nystatin | 1400-61-9

• 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
• 英文名称: nystatin
• 英文别名: nystatin A₁；nystatin A1；nystatin A；Mycostatin；(1S,15S,16R,17R,18S,19E,21E,25E,27E,29E,31E)-33-[(2S,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-1,3,4,7,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,25,27,29,31-hexaene-36-carboxylic acid
• CAS: 1400-61-9
• 化学式: C₄₇H₇₅NO₁₇
• 分子量: 926.109
• InChiKey: VQOXZBDYSJBXMA-RKEBNKJGSA-N

物化性质

• 熔点：
  >155°C (dec.)
• 比旋光度：
  D25 -10° (glacial acetic acid); +21° (pyridine); +12° (DMF); -7° (0.1N HCl in methanol)
• 溶解度：
  不溶于水
• 颜色/状态：
  Light yellow powder
• 气味：
  Odor suggestive of cereals
• 蒸汽压力：
  8.7X10-7 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Solutions and aqueous suspensions begin to lose activity soon after preparation. Aqueous suspensions are stable for 10 minutes on heating to 100 °C at pH 7; also stable in moderately alkaline media, but labile at pH 9 and pH 2. Heat, light, and oxygen accelerate decomposition.
• 旋光度：
  Optical rotation at 25 °C/D: -10 deg (glacial acetic acid); +21 deg (pyridine); +12 deg (dimethylformamide); max absorption (ethanol): 290, 307 and 322 nm; optical rotation at 25 °C/D: -7 deg (0.1 N HCl in methanol)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  65
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  320
• 氢给体数：
  12
• 氢受体数：
  18

ADMET

代谢

因为制霉菌素几乎不吸收进入系统，所以它不会以任何显著程度被代谢。

Because nystatin undergoes little-to-no systemic absorption it is not metabolized to any appreciable extent.

来源:DrugBank

毒理性

• 肝毒性

制霉菌素治疗与血清酶异常的低发生率有关，尽管很难将这些升高归因于制霉菌素。尽管使用了数十年，但没有确凿的急性肝损伤与制霉菌素治疗有关的病例。虽然制霉菌素通常不被吸收，但在胃肠道炎症和损伤的患者中，低浓度的制霉菌素可能会进入血液循环。尽管如此，制霉菌素被认为非常安全，不太可能引起肝损伤。

Nystatin therapy has been associated with a low rate of serum enzyme abnormalities, although it has been difficult to attribute these elevations to nystatin. Despite its use for several decades, there have been no convincing cases of acute hepatic injury linked to nystatin therapy. While nystatin is usually is not normally absorbed, low concentrations may enter the circulation in patients with inflammation and damage to the gastrointestinal tract. Nevertheless, nystatin is considered very safe and is unlikely to cause hepatic injury.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：尽管没有关于制霉菌素乳汁排出的信息，但它是几乎不被口服吸收的，因此大多数评论者和临床医生认为它可用于哺乳期母亲，包括外用涂抹乳头。只有水溶性乳膏或凝胶产品应涂抹在乳房上，因为软膏可能会通过婴儿舔舐使婴儿接触到高水平的矿物石蜡。在哺乳前应从乳头上清除多余的乳膏。与其他外用治疗念珠菌病的药物相比，制霉菌素的疗效较差。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ Summary of Use during Lactation:Although no information exists on the milk excretion of nystatin, it is virtually unabsorbed orally, therefore most reviewers and clinicians consider it acceptable for use in nursing mothers, including topical application to the nipples. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking. Any excess cream should be removed from the nipples before nursing. Nystatin is less effective than other topical agents for the treatment of thrush. ◉ 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

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。密切观察呼吸不足的迹象，如有需要，进行辅助通气。通过非重复呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预防癫痫发作，并在必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿...。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇...。监测心率和必要时治疗心律失常...。开始静脉输注5%葡萄糖水（D5W）/SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%盐水（NS）或乳酸林格液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象...。用地西泮或劳拉西泮治疗癫痫...。使用丙美卡因氢氯化物协助眼部冲洗...。 /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/病例报告/ ...已报告了几例局部过敏反应的病例。

/CASE REPORTS/ ...Few cases of local allergic reactions have been reported.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

系统性吸收制霉菌素在口服给药后是最小的，在局部或阴道给药后不会达到可检测的血浆浓度。

Systemic absorption of nystatin is minimal following oral administration, and no detectable plasma concentrations are attained following topical or vaginal administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大多数口服的制霉菌素以原形在粪便中排出。

The majority of orally administered nystatin is eliminated unchanged in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

制霉菌素不被吸收进入系统性循环，因此不会发生分布。

Nystatin is not absorbed into the systemic circulation and thus does not undergo distribution.

