Zusammenfassung
Die blutschizontozide Wirkung von Lumefantrin, Monodesbutyl-Benflumetol und einer 999:1 Kombination beider Substanzen wurde bei 26 frischen Isolaten von Plasmodium falciparum aus dem Nordwesten Thailands ermittelt. Als Methodik diente die Messung der Hemmung der Schizontenreifung (WHO Standardprotokoll Mikrotest Mark II). Die geometrischen Mittelkonzentrationen für volle Reifungshemmung (GMCOC) beliefen sich auf 943,2 nM für Lumefantrin, 146,3 nM für DBB und 182,2 nM für die 999:1 Kombination von Lumefantrin und DBB. Die EC50 Werte waren 27,3 nM für Lumefantrin, 44,1 nM für DBB, und 16,5 nM für die Kombination, die EC90 Werte 163,1nM für Lumefantrin, 44,1 nM für DBB, und 78,3 nM für die Kombination. Trotz des geringen Anteils in der Kombination zeigte DBB signifikanten Synergismus mit Lumefantrin, welcher bei EC90 und EC99 am stärksten ausgeprägt war. Gemäß Korrelationsanalyse ist DBB der maßgebliche Wirkungsfaktor in der Kombination.
Summary
The blood schizontocidal activity of lumefantrine, monodesbutyl-benflumetol (DBB) and a 999:1 combination of both compounds has been investigated in 26 fresh isolates of Plasmodium falciparum from northwestern Thailand, using the WHO standard protocol MarkII for determining the inhibition of schizont maturation. The geometric mean cut-off concentrations of schizont maturation (GMCOC) were 943.2 nM for lumefantrine, 146.3 nM for DBB and 182.2 nM for the 999:1 combination of lumefantrine and DBB. The EC50 values were 27.3nM for lumefantrine, 5.7 nM for DBB, and 16.5 nM for the combination, and the EC90 values 163.1 nM for lumefantrine, 44.1 nM for DBB, and 78.3 nM for the combination. Despite the very low concentration in the combination, DBB exerted significant synergistic activity with lumefantrine that was strongest at the EC90 and EC99 levels. Correlation analysis indicates that DBB is the leading determinant for the activity of the combination.
This is a preview of subscription content, log in via an institution to check access.
References
Yeung S, Pongtavompinyo W, Hastings IM, Mills AJ, White NJ (2004) Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. Am J Trop Med Hyg 71 [Suppl 2]: 179–186
Wernsdorfer G, Wernsdorfer WH (2003) Malaria at the turn from the 2nd to the 3rd millennium. Wien Klin Wochenschr 115 [Suppl 3]: 2–9
World Health Organization (1990) Practical chemotherapy of malaria. Report of a WHO Scientific Group. WHO Tech Rep Ser 805. WHO, Geneva, pp 124–126
Alin H, Björkman A, Wernsdorfer WH (1999) Synergism of benflumetol and artemether in Plasmodium falciparum. Am J Trop Med Hyg 61: 439–445
Wernsdorfer WH (2004) Coartemether (artemether and lumefantrine): an oral antimalarial drug. Expert Rev Anti-infect Ther 2: 181–196
Zeng MY, Lu ZL, Yang SC, Zhang M, Liao J, Liu SL, Teng XH (1996) Determination of benflumetol in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Appl 681: 299–306
Mansor SM, Navaratnam V, Yahaya N, Nair NK, Wernsdorfer WH, Degen PH (1996) Determination of a new antimalarial drug, benflumetol, in blood plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl 682: 321–325
Vugt MV, Wilairatana P, Gemperli B, Gathmann I, Phaipun L, Brockman A, et al (1999) Efficacy of six doses of artemether-lumefantrine (beflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 60: 936–942
Svensson USH, Mäki-Jouppila M, Hoffmann K-J, Ashton M (2003) Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto-induction in the rat by use of nonlinear mixed effects modeling. Biopharm Drug Dispos 24: 71–85
Gustafsson LL, Walker O, Alván G, Beermn B, Estevez F, Gleisner L, et al (1983) The disposition of chloroquine in man after single intravenous and oral doses. Brit J Clin Pharmacol 15: 471–479
Noedl H, Allmendinger T, Prajakwong S, Wernsdorfer G, Wernsdorfer WH (2001) Desbutyl-benflumetol, a novel antimalarial compound: in vitro activity in fresh isolates of Plasmodium falciparum from Thailand. Antimicrob Agents Chemother 45: 2106–2109
Pirker-Krassnig DK, Wernsdorfer G, Sirichaisinthop J, Rojanawatsirivet C, Kollaritsch H, Wernsdorfer WH (2004) Comparative study on the in vitro activity of lumefantrine and desbutyl-benflumetol in fresh isolates of Plasmodium vivax from Thailand. Wien Klin Wochenschr 116 [Suppl 4]: 47–52
World Health Organization (1991) Basic malaria microscopy. Part I. WHO, Geneva, pp 67–68
Wernsdorfer WH, Wernsdorfer MG (1995) The evaluation of in vitro tests for the assessment of drug response in Plasmodium falciparum. Mitteilungen Oesterr Gesellsch Tropenmed Parasitol 17: 221–228
Litchfield JT Jr, Wilcoxon F (1949) A simplified method for evaluating dose-effect experiments. J Pharm Exp Ther 96: 99–113
Sachs L (1984) Angewandte Statistik. Springer, Berlin, S 109–115, 329–342
Berenbaum MC (1978) A method for testing for synergy with any number of agents. J Infect Dis 137: 122–130
Mariga ST, Gil JP, Wernsdorfer WH, Bjorkman A (2005) Pharmacodynamic interactions of amodiaquine and its major metabolite desethylamodiaquine with artemisinin, quinine and atovaquone in Plasmodium falciparum in vitro. Acta Tropica 93: 221–231
Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M, Suter M (2004) Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol 484: 41–48
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Starzengruber, P., Wernsdorfer, G., Parizek, M. et al. Specific pharmacokinetic interaction between lumefantrine and monodesbutyl-benflumetol in Plasmodium falciparum . Wien Klin Wochenschr 119 (Suppl 3), 60–66 (2007). https://doi.org/10.1007/s00508-007-0861-9
Issue Date:
DOI: https://doi.org/10.1007/s00508-007-0861-9