRef26
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CrossRef27
Thomas Seebeck, Geert Jan Sterk, Hengming Ke. (2011) Phosphodiesterase inhibitors as a new generation of antiprotozoan drugs: exploiting the benefit of enzymes that are highly conserved between host and parasite. Future Medicinal Chemistry 3:10, 1289-1306
CrossRef28
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CrossRef30
Henry M Staines, Simon L Croft, Paul D Horrocks. (2011) Developing novel strategies to prevent parasitic infections. Expert Review of Anti-infective Therapy 9:7, 783-785
CrossRef31
Lin H. Chen. (2011) Clinical Trial Report: Double-Dose Chloroquine for Treatment of Plasmodium falciparum Malaria in Guinea-Bissau. Current Infectious Disease Reports 13:3, 205-206
CrossRef32
Grace O Gbotosho, Titilope M Okuboyejo, Christian T Happi, Akintunde Sowunmi. (2011) Plasmodium falciparum hyperparasitaemia in Nigerian children: epidemiology, clinical characteristics, and therapeutic responses to oral artemisinin-based combination treatments. Asian Pacific Journal of Tropical Disease 1:2, 85-93
CrossRef33
Case McNamara, Elizabeth A Winzeler. (2011) Target identification and validation of novel antimalarials. Future Microbiology 6:6, 693-704
CrossRef34
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CrossRef36
Tzu-Shean Feng, Eric M. Guantai, Margo J. Nell, Constance E.J. van Rensburg, Heinrich C. Hoppe, Kelly Chibale. (2011) Antiplasmodial and antitumor activity of dihydroartemisinin analogs derived via the aza-Michael addition reaction. Bioorganic & Medicinal Chemistry Letters 21:10, 2882-2886
CrossRef37
P. Murambiwa, B. Masola, T. Govender, S. Mukaratirwa, C.T. Musabayane. (2011) Anti-malarial drug formulations and novel delivery systems: A review. Acta Tropica 118:2, 71-79
CrossRef38
Vincent K. Zishiri, Roger Hunter, Peter J. Smith, Dale Taylor, Robert Summers, Kiaran Kirk, Rowena E. Martin, Timothy J. Egan. (2011) A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT. European Journal of Medicinal Chemistry 46:5, 1729-1742
CrossRef39
Jana Held, Shahid A. Soomro, Peter G. Kremsner, F. Herwig Jansen, Benjamin Mordmüller. (2011) In vitro activity of new artemisinin derivatives against Plasmodium falciparum clinical isolates from Gabon. International Journal of Antimicrobial Agents 37:5, 485-488
CrossRef40
Charles E. Schiaffo, Matthias Rottman, Sergio Wittlin, Patrick H. Dussault. (2011) 3-Alkoxy-1,2-Dioxolanes: Synthesis and Evaluation as Potential Antimalarial Agents. ACS Medicinal Chemistry Letters 2:4, 316-319
CrossRef41
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CrossRef42
Ann H Kelly, Uli Beisel. (2011) Neglected malarias: The frontlines and back alleys of global health. BioSocieties 6:1, 71-87
CrossRef43
J.W. Gathirwa, G.M. Rukunga, P.G. Mwitari, N.M. Mwikwabe, C.W. Kimani, C.N. Muthaura, D.M. Kiboi, R.M. Nyangacha, S.A. Omar. (2011) Traditional herbal antimalarial therapy in Kilifi district, Kenya. Journal of Ethnopharmacology 134:2, 434-442
CrossRef44
John N. Alumasa, Alexander P. Gorka, Leah B. Casabianca, Erica Comstock, Angel C. de Dios, Paul D. Roepe. (2011) The hydroxyl functionality and a rigid proximal N are required for forming a novel non-covalent quinine-heme complex. Journal of Inorganic Biochemistry 105:3, 467-475
CrossRef45
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CrossRef46
B. S. Franklin, S. T. Ishizaka, M. Lamphier, F. Gusovsky, H. Hansen, J. Rose, W. Zheng, M. A. Ataide, R. B. de Oliveira, D. T. Golenbock, R. T. Gazzinelli. (2011) Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Proceedings of the National Academy of Sciences 108:9, 3689-3694
