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European Journal of Heart Failure Mar 2023Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis,... (Randomized Controlled Trial)
Randomized Controlled Trial
β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE-HF): a double blind, placebo-controlled, randomized clinical trial.
AIMS
Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre- and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre- and post-capillary PH (CpcPH).
METHODS AND RESULTS
The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF) trial is a multicentre, randomized, parallel, placebo-controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n = 39) or placebo (n = 41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo-corrected mean difference of 0.62 Wood units, 95% confidence interval [CI] -0.38, 1.61, p = 0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo-corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p = 0.026), without significant differences in other pre-specified secondary outcomes.
CONCLUSIONS
SPHERE-HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre-specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.
Topics: Humans; Hypertension, Pulmonary; Heart Failure; Quality of Life; Stroke Volume; Adrenergic Agonists; Double-Blind Method; Treatment Outcome
PubMed: 36404400
DOI: 10.1002/ejhf.2745 -
Experimental Physiology May 2020What is the central question of this study? What is the role of β -adrenergic receptor (β AR) vasodilatation in older postmenopausal women as compared to premenopausal...
NEW FINDINGS
What is the central question of this study? What is the role of β -adrenergic receptor (β AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β AR-mediated vasodilatation in both groups of women? What is the main finding and its importance? β AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β AR-mediated vasodilatation in young premenopausal women.
ABSTRACT
β -Adrenergic receptor (β AR)-mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β AR agonist terbutaline is blunted in older postmenopausal women (59 ± 4 years) compared to young premenopausal women (27 ± 3 years) and to assess NO contribution to β AR-mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra-arterial infusions of terbutaline at 0.1-2.0 µg (100 ml tissue) min with and without the NO synthase inhibitor l-N -monomethylarginine (l-NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P = 0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P > 0.05) and rose significantly within each group during terbutaline infusion (P < 0.05). There were significant group × dose interactions for FBF (P = 0.01) and FVC (P = 0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l-NMMA co-infusion vs. without l-NMMA (P = 0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l-NMMA co-infusion (P > 0.05 for all). These data suggest that β AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β AR-mediated vasodilatation in young premenopausal women.
Topics: Adrenergic Agonists; Adult; Arterial Pressure; Female; Forearm; Humans; Middle Aged; Nitric Oxide; Plethysmography; Postmenopause; Premenopause; Terbutaline; Vasodilation
PubMed: 32170888
DOI: 10.1113/EP088452 -
Journal of Ocular Pharmacology and... Oct 2016Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are... (Review)
Review
Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A, A, and A. An AAR agonist is in clinical trials for glaucoma, AAR reduces neuroinflammation, AAR protects retinal ganglion cells from apoptosis, and both AAR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y and P2Y, lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.
Topics: Adrenergic Agonists; Dry Eye Syndromes; Glaucoma; Humans; Ligands; Molecular Structure; Receptors, Purinergic; Retinal Ganglion Cells; Structure-Activity Relationship
PubMed: 27574786
DOI: 10.1089/jop.2016.0090 -
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 -
Pharmacological Research Jan 2023Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of...
Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used β3-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)- and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipoprotein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis.
Topics: Animals; Humans; Mice; Adipose Tissue, Brown; Adrenergic Agonists; Apolipoproteins E; Atherosclerosis; Cholesterol; Fatty Acids; Lipoproteins, LDL; Liver; Triglycerides; Receptors, LDL
PubMed: 36574856
DOI: 10.1016/j.phrs.2022.106634 -
The Cochrane Database of Systematic... May 2017Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment.
OBJECTIVES
To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications.
SEARCH METHODS
We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies.
