Volume 98, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Pyronaridine, a Mannich base antimalarial agent with a high activity against chloroquine-resistant , has been combined with artesunate as a new artemisinin based combination therapy (ACT). Pyronaridine–artesunate combination could be one of the choices for the treatment of uncomplicated falciparum malaria in multidrug-resistant areas including Thailand. The aim of this study was to determine in vitro sensitivity and cross-resistance pattern of pyronaridine in Thai isolates of . In addition, the influence of resistant genes concerning in vitro pyronaridine sensitivity was determined. The mean pyronaridine 50% inhibitory concentration (IC) of 118 parasite isolates was 5.6 ± 3.1 nM (range = 0.2–15.4 nM) with a significant positive correlation with artesunate IC ( = 0.246, = 0.008) and amodiaquine IC ( = 0.220, = 0.042) and a significant negative correlation with quinine IC ( = 0.185, = 0.047). Parasites containing the 86Y allele exhibited significantly reduced pyronaridine sensitivity compared with those with the N86 allele (7.6 ± 3.3 nM and 5.4 ± 3.0 nM, respectively, = 0.032, independent test); however, the difference may not be clinically relevant. Pyronaridine–artesunate could be the candidate ACT to treat multidrug-resistant falciparum malaria in Thailand with careful monitoring.


