Skip to main content
Log in

Artemisinin-based combination therapies and their introduction in Japan

  • Review Article
  • Published:
Journal of Infection and Chemotherapy

Abstract

Artemisinin was discovered in 1971 from a herb, Artemisia annua, which had been used for more than 2,000 years in China against intermittent fever. Now, the artemisinin and its derivatives have become essential components of artemisinin-based combination therapies (ACTs). The ACTs are the recommended first-line treatments of malaria because they are effective against all four human malarias, produce rapid parasite/fever clearance, and show fewer adverse effects. Some ACTs are particularly important in cases of severe and complicated falciparum malaria, including cerebral malaria. However, neither the artemisinin and its derivatives nor any ACTs are registered in Japan. Indeed, the only licensed drugs for the treatment of malaria in Japan are quinine, mefloquine, and sulfadoxine/pyrimethamine. Although indigenous malaria has been eradicated in Japan since 1959, 60–100 imported malaria cases have been reported annually for the past decade. Some of the patients were, in fact, dying of the severe complications. Thus, the introduction of the ACTs and their application to imported malaria patients in Japan are urgently needed. A few clinical studies using the ACTs have been reported in Japan. The first application of an ACT, intramuscular artemether plus mefloquine, was reported in 1988 to be very effective against cerebral malaria with coma. Five cases with intravenous artesunate plus mefloquine were reported through 2001–2007, for severe or drug-resistant falciparum cases, resulting in successful treatment with some side effects such as hemolytic anemia or postmalaria neurological syndrome. Currently, a fixed-dose ACT, artemether–lumefantrine, is prescribed successfully for uncomplicated falciparum cases, with a limited number of recrudescences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. WHO Library Cataloguing-in-Publication Data. Impact of malaria control. In: World Malaria Report 2009. Geneva: WHO Press; 2009. p. 27–44.

  2. WHO Library Cataloguing-in-Publication Data. Antimalarial treatment policy. In: Guidelines for the treatment of malaria. 2nd ed. Geneva: Global Malaria Programme WHO; 2010. p. 8–9.

  3. Duffy PE, Mutabingwa TK. Drug combinations for malaria: time to ACT? Lancet. 2004;363:3–4.

    Article  PubMed  Google Scholar 

  4. Hsu E. The history of qing hao in the Chinese Materia Medica. Trans R Soc Trop Med Hyg. 2006;100:505–8.

    Article  CAS  PubMed  Google Scholar 

  5. WHO Library Cataloguing-in-Publication Data. Resistance to antimalarial medicines. In: Guidelines for the treatment of malaria. 2nd ed. Geneva: Global Malaria Programme WHO; 2010. p. 122–33.

  6. Ge H. Zhou hou bei ji fang (Emergency Prescriptions kept in one’s sleeve). In: Si ku quan shu (Collection of the works from the four storehouses, chap 3.16, Jin, 4th Century CE). References to Wen yuan ge Si ku quan shu. Taibei: Shangwu yinshuguan; 1983.

  7. Li S. Ben cao gang mu (Classified Materia Medica, Ming, 1596). vol. 4. Beijing: Renmin weisheng chubanshe; 1977–81.

  8. Qinghaosu Antimalarial Coordinating Research Group. Antimalarial studies on Qinghaosu. Chin Med J. 1979;92:811–6.

    Google Scholar 

  9. Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228:1049–55.

    Article  CAS  PubMed  Google Scholar 

  10. Jiang JB, Li GQ, Guo XB, Kong YC, Arnold K. Antimalarial activity of mefloquine and qinghaosu. Lancet. 1982;2:285–8.

    Article  CAS  PubMed  Google Scholar 

  11. Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol. 2002;32:1655–60.

    Article  CAS  PubMed  Google Scholar 

  12. Arreesrisom P, Dondorp AM, Looareesuwan S, Udomsangpetch R. Suppressive effects of the anti-oxidant N-acetylcysteine on the anti-malarial activity of artesunate. Parasitol Int. 2007;56:221–6.

