Adrenoceptor Agonist Research Articles

Effect of Dexmedetomidine on Intraoperative Hemodynamics and Blood Loss in Patients Undergoing Spine Surgery: A Systematic Review and Meta-Analysis

Objective Dexmedetomidine (Dex) is a highly selective α2 adrenoceptor agonist that reduces blood pressure and heart rate. However, its ability to provide stable hemodynamics and a clinically significant reduction in blood loss in spine surgery is still a matter of debate. This study aimed to investigate the effects of Dex on intraoperative hemodynamics and blood loss in patients undergoing spine surgery.Methods The Web of Science, MEDLINE, EMBASE, and the Cochrane Library were searched up to February 2023 for randomized controlled trials (RCTs) including patients undergoing spine surgeries under general anaesthesia and comparing Dex and saline. A fixed- or random-effect model was used depending on heterogeneity.Results Twenty-one RCTs, including 1388 patients, were identified. Dex added the overall risk of intraoperative hypotension (odds ratio [OR]: 2.11; 95% confidence interval [CI]: 1.24 - 3.58; P=0.006) and bradycardia (OR: 2.48; 95%CI: 1.57 - 3.93; P=0.0001). The use of a loading dose of Dex led to significantly increased risks of intraoperative hypotension (OR: 2.00; 95%CI: 1.06 - 3.79; P=0.03) and bradycardia (OR: 2.28; 95%CI: 1.42 - 3.66; P=0.0007). For patients receiving total intravenous anesthesia, there was an increased risk of hypotension (OR: 2.90; 95%CI: 1.24 - 6.82; P=0.01) and bradycardia (OR: 2.66; 95%CI: 1.53 - 4.61; P=0. 0005). For patients in the inhalation anesthesia group, only an increased risk of bradycardia (OR: 4.95; 95%CI: 1.41 - 17.37; P=0.01) was observed. No significant increase in the risk of hypotension and bradycardia was found in the combined intravenous-inhalation anesthesia group. The incidence of severe hypotension (OR: 2.57; 95%CI: 1.05 - 6.32; P=0.04), but not mild hypotension, was increased. Both mild (OR: 2.55; 95%CI: 1.06 - 6.15; P=0.04) and severe (OR: 2.45; 95%CI: 1.43 - 4.20; P=0.001) bradycardia were associated with a higher risk. The overall analyses did not reveal significant reduction in intraoperative blood loss. However, a significant decrease in blood loss was observed in total inhalation anesthesia subgroup (mean difference [MD]: -82.97; 95%CI: -109.04 - -56.90; P<0.001).Conclusions Dex increases the risks of intraoperative hypotension and bradycardia in major spine surgery. The administration of a loading dose of Dex and the utilization of various anesthesia maintenance methods may potentially impact hemodynamic stability and intraoperative blood loss.

β3 Adrenoceptor Agonism Prevents Hyperoxia-Induced Colonic Alterations.

Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not completely develop in utero. The β3-adrenoreceptor (β3-AR) is expressed in the colon and has an oxygen-dependent regulatory mechanism. This study shows the effects of the β3-AR agonist BRL37344 in a neonatal model of hyperoxia-driven colonic injury. For the first 14 days after birth, Sprague-Dawley rat pups were exposed to ambient oxygen levels (21%) or hyperoxia (85%) and treated daily with BRL37344 at 1, 3, 6 mg/kg or untreated. At the end of day 14, proximal colon samples were collected for analysis. Hyperoxia deeply influences the proximal colon development by reducing β3-AR-expressing cells (27%), colonic length (26%) and mucin production (47%), and altering the neuronal chemical coding in the myenteric plexus without changes in the neuron number. The administration of BRL37344 at 3 mg/kg, but not at 1 mg/kg, significantly prevented these alterations. Conversely, it was ineffective in preventing hyperoxia-induced body weight loss. BRL37344 at 6 mg/kg was toxic. These findings pave the way for β3-AR pharmacological targeting as a therapeutic option for diseases caused by hyperoxia-impaired development, typical prematurity disorders.

