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Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction, and the thoughtful regulation of attention, action, and emotion. For example, schizophrenia, depression, long COVID, and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often being focused in layer III. The dlPFC has extensive top-down projections, e.g., to the posterior association cortices to regulate attention and to the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors for most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research and are summarized in this review. For example, the layer III dlPFC circuits that generate working memory–related neuronal firing have unusual neurotransmission, depending on NMDA receptor and nicotinic α7 receptor actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP (cyclic adenosine monophosphate) opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α 2A adrenergic receptor and mGluR3 (metabotropic glutamate receptor 3) signaling but dysregulated by inflammation and/or chronic stress exposure, which contribute to spine loss. Treatments that strengthen the dlPFC via pharmacological (the α 2A adrenergic receptor agonist, guanfacine) or repetitive transcranial magnetic stimulation manipulation provide a rational basis for therapy. [ABSTRACT FROM AUTHOR]

In odontoblasts, intracellular Ca2+ signaling plays key roles in reactionary dentin formation and generation of dentinal pain. Odontoblasts also express several Gs protein-coupled receptors that promote production of cyclic AMP (cAMP). However, the crosstalk between intracellular cAMP and Ca2+ signaling, as well as the role of cAMP in the cellular functions of odontoblasts, remains unclear. In this study, we measured intracellular cAMP levels and intracellular free Ca2+ concentration ([Ca2+]i). We also investigated the effect of intracellular cAMP on mineralization by the odontoblasts. In the presence of extracellular Ca2+, the application of forskolin (adenylyl cyclase activator) or isoproterenol (Gs protein-coupled beta-2 adrenergic receptor agonist) increased intracellular cAMP levels and [Ca2+]i in odontoblasts. The [Ca2+]i increases could not be observed by removing extracellular Ca2+, indicating that cAMP is capable to activate Ca2+ entry. Forskolin-induced [Ca2+]i increase was inhibited by a protein kinase A inhibitor in odontoblasts. The [Ca2+]i increase was sensitive to Gd3+, 2APB, or Zn2+ but not verapamil, ML218, or La3+. In immunofluorescence analyses, odontoblasts were immunopositive for calcium homeostasis modulator 1 (CALHM1), which was found close to ionotropic ATP receptor subtype, P2X3 receptors. When CALHM1 was knocked down, forskolin-induced [Ca2+]i increase was suppressed. Alizarin red and von Kossa staining showed that forskolin decreased mineralization. These findings suggest that activation of adenylyl cyclase elicited increases in the intracellular cAMP level and Ca2+ influx via protein kinase A activation in odontoblasts. Subsequent cAMP-dependent Ca2+ influx was mediated by CALHM1 in odontoblasts. In addition, the intracellular cAMP signaling pathway in odontoblasts negatively mediated dentinogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Laryngoscopy and endotracheal intubation during anaesthesia administration provokes physiological stress responses like tachycardia, hypertension and can also lead to potential adverse events such as bronchospasm, myocardial ischaemia, arrythmias, cerebrovascular accidents etc. Dexmedetomidine, an alpha-2 adrenergic agonist has been extensively used perioperatively for stabilising intraoperative haemodynamics. Intravenous dexmedetomidine can cause major adverse effects such as bradycardia, hypotension, cardiac arrhythmias and biphasic response when used as premedication for attenuation of the laryngoscopy and intubation response which mandates exploration of other routes of administration of dexmedetomidine. Aim: To evaluate the efficacy of intramuscular dexmedetomidine and intravenous dexmedetomidine to attenuate the stress response of laryngoscopy and endotracheal intubation in patients undergoing general anaesthesia via these routes. Materials and Methods: This prospective, randomised clinical trial was single-blinded study conducted in the Department of Anaesthesia, Shrimati Bhikhiben Kanjibhai Shah Medical Institute and Research Centre (SBKS MIRC) in Piparia, Vadodara, Gujarat, India over a period of six months from January 2024 to June 2024 on 64 adult patients of American Soceity of Anaesthesiology (ASA) physical status I and II, aged between 18-60 years, posted for surgery under Materials and Methods: This prospective, randomised clinical trial was single-blinded study conducted in the Department of Anaesthesia, Shrimati Bhikhiben Kanjibhai Shah Medical Institute and Research Centre (SBKS MIRC) in Piparia, Vadodara, Gujarat, India over a period of six months from January 2024 to June 2024 on 64 adult patients of American Soceity of Anaesthesiology (ASA) physical status I and II, aged between 18-60 years, posted for surgery under general anaesthesia. The patients were divided in two groups: Group DIM (intramuscular Dexmedetomidine) received Inj. Dexmedetomidine 1 μg/kg intramuscularly 45 minutes prior to induction. Group DIV (intravenous Dexmedetomidine) received Inj. Dexmedetomidine 1 μg/kg intravenously as infusion in 100 mL Normal Saline (NS) over 10 minutes 45 minutes prior to induction. Haemodynamic changes during laryngoscopy and intubation, postoperative complications and sedation score were recorded. [ABSTRACT FROM AUTHOR]

