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Managing postoperative pain in patients with obesity is challenging. Although multimodal analgesia has proved effective for pain relief, the specific impacts of different nonopioid i.v. analgesics and adjuvants on these patients are not well-defined. This study aims to assess the effectiveness of nonsteroidal antiinflammatory drugs, paracetamol, ketamine, α-2 adrenergic receptor agonists, lidocaine, magnesium, and oral gabapentinoids in reducing perioperative opioid consumption and, secondarily, in mitigating the occurrence of general and postoperative pulmonary complications (POPCs), nausea, vomiting, PACU length of stay (LOS), and hospital LOS among surgical patients with obesity. A systematic review and network meta-analysis was performed. PubMed, Scopus, Web of Science, CINAHL, and EMBASE were searched. Only English-language RCTs investigating the use of nonopioid analgesics and adjuvants in adult surgical patients with obesity were included. The quality of evidence and certainty were assessed using the RoB 2 tool and GRADE framework, respectively. In total, 37 RCTs involving 3602 patients were included in the quantitative analysis. Compared with placebo/no intervention or a comparator, dexmedetomidine, ketamine, lidocaine, magnesium, and gabapentin significantly reduced postoperative opioid consumption after surgery. Ketamine/esketamine also significantly reduced POPCs. Ibuprofen, dexmedetomidine, and lidocaine significantly reduced postoperative nausea, whereas dexmedetomidine, either alone or combined with pregabalin, and lidocaine reduced postoperative vomiting. Dexmedetomidine significantly reduced PACU LOS, whereas both paracetamol and lidocaine reduced hospital LOS. Intravenous nonopioid analgesics and adjuvants are crucial in multimodal anaesthesia, reducing opioid consumption and enhancing postoperative care in adult surgical patients with obesity. CRD42023399373 (PROSPERO). [ABSTRACT FROM AUTHOR]

With the introduction of fentanyl and xylazine in the drug supply market, injection‐related skin injuries and wounds are becoming more common. Xylazine is an alpha‐2 adrenergic agonist thought to cause deep ulcerative wounds due to peripheral vasoconstriction leading to poor wound healing. This case series describes four patients with injection drug use leading to severe xylazine‐related skin injuries who were treated between 2022 and 2023. This paper provides visualization of the extent and severity of these "tranq wounds," as well as the healing progression when receiving medical treatment, addiction treatment, and wound care. Medical treatment and overall care were complicated by individual social determinants of health. Further understanding of xylazine‐related wounds is necessary as xylazine continued to be an emerging threat in the United States. Though some reports in the literature capture the appearances, only few displayed progressive improvements or success in treatment given the challenging nature of treating this high‐risk population. [ABSTRACT FROM AUTHOR]

ABSTRACT Salbutamol is a short‐acting and selective beta‐2 adrenergic agonist. Inhaled (IH) administration of salbutamol is widely used to control lower respiratory tract disease in horses. Here, we estimated the pharmacokinetic parameters of salbutamol after a single intravenous (IV) or IH administration in six horses, and we statistically analysed the detection times with various dosing regimens. Plasma and urine concentrations of salbutamol were measured by liquid chromatography–tandem mass spectrometry, and data were modelled by using a nonlinear mixed effect model followed by Monte Carlo simulation (MCS). With IH salbutamol, the maximum plasma concentration was 0.12 ± 0.06 ng/mL at 0.29 ± 0.17 h after administration. Typical values were, for clearance, 1.53 L/kg/h; distribution volume at steady state, 5.43 L/kg; terminal half‐life, 6.06 h; IH bioavailability, 19.0%; and urine to plasma ratio, 2057. Statistically estimated 95th percentile detection times in the urine at levels below the international screening limit (0.5 ng/mL) proposed by the International Federation of Horseracing Authorities, as simulated in 5000 horses by MCS, were 44 h after 1.6 μg/kg q 24 and 54 h after 1.6 μg/kg q 4 h over a 3‐day IH administration period. [ABSTRACT FROM AUTHOR]

The field of interventional pulmonology has grown immensely and is increasingly recognized as a subspecialty. The new procedures introduced in the last decade pose unique challenges, and anesthesiologists need to readapt to their specific demands. In this review, we extensively discuss the pathophysiology, technical aspects, preprocedural preparation, anesthetic management, and postprocedural challenges of many new procedures such as navigational bronchoscopy, endobronchial valve deployment, and bronchial thermoplasty. Majority of these procedures are performed under general anesthesia with an endotracheal tube. Total intravenous anesthesia with rocuronium as a muscle relaxant seems to be the standard US practice. The easy availability and proven safety and efficacy of sugammadex as a reversal agent of rocuronium has decreased the need for high-dose remifentanil as an agent to avoid muscle relaxants. Additional research is available with regard to the utility of nebulized lidocaine and is discussed. Finally, two newer drugs administered for conscious sedation (typically without the need of an anesthesiologist) are likely to gain popularity in the future. Remimazolam is a new short-acting benzodiazepine with a relatively faster offset of clinical effects. Dexmedetomidine, a selective adrenergic agonist, is increasingly employed in bronchoscopy as a sedative during bronchoscopic procedures. [ABSTRACT FROM AUTHOR]

