Atovaquone nanosuspensions show excellent therapeutic effect in a new murine model of reactivated toxoplasmosis

Immunocompromised patients are at risk of developing toxoplasma encephaliti s (TE). Standard therapy regimens (including sulfadiazine plus pyrimethamin e) are hampered by severe side effects. While atovaquone has potent in vitr o activity against Toxoplasma gondii, it is poorly absorbed after oral admi nistration and shows poor therapeutic efficacy against TE. To overcome the low absorption of atovaquone, we prepared atovaquone nanosuspensions (ANSs) for intravenous (i.v.) administration. At concentrations higher than 1.0 m ug/ml, ANS did not exert cytotoxicity and was as effective as free atovaquo ne (i.e., atovaquone suspended in medium) against T. gondii in freshly isol ated peritoneal macrophages, In a new murine model of TE that closely mimic s reactivated toxoplasmosis in immunocompromised hosts, using mice with a t argeted mutation in the gene encoding the interferon consensus sequence bin ding protein, i.v.-administered ANS doses of 10.0 mg/kg of body weight prot ected the animals against development of TE and death. Atovaquone was detec table in the sera, brains, livers, and lungs of mice by high-performance li quid chromatography. Development of TE and mortality in mice treated with 1 .0- or 0.1-mg/kg i.v. doses of ANS did not differ from that in mice treated orally with 100 mg of atovaquone/kg. In conclusion, i.v. ANSs may prove to be an effective treatment alternative for patients with TE.