来源:DrugBank

吸收、分配和排泄

制霉菌素对眼睛的渗透性较差。

Nystatin penetrates eye poorly.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

制霉菌素从胃肠道吸收不良，常规剂量后无法获得可检测的血药浓度。口服给药后，制霉菌素几乎全部以未改变的形式随粪便排出。

Nystatin is poorly absorbed from the GI tract, and detectable blood concentrations are not obtained after usual doses. Following oral administration, nystatin is excreted almost entirely in feces as unchanged drug.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  3
• 危险品标志：
  F,C
• 安全说明：
  S22,S24/25
• 危险类别码：
  R11
• WGK Germany：
  2,3
• 海关编码：
  2942000000
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  RF5950000
• 危险类别：
  3

制备方法与用途

多烯类抗真菌素——制霉菌素

制霉菌素简介 制霉菌素是一种多烯类抗真菌素，具有共轭多烯大环内酯结构。它能有效抑制真菌的活性，但对细菌没有抑制作用。该物质通过与真菌细胞膜上的甾醇结合，导致细胞膜通透性的改变，进而使得重要细胞内容物泄露，从而发挥其抗真菌作用。

应用 制霉菌素被广泛应用于多个领域，如防止细胞培养污染，并能诱导白细胞介素（IL）-1、IL-8以及TLR2在THP1细胞中表达。它还用作真菌膜（麦角甾醇结合）的造孔剂，在脂质双层中创建离子通道。

作为真菌抑制剂 制霉菌素常用于配置选择性培养基，特别是在防止细胞培养污染方面表现优异。推荐的工作浓度为0.05mg/ml，37℃下可稳定3天。可制备50mg/ml的悬液作为储存液，并在-20℃下保存。

抗菌谱 制霉菌素对念珠菌属具有强大的抗菌活性，对新型隐球菌、曲霉菌、毛癣菌、球孢子菌、荚膜组织胞浆菌、皮炎芽生菌以及皮肤癣菌等也表现出敏感性。

理化性质 制霉菌素为黄色或黄棕色粉末，带有特殊气味且具有吸湿性。该物质微溶于水和甲醇，但不溶于丙酮、乙醚及氯仿。它对空气、光、热、水、酸或碱均不稳定。

作用机制 通过与真菌细胞膜上的固醇结合，制霉菌素可以改变细胞膜的通透性，导致重要细胞内物质外泄，从而发挥其抗真菌效果。

应用范围 制霉菌素（又称米可定）为一种白色念珠菌、新型隐球菌、曲霉菌、毛霉菌和小孢子菌等敏感的抗真菌药物。建议遵医嘱使用该药物。它广泛应用于皮肤粘膜、口腔、阴道以及肠道的白色念珠菌感染治疗，尤其在高浓度时表现出杀菌作用。

药动学 口服后制霉菌素不会被胃肠道吸收，局部外用也不被皮肤和黏膜吸收。几乎全部服药量以原形形式从粪便中排出。局部给药用于念珠菌病的治疗，在用药后的24-72小时内达到最大效果。

反应信息

• 作为反应物：
  描述：

  nystatin 在 4-二甲氨基吡啶 、 triflic azide 、 copper(II) sulfate 作用下， 以 二甲基亚砜 为溶剂， 反应 96.0h， 生成
  参考文献：
  名称：

  β-Selective Glycosylations with Masked d-Mycosamine Precursors

  摘要：

  [GRAPHICS]Both an intramolecular aglycon delivery (IAD) method and an intermolecular S(N)2 displacement method were examined for beta -selective glycosylations of cholesterol with D-mycosamine. An anomeric sulfoxide, sulfide, selenide, and fluoride were all successfully used as glycosyl donors in IAD reactions. The alpha -bromo ketone 19 was synthesized from protected mycosamine and employed in an intermolecular S(N)2 glycosylation reaction, Both routes were successful for the model alcohol, cholesterol.