Strategic insight into the thresholds &amp; barriers to uptake of Electronic Repeat Dispensing (eRD) by therapeutic area

Abstract Introduction The use of eRD offers a simplified process compared to paper based repeat dispensing and electronic repeat prescribing, and has several benefits for GP practices, community pharmacies and patients. It is estimated that up to 80% of all repeat prescriptions could be replaced with repeat dispensing potentially saving 2.7 million hours of GP and practice time. eRD also has the benefit of reduced medicines and can contribute towards reducing overprescribing and supporting the NHS sustainability agenda. Aim To determine if there are specific thresholds of eRD implementation by GP practices at which barriers to uptake occur. Subsequently to understand if these thresholds are associated with specific therapeutics and if the difficulty in increasing uptake is related to drug specific requirements or differing prescription management processes needed. Methods Dispensed medicines data (Oct-Dec 22, ePACT2) was analysed at practice level nationally to test the hypothesis that there are multiple thresholds of eRD implementation uptake. The percentage of practices achieving less than or equal to each incremental %eRD value was plotted against % eRD implementation. Thresholds were identified by a change in the rate of implementation uptake. Prescribing data was then analysed by BNF chapter at the identified thresholds to determine how this variation was represented clinically. Dispensed medicines data (Jul-Sept 21, North of England (NoE)) was also reviewed by pharmacists at presentation level for appropriateness as an eRD item (excludes patient level considerations). The items considered prescribable by eRD were tagged and the data re-run to estimate the maximum %eRD that might have been achieved. Ethical approval was not required for this study as it utilised non-patient identifiable population level primary care prescribing data. Results There were 8 thresholds (changes in rate of implementation) identified from the national data; occurring at 3, 9, 35, 42, 50, 57, 64 and 72% eRD. There is consistency in three of the most prescribed drug groups for eRD across all the NoE Integrated Care Systems (ICSs), which includes: lipid regulating drugs, proton pump inhibitors and renin-angiotensin system; readily implemented as eRD from the 3% threshold. The other most commonly prescribed drugs by eRD were: Beta-blockers, calcium channel blockers, antiplatelets and antidiabetics. Retrospective data analysis by pharmacists determined that a maximum of 66.6% of items Jul-Sept 21 in the NoE could have been prescribed by eRD if patient factors at individual review had also considered it appropriate. Discussion/Conclusion Further clinical review and guidance on the appropriateness and requirements of specific therapeutics to be prescribed by eRD is required. For instance, rheumatic disease suppressant drugs, which require GP practices to establish monitoring arrangements in conjunction with eRD, increase from the 9% threshold. Whereas adrenoceptor agonists, requiring respiratory/inhaler reviews, increase from the 35% threshold. Further qualitative analysis is ongoing to understand the barriers occurring at different thresholds of eRD uptake. The maximum percentage of eRD achievable in the snapshot data was significantly lower than expected. This work is limited by the volume of items at presentation level that could potentially be prescribed.

The effects of dexmedetomidine on postoperative tumor recurrence and patient survival after breast cancer surgery: a feasibility study

PurposeDexmedetomidine (Dexmed) is a highly selective alpha 2 adrenoceptor (α2-AR) agonist with excellent sedation and analgesic effects and is frequently used in breast cancer surgery. However, the exact impact of Dexmed on breast cancer prognosis is still unclear. The primary objective of this pilot study was to explore study feasibility (recruitment and dropout rates) for future large-scale randomized controlled trial (RCT) to test the hypothesis that intraoperative Dexmed reduced recurrence-free survival (RFS) and overall survival (OS) in patients after breast cancer surgery.MethodsInterviews with patients were performed during the anesthetic preoperative visit for informed consent. Adult females scheduled for a mastectomy due to primary breast cancer were 1:1 randomised to saline (Group Control) or Dexmed (Group Dexmed) treatment groups. The primary outcomes were descriptions of study feasibility (recruitment and dropout rates). We also performed a preliminary analysis of RFS (time from surgery to the earliest date of recurrence/metastasis) and OS (time from surgery to the date of all-cause death) and collected data on percentages/numbers of circulating immune cells at pre- and 24 h post-operation.ResultsA total of 964 patients were screened; 40% (385/964) met the inclusion criteria, among which 39% (150/385) were enrolled and randomly assigned to either Group Control (n = 75) or Group Dexmed (n = 75). The median follow-up duration was 49 months (interquartile range (IQR): 34–58 months) for Group Control and 48 months (IQR: 33–60 months) for Group Dexmed. Five percent (5%, 8/150) patients were lost to follow-up and 1% (2/150) died. There was no significant difference in RFS and OS. The percentage/number of natural killer (NK), B and T-cell subsets and the CD4+/CD8+ ratio were similar between groups at 24 h post-operation.ConclusionThe pilot study was feasible to deliver. In a future definitive trial, the lower recruitment rate may be improved by increasing the number of anesthesiologists involved in the study. The study about the effects of Dexmed on long-term prognoses of breast cancer patients that is planned to follow this pilot study is a large-scaled randomized control study with the aim of providing evidence-based guidelines for rational use of Dexmed in patients undergoing breast cancer surgery.Trial registrationRegistered at ClinicalTrials.gov on October 20, 2016 (ID: NCT03109990).Graphical

