Etomidate enhances cerebellar CF-PC synaptic plasticity through CB1 receptor/PKA cascade in vitro in mice.

Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and synaptic transmission. In this study, we investigated the effects of ET on the cerebellar climbing fiber-Purkinje cells (CF-PC) plasticity in vitro in mice using whole-cell recording technique and pharmacological methods. Our results demonstrated that CF tetanic stimulation produced a mGluR1-dependent long-term depression (LTD) of CF-PC excitatory postsynaptic currents (EPSCs), which was enhanced by bath application of ET (10 µM). Blockade of mGluR1 receptor with JNJ16259685, ET triggered the tetanic stimulation to induce a CF-PC LTD accompanied with an increase in paired-pulse ratio (PPR). The ET-triggered CF-PC LTD was abolished by extracellular administration of an N-methyl-(D)-aspartate (NMDA) receptor antagonist, D-APV, as well as by intracellular blockade of NMDA receptors activity with MK801. Furthermore, blocking cannabinoids 1 (CB1) receptor with AM251 or chelating intracellular Ca2+ with BAPTA, ET failed to trigger the CF-PC LTD. Moreover, the ET-triggered CF-PC LTD was abolished by inhibition of protein kinase A (PKA), but not by inhibition of protein kinase C inhibiter. The present results suggest that ET acts on postsynaptic NMDA receptor resulting in an enhancement of the cerebellar CF-PC LTD through CB1 receptor/PKA cascade in vitro in mice. These results provide new evidence and possible mechanism for ET anesthesia to affect motor learning and motor coordination by regulating cerebellar CF-PC LTD.

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects.

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33-104.96% for the maximum plasma concentration (Cmax), 97.21-102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0-t), and 97.22-102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0-∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28-110.69% for the minimal BIS value (BISmin), 99.23-101.17% for the area under the BIS time curve from time 0-60 min after administration (BISAUC0-60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00-125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number: http://www.chinadrugtrials.org.cn/index.html . # CTR20191836.

Etomidate inhibits tumor growth of glioblastoma by regulating M1 macrophage polarization.

Glioblastoma (GBM) is a common primary central nervous system tumor. Although the multimodal integrated treatment for GBM has made great progress in recent years, the overall survival time of GBM is still short. Thus, novel treatments for GBM are worth further investigation and exploration. This study aimed to investigate the effects of etomidate on GBM tumor growth and the underlying mechanism. A xenograft tumor model was established and treated with etomidate to assess tumor growth. Immunohistochemistry (IHC) assay evaluated the positive rate of Ki67 cells in tumor tissues. Cell counting kit (CCK)-8 and EdU assays accessed the cell viability and proliferation. Immunofluorescence (IF) staining detected the distribution of macrophage markers in tumor tissues. The percentages of M1- and M2-like macrophages in tumor-associated macrophages (TAMs) and co-culture system (macrophages and GBM cells) were detected using flow cytometry. Macrophage polarization-related genes were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Etomidate treatment inhibited the tumor growth, and increased the CD86+ cells but decreased the CD206+ cells in TAMs. The gene expression of M1 markers was increased in TAMs of etomidate-treated mice, whereas that of M2 markers was decreased. Moreover, etomidate treatment increased the number of CD86+ M1-like macrophages co-cultured with tumor cells but decreased that of CD206+ M2-like macrophages, with the upregulation of M1 markers and downregulation of M2 markers. Etomidate inhibited GBM tumor growth by promoting M1 macrophage polarization, suggesting a new insight into the clinical treatment of GBM.

Promising activity of etomidate against mixed biofilms of fluconazole-resistant Candida albicans and methicillin-resistant Staphylococcus aureus.

