Α2-adrenergic Agonist Research Articles

Study on the protective mechanism of dexmedetomidine on the liver of perioperative diabetic patients: A randomized controlled trial.

Background:Although several studies have reported that dexmedetomidine is a highly selective α2-adrenergic receptor agonist that protects liver function in perioperative patients by inhibiting oxidative stress (OS) and inflammatory response, patients with type 2 diabetes mellitus (T2DM) have not been included in the previous studies. The purpose of this study was to investigate the effects of perioperative low-dose dexmedetomidine on perioperative liver function in T2DM patients.Methods:This was a single-center, placebo-controlled randomized trial. Fifty-four T2DM patients scheduled for debridement of lower extremity ulcers were included in this study and randomly divided into 2 groups (n = 27 per group): the dexmedetomidine group (DEX group) and the control group (CON group). Continuous intravenous infusion of dexmedetomidine (DEX group) or normal saline (CON group) was administered from the completion of monitoring to the end of surgery. All participants received femoral and sciatic nerve block with 0.33% ropivacaine. The main result was the activity of liver enzymes (AST, ALT) reflecting liver function. The secondary results included variables reflecting blood glucose (Glu), blood lipids (TG, HDL, LDL, total cholesterol), biomarkers of OS (MDA, SOD), and systemic inflammatory response (TNF-α, IL-6).Results:Compared with CON group, DEX group exhibited a reduction in hemodynamic parameters, Glu, systemic inflammatory response, and liver injury indicators. OS response MDA activity was lower in DEX group than in CON group, while SOD was higher than that in CON group. The variables reflecting lipid metabolism function showed no differences between the groups.Conclusion subsections:Dexmedetomidine administered perioperatively can reduce Glu levels and protect the liver by attenuating OS injury and inflammatory response in T2DM patients without any potential risk.

Dexmedetomidine protects cells from Angiotensin II-induced smooth muscle cell phenotype switch and endothelial cell dysfunction

ABSTRACT Abdominal aortic aneurysm (AAA) is a vascular disorder greatly threatening life of the elderly population. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist, has been shown to suppress AAA development. Nevertheless, the signaling pathways that might be mediated by DEX in AAA has not been clarified. Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) were treated with Angiotensin II (Ang II) to mimic AAA in vitro. BrdU, wound healing, and Transwell assays were utilized for measuring VSMC proliferation and migration. Western blotting was used for evaluating protein levels of contractile VSMC markers, collagens and matrix metalloproteinases (MMPs) in VSMCs as well as apoptosis- and HMGB1/TLR4/NF-κB signaling-related markers in ECs. Cell adhesion molecule expression and monocyte-endothelial adhesion were assessed by immunofluorescence staining and adhesion assays. Flow cytometry was implemented for analyzing EC apoptosis. Hematoxylin-eosin staining and ELISA were used to detect the effect of DEX in vivo. In this study, DEX inhibited Ang II-evoked VSMC phenotype switch and extracellular matrix degradation. DEX suppressed the inflammatory response and apoptosis of ECs induced by Ang II. DEX inhibited HMGB1/TLR4/NF-κB signaling pathway in Ang II-treated ECs. DEX attenuated Ang II-induced AAA and inflammation in mice. Overall, DEX ameliorates Ang II-induced VSMC phenotype switch, and inactivates HMGB1/TLR4/NF-κB signaling pathway to alleviate Ang II-induced EC dysfunction.

The contribution of autonomic mechanisms to pain in temporomandibular disorders: A narrative review.

