EFFECTS OF THE AGGREGATION STATE OF AMPHOTERICIN-B ON ITS TOXICITY TO MICE
EFFECTS OF THE AGGREGATION STATE OF AMPHOTERICIN-B ON ITS TOXICITY TO MICE
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DOI：
10.1128/aac.36.10.2310
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发表时间：
1992-10-01
影响因子：
4.9
通讯作者：
GRUDA, I
中科院分区：
文献类型：
--
作者：
BARWICZ, J;CHRISTIAN, S;GRUDA, I
两性霉素B（AmB）是一种治疗真菌感染的有效药物。然而，这种药物相对较高的毒性限制了其临床用途。目前这一领域的大部分工作都致力于寻找毒性较小的药物制剂。在这里，我们描述了三种表面活性剂，一种阴离子和其他两种非离子，对AmB在静脉注射到小鼠的溶液中的聚集状态的影响。AmB的聚集程度通过光谱和光散射监测。毒性以存活者的百分比表示。将这些结果与用与AmB的商业制剂Fungizone中存在的AmB剂量相同的AmB剂量获得的结果进行比较。两种表面活性剂，月桂基蔗糖和脱氧胆酸钠，使用的浓度，诱导单体化的AmB，大大降低了急性毒性的AmB小鼠。相反，第三种表面活性剂吐温80显示出抗生素毒性的协同增效作用。体内毒性与注射溶液中AmB的聚集状态之间存在良好的相关性。其中AmB几乎完全是单体的溶液在24小时后的毒性为一半，并且在1周后的毒性比相应的Fungizone溶液低约6倍。
Amphotericin B (AmB) is a very effective antifungal agent for most systemic fungal infections. However, the relatively high toxicity of this drug imposes limits on its clinical usefulness. Most of the current work in this field is devoted to the search for less-toxic formulations of the drug. Here we describe the effects of three surfactants, one anionic and the other two nonionic, on the aggregation state of AmB in solutions which were injected intravenously into mice. The degree of aggregation of AmB was monitored spectroscopically and by light scattering. The toxicity was expressed as percentage of survivors. These results were compared with those obtained with doses of AmB the same as those present in a commercial formulation of AmB, Fungizone. Two surfactants, lauryl sucrose and sodium deoxycholate, used at concentrations which induced monomerization of AmB, substantially decreased the acute toxicity of AmB to mice. Conversely, the third surfactant, Tween 80, showed a synergistic potentiation of the toxicity of the antibiotic. A good correlation was found between the in vivo toxicity and the aggregation state of AmB in injected solutions. Solutions in which AmB was almost entirely monomeric were half as toxic after 24 h and about six times less toxic after 1 week than the corresponding solutions of Fungizone.