-
The Journal of Clinical Psychiatry Oct 2022Determine if sublingual dexmedetomidine, a selective α adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or... (Randomized Controlled Trial)
Randomized Controlled Trial
Determine if sublingual dexmedetomidine, a selective α adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder. This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the , Fifth Edition () criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 μg, 120 μg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose. Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African American) were randomized; 380 (100%) self-administered study medication, and 372 (97.9%) completed the study. The mean PEC total score at baseline (17.6) indicated mild to moderate agitation. At 2 hours postdose, the least squares mean changes (SE) from baseline were -10.3 (0.4) for sublingual dexmedetomidine 180 μg, -8.5 (0.4) for 120 μg, and -4.8 (0.4) for placebo. Least squares mean differences (97.5% confidence intervals) in the sublingual dexmedetomidine groups were -5.5 (-6.7 to -4.3) for 180 μg and -3.7 (-4.9 to -2.5) for 120 μg (both < .001 vs placebo). The most commonly encountered adverse events with dexmedetomidine (incidence ≥ 5% and ≥ 2× rate observed with placebo) were somnolence, dry mouth, and hypotension for the 120 μg dose, and somnolence, dizziness, orthostatic hypotension, and oral hypoesthesia for the 180 μg dose. Treatment with sublingual dexmedetomidine 180 μg or 120 μg was more efficacious than placebo in reducing acute agitation associated with schizophrenia as measured by PEC scores at 2 hours postdose. ClinicalTrials.gov identifier: NCT04268303.
Topics: Adrenergic alpha-2 Receptor Agonists; Adult; Antipsychotic Agents; Dexmedetomidine; Double-Blind Method; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Sleepiness; Treatment Outcome
PubMed: 36198061
DOI: 10.4088/JCP.22m14447 -
British Journal of Anaesthesia Dec 2019Dexmedetomidine (DEX) is a highly selective alpha2 adrenoceptor agonist with broad pharmacological effects, including sedation, analgesia, anxiolysis, and sympathetic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dexmedetomidine (DEX) is a highly selective alpha2 adrenoceptor agonist with broad pharmacological effects, including sedation, analgesia, anxiolysis, and sympathetic tone inhibition. Here we report a systematic review and meta-analysis of its effects on stress, inflammation, and immunity in surgical patients during the perioperative period.
METHODS
We searched MEDLINE, METSTR, Embase, and Web of Science for clinical studies or trials to analyse the effects of DEX on perioperative stress, inflammation, and immune function.
RESULTS
Sixty-seven studies (including randomised controlled trials and eight cohort studies) with 4842 patients were assessed, of which 2454 patients were in DEX groups and 2388 patients were in control (without DEX) groups. DEX infusion during the perioperative period inhibited release of epinephrine, norepinephrine, and cortisol; decreased blood glucose, interleukin (IL)-6, tumour necrosis factor-α, and C-reactive protein; and increased interleukin-10 in surgical patients. In addition, the numbers of natural killer cells, B cells, and CD4 T cells, and the ratios of CD4:CD8 and Th1:Th2 were significantly increased; CD8 T-cells were decreased in the DEX group when compared with the control group.
CONCLUSIONS
DEX, an anaesthesia adjuvant, can attenuate perioperative stress and inflammation, and protect the immune function of surgical patients, all of which may contribute to decreased postoperative complications and improved clinical outcomes.
Topics: Adrenergic alpha-2 Receptor Agonists; Dexmedetomidine; Humans; Immunity; Inflammation; Intraoperative Complications; Postoperative Complications; Preoperative Period; Stress, Physiological
PubMed: 31668347
DOI: 10.1016/j.bja.2019.07.027 -
Respiratory Medicine Sep 2019The term ultra-LABA indicates once-daily β2-AR agonists (abediterol, indacaterol, olodaterol and vilanterol) that are single enantiomers of the (R)-configuration. All... (Review)
Review
The term ultra-LABA indicates once-daily β2-AR agonists (abediterol, indacaterol, olodaterol and vilanterol) that are single enantiomers of the (R)-configuration. All have a near full-agonist profile at human β2-AR. They can be prescribed in asthmatics only when associated with an with ICS, although further confirmations need to clarify what really these agents add if used in association to ICS and in what asthmatic patients this association may have more value. They are also under development in triple inhalers that include an ultra-LABA, a LAMA and an ICS. The once-daily posology might increase adherence in long-term treatment of asthma but superiority to twice-daily LABAs has not yet been fully demonstrated. In any case, still no ultra-LABA can be recommended as preferred.
