TRYPANOCIDAL EFFECT OF IR-(COD)-PENTAMIDINE TETRAPHENYLBORATE ON TRYPANOSOMA-BRUCEI AND T-B-GAMBIENSE RODENT MODELS AND SERUM KINETICS IN SHEEP

Pentamidine di-(iridium cyclo-octadiene)tetraphenylborate, called Ir-( COD)-pentamidine tetraphenylborate, was selected from a primary screen ing as a promising trypanocidal compound. The compound was evaluated a gainst three isolates: Trypanosoma brucei brucei CMP, T. b. brucei GVR 35 and T. b. gambiense Fee. On the T. b. brucei GVR 35 murine CNS mod el, no mouse was cured when the treatment was commenced 21 days post-i nfection whatever the treatment regimen. Nevertheless, in vitro the co mpound killed the trypomastigote forms of T. b. gambiense Feo at 0.6 m u M. In vivo, the compound cured all mice infected I hour previously w ith T. b. gambiense Feo after a 10 mg/kg (6.3 mu mol/kg) treatment sub cutaneously administered in a single dose. Moreover, the compound was active at I mg/kg (0.6 mu mol/kg) in a single dose against the early s tage of the T. b. brucei Antat 1-9 sheep model. Serum kinetics data sh owed that pentamidine di-(iridium cyclo-octadiene) tetraphenylborate w as distributed within deep compartment according to a monocompartmenta l model. The maximum iridium serum concentration was 198 mu g/l corres ponding to I mu mol/kg of iridium derivative and this value remained s table for 30-50 hours post-treatment. Iridium was completely eliminate d from the serum 700 hours post-treatment. All data obtained from thes e models are in favour of an activity in the early stage of the diseas e but indicate that the compound could not cross the blood-brain barri er despite its lipophilicity. Although iterative treatments with the c ompound rapidly induced the selection of iridium derivative refractory populations, the compound could be studied on pentamidine refractory strains.