Grögl M, Oduola A M, Cordero L D, Kyle D E
Division of Experimental Therapeutics, Walter Reed Army Medical Center, Washington, D.C. 20307-5100.
Exp Parasitol. 1989 Jul;69(1):78-90. doi: 10.1016/0014-4894(89)90173-2.
Antimony unresponsiveness in mucocutaneous and visceral leishmaniasis is a serious clinical problem. Information on the mechanisms and characteristics of drug resistance in parasites that suggest chemotherapeutic strategies to overcome resistance is of practical importance. We developed nine lines of Leishmania resistant to drugs, the major emphasis being on pentavalent antimony (Sb) complexed to carbohydrate in the form of sodium stibogluconate (Pentostam), one of the only two antileishmanial agents with a clearly favorable therapeutic index. Resistance to Pentostam (33- to 212-fold increase) was obtained in promastigotes of Leishmania in vitro by exposure to gradually increasing concentrations of drug over several passages. Resistance to Sb was found to be either stable or unstable. Stable resistance to Sb required (greater than 3) exposures of the initial sensitive clones to Pentostam and tended to stabilize with increased time under pressure. In general, resistance obtained in a clone after only a few (less than or equal to 3) step treatments was low and unstable. Differences in the susceptibility to Pentostam were found between strains isolated from patients with American cutaneous leishmaniasis. In addition, natural isolates of Leishmania from patients represented a heterogeneous population of parasites as demonstrated by a biphasic concentration response to Sb (typical of mixed population dynamics) and by marked differences in susceptibility to Pentostam among clones prepared from single isolates. These results suggest that the emergence of parasite resistance to antimonial treatment is a potential risk of inadequate dose therapy.
黏膜皮肤利什曼病和内脏利什曼病中锑无反应性是一个严重的临床问题。了解寄生虫耐药机制和特征，以提出克服耐药性的化疗策略具有实际意义。我们培育了9株对药物耐药的利什曼原虫株，主要侧重于对以葡萄糖酸锑钠（葡酸锑钠）形式与碳水化合物结合的五价锑（Sb）耐药，葡酸锑钠是仅有的两种治疗指数明显良好的抗利什曼原虫药物之一。通过在体外让利什曼原虫前鞭毛体在数代中逐渐接触浓度递增的药物，获得了对葡酸锑钠的耐药性（增加33至212倍）。发现对Sb的耐药性有稳定或不稳定之分。对Sb的稳定耐药性要求初始敏感克隆（超过3次）接触葡酸锑钠，并在压力下随着时间增加趋于稳定。一般来说，仅经过几次（小于或等于3次）逐步处理后在克隆中获得的耐药性较低且不稳定。从美洲皮肤利什曼病患者分离出的菌株对葡酸锑钠的敏感性存在差异。此外，从患者分离出的利什曼原虫天然分离株代表了寄生虫的异质群体，这通过对Sb的双相浓度反应（典型的混合群体动态）以及从单个分离株制备的克隆对葡酸锑钠敏感性的显著差异得以证明。这些结果表明，寄生虫对锑治疗产生耐药性是剂量治疗不足的潜在风险。
