Trypanosoma brucei: An evaluation of salicylhydroxamic acid as a trypanocidal drug

The chemotherapeutic potential of salicylhydroxamic acid (SHAM) was studied in adult rats infected with a strain of Trypanosoma brucei that kills the rats in about 100 hr. The median lethal dose, administered intraperitoneally in a carboxymethyl-cellulose suspension, is approximately 820 mg/kg body weight for male and 850 mg/kg for female rats. The apparent cause of death is severe depression of the central nervous system.Half-maximal inhibition of O₂ uptake by trypanosomes in vitro requires 15 μM SHAM, whereas 100 μM inhibits over 90%. This inhibitory effect on trypanosome respiration was used as a biological assay for the effective SHAM concentration in rat plasma. After administration of a sublethal SHAM dose to rats, the effective plasma SHAM concentration rose rapidly to about 500 μM and then fell to about 10 μM at 4 hr. Nevertheless, this dose did not significantly affect the survival time of rats infected with T. brucei. Even if, by repeated SHAM administration, the plasma SHAM concentration was kept at around 100 μM for more than 4 hr, no therapeutic effect was observed.These results show that O₂ uptake is not essential for the survival of trypanosomes in rats and they support the idea that bloodstream trypanosomes have an alternative pathway for glycolysis, allowing energy production in the absence of respiration.The possibility that SHAM or other inhibitors of trypanosome respiration could stilll be trypanocidal if used in conjunction with another inhibitor of glycolysis is discussed.