Age-dependent effects of the β3 adrenoceptor agonist CL316,243 on human and rat detrusor muscle strips

Motility of detrusor smooth muscle includes adrenergic relaxation and cholinergic contraction. Since the latter may be deregulated in overactive bladder (OAB) pathophysiology, anticholinergics are the standard therapy but occasionally less tolerated due to side effects such as dry mouth and constipation. β3 adrenoceptor agonists also alleviate OAB symptoms by relaxing the detrusor muscle. Their age dependence, however, is far from understood. To address this issue, we induced contractions with KCl (60 mM) and carbachol (from 10 nM to 100 μM) in the presence of the β3 adrenoceptor agonist CL316,243 (from 0.1 to 10 μM) in both human and rat muscle strips. Our results confirmed that both contractions were attenuated by β3 adrenoceptor activation in both species, but with differing age dependence. In humans, specimens from mid-life subjects showed a significantly more pronounced effect of CL316,243 in attenuating carbachol-induced contractions than those from aged subjects (Cohen’s d of maximal attenuation: 1.82 in mid-life versus 0.13 in aged) without altering EC50. Conversely, attenuation of KCl responses by CL316,243 increased during ageing (Spearman correlation coefficient = -0.584, P<0.01). In rats, both KCl- and carbachol-induced contractions were significantly more attenuated by CL316,243 in samples from adolescent as compared to aged samples. Immunohistochemistry in human detrusor sections proved β3 adrenoreceptor abundance to remain unaltered during ageing. In conclusion, our findings suggest differential age-dependent changes in human β3 adrenoceptor-dependent attenuation of detrusor contraction in terms of electromechanical versus pharmacomechanical coupling; they may help understand the differential responsiveness of OAB patients to β3 agents.

Urinary beta 3-adrenoceptor as a diagnostic biomarker for overactive bladder in women

This study was to investigate urinary beta 3-adrenoceptor concentration as a biomarker for overactive bladder (OAB) and predictor of treatment outcomes in women receiving the beta 3-adrenoceptor agonist mirabegron. The study comprised 50 women identified with OAB and 35 women considered as healthy controls. All women with OAB received daily dosage of 50 mg of mirabegron for 12 weeks. Bladder diaries, OAB-related questionnaires, and global response assessment scale (GRAS) data were collected. Urinary beta 3-adrenoceptor concentration was measured through enzyme-linked immunosorbent assay. All OAB-related questionnaires and GRAS indicated improved posttreatment urinary health. After mirabegron treatment, the frequency of micturition and urgency episodes decreased, but the urinary beta 3-adrenoceptor/creatinine (Cr) ratio increased. The urinary beta 3-adrenoceptor/creatinine ratio was identified as a sensitive biomarker for OAB with a confidence interval of 0.656 to 0.856 (p < 0.001). A negative correlation (− 0.431, p = 0.040) between this biomarker and health-related quality of life (HRQL) scores. The Beta 3-adrenoceptor/Cr levels increased significantly in the treatment-responsive group, while they remained unchanged in the unsatisfactory outcome group. This study shows that 12 weeks of mirabegron treatment improves OAB symptoms and HRQL. Furthermore, urinary beta 3-adrenoceptor concentration may be a diagnostic biomarker for OAB.

Enhancing fentanyl antinociception and preventing tolerance with α-2 adrenoceptor agonists in rats

