两性霉素B | 1397-89-3

• 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
• 中文别名: 芦山霉素；二性霉素B；两性霉素 B；两性霉素
• 英文名称: AmBisome
• 英文别名: amphotericin B；AmB；amphotericin；amphotericine B；fungizone；anfotericin B；(1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36R,37S)-33-[(2R,3S,4S,5S,6R)-4-azaniumyl-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-carboxylate
• CAS: 1397-89-3
• 化学式: C₄₇H₇₃NO₁₇
• 分子量: 924.093
• InChiKey: APKFDSVGJQXUKY-INPOYWNPSA-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。
• 物理描述：
  Amphotericin b is a bright yellow powder. (NTP, 1992)
• 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

代谢

专属于肾脏的

Exclusively renal

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：尽管没有关于两性霉素B乳汁排出的信息，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具有相加性，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、枯草菌素、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，美克洛昔林）可能会增加接受两性霉素B治疗的患者的肾脏毒性、支气管痉挛和低血压的风险，因此应非常谨慎地使用这种联合治疗。

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，或从基线计算肌酐清除率降低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治疗的成人和儿科患者中为31%，而接受常规两性霉素B并与这些药物同时治疗的患者中为68%。在未接受环孢素或他克莫司治疗的成人和儿科患者中，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

• 吸收

静脉输注的生物利用度为100%。

Bioavailability is 100% for intravenous infusion.

来源:DrugBank

吸收、分配和排泄

• 清除

39 +/- 22 mL/小时/公斤 [发热中性粒细胞减少的癌症和骨髓移植患者在第1天接受1 mg/公斤/天的输注] 17 +/- 6 mL/小时/公斤 [发热中性粒细胞减少的癌症和骨髓移植患者在第3到20天接受1 mg/公斤/天的输注] 51 +/- 44 mL/小时/公斤 [发热中性粒细胞减少的癌症和骨髓移植患者在第1天接受2.5 mg/公斤/天的输注] 22 +/- 15 mL/小时/公斤 [发热中性粒细胞减少的癌症和骨髓移植患者在第3到20天接受2.5 mg/公斤/天的输注] 21 +/- 14 mL/小时/公斤 [发热中性粒细胞减少的癌症和骨髓移植患者在第1天接受5 mg/公斤/天的输注] 11 +/- 6 mL/小时/公斤 [发热中性粒细胞减少的癌症和骨髓移植患者在第3到20天接受5 mg/公斤/天的输注]

39 +/- 22 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day at Day 1] 17 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day 3-20 days later] 51 +/- 44 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day at Day 1] 22 +/- 15 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day 3-20 days later] 21 +/- 14 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day at Day 1] 11 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day 3-20 days later]

来源:DrugBank

吸收、分配和排泄

两性霉素B的药代动力学因给药方式不同而有很大差异，无论是作为传统的两性霉素B（与去氧胆酸钠配伍）、两性霉素B胆固醇硫酸盐复合物、两性霉素B脂质复合物，还是两性霉素B脂质体，一种两性霉素B制剂的药代动力学参数不应用于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，尽管其分布显然是多室的。据报道，给予常规两性霉素B后，药物的分布体积为4 L/kg；而给予两性霉素B胆固醇硫酸盐后，稳态下的分布体积为3.8-4.1 L/kg。在给予常规两性霉素B静脉注射后，在炎症的胸膜、腹膜、滑膜和水状液中达到的两性霉素B浓度约为同时血浆浓度的60%；药物也分布到玻璃体、胸膜、心包、腹膜和滑液。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)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xi,Xn,T,C
• 安全说明：
  S26,S36,S36/37/39,S45
• 危险类别码：
  R22,R40,R36/37/38,R23/24/25
• WGK Germany：
  3
• 海关编码：
  29419090
• 危险品运输编号：
  UN 1759 8/PG 3
• RTECS号：
  BU2625000
• 包装等级：
  III
• 危险类别：
  6.1(b)

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。

反应信息

• 作为反应物：
  描述：

  两性霉素B 在 盐酸 、 iron(III) chloride 、 水 作用下， 反应 2.45h， 生成
  参考文献：
  名称：

  In vitro evaluation of antifungal and cytotoxic activities as also the therapeutic safety of the oxidized form of amphotericin B

  摘要：

  The aim of this study was to evaluate the antifungal and cytotoxic activities of the oxidized form of amphotericin B (AmB-Ox) as well as to determine whether oxidation process of AmB is therapeutically beneficial in vitro. The antifungal activity was estimated against Candida albicans ATCC 10231 and Candida parasilosis ATCC 22019 by broth microdilution method according to the NCCLS M27-A2 standards. The in vitro cytotoxicity was evaluated using normal green monkey kidney cells (GMK) by MTT assay. The obtained results demonstrated that AmB-Ox possesses 16-fold decreased antifungal properties against the two Candida strains and 5-fold lower cytotoxic activity towards GMK cells in comparison with AmB.The therapeutic safety in vitro assessed by calculating the ratio between cytotoxicity (CC50 value) to antifungal activity (MIC value) showed that oxidation of AmB is a very unfavourable process in vitro, because leads to formation of derivative (AmB-Ox) that lost antifungal properties much more rapidly than cytotoxic activity. Thus, the process of the oxidation of AmB in vivo (if it occurs) can be also highly harmful for patient. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  DOI：

