洛芬太尼 | 60645-00-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 洛芬太尼
• 英文名称: Lofentanyl
• 英文别名: methyl 3-methyl-1-(2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate
• CAS: 60645-00-3
• 化学式: C₂₅H₃₂N₂O₃
• 分子量: 408.5
• InChiKey: IMYHGORQCPYVBZ-UHFFFAOYSA-N

物化性质

• 颜色/状态：
  Solid
• 溶解度：
  In water, 0.6748mg/L at 25 °C (est)
• 蒸汽压力：
  3.5X10-10 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 8.36 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

毒理性

• 毒性总结

洛芬太尼是一种非常强效的阿片类止痛药。它在临床上用于疼痛管理。然而，这种药物的高止痛效力因长期使用后产生耐受性而受限。在患者研究中，非常低发生率的不良反应包括恶心、呕吐和镇静。另一项研究提到，三名患者出现嗜睡作为不良反应。在动物研究中，向大鼠静脉注射递增剂量的洛芬太尼（0、0.08、0.16、0.31、0.63、1.25、2.50、5.00 和 10.0 微克/千克），以检查中枢神经系统（CNS）抑制剂剂量、止痛程度（抑制尾撤反射）、麻醉（对骨碎伤无反应）和CNS阿片受体占有率之间的关系。递增剂量的洛芬太尼产生递增的止痛和麻醉效果，并最终达到阿片受体的完全占有率。当洛芬太尼的剂量（0.31 微克/千克）导致CNS阿片受体结合水平低到无法测量时，产生止痛效果，而当洛芬太尼的剂量（1.25 微克/千克）在大脑皮层和皮层下区域产生约25%的阿片受体占有率时，产生麻醉效果。在大鼠中，需要比麻醉剂量高八倍的洛芬太尼剂量（10.0 微克/千克）才能几乎饱和所有可用的CNS阿片受体。

IDENTIFICATION AND USE: Lofentanil is a very potent opioid analgesic. It is used clinically in the management of pain. However, the high analgesic potency of this drug is limited by the development of tolerance after chronic use. HUMAN STUDIES: In patients side effects of very low incidence included nausea, vomiting and sedation. Another study mentions drowsiness in three patients as a side effect. ANIMAL STUDIES: Increasing doses of lofentanil (0, 0.08, 0.16, 0.31, 0.63, 1.25, 2.50, 5.00, and 10.0 ug/kg) were administered intravenously to rats to examine the relationship among central nervous system (CNS) depressant dosage, degree of analgesia (inhibition of tail withdrawal reflex), anesthesia (no response to bone-crush injury), and CNS opiate-receptor occupancy. Increasing doses of lofentanil produce increasing analgesia and anesthesia and eventually complete opiate receptor occupancy. Analgesia occurs with doses of lofentanil (0.31 ug/kg) that result in levels of CNS opiate-receptor binding too low to be measured and anesthesia occurs with doses of lofentanil (1.25 ug/kg) that produce occupancy of about 25% of the available opiate receptors in subcortical areas and cortex. In rats a dose eight times the anesthetic dose of lofentanil is needed to saturate virtually all available CNS opiate receptors (10.0 ug/kg).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

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。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以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……。预防癫痫发作，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，如果患者能吞咽、有强烈的干呕反射且不流口水，则冲洗口腔并给予5毫升/千克，最多200毫升的水进行稀释……。/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 ... . /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D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液（LR）。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 TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) 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

