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Neuron May 2023Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric...
Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.
Topics: Mice; Animals; Dopamine; Propofol; Dopamine Plasma Membrane Transport Proteins; Molecular Docking Simulation; Receptors, Dopamine D1; Nucleus Accumbens; Anhedonia; Mice, Inbred C57BL
PubMed: 36917979
DOI: 10.1016/j.neuron.2023.02.017 -
BioMed Research International 2023Ciprofol is a novel compound that was independently developed in China. According to the Chinese product instructions approved by the China National Medical Products... (Review)
Review
Ciprofol is a novel compound that was independently developed in China. According to the Chinese product instructions approved by the China National Medical Products Administration and the information of official website, indications for ciprofol include sedation and anesthesia during the surgical/procedure of nontracheal intubation, induction and maintenance of general anesthesia, and sedation during intensive care. Ciprofol is a short-acting intravenous sedative based on the structural modification of propofol. Ciprofol has high efficacy, good selectivity, and fewer adverse reactions, indicating good clinical application potential. A series of clinical studies have been conducted to evaluate the sedative effect of ciprofol in various procedures and settings, including gastroscopy and colonoscopy, fiber-optic bronchoscopy, general anesthesia in elective surgeries, and mechanical ventilation in intensive care units. This review summarizes the chemical structure, pharmacodynamics, and pharmacokinetic properties of ciprofol. We also assessed the efficacy and safety of ciprofol by synthesizing the relevant clinical trial data.
Topics: Humans; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Intravenous; Critical Care; Hypnotics and Sedatives; Propofol; Clinical Trials as Topic
PubMed: 36714027
DOI: 10.1155/2023/7443226 -
Minerva Anestesiologica Dec 2022The aim of this systemic review and meta-analysis was to evaluate the efficacy and safety of remimazolam compared with propofol when used for procedural sedation and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The aim of this systemic review and meta-analysis was to evaluate the efficacy and safety of remimazolam compared with propofol when used for procedural sedation and general anesthesia.
EVIDENCE ACQUISITION
Data sources were PubMed, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicaTrials.gov, searched up to March 21, 2022. RCTs comparing remimazolam and propofol in patients undergoing procedural sedation or general anesthesia were searched. Pooled risk ratios (RRs) or standardized mean difference, 95% CIs, and P values were estimated for end points using the fixed- and random-effects statistical model. The trial sequential analysis was used for sensitivity analysis.
EVIDENCE SYNTHESIS
Ten studies with 1813 patients were included. Compared with propofol, remimazolam had lower success rate of sedation/general anesthesia (RR, 1.02; 95% CI: 1.01 to 1.03; P=0.004; N.=1402). However, remimazolam had lower incidence of hypoxia, hypotension, and injection pain than propofol. No difference in incidence of nausea and vomiting, time to awake and to discharge was found. Subgroup studies showed that remimazolam had lower success rate than propofol when used for procedural sedation, not general anesthesia. The trial sequential analysis adjusted confidence interval was 1.01 to 1.04 for success rate.
CONCLUSIONS
Remimazolam could be alternatively used in procedural sedation and general anesthesia. Additional research is needed to develop higher quality evidence on the use of remimazolam, especially in general anesthesia.
Topics: Humans; Anesthesia, General; Benzodiazepines; Hypnotics and Sedatives; Hypotension; Propofol
PubMed: 36326772
DOI: 10.23736/S0375-9393.22.16817-3 -
Critical Care (London, England) Apr 2023Propofol is one of the most widely used hypnotic agents in the world. Nonetheless, propofol might have detrimental effects on clinically relevant outcomes, possibly due... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Propofol is one of the most widely used hypnotic agents in the world. Nonetheless, propofol might have detrimental effects on clinically relevant outcomes, possibly due to inhibition of other interventions' organ protective properties. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate if propofol reduced survival compared to any other hypnotic agent in any clinical setting.
