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In vitro and in vivo evaluation of 28DAP010, a novel diamidine for treatment of second-stage African sleeping sickness.

Abstract
African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second simple diamidine found to cure mice with central nervous system infections by a parenteral route of administration. 28DAP010 showed efficacy similar to that of DB829 in dose-response studies in mouse models of first- and second-stage African sleeping sickness. The in vitro time to kill, determined by microcalorimetry, and the parasite clearance time in mice were shorter for 28DAP010 than for DB829. No cross-resistance was observed between 28DAP010 and pentamidine on the tested Trypanosoma brucei gambiense isolates from melarsoprol-refractory patients. 28DAP010 is the second promising preclinical candidate among the diamidines for the treatment of second-stage African sleeping sickness.
AuthorsTanja Wenzler, Sihyung Yang, Donald A Patrick, Olivier Braissant, Mohamed A Ismail, Richard R Tidwell, David W Boykin, Michael Zhuo Wang, Reto Brun
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 8 Pg. 4452-63 (Aug 2014) ISSN: 1098-6596 [Electronic] United States
PMID24867978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014, American Society for Microbiology. All Rights Reserved.
Chemical References
  • Amidines
  • CPD 0801
  • CPD0905
  • Pyridines
  • Trypanocidal Agents
  • Pentamidine
  • Melarsoprol
Topics
  • Amidines (chemical synthesis, pharmacokinetics, pharmacology)
  • Animals
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Melarsoprol (pharmacokinetics, pharmacology)
  • Mice
  • Pentamidine (pharmacokinetics, pharmacology)
  • Pyridines (chemical synthesis, pharmacokinetics, pharmacology)
  • Structure-Activity Relationship
  • Trypanocidal Agents (chemical synthesis, pharmacokinetics, pharmacology)
  • Trypanosoma brucei gambiense (drug effects, growth & development, pathogenicity)
  • Trypanosoma brucei rhodesiense (drug effects, growth & development, pathogenicity)
  • Trypanosomiasis, African (drug therapy, parasitology)

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