Sexual Dysfunction in Patients with Overactive Bladder Syndrome Treated with Botulinum Toxin.

Introduction: Overactive bladder (OAB) is a syndrome of the lower urinary tract characterized by urinary urgency, frequency, and nocturia, with or without urgency urinary incontinence. OAB significantly impacts all aspects of life-social, psychological, physical, professional, domestic, and sexual-for both women and men. The aim of this study was to investigate sexual dysfunction in both women and men with OAB treated with intravesical onabotulinumtoxinA (Botox) injections using the Sexual Quality of Life questionnaire in two versions: female (SQoL-F) and male (SQoL-M). Methods: Forty sexually active patients (thirty women and ten men) with idiopathic OAB were recruited. Patients completed the SQoL-F or SQoL-M questionnaire before treatment, and again at 3 and 6 months after treatment with intravesical onabotulinumtoxinA injections. Results: All 40 patients completed the study (30 women and 10 men). There were no statistically significant differences in SQoL results before the procedure or at 3- and 6-months post-treatment. Conclusions: OAB treatment with onabotulinumtoxinA did not significantly affect the quality of sexual life in either women or men. Further research is needed using questionnaires specifically designed to assess the sexual life of patients with OAB, especially in men.

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.

Evaluation of transurethral GreenLight laser-selective vaporization for refractory overactive bladder in women.

Background: Refractory overactive bladder (OAB) in women is a common yet challenging condition for which traditional treatments have been unsatisfactory. This study aimed to evaluate the efficacy and safety of transurethral bladder mucosal GreenLight laser-selective vaporization for treating refractory OAB in women. Methods: The female patients with refractory OAB who were admitted to the Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University between May 2022 and July 2023 were examined retrospectively in this study. Transurethral bladder mucosal GreenLight laser-selective vaporization was used to treat the patients, and the perioperative and postoperative parameters were reviewed and compared. Bladder mucosa was examined by immunohistochemical staining to explore the expressions of TRPV1, P2X3, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) before and after treatments. Results: Surgeries were performed successfully for all 32 patients in 57.38±11.22 minutes with minimal intraoperative bleeding. Twelve weeks post-surgery, there was a significant decrease (P<0.05) in the patients' Overactive Bladder Symptom Score (OABSS), 3-day bladder diary (daytime frequency, nocturia, urgency, and urgency incontinence), and Overactive Bladder questionnaire Short Form (OAB-qSF) score. After treatments, both first desire to void (FDV) and maximum bladder pressure capacity (MCBC) increased significantly (P<0.05). The immunohistochemical analysis revealed that the GreenLight laser significantly reduced the expressions of TRPV1, P2X3, TNF-α, and IL-6 in the bladder mucosa (P<0.05). No severe complications were observed after interventions. Conclusions: For female patients with refractory OAB who have shown poor response to conventional treatment approaches, transurethral bladder mucosal GreenLight laser-selective vaporization may represent a promising alternative treatment option.

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.

Immunomodulatory imide drugs inhibit human detrusor smooth muscle contraction and growth of human detrusor smooth muscle cells, and exhibit vaso-regulatory functions.

BACKGROUND: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). METHODS: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. CONCLUSIONS: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

Preliminary evidence for therapeutic impact of intravesical glucosamine on protamine sulfate and potassium chloride-induced bladder overactivity in rat model.

