脂质体两性霉素B

脂质体两性霉素Ｂ（ＬＡｍＢ）是由两性霉素Ｂ（ＡｍＢ）蚀埋入小的单层脂质体形成，改变了此药的药物动力学特性，而保存其显著的体内外抗真菌（包括白色念球菌、曲霉、隐球菌）活性及抗利什曼原虫活性，且毒性明显减少，ＬＡｍＢ最被美国食品与药品管理局批准的第一个治疗的内脏利什曼原虫（ＶＬ）的新药。其临床应用日益受到重视。     

两性霉素B与两性霉素B脂质体不良反应文献分析

目的探讨两性霉素B与两性霉素B脂质体所致不良反应的一般规律和特点,为临床合理用药提供参考。方法在CHKD期刊全文数据库、维普医药信息系统、万方数据医药系统、Medline数据库检索1977－2013年有关两性霉素B与两性霉素B脂质体不良反应的文献,并进行统计分析。结果共收集两性霉素B不良反应病例40例,两性霉素B脂质体不良反应病例24例,涉及的反应系统有泌尿系统、肝胆系统、离子紊乱、循环系统和消化系统等。结论两性霉素B与两性霉素B脂质体引起的不良反应相似,但应注意某些特殊不良反应。临床上应该做到合理用药,减少不良反应的发生。     

两性霉素B脂质体的制备及稳定性研究

采用薄膜－超声法制备了两性霉素B脂质体,稳定性考察的结果表明,制得的两性霉素B脂质在较低温度（4℃）条件下贮存时能保持良好的物理和化学稳定性;在近似生理条件下能较长时间地保持比较完整的脂质体结构,稳定性良好。     

两性霉素B脂质体的制备及药动学

目的:制备两性霉素B脂质体并对其药动学进行研究。方法:采用有机溶剂注入法制备两性霉素B脂质体,用微射流进行整粒,用动态光散射法测定粒径,采用Ultrafree-CL离心超滤管分离游离两性霉素B(F-AMB)与复合两性霉素B(L-AMB)检测包封率,用Wistar大鼠进行药动学研究。结果:两性霉素B脂质体平均粒径为(115±20)nm;包封率>99.9%;大鼠静脉注射,实验药与Amphotec的Cmax,AUC0~168 h和AUC0~∞无显著性差异(P>0.05)。结论:采用有机溶剂注入法制备两性霉素B脂质体具有较高包封率,在大鼠体内的药动学特征与Amphotec一致。     

注射用两性霉素B脂质体致呼吸困难

1例7岁女性儿童,确诊急性淋巴细胞白血病3年,既往无药物和食物过敏史。治疗期间在第一次使用注射用两性霉索B脂质体30min,出现呼吸困难、寒战、体温39℃,无头痛、低血压。立即停止输注注射用两性霉素B脂质体,给予盐酸异丙嗪注射液10mg肌肉注射、注射用赖氨匹林0．45g入莫菲氏管,30min后症状缓解,4h后体温降至正常,5h后继续使用该药物,未再发生类似反应。     

两性霉素B磁性脂质体的制备与质量控制

目的:制备稳定的两性霉素B磁性脂质体。方法:采用薄膜分散加超声法制备了两性霉素B磁性脂质体。以影响磁性脂质体稳定性和均匀度的两性霉素B浓度、卵磷脂与胆固醇用量比、磁性液体加入量及超声条件为考察因素,进行正交试验,以磁性脂质体溶液的均匀度和稳定性为考察指标,以溶液的状态、溶液的沉淀量和放置保存时沉淀量的增加量为评分标准对处方进行了筛选。建立了两性霉素B磁性脂质体的紫外分析方法。结果:按正交试验设计最优组合制备的磁性脂质体回收率为100.75%;包封率为76.07%。两性霉素B的线性范围为1~10mg.L-1,回归方程A=0.1547C 0.003,r=0.9998。结论:采用薄膜分散加超声法,用正交试验法筛选处方能够制备稳定的磁性脂质体溶液。     

