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Myelination subserves efficient neuronal communication, and alterations in white matter (WM) microstructure have been implicated in numerous psychiatric disorders, including pathological anxiety. Recent work in rodents suggests that muscarinic antagonists may enhance myelination with behavioral benefits; however, the neural and behavioral effects of muscarinic antagonists have yet to be explored in non-human primates (NHP). Here, as a potentially translatable therapeutic strategy for human pathological anxiety, we present data from a first-in-primate study exploring the effects of the muscarinic receptor antagonist solifenacin on anxious behaviors and WM microstructure. 12 preadolescent rhesus macaques (6 vehicle control, 6 experimental; 8F, 4M) were included in a pre-test/post-test between-group study design. The experimental group received solifenacin succinate for ~60 days. Subjects underwent pre- and post-assessments of: 1) anxious temperament (AT)-related behaviors in the potentially threatening no-eye-contact (NEC) paradigm (30-min); and 2) WM and regional brain metabolism imaging metrics, including diffusion tensor imaging (DTI), quantitative relaxometry (QR), and FDG-PET. In relation to anxiety-related behaviors expressed during the NEC, significant Group (vehicle control vs. solifenacin) by Session (pre vs. post) interactions were found for freezing, cooing, and locomotion. Compared to vehicle controls, solifenacin-treated subjects exhibited effects consistent with reduced anxiety, specifically decreased freezing duration, increased locomotion duration, and increased cooing frequency. Furthermore, the Group-by-Session-by-Sex interaction indicated that these effects occurred predominantly in the males. Exploratory whole-brain voxelwise analyses of post-minus-pre differences in DTI, QR, and FDG-PET metrics revealed some solifenacin-related changes in WM microstructure and brain metabolism. These findings in NHPs support the further investigation of the utility of antimuscarinic agents in targeting WM microstructure as a means to treat pathological anxiety., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Objective: The aim: To improve the results of treatment of hyperactive bladder syndrome in men of working age on the background of barotrauma and stress, as a consequence of combat trauma., Patients and Methods: Materials and methods: An analysis of the questionnaire and the results of the clinical examination of 32 patients, injured servicemen and people who were injured in combat zones was carried out. The drug solifenacin succinate was used in the treatment complex, which is a specific antagonist of M3 subtype cholinergic receptors. Its influence allows you to achieve relaxation of the bladder detrusor and reduce the contractility of hyperactive bladder., Results: Results: The main criterion for the effectiveness of the treatment was a decrease in the number of urgent cases, the frequency of urination and manifestations of nocturia by 50% or more, which was considered a positive effect. At the same time, the positive effect was differentiated as follows : an improvement of these parameters by 75% or more from the initial value which is a good result; reduction of symptoms in the range of 50-75% is satisfactory; less than 50% is an unsatisfactory result. A positive effect from the treatment after 8 weeks was observed in 88% of patients, of which 52% had a good result and 36% had a satisfactory result., Conclusion: Conclusions: The proposed complex of treatment of hyperactive bladder syndrome as a result of combat trauma against the background of barotrauma with neurological consequences and chronic stress allows to achieve a pronounced clinical effect in the vast majority of male patients of working age. And the diagnostic complex allows you to emphasize aspects of clinical vigilance, both for doctors of a specialized branch and of doctors of a general direction.

To summarize the differences in urodynamic outcomes between oral antimuscarinic drugs and OnabotulinumtoxinA, and finding a therapy that maintains good urodynamics in neurogenic detrusor overactivity (NDO). We conducted a literature search of EMBASE and PubMed, with the language limited to English. In the analysis, all of the published randomized trials of OnabotulinumtoxinA or antimuscarinic drugs used to treat NDO were found and the results were finally obtained through Bayesian model analysis. A total of 12 RCTs and 2208 patients were included. OnabotulinumtoxinA 300U was superior to other drugs in terms of MCC, volume at IDC, and Pdet max endpoints. OnabotulinumtoxinA 200U was more effective on the urodynamic endpoint of BC than other drugs or doses of OnabotulinumtoxinA. According to the MCC urodynamic results, oxybutynin, solifenacin 10 mg, and tolterodine 4 mg also had positive effects. OnabotulinumtoxinA 300U, 200U and 100U were better in improving the urodynamic results of NDO, and the current evidence also shows that selective injection of onabotulinumtoxinA can effectively improve the urodynamic results., (© 2022. The Author(s).)