Fentanyl (FEN) is a potent opioid analgesic used for pain management. Opioid analgesic tolerance poses a significant challenge to the clinical utility of opioid agonists. Preventing the development of tolerance to opioid analgesia is crucial for improving its efficacy and safety. The noradrenergic system is involved in pain regulation. This study examined the effects of α-2 adrenoceptor (AR) agonists, dexmedetomidine (DEX), and xylazine (XYL) on FEN tolerance and antinociception, and their impact on μ-opioid receptor (MOR) expression in the posterior horn of the spinal cord (SC). Male rats were divided into six groups and treated with different drug combinations for three consecutive days. Analgesia tests and motor performance assessments were conducted, followed by SC analysis using immunohistochemistry (IHC). Analgesia tests revealed the development of FEN tolerance on the second day, but the groups receiving combined drugs did not develop tolerance. Instead, FEN antinociception was enhanced, with a prolonged duration of its effects. None of the drugs caused sedation or motor impairment, and SC morphology appeared normal. MOR expression levels did not differ significantly between the groups based on IHC analysis. These findings suggest that changes in the secondary messenger system may play a role in the early development of FEN tolerance. Combining drugs can prevent tolerance, while enhancing FEN's antinociceptive effects. These results have promising implications for chronic pain management; however, further research is needed to explore the molecular effects of α-2 AR agonists on FEN tolerance. Overall, this study sheds light on the mechanism of FEN tolerance and identifies potential avenues for future research.

Social defeat stress enhances the rewarding effects of cocaine through α1A adrenoceptors in the medial prefrontal cortex of mice

Various stressors potentiate the rewarding effects of cocaine and contribute to cocaine cravings. However, it remains unclear whether psychosocial stress enhances the rewarding effects of cocaine. Accordingly, this study employed a cocaine-conditioned place preference (CPP) paradigm combined with social defeat (SD) exposure to investigate the effects of acute SD stress on cocaine reward in male mice. We found that SD stress immediately before the posttest significantly increased cocaine CPP, and systemic blockade of α1 adrenoceptors, but not β adrenoceptors, suppressed this increase. Fiber photometry recordings with GRABNE1m sensors revealed increased noradrenaline (NA) levels in the medial prefrontal cortex (mPFC) in test mice in response to attacks by aggressor mice during SD. Moreover, the SD stress-induced enhancement of CPP was effectively suppressed by intra-mPFC infusion of an α1 adrenoceptor antagonist. In vitro whole-cell recordings demonstrated that silodosin, an α1A, but not α1B or α1D, adrenoceptor antagonist, inhibited NA-induced depolarizing currents and facilitation of excitatory synaptic transmissions. Consistently, intra-mPFC silodosin infusion significantly suppressed the SD stress-induced CPP enhancement. Conversely, intra-mPFC infusion of α1A adrenoceptor agonist augmented cocaine CPP in the absence of stress exposure. Additionally, intranasal silodosin administration attenuated the SD stress-induced enhancement of CPP, and chemogenetic inhibition of mPFC excitatory neurons also suppressed the SD stress-induced CPP enhancement. Together, these findings suggest that NA stimulation of α1A adrenoceptors and the subsequent activation of mPFC pyramidal cells may contribute to SD stress-induced amplification of the rewarding effects of cocaine, and intranasal silodosin administration may hold therapeutic potential for mitigating stress-associated cocaine craving.

Foreign body ingestion due to detachment of pill dispenser tips in cats: a retrospective study of 13 cases.

The aim of this study was to evaluate and describe 13 cases in which a pet piller broke during the administration of medication, and the tip was accidentally ingested by the cat. A total of 15 presentations to the clinic were identified in a private practice database involving 13 cats in which the silicone tip broke. Two of these cats ingested foreign bodies on two separate occasions. Routine radiographic examination enabled the identification of silicone tips in all animals. On 2/15 occasions, the cats did not receive an emetic drug. Intramuscular xylazine (0.2 mg/kg) and dexmedetomidine (6 μg/kg) were administered to 12/15 and 1/15 cats, respectively. The cats were aged 3-17 years (mean age 11.00 ± 4.35 years). Vomiting occurred in 13 cats that received alpha-2 adrenoceptor agonists, although the silicone tip was recovered in only five occurrences. In 9/15 occurrences, endoscopy was performed under general inhalation anesthesia, and the silicone tip was successfully removed. Natural elimination occurred in only one case. The use of pet pillers with detachable silicone tips increases the risk of accidental foreign body ingestion by animals. Therefore, guidelines regarding safety standards for manufacturing would be beneficial. No cat in this series developed clinical signs related to the ingestion of the piller tip, probably because of the quick presentation by the owners and early intervention, including endoscopic retrieval. Surgical intervention was not required in any case, including one in which the foreign body was lodged within the small intestine before being passed naturally by the cat.

Comparative Study Between Behavior Therapy and Behavior Therapy Plus Mirabegron 50 mg in Sexually Active Men With Bothersome Overactive Bladder Symptoms - A Multicenter, Randomized Study.