Temporomandibular disorders (TMD) are diagnosed based on symptom presentation and, like other functional pain disorders, often lack definitive pathology. There is a strong association between elevated stress levels and the severity of TMD-related pain, which suggests that alterations in autonomic tone may contribute to this pain condition. This narrative review examines the association between altered autonomic function and pain in TMD. Relevant articles were identified by searching PubMed and through the reference list of those studies. TMD sufferers report an increased incidence of orthostatic hypotension. As in other chronic musculoskeletal pain conditions, TMD is associated with increased sympathetic tone, diminished baroreceptor reflex sensitivity and decreased parasympathetic tone. It remains to be determined whether ongoing pain drives these autonomic changes and/or is exacerbated by them. To examine whether increased sympathetic tone contributes to TMD-related pain through β2 adrenergic receptor activation, clinical trials with the beta blocker propranolol have been undertaken. Although evidence from small studies suggested propranolol reduced TMD-related pain, a larger clinical trial did not find a significant effect of propranolol treatment. This is consistent with human experimental pain studies that were unable to demonstrate an effect of β2 adrenergic receptor activation or inhibition on masticatory muscle pain. In preclinical models of temporomandibular joint arthritis, β2 adrenergic receptor activation appears to contribute to inflammation and nociception, whereas in masticatory muscle, α1 adrenergic receptor activation has been found to induce mechanical sensitisation. Some agents used to treat TMD, such as botulinum neurotoxin A, antidepressants and α2 adrenergic receptor agonists, may interact with the autonomic nervous system as part of their analgesic mechanism. Even if dysautonomia turns out to be a consequence rather than a causative factor of painful TMD, the study of its role has opened up a greater understanding of the pathogenesis of this condition.

Pre-formulation and Stability Study of 20-mcg Clonidine Hydrochloride Pediatric Capsules.

Clonidine hydrochloride is an antihypertensive, centrally acting α2 adrenergic agonist with various pediatric indications. For pediatric patients, 20-mcg clonidine hydrochloride capsules can be compounded from commercial tablets or from a pre-compounded titrated powder. These methods should be compared to ensure the best quality for the high-risk patients, and a beyond-use date should be established. Eight experimental batches were made from commercial tablets and 8 were made from microcrystalline cellulose (MCC)-based titrated powders. Quality controls were performed to determine the best compounding protocol. Stability study was conducted on capsules compounded with the best method. Of 8 batches manufactured from commercial tablets, 7 were compliant for both clonidine mean content and content uniformity, whereas 7 of 8 batches manufactured from titrated powders were not. A clonidine loss during compounding was evidenced by surface sampling analyses. Clonidine hydrochloride 20-mcg capsules' mean content remained higher than 90% of initial content for 1 year when stored at 25°C with 60% relative humidity and protected from light. Commercial tablets should be preferred to 1% clonidine hydrochloride and MCC titrated powder made from the active pharmaceutical ingredient. Twenty-microgram clonidine hydrochloride capsules made from commercial tablets are stable for 1 year when stored under managed ambient storage condition.

Amelioration of myocardial ischemia/reperfusion injury in diabetes: A narrative review of the mechanisms and clinical applications of dexmedetomidine.

Mechanisms contributing to the pathogenesis of myocardial ischemia-reperfusion (I/R) injury are complex and multifactorial. Many strategies have been developed to ameliorate myocardial I/R injuries based on these mechanisms. However, the cardioprotective effects of these strategies appear to diminish in diabetic states. Diabetes weakens myocardial responses to therapies by disrupting intracellular signaling pathways which may be responsible for enhancing cellular resistance to damage. Intriguingly, it was found that Dexmedetomidine (DEX), a potent and selective α2-adrenergic agonist, appears to have the property to reverse diabetes-related inhibition of most intervention-mediated myocardial protection and exert a protective effect. Several mechanisms were revealed to be involved in DEX’s protection in diabetic rodent myocardial I/R models, including PI3K/Akt and associated GSK-3β pathway stimulation, endoplasmic reticulum stress (ERS) alleviation, and apoptosis inhibition. In addition, DEX could attenuate diabetic myocardial I/R injury by up-regulating autophagy, reducing ROS production, and inhibiting the inflammatory response through HMGB1 pathways. The regulation of autonomic nervous function also appeared to be involved in the protective mechanisms of DEX. In the present review, the evidence and underlying mechanisms of DEX in ameliorating myocardial I/R injury in diabetes are summarized, and the potential of DEX for the treatment/prevention of myocardial I/R injury in diabetic patients is discussed.

Intranasal Dexmedetomidine as Sedative for Medical Imaging in Young Children: A Systematic Review to Provide a Roadmap for an Evidence-Guided Clinical Protocol.

