Therapeutic evaluation of free and nanocapsule-encapsulated atovaquone in the treatment of murine visceral leishmaniasis.
The activities of free atovaquone (ATV) and of poly(D,L-lactide) nanocapsules loaded with the drug, in the treatment of mice with visceral leishmaniasis caused by Leishmania infantum, were compared. Each mouse was infected intravenously with 2x10(7) promastigotes, on day 0. On days 15, 17 and 19, most of the infected mice were treated either with free ATV, in a dimethylsulphoxide/cremophor/water mixture, or with the ATV-loaded nanocapsules (at, respectively, 0.2-1.6 and 0.125-1.0 mg ATV/kg, on each treatment day). The rest of the mice were left untreated, as controls. All the mice were killed on day 21 and dissected so that their livers and spleens could be weighed. The liver parasite burdens, evaluated using the Stauber method, indicated that the ATV-loaded nanocapsules were significantly more effective than the free drug. In nanocapsules, for example, a total dose of 3.0 mg ATV/kg reduced liver burdens by 71.3%, whereas treatment with a higher total dose of the free drug (4.8 mg/kg) only cut the number of liver parasites by 34.4%. The dose-response data indicated that livers would have been cleared of parasites if the nanocapsule preparation had been given as three doses each equivalent to 3 mg ATV/kg, whereas the maximum suppression possible with the free drug would have been about 61%, whatever the dose.
Cauchetier
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Laboratoire de Pharmacotechnie, Service Pharmacie, Centre Hospitalier Universitaire Henri Mondor, Assistance Publique-Hôpitaux de Paris, 94010 Créteil, France. ecauchetier@ch-argenteuil.fr
Paul
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Rivollet
D
D
Fessi
H
H
Astier
A
A
Deniau
M
M
D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D053626:Atovaquone; D001672:Biocompatible Materials / Q000008:administration & dosage; D002214:Capsules; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009285:Naphthoquinones / Q000008:administration & dosage*; D011091:Polyesters / Q000008:administration & dosage
D000981:Antiprotozoal Agents; D001672:Biocompatible Materials; D002214:Capsules; D009285:Naphthoquinones; D011091:Polyesters; C033616:poly(lactide); D053626:Atovaquone