Evidence to support the effectiveness of β3-adrenoceptor agonist mirabegron and anti-muscarinic solifenacin in the management of bladder dysfunction caused by psychological stress is lacking. This study investigates whether mirabegron or solifenacin reduces the bladder overactivity caused by water avoidance stress (WAS) in mice. Female mice were exposed to WAS for 1 h/day for 10 days and received either placebo, solifenacin or mirabegron in drinking water. Controls were age-matched without stress exposure. Voiding behaviour and functional isolated whole bladder responses during distension and in response to pharmacological agents and electrical field stimulation was investigated. Urinary frequency was significantly increased following stress. Mice treated with mirabegron or solifenacin displayed significantly fewer voiding events compared to the stressed mice, and voiding frequency in drug-treated animals was comparable to unstressed controls. The maximal contractile responses of bladders to carbachol were significantly enhanced by stress and reduced by mirabegron but not solifenacin. The frequency of phasic bladder contractions following stimulation with carbachol was significantly enhanced following stress and remained elevated in the mirabegron treated group. However, treatment with solifenacin significantly reduced the frequency of phasic contractions to unstressed control levels. Solifenacin and mirabegron are beneficial in reducing the overall voiding dysfunction caused by WAS in mice., (© 2022. The Author(s).)

Solifenacin (Vesicare ® , SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH 3 cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K + current (I K(M) ) with effective EC 50 value of 0.34 μM. The activation time constant of I K(M) was concurrently shortened in the SOL presence, hence yielding the K D value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of I K(M) was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of I K(M) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated I K(M) ; however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in I K(M) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K + (K M ) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH 3 cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the I K(M) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with K M channels and hence in stimulating I K(M) in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH 3 or mHippoE-14 cells.

Objective: We evaluated a combination of transcutaneous electrical nerve stimulation (TENS) and solifenacin succinate versus solifenacin alone in the treatment of overactive bladder (OAB)., Methods: Ninety-seven female outpatients with OAB were screened for this double-blind randomized controlled study. Eighty-six patients who met our inclusion criteria were divided randomly into two groups. In group A (43 patients), patients received oral solifenacin and "fake" TENS on the foot; in group B (43 patients), patients received oral solifenacin and effective TENS on the foot. Improvements in OAB symptoms were assessed by Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire (OAB-q), voiding diaries and urodynamic tests. 70 of 86 patients (36 in group A, 34 in group B) completed the 2 months of treatment and 3 months of follow-up., Results: Statistically, the maximum bladder volume and OAB symptoms of both groups improved significantly after treatment. The improvement in group B was significantly better than that in group A, as indicated by the maximum bladder volume, OAB-q score and voiding diary. Some mild adverse effects were observed, including dry mouth, stomach upset, constipation, muscle pain and local paresthesia., Conclusion: The combination of TENS and solifenacin was more effective in improving OAB symptoms than solifenacin alone., Competing Interests: The authors have declared that no competing interests exist.