    Article  CAS  PubMed  Google Scholar 

  13. Wright CW, Warhurst DC. The mode of action of artemisinin and its derivatives. In: Write CW, editor. Artemisia. New York: Taylor & Francis; 2002. p. 249–88.

    Chapter  Google Scholar 

  14. Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, et al. Artemisinin targets the SERCA of Plasmodium falciparum. Nature (Lond). 2003;424:957–61.

    Article  CAS  Google Scholar 

  15. Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, et al. Resistance of Plasmodium falciparum field isolates to in vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet. 2005;366:1960–3.

    Article  CAS  PubMed  Google Scholar 

  16. Ashton M, Nguyen DS, Nguyen VH, Gordi T, Trinh NH, Dinh XH, et al. Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria. Clin Pharmacol Ther. 1998;63:482–93.

    Article  CAS  PubMed  Google Scholar 

  17. Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DX, Phu NH, et al. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimcrob Agents Chemother. 2004;48:4234–9.

    Article  CAS  Google Scholar 

  18. Price R, van Vugt M, Phaipun L, Luxemburger C, Simpson J, McGready R, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg. 1999;60:547–55.

    CAS  PubMed  Google Scholar 

  19. Leonardi E, Gilvary G, White NJ, Nosten F. Severe allergic reactions to oral artesunate: a report of two cases. Trans R Soc Trop Med Hyg. 2001;95:182–3.

    Article  CAS  PubMed  Google Scholar 

  20. Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore WF, et al. Neuropathological assessment of artemether-treated severe malaria. Lancet. 2003;362:295–6.

    Article  CAS  PubMed  Google Scholar 

  21. WHO Library Cataloguing-in-Publication Data. Pharmacology of antimalarial medicines. In: Guidelines for the treatment of malaria. 2nd ed. Geneva: Global Malaria Programme WHO; 2010. p. 73–108.

  22. Kawai S, Kano S, Suzuki M. Morphologic effects of artemether on Plasmodium falciparum in Aotus trivirgatus. Am J Trop Med Hyg. 1993;49:812–8.

    CAS  PubMed  Google Scholar 

  23. White NJ. Assessment of the pharmacodynamic properties of antimalarial drug in vivo. Antimicrob Agents Chemother. 1997;41:1413–22.

    CAS  PubMed  Google Scholar 

  24. Artemether-Quinine Meta-analysis Study Group. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg. 2001;95:637–50.

    Article  Google Scholar 

  25. Dondorp A, Nosten F, Stepniewska K, Day N, White N, South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) Group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomized trial. Lancet. 2005;366:717–25.

    Article  PubMed  CAS  Google Scholar 

  26. WHO Library Cataloguing-in-Publication Data. Treatment of severe P. falciparum malaria. In: Guidelines for the treatment of malaria. 2nd ed. Geneva: Global Malaria Programme WHO; 2010. p. 35–47.

  27. White NJ. Qinghaosu (artemisinin): the price of success. Science. 2008;320:330–4.

    Article  CAS  PubMed  Google Scholar 

  28. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, et al. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet. 1992;339:821–4.

    Article  CAS  PubMed  Google Scholar 

  29. Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Eh JP, Chongsuphajaisiddhi T, et al. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J Infect Dis. 1994;170:971–7 (Erratum in: J Infect Dis. 1995;171:519).

    Google Scholar 

  30. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, International Artemisinin Study Group. Artesunate combinations for treatment of malaria: meta-analysis. Lancet. 2004;363:9–17.

    Article  CAS  PubMed  Google Scholar 

  31. Nosten F, van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet. 2000;356:297–302.

    Article  CAS  PubMed  Google Scholar 

  32. Tangpukdee N, Krudsood S, Srivilairit S, Phophak N, Chonsawat P, Yanpanich W, et al. Gametocyte clearance in uncomplicated and severe Plasmodium falciparum malaria after artesunate-mefloquine treatment in Thailand. Korean J Parasitol. 2008;46:65–70.

