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. 2013 Nov;57(11):5330-43. doi: 10.1128/AAC.00398-13. Epub 2013 Aug 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidines / pharmacokinetics
  • Amidines / pharmacology*
  • Animals
  • Drug Administration Schedule
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Injections, Intraperitoneal
  • Melarsoprol / pharmacology
  • Mice
  • Parasitic Sensitivity Tests
  • Pentamidine / pharmacology
  • Time Factors
  • Trypanocidal Agents / pharmacokinetics
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei gambiense / drug effects*
  • Trypanosoma brucei gambiense / growth & development
  • Trypanosoma brucei rhodesiense / drug effects*
  • Trypanosoma brucei rhodesiense / growth & development
  • Trypanosomiasis, African / drug therapy*
  • Trypanosomiasis, African / parasitology


  • Amidines
  • CPD 0801
  • Trypanocidal Agents
  • Pentamidine
  • Melarsoprol