CrossRef47
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CrossRef48
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CrossRef49
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CrossRef50
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CrossRef51
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CrossRef52
Jakob P Cramer, Rogelio López-Vélez, Gerd D Burchard, Martin P Grobusch, Peter J de Vries. (2011) Treatment of imported severe malaria with artesunate instead of quinine - more evidence needed?. Malaria Journal 10:1, 256
CrossRef53
Anne EP Frosch, Meera Venkatesan, Miriam K Laufer. (2011) Patterns of chloroquine use and resistance in sub-Saharan Africa: a systematic review of household survey and molecular data. Malaria Journal 10:1, 116
CrossRef54
Sachel Mok, Mallika Imwong, Margaret J Mackinnon, Joan Sim, Ramya Ramadoss, Poravuth Yi, Mayfong Mayxay, Kesinee Chotivanich, Kek-Yee Liong, Bruce Russell, Duong Socheat, Paul N Newton, Nicholas PJ Day, Nicholas J White, Peter R Preiser, François Nosten, Arjen M Dondorp, Zbynek Bozdech. (2011) Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription. BMC Genomics 12:1, 391
CrossRef55
Bruno Pradines, Lionel Bertaux, Christelle Pomares, Pascal Delaunay, Pierre Marty. (2011) Reduced in vitro susceptibility to artemisinin derivatives associated with multi-resistance in a traveller returning from South-East Asia. Malaria Journal 10:1, 268
CrossRef56
Mark M Fukuda, Terry A Klein, Tadeusz Kochel, Talia M Quandelacy, Bryan L Smith, Jeff Villinski, Delia Bethell, Stuart Tyner, Youry Se, Chanthap Lon, David Saunders, Jacob Johnson, Eric Wagar, Douglas Walsh, Matthew Kasper, Jose L Sanchez, Clara J Witt, Qin Cheng, Norman Waters, Sanjaya K Shrestha, Julie A Pavlin, Andres G Lescano, Paul CF Graf, Jason H Richardson, Salomon Durand, William O Rogers, David L Blazes, Kevin L Russell, . (2011) Malaria and other vector-borne infection surveillance in the U.S. Department of Defense Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance program: review of 2009 accomplishments. BMC Public Health 11:Suppl 2, S9
CrossRef57
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CrossRef58
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CrossRef60
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CrossRef61
Charles J. Woodrow, Leyla Y. Bustamante. (2011) Mechanisms of artemisinin action and resistance: wider focus is needed. Trends in Parasitology 27:1, 2-3
CrossRef62
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CrossRef63
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CrossRef64
Ksenija Slavic, Sanjeev Krishna, Elvira T Derbyshire, Henry M Staines. (2011) Plasmodial sugar transporters as anti-malarial drug targets and comparisons with other protozoa. Malaria Journal 10:1, 165
CrossRef65
Jimee Hwang, Bereket H Alemayehu, David Hoos, Zenebe Melaku, Samuel G Tekleyohannes, Takele Teshi, Sintayehu G Birhanu, Leykun Demeke, Kedir Gobena, Moges Kassa, Daddi Jima, Richard Reithinger, Henry Nettey, Michael Green, Joseph L Malone, S Patrick Kachur, Scott Filler. (2011) In vivo efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria in Central Ethiopia. Malaria Journal 10:1, 209
CrossRef66
Ana Carolina AV Kayano, Stefanie CP Lopes, Fernanda G Bueno, Elaine C Cabral, Wanessa C Souza-Neiras, Lucy M Yamauchi, Mary A Foglio, Marcos N Eberlin, João Mello, Fabio TM Costa. (2011) In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa. Malaria Journal 10:1, 112
CrossRef67
