Cold Exposure Drives Weight Gain and Adiposity following Chronic Suppression of Brown Adipose Tissue.

Therapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality (~20 °C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold exposure (20 °C) and ß3-adrenoreceptor agonism (YM-178) under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28 °C to 20 °C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration, thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in the subcutaneous inguinal white adipose tissue (IWAT) in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e., G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e., eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality.

Monotherapy with mirabegron had a better tolerance than the anticholinergic agents on overactive bladder: A systematic review and meta-analysis.

BACKGROUND: We conducted this meta-analysis to explore the tolerance of monotherapy with mirabegron (50 mg) on an overactive bladder, compared with a common dosage of anticholinergic agents. MATERIALS AND METHODS: A comprehensive search for all randomized controlled trials that evaluated the safety of mirabegron and anticholinergic agents on overactive bladder was performed, and we searched the Cochrane Central Register of Controlled trials databases, Pubmed, Embase, and relevant trials from 2013.02 to 2019.10. RESULTS: Eight studies included 5500 patients with treatment of monotherapy on overactive bladder were identified. The total number of treatment-emergent adverse events had no significantly difference between two monotherapies (RR = 0.88 95%CI: 0.76-1.01; P = .08); however, patients would have a better tolerance with mirabegron (50 mg) in adverse events of dry mouth (RR = 0.42; 95%CI: 0.33-0.53; P < .01) and tachycardia (RR = 0.52; 95%CI: 0.29-0.94; P = .03); and there were no significant differences between two groups in hypertension (RR = 1.02; 95%CI: 0.80-1.30; P = .90), constipation (RR = 0.91; 95%CI: 0.65-1.26; P = 0.57), blurred vision (RR = 1.03; 95%CI: 0.60-1.77; P = 0.92), and urinary tract infection (RR = 0.90; 95%CI: 0.70-1.16; P = .41). CONCLUSIONS: Treatment-emergent adverse events in patients with overactive bladder who underwent monotherapy of mirabegron (50 mg) or the anticholinergic agents had no significant differences, but mirabegron has a better tolerance in the aspect of dry mouth and tachycardia.

Pharmacotherapy of patients with benign prostate enlargement and storage symptoms in everyday clinical practice.

OBJECTIVE: Storage symptoms significantly deteriorate the quality of life in men with benign prostate enlargement (BPE). Muscarinic receptor antagonists (MRAs) and ß3-adrenergic receptors agonists alone, or in combination with selective α1-alpha-antagonists, are considered the most effective medicines relieving storage symptoms. The aim of this study was to analyze the pharmacotherapy of storage symptoms in men with BPE, and their compliance with the European Association of Urology (EAU) guidelines. PATIENTS AND METHODS: The survey was conducted in 2018 by 261 urologists among 24,613 men with lower urinary tract symptoms (LUTS) and BPE treated pharmacologically. Data concerning recent severity of non-neurological LUTS, storage symptoms and pharmacotherapy were collected. RESULTS: Storage symptoms were reported by 12,356 patients (50.2%) with BPE, more frequently nocturia (75.8%), than urinary urgency (57.8%) and frequency (44.3%). Patients with storage symptoms were more frequently prescribed with MRAs and mirabegron (43.1% vs. 5.0% and 2.4% vs. 0.3%, respectively; p<0.001). Of note, 54.5% of patients with storage symptoms were treated neither with MRAs, nor ß3-adrenergic receptors agonists. In the subgroup with storage symptoms, the increasing severity of LUTS accounted for more frequent prescription of MRA (2.1% vs.  29.1% vs. 42.8% in patients with mild, moderate, and severe LUTS, respectively). Decision tree analysis revealed that patients with urinary urgency and urinary frequency, as well as younger ones with urinary urgency but without urinary frequency, were more frequently prescribed with MRAs. CONCLUSIONS: Urinary urgency and frequency are associated with increased utilization of MRAs in men with BPE in everyday clinical practice. The attitude of Polish urologists toward management of persistent storage symptoms in BPE patients is in line with the EAU guidelines.

Mirabegron: Pediatric First Approval.

Mirabegron (MYRBETRIQ®), a beta-3 adrenergic agonist developed by Astellas Pharma Inc., is well established as a treatment for overactive bladder in adults and is available as extended-release (ER) tablets administered once daily. More recently, mirabegron has been investigated in pediatric patients with neurogenic detrusor overactivity (NDO) and received its first approval in this indication in pediatric patients aged ≥ 3 years on 25 March 2021 in the USA. In addition to mirabegron ER tablets (which can be used in pediatric patients weighing ≥ 35 kg), mirabegron is available as an ER oral suspension (MYRBETRIQ® Granules) for pediatric patients; in those weighing < 35 kg, only the ER oral suspension formulation should be used. The ER tablet and ER oral suspension formulations are not substitutable on a mg-by-mg basis. This article summarizes the milestones in the development of mirabegron for NDO leading to this pediatric first approval.

Role of TRPA1 expressed in bone tissue and the antinociceptive effect of the TRPA1 antagonist repeated administration in a breast cancer pain model.

AIMS: Breast cancer-induced chronic pain is usually treated with opioids, but these compounds cause various adverse effects. Transient receptor potential ankyrin 1 (TRPA1) is involved in cancer pain; also, endogenous TRPA1 agonists are associated with cancer pain development. The aim of this study was to observe the antinociceptive effect of a repeated-dose TRPA1 antagonist administration and the production of endogenous TRPA1 agonists and TRPA1 expression in bone tissue in a model of breast cancer pain in mice. Second, we used a sequence reading archive (SRA) strategy to observe the presence of this channel in the mouse bone and in mouse bone cell lines. MAIN METHODS: We used BALB/c mice for experiments. The animals were subjected to the tumor cell inoculation (4 T1 strain). HC-030031 (a TRPA1 antagonist) treatment was done from day 11 to day 20 after tumor inoculation. TRPA1 expression and biochemical tests of oxidative stress were performed in the bone of mice (femur). SRA strategy was used to detect the TRPA1 presence. KEY FINDINGS: Repeated treatment with the TRPA1 antagonist produced an antinociceptive effect. There was an increase in hydrogen peroxide levels, NADPH oxidase and superoxide dismutase activities, but the expression of TRPA1 in the bone tissue was not altered. SRA did not show TRPA1 residual transcription in the osteoblast and osteoclast cell lines, as well as for mice cranial tissue and in mouse osteoclast precursors. SIGNIFICANCE: The TRPA1 receptor is a potential target for the development of new painkillers for the treatment of bone cancer pain.

Possible Involvement of Muscarinic Receptor Blockade in Mirabegron Therapy for Patients with Overactive Bladder.

The selective ß 3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 µM) inhibited specific [N-methyl-3H]scopolamine methyl chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart and significantly higher than those in the submaxillary gland and brain. Mirabegron induced the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high- and low-affinity components for mirabegron were 44.5% and 55.5%, respectively. Respective pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of mirabegron, muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg mirabegron was 37%-76%. The present results demonstrate for the first time that mirabegron may relax the detrusor smooth muscle not only by ß 3-adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective ß 3-adrenoceptor agonist, represents an alternative to antimuscarinic agents for management of overactive bladder (OAB). The present study aimed to clarify whether mirabegron directly binds to muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder and to predict muscarinic receptor occupancy in human bladder after oral administration of mirabegron. The results demonstrated that mirabegron therapy for patients with OAB may be due not only to ß 3-adrenoceptor activation but also muscarinic receptor blockade.

Pioglitazone does not synergize with mirabegron to increase beige fat or further improve glucose metabolism.

BACKGROUNDBeige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the ß3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages.METHODSWe measured BAT by PET CT scans, measured beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs.RESULTSTreatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments was evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The 3 treatments also had different effects on muscle fiber type switching and capillary density.CONCLUSIONThe addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants.TRIAL REGISTRATIONClinicalTrials.gov NCT02919176.FUNDINGNIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.

B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis?-A randomized study.

INTRODUCTION AND OBJECTIVE: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study's primary outcome is the LUTD symptom improvement. MATERIAL AND METHODS: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit. RESULTS: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects. CONCLUSIONS: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters.

The application of extreme value theory to pharmacometrics.

