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Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis.
Antimicrob Agents Chemother 2004; 48(12):4848-54AA

Abstract

Acute therapy with pyrimethamine plus sulfadiazine is the treatment of choice for reactivated toxoplasmic encephalitis (TE). Acute therapy is followed by lifelong maintenance therapy (secondary prophylaxis) with the same drugs at lower dosages. The use of pyrimethamine plus sulfadiazine is hampered by severe side effects including allergic reactions and hematotoxicity. Alternative treatment regimens with pyrimethamine plus clindamycin or other antiparasitic drugs are less efficacious. Atovaquone nanosuspensions show excellent therapeutic effects for "acute" intravenous (i.v.) treatment of reactivated TE in a murine model. In the present study, the therapeutic efficacy of atovaquone for oral "maintenance" therapy was investigated. Mice with a targeted mutation in the interferon regulatory factor 8 gene were latently infected with Toxoplasma gondii, developed reactivated TE, and received acute i.v. therapy with atovaquone nanosuspensions. Mice were then treated orally with atovaquone suspension or other antiparasitic drugs to prevent relapse of TE. Maintenance therapy with atovaquone at daily doses of 50 or 100 mg/kg (body weight) protected mice against reactivated TE and death. This maintenance treatment was superior to standard therapy with pyrimethamine plus sulfadiazine. The latter combination was superior to the combination of pyrimethamine plus clindamycin. Inflammatory changes in the brain parenchyma and meninges, as well as parasite numbers, in the brains of mice confirmed the therapeutic efficacy of atovaquone for maintenance therapy. Atovaquone was detectable in sera, brains, livers, and lungs of infected mice by high-performance liquid chromatography and/or mass spectrometry. In conclusion, atovaquone appears to be superior to the standard maintenance therapy regimens in a murine model of reactivated TE. The therapeutic efficacy of atovaquone for maintenance therapy against TE should be further investigated in clinical trials.

Authors+Show Affiliations

Department of Medical Microbiology and Immunology of Infection, Institute for Infection Medicine, Campus Benjamin Franklin, Charité Medical School, Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15561866

Citation

Dunay, Ildiko R., et al. "Atovaquone Maintenance Therapy Prevents Reactivation of Toxoplasmic Encephalitis in a Murine Model of Reactivated Toxoplasmosis." Antimicrobial Agents and Chemotherapy, vol. 48, no. 12, 2004, pp. 4848-54.
Dunay IR, Heimesaat MM, Bushrab FN, et al. Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis. Antimicrob Agents Chemother. 2004;48(12):4848-54.
Dunay, I. R., Heimesaat, M. M., Bushrab, F. N., Müller, R. H., Stocker, H., Arasteh, K., ... Liesenfeld, O. (2004). Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis. Antimicrobial Agents and Chemotherapy, 48(12), pp. 4848-54.
Dunay IR, et al. Atovaquone Maintenance Therapy Prevents Reactivation of Toxoplasmic Encephalitis in a Murine Model of Reactivated Toxoplasmosis. Antimicrob Agents Chemother. 2004;48(12):4848-54. PubMed PMID: 15561866.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis. AU - Dunay,Ildiko R, AU - Heimesaat,Markus M, AU - Bushrab,Faris Nadiem, AU - Müller,Rainer H, AU - Stocker,Hartmut, AU - Arasteh,Keikawus, AU - Kurowski,Michael, AU - Fitzner,Rudolf, AU - Borner,Klaus, AU - Liesenfeld,Oliver, PY - 2004/11/25/pubmed PY - 2005/1/19/medline PY - 2004/11/25/entrez SP - 4848 EP - 54 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 48 IS - 12 N2 - Acute therapy with pyrimethamine plus sulfadiazine is the treatment of choice for reactivated toxoplasmic encephalitis (TE). Acute therapy is followed by lifelong maintenance therapy (secondary prophylaxis) with the same drugs at lower dosages. The use of pyrimethamine plus sulfadiazine is hampered by severe side effects including allergic reactions and hematotoxicity. Alternative treatment regimens with pyrimethamine plus clindamycin or other antiparasitic drugs are less efficacious. Atovaquone nanosuspensions show excellent therapeutic effects for "acute" intravenous (i.v.) treatment of reactivated TE in a murine model. In the present study, the therapeutic efficacy of atovaquone for oral "maintenance" therapy was investigated. Mice with a targeted mutation in the interferon regulatory factor 8 gene were latently infected with Toxoplasma gondii, developed reactivated TE, and received acute i.v. therapy with atovaquone nanosuspensions. Mice were then treated orally with atovaquone suspension or other antiparasitic drugs to prevent relapse of TE. Maintenance therapy with atovaquone at daily doses of 50 or 100 mg/kg (body weight) protected mice against reactivated TE and death. This maintenance treatment was superior to standard therapy with pyrimethamine plus sulfadiazine. The latter combination was superior to the combination of pyrimethamine plus clindamycin. Inflammatory changes in the brain parenchyma and meninges, as well as parasite numbers, in the brains of mice confirmed the therapeutic efficacy of atovaquone for maintenance therapy. Atovaquone was detectable in sera, brains, livers, and lungs of infected mice by high-performance liquid chromatography and/or mass spectrometry. In conclusion, atovaquone appears to be superior to the standard maintenance therapy regimens in a murine model of reactivated TE. The therapeutic efficacy of atovaquone for maintenance therapy against TE should be further investigated in clinical trials. SN - 0066-4804 UR - https://www.unboundmedicine.com/medline/citation/15561866/Atovaquone_maintenance_therapy_prevents_reactivation_of_toxoplasmic_encephalitis_in_a_murine_model_of_reactivated_toxoplasmosis_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=15561866 DB - PRIME DP - Unbound Medicine ER -