Lofentanil | 61380-40-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: Lofentanil
• 英文别名: Lofentanilum；methyl (3S,4R)-3-methyl-1-(2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate
• CAS: 61380-40-3
• 化学式: C₂₅H₃₂N₂O₃
• 分子量: 408.541
• InChiKey: IMYHGORQCPYVBZ-NBGIEHNGSA-N

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，非常低发生率的副作用包括恶心、呕吐和镇静。另一项研究提到，三名患者出现嗜睡作为副作用。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，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，产生止痛作用；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，产生麻醉作用。在大鼠中，需要八倍于洛芬太尼麻醉剂量的剂量才能几乎饱和所有可用的CNS阿片受体（10.0 微克/千克）。

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和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，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。如果患者呕吐，让患者向前倾或将其置于左侧（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。寻求医疗救助。 /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）。必要时进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。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……。预见并处理癫痫发作，如有必要……。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，则用水冲洗口腔，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受体激动剂，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），保持静脉通路开放，最小流量/ SRP: "保持开放"。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……。使用丙美卡因盐酸协助眼部冲洗……。/毒素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 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。24小时和48小时后，结扎处两侧出现了放射性物质的积累。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处结扎之间没有积累。在体外测量的特异性(3)H-洛芬太尼结合点的积累仅在结扎上方，即神经的近端部分检测到。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动和静脉注射(3)H-洛芬太尼后体内标记的阿片受体可能回收相兼容。

(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前额皮质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，以及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

pH 值对培养介质中细胞积累氚标记的芬太尼、洛芬太尼和阿芬太尼的影响在离体豚鼠心房中进行了研究。芬太尼和洛芬太尼在心房组织中分别积累到大约 30 倍和 50 倍。当达到平衡时，结合的药物量被发现取决于介质的 pH 值。通过绘制结合平衡与浴液 pH 值的关系曲线，得到了类似于滴定曲线的曲线。在 pH 值接近芬太尼和洛芬太尼的 pKa 值时，达到一半最大结合。发现阿芬太尼积累较少。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 时会迅速释放该化合物，即使在浴液中持续存在芬太尼的情况下也是如此。本文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

• NASAL DRUG PRODUCTS AND METHODS OF THEIR USE
  申请人：Adapt Pharma Limited

  公开号：US20170071851A1

  公开（公告）日：2017-03-16

  Drug products adapted for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising an opioid receptor antagonist, are provided. Methods of treating opioid overdose or its symptoms with the inventive drug products are also provided.
• US3998834A
  申请人：——

  公开号：US3998834A

  公开（公告）日：1976-12-21
• US4179569A
  申请人：——

  公开号：US4179569A

  公开（公告）日：1979-12-18
• US7790905B2
  申请人：——

  公开号：US7790905B2

  公开（公告）日：2010-09-07
• US7927613B2
  申请人：——

  公开号：US7927613B2

  公开（公告）日：2011-04-19