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.     

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.     

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.     

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。     

The current role of amphotericin B lipid complex in managing systemic fungal infections

Abstract

Background:

An increase in the number of immunocompromised patients has led to a rising burden of systemic fungal infections. Historically, conventional amphotericin B has been used to treat these infections due to its broad spectrum of activity. The development of lipid-based amphotericin B agents, such as Abelcet^* (ABLC), has allowed clinicians to take advantage of the broad spectrum of activity of amphotericin B while reducing adverse events. As well as this, a number of new antifungal agents have been developed in recent years which have significantly added to the treating physician’s antifungal armamentarium.     

两性霉素 B经支气管镜肺部局部注入的理论依据和操作流程

肺部真菌感染播散迅速,需药物及时干预。短期内即可形成组织坏死及肺局部结构性毁损,经有效抗真 菌药物控制或经患者自身免疫局限后,可迅速形成纤维及肉芽组织包裹。两性霉素 B是多烯类抗真菌药,抗真菌谱 广且作用较强。经静脉应用时,常用治疗量在肺部所达到的药物浓度对真菌仅具有抑菌作用,毒性大,不良反应多 见;经气道黏膜吸收少而缓慢,刺激性不强。根据这些特点,两性霉素 B经支气管镜肺部局部注入具有较大优势,值 得临床推广。本文根据指南及临床实际应用经验,就两性霉素 B经支气管镜肺部局部注入的理论依据和操作流程做 详细说明,其中包括两性霉素 B的药理机制、局部应用剂量和溶液浓度以及具体操作方法。     

两性霉素B脂质体治疗白血病合并霉菌性肺炎6例

目的：探讨白血病患儿霉菌性肺炎的临床特征及两性霉素B脂质体的临床疗效和不良反应。方法：回顾性分析我院2004～2006年确诊为白血病合并霉菌性肺炎6例的临床表现和诊疗过程。结果：6例白血病患儿病原菌培养均为霉菌,两性霉素B脂质体治疗真菌感染疗效满意,主要不良反应是低钾血症。结论：霉菌是引起白血病患儿化疗后院内感染重要病原菌之一,肺炎常规治疗临床改善不明显时,要重视霉菌检查并及时改用两性霉素B治疗。     

两性霉素 B脂质体治疗侵袭性真菌感染病人发生急性肾损伤危险因素分析

目的研究两性霉素 B脂质体(L-AMB)治疗侵袭性真菌感染病人发生急性肾损伤(AKI)的危险因素。方法回顾性分析南京医科大学附属淮安第一医院 2018年 1月至 2021年 12月 61例两性霉素 B脂质体治疗侵袭性真菌感染病人的临床资料,根据是否发生两性霉素 B脂质体相关 AKI分为 AKI组 23例( 37.7%)非 AKI组 38例( 62.3%)。采用单因素分析法比较两组临床资料, logistic回归分析两性霉素 B脂质体( L-AMB)治疗侵袭性真菌感,染病人发生 AKI的危险因素,应用受试者操作特征曲线( ROC曲线)评价 L-AMB使用累积剂量及治疗前血清钾水平在诊断 AKI方面的能力。结果有 23例病人在使用 L-AMB治疗过程中发生 AKI,AKI发生率为 37.7%。L-AMB疗程、累积剂量、日剂量, L-AMB治疗前血钾水平在 AKI及非 AKI两组病人比较中均差异有统计学意义(均 P<0.05);累积剂量是发生 L-AMB相关 AKI的独立危险因素［ OR=1.46,95%CI:(1.08,1.98),P=     

复方两性霉素B溶液治疗耳真菌病临床疗效研究

目的：观察两性霉素B联合利福平复方溶液治疗耳真菌病的临床疗效,进而探讨有效的治疗方法。方法：（1）运用棋盘式微量液基稀释法测定两性霉素B联合利福平对白色念珠菌标准菌株（编号ATCC90028）的体外最低抑菌浓度（MIC）值,在此基础上计算部分抑菌浓度指数（FIC）;依据FIC值判断两药联用是否有协同作用;（2）经真菌培养及鉴定确定为耳真菌病的60例患者中,根据临床症状与体征轻重的得分标准,随机分为3组,分别用两性霉素B、两性霉素B联合利福平复方溶液和3%水杨酸酒精滴耳液外耳道局部治疗1周、2周后,观察3组愈显率;并随访1年。结果：（1）两药联用的FIC指数小于0.5;（2）3组愈显率比较,第1周：两性霉素B联合利福平复方溶液组愈显率最高,较其他2组有统计学意义（P<0.05）,第2周：两性霉素B和利福平组与两性霉素B组愈显率相比无统计学意义（P>0.05）,以上2组分别与3%水杨酸酒精滴耳液组愈显率相比有统计学意义（P<0.05）。随访一年,水杨酸酒精滴耳液组复发率比其他2组高,差异有统计学意义（P<0.05）。结论：（1）两性霉素B联合利福平对真菌有协同作用;（2）两性霉素B联合利福平复方溶液外用制剂是治疗耳真菌病较理想的外用药物,且具有便于取材、配制简单、使用方便、起效快等优点,值得向基层医院推广。     

