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"African sleeping sickness, also called human African trypanosomiasis (HAT), results from the infection of humans with either of two protozoan parasites, Trypanosoma brucei gambiense and T. b. rhodesiense. HAT is transmitted by tsetse flies (Glossina spp) and, like the vector, is found exclusively in Africa between the latitudes 14° North and 29° South. A total of 50 million people live in foci where active transmission is possible and are therefore at risk of infection; however, the annual incidence and estimated prevalence currently stand at 7139 and 30 000 cases respectively. When trypanosomes are inoculated into a human host, the resulting clinical disease is classified into a first (early) stage in which trypanosomes are localised within the haemo-lymphatic system and a second (late) stage in which trypanosomes have crossed the blood brain barrier (BBB) and invaded the central nervous system (CNS). Currently, pentamidine and suramin are used to treat the first stage of T. b. gambiense and T. b. rhodesiense HAT, respectively. On the other hand, eflornithine and the nifurtimox eflornithine combination therapy (NECT) are the prefered treatments for second stage T. b. gambiense HAT. The organoarsenic drug melarsoprol may be used for both forms of HAT but is mainly used against T. b. rhodesiense. Clearly, the therapeutic options for HAT are very limited. In addition, available drugs are associated with different levels of toxicity, especially melarsoprol which causes a post treatment reactive encephalopathy (PTRE) in 5-10% of treated patients, up to 50% of PTRE patients may die. There are also reports of high melarsoprol treatment failure rates in some foci and there is a lack of easy to use oral formulations for all the drugs. We have carried out biological and pharmacological investigations of potential new drug candidates in animal models of HAT with the objective of contributing to the development of safe, efficacious and easy to use treatments for HAT. The studies were carried out in the context of a PhD programme at the Swiss TPH/University of Basel and were anchored onto an ongoing diamidines development project of the Consortium for Parasitic Drug Development (CPDD). Vervet monkeys (Chlorocebus [Cercopithecus] aethiops) were the main model for this study. To prepare for the studies in monkeys, one prodrug (DB289) was evaluated in mouse models of first stage HAT. We obtained good activities against different trypanosome isolates, including the one that is used in the monkey model, T. b. rhodesiense KETRI2537. We further evaluated the metabolism of the prodrugs in monkey liver microsomes. In all cases, prodrugs were metabolized to generate expected intermediate and active metabolites, thus allowing us to proceed to test the compounds for safety in un-infected monkeys. We determined that in monkeys: i) diamidine toxicity was dependent on the dose and duration of dosing, ii) the plasma concentrations of active metabolites were potentially therapeutic for HAT, and iii) the dose level at which there were no observed adverse effects (NOAEL). Three prodrugs (DB289, DB844 and DB868) and one active compound (DB829) were subsequently evaluated for efficacy at dose rates that were equal or below NOAEL. In general, the prodrugs were highly active against first stage HAT after oral administration and one prodrug (DB844) had additionally an improved activity (43%) in the second stage monkey HAT model in comparison with pentamidine (0%). The intramuscularly administered parent compound DB829 was fully curative in the second stage HAT model at 2.5 mg/kg x 5 days. Our findings suggest that the two compounds (oral DB868 and intramuscular DB829) should be recommended to enter the regulatory phase of development as potential HAT drugs. Oral DB868 cured the first stage HAT model at a daily dose of 3 mg/kg for 7 days (cumulative dose, CD = 21 mg/kg) compared to a maximum tolerated daily dose of 30 mg/kg for 10 days (CD = 300 mg/kg). The efficacy, safety and pharmacokinetic profiles suggest that this compound would be a useful clinical candidate using an optimal dosing duration of 5-7 days. The second compound, intramuscular DB829, cured the second stage HAT model at a daily dose of 2.5 mg/kg for 5 days and was tolerated at 5 mg/kg for 5 days (CD = 25 mg/kg). Pharmacokinetic analysis indicated the intramuscular administration of DB829 resulted in better systemic bioavailability, thus accounting for the improved efficacy in comparison with oral dosing." |