We evaluated the therapeutic effects on overactive bladder (OAB) symptoms and sexual function of behavioral therapy with or without mirabegron in sexually active male patients with OAB. Mirabegron, a selective β3 adrenoceptor agonist for the treatment of OAB, has been shown to induce corpus cavernosum relaxation. In this 4-site, randomized controlled trial, 150 sexually active men with OAB were enrolled between June 2020 and May 2022. Participants were randomly allocated (1:2) into 2 treatment groups: (1) behavioral therapy alone (n = 50) and (2) a combination of mirabegron 50 mg daily and behavioral therapy (n = 100). The evaluation was based on the overactive bladder symptoms score (OABSS), the International Index of Erectile Function, the ejaculatory domain short form, the International Prostate Symptom Score, patient perception of bladder condition, quality of life, and urodynamic parameters. The therapeutic outcomes were assessed at baseline, 4 weeks, and 12 weeks. There were 65 patients (65%) in the combination subgroup and 36 patients in the behavioral therapy who completed all 12 weeks of treatment. Both groups had a statistically significant improvement in OABSS after 12 weeks of treatment. The combination therapy group achieved a statistically significant improvement in all 4 subscores of OABSS, however, the urinary frequency (P = 0.120) and urinary incontinence (P = 0.234) subscores in the behavioral therapy only group did not show a significant change. Additionally, the combination group had a significant improvement in functional bladder capacity, which was not seen in the behavioral therapy group. However, both groups did not have a significant change in erectile or ejaculatory function. Behavioral therapy combined with mirabegron had more significant impact on the improvement of OAB than behavior therapy alone. However, both groups did not have significant changes in erectile or ejaculatory function.

Effects of a new selective β3 -adrenoceptor agonist, vibegron, on bladder and urethral function in a rat model of Parkinson's disease.

Parkinson's disease caused by the loss of dopaminergic neurons induces not only motor dysfunction but also lower urinary tract dysfunction. Patients with Parkinson's disease have recently been reported to experience both urge urinary incontinence (overactive bladder) and stress urinary incontinence, the latter of which occurs when the pressure of the bladder exceeds that of the urethra. Vibegron is a highly selective novel β3 -adrenoceptor agonist approved for the treatment of overactive bladder. However, how β3 -adrenoceptor agonists affect urethral function remains unclear. In a clinical report, the urethral function of patients with Parkinson's disease was shown to be degraded. The present study aimed to investigate the effects of vibegron on lower urinary tract activity in a rat model of Parkinson's disease. In a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine injection into the substantia nigra pars compacta, we examined the effects of vibegron on bladder and urethral activity. Cystometric analysis revealed that, compared with vehicle injection, intravenous injection of 3 mg/kg vibegron significantly increased the inter-contraction interval (p < .05) and reduced voiding pressure (p < .01). However, no significant effects on urethral function were observed. The results of the present study provide corroborating evidence that bladder dysfunction is suppressed by the administration of vibegron in Parkinson's disease model rats, confirming that vibegron is effective for treating overactive bladder without further worsening urethral function. These findings may contribute to a better understanding of the mechanisms of β3 -adrenoceptor agonists.

Effects of intra-operative administration of intravenous dexmedetomidine on incidence of emergence phenomenon after general anaesthesia in adults; An observational study

Background: The occurrence of emergence agitation (EA) is the most common and practical problem faced in the immediate post-operative period during the process of Extubation under General Anaesthesia. Dexmedetomidine, an α2 adrenoceptor agonist is an excellent drug that has been shown effective to decrease the preoperative anxiety and smooth induction and emergence. Aims and Objectives: To assess the effect of intravenous dexmedetomidine primarily on EA and other complications that may occur during emergence from general anesthesia. Materials and Methods: 80 patients of either gender aged 18–65 years with ASA status I and II, undergoing various elective general and urological surgeries under general anesthesia were included in the study. Patients receiving adjuvant drug dexmedetomidine, were labelled as Group D (n=40) and those who didn’t receive any adjuvant were labelled as group C (n=40). Dexmedetomidine was given at 1 μg/kg and then maintained at infusion of 0.4 μg/kg/h till the end of the surgery for group D. The hemodynamic parameters and SpO2 were measured during the intraoperative period at various intervals of time till the end of surgery and also on arrival to the recovery room till patient was discharged from post-anesthesia care unit in both the groups. Results: The use of IV dexmedetomidine has proved significantly effective in prevention of incidence of EA with the overall incidence of agitation of 7.5% in Group D as compared to 42.5% in group C. Conclusion: Intraoperative administration of intravenous dexmedetomidine decreased the incidence of EA and other emergence phenomena like cough, pain and PONV with stable hemodynamics, safety profile, good analgesic properties and opioids sparing side effects.