PURPOSE: To investigate the protective effect of intravesical glucosamine in treating overactive bladder (OAB). METHODS: Ninety-two female Sprague-Dawley (SD) rats were divided into 4 groups i.e. protamine sulfate (PS), N-acetylcysteine (NAC), and glucosamine-treated PS (GPS), and normal saline control (NC) were used. We induced hyperactivity in rats via intravesical infusion of PS and potassium chloride (KCl), whereas the NC group underwent a sustained intravesical saline infusion for 1 h. N-acetylcysteine (NAC), a potential antioxidant as well as anti-inflammatory agent was employed as positive control. Cystometrography (CMG) was then conducted to determine urodynamic parameters, i.e., leak point pressure (LPP, n = 48) and inter-contractile interval, the duration between two voids (ICI, n = 32). RESULTS: LPP was significantly elevated in the GPS group (mean ± SD: 110.9 ± 6.2 mmHg) compared to the NC (81.0 ± 32.5 mmHg), PS (40.3 ± 10.9 mmHg), and NAC group (70.3 ± 19.4 mmHg). The cystometrogram data also reveals a prolonged ICI in the GPS group (241.3 ± 40.2 s) compared to the NC group (216.0 ± 41.7 s), PS group (128.8 ± 23.6 s), and NAC group (193.8 ± 28.3 s). CONCLUSION: This preliminary study implies the ameliorative impact of GPS treatment on OAB in terms of improved urodynamic parameters, including LPP and ICI.

Squatting-based exercises cure bedwetting in children and improve pain and bladder symptoms in premenopausal women.

This paper explores a practical approach to pelvic floor health called the Skilling technique. Unlike the commonly recommended "squeezing upwards" method which teaches a woman to voluntarily squeeze upwards (a learnt technique), the Skilling method is entirely reflex: the squatting-based exercises on which it is based, strengthen the three reflex pelvic muscle forces which pull against the suspensory ligaments pubourethral ligament (PUL) and uterosacral ligament (USL) to: close the urethra during effort (control of stress incontinence), open the urethra during micturition, and stretch the vagina in opposite directions to control inappropriate activation of the micturition reflex [overactive bladder (OAB)]. The strengthened ligaments better support the pelvic visceral plexuses (VPs), which unsupported, can fire off de novo impulses which the brain interprets as "chronic pelvic pain". This review investigates the impact of the Skilling technique on pain, bladder and bowel symptoms in women. In premenopausal women, results show a 50% symptom improvement in 68% to 82% of women who have chronic pelvic pain, urge, frequency, nocturia, abnormal emptying, and post-void residual urine. A modified Skilling technique was applied in children aged 6-11 years with day/night enuresis. Remarkably, an 86% cure rate was achieved over 4 months. It was hypothesized that this accelerated cure, which is achieved naturally with age, may be connected to the reinforcement of collagen which occurs with the increase in pubertal hormones. In summary, the Skilling technique is a promising and accessible method to enhance pelvic floor health for both women and children, offering a practical alternative to traditional approached like Kegel exercises.

Urodynamic insights: exploring the relationship between detrusor overactivity and pelvic organ prolapse in women with urge incontinence.

PURPOSE: Pelvic organ prolapse (POP) and overactive bladder (OAB) commonly affect the aging female population. We aimed to investigate the possible relationship between the two, as reflected by urodynamic studies. METHODS: A retrospective analysis was conducted on women who underwent urodynamic studies at a university-affiliated tertiary medical center from January 2018 to January 2021. Women presenting with urge incontinence and diagnosed with detrusor overactivity (DO) were included in the study. Based on the presence or absence of a modified POP-Q ≥ grade 2, these women were categorized into two groups. Data on general demographics, clinical symptoms, and urodynamic findings were extracted and compared using SPSS. RESULTS: During the study period, 949 urodynamic evaluations were performed. Of these, 303 (31.92%) reported urge incontinence. Out of this subset, 151 (49.83%) were diagnosed with DO. Within this group, 18 (11.9%) had POP, while 134 (88.1%) did not. The POP group had a notably higher incidence of prior vaginal hysterectomy and anterior colporrhaphy (p = 0.02 and p = 0.01, respectively). While most urodynamic parameters were similar between groups, there was a significant increase in hesitancy in the POP group (13 s vs 8 s, p = 0.03). There was a trend indicating a reduced median Q max (12 ml/s vs. 18 ml/s, p = 0.06) and an increased flow time (55 s vs 40 s, p = 0.08) in the POP group. CONCLUSION: The urodynamic profile of the POP group suggests an obstructive voiding pattern. Further longitudinal research is essential to fully understand the relationship between POP and OAB.

