新斯的明 | 59-99-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 新斯的明
• 英文名称: neostigmine
• 英文别名: 3-[(dimethylcarbamoyl)oxy]-N,N,N-trimethylanilinium；Neostigmin-Kation；prostigmine；ZINC00001792；synstigmine；[3-(dimethylcarbamoyloxy)phenyl]-trimethylazanium
• CAS: 59-99-4
• 化学式: C₁₂H₁₉N₂O₂
• 分子量: 223.295
• InChiKey: ALWKGYPQUAPLQC-UHFFFAOYSA-N

物化性质

• 沸点：
  364.59°C (rough estimate)
• 密度：
  1.0718 (rough estimate)
• 物理描述：
  Solid
• 溶解度：
  6.77e-02 g/L

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

尼奥司亭通过胆碱酯酶水解，并可以被肝脏中的微粒体酶代谢。

Neostigmine undergoes hydrolysis by cholinesterase and is also metabolized by microsomal enzymes in the liver.

来源:DrugBank

代谢

新斯的明被血浆酯酶破坏，季铵醇和母体化合物通过尿液排出。

NEOSTIGMINE IS DESTROYED BY PLASMA ESTERASES, AND THE QUATERNARY ALCOHOL AND PARENT COMPOUND ARE EXCRETED IN THE URINE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

尼奥司亭在大鼠体内产生3-羟基苯基三甲基铵。罗伯特斯，JB等人；生物化学药物17:9 (1968)。/来自表格/

NEOSTIGMINE YIELDS 3-HYDROXYPHENYL TRIMETHYLAMMONIUM IN THE RAT. ROBERTS, JB ET AL; BIOCHEM PHARMAC 17: 9 (1968). /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：有限的数据表明，在母乳喂养期间使用新斯的明治疗重症肌无力可能是可接受的，尽管可能更倾向于使用吡啶斯的明。监测新生儿，因为有人报告每次哺乳后出现腹部绞痛。由于其半衰期短，单次剂量的新斯的明用于手术后逆转神经肌肉阻滞不太可能对哺乳的婴儿产生超过短暂的不利影响。 ◉ 对哺乳婴儿的影响：据报道，有6名婴儿的母亲使用新斯的明治疗重症肌无力，并成功进行了母乳喂养。一名新生儿在每次哺乳后似乎都有腹部绞痛，这可能是新斯的明引起的，尽管在婴儿母亲的母乳中无法检测到。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到关于哺乳母亲的相关已发布信息。在动物中，胆碱能药物增加催产素的释放，并对血清催乳素有不同的影响。对于已经建立泌乳的母亲来说，催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Limited data indicate that use of neostigmine to treat myasthenia gravis may be acceptable during breastfeeding, although pyridostigmine may be preferred. Monitor newborns because abdominal cramps after each breastfeeding has been reported. Because of its short half-life, single doses of neostigmine to reverse neuromuscular blockade following surgery are unlikely to adversely affect the breastfed infant more than transiently. ◉ Effects in Breastfed Infants:Six infants of mothers treated with neostigmine for myasthenia gravis were reportedly breastfed successfully. One newborn infant appeared to have abdominal cramps after each breastfeeding, probably caused by neostigmine, although it could not be detected in the breastmilk of the infant's mother. ◉ Effects on Lactation and Breastmilk:Relevant published information in nursing mothers was not found as of the revision date. In animals, cholinergic drugs increase oxytocin release, and have variable effects on serum prolactin. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

乙酰胆碱酯酶抑制剂对自主神经效应器细胞以及大脑皮层和皮层下位点的作用，在这些位点上的受体主要是毒蕈碱型的，可被阿托品阻断。/抗胆碱酯酶药/

ACTIONS OF ANTICHOLINESTERASE AGENTS ON AUTONOMIC EFFECTOR CELLS & ON CORTICAL & SUBCORTICAL SITES IN CNS, WHERE RECEPTORS ARE LARGELY OF MUSCARINIC TYPE, ARE BLOCKED BY ATROPINE. /ANTI-CHE AGENTS/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

抗胆碱酯酶剂对骨骼肌的各种作用可被肾上腺素或麻黄碱增强，并被D-筒箭毒碱阻断。

VARIOUS ACTIONS OF ANTI-CHE AGENTS ON SKELETAL MUSCLE ARE AUGMENTED BY EPINEPHRINE OR EPHEDRINE...& BLOCKED BY D-TUBOCURARINE. /ANTICHOLINESTERASE AGENTS/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

