Title

Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys

Authors

John K. Thuita, TRC-KARIFollow
Kristina K. Wolf, University of North Carolina at Chapel Hill
Grace A. Murilla, TRC-KARI
Arlene S. Bridges, Georgia State University
David Boykin, Georgia State UniversityFollow
James N. Mutuku, TRC-KARI
Qiang Liu, University of North Carolina at Chapel Hill
Susan K. Jones, University of North Carolina at Chapel Hill
Charles O. Gem, TRC-KARI
Shelley Ching, SVC Associates inc, Apex, NC
Richard R. Tidwell, University of North Carolina at Chapel HillFollow
Michael Z. Wang, University of KansasFollow
Mary F. Paine, University of North Carolina at Chapel HillFollow
Reto Brun, University of Basel, SwitzerlandFollow

Document Type

Article

Publication Date

2-2015

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.

Comments

Originally Published in:

PLoS Negl Trop Dis, 9 (2), e0003409. doi: http://dx.doi.org/10.1371/journal.pntd.0003409

Recommended Citation

Thuita JK, Wolf KK, Murilla GA, Bridges AS, Boykin DW, Mutuku JN, et al. (2015) Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys. PLoS Negl Trop Dis 9(2): e0003409. doi: http://dx.doi.org/10.1371/journal.pntd.0003409

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This work is licensed under a Creative Commons Attribution 4.0 International License.