Efficacy of medication for overactive bladder symptoms in 70 patients with Parkinson's disease.

Background: Managing overactive bladder (OAB) symptoms in Parkinson's disease (PD) is challenging. This study aimed to investigate the medical management of OAB symptoms in patients with PD. Methods: Patients with OAB symptoms who were newly treated with tolterodine and/or tamsulosin were screened from a database of 187 PD patients. Before treatment, the Hoehn-Yahr scale, International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), and urodynamic evaluation were evaluated. On day 21 of treatment, the IPSS and OABSS were re-evaluated. The changes of these scores and urinary symptoms were analyzed. Results: Seventy patients with a mean age of 62.2±7.9 years and median Hoehn-Yahr stage of 2 (IQR 2-3) were enrolled. Tolterodine, tamsulosin, and tolterodine + tamsulosin were used in 43, 20, and 7 patients, respectively. The IPSS storage symptoms (9.4±3 vs. 3.5±2.3) and OABSS (9±2.8 vs. 4.8±3.3) improved significantly after treatment (both P<0.01). However, 28 (40%) patients displayed moderate urinary symptoms, and nocturia and urgency still affected more than half of the patients after treatment. Conclusions: Tolterodine and/or tamsulosin can significantly improve OAB symptoms in PD patients. Nocturia and urgency remain common after treatment.

The brain, gut, and bladder health nexus: A conceptual model linking stress and mental health disorders to overactive bladder in women.

OBJECTIVE: A small, but growing literature links stressors and mental health disorders (MHDs) across the life course to overactive bladder (OAB) and urinary incontinence symptoms. Mechanisms by which stressors and MHDs may impact bladder health are not fully understood, limiting novel prevention and treatment efforts. Moreover, potential biopsychosocial mechanisms involving the brain and gut have not been considered in an integrated, comprehensive fashion. METHODS: Members of the prevention of lower urinary tract symptoms Research Consortium developed conceptual models to inform research on biopsychosocial mechanisms through which stress and MDHs may impact bladder health among girls and women, focusing on brain and gut physiology. RESULTS: Two conceptual models were developed-one to explain central (brain-based) and peripheral (gut-based) mechanisms linking stressors and MHDs to OAB and bladder health, and one to highlight bidirectional communication between the brain, gut, and bladder. Traumatic events, chronic stressors, and MHDs may lead to a maladaptive stress response, including dysregulated communication and signaling between the brain, gut, and bladder. Gut bacteria produce molecules and metabolites that alter production of neurotransmitters, amino acids, short-chain fatty acids, and inflammatory immune response molecules that mediate communication between the gut and brain. Microbiota signal neurogenesis, microglia maturation, and synaptic pruning; they also calibrate brain-gut-bladder axis communication through neurotransmission and synaptogenesis, potentially influencing bladder symptom development. Life course trajectories of risk may be prevented or interrupted by central and peripheral resources for neuropsychological resilience. CONCLUSIONS: Depicted pathways, including brain-gut-bladder communication, have implications for research and development of novel prevention and treatment approaches.

Associations between exposure to organophosphate esters and overactive bladder in U.S. adults: a cross-sectional study.