Over the years, experimental and clinical evidence has given support to the idea that acetylcholine (Ach) plays an essential role in mnemonic phenomena. On the other hand, the Hippocampus is already known to have a key role in learning and memory. What is yet unclear is how the Ach receptors may contribute to this brain region role during memory retrieval. The Ach receptors are divided into two broad subtypes: the ionotropic nicotinic acetylcholine receptors and the metabotropic muscarinic acetylcholine receptors. Back in 2010, we demonstrated for the first time the critical role of hippocampal α7 nicotinic acetylcholine receptors in memory reconsolidation process of an inhibitory avoidance response in mice. In the present work, we further investigate the possible implication of hippocampal muscarinic Ach receptors (mAchRs) in this process using a pharmacological approach. By specifically administrating agonists and antagonists of the different mAchRs subtypes in the hippocampus, we found that M1 and M2 but not M3 subtype may be involved in memory reconsolidation processes in mice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The effects of solifenacin and mirabegron on vesical and urethral function were compared in rats with or without spinal cord injury (SCI). Isovolumetric cystometry and urethral pressure recording were initially performed in intact rats. Then, the bladder neck was ligated under urethane anesthesia, after which a catheter was inserted through the bladder dome for isovolumetric cystometry and another catheter was inserted into the urethra to measure urethral pressure. Solifenacin (0.03-3 mg/kg) or mirabegron (0.03-3 mg/kg) was injected intravenously, and bladder and urethral activity were recorded. To create rats with SCI, the spinal cord was transected at the lower thoracic level under isoflurane anesthesia. After 2 weeks, a catheter was inserted through the bladder dome for single cystometry and bladder activity was recorded without anesthesia following intravenous injection of solifenacin or mirabegron. Isovolumetric cystometry revealed a larger decrease in maximum bladder contraction pressure after injection of solifenacin, whereas prolongation of the interval between bladder contractions was greater with mirabegron. In SCI rats, single cystometry showed that solifenacin and mirabegron both increased bladder volume at the first non-voiding bladder contraction and decreased the maximum bladder contraction pressure. Mirabegron also increased the voided volume and decreased the percentage residual volume without altering bladder capacity. Solifenacin and mirabegron both inhibited bladder contractility, and mirabegron possibly also induced urethral relaxation. Mirabegron may be suitable for patients with overactive bladder and residual urine., (© 2019 John Wiley & Sons Australia, Ltd.)

Purpose: To compare the heart rate increase side effect of different antimuscarinic drugs used in overactive bladder (OAB)., Methods: Overall 341 patients were consecutively randomized to take seven different antimuscarinic drugs between January 2014 and June 2016 at three institutions, and 250 patients who completed the follow-up visits were accepted into this study. Ninety-one patients who never came to visits were excluded. Drugs were classified into two groups as selective (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride) and non-selective (fesoterodine fumarate, tolterodine tartrate, trospium chloride and propiverine hydrochloride) antimuscarinic drugs. The cardiac pulse rates and the blood pressures were recorded during the baseline, first visit (1 week) and second visit (1 month). Data were compared for drugs and two groups (selective versus non-selective) by using ANOVA test., Results: Baseline characteristics were similar among the patients using different antimuscarinic drugs. Statistically significant increase in heart rate occurred in patients treated with non-selective antimuscarinic drugs compared to those treated with selective drugs (p < 0.001), and this increase was especially evident in patients treated with trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride (p < 0.001, 0.003, 0.011 and 0.37, respectively). There was no statistical difference for the other side effects., Conclusions: Our results showed that heart rate significantly increased in OAB patients treated with non-selective antimuscarinic drugs. Trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride seem to have the most unfavorable properties with regard to increased heart rate side effect when compared to the other antimuscarinic drugs (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride).

Objective: The aim of this study was to perform a blood pressure (BP) safety evaluation in patients with an overactive bladder receiving solifenacin (an antimuscarinic agent), mirabegron (a β3-adrenoceptor agonist), or both compared with placebo in the SYNERGY trial., Patients and Methods: Patients were randomized to receive solifenacin 5 mg+mirabegron 50 mg (combination 5+50 mg); solifenacin 5 mg+mirabegron 25 mg (combination 5+25 mg); solifenacin 5 mg; mirabegron 50 mg; mirabegron 25 mg; or placebo for a double-blind 12-week treatment period. Systolic BP, diastolic BP, and heart rate were measured by ambulatory BP monitoring, and in the clinic or home., Results: A total of 715 patients were analyzed in an ambulatory BP monitoring substudy. At the end of treatment, ambulatory BP monitoring measurements showed no consistent increases from baseline in the mean 24-h systolic BP or diastolic BP for combination versus monotherapy groups or for monotherapy groups versus placebo. Analysis of 1-h BP averages during the 6 h range that included the Tmax values of both study drugs showed no significant BP effects. Shift analysis (switch between different normotension/hypertension stages) did not show differences among the active and placebo groups, nor did outlier analysis of major BP changes differ between placebo and active treatment. Similarly, there were no significant signals in the 24-h heart rate. Office and home measurements were consistent with ambulatory BP monitoring findings., Conclusions: A paradigm of ambulatory BP monitoring analysis designed to test BP safety of noncardiovascular drugs showed that solifenacin plus mirabegron combination therapy during 12 weeks produced no meaningful changes in BP or heart rate.

