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Inflammation Jun 2024This study aimed to investigate the potential protective effects of Dexmedetomidine (DEX) against acute kidney injury (AKI) induced by acute stress (AS). Wistar rats...
This study aimed to investigate the potential protective effects of Dexmedetomidine (DEX) against acute kidney injury (AKI) induced by acute stress (AS). Wistar rats were divided into five groups: Control, DEX, AS, AS + DEX, and AS + A438079. The results showed that AS led to AKI by increasing inflammatory biomarkers and oxidative stress-related indicators. The acute stress model in rats was successfully established. Renal function, histopathology, oxidative stress, and inflammation were assessed. Localization of P2X7 receptor (P2X7R) was determined by immunofluorescence. Additionally, the key inflammatory proteins of the P2X7R/NF-κB/NLRP3 signaling pathway were measured by Western blotting. DEX significantly improved kidney function, alleviated kidney injury, and reduced oxidative stress and inflammation. DEX inhibited the activation of the P2X7R, decreased the expression of NF-κB, NLRP3 inflammasome, and Caspase-1, and inhibited the expression of interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Furthermore, DEX also alleviated AS-induced AKI by inhibiting the excessive production of reactive oxygen species (ROS) and reducing oxidative stress. In conclusion, DEX attenuates AS-induced AKI by mitigating inflammation and oxidative stress through the inhibition of the P2X7R/NF-κB/NLRP3 pathway in rats.
PubMed: 38896231
DOI: 10.1007/s10753-024-02065-8 -
Acta Anaesthesiologica Scandinavica Jun 2024The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics.
BACKGROUND
The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics.
METHODS
We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 μg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (C) and time (T) were estimated using simulation (n = 1000) with parameter estimates and their associated variability.
RESULTS
There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) μg kg. C 0.273 μg L was achieved at 98 min after intranasal administration (T). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (T = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable.
CONCLUSIONS
Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after T for several hours.
PubMed: 38895976
DOI: 10.1111/aas.14473 -
Journal of Clinical Medicine May 2024: Our understanding of dexmedetomidine, as an adjuvant to nerve blocks in cancer surgery, is characterized by a current lack of compelling evidence, and it remains... (Review)
Review
: Our understanding of dexmedetomidine, as an adjuvant to nerve blocks in cancer surgery, is characterized by a current lack of compelling evidence, and it remains unknown whether the potential benefits of use outweigh the risks. The aim of the study was to evaluate the benefit and safety profiles of dexmedetomidine as an adjuvant to nerve blocks in cancer surgery. : Systematic searches were conducted in MEDLINE, ScienceDirect, Cochrane Library, Springer, medRxiv, and Scopus up to 17 May 2024. Risk ratios (RR) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes were quantified. : Twenty studies were identified. In breast cancer surgery, the use of dexmedetomidine reduced 24 h total morphine consumption (SMD = -1.99 [95% CI -3.01 to -0.98], = 0.0001, I2 = 91%, random effects) and prolonged the requirement for morphine rescue analgesia (SMD = 2.98 [95% CI 0.01 to 5.95], = 0.05, I2 = 98%, random effects). In abdominal cancer surgery, the dexmedetomidine group had lower total sufentanil consumption (SMD = -1.34 [95% CI -2.29 to -0.40], = 0.005, I2 = 84%, random effects). Dexmedetomidine reduced the VAS score and decreased postoperative nausea and vomiting (PONV). No studies using dexmedetomidine reported serious adverse events. : Using dexmedetomidine as an adjuvant to nerve blocks in cancer surgery could lower the VAS pain score and prolong the regional anesthesia duration, which would lead to a decrease in total opioid consumption and possibly contribute to fewer PONV events. Furthermore, the reports of no serious adverse events indicate its good safety profile.
