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"Fentanyl"
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ESRA19-0043 Efficacy of premixed versus succedent administration of fentanyl and bupivacaine in subarachnoid block for lower limb surgeries
Background and aimsMixing opioids and hyperbaric bupivacaine in a single syringe may alter the density of hyperbaric solution, affecting the spread in intrathecal space. To assess the efficacy of premixed versus succedent administration of fentanyl and hyperbaric bupivacaine in subarachnoid block for lower limb surgeries in terms of:Time taken to reach T10 sensory level and modified bromage score 3 for motor block and the duration of sensory and motor blockIncidence of hypotensionPatient and surgeon satisfaction scoreMethods120 patients aged 18–70 years ASA grade I, II and III scheduled for unilateral lower limb surgery were enrolled in this prospective randomized study. Patients were randomly allocated to 3 groups.Group a patients recieved premixed 0.5% hyperbaric bupivacaine 2.5 ml (12.5 mg) and 0.5 ml (25 mcg) of fentanyl in a single 3.0 ml syringeGroup B patients first received 0.5 ml (25 mcg) of fentanyl in a 3.0 ml syringe followed by 0.5% hyperbaric bupivacaine 2.5 ml (12.5 mg) in a 3.0 ml syringeGroup C patients received 0.5% hyperbaric bupivacaine 2.5 ml (12.5 mg) in a 3 ml syringe followed by 0.5 ml (25 mcg) of fentanyl in a 3 ml syringeResultsDifference in mean time to attain T10 sensory level and modified bromage score of 3 was statistically significant among groups a and B (p value <0.05), groups a and C (p value <0.05) and groups B and C (p value <0.05).ConclusionsAdministering hyperbaric bupivacaine first followed by fentanyl (i.e. succedent) leads to an early onset and prolonged duration of sensory and motor block.
Journal Article
Correlations between metabolism and structural elements of the alicyclic fentanyl analogs cyclopropyl fentanyl, cyclobutyl fentanyl, cyclopentyl fentanyl, cyclohexyl fentanyl and 2,2,3,3-tetramethylcyclopropyl fentanyl studied by human hepatocytes and LC-QTOF-MS
Recently, a number of fentanyl analogs have been implicated in overdose deaths in Europe and in the US. So far, little is known of the molecular behavior of the structurally related subgroup; the alicyclic fentanyls. In this study, reference standards of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 2,2,3,3-tetramethylcyclopropyl fentanyl (TMCPF) at a final concentration of 5 µM were incubated with cryopreserved human hepatocytes (1 × 106 cells/mL) for 0, 1, 3 and 5 h. The metabolites formed were identified by liquid chromatography–quadrupole time-of-flight mass spectrometry analysis. The most abundant biotransformation found was N-dealkylation (formation of normetabolites) and oxidation of the alicyclic rings. As ring size increased, the significance of N-dealkylation decreased in favor of alicyclic ring oxidation. An example of this was cyclopropyl fentanyl, with a three-carbon ring, whose normetabolite covered 82% of the total metabolic peak area and no oxidation of the alicyclic ring was observed. In contrast, TMCPF, with a seven-carbon ring structure, rendered as much as 85% of its metabolites oxidized on the alicyclic ring. Other biotransformations found included oxidation of the piperidine ethyl moiety and/or the phenethyl substructure, glucuronidation as well as amide hydrolysis to form metabolites identical to despropionyl fentanyl. Taken together, this study provides a base for understanding the metabolism of a number of structurally related fentanyl analogs formed upon intake.
Journal Article
CBP relying on new scanners to combat flow of fentanyl
Customs and Border Protection increasingly relying on multi-energy portals for scanning freight and private traffic coming from Mexico for fentanyl.
Streaming Video
Biden engages, sidesteps GOP heckles during address
Republican lawmakers heckled and interrupted President Biden multiple times during his State of the Union address on Feb. 7.
Streaming Video
America’s fentanyl epidemic, by the numbers
Reporter Nick Miroff explains how fentanyl became the most lethal narcotics crisis in U.S. history.
Streaming Video
Data-independent screening method for 14 fentanyl analogs in whole blood and oral fluid using LC-QTOF-MS
•Data independent screening method for fentanyl analogs in blood and oral fluid.•Limits of detection 0.1–0.25 ng/mL in blood and oral fluid, respectively.•Screening results of authentic blood and oral fluid samples presented.
Recently, fentanyl analogs account for significant number of opioid deaths in the United States. Routine forensic analyses are often unable to detect and differentiate these analogs due to low concentrations and presence of structural isomers. A data-independent screening method for 14 fentanyl analogs in whole blood and oral fluid was developed and validated using liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). Data were acquired using Time of Flight (TOF) and All Ions Fragmentation (AIF) modes. The limits of detection (LOD) in blood were 0.1–1.0 ng/mL and 0.1–1.0 ng/mL in TOF and AIF modes, respectively. In oral fluid, the LODs were 0.25 ng/mL and 0.25–2.5 ng/mL in TOF and AIF modes, respectively. Matrix effects in blood were acceptable for most analytes (1–14.4%), while the nor-metabolites exhibited ion suppression >25%. Matrix effects in oral fluid were −11.7 to 13.3%. Stability was assessed after 24 h in the autosampler (4 °C) and refrigerator (4 °C). Processed blood and oral fluid samples were considered stable with −14.6 to 4.6% and −10.1 to 2.3% bias, respectively. For refrigerated stability, bias was −23.3 to 8.2% (blood) and −20.1 to 20.0% (oral fluid). Remifentanil exhibited >20% loss in both matrices. For proof of applicability, postmortem blood (n = 30) and oral fluid samples (n = 20) were analyzed. As a result, six fentanyl analogs were detected in the blood samples with furanyl fentanyl and 4-ANPP being the most prevalent. No fentanyl analogs were detected in the oral fluid samples. This study presents a validated screening technique for fentanyl analogs in whole blood and oral fluid using LC-QTOF-MS with low limits of detection.
Journal Article
Structure-based design of bitopic ligands for the µ-opioid receptor
Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose
1
. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site
2
found in µOR
3
and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp
2.50
residue in the Na
+
site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G
i
subtypes and show strongly reduced arrestin recruitment—one (C6 guano) also shows the lowest G
z
efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G
i
, G
o
and G
z
subtypes and arrestins, thus modulating their in vivo pharmacology.
Bitopic functionalized ligands based on fentanyl can target the sodium ion-binding site of the mu-opioid receptor and selectively modulate downstream signalling pathways, potentially leading to safer analgesics.
Journal Article
Reinforcing effects of fentanyl analogs found in illicit drug markets
RationaleThe potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs).ObjectivesHere, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold.MethodsSprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction.ResultsSelf-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction.ConclusionsOur work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans.
Journal Article