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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]

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]

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]

Background: When an alpha 2 adrenergic agonist and a local anesthetic are coupled, the analgesic effect's quality and endurance are enhanced. While clonidine's effects on local anesthetics have been thoroughly investigated, there aren't many studies that show how epidural dexmedetomidine affects the same. Materials and Methods: The patients were randomly assigned to two groups, one receiving ropivacaine with clonidine (RC) and the other receiving ropivacaine with dexmedetomidine (RD), Group RC was administered 15 ml of 0.75% ropivacaine with 1 microgram per kilogram of clonidine, while group RD was given 15 ml of 0.75% ropivacaine with 1 microgram per kilogram of dexmedetomidine epidurally. Results: The dexmedetomidine group showed significantly improved start (RD-7.53 ± 1.81, RC-10.93 ± 1.96) and duration (RD-317 ± 29.5, RC-285 ± 37) of sensory blockade sedation. Hemodynamic alterations and the start of motor blockage did not differ significantly. Conclusion: Similar to clonidine, dexmedetomidine works as an efficient adjuvant to ropivacaine for epidural anesthesia at doses of 1 ⃬g/kg. [ABSTRACT FROM AUTHOR]

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.

Background: Xylazine is an alpha-2 adrenergic receptor agonist that has emerged as a contaminant in the illicit drug supply of fentanyl. Xylazine use may be suspected in naloxone-resistant overdoses and atypical, chronic wounds in people who use drugs (PWUD). This case is unique because it is the first case to our knowledge describing wound care for a xylazine-induced wound with a confirmatory xylazine test strip (XTS) in the setting of a syringe services program (SSP) and in the state of Florida. Case presentation: A 43-year-old woman with a past medical history of severe opioid use disorder and stimulant use disorder presented to a student-run clinic at a Miami SSP for wound care. She had multiple ulcerations diffusely over her bilateral forearms with surrounding erythema and warmth. Seven weeks later, she presented to clinic again for wound care because her wounds had progressed. At this visit, a XTS was used to confirm the presence of xylazine in her urine. Wound care management and harm reduction strategies employed at both visits were informed by best clinical judgement due to lack of formal guidelines at the time. Wound outcomes are unknown as the patient has not returned to clinic. Conclusions: Many PWUD at highest risk for acute and chronic health consequences of xylazine-adulterated fentanyl do not have access to healthcare outside of low barrier clinics and SSPs due to lack of insurance or mistrust of the traditional healthcare system due to stigma. There is an urgent need for access to XTS for PWUD and clinical practice guidelines for the treatment of xylazine-related wounds in outpatient clinics. [ABSTRACT FROM AUTHOR]

Introduction: Anaesthetic sedatives are widely used for bronchoscopy and Endobronchial Ultrasound (EBUS) to ensure patient cooperation and minimise patient discomfort. Dexmedetomidine is an α2 adrenergic agonist used for sedation. Aim: To evaluate the safety and efficacy of nebulised dexmedetomidine in EBUS. Materials and Methods: In this randomised doubleblinded controlled study, conducted in the Department of Anaesthesiology and Pulmonary Medicine at Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India from 2020 to 2022, 52 patients aged between 18 and 70 years undergoing EBUS were included. Patients were randomly assigned to the study group (S) and the control group (C). Group C received nebulised lidocaine (2%) 10 mL for 10-15 minutes in a sitting position. Group S received nebulised lidocaine (2%) 8 mL + Dexmedetomidine 2 mL (1 mcg/kg) for 10-15 minutes in a sitting position. Haemodynamic parameters, cough severity scores, patient and operator satisfaction scores, Midazolam requirements, and any complications were recorded and compared. The data were analysed statistically using the Student's t-test and Chi-square test, whichever was feasible. A p-value of <0.05 was considered statistically significant. Results: The demographic parameters including the mean age (years) of 46.3±14.01 in Group C vs. 44.5±14.35 in Group S, mean weight (kg) of 61.6±8.27 in Group C vs. 63.5±10.06 in Group S, and male/female ratio of 12/14 in Group C vs. 9/17 in Group S were comparable. Haemodynamic parameters were better postnebulisation in Group S compared to Group C. The authors observed that the incidence of coughing was significantly higher in Group C compared to Group S (73.1% vs. 46.2%). It was found that Group C had a significantly higher requirement for midazolam doses compared to Group S (53.8% vs. 19.2%). When the patient satisfaction score assessed on the Numerical Rating Scale (NRS) was analysed, it was found that Group S patients were highly satisfied compared to Group C patients, and the difference was highly significant (p-value <0.05). No drug or procedure-related complications were observed in the two groups. Conclusion: The present study demonstrated that nebulised dexmedetomidine-lidocaine was well-tolerated during bronchoscopies under moderated sedation and was associated with stable Haemodynamics, decreased incidence of severe coughing, and a lower consumption of sedation drugs. [ABSTRACT FROM AUTHOR]

