High purity amphotericin B.
High purity amphotericin B.
复制标题
DOI：
10.1093/jac/dkm322
复制
发表时间：
2007-12
期刊：
影响因子：
--
通讯作者：
J. Cleary;S. Chapman;E. Swiatlo;R. Kramer
中科院分区：
文献类型：
--
作者：
J. Cleary;S. Chapman;E. Swiatlo;R. Kramer
两性霉素B （AmB）是治疗播散性真菌感染的首选药物，但其使用通常伴有严重的不良反应。我们观察到AmB的通用配方含有多种多烯成分，这使我们提出去除其他多烯将产生高纯度的AmB (AmBHP)，并提高治疗指数。方法采用半制备反相高压液相色谱法，从仿制药AmB中分离出AmBHP，并将其体外和体内药效与市售AmB制剂进行比较。结果AmBHP在体外对白色念珠菌具有与普通AmB相同的活性，在念珠菌感染小鼠模型中与普通AmB和脂质复合AmB同样有效。在低浓度（<2微米）下，AmBHP对人THP-1单核细胞的毒性似乎低于通用AmB，这是通过排除台斑蓝和加入[(3)H]胸腺嘧啶所表明的。在较高浓度下，AmBHP和仿制AmB （Pharma-Tek AmB, PTAmB）对胸腺嘧啶掺入和胞质钙浓度的影响相似。AmBHP在体内的一般毒性，根据其表观LD（50）和念珠菌感染小鼠的存活率显示，大约比普通或脂质复合物AmB低两倍。同样，AmBHP降低平均肾小球滤过率的效果是低剂量PTAmB 10倍的一半。综上所述，这些数据表明AmBHP可能代表了目前上市的AmB制剂的改进，即使不是更好，也能提供相同的疗效和更低的毒性。
OBJECTIVES Amphotericin B (AmB) is a drug of choice for treatment of disseminated fungal infections, but its use is often associated with severe adverse effects. Our observation that generic formulations of AmB contain multiple polyene components led us to propose that removal of other polyenes would yield a high purity AmB (AmBHP) with an improved therapeutic index. METHODS To test that premise, AmBHP was first isolated from generic AmB by semi-preparative reverse phase high-pressure liquid chromatography and then its effects were compared in vitro and in vivo with those of commercial AmB formulations. RESULTS AmBHP proved to be as active as generic AmB against Candida albicans in vitro and as efficacious as both generic and lipid-complexed AmB in a Candida-infected mouse model. AmBHP appeared to be less toxic to human THP-1 monocytic cells than was generic AmB at low concentrations (<2 microM), as indicated by exclusion of Trypan Blue and incorporation of [(3)H]thymidine. At higher concentrations, effects of AmBHP and generic AmB (Pharma-Tek AmB, PTAmB) on thymidine incorporation and cytosolic calcium concentration were similar. General toxicity to AmBHP in vivo, as indicated by its apparent LD(50) and survival of Candida-infected mice, was roughly twofold less than that to generic or lipid-complexed AmB. Likewise, AmBHP decreased mean glomerular filtration rate about half as much as did a 10-fold lower dose of PTAmB. CONCLUSIONS Taken together, these data indicate that AmBHP may represent a refinement of currently marketed AmB formulations, offering equal, if not better, efficacy with less toxicity.