Antiproliferative synergism of the allylamine SF 86-327 and ketoconazole on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi

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Abstract
We have investigated the growth-inhibitory effects of two ergosterol biosynthesis inhibitors, the dioxolane imidazole ketoconazole and the allylamine SF 86-327, alone and in combination, on the proliferative stages of Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas'' disease. Proliferation of epimastigotes in liver infusion-tryptose medium at 28.degree. C was immediately arrested by any of these drugs at .gtoreq. 3 .times. 10-5 M; cell lysis occurred 24 h later. Below that concentration, SF 86-327 at concentrations down to 1 .times. 10-6 M stopped growth after 48 h. In contrast, ketoconazole slowed cell growth only moderatley, but proliferation finally stopped and cell lysis occurred after 120 h at 3 .times. 10-6 M. Synergistic effects could be observed when the two drugs were used in combination: the concentration of SF 86-327 required to reduce the cell growth to 25% of controls in 144 h was reduced 33-fold in the presence of 1 .times. 10-6 M ketoconazole, which by itself reduced growth only by 30%. Amastigotes, proliferating in Vero cells at 37.degree. C, were much more susceptible to both drugs, but ketoconazole was definitely a more potent antiparasitic agent than the allylamine in this system: whereas the concentration of SF 86-327 required to reduce the number of infected cells to 50% of controls was 1 .times. 10-7 M and that required to completely eradicate the parasite was 3 .times. 10-6 M, for ketoconazole these concentrations were 1 .times. 10-10 M and 1 .times. 10-8 M, respectively. Again, strong synergistic effects were observed when the drugs were used in combination: the concentration of SF 86-327 required to reduce the number of infected cells to 50% of controls was 100-fold lower in the presence of 10-11 M ketoconazole, which by itself had no effects on amastigote proliferation. The parasite was completely eradicated when the drugs were used in combination at concentrations as low as 10-9 M. Synergy of the antiproliferative effects of the drugs on both forms of the parasite was further demonstrated by concave isobolograms. On the other hand, SF 86-327 at 10-5 M had no effects on the proliferation of Vero cells, whereas ketoconazole at 10-7 M redcued the proliferation of these cells by 50%.