Background: The mechanism of pain symptoms in Parkinson's disease (PD) is unclear. Norepinephrine (NE) regulates neuropathic pain through ascending and descending pathways. However, the loss of NE neurons in the brain of patients with PD is obvious, it is speculated that NE is involved in the occurrence of PD pain symptoms. Aims: To investigate the effect of NE on the activation of brain cells through adrenergic α2 receptor, so as to regulate the nociception threshold in a 6‐OHDA‐induced animal model of PD. Methods: PD rat model was established by 6‐OHDA injection (6‐OHDA group). DSP‐4 (or anti‐DBH‐saporin) was used to reduce the NE level of the PD rat brain. The heat sensitivity threshold (HST) and pressure withdrawal threshold (PWT) were measured. Tyrosine hydroxylase and NE in rat brains were detected by Elisa. The percentage of GFAP‐positive cells in the prefrontal cortex, cingulate gyrus and striatum of rats was detected by immunohistochemistry and immunofluorescence. GFAP protein was semiquantified by method of western blot. Then yohimbine and guanfacine were used to increase the NE level in PD rats, and the above experimental changes were observed after drug application. Results: The contents of NE in the brain of 6‐OHDA‐induced PD rats were lower than that of control group. After DSP‐4 (or anti‐DBH‐saporin) injection, PD rats showed the lowest NE level (compared with 6‐OHDA group, p ≤ 0.05), and after yohimbine and guanfacine were applied to 6‐OHDA group, the contents of NE increased in the prefrontal cortex of rats. The HST and PWT of 6‐OHDA group were significantly lower than those of control group, and after DSP‐4 (or anti‐DBH‐saporin) injection, the HST and PWT of rats were lower than those of 6‐OHDA group, and after the administration of yohimbine and guanfacine, both HST and PWT were significantly increased. GFAP‐positive cells increased in prefrontal cortex and anterior cingulate gyrus of 6‐OHDA group rats, and more significantly increased after DSP‐4 (or anti‐DBH‐saporin) injection, and significantly reduced after yohimbine and guanfacine were used. Conclusions: The change of norepinephrine content can affect the activation of prefrontal and cingulate gyrus glial cells and participate in the regulation of nociception threshold in PD rats. Adrenergic α2 receptor agonist and central presynaptic membrane α2 receptor blocker both affect cell activation and improve hyperalgesia. [ABSTRACT FROM AUTHOR]

This article examines the effects of inhaled salbutamol on the cardiac electrical system in children. The study found that salbutamol inhalation led to changes in heart rate and certain electrocardiogram parameters, indicating a potential increased risk of arrhythmias. The study emphasizes the need for cautious use of high doses of salbutamol in children with asthma. The researchers also found that salbutamol can affect the T wave axis in the heart, increasing the risk of cardiac re-entry and arrhythmias. It is important to note that these findings may not apply to all populations and further research is needed. [Extracted from the article]

Stress-induced fetal programming diminishes β2 adrenergic tone, which coincides with intrauterine growth restriction (IUGR) and lifelong metabolic dysfunction. We determined if stimulating β2 adrenergic activity in IUGR-born lambs would improve metabolic outcomes. IUGR lambs that received daily injections of saline or the β2 agonist clenbuterol from birth to 60 days were compared with controls from pair-fed thermoneutral pregnancies. As juveniles, IUGR lambs exhibited systemic inflammation and robust metabolic dysfunction, including greater (p < 0.05) circulating TNFα, IL-6, and non-esterified fatty acids, increased (p < 0.05) intramuscular glycogen, reduced (p < 0.05) circulating IGF-1, hindlimb blood flow, glucose-stimulated insulin secretion, and muscle glucose oxidation. Daily clenbuterol fully recovered (p < 0.05) circulating TNFα, IL-6, and non-esterified fatty acids, hindlimb blood flow, muscle glucose oxidation, and intramuscular glycogen. Glucose-stimulated insulin secretion was partially recovered (p < 0.05) in clenbuterol-treated IUGR lambs, but circulating IGF-1 was not improved. Circulating triglycerides and HDL cholesterol were elevated (p < 0.05) in clenbuterol-treated IUGR lambs, despite being normal in untreated IUGR lambs. We conclude that deficient β2 adrenergic regulation is a primary mechanism for several components of metabolic dysfunction in IUGR-born offspring and thus represents a potential therapeutic target for improving metabolic outcomes. Moreover, benefits from the β2 agonist were likely complemented by its suppression of IUGR-associated inflammation. [ABSTRACT FROM AUTHOR]