Introduction. Candida albicans and Staphylococcus aureus are recognized for their development of resistance and biofilm formation. New therapeutic alternatives are necessary in this context.Hypothesis. Etomidate shows potential application in catheters against mixed biofilms of fluconazole-resistant C. albicans and methicillin-resistant S. aureus (MRSA).Aim. The present study aimed to evaluate the activity of etomidate against mixed biofilms of fluconazole-resistant C. albicans and MRSA.Methodology. The action of etomidate against mature biofilms was verified through the evaluation of biomass and cell viability, and its ability to prevent biofilm formation in peripheral venous catheters was determined based on counts of colony forming units (c.f.u.) and confirmed by morphological analysis through scanning electron microscopy (SEM).Results. Etomidate generated a reduction (P<0.05) in biomass and cell viability starting from a concentration of 250 µg ml-1. In addition, it showed significant ability to prevent the formation of mixed biofilms in a peripheral venous catheter, as shown by a reduction in c.f.u. SEM revealed that treatment with etomidate caused substantial damage to the fungal cells.Conclusion. The results showed the potential of etomidate against polymicrobial biofilms of fluconazole-resistant C. albicans and MRSA.

General intravenous anesthetics - pharmacodynamics, pharmacokinetics and chiral properties.

In continuation of our published review on general inhalational anesthetics, the current article presents a survey of intravenous agents for general anaesthesia. From chemical point of view these compounds belong to structurally diverse categories, such as barbiturates - thiopental (Sodium pentothal®, Trapanal®, Pentothal®), methohexital (Brevital®), and hexobarbital (Evipan®, Hexenal®, Citopan®, Tobinal®); non-barbiturate derivatives - ketamine (Ketalar® Ketaset®), esketamine (Ketanest®), and etomidate (Amidate®, Hypnomidate®), phenolic derivatives - propofol (Diprivan®); steroid derivatives - mixture of alfadolone and alfaxalone (Althesin® in human and Saffan® in veterinary anesthesia); and derivatives of phenylacetic acid - propanidid (Epontol®, Sombrevin®). Most of these compounds are chiral, with the exception of propofol and propanidid. Apart from etomidate and esketamine, they are used in the form of their racemates. Besides their characteristics and mechanism of action, attention is centred also on their chiral properties.

Bilirubin potentiates etomidate-induced sedation by enhancing GABA-induced currents after bile duct ligation.

OBJECTIVES: Our previous clinical trial showed that etomidate requirements to reach an appropriate level of anesthesia in patients with obstructive jaundice were reduced, which means that these patients are more sensitive to etomidate. However, the mechanism is still not completely clear. The present study was aimed to investigate the mechanism by which bilirubin facilitates etomidate induced sedation. METHODS: A bile duct ligation (BDL) rat model was used to simulate obstructive jaundice. Anesthesia sensitivity to etomidate was determined by the time to loss of righting reflex (LORR). Intrathecal injection of bilirubin was used to test the effects of bilirubin on etomidate induced sedation. The modulating effects of bilirubin on GABA responses were studied using the whole-cell patch clamp technique. RESULTS: The time to LORR induced by etomidate was significantly decreased in the BDL groups (p < 0.05), and unconjugated bilirubin in serum and cerebrospinal fluid (CSF) were markedly increased (p < 0.05). The time to LORR induced by etomidate was decreased after intrathecal injection of bilirubin (p < 0.05). A bilirubin concentration of 1.0 µM increased the GABA-induced currents of rat cortical pyramidal neurons (p < 0.05). Furthermore, 1.0 µM bilirubin enhanced GABA-induced currents modulated by etomidate (p < 0.05). CONCLUSIONS: Our results demonstrated that pathologic bilirubin in CSF could enhance etomidate induced sedation. The mechanism may be that bilirubin increase the GABA-induced currents of rat pyramidal neurons.

Requirement for Discharge in the Care of a Responsible Adult in Procedural Sedation in the Emergency Department: Necessity or Potential Barrier to Health Equity?

