(1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19Z,21Z,23Z,25Z,27Z,29Z,31Z,33R,35S,36R,37S)-33-[(2R,3S,4S,5S,6R)-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

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19Z,21Z,23Z,25Z,27Z,29Z,31Z,33R,35S,36R,37S)-33-[(2R,3S,4S,5S,6R)-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
• 化学式: C₄₇H₇₃NO₁₇
• 分子量: 924.1
• InChiKey: APKFDSVGJQXUKY-ZNVUZQDLSA-N

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

• 肝毒性

多达20%的使用两性霉素的患者会出现轻度和短暂的肝酶升高。临床上明显的肝毒性很少见，但已经发表了一些确信的病例。肝脏损伤可能在开始治疗后的4到14天就出现，通常表现为肝细胞或混合模式的酶升高。大多数患者没有症状或黄疸。停止治疗后，恢复会很快发生。此外，尽管罕见，但已经报告了在开始使用两性霉素几天内出现的孤立但明显的胆红素血症案例，升高中大部分是直接（结合）胆红素部分。这些患者出现肉眼可见的黄疸，但没有全身症状，血清ALT或碱性磷酸酶水平升高的情况很少，没有明显肝损伤的证据。最后，已经罕见报道了在接受两性霉素的患者中出现急性胆汁淤积性肝炎伴黄疸的案例，但这些患者通常病情危重，并且接触了多种可能具有肝毒性的药物，因此将病因归咎于两性霉素的依据不强。

Mild and transient elevations in liver enzymes occur in up to 20% of patients receiving amphotericin. Clinically apparent hepatotoxicity is rare, but several convincing cases have been published. The liver injury arises as early as 4 to 14 days after starting therapy, typically with a hepatocellular or mixed pattern of enzyme elevation. Most patients have no symptoms or jaundice. Recovery occurs promptly upon stopping therapy. In addition, isolated but dramatic instances of hyperbilirubinemia arising within days of starting amphotericin have been reported with elevations largely in the direct (conjugated) bilirubin fraction. These patients become visually jaundiced but have no constitutional symptoms, minimal if any elevations in serum ALT or alkaline phosphatase levels, and no evidence of frank hepatic injury. Finally, rare instances of acute cholestatic hepatitis with jaundice have been reported in patients receiving amphotericin, but these patients have generally been critically ill and exposed to multiple potentially hepatotoxic agents, so that the attribution to amphotericin has been weak.

来源:LiverTox

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，除非有必要用来控制对两性霉素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)

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峰值浓度达到0.5-0.8微克/毫升；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)

文献信息

• Novel alkyl phospholipid derivatives and uses thereof
  申请人：Zentaris GmbH

  公开号：EP1800684A1

  公开（公告）日：2007-06-27

  The present invention provides novel alkyl phospholipid derivatives that are useful for treating various diseases including tumors and/or pathophysiological conditions in mammals, preferably humans, that are caused by microorganisms, in particular fungi, protozoa, bacteria and/or viruses. Such alkyl phospholipids can be employed as single drugs or in the course of combination therapies, in particular for the treatment of leishmaniasis, trypanosomiasis and/or malaria.

  本发明提供了新型烷基磷脂衍生物，可用于治疗包括肿瘤和/或哺乳动物（尤其是人类）中由微生物，特别是真菌、原虫、细菌和/或病毒引起的各种疾病，这些烷基磷脂可作为单一药物或结合疗法的一部分，特别是用于治疗利什曼病、锥虫病和/或疟疾。
• [EN] TLR7/8 AGONISTS AND LIPOSOME COMPOSITIONS<br/>[FR] AGONISTES DE TLR7/8 ET COMPOSITIONS LIPOSOMALES
  申请人：TORQUE THERAPEUTICS INC

  公开号：WO2020023680A1

  公开（公告）日：2020-01-30

  The present disclosure relates to a method of loading a toll like receptor (TLR)7/8 agonist into a liposome using remote loading and a kit of parts suitable for the loading of a TLR7/8 agonist into a liposome by said method. The present disclosure further relates to a liposome comprising a salt of a TLR7/8 agonist in the liposome interior and to the use of said liposome for stimulation of an immune response and/or treatment of a clinical condition. Finally, the present disclosure relates to a TLR7/8 agonist which is suitable for being remotely loaded into a liposome.