Background: The relationship between exposure to organophosphate esters (OPEs) and the risk of developing overactive bladder (OAB) is uncertain. The purpose of this study is to examine the potential link between urinary metabolites of organophosphate esters and OAB. Method: Data from the National Health and Nutrition Examination Survey (NHANES) database of the 2011-2016 cycles were utilized. Four urinary metabolites of organophosphate esters: diphenyl phosphate (DPHP), bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), and dibutyl phosphate (DBUP) were included in the study. Multivariate logistic regression and restricted cubic spline (RCS) were used to evaluate the relationship between urinary OPEs metabolites and OAB. Interaction analysis was conducted on subgroups to confirm the findings. Results: A total of 3,443 United States (US) adults aged 20 years or older were included in the study, of whom 597 participants were considered to have OAB. After adjusting for potential confounding factors, we found a positive association between DPHP and the risk of overactive bladder. The risk of overactive bladder increased with increasing DPHP concentrations compared with quartile 1 (quartile 2, OR = 1.19, 95% CI, 0.82-1.73, P = 0.34; quartile 3, OR = 1.67, 95% CI, 1.10-2.53, P = 0.02; Q4, OR = 1.75, 95% CI, 1.26-2.43, P = 0.002). However, after dividing the participants by gender, only the female group retained consistent results. Additionally, restricted cubic spline analysis revealed a nonlinear dose-response correlation between DPHP and OAB in female participants. In the subgroup analysis based on age, race, body mass index (BMI), recreational activity, smoking status, drinking status, hypertension, diabetes, and stroke, the interaction analysis revealed that the findings were uniform. Conclusion: Our findings indicate that exposure to DPHP could elevate the risk of OAB in US adult females. Further experimental studies are needed to explore the underlying mechanism in the future.

De Novo Lower Urinary Tract Symptoms in COVID-19 Patients.

Background and objective Since early 2020, the novel coronavirus disease 2019 (COVID-19) has turned into a global healthcare concern. The usual clinical presentation of COVID-19 infection includes myalgia, headache associated with pyrexia, and sore throat. Our study aimed to assess the severity of lower urinary tract symptoms (LUTS) in COVID-19 patients and determine its correlation with the prognosis of the disease. Methods We conducted an observational study in the COVID-19 care unit at a tertiary care teaching center in Rajasthan on patients diagnosed as COVID-19-positive. The overactive bladder (OAB) symptom scoring system for LUTS and the CT scoring system for lung involvement in COVID-19 patients were used to evaluate the sample population. Results While our findings showed a non-significant association between OAB and CT score (p>0.05), correlation analysis revealed that the length of hospital stay was significantly longer and oxygen needs were significantly more frequent with severe LUTS. Conclusions Based on our findings, de novo LUTS, particularly storage symptoms, may be present in COVID-19-positive cases, and the severity of these symptoms may have an impact on the patient's length of stay in the hospital. Hence, doctors and other medical professionals should consider COVID-19-related bladder dysfunctions such as de novo LUTS as part of COVID-19 symptomatology.

An analysis of factors that influence patient preference of third-line therapy for overactive bladder.

OBJECTIVE: Patients with overactive bladder (OAB) refractory to first- and second-line therapy may pursue third-line therapies, including intradetrusor onabotulinum toxin-A (BTX), peripheral tibial nerve stimulation (PTNS), and sacral neuromodulation (SNM). The factors that influence patient preference for each treatment modality have not yet been explored. This study sought to investigate the specific parameters that patients consider in choosing a third-line therapy for OAB. METHODS: Patients refractory to first- and second-line therapies for OAB were identified in our outpatient clinic and asked to watch an educational video providing information on the risks and benefits of each third-line treatment option. They were then given a questionnaire to rank their preference of therapy and select reasons for why they found each therapy favorable and unfavorable. Patients under age 18 years, non-English speakers, those with a developmental disability, and those with a diagnosis of neurogenic bladder were excluded. RESULTS: Of the 98 patients included in the study, 40 participants (40.8%) chose intradetrusor BTX injections, 34 (34.7%) chose PTNS, and 16 (16.3%) chose SNM as their first choice. Seven patients (7.1%) chose none of the offered therapies, and one patient (1.0%) chose all three therapies with equal preference. BTX was found most attractive for its long efficacy (47%); its least attractive feature was the potential need for self-catheterization due to urinary retention (54%). PTNS was found most attractive for being a nonsurgical option (32%) and having no reported significant complications (39%); its least attractive feature was need for frequent office visits (61%). SNM was found most attractive for its potential for long-term relief without frequent office visits (53%); its least attractive feature was need for an implanted device (33%). Patients opting for SNM had higher scores on Urinary Distress Inventory-6 and Incontinence Impact Questionnaire-7 questionnaires when compared to patients opting for BTX injections or PTNS (p < 0.05). 47.4% of patients eventually pursued a third-line therapy. Of those, there was a 67.6% concordance rate between the therapy patients ranked first and the therapy they eventually underwent. CONCLUSIONS: Patients with more severe OAB symptoms opt for more invasive and less time-consuming therapy with the potential for long-term relief, namely SNM. Despite thorough counseling, many patients do not progress to advanced OAB therapies. Understanding factors that influence patients' affinity toward a specific type of treatment can aid with individualized counseling on third-line OAB therapies.