METHODS
We searched eligible studies in PubMed, Google Scholar, and the Cochrane Register of Clinical Trials. The following inclusion criteria were used: random treatment allocation and comparison between propofol and any comparator in any clinical setting. The primary outcome was mortality at the longest follow-up available. We conducted a fixed-effects meta-analysis for the risk ratio (RR). Using this RR and 95% confidence interval, we estimated the probability of any harm (RR > 1) through Bayesian statistics. We registered this systematic review and meta-analysis in PROSPERO International Prospective Register of Systematic Reviews (CRD42022323143).
RESULTS
We identified 252 randomized trials comprising 30,757 patients. Mortality was higher in the propofol group than in the comparator group (760/14,754 [5.2%] vs. 682/16,003 [4.3%]; RR = 1.10; 95% confidence interval, 1.01-1.20; p = 0.03; I = 0%; number needed to harm = 235), corresponding to a 98.4% probability of any increase in mortality. A statistically significant mortality increase in the propofol group was confirmed in subgroups of cardiac surgery, adult patients, volatile agent as comparator, large studies, and studies with low mortality in the comparator arm.
CONCLUSIONS
Propofol may reduce survival in perioperative and critically ill patients. This needs careful assessment of the risk versus benefit of propofol compared to other agents while planning for large, pragmatic multicentric randomized controlled trials to provide a definitive answer.
Topics: Adult; Humans; Propofol; Bayes Theorem; Randomized Controlled Trials as Topic; Systematic Reviews as Topic; Hypnotics and Sedatives
PubMed: 37046269
DOI: 10.1186/s13054-023-04431-8 -
British Journal of Anaesthesia Mar 2021Postoperative delirium (POD) is a frequent complication in older patients. Dexmedetomidine might be effective in decreasing the incidence of POD. We hypothesised that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Postoperative delirium (POD) is a frequent complication in older patients. Dexmedetomidine might be effective in decreasing the incidence of POD. We hypothesised that adding low-dose rate dexmedetomidine infusion to a propofol sedation regimen would have fewer side-effects and would counteract the possible delirium producing properties of propofol, resulting in a lower risk of POD than propofol with placebo.
METHODS
In this double-blind placebo-controlled trial, patients ≥60 yr old undergoing on-pump cardiac surgery were randomised 1:1 to the following postoperative sedative regimens: a propofol infusion and dexmedetomidine (0.4 μg kg h) or a propofol infusion and saline 0.9% (placebo group). The study drug was started at chest closure and continued for 10 h. The primary endpoint was in-hospital POD, assessed using the Confusion Assessment Method and chart review method.
RESULTS
POD over the course of hospital stay occurred in 31/177 (18%) and 33/172 (19%) patients in the dexmedetomidine and placebo arm, respectively (P=0.687; odds ratio=0.89; 95% confidence interval, 0.52-1.54). The incidence of POD in the intensive care alone, or on the ward alone, was also not significantly different between the groups. Subjects in the dexmedetomidine group spent less median time in a delirious state (P=0.026). Median administered postoperative norepinephrine was significantly higher in the dexmedetomidine group (P<0.001). One patient in the dexmedetomidine group and 10 patients in the placebo group died in the hospital.
CONCLUSIONS
Adding low-dose rate dexmedetomidine to a sedative regimen based on propofol did not result in a different risk of in-hospital delirium in older patients undergoing cardiac surgery. With a suggestion of both harm and benefit in secondary outcomes, supplementing postoperative propofol with dexmedetomidine cannot be recommended based on this study.
CLINICAL TRIAL REGISTRATION
NCT03388541.
Topics: Aged; Cardiac Surgical Procedures; Delirium; Dexmedetomidine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Infusions, Intravenous; Male; Postoperative Complications; Propofol; Treatment Outcome
PubMed: 33358336
DOI: 10.1016/j.bja.2020.10.041 -
Critical Care (London, England) Sep 2022The aim of this study was to evaluate the efficacy and safety of remimazolam besylate compared with propofol in maintaining mild-to-moderate sedation in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The aim of this study was to evaluate the efficacy and safety of remimazolam besylate compared with propofol in maintaining mild-to-moderate sedation in patients receiving long-term mechanical ventilation.