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  1. World Health Organization, 2012. World Malaria Report 2012. Geneva, Switzerland: World Health Organization.
  2. Takala-Harrison S, 2013. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in southeast Asia. Proc Natl Acad Sci USA 110: 240245. [Google Scholar]
  3. Dondorp AM, 2009. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361: 455467. [Google Scholar]
  4. Ashley EA, Tracking Resistance to Artemisinin Collaboration.; , 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 371: 411423. [Google Scholar]
  5. Price RN, 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364: 438447. [Google Scholar]
  6. Chavchich M, Gerena L, Peters J, Chen N, Cheng Q, Kyle DE, , 2010. Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum. Antimicrob Agents Chemother 54: 24552464. [Google Scholar]
  7. Slater HC, Griffin JT, Ghani AC, Okell LC, , 2016. Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa. Malar J 15: 10. [Google Scholar]
  8. Croft SL, Duparc S, Arbe-Barnes SJ, Craft JC, Shin CS, Fleckenstein L, Borghini-Fuhrer I, Rim HJ, , 2012. Review of pyronaridine anti-malarial properties and product characteristics. Malar J 11: 270. [Google Scholar]
  9. Rueangweerayut R, Pyronaridine-Artesunate Study Team , 2012. Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. N Engl J Med 366: 12981309. [Google Scholar]
  10. Kayentao K, 2012. Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. Malar J 11: 364. [Google Scholar]
  11. Poravuth Y, 2011. Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS One 6: e14501. [Google Scholar]
  12. Tshefu AK, Pyronaridine-artesunate Study Team.; , 2010. Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet 375: 14571467. [Google Scholar]
  13. Duparc S, Borghini-Fuhrer I, Craft CJ, Arbe-Barnes S, Miller RM, Shin CS, Fleckenstein L, , 2013. Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malar J 12: 70. [Google Scholar]
  14. Ramharter M, 2008. Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. J Infect Dis 198: 911919. [Google Scholar]
  15. Pradines B, Tall A, Fusai T, Spiegel A, Hienne R, Rogier C, Trape JF, Le Bras J, Parzy D, , 1999. In vitro activities of benflumetol against 158 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs. Antimicrob Agents Chemother 43: 418420. [Google Scholar]
  16. Pradines B, Tall A, Parzy D, Spiegel A, Fusai T, Hienne R, Trape JF, Doury JC, , 1998. In-vitro activity of pyronaridine and amodiaquine against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial agents. J Antimicrob Chemother 42: 333339. [Google Scholar]
  17. Schildbach S, Wernsdorfer WH, Suebsaeng L, Rooney W, , 1990. In vitro sensitivity of multiresistant Plasmodium falciparum to new candidate antimalarial drugs in western Thailand. Southeast Asian J Trop Med Public Health 21: 2938. [Google Scholar]
  18. Warsame M, Wernsdorfer WH, Payne D, Bjorkman A, , 1991. Positive relationship between the response of Plasmodium falciparum to chloroquine and pyronaridine. Trans R Soc Trop Med Hyg 85: 570571. [Google Scholar]
  19. Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, Cowman AF, , 1990. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 345: 255258. [Google Scholar]
  20. Djimde A, 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257263. [Google Scholar]
  21. Duraisingh MT, Jones P, Sambou I, von Seidlein L, Pinder M, Warhurst DC, , 2000. The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Mol Biochem Parasitol 108: 1323. [Google Scholar]
  22. Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF, , 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403: 906909. [Google Scholar]
  23. Setthaudom C, Tan-ariya P, Sitthichot N, Khositnithikul R, Suwandittakul N, Leelayoova S, Mungthin M, , 2011. Role of Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes on in vitro chloroquine resistance in isolates of Plasmodium falciparum from Thailand. Am J Trop Med Hyg 85: 606611. [Google Scholar]
  24. Cowman AF, Galatis D, Thompson JK, , 1994. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc Natl Acad Sci USA 91: 11431147. [Google Scholar]
  25. Wilson CM, Volkman SK, Thaithong S, Martin RK, Kyle DE, Milhous WK, Wirth DF, , 1993. Amplification of pfmdr1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand. Mol Biochem Parasitol 57: 151160. [Google Scholar]
  26. Pickard AL, Wongsrichanalai C, Purfield A, Kamwendo D, Emery K, Zalewski C, Kawamoto F, Miller RS, Meshnick SR, , 2003. Resistance to antimalarials in southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob Agents Chemother 47: 24182423. [Google Scholar]
  27. Sidhu AB, Valderramos SG, Fidock DA, , 2005. pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Mol Microbiol 57: 913926. [Google Scholar]
  28. Uhlemann AC, Ramharter M, Lell B, Kremsner PG, Krishna S, , 2005. Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon. J Infect Dis 192: 18301835. [Google Scholar]
  29. Pradines B, Briolant S, Henry M, Oeuvray C, Baret E, Amalvict R, Didillon E, Rogier C, , 2010. Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum. Malar J 9: 339. [Google Scholar]
  30. Trager W, Jensen JB, , 1976. Human malaria parasites in continuous culture. Science 193: 673675. [Google Scholar]
  31. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD, , 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16: 710718. [Google Scholar]
  32. Wooden J, Kyes S, Sibley CH, , 1993. PCR and strain identification in Plasmodium falciparum. Parasitol Today 9: 303305. [Google Scholar]
  33. Ariey F, 2014. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505: 5055. [Google Scholar]
  34. Vijaykadga S, Rojanawatsirivej C, Cholpol S, Phoungmanee D, Nakavej A, Wongsrichanalai C, , 2006. 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 11: 211219. [Google Scholar]
  35. Looareesuwan S, Kyle DE, Viravan C, Vanijanonta S, Wilairatana P, Wernsdorfer WH, , 1996. Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand. Am J Trop Med Hyg 54: 205209. [Google Scholar]
  36. Childs GE, Hausler B, Milhous W, Chen C, Wimonwattrawatee T, Pooyindee N, Boudreau EF, , 1988. In vitro activity of pyronaridine against field isolates and reference clones of Plasmodium falciparum. Am J Trop Med Hyg 38: 2429. [Google Scholar]
  37. Witkowski B, 2013. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis 13: 10431049. [Google Scholar]
  38. Elueze EI, Croft SL, Warhurst DC, , 1996. Activity of pyronaridine and mepacrine against twelve strains of Plasmodium falciparum in vitro. J Antimicrob Chemother 37: 511518. [Google Scholar]
  39. Pradines B, Mabika Mamfoumbi M, Parzy D, Owono Medang M, Lebeau C, Mourou Mbina JR, Doury JC, Kombila M, , 1999. In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine. Am J Trop Med Hyg 60: 105108. [Google Scholar]
  40. Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B, , 2010. In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax. Antimicrob Agents Chemother 54: 51465150. [Google Scholar]
  41. Okombo J, Kiara SM, Mwai L, Pole L, Ohuma E, Ochola LI, Nzila A, , 2012. Baseline in vitro activities of the antimalarials pyronaridine and methylene blue against Plasmodium falciparum isolates from Kenya. Antimicrob Agents Chemother 56: 11051107. [Google Scholar]
  42. Kurth F, Pongratz P, Belard S, Mordmuller B, Kremsner PG, Ramharter M, , 2009. In vitro activity of pyronaridine against Plasmodium falciparum and comparative evaluation of anti-malarial drug susceptibility assays. Malar J 8: 79. [Google Scholar]
  43. Pascual A, Madamet M, Briolant S, Gaillard T, Amalvict R, Benoit N, Travers D, Pradines B, French National Reference Centre for Imported Malaria Study Group; , 2015. Multinormal in vitro distribution of Plasmodium falciparum susceptibility to piperaquine and pyronaridine. Malar J 14: 49. [Google Scholar]
  44. White NJ, , 2004. Antimalarial drug resistance. J Clin Invest 113: 10841092. [Google Scholar]
  45. Madamet M, Briolant S, Amalvict R, Benoit N, Bouchiba H, Cren J, Pradines B, French National Centre for Imported Malaria Study Group; , 2016. The Plasmodium falciparum chloroquine resistance transporter is associated with the ex vivo P. falciparum African parasite response to pyronaridine. Parasit Vectors 9: 77. [Google Scholar]
  46. Leang R, 2015. Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western Cambodia: dihydroartemisinin-piperaquine open-label multicenter clinical assessment. Antimicrob Agents Chemother 59: 47194726. [Google Scholar]
  47. Amaratunga C, 2016. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis 16: 357365. [Google Scholar]
  48. Mungthin M, Suwandittakul N, Chaijaroenkul W, Rungsrihirunrat K, Harnyuttanakorn P, Seugorn A, Na Bangchang K, , 2010. The patterns of mutation and amplification of Plasmodium falciparum pfcrt and pfmdr1 genes in Thailand during the year 1988 to 2003. Parasitol Res 107: 539545. [Google Scholar]
  49. Mungthin M, Intanakom S, Suwandittakul N, Suida P, Amsakul S, Sitthichot N, Thammapalo S, Leelayoova S, , 2014. Distribution of pfmdr1 polymorphisms in Plasmodium falciparum isolated from southern Thailand. Malar J 13: 117. [Google Scholar]

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  • Received : 06 Apr 2017
  • Accepted : 23 Aug 2017
  • Published online : 23 Oct 2017

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