The antitrypanosomal activity of two 5-substituted 2-nitro-imidazoles (
Ro 15-0216 and
benznidazole) and alpha-DL-difluoro-methylornithine (DFMO) was tested in four stocks of Trypanosoma brucei brucei in vitro. The IC50 (
drug concentration which inhibits growth of trypanosome populations by 50%) values ranged from 0.27-1.0 for
Ro 15-0216, 84-265 for
benznidazole, and 147-691 microM for DFMO. Potentiation of antitrypanosomal activity of the combination of
Ro 15-0216 and DFMO was demonstrated in a 24 h growth inhibition test. A synergistic effect was also demonstrated when
benznidazole and DFMO were combined in a long term viability assay in vitro. Although 40 microM DFMO and 20 microM
benznidazole were ineffective when used individually, trypanosomes of all stocks were killed when both drugs were present simultaneously at these concentrations. The combination of 40 microM DFMO and 4 microM
benznidazole led to growth suppression. At an early stage of
infection, a single injection of 100 mg/kg
Ro 15-0216 at the end of a 3-day treatment period with DFMO (2% in
drinking water) resulted in a 100% cure of T. b. brucei-infected mice, whereas monotherapy with either
drug at the same dose levels was completely ineffective.
Nitroimidazoles and DFMO given simultaneously might improve the
therapy of human sleeping sickness.