    Article  PubMed  Google Scholar 

  33. WHO Library Cataloguing-in-Publication Data. Treatment of uncomplicated P. falciparum malaria. In: Guidelines for the treatment of malaria. 2nd ed. Geneva: Global Malaria Programme WHO; 2010. p. 13–34.

  34. Djimde A, Lefevre G. Understanding the pharmacokinetics of Coartem®. Malar J. 2009;8(suppl I):S4.

    Article  PubMed  CAS  Google Scholar 

  35. Premji ZG. Coartem®: the journey to the clinic. Malar J. 2009;8(suppl I):S3.

    Article  PubMed  CAS  Google Scholar 

  36. Mueller EA, van Vugt M, Kirch W, Andriano K, Hunt P, de Palacios PI. Efficacy and safety of the six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in adolescents and adults: a pooled analysis of individual patient data from randomized clinical trials. Acta Trop. 2006;100:41–53.

    Article  CAS  PubMed  Google Scholar 

  37. Makanga M, Premji Z, Falade C, Karbwang J, Mueller EA, Andriano K, et al. Efficacy and safety of the six-dose regimen of artemether-lumefantrine in pediatrics with uncomplicated Plasmodium falciparum malaria: a pooled analysis of individual patient data. Am J Trop Med Hyg. 2006;74:991–8.

    CAS  PubMed  Google Scholar 

  38. Hatz C, Soto J, Nothdurft HD, Zoller T, Weitzel T, Loutan L, et al. Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in non-immune populations: a safety, efficacy, and pharmacokinetic study. Am J Trop Med Hyg. 2008;78:241–7.

    CAS  PubMed  Google Scholar 

  39. Abdulla S, Sagara I, Borrmann S, D’Alessandro U, Gonzalez R, Hamel M, et al. Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomized, single-blind, multicentre trial. Lancet. 2008;372:1819–27.

    Article  CAS  PubMed  Google Scholar 

  40. Makanga M, Krudsood S. The clinical efficacy of artemether/lumefantrine (Coartem®). Malar J. 2009;8(suppl I):S5.

    Article  PubMed  CAS  Google Scholar 

  41. Na-Bangchang K, Krudsood S, Silachamroon U, Molunto P, Tasanor O, Chalermrut K, et al. The pharmacokinetics of oral dihydroartemisinin and artesunate in healthy Thai volunteers. Southeast Asian J Trop Med Public Health. 2004;35:575–82.

    CAS  PubMed  Google Scholar 

  42. Tangpukdee N, Krudsood S, Thanachartwet W, Chalermrut K, Pengruksa C, Srivilairit S, et al. An open randomized clinical trial of Artekin vs. artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health. 2005;36:1085–91.

    CAS  PubMed  Google Scholar 

  43. Krudsood S, Tangpukdee N, Thanchatwet V, Wilairatana P, Srivilairit S, Pothipak N, et al. Dose ranging studies of ne artemisinin-piperaquine fixed combinations compared to standard regimens of artemisinin combination therapies for acute uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health. 2007;38:971–8.

    CAS  PubMed  Google Scholar 

  44. WHO Library Cataloguing-in-Publication Data. Uncomplicated Plasmodium falciparum malaria. In: Guidelines for the treatment of malaria. 2nd ed. Geneva: Global Malaria Programme WHO; 2010. p. 134–153.

  45. Tangpukdee N, Krudsood S, Thanachartwet V, Pengruksa C, Phophak N, Kano S, et al. Efficacy of Artequick versus artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health. 2008;39:1–8.

    CAS  PubMed  Google Scholar 

  46. Home page of the Research Group on Chemotherapy of Tropical Diseases in Japan (in Japanese). (http://www.med.miyazaki-u.ac.jp/parasitology/orphan/index.html). Accessed 1 May 2010.