两性霉素B联合用药的研究进展

两性霉素B （amphotericin B,AmB）属于多烯类抗真菌药物,因其耐药率低、抗菌谱广,被称为治疗深部真菌感染的“金标准”,但是严重的毒副作用（尤其是肾毒性）大大限制了AmB在临床上的应用.在目前高效、低毒的抗真菌药物较少的情况下,联合使用不同作用机制的抗真菌药物,使其发挥协同作用,缩短疗程、减少药物毒副作用、扩大药物抗菌谱、避免耐药性的出现,是当前深部真菌感染治疗研究领域的一个重要研究方向.本文对AmB与不同种类抗真菌药物联合使用的研究进展作一综述.     

国产两性霉素B脂质体治疗艾滋病合并侵袭性真菌病的病例报道

本文报道国产两性霉素B脂质体（锋克松）治疗11例艾滋病合并侵袭性真菌病（IFD）病例的临床疗效。结果显示,治愈6例,显效4例,1例中断治疗。其中1例合并侵袭性肺曲霉菌病患者治疗7d后因胸部CT提示病情加重而加大剂量至2mg／kg／d继续治疗1周,复查CT显示肺部病灶开始吸收。患者主要不良反应为贫血、低血钾和血肌酐升高。除1例因再度贫血中断治疗,其余患者经对症治疗后均好转。提示国产两性霉素B治疗艾滋病合并IFD疗效好,不良反应小。     

Population pharmacokinetics of amphotericin B in children with malignant diseases

AIMS: To construct a population pharmacokinetic model for the antifungal agent, amphotericin B (AmB), in children with malignant diseases. METHODS: A two compartment population pharmacokinetic model for AmB was developed using concentration-time data from 57 children aged between 9 months and 16 years who had received 1 mg kg(-1) day(-1) doses in either dextrose (doseform=1) or lipid emulsion (doseform=2). P-Pharm (version 1.5) was used to estimate the basic population parameters, to identify covariates with significant relationships with the pharmacokinetic parameters and to construct a Covariate model. The predictive performance of the Covariate model was assessed in an independent group of 26 children (the validation group). RESULTS: The Covariate model had population mean estimates for clearance (CL), volume of distribution into the central compartment (V) and the distributional rate constants (k12 and k21) of 0.88 l h(-1), 9.97 l, 0.27 h(-1) and 0.16 h(-1), respectively, and the intersubject variability of these parameters was 19%, 49%, 55% and 48%, respectively. The following covariate relationships were identified: CL (l h(-1)) = 0.053 + 0.0456 weight (0.75) (kg) + 0.242 doseform and V (l) = 7.11 + 0.107 weight (kg). Our Covariate model provided unbiased and precise predictions of AmB concentrations in the validation group of children: the mean prediction error was 0.0089 mg l(-1) (95% confidence interval: -0.0075, 0.0252 mg l(-1)) and the root mean square prediction error was 0.1245 mg l(-1) (95% confidence interval: 0.1131, 0.1349 mg l(-1)). CONCLUSIONS: A valid population pharmacokinetic model for AmB has been developed and may now be used in conjunction with AmB toxicity and efficacy data to develop dosing guidelines for safe and effective AmB therapy in children with malignancy.     

Mucoadhesive chitosan-coated nanostructured lipid carriers for oral delivery of amphotericin B

This study describes the properties of an amphotericin B-containing mucoadhesive nanostructured lipid carrier (NLC), with the intent to maximize uptake within the gastrointestinal tract. We have reported previously that lipid nanoparticles can significantly improve the oral bioavailability of amphotericin B (AmpB). On the other hand, the aggregation state of AmpB within the NLC has been ascribed to some of the side effects resulting from IV administration. In the undissolved state, AmpB (UAmpB) exhibited the safer monomeric conformation in contrast to AmpB in the dissolved state (DAmpB), which was aggregated. Chitosan-coated NLC (ChiAmpB NLC) presented a slightly slower AmpB release profile as compared to the uncoated formulation, achieving 26.1% release in 5?hours. Furthermore, the ChiAmpB NLC formulation appeared to prevent the expulsion of AmpB upon exposure to simulated gastrointestinal pH media, whereby up to 63.9% of AmpB was retained in the NLC compared to 56.1% in the uncoated formulation. The ChiAmpB NLC demonstrated mucoadhesive properties in pH 5.8 and 6.8. Thus, the ChiAmpB NLC formulation is well-primed for pharmacokinetic studies to investigate whether delayed gastrointestinal transit may be exploited to improve the systemic bioavailability of AmpB, whilst simultaneously addressing the side-effect concerns of AmpB.     

