Brajtburg J, Bolard J
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Clin Microbiol Rev. 1996 Oct;9(4):512-31. doi: 10.1128/CMR.9.4.512.
Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.
两性霉素B（AmB）是治疗大多数系统性真菌感染的首选药物，以商标名Fungizone销售，是一种适用于静脉给药的AmB - 脱氧胆酸盐复合物。AmB与脱氧胆酸盐之间的结合相对较弱；因此，在血液中会发生解离。该药物本身与哺乳动物和真菌细胞膜相互作用以损伤细胞，但真菌细胞对其作用更敏感，这构成了其临床应用的基础。该药物与脂质形成稳定复合物的能力促使基于此特性开发了AmB的新制剂。已经开发出几种基于脂质的制剂，这些制剂在损伤真菌或寄生虫细胞方面比哺乳动物细胞更具选择性，其中一些制剂的治疗指数也优于Fungizone。体外研究得出的结论是，观察到的选择性增加是由于AmB从脂质复合物选择性转移到真菌细胞，或者是由于脂质制剂具有更高的热力学稳定性。与脂质结合可调节AmB在体内与脂蛋白的结合，从而影响组织分布和毒性。例如，AmB的脂质复合物可被巨噬细胞内化，然后巨噬细胞充当药物的储存库。此外，稳定的AmB - 脂质复合物对宿主的毒性比Fungizone小得多，因此可以更高剂量给药。在实验中，与Fungizone相比，AmB - 脂质制剂的疗效取决于所使用的动物模型。在临床试验中已证明AmB - 脂质制剂的治疗指数有所改善，但尚未进行确定最佳制剂和治疗方案选择的决定性试验。
