Mirabegron 50†mg once daily, long-term treatment maximizes benefit in middle-aged and older people with overactive bladder syndrome: a systematic review and meta-analysis of nine phase II/III, randomized, double-blind, parallel-design, placebo-controlled, multicenter, and multinational trials.

The prevalence and severity of overactive bladder increase with age, and mirabegron is an approved treatment for this condition. This meta-analysis systematically evaluated the efficacy and safety of mirabegron compared with placebo for overactive bladder treatment. We searched PubMed and the Cochrane Library (30 October 2023) for relevant articles (source: MEDLINE, EMBASE, ClinicalTrials.gov, ICTRP, CINAHL). We included randomized controlled trials involving adults with overactive bladder syndrome that compared mirabegron with placebo treatment. Data were analyzed according to the Cochrane Handbook for Systematic Reviews of Interventions [Review Manager (computer program) Version 5.4]. Nine parallel-group trials (10 articles) were included. The evaluation included a total of 8,527 adults, including 6,445 women and 2,082 men, of whom 5,726 were White, 2,462 were Asian, and 161 were Black. The mean age of the participants ranged from 53.4 to 60.3 years. This evaluation involved three specifications of mirabegron: 25 mg, 50 mg, and 100 mg. In all trials, patients were enrolled in a 12-week double-blind treatment period, and the dose was once daily. The review of trials found that on average, people taking mirabegron had about 13 ml more volume voided per micturition, five fewer micturitions, and four fewer incontinence episodes every week, with moderate improvements in quality of life. About one in five people taking the drug reported TRAEs. Mirabegron treatment is well tolerated, with the risk of adverse events similar to that of a placebo. For best results, a dose of 50 mg once daily is recommended for long-term use. It is unclear whether any benefits are sustained after treatment discontinuation. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO (CRD42023430737).

Mirabegron Versus Placebo and Other Therapeutic Modalities in the Treatment of Patients with Overactive Bladder Syndrome-A Systematic Review.

BACKGROUND AND OBJECTIVE: The prevalence of overactive bladder (OAB) increases with age. Mirabegron and other drugs are used for the management of patients with OAB. To evaluate mirabegron versus other treatments for overactive bladder syndrome (OAB). METHODS: This randomised controlled trial (RCT)-based systematic review (CRD42020200394) was conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, with standards reported in the Cochrane Handbook for Systematic Reviews of Interventions. KEY FINDINGS AND LIMITATIONS: We included 28 RCTs (n = 27 481 adults), comparing the following: mirabegron 25 mg versus placebo (n = 8798; six RCTs): significant changes in urgency urinary incontinence (mean difference [MD] -0.41, 95% confidence interval [CI] -0.56 to -0.26), total incontinence (MD -0.47, 95% CI -0.63 to -0.30), and nocturia (MD -0.10, 95% CI -0.17 to -0.02), and mirabegron 50 mg versus placebo (n = 14 933; 12 RCTs): significant changes in urgency urinary incontinence (MD -0.41, 95% CI -0.52 to -0.31), urgency (MD -0.49, 95% CI -0.64 to -0.33), total incontinence (MD -0.44, 95% CI -0.55 to -0.33), favouring mirabegron 25/50 mg; mirabegron 50 mg versus tolterodine 4 mg (n = 8008; five RCTs): significant changes in micturition (MD -0.16, 95% CI -0.31 to -0.02) and overall adverse events (AEs; odds ratio [OR] 0.71, 95% CI 0.59-0.86), favouring mirabegron 50 mg; mirabegron 50 mg versus solifenacin 5 mg (n = 8911; four RCTs): significant changes in voided volume/micturition in millilitres (MD -7.77, 95% CI -12.93 to -2.61), favouring mirabegron 50 mg; and mirabegron 50 mg versus oxybutynin 73.5 mg (n = 302; one RCT): significant changes in overall AEs (OR 0.02, 95% CI 0.00-0.16), favouring mirabegron 50 mg. CONCLUSIONS AND CLINICAL IMPLICATIONS: Mirabegron is effective, safe, and well tolerated. Coadministration with anticholinergics provides an advantageous additive effect without a higher occurrence of side effects. PATIENT SUMMARY: Mirabegron is effective, safe, and well tolerated for treating overactive bladder. When used in conjunction with anticholinergic medications, it provides extra benefits without causing more side effects.

Safety and effectiveness of mirabegron for children and adolescents with refractory idiopathic overactive bladder for improving urinary symptoms: a systematic review.

Introduction: The aim of this study was to determine the safety and effectiveness of mirabegron in children with refractory overactive bladder (OAB) for improving urinary symptoms. Material and methods: We conducted a search strategy in MEDLINE (OVID), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS from inception to September 2023. We performed a systematic review of studies evaluating the effectiveness of improving urinary symptoms and the safety of mirabegron at any dose in children and adolescents with idiopathic refractory OAB. We searched the interception to September 2023. The risk of bias was assessed using the Cochrane risk of bias tool for clinical trials and the MINORS tool for non-randomized studies. Results: We included three studies in the analysis. All of them included children and adolescents receiving mirabegron as monotherapy at different doses. Also, none of them reported a control group. Improvement and safety rates were high in every study in objective and subjective measurements. Compliance was also high in all studies. Most of the evaluated items had a low risk of bias within and across studies. Conclusions: Mirabegron as monotherapy appears to be a safe and effective alternative for children with refractory idiopathic OAB or those who are intolerant to antimuscarinic therapy.

Comparing silodosin and mirabegron as medical expulsive therapy for distal ureteral calculus: a prospective, randomised study.

Introduction: In this study we aimed to compare the efficacy of mirabegron and silodosin as medical expulsive therapy (MET) for distal ureteric calculus ≤10 mm. Material and methods: A total of 114 patients who met the inclusion criteria were prospectively randomised into 2 groups, 58 patients in the silodosin group and 56 patients in the mirabegron group. The drugs were given for a maximum of 4 weeks. The primary endpoint was the stone expulsion rate, and secondary endpoints were stone expulsion time and number of pain episodes. Results: There were no statistically significant differences between the two groups in terms of mean age, gender, mean stone size, side, or hydronephrosis. Both groups exhibited similar rates of stone expulsion and expulsion time. Regarding pain management, the frequency of renal colic episodes was significantly lower with mirabegron compared to silodosin (2.3 ±0.2 vs 1.9 ±0.2, P <0.0001). Six patients were excluded from the study due to adverse drug reactions: 4 (6.15%) in the silodosin group (retrograde ejaculation, hypotension) and 2 (3.27%) in the mirabegron group (hypertension). Conclusions: In among patients with distal ureteric stones measuring 5-10 mm, mirabegron did not demonstrate superiority in stone expulsion rate or expulsion time compared to silodosin. However, mirabegron significantly reduced the frequency of renal colic episodes. Therefore, mirabegron may be considered a preferable option for medical expulsive therapy for distal ureter stones over silodosin.

Activation of ß3-AR by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue.

AIMS: ß3-AR (ß3-adrenergic receptor) is essential for cardiovascular homeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate ß3-AR activation-mediated PVAT function in AD/AA. METHODS AND RESULTS: Aortas from patients with thoracic aortic dissection (TAD) were collected to detect ß3-AR expression in PVAT. ApoE-/- and ß-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA, and subsequently received either placebo or mirabegron, a ß3-AR agonist. The results demonstrated an up-regulation of ß3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of ß3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor VEGF-C in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes (LNs) of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. CONCLUSIONS: Our findings illustrated the therapeutic potential of ß3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.

Investigation of Mirabegron-loaded Nanostructured Lipid Carriers for Improved Bioabsorption: Formulation, Statistical Optimization, and In-Vivo Evaluation.

