Biological and pharmacological investigations of novel diamidines in animal models of human African trypanosomiasis

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