title: Chemotherapy of second stage human African trypanosomiasis: comparison between the parenteral diamidine DB829 and its oral prodrug DB868 in vervet monkeys.
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.
authors: Trypanosomiasis Research Centre, Kenya Agricultural Research Institute (TRC-KARI), Kikuyu, Kenya.
authors: John K
authors: JK
authors: Thuita
authors: University of North Carolina Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Kristina K
authors: KK
authors: Wolf
authors: Trypanosomiasis Research Centre, Kenya Agricultural Research Institute (TRC-KARI), Kikuyu, Kenya.
authors: Grace A
authors: GA
authors: Murilla
authors: 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.
authors: Arlene S
authors: AS
authors: Bridges
authors: Department of Chemistry, Georgia State University, Atlanta, Georgia, United States of America.
authors: David W
authors: DW
authors: Boykin
authors: Trypanosomiasis Research Centre, Kenya Agricultural Research Institute (TRC-KARI), Kikuyu, Kenya.
authors: James N
authors: JN
authors: Mutuku
authors: University of North Carolina Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Qiang
authors: Q
authors: Liu
authors: 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.
authors: Susan K
authors: SK
authors: Jones
authors: Trypanosomiasis Research Centre, Kenya Agricultural Research Institute (TRC-KARI), Kikuyu, Kenya.
authors: Charles O
authors: CO
authors: Gem
authors: SVC Associates, Inc., Apex, North Carolina, United States of America.
authors: Shelley
authors: S
authors: Ching
authors: 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.
authors: Richard R
authors: RR
authors: Tidwell
authors: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, United States of America.
authors: Michael Z
authors: MZ
authors: Wang
authors: University of North Carolina Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Mary F
authors: MF
authors: Paine
authors: Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors: Reto
authors: R
authors: Brun
mesh_terms: D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005663:Furans / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D058069:Neglected Diseases / Q000188:drug therapy* / Q000469:parasitology; D010419:Pentamidine / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014347:Trypanosoma brucei gambiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000578:Amidines; C555517:CPD 0801; D005663:Furans; D011355:Prodrugs; D014344:Trypanocidal Agents; D010419:Pentamidine
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