Clinical trials are often analyzed by examining the means, e.g., what is the mean treatment effect or what is the mean treatment difference, but there are times when analysis of the maximums (or minimums) are of interest. For instance, what is the highest heart rate that could be observed or what the smallest treatment effect that could be expected? While inference on the means is based on the central limit theorem, the corresponding theorem for maximums or minimums is the Fisher-Tippett theorem, also called the extreme value theorem (EVT). This manuscript will introduce EVT to pharmacometricians, particularly block maxima analysis and peak over threshold analysis, and provide examples for how it can be applied to pharmacometric data, particularly the analysis of pharmacokinetics and ECG safety data, like QTcF intervals.

Mirabegron, A Selective ß3-Adrenoceptor Agonist Causes an Improvement in Erectile Dysfunction in Diabetic Rats.

AIM: To investigate the possible beneficial effect of mirabegron [a selective ß3-adrenoceptor (AR) agonist] treatment on erectile dysfunction (ED) in streptozotocin-induced diabetic rats. METHODS: Sprague-Dawley rats (n=20) were divided into two groups: control group and streptozotocin-induced diabetic group. In vivo erectile responses were evaluated after intracavernosal injection of mirabegron (0.4 mg/kg) in rats. The relaxation responses to electrical field stimulation (EFS, 10 Hz), sodium nitroprusside (SNP, 10 nM) and sildenafil (1 µM) of corpus cavernosum (CC) strips were examined after the incubation with mirabegron (10 µM). ß3-ARs expression and localization were determined by Western blot and immunohistochemical analyses in CC tissue. RESULTS: In vivo erectile responses of diabetic rats [intracavernasal pressure (ICP) / mean arterial pressure, 0.17±0.01] were decreased, which were restored after administration of mirabegron (0.75±0.01, P<0.001). The basal ICP (7.1±0.6 mmHg) in diabetic rats was markedly increased after mirabegron (36.1 ±5.4 mmHg, P<0.01). Mirabegron caused markedly relaxation in diabetic rat CC after phenylephrine precontraction. The relaxation responses to EFS and sildenafil were reduced in diabetic CC, which were increased in the presence of mirabegron. Mirabegron enhanced SNP-induced relaxation response in both groups. The expression and immunoreactivity of ß3-ARs localized to CC smooth muscle were observed in control and diabetic rats. CONCLUSIONS: This is the first study to show that intracavernosal administration of mirabegron improved erectile function and neurogenic relaxation of CC in diabetic rats. These results may be supported by further studies using combinations of mirabegron and phosphodiesterase type 5 (PDE5) inhibitors for the treatment of diabetic ED, especially in patients who do not respond to PDE5 inhibitor therapy.

Cardiovascular safety of mirabegron add-on therapy to tamsulosin for the treatment of overactive bladder in men with lower urinary tract symptoms: A post hoc analysis from the MATCH study.

OBJECTIVES: To investigate the cardiovascular safety of mirabegron add-on treatment to tamsulosin in male patients with residual overactive bladder symptoms. METHODS: This was a post hoc analysis of MATCH, the first double-blind, placebo-controlled study comparing mirabegron and placebo as add-on therapy to tamsulosin for treatment of overactive bladder in men with lower urinary tract symptoms. The analysis focused on treatment-emergent adverse events relating to the cardiovascular system or blood pressure, and changes in vital signs during 12 weeks of follow-up. RESULTS: Cardiovascular-related treatment-emergent adverse events were reported by 6/566 patients, although only one serious treatment-emergent adverse event was related to treatment (unstable angina in the tamsulosin + placebo group). Hypertension (two patients) and increased blood pressure (one patient) were reported in the tamsulosin + placebo group, but there were no blood pressure-related treatment-emergent adverse events among tamsulosin + mirabegron patients. There were no clinically meaningful changes from baseline in blood pressure, and changes in pulse rate were small (+1.2 bpm in the tamsulosin + mirabegron group). Increased pulse rate was more frequent with tamsulosin + mirabegron than with tamsulosin + placebo in older patients, although within the normal range. CONCLUSIONS: Cardiovascular-related adverse events were uncommon in both treatment groups. Mirabegron is a well-tolerated add-on therapy to tamsulosin in Japanese and Korean males with residual overactive bladder symptoms.

