Parasitaemia progression in vervet monkeys following infection.

<p>Monkeys were infected with <i>T. b. rhodesiense</i> KETRI 2537 on Day 0. Symbols represent means and standard error of the mean (n = 16).</p

Pharmacokinetics of DB829 Pharmacokinetics of DB829 in vervet monkeys with second stage HAT after the 10^th oral dose of DB868.

<p>T_max, time to reach C_max; C_max, maximum concentration; AUC_0–63, AUC from 0 to 63 days; t_½, terminal half-life; F, female; M, male; NC, not calculable;</p><p>* = data was too sparse to determine the T_max, C_max, AUC_0–63, and t_½ with confidence;</p><p>^† = data was too sparse to determine the AUC_0–63, and t_½ with confidence;</p><p>^‡ = data was insufficient in the terminal phase to determine the t_½ with confidence.</p><p>Pharmacokinetics of DB829 Pharmacokinetics of DB829 in vervet monkeys with second stage HAT after the 10^th oral dose of DB868.</p

White cell changes in the blood of three infected monkeys treated with the diamidine prodrug DB868.

<p>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 <i>T. b. rhodesiense</i> 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 (<b>A</b>) -14 to 93 days and (<b>B</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.</p

Pharmacokinetics of DB829 in vervet monkeys with second stage HAT after the 5^th intramuscular dose.

<p>Group 1 = 5 mg/kg × 5 consecutive days; Group 2 = 5 mg/kg × 5 alternating days; Group 3 = 2.5 mg/kg × 5 consecutive days; F, female; M, male; T_max, time to reach C_max; C_max, maximum concentration; AUC_last, AUC from time 0 to the last measurable concentration; AUC_(0-∞), AUC from 0 to infinite time; Cl/F, apparent clearance; t_½, terminal half-life;</p><p>^† = last measurable concentration varied between monkeys (112–490 days).</p><p>Pharmacokinetics of DB829 in vervet monkeys with second stage HAT after the 5^th intramuscular dose.</p

Structures of active diamidines and corresponding prodrugs.

<p>Structures of active diamidines and corresponding prodrugs.</p

Plasma concentration-time profiles of DB829 following administration of the diamidine prodrug DB868 to infected vervet monkeys.

<p>Monkeys confirmed to have second stage HAT were administered DB868 orally, beginning at 28 days post-infection with <i>T. b. rhodesiense</i> 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.</p

Red blood cell density changes in infected vervet monkeys treated with experimental drugs.

<p>Monkeys were infected with <i>T. b. rhodesiense</i> KETRI 2537 and upon confirmation of onset of second stage HAT, treated with (<b>A</b>) DB829 or (<b>B</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 (<b>A</b>; n = 2) or means and standard error of the mean (<b>B</b>; n = 4).</p

Changes in blood platelet and white cell counts following infection of monkeys with <i>T. b. rhodesiense</i> and subsequent treatment within tramuscular DB829 and oral DB868.

<p>Key: d, day;DPI, days post-infection; DPT, days post-treatment (post-last drug dose of DB829 or DB868); a, consecutive-day dosing; b, alternate-day dosing; PLT, platelet counts;WBC, white blood cell counts; N/A, not applicable; S, <i>p</i> < 0.05 (repeated measures ANOVA with Fisher’s PLSD post hoc test).</p><p>Changes in blood platelet and white cell counts following infection of monkeys with <i>T. b. rhodesiense</i> and subsequent treatment within tramuscular DB829 and oral DB868.</p

Plasma concentration-time profiles following administration of the active diamidine DB829 to infected vervet monkeys.

<p>Monkeys confirmed to have second stage HAT were administered DB829 intramuscularly, beginning at 28 days post-infection with <i>T. b. rhodesiense</i> 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.</p

Primary and relapse parasitaemia in infected vervet monkeys treated with the diamidine prodrug DB868.

<p>DB868 was administered orally at (<b>A</b>) 20 mg/kg/day, (<b>B</b>) 10 mg/kg/day, or (<b>C</b>) 3 mg/kg/day for 10 consecutive days following infection with <i>T. b. rhodesiense</i> 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.</p