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Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts.
Doggett, J Stone; Schultz, Tracey; Miller, Alyssa J; Bruzual, Igor; Pou, Sovitj; Winter, Rolf; Dodean, Rozalia; Zakharov, Lev N; Nilsen, Aaron; Riscoe, Michael K; Carruthers, Vern B.
Afiliação
  • Doggett JS; Division of Infectious Diseases, Oregon Health and Science University School of Medicine, Portland, Oregon, USA doggettj@ohsu.edu.
  • Schultz T; Department of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA.
  • Miller AJ; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • Bruzual I; Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • Pou S; Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • Winter R; Department of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA.
  • Dodean R; Department of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA.
  • Zakharov LN; Department of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA.
  • Nilsen A; Department of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA.
  • Riscoe MK; Department of Chemistry, University of Oregon, Eugene, Oregon, USA.
  • Carruthers VB; Division of Infectious Diseases, Oregon Health and Science University School of Medicine, Portland, Oregon, USA.
Article em En | MEDLINE | ID: mdl-32540978
ABSTRACT
Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for T. gondii cytochrome b over human cytochrome b Despite its oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations, and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a 6-fold increase in both the maximum plasma concentration (Cmax) and the area under the curve (AUC) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in efficacy against acute toxoplasmosis greater than that of an equivalent dose of ELQ-316 and had efficacy against latent toxoplasmosis similar to that of ELQ-316 administered intraperitoneally. Treatment with carbonate ester prodrugs is a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Toxoplasma / Pró-Fármacos / Toxoplasmose Animal / Quinolonas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Toxoplasma / Pró-Fármacos / Toxoplasmose Animal / Quinolonas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article