The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high-risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, most will relapse, resulting in chemoresistant disease. After relapse, there is growing evidence of p53 inactivation. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. MDM2 inhibitors and Bromodomain and Extra-Terminal domain (BET) inhibitors have both shown promise in treating NB by increasing the expression of p53 and decreasing MYC/MYCN expression, respectively. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) in neuroblastoma. METHODS: Two p53 wild-type and two p53 mutant established neuroblastoma cells lines were used to test this combination. Ray design assays were used to test whether this combination was synergistically cytotoxic to NB cells. Western blots were performed to check signaling pathways of interest after drug treatment. IncuCyte imaging and flow cytometry were utilized to quantify the apoptotic and cytostatic effects of these drugs on NB cells. In vivo studies were carried out to test the antitumor effect of this combination in a living host. RESULTS: The combination of CGM097 and OTX015 resulted in p53 activation, decreased expression of MYC family proteins and a subsequent synergistic increase in NB cell death. CONCLUSION: This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB.

The metabolic effects of mirabegron are mediated primarily by ß3 -adrenoceptors.

The ß3 -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at ß-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [3 H]-2-deoxyglucose uptake, cellular glycolysis, and O2 consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at ß3 -adrenoceptors as they were largely absent in adipocytes derived from ß3 -adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the ß3 -adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the ß3 -adrenoceptor.

Mirabegron Versus Solifenacin in Multiple Sclerosis Patients With Overactive Bladder Symptoms: A Prospective Comparative Nonrandomized Study.

OBJECTIVE: To determine the patient-perceived effectiveness and tolerability of mirabegron compared to solifenacin in a multiple sclerosis (MS) population with overactive bladder (OAB) symptoms. MATERIALS AND METHODS: MS patients with OAB symptoms who were not on medication for their urinary symptoms at enrollment were prospectively recruited. Patients enrolled in years 1-2 were prescribed mirabegron, whereas patients enrolled in years 3-4 were prescribed solifenacin. At enrollment and 6-week follow-up, patients completed several patient reported outcome measures. The primary outcome was change in OAB Questionnaire Short Form (OAB-q SF) symptom severity and minimal clinically important difference (MCID) achievement. The Patient Assessment of Constipation Symptoms (PAC-SYM) was used to assess bowel function over the treatment period. RESULTS: Sixty-one patients were enrolled. The majority of the mirabegron (70%) and the solifenacin (69%) group achieved the OAB-q SF symptom severity MCID. The solifenacin group had a statistically significant greater decrease in its end of study OAB-q SF score (Δ = -37.87 vs -20.43, P = .02). Constipation improved in the mirabegron group and worsened in the solifenacin group (ΔPAC-SYM = -0.38 vs +0.22; P = .02), with 30% of patients prescribed solifenacin experiencing worsening above the MCID threshold. CONCLUSION: Among MS patients, we demonstrated similar response rates to mirabegron and solifenacin, with approximately 50%-70% achieving each patient reported outcome measure's MCID. Though this small study showed some short-term evidence that improvement in urinary symptom severity was greater with solifenacin, this potential benefit must be weighed against the observed risk of worsening constipation. Further studies are needed to confirm these findings.

Safety and Tolerability Results from the PILLAR Study: A Phase IV, Double-Blind, Randomized, Placebo-Controlled Study of Mirabegron in Patients ≥ 65 years with Overactive Bladder-Wet.

BACKGROUND: In older patients with overactive bladder (OAB), mirabegron, a ß3-adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk-benefit profile. OBJECTIVES: Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged ≥ 65 years with OAB-wet. METHODS: We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placebo. Community-dwelling patients aged ≥ 65 years with OAB-wet (one or more incontinence episode and three or more urgency episodes, and an average of eight or more micturitions/24 h over a 3-day diary) were randomized to receive placebo or mirabegron 25 mg/day (optional dose escalation to 50 mg/day at week 4 or 8). Safety analyses were performed for adverse events (AEs) and vital signs on all randomized patients who received one or more dose of study drug. RESULTS: Treatment-emergent AEs (TEAEs), the majority mild or moderate in severity, were reported in 39.4% of placebo patients and 44.2 and 49.8% of those who received mirabegron 25 mg or 50 mg, respectively. The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhea. The incidence of TEAEs was slightly higher in mirabegron patients aged ≥ 75 years than in those aged < 75 years. There were no clinically meaningful differences in changes in vital signs from baseline to end of treatment for any treatment group, and no differences were observed between mirabegron and placebo treatment groups. TEAEs tended to occur early post exposure and were not dose related. CONCLUSIONS: Mirabegron treatment was well-tolerated in older adults with OAB-wet. Safety and tolerability were consistent with the known mirabegron safety profile. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov: NCT02216214.