SELECTION CRITERIA
We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha-adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient without indicating the level of care provided.The included studies were heterogeneous in terms of the type of opioid antagonist treatment regimen, the comparator, the outcome measures assessed, and the means of assessing outcomes. As a result, the validity of any estimates of overall effect is doubtful, therefore we did not calculate pooled results for any of the analyses.The quality of the evidence for treatment with an opioid antagonist-adrenergic agonist combination versus an alpha-adrenergic agonist is very low. Two studies reported data on peak withdrawal severity, and four studies reported data on the average severity over the period of withdrawal. Peak withdrawal induced by opioid antagonists in combination with an adrenergic agonist appears to be more severe than withdrawal managed with clonidine or lofexidine alone, but the average severity over the withdrawal period is less. In some situations antagonist-induced withdrawal may be associated with significantly higher rates of treatment completion compared to withdrawal managed with adrenergic agonists. However, this result was not consistent across studies, and the extent of any benefit is highly uncertain.We could not extract any data on the occurrence of adverse events, but two studies reported delirium or confusion following the first dose of naltrexone. Delirium may be more likely with higher initial doses and with naltrexone rather than naloxone (which has a shorter half-life), but we could not confirm this from the available evidence.Insufficient data were available to make any conclusions on the best duration of treatment.
AUTHORS' CONCLUSIONS
Using opioid antagonists plus alpha-adrenergic agonists is a feasible approach for managing opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist.A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium.Using opioid antagonists to induce and accelerate opioid withdrawal is not currently an active area of research or clinical practice, and the research community should give greater priority to investigating approaches, such as those based on buprenorphine, that facilitate the transition to sustained-release preparations of naltrexone.
Topics: Adrenergic alpha-Agonists; Clonidine; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Non-Randomized Controlled Trials as Topic; Opioid-Related Disorders; Prospective Studies; Randomized Controlled Trials as Topic; Severity of Illness Index; Substance Withdrawal Syndrome
PubMed: 28553701
DOI: 10.1002/14651858.CD002021.pub4 -
Environmental Health Perspectives Feb 2003Food allergy affects between 5% and 7.5% of children and between 1% and 2% of adults. The greater prevalence of food allergy in children reflects both the increased... (Review)
Review
Food allergy affects between 5% and 7.5% of children and between 1% and 2% of adults. The greater prevalence of food allergy in children reflects both the increased predisposition of children to develop food allergies and the development of immunologic tolerance to certain foods over time. Immunoglobulin (Ig) E-mediated food allergies can be classified as those that persist indefinitely and those that are predominantly transient. Although there is overlap between the two groups, certain foods are more likely than others to be tolerated in late childhood and adulthood. The diagnosis of food allergy rests with the detection of food-specific IgE in the context of a convincing history of type I hypersensitivity-mediated symptoms after ingestion of the suspected food or by eliciting IgE-mediated symptoms after controlled administration of the suspected food. Presently, the only available treatment of food allergies is dietary vigilance and administration of self-injectable epinephrine.
Topics: Adolescent; Adrenergic Agonists; Adult; Age Factors; Child; Child, Preschool; Diet; Epinephrine; Food Hypersensitivity; Humans; Immunoglobulin E; Infant; Infant, Newborn
PubMed: 12573910
DOI: 10.1289/ehp.5702 -
Cells Jan 2023Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β...
Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β adrenergic receptor (βAR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and βAR agonist functions, currently in development as a COPD therapeutic. In precision-cut human lung slices (hPCLS), we investigated the bronchoprotective effect of navafenterol against two non-muscarinic contractile agonists, histamine and thromboxane A (TxA) analog (U46619). Navafenterol pre-treatment significantly attenuated histamine-induced bronchoconstriction and βAR antagonist propranolol reversed this inhibitory effect. TxA analog-induced bronchoconstriction was attenuated by navafenterol pre-treatment, albeit to a lesser magnitude than that of histamine-induced bronchoconstriction. Propranolol completely reversed the inhibitory effect of navafenterol on TxA analog-induced bronchoconstriction. In the presence of histamine or TxA analog, navafenterol exhibits bronchoprotective effect in human airways and it is primarily mediated by βAR agonism of navafenterol.
