Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis
Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis
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DOI：
10.1128/aac.00090-17
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发表时间：
2017-06-01
影响因子：
4.9
通讯作者：
Hope, William
中科院分区：
文献类型：
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作者：
Lestner, Jodi;McEntee, Laura;Hope, William
隐球菌脑膜脑炎是一种免疫功能低下的患者迅速致命的感染。诱导方案通常给药2周。脂质体阿霉素B（LAMB）诱导治疗的最短有效期未知。在隐球菌脑膜脑炎小鼠和兔模型中研究了LAMB的药效学。使用高效液相色谱法（HPLC）测定小鼠血浆和脑中LAMB的浓度。测定组织学变化。通过免疫组织化学，使用针对阿替霉素B的抗体测定LAMB向脑中的渗透。在小鼠脑中观察到真菌负荷呈剂量依赖性下降，LAMB在10 - 20 mg/kg/天剂量下达到接近最大疗效。脑中的终末消除半衰期为133 h。20 mg/kg单次给药的药效学与20 mg/kg/天给药2周的药效学相同。定量计数的变化通过脑组织病理学变化反映。需要在兔中以5 mg/kg/天的三个剂量的LAMB以在脑脊液中实现杀真菌活性（浓度-时间曲线下的累积面积，2，500 mg . h/升）。在血管内和血管周围间隙、软脑膜和脉络丛中可见两性霉素B。延长的平均停留时间的阿替霉素B在大脑中表明，LAMB的简化诱导方案是可能的隐球菌脑膜脑炎。
Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2 weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAMB) is unknown. The pharmacodynamics of LAMB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAMB in the plasma and brains of mice were measured using high-performance liquid chromatography (HPLC). Histopathological changes were determined. The penetration of LAMB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brains of mice, with near-maximal efficacy achieved with LAMB at 10 to 20 mg/kg/day. The terminal elimination half-life in the brain was 133 h. The pharmacodynamics of a single dose of 20 mg/kg was the same as that of 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAMB at 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative area under the concentration-time curve, 2,500 mg . h/liter). Amphotericin B was visible in the intra-and perivascular spaces, the leptomeninges, and the choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggests that abbreviated induction regimens of LAMB are possible for cryptococcal meningoencephalitis.