There is an increasing need for effective anxiety and pain reduction during medical imaging procedures in children, addressed by non-pharmacological or pharmacological approaches. Dexmedetomidine is a fairly recently marketed, selective α2-adrenergic agonist that can be administered intranasally. To develop an evidence-guided clinical protocol, we investigated the (side) effects, preconditions and safety aspects following intranasal dexmedetomidine administration in children (1 month–5 years) for procedural sedation during medical imaging. To this end, a systematic search (PubMed, Embase and CINAHL (12/2021)) was performed to identify studies on intranasal dexmedetomidine for procedural sedation for medical imaging (computer tomography and magnetic resonance imaging). Following screening and quality assessment, eight studies were retained. Nasal nebulization was considered the best administration method, dosing varied between 2 and 4 µg/kg (age-dependent) 30–45 min prior to imaging and contraindications or restrictions with respect to oral intake were somewhat consistent across studies. Valid sedation scores and monitoring of vital signs were routinely used to assess sedation and the need for rescue dosing (different approaches), whereas discharge was generally based on Aldrete score (score ≥ 9). Heart rate, blood pressure and saturation were routinely monitored, with commonly observed bradycardia or hypotension (decrease by 20%). Based on these findings, a roadmap for evidence-guided clinical protocol was generated.

Dex modulates the balance of water-electrolyte metabolism by depressing the expression of AVP in PVN.

Dexmedetomidine (Dex) is a highly selective α2 adrenergic agonist used in clinical anesthesia. Studies have shown that Dex can act on the collecting duct and reduce the body’s water reabsorption, thereby increasing water discharge. However, the specific mechanism of Dex on water homeostasis remains unclear. The hypothalamus is the regulatory center of water and salt balance and secretes related neurochemical hormones, such as arginine vasopressin (AVP), to regulate the discharge of water and salt. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) in the hypothalamus are also considered to be the key targets of the thirst loop. They are responsible for the secretion of AVP. The suprachiasmatic nucleus (SCN) is also one of the brain regions where AVP neurons are densely distributed in the hypothalamus. This study used C57BL/6J mice for behavior, immunofluorescence, and blood analysis experiments. Our results showed that Dex could not only depress the expression of AVP in the PVN but also reduce serum AVP concentration. The animal water intake was decreased without impairing the difference in food consumption and the urine excretion was enhanced after the intraperitoneal injection of Dex, while AVP supplementation restored the water intake and inhibited the urine excretion of mice in the Dex group. In addition, the renin-angiotensin-aldosterone system is vital to maintaining serum sodium concentration and extracellular volume. We found that serum sodium, serum chloride, serum aldosterone (ALD) concentration, and plasma osmolality were decreased in the Dex group, which inhibited water reabsorption, and the plasma osmolarity of mice in the Dex group supplemented with AVP was significantly higher than that in Dex group. We also found that Dex significantly increased the concentration of blood urea nitrogen and decreased the concentration of creatinine within the normal range of clinical indicators, indicating that there was no substantive lesion in the renal parenchyma. These results showed that Dex could modulate the balance of water-electrolyte metabolism by depressing the expression of AVP in PVN without impairing renal function.

Dexmedetomidine prevents hemorrhagic brain injury by reducing damage induced by ferroptosis in mice

Intracerebral hemorrhage (ICH) is a devastating condition with significant morbidity and mortality for which few effective treatments are clinically available. After ICH, iron overload within the perihaematomal region can induce lethal reactive oxygen species (ROS) production and lipid peroxidation, which contribute to secondary brain injury. An iron-dependent form of non-apoptotic cell death known as ferroptosis was recently identified. Ferroptosis plays an important role in ICH pathology. It is characterized by an accumulation of iron-induced lipid ROS, which leads to intracellular oxidative stress. Dexmedetomidine (DEX), an α2-adrenergic agonist, is widely used for anesthesia, pain control, and intensive care unit sedation. DEX has numerous beneficial activities, including anti-inflammatory, anti-oxidative, and anti-cell death activities. Here, we established a mouse model of ICH using collagenase VII and evaluated the effect of DEX in preventing ICH-induced brain injury. Our study showed that administering DEX reduced the damage induced by ferroptosis after ICH by regulating iron metabolism, amino acid metabolism and lipid peroxidation processes.