Topics: Adrenergic beta-2 Receptor Agonists; Asthma; Benzoxazines; Benzyl Alcohols; Chlorobenzenes; Humans; Indans; Patient Compliance; Quinolones
PubMed: 31425937
DOI: 10.1016/j.rmed.2019.08.005 -
Cellular Signalling Apr 2021The β-adrenergic receptors (βARs) include three subtypes, β, β and β. These receptors are widely expressed and regulate numerous physiological processes including... (Review)
Review
The β-adrenergic receptors (βARs) include three subtypes, β, β and β. These receptors are widely expressed and regulate numerous physiological processes including cardiovascular and metabolic functions and airway tone. The βARs are also important targets in the treatment of many diseases including hypertension, heart failure and asthma. In some cases, the use of current βAR ligands to treat a disease is suboptimal and can lead to severe side effects. One strategy to potentially improve such treatments is the development of biased agonists that selectively regulate a subset of βAR signaling pathways and responses. Here we discuss the compounds identified to date that preferentially activate a G- or β-arrestin-mediated signaling pathway through βARs. Mechanistic insight on how these compounds bias signaling sheds light on the potential development of even more selective compounds that should have increased utility in treating disease.
Topics: Adrenergic beta-Agonists; Humans; Hypertension; Ligands; Protein Isoforms; Receptors, Adrenergic, beta; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestin 1
PubMed: 33385503
DOI: 10.1016/j.cellsig.2020.109905 -
European Review For Medical and... Aug 2023The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for... (Review)
Review
The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for human use but is commonly used in veterinary medicine due to its sedative and muscle-relaxant properties. Cases of human intoxication due to accidental or voluntary use have been reported since the 1980s. However, reports of adulteration of illicit opioids (heroin and illicit fentanyl) with xylazine have been increasing all over Western countries. In humans, xylazine causes respiratory depression, bradycardia, and hypotension-posing individuals, using xylazine-adulterated opioids. We present a narrative review of the latest intoxication cases related to xylazine, to bring awareness to readers and also to help pathologists to detect and deal with xylazine cases.
Topics: Humans; Xylazine; Analgesics, Opioid; Adrenergic alpha-2 Receptor Agonists; Hypnotics and Sedatives; Bradycardia
PubMed: 37606142
DOI: 10.26355/eurrev_202308_33305 -
Drug Testing and Analysis Feb 2021Higenamine was included in the World Anti-Doping Agency (WADA) Prohibited Substances and Methods List as a β -adrenoceptor agonist in 2017, thereby resulting in its... (Review)
Review
Higenamine was included in the World Anti-Doping Agency (WADA) Prohibited Substances and Methods List as a β -adrenoceptor agonist in 2017, thereby resulting in its prohibition both in and out of competition. The present mini review describes the physiology and pharmacology of adrenoceptors, summarizes the literature addressing the mechanism of action of higenamine and extends these findings with previously unpublished in silico and in vitro work. Studies conducted in isolated in vitro systems, whole-animal preparations and a small number of clinical studies suggest that higenamine acts in part as a β -adrenoceptor agonist. In silico predictive tools indicated that higenamine and possibly a metabolite have a high probability of interacting with the β -receptor as an agonist. Stable expression of human β -receptors in Chinese hamster ovary (CHO) cells to measure agonist activity not only confirmed the activity of higenamine at β but also closely agreed with the in silico prediction of potency for this compound. These data confirm and extend literature findings supporting the inclusion of higenamine in the Prohibited List.
Topics: Adrenergic beta-Agonists; Alkaloids; Animals; Athletic Performance; Doping in Sports; Humans; Performance-Enhancing Substances; Receptors, Adrenergic, beta-2; Tetrahydroisoquinolines
PubMed: 33369180
DOI: 10.1002/dta.2992 -
Therapeutic Advances in Respiratory... 2023Inhaled bronchodilator therapy with long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists (LABAs) in combination is currently the mainstay of treatment... (Review)
Review
Inhaled bronchodilator therapy with long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists (LABAs) in combination is currently the mainstay of treatment for chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend the addition of inhaled corticosteroids (ICS) to LABA/LAMA only in patients with a history of frequent/severe exacerbations and high blood eosinophil counts, or in those with concomitant asthma. Despite this, real-world data suggest that clinicians are not adhering to this guidance and that ICS are frequently overused. This is possibly due to the incorrect assumption that when LABA/LAMA therapy is not sufficient, adding an ICS to the treatment regimen is the logical next step. In this narrative review, we describe global and country-specific guideline recommendations from Germany, Spain, and Japan and compare these with real-world data on LABA/LAMA and ICS use in clinical practice. We also provide a clinical guide to the use of add-on therapies with LABA/LAMA for different patient phenotypes, including (1) patients still symptomatic (but not exacerbating) despite LABA/LAMA treatment; (2) patients still exacerbating despite LABA/LAMA treatment who have high blood eosinophil counts; and (3) patients still exacerbating despite LABA/LAMA treatment who do not have high blood eosinophils or concomitant asthma.