  DOI：

  10.1021/ol016617i

文献信息

• [EN] SEMISYNTHETIC DERIVATIVES OF NYSTATIN A1<br/>[FR] DÉRIVÉS SEMI-SYNTHÉTIQUES DE NYSTATINE A1
  申请人：BLIRT S A

  公开号：WO2013132014A1

  公开（公告）日：2013-09-12

  The invention provides semisynthetic derivatives of Nystatin A1, water soluble salts and complexes, pharmaceutical compositions and plant protection products comprising the derivatives and their use, as antifungal antibiotics (Formula 1a).

  该发明提供了Nystatin A1的半合成衍生物，水溶性盐和络合物，包括这些衍生物的药物组合物和植物保护产品，以及它们作为抗真菌抗生素的用途（公式1a）。
• SEMISYNTHETIC DERIVATIVES OF NYSTATIN A1
  申请人：BLIRT S.A.

  公开号：US20150045316A1

  公开（公告）日：2015-02-12

  The invention provides semisynthetic derivatives of Nystatin A 1 , water soluble salts and complexes, pharmaceutical compositions and plant protection products comprising the derivatives and their use, as antifungal antibiotics (Formula 1a).

  这项发明提供了Nystatin A1的半合成衍生物，水溶性盐和络合物，包括这些衍生物的药物组合物和植物保护产品，以及它们作为抗真菌抗生素的用途（公式1a）。
• HIGHLY PURE PENTAMYCIN
  申请人：Reuter Karl

  公开号：US20110077398A1

  公开（公告）日：2011-03-31

  Described is pentamycin in a purity exceeding 95%, certain polymorphs and solvates of pentamycin, processes for their manufacture, and a method for decreasing the rate of degradation of pentamycin.

  本文描述了纯度超过95%的五环霉素、五环霉素的某些多晶形和溶剂化物、它们的制造方法，以及一种降低五环霉素降解速率的方法。
• PHARMACEUTICAL, WATER-SOLUBLE AND ANTIFUNGAL MACROMOLECULAR COMPOUND
  申请人：BEIJING LABWORLD BIO-MEDICINE TECHNOLOGY CORP. LTD

  公开号：US20160158376A1

  公开（公告）日：2016-06-09

  The present invention relates to a medicinal water-soluble antifungal macromolecular compound used for treating infectious diseases, especially, relates to a poly-conjugate which includes an active drug substance and a macro-molecular polymer which are combined with each other through chemical bonds. The active drug substance is a polyene macrolide compound such as amphotericin B. Also provided are a method of preparing the poly-conjugate, a method for increasing solubility of the active drug substance and a method for treating fungal infection, which is any disease related to fungus, such as sepsis, endocarditis, meningitis (caused by cryptococcus and other fungus), abdominal infection (including those related to dialysis), pulmonary infection, urinary tract infection and the like. The poly-conjugate has excellent properties in biological performance and/or physical performance and/or chemical performance.

  本发明涉及一种用于治疗传染病的药用水溶性抗真菌大分子化合物，特别是涉及一种包括活性药物物质和大分子聚合物的聚合物共轭物，它们通过化学键结合在一起。活性药物物质是一种多烯类大环内酯化合物，例如两性霉素B。还提供了制备聚合物共轭物的方法、增加活性药物物质溶解度的方法以及治疗真菌感染的方法，该感染是与真菌有关的任何疾病，例如败血症、心内膜炎、脑膜炎（由隐球菌和其他真菌引起）、腹部感染（包括与透析有关的感染）、肺部感染、尿路感染等。聚合物共轭物具有优异的生物性能和/或物理性能和/或化学性能。
• Novel antibiotic NK130119, process for production of the same and application of the same
  申请人：Nippon Kayaku Kabushiki Kaisha

  公开号：EP0381124A2

  公开（公告）日：1990-08-08

  This invention relates to an antibiotic NK130119 of the formula: which exhibits antifungal, antitumor, vascularizations-­inhibitory and insecticidal activities.

  本发明涉及一种式 NK130119 抗生素： NK130119 具有抗真菌、抗肿瘤、抑制血管生成和杀虫活性。