PubMed: 38892876
DOI: 10.3390/jcm13113166 -
Journal of Clinical Medicine May 2024Optimizing pain management in spinal surgery is crucial for preventing adverse events due to delayed mobilization. Magnesium sulfate has potential benefits in spinal... (Review)
Review
Optimizing pain management in spinal surgery is crucial for preventing adverse events due to delayed mobilization. Magnesium sulfate has potential benefits in spinal surgery because of its analgesic properties and modulation of neurotransmitters and autonomic nervous system. Existing evidence regarding the use of magnesium sulfate is partial and controversial, necessitating a comprehensive meta-analysis to evaluate its efficacy and safety. The aim of this study was to conduct a comprehensive meta-analysis to evaluate the efficacy and safety of magnesium sulfate in spinal surgery compared to other available options. This meta-analysis adhered to the PRISMA guidelines. Patients undergoing spinal surgery were included, with the intervention group receiving intravenous magnesium sulfate (MS) at various doses or combinations, whereas the comparison group received other alternatives or a placebo. The efficacy and safety outcomes were assessed. Data were collected from multiple databases and analyzed using Review Manager version 5.4. Heterogeneity was assessed and fixed- or random-effects models were applied. The meta-analysis included eight studies ( = 541). Magnesium sulfate demonstrated significant reductions in pain at 24 h (MD -0.20, 95% CI: -0.39 to -0.02) and opioid consumption (SMD -0.66, 95% CI: -0.95 to -0.38) compared to placebo. Additionally, a decrease in the use of muscle relaxants (SMD -0.91, 95% CI: -1.65 to -0.17) and remifentanil (SMD -1.52, 95% CI: -1.98 to -1.05) was observed. In contrast, an increase in extubation time (MD 2.42, 95% CI: 1.14 to 3.71) and verbal response (MD 1.85, 95% CI: 1.13 to 2.58) was observed compared to dexmedetomidine. In conclusion, magnesium sulfate administration in spinal surgery reduced pain and opioid consumption, and prolonged orientation and verbal response. No significant differences in blood pressure or heart rate were observed between the groups.
PubMed: 38892833
DOI: 10.3390/jcm13113122 -
Healthcare (Basel, Switzerland) May 2024Opioid-free anesthesia (OFA) is a heterogeneous group of general anesthesia techniques in which the intraoperative use of opioids is eliminated. This strategy aims to... (Review)
Review
Opioid-free anesthesia (OFA) is a heterogeneous group of general anesthesia techniques in which the intraoperative use of opioids is eliminated. This strategy aims to decrease the risk of complications and improve the patient's safety and comfort. Such potential advantages are particularly beneficial for selected groups of patients, among them obese patients undergoing laparoscopic bariatric surgery. Opioids have been traditionally used as an element of balanced anesthesia, and replacing them requires using a combination of coanalgesics and various types of local and regional anesthesia, which also have their side effects, limitations, and potential disadvantages. Moreover, despite the growing amount of evidence, the empirical data on the superiority of OFA compared to standard anesthesia with multimodal analgesia are contradictory, and potential benefits in many studies are being questioned. Additionally, little is known about the long-term sequelae of such a strategy. Considering the above-mentioned issues, this study aims to present the potential benefits, risks, and difficulties of implementing OFA in bariatric surgery, considering the current state of knowledge and literature.
PubMed: 38891169
DOI: 10.3390/healthcare12111094 -
The Thoracic and Cardiovascular Surgeon Jun 2024Ferroptosis is emerging as a critical pathway in ischemia/reperfusion (I/R) injury, contributing to compromised cardiac function and predisposing individuals to...
BACKGROUND
Ferroptosis is emerging as a critical pathway in ischemia/reperfusion (I/R) injury, contributing to compromised cardiac function and predisposing individuals to sepsis and myocardial failure. The study investigates the underlying mechanism of dexmedetomidine (DEX) in hypoxia/reoxygenation (H/R)-induced ferroptosis in cardiomyocytes, aiming to identify novel targets for myocardial I/R injury treatment.
METHODS
H9C2 cells were subjected to H/R and treated with varying concentrations of DEX. Additionally, H9C2 cells were transfected with miR-141-3p inhibitor followed by H/R treatment. Levels of miR-141-3p, long noncoding RNA (lncRNA) taurine upregulated 1 (TUG1), Fe, glutathione (GSH), and malondialdehyde were assessed. Reactive oxygen species (ROS) generation was measured via fluorescent labeling. Expression of ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) was determined using Western blot. The interaction between miR-141-3p and lncRNA TUG1 was evaluated through RNA pull-down assay and dual-luciferase reporter gene assays. The stability of lncRNA TUG1 was assessed using actinomycin D.