Background: Despite enormous progresses in understanding pathophysiology of the lower urinary tract, antimuscarinics remain the chief clinically well-established approach for improving symptoms of overactive bladder (OAB). Dry mouth on the other hand remains one of the most untolerated systemic side effects of these drugs that limits their uses and results in high discontinuation rate. Three novel drugs have been recently approved by US Food and Drug Administration for treatment of OAB: trospium, darifenacin, and solifenacin., Aims: This study has been conducted to provide clear head to head comparative studying of histological and ultrastructural effect of those newly emerging drugs on parotid and submandibular salivary glands and to demonstrate the differential expression of CXCL10 to make a cogent structural and molecular assessment of the relative tolerability of these drugs and the potential mechanisms of occurrence of dry mouth., Methods: Fifty male Sprague Dawley rats were equally divided into five groups: Group I (control), Group II (oxybutynin-treated), Group III (trospium-treated), Group IV (darifenacin-treated) and Group V (solifenacin-treated). Histological and ultrastructural studies were performed on parotid and submandibular glands. Measurement of salivary flow, PCR analysis and immunohistochemical assessment of CXCL10 expression have been carried-out., Results: Muscarinic receptor antagonists led to various histological, morphometric and ultrastructural changes together with diminished salivary secretion and up-regulation of CXCL10 expression with the mildest alterations observed with solifenacin., Conclusions: Solifenacin has shown the least adverse effects to salivary glands. CXCL10 is involved in degenerative changes of salivary glands induced by muscarinic antagonists., (Published by Elsevier GmbH.)

BACKGROUND The purpose of the present study was to assess the effect of luteolin and solifenacin on diabetic cystopathy (DCP) and to investigate the mechanism of action. A novel link between the overexpression of c-Kit in the bladder and voiding dysfunction was identified in rats with DCP. MATERIAL AND METHODS A rat model of DCP was successfully established by intraperitoneal injection of streptozotocin and a diet high in glucose and lipids, and animals were treated with luteolin and solifenacin. The effect of luteolin and solifenacin on urinary dysfunction in DCP rats was investigated by assessing bladder pressure and performing a volume test. The protein levels of c-Kit, stem cell factor (SCF), p110, and phosphorylated p110 in the bladder were detected by Western blot analysis and immunohistochemical staining. RESULTS In DCP rats, the protein levels of c-Kit, SCF and phosphorylated p110 in the bladder were significantly increased. However, oral treatment of DCP rats with luteolin combined with solifenacin resulted in effective improvement of overactive bladder and reduced the protein expression of c-Kit, SCF, and phosphorylated p110. Moreover, the effect of luteolin combined with solifenacin on maximum voiding pressure and residual urine volume was improved compared to that of luteolin alone. CONCLUSIONS Luteolin improved overactive bladder in DCP rats, which may be due to SCF/c-kit inhibition, as well as the downregulation of the phosphoinositide-3 kinase signaling pathway. Moreover, solifenacin enhanced the potential pharmacological effect of luteolin in the treatment of DCP.

Aim: The aim of this study was to compare the efficacy and tolerability of solifenacin and mirabegron in patients with overactive bladder (OAB) syndrome., Methods: We carried out a retrospective analysis in 342 women affected by OAB syndrome; 168 were treated with solifenacin 5 mg/daily and 174 with mirabegron 50 mg/daily. A clinical evaluation, 3-day voiding diary, and urodynamic testing was performed. Patients completed the Overactive Bladder Questionnaire - Short Form, the King's Health Questionnaire, and the Patient Global Impression of Improvement questionnaire. The adverse effects were evaluated. The two groups were compared at baseline and at 12 weeks., Results: After 12 weeks, a significant reduction in the mean number/24 h of voids and urgent micturition episodes/24 h was observed in both groups. Detrusor overactivity decreased from 58.3% to 13.1% in the solifenacin group and from 58% to 11% in the mirabegron group. Twenty (12%) and 18 (10.7%) patients taking solifenacin reported constipation and dry mouth, respectively, versus four (2.3%) and five (2.9%) patients taking mirabegron, respectively, but there was no difference between the groups in the change in vital signs. The Overactive Bladder Questionnaire - Short Form and King's Health Questionnaire scores did not demonstrate significant differences and the abandonment rates in the solifenacin and mirabegron groups were 25.5% and 20%, respectively., Conclusion: Solifenacin and mirabegron showed the same efficacy in the treatment of OAB but solifenacin had more adverse effects., (© 2017 Japan Society of Obstetrics and Gynecology.)