Dexmedetomidine alleviates pulmonary fibrosis through the ADORA2B-Mediated MAPK signaling pathway

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronically progressive fibrotic pulmonary disease characterized by an uncertain etiology, a poor prognosis, and a paucity of efficacious treatment options. Dexmedetomidine (Dex), an anesthetic-sparing alpha-2 adrenoceptor (α2AR) agonist, plays a crucial role in organ injury and fibrosis. However, the underlying mechanisms of IPF remain unknown.MethodsIn our study, the role of Dex in murine pulmonary fibrosis models was determined by Dex injection intraperitoneally in vivo. Fibroblast activation and myofibroblast differentiation were assessed after Dex treatment in vitro. The activation of MAPK pathway and the expression of Adenosine A2B receptor (ADORA2B) were examined in lung myofibroblasts. Moreover, the role of ADORA2B in Dex suppressing myofibroblast differentiation and pulmonary fibrosis was determined using the ADORA2B agonist BAY60-6583.ResultsThe results revealed that Dex could inhibit Bleo-induced pulmonary fibrosis in mice. In vitro studies revealed that Dex suppressed TGF-β-mediated MAPK pathway activation and myofibroblast differentiation. Furthermore, Dex inhibits myofibroblast differentiation and pulmonary fibrosis via downregulating ADORA2B expression.ConclusionsOur findings suggest Dex as a potential therapeutic agent for pulmonary fibrosis. Dex may alleviate lung fibrosis and myofibroblast differentiation through the ADORA2B-mediated MAPK signaling pathway.

The Limited Use Of Dexmedetomidine For Subarachnoid Blocks In Pakistan.

Respected Madam, Dexmedetomidine is a selective alpha-2 adrenoceptor agonist. It acts by binding to the presynaptic alpha-2 adrenoceptors and inhibits the release of norepinephrine. Thereafter, it causes a decrease in the sympathetic tone and terminates the propagation of pain signals. As a result, the haemodynamic and the endocrine stress responses of the body to surgery and anesthesia are attenuated, the blood pressure and heart rate are decreased, and the requirement for other anaesthetic agents is reduced. These effects have meant that dexmedetomidine has been widely used prior to endotracheal intubation to optimize the patients and prevent the likelihood of hemodynamic adverse effects (1). In addition to its use in general anesthesia, peri-operative physicians worldwide are now becoming increasingly aware of the dexmedetomidine’s potential usefor subarachnoid blocks. A few studies have documented the efficacy of intravenous (IV) dexmedetomidine in prolonging the duration of sensory and motor blockade induced by agents such as bupivacaine, prilocaine, and ropivacaine up to 4 hours (2), (3). Recent studies have found that intrathecal administration of dexmedetomidine in combination with the local anesthetic agent yields similar benefits (4). This has been attributed to the activation of presynaptic alpha2-A receptors at locus ceruleus and the termination of pain signal propagation via the medullospinal noradrenergic pathway (4). Therefore, it is no surprise that the use of dexmedetomidine in conjunction with local anesthetics for the subarachnoid block is common practice in peri-operative physicians throughout the globe. While Pakistani peri-operative physicians are aware of the benefits of dexmedetomidine prior to endotracheal intubation (5), the same cannot be said for subarachnoid blocks induced in Pakistan. Peri-operative physicians in Pakistan are either yet to realize the potential benefits the use of dexmedetomidine can provide for subarachnoid blocks or still adhere to conventional spinal anesthesia practices. Since the effects of a conventional subarachnoid block last from 2 to 3 hours, in any case of a surgical adverse event that prolongs the surgery, severe pain, nausea, vomiting, and derangement of the hemodynamic status have been noted in patients. Often times, this results in a shift towards general anesthesia midway through the procedure. Ultimately, the postoperative stay is prolonged which directly impacts the clinical outcome and the quality of life for these patients. ---Continue

Dexmedetomidine alleviates propofol-induced neural injury in developing rats.