RESULTS
DEX ameliorated H/R-induced cardiomyocyte injury and elevated miR-141-3p expression in cardiomyocytes. DEX treatment increased cell viability, Fe, and ROS levels while decreasing ACSL4 protein expression. Furthermore, DEX upregulated GSH and GPX4 protein levels. miR-141-3p targeted lncRNA TUG1, reducing its stability and overall expression. Inhibition of miR-141-3p or overexpression of lncRNA TUG1 partially reversed the inhibitory effect of DEX on H/R-induced ferroptosis in cardiomyocytes.
CONCLUSION
DEX mitigated H/R-induced ferroptosis in cardiomyocytes by upregulating miR-141-3p expression and downregulating lncRNA TUG1 expression, unveiling a potential therapeutic strategy for myocardial I/R injury.
PubMed: 38889747
DOI: 10.1055/s-0044-1787691 -
Journal of Medicinal Chemistry Jun 2024Enhancing the selectivity of alpha-adrenoceptor (α-AR) agonists remains an unresolved issue. Herein, we reported the design of an α-AR agonist using the conformation...
Enhancing the selectivity of alpha-adrenoceptor (α-AR) agonists remains an unresolved issue. Herein, we reported the design of an α-AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α-AR agonistic activity. Compounds and were identified as the most promising, exhibiting EC values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10-80 fold. In vivo studies demonstrated that both and dose-dependently increased the loss of righting reflex in mice, with ED values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP128 and α-AR agonist. In particular, and showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α-AR activation.
PubMed: 38889119
DOI: 10.1021/acs.jmedchem.4c01239 -
PloS One 2024Effective labor pain management is crucial for parturient well-being, as it can improve the delivery experience of pregnant women and reduce anxiety and tension. This... (Meta-Analysis)
Meta-Analysis Comparative Study
BACKGROUND
Effective labor pain management is crucial for parturient well-being, as it can improve the delivery experience of pregnant women and reduce anxiety and tension. This systematic review and network meta-analysis compared the efficacy and safety of various analgesics, classified by drug category and individual treatment methods, for labor pain control.
METHODS
A comprehensive literature search was conducted in Pubmed, EMBASE, Cochrane Library, and Web of Science databases. All searches commenced from the database's inception to the date of the literature search (May 31, 2023). The Cochrane Risk of Bias 2 tool assessed study bias risk. Network meta-analyses using a random-effects model and odds ratios (ORs) with 95% confidence intervals (CIs) were performed.
RESULTS
Fifteen randomized controlled trials evaluating analgesic interventions in ASA I or II parturients were included. Combination therapies (OR: 5.81; 95% CI, 3.76-7.84; probability: 60%) and non-opioid analgesics (OR: 5.61; 95% CI, 2.91-8.30; probability: 39.2%) were superior to placebo for labor pain relief. Specifically, dexmedetomidine/ropivacaine/sufentanil (OR: 7.32; 95% CI, 2.73-11.89; probability: 40.6%) and dexmedetomidine/ropivacaine (OR: 6.50; 95% CI, 2.51-10.33; probability: 11.9%) combinations, bupivacaine/fentanyl and ropivacaine/sufentanil combinations, and remifentanil monotherapy showed improved analgesic efficacy versus placebo. Dexmedetomidine/ropivacaine reduced parturient nausea and vomiting versus alternatives.
CONCLUSION
Non-opioids, opioids and combinations thereof effectively relieved labor pain. In addition, dexmedetomidine/ropivacaine combination demonstrated analgesic efficacy and lower nausea and vomiting incidence.
Topics: Humans; Pregnancy; Female; Analgesics, Opioid; Labor Pain; Network Meta-Analysis; Pain Management; Analgesics, Non-Narcotic; Randomized Controlled Trials as Topic; Dexmedetomidine
PubMed: 38889108
DOI: 10.1371/journal.pone.0303174 -
Drug Design, Development and Therapy 2024Thoracic paravertebral block (TPVB) analgesia can be prolonged by local anesthetic adjuvants such as dexmedetomidine. This study aimed to evaluate the two administration... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of Ultrasound-Guided Thoracic Paravertebral Nerve Block Combined with Perineural or IV Dexmedetomidine on Acute and Chronic Pain After Thoracoscopic Resection of Lung Lesions: A Double-Blind Randomized Trial.
