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British Journal of Pharmacology Sep 2023The illicit use of fentanyl-like drugs (fentanyls), which are μ opioid receptor agonists, and the many overdose deaths that result, has become a major problem....
BACKGROUND AND PURPOSE
The illicit use of fentanyl-like drugs (fentanyls), which are μ opioid receptor agonists, and the many overdose deaths that result, has become a major problem. Fentanyls are very potent in vivo, leading to respiratory depression and death. However, the efficacy and possible signalling bias of different fentanyls is not clearly known. Here, we compared the relative efficacy and bias of a series of fentanyls.
EXPERIMENTAL APPROACH
For agonist signalling bias and efficacy measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken in HEK293T cells transiently transfected with μ opioid receptors, to assess Gi protein activation and β-arrestin 2 recruitment. Agonist-induced cell surface receptor loss was assessed using an enzyme-linked immunosorbent assay, whilst agonist-induced G protein-coupled inwardly rectifying potassium channel current activation was measured electrophysiologically from rat locus coeruleus slices. Ligand poses in the μ opioid receptor were determined in silico using molecular dynamics simulations.
KEY RESULTS
Relative to the reference ligand DAMGO, carfentanil was β-arrestin-biased, whereas fentanyl, sufentanil and alfentanil did not display bias. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein-coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor. Molecular dynamics simulations suggested unique interactions of carfentanil with the orthosteric site of the receptor that could underlie the bias.
CONCLUSIONS AND IMPLICATIONS
Carfentanil is a β-arrestin-biased opioid drug at the μ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls.
Topics: Rats; Humans; Animals; Receptors, Opioid, mu; beta-Arrestins; Arrestin; Ligands; HEK293 Cells; Fentanyl; Analgesics, Opioid; GTP-Binding Proteins; beta-Arrestin 1; Potassium Channels, Inwardly Rectifying
PubMed: 37005796
DOI: 10.1111/bph.16084 -
BMJ Supportive & Palliative Care Jan 2024
Topics: Humans; Alfentanil; Analgesia; Pain; Pain Management; Analgesics, Opioid
PubMed: 35365483
DOI: 10.1136/bmjspcare-2022-003621 -
Digestive and Liver Disease : Official... Apr 2024Although propofol is widely used for gastrointestinal endoscopic sedation, cardiopulmonary adverse events remain common. Ciprofol is a new intravenous anaesthetic agent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Although propofol is widely used for gastrointestinal endoscopic sedation, cardiopulmonary adverse events remain common. Ciprofol is a new intravenous anaesthetic agent demonstrating respiratory and hemodynamic stability.
AIMS
This study aimed to clarify the benefits of ciprofol combined with alfentanil in bidirectional endoscopy (esophagogastroduodenoscopy followed by colonoscopy) to reduce adverse events and improve post-endoscopic recovery.
METHODS
A total of 185 patients scheduled to undergo bidirectional endoscopy were randomly divided into two groups: ciprofol combined with alfentanil or propofol combined with alfentanil. All patients received 7 µg/kg alfentanil intravenously before the study drugs were administered. The propofol group received a bolus of 1.2 mg/kg (0.12 ml/kg) propofol intravenously, whereas the ciprofol group received a bolus of 0.3 mg/kg (0.12 ml/kg) ciprofol intravenously. The primary outcome was the proportion of patients with cardiopulmonary adverse events (i.e., any one of the airway obstruction, apnoea, hypotension, hypertension, bradycardia, tachycardia or arrhythmias).
RESULTS
Compared with propofol, ciprofol reduced cardiopulmonary adverse events by 43.51 % (34.4% vs. 60.9 %, P <0.001), mitigated respiratory adverse events by 54.74 % (17.2% vs. 38.0 %, P = 0.002) overall and by 59.05 % (12.9% vs. 31.5 %, P = 0.002) during the induction period.
CONCLUSIONS
Ciprofol can significantly decrease respiratory depression events and provides a better sedative efficacy than propofol with higher recovery quality and satisfaction.
Topics: Humans; Propofol; Alfentanil; Prospective Studies; Anesthetics, Intravenous; Endoscopy, Gastrointestinal; Double-Blind Method
PubMed: 37813808
DOI: 10.1016/j.dld.2023.09.016 -
Mikrochimica Acta Sep 2023A novel electrochemical method has been developed, based on a covalent organic framework (COF) and reduced graphene oxide (rGO), to detect fentanyl and alfentanil. COF...