The core symptoms of attention deficit hyperactivity disorder (ADHD) are due to the hypofunction of the brain's adrenergic (NE) and dopamine (DA) systems. Drugs that enhance DA and NE neurotransmission in the brain by blocking their transporters or receptors are the current therapeutic strategies. Of late, the emerging results point out the serotonergic (5-HT) system, which indirectly modulates the DA activity in reducing the core symptoms of ADHD. On this basis, second-generation antipsychotics, which utilize 5-HT receptors, were prescribed to children with ADHD. However, it is not clear how serotonergic receptors modulate the DA activity to minimize the symptoms of ADHD. The present study investigates the efficacy of serotonergic and alpha-2 adrenergic receptor manipulation in tackling the core symptoms of ADHD and how it affects the DA neuroreceptors in the brain regions involved in ADHD. Fifteen-day-old male spontaneously hypertensive rats (SHRs) received 5-HT1A agonist (ipsapirone) or 5-HT2A antagonist (MDL 100907) (i.p.) or alpha-2 agonist (GFC) from postnatal days 15 to 42 along with age-matched Wistar Kyoto rats (WKY) (n = 8 in each group). ADHD-like behaviors were assessed using a battery of behavioral tests during postnatal days 44 to 65. After the behavioral tests, rat brains were processed to estimate the density of 5-HT1A, 5-HT2A, DA-D1, and DA-D2 neuroreceptors in the prefrontal cortex, the striatum, and the substantia nigra. All three neuroreceptor manipulations were able to minimize the core symptoms of ADHD in SHRs. The positive effect was mainly associated with the upregulation of 5-HT2A receptors in all three areas investigated, while 5-HT1A was in the prefrontal cortex and the substantia nigra. Further, the DA-D1 receptor expression was downregulated by all three neuroreceptor manipulations except for alpha-2 adrenergic receptor agonists in the striatum and 5-HT2A antagonists in the substantia nigra. The DA-D2 expression was upregulated in the striatum while downregulated in the prefrontal cortex and the substantia nigra. In this animal model study, the 5-HT1A agonist or 5-HT2A antagonist monotherapies were able to curtail the ADHD symptoms by differential expression of DA receptors in different regions of the brain. [ABSTRACT FROM AUTHOR]

Noradrenaline and adrenaline, and their cognate receptors, are currently accepted to participate in cancer progression. They may also participate in cancer initiation, although their role in this phase is much less explored. The aim of this work was to study the influence of adrenergic stimulation in several processes related to breast cancer carcinogenesis, using several adrenergic agonists in the MCF-10A non-tumorigenic breast cells. Activation of the β-adrenoceptors promoted an epithelial phenotype in MCF-10A cells, revealed by an increased expression of the epithelial marker E-cadherin and a decrease in the mesenchymal markers, N-cadherin and vimentin. MCF-10A cell motility and migration were also impaired after the β-adrenoceptors activation. Concomitant with this effect, β-adrenoceptors decrease cell protrusions (lamellipodia and filopodia) while increasing cell adhesion. Activation of the β-adrenoceptors also decreases MCF-10A cell proliferation. When the MCF-10A cells were cultured under low attachment conditions, activation the of β- (likely β2) or of α2-adrenoceptors had protective effects against cell death, suggesting a pro-survival role of these adrenoceptors. Overall, our results showed that, in breast cells, adrenoceptor activation (mainly through β-adrenoceptors) may be a risk factor in breast cancer by inducing some cancer hallmarks, providing a mechanistic explanation for the increase in breast cancer incidences that may be associated with conditions that cause massive adrenergic stimulation, such as stress. [ABSTRACT FROM AUTHOR]