两性霉素B脂质体治疗深部真菌感染30例

观察两性霉素Ｂ脂质体治疗深部真菌感染的临床疗效。方法应用两性霉素Ｂ脂质体无菌冻干制剂，从１ｍｇ／ｄ起逐渐加量至１ｍｇ／（ｋｇ．ｄ）左右维持治疗至学部霉素感染被控制，甚至病原体转阴。结果３０例各系统严重疾病合并深部真菌感染患者中，有１９例在用药３－６０天的体转阴，痊愈１９例，显效９例，进步１例，无效１例，总有效率达９６．７％。结论两性霉素Ｂ脂质体治疗各系统严重疾病合并真菌感染疗效显著，与传统游离两性     

用RP-HPLC法测定注射用两性霉素B脂质体中两性霉素B的含量

两性霉素B（amphotericin B）是一种多烯类广谱抗真菌抗生素，是目前临床上治疗全身隐球菌、曲霉菌等真菌感染的一种有效药物，但该药在治疗剂量下比较严重的毒副作用限制了它在临床上的使用。研究表明，脂质体作为药物载体可以有效地降低药物的毒副作用，提高药物的治疗指数。     

深部霉菌感染两性霉素B脂质体的临床应用体会

目的介绍两性霉素B脂质体在治疗深部感染中的临床应用体会.方法对我院1年来使用两性霉素B脂质体,针对治疗深部真菌感染的实践中产生的毒副作用及采取的相应处理办法,进行整理、分析和归纳.结果两性霉素B脂质体使用疗效显著,但亦产生一些毒副作用,采取相应措施减少其副作用,使患者耐受性提高.结论两性霉素B脂质体在临床上的应用不断扩展,并积累了一些减少其毒副作用的方法.     

两性霉素B脂质体的紫外分光光度测定

采用紫外分光光度法,在４０５ｎｍ波长处测定两性霉素Ｂ脂质体的含量。平均回收率为９８．９％,ＲＳＤ为０．９７％,测定结果与生物效价法基本一致。／     

两性霉素B脂质体粒度测定方法研究

目的：建立两性霉素B脂质体粒度检测方法，通过测定一组性质不同的样品，找出最佳测定方法。方法：用计算机的图像一数字处理技术结合扫描电镜、透射电镜和激光光散射粒度测定仪分别测定两性霉素B脂质体的粒度。结果：电镜法测定两性霉素B脂质体的粒度为20—100nln，平均粒径为55—75nm；激光光散射法测定两性霉素B脂质体的粒度为30—200nm，平均粒径为50—180nm。结论：激光光散射法能较好反映两性霉素B脂质体在使用时的真实粒度，且方法快速、简便，是一种较好的两性霉素B脂质体粒度测定方法。     

Amphotericin B colloidal dispersion

Amphotericin B colloidal dispersion (ABCD) is a colloidal dispersion of a stable complex of amphotericin B with cholesteryl sulphate in a 1:1 proportion, forming uniform disk-shaped particles. ABCD is associated with less nephrotoxicity than conventional amphotericin B deoxycholate. Infusion-related adverse events are more frequent in patients receiving ABCD than in patients receiving liposomal amphotericin B or amphotericin B deoxycholate. ABCD has been shown in a randomised, double-blind study, to be an effective alternative to amphotericin B deoxycholate for empirical treatment of patients with fever and neutropenia. ABCD is active in the treatment of invasive Candida spp. and Aspergillus spp. infections in immunocompromised hosts, however most of the data supporting its use for these types of infections is derived from non-comparative open-label clinical trials of patient refractory to or intolerant of conventional antifungal therapy. ABCD is approved by the US FDA for the treatment of invasive aspergillosis in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate in effective doses, and in patients with invasive aspergillosis where prior amphotericin B deoxycholate therapy has failed. Two other lipid formulations of amphotericin B, amphotericin B lipid complex and liposomal amphotericin B, are available and, like ABCD, are associated with reduced nephrotoxicity as compared to amphotericin B deoxycholate. The role of ABCD in comparison with these other lipid formulations of amphotericin B is discussed herein. High cost remains an issue with all lipid formulations of amphotericin B.     

