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Expert Opinion on Pharmacotherapy Sep 2022Overactive bladder (OAB) is associated with physical, emotional, and financial burden. After failed conservative measures, second-line therapy includes medications, such...
INTRODUCTION
Overactive bladder (OAB) is associated with physical, emotional, and financial burden. After failed conservative measures, second-line therapy includes medications, such as antimuscarinics and beta-3 adrenergic receptor (β3AR) agonists. Antimuscarinics are most commonly prescribed but have systemic side effects that lead to poor compliance. β3AR agonists include mirabegron and vibegron. Mirabegron is a first-generation β3AR agonist that is effective for frequency, urgency urinary incontinence (UUI) and urgency, but has interactions with cytochrome P450 enzymes (CYPs) and cardiovascular sequelae. Vibegron is a second-generation β3AR agonist that is highly selective and does not interact with CYPs. It is effective for reducing UUI episodes and daily micturition number and has a favorable side effect profile.
AREAS COVERED
Clinical background, pharmacology, and clinical studies for vibegron.
EXPERT OPINION
Vibegron is a welcomed addition to the OAB therapeutic landscape. This single dose, once daily option is effective, especially for patients with wet OAB, with a favorable side effect profile. Sub-analyses of patients ≥ 65 years have shown continued efficacy and safety. The few drug interactions are of benefit, especially for older patients with polypharmacy. As long-term data accrues, vibegron has the potential to drive the OAB therapeutic market.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Humans; Muscarinic Antagonists; Pyrimidinones; Pyrrolidines; Receptors, Adrenergic, beta-3; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive; Urinary Incontinence
PubMed: 36124780
DOI: 10.1080/14656566.2022.2126311 -
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 -
Annals of Allergy, Asthma & Immunology... Oct 2019To evaluate relevant studies and documents that address treatment strategies for acute loss of asthma control (yellow zone). (Review)
Review
OBJECTIVE
To evaluate relevant studies and documents that address treatment strategies for acute loss of asthma control (yellow zone).
DATA SOURCES
Publications available on various treatment strategies for the yellow zone, Global Initiative for Asthma, and FDA Drug Safety Communication.
STUDY SELECTIONS
Studies that assessed the effectiveness of specific therapies as yellow zone strategies were included in this review.
RESULTS
Multiple yellow zone strategies exist, but only a few have been shown consistently effective. No specific evidence suggests that scheduled SABA can prevent exacerbation. Results for intermittent leukotriene receptor antagonist use have been mixed. Strong evidence supports intermittent inhaled corticosteroid (ICS) dosing for preschool-aged children with intermittent viral-induced wheeze, but data regarding this strategy for older children and adults are limited. As for short-term increase in scheduled ICS controller, doubling the dose seems to be ineffective, whereas results for a more substantial increase in ICS dose (quadrupling and quintupling) have been mixed. Dynamic dosing appears most promising, because symptom-driven ICS in tandem with rescue beta agonist use (whether short- or long-acting) is the strategy with the most robust data demonstrating reduction in exacerbations while minimizing ICS exposure.
CONCLUSION
Varying study designs and the heterogeneity of asthma itself likely account for the difference in outcomes seen with the various yellow zone intervention strategies studied. More studies are needed to determine the right yellow zone therapies for the right patients, but this is likely to be most effective through a personalized approach.
Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Anti-Asthmatic Agents; Asthma; Child; Disease Progression; Drug Therapy, Combination; Humans; Leukotriene Antagonists; Symptom Flare Up
PubMed: 31330241
DOI: 10.1016/j.anai.2019.07.010 -
BMC Urology Apr 2023Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective... (Observational Study)
Observational Study Randomized Controlled Trial
BACKGROUND
Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective β-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence.
METHODS
This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence.
DISCUSSION
OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.
Topics: Adult; Humans; Adolescent; Urinary Bladder, Overactive; Quality of Life; Prospective Studies; Treatment Outcome; Acetanilides; Double-Blind Method; Cholinergic Antagonists; Adrenergic beta-3 Receptor Agonists; Muscarinic Antagonists
PubMed: 37095473
DOI: 10.1186/s12894-023-01240-7 -
GeroScience Aug 2021The aging heart is well-characterized by a diminished responsiveness to adrenergic activation. However, the precise mechanisms by which age and sex impact...