  10.1016/j.cbi.2016.06.022
• 作为产物：
  描述：

  两性霉素B甲酯 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.0h， 以80%的产率得到两性霉素B
  参考文献：
  名称：

  Total synthesis of amphotericin B

  摘要：

  DOI：

  10.1021/ja00243a043
• 作为试剂：
  描述：

  雄烯二酮 在 L-谷氨酰胺 、 二氧化碳 、 Eagle's minimum essential medium 、 granulosa cells of human follicles 、 penicillin G 、 两性霉素B 、 链霉素 、 fetal calf serum 作用下， 反应 24.0h， 生成 雌二醇 、 雌酚酮 、 睾酮 、 5a-雄甾烷二酮 、 19-羟基睾酮 、 5a-雄甾烷-3a,17b-二醇
  参考文献：
  名称：

  Comparative studies of androgen metabolism in theca and granulosa cells of human follicles in vitro

  摘要：

  In eight separate experiments, theca and granulosa were isolated from human follicles (5-25 mm in diameter), and their capacities to metabolize radiolabelled testosterone in 24 hour cultures were assessed. Theca metabolized testosterone primarily to androstenedione, however significant aromatization to estradiol-17 beta and to estrone was also observed. Granulosa metabolized testosterone primarily to estra-diol-17 beta and estrone, while smaller quantities were converted to androstenedione. In seven of these experiments, the intermediate of aromatization, 19-hydroxytestosterone, was identified. In six of these experiments, theca, when compared to granulosa, produced more androstenedione but less estradiol-17 beta and estrone. 5 alpha-Reduced androgens were non-detectable or produced in small quantities. In a single experiment, metabolism of androstenedione was compared to metabolism of testosterone by both theca and granulosa. Theca metabolized androstenedione to testosterone in smaller quantities than testosterone to androstenedione. Granulosa metabolized androstenedione to testosterone in higher quantities than testosterone to androstenedione. Both theca and granulosa aromatized androstenedione more readily than testosterone.

  DOI：

  10.1016/0039-128x(82)90066-6

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• NEW STRIGOLACTONE ANALOGUES AND THE USE THEREOF FOR THE TREATMENT OF PLANTS
  申请人：INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE

  公开号：US20150141255A1

  公开（公告）日：2015-05-21

  A compound of general formula (I): in which X represents O, S, NH or an N-alkyl radical, R 1 and R 2 , identical or different, each represent H or a C 1 -C 10 hydrocarbon radical, R 1 and R 2 not both representing H, R 3 represents a C 1 -C 10 hydrocarbon radical, and R represents a phenyl radical monosubstituted or disubstituted by a substituent Y and, if applicable, a substituent Z, chosen from Cl, Br, I and CF 3 , or R represents a C═R 4 (R 5 ) radical in which R 4 represents an hydrocarbon radical and R 5 represents a linear or branched, saturated or unsaturated, hydrocarbon radical, optionally substituted, a COR 6 group or a CO 2 R 6 group, where R 6 represents a hydrogen atom or a linear or branched, saturated or unsaturated, hydrocarbon radical. This compound can be used for the treatment of higher plants for controlling their growth and architecture.

  通式（I）的化合物： 其中X代表O、S、NH或N-烷基基团，R1和R2，相同或不同，各自代表H或C1-C10烃基，R1和R2不同时代表H，R3代表C1-C10烃基，R代表被取代基团Y和如适用的取代基团Z选择自Cl、Br、I和CF3的苯基单取代或双取代基团，或R代表C═R4（R5）基团，其中R4代表烃基团，R5代表线性或支链、饱和或不饱和、可选择取代的烃基团、COR6基团或CO2R6基团，其中R6代表氢原子或线性或支链、饱和或不饱和的烃基团。该化合物可用于治疗高等植物，控制其生长和结构。
• Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20150231142A1

  公开（公告）日：2015-08-20

  The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

  本发明涉及含有上皮钠通道活性抑制剂与至少一种ABC转运蛋白调节剂化合物（A式、B式、C式或D式）的药物组合物。该发明还涉及这些药物配方，以及使用这些组合物治疗CFTR介导的疾病，特别是囊性纤维化的方法。
• Integrase inhibitors
  申请人：Cai R. Zhenhong

  公开号：US20080058315A1

  公开（公告）日：2008-03-06

  Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

  三环化合物，其受保护的中间体，以及用于抑制HIV整合酶的方法被披露。
• PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
  申请人：Rewcastle Gordon William

  公开号：US20110009405A1

  公开（公告）日：2011-01-13

  Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

  本文提供了式I的嘧啶基和1,3,5-三嗪基苯并咪唑化合物，以及它们的药物组合物、制备方法，以及作为抗癌治疗药物或药剂的用途，可以单独使用，也可以与放疗和/或其他抗癌药物联合使用。