Norepinephrine modulation of heat dissipation in female rats lacking estrogen.

Postmenopausal hot flushes are caused by lack of estradiol (E2) but their neuroendocrine basis is still poorly understood. Here, we investigated the interrelationship between norepinephrine and hypothalamic neurons, with emphasis on kisspeptin neurons in the arcuate nucleus (ARC), as a regulatory pathway in the vasomotor effects of E2. Ovariectomized (OVX) rats displayed increased tail skin temperature (TST), and this increase was prevented in OVX rats treated with E2 (OVX + E2). Expression of Fos in the hypothalamus and the number of ARC kisspeptin neurons coexpressing Fos were increased in OVX rats. Likewise, brainstem norepinephrine neurons of OVX rats displayed higher Fos immunoreactivity associated with the increase in TST. In the ARC, the density of dopamine-ß-hydroxylase (DBH)-immunoreactive (ir) fibers was not altered by E2 but, importantly, DBH-ir terminals were found in close apposition to kisspeptin cells, revealing norepinephrine inputs to ARC kisspeptin neurons. Intracerebroventricular injection of the α2-adrenergic agonist clonidine (CLO) was used to reduce central norepinephrine release, confirmed by the decreased 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratio in the preoptic area and ARC. Accordingly, CLO treatment in OVX rats reduced ARC Kiss1 mRNA levels and TST to the values of OVX + E2 rats. Conversely, CLO stimulated Kiss1 expression in the anteroventral periventricular nucleus (AVPV) and increased luteinizing hormone secretion. These findings provide evidence that augmented heat dissipation in OVX rats involves the increase in central norepinephrine that modulates hypothalamic areas related to thermoregulation, including ARC kisspeptin neurons. This neuronal network is suppressed by E2 and its imbalance may be implicated in the vasomotor symptoms of postmenopausal hot flushes.

Comparative Study between Dexmedetomidine and Nalbuphine for prevention of post spinal shivering in Obstetrics cases- A randomized controlled trial

Background: Shivering is a physiological response to core hypothermia in an attempt to raise themetabolic heat production. The main causes of intra/post-operative shivering are temperature loss,increased sympathetic tone, pain, and systemic release of pyrogens. Spinal anaesthesia significantlyimpairs the thermoregulation system by inhibiting tonic vasoconstriction, which plays a significant rolein temperature regulation. It also causes a redistribution of core heat from the trunk (below the blocklevel) to the peripheral tissues. These factors predispose patients to hypothermia and shivering. Severalpharmacological agents are used for control of Post spinal shivering. Nalbuphine has become afavoured and commonly used drug for post-spinal shivering. However, it has many adverse effects likenausea, vomiting, dizziness etc. Dexmedetomidine is another agent which has gained popularity duringthe last few years. Dexmedetomidine is an α2-adrenergic receptor agonist, has been used as a sedativeagent and is documented to increase the shivering threshold. Objectives: To assess the superiority of Dexmedetomidine over Nalbuphine in prevention of post spinalshivering. Materials & method: This prospective, randomized clinical trial was conducted in Department ofAnaesthesia, Analgesia, Palliative and Intensive Care Medicine, Dhaka Medical College Hospital, from18th October 2019 to 17th April 2020. Total 120 patients were selected and allocated into two groups,group N (Nalbuphine) and group D (Dexmedetomidine). Patients of Group N was given intravenousNalbuphine 0.07 mg/kg mixed with 0.9% normal saline to a volume of 10ml. Patients of Group D wasgiven intravenous Dexmedetomidine hydrochloride 1 μg/kg mixed with 0.9% normal saline to a volumeof 10ml. Then shivering grade and haemodynamic status were recorded at different follow-up time andcompared between groups. Result: Majority of the patients i.e. 58.33% (n=70) were between 25-30 years, mean age was found to26.7±8.4 years and 26.7±8.4 years in Group D & N respectively. The heart rate after 5 min (56, 62beat/min respectively), after 10 min (58, 68 beat/min respectively) and 15 min (63, 72 beat/min respectively)after of anaesthesia were statistically significant. Shivering grade 3 or 4 was existed in bothgroups, but more in group N. Rescue medication for shivering (Inj. Pethedine 25 mg) requirement washigher in Group-N & difference was statistically significant. Shivering was controlled within 15 minutein maximum 13(21.66%) of patients in group D. Comparison of sedation, 45 minute after mean sedationscore was found 2.03±0.07 in group D, but in group N score is reduced and found 1.43±0.127. Meansedation score difference was statistically significant (p<0.05) between two groups. Conclusion: Post spinal shivering is very distressing for patients and may induce a variety of complications.Present study concluded that Dexmedetomidine was more effective compared to Nalbuphineinattenuating the post spinal shivering. JBSA 2022; 35 (2) : 3-11

