(5R)-2-[4,6-diamino-3-[3-amino-6-[1-(methylamino)ethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol | 1403-66-3

• 物质功能分类: 原料药 - 抗生素类药物 - 氨基糖苷类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (5R)-2-[4,6-diamino-3-[3-amino-6-[1-(methylamino)ethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol
• CAS: 1403-66-3
• 化学式: C₂₁H₄₃N₅O₇
• 分子量: 477.6
• InChiKey: CEAZRRDELHUEMR-NWNXOGAHSA-N

物化性质

• 熔点：
  102-108°
• 比旋光度：
  D25 +146°
• 颜色/状态：
  White amorphous powder
• 溶解度：
  Freely soluble in water
• 蒸汽压力：
  1.75X10-13 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 9.78X10-31 atm-cu m/mol at 25 °C (est)
• 稳定性/保质期：

  Stable in light, air, and heat /Gentamycin sulfate/

• 旋光度：
  Specific optical rotation: +146 deg at 25 °C/D
• 分解：
  Melts with decomposition between 220 °C and 240 °C. /Gentamycin sulfate/
• 解离常数：
  pKb = 9.0 (amine moieties) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -4.1
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  200
• 氢给体数：
  8
• 氢受体数：
  12

ADMET

代谢

庆大霉素不被代谢。它以活性、未改变的形式通过肾小球滤过被排出。

Gentamicin is not metabolized. It is excreted by glomerular filtration in an active, unchanged form.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

硫酸庆大霉素是一种氨基糖苷类抗生素。庆大霉素广泛用于治疗严重感染。它对许多革兰氏阴性细菌和金黄色葡萄球菌具有活性。它对厌氧菌无效，对溶血性链球菌和肺炎球菌的作用较差。人类暴露和毒性：主要风险和靶器官：主要的有毒效果包括前庭损伤、耳聋和肾功能不全。前庭部分的第八对脑神经损伤似乎大于耳蜗部分。主要的靶器官是第八对脑神经和肾脏。第八对脑神经（两个分支）损伤导致耳鸣、耳聋、恶心、呕吐、眩晕、头晕和眼球震颤，以及肾毒性导致急性管状坏死进而导致肾衰竭。在接受庆大霉素治疗的病人中出现听力丧失、头晕、眩晕、共济失调、恶心、呕吐和肾功能损害提示庆大霉素中毒的诊断。其他有毒特征包括肌肉麻痹和呼吸抑制。由于庆大霉素在肾皮质中积累，当肾脏的浓缩能力受损时，就会达到临界浓度。肾毒性似乎与低谷血清浓度超过2微克/毫升的时间有关。确切的毒性机制尚不清楚。耳毒性和前庭毒性似乎与庆大霉素高峰浓度（大于10微克/毫升）升高密切相关。庆大霉素在内淋巴和周围淋巴中积累，导致室管膜和耳蜗细胞的进行性破坏。重复使用庆大霉素可能会产生细胞的进行性破坏，导致耳聋。庆大霉素似乎对前庭部分的损伤大于耳蜗部分。神经肌肉阻滞伴急性肌肉麻痹和呼吸暂停可能会偶尔发生。大多数事件发生在麻醉或给予其他神经肌肉阻滞剂的情况下，但在大剂量庆大霉素或其他氨基糖苷类药物腹膜内或胸膜内给药后也可能发生。这种现象可能在静脉或肌内给药后发生。动物研究：啮齿动物的中毒临床体征包括惊厥、卧地、活动减少、多饮、呼吸困难和不协调。狗出现肌肉震颤、流涎和厌食。对在给药后13天内死亡的狗的肾脏进行组织病理学检查，发现近端曲小管坏死。将3只雌性恒河猴（每组3只）以0、6或30毫克/千克体重的剂量肌内注射庆大霉素水溶液，持续3周。只有30毫克/千克体重/天的组出现了不良的临床体征，包括明显的面部苍白和眼睑下垂，从第20天起明显平衡失调，从第2周起食欲下降和体重增加减少。对30毫克/千克体重/天的猴子肾小管的电子显微镜检查发现，肾小管细胞和管腔中都有髓样体存在，吞噬体增加，刷状缘消失，基底膜上的上皮细胞脱落。将比格犬（每组4只/性别）口服0、2、10或60毫克/千克体重/天的庆大霉素胶囊，持续14周。治疗犬偶尔观察到呕吐和腹泻。唯一的大体变化是高剂量组2只动物中观察到的间质性肾炎。庆大霉素对大鼠的精子参数和睾丸凋亡有负面影响。在两代大鼠研究中，没有报道与治疗相关的怀孕率、窝大小和重量、胎前死亡或胎儿异常。在体外测试了庆大霉素在128-5000微克/毫升的浓度下诱导中国仓鼠卵巢细胞正向基因突变的能力，以及在这些细胞中800-5000微克/毫升的浓度下诱导染色体畸变的能力，无论是否进行代谢激活。它还在体内测试了在静脉内剂量为20-80毫克/千克的浓度下诱导小鼠骨髓细胞核异常的能力，最高剂量为最大耐受剂量。没有显示出致突变活性。