Background: Although brimonidine is currently used in the clinical treatment of glaucoma and rosacea, research of the deep sedative effect on animals after systemic administration is reported firstly and has shown promising results. Methods: The median effective dose (ED50), the median lethal dose (LD50), and the therapeutic index of brimonidine for deep sedation and formalin stimulation assay were determined by various animal experiments. The effect of synergistic anesthesia in rabbits with brimonidine and chloral hydrate was preliminarily evaluated. Results: The ED50 of brimonidine for highly effective sedation by intraperitoneal injection in rats was calculated to be 2.05 mg kg−1 with a 95% confidence interval (CI) of 1.87 to 2.25 mg kg−1. The ED50 of brimonidine for deep sedation by intravenous and intrarectal injection in rabbits was calculated to be 0.087 mg kg−1 with a 95% CI of 0.084 to 0.091 mg kg−1 and 1.65 mg kg−1 with a 95% CI of 1.43 to 1.91 mg kg−1, respectively. The LD50 of intraperitoneal brimonidine injection in rats was calculated to be 468 mg kg−1 with a 95% CI of 441 to 497 mg kg−1 and a therapeutic index of 228. Brimonidine has a certain analgesic and heart rate lowering effects. Conclusion: The results confirmed that brimonidine has deep sedation and analgesic effects after systemic administration and has high safety. It can be used in combination with other types of sedative drugs to achieve better effects. [ABSTRACT FROM AUTHOR]

Introduction: Pneumoperitoneum is a surgical technique used in abdominal surgery, often involving general anesthesia. It can cause a transient sympathetic response, increased plasma catecholamines and vasopressin levels, and increased intra-abdominal pressure, potentially causing hypertension and tachycardia. Various pharmacological agents have been attempted to mitigate this response, but none have been found ideal. This study compares dexmedetomidine and magnesium sulphate in pneumoperitoneum. Methods: The study at Burdwan Medical College examined the effectiveness of dexmedetomidine and magnesium sulphate infusion in reducing stress during laparoscopic surgical procedures over a 1.5-year period. Results: The study analyzed 35 patients' changes after following the protocol, using Pearson's Chi Square test and Mann-Whitney U test. Statistical software SPSS version 20 was used, with an alpha level of 5% and p value less than 0.05 considered significant. Discussion: Pneumoperitoneum, a surgical technique causing hypertension and tachycardia, can be mitigated using various pharmacological agents. Dexmedetomidine, a selective a2 adrenergic agonist, provides hemodynamic stability and reduces pressor response. Magnesium sulphate, a noncompetitive NMDA receptor antagonist, attenuates reflexes and vasodilation. Both drugs are equally effective in decreasing blood pressure in response to laryngoscopy and intubation. Conclusion: Dexmedetomidine and magnesium sulphate infusions effectively reduce stress during endotracheal intubation and pneumoperitoneum without adverse effects, maintaining heart rate and arterial pressure, and taking longer for patients in Group D. [ABSTRACT FROM AUTHOR]

Background and Objectives: Until now, overactive bladder (OAB) with or without urge urinary incontinence (UUI) has been treated mainly in two ways: with behavioral methods and patient education, or using antimuscarinic drugs and/or beta-3 adrenergic receptor agonists. Unfortunately, these drugs may cause side effects in some women or are insufficiently effective, so patients abandon them. Therefore, in this pilot study, radiofrequency was evaluated as a new option in the treatment of OAB and UUI. Materials and Methods: Nineteen patients were enrolled in this pilot study using radiofrequency (RF), where the level of OAB and UUI was assessed using the validated ICIQ-OAB questionnaire. RF was applied four times for 20 min, once a week. Two weeks after treatment, the level of OAB and UUI was reassessed and processed statistically and the treatment effect evaluated. Results: Using the ICIQ-OAB, the severity of OAB and UUI was assessed: 0–3 mild symptoms; 4–7 moderate symptoms; 8–11 severe symptoms; 12–16 very severe symptoms. Before treatment, 10.5% of patients had mild symptoms, 21.1% moderate symptoms, 63.2% severe symptoms and 5.3% very severe symptoms. After treatment, 42.9% had mild symptoms, 50% moderate symptoms and 7% severe OAB and UUI symptoms. All four main symptoms—frequency, nocturia, urgency and incontinence—decreased statistically significantly, with the best results being found in urgency (p = 0.002). Conclusions: Based on this pilot study, RF seems a very promising method in the treatment of OAB and UUI. To extend our initial findings, it is necessary to perform a prospective, randomized and placebo-controlled study in order to obtain reliable results and to determine for how long one set of treatment maintains the results obtained immediately after the end of that treatment. In this way, we may determine how often the treatment needs to be repeated, if necessary, and when. [ABSTRACT FROM AUTHOR]

