卷曲霉素 | 11003-38-6

• 物质功能分类: 原料药 - 抗生素类药物 - 多肽类药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 卷曲霉素
• 英文名称: Capreomycin Sulfate Standard
• 英文别名: (3S)-3,6-diamino-N-[[(2S,5S,8E,11S,15S)-15-amino-11-[(4R)-2-amino-1,4,5,6-tetrahydropyrimidin-4-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide;(3S)-3,6-diamino-N-[[(2S,5S,8E,11S,15S)-15-amino-11-[(4R)-2-amino-1,4,5,6-tetrahydropyrimidin-4-yl]-8-[(carbamoylamino)methylidene]-2-methyl-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide
• CAS: 11003-38-6
• 化学式: C50H88N28O15
• 分子量: 1321.4
• InChiKey: VCOPTHOUUNAYKQ-WBTCAYNUSA-N

物化性质

• 溶解度：
  Soluble in water as disulfate salt.

计算性质

• 辛醇/水分配系数(LogP)：
  -15.44
• 重原子数：
  93
• 可旋转键数：
  19
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  737
• 氢给体数：
  27
• 氢受体数：
  23

ADMET

代谢

纸层析研究表明，卡普里霉素几乎未发生改变就被排出体外。在服用1克剂量后的6小时内，尿液中卡普里霉素的平均浓度为1.68毫克/毫升（平均尿量为228毫升）。

Paper chromatographic studies indicated that capreomycin is excreted essentially unaltered. Urine concentrations averaged 1.68 mg/mL (average urine volume, 228 mL) during the 6 hours following a 1-g dose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

肌肉内注射卷曲霉素尚未明确与肝脏损伤有关联，无论是无症状的血清酶水平升高，还是临床上明显的肝脏损伤。然而，这种药物很少单独使用，通常与其他抗结核药物联合使用，其中许多药物已知会引起肝脏损伤。尽管如此，在少数已完成的研究中，卷曲霉素并未与血清酶升高率或急性肝损伤发作的增加有关，这些情况并未超过对照臂报告的水平。

Intramuscular therapy with capreomycin has not been definitely linked to liver injury, either in the form of asymptomatic elevations in serum enzymes or of clinically apparent liver injury. However, the agent is rarely used and is always used in combination with other antituberculosis medications, many of which are well known to cause liver injury. Nevertheless, in the few studies done, capreomycin has not been associated with an increase in the rate of serum enzyme elevations or in episodes of acute liver injury above or beyond what was reported in the comparator arm.

来源:LiverTox

毒理性

• 相互作用

氨基糖苷类药物与其他具有神经毒性、耳毒性和肾毒性的系统性、口服或局部药物（例如：其他氨基糖苷类、阿昔洛韦、两性霉素B、杆菌肽、卷曲霉素、某些头孢菌素、黏菌素、顺铂、甲氧氟烷、多粘菌素B、万古霉素）的伴随和/或序贯使用可能会导致毒性相加，应尽可能避免。/氨基糖苷类药物/

Concomitant and/or sequential use of an aminoglycoside and other systemic, oral, or topical drugs that have neurotoxic, ototoxic, or nephrotoxic effects (e.g. other aminoglycosides, acyclovir, amphotericin B, bacitracin, capreomycin, certain cephalosporins, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin) may result in additive toxicity and should be avoided, if possible. /Aminoglycosides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

由于强效利尿剂（如依他尼酸、呋塞米、尿素或甘露醇）可能增加耳毒性风险，因为它们可能通过增加效果或改变血清和组织中氨基糖苷类药物的浓度，所以不应同时给予氨基糖苷类药物和这些利尿剂。/氨基糖苷类药物/

Because of the possibility of an increased risk of ototoxicity due to additive effects or altered serum and tissue aminoglycoside concentrations, aminoglycosides should not be given concomitantly with potent diuretics such as ethacrynic acid, furosemide, urea, or mannitol. /Aminoglycosides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

有人建议，同时使用某些抑制前庭源性恶心、呕吐和眩晕的抗组胺药（例如，盐酸苯海拉明，美克洛嗪）可能会掩盖氨基糖苷类药物相关的前庭耳毒性症状。/氨基糖苷类药物/

It has been suggested that concomitant use of certain anti-emetics that suppress nausea and vomiting of vestibular origin and vertigo (e.g., dimenhydrinate, meclizine) may mask symptoms of aminoglycoside-associated vestibular ototoxicity. /Aminoglycosides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

