Fig 1.
Structures of active diamidines and corresponding prodrugs.
Table 1.
Efficacy of intramuscular DB829 against second stage T. b. rhodesiense infection in vervet monkeys.
Table 2.
Efficacy of oral prodrug DB868 against second stage T. b. rhodesiense infection in vervet monkeys.
Fig 2.
Parasitaemia progression in vervet monkeys following infection.
Monkeys were infected with T. b. rhodesiense KETRI 2537 on Day 0. Symbols represent means and standard error of the mean (n = 16).
Fig 3.
White cell changes in the cerebrospinal fluid of infected monkeys treated with the diamidine prodrug DB868.
DB868 was administered orally at 20, 10, or 3 mg/kg/day for 10 days 28–37 days post-infection with T. b. rhodesiense KETRI 2537. M, male.
Table 3.
Time to clearance of trypanosomes from body fluids of monkeys treated with DB829 or DB868.
Fig 4.
Resolution of parasitaemia in infected vervet monkeys treated with the active diamidine DB829.
Monkeys were infected with T. b. rhodesiense KETRI 2537 and later confirmed to have progressed to second stage HAT, were administered with DB829 intramuscularly at (A) 5 mg/kg/day for 5 consecutive days (28–32 days post-infection), (B) 5 mg/kg/day for 5 alternate days (28, 30, 32, 34 and 36 days post-infection), or (C) 2.5 mg/kg/day for 5 consecutive days (28–32 days post-infection). F, female; M, male.
Fig 5.
Primary and relapse parasitaemia in infected vervet monkeys treated with the diamidine prodrug DB868.
DB868 was administered orally at (A) 20 mg/kg/day, (B) 10 mg/kg/day, or (C) 3 mg/kg/day for 10 consecutive days following infection with T. b. rhodesiense KETRI 2537 (28–37 days post-infection); the monkeys were confirmed to have progressed to second stage HAT before initiation of treatment. Relapse infections occurred at different times in specific individuals. Relapsed monkeys were rescue-treated with melarsoprol administered intravenously at 3.6 mg/kg/day for 4 consecutive days. F, female; M, male.
Fig 6.
Red blood cell density changes in infected vervet monkeys treated with experimental drugs.
Monkeys were infected with T. b. rhodesiense KETRI 2537 and upon confirmation of onset of second stage HAT, treated with (A) DB829 or (B) DB868. DB829 was administered intramuscularly for either 5 consecutive days (28–32 days post-infection) or 5 alternate (*) days (28, 30, 32, 34 and 36 days post-infection). DB868 was administered orally for 10 consecutive days (28–37 days post-infection). Symbols represent means (A; n = 2) or means and standard error of the mean (B; n = 4).
Table 4.
Changes in blood platelet and white cell counts following infection of monkeys with T. b. rhodesiense and subsequent treatment within tramuscular DB829 and oral DB868.
Fig 7.
White cell changes in the blood of three infected monkeys treated with the diamidine prodrug DB868.
DB868 was administered orally at 20 mg/kg/day (689M), 10 mg/kg/day (688M), or 3 mg/kg/day (687M) for 10 days after infection with T. b. rhodesiense KETRI 2537 (28–37 days post-infection). Confirmed relapses were rescue-treated with melarsoprol intravenously at 3.6 mg/kg/day for 4 consecutive days. White blood cell changes from (A) -14 to 93 days and (B) 93 to 268 days post-infection. M, male; WBC, white blood cells; LY, lymphocytes; GR, granulocytes. Dashed arrows, last DB868 dose; bold arrows, last melarsoprol dose.
Fig 8.
Plasma concentration-time profiles following administration of the active diamidine DB829 to infected vervet monkeys.
Monkeys confirmed to have second stage HAT were administered DB829 intramuscularly, beginning at 28 days post-infection with T. b. rhodesiense KETRI 2537, at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day for 5 alternate days or 2.5 mg/kg/day for 5 consecutive days. The inset graph shows the extended profile out to the end of the study. * denotes the time (91 days post-last drug dose) that monkey 659 was euthanized due to non-drug related complications (pneumonia). F, female; M, male.
Table 5.
Pharmacokinetics of DB829 in vervet monkeys with second stage HAT after the 5th intramuscular dose.
Fig 9.
Plasma concentration-time profiles of DB829 following administration of the diamidine prodrug DB868 to infected vervet monkeys.
Monkeys confirmed to have second stage HAT were administered DB868 orally, beginning at 28 days post-infection with T. b. rhodesiense KETRI 2537, at 20, 10 or 3 mg/kg/day for 10 consecutive days. The inset graph shows the extended profile out to the end of the study. * denotes the time that monkey 670 (1 day post-last drug dose), monkey 687 (82 days post-last drug dose) and monkey 696 (130 days post-last drug dose) were euthanized due to clinical morbidity. F, female; M, male.
Table 6.
Pharmacokinetics of DB829 Pharmacokinetics of DB829 in vervet monkeys with second stage HAT after the 10th oral dose of DB868.