Jose L Sanchez, Matthew C Johns, Ronald L Burke, Kelly G Vest, Mark M Fukuda, In-Kyu Yoon, Chanthap Lon, Miguel Quintana, David C Schnabel, Guillermo Pimentel, Moustafa Mansour, Steven Tobias, Joel M Montgomery, Gregory C Gray, Karen Saylors, Lucy M Ndip, Sheri Lewis, Patrick J Blair, Paul A Sjoberg, Robert A Kuschner, Kevin L Russell, David L Blazes, . (2011) Capacity-building efforts by the AFHSC-GEIS program. BMC Public Health 11:Suppl 2, S4
CrossRef68
Eric M. Guantai, Kanyile Ncokazi, Timothy J. Egan, Jiri Gut, Philip J. Rosenthal, Peter J. Smith, Kelly Chibale. (2010) Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds. Bioorganic & Medicinal Chemistry 18:23, 8243-8256
CrossRef69
Ingrid B Müller, John E Hyde. (2010) Antimalarial drugs: modes of action and mechanisms of parasite resistance. Future Microbiology 5:12, 1857-1873
CrossRef70
Sanjeev Krishna, Serena Pulcini, Farrah Fatih, Henry Staines. (2010) Artemisinins and the biological basis for the PfATP6/SERCA hypothesis. Trends in Parasitology 26:11, 517-523
CrossRef71
Alexander Leeb, Gunther Wernsdorfer, Wichai Satimai, Ursula Wiedermann, Kanungnit Congpuong, Walther H. Wernsdorfer. (2010) Pharmacodynamic interaction between lumefantrine and desbutyl-benflumetol in Plasmodium falciparum in vitro. Wiener klinische Wochenschrift 122:S3, 61-65
CrossRef72
Felix Hüttinger, Wichai Satimai, Gunther Wernsdorfer, Ursula Wiedermann, Kanungnit Congpuong, Walther H. Wernsdorfer. (2010) Sensitivity to artemisinin, mefloquine and quinine of Plasmodium falciparum in northwestern Thailand. Wiener klinische Wochenschrift 122:S3, 52-56
CrossRef73
Martin Peter Grobusch, Michèle van Vugt. (2010) Malaria therapy: where do we stand, what next?. Future Microbiology 5:10, 1447-1449
CrossRef74
David C. Smithson, W. Armand Guiguemde, R. Kiplin Guy. 2010. Antimalarials. .
CrossRef75
M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B. Zou, B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B. Cohen, K. R. Spencer, G. E. Gonzalez-Paez, S. B. Lakshminarayana, A. Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock, E. A. Winzeler, T. T. Diagana. (2010) Spiroindolones, a Potent Compound Class for the Treatment of Malaria. Science 329:5996, 1175-1180
CrossRef76
Cecilia P. Sanchez, Anurag Dave, Wilfred D. Stein, Michael Lanzer. (2010) Transporters as mediators of drug resistance in Plasmodium falciparum. International Journal for Parasitology 40:10, 1109-1118
CrossRef77
Bhavna Gupta, Gauri Awasthi, Aparup Das. (2010) Malaria parasite genome scan: insights into antimalarial resistance. Parasitology Research 107:2, 495-499
CrossRef78
Henry M. Staines, Elvira T. Derbyshire, Ksenija Slavic, Amanda Tattersall, Henri Vial, Sanjeev Krishna. (2010) Exploiting the therapeutic potential of Plasmodium falciparum solute transporters. Trends in Parasitology 26:6, 284-296
CrossRef79
Guillaume Marti, Véronique Eparvier, Christian Moretti, Soizic Prado, Philippe Grellier, Nathalie Hue, Odile Thoison, Bernard Delpech, Françoise Guéritte, Marc Litaudon. (2010) Antiplasmodial benzophenone derivatives from the root barks of Symphonia globulifera (Clusiaceae). Phytochemistry 71:8-9, 964-974
CrossRef80
Patrícia Machado, Rui Pereira, Ana Mafalda Rocha, Licínio Manco, Natércia Fernandes, Juliana Miranda, Letícia Ribeiro, Virgílio E. Do Rosário, António Amorim, Leonor Gusmão, Ana Paula Arez. (2010) Malaria: looking for selection signatures in the human PKLR gene region. British Journal of Haematology 149:5, 775-784
CrossRef81
Jessica T. Lin, Jonathan J. Juliano, Chansuda Wongsrichanalai. (2010) Drug-Resistant Malaria: The Era of ACT. Current Infectious Disease Reports 12:3, 165-173