使用氨基糖苷类药物的同时使用全身麻醉药或神经肌肉阻滞剂（例如，琥珀胆碱、罗库溴铵、管箭毒碱）可能会增强神经肌肉阻滞作用，并可能导致呼吸麻痹。/氨基糖苷类药物/

Concurrent use of an aminoglycoside with general anesthetics or neuromuscular blocking agents (e.g., succinylcholine, rocuronium, tubocurarine) may potentiate neuromuscular blockade and cause respiratory paralysis. /Aminoglycosides/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫酸卷曲霉素从胃肠道吸收不良，因此必须通过非胃肠道途径给药。在健康成人单次肌内注射1克卷曲霉素后，血浆中卷曲霉素的峰值浓度在1-2小时内达到20-47微克/毫升（平均分别为1小时和2小时的28和32微克/毫升）；药物在血浆中的浓度在6小时时平均为10微克/毫升，在24小时时小于1微克/毫升。单次1克剂量通过肌内注射或1小时静脉输注给药后，血清浓度-时间曲线下面积（AUC）对于两种给药途径是相似的。然而，静脉输注后的血清卷曲霉素峰值浓度比肌内注射后的高出30%。

Capreomycin sulfate is not appreciably absorbed from the GI tract and therefore must be given parenterally. Following im administration of a single 1 g dose of capreomycin in healthy adults, peak plasma capreomycin concentrations ranging from 20-47 ug/mL are attained within 1-2 hours (averaging 28 and 32 ug/mL at 1 and 2 hours, respectively); plasma concentrations of the drug average 10 ug/mL at 6 hours and less than 1 ug/mL at 24 hours. Following administration of a single 1-g dose im or by iv infusion over 1 hour, the area under the serum concentration-time curve (AUC) was similar for both routes of administration. However, peak serum capreomycin concentrations after iv infusion were 30% higher than those following IM injection.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

调查人员对6名健康志愿者单次肌肉注射和静脉输注（1小时）给药的卡普里霉素（1.0克）的药代动力学进行了研究。两种给药方式的血药浓度-时间曲线下面积相似。静脉输注后的卡普里霉素峰浓度比肌肉注射高30 +/- 47%。

/Investigators/ examined the pharmacokinetics of single dose capreomycin (1.0 g) administered intramuscularly and by intravenous infusion (1 hour) in 6 healthy volunteers. The area under the serum concentration versus time curve was similar for the two routes of administration. Capreomycin peak concentrations after intravenous infusion were 30 +/- 47% higher than after intramuscular administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

卡普霉素不会分布到脑脊液中。目前没有关于卡普霉素分布到其他身体组织或体液的信息。尚不清楚该药物是否穿过胎盘或分布到乳汁中。

Capreomycin does not distribute into CSF. Information is not available on the distribution of capreomycin into other body tissue or fluids. It is not known if the drug crosses the placenta or is distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

卡普霉素主要通过肾小球滤过作用以原形在尿液中排泄。动物研究结果表明，少量的药物也可能通过胆汁排泄。在肾功能正常的成人单次1克肌肉注射卡普霉素后，大约52%的剂量在12小时内通过尿液排出。

Capreomycin is excreted mainly unchanged in urine by glomerular filtration. Results of animal studies suggest that small amounts of the drug may also be excreted in bile. Following a single 1g IM dose of capreomycin in adults with normal renal function, approximately 52% of the dose is excreted in urine within 12 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

不能从胃肠道大量吸收，必须通过肠外给药。

Not absorbed in significant quantities from the gastrointestinal tract and must be administered parenterally.