To assess attitudes of Thai veterinarians towards perioperative pain management in dogs and cats, and explore associations between demographic characteristics and use of analgesics and pain assessment. Paper-based survey distributed in person during various small animal practitioner conferences in 2022. The questionnaire encompassed six sections: demographic information, use of analgesic techniques, postoperative pain evaluation, pain indicators, general opinions and confidence in managing postoperative pain in dogs and cats. Chi-square test, logistic regression model and Mann–Whitney U or Kruskal–Wallis tests were used for data analysis; p < 0.05 was considered significant. A total of 390 completed questionnaires were collected, with one discarded owing to potential erroneous responses. The most widely used analgesics were alpha-2 adrenergic receptor agonists (84%), postoperative non-steroidal anti-inflammatory drugs (NSAIDs; 83.5%) and preoperative opioids (74.3%). Carprofen (87.3%) and tolfenamic acid (80.9%) were the most frequently administered NSAIDs, while tramadol (86%) and morphine (71%) were the most widely used opioids. Preoperative and postoperative opioid administration were less common among males than females, with odds ratios (ORs) of 0.53 and 0.56, respectively (both p = 0.009). Veterinarians who graduated after 2014 were less likely to prescribe preoperative NSAIDs than those who graduated before 2009 (OR = 0.25; p < 0.001). Epidural anesthesia, nerve blocks and pre- and postincisional blocks were more frequently used by referral center veterinarians than those working in non-referral clinics (ORs = 30.5, 14.7, 4.29 and 8.85, respectively; all p < 0.001) and by veterinarians holding advanced degrees beyond the Doctor of Veterinary Medicine (DVM) compared with those with a DVM degree (OR = 6.25, 4.83, 2.25 and 5.75, respectively; all p < 0.001). This study reveals variations in perioperative pain management practices in dogs and cats among veterinarians, influenced by sex, graduation year, education and workplace. [ABSTRACT FROM AUTHOR]

Purpose: Mirabegron, the first-in-class beta-3 agonist, is the mainstay medication for overactive bladder (OAB). The aim of this study was to investigate the efficacy and safety of generic drugs of mirabegron (Mirabek®) in adults diagnosed with OAB through a multicenter, prospective, non-interventional observational study. Materials and Methods: Adult patients with OAB prescribed Mirabek® SR Tab. 50 mg for the first time were recruited from hospitals between September 2021 and September 2022. Participants underwent baseline registration followed by two follow-ups at 4- and 8-week intervals. Data on demographics, medical history, OAB symptoms, vital signs, medication administration, and adverse events were collected. Results: Among 1,714 patients, Mirabek® SR Tab. 50 mg effectively improved OAB symptoms over an 8-week treatment period, with significant differences in symptom improvement between baseline and both 4- and 8-week time points as well as between 4 weeks and 8 weeks. The incidence rate of adverse events was 0.70%; most cases were mild with no severe reactions. Conclusions: This study demonstrated that Mirabek®, a generic drug of betmiga, is an effective and safe treatment option for adults with OAB. Furthermore, the introduction of generic drug reduced the costs of prescription drugs and expanded the opportunity for many patients to access mirabegron. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are currently among the most devastating diseases with no effective disease-modifying drugs in the market, with Alzheimer's disease (AD) being the most prevalent. AD is a complex multifactorial neurodegenerative disorder characterized by progressive and severe cognitive impairment and memory loss. It is the most common cause of progressive memory loss (dementia) in the elderly, and to date, there is no effective treatment to cure or slow disease progression substantially. The role of adrenergic receptors in the pathogenesis of Alzheimer's disease and other tauopathies is poorly understood or investigated. Recently, some studies indicated a potential benefit of drugs acting on the adrenergic receptors for AD and dementias, although due to the heterogeneity of the drug classes used, the results on the whole remain inconclusive. The scope of this review article is to comprehensively review the literature on the possible role of adrenergic receptors in neurodegenerative diseases, stemming from the use of agonists and antagonists including antihypertensive and asthma drugs acting on the adrenergic receptors, but also from animal models and in vitro models where these receptors have been studied. Ultimately, we hope to obtain a better understanding of the role of these receptors, identify the gaps in knowledge, and explore the possibility of repurposing such drugs for AD, given their long history of use and safety. [ABSTRACT FROM AUTHOR]

