-
Journal of the National Medical... Feb 2021Outcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This... (Review)
Review
PURPOSE
Outcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This review assessed systematic variation in β agonist treatment outcomes among Blacks compared to other groups.
METHODS
We conducted a systematic review of studies reporting differential response to β agonists among Blacks, including studies identifying pharmacogenetic variants.
RESULTS
Of 3158 papers, 20 compared safety or efficacy of β agonists among Blacks as compared with other subgroups. Six papers evaluating efficacy of short-acting β agonists (SABA) found similar or improved results among Blacks compared with other groups, while one small study found reduced response to SABA therapy among Blacks. Reports of safety and efficacy of long-acting β agonists (LABA) indicated similar results among Blacks in four papers, while four reports found reduced safety among Blacks, as compared with other groups. Four papers assessed genomic variation and relative treatment response in Blacks, with two finding significant effects of the p.Arg16Gly variant in ADRB2 on β agonist response and one finding significant gene-gene IL6/IL6R interaction effects on albuterol response.
CONCLUSIONS
Evidence suggests the potential for differences in β agonist outcomes among Blacks compared with other groups. This literature, however, remains small and significantly underpowered for substantive conclusions. There are notable opportunities for adequately-powered investigations exploring safety and efficacy of β agonists among Blacks, including pharmacogenomic modifiers of response.
Topics: Administration, Inhalation; Adrenergic Agonists; Black or African American; Asthma; Drug Therapy, Combination; Humans
PubMed: 32732018
DOI: 10.1016/j.jnma.2020.07.001 -
European Urology Dec 2019Oral pharmacotherapy consisting of antimuscarinics, β3-adrenoreceptor agonists, or combinations of these agents forms the mainstay of overactive bladder (OAB) management. (Review)
Review
CONTEXT
Oral pharmacotherapy consisting of antimuscarinics, β3-adrenoreceptor agonists, or combinations of these agents forms the mainstay of overactive bladder (OAB) management.
OBJECTIVE
To evaluate the efficacy and safety of combination therapy in patients with OAB.
EVIDENCE ACQUISITION
A literature search was conducted in June 2018 using Embase, MEDLINE, and Cochrane databases via Ovid and relevant congress abstracts. Studies reporting the efficacy/safety of two antimuscarinics or a β3-adrenoreceptor agonist plus an antimuscarinic were included.
EVIDENCE SYNTHESIS
Publications reported on clinical efficacy, safety, and health-related quality of life (HRQoL) for mirabegron (M) plus solifenacin (S) from three 12-wk randomised controlled trials (RCTs)-SYMPHONY, SYNERGY, and BESIDE-and a 12-mo RCT, SYNERGY II. SYMPHONY reported statistically significant improvements in clinical symptoms and HRQoL with combination therapy versus solifenacin 5 mg (S5) and placebo. In SYNERGY, there were consistent improvements in urinary incontinence (UI) episodes/24 h and micturitions/24 h (coprimary endpoints), and in secondary efficacy parameters with mirabegron 25 mg (M25) + S5 and mirabegron 50 mg (M50) + S5 versus respective monotherapies. In patients with an inadequate response to S5 monotherapy (BESIDE), greater improvements in UI (primary endpoint) were noted for M50 + S5 versus S5 (p = 0.001). Combination therapy was noninferior to solifenacin 10 mg (S10) for reduction in UI and superior to S10 for improvement in micturition frequency (p < 0.001), and resulted in greater improvements from baseline in OAB-5 Dimension scores versus S5 and S10 (p < 0.01). In SYNERGY II, clinically meaningful and sustained improvements in clinical outcomes were observed for M50 + S5 versus M50 or S5. Combination therapy was well tolerated in all four trials. The incidence of adverse events (AEs) was similar across groups, and there were no notable differences in the incidence of specific AEs. Positive efficacy outcomes were observed in five studies of dual antimuscarinic therapy (trospium + solifenacin).
CONCLUSIONS
Mirabegron plus solifenacin provides effective, well-tolerated treatment for patients with OAB. Limited data for dual antimuscarinic therapy suggest a benefit in patients with moderate-to-severe symptoms.
PATIENT SUMMARY
Overactive bladder (OAB) is treated with medicines called antimuscarinics, such as solifenacin, propiverine, or trospium, or another β-adrenoreceptor agonist medicine called mirabegron, which works in a different way. We looked at published scientific studies of patients with OAB treated with mirabegron plus solifenacin together, or with two antimuscarinics. We found that mirabegron plus solifenacin can help reduce symptoms and improve quality of life. Patients tolerate this treatment well, with few patients experiencing side effects.