两性霉素B复合磷脂纳米脂质体Beagle犬体内药动学研究

目的 采用LC-MS/MS测定Beagle犬血浆中两性霉素B的含量,研究受试物两性霉素B复合磷脂纳米脂质体(liposomal amphotericin B,L-AmB)和参比药物AmBisome在Beagle犬体内的药动学行为。方法 选取成年健康Beagle犬12只,♀♂各半。采用双交叉试验设计,周期间洗脱期为2周。经前肢静脉注射给药(6 mg·kg^-1,1.0 mg·mL^-1),采集给药前以及给药后各时间点血浆样品,应用经验证的LC-MS/MS方法测定血浆中两性霉素B浓度,DAS 2.1.1中求算药动学参数。结果 Beagle犬静脉注射给予6 mg·kg^-1的受试物和参比药物后,动物体内两性霉素B的AUC_(0-t)分别为(705 520±178 252),(677 310±166 326)μg·h·L^-1;C_max分别为(142 683±29 823),(121 992±37 983)ng·mL^-1;t_1/2分别为(8.9±1.5),(9.7±0.6)h。结论 L-AmB及参比制剂AmBisome在Beagle犬体内的药动学参数差异无统计学意义。     

HPLC法测定复方两性霉素B眼用凝胶的含量

目的建立同时测定复方两性霉素B眼用凝胶中两性霉素B和利福平含量的高效液相色谱法。方法采用DiamonsilC18柱(250mm×4.6mm,5μm),以0.005mol/L乙二胺四乙酸二钠-乙腈(65∶35)为流动相,流速为1.0ml/min,检测波长为334nm,柱温为20℃。结果两性霉素B的线性范围为4.816～48.16μg/ml,r=0.9999,平均回收率为99.3%,RSD=1.0%(n=9);利福平的线性范围为1.739～17.39μg/ml,r=0.9999,平均回收率为99.4%,RSD=1.1%(n=9)。结论该方法操作简便,快速,结果准确,可适用于产品的质量控制。     

Role of Phospholipid Transfer Protein on the Plasma Distribution of Amphotericin B Following the Incubation of Different Amphotericin B Formulations

Purpose The purpose of this study was to investigate the role of phospholipid transfer protein (PLTP) on the plasma distribution of amphotericin B (AmpB) following incubation with different AmpB formulations in human plasmas with varying lipid profiles. Methods In a first set of experiments, plasma distribution profiles of AmpB were determined following the incubation of Fungizone? and lipid-based formulations (Abelcet? and AmBisome?) at a concentration of 20 μg AmpB/mL for 5–120 min at 37°C in the plasma obtained from six different individuals (total cholesterol concentrations range between 62 and 332 mg/dL). In a second set of experiments, Abelcet?, and AmBisome? at a concentration of 20 μg AmpB/mL were incubated for 5 min at 37°C in human plasma (total cholesterol = 163 mg/dL) that had been pretreated with an antibody raised up against PLTP (1:400 v/v dilution from stock solution) for 20 min at 37°C. Following incubation, the human plasma was separated into its lipoprotein and lipoprotein-deficient fractions by density gradient ultracentrifugation and analyzed for AmpB content by high-performance liquid chromatography. Results The majority of AmpB was covered in the lipoprotein-deficient plasma and high-density lipoprotein (HDL) fractions following incubation of Fungizone? in human plasma. The majority of AmpB (48.7–87.2%) was recovered in the HDL fraction following incubation of Abelcet? and AmBisome? in human plasma. The presence of the PLTP antibody resulted in a 20% decrease in the percentage AmpB recovered in the HDL fraction following the incubation of Abelcet?. However, the plasma distribution of AmpB remained unchanged following the incubation of AmBisome? in plasma containing the PLTP antibody. Conclusions Taken together, these findings suggest indirect evidence that PLTP may play an important role in the plasma distribution profile of AmpB following the incubation of Abelcet? and may be one of the factors responsible for the preferential association of AmpB with HDL when administered as Abelcet?.     

Enhanced Encapsulation of Amphotericin B into Liposomes by Complex Formation with Polyethylene Glycol Derivatives

Purpose. A highly efficient method was developed for the encapsulation of amphotericin B (AmB) in liposomes, and the mechanism involved was characterized. Methods. AmB was encapsulated in dipalmitoylphosphatidylcholine/cholesterol (DPPC/CH, 2:1) liposomes after complex formation with distearoyl-N-(monomethoxy poly(ethylene glycol) succinyl) phosphatidylethanolamine (DSPE-PEG). Hydration of lipids was done with 9% sucrose solution. Results. The encapsulated amount of AmB was 111 g/mg lipid, which was much higher than that obtained by the same method without DSPE-PEG (14 g/mg lipid). The amount encapsulated increased with amount of DSPE-PEG used and with PEG molecular weight. Encapsulation efficacy was also influenced by the type of PEG derivatives used and by the modification of AmB, suggesting the involvement of complex formation between AmB and DSPE-PEG. Absorption and ³¹P-NMR spectral analyses indicated that interactions between the amino and phosphate groups and between the polyene and PEG moieties in AmB and DSPE-PEG, respectively, play an important role in the complex formation. Conclusions. Complex formation of AmB with DSPE-PEG allows the highly efficient encapsulation of the drug in liposomes. This simple technique should be applicable to other hydrophobic drugs.     

银杏内酯B脂质体的处方与制备工艺研究

目的 将银杏内酯B（ginkgolide B,GB）制备成脂质体,增加GB在水中的分散性和稳定性。方法 采用超滤离心法分离脂质体与游离药物,HPLC测定脂质体中GB的含量与包封率,采用薄膜分散法制备GB脂质体;通过单因素与正交试验分析药脂比、胆固醇用量、装载量、水化温度和水化时间等因素对包封率的影响,以外观、包封率、粒径为评价指标确定GB脂质体的最佳处方和制备工艺。结果 GB脂质体的最佳处方为10 mg GB、160 mg蛋黄卵磷脂、40 mg胆固醇、8 mg维生素E、58 mg DSPE-PEG2000、5 mL PBS缓冲液;优化后的工艺条件为GB与脂质辅料溶于无水乙醇中,33℃水浴条件下减压旋转蒸发除乙醇,pH 6.5 PBS缓冲液水化脂质薄膜,水化温度35℃,时间120 min,粗脂质体混悬液冰水浴超声6 min,超声功率120 W。制备的GB脂质体混悬液微泛蓝色乳光、可透光,粒径为（126±4） nm,包封率>87%,放置24 h无聚集、无沉降。结论 采用薄膜法在实验室阶段成功制备了稳定的GB脂质体,确定了最优制备处方和制备工艺,为GB制剂的剂型研究做出探索和提供参考。     

两性霉素B脂质体鞘内注射治疗新型隐球菌性脑膜炎疗效观察

目的：探讨两性霉素B鞘内注射治疗新型隐球菌性脑膜炎的可行性。方法：将常规静脉注射两性霉素B后、病情仍难以控制的（脑脊液中新型隐球菌性仍难以转阴,颅内高压持续不降）24例新型隐球菌性脑膜炎患者,随机分为两性霉素B鞘内注射组、两性霉素B脂质体鞘内注射组,鞘内注射剂量从0.1 mg开始,逐渐增加剂量,直到出现难以耐受的不良反应或每次注射剂量达到1 mg。结果：患者可以较好地耐受两性霉素B脂质体鞘内注射,鞘内注射两性霉素B脂质体发生不良反应的几率及严重程度明显低于普通两性霉素B。结论：两性霉素B脂质体鞘内注射治疗新型隐球菌性脑膜炎具有可行性。