Effect of intraoperative dexmedetomidine on hepatic ischemia-reperfusion injury in pediatric living-related liver transplantation: A propensity score matching analysis

BackgroundHepatic ischemia-reperfusion injury (HIRI) is largely unavoidable during liver transplantation (LT). Dexmedetomidine (DEX), an α2-adrenergic agonist, exerts a variety of organ-protective effects in pediatric populations. However, evidence remains relatively limited about its hepatoprotective effects in pediatric living-related LT.MethodsA total of 121 pediatric patients undergoing living-related LT from June 2015 to December 2018 in our hospital were enrolled. They were classified into DEX or non-DEX groups according to whether an infusion of DEX was initiated from incision to the end of surgery. Primary outcomes were postoperative liver graft function and the severity of HIRI. Multivariate logistic regression and propensity score matching (PSM) analyses were performed to identify any association.ResultsA 1:1 matching yielded 35 well-balanced pairs. Before matching, no significant difference was found in baseline characteristics between groups except for warm ischemia time, which was longer in the non-DEX group (44 [38–50] vs. 40 [37–44] min, p = 0.017). After matching, the postoperative peak lactic dehydrogenase levels decreased significantly in the DEX group than in the non-DEX group (622 [516–909] vs. 970 [648–1,490] IU/L, p = 0.002). Although there was no statistical significance, a tendency toward a decrease in moderate-to-extreme HIRI rate was noted in the DEX group compared to the non-DEX group (68.6% vs. 82.9%, p = 0.163). Patients in the DEX group also received a significantly larger dosage of epinephrine as postreperfusion syndrome (PRS) treatment (0.28 [0.17–0.32] vs. 0.17 [0.06–0.30] µg/kg, p = 0.010). However, there were no significant differences between groups in PRS and acute kidney injury incidences, mechanical ventilation duration, intensive care unit, and hospital lengths of stay. Multivariate analysis revealed a larger graft-to-recipient weight ratio (odds ratio [OR] 2.657, 95% confidence interval [CI], 1.132–6.239, p = 0.025) and intraoperative DEX administration (OR 0.333, 95% CI, 0.130–0.851, p = 0.022) to be independent predictors of moderate-to-extreme HIRI.ConclusionThis study demonstrated that intraoperative DEX could potentially decrease the risk of HIRI but was associated with a significant increase in epinephrine requirement for PRS in pediatric living-related LT. Further studies, including randomized controlled studies, are warranted to provide more robust evidence.