Xylazine, a veterinary sedative, has emerged as a concerning element in the landscape of substance use in the United States. This integrative review synthesizes evidence from a systematic examination of 14 selected studies conducted between 2008 and 2023. The primary objective is to comprehensively understand the epidemiology and prevalence of xylazine use, particularly its involvement in drug-related deaths, regional variations, national impact, co-occurrence with opioids, and challenges associated with detection and intervention. The results underscore stark regional disparities in xylazine prevalence. West Virginia and Miami-Dade County have experienced alarming surges in xylazine-involved drug-related deaths. Nationally, its influence extends beyond regional boundaries, predominantly affecting white males in the Northeast. The co-occurrence of xylazine with opioids, especially fentanyl and heroin, significantly amplifies the risks of fatal overdoses. Detecting xylazine presents formidable challenges due to its frequent presence alongside other substances, necessitating enhanced surveillance and more effective detection methods. User perspectives emerge as pivotal, emphasizing the importance of user-informed harm reduction strategies. In conclusion, this review has significant policy implications. Tailored, region-specific strategies are imperative to address the diverse prevalence of xylazine use. A nationwide response is indispensable, prioritizing harm reduction initiatives, enhanced detection methods, and active user engagement. The multifaceted nature of the xylazine issue requires comprehensive approaches to mitigate its profound risks effectively. Policymakers are urged to consider regional disparities and the co-occurrence of xylazine with opioids when crafting targeted interventions. Immediate, user-informed harm reduction is vital to address the evolving landscape of xylazine use in the United States. [ABSTRACT FROM AUTHOR]

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Background Succinylcholine is commonly used as a neuromuscular blocker during electroconvulsive therapy (ECT), but it can induce myalgia in patients. Dexmedetomidine, an alpha-2 adrenergic agonist, may mitigate this side effect. This study investigates the efficacy of dexmedetomidine in reducing succinylcholine-induced myalgia in ECT patients. Materials and Methods We conducted a randomized, double-blind clinical trial involving 100 patients scheduled for ECT. Participants were divided into two groups: the dexmedetomidine group (n=50) received 1 µg/kg dexmedetomidine prior to succinylcholine administration, while the control group (n=50) received a placebo. Myalgia was assessed using a numerical rating scale (0-10) 24 hours post-ECT. Results The dexmedetomidine group reported a significantly lower incidence of myalgia (20%) compared to the control group (48%) (p < 0.01). The mean myalgia score in the dexmedetomidine group was 2.1 ± 1.3, while the control group had a mean score of 4.8 ± 2.5 (p < 0.01). No significant adverse effects were noted in either group. Conclusion Dexmedetomidine significantly reduces the incidence and severity of succinylcholine-induced myalgia in patients undergoing ECT. This finding supports the use of dexmedetomidine as a premedication option in this population. [ABSTRACT FROM AUTHOR]

Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistance training impractical. The beta2‐adrenergic receptor has been highlighted as a potential target to promote muscle hypertrophy and treat atrophic conditions. Here, we investigate the proteomic changes associated with beta2‐adrenergic‐mediated muscle hypertrophy, using resistance training as a hypertrophic comparator. We utilize MS‐based proteomics to map skeletal muscle proteome remodeling in response to beta2‐adrenergic stimulation or resistance training as well as cell model validation. We report that beta2‐adrenergic stimulation mimics multiple features of resistance training in proteome‐wide remodeling, comprising systematic upregulation of ribosomal subunits and concomitant downregulation of mitochondrial proteins. Approximately 20% of proteins were regulated in both conditions, comprising proteins involved in steroid metabolism (AKR1C1, AKR1C2, AKRC1C3), protein‐folding (SERPINB1), and extracellular matrix organization (COL1A1, COL1A2). Among overall most significantly upregulated proteins were kelch‐like family members (KLHL) 40 and 41. In follow‐up experiments, we identify KLHL41 as having novel implications for beta2‐adrenergic‐mediated muscle hypertrophy. Treating C2C12 cells with beta2‐agonist for 96 h increased myotube diameter by 48% (p < 0.001). This anabolic effect was abolished by prior knockdown of KLHL41. Using siRNA, KLHL41 abundance was decreased by 60%, and the anabolic response to beta2‐agonist was diminished (+ 15%, i.e., greater in the presence of KLHL41, knock‐down × treatment: p = 0.004). In conclusion, protein‐wide remodeling induced by beta2‐adrenergic stimulation mimics multiple features of resistance training, and thus the beta2‐adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we evaluate dexmedetomidine as a potential alternative to xylazine for providing general anesthesia in pigs. Xylazine, a commonly used alpha-2 (α-2) adrenergic agonist, provides sedative, muscle relaxant, and analgesic effects with rapid onset but is often associated with side effects such as bradycardia, respiratory depression, and hypotension, which can limit its use. Dexmedetomidine, a more selective α-2 agonist, is gaining popularity in veterinary medicine for its enhanced sedation and analgesia, despite similar risks of cardiorespiratory suppression. We proposed that combining dexmedetomidine with tiletamine/zolazepam and ketamine (TKD) could reduce drug dosages, potentially minimizing side effects. While tiletamine/zolazepam, ketamine, and xylazine (TKX) is widely used in pigs, research on TKD is limited. This study aimed to compare the anesthetic efficacy of TKD with TKX in pigs undergoing short-term (45-min) and long-term (90-min) surgeries, hypothesizing that TKD would provide anesthesia comparable to, or even better than, TKX for both durations. This study aimed to evaluate dexmedetomidine as an alternative to xylazine in pigs. We compared TKD (0.05 mL/kg) to TKX (0.05 mL/kg) in 20 male pigs undergoing unilateral cryptorchid castration (short-term, 45-min) or bilateral cryptorchid castration (long-term, 90-min). We hypothesized that TKD would be comparable to TKX for both short-term and long-term anesthesia. Monitored parameters were classified into duration and physiological categories, including induction and recovery times, reflexes, heart rate (HR), respiratory rate (RR), arterial blood pressure, oxygen saturation (%SpO2), end-tidal carbon dioxide (ETCO2), and body temperature (TEMP). Isoflurane levels were also recorded, if used. Results showed no significant differences in duration parameters between TKD and TKX for either short-term or long-term anesthesia (induction: 1 min; recovery: 18–35 min). Physiological parameters were mostly similar between groups, although TKD caused slightly higher blood pressure during short-term anesthesia. Isoflurane levels (0.1–0.6%) were comparable between groups. Overall, the results suggest that TKD provides anesthesia comparable to TKX in pigs undergoing unilateral or bilateral cryptorchid surgery requiring short-term and long-term anesthesia. [ABSTRACT FROM AUTHOR]