盐酸奎宁可能拮抗新斯的明（普鲁斯的明）...在治疗重症肌无力。 ...盐酸奎宁的抗胆碱能作用可能拮抗胆碱能药物的迷走神经刺激作用。 在使用胆碱能药物治疗的重症肌无力患者中应谨慎使用盐酸奎宁。

QUINIDINE MAY ANTAGONIZE THE EFFECTS OF NEOSTIGMINE (PROSTIGMINE)...IN THE TREATMENT OF MYASTHENIA GRAVIS. ...THE ANTICHOLINERGIC EFFECT OF QUINIDINE MAY ANTAGONIZE THE VAGAL-STIMULATING EFFECT OF CHOLINERGIC DRUGS. QUINIDINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH MYASTHENIA GRAVIS WHO ARE BEING TREATED WITH CHOLINERGIC DRUGS.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

新斯的明未能改变在高浓度管箭毒碱存在下神经肌肉阻滞的发展。

Neostigmine failed to modify the development of neuromuscular block in the presence of a high local concn of tubocurarine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

溴新斯的明口服给药后从胃肠道吸收不良

Neostigmine bromide is poorly absorbed from the gastrointestinal tract following oral administration

来源:DrugBank

吸收、分配和排泄

新斯的明通过口服给药吸收不良，因此需要的剂量比通过非肠道途径的剂量要大得多。新斯的明在人身上的有效非肠道剂量是0.5到2.0毫克，而等效的口服剂量可能需要30毫克或更多。如果由于任何原因增强了肠道的吸收，大剂量的口服可能会产生毒性。

NEOSTIGMINE...IS ABSORBED POORLY AFTER ORAL ADMINISTRATION, SUCH THAT MUCH LARGER DOSES ARE NEEDED THAN BY THE PARENTERAL ROUTE. ...THE EFFECTIVE PARENTERAL DOSE OF NEOSTIGMINE IN MAN IS 0.5 TO 2.0 MG, THE EQUIVALENT ORAL DOSE MAY BE 30 MG OR MORE. LARGE ORAL DOSES MAY PROVE TOXIC IF INTESTINAL ABSORPTION IS ENHANCED FOR ANY REASON.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

...新斯的明在严重肾病患者中的排泄会延迟，这使得这种抗胆碱酯酶药物成为肾衰竭患者的可接受选择。

...THE EXCRETION OF NEOSTIGMINE IS RETARDED IN PATIENTS WITH SEVERE KIDNEY DISEASE, MAKING THIS ANTICHOLINESTERASE DRUG AN ACCEPTABLE CHOICE IN PATIENTS WITH RENAL FAILURE.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

确定正常肾功能患者新斯的明的药代动力学，并将其与接受肾移植或双侧肾切除术的患者的药代动力学进行比较。在手术和麻醉结束前10至15分钟，停止d-筒箭毒碱输注，并在2分钟内通过输注给予新斯的明，剂量为0.07毫克/千克，阿托品为0.03毫克/千克。无肾患者消除半衰期延长。总血清清除率从正常肾功能患者的16.7毫升/千克/分钟降低到无肾患者的7.8毫升/千克/分钟。肾移植后新斯的明的药代动力学与正常肾功能患者无差异。肾脏排泄占新斯的明清除率的50%。

The pharmacokinetics of neostigmine in patients with normal renal function were determined and compared with those of patients undergoing renal transplantation or bilateral nephrectomy. Ten to 15 min prior to the end of operation and anesthesia, d-tubocurarine infusion was terminated and neostigmine, 0.07 mg/kg and atropine 0.03 mg/kg were given by infusion over a 2-min period. In anephric patients the elimination half-life was prolonged. Total serum clearance was decr from 16.7 ml/kg/min in patients with normal renal function to 7.8 ml/kg/min in anephric patients. Neostigmine pharmacokinetics following renal transplantation were not different from those in patients with normal renal function. Renal excretion accounts for 50% of neostigmine clearance.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  库房应保持低温、通风和干燥，并将物品与食品原料分开存放。

制备方法与用途

新斯的明试验

重症肌无力（MG）是一种由乙酰胆碱受体抗体介导、细胞免疫依赖、补体参与的自身免疫性疾病，主要影响神经肌肉接头突触后膜上的乙酰胆碱受体。最终导致乙酰胆碱传递功能减弱，引发随意肌疲劳性无力。新斯的明作为乙酰胆碱酯酶抑制剂可以减少外周神经突触间隙中的乙酰胆碱降解，增加其含量，从而恢复骨骼肌力量。因此，临床常用新斯的明试验来判定患者肌无力是否由神经肌肉接触处的乙酰胆碱受体受损引起。新斯的明试验阳性对MG诊断有重要辅助作用。

