nystatin A1 | 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 A1
• 英文别名: nystatin；(1S,15S,16R,17R,18S)-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-DZCKSEKHSA-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

毒理性

• 肝毒性

曲霉菌素治疗与血清酶异常的低发生率有关，尽管将这些升高归因于曲霉菌素一直很困难。尽管使用了数十年，但没有令人信服的案例表明急性肝损伤与曲霉菌素治疗有关。虽然曲霉菌素通常不被吸收，但在胃肠道炎症和损伤的患者中，低浓度的曲霉菌素可能会进入血液循环。尽管如此，曲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

◉ 母乳喂养期间使用概述：尽管没有关于制霉菌素从乳汁中排出的信息，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，因为软膏可能会使婴儿通过舔食接触到高水平的矿物石蜡。在哺乳前应从乳头上除去多余的乳膏。与其他局部抗真菌药相比，制霉菌素治疗鹅口疮的效果较差。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关已发布信息。 ◉ 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，进行抽吸。观察呼吸不足的迹象，如有需要，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，如有必要，进行治疗...。监测休克，如有必要，进行治疗...。预见癫痫发作，如有必要，进行治疗...。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）连续冲洗每只眼睛...。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的呕吐反射且不流口水，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，用干燥的灭菌敷料覆盖皮肤烧伤...。/毒物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：对于无意识、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）或乳酸钠林格氏液。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...。/毒物A和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。

/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

Nystatin 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差，在常规剂量下不会获得可检测到的血药浓度。口服给药后，制霉菌素几乎全部以原药形式在粪便中排出。

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)

吸收、分配和排泄

在健康的个体中，口服同时溶解两片制霉菌素含片（400,000单位）后，唾液中制霉菌素的平均浓度超过体外抑制临床重要念珠菌生长所需的浓度，持续时间大约为2小时。

In healthy individuals, mean salivary nystatin concentrations in excess of those required in vitro for growth inhibition of clinically important Candida persist for approximately 2 hours after the beginning of oral dissolution of two nystatin lozenges (400,000 units) administered simultaneously.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

未通过完整皮肤或粘膜的局部应用被吸收。

Not absorbed following topical application to intact skin or mucous membranes.

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 A1 、 γ-环糊精 以 水 为溶剂， 反应 48.0h， 生成
  参考文献：
  名称：

  Gamma-cyclodextrin on enhancement of water solubility and store stability of nystatin

  摘要：

  研究发现，通过与γ-环糊精（γ-CD）形成包合物，提高了奈司他丁的水溶性。进一步的惊喜发现表明，恩司他丁在β-CD和γ-CD水溶液中的相溶解度曲线为AL型，而α-CD为BS型，这表明β-CD、γ-CD与恩司他丁形成了1:1的包合物，而α-CD则没有包合物，此外，环较大的CD更适合与大环内酯类抗生素形成包合物。研究发现，随着γ-CD浓度的增加，奈司他丁在γ-CD溶液中的水溶性也随之增加。当γ-CD水溶液的浓度为24 g/100 ml（接近饱和溶液）时，奈司他丁的水溶性为104 μg/ml，是原来奈司他丁的103倍。γ-CD-nystatin复合物的包合常数为0.539 l/mmol，大于β-CD-nystatin复合物的包合常数（0.375 l/mmol）。制备了γ-CD 与奈司他丁的包合物，并进行了红外光谱检测，结果表明，酯键和二烯被包含在 CD 的空腔中，而共轭花生四烯酸、羧基和氨基则被留在 CD 的外面。储存实验表明，包合复合物的形成大大提高了奈司他丁对光和氧的稳定性。

  DOI：

  10.1007/s10847-012-0281-y

文献信息

• Gamma-cyclodextrin on enhancement of water solubility and store stability of nystatin
  作者：Jinpeng Wang、Zhengyu Jin、Xueming Xu

  DOI：10.1007/s10847-012-0281-y

  日期：2014.4

  The water solubility of nystatin was found enhanced by forming inclusion complex with gamma-cyclodextrin (γ-CD). Further discovery of a pleased surprise showed that the phase solubility curves of nystatin in β- and γ-CD aqueous solution were AL type, while BS type for α-CD, indicating 1:1 inclusion complexes were formed between β-CD, γ-CD and nystatin, but no inclusion complexes for α-CD, in addition, CDs with much larger ring would be more suitable for forming inclusion complexes with macrolide antibiotics. The aqueous solubility of nystatin in γ-CD solution was investigated increased with γ-CD concentration increasing. At the concentration of 24 g/100 ml for γ-CD aqueous solution, which is near to the saturated solution, water solubility of nystatin was found to be 104 μg/ml, which was 103 folds over original nystatin. Inclusion constants for γ-CD–nystatin complexes were 0.539 l/mmol, which is larger than that of β-CD–nystatin complex (0.375 l/mmol). The inclusion complex of γ-CD with nystatin was prepared and detected by infrared spectrum, results showing that the ester linkage and diene were included in the cavity of CDs, while conjugate arachidonic, carboxyl and amino group were left outside of CDs. Storing experiment showed that forming of the inclusion complexes greatly enhanced the stability of nystatin against light and oxygen.

  研究发现，通过与γ-环糊精（γ-CD）形成包合物，提高了奈司他丁的水溶性。进一步的惊喜发现表明，恩司他丁在β-CD和γ-CD水溶液中的相溶解度曲线为AL型，而α-CD为BS型，这表明β-CD、γ-CD与恩司他丁形成了1:1的包合物，而α-CD则没有包合物，此外，环较大的CD更适合与大环内酯类抗生素形成包合物。研究发现，随着γ-CD浓度的增加，奈司他丁在γ-CD溶液中的水溶性也随之增加。当γ-CD水溶液的浓度为24 g/100 ml（接近饱和溶液）时，奈司他丁的水溶性为104 μg/ml，是原来奈司他丁的103倍。γ-CD-nystatin复合物的包合常数为0.539 l/mmol，大于β-CD-nystatin复合物的包合常数（0.375 l/mmol）。制备了γ-CD 与奈司他丁的包合物，并进行了红外光谱检测，结果表明，酯键和二烯被包含在 CD 的空腔中，而共轭花生四烯酸、羧基和氨基则被留在 CD 的外面。储存实验表明，包合复合物的形成大大提高了奈司他丁对光和氧的稳定性。