Background: Tourette disorder (TD) is a neurodevelopmental disorder characterized by childhood onset of tics lasting more than one year, with multiple motor tics and at least one phonic tic at some point during the course of the symptoms. Treatment of tics may include psychoeducation, non-pharmacologic treatment, or pharmacologic treatment. We review pharmacologic treatment here. Methods: We performed a literature review on pharmacologic treatments for TD. Results: There is no current evidence to suggest that medications impact the prognosis of tic disorders, so current clinical guidelines recommend reassurance of the patient and family and monitoring if there is no change in function or quality of life due to tics. If treatment is indicated, it must be chosen based on the needs of each individual patient. Comprehensive behavioral intervention for tics (CBIT) is considered first-line management for most individuals with bothersome tics, especially if they are mild to moderate in severity. Pharmacotherapy should be considered when tics are impairing daily functioning, causing social problems, accompanied by other neuropsychiatric symptoms, or when the patient is not likely to benefit from CBIT. Current recommended pharmacotherapy options include alpha-2 adrenergic agonists, dopamine modulators, GABAergic medications, dopamine depleters, and botulinum toxin injections. Additionally, there are other novel medications that are being studied in ongoing clinical trials. Conclusions: This review summarizes available pharmacotherapy options for TD in children. It provides an overview of new medications and offers guidance to physicians when selecting appropriate treatments. If medications are indicated for tic management, treatment should be chosen based on the needs of the individual patient. [ABSTRACT FROM AUTHOR]

Background: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1 R,2 S/1 S,2 R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. Objective: In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion. Methods: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist just prior to the beginning of each behavioral testing session. Results: While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Conclusions: Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer's disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX's protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses. [ABSTRACT FROM AUTHOR]

Adrenergic modulation of voltage gated Ca2+ currents is a context specific process. In the heart Cav1.2 channels initiate excitation–contraction coupling. This requires PKA phosphorylation of the small GTPase Rad (Ras associated with diabetes) and involves direct phosphorylation of the Cav1.2 α1 subunit at Ser1700. A contributing factor is the proximity of PKA to the channel through association with A-kinase anchoring proteins (AKAPs). Disruption of PKA anchoring by the disruptor peptide AKAP-IS prevents upregulation of Cav1.2 currents in tsA-201 cells. Biochemical analyses demonstrate that Rad does not function as an AKAP. Electrophysiological recording shows that channel mutants lacking phosphorylation sites (Cav1.2 STAA) lose responsivity to the second messenger cAMP. Measurements in cardiomyocytes isolated from Rad−/− mice show that adrenergic activation of Cav1.2 is attenuated but not completely abolished. Whole animal electrocardiography studies reveal that cardiac selective Rad KO mice exhibited higher baseline left ventricular ejection fraction, greater fractional shortening, and increased heart rate as compared to control animals. Yet, each parameter of cardiac function was slightly elevated when Rad−/− mice were treated with the adrenergic agonist isoproterenol. Thus, phosphorylation of Cav1.2 and dissociation of phospho-Rad from the channel are local cAMP responsive events that act in concert to enhance L-type calcium currents. This convergence of local PKA regulatory events at the cardiac L-type calcium channel may permit maximal β-adrenergic influence on the fight-or-flight response. [ABSTRACT FROM AUTHOR]

Background Hemodynamic stability is crucial during coronary artery bypass grafting (CABG) surgery to reduce perioperative complications. Dexmedetomidine, an alpha-2 adrenergic agonist, has been increasingly used for its sedative, analgesic, and sympatholytic properties. This study aims to evaluate the effects of intraoperative dexmedetomidine administration on hemodynamic parameters during CABG surgery. Materials and Methods A randomized controlled trial was conducted on 120 patients undergoing elective CABG surgery. Patients were randomly assigned into two groups: Group D (dexmedetomidine, n=60) and Group C (control, n=60). Group D received a loading dose of dexmedetomidine (0.5 μg/kg) followed by a maintenance infusion of 0.4 μg/kg/h until the end of surgery. Group C received an equivalent volume of saline as placebo. Hemodynamic parameters, including heart rate (HR), mean arterial pressure (MAP), and cardiac output (CO), were recorded at baseline, after induction, during cardiopulmonary bypass, and postoperatively. Statistical analysis was performed using ANOVA and t-tests. Results The administration of dexmedetomidine significantly reduced HR and MAP compared to the control group. At the end of surgery, Group D showed a 15% reduction in HR (p<0.001) and a 20% decrease in MAP (p<0.001) compared to baseline. Additionally, CO was better maintained in Group D, with an average CO of 5.5 L/min compared to 4.8 L/min in Group C (p=0.03). The incidence of intraoperative hypotension was lower in Group D (10%) compared to Group C (25%) (p=0.02). Postoperative recovery was also smoother in Group D, with a lower requirement for vasoactive drugs. Conclusion Intraoperative administration of dexmedetomidine during CABG surgery significantly improves hemodynamic stability, reducing the incidence of intraoperative hypotension and maintaining cardiac output. Dexmedetomidine may be a valuable adjunct in managing patients undergoing cardiac surgery. [ABSTRACT FROM AUTHOR]