METHODS
In this single-centered randomized pilot study, adult patients mechanically ventilated longer than 24 h were randomized to receive remimazolam besylate or propofol. The target sedation range was - 3 to 0 on the Richmond Agitation and Sedation Scale (RASS). The primary outcome was the percentage of time in the target sedation range without rescue sedation. The secondary outcomes were ventilator-free days at day 7, the length of ICU stay and 28-day mortality.
RESULTS
Thirty patients were assigned to each group. No difference was identified between the remimazolam group and propofol group in median age [60.0 (IQR, 51.5-66.3) years vs. 64.0 (IQR, 55.0-69.3) years, respectively, p = 0.437] or the median duration of study drug infusion [55.0 (IQR, 28.3-102.0) hours vs. 41.0 (IQR, 24.8-74.3) hours, respectively, p = 0.255]. The median percentage of time in the target RASS range without rescue sedation was similar in remimazolam and propofol groups [73.2% (IQR, 41.5-97.3%) vs. 82.8% (IQR, 65.6-100%), p = 0.269]. No differences were identified between the two groups in terms of ventilator-free days at day 7, length of ICU stay, 28-day mortality or adverse events.
CONCLUSIONS
This pilot study suggested that remimazolam besylate was effective and safe for long-term sedation in mechanically ventilated patients compared with propofol.
Topics: Adult; Aged; Benzodiazepines; Humans; Hypnotics and Sedatives; Middle Aged; Pilot Projects; Propofol; Respiration, Artificial
PubMed: 36114552
DOI: 10.1186/s13054-022-04168-w -
Chinese Medical Journal May 2022Ciprofol (HSK3486; Haisco Pharmaceutical Group Co., Ltd., Chengdu, China), developed as a novel 2,6-disubstituted phenol derivative showed similar tolerability and... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of ciprofol vs. propofol for sedation in intensive care unit patients with mechanical ventilation: a multi-center, open label, randomized, phase 2 trial.
BACKGROUND
Ciprofol (HSK3486; Haisco Pharmaceutical Group Co., Ltd., Chengdu, China), developed as a novel 2,6-disubstituted phenol derivative showed similar tolerability and efficacy characteristics as propofol when applicated as continuous intravenous infusion for 12 h maintenance sedation in a previous phase 1 trial. The phase 2 trial was designed to investigate the safety, efficacy, and pharmacokinetic characteristics of ciprofol for sedation of patients undergoing mechanical ventilation.
METHODS
In this multicenter, open label, randomized, propofol positive-controlled, phase 2 trial, 39 Chinese intensive care unit patients receiving mechanical ventilation were enrolled and randomly assigned to a ciprofol or propofol group in a 2:1 ratio. The ciprofol infusion was started with a loading infusion of 0.1-0.2 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 0.30 mg·kg -1 ·h -1 , which could be adjusted to an infusion rate of 0.06 to 0.80 mg·kg -1 ·h -1 , whereas for propofol the loading infusion dose was 0.5-1.0 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 1.50 mg·kg -1 ·h -1 , which could be adjusted to 0.30-4.00 mg·kg -1 ·h -1 to achieve -2 to +1 Richmond Agitation-Sedation Scale sedation within 6-24 h of drug administration.
RESULTS
Of the 39 enrolled patients, 36 completed the trial. The median (min, max) of the average time to sedation compliance values for ciprofol and propofol were 60.0 (52.6, 60.0) min and 60.0 (55.2, 60.0) min, with median difference of 0.00 (95% confidence interval: 0.00, 0.00). In total, 29 (74.4%) patients comprising 18 (69.2%) in the ciprofol and 11 (84.6%) in the propofol group experienced 86 treatment emergent adverse events (TEAEs), the majority being of severity grade 1 or 2. Drug- and sedation-related TEAEs were hypotension (7.7% vs. 23.1%, P = 0.310) and sinus bradycardia (3.8% vs. 7.7%, P = 1.000) in the ciprofol and propofol groups, respectively. The plasma concentration-time curves for ciprofol and propofol were similar.