Efficacy of adding mirabegron to alpha-adrenoreceptor blocker in patients with benign prostatic hyperplasia with persistent overactive bladder symptoms: A prospective study.

Purpose: To compare the efficacies of mirabegron 50 mg addition after alpha-adrenoreceptor blocker in terms of reducing storage symptoms in patients with BPH. Materials and Methods: Fifty-eight patients that had been taking alpha-adrenoreceptor blocker for more than 8 weeks, but had an OABSS of greater than 3 points, were initially enrolled. One group added any alpha-adrenoreceptor blocker with mirabegron 50 mg (n=39; the mirabegron group) and the other group received alpha-adrenoreceptor blocker only (n=19; the control group) for 8 weeks. Results: In the control group, mean total IPSS decreased from 15.7 to 13.1 (p=0.298) and in mirabegron group, mean total IPSS decreased from 19.4 to 16.5 (p=0.024). Mean storage symptom scores reduced in the control and mirabegron groups from 8.5 to 7.9 (p=0.584) and from 9.1 to 7.6 (p=0.015), respectively, and mean QoL scores from 3.7 to 3.1 (p=0.052) and 3.6 to 3.2 (p=0.027), respectively. Mean overall OABSS in the control and mirabegron groups reduced from 8.4 to 7.2 (p=0.173) and from 8.8 to 7.3, respectively (p=0.005); mean OABSS Q3 from 3.6 to 2.9 (p=0.073) and from 3.5 to 2.7 (p=0.002), respectively; and mean OABSS Q4 from 2.4 to 2.0 (p=0.306) and from 2.7 to 2.0 (p=0.016), respectively. The change of mean Qmax and PVR was insignificant in 2 groups. Conclusions: IPSS total scores, storage symptom scores, QoL, overall OABSS, OABSS Q3 and Q4 were more improved significantly by alpha-adrenoreceptor blocker with mirabegron 50 mg in BPH patients with persistent overactive symptoms. Mirabegron 50 mg addition is considered to patients with persistent storage symptoms after alpha-adrenoreceptor blocker.

The Efficacy of Mirabegron for the Relief of Ureteral Stent-Related Symptoms.

To investigate the efficacy of mirabegron for lower urinary tract symptoms in patients with an indwelling ureteral stent after ureterorenoscopic lithotripsy. This was a prospective follow-up study of 76 patients with stent-related symptoms (SRSs). Patients with upper urinary calculi who were pre-stented for > 2 weeks before lithotripsy were examined for the presence of SRSs by tests including the International Prostate Symptom Score (IPSS), OAB Symptom Score (OABSS), and urinary bother and pain measured by a Visual Analogue Scale (VAS) before lithotripsy. Mirabegron (50 mg/day) was prescribed post-lithotripsy for 2 weeks. SRSs were assessed at the time of stent removal. The IPSS scores improved significantly from 16.2 to 14.3 (p<0.001) and the IPSS-QoL scores decreased significantly from 5.0 to 4.6 (p=0.012). The OABSS scores improved significantly from 7.7 to 6.8 (p=0.006), and the urinary urgency scores (OABSS-Q3) decreased significantly from 3.24 to 2.68 (p<0.001). The number of nocturia episodes decreased significantly from 2.5 to 2.2 (p=0.045). Urinary bother and pain assessed by the VAS declined from 4.2 and 3.1 to 3.8 (p=0.15) and 2.5 (p=0.075), respectively. Mirabegron significantly improved SRSs and the number of nocturia episodes due to a ureteral stent.

Potential of Mirabegron and its Extended-release Formulations for the Treatment of Overactive Bladder Syndrome.