Introduction: Vibegron is a selective β3‐adrenergic receptor agonist that was approved by the US Food and Drug Administration in December 2020 for the treatment of overactive bladder in adults. This retrospective study assessed US pharmacy claims data to evaluate the real‐world adherence and persistence of vibegron compared with mirabegron and with anticholinergics. Materials and Methods: This analysis used the Optum Research Database to identify adults with ≥1 pharmacy claim for vibegron, mirabegron, or an anticholinergic from April 1, 2021, to August 31, 2022. Patients had ≥ 90 days of continuous commercial or Medicare medical and pharmacy coverage preindex and ≥ 60 days of continuous pharmacy coverage postindex. Two independent propensity‐score models matched patients treated with (1) vibegron versus mirabegron and (2) vibegron versus anticholinergics on key variables such as demographics and clinical characteristics, index copay, days' supply, and time of entry into analysis (index quarter). Adherence was measured by proportion of days covered (PDC) from index to the end of follow‐up and was defined as PDC ≥ 80%. Persistence was defined as days to discontinuation of index medication (first 30‐day gap) or end of follow‐up. Results: The matched vibegron and mirabegron cohorts included 4921 and 9842 patients, respectively, and the matched vibegron and anticholinergic cohorts included 4676 and 9352 patients, respectively. Patients receiving vibegron had greater mean PDC versus patients receiving mirabegron (0.67 vs. 0.64, respectively; p < 0.001) or anticholinergics (0.67 vs. 0.58; p < 0.001). A greater percentage of patients receiving vibegron were adherent versus those receiving mirabegron (49.0% vs. 45.1%, respectively; p < 0.001) or anticholinergics (49.1% vs. 38.5%; p < 0.001). Persistence was longer with vibegron compared with both mirabegron (median [95% CI], 171 [159–182] vs. 128 [122–137] days, respectively; p < 0.001) and anticholinergics (172 [159–183] vs. 91 [91] days; p < 0.001). Conclusion: In this retrospective analysis of pharmacy claims data, patients receiving vibegron exhibited significantly higher adherence and demonstrated longer persistence in comparison to matched patient cohorts receiving either mirabegron or anticholinergics. [ABSTRACT FROM AUTHOR]

Sepsis/septic shock activates the sympathetic nervous system (SNS) to deal with the infection stress. However, an imbalanced or maladaptive response due to excessive or uncontrolled activation characterizes autonomic dysfunction. Our hypothesis was that reducing this excessive activation of the autonomic nervous system would impact positively in sepsis. Using ganglionic blockers as a pharmacological approach, the main aim of the present report was to assess the role of ganglionic transmission in the vascular dysfunction associated with sepsis. Sepsis was induced in rats by cecal ligation and puncture (CLP). One hour after CLP surgery, rats were treated subcutaneously with hexamethonium (15 mg/kg; ganglionic blocker), pentolinium (5 mg/kg; a blocker with a higher selectivity for sympathetic ganglia compared to hexamethonium), or vehicle (PBS). Basal blood pressure and the response to adrenergic agonists were evaluated at 6 and 24 h after CLP surgery. Reactivity to vasoconstrictors, nitric oxide (NO) synthase 2 (NOS-2) expression, IL-1 and TNF plasma levels, and density of α1 adrenergic receptors were evaluated in the aorta 24 h after CLP. Septic shock resulted in hypotension and hyporesponsiveness to norepinephrine and phenylephrine, increased plasma cytokine levels and NOS-2 expression in the aorta, and decreased α1 receptor density in the same vessel. Pentolinium but not hexamethonium recovered responsiveness and α1 adrenergic receptor density in the aorta. Both blockers normalized the in vivo response to vasoconstrictors, and reduced plasma IL-1 and NOx levels and NOS-2 expression in the aorta. Blockade of ganglionic sympathetic transmission reduced the vascular dysfunction in experimental sepsis. This beneficial effect seems to be, at least in part, due to the preservation of α1 adrenergic receptor density and to reduced NOS-2 expression and may lead to adjuvant ways to treat human sepsis. [ABSTRACT FROM AUTHOR]

The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide. [ABSTRACT FROM AUTHOR]

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle‐aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age‐related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3‐adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18‐month‐old) C57BL/6JN mice. Sustained β3‐AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)‐dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1‐independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose‐dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3‐AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age‐related metabolic dysfunction. [ABSTRACT FROM AUTHOR]

The article explores the potential use of curcumin nanoparticles (CUR-NPs) as a treatment for bronchial remodeling in asthma. The study shows that CUR-NPs improve the uptake and accumulation of curcumin in cells and decrease the expression of proteins involved in airway remodeling. However, the study has limitations, such as the lack of assessment of cell phenotype and the need for further investigation into the effects of CUR-NPs on cell proliferation and migration. The researchers suggest that more studies are needed to fully evaluate the effectiveness of CUR-NPs as a treatment for airway remodeling in asthma. [Extracted from the article]