IDENTIFICATION AND USE: Gentamicin sulfate is an aminoglycoside antibiotic. Gentamicin is widely used in the treatment of severe infections. It is active against many strains of Gram-negative bacteria and Streptococus aureus. It is inactive against anaerobes and poorly active against Streptococus hemolyticus and Pneumococcus. HUMAN EXPOSURE AND TOXICITY: Main risks and target organs: The main toxic effects are vestibular damage, deafness and renal dysfunction. The damage on the vestibular portion of the eighth cranial nerve appears to be greater than that on the cochlear portion. The main target organs are the eighth cranial nerves and the kidneys. Damage to eighth cranial nerve (both divisions) resulting in tinnitus, deafness, nausea, vomiting, vertigo, dizziness and nystagmus, and nephrotoxicity causing acute tubular necrosis resulting in renal failure. Loss of hearing, dizziness, vertigo, ataxia, nausea, vomiting and renal impairment developing in a patient on gentamicin therapy suggests a diagnosis of gentamicin toxicity. Other toxic features are muscular paralysis and respiratory depression. As gentamicin accumulates in the renal cortex, a critical concentration is reached when the concentrating ability of the kidney becomes impaired. Nephrotoxicity appears to be related to the duration for which the trough serum concentration exceeds 2 ug/ml. The exact mechanism of toxicity is unknown. Ototoxicity and vestibular toxicity seem most highly correlated with elevated peak concentrations (greater than 10 ug/mL) of gentamicin. Gentamicin accumulates in endolymph and perilymph and progressive destruction of ventricular and cochlear cells occurs. Repeated courses of gentamicin may produce progressive destruction of cells leading to deafness. Gentamicin appears to damage the vestibular portion more than the cochlear portion. Neuromuscular blockade with acute muscular paralysis and apnea may occur rarely. Most episodes have occurred in association with anesthesia or administration of other neuromuscular blockers but may also occur after intrapleural or intraperitoneal instillation of large doses of gentamicin or other aminoglycosides. This phenomenon may occur after intravenous or intramuscular administration. ANIMAL STUDIES: Clinical signs of intoxication in rodents included convulsions, prostration, hypoactivity, polydipsia, dyspnoea and ataxia. Dogs exhibited muscle tremors, salivation, and anorexia. Histopathological examination of kidneys from dogs that died up to 13 days after dosing revealed necrosis of the proximal convoluted tubule. Groups of 3 female Rhesus monkeys were injected i.m. with doses of 0, 6 or 30 mg/kg bw/day gentamicin in an aqueous vehicle for 3 weeks. Adverse clinical signs were limited to the 30 mg/kg bw/day group, which included pronounced facial paling and ptosis, markedly disturbed equilibrium from day 20, and depressed food intake and body- weight gain from week 2 onwards. Electron microscopy of renal tubules from the 30 mg/kg bw/day monkeys revealed myeloid bodies present in both tubular cells and lumen, increased phagosomes, disappearance of brush borders and sloughing of epithelial cells from the basement membrane. Groups of beagle dogs (4/sex/group) were administered oral doses of 0, 2, 10, or 60 mg/kg bw/day gentamicin in capsules for 14 weeks. Emesis and diarrhoea were observed occasionally in treated dogs. The only postmortem change was interstitial nephritis observed in 2 animals in the high-dose group. Gentamicin had negative effects on sperm parameters and testis apoptosis in rats. No treatment-related changes in pregnancy rate, litter size and weight, prenatal mortality or fetal abnormalities were reported in 2 generation study in rats. Gentamicin was tested in vitro for its ability to induce forward gene mutation in Chinese hamster ovary cells at concentrations of 128-5000 ug/mL and chromosomal aberrations in these cells at concentrations of 800-5000 ug/mL, both with and without metabolic activation. It was also tested in vivo for its ability to induce nuclear anomalies in mouse bone-marrow cells at intravenous doses of 20-80 mg/kg bw, the highest dose being the maximum tolerated dose. There was no indication of mutagenic activity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