BACKGROUND: Procedural sedation is commonly practiced by emergency physicians to facilitate patient care in the emergency department (ED). Although various guidelines have modernized our approach to procedural sedation, many procedural sedation guidelines and practices still often require that patients be discharged into the care of a responsible adult. DISCUSSION: Such requirement for discharge often cannot be met by underserved and undomiciled patients. Benzodiazepines, opioids, propofol, ketamine, "ketofol," etomidate, and methohexital have all been utilized for procedural sedation in the ED. For patients who may require discharge without the presence of an accompanying responsible adult, ketamine, propofol, methohexital, "ketofol," and etomidate are ideal agents for procedural sedation given rapid onsets, short durations of action, and rapid recovery times in patients without renal or hepatic impairment. Proper pre- and postprocedure protocols should be utilized when performing procedural sedation to ensure patient safety. Through the use of appropriate medications and observation protocols, patients can safely be discharged 2 to 4 h postprocedure. CONCLUSION: There is no pharmacodynamic or pharmacokinetic basis to require discharge in the care of a responsible adult after procedural sedation. Thoughtful medication selection and the use of evidence-based pre- and postprocedure protocols in the ED can help circumvent this requirement, which likely disproportionally impacts patients who are of low socioeconomic status or undomiciled.

Substituted Cysteine Modification and Protection with n-Alkyl-MTS Reagents Quantifies Steric Changes Induced by a Mutation in Anesthetic Binding Sites on GABA Type A Receptors.

Multiple approaches, including cryogenic electron microscopy (cryo-EM), indicate that the anesthetics etomidate and propofol modulate α1ß2/3γ2 GABAA receptors by binding in overlapping transmembrane inter-subunit sites near ßM286 and αL232 sidechains. High-precision approaches in functional receptors are needed for comparisons with cryo-EM. We previously used substituted cysteine modification and protection (SCAMP) with n-alkyl-methanethiosulfonate (MTS) reagents and electrophysiology in α1ß3M286Cγ2L receptors to estimate the distance from etomidate to ß3M286 with precision near 1.3 Å. Here, we address three more aims using this approach: (i) SCAMP with etomidate was tested in α1L232Cß3γ2L receptors; (ii) studies in α1L232Wß3M286Cγ2L receptors assessed whether α1L232W displaces etomidate relative to ß3M286C; and (iii) results with propofol were compared with those with etomidate. Voltage-clamp electrophysiology in Xenopus oocytes was used to assess persistent functional changes after exposing cysteine-substituted receptors to methyl-MTS through n-decyl-MTS. Overlap of modified cysteine sidechains with bound anesthetic was inferred when anesthetic co-application with alkyl-MTS reagent blocked the development of persistent effects. In α1L232Cß3γ2L receptors, only pentyl-MTS and hexyl-MTS induced persistent effects that were unaltered by etomidate co-application, precluding a direct estimate of intermolecular distance. In α1L232Wß3M286Cγ2L receptors, sidechain overlap with bound etomidate was inferred for modifications with ethyl-MTS through n-pentyl-MTS, with unambiguous cut-on and cut-off. Comparison with results in α1ß3M286Cγ2L reveals that α1L232W, which increases maximal sidechain length by 2.1 Å, displaces etomidate closer to ß3M286C by about 1.3 Å. Propofol results largely mirrored those with etomidate. These findings indicate that both etomidate and propofol bind within 1 Å of α1L232, consistent with cryo-EM structures. SIGNIFICANCE STATEMENT: We combined electrophysiology, cysteine substitutions, and n-alkyl-methanethiosulfonate modifiers in functional GABAA receptors to enable precise estimates of the distance between ß3M286C sidechains and anesthetics (etomidate and propofol) bound in transmembrane ß+/α- inter-subunit pockets. Comparing results in α1ß3M286Cγ2L and α1L232Wß3M286Cγ2L receptors reveals that α1L232W mutations displace both anesthetics toward ß3M286C, indicating that these anesthetics bind within 1 Å of the α1L232 sidechain in functional receptors, consistent with cryogenic electron microscopy structures derived under nonphysiologic conditions.

Etomidate Depresses Spontaneous Complex Spikes Activity of Cerebellar Purkinje Cells via Cannabinoid 1 Receptor in vivo in Mice.