A novel electrochemical method has been developed, based on a covalent organic framework (COF) and reduced graphene oxide (rGO), to detect fentanyl and alfentanil. COF nanomaterials with chrysanthemum morphology obtained by solvothermal reaction contain rich active sites for electrochemical catalytic reaction, thus improving the detection performance of the designed sensor. Reduced graphene oxide improves the sensor's sensitivity due to enhanced electron transfer. Under optimized experimental conditions, the fabricated electrode presents a linear range of 0.02 to 7.26 μM for alfentanil and 0.1 to 6.54 μM for fentanyl, with detection limits of 6.7 nM and 33 nM, respectively. In addition, the sensor possesses excellent selectivity, outstanding reproducibility, and acceptable stability. The proposed sensor is feasible for the reliable monitoring of fentanyl and alfentanil in human serum samples, with acceptable reliability and high potential in real-world applications. Finally, the electrochemical characteristic fingerprint of fentanyl is investigated by studying the electrochemical behavior of alfentanil and fentanyl on the electrode surface.
Topics: Humans; Fentanyl; Alfentanil; Reproducibility of Results; Limit of Detection; Biosensing Techniques
PubMed: 37749328
DOI: 10.1007/s00604-023-05977-8 -
Medicine Aug 2023To systematically evaluate the efficacy and safety of alfentanil plus propofol versus propofol only for painless gastrointestinal endoscopy. (Meta-Analysis)
Meta-Analysis
BACKGROUND
To systematically evaluate the efficacy and safety of alfentanil plus propofol versus propofol only for painless gastrointestinal endoscopy.
METHODS
The Cochrane Library, PubMed, Embase, China Biology Medicine, CNKI, WanFang, and VIP databases were searched to identify randomized controlled trials on alfentanil combined with propofol versus propofol only for painless gastrointestinal endoscopy from the inception of the database to August 2022. The Rev Man 5.4 software was used for statistical analyses.
RESULTS
Thirteen randomized controlled trials involving 1762 patients were identified as eligible for this study. The meta-analysis showed that compared with propofol, alfentanil combined with propofol had a more stable mean arterial pressure [mean difference (MD) = 5.38, 95% confidence interval (CI): 1.97-8.80; P = .002], heart rate (MD = 3.78, 95% CI: 1.30-6.26; P = .003) and pulse oxygen saturation (MD = 1.90, 95% CI: 0.93-2.78; P = .0001); a lower propofol dose (standard mean difference = -2.82, 95% CI: -3.70 to -1.94; P < .00001), lower awakening time (MD = -3.23, 95% CI: -4.01 to -2.45; P < .00001) and lower directional force recovery time (MD = -3.62, 95% CI: -4.22 to -3.03; P < .00001); a lower incidence of nausea and vomiting (relative risk [RR] = 0.32, 95% CI: 0.14-0.71; P = .005), body movement (RR = 0.27, 95% CI: 0.13-0.54; P = .0002), hypotension (RR = 0.23, 95% CI: 0.12-0.46; P < .0001), respiratory depression (RR = 0.37, 95% CI: 0.15-0.89; P = .03) and cough reflex (RR = 0.33, 95% CI: 0.12-0.89; P = .03).
CONCLUSION
This meta-study found that current evidence indicates that alfentanil plus propofol is better than propofol alone for painless gastrointestinal endoscopy and is associated with a lower incidence of adverse reactions. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to validate these above conclusions.
Topics: Humans; Propofol; Alfentanil; Endoscopy, Gastrointestinal; Vomiting; Nausea; Randomized Controlled Trials as Topic
PubMed: 37565872
DOI: 10.1097/MD.0000000000034745 -
Molecular Neurobiology Aug 2023Sevoflurane, commonly administered to children as anesthesia, often leads to emergence delirium (ED). Currently, a consensus is lacking among clinicians regarding... (Meta-Analysis)
Meta-Analysis
Sevoflurane, commonly administered to children as anesthesia, often leads to emergence delirium (ED). Currently, a consensus is lacking among clinicians regarding pharmacological interventions to improve recovery. To determine an effective approach, we compared the effects of several drugs in lowering the incidence of ED after sevoflurane anesthesia in children.We searched online databases for relevant randomized controlled trials (59 studies selected; 5199 NMA-eligible participants) and performed a frequentist network meta-analysis (NMA). This study was registered on PROSPERO (number CRD: 42022329939).All included studies had a low to moderate risk of overall bias. The incidence of ED after sevoflurane anesthesia in children differed according to other drugs administered, and were ranked from high to low according to the surface under the cumulative ranking curve (SUCRA).Sufentanil (91.2%) and dexmedetomidine (77.6%) were more likely to reduce the incidence (SUCRA value) of ED, whereas the placebo (6.5%), ramelteon (11.1%), and magnesium (18%) were less likely to reduce the incidence of ED. Remifentanil (89.3%) ranked first in shortening emergence time, followed by placebo (82.4%) and ketamine (69.7%). Placebo shortened extubation time, followed by remifentanil (66.5%) and alfentanil (61.4%).Sufentanil and remifentanil lowered sevoflurane-induced ED incidences among children and shortened the emergence time more effectively than other drugs. Most adjuvant drugs that are combined with sevoflurane either do not change or may even prolong extubation time. Further research and clinical trials are required to support and update these conclusions.
