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.

Diglycosyl diselenides alter redox homeostasis and glucose consumption of infective African trypanosomes

“…Arsenobenzene derivatives of melamine: melarsene, melarsene oxide and melarsoprol have also long been known and are still being used against human African trypanosomiasis (HAT; sleeping sickness). The third group of anti-HAT structures comprises aromatic bis(amidines) like pentamidine or DB289 ( Thuita et al., 2015 ). Nifurtimox has long been in use for the treatment of Trypanosoma cruzi -induced Chagas disease but it has recently been found effective against sleeping sickness, particularly in combination with eflornithine, itself an anti-HAT drug.…”

The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

“…However, DB829 (2,5-bis(5-amidino-2-pyridyl)furan; (9)), a close analogue of furamidine, did display remarkable efficacy against cerebral trypanosomiasis in mice and in vervet monkeys [42,43]. This was taken as evidence that DB829 is either recognized more efficiently than furamidine by a BBB transporter importing it into the CSF, or less efficiently extruded from the CSF by a P-gp-type transporter; both compounds have a similar pK a and are dications at physiological pH, precluding any notion that they could simply diffuse across the barrier.…”

Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents

“…The development of a novel prodrug from the bisbenzamidine class, parafuramidine maleate (DB289) against HAT and Pneumocystis pneumonia, was halted in a phase III sleeping sickness clinical trial because of nephrotoxicity in healthy volunteers [ 6 ]. Despite this setback, there is considerable interest in developing novel and safer bisbenzamidines [ 7 ] and several of these compounds are in various stages of drug development [ 8 ].…”