艾滋病毒感染患者的骨量减少与骨质疏松问题

骨量减少和骨质疏松是艾滋病毒感染者的重要并发症。本文介绍艾滋病毒感染者中骨量减少和骨质疏松的流行病学概况,探讨可能的危险因素和发生机制,并阐述筛查、诊断和监测的合理策略以及非药物和药物干预的治疗方法。     

大孔树脂在两性霉素B原料药纯化工艺中的应用研究

通过考察多种型号树脂对两性霉素B原料药中杂质的吸附效果,筛选出几种对两性霉素B原料药中杂质有选择吸附性的树脂,然后对这几种树脂的吸附条件进行研究,确定了30倍树脂和500 mm:60 mm柱径比的最佳吸附条件.最后,利用不同极性树脂对两性霉素B原料药中杂质的吸附效果的差异性,研究不同树脂混合的最佳比例,结果发现在树脂M-1:M-2为3.6:6.4时,两性霉素B原料药中总杂质和最大单一杂质含量下降最明显.     

两性霉素B合并氟康唑对体外培养新生隐球菌酚氧化酶的影响

目的：研究两性霉素B合并氟康唑对体外培养新生隐球菌酚氧化酶活性的影响。方法：Novozyme234酶消化法获取原生质体；冷冻玻璃珠粉碎原生质体；Polecheck法测定酚氧化酶活性。结果：两性霉素B合并氟康唑组的新生隐球菌酚氧化酶活性较空白对照组明显降低（P＜0．001），但在大于和接近最低抑菌浓度上限的组间无明显差异。结论：两性霉素B合并氟康唑可降低新生隐球菌酚氧化酶活性，在大于或接近最低抑菌浓度上限时与药物浓度无关。     

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.     

两性霉素B脂质体治疗14例肺毛霉菌病患者的疗效观察

目的调查与分析肺毛霉菌病患者应用两性霉素B脂质体的疗效及安全性。方法回顾性分析接受两性霉素B脂质体治疗的14例肺毛霉菌病患者的临床资料。结果 14例患者中5例痊愈,显效7例,进步1例,无效1例,有效率为85.7%。治疗过程中,仅1例在用药10 d出现肾功能损害,减量后症状消失,余均未见严重不良反应。结论两性霉素B脂质体作为肺毛霉菌病的一线药物,疗效可靠,不良反应少,严密观察和调整剂量可使患者疗效满意。     

Interaction of amphotericin B and its low toxic derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester, with fungal, mammalian and bacterial cells measured by the energy transfer method

Amphotericin B (AMB) derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME) retains the broad antifungal spectrum and potency of the parent antibiotic, whereas its toxicity towards mammalian cells is reduced by about two orders of magnitude. The purpose of this work was to find out whether the differences observed in the toxicity of MFAME and native AMB are due to the differential drugs affinity to fungal and mammalian cell membranes. Comparative studies on AMB and MFAME biological activity and their affinity to fungal, mammalian and bacterial cells were performed. The interaction of AMB and MFAME with cells have been studied by fluorescence method based on the energy transfer between membrane fluorescent probe (donor) and the polyenic chromophore of the antibiotic (acceptor) simultaneously present in the cell membrane. The amount of the antibiotic bound to cells was indicated by the extent of fluorescence quenching of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) or 1,6-diphenyl-1,3,5-hexatriene (DPH) by polyenic chromophore of the antibiotic. The results obtained indicate that binding extent and characteristics for both antibiotics are comparable in the three types of cells studied. Dramatically lower toxicity of MFAME as compared to AMB towards mammalian cells is not related to the antibiotic-cell affinity, but rather to different consequences of these interactions for cells, reflected in membrane permeabilization. MFAME is definitely less effective than parent AMB in the permeabilizing species formation in mammalian cell membrane.     

鞘内注射两性霉素B联合静脉滴注伏立康唑成功救治1例脑曲霉菌病患者

目的脑曲霉菌病的发病率日益增多,治疗药物有限,病死率很高。总结成功救治1例脑曲霉菌病患者的经验。方法立体定向下行脑穿刺活检术,脑组织病理活检结果明确诊断。治疗采用联合抗真菌治疗,伏立康唑0.2 g,2/d,静脉滴注,疗程70 d;间断小剂量鞘内注射两性霉素B,剂量0.1 mg,1/周。结果复查头颅磁共振,与初起病时比较病变明显吸收,临床症状好转。随访3年无复发。结论小剂量两性霉素B鞘内注射联合静脉滴注伏立康唑治疗脑曲霉菌病有较好疗效,无明显不良反应。