CrossRef82
N. B. Quashie. (2010) Detection of Artemisinin-resistant Plasmodium falciparum in Malarial Infection: A Brief Review of Methods. Journal of Tropical Pediatrics 56:2, 119-121
CrossRef83
Rina P. M. Wong, Dulcie Lautu, Livingstone Tavul, Sara L. Hackett, Peter Siba, Harin A. Karunajeewa, Kenneth F. Ilett, Ivo Mueller, Timothy M. E. Davis. (2010) In vitro sensitivity of Plasmodium falciparum to conventional and novel antimalarial drugs in Papua New Guinea. Tropical Medicine & International Health 15:3, 342-349
CrossRef84
Ksenija Slavic, Ursula Straschil, Luc Reininger, Christian Doerig, Christophe Morin, Rita Tewari, Sanjeev Krishna. (2010) Life cycle studies of the hexose transporter of Plasmodium species and genetic validation of their essentiality. Molecular Microbiology 75:6, 1402-1413
CrossRef85
Jianbing Mu, Rachel A Myers, Hongying Jiang, Shengfa Liu, Stacy Ricklefs, Michael Waisberg, Kesinee Chotivanich, Polrat Wilairatana, Srivicha Krudsood, Nicholas J White, Rachanee Udomsangpetch, Liwang Cui, May Ho, Fengzhen Ou, Haibo Li, Jianping Song, Guoqiao Li, Xinhua Wang, Suon Seila, Sreng Sokunthea, Duong Socheat, Daniel E Sturdevant, Stephen F Porcella, Rick M Fairhurst, Thomas E Wellems, Philip Awadalla, Xin-zhuan Su. (2010) Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nature Genetics 42:3, 268-271
CrossRef86
Johan van Griensven, Manica Balasegaram, Filip Meheus, Jorge Alvar, Lutgarde Lynen, Marleen Boelaert. (2010) Combination therapy for visceral leishmaniasis. The Lancet Infectious Diseases 10:3, 184-194
CrossRef87
Hayder A. Giha. (2010) Artemisinin derivatives for treatment of uncomplicated Plasmodium falciparum malaria in Sudan: too early for too much hope. Parasitology Research 106:3, 549-552
CrossRef88
Wanna Chaijaroenkul, Raewadee Wisedpanichkij, Kesara Na-Bangchang. (2010) Monitoring of in vitro susceptibilities and molecular markers of resistance of Plasmodium falciparum isolates from Thai-Myanmar border to chloroquine, quinine, mefloquine and artesunate. Acta Tropica 113:2, 190-194
CrossRef89
Stéphanie Ortial, Séverine Denoyelle, Sharon Wein, Olivier Berger, Thierry Durand, Roger Escale, Alain Pellet, Henri Vial, Yen Vo-Hoang. (2010) Synthesis and Evaluation of Hybrid Bis-cationic Salts as Antimalarial Drugs. ChemMedChem 5:1, 52-55
CrossRef90
Cosima Chrubasik, Raymond L. Jacobson. (2010) The development of artemisinin resistance in malaria: reasons and solutions. Phytotherapy Researchn/a-n/a
CrossRef91
Jürgen FJ Kun, Jürgen May, Harald Noedl. (2010) Surveillance of malaria drug resistance: improvement needed?. Therapy 7:1, 3-6
CrossRef92
Tina S. Skinner-Adams, Colin M. Stack, Katharine R. Trenholme, Chris L. Brown, Jolanta Grembecka, Jonathan Lowther, Artur Mucha, Marcin Drag, Pawel Kafarski, Sheena McGowan, James C. Whisstock, Donald L. Gardiner, John P. Dalton. (2010) Plasmodium falciparum neutral aminopeptidases: new targets for anti-malarials. Trends in Biochemical Sciences 35:1, 53-61
CrossRef93
Sang Hyun Park, Kannampalli Pradeep. (2010) Absorption, Distribution, Excretion, and Pharmacokinetics of C14-Pyronaridine Tetraphosphate in Male and Female Sprague-Dawley Rats. Journal of Biomedicine and Biotechnology 2010, 1-10
CrossRef94
A. Enayati, J. Hemingway. (2010) Malaria Management: Past, Present, and Future. Annual Review of Entomology 55:1, 569-591
CrossRef95
Philippe J Guerin, Sarah J Bates, Carol H Sibley. (2009) Global resistance surveillance: ensuring antimalarial efficacy in the future. Current Opinion in Infectious Diseases 22:6, 593-600
CrossRef96
