Roberts W L, Rainey P M
Department of Laboratory Medicine, Yale University, New Haven, Connecticut 06510.
Antimicrob Agents Chemother. 1993 Sep;37(9):1842-6. doi: 10.1128/AAC.37.9.1842.
Sodium stibogluconate, a pentavalent antimony derivative produced by the reaction of stibonic and gluconic acids, is the drug of choice for the treatment of leishmaniasis. It has been reported to be a complex mixture rather than a single compound. We separated sodium stibogluconate into 12 fractions by anion-exchange chromatography. One fraction accounted for virtually all the leishmanicidal activity of the fractionated material against Leishmania panamensis promastigotes, with a 50% inhibitory concentration (IC50) of 12 micrograms of Sb per ml; that of unfractionated sodium stibogluconate was 154 micrograms of Sb per ml. Further analysis of this active fraction revealed that a major component was m-chlorocresol, which had been included in the sodium stibogluconate formulation as a preservative. The IC50 of pure m-chlorocresol was 1.6 micrograms/ml, a concentration equivalent to that present in unfractionated sodium stibogluconate at a concentration of 160 micrograms of Sb per ml. After ether extraction to remove m-chlorocresol, the IC50 of sodium stibogluconate was > 4,000 micrograms of Sb per ml. In contrast, when L. panamensis amastigotes were grown in macrophages, the IC50 of ether-extracted sodium stibogluconate was 10.3 micrograms of Sb per ml. The 12 fractions of ether-extracted sodium stibogluconate obtained by anion-exchange chromatography had IC50s of 10.1 to 15.4 micrograms of Sb per ml. We conclude that preservative-free sodium stibogluconate has little activity against L. panamensis promastigotes but is highly active against L. panamensis amastigotes in macrophages. This activity is associated with multiple chemical species.
葡萄糖酸锑钠是由锑酸和葡萄糖酸反应生成的五价锑衍生物，是治疗利什曼病的首选药物。据报道，它是一种复杂混合物而非单一化合物。我们通过阴离子交换色谱法将葡萄糖酸锑钠分离成12个馏分。其中一个馏分几乎占了分级分离物质对巴拿马利什曼原虫前鞭毛体所有的杀利什曼活性，其50%抑制浓度（IC50）为每毫升12微克锑；未分级的葡萄糖酸锑钠的IC50为每毫升154微克锑。对该活性馏分的进一步分析表明，主要成分是间氯甲酚，它作为防腐剂包含在葡萄糖酸锑钠制剂中。纯间氯甲酚的IC50为1.6微克/毫升，该浓度相当于未分级的葡萄糖酸锑钠中每毫升含160微克锑时的浓度。用乙醚萃取以去除间氯甲酚后，葡萄糖酸锑钠的IC50大于每毫升4000微克锑。相比之下，当巴拿马利什曼原虫无鞭毛体在巨噬细胞中生长时，经乙醚萃取的葡萄糖酸锑钠的IC50为每毫升10.3微克锑。通过阴离子交换色谱法获得的经乙醚萃取的葡萄糖酸锑钠的12个馏分的IC50为每毫升10.1至15.4微克锑。我们得出结论，无防腐剂的葡萄糖酸锑钠对巴拿马利什曼原虫前鞭毛体几乎没有活性，但对巨噬细胞中的巴拿马利什曼原虫无鞭毛体具有高度活性。这种活性与多种化学物质有关。