Study of female pelvic floor muscle in overactive bladder based on MRI 3D reconstruction.

BACKGROUND: This study examined the three-dimensional (3D) morphological changes of the urination and urinary continence anatomical structures in overactive bladder (OAB) patients, to offer a morphological data for OAB diagnosis and treatment. METHODS: Eleven OAB patients, 9 healthy females and 22 pelvic organ prolapse (POP) patients were enrolled and underwent MRI scans. The anatomical components of urination (bladder detrusor) and the urinary continence (main part of the urethral sphincter, compressor urethrae, and levator ani muscle (LAM) were 3D reconstructed and measured with Amira software. We also analyze the relativity between pelvic floor muscle's morphological parameters among the volunteers, OAB and POP group. RESULTS: Through 3D reconstruction, increased thickness and volume of the bladder detrusor were found in the OAB patients compared with volunteers (3.1 ± 0.7 mm vs. 1.9 ± 0.3 mm; P = 0.000 and 50,632.0 ± 19,724.7 mm3 vs. 23,386.6 ± 7826.3 mm3; P = 0.001). The volume of LAM showed no significant difference between the OAB patients and volunteers (27,089.4 ± 5015.0 mm3 vs. 27,294.4 ± 4461.4 mm3; P = 0.924); whereas, LAM's volume of the POP patients was significantly larger than that of the volunteers (34,130.6 ± 7968.3 mm3 vs. 27,294.4 ± 4461.4 mm3; P = 0.023). The thickness and volume of the main part of urethral sphincter were significantly lower in the OAB patients compared with volunteers (2.2 ± 0.5 mm vs. 2.7 ± 0.3 mm; P = 0.018 and 2558.6 ± 703.2 mm3 vs. 23,267.3 ± 681.9 mm3; P = 0.035). The volume of the compressor urethrae was significantly lower in the OAB patients than that in the volunteers (630.3 ± 301.2 mm3 vs. 866.1 ± 514.2 mm3; P = 0.247). CONCLUSIONS: In OAB patients, the bladder detrusor has long-term tension and contraction, which thickened muscle and increased volume, and aggravate urination. The compressor urethral and main part of urethral sphincter are weaker and the anterior part of LAM hiatus is relaxed, easily resulting in leakage of urine and ultimately incontinence. The MRI 3D reconstruction and measurement can help to evaluate pelvic floor urination and continence function, and accurately diagnose.

Exposure to DEHP is potential to increase the risk of overactive bladder, evidence from NHANES 2003-2008.

Overactive bladder (OAB) is a group of clinical symptoms that are highly bothersome to the life and spirit of patients. However, little is known about the role of ubiquitous di-(2-ethylhexyl) phthalate (DEHP) exposure in the disorder. Hence, the study was conducted. The data were collected using the 2003-2008 National Health and Nutrition Examination Survey (NHANES) data (n = 2121), and multiple logistic regression was adapted. The concentrations of DEHP (∑DEHP) were calculated for each metabolite and split into quartiles for analysis. After adjusting for confounding factors, ∑DEHP was associated with increased odds of OAB for the highest quartile (OR = 1.15, 95% CI [1.06, 1.25], p < 0.05), and the highest quartile of metabolites showed similar results, such as mono-(2-ethyl-5-hydroxyhexyl) phthalate (OR = 1.09, 95% CI [1.01, 1.19], p < 0.05), mono-(2-ethyl-5-oxohexyl) phthalate (OR = 1.21, 95% CI [1.11, 1.32], p < 0.05) and mono-(2-ethyl-5-carboxypentyl) phthalate (OR = 1.22, 95% CI [1.12, 1.33], p < 0.05). The association remained when the analyses were stratified by age and sex. Our study adds evidence for understanding the potential role of environmental factors in OAB, and further research is needed to determine whether the status of OAB can be changed by controlling DEHP exposure.