Objective: To investigate the improvement of perioperative sleep quality and neurocognitive impairment in elderly patients under general anesthesia by nasal administration of dexmedetomidine. Methods: One hundred and twenty patients admitted to our hospital for various laparoscopic elective gynecological surgeries lasting more than 1 h under general anesthesia from July 2021 to March 2023 were selected. All subjects were divided into 3 groups according to the random number table method. From 21:00 to 21:30 every night from one day before to 5 days after surgery, group A was given alprazolam 0.4 mg orally; group B was given dexmedetomidine 1.5ug/kg nasal drip; group C was given saline nasal drip. All subjects were observed for general information, sleep quality, postoperative cognitive function, anxiety status, sleep quality, adverse effects and complication occurrence. Results: The difference in general information between the three groups was not statistically significant, P > 0.05; the sleep quality scores of the three groups on admission were not statistically significant, P > 0.05. At the Preoperative 1d, postoperative 1d, 3d and 5d, the RCSQ scores of the subjects in group A and group B were higher than those in groups C, and with the postoperative RCSQ scores of subjects in group B were higher as the time increased; the assessment of anxiety status in the three groups 1d before surgery was not statistically significant, P > 0.05. The cognitive function scores of subjects in the three groups were not statistically significant in the preoperative 1d, P > 0.05. The postoperative 1d (24.63 ± 2.23), 3d (25.83 ± 2.53), and 5d (26.15 ± 2.01) scores of the subjects in group B were higher than those in groups A and C (P < 0.05), and the subjects in group B had better recovery of postoperative cognitive function with increasing time; the occurrence of postoperative delirium (POD) in group B (12.5%) were lower on postoperative 5d than those in groups A (37.5%) and C (32.5%) (P < 0.05). There was no statistical significance in the evaluation of anxiety state of the three groups on the first day before operation (P > 0.05). The scores in group B were lower than those in group C on the postoperative 1d, 3d, 5 d (P < 0.05). The overall incidence of adverse reactions and complications in subjects in group B was 17.5% significantly lower than that in groups A and C (P < 0.05). Conclusion: Dexmedetomidine can effectively improve the sleep disorder of elderly general anesthesia patients, reduce the damage to their neurocognitive function and the occurrence of POD, effectively reduce the anxiety of patients and the occurrence of adverse reactions and complications, and has better sedative, improve postoperative cognitive function and anti-anxiety effects, with a high drug safety, worthy of clinical application and promotion. [ABSTRACT FROM AUTHOR]

Background: While symptoms related to lower urinary tract dysfunction (LUTD) are common in individuals with Alzheimer's disease (AD), pathophysiological links between AD and LUTD remain unclear. Objective: This study aimed to investigate whether AD neuropathology would cause autonomic dysfunction along the spinal cord-bladder axis, which could result in alterations in bladder muscle kinetics. Methods: We utilized APPNL-G-F/NL-G-F knock-in (APP KI) and APPwt/wt (wild-type) mice at two different ages, 4- and 10-month-old, to investigate how AD impacts bladder tissue function by immunohistochemistry, western blotting, and pharmacomyography. Results: We showed that the mucosal layer partially separated from the detrusor in 10-month-old APP KI mouse bladders. Although there was no detectable amyloid deposition in the APP KI bladder, we found amyloid plaques in APP KI lumbar spinal cord. Further immunoblot analysis revealed that tyrosine hydroxylase protein levels were significantly reduced in both 4- and 10-month-old bladder tissues, suggesting reduction of norepinephrine synthesis in APP KI mouse bladders. In contrast, the level of β2 adrenergic receptor was increased in 4-month-old but not 10-month-old APP KI bladders. In bladder strips, the adrenergic agonist isoproterenol induced increased relaxation in 4- but not 10-month-old APP KI bladders. With 10 Hz electrical field stimulation, 10-month-old APP KI bladder strips were more responsive than wild-type controls, with no differences observed in 4-month-old APP KI bladders. Conclusions: APP KI mice exhibit LUTD, which is likely arising from amyloid pathology in the spinal cord, and results in maturational declines in presynaptic activity combined with compensatory postsynaptic upregulation. [ABSTRACT FROM AUTHOR]

