JAC Advance Access published online on August 21, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm303
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In vivo studies on the antileishmanial activity of buparvaquone and its prodrugs
1 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 2 Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland 3 Pharmaceutical Sciences Research Division, Kings College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK 4 Drugs for Neglected Diseases Initiative (DNDi), 1 Place St Gervais, Ch-1201 Geneva, Switzerland
Received 8 February 2007; returned 24 April 2007; revised 25 May 2007; accepted 13 July 2007
* Correspondence address. School of Pharmacy, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK. Tel: +44-1707-284392; Fax: +44-1701-284506; E-mail: t.garnier{at}herts.ac.uk
Objectives: The efficacy of different formulations of the naphthoquinone buparvaquone and two phosphate prodrugs in in vivo models of both visceral and cutaneous leishmaniasis is described.
Methods: Several topical formulations of buparvaquone containing acceptable excipients were tested in vivo against Leishmania major cutaneous lesions in BALB/c mice. In vivo studies against Leishmania donovani investigated whether the prodrugs had improved efficacy when compared with buparvaquone.
Results: Both a hydrous gel and water-in-oil emulsion of buparvaquone significantly reduced cutaneous parasite burden (P < 0.05, 22 days post-infection) and lesion size, compared with the untreated control (P < 0.0001, 16 days post-infection). The prodrug 3-phosphonooxymethyl-buparvaquone was formulated into an anhydrous gel and this also significantly reduced parasite burden and lesion size (P < 0.0001, 16 days post-infection). Histology confirmed this efficacy. In the visceral model, both prodrugs were significantly more effective at reducing liver parasite burden than the parent drug, buparvaquone. Buparvaquone-3-phosphate was shown to be the most effective antileishmanial (P = 0.0003, 50 mg buparvaquone molar equivalent/kg/day five times), reducing the liver parasite burden by 
34% when compared with the untreated control.
Conclusions: The introduction of a topical formulation, such as buparvaquone (or its prodrug), would be a significant advance for the treatment of simple cutaneous lesions. In particular, the avoidance of the parenteral antimonials would greatly increase patient compliance and reduce treatment costs.
Key Words: leishmaniasis , chemotherapy , cutaneous , visceral naphthoquinones
Present address. School of Pharmacy, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK.