Search Results (24)

Background and Objectives: This study aimed to assess whether the addition of fractional CO₂ laser therapy to standard pharmacologic treatment with Mirabegron, a β3-adrenoceptor agonist, enhances the clinical outcomes in the management of overactive bladder syndrome (OAB) in postmenopausal women. Materials and Methods: Τhis was a prospective, randomized, double-blind, sham-controlled trial including 50 postmenopausal women with moderate-to-severe OAB symptoms. Participants were randomized (1:1) to receive mirabegron 50 mg daily in combination with either active fractional CO₂ laser therapy (Group A) or sham laser treatment (Group B). Both groups underwent three monthly sessions of vaginal laser treatment and were followed for a total of four months. Clinical assessments were performed at baseline and monthly visits (T0–T3), using validated instruments including the Overactive Bladder Questionnaire (OAB-q), King’s Health Questionnaire (KHQ), Urinary Distress Inventory (UDI-6), Pelvic Floor Impact Questionnaire (PFIQ-7), Patient Global Impression of Improvement (PGI-I), and 3-day voiding diaries. The trial was registered at ClinicalTrials.gov (Identifier: NCT03846895). Results: Significant symptom improvement was observed within both groups over time, with reductions in urinary frequency, urgency, nocturia, and incontinence episodes, as well as improvements in quality-of-life scores. However, intergroup comparisons revealed no statistically significant differences in any primary or secondary outcomes. Both treatment modalities demonstrated similar effectiveness across all measured parameters. Conclusions: In this randomized controlled trial, the adjunctive use of fractional CO₂ laser therapy did not offer additional clinical benefit beyond mirabegron monotherapy in the short-term management of OAB. These findings underscore the need for further investigation into tailored therapeutic strategies, particularly in populations with overlapping genitourinary syndrome of menopause or more refractory OAB symptoms. Full article

Background and Objectives: Ureteral stents are widely used in the field of urology but can cause varying degrees of side effects. This study utilized a network meta-analysis to evaluate stent-related discomfort (SRD) in patients with alpha-blockers (alfuzosin, tamsulosin, and silodosin), antimuscarinics (solifenacin), beta 3-agonists (mirabegron), and phosphodiesterase 5-inhibitors (tadalafil) versus a placebo. Materials and Methods: Relevant randomized controlled trials (RCTs) from 2006 to 2021 were identified from electronic databases, including PubMed, EMBASE, and the Cochrane Library. The following identifiers were included to assess the urinary symptom score (USS): participants (patients with ureteral stents), interventions (patients who took medication for stent discomfort), and outcomes (comparisons of the Ureteric Stent Symptoms Questionnaire (USSQ)). We also executed an independent quality assessment using the Scottish Intercollegiate Guidelines Network (SIGN). Results: A total of 16 RCTs were identified, and they included 1865 patients. Compared with the placebo, mirabegron (mean difference (MD): −3.87; 95% confidence interval (CI): −10.6–2.35), tadalafil (MD: −4.47; 95% CI: −10.8–1.63), and silodosin (MD: −4.02; 95% CI: −12–4.01) did not show significant differences to the placebo, whereas others did. Alfuzosin, mirabegron, silodosin, solifenacin, and tadalafil were not inferior to tamsulosin in terms of the USS using Bayesian analyses. In the random effect model, P-score tests showed that solifenacin possessed the highest P-score (p = 0.8484); tamsulosin was the second highest (p = 0.7054). As a result of the rank-probability test, solifenacin was also ranked highest in terms of USS, and tamsulosin was ranked second. Conclusions: Compared with the placebo, solifenacin, tamsulosin, and alfuzosin significantly decreased the USS. In our study, solifenacin may be considered the most effective medication for SRD. Full article

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t_1/2) (univariate p-value (p_uv) = 0.018) and incidence of adverse reactions (ADRs) (p_uv = 0.008, multivariate p (p_mv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t_1/2 than the T/T genotype (p_uv = 0.002, p_mv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (p_uv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (p_uv = 0.007, p_mv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics. Full article

Introduction: The application of double-J ureteral stents in urology is widespread, but their use is often accompanied by complications and bothersome symptoms, affecting patients’ quality of life (QoL). While various medications have been tested for alleviating the symptoms associated with double-J stents, consensus on their effectiveness remains elusive. This study aims to investigate the effectiveness of tamsulosin, solifenacin, mirabegron, desloratadine, and combination therapy using a Romanian-adapted version of the Ureteral Stent Symptom Questionnaire (USSQ). Materials and Methods: A prospective, observational, randomised trial was conducted at the Urology and Renal Transplant Clinic of Dr. “C.I. Parhon” Clinical Hospital in Iasi between 1 January 2022 and 1 August 2023. Three hundred twenty seven patients who underwent their first double-J stent insertion were evaluated with the Romanian-adapted USSQ at baseline and 30 days post-insertion. Patients were randomly divided into six groups based on the prescribed medications: control, tamsulosin, mirabegron, solifenacin, desloratadine, and combination therapy. Results: The data suggest a significant reduction in symptoms in patients who received medication compared with the control group. Furthermore, the combined medication of solifenacin 10 mg and tamsulosin 0.4 mg was particularly effective in reducing pain with statistical significance compared to the control group (p = 0.001). The highest mean scores for urinary symptom severity were observed in the control group (12.37 ± 6.82), and the lowest was in the mirabegron group (9.94 ± 5.82). The individuals who received a daily dose of 50 mg of mirabegron saw the most notable influence on their job. Conclusions: While no single medication emerged as a “miracle drug” for managing symptoms related to double-J stent insertion, the combination therapy of solifenacin and tamsulosin is the most promising option for improving symptoms related to double-J stent insertion and QoL. Additional extensive research is required to validate these initial results. Full article

The β₃-adrenoceptor agonist mirabegron is available for the treatment of storage symptoms of overactive bladder, including frequency, urgency, and incontinence. The off-target effects of mirabegron include binding to α₁-adrenoceptors, which are central in the treatment of voiding symptoms. Here, we examined the structure–function relationships in the binding of mirabegron to a cryo-electron microscopy structure of α_1A. The binding was simulated by docking mirabegron to a 3D structure of a human α_1A-adrenoceptor (7YMH) using Autodock Vina. The simulations identified two binding states: slope orientation involving 10 positions and horizontal binding to the receptor surface involving 4 positions. No interactions occurred with positions constituting the α_1A binding pocket, including Asp-106, Ser-188, or Phe-312, despite the positioning of the phenylethanolamine moiety in transmembrane regions close to the binding pocket by contact with Phe-288, -289, and Val-107. Contact with the unique positions of α_1A included the transmembrane Met-292 during slope binding and exosite Phe-86 during horizontal binding. Exosite binding in slope orientation involved contact of the anilino part, rather than the aminothiazol end, to Ile-178, Ala-103, and Asn-179. In conclusion, contact with Met-292 and Phe-86, which are unique positions of α_1A, accounts for mirabegron binding to α_1A. Because of its lack of interactions with the binding pocket, mirabegron has lower affinity compared to α_1A-blockers and no effects on voiding symptoms. Full article

The β-adrenergic drug Mirabegron, a drug initially used for the treatment of an overactive bladder, has new potential indications and is hydrolyzed by butyrylcholinesterase (BChE). This compound is one of the only arylacylamide substrates to be catabolized by BChE. A steady-state kinetic analysis at 25 °C and pH 7.0 showed that the enzyme behavior is Michaelian with this substrate and displays a long pre-steady-state phase characterized by a burst. The induction time, τ, increased with substrate concentration (τ ≈ 18 min at maximum velocity). The kinetic behavior was interpreted in terms of hysteretic behavior, resulting from a slow equilibrium between two enzyme active forms, E and E′. The pre-steady-state phase with the highest activity corresponds to action of the E form, and the steady state corresponds to action of the E′ form. The catalytic parameters were determined as k_cat = 7.3 min⁻¹ and K_m = 23.5 μM for the initial (burst) form E, and k_cat = 1.6 min⁻¹ and K_m = 3.9 μM for the final form E′. Thus, the higher affinity of E′ for Mirabegron triggers the slow enzyme state equilibrium toward a slow steady state. Despite the complexity of the reaction mechanism of Mirabegron with BChE, slow BChE-catalyzed degradation of Mirabegron in blood should have no impact on the pharmacological activities of this drug. Full article

While essential hypertension (HTN) is very prevalent, pulmonary arterial hypertension (PAH) is very rare in the general population. However, due to progressive heart failure, prognoses and survival rates are much worse in PAH. Patients with PAH are at a higher risk of developing supraventricular arrhythmias and malignant ventricular arrhythmias. The latter underlie sudden cardiac death regardless of the mechanical cardiac dysfunction. Systemic chronic inflammation and oxidative stress are causal factors that increase the risk of the occurrence of cardiac arrhythmias in hypertension. These stressful factors contribute to endothelial dysfunction and arterial pressure overload, resulting in the development of cardiac pro-arrhythmic conditions, including myocardial structural, ion channel and connexin43 (Cx43) channel remodeling and their dysfunction. Myocardial fibrosis appears to be a crucial proarrhythmic substrate linked with myocardial electrical instability due to the downregulation and abnormal topology of electrical coupling protein Cx43. Furthermore, these conditions promote ventricular mechanical dysfunction and heart failure. The treatment algorithm in HTN is superior to PAH, likely due to the paucity of comprehensive pathomechanisms and causal factors for a multitargeted approach in PAH. The intention of this review is to provide information regarding the role of Cx43 in the development of cardiac arrhythmias in hypertensive heart disease. Furthermore, information on the progress of therapy in terms of its cardioprotective and potentially antiarrhythmic effects is included. Specifically, the benefits of sodium glucose co-transporter inhibitors (SGLT2i), as well as sotatercept, pirfenidone, ranolazine, nintedanib, mirabegron and melatonin are discussed. Discovering novel therapeutic and antiarrhythmic strategies may be challenging for further research. Undoubtedly, such research should include protection of the heart from inflammation and oxidative stress, as these are primary pro-arrhythmic factors that jeopardize cardiac Cx43 homeostasis, the integrity of intercalated disk and extracellular matrix, and, thereby, heart function. Full article

(1) Background: The purpose of our prospective, single-blinded, randomized, sham-controlled study was to investigate the effect of the additional extracorporeal magnetic stimulation (ExMI) to pharmacological treatment in overactive bladder syndrome (OAB) in women. (2) Methods: We recruited 56 women with OAB, who were allocated into two study groups: the active group received mirabegron 50 mg daily and a total of 16 sessions of ExMI in 8 weeks, whereas the sham group received mirabegron 50 mg daily and sham stimulation following the same treatment protocol. Treatment success was evaluated after 4 and 8 weeks. (3) Results: Both groups experienced significant reduction in daytime urinary frequency, nocturia, and number of weekly incontinence episodes after 8 weeks. There were no statistically significant differences in end-point daytime urinary frequency and nocturia between groups. However, the overall average reduction rate in weekly number of incontinence episodes was 43.7% in treatment group and 24.2% in the control group. The number of urinary incontinence episodes in the treatment and control group was reduced for 3.8 ± 11.8 vs. 2.5 ± 4.3 episodes at week 4 and additional 3.3 ± 6 vs. 0.4 ± 3.2 episodes at week 8, respectively (p = 0.013). Moreover, IIQ-7 score showed a significantly greater score reduction and patients’ evaluated improvement of symptoms was higher in the active group. (4) Conclusions: The addition of ExMI to mirabegron in OAB treatment further improves the weekly incontinence episode reduction rate and also leads to grater improvement in symptoms. Full article

Annually, peripheral arterial disease is estimated to cost over USD 21 billion and diabetic foot disease an estimated at USD 9–13 billion. Mirabegron is a TGA-approved beta-3 adrenoreceptor agonist, shown to be safe and effective in the treatment of overactive bladder syndrome by stimulating bladder smooth muscle relaxation. In this review, we discuss the potential use of beta-3 adrenoreceptor agonists as therapeutic agents repurposed for peripheral arterial disease and diabetic foot ulcers. The development of both conditions is underpinned by the upregulation of oxidative stress pathways and consequential inflammation and hypoxia. In oxidative stress, there is an imbalance of reactive oxygen species and nitric oxide. Endothelial nitric oxide synthase becomes uncoupled in disease states, producing superoxide and worsening oxidative stress. Agonist stimulation of the beta-3 adrenoreceptor recouples and activates endothelial nitric oxide synthase, increasing the production of nitric oxide. This reduces circulating reactive oxygen species, thus decreasing redox modification and dysregulation of cellular proteins, causing downstream smooth muscle relaxation, improved endothelial function and increased angiogenesis. These mechanisms lead to endothelial repair in peripheral arterial disease and an enhanced perfusion in hypoxic tissue, which will likely improve the healing of chronic ulcers. Full article

Obesity is becoming a global health epidemic. Brown and “beige” adipose tissue may produce heat, leading to energy expenditure enhancement and weight loss. Mirabegron, a selective β3-adrenergic receptor agonist, has been found to be effective as a brown adipose tissue activator, a “beige” cells stimulator and a metabolic homeostasis controller in animal and human studies. Although in animal studies, administration of mirabegron led to obesity improvement, significant weight loss in obese patients after mirabegron treatment has not been demonstrated so far, which may be associated with the too-short duration of the trials and the small number of participants in the studies. In humans, the most effective treatment for adipose tissue stimulation was high doses of mirabegron; however, cardiovascular side effects may limit the use of such doses, so the long-term safety must be evaluated. In cases of tachycardia or blood pressure elevation, the co-administration of a β1-adrenergic receptor blocker may be useful. It should be checked whether smaller doses of mirabegron, taken for a longer time, will be sufficient to stimulate brown and “beige” adipose tissue, leading to weight loss. The introduction of mirabegron into obesity treatment in the future will require long-term trials with larger numbers of subjects, to assess mirabegron efficacy, tolerability, and safety. Full article

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, substantially affecting quality of life. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, three-period, drug–drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), or a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron was reduced by approximately 17% when administered with tamsulosin. No clinically significant changes in the safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug–drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination could be a promising treatment option for patients with OAB. Full article