Overactive bladder (OAB) is a usual medical syndrome that affects the bladder, and Mirabegron (MBG) is preferred medicine for its control. Currently, available marketed formulations (MYRBETRIQ® granules and MYRBETRIQ® ER tablets) suffer from low bioavailability (29-35%) hampering their therapeutic effectiveness and compromising patient compliance. By creating MBG nanostructured lipid carriers (MBG-NLCs) for improved systemic availability and drug release, specifically in oral administration of OAB treatment, this study aimed to address these issues. MBG-NLCs were fabricated using a hot-melt ultrasonication technique. MBG-GMS; MBG-oleic acid interaction was assessed by in silico molecular docking. QbD relied on the concentration of Span 80 (X1) and homogenizer speed (X2) as critical material attribute (CMA) and critical process parameter (CPP) respectively, while critical quality attributes (CQA) such as particle size (Y1) and cumulative drug release at 24 h (Y2) were estimated as dependent variables. 32 factorial design was utilized to investigate the interconnection in variables that are dependent and independents. Optimized MBG-NLCs with a particle size of 194.4 ± 2.25 nm were suitable for lymphatic uptake. A PDI score of 0.275 ± 0.02 and zeta potential of -36.2 ± 0.721 mV indicated a uniform monodisperse system with stable dispersion properties. MBG-NLCs exhibited entrapment efficiency of 77.3 ± 1.17% and a sustained release in SIF of 94.75 ± 1.60% for 24 h. MBG-NLCs exhibited the Higuchi model with diffusion as a release mechanism. A pharmacokinetic study in Wistar rats exhibited a 1.67-fold higher bioavailability as compared to MBG suspension. Hence, MBG-NLCs hold promise for treating OAB by improving MBG's oral bio absorption.

Enhanced browning of adipose tissue by mirabegron-microspheres.

Thermogenic brown adipose tissue (BAT) has emerged as an attractive target for combating obesity. However, pharmacological activation of energy expenditure by BAT and/or induction of browning of white adipose tissue (WAT) has been hampered by cardiovascular side effects. To address these concerns, we developed polylactide-co-glycolide acid (PLGA) microspheres loaded with mirabegron (MIR), a selective beta-3 adrenergic receptor (ADRB3) agonist, to achieve sustained local induction and activation of thermogenic adipocytes. MIR-loaded PLGA microspheres (MIR-MS) effectively activated brown adipocytes and enhanced the thermogenic program in white adipocytes. Moreover, treating isolated inguinal WAT (iWAT) with MIR-MS resulted in increased expression of browning markers and elevated lipolysis mainly via ADRB3. In mice, injection of MIR-MS over four weeks induced browning of iWAT at the injection site. Importantly, local MIR-MS injection successfully mitigated unwanted cardiovascular risks, including high systolic blood pressure (SBP) and heart rate, as compared to MIR-treated mice. Finally, injecting MIR-MS into human subcutaneous WAT led to a significant induction of lipolysis and an increase in the expression of thermogenic marker uncoupling protein 1 (UCP1). Taken together, our findings indicate that MIR-MS function as a local drug release system that induces browning of human and murine subcutaneous WAT while mitigating undesirable cardiovascular effects.

Posterior Tibial Nerve Stimulation With versus Without Mirabegron: A Randomized Controlled Trial.

INTRODUCTION AND HYPOTHESIS: To compare change in urgency urinary incontinence episodes (UUIEs) in women undergoing posterior tibial nerve stimulation (PTNS) plus mirabegron versus PTNS plus placebo for the treatment of refractory urgency urinary incontinence (UUI). The primary hypothesis was that combination therapy is superior to monotherapy. METHODS: A randomized controlled trial was performed in individuals identifying as female aged ≥ 18 years with UUI symptoms refractory to second-line treatment or who could not tolerate antimuscarinic medications. Both participants and providers were blinded to medication treatment allocation. Participants were randomized (1:1) to PTNS plus mirabegron or PTNS plus placebo. Participants completed a 3-day bladder diary prior to and after 12-week treatment. Validated symptom distress and impact questionnaires were obtained pre- and post-treatment. The primary outcome was change in mean number of UUIEs on a 3-day bladder diary pre- versus post-treatment between arms. Primary and secondary outcomes were analyzed via sample t tests. RESULTS: Fifty-four subjects were randomized, mean ± SD baseline age 56.2±15.6 years and body mass index 35.0±9.4 (kg/m2); no differences were noted in any clinical-demographic characteristics. There was a significant difference between arms in mean pre- to post-treatment UUIEs, 9.4±3.9, mirabegron versus 5.3±5.5, placebo (p=0.007). Significant differences were found pre- compared with post-treatment in urinary frequency, Overactive Bladder Questionnaire Short Form Symptom Bother and Symptom Health-Related Quality of Life scores. CONCLUSIONS: In subjects undergoing PTNS treatment for refractory UUI and OAB-wet symptoms, the addition of a ß-3 agonist produced significant improvement in both objective and subjective overactive bladder symptom outcomes compared with PTNS plus placebo.

Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories.

Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.

Dynamic phenotypic shifts and M2 receptor downregulation in bladder smooth muscle cells induced by mirabegron.

Introduction: Mirabegron is available for treatment of overactive bladder (OAB). However, mechanisms underlying symptom improvements and long-term effects on bladder smooth muscle cells are uncertain. Contractility and growth of bladder smooth muscle contribute to OAB, and depend on smooth muscle phenotypes, and on muscarinic receptor expression. Here, we examined prolonged exposure to mirabegron (20-48 h) on phenotype markers, muscarinic receptor expression, and phenotype-dependent functions in human bladder smooth muscle cells (hBSMC). Methods: Expression of markers for contractile (calponin, MYH11) and proliferative (MYH10, vimentin) phenotypes, proliferation (Ki-67), and of muscarinic receptors were assessed by RT-PCR. Proliferation, viability, actin organization and contractions in cultured hBSMC were examined by EdU, CCK-8, phalloidin staining and matrix contraction assays. Results: Calponin-1 mRNA decreased with 100 nM and 150 nM mirabegron applied for 20 h (0.56-0.6 fold of controls). Decreases were resistant to the ß3-AR antagonist L-748,337 (0.34-0.55 fold, 100-150 nM, 20 h). After 40 h, decreases occured in the presence of L-748,337, but not without L-748,337. MYH11 mRNA increased with 150 nM mirabegron (40 h, 1.9 fold). This was partly preserved with L-748,337, but not observed after 20 h mirabegron exposure. Vimentin mRNA reduced with 150 nM mirabegron after 20 h, but not after 40 h, with and without L-748,337 (0.71-0.63 fold). MYH10 mRNA expression remained unaffected by mirabegron. Exposure to 150 nM mirabegron increased Ki-67 mRNA after 20 h in the presence of, but not without L-748,337, and after 40 h without, but not with L-748,337. Proliferation rates and actin organization were stable with 50-150 nM mirabegron (24 h, 48 h). Viability increased significantly after mirabegron exposure for 20 h, and by trend after 40 h, which was fully sensitive to L-748,337. M2 mRNA was reduced by 20 h mirabegron, which was resistant to L-748,337. Carbachol (3 µM) enhanced time-dependent contractions of hBSMC, which was inhibited by mirabegron (150 nM) in late phases (24 h), but not in early phases of contractions. Conclusion: Mirabegron induces dynamic phenotype alterations and M2 downregulation in hBSMC, which is paralleled by time-shifted anticontractile effects. Phenotype transitions may be involved in improvements of storage symptoms in OAB by mirabegron.

Therapeutic effectiveness and adverse drug reactions of mirabegron versus solifenacin in the treatment of overactive bladder syndrome.

