两性霉素B | 30652-87-0

• 物质功能分类: 原料药 - 抗生素类药物 - 多烯类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 两性霉素B
• 英文名称: (1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36R,37S)-33-(4-amino-3,5-dihydroxy-6-methyloxan-2-yl)oxy-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid
• CAS: 30652-87-0；1397-89-3
• 化学式: C₄₇H₇₃NO₁₇
• 分子量: 924.1
• InChiKey: APKFDSVGJQXUKY-UPWJBAEMSA-N

物化性质

• 熔点：
  >170°C
• 比旋光度：
  D24 +333° (acidic DMF); -33.6° (0.1N methanolic HCl)
• 沸点：
  804.34°C (rough estimate)
• 密度：
  1.34
• 溶解度：
  无菌水：20 mg/mL作为储存液。储存液应储存在−20°C。在37℃下稳定保存3天。
• 颜色/状态：
  Deep yellow prisms or needles from n,n-dimethylformamide
• 气味：
  ODORLESS OR PRACTICALLY SO
• 稳定性/保质期：

  Solids and solutions appear stable for long periods between pH 4 and 10 when stored at moderate temperature out of light and air.

• 旋光度：
  Specific optical rotation at 24 °C/D: +333 deg (acidic N,N-dimethylformamide); -33.6 deg (0.1 N methanolic hydrochloric acid)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  65
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  320
• 氢给体数：
  12
• 氢受体数：
  18

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：尽管没有关于两性霉素B在乳汁中排泄的信息，但由于它高度与蛋白质结合，分子量大，几乎不被口服吸收，并且已经直接用于婴儿口腔；因此，大多数审阅者认为在哺乳期母亲中使用是可以接受的。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Although no information exists on the milk excretion of amphotericin B, it is highly protein bound, has a large molecular weight, is virtually unabsorbed orally and has been use directly in the mouths of infants; therefore, most reviewers consider it acceptable to use in nursing mothers. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

由于肾毒性作用可能叠加，应尽可能避免同时或连续使用两性霉素B和其他具有类似毒性潜力的药物（例如，氨基糖苷类抗生素、卡泊霉素、粘菌素、顺铂、环孢素、甲氧氟烷、戊烷脒、多粘菌素B、万古霉素）。

Since nephrotoxic effects may be additive, the concurrent or sequential use of amphotericin B and other drugs with similar toxic potentials (eg, aminoglycosides, capreomycin, colistill, cisplatin, cyclosporine, methoxyflurane, pentamidine, polymyxin B, vancomycin) should be avoided, if possible.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

据报道，皮质类固醇可能会增强两性霉素B引起的钾流失，除非有必要控制对两性霉素B的不良反应，否则不应同时使用。

Corticosteroids reportedly may enhance the potassium depletion caused by amphotericin B and should not be used concomitantly unless necessary to control adverse reactions to amphotericin B.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

抗肿瘤药物（例如，美克洛塞）可能会增加接受两性霉素B治疗的患者出现肾毒性、支气管痉挛和低血压的风险，因此此类联合治疗应非常谨慎使用。

Antineoplastic agents (eg, mechlorethamine) may enhance the potential for renal toxicity, bronchospasm, and hypotension in patients receiving amphotericin B and such concomitant therapy should be used only with great caution.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一项随机双盲研究中，评估了常规静脉注射两性霉素B和两性霉素B胆固醇硫酸盐复合物在发热性中性粒细胞减少症患者中的使用，这些患者的基线血清肌酐浓度正常。研究中，肾毒性（定义为血清肌酐从基线翻倍或增加1 mg/dL以上，或从基线计算出的肌酐清除率下降50%或更多）的发生率在接受两性霉素B胆固醇硫酸盐复合物并与环孢素或他克莫司同时使用的成人和儿童患者中为31%，而接受常规两性霉素B并与这些药物同时使用的患者中为68%。在未接受环孢素或他克莫司治疗的成人和儿童患者中，接受两性霉素B胆固醇硫酸盐复合物的肾毒性发生率为8%，而接受常规两性霉素B的患者为35%。