Background: Overactive bladder syndrome (OAB) is a chronic and prevalent condition which has a negative impact on Quality of Life. The National Institute of Clinical Excellence issued two documents which give slightly varying algorithms of pharmacotherapy for OAB, offering mirabegron as a possible treatment in certain circumstances. In the absence of trials involving a direct comparison of therapies, an indirect comparison can provide useful information on the difference in treatment effects between competing interventions., Objective: To compare effectiveness of available medical therapies for OAB using Bucher indirect treatment comparison (ITC) model., Methods: A systematic literature search identified randomised controlled trials (RCT) assessing effectiveness of drugs for OAB versus placebo. Then indirect comparisons of the treatments effects were made, preserving the randomisation of the originally assigned patient groups, using Bucher method., Main Results: 25 RCTs met inclusion criteria. In keeping with ITC method validity, four assessments were undertaken of mirabegron against anticholinergics, which were number of incontinence episodes, micturition episodes, urgency episodes in 24 h and volume of micturition. This indirect treatment analysis suggests that mirabegron is as effective as anticholinergics in managing of OAB, except for solifenacin which appears to be superior., Conclusions: These findings suggest that work looking into treatment choice should be individualized to patient characteristics rather than fitting patients to a treatment. Further work is required to identify what patient characteristics may be crucial and indicate that studies exploring the most effective sequence of managing treatment naïve patients and those with refractory disease., (© 2017 Wiley Periodicals, Inc.)

Chronic prostatitis (CP) is a common urological disorder, with bladder voiding dysfunction being the primary clinical manifestation. Resveratrol is polyphenolic compound isolated from numerous plants, with widely‑reported anti-inflammatory properties. The present study aimed to investigate whether resveratrol may improve overactive bladder in rats with CP and to investigate the underlying molecular mechanisms. Furthermore, the potential pharmacological synergy between resveratrol and solifenacin was also investigated as a potential treatment for CP. Following the successful establishment of a rat model of CP by subcutaneously injecting DPT vaccine, rats were treated with resveratrol or a combination of resveratrol + solifenacin. Bladder pressure and volume tests were performed to investigate the effect of resveratrol and solifenacin on urinary dysfunction in rats with chronic prostatitis. Western blot analysis and immunohistochemical staining were used to examine the expression of c‑Kit receptor, stem cell factor (SCF), AKT and phosphorylated‑AKT (p‑AKT) in the bladder tissue. The results of the bladder pressure and volume test indicated that the maximum capacity of the bladder, residual urine volume and maximum voiding pressure in the control group were 0.57 ml, 0.17 ml and 29.62 cm H2O, respectively. These values were increased by 71, 27 and 206% in rats in the CP group compared with the control group. Following treatment with resveratrol, the results in the resveratrol group were reduced by 25.77, 44.23 and 13.32% compared with the CP group. The results of western blot analysis, immunohistochemical staining and immunofluorescence labeling demonstrate that the protein expression of SCF, c‑Kit and p‑AKT in the bladder of rats in the CP group was 4.32, 6.13 and 6.31 times higher compared with the control group, respectively. Following treatment with resveratrol, protein expression was significantly reduced. However, no significant differences were observed between the protein expression of the SCF, c‑Kit and p‑AKT in the bladder between the resveratrol and combination groups. In conclusion, resveratrol may improve overactive bladder by downregulating the protein expression of SCF, c‑Kit and p‑AKT in the bladder of rats with CP. Furthermore, a combination of resveratrol and solifenacin may have potential pharmacological synergy as a treatment for patients with CP.