Given the prevalent use of inhaled beta2‐agonists in sports, there is an ongoing debate as to whether they enhance athletic performance. Over the last decades, inhaled beta2‐agonists have been claimed not to enhance performance with little consideration of dose or exercise modality. In contrast, orally administered beta2‐agonists are perceived as being performance enhancing, predominantly on muscle strength and sprint ability, but can also induce muscle hypertrophy and slow‐to‐fast fiber phenotypic switching. But because inhaled beta2‐agonists are more efficient to achieve high systemic concentrations than oral delivery relative to dose, it follows that the inhaled route has the potential to enhance performance too. The question is at which inhaled doses such effects occur. While supratherapeutic doses of inhaled beta2‐agonists enhance muscle strength and short intense exercise performance, effects at low therapeutic doses are less apparent. However, even high therapeutic inhaled doses of commonly used beta2‐agonists have been shown to induce muscle hypertrophy and to enhance sprint performance. This is concerning from an anti‐doping perspective. In this paper, we raise awareness of the circumstances under which inhaled beta2‐agonists can constitute a performance‐enhancing benefit. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes (CMS) are a rare group of inherited disorders caused by gene defects associated with the neuromuscular junction and potentially treatable with commonly available medications such as acetylcholinesterase inhibitors and β2 adrenergic receptor agonists. In this study, we identified and genetically characterized the largest cohort of CMS patients from India to date. Genetic testing of clinically suspected patients evaluated in a South Indian hospital during the period 2014–19 was carried out by standard diagnostic gene panel testing or using a two-step method that included hotspot screening followed by whole-exome sequencing. In total, 156 genetically diagnosed patients (141 families) were characterized and the mutational spectrum and genotype-phenotype correlation described. Overall, 87 males and 69 females were evaluated, with the age of onset ranging from congenital to fourth decade (mean 6.6 ± 9.8 years). The mean age at diagnosis was 19 ± 12.8 (1–56 years), with a mean diagnostic delay of 12.5 ± 9.9 (0–49 years). Disease-causing variants in 17 CMS-associated genes were identified in 132 families (93.6%), while in nine families (6.4%), variants in genes not associated with CMS were found. Overall, postsynaptic defects were most common (62.4%), followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%). Other genes found to cause neuromuscular junction defects (DES , TEFM) in our cohort accounted for 2.8%. Among the individual CMS genes, the most commonly affected gene was CHRNE (39.4%), followed by DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%) and COLQ (4.5%). We identified 22 recurrent variants in this study, out of which eight were found to be geographically specific to the Indian subcontinent. Apart from the known common CHRNE variants p.E443Kfs*64 (11.4%) and DOK7 p.A378Sfs*30 (9.3%), we identified seven novel recurrent variants specific to this cohort, including DPAGT1 p.T380I and DES c.1023+5G>A, for which founder haplotypes are suspected. This study highlights the geographic differences in the frequencies of various causative CMS genes and underlines the increasing significance of glycosylation genes (DPAGT1 , GFPT1 and GMPPB) as a cause of neuromuscular junction defects. Myopathy and muscular dystrophy genes such as GMPPB and DES , presenting as gradually progressive limb girdle CMS, expand the phenotypic spectrum. The novel genes MACF1 and TEFM identified in this cohort add to the expanding list of genes with new mechanisms causing neuromuscular junction defects. [ABSTRACT FROM AUTHOR]

Agonists of the β2 adrenergic receptor (ADRB2) are an important class of medications used for the treatment of respiratory diseases. They can be classified as short acting (SABA) or long acting (LABA), with each class playing a different role in patient management. In this work we explored both ligand‐based and structure‐based high‐throughput approaches to classify β2‐agonists based on their duration of action. A completely in‐silico prediction pipeline using an AlphaFold generated structure was used for structure‐based modelling. Our analysis identified the ligands' 3D structure and lipophilicity as the most relevant features for the prediction of the duration of action. Interaction‐based methods were also able to select ligands with the desired duration of action, incorporating the bias directly in the structure‐based drug discovery pipeline without the need for further processing. [ABSTRACT FROM AUTHOR]