Adrenergic Agonists Research Articles

Abstract We007: High Throughput 3D-Printed Human Engineered Heart Tissues for Cardiac Disease Modeling

While cell models have been used to study cardiac diseases, there is currently no standardization or fully mature in vitro system. Obtaining a mature cardiomyocyte (CM) phenotype is necessary to create a physiologically relevant environment and accurately model and study cardiac diseases. Increased success in maturation of human induced pluripotent stem cell derived CMs (hiPS-CMs) has been achieved in 3D in vitro models in the form of engineered heart tissues (EHTs). Digital light processing (DLP) offers a high throughput and efficient method to fabricate hydrogels that recapitulate properties of native tissues. In this study, we use DLP-printed EHTs to seed and mature differentiated hiPS-CMs and test their potential for modeling pathological cardiac hypertrophy. To further encourage maturity of CMs, we utilized a low glucose maturation medium supplemented with fatty acids. DLP-printed EHTs displayed high reproducibility and increased CM maturity. To determine degree of maturity of our system, we performed RT-qPCR, western blot analysis, and immunofluorescence (IF) microscopy. We found increased expression of fatty-acid transport and beta oxidation genes and improved sarcomere alignment compared to 2D hiPS-CMs. To model pathological cardiac hypertrophy, we used two different approaches: 1. acute adrenergic agonism with isoproterenol and phenylephrine; 2. chronic culturing of EHTs in pathologically stiff conditions. To assess pathology, we conducted RT-qPCR, western blot, ELISA, IF microscopy, and functional analyses. We found that agonist-treated EHTs displayed increased pathology-associated gene expression compared to standard 2D hiPS-CMs. Both agonist-treated and stiff EHTs had increased secreted B-Type Natriuretic Peptide (BNP) and phosphorylation of proteins involved in pathological remodeling, including ERK and P38. Additionally, we observed increased nuclear area, increased calcium handling, and increased contractile force in the treatment groups. In conclusion, we have established a high throughput, reproducible, mature EHT platform that can be used to model pathological cardiac hypertrophy. This platform can be easily adopted by other laboratories to study a wide array of cardiac diseases.

Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome.

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either KATP GOF or acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cantú syndrome.

Adrenergic Agonists Activate Transcriptional Activity in Immortalized Neuronal Cells From the Mouse Suprachiasmatic Nucleus.

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.

ADVANTAGES OF USING DEXMEDETOMIDINE AS AN ADJUVANT IN LAPAROSCOPIC BARIATRIC SURGERIES

The global rise in obesity rates has necessitated an increased frequency of bariatric surgeries, posing intricate challenges in anesthesia management. Dexmedetomidine, an α2-adrenergic receptor agonist, has emerged as a potential adjunct to general anesthesia in this context. This study aimed to evaluate the efficacy and safety of dexmedetomidine in 1306 adult patients undergoing elective bariatric surgery between January 2017 and September 2023, comparing outcomes with a placebo group.Dexmedetomidine was administered during both the maintenance phase of anesthesia. Key parameters including intraoperative and postoperative complications, analgesic requirements, hemodynamics, and recovery profiles were meticulously monitored and analyzed. Dexmedetomidine demonstrated sedative and analgesic-sparing effects, coupled with cardiovascular stabilization and preservation of respiratory function. Notably, it significantly reduced the utilization of anesthetic drugs, postoperative opioids, and propofol during the surgical procedure. Furthermore, dexmedetomidine exhibited efficacy in attenuating propofol injection pain, mitigating stress responses during the critical phase of extubation, and diminishing postoperative pain along with associated analgesic requirements. However, a nuanced approach to dosage was imperative, as higher doses correlated with delayed respiratory recovery and an increased incidence of bradycardia.To summarize, dexmedetomidine as an adjuvant to general anesthesia in bariatric surgery presents notable advantages in enhancing recovery profiles, mitigating complications, and improving patient comfort. Optimal dosing strategies are paramount to harnessing its benefits while mitigating potential adverse effects, thereby optimizing perioperative care in this patient population.

Utility of an Alpha-1 Adrenergic Agonist in the Management of Chylothorax: A Case Series and Management Algorithm.

The initial diagnosis of chylothorax is based on clinical suspicion and proper imaging.The clinical success of midodrine use as a first-line medical treatment for chylothorax will support the use of midodrine before considering invasive procedures.We propose a management algorithm for patients with chylothorax that will stimulate researchers to conduct prospective studies to assess its efficacy.

Perioperative use of erythrocyte-containing blood components in children during the first months of life

BACKGROUND: Anemia can be diagnosed before surgery, occur during surgical treatment, and develop and worsen in the postoperative period in children with surgical diseases. Anemia is associated with increased morbidity, severe complications, and even death after surgical treatment. AIM: This study aimed to determine the frequency and indications for transfusion of red blood cell-containing components in the perioperative period in children in the first months of life. MATERIALS AND METHODS: This cohort study included 187 children from the G.N. Speransky Children’s Hospital No. 9. The hemoglobin, hematocrit, and red blood cell levels were studied as well as the volume of intraoperative blood loss, hemodynamic parameters, the presence of hemorrhagic syndrome, and the use of adrenomimetics in the perioperative period. The stage of the perioperative (pre, intra, or post) period at which the transfusion of erythrocyte-containing components was conducted was recorded. Statistical data analysis was performed using the statistical computing environment R 4.3.0. RESULTS: The average age of the children at the time of surgery was 41 (16.5–63) days [5.9 (2.4–9) weeks]. Sixty-four (34.2%) children were in their first month of life, 72 (38.5%) in their second month, and 51 (27.3%) in their third month, and 76 (40.6%) children were premature. The surgeries were emergent and urgent in 102 (54.5%) children and planned in 85 (45.5). The hemoglobin, hematocrit, and erythrocyte levels at which erythrocyte-containing components were transfused were 82 (77–90) g/l, 25% (22%–28%), and 2.8 (2.3–3.0) × 1012/l, respectively. The volume of erythrocyte-containing components was 54.0 (32.9–74.4) ml (10–30 ml/kg/child’s body weight). The need for and duration of artificial pulmonary ventilation in the postoperative period were 31 (72.1%) cases and 48.5 (22.5–190) hours, respectively, in contrast to children who did not receive transfusions of red blood cell-containing components—57 (39.6%) cases and 40 (22–96) hours. The indication for transfusion was anemia of varying degrees; however, 74.4% of children received adrenergic agonists simultaneously with transfusion to stabilize hemodynamics: dopamine monotherapy in 23 (74.2%) and combinations of dopamine and norepinephrine in 8 (25.8%) at 10 (8–12) mcg/kg/min and 0.2 (0.15–0.4) mcg/kg/min, respectively. CONCLUSION: The frequency of use of red blood cell-containing components was 23%. Threshold values for transfusion of erythrocyte-containing components Hb, Ht, and erythrocytes were 82 (77–90) g/l, 25% (22%–28%), and 2.8 (2.3–3.0) × 1012/l, respectively.

Chronic β3 adrenergic agonist treatment improves brain microvascular endothelial function and cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction. Hence, in the present study, we aimed to test whether thermogenic stimulation, an intervention known to improve adipose and systemic metabolism by increasing cellular energy expenditure, could mitigate brain endothelial dysfunction and improve cognition in the aging population. Eighteen-month-old old C57BL/6J mice were treated with saline or CL (β3-adrenergic agonist) for 6 weeks followed by functional analysis to assess endothelial function and cognition. CL treatment improved neurovascular coupling responses and rescued brain glucose uptake in aged animals. In addition, CL treatment also attenuated blood-brain barrier leakage and associated neuroinflammation in the cortex of aged animals. More importantly, these beneficial changes in microvascular function translated to improved cognitive performance in radial arm water maze and Y-maze tests. Our results suggest that β3-adrenergic agonist treatment improves multiple aspects of brain microvascular endothelial function and can be potentially repurposed for treating age-associated cognitive decline.

Salbutamol, a Short Acting Beta-2 Agonist, Reduces Risk and Improves Prognosis of Prostate Cancer.

Beta-blockers, a class of drugs commonly used to manage blood pressure, have been the subject of research regarding their relationship to prostate cancer (PC) risk, prognosis, and treatment. Beta-blockers reduce risk and improve the prognosis of PC. Perioperative use of a nonselective beta-blocker improves outcomes after radical prostatectomy. However, a related class of drugs, beta-2 adrenergic agonists, has received little attention in PC. We studied the relationship of the beta-2 adrenergic agonist salbutamol to PC risk and survival. We analyzed Food and Drug Administration MedWatch data to determine whether salbutamol could influence the risk of PC. We used UK Biobank data to assess the effect of salbutamol on PC survival. Salbutamol significantly reduces PC risk, proportional reporting ratio, and 95% CI (lower bound; upper bound): 0.131 (0.11; 0.155) and improves prognosis. Mean survival was 7.35 years for subjects not taking salbutamol, and 10.5 years for subjects taking salbutamol (P = 0.041, log-rank test. To adjust for the effect of age, we performed proportional hazards regression, survival time-dependent variable, age, and salbutamol use independent variables. Salbutamol use was significantly related to survival time (P = 0.016) and independent of the significant effect of age (P < 0.001). We found a lower proportion of PCs in salbutamol-treated people, but we have not demonstrated that PC risk is reduced (there is no proof of causality). There is no causality relationship between salbutamol and the survival of patients with PC treated with salbutamol versus those not treated with the drug. Yet, there is a trend in favor of salbutamol-treated patient survival. Therefore, salbutamol and other beta-adrenergic agonists might represent a new class of drugs for the treatment of PC.

Local Anaesthesia Techniques in Dogs and Cats: A Review Study

The use of multimodal anaesthesia and analgesia is desirable as part of a complete analgesic plan. Analgesic strategies for perioperative pain treatment include combinations of drugs with different means of action to increase their efficacy and to reduce the required doses and adverse effects. Local anaesthetics prevent the transduction and transmission of painful stimuli through their action on neuronal cell membranes. They undergo minimal systemic absorption and are therefore ideal alternatives to drugs that could result in systemic toxicity. Numerous benefits have been recognised for the use of local anaesthesia, such as a decreased need for systemic analgesics and decreased hospitalisation periods. Local anaesthetics have been used in veterinary medicine in several ways. Anatomical landmarks can be used to identify the target nerves and the clinician can employ an electrical nerve stimulator or ultrasound guidance to perform a more accurate injection. Local anaesthetic techniques can implement other drugs, apart from or in combination with local anaesthetics, such as opioids, α2−adrenergic agonists or vasoconstricting agents. This review article presents and discusses the most common techniques of local anaesthetic use in small animals, with the aim of providing the clinician with further and comprehensive information regarding the analgesic options during the perioperative period.

Prenatal LPS leads to increases in RAS expression within the PVN and overactivation of sympathetic outflow in offspring rats

The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) are two major blood pressure-regulating systems. The link between the renal and cerebral RAS axes was provided by reflex activation of renal afferents and efferent sympathetic nerves. There is a self-sustaining enhancement of the brain and the intrarenal RAS. In this study, prenatal exposure to lipopolysaccharide (LPS) led to increased RAS activity in the paraventricular nucleus (PVN) and overactivation of sympathetic outflow, accompanied by increased production of reactive oxygen species (ROS) and disturbances between inhibitory and excitatory neurons in PVN. The AT1 receptor blocker losartan and α2 adrenergic receptor agonist clonidine in the PVN significantly decreased renal sympathetic nerve activity (RSNA) and synchronously reduced systolic blood pressure. Prenatal LPS stimulation caused H3 acetylation at H3K9 and H3K14 in the PVN, which suggested that epigenetic changes are involved in transmitting the prenatal adverse stimulative information to the next generation. Additionally, melatonin treatment during pregnancy reduced RAS activity and ROS levels in the PVN; balanced the activity of inhibitory and excitatory neurons in the PVN; increased urine sodium secretion; reduced RSNA and blood pressure. In conclusion, prenatal LPS leads to increased RAS expression within the PVN and overactivation of the sympathetic outflow, thereby contributing to hypertension in offspring rats. Melatonin is expected to be a promising agent for preventing prenatal LPS exposure-induced hypertension.

Update on Overactive Bladder Therapeutic Options.

Millions of Americans are burdened by overactive bladder (OAB) syndrome and the psychogenic and economic hardships that accompany it. Several theories attempt to explain OAB as a neurogenic dysfunction, myogenic dysfunction, urothelial dysfunction, or decreased expression of a channel protein secondary to bladder outlet obstruction. Given that the etiology of OAB is a working theory, the management of OAB is also an evolving subject matter in medicine. There are uncertainties surrounding the pathophysiology of OAB, the strength of a clinical diagnosis, and accurate reporting because of the disease's stigma and decreased use of health care. This is a narrative review that used PubMed, Google Scholar, Medline, and ScienceDirect to review literature on current and future OAB therapies. Currently, first-line treatment for OAB is behavioral therapy that uses lifestyle modifications, bladder-control techniques, and psychotherapy. Second-line therapy includes antimuscarinic agents or beta 3 adrenergic agonists, and studies have shown that combination therapy with antimuscarinics and beta 3 adrenergic agonists provides even greater efficacy than monotherapy. Third-line therapies discussed include onabotulinumtoxinA, posterior tibial nerve stimulation, and sacral neuromodulation. OnabotulinumtoxinA has been FDA-approved as a nonpharmaceutical treatment option for refractory OAB with minimal side effects restricted to the urinary tract. Posterior tibial nerve modulation and sacral neuromodulation are successful in treating refractory OAB, but the costs and complication rates make them high-risk procedures. Therefore, surgical intervention should be a last resort. Estrogen therapy is effective in alleviating urinary incontinence in postmenopausal women, consistent with the association between estrogen deficiency and genitourinary syndrome. Potassium channel activators, voltage-gated calcium channel blockers, and phosphodiesterase inhibitors look to be promising options for the future of OAB management. As new therapies are developed, individuals with OAB can better personalize their treatment to maximize their quality of life and cost-effective care.

A comparative study of efficacy of intravenous dexmedetomidine with perineural dexmedetomidine as adjuvant to ropivacaine in supraclavicular brachial plexus block in upper limb surgery

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

The Discovery of Novel α2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening.

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.

A Comparative Study of Epidural 0.75% Ropivacaine with Dexmedetomidine and 0.75% Ropivacaine Alone in Infra Umbilical Surgeries

Background: Different adjuvants are currently being employed alongside local anesthetics to extend the duration of pain relief during and after epidural block procedures for infra-umbilical surgeries. Dexmedetomidine is a recently popular neuroaxial adjuvant that acts as an extremely specific α2 adrenergic agonist. The purpose of this research is to evaluate and contrast the impacts of combining epidural giving of 0.75% ropivacaine with dexmedetomidine to the effects of using 0.75% ropivacaine alone. The focus was on evaluating the cardiovascular, sedative with analgesics potentiating The facets of these treatments.Methods: The research was randomized and studied in a double-blind, prospective fashion. It comprised 50 patients from the The individuals included in this study were classified as undertaking lower limb procedures were those who met the following criteria: Female, the age from 20 to 65, and holding American Society of Anesthesiologists Grades I and II. Informed agreement was given before the start of the study. Randomly, participants were divided into two groups, each consisting of 25 individuals. A 15 mL ropivacaine solution containing 0.75% was utilized to administrate epidural anesthesia to a group I (n = 25). In contrast, group II (n = 25) received the same 15 mL ropivacaine solution supplemented with 0.6 μg/kg of dexmedetomidine. The study compared two groups in terms of their hemodynamic changes and block characteristics. These characteristics included the time it took for analgesia to start at T10, the peak level of sensory perception analgesia achieved, the time it took for the sensory and motor block to reach their maximum levels, the time it took for the block to regress at the dermatome S1, and the time required to administer the initial quantity rescue effort analgesics to be administered within a 24-hour period.Results: Sedation score (p = 0.001), motor block intensity (p 0.001), and onset of action (p 0.001) were all significantly greater in the dexmedetomidine group. Additionally, motor block duration (p 0.001) was significantly longer. No significant differences were observed in the occurrence of maximal pain relief, low BP, or slow HR (p &gt; 0.05), according to the study. There was a negligible and comparable occurrence of adverse effects (such as vertigo, tremor, and SpO2&amp;LT;90%) across all categories (p &gt; 0.05). Conclusion: The research revealed noteworthy distinctions commencing with the inhibition of neural functions differs between the dexmedetomidine and ropivacaine groups, with dexmedetomidine producing more intense sustained motor block and sensory block. Both groups had greater sedation scores.

Ophthalmic phentolamine (Ryzumvi) for drug-induced mydriasis.

The FDA has approved a 0.75% ophthalmic solution of the alpha-adrenergic antagonist phentolamine (Ryzumvi – Viatris) for treatment of mydriasis produced by adrenergic agonists such as phenylephrine or parasympatholytic agents such as tropicamide in patients ≥3 years old. Ryzumvi is the first drug to be approved in the US for reversal of pharmacologically induced mydriasis.

β2-adrenergic receptor activation decreases the mechanical sensitivity of rat masticatory muscle afferent fibres.

Activation of β2 adrenergic receptors reduces cutaneous mechanical pain thresholds in rats. While β2 adrenergic receptor activation may contribute to mechanisms that underlie temporomandibular joint pain, its effect on masticatory muscle pain sensitivity is uncertain. The current study sought to determine the extent to which β adrenergic receptors are expressed by masticatory muscle afferent fibres, and to assess the effect of local activation of these receptors on the mechanical sensitivity of masticatory muscle afferent fibres in rats. Trigeminal ganglion neurons that innervate the rat (n = 12) masseter muscle and lower lip were identified by tissue injection of fluorescent dyes and were then stained with antibodies against β1 or β2 adrenergic receptors. Extracellular recordings from 60 trigeminal ganglion neurons that innervate the masticatory muscle were undertaken in a second group of anaesthetised rats of both sexes (n = 37) to assess afferent mechanical activation thresholds. Thresholds were assessed before and after injection of the β adrenergic receptor agonists into masticatory muscle. β1 and β2 adrenergic receptor expression was greater in labial skin than in masticatory muscle ganglion neurons (p < .05, one-way ANOVA, Holm-Sidak test). There was a higher expression of β2 adrenergic receptors in masticatory muscle ganglion neurons in males than in females. The mixed β agonist isoproterenol increased afferent mechanical activation threshold in male but not female rats (p < .05, Mann-Whitney test). In male rats, salbutamol, a β2 selective agonist, also increased afferent mechanical activation threshold but hydralazine, a vasodilator, did not (p < .05, Mann-Whitney test). Activation of β2 adrenergic receptors decreases the mechanical sensitivity of masticatory muscle afferent fibres in a sex-related manner.

Ingestion of Fluids of the Ocular Surface Containing Eye Drops of Imidazole Derivatives-Alpha Adrenergic Receptor Agonists as Paragons.

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

Xylazine awareness, desire, use and exposure: Preliminary findings from the Rhode Island community-based drug checking cohort study

BackgroundXylazine is an ⍺2 adrenergic receptor agonist and a veterinary sedative that can cause severe health complications yet interventions to detect and treat human exposure remain underdeveloped. Community-based drug checking services (DCS) involve the testing of small amounts of drugs to increase community knowledge of unregulated supplies and decrease harms. This study characterized xylazine awareness, desire, use and exposure among people who use drugs (PWUD) in Rhode Island, US. MethodsWe analyzed data from an ongoing PWUD cohort study. In 2023, 125 PWUD were enrolled and surveyed. Using point-of-care Fourier Transform infrared spectroscopy (FTIR-S), we tested a drug sample from each participant onsite and confirmed the results offsite at a laboratory. Results were conveyed in real-time, along with harm reduction education, referrals to resources and care. ResultsVirtually all participants (99.2 %) wanted to avoid xylazine exposure. Half (51.2 %) knew what xylazine was, and a quarter (26.1 %) suspected previous exposure. Xylazine exposure was primarily surmised through sedating (45.2 %) and ulcerative (29.0 %) effects. Only 8.8 % of participants submitted a sample that they expected to contain xylazine. Xylazine was detected in 14.5 % of samples using FTIR-S and in 21.4 % of samples using a dual laboratory approach of gas chromatography mass spectrometry (GC-MS) and liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). Participants thought that these xylazine-positive samples were fentanyl (78.3 %), heroin (13.0 %), or Percocet® (8.7 %). ConclusionImplementing point-of-care DCS at harm reduction organizations could be useful in rapidly increasing xylazine awareness and engaging at-risk individuals in prevention, harm reduction, treatment, and rapid care for xylazine-related wounds.

Dexmedetomidine for reducing succinylcholine-induced myalgia in patients undergoing electroconvulsive therapy: A randomised controlled trial.

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

Ryzumvi: pioneering advances in countering drug-induced mydriasis

This article discusses the prevalence and impact of pharmacologically-induced mydriasis, a condition where the pupil becomes excessively dilated due to certain drugs. It highlights the challenges faced by medical professionals in dealing with this condition and the limitations of current treatments, like pilocarpine and dapiprazole, which come with systemic side effects and specific contraindications, limiting their regular use. The article introduces Ryzumvi, a novel ophthalmic solution approved by the US FDA, which effectively reverses mydriasis caused by adrenergic agonists and antimuscarinic drugs. The article provides insights into its mechanism of action, clinical efficacy, pharmacokinetics, safety, and tolerance based on extensive clinical trials. It emphasizes its rapid onset of action and effectiveness in restoring pupils to their initial size. It also underlines the potential for expanded applications, including in pediatric patients, solidifying its importance in the field of ophthalmology. Furthermore, Ryzumvi represents a promising advancement in managing pharmacologically-induced mydriasis, offering swift and effective relief while highlighting the importance of adhering to safety precautions and the continuous research and development efforts in ophthalmology to comprehensively address vision-related disorders and enhance patient outcomes.