BACKGROUND: Overactive bladder syndrome is a broadly occurring urological disorder with a distressing impact on the quality of life. The commonly used antimuscarinic drugs show poor patient compliance because of unsatisfactory potency, tolerability and high occurrence of adverse effects such as dry mouth, blurred vision, constipation, dizziness etc. Mirabegron is the first approved ß3-adrenoreceptor agonist, used as mono or in combination therapies for overactive bladder syndrome. OBJECTIVE: The present review provides an insight into the mechanism, pharmacokinetics, toxicokinetics, clinical trials and the development of various conventional and modified-release dosage forms of mirabegron for the treatment of overactive bladder syndrome. RESULTS: The clinical trials of phase II and phase III of mirabegron demonstrated symptomatic relief from the overactive bladder without disturbing the micturition cycle. To date, mirabegron showed promising results for safety, tolerability and efficacy in patients with overactive bladder syndrome. The modified-release tablet dosage form of mirabegron appear to be a proficient and suitable replacement for antimuscarinics and revealed the tremendous potential to overcome the adverse effects of conventional antimuscarinic drugs like Oxybutyline chloride ER, Detrol LA, VESIcare, etc. Conclusion: Mirabegron shows a distinct mode of action, i.e., targeting ß3-adrenoreceptors and improving bladder storage without altering void contractions. The limited side effects, high safety, efficacy and tolerability of mirabegron present an adequate substitute to antimuscarinics. However, long-term analysis and clinical studies are prerequisites for assessing the safety, tolerability and efficacy profile of mirabegron.

Combination drug therapy against OAB normalizes micturition parameters and increases the release of nitric oxide during chemically induced cystitis.

Today, monotherapy is the most common pharmacological treatment option for patients suffering from overactive bladder (OAB). Recent reports have indicated potential benefits of combination therapy, using a muscarinic antagonist and a ß3 -adrenoceptor agonist. This may be of particular interest for therapy-resistant patients with OAB and concomitant cystitis. The objective of the current study was to assess how combination therapy affects bladder parameters in health and cystitis and if the efficacy of the drugs can be linked to altered release of nitric oxide (NO). Rats were pretreated with either a combination of the muscarinic antagonist tolterodine and ß3 -selective adrenoceptor agonist mirabegron or saline for 10 days. Forty-eight hours prior to assessing micturition parameters in a metabolic cage, the rats were intraperitoneally injected with cyclophosphamide, causing cystitis, or saline. Urine samples were collected and analyzed for NO content. Bladder contractile properties were assessed in an organ bath setup. Induction of cystitis led to bladder overactivity. Combination therapy normalized bladder parameters. Both induction of cystitis and drug treatment increased the release of NO. The innate contractile properties of the bladder were unaffected by combination therapy. This study demonstrates positive effects of combination drug therapy on symptoms of OAB, possibly indicating it to be a good option for treatment of OAB during concomitant cystitis. It remains to be determined if increased release of NO is crucial for successful pharmacological treatment of bladder overactivity during cystitis.

Topical transient receptor potential ankyrin 1 antagonist treatment attenuates nociception and inflammation in an ultraviolet B radiation-induced burn model in mice.

BACKGROUND: Ultraviolet B (UVB) radiation exposure promotes sunburn and thereby acute and chronic inflammatory processes, contributing to pain development and maintenance. New therapeutic alternatives are necessary because typical treatments can cause adverse effects. An attractive alternative would be to target the transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable, non-selective cation channel, which is involved in a variety of inflammatory pain models. OBJECTIVE: Evaluate the peripheral participation of TRPA1 using a topical treatment (HC030031 gel formulation; a selective TRPA1 antagonist) in nociception and inflammation caused by a UVB radiation-induced burn model in male mice (25-30 g). METHODS: The mice were anaesthetised, and just the right hind paw was exposed to UVB radiation (0.75 J/cm2). Topical treatments were applied immediately after irradiation and once a day for 8 days. RESULTS: HC030031 gel presented suitable pH and spreadability factor, ensuring its quality and the therapeutic effect. HC030031 0.05 % reversed UVB-induced mechanical and cold allodynia, with maximum inhibition (Imax) of 69 ± 13 % and 100 % (on day 4), respectively. HC030031 0.05 % also reduced the paw edema and MPO activity, with Imax of 77 ± 6 % (on day 5) and 69 ± 28 %, respectively. Likewise, UVB radiation increased the H2O2 levels (a TRPA1 agonist) and the Ca2+ influx in mice spinal cord synaptosomes. UVB radiation-induced Ca2+ influx was reduced by HC030031. CONCLUSION: These findings confirm the activation of the TRPA1 channel by UVB radiation, suggesting that topical TRPA1 antagonists can be a new strategy for the adjuvant treatment of sunburn-associated pain and inflammation.