Brimonidine Modulates the ROCK1 Signaling Effects on Adipogenic Differentiation in 2D and 3D 3T3-L1 Cells

The additive effects of an α2-adrenergic agonist, brimonidine (BRI), on the pan-ROCK inhibitor (ROCK-i), ripasudil (Rip), and the ROCK2-I, KD025, on adipogenic differentiation (DIF+) were examined using two- or three-dimension (2D or 3D) cultures of 3T3-L1 cells. The following analyses were carried out: (1) lipid staining (2D and 3D), (2) real-time measurements of cellular metabolism (2D), (3) mRNA expression of DIF+ related genes and extracellular matrix molecules (ECMs) including collagen (Col)-1, -4, and -6, and fibronectin (Fn), and (4) the sizes and physical properties of the 3D spheroids. The findings indicate that DIF+ induced (1) a substantial enhancement in lipid staining and enhanced expression of the Pparγ and Fabp4 genes, (2) significantly larger and softer 3D spheroids, and (3) down-regulation of Col1 and Fn and up-regulation of Col4 and Col6 genes. Treatment with Rip alone caused a significant enhancement in adipogenesis of both the 2D and 3D cultured 3T3-L1 cells and in the physical properties of the 3D spheroids; these effects were substantially inhibited by BRI, and the effects induced by BRI or KD025 were not insignificant. These collective findings indicate that the addition of BRI inhibited the Rip-induced enhancement of DIF+ in 3T3-L1 cells, presumably by modulating ROCK1 signaling.

An α2-Adrenergic Agonist, Brimonidine, Beneficially Affects the TGF-β2-Treated Cellular Properties in an In Vitro Culture Model.

We report herein on the effects of brimonidine (BRI), an α2-adrenergic agonist, on two-dimensional (2D) and three-dimensional (3D) cell-cultured TGF-β2-untreated and -treated human trabecular meshwork (HTM) cells. In the presence of TGF-β2 (5 ng/mL), (1) the effects of BRI on (1) the 2D HTM monolayers’ barrier function were investigated as estimated using trans-endothelial electrical resistance (TEER) measurement and FITC dextran permeability; (2) real-time analyses of cellular metabolism using a Seahorse Bioanalyzer; (3) the largeness and hardness of 3D spheroids; and (4) the expression of genes that encode extracellular matrix (ECM) proteins, including collagens (COL) 1, 4, and 6; fibronectin (FN) and α-smooth muscle actin (α-SMA); ECM modulators, including a tissue inhibitor of matrix proteinase (TIMP) 1–4; matrix metalloproteinase (MMP) 2, 9, and 14; and several endoplasmic reticulum (ER) stress-related genes, including the X-box-binding protein 1 (XBP1), the spliced XBP1 (sXBP1), glucose-regulated protein (GRP)78, GRP94, and CCAAT-enhancer-binding protein homologous protein (CHOP). BRI markedly inhibited the TGF-β2-induced increase in the values of TEER of the 2D cell monolayer and the hardness of the 3D spheroids, although it had no effect on their sizes. BRI also cancelled the TGF-β2-induced reduction in mitochondrial maximal respiration but had no effect on the glycolytic capacity. In addition, the gene expression of these molecules was quite different between the 2D and 3D cultures of HTM cells. The present observations found in this study indicate that BRI may beneficially affect TGF-β2-induced changes in both cultures, 2D and 3D, of HTM cells, although their structural and functional properties that were altered varied significantly between both cultures of HTM cells.

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1.

ObjectiveVanishing white matter (VWM) is a leukodystrophy, characterized by stress‐sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi‐allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for the regulation of the integrated stress response (ISR), a physiological response to cellular stress. Preclinical studies on VWM mouse models revealed that deregulated ISR is key in the pathophysiology of VWM and an effective treatment target. Guanabenz, an α2‐adrenergic agonist, attenuates the ISR and has beneficial effects on VWM neuropathology. The current study aimed at elucidating guanabenz's disease‐modifying potential and mechanism of action in VWM mice. Sephin1, an ISR‐modulating guanabenz analog without α2‐adrenergic agonistic properties, was included to separate effects on the ISR from α2‐adrenergic effects.MethodsWild‐type and VWM mice were subjected to placebo, guanabenz or sephin1 treatments. Effects on clinical signs, neuropathology, and ISR deregulation were determined. Guanabenz's and sephin1's ISR‐modifying effects were tested in cultured cells that expressed or lacked the α2‐adrenergic receptor.ResultsGuanabenz improved clinical signs, neuropathological hallmarks, and ISR regulation in VWM mice, but sephin1 did not. Guanabenz's effects on the ISR in VWM mice were not replicated in cell cultures and the contribution of α2‐adrenergic effects on the deregulated ISR could therefore not be assessed.InterpretationGuanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without α2‐adrenergic effects.