In a randomized, double-blind study that evaluated use of conventional IV amphotericin B and amphotericin B cholesteryl sulfate complex in febrile neutropenic patients with normal baseline serum creatinine concentrations, the incidence of renal toxicity (defined as a doubling or an increase of 1 mg/dL or more from baseline serum creatinine or a 50% or greater decrease from baseline in calculated creatinine clearance) was 31% in adults and pediatric patients who received amphotericin B cholesteryl sulfate complex concomitantly with cyclosporine or tacrolimus compared with 68% in those who received conventional amphotericin B concomitantly with these agents. In adults and pediatric patients who did not receive cyclosporine or tacrolimus therapy, the incidence of renal toxicity was 8% in those who received amphotericin B cholesteryl sulfate complex and 35% in those who received conventional amphotericin B.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

两性霉素B的药代动力学因药物是以传统两性霉素B（与去氧胆酸钠配方）、两性霉素B胆固醇硫酸盐复合物、两性霉素B脂质体复合物还是两性霉素B脂质体形式给药而有很大差异，一种两性霉素B制剂的药代动力学参数不应用来预测任何其他两性霉素B制剂的药代动力学。

The pharmacokinetics of amphotericin B vary substantially depending on whether the drug is administered as conventional amphotericin B (formulated with sodium desoxycholate), amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal, and pharmacokinetic parameters reported for one amphotericin B formulation should not be used to predict the pharmacokinetics of any other amphotericin B formulation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

两性霉素B从胃肠道吸收不良，必须通过胃肠道外给药来治疗全身性真菌感染。在一项研究中，静脉输注30毫克两性霉素B（在几小时内给药）后立即，平均血药峰浓度约为1微克/毫升；当剂量为50毫克时，平均血药峰浓度大约为2微克/毫升。输注后立即，血清中最多只能解释10%的两性霉素B剂量。当每天给予30毫克的剂量或每隔一天给予60毫克的剂量时，记录的平均最低血药浓度约为0.4微克/毫升。

Amphotericin B is poorly absorbed from the GI tract and must be given parenterally to treat systemic fungal infections. In one study, immediately after completion of iv infusion of 30 mg of amphotericin B (administered over a period of several hours), average peak serum concentrations were about 1 ug/ml; when the dose was 50 mg, average peak serum concentrations were approximately 2 ug/ml. Immediately after infusion, no more than 10% of the amphotericin B dose can be accounted for in serum. Average minimum serum concentrations (recorded just prior to the next drug infusion) of approximately 0.4 ug/ml have been reported when doses of 30 mg were given daily or when doses of 60 mg were given every other day.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

两性霉素B的分布信息有限，尽管分布显然是多室的。据报道，给予常规两性霉素B后，药物的体积分布为4 L/kg；给予两性霉素B胆固醇硫酸盐后，稳态时的体积分布为3.8-4.1 L/kg。据报道，在给予常规两性霉素B后，药物在炎症胸膜、腹膜、滑膜和水状液中的浓度约为同期血浆浓度的60%；药物也分布到玻璃体液、胸膜、心包、腹膜和滑膜液中。据报道，两性霉素B能穿过胎盘，在羊水中达到低浓度。