来源:DrugBank

制备方法与用途

卷曲霉素是一种碱性环状多肽类抗生素,主要用于治疗结核病。其化学性质和药理特点如下:

1. 化学结构:

• 为碱性环状多肽化合物
• 主要由ⅠA、ⅠB两种成分组成
• 溶于水而不溶于多数有机溶剂
• 在pH4-8的水中稳定,但在强酸或强碱中不稳定

2. 物理性质:

• 白色至淡黄色粉末固体
• 稳定性较好,但需注意保存条件以防止分解

3. 药理作用:

• 对结核杆菌具有抑制作用
• 抗菌效力:
  • 链霉素的1/2
  • 对氨水杨酸、乙胺丁醇的1/2
  • 异烟肼的1/10
  • 是异烟肼较弱的一种抗结核药物

4. 主要用途:

• 治疗各型肺结核杆菌感染,尤其是具有可逆病变者或空洞患者
• 需与其他抗结核药联合使用,不能单独应用

5. 注意事项:

• 单用易导致细菌耐药性产生
• 肾功能不全、听力减退等患者应慎用
• 孕妇及哺乳期妇女禁用
• 儿童和老年人需调整剂量

6. 生产方法:

• 由卷曲链霉菌发酵产生
• 经阳离子交换树脂提纯浓缩,再经脱色、除热源等步骤制得成品

综上所述,卷曲霉素是一种专用于结核病治疗的抗生素,但由于其抗菌谱较窄且易产生耐药性,在临床应用中需与其他抗结核药物联合使用。

文献信息

• [EN] PHOSPHODIESTERASE INHIBITORS<br/>[FR] INHIBITEURS DE PHOSPHODIESTÉRASE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2009089027A1

  公开（公告）日：2009-07-16

  The invention relates to compounds of formula I useful for inhibiting phosphodiesterase-4.

  这项发明涉及到公式I的化合物，用于抑制磷酸二酯酶-4。
• [EN] OXAZOLIDINONE COMPOUNDS AND METHODS OF USE THEREOF AS ANTIBACTERIAL AGENTS<br/>[FR] COMPOSÉS OXAZOLIDINONE ET PROCÉDÉS D'UTILISATION DE CES DERNIERS EN TANT QU'AGENTS ANTIBACTÉRIENS
  申请人：MERCK SHARP & DOHME

  公开号：WO2017066964A1

  公开（公告）日：2017-04-27

  The present invention relates to oxazolidinone compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, E, and R1 are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosiscomprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or apharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.

  本发明涉及式(I)的噁唑烷酮化合物及其药学上可接受的盐，其中A、E和R1如本文所定义。本发明还涉及包含本发明至少一种噁唑烷酮化合物的组合物。该发明还提供了抑制分枝杆菌细胞生长的方法，以及通过给予治疗有效量的本发明的噁唑烷酮和/或其药学上可接受的盐，或包含该化合物和/或盐的组合物来治疗结核分枝杆菌感染的方法。
• [EN] HETEROCYCLIC AMIDES USEFUL AS PROTEIN MODULATORS<br/>[FR] AMIDES HÉTÉROCYCLIQUES UTILES EN TANT QUE MODULATEURS DE PROTÉINE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2017175147A1

  公开（公告）日：2017-10-12

  Disclosed are compounds having the formula (I-N), wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.

  揭示了具有化学式（I-N）的化合物，其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐。
• [EN] MODULATORS OF STIMULATOR OF INTERFERON GENES (STING) USEFUL IN TREATING HIV<br/>[FR] MODULATEURS DE STIMULATEUR DES GÈNES (STING) D'INTERFÉRON UTILES DANS LE TRAITEMENT DU VIH
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2019069269A1

  公开（公告）日：2019-04-11

  Disclosed are compounds having the formula: (I-N) wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof, along with combinations thereof, all of which are useful in HIV therapies.

  揭示了具有以下式的化合物：(I-N)其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐，以及其组合物，所有这些在HIV疗法中是有用的。
• [EN] FUSED POLYCYCLIC 2-PYRIDINONE ANTIBACTERIAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIBACTÉRIENS DE 2-PYRIDINONE POLYCYCLIQUE
  申请人：PTC THERAPEUTICS INC

  公开号：WO2016109706A1

  公开（公告）日：2016-07-07

  The present description relates to fused polycyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae or N. meningitides. A compound of Formula (la), Formula (lb) or Formula (Ic), or a form thereof, wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences.

  本描述涉及融合的多环2-吡啶酮化合物及其形式和药物组合物，以及使用这些化合物、形式或组合物治疗或改善N. gonorrhoeae或N. meningitides的野生型或耐药型的方法。其中，化合物的化学式为（la）、（lb）或（Ic），或其形式，其中虚线代表一个或多个双键，根据可用的价键允许的情况下可选择地存在。