INTRODUCTION: Complex spikes (CSs) activity of cerebellar Purkinje cells plays critical roles in motor coordination and motor learning by transferring information to cerebellar cortex, which is an accessible and useful model for neurophysiological investigation. Etomidate is an ultrashort-acting nonbarbiturate intravenous anesthetic, which inhibits the spontaneous activity of cerebellar Purkinje cells through activation of GABAA and glycine receptors in vivo in mice. However, the effect of etomidate on the spontaneous CSs activity of cerebellar Purkinje cells in living mouse is not clear. METHODS: We here investigated the effects of etomidate on spontaneous CSs activity of cerebellar Purkinje cell in urethane-anesthetized mice by electrophysiology recording technique and pharmacological methods. RESULTS: Our results showed that cerebellar surface perfusion of etomidate significantly depressed the activity of spontaneous CSs, which exhibited decreases in the number of spikelets and the area under curve (AUC) of the CSs. The etomidate-produced inhibition of CSs activity was persisted in the presence of GABAA and glycine receptors antagonists. However, application of cannabinoid 1 (CB1) receptor antagonist, AM-251, completely blocked the etomidate-induced inhibition of CSs. Furthermore, application of the CB1 receptor agonist, WIN55212-2, induced a decrease of CSs. Moreover, in the presence of a specific protein kinase A (PKA) inhibitor, KT5720, etomidate failed to produce decreases in the spikelets number and the AUC of the spontaneous CSs. CONCLUSION: These results indicate that cerebellar surface application of etomidate facilitates CB1 receptor activity resulting in a depression of spontaneous CSs activity of Purkinje cells via PKA signaling pathway in mouse cerebellar cortex. Our present results suggest that the etomidate administration may impair the function of cerebellar cortical neuronal circuitry by inhibition of the climbing fiber - Purkinje cells synaptic transmission through activation of CB1 receptors in vivo in mice.

Etomidate Improves the Antidepressant Effect of Electroconvulsive Therapy by Suppressing Hippocampal Neuronal Ferroptosis via Upregulating BDNF/Nrf2.

Electroconvulsive therapy (ECT) performed under general anesthesia is an effective treatment for severe depression. Etomidate is an intravenous anesthetic that shows beneficial effects on ECT. However, the potential mechanisms have rarely been reported. In this study, male rats were exposed to chronic unpredictable mild stress for 4 weeks, followed by ECT for 10 days, with or without intervention with ferrostatin-1 (2 mg/kg) or all-trans retinoic acid (ATRA, 5 mg/kg). Rats subjected to etomidate (20 mg/kg) or propofol (120 mg/kg) treatment were administered with designated anesthetic before ECT. Compared to depressive rats without ECT, those who received ECT showed increased numbers of hippocampal neurons, increased expression of negative regulators of ferroptosis including glutathione peroxidase 4, ferritin heavy chain 1, and ferroptosis suppressor protein 1, upregulation of brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor, and downregulation of acyl-CoA synthetase long-chain family member 4, a positive regulator of ferroptosis in the hippocampus. Additionally, compared with propofol, etomidate used in ECT resulted in higher upregulation of BDNF/Nrf2 and inhibited neuronal ferroptosis in hippocampus. These results showed etomidate may enhance the antidepressant effect of ECT by protecting hippocampal neurons against ferroptosis.

Structural interplay of anesthetics and paralytics on muscle nicotinic receptors.

General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.

Influences of Etomidate Combined with Propofol on Cognitive Function, Inflammation and Immunity in Patients Undergoing Gastric Cancer Surgery.

This study examined how etomidate combined with propofol affected cognitive function, inflammation, and immunity in patients undergoing gastric cancer surgery. 182 gastric cancer patients treated in our hospital were enrolled and randomly divided into two groups, namely group A (anesthetized using etomidate) and group B (anesthetized using etomidate combined with propofol). Then the cognitive function, inflammation and immunity indicators were determined in the two groups. Compared with group A, group B exhibited shorter operation duration and hospital stay and smaller bleeding volume (p<0.01). At 3 d after the operation, group B had a higher Ramsay score, but a lower visual analogue scale (VAS) score than group A (p<0.05). Moreover, the mini-mental state examination (MMSE) score was lower in group A than that in group B (p<0.01). At the end of the operation, the heart rate (HR), mean arterial pressure (MAP) and saturation of pulse oxygen (SpO2) were decreased to a great extent in both groups compared with those before anesthesia (p<0.05). Compared with those before anesthesia, the levels of immunoglobulin (Ig)M, IgG and IgA were lower in group A at the end of the operation and 1 and 3 d after the operation (p<0.05), but they were substantially higher in group B than those in group A (p<0.05). At the end of the operation and 1 and 3 d after the operation, the levels of the T-cell subset indicators decreases in group A were greater than those in group B (p<0.05). Etomidate combined with propofol has few influences on the immune and cognitive functions of gastric cancer patients and can effectively lower the expression levels of inflammatory factors in these patients.