Information on the distribution of amphotericin B is limited, although distribution is apparently multicompartmental. The volume of distribution of the drug following administration of conventional amphotericin B has been reported to be 4 L/kg; the volume of distribution at steady state after administration of amphotericin B cholesteryl sulfate is reported to be 3.8-4.1 L/kg. Amphotericin B concentrations attained in inflamed pleura, peritoneum, synovium, and aqueous humor following IV administration of conventional amphotericin B reportedly are about 60% of concurrent plasma concentrations; the drug also is distributed into vitreous humor, pleural, pericardial, peritoneal, and synovial fluid. Amphotericin B reportedly crosses the placenta and low concentrations are attained in amniotic fluid.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经静脉注射常规两性霉素B后，脑脊液中的药物浓度大约为同时血清浓度的3%。为了达到抑菌作用的脑脊液浓度，通常需要通过鞘内给药。对于患有脑膜炎的患者，通过皮下储液器给予0.2-0.3毫克常规两性霉素B，可以使脑脊液中的药物浓度达到0.5-0.8微克/毫升的峰值；给药24小时后，脑脊液中的药物浓度为0.11-0.29微克/毫升。两性霉素B通过蛛网膜绒毛从脑脊液中移除，并似乎储存在大脑的细胞外间隙，这可能成为药物的储存库。

Following IV administration of conventional amphotericin B, CSF concentrations of the drug are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, the drug must usually be administered intrathecally. In patients with meningitis, intrathecal administration of 0.2-0.3 mg of conventional amphotericin B via a subcutaneous reservoir has produced peak CSF concentrations of 0.5-0.8 ug/mL; 24 hours after the dose, CSF concentrations were 0.11-0.29 ug/mL. Amphotericin B is removed from the CSF by arachnoid villi and appears to be stored in the extracellular compartment of the brain, which may act as a reservoir for the drug.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 安全说明：
  S26

制备方法与用途

两性霉素B是一种用于治疗严重真菌感染的重要药物。它通过与真菌细胞膜上的固醇结合，破坏细胞膜的通透性，导致重要物质流失，从而杀死或抑制真菌生长。

主要特点

• 抗菌谱广：对多种真菌包括新型隐球菌、白色念珠菌等都有强大作用。
• 毒性较高：治疗剂量下可能会引起一些副作用如肾功能损害、发热和寒战、低钾血症等。
• 不同剂型：
  • 普通两性霉素B
  • 脂质体两性霉素B，减少了对肾脏的毒性。

化学性质

• 外观与溶解性：淡黄色至橙黄色针状结晶或粉末。不溶于水和乙醇。
• 稳定性：容易被光、热和酸破坏。
• 气味与味道：几乎无味。

生产方法

使用节链霉菌进行发酵提取，经过一系列纯化步骤得到最终产品。

使用注意事项

1. 严格按照医嘱用药，避免过量。
2. 注意观察可能出现的副作用，并及时报告医生。
3. 长期或高剂量使用可能需要定期监测肾功能和电解质平衡。

替代品与新制剂

为了减少传统两性霉素B的一些毒性反应，开发了脂质体形式的两性霉素B。这种制剂能够更有效地靶向真菌细胞，并减少对正常人体组织的影响。

总之，两性霉素B是一种非常有效的抗真菌药物，但由于其较强的毒性和某些限制，在使用时需要高度谨慎并严格遵循医疗指导。

文献信息

• AMPHOTERICIN B DERIVATIVES WITH IMPROVED THERAPEUTIC INDEX
  申请人：THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS

  公开号：US20160215012A1

  公开（公告）日：2016-07-28

  Provided are certain derivatives of amphotericin B (AmB) characterized by reduced toxicity and retained anti-fungal activity. Certain of the derivatives are C16 urea derivatives of AmB. Certain of the derivatives are C3, C5, C8, C9, C11, C13, or C15 deoxy derivatives of AmB. Certain of the derivatives include C3′ or C4′ modifications of the mycosamine appendage of AmB. Also provided are methods of making AmB derivatives of the invention, pharmaceutical compositions comprising AmB derivatives of the invention, and methods of use of AmB derivatives of the invention.

