Lincopan Nilton, Carmona-Ribeiro Ana M
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo CP 26077, Avenida Lineu Prestes 748-Butantã, CEP 05513-970, São Paulo-SP, Brazil.
J Antimicrob Chemother. 2006 Jul;58(1):66-75. doi: 10.1093/jac/dkl153. Epub 2006 Apr 24.
Coverage of antifungal drug particles (miconazole and amphotericin B) with cationic lipid and evaluation of a synergistic action between lipid and drug.
Miconazole and amphotericin B were mixed with cationic bilayer fragments (BF) of dioctadecyldimethylammonium bromide (DODAB) at extreme drug to lipid molar proportions (P). Light scattering for particle sizing and zeta-potential analysis evaluated effects of cationic lipid on drug particle size and charge. Colony counts evaluated viability of Candida spp. and Cryptococcus neoformans over a range of P.
BF loading capacity for monomeric amphotericin B is 0.1 mM amphotericin B at 2 mM DODAB (P = 1:20). Above this low P, amphotericin B aggregates in the dispersion. At high P, addition of chaotropic K2HPO4 (0.2-2 mM) converts miconazole or amphotericin B aggregates into negatively charged particles with affinity for cationic lipid, which then surrounds each drug particle with a cationic layer. The combined in vitro action of lipid-covered drug particles against Candida and C. neoformans depends on P and interaction time. DODAB by itself kills C. neoformans and Candida at 2 and 2 to > 250 mg/L minimal fungicidal concentration (MFC). In combination, over the first hour, fungicidal activity is due to DODAB with lipid capsules retarding drug action. At 48 h interaction time and 10(4) cfu/mL, MFC (mg/L) against Candida albicans is reduced from 4 to 1 amphotericin B (at 2 DODAB), and from 8 to 1 miconazole (at 1 DODAB).
DODAB may be a suitable candidate for use in combination with miconazole for antifungal therapy.
用阳离子脂质包裹抗真菌药物颗粒（咪康唑和两性霉素B）并评估脂质与药物之间的协同作用。
将咪康唑和两性霉素B与二辛基二甲基溴化铵（DODAB）的阳离子双层片段（BF）以极高的药物与脂质摩尔比（P）混合。通过光散射进行粒度分析和ζ电位分析，评估阳离子脂质对药物颗粒大小和电荷的影响。通过菌落计数评估一系列P值下白色念珠菌和新型隐球菌的生存能力。
在2 mM DODAB（P = 1:20）时，BF对单体两性霉素B的负载能力为0.1 mM两性霉素B。高于这个低P值时，两性霉素B在分散体中聚集。在高P值下，加入离液剂K2HPO4（0.2 - 2 mM）可将咪康唑或两性霉素B聚集体转化为带负电荷的颗粒，这些颗粒对阳离子脂质具有亲和力，然后阳离子脂质会用阳离子层包裹每个药物颗粒。脂质包裹的药物颗粒对白色念珠菌和新型隐球菌的体外联合作用取决于P值和相互作用时间。DODAB自身在最低杀菌浓度（MFC）为2和2至>250 mg/L时可杀死新型隐球菌和白色念珠菌。联合使用时，在最初一小时内，杀菌活性归因于DODAB，脂质胶囊会延缓药物作用。在48小时的相互作用时间和10(4) cfu/mL时，针对白色念珠菌的MFC（mg/L）从4降至1（两性霉素B在2 DODAB时），从8降至1（咪康唑在1 DODAB时）。
DODAB可能是与咪康唑联合用于抗真菌治疗的合适候选物。