Introduction: Retinal vein occlusion (RVO) often causes irreversible visual impairment, making early prevention crucial. This study aims to identify associations between different medications and RVO and provide information for clinical practice. Method: This study included reports of RVO from the FDA Adverse Event Reporting System (FAERS) database from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2023. The reported drugs were analyzed for adverse drug reaction (ADR) signals using four disproportionality algorithms. Kaplan-Meier curves and median time to onset were used to evaluate the drugs. Results: From 2004 to 2023, the FAERS database recorded 6,151 reports associated with RVO. Disproportionality analyses identified 25 drugs significantly associated with RVO. Mirabegron showed the highest risk signal, followed by Raloxifene, Tadalafil, Fingolimod, and Bimatoprost. These high-risk drugs are distributed across different therapeutic areas, including urogenital system and sex hormones, ophthalmic drugs, nervous system drugs, musculoskeletal system drugs, anti-tumor and immune-modulating drugs, and anti-parasitic drugs. Specific drug targets such as adrenergic receptor agonists, hormone regulators, and PDE5 inhibitors were identified as high risk. Ophthalmic drugs exhibited the longest median time to adverse ocular reactions at 532.01 days, followed by anti-parasitic drugs, nervous system drugs, urogenital system and sex hormone drugs, anti-tumor and immune-modulating drugs, and musculoskeletal system drugs. Conclusion: This study provides an overview of drug-induced RVO, identifying potential culprit drugs and their distribution characteristics. These findings enhance understanding of medication safety and help optimize clinical practice. [ABSTRACT FROM AUTHOR]

Background: Major abdominal surgery is a kind of high-risk surgery type for postoperative acute kidney injury (AKI) among non-cardiac surgeries. Despite dexmedetomidine exerts significant renal protective effects in cardiac surgeries and animal studies, whether it is associated with a lower incidence of AKI in major abdominal surgeries remains unclear. Methods: From January 2019 to July 2021, patients undergoing elective major abdominal surgery in West China Hospital were enrolled. Participants were divided into two groups based on exposure to continuous intravenous dexmedetomidine: the Dex group (exposed) and the Control group (not exposed). The primary outcome was the incidence of AKI in the postoperative 7 days. Secondary outcomes included intraopertive average urine output, renal function on the first day after surgery, incidence of postoperative dialysis, postoperative intensive care unit (ICU) admission, in-hospital mortality, length of hospital stay, incidence of intraoperative hypotension and bradycardia, and intraoperative use of inotropes and vasopressors. Propensity score matching (PSM), based on participants' baseline and intraoperative characteristics, was performed to minimize potential bias. Furthermore, a subgroup analysis was conducted based on the infusion rate and the use of a loading dose to explore the effects of different methods of dexmedetomidine administration on AKI. The subgroups included: loading dose, non-loading dose, low-infusion rate (infusion rate ≤ 0.4 µg/kg/h), and high-infusion rate (infusion rate > 0.4 µg/kg/h). Results: After PSM with a ratio of 1:1, a total of 8836 patients were successfully matched. Dexmedetomidine administration had no association with the incidence of postoperative AKI, serum creatinine (Scr) level on the first postoperative day, incidence of postoperative dialysis, postoperative ICU admission, in-hospital mortality, length of hospital stay, intraoperative hypotension, or the use of inotropes and vasopressors, but had association with increased intraoperative average urine output (122.95 (76.80, 189.27) vs. 104.65 (67.04, 161.07) ml/h, P < 0.001), higher value of estimated glomerular filtration rate (eGFR) (97.33 ± 15.95 vs. 96.13 ± 16.35 ml/min/1.73m2, P < 0.001) on the first day after surgery and a higher incidence of intraoperative bradycardia (37.0% vs. 30.6%; P < 0.001). In the loading dose subgroup, dexmedetomidine use was significantly associated with a reduced incidence of postoperative AKI (odds ratio (OR): 0.44, 95% confidence interval (CI): 0.23–0.76, P = 0.006).The association between dexmedetomidine and postoperative AKI was absent in subgroups of high or low infusion rate and no loading dose use. Conclusion: In this single-center retrospective propensity-matched study, we did not detect a significant overall difference in post-operative AKI rates between patients treated with or without dexmedetomidine during major abdominal surgery. However, though additional prospective data are needed, our study found that administering dexmedetomidine with a loading dose may be associated with lower rates of AKI, potentially indicating a renoprotective effect of loading-dose dexmedetomidine in this setting. [ABSTRACT FROM AUTHOR]

