In Vitro and In Vivo Activities of Trybizine Hydrochloride against Various Pathogenic Trypanosome Species

Abstract

ABSTRACT Trybizine hydrochloride [ O , O′- bis(4,6-diamino-1,2-dihydro-2,2-tetramethylene- s- triazine-1-yl)-1,6-hexanediol dihydrochloride] was active in vitro against the sleeping sickness-causing agents Trypanosoma brucei subsp. rhodesiense and T. brucei subsp. gambiense ; against a multidrug-resistant organism, T. brucei subsp. brucei ; and against animal-pathogenic organisms Trypanosoma evansi , Trypanosoma equiperdum , and Trypanosoma congolense ; but not against the intracellular parasites Trypanosoma cruzi and Leishmania donovani . Cytotoxic effects against mammalian cells were observed at approximately 10 6 -fold higher concentrations than those necessary to inhibit T. brucei subsp. rhodesiense . Trybizine hydrochloride was able to eliminate T. brucei subsp. rhodesiense and T. brucei subsp. gambiense in an acute rodent model with four intraperitoneal doses of 0.25 mg kg of body weight −1 or four doses of 1 mg kg −1 , respectively, or with four oral doses of 20 mg kg −1 . The compound expressed activity against suramin-resistant T. evansi strains in mice. However, these concentrations were not sufficient to cure mice infected with multidrug-resistant T. brucei subsp. brucei . A late-stage rodent model with central nervous system involvement could not be cured, indicating that trybizine may not pass the blood-brain barrier in sufficient quantities.