The aging heart is well-characterized by a diminished responsiveness to adrenergic activation. However, the precise mechanisms by which age and sex impact adrenergic-mediated cardiac function remain poorly described. In the current investigation, we compared the cardiac response to adrenergic stress to gain mechanistic understanding of how the response to an adrenergic challenge differs by sex and age. Juvenile (4 weeks), adult (4-6 months), and aged (18-20 months) male and female mice were treated with the β-agonist isoproterenol (ISO) for 1 week. ISO-induced morphometric changes were age- and sex-dependent as juvenile and adult mice of both sexes had higher left ventricle weights while aged mice did not increase cardiac mass. Adults increased myocyte cell size and deposited fibrotic matrix in response to ISO, while juvenile and aged animals did not show evidence of hypertrophy or fibrosis. Juvenile females and adults underwent expected changes in systolic function with higher heart rate, ejection fraction, and fractional shortening. However, cardiac function in aged animals was not altered in response to ISO. Transcriptomic analysis identified significant differences in gene expression by age and sex, with few overlapping genes and pathways between groups. Fibrotic and adrenergic signaling pathways were upregulated in adult hearts. Juvenile hearts upregulated genes in the adrenergic pathway with few changes in fibrosis, while aged mice robustly upregulated fibrotic gene expression without changes in adrenergic genes. We suggest that the response to adrenergic stress significantly differs across the lifespan and by sex. Mechanistic definition of these age-related pathways by sex is critical for future research aimed at treating age-related cardiac adrenergic desensitization.
Topics: Adrenergic Agents; Adrenergic beta-Agonists; Animals; Female; Isoproterenol; Longevity; Male; Mice; Myocytes, Cardiac
PubMed: 33651247
DOI: 10.1007/s11357-021-00345-x -
Drug Testing and Analysis May 2020Inhaled beta -adrenoceptor agonists (beta -agonists) are among the most used substances in competitive sports. The 2020 Prohibited List issued by the World Anti-Doping... (Review)
Review
Inhaled beta -adrenoceptor agonists (beta -agonists) are among the most used substances in competitive sports. The 2020 Prohibited List issued by the World Anti-Doping Agency restricts use of all selective and non-selective beta -agonists in- and out- of competition with few exemptions. Formoterol, salbutamol, and salmeterol are allowed by inhalation within defined dosing limits. These restrictions are in place because supratherapeutic use of beta -agonist has the potential to be anabolic and to enhance performance, as well as due to potential side effects. Despite substantial documentation that beta -agonists exert anabolic and lipolytic actions, these actions are not widely recognized. Furthermore, a common misconception is that the inhaled route does not exert these effects. However, given the high relative systemic bioavailability via the inhaled route, inhalation at high doses can also exert anabolic and lipolytic actions. In this review, we highlight the anabolic and lipolytic actions beta -agonists can exert, regardless of the type of beta -agonist and the route of administration. The doses needed to provide such effects are also associated with adverse effects and would in most cases be detected in routine doping control. Notwithstanding, the beta -agonist regulations are associated with some challenges and given their ability to induce muscle growth and to enhance performance, it is important to continue developing effective detection strategies to prevent potential misuse of beta -agonists while allowing treatment of asthmatic subjects without causing adverse side effects or ergogenic actions.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Doping in Sports; Humans; Lipolysis; Performance-Enhancing Substances
PubMed: 31960603
DOI: 10.1002/dta.2728 -
Cancer Chemotherapy and Pharmacology Dec 2023Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with...
PURPOSE
Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with chemotherapy, resulting in significant side-effects. We aimed to investigate if the dose of chemotherapeutic drugs could be diminished by co-administering it with the β2-agonist salbutamol.
METHODS
Cell proliferation was measured by thymidine incorporation; gene expression, by real-time PCR and protein phosphorylation by WB. Apoptosis was assessed by acridine orange / ethidium bromide and TUNEL tests. Public patient databases were consulted. Cells were inoculated to nude mice and their growth assessed.
RESULTS
The β-agonist salbutamol synergizes in MDA-MB-231 cells in vitro with paclitaxel and doxorubicin on cell proliferation through ADRB2 receptors, while the β-blocker propranolol does not. The expression of this receptor was assessed in patient databases and other cell lines. Triple negative samples had the lowest expression. Salbutamol and paclitaxel decreased MDA-MB-231 cell proliferation while their combination further inhibited it. The pathways involved were analyzed. When these cells were inoculated to nude mice, paclitaxel and salbutamol inhibited tumor growth. The combined effect was significantly greater. Paclitaxel increased the expression of MDR1 while salbutamol partially reversed this increase.
CONCLUSION
While the effect of salbutamol was mainly on cell proliferation, suboptimal concentrations of paclitaxel provoked a very important enhancement of apoptosis. The latter enhanced transporter proteins as MDR1, whose expression were diminished by salbutamol. The expression of ADRB2 should be assessed in the biopsy or tumor to eventually select patients that could benefit from salbutamol repurposing.