  提供了一些特定的两性霉素B（AmB）衍生物，其具有降低毒性和保留抗真菌活性的特点。其中一些衍生物是AmB的C16脲衍生物。其中一些衍生物是AmB的C3、C5、C8、C9、C11、C13或C15去氧衍生物。其中一些衍生物包括对AmB的甲氨葡萄糖胺附属物的C3′或C4′修饰。还提供了制备该发明的AmB衍生物的方法，包括该发明的AmB衍生物的药物组合物，以及该发明的AmB衍生物的使用方法。
• [EN] UREA DERIVATIVES OF AMPHOTERICIN B DERIVED FROM SECONDARY AMINES<br/>[FR] DÉRIVÉS D'URÉE DE L'AMPHOTÉRICINE B DÉRIVÉE D'AMINES SECONDAIRES
  申请人：UNIV ILLINOIS

  公开号：WO2016112243A1

  公开（公告）日：2016-07-14

  Provided are certain urea derivatives of amphotericin B (AmB) having improved therapeutic index compared to AmB. The compounds of the invention are less toxic than AmB and are useful to treat fungal infections. In certain embodiments the urea derivative of AmB is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: wherein, independently for each occurrence: R represents methyl, ethyl, propyl, or isopropyl; R' represents methyl, ethyl, propyl, or isopropyl; or R and R', taken together with the nitrogen atom to which they are attached, represent a radical of a cyclic secondary amine. Also provided are methods for making the urea derivatives of AmB.

  提供了与两性霉素B（AmB）相比具有改善的治疗指数的某些尿素衍生物。本发明的化合物比AmB毒性更小，并且可用于治疗真菌感染。在某些实施例中，AmB的尿素衍生物是由以下式（I）表示的化合物或其药用可接受的盐：其中，对于每次出现独立地：R代表甲基、乙基、丙基或异丙基；R'代表甲基、乙基、丙基或异丙基；或R和R'与它们连接的氮原子一起表示环状二级胺的基团。还提供了制备AmB的尿素衍生物的方法。
• POLYENE DIESTER ANTIBIOTICS
  申请人：WANG WEN-MEI

  公开号：US20100210576A1

  公开（公告）日：2010-08-19

  The present invention discloses a new polyene diester and its preparation. This polyene diester has a structure of Formula 1, which is used as prodrugs by introducing diester group to polyene antibiotics, and these prodrugs exhibit antifungal or antiviral activities through releasing parent polyenes by esterase in vivo. The new derivatives have good antimicrobial activity and better safety. These new derivatives are useful for the antifungal and antiviral treatment. PA-COOR Formula 1

  本发明公开了一种新的聚烯二酯及其制备方法。该聚烯二酯具有Formula 1的结构，通过在聚烯抗生素中引入二酯基团作为前药，这些前药通过体内酯酶释放出母体聚烯，表现出抗真菌或抗病毒活性。这些新衍生物具有良好的抗微生物活性和更好的安全性。这些新衍生物对抗真菌和抗病毒治疗有用。PA-COOR Formula 1
• Antifungal Compounds
  申请人：University of Kentucky Research Foundation

  公开号：US20180194742A1

  公开（公告）日：2018-07-12

  Compounds and compositions having antifungal activity, and methods of using the antifungal compounds and compositions, are described for use in treating fungal infections.

  描述了具有抗真菌活性的化合物和组合物，以及使用这些抗真菌化合物和组合物治疗真菌感染的方法。
• REDUCED TOXICITY MOLECULAR CONJUGATES OF ANTI-FUNGAL AGENTS
  申请人：Lehigh University

  公开号：US20170042923A1

  公开（公告）日：2017-02-16

  Compositions, compounds and methods are described for addressing both toxicity of membrane disruptive anti-microbial agents as well as poor transport of such agents across the blood-brain-barrier (BBB) via the use of molecular appendages including one or more facial amphiphiles. These molecules have in vitro anti-fungal activity that is very similar to that of the native drug but with hemolytic activity and toxicity towards mammalian cells that is greatly reduced.

  描述了用于解决膜破坏型抗微生物药物的毒性以及这些药物在穿越血脑屏障（BBB）时的运输不良的构成物、化合物和方法，通过使用包括一个或多个脸部两性分子在内的分子附件。这些分子在体外具有与原始药物非常相似的抗真菌活性，但对哺乳动物细胞的溶血活性和毒性大大降低。