Topics: Adrenergic beta-3 Receptor Agonists; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Randomized Controlled Trials as Topic; Treatment Outcome; Urinary Bladder, Overactive
PubMed: 31416636
DOI: 10.1016/j.eururo.2019.07.010 -
Obesity (Silver Spring, Md.) Jan 2022Beta-3 adrenergic receptors (β3-AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and...
OBJECTIVES
Beta-3 adrenergic receptors (β3-AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and inflammation that attenuate AT β3-AR signaling. The objective of this study was to test the hypothesis that the combination of the β3-AR agonist CL-316,243 (CL) and the antioxidant alpha-lipoic acid (ALA) would lower inflammation in diet-induced obesity (DIO) and improve β3-AR function.
METHODS
A total of 40 DIO mice were separated into four groups: Control (per os and intraperitoneal [IP] vehicle); CL alone (0.01 mg/kg IP daily); ALA alone (250 mg/kg in drinking water); or ALA+CL combination, all for 5 weeks.
RESULTS
Food intake was similar in all groups; however, mice receiving ALA+CL showed improved body composition and inflammation as well as lower body weight (+1.7 g Control vs. -2.5 g ALA+CL [-7%]; p < 0.01) and percentage of body fat (-9%, p < 0.001). Systemic and epididymal WAT inflammation was lower with ALA+CL than all other groups, with enhanced recruitment of epididymal WAT anti-inflammatory CD206+ M2 macrophages. β3-AR signaling in WAT was enhanced in the combination-treatment group, with higher mRNA and protein levels of thermogenic uncoupling protein 1 and AT lipases.
CONCLUSIONS
Chronic treatment with ALA and a β3-AR agonist reduces DIO-induced inflammation. AT immune modulation could be a therapeutic target in patients with obesity.
Topics: Adipose Tissue, Brown; Adrenergic Agonists; Animals; Diet, High-Fat; Humans; Inflammation; Male; Mice; Mice, Obese; Obesity; Thioctic Acid
PubMed: 34825496
DOI: 10.1002/oby.23309 -
Journal of Shoulder and Elbow Surgery Feb 2021Rotator cuff (RC) muscle atrophy and fatty infiltration (FI) are independent factors correlated with failure of attempted tendon repair in larger RC tears. However,...
BACKGROUND
Rotator cuff (RC) muscle atrophy and fatty infiltration (FI) are independent factors correlated with failure of attempted tendon repair in larger RC tears. However, there is no effective treatment for RC muscle atrophy and FI at this time. The recent discovery of beige adipose tissue (BAT) in adults shed light on a new avenue in treating obesity and excessive fat deposition by promoting BAT activity. The goal of this study was to define the role of intramuscular BAT in RC muscle FI and the effect of β-adrenergic receptor agonists in treating RC muscle FI by promoting BAT activity.
MATERIALS AND METHODS
Three-month-old wild-type C57BL/6J, platelet derived growth factor receptor-alpha (PDGFRα) green fluorescent protein (GFP) reporter and uncoupling protein 1 (UCP-1) knockout mice underwent a unilateral RC injury procedure, which included supraspinatus (SS) and infraspinatus tendon resection and suprascapular nerve transection. To stimulate BAT activity, amibegron, a selective β-adrenergic receptor agonist, was administered to C57BL/6J mice either on the same day as surgery or 6 weeks after surgery through daily intraperitoneal injections. Gait analysis was conducted to measure forelimb function at 6 weeks or 12 weeks (in groups receiving delayed amibegron treatment) after surgery. Animals were killed humanely at 6 weeks (or 12 weeks for delayed amibegron groups) after surgery. SS muscles were harvested and analyzed histologically and biochemically.
RESULTS
Histologic analysis of SS muscles from PDGFRα-GFP reporter mice showed that PDGFRα-positive fibroadipogenic progenitors in RC muscle expressed UCP-1, a hallmark of BAT during the development of FI after RC tears. Impairing BAT activity by knocking out UCP-1 resulted in more severe muscle atrophy and FI with inferior forelimb function in UCP-1 knockout mice compared with wild-type mice. Promoting BAT activity with amibegron significantly reduced muscle atrophy and FI after RC tears and improved forelimb function. Delayed treatment with amibegron reversed muscle atrophy and FI in muscle.
CONCLUSIONS
Fat accumulated in muscle after RC tears possesses BAT characteristics. Impairing BAT activity results in worse RC muscle atrophy and FI. Amibegron reduces and reverses RC atrophy and FI by promoting BAT activity.