静脉和肌肉内注射庆大霉素已与血清碱性磷酸酶水平的轻度和无症状升高有关联，但很少影响转氨酶水平或胆红素，一旦停止使用庆大霉素，变化就会迅速解决。只有少数急性肝损伤并伴有黄疸的病例报告与包括庆大霉素在内的氨基糖苷类治疗有关，其中大多数并不十分令人信服。这些报告中描述的肝脏损伤通常是混合型的，但可以演变成胆汁淤积性肝炎。发病的潜伏期很短，发生在1到3周内，通常伴有皮疹、发热，有时还伴有嗜酸性粒细胞增多。恢复通常发生在1到2个月内，没有描述慢性损伤。在药物引起的肝病和急性肝衰竭的大型病例系列中，并没有列出或提到氨基糖苷类药物；因此，如果发生的话，庆大霉素引起的肝损伤是罕见的。

Intravenous and intramuscular therapy with gentamicin has been linked to mild and asymptomatic elevations in serum alkaline phosphatase levels, but rarely affects aminotransferase levels or bilirubin, and changes resolve rapidly once gentamicin is stopped. Only isolated case reports of acute liver injury with jaundice have been associated with aminoglycoside therapy including gentamicin, most of which are not very convincing. The hepatic injury described in these reports is typically mixed but can evolve into a cholestatic hepatitis. The latency to onset is rapid, occurring within 1 to 3 weeks and is typically associated with skin rash, fever and sometimes eosinophilia. Recovery typically occurs within 1 to 2 months and chronic injury has not been described. Aminoglycosides are not listed or mentioned in large case series of drug induced liver disease and acute liver failure; thus, hepatic injury due to gentamicin is rare if it occurs at all.

来源:LiverTox

毒理性

• 相互作用

一项体外研究表明，阿糖胞苷可能拮抗庆大霉素对肺炎克雷伯菌的活性。

One in vitro study indicates that cytarabine may antagonize the activity of gentamicin against Klebsiella pneumoniae.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

庆大霉素在体外和肾衰竭患者的体内似乎比阿米卡星更容易被抗假单胞菌青霉素（例如，替卡西林）灭活。

Gentamicin appears to be more readily inactivated by antipseudomonal penicillins (eg, ticarcillin) than amikacin both in vitro and in vivo in patients with renal failure.

来源:Hazardous Substances Data Bank (HSDB)

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)

吸收、分配和排泄

静脉注射后，庆大霉素会分布到乳汁中。

/MILK/ Gentamicin is distributed into milk following IM administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

庆大霉素在肌肉注射或静脉注射后以低浓度分布进入脑脊液（CSF）。鞘内给药后脑脊液中的庆大霉素浓度取决于给药剂量、注射部位、稀释剂量体积以及脑脊液流动是否存在阻塞。患者之间的浓度可能存在较大差异。在一项研究中，鞘内注射4毫克庆大霉素导致脑脊液中药物浓度在8小时内为19-46微克/毫升，在20小时时低于3微克/毫升。庆大霉素可穿过胎盘。

Gentamicin is distributed into cerebrospinal fluid (CSF) in low concentrations following IM or IV administration. CSF concentrations of gentamicin following intrathecal administration depend on the dose administered, the site of injection, the volume in which the dose is diluted, and the presence or absence of obstruction to CSF flow. There may be considerable interpatient variation in concentrations achieved. In one study, intrathecal administration of 4 mg of gentamicin resulted in CSF concentrations of the drug of 19-46 ug/mL for 8 hours and less than 3 ug/mL at 20 hours. Gentamicin crosses the placenta.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射常规剂量的庆大霉素后，药物可以在淋巴液、皮下组织、肺部、痰液以及支气管、胸膜、心包、关节腔、腹水和腹膜液中检测到。胆汁中的浓度可能较低，提示胆汁排泄量很小。在接受静脉注射庆大霉素（每天一次240毫克）的呼吸机相关性肺炎患者中，肺泡上皮液中的药物浓度约为血清浓度的32%，在给药后2小时平均为4.24微克/毫升。通过肌肉注射或静脉注射后，眼部组织中庆大霉素的浓度仅为微量。