Topics: Humans; Bronchodilator Agents; Muscarinic Antagonists; Histamine; Propranolol; Lung; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Adrenergic Agonists
PubMed: 36672178
DOI: 10.3390/cells12020240 -
Psychopharmacology Bulletin Oct 2020This evidence-based systematic review will focus on the use of dexmedetomidine and its role as adjuvant anesthetics in regional blocks to help better guide physicians in... (Review)
Review
PURPOSE OF REVIEW
This evidence-based systematic review will focus on the use of dexmedetomidine and its role as adjuvant anesthetics in regional blocks to help better guide physicians in their practice. This review will cover background and mechanism of dexmedetomidine as well as the use in various regional blocks.
RECENT FINDINGS
Local anesthetics are preferred for nerve blocks over opioids; however, both due come with its own side effects. Local anesthetics may be toxic as they disrupt cell membrane and proteins, but by using adjuvants such as dexmedetomidine, that can prolong sensory and motor blocks can reduce total amount of local anesthetics needed. Dexmedetomidine is an alpha-2-adrenergic agonist used as additive for regional nerve block. It has a relatively low side effect profile and have been researched in various regional blocks (intrathecal, paravertebral, axillary, infraclavicular brachial plexus, interscalene). Dexmedetomidine shows promising results as adjuvant anesthetics in most regional blocks.
SUMMARY
Many studies have been done and many show promising results for the use of dexmedetomidine in regional blocks. It may significantly increase in duration of sensory and motor blocks that correlates with lower pain scores and less need of morphine in various regional blocks.
Topics: Adrenergic alpha-2 Receptor Agonists; Anesthesia, Conduction; Anesthetics, Local; Brachial Plexus Block; Dexmedetomidine
PubMed: 33633422
DOI: No ID Found -
The Cochrane Database of Systematic... Jul 2005Adrenergic drugs have been used for the treatment of urinary incontinence. However, they have generally been considered to be ineffective or to have side effects which... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Adrenergic drugs have been used for the treatment of urinary incontinence. However, they have generally been considered to be ineffective or to have side effects which may limit their clinical use.
OBJECTIVES
To determine the effectiveness of adrenergic agonists in the treatment of urinary incontinence in adults.
SEARCH STRATEGY
We searched the Cochrane Incontinence Group specialised trials register (searched 9 March 2005) and the reference lists of relevant articles.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials in adults with urinary incontinence which included an adrenergic agonist drug in at least one arm of the trial.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Reviewers' Handbook.
MAIN RESULTS
Twenty-two eligible randomised trials were identified, of which 11 were crossover trials. The trials included 1099 women with 673 receiving an adrenergic drug (phenylpropanolamine in 11 trials, midodrine in two, norepinephrine in three, clenbuterol in another three, terbutaline in one, eskornade in one and Ro-115-1240 in one). No trials included men. The limited evidence suggested that an adrenergic agonist drug is better than placebo in reducing the number of pad changes and incontinence episodes, as well as improving subjective symptoms. In two small trials, the drugs also appeared to be better than pelvic floor muscle training, possibly reflecting relative acceptability of the treatments to women but perhaps due to differential withdrawal of women from the trial groups. There was not enough evidence to evaluate the use of higher compared to lower doses of adrenergic agonists nor the relative merits of an adrenergic agonist drug compared with oestrogen, whether used alone or in combination. Over a quarter of women reported adverse effects. There were similar numbers of adverse effects with adrenergics, placebo or alternative drug treatment. However, when these were due to recognised adrenergic stimulation (insomnia, restlessness and vasomotor stimulation) they were only severe enough to stop treatment in 4% of women.
AUTHORS' CONCLUSIONS
There was weak evidence to suggest that use of an adrenergic agonist was better than placebo treatment. There was not enough evidence to assess the effects of adrenergic agonists when compared to or combined with other treatments. Further larger trials are needed to identify when adrenergics may be useful. Patients using adrenergic agonists may suffer from minor side effects, which sometimes cause them to stop treatment. Rare but serious side effects, such as cardiac arrhythmias and hypertension, have been reported.
Topics: Adrenergic Agonists; Adult; Clenbuterol; Female; Humans; Midodrine; Phenylpropanolamine; Randomized Controlled Trials as Topic; Urinary Incontinence; Urinary Incontinence, Stress
PubMed: 16034867
DOI: 10.1002/14651858.CD001842.pub2