dc.contributor.author | Wenzler, Tanja | |
dc.contributor.author | Yang, Sihyung | |
dc.contributor.author | Braissant, Olivier | |
dc.contributor.author | Boykin, David W. | |
dc.contributor.author | Brun, Reto | |
dc.contributor.author | Wang, Michael Zhuo | |
dc.date.accessioned | 2015-05-05T20:51:09Z | |
dc.date.available | 2015-05-05T20:51:09Z | |
dc.date.issued | 2013-11 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/17605 | |
dc.description.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. | en_US |
dc.description.sponsorship | We thank Pati Pyana and Anne Clarisse Lekane Likeufack for isolating T. b. gambiense strains from patients in the Democratic Republic of the Congo, Jennifer Jenkins for critical reading and inputs to the manuscript,Guy Riccio and Christiane Braghiroli for carrying out experiments on in vivo efficacy and time to kill in mice, and Kirsten Gillingwater for time-to-kill experiments in mice.
This work was supported by the Bill and Melinda Gates Foundation through the Consortium for Parasitic Drug Development (CPDD). | en_US |
dc.publisher | American Society for Microbiology | en_US |
dc.title | Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis | en_US |
dc.type | Article | |
kusw.kuauthor | Yang, Sihyung | |
kusw.kuauthor | Wang, Michael Zhuo | |
kusw.kudepartment | Department of Pharmaceutical Chemistry | en_US |
dc.identifier.doi | 10.1128/AAC.00398-13 | |
dc.identifier.orcid | https://orcid.org/0000-0003-1751-4975 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess | |