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 of 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.     

Best practice guidelines for the management of adverse events associated with amphotericin B lipid complex

Importance of the field: Amphotericin B lipid complex is a widely used lipid-based formulation of amphotericin B, which has a broad spectrum of activity against a variety of fungal pathogens. It has also been shown to be significantly less nephrotoxic than conventional amphotericin B. However, infusional drug reactions, similar to those seen when using conventional amphotericin B, have been reported in a significant number of patients, so it is important that these are prevented or managed effectively, particularly in light of the changing epidemiology of systemic fungal infections.

Areas covered in this review: This article reviews effective strategies that can be used to reduce the risk of drug delivery reactions associated with amphotericin B lipid complex. Preserving renal function and managing spikes in serum creatinine levels are also discussed.

What the reader will gain: The aim of this paper is to provide healthcare professionals with clear guidance on the management of adverse events associated with amphotericin B lipid complex. Recommendations are based upon the published evidence and clinical experience from a number of different centres.

Take home message: Amphotericin B lipid complex represents a valuable therapeutic option in the treatment of fungal infections but improved strategies for the management of infusion-related adverse events are required.     

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?.     

Amphotericin B lipid complex for the treatment of invasive fungal infections

Amphotericin B lipid complex (ABLC; Abelcet^®, Enzon Pharmaceuticals) has become the dominant marketed lipid amphotericin B compound to emerge since the approval of these agents from the mid-1990s onwards. This agent is a 1:1 combination of amphotericin B and a lipid moiety consisting of dimyristoyl phosphatidylcholine and dimyrisoyl phosphatidylcholine, which exists in a ribbon-like molecular structure. ABLC undergoes rapid reticuloendothelial uptake from the circulation and achieves significantly higher tissue concentrations in the liver, spleen and lung compared to comparably dosed conventional amphotericin B. ABLC is approved by the FDA for all mycoses in amphotericin B-intolerant or -refractory infection. Randomised, controlled trials of amphotericin B have shown comparable efficacy in candidiasis and an improved outcome in invasive aspergillosis versus historical controls. ABLC has demonstrated a reduced incidence of nephrotoxicity and infusion reactions versus amphotericin B. Comparative studies against other lipid formulations are quite limited and have shown variable differences in infusion toxicity, nephrotoxicity, hepatotoxicity and clinical efficacy. Postapproval experience has shown substantial efficacy for less common mycotic pathogens including zygomycosis. The precise position of ABLC versus both other lipid formulations and expanding formulary of new antifungal agents is in flux. Future studies which examine its clinical efficacy, role in combination therapy, toxicity and cost-effectiveness in these complex patients are needed.     

Block Copolymer Micelles for the Encapsulation and Delivery of Amphotericin B

Purpose. To assess the effect of fatty acid substitution of a micelle-forming poly(ethylene oxide)-block-poly(N-hexyl stearate-L-aspartamide) (PEO-b-PHSA) on the encapsulation, hemolytic properties and antifungal activity of amphotericin B (AmB). Methods. PEO-b-PHSA with three levels of stearic acid substitution were synthesized and used to encapsulate AmB by a solvent evaporation method. Size exclusion chromatography and UV spectroscopy were used to confirm and measure levels of encapsulated AmB. The hemolytic activity of encapsulated AmB toward human red blood cells and its minimum inhibitory concentration against Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans were obtained and compared to AmB alone. Results. An increase in the level of stearic acid substitution on PEO-b-PHSA improved the encapsulation of AmB while reducing its hemolytic activity. PEO-b-PHSA micelles having 50% and 70% stearic acid substitution (mol fatty acid: mol reacted and unreacted hydroxyls) were completely non-hemolytic at 22 g/ml. At 11% stearic acid substitution, AmB caused 50% hemolysis at 1 g/ml. AmB in PEO-b-PHSA micelles was as effective as AmB alone against pathogenic fungi. Conclusions. PEO-b-PHSA micelles with a high level of stearic acid side chain substitution can effectively solubilize AmB, reduce its hemolytic activity yet retain its potent antifungal effects.     

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。     

两性霉素B脂质体的临床合理应用

目的 介绍临床如何合理使用两性霉素B脂质体(L-AmB).方法 综述国内外文献,分析其药理特点、适应症和临床合理应用原则.结果 两性霉素B(AMB)仍是治疗侵袭性真菌感染的主要药物,但众多的不良反应也限制了其在临床的广泛应用.L-AmB在保留AMB相似的抗真菌疗效的同时,减少了毒副作用.L-AmB具有抗真菌谱广、疗效稳定以及不易诱导真菌耐药等优点,可用于念珠菌病、曲霉、隐球菌病、马尔尼菲青霉病、组织胞浆菌病以及毛霉病等真菌病的治疗,尤其适于重症患者、孕妇以及因基础疾病而不适合使用或不能耐受AMB的患者以及对三唑类药物耐药的真菌感染和存在较多药物间相互作用的情况下,也可作为经验性抗真菌治疗的药物选择及高危人群侵袭性真菌感染的预防性用药.L-AmB价格较高,限制了其在临床的推广和使用.结论 临床上应根据真菌感染的类型、感染部位、感染人群、基础疾病、肝肾功能状态、合并用药情况、不良反应、药物的可及性和可接受性等情况来合理使用L-AmB.有必要对L-AmB的临床应用价值和成本-效益进行进一步的研究.     

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。     

基于FAERS数据库两性霉素B脱氧胆酸盐与脂质体不良事件信号挖掘研究

目的 利用美国食品药品监督管理局不良事件报告系统（FAERS）数据库分析两性霉素B脱氧胆酸盐（AmB-D）与两性霉素B脂质体（L-AmB）的风险信号,为临床合理用药提供参考。方法 基于FAERS数据库提取AmB-D和L-AmB 2004年第1季度—2023年第4季度的不良事件报告,并导入SAS 9.4软件中进行数据清理与分析,采用报告比值比法（ROR）、比例报告比值法（PRR）、英国药品和健康产品管理局综合标准（MHRA）及贝叶斯可信区间递进神经网络法（BCPNN）进行不良事件信号挖掘。结果 分别检索到AmB-D与L-AmB的药品不良事件报告1 308、4 304份。AmB-D与L-AmB发生频次最多的不良反应均为低钾血症和急性肾损伤。AmB-D与L-AmB肾脏及泌尿系统疾病不良事件报告比例接近,提示临床可能低估了脂质体的肾毒性。并挖掘到AmB-D较强的可疑不良事件信号为免疫重建炎性综合征、白质病变;L-AmB的可疑信号为中毒性表皮坏死松解症、免疫重建炎性综合征、β2微球蛋白升高、脾损害和血管内溶血,说明书中未注明,应予以重视。结论 AmB-D与L-AmB可疑不良事件信号的挖掘,大多数与说明书记录的一致,但仍发现新的信号,需积极监测。     

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。／     

Amphotericin B colloidal dispersion: an improved antifungal therapy

Amphotericin B colloidal dispersion (ABCD) is a near 1:1 discoidal complex of amphotericin B (AMB) and sodium cholesteryl sulfate (SCS) arranged as a bilayer of SCS interspersed with AMB via noncovalent interactions. The complex is stable in blood and plasma with minimal dissociation. In vitro and in vivo studies show that ABCD is as effective and four to five times safer than conventional AMB (CAB) for fungal infection. Compared with CAB treatment, ABCD demonstrates reduced peak plasma levels, prolonged residence time, and lowered AMB levels in most tissues including kidney, the major target of toxicity for CAB. In 572 patients with systemic fungal infections secondary to severe underlying disease, ABCD doses < or = 6 mg/kg/day were well tolerated, even in those who failed to tolerate or respond to CAB. Mild-to-moderate, dose-dependent, infusion-related adverse events typically seen with CAB were also observed with ABCD, with no sign of renal or hepatic toxicity. Complete or partial recovery was seen in 57.3%. Therefore, ABCD should be considered as an alternative treatment of systemic fungal infections.     

挤压器联动装置制备两性霉素B脂质体

目的考察挤压器联动装置制备两性霉素B脂质体制剂的稳定性。方法使用联动装置制备两性霉素B脂质体,用透析法检测两性霉素B脂质体的药物包封率,粒径仪器跟踪脂质体制剂的粒径及其分布,测定稳定性、泄漏率及毒性。结果所用联动装置可使脂质体的制备工艺简化,投料成品一步完成,同时可在线监控粒径。采用此装置制备的两性霉素B脂质体的粒径显著小于手动方式所制备,且粒径分布较窄;药物包封率为97．3％。通过与手动方法制备的脂质体制剂的多项技术指标对比,表明采用联动装置制备的两性霉素B脂质体制剂的药物包封率高,制剂稳定性好,药物渗漏率低。结论挤压器联动装置可用于工业化生产两性霉素B脂质体制剂的产品质量稳定、可控。     

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。     

国外两性霉素B新剂型在临床的应用评价

目的:介绍国外治疗深部真菌病药物两性霉素B新剂型在临床的应用。方法:主要进入全球权威的临床医学文献数据库美国国立医学图书馆(NLN)的Mediline数据库,检索了近10年来有关两性霉素B新剂型在临床应用的大量文献,概括地进行综述和分析。结果及结论:国外临床应用的两性霉素B的剂型有10余种,并且很多剂型已经收入各国药典之中,而国内目前仅有3种,建议尽快开发各种新剂型,以满足临床各方面的需求。     