The effect-site concentration of remifentanil blunting endotracheal intubation responses during anesthesia induction with etomidate: a dose-finding study.

BACKGROUND: Remifentanil can inhibit the hemodynamic responses caused by endotracheal intubation, but the effect-site concentration of it required to control intubation responses when combined with etomidate has not been demonstrated. The purpose of this study was to determine the effect-site concentration of remifentanil blunting tracheal intubation responses in 50% and 95% of patients (EC50 and EC95) during etomidate anesthesia. METHODS: American Society of Anesthesiologists physical status (ASA) I-II elective surgical patients receiving target-controlled infusion (TCI) of remifentanil, followed by etomidate and rocuronium for anesthesia were enrolled. The Belive Drive A2 monitor was used to calculate the MGRSSI (Maygreen Sedative state index) of hypnotic effect and the MGRNOX (Maygreen Nociception index) of nociception. The MGRSSI and the MGRNOX value were generated every 1 s. Mean arterial pressure (MAP) and heart rate (HR) were measured every minute, noninvasively. Using the modified Dixon's up-and-down method, the concentration of remifentanil was determined based on the intubation response of the previous patient. The cardiovascular response during endotracheal intubation was defined as positive when MAP or HR is 20% higher than the pre-intubation value. A probit analysis was used for calculating EC50, EC95 and 95% confidence interval (CI). RESULTS: The EC50 and EC95 of remifentanil blunting tracheal intubation responses were found to be 7.731 ng/ml (95%CI: 7.212-8.278 ng/ml) and 8.701 ng/ml (95%CI: 8.199-11.834 ng/ml). There were statistically significant increases in HR, MGRSSI and MGRNOX value to tracheal intubation in the positive responses group compared to the negative group. The most common adverse event was postoperative nausea and vomiting, which occurred in 3 patients. CONCLUSION: Remifentanil effect-site concentration of 7.731 ng/ml is effective in blunting sympathetic responses to tracheal intubation in 50% of patients when combined with etomidate anesthesia. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trials Registry ( www.chictr.org.cn , registration number: ChiCTR2100054565, date of registration: 20/12/2021).

Effect of vitamin C on adrenal suppression following etomidate for rapid sequence induction in trauma patients: a randomized clinical trial.

BACKGROUND: Etomidate is an imidazole derivative that is widely used in the emergency department for Rapid Sequence Intubation (RSI). Although it has a safe hemodynamic profile, there are some concerns about its suppressant effects on the adreno-cortical axis. Vitamin C, as an antioxidant, can play a protective role in this issue. METHOD: In a controlled clinical trial, we studied adult traumatic patients who needed RSI with etomidate. In one group underwent RSI with etomidate and cortisol levels were measured three hours later. In the other group, we administered one gram of vitamin C before etomidate administration, and the cortisol level was measured three hours later. RESULTS: Fifty-one patients have been studied. The serum cortisol level was significantly lower after RSI with etomidate in both groups. In the Vitamin C group, there was a significantly higher cortisol level after RSI in comparison to the control group. CONCLUSION: Etomidate can suppress the cortisol level in trauma patients who undergo RSI. Vitamin C can reduce this suppressant effect of etomidate. TRIAL REGISTRATION: IRCT registration number: IRCT20090923002496N11, URL of trial registry record: https://en.irct.ir/trial/34586 , Date of trial registration: 19/04/2019. Full date of the first registration: 30/05/2019.

