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Molecules (Basel, Switzerland) Nov 2021Herein, we report a continuous flow process for the synthesis of 2,6-diisopropylphenol-also known as Propofol-a short-acting intravenous anesthesia, widely used in...
Herein, we report a continuous flow process for the synthesis of 2,6-diisopropylphenol-also known as Propofol-a short-acting intravenous anesthesia, widely used in intensive care medicine to provide sedation and hypnosis. The synthesis is based on a two-step procedure: a double Friedel-Crafts alkylation followed by a decarboxylation step, both under continuous flow.
Topics: Anesthesia, Intravenous; Humans; Hypnosis, Anesthetic; Propofol
PubMed: 34885756
DOI: 10.3390/molecules26237183 -
Journal of Translational Medicine Mar 2024Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the...
BACKGROUND
Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol.
METHODS
The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers.
RESULTS
We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells.
CONCLUSIONS
We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.
Topics: Mice; Humans; Animals; Propofol; Toll-Like Receptor 4; Disease Models, Animal; Macrophages; Sepsis; Lipopolysaccharides
PubMed: 38549133
DOI: 10.1186/s12967-024-05107-9 -
British Journal of Anaesthesia Nov 2004Efforts to develop new hypnotic compounds continue, although several have recently failed in development. Propofol has been reformulated in various presentations with... (Review)
Review
Efforts to develop new hypnotic compounds continue, although several have recently failed in development. Propofol has been reformulated in various presentations with and without preservatives. Pharmacokinetic and pharmacodynamic differences exist between some of these preparations, and it is currently unclear whether any have substantial advantages over the original presentation. The use of target-controlled infusion (TCI) has been extended to include paediatric anaesthesia and sedation. Application of TCI to remifentanil is now licensed. Linking of electroencephalogram (EEG) monitoring to TCI for closed-loop anaesthesia remains a research tool, although commercial development may follow. The availability of stereoisomer ketamine and improved understanding of its pharmacology have increased non-anaesthetic use of ketamine as an adjunct analgesic. It may be useful in subhypnotic doses for postsurgical patients with pain refractory to morphine administration.
Topics: Anesthesia, Intravenous; Anesthetics, Intravenous; Chemistry, Pharmaceutical; Humans; Ketamine; Piperidines; Propofol; Remifentanil
PubMed: 15347606
DOI: 10.1093/bja/aeh253 -
British Journal of Anaesthesia Jan 2017
Topics: Conscious Sedation; Endoscopy, Gastrointestinal; Humans; Propofol
PubMed: 28039236
DOI: 10.1093/bja/aew334 -
The Journal of General Physiology Sep 2018Tandem studies investigate how propofol affects voltage-gated sodium channels.
Tandem studies investigate how propofol affects voltage-gated sodium channels.
Topics: Anesthetics, Intravenous; Propofol
PubMed: 30115662
DOI: 10.1085/jgp.201812197 -
American Journal of Respiratory and... Jan 2022
Topics: Anesthetics, Intravenous; Consciousness; Electroencephalography; Humans; Prognosis; Propofol
PubMed: 34818124
DOI: 10.1164/rccm.202111-2504ED -
International Journal of Pharmaceutics Jun 2023Propofol is the preferred anaesthetic for induction and maintenance of sedation in critically ill mechanically ventilated COVID-19 patients. However, during the outbreak...
Propofol is the preferred anaesthetic for induction and maintenance of sedation in critically ill mechanically ventilated COVID-19 patients. However, during the outbreak of the COVID-19 pandemic, regular supply chains could not keep up with the sudden increase in global demand, causing drug shortages. Propofol is formulated as an oil-in-water emulsion which is administered intravenously. This study explores the extemporaneous preparation of a propofol emulsion without specialized manufacturing equipment to temporally alleviate such shortages. A commercially available lipid emulsion (IVLE, SMOFlipid 20 %), intended for parenteral nutrition, was used to create a propofol loaded nanoemulsion via addition of liquid propofol drug substance and subsequent mixing. Critical quality attributes such as mean droplet size and the volume-weighted percentage of large-diameter (>5µm) droplets were studied. The evolution of droplet size and propofol distribution was monitored in situ and non-destructively, maintaining sterility, using Spatially Resolved Dynamic Light Scattering and Near Infrared Spectroscopy, respectively. Using response surface methodology, an optimum was found for a 4 % w/v propofol formulation with a ∼15 min mixing time in a flask shaker at a 40° shaking angle. This study shows that extemporaneous compounding is a viable option for emergency supply of propofol drug product during global drug shortages.
Topics: Humans; Propofol; Emulsions; Pandemics; COVID-19; Parenteral Nutrition
PubMed: 37061210
DOI: 10.1016/j.ijpharm.2023.122960 -
BMC Anesthesiology May 2021Remimazolam besylate is a newer benzodiazepine with characteristics of quick onset of effects, short maintenance and recovery times without accumulation in tissues. This... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Remimazolam besylate is a newer benzodiazepine with characteristics of quick onset of effects, short maintenance and recovery times without accumulation in tissues. This trial was conducted to confirm the efficacy and safety of remimazolam besylate versus propofol during hysteroscopy.
METHODS
Patients undergoing hysteroscopy were randomly assigned to either the remimazolam (Group R) or the propofol group (Group P). Group R was administered an induction dose of 0.2 mg/kg and a maintenance dosage of 1.0 mg/kg/h. In Group P, propofol was started at 1.5-2.0 mg/kg and then maintained at 3.0-6.0 mg/kg/h. After remimazolam besylate or propofol induction, remifentanil was infused using a target-controlled infusion system with a target concentration of 1.5 ng/ml and titrated during the procedure. The incidence rates of injection pain, low oxygen saturation (SpO) and adverse effects in both groups were compared.
