Volume 76, Issue 3
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Emergence of drug-resistant strains to conventional first-line antimalarial drugs has compelled many countries to reorient their drug policies to adopt artemisinin-based combination therapies (ACTs) for treatment of uncomplicated malaria. This has increased the demand of artemisinin, already a scarce commodity. Synthesis of artemisinin is not yet commercially viable. Extensive use of available ACTs will invariably lead to emergence of resistance to these combinations. Thus, there is need to search for new artemisinin-based synthetic, inexpensive, synergistic combinations to reduce dependence on artemisinin. In vitro cultures of provide an appropriate system for identification of such new combinations. We evaluated interactions of artemisinin with triclosan or ketoconazole against blood stages of by a fixed-ratio isobologram method. Artemisinin shows mild synergistic interaction with triclosan and slight to marked antagonism with ketoconazole in vitro. These antiplasmodial interactions, however, require confirmation using in vivo model systems.


Article metrics loading...

Loading full text...

Full text loading...



  1. Fivelman QL, Adagu IS, Warhurt DC, 2004. Modified fixed ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug resistant strains of Plasmodium falciparum. Antimicrob Agents Chemother 48 : 4097–4102.
  2. Bhargava HN, Leonard PA, 1996. Triclosan: applications and safety. Am J Infect Control 6 : 209–218.
  3. Chong CR, Sullivan DJ Jr, 2003. Inhibition of heme crystal growth by antimalarials and other compounds: implications for drug discovery. Biochem Pharmacol 66 : 2201–2212.
  4. Pfaller MA, Krogstad DJ, 1981. Imidazole and polyene activity against chloroquine-resistant Plasmodium falciparum. J Infect Dis 144 : 372–375.
  5. Pfaller MA, Segal JJ, Krogstad DJ, 1982. Activity of ketoconazole and its deacyl derivative against Plasmodium falciparum and Candida isolates. Antimicrob Agents Chemother 22 : 917–919.
  6. Surolia N, Surolia A, 2001. Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP of plasmodium falciparum. Nat Med 7 : 167–173.
  7. Bell A, 2005. Antimalarial drug synergism and antagonism: mechanistic and clinical significance. FEMS Microbiol Lett 253 : 171–184.
  8. Trager W, Jensen JB, 1976. Human malaria parasites in continuous culture. Science 193 : 673–675.
  9. Lambros C, Vanderberg JP, 1979. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol 65 : 418–420.
  10. Gupta S, Thapar MM, Wernsdorfer WH, Bjorkman A, 2002. In vitro interaction of artemisinin with atovaquone, quinine, and mefloquine against Plasmodium falciparum. Antimicrob Agents Chemother 46 : 1510–1515.
  11. Berenbaum MC, 1978. A method for testing synergy with any number of agents. J Infect Dis 137 : 122–130.
  12. Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, Bruneton C, Phanouvong S, Millet P, Whitty CJM, Talisuna AO, Proux S, Christophel EM, Malenga G, Singhasivanon P, Bojang K, Kaur H, Palmer K, Day NPJ, Greenwood BM, Nosten F, White NJ, 2006. Manslaughter by fake artesunate in Asia—will Africa be next? PLoS Med 3 : e197.
  13. Martinez-Irujo JJ, Villahermosa ML, Alberdi E, Santiago E, 1996. A checkerboard method to evaluate interactions between drugs. Biochem Pharmacol 51 : 635–644.
  14. Ryungsa K, Tanabe K, Inoue H, Toge T, 2002. Mechanism(s) of antitumor action in protracted infusion of low dose 5-fluorouracil and cisplatin in gastric carcinoma. Int J Oncol 20 : 549–555.
  15. Hall MJ, Middleton RF, Westmacott D, 1983. The fractional inhibitory concentration (FIC) index as a measure of synergy. J Antimicrob Chemother 11 : 427–433.
  16. Meletiadis J, Mouton JW, Meis JFGM, Verweij PE, 2003. In vitro drug interaction modeling of combinations of azoles with terbinafine against clinical Scedosporium prolificans isolates. Antimicrob Agents Chemother 47 : 106–117.
  17. Meshnick SR, 1994. The mode of action of antimalarial endo-peroxides. Trans R Soc Trop Med Hyg 88 : 31–32.
  18. Ridley RG, 2003. Malaria: to kill a parasite. Nature 424 : 887–889.
  19. Li W, Mo W, Shen D, Sun L, Wang J, 2005. Yeast model uncovers dual roles of mitochondria in the action of artemisinin. PLoS Genet 1 : e36.
  20. Ludwig UE, Webb RJ, van Goethem IDA, East JM, Lee AG, Kimura M, O’Neill PM, Bray PG, Ward SA, Krishna S, 2003. Artemisinins target the SERCA of Plasmodium falciparum. Nature 424 : 957–961.
  21. Beeson JG, Winstanley PA, McFadden GI, Brown GV, 2001. New agents to combat malaria. Nat Med 7 : 149–150.
  22. Rao SP, Surolia A, Surolia N, 2003. Triclosan: a shot in the arm for antimalarial chemotherapy. Mol Cell Biochem 253 : 55–63.
  23. White NJ, 1997. Assessment of the pharmacodynamic property of antimalarial drugs in vivo. Antimicrob Agents Chemother 41 : 1413–1422.
  24. Siddiqui WH, Buttar HS, 1979. Pharmacokinetics of triclosan in rat after intravenous and intravaginal administration. J Environ Pathol Toxicol 2 : 861–871.
  25. Docampo R, Moreno SNJ, 2001. Bisphosphonates as chemotherapeutic agents against trypanosomatid and apicomplexan parasites. Curr Drug Targets Infect Disord 1 : 51–61.
  26. Hogg T, Nagarajan K, Herzberg S, Chen L, Shen X, Jiang H, Wecke M, Blohmke CJ, Hilgenfeld R, Schmidt CL, 2006. Structural and functional characterization of falcipain-2, a he-moglobinase from the malarial parasite Plasmodium falciparum. J. Boil. Chem. 281 : 25425–25437.
  27. Pfaller MA, Krogstad DJ, 1983. Oxygen enhances the antimalarial activity of the imidazoles. Am J Trop Med Hyg 32 : 660–665.
  28. Tiffert TH, Ginsburg H, Krugliak M, Elford BC, Lew VL, 2000. Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum. Proc Natl Acad Sci USA 97 : 331– 336.
  29. McClom AA, McHardy N, 1984. Evaluation of a range of antimicrobial agents against the parasitic protozoa, Plasmodium falciparum, Babesia rodhaini and Theileria parva in vitro. Ann Trop Med Parasitol 78 : 345–354.

Data & Media loading...

  • Received : 26 Sep 2006
  • Accepted : 07 Nov 2006

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error