The Role of Dexmedetomidine in Tumor-Progressive Factors in the Perioperative Period and Cancer Recurrence: A Narrative Review.

Dexmedetomidine, a specific α2 adrenergic receptor agonist, is highly frequently used in the perioperatively for its favorable pharmacology, such as mitigating postoperative cognitive dysfunction. Increasing attention has been recently focused on the effect of whether dexmedetomidine influences cancer recurrence, which urges the discussion of the role of dexmedetomidine in tumor-progressive factors. The pharmacologic characteristics of dexmedetomidine, the tumor-progressive factors in the perioperative period, and the relationships between dexmedetomidine and tumor-progressive factors were described in this review. Available evidence suggests that dexmedetomidine could reduce the degree of immune function suppression, such as keeping the number of CD3+ cells, NK cells, CD4+/CD8+ ratio, and Th1/Th2 ratio stable and decreasing the level of proinflammatory cytokine (interleukin 6 and tumor necrosis factor-alpha) during cancer operations. However, dexmedetomidine exhibits different roles in cell biological behavior depending on cancer cell types. The conclusions on whether dexmedetomidine would influence cancer recurrence could not be currently drawn for the lack of strong clinical evidence. Therefore, this is still a new area that needs further exploration.

Neurobehavioural Evaluation of Antidepressant and Anticonvulsant Potentials of Tizanidine in Balb/c Mice

Tizanidine is a selective α2-adrenergic receptor agonist that stimulates the central nervous system through the adrenergic pathway. This study evaluated the antidepressant and anticonvulsant activity of tizanidine in mice. The various limitations of currently available anti-depressive and epileptic drugs and the bidirectional relationship between the two neurological disorders warrant improved pharmacotherapy interventions. 125 Balb/c mice were divided into 75 and 50 for antidepressant and anticonvulsant stud-ies, respectively. Forced swim (FST), tail suspension (TST), and open field (OFT) antidepressant models were used. In each model, twenty-five mice were divided into five groups (n=5); 1 mL/kg dis-tilled water group (negative control), 15 mg/kg imipramine (positive control in FST and TST), 0.05 mg/kg diazepam (positive control for OFT) group, and 1 mg/kg, 2 mg/kg, and 4 mg/kg tizanidine groups respectively. Anticonvulsant screening was conducted using pentylenetetrazole (PTZ) and picrotoxin models of seizure in which mice were treated with 2 mg/kg, 4 mg/kg and 8 mg/kg tizanidine. Tizanidine at all the doses significantly reduced the immobility time of the mice in FST (p≤0.0001) and TST (p≤ 0.05). There was no significant increase in line crossing frequency between tizanidine and 0.05 mg/kg diazepam in the OFT (p˃0.05). Tizanidine significantly delayed the onset of myoclonic jerks (p≤0.001) in the PTZ model but not in the picrotoxin model (p˃0.05). This study showed that tizanidine possesses antidepressant-like activity, but little anticonvulsant activity.

Dexmedetomidine in the Program of Multimodal Low-opioid Anesthesia During Laparoscopic Surgery in Urology