Topics: Adipose Tissue; Adipose Tissue, Beige; Adrenergic Agonists; Animals; Mice; Mice, Inbred C57BL; Muscular Atrophy; Rotator Cuff; Rotator Cuff Injuries
PubMed: 32599287
DOI: 10.1016/j.jse.2020.06.006 -
Journal of Veterinary Pharmacology and... Jul 2021Alpha -adrenergic agonists have been implicated in the development of pulmonary edema (PE) and sustained hypoxemia that lead to life-threatening pulmonary distress in... (Review)
Review
Application of α -adrenergic agonists combined with anesthetics and their implication in pulmonary intravascular macrophages-insulted pulmonary edema and hypoxemia in ruminants.
Alpha -adrenergic agonists have been implicated in the development of pulmonary edema (PE) and sustained hypoxemia that lead to life-threatening pulmonary distress in ruminants, especially with sensitive and compromised animals. Recently, there is limited understanding of exact mechanism underlying pulmonary alterations associated with α -adrenergic agonist administration. Ruminants have a rich population of pulmonary intravascular macrophages (PIMs) in the pulmonary circulation, which may be involved in the development of pulmonary alveolo-capillary barrier damage. Hence, the central thesis of this review is overviewing the literatures regarding the systemic use of α -adrenergic agonists in domestic ruminants, focusing on their pulmonary side effects, especially on the influence of PIMs on the lung. At this moment, further studies are needed to provide a clear emphasis and better understanding of the potential role of PIMs in the lung pathophysiology associated with α -adrenergic agonists. These preliminary studies would be potentially to develop future medications and intervention targets that may be helpful to alleviate or prevent the critical striking pulmonary effects, and thereby improving the safety of α -agonist application in ruminants.
Topics: Adrenergic alpha-2 Receptor Agonists; Anesthetics; Animals; Hypoxia; Macrophages; Pulmonary Edema; Ruminants
PubMed: 33709435
DOI: 10.1111/jvp.12960 -
Methods in Molecular Biology (Clifton,... 2022An appealing strategy for treatment of metabolic disease in humans is activation of brown adipose tissue (BAT), a thermogenic organ best visualized through F-FDG PET/CT....
An appealing strategy for treatment of metabolic disease in humans is activation of brown adipose tissue (BAT), a thermogenic organ best visualized through F-FDG PET/CT. BAT has been activated to varying degrees by mild cold exposure. However, this approach can cause undesirable stress, and there remains no consensus protocol. Here, we describe standardized methods for both acute and chronic activation of BAT using the orally administered β3-adrenergic receptor (AR) agonist, mirabegron. Acute pharmacological stimulation has enabled quantification of whole-body BAT volume and metabolic activity using PET/CT imaging, and chronic stimulation increases these properties of BAT over time.
Topics: Acetanilides; Adipose Tissue, Brown; Adrenergic beta-Agonists; Fluorodeoxyglucose F18; Humans; Positron Emission Tomography Computed Tomography; Thiazoles
PubMed: 35167091
DOI: 10.1007/978-1-0716-2087-8_5 -
Drugs of Today (Barcelona, Spain : 1998) Aug 2021Overactive bladder (OAB) is an extremely common condition in adults of both sexes. It is characterized by an urgent need to micturate often accompanied by incontinence....
Overactive bladder (OAB) is an extremely common condition in adults of both sexes. It is characterized by an urgent need to micturate often accompanied by incontinence. The condition may also increase the number of micturitions in a 24-hour period as well as nocturia. The syndrome is not due to a urinary infection or other obvious pathology. In terms of drug treatment of OAB, there are two main approaches. One is the use of anticholinergic drugs that reduce the effect of the parasympathetic nervous system on the bladder. The other involves the use of drugs that are agonists at β-adrenergic receptors in the bladder. These drugs increase the capacity of the bladder and cause reductions in the number of daily micturitions and nocturia and also importantly reduce the frequency of urinary urgency and urinary urgency incontinence. Vibegron is the second β-adrenergic agonist to be approved for the treatment of OAB.