CONCLUSIONS
ciprofol is comparable to propofol with good tolerance and efficacy for sedation of Chinese intensive care unit patients undergoing mechanical ventilation in the present study setting.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT04147416.
Topics: Critical Care; Humans; Hypnotics and Sedatives; Intensive Care Units; Propofol; Respiration, Artificial
PubMed: 34924506
DOI: 10.1097/CM9.0000000000001912 -
European Journal of Anaesthesiology Jun 2023HSK3486 (ciprofol) is a 2,6-disubstituted phenol derivative that acts like propofol as an agonist at the gamma-aminobutyric acid-A (GABA A ) receptor. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of ciprofol vs. propofol for the induction and maintenance of general anaesthesia: A multicentre, single-blind, randomised, parallel-group, phase 3 clinical trial.
BACKGROUND
HSK3486 (ciprofol) is a 2,6-disubstituted phenol derivative that acts like propofol as an agonist at the gamma-aminobutyric acid-A (GABA A ) receptor.
OBJECTIVE
To investigate the efficacy and safety of HSK3486 for general anaesthesia induction and maintenance.
DESIGN
A single-blinded, randomised, parallel-group, phase 3 trial.
SETTING
Involving 10 study centres, from November 24, 2020 to January 25, 2021.
PATIENTS
A total of 129 patients undergoing nonemergency, noncardiothoracic, and nonneurosurgical elective surgery.
INTERVENTION
Patients were randomly assigned at a 2:1 ratio into HSK3486 or propofol groups, to receive HSK3486 (0.4 mg kg -1 ) or propofol (2.0 mg kg -1 ) for induction before a maintenance infusion at initial rates of 0.8 and 5.0 mg kg -1 h -1 , and were adjusted to maintain a bispectral index (BIS) of 40-60 until the end of surgery.
MAIN OUTCOME MEASURES
Noninferiority between the drugs was evaluated as the lower limit of the 95% confidence interval (CI) for the between-group difference in the success rate of anesthetic maintenance (primary outcome) >-8%. Secondary outcomes included successful anaesthetic induction, full alertness and spontaneous breathing recovery, time until leaving the postanaesthesia care unit and changes in BIS. Safety profiles were also measured.
RESULTS
Of 129 enrolled patients, 128 completed the trial, with 86 in the HSK3486 group and 42 in the propofol group. The success rate for the maintenance of general anaesthesia was 100% for both groups, and noninferiority of HSK3486 was confirmed (95% CI -4.28% to 8.38%). No significant differences were found between the two groups of patients with regard to secondary outcomes (all P > 0.05). There appeared to be a comparable incidence of treatment for emergency adverse events (TEAEs) (80.2% vs. 81.0%, P = 1.000) and drug-related TEAEs (57.0% vs. 64.3%, P = 0.451) in the HSK3486 and propofol groups.
CONCLUSION
HSK3486 had a noninferior efficacy profile compared to propofol, exhibiting excellent tolerance.
TRIAL REGISTRATION
Clinicaltrials.gov, identifier: NCT04511728.
Topics: Humans; Propofol; Single-Blind Method; Anesthesia, General; Anesthetics; Elective Surgical Procedures; Anesthetics, Intravenous
PubMed: 36647565
DOI: 10.1097/EJA.0000000000001799 -
British Journal of Anaesthesia Feb 2021Target-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing... (Clinical Trial)
Clinical Trial
BACKGROUND
Target-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing models were developed using data from select populations, the use of which is, strictly speaking, limited to these populations. Recently a propofol PK-PD model was developed for a broad population range. The aim of the study was to prospectively validate this model in children, adults, older subjects, and obese adults undergoing general anaesthesia.
