In vivo studies on the antileishmanial activity of buparvaquone and its prodrugs.
OBJECTIVE
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 approximately 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.
Garnier
Tracy
T
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. t.garnier@herts.ac.uk
Mäntylä
Antti
A
Järvinen
Tomi
T
Lawrence
Jayne
J
Brown
Marc
M
Croft
Simon
S
D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D005260:Female; D007893:Leishmania donovani / Q000187:drug effects*; D018320:Leishmania major / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D008099:Liver / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000008:administration & dosage / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use*; D012867:Skin / Q000469:parasitology / Q000473:pathology
D000981:Antiprotozoal Agents; D009285:Naphthoquinones; D011355:Prodrugs; C046326:buparvaquone