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PLoS Negl Trop Dis. 2015 Feb 5;9(2):e0003409. doi: 10.1371/journal.pntd.0003409. eCollection 2015 Feb.

Chemotherapy of second stage human African trypanosomiasis: comparison between the parenteral diamidine DB829 and its oral prodrug DB868 in vervet monkeys.

Author information

1
Trypanosomiasis Research Centre, Kenya Agricultural Research Institute (TRC-KARI), Kikuyu, Kenya.
2
University of North Carolina Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
3
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
4
Department of Chemistry, Georgia State University, Atlanta, Georgia, United States of America.
5
SVC Associates, Inc., Apex, North Carolina, United States of America.
6
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, United States of America.
7
Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.

Abstract

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT.

PMID:
25654243
PMCID:
PMC4318582
DOI:
10.1371/journal.pntd.0003409
[Indexed for MEDLINE]
Free PMC Article

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