Background Regional anesthesia is preferred for lower abdominal surgeries due to its ability to keep patients awake and reduce airway management issues. While 0.5% hyperbaric bupivacaine is commonly used, it does not ensure prolonged postoperative analgesia. Clonidine, an α2 adrenergic agonist, has shown promise in prolonging sensory and motor blockade when used as an adjuvant. This study evaluates the efficacy of intrathecal clonidine as an adjuvant to 0.5% bupivacaine in prolonging analgesia for lower abdominal surgeries. Methods This prospective, randomized controlled study was conducted at MGM Medical College, Navi Mumbai, from November 2021 to September 2023. Sixty patients undergoing elective lower abdominal surgeries were randomly allocated into two groups of 30 each. Group 1 received 3 ml of 0.5% heavy bupivacaine with 30 µg clonidine, while Group 2 received 3 ml of 0.5% heavy bupivacaine with 0.2 ml saline. Onset and duration of sensory and motor blockade, duration of analgesia, hemodynamic parameters, and complications were recorded and analyzed statistically. Results Group 1 showed a significantly quicker onset of analgesia (2.25±0.18 minutes) and motor blockade (8.51±0.175 minutes) compared to Group 2. The duration of motor blockade (220±9.55 minutes) and analgesia (650±9.22 minutes) was significantly longer in Group 1. Hemodynamic parameters remained stable in both groups, but Group 1 experienced a higher incidence of mild postoperative complications such as nausea, sedation, and dry mouth. Conclusion Intrathecal clonidine as an adjuvant to 0.5% bupivacaine significantly prolongs the duration of sensory and motor blockade, as well as postoperative analgesia, making it a valuable addition to regional anesthesia protocols for lower abdominal surgeries. Future studies with larger, multicenter designs and extended follow-up periods are recommended to further validate these findings. [ABSTRACT FROM AUTHOR]

The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ‐amino‐butyric acid, arginine‐vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary‐derived adenylate cyclase‐activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin‐releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of β‐adrenergic receptors in SCN and a mouse SCN‐derived immortalized cell line by immunohistochemical, immuno‐cytochemical, and pharmacological techniques. We then characterized the effects of β‐adrenergic agonists and antagonists on cAMP‐regulated element (CRE) signaling. Moreover, we investigated the interaction of β‐adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of β‐blockers applied as anti‐hypertensive drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Administration of dexmedetomidine alleviates social deficits in BTBR mice. • Dexmedetomidine acts on the prelimbic cortex and influence social behavior. • Abnormal elevation of IL-6 in the prelimbic cortex impairs social communication. • Dexmedetomidine improves social deficits through NF-κb/IL-6 signal pathway. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals' daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD. [ABSTRACT FROM AUTHOR]

Most α2-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed virtual screening for human α2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity. Compound P300–2342 and its three analogs significantly decreased the locomotor activity of mice (p < 0.05). Furthermore, P300–2342 and its three analogs inhibited the binding of [3H] Rauwolscine with IC50 values of 7.72 ± 0.76 and 12.23 ± 0.11 μM, respectively, to α2A-AR and α2B-AR. In α2A-AR-HEK293 cells, P300–2342 decreased forskolin-stimulated cAMP production without increasing cAMP production, which indicated that P300–2342 activated α2A-AR with coupling to the Gαi/o pathway but without Gαs coupling. P300–2342 exhibited no agonist but slight antagonist activities in α2B-AR. Similar results were obtained for the analogs of P300–2342. The docking results showed that P300–2342 formed π-hydrogen bonds with Y394, V114 in α2A-AR, and V93 in α2B-AR. Three analogs of P300–2342 formed several π-hydrogen bonds with V114, Y196, F390 in α2A-AR, and V93 in α2B-AR. We believe that these molecules can serve as leads for the further optimization of α2A-AR agonists with potentially few side effects. [ABSTRACT FROM AUTHOR]

Background: In supraclavicular brachial plexus block, to prolong the duration of analgesia, many adjuvants have been tried in the past in many studies but an ideal adjuvant remains yet to be discovered. Dexmedetomidine, a selective Alfa-2 adrenergic agonist when added to local anesthetic has been reported to prolong the block duration and post-operative analgesia in various regional blocks. Aims and Objectives: The aims and objectives are to study the onset and duration of sensory and motor blockade, postoperative analgesia, and hemodynamic effects of addition of dexmedetomidine with ropivacaine in supraclavicular brachial plexus block. Materials and Methods: Sixty patients aged between 18 and 60 years, American Society of Anesthesiologists class I and II, of both sexes, scheduled for upper limb surgery under supraclavicular brachial plexus block were randomly allocated into 2 groups. Group-A received 20 mL of 0.5% ropivacaine in brachial plexus block with 1 µg/kg dexmedetomidine as adjuvant perineurally and Group-B received 20 mL 0.5% ropivacaine in brachial plexus block with dexmedetomidine intravenous infusion at 1 µg/kg over 10 min. Intraoperatively non-invasive blood pressure, heart rate, SpO2, and sedation were recorded every 5 min for the first 10 min and every 15 min thereafter till the end. Time of first rescue analgesic, intensity of postoperative pain, and total analgesic required were recorded. Results: Onset of sensory and motor block was faster in Group-A than Group-B. Duration of analgesia was prolonged in Group-A than Group-B. Hemodynamic stability was better maintained in Group-A than Group-B. Sedation was better in Group B. Conclusion: Dexmedetomidine as adjuvant to ropivacaine in supraclavicular brachial plexus block is more efficacious in providing faster onset of motor and sensory blocks and prolonging duration of postoperative analgesia with better hemodynamic stability. [ABSTRACT FROM AUTHOR]