Introduction: Overactive bladder (OAB) syndrome is a chronic disease characterized by urinary urgency with or without urge incontinence, frequency, and nocturia and antimuscarinic drugs such as solifenacin have been the mainstay of treatment. Mirabegron a beta 3 adrenoreceptor agonist has recently gained importance in the management of OAB. The rationale of the study is that mirabegron improves the storage function without affecting voiding which increases the therapeutic effectiveness. The objective was to determine the therapeutic effectiveness of mirabegron versus solifenacin. Methods: A prospective observational study was conducted on 298 patients with OAB syndrome attending the urology outpatient department of government medical college after obtaining institutional review board clearance. Patients of both genders, belonging to the 18-65 years of age group, attending the urology outpatient department were selected for the study. Patients were evaluated using the OAB-validated 8-question awareness tool (OAB-V8 score) before and after receiving drugs by direct questionnaire method after receiving informed consent. Patients were prescribed either solifenacin 5 mg or mirabegron 25 mg once daily by the urologist. Follow-up was done after 4 and 12 weeks. Adverse drug reactions of the drugs were assessed using the Central Drug Standard Control Organization suspected adverse reaction (ADR) form, and ADRs were notified to the nearest ADR monitoring center. Results: The mirabegron group showed maximum improvement in the mean OAB-V8 score values from baseline at 4 weeks (12.82 ± 5.86, P < 0.001) and 12 weeks (5.74 ± 3.31, P < 0.001) when compared to solifenacin. OAB-V8 scores of the solifenacin group also showed significant improvement from the baseline at 4 weeks (15.30 ± 5.54, P < 0.001) and 12 weeks (8.05 ± 4.59, P < 0.001). Heart rate, systolic, and diastolic blood pressures did not show significant changes during the follow-up in both the study groups. Thirteen patients developed ADRs such as dry mouth (four patients) and constipation (nine patients) in the solifenacin group. No ADRs were noted in the mirabegron group. Conclusion: Mirabegron showed maximum improvement in the OAB-V8 scores in patients with OAB syndrome, although the solifenacin group also showed improvement. Adverse effects were less in the mirabegron group when compared to the solifenacin group.

Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron.

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 (t1/2) (univariate p-value (puv) = 0.018) and incidence of adverse reactions (ADRs) (puv = 0.008, multivariate p (pmv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t1/2 than the T/T genotype (puv = 0.002, pmv = 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 (puv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (puv = 0.007, pmv = 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.

Comparative Approaches in Treating Double-J Stent Syndrome: Monotherapy or Combination Therapy?

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.

Silencing of ultradian rhythms and metabolic depression during spontaneous daily torpor in Djungarian hamsters.

Ultradian rhythms of metabolism, body temperature and activity are attenuated or disappear completely during torpor in Djungarian hamsters, for all three ultradian periodicities (URsmall, URmedium and URlarge). URsmall and URmedium disappear during entrance into torpor, whereas URlarge disappear later or continue with a low amplitude. This suggests a tight functional link between torpor and the expression of ultradian rhythms, i.e. torpor is achieved by suppression of metabolic rate as well as silencing of ultradian rhythms. Spontaneous torpor is often initiated after an ultradian burst of activity and metabolic rate, beginning with a period of motionless rest and accompanied by a decrease of metabolic rate and body temperature. To extend previous findings on the potential role of the adrenergic system on torpor induction we analysed the influence of the ß3-adrenergic agonist Mirabegron on torpor in Djungarian hamsters, as compared to the influence of the ß-adrenergic antagonist Propranolol. Hamsters were implanted with 10 day release pellets of Mirabegron (0.06 mg day-1) or Propranolol (0.3 mg day-1). Mirabegron transiently supressed and accelerated ultradian rhythms but had no effect on torpor behaviour. Propranolol did not affect torpor behaviour nor the expression of ultradian rhythms with the dosage applied during this study.

Intestinal Absorption Site-Guided Development and Evaluation of Oral Disintegrating Controlled Release Tablets of Mirabegron.