METHODS
The 25 subjects included in each of four groups were stratified by age and weight. Subjects received propofol through TCI with the Eleveld model, titrated to a bispectral index (BIS) of 40-60. Arterial blood samples were collected at 5, 10, 20, 30, 40, and 60 min after the start of propofol infusion, and every 30 min thereafter, to a maximum of 10 samples. BIS was recorded continuously. Predictive performance was assessed using the Varvel criteria.
RESULTS
For PK, the Eleveld model showed a bias < ±20% in children, adults, and obese adults, but a greater bias (-27%) in older subjects. Precision was <30% in all groups. For PD, the bias and wobble were <5 BIS units and the precision was close to 10 BIS units in all groups. Anaesthetists were able to achieve intraoperative BIS values of 40-60 using effect-site target concentrations about 85-140% of the age-adjusted Ce.
CONCLUSIONS
The Eleveld propofol PK-PD model showed predictive precision <30% for arterial plasma concentrations and BIS predictions with a low (population) bias when used in TCI in clinical anaesthesia practice.
Topics: Adolescent; Adult; Age Factors; Aged; Anesthesia, General; Anesthetics, Intravenous; Body Weight; Child; Child, Preschool; Consciousness; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Models, Biological; Obesity; Propofol; Prospective Studies; Reproducibility of Results; Young Adult
PubMed: 33317804
DOI: 10.1016/j.bja.2020.10.027 -
Military Medical Research Nov 2021Administration of propofol, an intravenous anesthetic with antioxidant property, immediately at the onset of post-ischemic reperfusion (propofol postconditioning,...
BACKGROUND
Administration of propofol, an intravenous anesthetic with antioxidant property, immediately at the onset of post-ischemic reperfusion (propofol postconditioning, P-PostC) has been shown to confer cardioprotection against ischemia-reperfusion injury, while the underlying mechanism remains incompletely understood. The FoxO transcription factors are reported to play critical roles in activating cardiomyocyte survival signaling throughout the process of cellular injuries induced by oxidative stress and are also involved in hypoxic postconditioning mediated neuroprotection, however, the role of FoxO in postconditioning mediated protection in the heart and in particular in high glucose condition is unknown.
METHODS
Rat heart-derived H9c2 cells were exposed to high glucose (HG) for 48 h (h), then subjected to hypoxia/reoxygenation (H/R, composed of 8 h of hypoxia followed by 12 h of reoxygenation) in the absence or presence of postconditioning with various concentrations of propofol (P-PostC) at the onset of reoxygenation. After having identified the optical concentration of propofol, H9c2 cells were subjected to H/R and P-PostC in the absence or presence of FoxO1 or FoxO3a gene silencing to explore their roles in P-PostC mediated protection against apoptotic and autophagic cell deaths under hyperglycemia.
RESULTS
The results showed that HG with or without H/R decreased cell viability, increased lactate dehydrogenase (LDH) leakage and the production of reactive oxygen species (ROS) in H9c2 cells, all of which were significantly reversed by propofol (P-PostC), especially at the concentration of 25 µmol/L (P25) (all P < 0.05, NC vs. HG; HG vs. HG + HR; HG + HR + P12.5 or HG + HR + P25 or HG + HR + P50 vs. HG + HR). Moreover, we found that propofol (P25) decreased H9c2 cells apoptosis and autophagy that were concomitant with increased FoxO1 and FoxO3a expression (all P < 0.05, HG + HR + P25 vs. HG + HR). The protective effects of propofol (P25) against H/R injury were reversed by silencing FoxO1 or FoxO3a (all P < 0.05, HG + HR + P25 vs. HG + HR + P25 + siRNA-1 or HG + HR + P25 + siRNA-5).
CONCLUSION
It is concluded that propofol postconditioning attenuated H9c2 cardiac cells apoptosis and autophagy induced by H/R injury through upregulating FoxO1 and FoxO3a under hyperglycemia.
Topics: Animals; Apoptosis; Autophagy; Forkhead Transcription Factors; Hyperglycemia; Hypoxia; Ischemic Postconditioning; Propofol; Rats
PubMed: 34753510
DOI: 10.1186/s40779-021-00353-0