Antagonism of α1-adrenoceptors by ß3-adrenergic agonists: Structure-function relations of different agonists in prostate smooth muscle contraction.

Effects of ß3-adrenergic agonists on prostate smooth muscle contraction are poorly characterized, although mirabegron is used for treatment of lower urinary tract symptoms. Off-target effects of several ß3-adrenergic agonists include antagonism of α1-adrenoceptors. Proposed, but unconfirmed explanations include phenylethanolamine backbones, found in some ß3-adrenergic agonists and imparting interaction with catecholamine binding pockets of adrenoceptors. Here, we examined effects of ß3-adrenergic agonists on contractions of human prostate tissues, including ZD7114 (without phenylethanolamine moiety), ZD2079 (phenylethanolamine backbone), BRL37344 and CL316243 (chloride-substituted phenylethanolamine deriatives). Prostate tissues were obtained from radical prostatectomy. Contractions by α1-adrenergic agonists and electric field stimulation (EFS) were studied in an organ bath. ZD7114 (10 µM) right-shifted concentration responses curves for α1-adrenergic agonists, resulting in increased EC50 values for phenylephrine, methoxamine and noradrenaline up to one magnitude, without affecting Emax values. ZD7114 (10 µM) inhibited EFS-induced contractions, resulting in reduced Emax values. All effects of ZD7114 were resistant to the ß3-adrenergic antagonist L-748337, including increases in EC50 values for α1-adrenergic agonists, up to more than two magnitudes. Using 10 µM, neither ZD2079, BRL37344 or CL316243 affected α1-adrenergic or EFS-induced contractions. At escalated concentrations, BRL37344 (200 µM) right-shifted concentration response curves for phenylephrine, increased EC50 values for phenylephrine, and inhibited EFS-induced contractions, while CL316243 (300 µM) did not affect phenylephrine- or EFS-induced contractions. In conclusion, phenylethanolamine backbones are not decisive to impart α1-adrenoceptor antagonism to ß3-agonists. Effects of ß3-adrenergic agonists on prostate smooth muscle contraction are limited to off-target effects, including α1-adrenoceptor antagonism by ZD7114 and BRL37344.

Trigonal-Sparing vs. Trigonal-Involved OnabotulinumtoxinA Injection for the Treatment of Overactive Bladder: A Systematic Review and Meta-Analysis.

Objective: Overactive bladder (OAB) is a disease characterized by the presence of urinary urgency. We carried out a meta-analysis to assess the effectiveness and safety of trigonal-involved injection of onabotulinumtoxinA (BoNT-A) in comparison with the trigonal-sparing technique in cases with OAB [neurogenic detrusor overactivity (NDO) and idiopathic detrusor overactivity (IDO)]. Methods: Randomized controlled trials (RCTs) of BoNT-A injection for OAB were searched systematically by using EMBASE, MEDLINE, and the Cochrane Controlled Trials Register. The datum was calculated by RevMan version 5.3.0. The original references of relating articles were also reviewed. Results: In total, six RCTs involving 437 patients were included in our analysis. For OAB, the trigone-including group showed a different patient symptom score (p = 0.03), complete dryness rate (p = 0.002), frequency of incontinence episodes (p = 0.01), detrusor pressure at maximum flow rate (p = 0.01), and volume at the first desire to void (p = 0.0004) compared with the trigone-sparing group. Also, a trigone-including intradetrusor injection demonstrated a significant improvement in the patient symptom score (p = 0.0004), complete dryness rate (p = 0.0002), frequency of incontinence episodes (p = 0.0003), detrusor pressure at maximum flow rate (p = 0.01), and volume at the first desire to void (p = 0.00006) compared with the trigone-sparing group for treatment of NDO. The adverse events rates were similar in both groups. Conclusions: The meta-analysis has demonstrated that trigone-including BoNT-A injection was more effective compared with the trigone-sparing injection for the treatment of OAB, especially for NDO.