The aim was to employ site-dependent absorption of mirabegron (MB) as a guide for fabrication of oral disintegrating controlled release tablet (ODCRT) which undergoes instantaneous release of loading fraction followed by delayed release of the rest of MB. The goal was to release MB in a manner consistent with the chronobiology of overactive bladder (OAB) syndrome. In situ rabbit intestinal permeability of MB was adopted to assess absorption sites. MB was subjected to dry co-grinding with citric acid to develop the fast-dissolving fraction in the mouth. Delayed release fraction was formulated by ethanol-assisted co-processing with increasing proportions of Eudragit polymer (S100) as pH responsive polymer. The developed dry mixtures underwent thermal (DSC) and physical (X-ray diffraction) characterization, in addition to in vitro release behavior. Optimized fast dissolving and delayed release formulations were mixed with tablet excipient before compression in ODCRT which was assessed for release profile using continuous pH variation. MB underwent preferential permeation through ileum and colon. Co-grinding with citric acid provided co-amorphous powder with fast dissolution. Co-amorphization of MB with Eudragit S100 (1:5) showed pH-dependent release to release most of the dose at pH 7.4. The developed ODCRT released 43.5% of MB in the buccal environment and retained MB at acidic pH to start release at pH 7.4. The study successfully fabricated ODCRT guided by site-dependent absorption. The ODCRT instantaneously released loading fraction to support the patient after administration with delayed fraction to sustain the effect.

Ligand-Receptor Interactions and Structure-Function Relationships in Off-Target Binding of the ß3-Adrenergic Agonist Mirabegron to α1A-Adrenergic Receptors.

The ß3-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 α1A. The binding was simulated by docking mirabegron to a 3D structure of a human α1A-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 α1A 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 α1A 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 α1A, accounts for mirabegron binding to α1A. Because of its lack of interactions with the binding pocket, mirabegron has lower affinity compared to α1A-blockers and no effects on voiding symptoms.

Comparing efficacy and safety of mirabegron, tamsulosin, and solifenacin in ureteral stent-related symptoms: outcomes from a network meta-analysis.

Background: Although ureteral stents are a well-established and commonly used method for renal drainage, the ureteral stent-related symptoms (SRSs) they cause in patients cannot be ignored. It is currently unclear whether mirabegron has a place in the treatment of SRSs. Our study aims to systematically evaluate the efficacy and safety of mirabegron in treating SRSs in adult patients. Methods: Through a systematical search of multiple scientific databases before August 2023, we performed a systematic review and meta-analysis of the primary outcomes of interest according to the PRISMA. Analysis was performed under multivariate random-effects network models and effects of drugs was ranked with surface under the cumulative ranking curves (SUCRA) probabilities. Results: Sixteen studies involving 2,002 patients were included. All regimens (including mirabegron, solifenacin, and tamsulosin) were significantly better than placebo in urinary symptoms. Solifenacin was associated with more adverse drug events than mirabegron and tamsulosin. The SUCRA values showed that mirabegron was the best in the outcomes of body pain (71.5%), sexual matters (76.4%), and adverse events (70.5%). Solifenacin was the best in the outcomes of urinary symptoms (73.1%), general health (81.0%), and work performance (85.1%). Tamsulosin had the lowest rate of all outcomes. Conclusions: Compared with traditional drugs for relieving SRSs, mirabegron performs best in terms of alleviating body pain, sexual matters, and adverse events, with little difference in urinary symptoms and general health. Further high-quality prospective double-blinded randomized controlled trials (RCTs) are required to provide sufficient evidence supporting our observations.

Integrated approach of white analytical chemistry and design of experiments to microwave-assisted sensitive and eco-friendly spectrofluorimetric estimation of mirabegron using 4-chloro-7-nitrobezofuran as biosensing fluorescent probe.

The USFDA recently approved mirabegron, a novel once-daily ß-3 adrenoceptor agonist for oral administration, as a transformative treatment for overactive bladder. Despite the existence of numerous analytical methods for the assay and bioanalysis of mirabegron, it's perplexing that none have explored the domain of microwave-assisted sensitive spectrofluorimetric method for mirabegron estimation, even after extensive literature review. Adding to the enigma is the insistence of current analytical methods on using expensive and harmful organic solvents, posing a threat to marine life and the broader environment. Recently, the white analytical chemistry approach has been introduced to develop analytical methods that are cost-effective, environmentally friendly, and user-friendly. Consequently, a white analytical chemistry-based, sensitive, and eco-friendly spectrofluorimetric estimation of mirabegron has been initiated, using 4-Chloro-7-nitrobenzofurazan as a fluorescent biosensing probe. The development of this robust method involved a series of experiments designed to minimize solvent and time wastage. Through a combination of fractional factorial and Box-Behnken designs, researchers identified the critical variables and optimized the method to perfection. This method was validated according to the stringent ICH Q2 (R2) and USFDA guidelines, ensuring its reliability and accuracy. Once approved, this sensitive spectrofluorimetric method was tested, accurately estimating mirabegron levels in commercial formulations and rat plasma samples. To further enrich the study, a comprehensive evaluation of existing analytical methods was conducted alongside the proposed spectrofluorimetric method, using advanced tools like the AGREE calculator, GAPI software, and RGB model to assess their eco-friendliness and effectiveness in mirabegron estimation.