BACKGROUND
Thoracic paravertebral block (TPVB) analgesia can be prolonged by local anesthetic adjuvants such as dexmedetomidine. This study aimed to evaluate the two administration routes of dexmedetomidine on acute pain and chronic neuropathic pain (NeuP) prevention compared with no dexmedetomidine.
METHODS
A total of 216 patients were randomized to receive TPVB using 0.4% ropivacaine alone (R Group), with perineural dexmedetomidine 0.5 μg·kg (RD Group) or 1.0 μg·kg (RD Group), or intravenous (IV) dexmedetomidine 0.5 μg·kg·h (RD Group). The primary outcome was the incidence of chronic NeuP, defined as a Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain score > 12 points at 3-month after surgery.
RESULTS
(1) For the primary outcome, RD Group and RD Group demonstrated a decreased incidence of chronic NeuP at 3-month after surgery; (2) Compared with R Group, RD Group, RD Group, and RD Group can reduce VAS scores at rest and movement and Prince-Henry Pain scores at 12 and 24-h after surgery, the consumption of oral morphine equivalent (OME) and improve QOD-15 at POD1; (3) Compared with RD Group, RD Group and RD Group can reduce VAS scores at rest and movement and Prince-Henry Pain scores at 12 and 24-h after surgery, the consumption of postoperative OME and improve QOD-15 at POD1; (4) Compared with RD Group, RD Group effectively reduced VAS scores at rest at 12 and 24-h after surgery, VAS scores in movement and Prince-Henry Pain scores at 12-h after surgery. However, RD Group showed an increased incidence of drowsiness.
CONCLUSION
Perineural or IV dexmedetomidine are similarly effective in reducing acute pain, but only perineural dexmedetomidine reduced chronic NeuP. Moreover, considering postoperative complications such as drowsiness, perineural dexmedetomidine (0.5 μg·kg) may be a more appropriate choice.
CLINICAL TRIAL REGISTRATION
Chinese Clinical Trial Registry (ChiCTR2200058982).
Topics: Humans; Dexmedetomidine; Double-Blind Method; Male; Nerve Block; Female; Middle Aged; Chronic Pain; Acute Pain; Pain, Postoperative; Aged; Ultrasonography, Interventional; Thoracoscopy; Lung Neoplasms; Adult; Administration, Intravenous
PubMed: 38882043
DOI: 10.2147/DDDT.S457334 -
Journal of Intensive Care Medicine Jun 2024Patients in the intensive care unit (ICU) often experience poor sleep quality. Pharmacologic sleep aids are frequently used as primary or adjunctive therapy to improve... (Review)
Review
Patients in the intensive care unit (ICU) often experience poor sleep quality. Pharmacologic sleep aids are frequently used as primary or adjunctive therapy to improve sleep, although their benefits in the ICU remain uncertain. This review aims to provide a comprehensive assessment of the objective and subjective effects of medications used for sleep in the ICU, as well as their adverse effects. PubMed, Web of Science, Scopus, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from their inception until June 2023 for comparative studies assessing the effects of pharmacologic sleep aids on objective and subjective metrics of sleep. Thirty-four studies with 3498 participants were included. Medications evaluated were melatonin, ramelteon, suvorexant, propofol, and dexmedetomidine. The majority of studies were randomized controlled trials. Melatonin and dexmedetomidine were the best studied agents. Objective sleep metrics included polysomnography (PSG), electroencephalography (EEG), bispectral index, and actigraphy. Subjective outcome measures included patient questionnaires and nursing observations. Evidence for melatonin as a sleep aid in the ICU was mixed but largely not supportive for improving sleep. Evidence for ramelteon, suvorexant, and propofol was too limited to offer definitive recommendations. Both objective and subjective data supported dexmedetomidine as an effective sleep aid in the ICU, with PSG/EEG in 303 ICU patients demonstrating increased sleep duration and efficiency, decreased arousal index, decreased percentage of stage N1 sleep, and increased absolute and percentage of stage N2 sleep. Mild bradycardia and hypotension were reported as side effects of dexmedetomidine, whereas the other medications were reported to be safe. Several ongoing studies have not yet been published, mostly on melatonin and dexmedetomidine. While definitive conclusions cannot be made for most medications, dexmedetomidine improved sleep quantity and quality in the ICU. These benefits need to be balanced with possible hemodynamic side effects.
PubMed: 38881385
DOI: 10.1177/08850666241255345