Harald Noedl. (2009) ABC - antibiotics-based combinations for the treatment of severe malaria?. Trends in Parasitology 25:12, 540-544
CrossRef97
Tao Wu, Advait Nagle, Tomoyo Sakata, Kerstin Henson, Rachel Borboa, Zhong Chen, Kelli Kuhen, David Plouffe, Elizabeth Winzeler, Francisco Adrian, Tove Tuntland, Jonathan Chang, Susan Simerson, Steven Howard, Jared Ek, John Isbell, Xianming Deng, Nathanael S. Gray, David C. Tully, Arnab K. Chatterjee. (2009) Cell-based optimization of novel benzamides as potential antimalarial leads. Bioorganic & Medicinal Chemistry Letters 19:24, 6970-6974
CrossRef98
Panan Kanchanaphum, Jerapan Krungkrai. (2009) Kinetic benefits and thermal stability of orotate phosphoribosyltransferase and orotidine 5′-monophosphate decarboxylase enzyme complex in human malaria parasite Plasmodium falciparum. Biochemical and Biophysical Research Communications 390:2, 337-341
CrossRef99
Desmond Slade, Ahmed M. Galal, Waseem Gul, Mohamed M. Radwan, Safwat A. Ahmed, Shabana I. Khan, Babu L. Tekwani, Melissa R. Jacob, Samir A. Ross, Mahmoud A. ElSohly. (2009) Antiprotozoal, anticancer and antimicrobial activities of dihydroartemisinin acetal dimers and monomers. Bioorganic & Medicinal Chemistry 17:23, 7949-7957
CrossRef100
Dominique Mazier, Laurent Rénia, Georges Snounou. (2009) A pre-emptive strike against malaria's stealthy hepatic forms. Nature Reviews Drug Discovery 8:11, 854-864
CrossRef101
Timothy N. C. Wells, Pedro L. Alonso, Winston E. Gutteridge. (2009) New medicines to improve control and contribute to the eradication of malaria. Nature Reviews Drug Discovery 8:11, 879-891
CrossRef102
Pragyan Acharya, Rani Pallavi, Syama Chandran, Harshini Chakravarti, Sheetal Middha, Jyoti Acharya, Sanjay Kochar, Dhanpat Kochar, Amit Subudhi, Arun P. Boopathi, Shilpi Garg, Ashis Das, Utpal Tatu. (2009) A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivax. PROTEOMICS
CLINICAL APPLICATIONS 3:11, 1314-1325
CrossRef103
Patricia Schlagenhauf, Eskild Petersen. (2009) Antimalaria drug resistance: the mono–combi–counterfeit triangle. Expert Review of Anti-infective Therapy 7:9, 1039-1042
CrossRef104
Jing Yuan, Ronald L Johnson, Ruili Huang, Jennifer Wichterman, Hongying Jiang, Karen Hayton, David A Fidock, Thomas E Wellems, James Inglese, Christopher P Austin, Xin-zhuan Su. (2009) Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum. Nature Chemical Biology 5:10, 765-771
CrossRef105
Maria Gruber, Gunther Wernsdorfer, Wichai Satimai, Ursula Wiedermann, Kanungnit Congpuong, Walther H. Wernsdorfer. (2009) Pharmacodynamic interaction between mefloquine and retinol in Plasmodium falciparum in vitro. Wiener klinische Wochenschrift 121:S3, 27-31
CrossRef106
Liwang Cui, Xin-zhuan Su. (2009) Discovery, mechanisms of action and combination therapy of artemisinin. Expert Review of Anti-infective Therapy 7:8, 999-1013
CrossRef107
Michela Menegon, Richard J. Pearce, Walter O. Inojosa, Vincenzo Pisani, Paulo M. Abel, Alexandre Matondo, Zeno Bisoffi, Giancarlo Majori, Rosalynn Ord, David C. Warhurst, Cally Roper, Carlo Severini. (2009) Monitoring for multidrug-resistant Plasmodium falciparum isolates and analysis of pyrimethamine resistance evolution in Uige province, Angola. Tropical Medicine & International Health 14:10, 1251-1257
CrossRef108
Miguel Prudêncio, Elvira T. Derbyshire, Catarina A. Marques, Sanjeev Krishna, Maria M. Mota, Henry M. Staines. (2009) Plasmodium berghei -infection induces volume-regulated anion channel-like activity in human hepatoma cells. Cellular Microbiology 11:10, 1492-1501
CrossRef109
Thomas E. Wellems, Karen Hayton, Rick M. Fairhurst. (2009) The impact of malaria parasitism: from corpuscles to communities. Journal of Clinical Investigation 119:9, 2496-2505