Pemafibrate abrogates SLD in a rat experimental dietary model, inducing a shift in fecal bile acids and microbiota composition.

BACKGROUND AND AIMS: Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only efficacy, but also a high safety profile. Repurposing of drugs in clinical use, such as pemafibrate and mirabegron, could facilitate the finding of an effective and safe drug-treatment for SLD. APPROACH AND RESULTS: The SLD High Fat High Fructose (HFHFr) rat model develops steatosis without the influence of other metabolic disturbances, such as obesity, inflammation, or type 2 diabetes. Further, liver fatty acids are provided, as in human pathology, both from dietary origin and de novo lipid synthesis. We used the HFHFr model to evaluate the efficacy of pemafibrate and mirabegron, alone or in combination, in the resolution of SLD, analyzing zoometric, biochemical, histological, transcriptomic, fecal metabolomic and microbiome data. We provide evidence showing that pemafibrate, but not mirabegron, completely reverted liver steatosis, due to a direct effect on liver PPARα-driven fatty acid catabolism, without changes in total energy consumption, subcutaneous, perigonadal and brown fat, blood lipids and body weight. Moreover, pemafibrate treatment showed a neutral effect on whole-body glucose metabolism, but deeply modified fecal bile acid composition and microbiota. CONCLUSIONS: Pemafibrate administration reverts liver steatosis in the HFHFr dietary rat SLD model without altering parameters related to metabolic or organ toxicity. Our results strongly support further clinical research to reposition pemafibrate for the treatment of SLD/MASLD.

Efficacy of transcutaneous electrical nerve stimulation combined with mirabegron therapy compared with mirabegron monotherapy for overactive bladder: a prospective randomized controlled study.

PURPOSE: The objective was to evaluate the efficacy of transcutaneous electrical nerve stimulation (TENS) combined with mirabegron therapy compared with mirabegron monotherapy in the treatment of female patients with overactive bladder (OAB). METHODS: In this randomized controlled study, 100 female outpatients with OAB were screened. Among these patients, 86 who met the inclusion criteria were randomly divided into the TENS combined with mirabegron treatment group and mirabegron monotherapy treatment group, with 43 patients in each group. The voiding diary, Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Symptom Bother Score (OAB-q SBS), total health-related quality of life (OAB-q HRQoL), and treatment satisfaction-visual analog scale (TS-VAS) score before and after treatment were recorded to evaluate the efficacy of OAB treatment. Seventy-nine of the 86 patients (40 in the TENS plus mirabegron group and 39 in the mirabegron monotherapy group) completed 12 weeks of treatment. RESULTS: TENS combined with mirabegron therapy was superior to mirabegron monotherapy in improving the primary endpoints, including the daily number of micturition episodes and the daily MVV/micturition and secondary endpoints, including the daily number of urgency episodes, the OABSS, the OAB-q SBS, the HRQoL score and TS-VAS score. There were no statistically significant differences in urgency urinary incontinence and nocturia between the groups. Some minor adverse effects were observed, including muscle pain, local paresthesia and constipation. CONCLUSIONS: The combination of TENS and mirabegron was more effective than mirabegron alone in the treatment of female patients with OAB. TRIAL REGISTRATION NUMBER: ChiCTR2400080528 (31.01.2024, retrospectively registered).