• 解毒与急救

紧急和支持性措施。1. 保持呼吸道通畅，必要时协助通气。给予补充氧气。如果出现昏迷、癫痫、低血压和非心源性肺水肿，则进行治疗。/阿片类药物和鸦片类药物/

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, hypotension, and noncardiogenic pulmonary edema if they occur. /Opiates and opioids/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(3)H-洛芬太尼，一种非常强效且作用时间极长的阿片类药物，在大鼠迷走神经周围结扎后立即静脉注射。放射性物质在注射后24小时及48小时在结扎线两侧积聚。相比之下，预先用纳洛酮处理的大鼠，在坐骨神经结扎处或迷走神经两个结扎线之间没有积聚。体外测量的特异性(3)H-洛芬太尼结合点的积聚仅在结扎线以上，即神经近端部分检测到。当在不同时间间隔结扎后注射(3)H-洛芬太尼时，我们观察到远端部分的标记急剧下降，近端部分虽然较慢，但也有下降。这可能是由于(3)H-洛芬太尼结合点的可能回收或再利用。目前的数据与轴浆流和静脉注射(3)H-洛芬太尼后阿片受体标记的可能的再循环相兼容。

(3)H-Lofentanil, an extremely potent opiate drug with a very long duration of action was injected intravenously into rats immediately after a ligature had been tied around the vagus nerve. Radioactivity accumulated on both sides of the ligature 24 hours and, to a larger extent, 48 hours after the injection. In contrast, there was no accumulation in animals pretreated with naloxone, neither in ligated sciatic nerves nor between two ligatures in the vagus nerve. An accumulation of stereospecific (3)H-lofentanil binding sites measured in vitro was only detected above the ligature, thus in the proximal part of the nerve. When (3)H-lofentanil was injected at different time intervals after ligation, we observed a tremendous drop of labelling in the distal and also but more slowly in the proximal part of the nerve. This could be due to a possible recycling or re-utilization of (3)H-lofentanil binding sites. The present data are compatible with an axoplasmic flow and a possible recycling of opiate receptors labelled in vivo after intravenous injection of (3)H-lofentanil.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(3)H-洛芬太尼在大鼠大脑各区域的活体结合进行了研究。静脉注射(3)H-洛芬太尼后，标记药物在大脑中的分布与体外结合实验测得的阿片受体区域分布完全平行。这种标记是可饱和的，并且在给予(3)H-洛芬太尼之前通过纳洛酮可以预防，但在小脑区域除外。特异性标记的长期存在与洛芬太尼极慢的解离速率和其长效作用完全一致。这解释了为什么(3)H-洛芬太尼在活体中不能被纳洛酮置换。亚细胞分级实验揭示了额叶皮层中所有的标记都是颗粒结合的，并且可以通过纳洛酮完全置换，而在小脑中则不是。(3)H-洛芬太尼在活体中的优点是其极低的非特异性结合能力和能够揭示大脑中阿片受体极低占有率的能力。

The in vivo binding of (3)H-lofentanil was studied in various regions of the brain in rat. After intravenous injection of (3)H-lofentanil the disposition of the labelled drug in the brain paralleled exactly the regional distribution of opiate receptors measured in in vitro binding assays. The labelling was saturable and could be prevented by naloxone when given before (3)H-lofentanil, in all the regions except in the cerebellum. The long-lasting occurrence of the specific labelling was entirely compatible with the extremely slow dissociation rate of lofentanil and its long duration of action. This explains why (3)H-lofentanil is not displaceable by naloxone in vivo. Subcellular fractionation experiments revealed that all the labelling in the frontal cortex but not in the cerebellum was particulate-bound and entirely displaceable by naloxone. The advantages of (3)H-lofentanil in vivo are its extremely low non-specific binding and its ability to reveal very low occupancy of opiate receptors in brain.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠、狗和健康志愿者中研究了芬太尼和三种类似物在体外的血浆蛋白结合和在血液中的分布。在人体血浆中，芬太尼的结合率为84.4%，舒芬太尼为92.5%，阿芬太尼为92.1%，洛芬太尼为93.6%。这四种镇痛药的血浆蛋白结合与其浓度在整个治疗范围内无关。阿芬太尼的血浆蛋白结合对pH的依赖性远小于其他三种镇痛药。注意到了“急性相”蛋白α1-酸性糖蛋白（α1-AGP）、脂蛋白和血细胞可能对芬太尼及其类似物在血液中的结合有所贡献。

