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JAC Advance Access originally published online on March 2, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):658-665; doi:10.1093/jac/dkl563
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Antimalarial efficacy and drug interactions of the novel semi-synthetic endoperoxide artemisone in vitro and in vivo

L. Vivas1,*, L. Rattray1, L. B. Stewart1,2, B. L. Robinson2, B. Fugmann3, R. K. Haynes4, W. Peters1,2 and S. L. Croft1,{dagger}

1 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK 2 Centre for Tropical Antiprotozoal Chemotherapy, Northwick Park Institute for Medical Research, Block Y, Watford Road, Harrow, Middlesex HA1 3UJ, UK 3 Bayer Innovation GmbH, Merowingerplatz 1, 40225 Düsseldorf, Germany 4 Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's Republic of China

Received 26 June 2006; returned 18 September 2006; revised 5 January 2007; accepted 5 January 2007

* Corresponding author. Tel: +44-20-79272062; Fax: +44-20-76374314; E-mail: livia.vivas{at}lshtm.ac.uk

Objectives: The in vitro and in vivo efficacy and drug–drug interactions of the novel semi-synthetic endoperoxide artemisone with standard antimalarials were investigated in order to provide the basis for the selection of the best partner drug.

Methods: Antimalarial activity and drug interactions were evaluated in vitro against Plasmodium falciparum by the incorporation of [3H]hypoxanthine. In vivo efficacy and drug interactions were assessed using the standard 4-day Peters' test.

Results: Artemisone was 10 times more potent than artesunate in vitro against a panel of 12 P. falciparum strains, independent of their susceptibility profile to antimalarial drugs, and consistently 4 to 10 times more potent than artesunate in rodent models against drug-susceptible and primaquine- or sulfadoxine/pyrimethamine-resistant Plasmodium berghei lines and chloroquine- or artemisinin-resistant lines of Plasmodium yoelii. Slight antagonistic trends were found between artemisone and chloroquine, amodiaquine, tafenoquine, atovaquone or pyrimethamine and additive to slight synergistic trends with artemisone and mefloquine, lumefantrine or quinine. Various degrees of synergy were observed in vivo between artemisone and mefloquine, chloroquine or clindamycin.

Conclusions: These results confirm the increased efficacy of artemisone over artesunate against multidrug-resistant P. falciparum and provide the basis for the selection of potential partner drugs for future deployment in areas of multidrug-resistant malaria. Artemisone represents an important addition to the repertoire of artemisinin combination therapies currently in use, as it has enhanced antimalarial activity, improved bioavailability and stability over current endoperoxides.

Keywords: P. falciparum , artemisinins , drug combination

{dagger} Present address. DNDi (Drugs for Neglected Diseases initiative), 1 Place St Gervais, CH-1201 Geneva, Switzerland.


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