RESULTS
Eighty-two patients were included in this study. The incidence of adverse events in Group R (3.7%) was significantly lower than that in Group P (36.6%) (p < 0.001). The incidence of injection pain in Group P (80.5%) was much higher than that in Group R (2.4%) (p < 0.001). The incidence of other adverse events, such as low SpO, bradycardia, and hypotension in Group R was lower than that in Group P (p < 0.05).
CONCLUSIONS
Remimazolam besylate proves to be a safer alternative for anesthesia during hysteroscopy. Moreover, adverse events caused by propofol, such as low SpO and injection pain, are largely avoided.
TRIAL REGISTRATION
This study was approved by the Clinical Research Ethics Committee of Mengcheng County No. 1 People's Hospital (2020MYL20003) and registered at http://www.chictr.org.cn (15/09/2020, ChiCTR-2000038252 ). The study protocol followed the CONSORT guidelines. The study protocol was performed in the relevant guidelines.
Topics: Adult; Benzodiazepines; Female; Humans; Hypnotics and Sedatives; Hysteroscopy; Male; Middle Aged; Propofol; Treatment Outcome
PubMed: 34016045
DOI: 10.1186/s12871-021-01373-y -
British Journal of Pharmacology Nov 2016Glycine receptors are important players in pain perception and movement disorders and therefore important therapeutic targets. Glycine receptors can be modulated by the...
BACKGROUND AND PURPOSE
Glycine receptors are important players in pain perception and movement disorders and therefore important therapeutic targets. Glycine receptors can be modulated by the intravenous anaesthetic propofol (2,6-diisopropylphenol). However, the drug is more potent, by at least one order of magnitude, on GABA receptors. It has been proposed that halogenation of the propofol molecule generates compounds with selective enhancement of glycinergic modulatory properties.
EXPERIMENTAL APPROACH
We synthesized 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol. The direct activating and modulatory effects of these drugs and propofol were compared on recombinant rat glycine and human GABA receptors expressed in oocytes. Behavioural effects of the compounds were compared in the tadpole loss-of-righting assay.
KEY RESULTS
Concentration-response curves for potentiation of homomeric α1, α2 and α3 glycine receptors were shifted to lower drug concentrations, by 2-10-fold, for the halogenated compounds. Direct activation by all compounds was minimal with all subtypes of the glycine receptor. The four compounds were essentially equally potent modulators of the α1β3γ2L GABA receptor with EC between 4 and 7 μM. The EC for loss-of-righting in Xenopus tadpoles, a proxy for loss of consciousness and considered to be mediated by actions on GABA receptors, ranged from 0.35 to 0.87 μM.
CONCLUSIONS AND IMPLICATIONS
We confirm that halogenation of propofol more strongly affects modulation of homomeric glycine receptors than α1β3γ2L GABA receptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABA receptors. We infer that 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol are not selective homomeric glycine receptor modulators.
Topics: Animals; Dose-Response Relationship, Drug; Humans; Propofol; Rats; Receptors, GABA-A; Receptors, Glycine; Recombinant Proteins; Structure-Activity Relationship; Xenopus laevis
PubMed: 27459129
DOI: 10.1111/bph.13566 -
PloS One 2024When assessing the spatio-temporal distribution of electroencephalographic (EEG) activity, characteristic patterns have been identified for several anesthetic drugs in...
INTRODUCTION
When assessing the spatio-temporal distribution of electroencephalographic (EEG) activity, characteristic patterns have been identified for several anesthetic drugs in humans. A shift in EEG power from the occipital to the prefrontal regions has been widely observed during anesthesia induction. This has been called "anteriorization" and has been correlated with loss of consciousness in humans. The spatio-temporal distribution of EEG spectral power in pigs and its modulation by anesthetics have not been described previously. The aim of the present study was to analyze EEG power across an anterior-posterior axis in pigs receiving increasing doses of propofol to 1) characterize the region of highest EEG power during wakefulness, 2) depict its spatio-temporal modification during propofol infusion, and 3) determine the region demonstrating the most significant modulations across different doses administered.
MATERIALS AND METHODS
Six pigs with a body weight of 33.3 ± 3.6 kg and aged 11.3 ± 0.5 weeks were included in a prospective experimental study. Electroencephalographic activity was collected at the occipital, parietal and prefrontal regions at increasing doses of propofol (starting at 10 mg kg-1 h-1 and increasing it by 10 mg kg-1 h-1 every 15 minutes). The EEG power was assessed using a generalized linear mixed model in which propofol doses and regions were treated as fixed effects, whereas pig was used as a random effect. Pairwise comparisons of marginal linear predictions were used to assess the change in power when the specific propofol dose (or region) was considered.
RESULTS
During both wakefulness and propofol infusion, the highest EEG power was located in the prefrontal region (p<0.001). The EEG power, both total and for each frequency band, mostly followed the same pattern, increasing from awake until propofol 20 mg kg-1 h-1 and then decreasing at propofol 30 mg kg-1 h-1. The region showing the strongest differences in EEG power across propofol doses was the prefrontal.
CONCLUSION
In juvenile pigs receiving increasing doses of propofol, the prefrontal region showed the highest EEG power both during wakefulness and propofol administration and was the area in which the largest frequency-band specific variations were observed across different anesthetic doses. The assessment of the spectral EEG activity at this region could be favorable to distinguish DoA levels in pigs.
Topics: Animals; Propofol; Electroencephalography; Swine; Anesthetics, Intravenous; Wakefulness; Female
PubMed: 38743713
DOI: 10.1371/journal.pone.0303146