Dexmedetomidine, a highly selective α2-adrenergic agonist, has become a valuable component of low-opioid multimodal anesthesia, providing sedative, anxiolytic and analgesic effects. The objective: to evaluate the effectiveness of using dexmedetomidine in a multimodal low opioid anesthesia program for laparoscopic renal surgery. Materials and methods. 55 patients who underwent laparoscopic renal surgery under two types of general anesthesia were included. All patients underwent surgery under general anesthesia with tracheal intubation. Induction: intravenous propofol 2 mg/kg, fentanyl 1.5–2 μg/kg, atracurium 0.6 mg/kg. Anesthesia maintenance: sevoflurane (MAC – 1.44±0.25 vol.%). In group 1 analgesia was provided with fentanyl 3.89±2.1 μg/kg/h. Multimodal low-opioid anesthesia with fentanyl 2.38±1.01 μg/kg/h combined with dexmedetomidine 0.7 μg/kg/h was used in group 2. The efficacy of antinociceptive protection was assessed by the dynamics of changes in the levels of stress hormones, hemodynamic parameters, and blood glucose concentrations. Results. The total average doses of fentanyl used during the entire period of anesthesia were: 369.23±16.42 μg in group 1, 272.41±10,98 μg in group 2 (p<0.001). In patients of the control group 1, an increase in the plasma concentration of adrenocorticotropic hormone by 111.86% (p<0.01) from 25.7±2.1 pg/ml to 54.45±5.43 pg/ml was recorded (the study was conducted before the start of surgery and after the end of the operation), which was accompanied by a statistically significant increase cortisol concentration from 371.0±32.32 nmol/l to 562.72±45.37 nmol/l (by 51.67%) (p<0.01). In patients of the second group (dexmedetomidine group), an intraoperative increase in the plasma concentration of adrenocorticotropic hormone was recorded from 26.25±2.3 pg/l to 46.88±2.36 pg/l (by 78.59%) (p<0.01), which was accompanied by a statistically insignificant intraoperative increase in cortisol concentration from 393.51±25.0 nmol/l to 436.37±34.92 nmol/l – only by 10.89% (p>0.05). Blood glucose concentrations in the early postoperative period in the both groups were 6.79±0.31 mmol/l and 6.29±0.24 mmol/l, respectively (p>0.05). Hemodynamic parameters and BIS, which was maintained within 44±6.4%, indicated the adequacy of anesthesia and analgesia in both groups. Conclusions. The use of dexmedetomidine in multimodal low-opioid anesthesia for laparoscopic renal surgery provides the greatest antinociceptive protection and reduces the stress response to surgery.

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.

Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

Analgesia and Sedation in Critically Ill Patients With Burns.

Analgesia and Sedation in Critically Ill Patients With Burns.

Antagonism of α1-adrenoceptors by β3-adrenergic agonists: Structure–function relations of different agonists in prostate smooth muscle contraction

Effects of β3-adrenergic agonists on prostate smooth muscle contraction are poorly characterized, although mirabegron is used for treatment of lower urinary tract symptoms. Off-target effects of several β3-adrenergic agonists include antagonism of α1-adrenoceptors. Proposed, but unconfirmed explanations include phenylethanolamine backbones, found in some β3-adrenergic agonists and imparting interaction with catecholamine binding pockets of adrenoceptors. Here, we examined effects of β3-adrenergic agonists on contractions of human prostate tissues, including ZD7114 (without phenylethanolamine moiety), ZD2079 (phenylethanolamine backbone), BRL37344 and CL316243 (chloride-substituted phenylethanolamine deriatives). Prostate tissues were obtained from radical prostatectomy. Contractions by α1-adrenergic agonists and electric field stimulation (EFS) were studied in an organ bath. ZD7114 (10 µM) right-shifted concentration responses curves for α1-adrenergic agonists, resulting in increased EC50 values for phenylephrine, methoxamine and noradrenaline up to one magnitude, without affecting Emax values. ZD7114 (10 µM) inhibited EFS-induced contractions, resulting in reduced Emax values. All effects of ZD7114 were resistant to the β3-adrenergic antagonist L-748337, including increases in EC50 values for α1-adrenergic agonists, up to more than two magnitudes. Using 10 µM, neither ZD2079, BRL37344 or CL316243 affected α1-adrenergic or EFS-induced contractions. At escalated concentrations, BRL37344 (200 µM) right-shifted concentration response curves for phenylephrine, increased EC50 values for phenylephrine, and inhibited EFS-induced contractions, while CL316243 (300 µM) did not affect phenylephrine- or EFS-induced contractions. In conclusion, phenylethanolamine backbones are not decisive to impart α1-adrenoceptor antagonism to β3-agonists. Effects of β3-adrenergic agonists on prostate smooth muscle contraction are limited to off-target effects, including α1-adrenoceptor antagonism by ZD7114 and BRL37344.