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Antimicrobial Agents and Chemotherapy, June 2001, p. 1771-1779, Vol. 45, No. 6
Institute for Infection Medicine, Department of Medical
Microbiology and Immunology of Infection,1 and
Institute of Clinical Chemistry and
Pathobiochemistry,3 Benjamin Franklin Medical
Center, D-12203 Berlin, and Department of Pharmaceutics,
Biopharmaceutics and Biotechnology, Free
University of Berlin, D-12169 Berlin,2 Germany
Received 4 December 2000/Returned for modification 6 February
2001/Accepted 27 February 2001
Immunocompromised patients are at risk of developing toxoplasma
encephalitis (TE). Standard therapy regimens (including sulfadiazine plus pyrimethamine) are hampered by severe side effects. While atovaquone has potent in vitro activity against Toxoplasma
gondii, it is poorly absorbed after oral administration 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 µg/ml, ANS did not exert cytotoxicity and was as effective as
free atovaquone (i.e., atovaquone suspended in medium) against T. gondii in freshly isolated peritoneal macrophages. In
a new murine model of TE that closely mimics reactivated toxoplasmosis in immunocompromised hosts, using mice with a targeted mutation in the
gene encoding the interferon consensus sequence binding protein,
i.v.-administered ANS doses of 10.0 mg/kg of body weight protected the
animals against development of TE and death. Atovaquone was detectable
in the sera, brains, livers, and lungs of mice by high-performance
liquid 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.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1771-1779.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Atovaquone Nanosuspensions Show Excellent Therapeutic Effect
in a New Murine Model of Reactivated Toxoplasmosis
*
Corresponding author. Mailing address: Institute for
Infection Medicine, Department of Medical Microbiology and Immunology of Infection, Benjamin Franklin Medical Center, Free University of
Berlin, Hindenburgdamm 27, D-12203 Berlin, Germany. Phone: (49-30)
8445-3630. Fax: (49-30) 8445-3830. E-mail:
olitoxo{at}zedat.fu-berlin.de.
Antimicrobial Agents and Chemotherapy, June 2001, p. 1771-1779, Vol. 45, No. 6
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.6.1771-1779.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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