Control of biological activity with light is a fascinating idea. "Caged" compounds, molecules modified with photolabile protecting group, are one of the instruments for this purpose. Adrenergic receptors are essential regulators of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. These receptors are largely used as pharmacologic targets. Photolabile "caged" analogs of adrenergic receptor agonists has been reported more than 30 years ago. We report that the photolysis of epinephrine analogs, apart from liberation of the epinephrine, is accompanied by a formation of significant amount of adrenochrome, a compound with neuro- and cardiotoxic effect. [ABSTRACT FROM AUTHOR]

Dexmedetomidine (DEX) is a selective alpha-2 adrenergic receptor agonist with sedative and anxiolytic properties. Increasing evidence reports that DEX has a neuroprotective effect. In this study, we investigated the potential effects of DEX on learning and memory functions in rats with experimental cognitive impairment. In the study, 21 adult male rats were used. The rats were divided into three groups, namely control, Scopolamine (SCOP) and SCOP + DEX. Cognitive impairment was induced with 1 mg/kg SCOP daily for 21 days. DEX was administered at a dose of 10 µg/kg between days 14 and 21 of the experiment. Following the injections, a spatial memory test was performed with a Morris Water Maze (MWM). At the end of the experiment, the hippocampus was dissected. The brain-derived neurotrophic factor (BDNF), acetylcholine (ACh) and acetylcholinesterase (AChE) levels were determined by ELISA. The tropomyosin receptor kinase B (TrkB) and Cyclic AMP-Response Element-Binding Protein (CREB) levels were measured by immunohistochemistry. DEX treatment improved the learning performance of rats compared to SCOP for 5 days. However, it did not significantly change memory performance. DEX increased the BDNF and ACh levels in the hippocampus while decreasing the AChE levels. Similarly, DEX treatment significantly increased CREB phosphorylation. No significant difference was observed between the TrkB receptor levels of the groups. This study demonstrated that the role of DEX in reducing SCOP-induced cognitive impairment is partially mediated by the increase in BDNF/TrkB/CREB signaling pathway activity. [ABSTRACT FROM AUTHOR]