Obesity is a complex medical condition caused by a positive imbalance between calorie intake and calorie consumption. Brown adipose tissue (BAT), along with the newly discovered "brown-like" adipocytes (called beige cells), functions as a promising therapeutic tool to ameliorate obesity and metabolic disorders by burning out extra nutrients in the form of heat. Many studies in animal models and humans have proved the feasibility of this concept. In this review, we aim to summarize the endeavors over the last decade to achieve a higher number/activity of these heat-generating adipocytes. In particular, pharmacological compounds, especially agonists to the β3 adrenergic receptor (β3-AR), are reviewed in terms of their feasibility and efficacy in elevating BAT function and improving metabolic parameters in human subjects. Alternatively, allograft transplantation of BAT and the transplantation of functional brown or beige adipocytes from mesenchymal stromal cells or human induced pluripotent stem cells (hiPSCs) make it possible to increase the number of these beneficial adipocytes in patients. However, practical and ethical issues still need to be considered before the therapy can eventually be applied in the clinical setting. This review provides insights and guidance on brown- and beige-cell-based strategies for the management of obesity and its associated metabolic comorbidities. [ABSTRACT FROM AUTHOR]

The article focuses on the effects of xylazine, particularly when combined with fentanyl, on dopamine release and behavior. Topics include the mechanism of xylazine's impact on dopamine via α2 adrenergic receptors, the interaction between fentanyl and xylazine in affecting dopamine levels, and the implications for understanding opioid use disorder and its treatment.

BackgroundUrgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women.MethodsThe TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function.DiscussionThe TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age.Trial registrationClinicalTrials.gov NCT05362292. Registered on May 5, 2022.

OBJECTIVE To determine a conversion factor for use when switching from dexmedetomidine infusion to enteral clonidine in critically ill neonates. METHODS This was an observational, retrospective review of conversions from dexmedetomidine to clonidine, performed in a neonatal intensive care unit (NICU) between January 2020 and December 2021. Both initial conversion factors and those resulting after a 48-hour titration period were examined. Sedation and withdrawal scores were measured, and doses were titrated based on a standardized practice within the unit. RESULTS A total of 43 dexmedetomidine to clonidine conversions were included. The median (IQR) dexmedetomidine dose prior to conversion was 17.4 (11.3-24.0) mcg/kg/day (0.7 mcg/kg/hr) and the median (IQR) enteral clonidine dose post titration was 7.8 (4.7-9.3) mcg/kg/day (2 mcg/kg every 6 hours). This equated to a post-titration conversion factor of approximately 0.42. All neonates had also received opioid infusions while on dexmedetomidine and 60% were on concurrent opioids at the time of the clonidine conversion. CONCLUSIONS Neonatal clinicians may find the conversion factor identified in this study a useful starting point when converting from dexmedetomidine infusion to enteral clonidine in practice and should be reminded of the most important steps in conversions (monitoring and follow-up) owing to the variability in this patient group. More studies are needed to elucidate the impact of patient-specific factors on this conversion process. [ABSTRACT FROM AUTHOR]

Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention. [ABSTRACT FROM AUTHOR]

Background and Aim: Electroconvulsive therapy (ECT) is an effective intervention for psychiatric patients. Succinylcholine is considered the drug of choice for muscle relaxation for ECT. Significant adverse effects of succinylcholine include fasciculation and myalgia. Dexmedetomidine is a highly selective a-2 adrenergic agonist. This study aims to determine the efficacy of a low dose of dexmedetomidine in reducing succinylcholine-induced myalgia in patients receiving ECT. Methods: This randomised controlled trial was conducted on 100 patients, aged 18-65 years, undergoing ECT, who were randomly allocated into two groups with an allocation ratio of 1:1. Group D received intravenous (IV) dexmedetomidine 0.25 µg/kg, and Group C received IV normal saline (0.9%). Patients' self-reported myalgia scores were measured after 60 min of the procedure. Fasciculations were noted after IV succinylcholine administration. Heart rate (HR) and mean blood pressure (MBP) were measured at baseline, after infusion (5 min) and after ECT (0, 2.5, 5, 10, 15, 30 min). Continuous data were analysed using a Student's t-test for two-group comparisons, a mixed model analysis of variance for group comparisons and various time point analyses. Categorical data were analysed using the Chi-square/Fisher's exact test. Results: There were no differences between the groups regarding demographics. Myalgia and fasciculations were less in Group D than in Group C (P < 0.001). MBP and HR changes were comparable (P > 0.05). Conclusion: A low dose of dexmedetomidine (0.25 µg/kg) effectively reduces myalgia and fasciculations due to succinylcholine in patients undergoing electroconvulsive therapy. [ABSTRACT FROM AUTHOR]