Brown and beige adipocytes are renowned for their unique ability to generate heat through a mechanism known as thermogenesis. This process can be induced by exposure to cold, hormonal signals, drugs, and dietary factors. The activation of these thermogenic adipocytes holds promise for improving glucose metabolism, reducing fat accumulation, and enhancing insulin sensitivity. However, the translation of preclinical findings into effective clinical therapies poses challenges, warranting further research to identify the molecular mechanisms underlying the differentiation and function of brown and beige adipocytes. Consequently, research has focused on the development of drugs, such as mirabegron, ephedrine, and thyroid hormone, that mimic the effects of cold exposure to activate brown fat activity. Additionally, nutritional interventions have been explored as an alternative approach to minimize potential side effects. Brown fat and beige fat have emerged as promising targets for addressing nutritional imbalances, with the potential to develop strategies for mitigating the impact of metabolic diseases. Understanding the influence of nutritional factors on brown fat activity can facilitate the development of strategies to promote its activation and mitigate metabolic disorders. Full article

Mirabegron (MBR) is a β₃-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability. Nevertheless, the pharmacokinetic feasibility of these co-amorphous dispersions has not been evaluated. Therefore, this study aimed to characterize the pharmacokinetic profiles of MBR-EFA, MBR-NDA, and MBR-PG in rats and mice. Our results exhibited that relative F_24h and AUC_0–24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143–195% compared with the MBR rats. The absolute F_24h, relative F_24h, and AUC_0–24h values of MBR in MBR-EFA and MBR-NDA mice were enhanced by 178–234% compared with the MBR mice. In tissue distribution, MBR was extensively distributed in the gastrointestinal tract, liver, kidneys, lung, and heart of mice. Notably, MBR distribution in the liver, kidneys, and lung was considerably high in MBR-EFA, MBR-NDA, or MBR-PG mice compared with MBR mice. These findings highlight the potential of these co-amorphous dispersions to enhance oral F of MBR. Full article

Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The knowledge that agonists of the β2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that β2 mimetics would prevent preterm birth by relaxing uterine smooth muscle. The activation of cAMP-dependent protein kinase by β2 receptors is unable to provide meaningful tocolysis. The failure of β2 agonists such as ritodrine and terbutaline to prevent preterm birth suggests that the regulation of uterine smooth muscle is disparate from that of airway. Other smooth muscle quiescent-mediating molecules, such as nitric oxide, relax vascular smooth muscle in a cGMP-protein kinase G-dependent manner; however, nitric oxide activation of protein kinase G fails to explain the relaxation of the myometrium to nitric oxide. Moreover, nitric oxide-mediated relaxation is blunted in preterm labor, and thus, for this reason and because of the fall in maternal blood pressure, nitric oxide cannot be employed as a tocolytic. The β3 adrenergic receptor-mediated relaxation of the human myometrium is claimed to be cAMP-dependent protein kinase-dependent. This is scientifically displeasing given the failure of β2 agonists as tocolytics and suggests a non-canonical signaling role for β3AR in myometrium. The addition of the β3 agonist mirabegron to pregnant human myometrial strips in the tissue bath relaxes oxytocin-induced contractions. Mirabegron stimulates nitric oxide production in myometrial microvascular endothelial cells, and the relaxation of uterine tissue in vitro is partially blocked by the addition of the endothelial nitric oxide synthase blocker Nω-Nitro-L-arginine. Recent data suggest that both endothelial and smooth muscle cells respond to β3 stimulation and contribute to relaxation through disparate signaling pathways. The repurposing of approved medications such as mirabegron (Mybetriq™) tested in human myometrium as uterine tocolytics can advance the prevention of preterm birth. Full article

We previously reported the novel finding that β3-AR is functionally expressed in the renal tubule and shares its cellular localization with the vasopressin receptor AVPR2, whose physiological stimulation triggers antidiuresis by increasing the plasma membrane expression of the water channel AQP2 and the NKCC2 symporter in renal cells. We also showed that pharmacologic stimulation of β3-AR is capable of triggering antidiuresis and correcting polyuria, in the knockout mice for the AVPR2 receptor, the animal model of human X-linked nephrogenic diabetes insipidus (XNDI), a rare genetic disease still missing a cure. Here, to demonstrate that the same response can be evoked in humans, we evaluated the effect of treatment with the β3-AR agonist mirabegron on AQP2 and NKCC2 trafficking, by evaluating their urinary excretion in a cohort of patients with overactive bladder syndrome, for the treatment of which the drug is already approved. Compared to baseline, treatment with mirabegron significantly increased AQP2 and NKCC2 excretion for the 12 weeks of treatment. This data is a step forward in corroborating the hypothesis that in patients with XNDI, treatment with mirabegron could bypass the inactivation of AVPR2, trigger antidiuresis and correct the dramatic polyuria which is the main hallmark of this disease. Full article