类别

有毒物质

毒性分级

剧毒

急性毒性

• 静脉注射-大鼠 LD50: 0.225 毫克/公斤
• 静脉注射-小鼠 LD50: 0.380 毫克/公斤

可燃性危险特性

可燃，燃烧时分解产生有毒氮氧化物气体

储运特性

库房低温、通风、干燥；与食品原料分开存放

灭火剂

水、二氧化碳、干粉、砂土

文献信息

• [EN] PROCESS FOR PREPARATION OF HIGHLY PURE 3-DIMETHYLAMINOPHENYL DIMETHYLCARBAMATE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE DIMÉTHYLCARBAMATE DE 3-DIMÉTHYLAMINOPHÉNYLE HAUTEMENT PUR
  申请人：NEON LAB LTD

  公开号：WO2012131699A1

  公开（公告）日：2012-10-04

  The invention discloses a novel process for preparation of highly pure 3-dimethylaminophenyl dimethylcarbamate via formation of aryl dimethylcarbamate which can be easily obtained from diaryl carbonate and dimethylamine.

  该发明揭示了一种新的制备高纯度3-二甲基氨基苯基二甲基氨基甲酸酯的方法，通过生成芳基二甲基氨基甲酸酯，该芳基二甲基氨基甲酸酯可以很容易地从二芳基碳酸酯和二甲胺中获得。
• [EN] BIS-HETEROARYL DERIVATIVES AS MODULATORS OF PROTEIN AGGREGATION<br/>[FR] DÉRIVÉS BIS-HÉTÉROARYLIQUES EN TANT QUE MODULATEURS DE L'AGRÉGATION DES PROTÉINES
  申请人：NEUROPORE THERAPIES INC

  公开号：WO2017020010A1

  公开（公告）日：2017-02-02

  The present invention relates to certain bis-heteroaryl compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto- temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer including melanoma.

  本发明涉及某些双杂环芳基化合物，含有它们的药物组合物，以及使用它们的方法，包括用于预防、逆转、减缓或抑制蛋白聚集的方法，以及治疗与蛋白聚集相关的疾病的方法，包括帕金森病、阿尔茨海默病、路易体病、帕金森病伴痴呆、额颞型痴呆、亨廷顿病、肌萎缩侧索硬化和多系统萎缩等神经退行性疾病，以及包括黑色素瘤在内的癌症。
• [EN] NMDA RECEPTOR MODULATORS AND USES THEREOF<br/>[FR] MODULATEURS DES RÉCEPTEURS NMDA ET UTILISATIONS DE CEUX-CI
  申请人：CADENT THERAPEUTICS

  公开号：WO2018119374A1

  公开（公告）日：2018-06-28

  Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated to modulate the NMDA receptor.

  本文披露了部分杂芳化合物及其在治疗神经精神障碍，例如精神分裂症和重度抑郁症中的用途方法。提供了药物组合物和制备杂芳化合物的方法。这些化合物被认为可以调节NMDA受体。
• [EN] ALKOXY BIS-HETEROARYL DERIVATIVES AS MODULATORS OF PROTEIN AGGREGATION<br/>[FR] DÉRIVÉS BIS-HÉTÉROARYLIQUES D'ALCOXY UTILISÉS EN TANT QUE MODULATEURS DE L'AGRÉGATION DE PROTÉINES
  申请人：UCB BIOPHARMA SPRL

  公开号：WO2018138085A1

  公开（公告）日：2018-08-02

  The present invention relates to certain bis-heteroaryl compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer including melanoma.

  本发明涉及某些双杂环芳基化合物，含有它们的药物组合物，以及使用它们的方法，包括用于预防、逆转、减缓或抑制蛋白聚集的方法，以及治疗与蛋白聚集相关的疾病的方法，包括帕金森病、阿尔茨海默病、路易体病、帕金森病合并痴呆、额颞叶痴呆、亨廷顿病、肌萎缩侧索硬化和多系统萎缩等神经退行性疾病，以及包括黑色素瘤在内的癌症。
• Therapeutic Uses Of Compounds Having Affinity To The Serotonin Transporter, Serotonin Receptors And Noradrenalin Transporter
  申请人：H. Lundbeck A/S

  公开号：US20170087138A1

  公开（公告）日：2017-03-30

  Therapeutic uses of 4-[2-(4-methylphenylsulfanyl)phenyl]piperidine and therapeutically acceptable salts thereof are provide.

  4-[2-(4-甲基苯基硫基)苯基]哌啶及其治疗上可接受的盐的治疗用途已提供。

表征谱图