Rosacea is a chronic, inflammatory condition of facial skin. Treatment of rosacea should be based on its presenting features i.e. inflammatory lesions, erythema, phymas and/or telangiectasia. First-line treatment options for inflammatory lesions include metronidazole, azelaic acid, ivermectin and modified-release doxycycline, but topical formulations of minocycline foam and encapsulated benzoyl peroxide are also now available. Persistent erythema can be treated with topical α-adrenergic receptor agonists or light-based therapies. Approved pharmacological options for phymas and telangiectasia are limited; nonpharmacological procedures should be considered in some cases. [ABSTRACT FROM AUTHOR]

A new detection platform based on a hydroxylated covalent organic framework (COF) integrated with liquid chromatography–tandem mass spectrometry (LC–MS/MS) was constructed and used for detecting adrenergic receptor agonists (ARAs) residues in milk. The hydroxylated COF was prepared by polymerization of tris(4-aminophenyl)amine and 1,3,5-tris(4-formyl-3-hydroxyphenyl)benzene and applied to solid-phase extraction (SPE) of ARAs. This hydroxylated COF was featured with hierarchical flower-like morphology, easy preparation, and copious active adsorption sites. The adsorption model fittings and molecular simulation were applied to explore the potential adsorption mechanism. This detection platform was suitable for detecting four α2- and five β2-ARAs residues in milk. The linear ranges of the ARAs were from 0.25 to 50 µg·kg−1; the intra-day and the inter-day repeatability were in the range 2.9–7.9% and 2.0–10.1%, respectively. This work demonstrates this hydroxylated COF has great potential as SPE cartridge packing, and provides a new way to determine ARAs residues in milk. [ABSTRACT FROM AUTHOR]

This study compared cardiovascular and respiratory effects of dexmedetomidine and xylazine in total intravenous anesthesia with propofol, ketamine, and lidocaine. Twenty-one female dogs were submitted to ovariohysterectomy, premedicated with acepromazine and anesthetized with propofol at a variable rate. The dogs were intubated and supplemented with 100% oxygen in a circuit without rebreathing gases in spontaneous ventilation. They were divided into three groups (n=21) after induction: control (CON) with ketamine (2 mg/kg + 0.6 mg/kg/h) and lidocaine (2 mg/kg + 3 mg/kg/h), DEX and XIL with the same drugs as CON, associated with dexmedetomidine (2 µg/kg + 1 µg/kg/h) or xylazine (0.2 mg/kg + 0.1 mg/kg/h). Propofol consumption, fentanyl analgesic rescue, and cardiorespiratory and blood gas parameters were evaluated during anesthesia. The DEX group had a lower consumption of propofol (0.16 ± 0.09 mg/kg/min) compared to CON (0.24 ± 0.09 mg/kg/min), both not differing from XIL (0.23 ± 0.09 mg/kg/min). The mean arterial pressure was higher after the initial bolus in DEX (107 ± 8 mmHg) and XIL (96 ± 11 mmHg) compared to the CON group (80 ± 10 mmHg). Higher accumulation of arterial carbon dioxide and a decrease in pH were observed in the CON group. The total number of fentanyl rescues did not differ between DEX (7) and XIL (6) and were lower than CON (16). Therefore, dexmedetomidine and xylazine reduced intraoperative fentanyl consumption compared to ketamine and lidocaine infusion alone. However, only dexmedetomidine promoted lower propofol consumption and higher blood pressure values. [ABSTRACT FROM AUTHOR]

To clarify the regulation of drug absorption by the enteric nervous system, we investigated how adrenergic agonists (adrenaline (ADR), clonidine (CLO), dobutamine (DOB)) and dibutyryl cAMP (DBcAMP) affected P-glycoprotein (P-gp) function by utilizing isolated rat jejunal sheets and Caco-2 cell monolayers. ADR and CLO significantly decreased the secretory transport (P app total) of rhodamine-123 and tended to decrease the transport via P-gp (P app P − gp) and passive transport (P app passive). In contrast, DBcAMP significantly increased and DOB tended to increase P app total and both tended to increase P app P − gp and P app passive. Changes in P-gp expression on brush border membrane by adrenergic agonists and DBcAMP were significantly correlated with P app P − gp , while P-gp expression was not changed in whole cell homogenates, suggesting that the trafficking of P-gp would be responsible for its functional changes. P app passive was inversely correlated with transmucosal or transepithelial electrical resistance, indicating that adrenergic agonists affected the paracellular permeability. Adrenergic agonists also changed cAMP levels, which were significantly correlated with P app P − gp. Furthermore, protein kinase A (PKA) or PKC inhibitor significantly decreased P app P − gp in Caco-2 cell monolayers, suggesting that they would partly contribute to the changes in P-gp activity. In conclusion, adrenergic agonists regulated P-gp function and paracellular permeability, which would be caused via adrenoceptor stimulation. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate efficacy and safety of beta-3 adrenergic agonists in adults with neurogenic lower urinary tract dysfunction. Materials and Methods: According to a protocol (CRD42022350079), we searched multiple data sources for published and unpublished randomized controlled trials (RCTs) up to 2nd August 2022. Two review authors independently screened studies and abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence (CoE). Results: We found data to inform two comparisons: beta-3 adrenergic agonists versus placebo (4 RCTs) and anticholinergics (2 RCTs). Only mirabegron was used for intervention in all included studies. Compared to placebo, beta-3 adrenergic agonists may have a clinically unimportant effect on urinary symptoms score (mean difference [MD] -2.50, 95% confidence interval [CI] -4.78 to -0.22; I2=92%; 2 RCTs; 192 participants; low CoE) based on minimal clinically important difference of 3. We are very uncertain of the effects of beta-3 adrenergic agonists on quality of life (MD 10.86, 95% CI 1.21 to 20.50; I2=41%; 2 RCTs; 98 participants; very low CoE). Beta-3 adrenergic agonists may result in little to no difference in major adverse events (cardiovascular adverse events) (risk ratio 0.57, 95% CI 0.14 to 2.37; I2=0%; 4 RCTs; 310 participants; low CoE). Compared to anticholinergics, no study reported urinary symptom scores and quality of life. There were no major adverse events (cardiovascular adverse events) in either study group (1 study; 60 participants; very low CoE). Conclusions: Compared to placebo, beta-3 adrenergic agonists may have similar effects on urinary symptom scores and major adverse events. There were uncertainties about their effects on quality of life. Compared to anticholinergics, we are either very uncertain or have no evidence about urinary symptom scores, quality of life, and major adverse events. [ABSTRACT FROM AUTHOR]

