烯丙胺SF 86 - 327与酮康唑对克氏锥虫（裂殖锥虫）前鞭毛体和无鞭毛体的抗增殖协同作用。
Antiproliferative synergism of the allylamine SF 86-327 and ketoconazole on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi.
作者信息
Urbina J A, Lazardi K, Aguirre T, Piras M M, Piras R
机构信息
Centro de Biologia Celular, Escuela de Biologia, Facultad de Ciencias, Universidad Central de Venezuela, Caracas.
出版信息
Antimicrob Agents Chemother. 1988 Aug;32(8):1237-42. doi: 10.1128/AAC.32.8.1237.
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 degrees C was immediately arrested by any of these drugs at greater than or equal to 3 x 10(-5) M; cell lysis occurred 24 h later. Below that concentration, SF 86-327 at concentrations down to 1 x 10(-6) M stopped growth after 48 h. In contrast, ketoconazole slowed cell growth only moderately, but proliferation finally stopped and cell lysis occurred after 120 h at 3 x 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 x 10(-6) M ketoconazole, which by itself reduced growth only by 30%. Amastigotes, proliferating in Vero cells at 37 degrees 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 x 10(-7) M and that required to completely eradicate the parasite was 3 x 10(-6) M, for ketoconazole these concentrations were 1 x 10(-10) M and 1 x 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 froms 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 reduced the proliferation of these cells by 50%.
我们研究了两种麦角甾醇生物合成抑制剂，二氧戊环咪唑酮康唑和烯丙胺SF 86 - 327单独及联合使用时，对恰加斯病病原体克氏锥虫（裂殖锥虫）增殖阶段的生长抑制作用。在28摄氏度的肝浸液 - 胰蛋白胨培养基中，当这些药物中的任何一种浓度大于或等于3×10⁻⁵ M时，无鞭毛体的增殖会立即停止；24小时后细胞发生裂解。低于该浓度时，浓度低至1×10⁻⁶ M的SF 86 - 327在48小时后停止生长。相比之下，酮康唑仅适度减缓细胞生长，但在3×10⁻⁶ M时，增殖最终停止且细胞在120小时后发生裂解。当两种药物联合使用时可观察到协同作用：在存在1×10⁻⁶ M酮康唑的情况下，将细胞生长在144小时内降至对照的25%所需的SF 86 - 327浓度降低了33倍，而酮康唑自身仅使生长降低30%。在37摄氏度的Vero细胞中增殖的无鞭毛体对两种药物更敏感，但在该系统中酮康唑肯定比烯丙胺更具强效抗寄生虫作用：将感染细胞数量降至对照的50%所需的SF 86 - 327浓度为1×10⁻⁷ M，完全根除寄生虫所需的浓度为3×10⁻⁶ M，而对于酮康唑，这些浓度分别为1×10⁻¹⁰ M和1×10⁻⁸ M。同样，当联合使用药物时观察到强烈的协同作用：在存在10⁻¹¹ M酮康唑的情况下，将感染细胞数量降至对照的50%所需的SF 86 - 327浓度降低了100倍，而酮康唑自身对无鞭毛体增殖无影响。当两种药物以低至10⁻⁹ M的浓度联合使用时，寄生虫被完全根除。药物对寄生虫两种形态的抗增殖作用的协同性通过凹形等效线图进一步得到证明。另一方面，10⁻⁵ M的SF 86 - 327对Vero细胞的增殖无影响，而10⁻⁷ M的酮康唑使这些细胞的增殖降低了50%。
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