The effects of etomidate on expression of high mobility group box 1 via the nuclear factor kappa B pathway in rat model of sepsis.

Etomidate is an anesthetic agent used in hemodynamically unstable patients, but its use has been controversial in septic patients. The response of high-mobility group box 1 (HMGB1), a late-phase lethal cytokine in sepsis, to etomidate has not been reported. This study investigated the effects of etomidate on the expression and release of HMGB1 and the underlying mechanism using a cecal ligation and puncture (CLP) model. Thirty-six male Sprague-Dawley rats were divided into sham, CLP, and Etomi groups. Sepsis was induced in the CLP and Etomi groups, and intravenous etomidate (4 mg/kg) was infused for 40 min immediately after operation in the Etomi group. Serum creatinine, alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and HMGB1 levels were measured 6 and 24 hours after surgery. Activation of nuclear factor (NF)-ĸB and HMGB1 mRNA expression in the liver, lung, kidney, and ileum tissues were measured, and immunohistochemical staining of HMGB1 was implemented. Increases of the TNF-α level 6 h after CLP and ALT and IL-6 levels 24 h after CLP were significantly inhibited by etomidate treatment. Etomidate treatment also significantly attenuated the increase in serum HMGB1 level at 6 and 24 h after CLP and suppressed the NF-ĸB and HMGB1 mRNA in multiple organs 24 h after CLP. Immunohistochemical staining also revealed that etomidate treatment inhibited HMGB1 expression. Etomidate inhibited the systemic release of HMGB1 and its expression in various organs. The mechanism may be associated with the inhibitory effects of etomidate on pro-inflammatory cytokine release and NF-ĸB activity.

Changes in Memory, Sedation, and Receptor Kinetics Imparted by the ß2-N265M and ß3-N265M GABAA Receptor Point Mutations.

Point mutations in the ß2 (N265S) and ß3 (N265M) subunits of γ-amino butyric acid type A receptors (GABAARs) that render them insensitive to the general anesthetics etomidate and propofol have been used to link modulation of ß2-GABAARs to sedation and ß3-GABAARs to surgical immobility. These mutations also alter GABA sensitivity, and mice carrying the ß3-N265M mutation have been reported to have impaired baseline memory. Here, we tested the effects of the ß2-N265M and ß3-N265M mutations on memory, movement, hotplate sensitivity, anxiety, etomidate-induced sedation, and intrinsic kinetics. We found that both ß2-N265M and ß3-N265M mice exhibited baseline deficits in the Context Preexposure Facilitation Effect learning paradigm. Exploratory activity was slightly greater in ß2-N265M mice, but there were no changes in either genotype in anxiety or hotplate sensitivity. ß2-N265M mice were highly resistant to etomidate-induced sedation, and heterozygous mice were partially resistant. In rapid solution exchange experiments, both mutations accelerated deactivation two- to three-fold compared to wild type receptors and prevented modulation by etomidate. This degree of change in the receptor deactivation rate is comparable to that produced by an amnestic dose of etomidate but in the opposite direction, indicating that intrinsic characteristics of GABAARs are optimally tuned under baseline conditions to support mnemonic function.

Etomidate elicits anti-tumor capacity by disrupting the JAK2/STAT3 signaling pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading malignancy of the digestive system, especially in China. Although radiotherapy, chemotherapy, and transarterial chemoembolization have achieved tremendous success, surgical resection remains the primary treatment for HCC patients. Recent studies have shown that intravenous anesthetic drugs may affect the malignant behaviors of tumor cells, ultimately leading to differences in the postoperative prognosis of patients. Etomidate is one of the most widely used intravenous anesthetic drugs for the induction and maintenance of anesthesia in tumor patients undergoing surgery. However, the effects and underlying mechanisms of etomidate on HCC cells have not yet been characterized. Our study indicated that etomidate significantly impedes the malignant progression of HCC cells. Mechanistically, etomidate inhibits phosphorylation and, ultimately, the activity of Janus kinase 2 (JAK2) by competing with ATP for binding to the ATP-binding pocket of JAK2. Thus, it suppresses the JAK2/STAT3 signaling pathway in HCC cells to exert its anti-tumor efficacy. Herein, we provide preclinical evidence that etomidate is the optimal choice for surgical treatment of HCC patients.