The use of mono- and combination drug therapy in men and women with lower urinary tract symptoms (LUTS) in the UK: a retrospective observational study.

BACKGROUND: Combination drug therapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination drug therapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB). The objective was to describe mono- and combination drug therapy use for LUTS in patients in UK clinical practice. METHODS: This was a retrospective, descriptive, observational database study using UK Clinical Practice Research Datalink GOLD and linked databases. Men and women ≥ 18 years with a first prescription for any LUTS drug from 2014 to 2016 with ≥ 12 months continuous enrollment pre- and post-index date were included. Primary endpoints were mono- or combination drug therapy use for LUTS in male and female cohorts. Secondary endpoints were description of treatment prescribed, treatment persistence and patient demographics. Data were analyzed descriptively. Sub-cohorts were defined by drugs prescribed at index date. RESULTS: 79,472 patients (61.3% male) were included, based on index treatments. Of all men, 82.5% received any benign prostatic obstruction (BPO) drug, 25.4% any OAB drug, and 7.9% any BPO drug plus any OAB drug. As either mono- or combination drug therapy, 77.1% received an alpha-blocker, 18.9% a 5-alpha reductase inhibitor, 23.9% an antimuscarinic agent, and 2.1% mirabegron. Of all women, 94.5% received any OAB drug, 6.0% duloxetine, and 0.5% any OAB drug plus duloxetine. As either mono- or combination drug therapy, 87.7% received an antimuscarinic, and 9.7% mirabegron. In men or women receiving OAB treatment, approximately 2.5% received combination drug therapy with an antimuscarinic agent and mirabegron. For OAB drug monotherapies, mirabegron had the highest persistence in both male and female cohorts. CONCLUSIONS: This study provides a better understanding of the recent landscape of LUTS drug use in UK clinical practice. It highlights potential undertreatment of storage symptoms in men with LUTS and the low use of combination OAB treatments.

Inhibition of LIM kinase reduces contraction and proliferation in bladder smooth muscle.

Overactive bladder (OAB) is the most bothersome symptom in lower urinary tract symptoms (LUTS). Current pharmacologic treatment aims to inhibit detrusor contraction; however, shows unsatisfied efficacy and high discontinuation rate. LIM kinases (LIMKs) promote smooth muscle contraction in the prostate; however, their function in the bladder smooth muscle remains unclear. Here, we studied effects of the LIMK inhibitors on bladder smooth muscle contraction and proliferation both in vitro and in vivo experiments. Bladder expressions of LIMKs are elevated in OAB rat detrusor tissues. Two LIMK inhibitors, SR7826 and LIMKi3, inhibit contraction of human detrusor strip, and cause actin filament breakdown, as well as cell proliferation reduction in cultured human bladder smooth muscle cells (HBSMCs), paralleled by reduced cofilin phosphorylation. Silencing of LIMK1 and LIMK2 in HBSMCs resulted in breakdown of actin filaments and decreased cell proliferation. Treatment with SR7826 or LIMKi3 decreased micturition frequency and bladder detrusor hypertrophy in rats with bladder outlet obstruction. Our study suggests that LIMKs may promote contraction and proliferation in the bladder smooth muscle, which could be inhibited by small molecule LIMK inhibitors. LIMK inhibitors could be a potential therapeutic strategy for OAB- related LUTS.