The fixed-dose combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) delivered via pressurised metered-dose inhaler (pMDI) has demonstrated efficacy in chronic obstructive pulmonary disease (COPD), in studies predominantly conducted in Caucasian adults. The current study evaluated the efficacy and safety of BDP/FF pMDI in Chinese patients with COPD, as part of registration for COPD in China. This double-blind, double-dummy, randomised, parallel-group study was conducted in patients with COPD of Chinese ethnicity aged ≥40 years. After a 4-week open-label budesonide/formoterol fumarate (BUD/FF) run-in period, patients were randomised to BUD/FF or BDP/FF for 24 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF to BUD/FF in terms of change from baseline in pre-dose morning forced expiratory volume in 1 sec (FEV1) at Week 24 (i.e. the lower 95% CI limit of the difference was above the pre-defined non-inferiority margin of −0.07 L). Of 750 patients randomised (377 BDP/FF; 373 BUD/FF), 87.6% completed the study. The primary endpoint was met in both the per-protocol (adjusted mean difference −0.001 L [95% CI: −0.025, 0.022], non-inferiority p < 0.001) and intention-to-treat populations (–0.001 L [–0.024, 0.022]; non-inferiority p < 0.001). There were no statistically significant BDP/FF–BUD/FF differences for the secondary endpoints, and a similar proportion of patients had adverse events (BDP/FF, 51.7%; BUD/FF, 51.2%), with most mild/moderate in severity. In conclusion, BDP/FF pMDI was non-inferior to BUD/FF in terms of pre-dose morning FEV1, supported by a range of secondary endpoints. Both treatments were similarly tolerated. The study supports the use of BDP/FF pMDI in Chinese patients with COPD. STUDY REGISTRATION: China Centre for Drug Evaluation (CTR20180475). [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]

Introduction: Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the exploration of novel therapeutic avenues. To address this need, we have developed a novel mouse model of anaphylaxis, denoted as anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS). ASDIS manifests as distinct dotted symptoms in the skin, detectable through in vivo imaging, resembling urticarial symptoms. In this study, we investigated the potential underlying mechanisms giving rise to these dotted symptoms, exploring the role of vascular permeability and characterizing the ASDIS model as a new urticaria model. Methods: We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue – a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined. Results: In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom. Conclusion: Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions. Plain Language Summary: Urticaria, a skin allergy causing itchy bumps, is often treated with antihistamines. However, these treatments may not always be effective. To address this, researchers aim to develop new anti-allergic drugs. While several methods to induce urticaria-like symptoms in experimental animals have been explored, few are currently available. In a previous study, we successfully induced anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS) in hairless mice, resembling human urticaria. In this study, we investigated and clarified several key aspects using this method. First, we found that ASDIS in mice is mediated by an increase in vascular permeability, similar to human urticaria. This discovery supports the idea of considering mouse ASDIS as a model for human urticaria. Second, we demonstrated that ASDIS could be induced by IgE but not by histamine, a key mediator of vascular permeability increase. The unique plasma leakage induced by IgE was identified as a contributing factor to the urticaria-like symptoms in ASDIS. Third, a comparison of ASDIS and histamine-induced anaphylaxis in haired and hairless mice revealed that hairless mice were more sensitive. This suggests that hairless mice possess a unique mechanism induced by IgE, partially associated with histamine function. Finally, the inhibition of ASDIS by applying an adrenaline α1 receptor agonist to the skin strongly suggested the potential of this drug as an anti-allergic ointment. In summary, our mouse ASDIS model can be utilized as an urticaria model. Further detailed clarification of the underlying mechanisms of ASDIS induction will expedite the development of new anti-allergic drugs. [ABSTRACT FROM AUTHOR]

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]

Urinary incontinence is the involuntary loss of urine. It is a prevalent and bothersome condition in females, with subtypes including stress, urge, mixed stress/urge, and overflow. Evaluation begins with a history to identify symptoms of the different subtypes and information about comorbid conditions, incontinence frequency and severity, and effect on quality of life. Based on patient history, other assessments could include urinalysis, a voiding diary, pelvic examination, urinary stress testing, and measurement of postvoid residual urine volume. Treatment varies by subtype, but begins with lifestyle modifications, including decreasing caffeine intake, engaging in physical activity to strengthen pelvic floor muscles, and avoiding excessive fluid consumption. Pelvic floor physical therapy can help with urge and stress incontinence, pessaries and vaginal inserts can help with stress incontinence, and timed or prompted voiding can be useful for both subtypes. Pharmacotherapy for urge incontinence has typically involved anticholinergic drugs, but because of adverse effects, beta-3 adrenergic agonists are being more widely used. If needed for urge incontinence, procedural treatments can be considered, including onabotulinumtoxinA injections, percutaneous tibial nerve stimulation, and sacral neuromodulation. Numerous procedural treatments are available for stress incontinence; placement of midurethral slings is the most common. For overflow incontinence, treatments include catheterization or targeting the source of obstruction or detrusor hypoactivity. [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]