The preclinical pharmacological study of a novel intravenous anesthetic, ET-26 hydrochloride, in aged rats.

Background: ET-26 hydrochloride (ET-26HCl) is a novel analogue of etomidate approved for clinical trials. However, all results from recent studies were accomplished in young adult animals. The objective of this study was to evaluate the efficacy and safety of ET-26HCl in aged rats. Methods: Aged Sprague-Dawley rats were randomly divided into three groups (three males and three females in each group) were given dose of two-fold of median effective dose (ED50) of ET-26HCl, etomidate and propofol: the measurements of loss of the righting reflex (LORR) and cardiovascular and respiratory function after injection at the two-fold dose of the median effective dose were used for evaluation of effectiveness and safety, and the modified adrenocorticotropic hormone-stimulation experiment was used to evaluate the inhibition effect of the drugs on the synthesis of adrenal cortical hormones. Results: There was no significant difference in the onset time among propofol, etomidate and ET-26HCl. The duration of propofol (850.5 ± 77.4 s) was significantly longer than that caused by etomidate (489.8 ± 77.0 s, p = 0.007) and ET-26HCl (347.3 ± 49.0 s, p = 0.0004). No significant difference was observed in the time to stand and normal activity among drugs. A total of 66.7% of rats in the ET-26HCl group were evaluated to have mild hematuria. Then, etomidate and ET-26HCl had a milder blood pressure inhibition effect than propofol. Apnea was observed in all rats administered propofol and the duration for this side effect was 45.0 ± 9.0 s. For etomidate and ET-26HCl, no apnea was observed. No other clinical signs of side-effect were observed, and no rats died. No significant difference was observed in corticosterone concentrations between ET-26HCl and solvent group. However, rats administered etomidate had lower corticosterone concentrations than those administered ET-26HCl at 15, 30, and 60 min. Conclusions: Our results indicate ET-26HCl in aged rats is an effective sedative-hypnotic with stable myocardial and respiratory performance and also have mild adrenocortical suppression. Thus, these findings increase the potential for the clinical use of ET-26HCl in the elderly population.

Effect of Propofol and Etomidate on the Proliferation, Cell-cycle Distribution, Apoptosis and Necrosis of Pancreatic Tumour Cells.

BACKGROUND/AIM: The influence of surgical interventions and anaesthesiological procedures on tumour progression was investigated as early as the 1920s. In current cancer management, the perioperative phase is increasingly being considered a vulnerable period with an increased risk of tumour cell dissemination due to medication, surgical manipulation, and immunosuppression. The extent to which narcotics administered in the perioperative setting influence the oncological outcomes of patients with pancreatic cancer is still unclear. MATERIALS AND METHODS: To investigate the effect of propofol and etomidate on the proliferation, cell-cycle distribution, apoptosis, and necrosis of pancreatic tumour cells in vitro, PaTu 8988t and Panc-1 pancreatic cancer cells were treated with 0-1,000 µM propofol or etomidate for 24 h each. Cell proliferation was measured with enzyme-linked immunosorbent-bromodeoxyuridine assay. The apoptosis rate was analysed with annexin V staining and the cell-cycle distribution with flow cytometry. RESULTS: Propofol at 1,000 µM induced apoptosis and inhibited cell proliferation. The cell cycle showed an increased S-phase and reduced cells in the G1-phase. At 100 µM, propofol significantly inhibited proliferation of the pancreatic cancer cell line PaTu 8988t and reduced cells in the G2-phase in the cell cycle. Etomidate had no effects on cell-cycle distribution, proliferation, apoptosis, and necrosis at the concentrations used. CONCLUSION: In this study, propofol was shown to have anticancer effects by induction of apoptosis and inhibition of cell proliferation, while etomidate did not affect pancreatic cancer cells. However, it is too early to make any recommendation for changes in clinical practice and further clinical studies are warranted to investigate the effect of anaesthetics on cancer progression.