Following parenteral administration of usual dosages of gentamicin, the drug can be detected in lymph, subcutaneous tissue, lung, sputum, and bronchial, pleural, pericardial, synovial, ascitic, and peritoneal fluids. Concentrations in bile may be low, suggesting minimal biliary excretion. In patients with ventilator-associated pneumonia receiving IV gentamicin (240 mg once daily), drug concentrations in alveolar lining fluid were 32% of serum concentrations and averaged 4.24 ug/mL 2 hours after a dose. Only minimal concentrations of gentamicin are attained in ocular tissue following IM or IV administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

庆大霉素在肾功能正常、每8小时接受1毫克/千克剂量、连续使用7-10天的患者中似乎不会发生累积。然而，在使用更高剂量和/或药物长期给药时，尤其是在肾功能受损的患者中，可能会发生累积。

Accumulation of gentamicin does not appear to occur in patients with normal renal function receiving 1-mg/kg doses every 8 hours for 7-10 days. However, accumulation may occur with higher doses and/or when the drug is given for prolonged periods, especially in patients with renal impairment.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  3004909090

制备方法与用途

氨基苷类抗生素：庆大霉素 庆大霉素简介

庆大霉素（Gentamicin）是中国独立自主研制成功的广谱抗生素，是新中国成立以来的伟大科技成果之一。它开始于1967年的研发，并在1969年底成功鉴定并命名“庆大霉素”，意指庆祝“九大”以及庆祝工人阶级的伟大。庆大霉素系从放线菌科单孢子属发酵培养液中提取的碱性化合物，是常用的氨基糖苷类抗生素。

庆大霉素主要用于治疗细菌感染，特别是革兰氏阴性菌引起的感染，并且因其热稳定性而广泛应用于培养基配置。

庆大霉素与β内酰胺类抗生素联合使用

庆大霉素常与其他β内酰胺类抗生素（如青霉素或头孢菌素）联合使用。在兽医临床中，它通常用来治疗败血症、尿路感染和心内膜炎等疾病，并且适用于葡萄球菌感染及其他类型细菌引起的局部或系统性感染。

联合用药与相互作用 与其他抗生素的协同效应

• 庆大霉素与足量羧苄西林联合使用对铜绿假单胞菌某些敏感菌株具有协同抗菌作用。
• 与青霉素联用可能对粪球菌及其变种如屎球菌、坚忍球菌具有协同抗菌作用。

毒性相互影响

• 庆大霉素与其他氨基糖苷类抗生素合用或先后连续应用，可能会增加耳毒性、肾毒性和神经肌肉阻滞的作用。
• 与卷曲霉素、顺铂、依他尼酸、呋塞米等药物合用时也可能增强毒性。

其他相互作用

• 与两性霉素B、头孢噻吩、头孢唑林、右旋糖酐同用或先后使用可能加重肾毒性。
• 与多粘菌素类注射剂合用可增加肾毒性和神经肌肉阻滞作用。
• 与其他具有神经肌肉阻滞作用的药物如地西泮联用，可能会加重此副作用。

不良反应

庆大霉素的不良反应包括耳毒性、肾毒性及神经肌肉阻滞等。当血药峰浓度超过12μg/ml时，谷浓度超过2μg/ml以上的情况下可能发生毒性反应。因此对于肾功能不全或长期用药者应进行药物监测。

治疗用途

庆大霉素主要用于治疗由大肠埃希菌、产气杆菌等革兰氏阴性菌引起的系统或局部感染（对中枢感染无效）。此外，它也适用于败血症、尿路感染和葡萄球菌感染等情况。在特定情况下，庆大霉素还可能用于其他类型的细菌感染。

药物相互作用

• 庆大霉素与青霉素联用可能会增强粪球菌及其变种的抗菌效果。
• 与足量羧苄西林合用可以增强对铜绿假单胞菌某些敏感菌株的抗菌效果。

文献信息

• SYSTEMS AND METHODS FOR INTRACELLULAR DELIVERY VIA NON-CHARGED SEQUENCE-DEFINED CELL-PENETRATING OLIGOMERS
  申请人：Cornell University

  公开号：US20210308270A1

  公开（公告）日：2021-10-07

  The present disclosure provides oligoTEAs and methods of using the oligoTEAs. The oligoTEAs may be functionalized with one or more cargo group. The oligoTEAs may be made by iterative thiol-ene and Michael reactions. The oligoTEAs functionalized with one or more cargo group may be used to treat bacterial infections, cancers, viral infections, urinary tract infections, skin infections, cystic fibrosis, sepsis, fungal infections, or a combination thereof.