Topics: Acetanilides; Adrenergic Agonists; Adrenergic beta-3 Receptor Agonists; Adult; Female; Humans; Male; Pyrimidinones; Pyrrolidines; Treatment Outcome; Urinary Bladder, Overactive
PubMed: 34405208
DOI: 10.1358/dot.2021.57.8.3293588 -
Journal of Clinical Pharmacy and... Mar 2022Acute kidney injury (AKI) is a complication following surgery and has been associated with worsened patient outcomes. Providers have used agents that may confer a degree... (Meta-Analysis)
Meta-Analysis Review
WHAT IS KNOWN AND OBJECTIVE
Acute kidney injury (AKI) is a complication following surgery and has been associated with worsened patient outcomes. Providers have used agents that may confer a degree of renal protection in the perioperative stage. Such is the case of dexmedetomidine, a selective alpha-2 adrenergic agonist used in the intensive care unit (ICU) as a sedative agent. The primary objective of this meta-analysis was to characterize the use of dexmedetomidine and to evaluate its impact on renal markers and outcomes in patients after surgery.
METHODS
A systematic review of manuscripts was performed to identify patients who received dexmedetomidine after surgery by searching the PubMed, Embase, and Cochrane databases. The following parameters were captured: blood urea nitrogen (BUN), serum creatinine, creatinine clearance, neutrophil gelatinase-associated lipoprotein (NGAL), cystatin C, urine output, duration of mechanical ventilation, ICU length of stay, AKI, need for dialysis, and mortality.
RESULTS AND DISCUSSION
Nineteen studies with 3,395 patients were included in the analyses. The mean bolus and infusion dose of dexmedetomidine were 0.82 µg/kg and 0.54 mcg/kg/hr, respectively. There was a significant difference in creatinine clearance and NGAL in favour of the dexmedetomidine group. In addition, the dexmedetomidine group had a shorter ICU length of stay, and a lower risk of acute kidney injury and mortality compared to the control. There was no difference in the rest of the parameters.
WHAT IS NEW AND CONCLUSION
Dexmedetomidine appears to have postoperative renal protective effects. This is evidenced by lower NGAL levels and increased creatinine clearance in those who received dexmedetomidine. These effects are associated with decreases in ICU length of stay and risk of AKI and mortality.
Topics: Acute Kidney Injury; Adrenergic alpha-2 Receptor Agonists; Dexmedetomidine; Humans; Hypnotics and Sedatives; Kidney
PubMed: 34510502
DOI: 10.1111/jcpt.13527 -
Revista Brasileira de Terapia Intensiva 2021Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last...
Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.
Topics: Adrenergic alpha-2 Receptor Agonists; Clonidine; Critical Care; Dexmedetomidine; Humans; Hypnotics and Sedatives
PubMed: 35081245
DOI: 10.5935/0103-507X.20210087 -
American Journal of Hypertension Aug 2020Masked hypertension (nonhypertensive in the clinic setting but hypertensive outside the clinic during wakefulness) is characterized by increased blood pressure in...
BACKGROUND
Masked hypertension (nonhypertensive in the clinic setting but hypertensive outside the clinic during wakefulness) is characterized by increased blood pressure in response to physical and emotional stressors that activate the sympathetic nervous system (SNS). However, no studies have assessed vascular reactivity to a pharmacological SNS challenge in individuals with masked hypertension.
METHODS
We analyzed data from 161 adults aged 25 to 45 years (mean ± standard deviation age 33 ± 6 years; 48% were African American and 43% were female). Participants completed ambulatory blood pressure monitoring, and a standardized α 1-adrenergic agonist phenylephrine test that determines the dose of phenylephrine required to increase a participant's mean arterial pressure by 25 mm Hg (PD25).
RESULTS
Twenty-one participants were considered to have masked hypertension (clinic systolic blood pressure (SBP) <140 and diastolic blood pressure (DBP) <90 mm Hg but awake SBP ≥135 or DBP ≥85 mm Hg), 28 had sustained hypertension (clinic SBP ≥140 or DBP ≥90 mm Hg and awake SBP ≥135 or DBP ≥85 mm Hg), and 106 had sustained normotension (clinic SBP <140 and DBP <90 mm Hg and awake SBP <135 and DBP <85 mm Hg). After multivariable adjustment, the mean (±SE) PD25 was less in participants with masked hypertension compared with their counterparts with sustained normotension (222.1 ± 33.2 vs. 328.7 ± 15.0; P = 0.012), but similar to that observed in subjects with sustained hypertension (254.8 ± 31.0; P =0.12).
CONCLUSIONS
Among young and middle-aged adults, masked hypertension is associated with increased vascular reactivity to a SNS challenge, which may contribute to elevated awake BPs as well as to increased cardiovascular disease risk.
Topics: Adrenergic alpha-1 Receptor Agonists; Adult; Black or African American; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Female; Humans; Male; Masked Hypertension; Multivariate Analysis; Phenylephrine; Receptors, Adrenergic, alpha-1; Sympathetic Nervous System; White People
PubMed: 32128568
DOI: 10.1093/ajh/hpaa032