Aim: The aims of this study were: (i) to evaluate change of Overactive Bladder Symptom Scores (OABSS) from before to after solifenacin treatment; and (ii) to evaluate correlation between change of OABSS and 3-day micturition diary, International Prostate Symptom Score (IPSS), and Patient Perception of Bladder Condition (PPBC)., Methods: Thirty-six women, aged > 18 years, diagnosed as having overactive bladder (OAB) at King Chulalongkorn Memorial Hospital, with the symptoms of urgency, frequency with or without urge incontinence for more than 3 months, and at least three episodes of urgency with or without incontinence during the last 3 days prior to the study, were recruited during January 2010-May 2011. All cases received solifenacin 5-mg treatment once a day and were asked to record a 3-day micturition diary and to complete the Thai version of the OABSS, IPSS, and PPBC questionnaires at weeks 0, 4, and 12 after treatment., Results: The OABSS, IPSS, and PPBC scores and all parameters of the 3-day micturition diary had changed significantly by weeks 4 and 12. The OABSS correlated significantly with IPSS score (r = 0.44), PPBC score (r = 0.39), and urgency episodes (r = 0.48)., Conclusion: The OABSS had good responsiveness, similar to the other questionnaires (the IPSS and PPBC) and the 3-day micturition diary. The use of OABSS is recommended in OAB women for evaluation after anticholinergic drug treatment., (© 2017 Japan Society of Obstetrics and Gynecology.)

Aims: This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the β 3 -adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs)., Methods: Thirty-two female 10-week-old SHRs were fed an 8% NaCl-supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the β 3 -ARs and M 3 -MRs expressed within the urinary bladders were analyzed., Results: Just after transfer from RT to LT, vehicle-, solifenacin-, and mirabegron-treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress-induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination-treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M 3 -MR and β 3 -AR mRNA. The tissue distribution of M 3 -MRs was similar to that of the β 3 -ARs., Conclusions: This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress-induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026-1033, 2017. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc., (© 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.)

Introduction: Depression is frequently found in patients suffering from overactive bladder. The aim of the study was to verify whether the 13-cis-retinoic acid, a synthetic retinoid used in the treatment of acne, which was proven to induce depressive changes in both humans and animals, can cause detrusor overactivity symptoms in conscious rats., Methods: In order to assess the 13-cis-retinoic acid impact on the behavioural parameters, after 6weeks of intraperitoneal administration of retinoid in a dose of 1mg/kg/day, a forced swim test and cystometry were performed, and the locomotor activity of animals was assessed. The control group received a mixture of DMSO and physiological saline at a 1:1 ratio., Results: 13-cis-retinoic acid caused cystometric parameter changes analogous to those observed in people with a urodynamic diagnosis of detrusor overactivity. The retinoid caused also an extension of the immobility time in the forced swim test which is consistent with increased depression-related behaviour, with no impact on the locomotor activity of rats. The intravenous administration of solifenacin succinate in a single dose of 0.03mg/kg turned out to reverse changes in the cystometric parameters modified by 13-cis-retinoic acid treatment. The histopathological analysis of bladders did not show any lesions in the upper layer of the umbrella cells, urothelium or muscles. The retinoid concentration level achieved in the animals tested turned out to be identical to that occurring in humans., Discussion: 13-cis-retinoic acid can induce detrusor overactivity symptoms that are reversed by solifenacin succinate., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Solifenacin is an antimuscarinic agent used to treat symptoms of overactive bladder. Pharmacologically significant amounts of solifenacin were excreted in the urine of humans taking a clinical dose of this drug. The aim of this study is to measure muscarinic receptor binding in the bladder urothelium and detrusor muscles of rats following the intravesical instillation of solifenacin. Muscarinic receptors were measured by radioreceptor assay using [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS), a selective radioligand of muscarinic receptors. Solifenacin showed concentration-dependent inhibition of specific [(3)H]NMS binding in the bladder urothelium and detrusor muscle of rats, with no significant difference in Ki values or Hill coefficients between these tissues. Following the intravesical instillation of solifenacin, there was significant muscarinic receptor binding (increase in Kd for specific [(3)H]NMS binding) in the bladder urothelium and detrusor muscle of rats. Similar bladder muscarinic receptor binding was observed by the intravesical instillation of oxybutynin, but not with trospium. In conclusion, the present study has demonstrated that solifenacin binds muscarinic receptors not only in the detrusor muscle but also in the bladder urothelium with high affinity. These bladder muscarinic receptors may be significantly affected by solifenacin excreted in the urine.