CrossRef110
Kesara Na-Bangchang. (2009) Pharmacodynamics of antimalarial chemotherapy. Expert Review of Clinical Pharmacology 2:5, 491-515
CrossRef111
Kesara Na-Bangchang, Juntra Karbwang. (2009) Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and development. Fundamental & Clinical Pharmacology 23:4, 387-409
CrossRef112
Visweswaran Navaratnam, Surash Ramanathan, Mohd Suhaimi Ab. Wahab, Gan Siew Hua, Sharif Mahsufi Mansor, Jean-René Kiechel, Michel Vaillant, Walter R. J. Taylor, Piero Olliaro. (2009) Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers. European Journal of Clinical Pharmacology 65:8, 809-821
CrossRef113
Markus Jensen, Heinz Mehlhorn. (2009) Seventy-five years of Resochin® in the fight against malaria. Parasitology Research 105:3, 609-627
CrossRef114
George O Adjei, Bamenla Q Goka, Fred Binka, Jorgen AL Kurtzhals. (2009) Artemether–lumefantrine: an oral antimalarial for uncomplicated malaria in children. Expert Review of Anti-infective Therapy 7:6, 669-681
CrossRef115
Timothy J Egan. (2009) Artemisinin-resistant Plasmodium falciparum : can the genie be put back in the bottle?. Future Microbiology 4:6, 637-639
CrossRef116
Dondorp, Arjen M., Nosten, François, Yi, Poravuth, Das, Debashish, Phyo, Aung Phae, Tarning, Joel, Lwin, Khin Maung, Ariey, Frederic, Hanpithakpong, Warunee, Lee, Sue J., Ringwald, Pascal, Silamut, Kamolrat, Imwong, Mallika, Chotivanich, Kesinee, Lim, Pharath, Herdman, Trent, An, Sen SamYeung, Shunmay, Singhasivanon, Pratap, Day, Nicholas P.J., Lindegardh, Niklas, Socheat, Duong, White, Nicholas J., . (2009) Artemisinin Resistance in Plasmodium falciparum Malaria. New England Journal of Medicine 361:5, 455-467
Full Text117
Noedl, Harald, , Socheat, Duong, , Satimai, Wichai, . (2009) Artemisinin-Resistant Malaria in Asia. New England Journal of Medicine 361:5, 540-541
Full Text118
Katharine Sanderson. (2009) Malaria becoming more drug resistant. Nature
CrossRef119
Irene Kuepfer, Christian Burri. (2009) Reflections on clinical research in sub-Saharan Africa. International Journal for Parasitology 39:9, 947-954
CrossRef120
P Olliaro, TNC Wells. (2009) The Global Portfolio of New Antimalarial Medicines Under Development. Clinical Pharmacology & Therapeutics 85:6, 584-595
CrossRef121
Paul D Roepe. (2009) Molecular and physiologic basis of quinoline drug resistance in Plasmodium falciparum malaria. Future Microbiology 4:4, 441-455
CrossRef122
MARK A. TRAVASSOS, MIRIAM K. LAUFER. (2009) Resistance to Antimalarial Drugs: Molecular, Pharmacologic, and Clinical Considerations. Pediatric Research 65:Supplement, 64R-70R
CrossRef123
Martin P Grobusch. (2009) Early rectal artesunate administration: a life-saver in remote areas?. Future Microbiology 4:4, 397-400
CrossRef124
Benoit Witkowski, Antoine Berry, Françoise Benoit-Vical. (2009) Resistance to antimalarial compounds: Methods and applications. Drug Resistance Updates 12:1-2, 42-50
CrossRef125
Richard J. Maude, Charles J. Woodrow, Lisa J. White. (2009) Artemisinin antimalarials: preserving the âmagic bulletâ. Drug Development Researchn/a-n/a
CrossRef126
Francis W. Muregi, Akira Ishih. (2009) Next-generation antimalarial drugs: hybrid molecules as a new strategy in drug design. Drug Development Researchn/a-n/a
CrossRef127
John R. Gallagher, Sean T. Prigge. (2009) Plasmodium falciparum acyl carrier protein crystal structures in disulfide-linked and reduced states and their prevalence during blood stage growth. Proteins: Structure, Function, and BioinformaticsNA-NA
CrossRef