  47. Kano S, Tsuji M, Hosoya J, Suzuki M. A case of severe malaria treated with Qinghaosu. Jpn J Trop Med. 1988;16:301–7 (in Japanese, English abstract available).

    Google Scholar 

  48. Kondou H, Tahara D, Simomura A, Terada M, Kano S, Suzuki M, et al. Recrudescence of falciparum malaria treated with artesunate. Clin Parasitol. 1994;5:45–7 (in Japanese, English abstract available).

    Google Scholar 

  49. Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T. Double blind randomized clinical trial of two different regimens of oral artesunate in falciparum malaria. Southeast Asian J Trop Med Public Health. 1991;22:539–43.

    CAS  PubMed  Google Scholar 

  50. Nguyen DS, Dao BH, Nguyen PD, Nguyen VH, Le NB, May VS, et al. Treatment of malaria in Vietnam with oral artemisinin. Am J Trop Med Hyg. 1993;48:398–402.

    CAS  PubMed  Google Scholar 

  51. Yasuoka C, Yasuoka A, Yamamoto Y, Genka I, Hatabu T, Kohno S, et al. A case of falciparum malaria successfully treated with intravenous artesunate. Kansenshogaku Zasshi. 2001;75:822–5 (in Japanese, English abstract available).

    Google Scholar 

  52. WHO. Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94(suppl):1–31.

    Google Scholar 

  53. Yoshizawa S, HikeK, Kimura K, Matsumoto T, Furuya N, Takeda K, et al. A case of falciparum malaria successfully treated with intravenous artesunate. Kansenshogaku Zasshi. 2002;76:888–92 (in Japanese, English abstract available).

  54. Itoda I, Yasunami T, Kikuchi K, Yamaura H, Totsuka K, Yoshinaga K, et al. Severe falciparum malaria with prolonged hemolytic anemia after successful treatment with intravenous artesunate. Kansenshogaku Zasshi. 2002;76:600–3 (in Japanese, English abstract available).

    Google Scholar 

  55. Mizuno Y, Fujimoto H, Yokota K, Kato Y, Genka I, Kanagawa S, et al. A case of severe falciparum malaria successfully treated with intravenous artesunate and continuous hemodiafiltration. Kansenshogaku Zasshi. 2006;80:706–10 (in Japanese, English abstract available).

    Google Scholar 

  56. Mizuno Y, Kato Y, Kanagawa S, Kudo K, Hashimoto M, Kunimoto M, et al. A case of postmalaria neurological syndrome in Japan. J Infect Chemother. 2006;12:399–401.

    Article  PubMed  Google Scholar 

  57. Naha Y, Haranaga S, Higa F, Tateyama M, Fujita J, Kano S. A case of severe falciparum malaria successfully treated with intravenous artesunate. Clin Parasitol. 2007;18:72–5 (in Japanese).

    Google Scholar 

  58. Ishizaki A, Kikuchi Y, Hatabu T, Kano S, Yasuoka A, Oka S. An imported case of falciparum malaria successfully treated with artemether-lumefantrine in Japan. Kansenshogaku Zasshi. 2003;77:34–7.

    PubMed  Google Scholar 

  59. Mizuno Y, Kato Y, Kudo K, Kano S. First case of treatment failure of artemether-lumefantrine in a Japanese traveler with imported falciparum malaria. Jpn J Infect Dis. 2009;62:139–41.

    PubMed  Google Scholar 

  60. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;61:455–67.

    Article  Google Scholar 

Download references

Acknowledgments

This study was partly supported by a Grant of National Center for Global Health and Medicine (21A107).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shigeyuki Kano.

About this article

Cite this article

Kano, S. Artemisinin-based combination therapies and their introduction in Japan. J Infect Chemother 16, 375–382 (2010). https://doi.org/10.1007/s10156-010-0077-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10156-010-0077-1

Keywords

Navigation