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    Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

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    Issue Date
    2013-11
    Author
    Wenzler, Tanja
    Yang, Sihyung
    Braissant, Olivier
    Boykin, David W.
    Brun, Reto
    Wang, Michael Zhuo
    Publisher
    American Society for Microbiology
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites Trypanosoma brucei gambiense and T. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with T. b. rhodesiense or T. b. brucei parasites. The current study examined the pharmacokinetics, in vitro and in vivo activity against T. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding in vivo efficacy in mice infected with parasites of T. b. gambiense strains, despite having higher in vitro 50% inhibitory concentrations (IC50s) than against T. b. rhodesiense strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different T. b. gambiense strains. No cross-resistance was observed between DB829 and pentamidine in T. b. gambiense strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and in vivo time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both Trypanosoma brucei subspecies.
    URI
    http://hdl.handle.net/1808/17605
    DOI
    https://doi.org/10.1128/AAC.00398-13
    Collections
    • Pharmaceutical Chemistry Scholarly Works [288]
    Citation
    Wenzler et. al. "Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis" Antimicrob. Agents Chemother. November 2013 vol. 57 no. 11 5330-5343 http://dx.doi.org/10.1128/AAC.00398-13

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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