The in vitro plasma protein binding and distribution in blood of fentanyl and three analogues were studied in rats, dogs and healthy volunteers. In human plasma, 84.4% of fentanyl was bound, 92.5% of sufentanil, 92.1% of alfentanil and 93.6% of lofentanil. Plasma protein binding of the four analgesics was independent of their concentration over the whole therapeutic range. Plasma protein binding of alfentanil was much less pH dependent than that of the three other analgesics. Attention was drawn to the possible contribution of the "acute phase" protein alpha 1-acid glycoprotein (alpha 1-AGP), of lipoproteins and of blood cells to the binding of fentanyl and its analogues in blood.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

孵化介质pH对豚鼠孤立心房细胞内三氚芬太尼、洛芬太尼和阿芬太尼积累的影响进行了研究。芬太尼和洛芬太尼在心房组织中分别积累了大约30倍和50倍。当达到平衡时，结合的药物量被发现依赖于介质的pH。通过绘制结合平衡与浴液pH的关系曲线，得到了类似于滴定曲线的曲线。在接近芬太尼和洛芬太尼的pKa值的pH值时，达到了一半的最大结合。阿芬太尼被发现积累较少。组织的摄取与细胞外浓度强烈成正比。在pH 8.5下与芬太尼平衡的心房，在暴露于pH 7.0时迅速释放该化合物，即使在浴液中持续存在芬太尼的情况下也是如此。讨论了这些发现在体内条件下的可能影响，特别是关于呼吸性酸中毒可能增强芬太尼作用的后果。

The influence of the pH of the incubation medium on the cellular accumulation of tritiated fentanyl, lofentanil, and alfentanil was investigated in isolated guinea pig atria. Fentanyl and lofentanil accumulated in atrial tissue up to about 30- and 50-fold, respectively. The amount of drug bound when equilibrium was attained was found to be dependent upon the pH of the medium. By plotting binding equilibria v. pH of the bath, curves were obtained which resembled titration curves. Half-maximal binding was attained at pH values close to the pKa values of fentanyl and lofentanil. Alfentanil was found to accumulate less. The uptake by the tissue was strongly proportional to the extracellular concentration. Atria equilibrated with fentanyl at pH 8.5 released the compound rapidly when exposed to a pH of 7.0, even in the continuous presence of fentanyl in the bath. The consequences of the findings for in vivo conditions are discussed with respect to a possible augmentation of the actions of fentanyl by respiratory acidosis.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• Devices and methods for pain management
  申请人：——

  公开号：US20030171401A1

  公开（公告）日：2003-09-11

  The invention features devices and methods for the systemic delivery of fentanyl or a fentanyl congener (e.g., sufentanil) to treat pain. In the present invention, a drug formulation comprising fentanyl or a fentanyl congener is stored within a drug delivery device (e.g., contained in a reservoir or impregnated within a matrix within the controlled drug delivery device). The drug formulation comprises an amount of drug sufficient for treatment and is stable at body temperatures (i.e., no unacceptable degradation) for the entire pre-selected treatment period. The drug delivery devices store the drug formulation safely (e.g., without dose dumping), provide sufficient protection from bodily processes to prevent unacceptable degradation of the formulation, and release the drug formulation in a controlled fashion at a therapeutically effective rate to treat pain. In use, the drug delivery device is implanted in the subject's body at an implantation site, and the drug formulation is released from the drug delivery device to a delivery site. The delivery site may be the same as, near, or distant from the implantation site. Once released at the delivery site, the drug formulation enters the systemic circulation and is transported to the site of action in the body to modulate the pain response (e.g., the brain or other pain sensory location).