Propofol, a commonly used intravenous anesthetic, has been associated with neurodegeneration in the developing brain upon repeated exposure. Dexmedetomidine is an α2 adrenoceptor agonist that was previously reported to possess neuroprotective properties. Here, we confirmed the impacts of dexmedetomidine on propofol-induced neuroapoptosis and subsequent spatial learning and memory deficits in neonatal rats. We found that dexmedetomidine effectively mitigated propofol-induced spatial learning and memory impairments and improved aversive memory in developing rats. Dexmedetomidine reduced propofol-induced cell apoptosis in the hippocampus and modulated the mRNA expression of Bcl-2 and Bax. Additionally, dexmedetomidine attenuated the propofol-induced increase of inflammatory factors IL-6 and TNF-α. The reduced phosphorylation levels of Akt and CREB levels by propofol were re-activated by dexmedetomidine. In conclusion, our findings demonstrated that dexmedetomidine effectively mitigated propofol-induced cognitive and memory impairments in developing rats by modulating apoptosis and reducing inflammation via activating the Akt/CREB/BDNF signaling pathway. These findings suggest potential strategies to protect the developing brain from the adverse effects of anesthetics and improve patient care in pediatric anesthesia practice.

Postoperative analgesic effect of hyaluronidase versus dexamethasone as additives to bupivacaine in transversus abdominis plane block for inguinal hernia repair: prospective, randomized, and double-blinded controlled study

Background Inguinal hernia repair is associated with severe postoperative pain. Transversus abdominus plain block has been proved to provide effective analgesia for somatic lower abdominal pain. Several adjuvants have been added to local anesthetic to improve the quality of analgesia. This study compares the additive effect of hyaluronidase versus dexamethasone to improve the quality of analgesia of transversus abdominus plain block for inguinal hernia repair. Patients and methods This prospective, randomized, controlled, and double-blind study was carried out in Sohag University Hospital between November 2020 and February 2021. Seventy-five participants scheduled for inguinal hernia repair were included and randomly assigned into control, hyaluronidase, and dexamethasone groups. Exclusion criteria were neurological, psychiatric, neuromuscular, cardiovascular, pulmonary, renal, hepatic disease, alcoholism or drug abuse, pregnancy or lactating women, and patients receiving adrenoceptor agonist or antagonist therapy or chronic analgesic therapy, patients with morbid obesity, coagulopathy, and known allergy to study medications, and sepsis surgical scar at the site to be operated upon and those who refuse. We targeted from this study to assess time to first analgesia, consumption of morphine, and visual analog scale at rest and during physical activity. Also, we targeted to assess heart rate, noninvasive blood pressure, SpO2%, and adverse effects (nausea and vomiting, respiratory depression). Results Our study showed comparable analgesic efficacy for hyaluronidase versus dexamethasone with longer time to the first request of analgesia, less morphine consumption, and less side effects compared with these two groups to the control group. Conclusion Adding hyaluronidase or dexamethasone to bupivacaine not only prolonged the duration of analgesia and decreased the consumption of opioids but also decreased the incidence of adverse effects.

Effect of Oral Clonidine on Epidural Anaesthesia in Hip Replacement Surgery

Background: Analgesia, sedation, hemodynamic stability, and improved postoperative outcomes are important for orthopedic surgery. Researchers have found clonidine, a centrally acting partial α2 adrenoceptor agonist serves this well. This study was conducted to find out the effect of oral clonidine on epidural anesthesia in hip replacement surgery.Methods: This open-level, randomized control trial (RCT) was conducted at the Department of Anesthesia, Analgesia, and Intensive Care Medicine, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. A total of 60 patients were included in the trial; 30 in the Intervention (clonidine) group and another 30 in the control group (placebo). Sensory block, motor block, visual analog scale (VAS), and vital parameters were assessed. Ethical approval was taken from the institutional review board (IRB) of BSMMU and informed written consent was taken from each participant.Results: The onset of sensory blockade was significantly quick (intervention group vs control group:15.8±1.3 min vs 19.4±2.0 min) and analgesia sustained significantly for a prolonged period (p-value: 0.003) higher in the intervention group (256.1±18.7 min) than the control group (192.9±16.1 min). After 5 and 10 minutes of intervention; significantly (p-value: 0.001) lower systolic blood pressure was observed in the intervention group. And in 15 and 45 minutes, diastolic blood pressure was significantly (p-value: 0.013, 0.001; respectively) higher in the intervention group.Conclusion: Oral clonidine gave early onset and prolonged duration of sensory blocking, analgesia without major hemodynamic instability, and post-operative side effects.

Dexmedetomidine attenuates sleep deprivation-induced inhibition of hippocampal neurogenesis via VEGF-VEGFR2 signaling and inhibits neuroinflammation

Long periods of sleep deprivation (SD) have serious effects on health. While the α2 adrenoceptor agonist dexmedetomidine (DEX) can improve sleep quality for patients who have insomnia, the effect of DEX on cognition and mechanisms after SD remains elusive. C57BL/6 mice were subjected to 20 h SD daily for seven days. DEX (100 μg/kg) was administered intravenously twice daily (at 1:00 p.m. and 3:00 p.m.) during seven days of SD. We found that systemic administration of DEX attenuated cognitive deficits by performing the Y maze and novel object recognition tests and increased DCX+, SOX2+, Ki67+, and BrdU+NeuN+/NeuN+ cell numbers in the dentate gyrus (DG) region of SD mice by using immunofluorescence, western blotting, and BrdU staining. DEX did not reverse the decrease in DCX+, SOX2+, or Ki67+ cell numbers in SD mice after administration of the α2A-adrenoceptor antagonist BRL-44408. Furthermore, the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) expression was upregulated in SD+DEX mice compared with SD mice. Luminex analysis showed that the neurogenic effects of DEX were possibly related to the inhibition of neuroinflammation, including IL-1α, IL-2, CCL5, and CXCL1. Our results suggested that DEX alleviated the impaired learning and memory of SD mice potentially by inducing hippocampal neurogenesis via the VEGF-VEGFR2 signaling pathway and by suppressing neuroinflammation, and α2A adrenoceptors are required for the neurogenic effects of DEX after SD. This novel mechanism may add to our knowledge of DEX in the clinical treatment of impaired memory caused by SD.

ANTI-INFLAMMATORY EFFECTS OF SALBUTAMOL ON HUMAN BRONCHIAL EPITHELIAL CELLS STIMULATED BY CIGARETTE SMOKE EXTRACT

Cigarette smoking, the major cause of chronic obstructive pulmonary disease (COPD), induces activation of pro-inflammatory pathways in the airway epithelium. Salbutamol, a selective and short-acting ?2-adrenoceptor agonist, is used for bronchospasm relief in patients with asthma and COPD. In addition, salbutamol also presents anti-inflammatory effects. Here, we evaluated whether salbutamol (10-5-10- 7 M) can reduce on bronchial epithelial cells (BEAS-2B cells) the inflammatory parameters induced by cigarette smoke extract (CSE; 1%). After 24h, Salbutamol reduced the IL-1? production induced by CSE in a concentration-response manner. Salbutamol (10-6 M) reduced the IL-8 production and increased the IL-10 production on CSE-stimulated cells. Also, salbutamol (10-6 M) decreased the ICAM-1 expression and the reactive oxygen species production. These anti-inflammatory effects could be associated with the down regulation of activation of NF-?B. Salbutamol may be a potential alternative treatment to airway inflammation caused by cigarette smoking such as in COPD patients.

Analysis of Urinary Retention Caused by Selective β 3-adrenoceptor Agonists Using the Japanese Adverse Drug Event Report Database (JADER).

Overactive bladder (OAB) is a frequent chronic disorder which impairs quality of life by frequent, uncontrollable urination. Newly developed selectiveβ 3-adrenoceptor agonists (sβ 3-agonists) have the same efficacy in treating OAB but significantly fewer side effects than the traditionally used anti-muscarinics. However, safety data on these compounds are scarce. In this study, we analysed the occurrence of adverse effects in patients taking sβ 3-agonists and their characteristics using the JADER database. The most frequently reported adverse effect associated with the use of sβ 3-agonists was urinary retention [mirabegron; crude reporting odds ratios (ROR): 62.1, 95% confidence interval (CI): 52.0-73.6, P<0.001, vibegron; crude ROR: 250, 95% CI : 134-483, P<0.001]. Data from patients with urinary retention were stratified by sex. In both men and women, the rate of urinary retention was higher when using the mirabegron/anti-muscarinic drug when compared to mirabegron monotherapy; its occurrence was higher in men with a history of benign prostatic hypertrophy than in those without. Weibull analysis showed that approximately 50% of sβ 3 agonist-induced urinary retention occurred within 15 days after initiation of treatment, and then gradually decreased. Although sβ 3-agonists are useful against OAB, they may induce several side effects, especially urinary retention, which can further evolve into more severe conditions. Urinary retention occurs more frequently in patients concomitantly taking medication that either increases urethral resistance or has organic factors that block the urethra. When using sβ 3-agonists, the concomitantly used medications and underlying diseases should be thoroughly reviewed, and safety monitoring should be instituted early during the treatment.