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]

Intradialytic hypotension (IDH) is a common occurrence in hemodialysis. IDH occurs when there is a drop in blood pressure along with hypotensive symptoms. There are various causes of IDH, and it is important to consider proper management of this condition. One strategy is to administer vasoconstrictor medication before the hemodialysis session to decrease the risk of IDH. A vasoconstrictor medication used for IDH is midodrine. Midodrine is an oral alpha-1 adrenergic receptor agonist. Evidence on its longterm efficacy and safety data is lacking. This article describes important information on midodrine for nephrology practitioners. [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]

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]

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Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disorder characterized by airway abnormalities which lead to persistent and often progressive airflow obstruction. COPD is compounded with complex pathophysiology, involving interplay of several environmental and genetic risk factors. Patients present with chronic respiratory symptoms of progressive dyspnea, cough, and sputum production, which, if inadequately treated, are often associated with exacerbations and hospitalization. With an ageing population and exposure to tobacco smoke and/or air pollutants, the burden of COPD is only expected to increase in the coming years in our state and country. Already it is the third leading cause of mortality and is expected to become the second by 2030. Management modalities are currently centered on relieving symptoms of airway obstruction, delaying decline in lung function, reducing exposureto risk factors like tobacco smoke, infections and increasing respiratory muscle strength through interventions like nutrition and rehabilitation on the other. [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]

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]

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]

Here, we report retrospective data regarding cardiorespiratory and body temperature effects of anaesthetic protocols used on the binturong (Arctictis binturong), a viverrid species facing increasing threats from habitat loss and illegal trade. Between 2017 and 2024, 16 binturong (9 females, body mass 9.1-19.3 kg; 7 males, 12-18.7 kg) aged 1.5 to 20.5 years were anaesthetised on 38 occasions in a rescue centre in Laos using one of three anaesthetic protocols based on combinations of ketamine plus the α2 adrenergic receptor agonists medetomidine (n = 12) and/or xylazine (n = 20) plus diazepam (n = 6). No anaesthesia-related health problems or deaths were observed. Binturong administered different anaesthetic protocols showed no differences in time to observation of first signs of sedation (2-7 min) and onset of deep anaesthesia (3-39 min). Heart rate gradually decreased to bradycardia over the 75 min of anaesthesia with ketamine plus medetomidine and, while respiratory rate remained steady, males became hypothermic. Male body temperatures decreased even further when injected with ketamine plus xylazine. All three combined anaesthetic protocols proved safe and effective for repeated use. However, the cardiorespiratory and hypothermic effects observed suggest that medetomidine may be superior to xylazine. Nevertheless, perioperative body temperature monitoring and management will be imperative to prevent inadvertent temperature complications. Our findings improve understanding of binturong responses to anaesthesia and will have positive implications for wildlife veterinarians and conservation medicine. [ABSTRACT FROM AUTHOR]

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]

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 article discusses the safety and sustainability of eye drops, emphasizing that while they are effective in treating ocular conditions, they can have both local and systemic side effects. Factors such as systemic absorption pathways, preservatives, and specific types of eye drops like antiglaucoma medications and mydriatics are highlighted for their potential adverse effects. The article also addresses the environmental impact of improper disposal of eye medications. It concludes by stressing the importance of understanding the safety profiles of eye drops, monitoring for side effects, and considering environmental implications when prescribing these medications. [Extracted from the article]

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]

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]

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]

Purpose: The efficacy and safety of vibegron, a β3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. Materials and Methods: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). Results: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], –0.74 [–1.02, –0.46]; P <.0001) and urgency episodes (–0.95 [–1.37, –0.54]; P <.0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, –0.22 [−0.36, −0.09]; P =.002), urge urinary incontinence episodes (–0.80 [−1.33, −0.27]; P =.003), International Prostate Symptom Score‒storage scores (–0.9 [–1.2, –0.6]; P <.0001), and volume voided (15.07 mL [9.13-21.02]; P <.0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). Conclusions: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH. [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]