Chemotherapy of Second stage Human african Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys
dc.contributor.author | Thuita, John K. | |
dc.contributor.author | Wolf, Kristina K. | |
dc.contributor.author | Murilla, Grace A. | |
dc.contributor.author | Bridges, Arlene S. | |
dc.contributor.author | Boykin, David W. | |
dc.contributor.author | Mutuku, James N. | |
dc.contributor.author | Liu, Qiang | |
dc.contributor.author | Jones, Susan K. | |
dc.contributor.author | Gem, Charles O. | |
dc.contributor.author | Ching, Shelley | |
dc.contributor.author | Tidwell, Richard R. | |
dc.contributor.author | Wang, Michael Zhuo | |
dc.contributor.author | Piane, Mary F. | |
dc.contributor.author | Brun, Reto | |
dc.date.accessioned | 2015-03-03T22:17:41Z | |
dc.date.available | 2015-03-03T22:17:41Z | |
dc.date.issued | 2015-02-05 | |
dc.identifier.citation | Thuita JK, Wolf KK, Murilla GA, Bridges AS, Boykin DW, 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. http://dx.doi.org/10.1371/journal.pntd.0003409 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/16959 | |
dc.description.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. | en_US |
dc.description.sponsorship | This investigation received financial support from the Bill and Melinda Gates Foundation through the Consortium for Parasitic Drug. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | en_US |
dc.publisher | Public Library of Science | en_US |
dc.rights | © 2015 Thuita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Monkeys | en_US |
dc.subject | Cerebrospinal fluid | en_US |
dc.subject | Parasitic diseases | en_US |
dc.subject | African trypanosomiasis | en_US |
dc.subject | Pro-Drugs | en_US |
dc.subject | Blood | en_US |
dc.subject | Drug therapy | en_US |
dc.subject | Drug administration | en_US |
dc.title | Chemotherapy of Second stage Human african Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys | en_US |
dc.type | Article | |
kusw.kuauthor | Wang, Michael Z. | |
kusw.kudepartment | Department of Pharmaceutical Chemistry | en_US |
dc.identifier.doi | 10.1371/journal.pntd.0003409 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: © 2015 Thuita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited