-
Veterinary Immunology and... Jun 2024Polymorphonuclear cells (PMN) provide a rapid response to infection and tissue damage and stress can modify these critical innate immune defences. The study of...
Polymorphonuclear cells (PMN) provide a rapid response to infection and tissue damage and stress can modify these critical innate immune defences. The study of adrenergic receptor (AR) expression and function in bovine PMNs is limited but both neutrophils and eosinophils express numerous AR genes but differ significantly in their expression of individual AR genes. A flow cytometric technique was developed to differentiate between bovine neutrophils and eosinophils so both neutrophil and eosinophil responses to adrenergic agonists could be analysed. Neutrophils and eosinophils displayed significantly different changes in CD11b, L-selectin, and CD44 expression when activated by bovine serum opsonized zymosan and recombinant bovine interferon gamma. The responses of activated and resting neutrophils and eosinophils were then compared following stimulation with endogenous adrenergic agonists, epinephrine (E) norepinephrine (NE), and synthetic agonists targeting α1-, α2-, or β-ARs. Both resting and activated neutrophils and eosinophils displayed differences in iROS, CD44, and L-selectin expression following stimulation with E and NE. Resting neutrophils displayed pro-inflammatory responses to both E and NE, while resting eosinophils displayed a pro-inflammatory response to only NE. No single synthetic adrenergic agonist fully recapitulated responses observed with either E or NE and responses to adrenergic agonists were dose-dependent. In conclusion, bovine eosinophils and neutrophils responded to multiple adrenergic agonists by altering expression of proteins involved in immune surveillance and pro-inflammatory responses. Significant differences in neutrophil and eosinophil responses to adrenergic agonists are consistent with their differences in AR gene expression. This highlights the importance of analysing separately these two PMN subpopulations when investigating the effects of either endogenous or synthetic AR agonists.
Topics: Animals; Cattle; Neutrophils; Eosinophils; L-Selectin; Norepinephrine; Epinephrine; Adrenergic Agonists; Hyaluronan Receptors; Flow Cytometry; CD11b Antigen; Neutrophil Activation; Receptors, Adrenergic
PubMed: 38669937
DOI: 10.1016/j.vetimm.2024.110758 -
Current Neurovascular Research 2021Neovascular age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of blindness in elderly people. Anti-vascular endothelial...
BACKGROUND
Neovascular age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of blindness in elderly people. Anti-vascular endothelial growth factor (anti-VEGF)-drugs are used to treat AMD patients; however, some patients are resistant to these therapies.
OBJECTIVE
The purpose of this study was to investigate the anti-angiogenic effects of α2-adrenergic agonists, including guanabenz and clonidine.
METHODS
We evaluated the anti-angiogenic effects of α2-adrenergic agonists in human retinal microvascular endothelial cells (HRMECs). A proliferation assay was conducted, and the migration ratio was evaluated. In a laser-induced CNV model, guanabenz and clonidine were delivered via intraperitoneal injection or implantation of an osmotic pump device. Fourteen days following CNV induction, CNV lesion size and fundus fluorescein angiography (FFA) were evaluated.
RESULTS
Guanabenz and clonidine inhibited VEGF-induced retinal endothelial cell growth and migration. In the CNV model mice, CNV lesion sizes were reduced by intraperitoneal administration of guanabenz or clonidine. Data, including body weight, systolic blood pressure, and heart rate showed that guanabenz (0.5 and 2.0 mg/kg/day) had little effect on these parameters; conversely, a high dose of clonidine (1.0 mg/kg/day) did affect these parameters. Additionally, clonidine did not affect CNV size, but continuous administration of guanabenz attenuated both CNV size and leakage from neovessels.
CONCLUSION
Our study suggests a key role for α2-adrenergic receptors during CNV formation. Therefore, we suggest that α2-adrenergic receptor agonists may represent novel therapeutic drugs for patients with neovascular AMD.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Cell Movement; Cell Proliferation; Choroidal Neovascularization; Clonidine; Disease Models, Animal; Endothelial Cells; Guanabenz; Humans; Male; Mice; Retina; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 34011258
DOI: 10.2174/1567202618666210518133634 -
Allergy Jul 2021
Topics: Adrenergic beta-2 Receptor Agonists; Asthma; Doping in Sports; Humans; Sympathomimetics
PubMed: 34192372
DOI: 10.1111/all.14830 -
American Journal of Physiology.... Mar 2021Prolonged supplementation with the β-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β-adrenoceptor (β-AR)-mediated effects in the...
Prolonged supplementation with the β-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β-adrenoceptor (β-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to-especially diabetic-humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to β- and β-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient () mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between and . Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in and , respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, β-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans. Improvements in whole body glucose homeostasis of rodents upon prolonged β-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the β-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and mice, indicating that β-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.
Topics: Adipose Tissue, Brown; Adrenergic beta-2 Receptor Agonists; Animals; Clenbuterol; Diet, High-Fat; Drug Administration Schedule; Glucose; Glucose Intolerance; Homeostasis; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, Adrenergic, beta-2; Thermogenesis; Time Factors; Uncoupling Protein 1
PubMed: 33522400
DOI: 10.1152/ajpendo.00324.2020 -
Current Urology Reports Oct 2020This paper discusses the recent evidence supporting beta 3 adrenergic agonists as the preferred pharmacological management of overactive bladder syndrome. (Review)
Review
PURPOSE OF THE REVIEW
This paper discusses the recent evidence supporting beta 3 adrenergic agonists as the preferred pharmacological management of overactive bladder syndrome.
RECENT FINDINGS
Mirabegron has a similar efficacy profile to first-line antimuscarinics with favorable adverse effects profile. Treatment of OAB with beta-3 adrenergic agonist should be favored in patients at higher risk of anticholinergic adverse events. The efficacy and tolerability of beta-3 adrenergic agonists are consistently reported in older OAB patients, whether used alone or with other antimuscarinics. Mirabegron is cost-effective in treating OAB unless the symptoms were severe or refractory. Combination therapy of mirabegron and other pharmacotherapy has proven to be efficient in controlling OAB symptoms without inducing serious add-on adverse effects. While beta-3 adrenergic agonists bear favorable advantages in OAB treatment, physicians should perform a thorough and careful pre-treatment planning to optimize treatment benefits and adherence.
Topics: Acetanilides; Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-3 Receptor Agonists; Cholinergic Antagonists; Cost-Benefit Analysis; Humans; Muscarinic Antagonists; Phosphodiesterase Inhibitors; Pyrimidinones; Pyrrolidines; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive; Urological Agents
PubMed: 33090278
DOI: 10.1007/s11934-020-01003-z -
Acta Clinica Croatica Sep 2022Modern approach in surgical treatment and in managing acute and chronic pain is nowadays more and more based on the implementation of all possible techniques of regional... (Review)
Review
Modern approach in surgical treatment and in managing acute and chronic pain is nowadays more and more based on the implementation of all possible techniques of regional anesthesia (RA). Local anesthetics (LA) are needed to achieve standard regional anesthesia. Local anesthetics are primarily characterized by time constraints and duration of action, and depending on the amount applied, adverse effects on the cardiac and central nervous system may occur. Adjuvants are drugs used together with LA due to their synergistic effect, i.e. they improve start latency and duration of sensory and motor blockade and enable reduction of cumulative dose of LA and reduction of adverse effects on cardiac and nervous system. Nowadays, there is a huge variety of drugs that can be administered in combination with LA, and they, in general, can be divided into opioid and non-opioid adjuvants. The administration of opioids in RA over an extended time period was accompanied by some negative characteristics as respiratory depression, nausea, vomiting. So, their usage is still under a special control. Due to the positive effects shown by drugs from non-opioid adjuvants group (e.g. adrenaline, alpha adrenergic agonists, steroids, magnesium, midazolam, ketamine etc.), indications for their administration broadened. However, there are still some restrains in clinical practice based on the fact that neurotoxicity and demonstration of neurological complications in regional anesthesia haven't been properly researched yet.
Topics: Humans; Anesthetics, Local; Anesthesia, Conduction; Adrenergic alpha-Agonists; Analgesics, Opioid; Peripheral Nerves
PubMed: 36824635
DOI: 10.20471/acc.2022.61.s2.07 -
Journal of Neuroimmune Pharmacology :... Mar 2020Evidence supporting the use of β2AR agonists in synucleinopathies is rapidly growing. Findings come from different scientific approaches. Molecular and immunological... (Review)
Review
Evidence supporting the use of β2AR agonists in synucleinopathies is rapidly growing. Findings come from different scientific approaches. Molecular and immunological data suggest that adrenergic stimulation may decrease both α-synuclein (α-syn) deposition and pro-inflammatory/neurotoxic molecules release. Small open label clinical trials including a total number of 25 Parkinson's disease (PD) patients, in which the β2AR agonist salbutamol was added to levodopa, suggest a promising symptomatic benefit. In line with these findings, epidemiological studies investigating the risk of PD development suggest that long term exposure to the agonist salbutamol might be protective, while the antagonist propranolol possibly detrimental. Nonetheless, in both lines of investigation the studies performed so far present important limitations. On the clinical side, large randomized controlled trials are lacking, whereas on the epidemiological side the presence of co-morbid conditions (i.e. smoking and essential tremor) potentially influencing PD risk should taken into consideration. In summary, it is our opinion that β2AR stimulation in synucleinopathies has a rationale and therefore merits further investigation. Graphical Abstract.
Topics: Adrenergic beta-2 Receptor Agonists; Animals; Catecholamines; Clinical Trials as Topic; Humans; Parkinson Disease; Receptors, Adrenergic, beta-2; Synucleinopathies; T-Lymphocytes
PubMed: 30617750
DOI: 10.1007/s11481-018-09831-0 -
JAMA May 2021Attention-deficit/hyperactivity disorder (ADHD) is diagnosed in approximately 2.4% of preschool-age children. Stimulants are recommended as first-line medication...
IMPORTANCE
Attention-deficit/hyperactivity disorder (ADHD) is diagnosed in approximately 2.4% of preschool-age children. Stimulants are recommended as first-line medication treatment. However, up to 25% of preschool-age children with ADHD are treated with α2-adrenergic agonist medications, despite minimal evidence about their efficacy or adverse effects in this age range.
OBJECTIVE
To determine the frequency of reported improvement in ADHD symptoms and adverse effects associated with α2-adrenergic agonists and stimulant medication for initial ADHD medication treatment in preschool-age children.
DESIGN, SETTING, AND PARTICIPANTS
Retrospective electronic health record review. Data were obtained from health records of children seen at 7 outpatient developmental-behavioral pediatric practices in the Developmental Behavioral Pediatrics Research Network in the US. Data were abstracted for 497 consecutive children who were younger than 72 months when treatment with an α2-adrenergic agonist or stimulant medication was initiated by a developmental-behavioral pediatrician for ADHD and were treated between January 1, 2013, and July 1, 2017. Follow-up was complete on February 27, 2019.
EXPOSURES
α2-Adrenergic agonist vs stimulant medication as initial ADHD medication treatment.
MAIN OUTCOMES AND MEASURES
Reported improvement in ADHD symptoms and adverse effects.
RESULTS
Data were abstracted from electronic health records of 497 preschool-age children with ADHD receiving α2-adrenergic agonists or stimulants. Median child age was 62 months at ADHD medication initiation, and 409 children (82%) were males. For initial ADHD medication treatment, α2-adrenergic agonists were prescribed to 175 children (35%; median length of α2-adrenergic agonist use, 136 days) and stimulants were prescribed to 322 children (65%; median length of stimulant use, 133 days). Improvement was reported in 66% (95% CI, 57.5%-73.9%) of children who initiated α2-adrenergic agonists and 78% (95% CI, 72.4%-83.4%) of children who initiated stimulants. Only daytime sleepiness was more common for those receiving α2-adrenergic agonists vs stimulants (38% vs 3%); several adverse effects were reported more commonly for those receiving stimulants vs α2-adrenergic agonists, including moodiness/irritability (50% vs 29%), appetite suppression (38% vs 7%), and difficulty sleeping (21% vs 11%).
CONCLUSIONS AND RELEVANCE
In this retrospective review of health records of preschool-age children with ADHD treated in developmental-behavioral pediatric practices, improvement was noted in the majority of children who received α2-adrenergic agonists or stimulants, with differing adverse effect profiles between medication classes. Further research, including from randomized clinical trials, is needed to assess comparative effectiveness of α2-adrenergic agonists vs stimulants.
Topics: Adrenergic alpha-2 Receptor Agonists; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child, Preschool; Disorders of Excessive Somnolence; Electronic Health Records; Feeding and Eating Disorders; Female; Guanfacine; Humans; Irritable Mood; Male; Methylphenidate; Retrospective Studies
PubMed: 33946100
DOI: 10.1001/jama.2021.6118 -
Journal of Perinatology : Official... Feb 2024Opioids and benzodiazepines have historically been employed for pain relief; however, they are associated with detrimental long-term neurodevelopmental consequences.... (Review)
Review
Opioids and benzodiazepines have historically been employed for pain relief; however, they are associated with detrimental long-term neurodevelopmental consequences. Dexmedetomidine, a highly selective alpha-2-adrenoreceptor agonist, has piqued interest as a viable alternative for neonates, owing to its potential analgesic and neuroprotective attributes. We conducted a systematic review to assess the efficacy and safety of dexmedetomidine utilization in neonates. We conducted a comprehensive search of Ovid, MEDLINE, EMBASE, PubMed, Cochrane, and CINAHL, spanning from January 2010 to September 2022. Our review encompassed six studies involving 252 neonates. Overall, dexmedetomidine may be effective in achieving sedation and analgesia. Furthermore, it may reduce the need for adjunctive sedation or analgesia, shorten the time to extubation, decrease the duration of mechanical ventilation, and accelerate the attainment of full enteral feeds. Notably, no significant adverse effects associated with dexmedetomidine were reported. Nevertheless, additional well-designed studies to establish both the efficacy and safety of dexmedetomidine in neonatal care are needed.
Topics: Infant, Newborn; Humans; Dexmedetomidine; Pain; Adrenergic alpha-2 Receptor Agonists; Pain Management; Analgesia
PubMed: 37845426
DOI: 10.1038/s41372-023-01802-5 -
Investigative and Clinical Urology May 2024To evaluate efficacy and safety of beta-3 adrenergic agonists in adults with neurogenic lower urinary tract dysfunction. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To evaluate efficacy and safety of beta-3 adrenergic agonists in adults with neurogenic lower urinary tract dysfunction.
MATERIALS AND METHODS
According to a protocol (CRD42022350079), we searched multiple data sources for published and unpublished randomized controlled trials (RCTs) up to 2nd August 2022. Two review authors independently screened studies and abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence (CoE).
RESULTS
We found data to inform two comparisons: beta-3 adrenergic agonists versus placebo (4 RCTs) and anticholinergics (2 RCTs). Only mirabegron was used for intervention in all included studies. Compared to placebo, beta-3 adrenergic agonists may have a clinically unimportant effect on urinary symptoms score (mean difference [MD] -2.50, 95% confidence interval [CI] -4.78 to -0.22; ²=92%; 2 RCTs; 192 participants; low CoE) based on minimal clinically important difference of 3. We are very uncertain of the effects of beta-3 adrenergic agonists on quality of life (MD 10.86, 95% CI 1.21 to 20.50; ²=41%; 2 RCTs; 98 participants; very low CoE). Beta-3 adrenergic agonists may result in little to no difference in major adverse events (cardiovascular adverse events) (risk ratio 0.57, 95% CI 0.14 to 2.37; ²=0%; 4 RCTs; 310 participants; low CoE). Compared to anticholinergics, no study reported urinary symptom scores and quality of life. There were no major adverse events (cardiovascular adverse events) in either study group (1 study; 60 participants; very low CoE).
CONCLUSIONS
Compared to placebo, beta-3 adrenergic agonists may have similar effects on urinary symptom scores and major adverse events. There were uncertainties about their effects on quality of life. Compared to anticholinergics, we are either very uncertain or have no evidence about urinary symptom scores, quality of life, and major adverse events.
Topics: Humans; Adrenergic beta-3 Receptor Agonists; Urinary Bladder, Neurogenic; Treatment Outcome; Lower Urinary Tract Symptoms; Randomized Controlled Trials as Topic
PubMed: 38714512
DOI: 10.4111/icu.20230271