Trypanosoma brucei brucei: antitrypanosomal evaluation of stilbamidinium hexachloroiridiate on the murine CNS model and iridium serum kinetics in infected sheep.

Abstract

Stilbamidinium hexachloroiridiate was found trypanocidal in vitro against Trypanosoma brucei brucei IPP at 600 microM after a 1 h incubation period and 30 microM after 24 h. This activity was confirmed in mice with a subcutaneous treatment at 20 mg/kg in a single dose. It was then evaluated on T.b. brucei murine CNS model. At the early stage, a subcutaneous treatment at 2 mg/kg/day x 5 cured 50% mice where-as one single dose at 10 mg/kg was completely inactive. Higher doses failed to cure the mice. Nevertheless, hexachloroiridiate salt of stilbamidine was 3.3 fold less toxic than dihydrochloride salt. Although the compound appeared inactive at the late stage of the murine trypanosomiasis, the difference of toxicity justified its evaluation on the early stage of sheep trypanosomiasis. The compound was trypanocidal at 2 mg/kg in a single dose when administered 8 days after infection. The study of iridium serum kinetic showed that stilbamidinium hexachloroiridiate was distributed rapidly according to a monocompartmental model. Moreover, iridium persisted in serum for a long time. The compound in aqueous suspension with 1% carboxymethylcellulose acted therefore as a controlled release system with a bioavailability allowing its trypanocidal action at the early stage.