Aim: The aim of this study was to characterize urethral neuromuscular function before and 2 weeks after medication therapy., Methods: Premenopausal women without lower urinary tract symptoms were randomly allocated to 1 of the 6 medications for 2 weeks (pseudoephedrine ER of 120 mg, imipramine of 25 mg, cyclobenzaprine of 10 mg, tamsulosin of 0.4 mg, solifenacin of 5 mg, or placebo). At baseline and after medication, participants underwent testing: quantitative concentric needle electromyography (CNE) of the urethral sphincter using automated multimotor unit action potential software, current perception threshold (CPT) testing to measure periurethral sensation, and standard urodynamic pressure flow studies (PFS). Nonparametric tests were used to compare pre-post differences., Results: Fifty-six women had baseline testing, 48 (85.7%) completed follow-up CNE, and 49 (87.5%) completed follow-up CPT and PFS testing. Demographics showed no significant differences among medication groups with respect to age (mean, 34.3; SD, 10.1), body mass index (mean, 31.8; SD, 7.5), parity (median, 1; range, 0-7), or race (14% Caucasian, 80% African American). The PFS parameters were not significantly different within medication groups. No significant pre-post changes in CNE values were noted; however, trends in amplitudes were in a direction consistent with the expected physiologic effect of the medications. With CPT testing, a trend toward increased urethral sensation at the 5-Hz stimulation level was observed after treatment with pseudoephedrine (0.15-0.09 mA at 5 Hz, P = 0.03)., Conclusions: In women without lower urinary tract symptoms, pseudoephedrine improved urethral sensation but not urethral neuromuscular function on CNE or PFS. Imipramine, cyclobenzaprine, tamsulosin, solifenacin, and placebo did not change urethral sensation or neuromuscular function.

Aims: In spite of the reported efficacy and safety of antimuscarinics in men with OAB (overactive bladder) and BPO (benign prostatic obstruction), many patients do not persist with the treatment. We aimed to evaluate persistence and the reasons for the discontinuation of solifenacin add-on therapy in men with residual symptoms of OAB after tamsulosin monotherapy for BPO in a real clinical environment., Methods: Men aged ≥ 45 years with IPSS ≥ 12 and symptoms of OAB (OAB-V8 ≥ 8, micturition ≥ 8/24 h, urgency ≥ 2/24 h) were prescribed tamsulosin 0.2 mg. After 4 weeks, men who had residual symptoms of OAB (OAB-V8 ≥ 8, micturition ≥ 8/24 h, urgency ≥ 1/24 h) and reported that they were 'dissatisfied' or 'a little satisfied' with the therapy were enrolled and prescribed solifenacin 5 mg in combination with tamsulosin. After 52 weeks, persistence and the reasons for the discontinuation of solifenacin were evaluated. Factors related to persistence were analysed., Results: Of the 305 men who had been treated with tamsulosin, 176 were prescribed solifenacin. After 52 weeks, 44 (25%) remained on solifenacin therapy. Of the 132 who discontinued solifenacin, 85 were evaluated on the reason for discontinuation. The three most common reasons for discontinuation were adverse events (AEs) (35%), lack of efficacy (33%), and improvement in symptoms (16%). The aggravation of voiding symptoms was the most common AE leading to discontinuation. Retention was observed in 11 men. None of the demographical or clinical characteristics were significantly related to persistence., Conclusions: Only 25% men with OAB and BPO remained on antimuscarinic add-on therapy after 1 year, mostly because of AEs and lack of efficacy. Realistic data should be added to what is already known about antimuscarinic treatment in men by including patients who were excluded or who dropped out of well-designed clinical trials., (© 2014 John Wiley & Sons Ltd.)