Topics: Humans; Child; Sevoflurane; Sufentanil; Remifentanil; Network Meta-Analysis; Randomized Controlled Trials as Topic; Anesthesia; Emergence Delirium; Anesthetics, Inhalation; Methyl Ethers; Anesthesia, General
PubMed: 37115403
DOI: 10.1007/s12035-023-03349-0 -
Drug Design, Development and Therapy 2024To evaluate the effect of flumazenil antagonizing remimazolam on postoperative nausea and vomiting (PONV) after gynecologic day surgery. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the effect of flumazenil antagonizing remimazolam on postoperative nausea and vomiting (PONV) after gynecologic day surgery.
PATIENTS AND METHODS
141 cases of gynaecological daycase surgery patients in Weifang People's Hospital were selected, randomized into group F (flumazenil group, 71 cases) and group C (control group, 70 cases). Dexamethasone 5 mg, flurbiprofen axetil 50 mg, and droperidol 1 mg were given intravenously before induction of anesthesia in both groups. Anesthesia induction: Remimazolam 0.25mg / kg was injected within 1 minute. After the patient fell asleep, mivacurium chloride 0.2mg / kg was injected for 30 seconds and alfentanil 20ug / kg was injected for 30 seconds. Anesthesia maintenance: Remimazolam 1mg/kg/h and alfentanil 40ug/kg/h were continuously pumped by micro pump. Stopping the injection of remimazolam and alfentanil at the end of the operation. Flumazenil 0.2 mg was given to antagonize remimazolam in group F after 1 minute. Group C was given an equal volume of saline. The incidence of PONV in the postoperative PACU and over a 24-hour period, patient awakening time, and general patient information were recorded.
RESULTS
The incidence of PONV in both groups within 24 hours was 50.70% in group F was significantly higher than 32.86% in group C. The difference was statistically significant (P < 0.05). The incidence of PONV in the PACU was 5.6% in group F and 8.6% in group C. The difference was not statistically significant (p > 0.05).
CONCLUSION
Flumazenil antagonism of remimazolam increases the incidence of PONV within 24 hours in gynecologic day surgery patients and has no significant effect on the incidence of PONV in the PACU.
Topics: Female; Humans; Alfentanil; Ambulatory Surgical Procedures; Antiemetics; Benzodiazepines; Flumazenil; Gynecologic Surgical Procedures; Postoperative Nausea and Vomiting
PubMed: 38465267
DOI: 10.2147/DDDT.S444313 -
Frontiers in Medicine 2023Bispectral index (BIS), an index used to monitor the depth of anesthesia, can be interfered with by the electromyogram (EMG) signal. The 95% spectral edge frequency...
Comparative analysis of the effect of electromyogram to bispectral index and 95% spectral edge frequency under remimazolam and propofol anesthesia: a prospective, randomized, controlled clinical trial.
BACKGROUND
Bispectral index (BIS), an index used to monitor the depth of anesthesia, can be interfered with by the electromyogram (EMG) signal. The 95% spectral edge frequency (SEF95) also can reflect the sedation depth. Remimazolam in monitored anesthesia care results in higher BIS values than propofol, though in the same sedation level assessed by Modified Observers Assessment of Alertness and Sedation (MOAA/S). Our study aims to illustrate whether EMG is involved in remimazolam causing higher BIS value than propofol preliminarily and to explore the correlations among BIS, EMG, and SEF95 under propofol and remimazolam anesthesia.
PATIENTS AND METHODS
Twenty-eight patients were randomly divided into propofol (P) and remimazolam (RM) groups. Patients in the two groups received alfentanil 10 μg/kg, followed by propofol 2 mg/kg and remimazolam 0.15 mg/kg. Blood pressure (BP), heart rate (HR), and oxygen saturation (SpO) were routinely monitored. The BIS, EMG, and SEF95 were obtained through BIS VISTATM. The primary outcomes were BIS, EMG, and the correlation between BIS and EMG in both groups. Other outcomes were SEF95, the correlation between BIS and SEF95, and the correlation between EMG and SEF95. And all the statistical and comparative analysis between these signals was conducted with SPSS 26.0 and GraphPad Prism 8.
RESULTS
BIS values, EMG, and SEF95 were significantly higher in the RM group than in the P group (all < 0.001). There was a strong positive correlation between BIS and EMG in the RM group ( = 0.416). Nevertheless, the BIS in the P group showed a weak negative correlation with EMG ( = -0.219). Both P ( = 0.787) and RM group ( = 0.559) had a reasonably significant correlation coefficient between BIS and SEF95. SEF95 almost did not correlate with EMG in the RM group ( = 0.101).
CONCLUSION
Bispectral index can be interfered with high EMG intensity under remimazolam anesthesia. However, EMG can hardly affect the accuracy of BIS under propofol anesthesia due to low EMG intensity and a weak negative correlation between EMG and BIS. Moreover, SEF95 may have a great application prospect in predicting the sedation condition of remimazolam.
PubMed: 37608826
DOI: 10.3389/fmed.2023.1128030