Takemoto Koji, Yamamoto Yutaka, Ueda Yutaka
Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan.
Microbiol Immunol. 2006;50(8):579-86. doi: 10.1111/j.1348-0421.2006.tb03832.x.
A liposomal formulation of Amphotericin B (AmBisome), with small unilamellar vesicles containing amphotericin B, shows characteristic pharmacokinetics as liposomes, and in consequence, has different pharmacological activity and toxicity from amphotericin B deoxycholate (Fungizone). In this study, we evaluated the antifungal pharmacodynamic characteristics of AmBisome against Candida albicans using the in vitro time-kill method and murine systemic infection model. A time-kill study indicated that the in vitro fungicidal activities of AmBisome and Fungizone against C. albicans ATCC 90029 increased with increasing drug concentration. For in vivo experiments, leucopenic mice were infected intravenously with the isolate 4 hr prior to the start of therapy. The infected mice were treated for 24 hr with twelve dosing regimens of AmBisome administered at 8-, 12-, 24-hr dosing intervals. Correlation analysis between the fungal burden in the kidney after 24 hr of therapy and each pharmacokinetic/pharmacodynamic parameter showed that the peak level/MIC ratio was the best predictive parameter of the in vivo outcome of AmBisome. These results suggest that AmBisome, as well as Fungizone, has concentration-dependent antifungal activity. Furthermore, since AmBisome can safely achieve higher concentrations in serum than Fungizone, AmBisome is thought to have superior potency to Fungizone against fungal infections.
两性霉素B的脂质体制剂（安必素），其小单层囊泡中含有两性霉素B，具有脂质体特有的药代动力学，因此，其药理活性和毒性与两性霉素B脱氧胆酸盐（两性霉素B）不同。在本研究中，我们使用体外时间杀菌法和小鼠全身感染模型评估了安必素对白色念珠菌的抗真菌药效学特征。一项时间杀菌研究表明，安必素和两性霉素B对白色念珠菌ATCC 90029的体外杀菌活性随药物浓度增加而增强。对于体内实验，在治疗开始前4小时，给白细胞减少的小鼠静脉注射分离株。感染的小鼠用安必素的12种给药方案治疗24小时，给药间隔为8、12、24小时。治疗24小时后肾脏中的真菌负荷与每个药代动力学/药效学参数之间的相关性分析表明，峰浓度/MIC比值是安必素体内疗效的最佳预测参数。这些结果表明，安必素以及两性霉素B具有浓度依赖性抗真菌活性。此外，由于安必素在血清中能够比两性霉素B更安全地达到更高的浓度，因此认为安必素在抗真菌感染方面比两性霉素B具有更高的效力。