  本公开涉及一种利用远程加载的方法将调节剂（TLR）7/8激动剂装载到脂质体中，以及适用于通过该方法将TLR7/8激动剂装载到脂质体的部件套件。本公开进一步涉及包含TLR7/8激动剂盐的脂质体，并且利用该脂质体用于刺激免疫反应和/或治疗临床疾病。最后，本公开涉及一种适合远程装载到脂质体中的TLR7/8激动剂。
• ANTIMYKOTISCHER POLYMERISIERBARER KNOCHENZEMENT UND EIN VERFAHREN ZU SEINER HERSTELLUNG
  申请人：Heraeus Medical GmbH

  公开号：EP3056227A1

  公开（公告）日：2016-08-17

  Es wird ein antimykotisch wirksamer Knochenzement basierend auf organischen Polymeren, wie Polymethylmethacrylat, beschrieben. Der Knochenzement umfasst ein Antimykotikum, insbesondere Amphotericin B, das in Gegenwart von Wasser oder wässrigen Medien, wie Köperflüssigkeit, aus dem polymerisierten Knochenzement freigesetzt wird. Entsprechend einer Alternative liegt das Antimykotikum partikulär vor und ist mindestens teilweise mit einem Gemisch aus mindestens einem 1-Methylamino-1-desoxy-zuckeralkohol und mindestens einer Fettsäure umhüllt. Gleichfalls wird ein Verfahren zur Herstellung des Gemisches umfassend ein Antimykotikum, wie Amphotericin B-Partikel, und 1-Methylamino-1-desoxy-zuckeralkohol und mindestens einer Fettsäure vorgeschlagen. Bevorzugt ist das Antimykotikum zumindest teilweise umhüllt von 1-Methylamino-1-desoxy-zuckeralkohol und mindestens einer Fettsäure.

  本文描述了一种基于有机聚合物（如聚甲基丙烯酸甲酯）的抗真菌骨水泥。这种骨水泥包括一种抗真菌剂，特别是两性霉素 B，在有水或水介质（如体液）存在的情况下，两性霉素 B 会从聚合骨水泥中释放出来。另一种方法是，抗真菌剂以颗粒形式存在，并至少部分包覆有至少一种 1-甲基氨基-1-脱氧糖醇和至少一种脂肪酸的混合物。还提出了一种制备混合物的工艺，该混合物包括抗真菌剂（如两性霉素 B 颗粒）、1-甲基氨基-1-脱氧-糖醇和至少一种脂肪酸。优选地，抗真菌剂至少部分包覆有 1-甲基氨基-1-脱氧糖醇和至少一种脂肪酸。
• CANCER STEM CELL PROLIFERATION INHIBITOR AND INTRACELLULAR ACTIVE OXYGEN ACCUMULATION INDUCER
  申请人：Keio University

  公开号：EP3120849A1

  公开（公告）日：2017-01-25

  The present invention is directed to provide cancer stem cell proliferation inhibitors and inducers of intracellular accumulation of reactive oxygen species. To this end, provided are cancer stem cell proliferation inhibitors and inducers of intracellular accumulation of reactive oxygen species in a cancer stem cell each containing pimozide or sertindole as an active ingredient.

  本发明旨在提供癌症干细胞增殖抑制剂和活性氧细胞内积累诱导剂。为此，本发明提供了癌症干细胞增殖抑制剂和癌症干细胞活性氧细胞内积累诱导剂，每种抑制剂和诱导剂都含有吡莫齐德或舍吲哚作为活性成分。
• Intracorporal ultra high purity calcium sulfate cast mixed with antimicrobials for the treatment of penile implant infections
  申请人：Carrion Rafael

  公开号：US10328177B2

  公开（公告）日：2019-06-25

  The present invention includes a method for treating penile implant infections that uses a synthetic high-purity calcium sulfate mixed with antimicrobials, which is capable of providing prolonged exposure of antimicrobials to the infection site and capable of acting as an intracorporal filler preventing fibrosis and loss of phallic length. The technique is especially useful for high-risk patients, and provides another medium for which antimicrobial agents can be delivered to a surgical infection site while at the same time acting as a filler, preventing fibrosis, and loss of the space. The antimicrobial cast lasts 4-6 weeks, making timely re-implantation easier, and preventing intracorporal fibrosis and loss of phallic length.

  本发明包括一种治疗阴茎植入感染的方法，该方法使用一种与抗菌剂混合的合成高纯度硫酸钙，它能够使抗菌剂长时间暴露于感染部位，并能够作为一种椎体内填充物，防止纤维化和阴茎长度的损失。这种技术对高危患者特别有用，它提供了另一种媒介，可以将抗菌剂输送到手术感染部位，同时起到填充、防止纤维化和空间缩小的作用。抗菌石膏可持续 4-6 周，便于及时重新植入，并防止椎体内纤维化和阴茎长度损失。