Topics: Humans; Adrenergic beta-2 Receptor Agonists; Drug Therapy, Combination; Pulmonary Disease, Chronic Obstructive; Muscarinic Antagonists; Asthma; Eosinophilia; Adrenal Cortex Hormones; Administration, Inhalation; Bronchodilator Agents
PubMed: 37936381
DOI: 10.1177/17534666231208630 -
Current Neuropharmacology 2023Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of... (Review)
Review Meta-Analysis
BACKGROUND
Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of asymmetric acetylcholinesterase () is the second-most common cause of CMS. However, data on pharmacological treatments are limited.
OBJECTIVE
In this study, we reviewed related reports to determine the most appropriate pharmacological strategy for CMS caused by mutations. A literature review and meta-analysis were also performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched to identify studies published in English before July 22, 2022.
RESULTS
A total of 42 studies including 164 patients with CMS due to 72 different mutations were selected for evaluation. Most studies were case reports, and none were randomized clinical trials. Our meta-analysis revealed evidence that β-adrenergic agonists, including salbutamol and ephedrine, can be used as first-line pharmacological treatments for CMS patients with mutations, as 98.7% of patients (74/75) treated with β-adrenergic agonists showed positive effects. In addition, AChEIs should be avoided in CMS patients with mutations, as 90.5% (105/116) of patients treated with AChEIs showed either no or negative effects.
CONCLUSION
(1) β-adrenergic agonist therapy is the first pharmacological strategy for treating CMS with mutations. (2) AChEIs should be avoided in patients with CMS with mutations.
Topics: Humans; Myasthenic Syndromes, Congenital; Acetylcholinesterase; Muscle Proteins; Mutation; Adrenergic beta-Agonists; Collagen
PubMed: 36703579
DOI: 10.2174/1570159X21666230126145652 -
Communications Biology Nov 2022Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission....
Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission. VMAT2 inhibitors are approved for symptomatic treatment of tardive dyskinesia and Huntington's chorea, but despite being much-studied inhibitors their exact binding site and mechanism behind binding and inhibition of monoamine transport are not known. Here we report the identification of several approved drugs, notably β2-adrenergic agonists salmeterol, vilanterol and formoterol, β2-adrenergic antagonist carvedilol and the atypical antipsychotic ziprasidone as inhibitors of rat VMAT2. Further, plausible binding modes of the established VMAT2 inhibitors reserpine and tetrabenazine and hit compounds salmeterol and ziprasidone were identified using molecular dynamics simulations and functional assays using VMAT2 wild-type and mutants. Our findings show VMAT2 as a potential off-target of treatments with several approved drugs in use today and can also provide important first steps in both drug repurposing and therapy development targeting VMAT2 function.
Topics: Animals; Rats; Adrenergic Agonists; Antipsychotic Agents; Piperazines; Vesicular Monoamine Transport Proteins; Adrenergic Antagonists
PubMed: 36418492
DOI: 10.1038/s42003-022-04121-1 -
JAMA Cardiology Nov 2023Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The β3-adrenergic receptors (β3ARs) may represent a new target, as their activation attenuates LV remodeling.
OBJECTIVE
To determine whether activation of β3ARs by repurposing a β3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF.
DESIGN, SETTING, AND PARTICIPANTS
The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022.
INTERVENTION
Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months.
MAIN OUTCOMES AND MEASURES
The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication.
RESULTS
Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial.
CONCLUSIONS
In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02599480.
Topics: Female; Humans; Male; Middle Aged; Adrenergic Agonists; Diabetes Mellitus, Type 2; Heart Failure; Hypertrophy, Left Ventricular; Prospective Studies; Aged
PubMed: 37728907
DOI: 10.1001/jamacardio.2023.3003