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).
/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/
/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/
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/
(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.
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.
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.
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).
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.