Background: A high proportion of patients who undergo surgery continue to suffer from moderate to severe pain in the early postoperative period despite advances in pain management strategies. Previous studies suggest that clonidine, an alpha2 adrenergic agonist, administered during the perioperative period could reduce acute postoperative pain intensity and opioid consumption. However, these studies have several limitations related to study design and sample size and hence, further studies are needed. Aim: To investigate the effect of a single intravenous (IV) dose of intraoperative clonidine on postoperative opioid consumption, pain intensity, nausea, vomiting and sedation after endometriosis and spine surgery. Methods: Two separate randomised, blinded, placebo‐controlled trials are planned. Patients scheduled for endometriosis (CLONIPAIN) will be randomised to receive either 150 μg intraoperative IV clonidine or placebo (isotonic saline). Patients undergoing spine surgery (CLONISPINE) will receive 3 μg/kg intraoperative IV clonidine or placebo. We aim to include 120 patients in each trial to achieve power of 90% at an alpha level of 0.05. Outcomes: The primary outcome is opioid consumption within the first three postoperative hours. Secondary outcomes include pain intensity at rest and during coughing, nausea, vomiting and sedation within the first two postoperative hours and opioid consumption within the first six postoperative hours. Time to discharge from the PACU will be registered. Conclusion: This study is expected to provide valuable information on the efficacy of intraoperative clonidine in acute postoperative pain management in patients undergoing endometriosis and spine surgery. [ABSTRACT FROM AUTHOR]

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Rationale: Win-paired stimuli can promote risk taking in experimental gambling paradigms in both rats and humans. We previously demonstrated that atomoxetine, a noradrenaline reuptake inhibitor, and guanfacine, a selective α2A adrenergic receptor agonist, reduced risk taking on the cued rat gambling task (crGT), a rodent assay of risky choice in which wins are accompanied by salient cues. Both compounds also decreased impulsive premature responding. Objective: The key neural loci mediating these effects were unknown. The lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC), which are highly implicated in risk assessment, action selection, and impulse control, receive dense noradrenergic innervation. We therefore infused atomoxetine and guanfacine directly into either the lOFC or prelimbic (PrL) mPFC prior to task performance. Results: When infused into the lOFC, atomoxetine improved decision making score and adaptive lose-shift behaviour in males, but not in females, without altering motor impulsivity. Conversely, intra-PrL atomoxetine improved impulse control in risk preferring animals of both sexes, but did not alter decision making. Guanfacine administered into the PrL, but not lOFC, also altered motor impulsivity in all subjects, though in the opposite direction to atomoxetine. Conclusions: These data highlight a double dissociation between the behavioural effects of noradrenergic signaling across frontal regions with respect to risky choice and impulsive action. Given that the influence of noradrenergic manipulations on motor impulsivity could depend on baseline risk preference, these data also suggest that the noradrenaline system may function differently in subjects that are susceptible to the risk-promoting lure of win-associated cues. [ABSTRACT FROM AUTHOR]

Background: Mirabegron, the first ß-3 adrenergic receptor agonist, received approval from the Food and Drug Administration (FDA) in 2012 for the treatment of overactive bladder (OAB). This pharmacovigilance study investigated the safety profile of mirabegron treatment using the US FDA Adverse Event Reporting System (FAERS) database. Methods: This study employed disproportionality analyses, including the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) algorithm, to quantify signals of adverse events associated with mirabegron. Results: From the first quarter of 2012 to the third quarter of 2023, a comprehensive total of 14,356,234 adverse event (AE) reports were submitted to the FDA Adverse Event Reporting System database. Within this dataset, encompassing 18,763 reports specifically associated with mirabegron, healthcare professionals notably contributed 2,902 of these reports. A total of 80 preferred terms (PTs) of interest were identified using both the ROR and information component algorithms. The most common AEs included blood pressure increased, urinary retention, atrial fibrillation, dry mouth, and tachycardia, which were consistent with the product instructions. Unexpected significant AEs, such as arrhythmia, palpitations, dementia, transient ischemic attack, Parkinson's disease, anti-neutrophil cytoplasmic antibody positive vasculitis, lip swelling, and swollen tongue, were also identified. The study findings indicated that the majority of onset time occurred within 30 days (n = 358, 55.68%). However, AEs were still possible after 1 year of mirabegron treatment. Conclusion: This study provided valuable evidence for the real-world safety of mirabegron, helping clinical professionals enhance their understanding of mirabegron's safety in clinical practice. It also contributed valuable evidence for further safety studies on mirabegron. [ABSTRACT FROM AUTHOR]