Topics: Animals; Mice; Humans; Female; Paclitaxel; Breast Neoplasms; Triple Negative Breast Neoplasms; Mice, Nude; Albuterol; Cell Line, Tumor; Cell Proliferation; Propranolol; Adrenergic Agonists; Apoptosis
PubMed: 37725114
DOI: 10.1007/s00280-023-04586-9 -
Brain Research Apr 2020Emotionally significant stimuli, including potential threats from the external environment, trigger an increase in body temperature, a response known as emotional...
Emotionally significant stimuli, including potential threats from the external environment, trigger an increase in body temperature, a response known as emotional hyperthermia. Sympathetically-mediated brown adipose tissue (BAT) thermogenesis contributes substantially to this hyperthermic response. The systemic administration of α-adrenergic agonists is known to inhibit both febrile and shivering responses. In the present study, we investigated whether systemic administration of clonidine, a α-adrenoceptor agonist, attenuates the emotional hyperthermia evoked in conscious unrestrained rats suddenly confronted with a second (intruder) rat, itself confined to a small cage. Pre-implanted thermistors were used to measure BAT and body temperature in conscious, freely moving, male Sprague-Dawley rats. The rats were pre-treated with intraperitoneally administered vehicle (Ringer solution) or clonidine (1, 10 and 100 µg/kg). Clonidine, in a dose-dependent manner, reduced the intruder-elicited increases in BAT (log-dose linear regression F(1,16) = 9.52, R = 0.37, P < 0.01) and body temperature (F(1,16) = 6.48, R = 0.29, P < 0.05). We also investigated, in anesthetized rats, whether systemic clonidine administration inhibits BAT sympathetic nerve discharge evoked via activation of neurons in the lateral habenula (LHb) - a nucleus involved in the regulation of emotional hyperthermia. In anesthetized rats, clonidine abolished the BAT sympathetic nerve discharges elicited via bicuculline-mediated disinhibition of the LHb. These results suggest that activation of central α-adrenergic receptors attenuates the process of emotional hyperthermia by reduction of BAT thermogenesis.
Topics: Adipose Tissue, Brown; Adrenergic alpha-2 Receptor Agonists; Animals; Body Temperature; Clonidine; Emotions; Habenula; Hyperthermia; Male; Rats; Rats, Sprague-Dawley; Thermogenesis
PubMed: 31981679
DOI: 10.1016/j.brainres.2020.146678 -
Biochemistry. Biokhimiia Jul 2022In this study, we conducted a comparative analysis of the structure of agonists and antagonists of transmembrane (TM) β-adrenoceptors (β-ARs) and their interactions...
In this study, we conducted a comparative analysis of the structure of agonists and antagonists of transmembrane (TM) β-adrenoceptors (β-ARs) and their interactions with the β-ARs and proposed the mechanism of receptor activation. A characteristic feature of agonist and antagonist molecules is the presence of a hydrophobic head (most often, one or two aromatic rings) and a tail with a positively charged amino group. All β-adrenergic agonists have two carbon atoms between the aromatic ring of the head and the nitrogen atom of the amino group. In antagonist molecules, this fragment can be either reduced or increased to four atoms due to the additional carbon and oxygen atoms. The agonist head, as a rule, has two H-bond donors or acceptors in the para- and meta-positions of the aromatic rings, while in the antagonist heads, these donors/acceptors are absent or located in other positions. Analysis of known three-dimensional structures of β-AR complexes with agonists showed that the agonist head forms two H-bonds with the TM5 helix, and the tail forms an ionic bond with the D3.32 residue of the TM3 helix and one or two H-bonds with the TM7 helix. The tail of the antagonist can form similar bonds, but the interaction between the head and the TM5 helix is much weaker. As a result of these interactions, the agonist molecule acquires an extended "strained string" conformation, in contrast to the antagonist molecule, which has a longer, bended, and flexible tail. The "strained string" of the agonist interacts with the TM6 helix (primarily with the W6.48 residue) and turns it, which leads to the opening of the G protein-binding site on the intracellular side of the receptor, while flexible and larger antagonist molecules do not have the same effect on the receptor.
Topics: Adrenergic beta-Agonists; Carbon; Models, Molecular; Nitrogen; Oxygen; Protein Conformation; Protein Structure, Secondary; Receptors, Adrenergic
PubMed: 36154885
DOI: 10.1134/S0006297922070057 -
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