Unidirectional Inhibition of Lipid Transfer Protein I-Mediated Transfer of Cholesteryl Esters Between High-Density and Low-Density Lipoproteins by Amphotericin B Lipid Complex

No HeadingPurpose. The purpose of this study was to determine whether Fungizone or amphotericin B lipid complex (ABLC; ABELCET^®) affects the transfer of cholesteryl ester (CE) by lipid transfer protein I (LTP I; also known as cholesteryl ester transfer protein) between HDL and LDL (bidirectional transfer HDL to LDL and LDL to HDL).Methods. Increasing concentrations of either Fungizone or ABELCET^® (1.25–12.5 g AmpB/ml) were incubated with HDL and [3H]CE-LDL or [3H]CE-HDL and LDL (the amount of each fraction added was equivalent to 10 g of cholesterol) and LTP I in delipidated human plasma at 37C for 90 min. As a positive control, TP2, a monoclonal antibody directed against LTP-1, was added instead of drug. After incubation, manganese and phosphate reagents were then added to precipitate out all of the LDL. The supernatant, consisted of only HDL, was counted for radioactivity to determine the amount of CE transferred from LDL. Similarly, the precipitate consisted of only LDL, was counted for radioactivity to determine the amount of CE transferred from HDL.Results. For Fungizone, the transfer of cholesteryl ester (CE) between HDL and LDL were not significantly different compared to nontreated controls. For ABELCET^®, CE transfer from HDL to LDL was significantly decreased at 12.5 g AmpB/ml compared to control. However, transfer from LDL to HDL was not significantly different compared to non-treated controls. Similar results were observed with the major lipid component of ABELCET^®, dimyristoylphosphatidylcholine. CE transfer from HDL to LDL and LDL to HDL was significantly decreased when using the positive control (TP2).Conclusions. Fungizone does not affect LTP I–mediated transfer of CE between HDL and LDL. ABELCET^® inhibits transfer from HDL to LDL, but has no effect on CE transfer from LDL to HDL. This uni-directional inhibition may contribute to the high recovery of AmpB in HDL but the very low presence of drug in the LDL fraction following ABELCET^® incubation.     

Liposome-based drug delivery to alveolar macrophages

The recent development of liposomal formulations compatible with aerosol delivery has expanded the potential to utilise chemotherapeutic agents directly targeted to the lungs more effectively. These are agents that would otherwise not be used because of their low solubility or toxicity. Various properties of liposomal carriers, including size, surface charge, composition and the presence of ligands, alter their efficacy and specificity towards alveolar macrophages to a great extent. This editorial summarises the advances in liposome-based drug delivery to alveolar macrophages.     

The reformulation of Amphotericin B for oral administration to treat systemic fungal infections and visceral leishmaniasis

Amphotericin B (AmB) is a parenterally administered broad-spectrum antifungal and leishmanicidal drug that has been on the market for over sixty years. Unfortunately, significant infusion-related side effects and renal toxicity often accompany treatment, limiting its clinical applications. Lipid-based formulations have somewhat ameliorated the associated toxicity, but the increased cost of formulations restricts widespread use. AmB is amphipathic and exhibits low solubility and permeability, resulting in negligible absorption when administered orally. Advances in drug delivery systems have overcome some of the solubility issues that prevent oral bioavailability and new formulations are currently in development. The existence of an effective, safe and inexpensive oral formulation of amphotericin B would have significant applications for the treatment of disseminated fungal infections and would dramatically expand access to treatment of visceral leishmaniasis by introducing a readily available highly tolerated oral formulation of a drug with known efficacy.     

Altered Pharmacokinetics and Dosing of Liposomal Amphotericin B and Isavuconazole during Extracorporeal Membrane Oxygenation

Drug pharmacokinetics may be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). Ensuring the optimized effective dosing of antimicrobials on ECMO remains a challenge. To date, limited data are available regarding the optimal use of amphotericin and triazoles during ECMO. We report a case of altered pharmacokinetics, insufficient liposomal amphotericin B and isavuconazole levels, and the need for escalated doses during ECMO in a patient with severe acute respiratory distress syndrome secondary to pulmonary blastomycosis. A 2-fold increase in the standard total daily dose of both drugs was necessary to overcome low serum concentrations thought to be secondary to drug loss from ECMO circuit sequestration. These findings have important implications for optimizing antimicrobial therapy in patients receiving ECMO to maximize therapeutic efficacy. The use of therapeutic drug monitoring for patients receiving antimicrobial therapy with concurrent ECMO may facilitate appropriate drug dosing to achieve adequate serum concentrations and optimize favorable patient outcomes. Further studies exploring antimicrobial pharmacokinetics during ECMO are needed to inform dosing recommendations in critically ill patients.     

Poor and Unusually Prolonged Oral Absorption of Amphotericin B in Rats

Pharmaceutical Research -     

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。