  本发明的特点是全身给药芬太尼或芬太尼同系物（如舒芬太尼）治疗疼痛的装置和方法。在本发明中，由芬太尼或芬太尼同系物组成的药物制剂储存在给药装置中（例如，包含在贮存器中或浸渍在受控给药装置的基质中）。药物制剂包含足够治疗量的药物，并且在整个预选治疗期间在体温下稳定（即没有不可接受的降解）。给药装置可以安全地储存药物制剂（例如，没有剂量倾倒），提供足够的保护以防止药物制剂发生不可接受的降解，并以治疗有效的速度有控制地释放药物制剂以治疗疼痛。使用时，将给药装置植入受试者体内的植入部位，药物制剂从给药装置释放到给药部位。给药部位可以与植入部位相同、靠近或远离植入部位。一旦在给药部位释放，药物制剂就会进入全身循环，并被输送到体内的作用部位（如大脑或其他痛觉部位），以调节疼痛反应。
• High concentration formulations of opioids and opioid derivatives
  申请人：——

  公开号：US20040102476A1

  公开（公告）日：2004-05-27

  The present invention provides opioid formulations suitable for long-term delivery to a subject. The formulation of the invention comprises an opioid or opioid derivative (e.g., morphine, hydromorphone, fentanyl or a fentanyl congener), and an aqueous solvent comprising a low molecular weight carboxylic acid (e.g., C 2-4 , C 2-7 ). The invention thus provides for formulations comprising morphine, hydromorphone, fentanyl or fentanyl congeners in concentrations significantly in excess of conventional aqueous formulations, e.g., on the order about 2-fold to about 10,000-fold greater than conventional formulations, e.g., currently commercially available formulations.

  本发明提供了适用于长期给药的阿片制剂。本发明的制剂包括阿片类药物或阿片类药物衍生物（如吗啡、氢吗啡酮、芬太尼或芬太尼同系物），以及由低分子量羧酸（如 C 2-4 , C 2-7 ).因此，本发明提供了包含吗啡、氢吗啡酮、芬太尼或芬太尼同系物的制剂，其浓度大大超过传统的水性制剂，例如，比传统制剂（如目前市售制剂）高约 2 倍至约 10,000 倍。
• Opioid formulations
  申请人：——

  公开号：US20030212106A1

  公开（公告）日：2003-11-13

  The present invention provides high-concentration formulations of opioids such as fentanyl or fentanyl congeners. The formulation of the invention comprises fentanyl or a fentanyl congener in concentrations significantly in excess of conventional formulations, e.g., on the order about 2-fold to about 10,000-fold greater than conventional formulations, e.g., currently commercially available formulations. These formulations are particularly useful for long-term delivery to a subject suffering from pain. The invention further provides drug delivery devices comprising the high-concentration opioid formulations, and further provides methods of alleviating pain in a subject, comprising administering the high-concentration formulations to a subject in need thereof.
• High Concentration Formulations of Opioids and Opioid Derivatives
  申请人：Chan Tai Wah

  公开号：US20110136847A1

  公开（公告）日：2011-06-09

  The present invention provides opioid formulations suitable for long-term delivery to a subject. The formulation of the invention comprises an opioid or opioid derivative (e.g., morphine, hydromorphone, fentanyl or a fentanyl congener), and an aqueous solvent comprising a low molecular weight carboxylic acid (e.g., C 2-4 , C 2-7 ). The invention thus provides for formulations comprising morphine, hydromorphone, fentanyl or fentanyl congeners in concentrations significantly in excess of conventional aqueous formulations, e.g., on the order about 2-fold to about 10,000-fold greater than conventional formulations, e.g., currently commercially available formulations.
• OPIOID FORMULATIONS
  申请人：DURECT CORPORATION

  公开号：US20140350053A1

  公开（公告）日：2014-11-27

  The present invention provides high-concentration formulations of opioids such as fentanyl or fentanyl congeners. The formulation of the invention comprises fentanyl or a fentanyl congener in concentrations significantly in excess of conventional formulations, e.g., on the order about 2-fold to about 10,000-fold greater than conventional formulations, e.g., currently commercially available formulations. These formulations are particularly useful for long-term delivery to a subject suffering from pain. The invention further provides drug delivery devices comprising the high-concentration opioid formulations, and further provides methods of alleviating pain in a subject, comprising administering the high-concentration formulations to a subject in need thereof.