Efficacy and Safety of TAS-303 in Female Patients With Stress Urinary Incontinence: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). MATERIALS AND METHODS: A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. RESULTS: In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. CONCLUSIONS: Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).

Pharmacotherapy in Stress Urinary Incontinence; A Literature Review.

PURPOSE OF REVIEW: Stress urinary incontinence (SUI) is a commonly observed condition in females, as well as in males who have undergone prostatectomy. Despite the significant progress made in surgical techniques, pharmacotherapy has not yielded substantial outcomes within the clinical domain. This review aims to present a comprehensive overview of the existing pharmacotherapy options for stress urinary incontinence (SUI) and the emerging therapeutic targets in this field. RECENT FINDINGS: One meta-analysis demonstrated that α-adrenergic medications are more efficacious in improving rather than curing SUI symptoms. One trial showed reduced pad weight gain with PSD-503, a locally administered α-adrenergic receptor agonist. New data show that duloxetine's risk outweighs its benefits. One small-scale trial was found to support the use of locally administered estriol in improving subjective outcomes. Emerging targets include serotonin 5HT2C agonists, selective inhibitors of norepinephrine uptake, and myostatin inhibitors. Only one of the evaluated drugs, duloxetine, has been approved by some countries. Currently, trials are evaluating novel targets. Systemic adverse effects such as gastrointestinal upset with duloxetine and orthostatic hypotension with α-adrenoceptor agonists have hampered the efficacy of drugs used to treat SUI in women and men.

The effect of duloxetine on female sexual functions in the treatment of stress incontinence.

OBJECTIVES: Stress urinary incontinence (SUI) is defined as urinary incontinence that occurs with coughing, sneezing, and physical exercise. It is frequently observed in women after middle age and has a negative impact on their sexual function. Duloxetine as one of the Serotonin-noradrenaline reuptake inhibitors (SNRIs) is commonly used in the non-surgical treatment of SUI. The aim of our study is to investigate the effect of duloxetine, which is used in the treatment of SUI, on sexual functions in female patients. METHODS: The study included 40 sexually active patients who received duloxetine 40 mg twice a day for the treatment of SUI. All patients had female sexual function index (FSFI), Beck's depression inventory (BDI), and incontinence quality of life score (I-QOL) applied before and 2 months after starting duloxetine treatment. RESULTS: FSFI total score significantly increased from 19.9 to 25.7 (p < 0.001). In addition, significant improvement was observed in all sub-parameters of FSFI, including arousal, lubrication, orgasm, satisfaction, and pain/discomfort (p < 0.001, for each FSFI subtotal score). BDI significantly decreased from 4.5 to 1.5 (p < 0.001). I-QOL score significantly increased from 57.6 to 92.7 after the duloxetine treatment. CONCLUSIONS: Although SNRIs carry a high risk of sexual dysfunction, duloxetine may have an indirect positive effect on female sexual activity, both through its stress incontinence treatment and its antidepressant effect. In our study, Duloxetine, one of the treatment options for stress urinary incontinence and an SNRI, has a positive effect on stress urinary incontinence, mental health, and sexual activity in patients with SUI.

Effect of single doses of citalopram and reboxetine on urethral pressure: A randomized, double-blind, placebo- and active-controlled three-period crossover study in healthy women.

AIMS: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women. METHODS: We conducted a randomized, double-blind, placebo- and active-controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine ), 8 mg reboxetine (and placebocitalopram ), or two placebos. Study drugs were administered at a 1-h interval due to a difference in estimated time to peak plasma concentration (tmax ). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated tmax for both study drugs (one timepoint). RESULTS: Compared to placebo, citalopram increased OUP by 6.6 cmH2 0 (95% confidence interval [CI] 0.04-13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH2 0 (95% CI: 1.3-12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH2 0 in resting condition compared to placebo (95% CI: 23.5-36.5, p < 0.001), and 27.0 cmH2 0 (95% CI: 21.2-32.8, p < 0.001) in squeezing condition. CONCLUSION: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.

Effect of vitamin D supplementation on the severity of stress urinary incontinence in premenopausal women with vitamin D insufficiency: a randomized controlled clinical trial.

BACKGROUND: Urinary incontinence, especially stress urinary incontinence (SUI), is one of the problems experienced by premenopausal women. Given the role of vitamin D in enhancing muscle strength and function, this study explored the effect of vitamin D3 supplementation on SUI in premenopausal women. METHODS: A randomized controlled trial was performed with 60 premenopausal women referring to Kerman gynecological clinic in 2020 and 2021. Eligible women received a 5000-unit vitamin D supplement or placebo weekly for 3 months. The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-SF) was utilized to assess SUI severity before and after the intervention. The t-test, Chi-square test, and repeated measures ANOVA were carried out in SPSS software (version 22) to analyze the data. P-values smaller than 0.05 were considered significant. RESULTS: Before the intervention, there was no significant difference between the intervention and control groups in SUI severity (P = 0.652) and the impact of SUI severity on premenopausal women's lives (P = 0.804). In contrast, after 8-12 weeks of vitamin D supplementation, these scores decreased significantly in the intervention group relative to the control group (P <  0.001). In addition, after vitamin D supplementation, the number of SUI and urinary leakage symptoms decreased in the intervention group (P <  0.001). CONCLUSION: Vitamin D supplementation improves SUI in premenopausal women. TRIAL REGISTRATION: This trial was registered with the Iranian Registry of Clinical Trials; https://fa.irct.ir/trial/53474 (IRCT20190724044318N2) on 11/02/2021.

Application of estrogen for the treatment of stress urinary incontinence in mice.

BACKGROUND: Stress urinary incontinence (SUI) is a pervasive health tissue among women, which seriously affects the quality of life. The etiology of SUI is complex and diverse in women, with past studies having demonstrated that estrogen deficiency plays an important role in pelvic floor muscle atrophy and urethral degeneration. We comprehensively investigated the effects of estrogen in the treatment of SUI in female mice at cellular and animal levels. METHODS: L929 fibroblasts mechanical injury model was established by four-point bending device, and SUI mouse model was established by vaginal dilation method commonly used to simulate labor injury. After estrogen treatment, the expressions of Collagen I, Collagen III, Elastin, TIMP-1, TIMP-2, MMP-2, and MMP-9 were detected, the leak point pressure (LPP) and abdominal leak point pressure (ALPP) of mice in each group were detected, and both the effect of estrogen on extracellular matrix remodeling of mouse urethra and anterior vaginal wall was observed from the histological level. RESULTS: The results revealed that an appropriate amount of estrogen can promote the expression of Collagen I, Collagen III, Elastin, TIMP-1, and TIMP-2, decrease the expression of MMP-2 and MMP-9, and maintain the dynamic balance of MMPs/TIMPs at both cellular and animal levels. Meanwhile, we determined that estrogen can increase the LPP and ALPP values of SUI mice. The collagen fibers' content in the mice treated with estrogen was significantly greater than in the control group mice. CONCLUSIONS: The estrogen may alleviate the symptoms of SUI by reconstituting ECM, thus laying a solid foundation for further exploration of estrogen therapy.

Urethral bulking agents for the treatment of stress urinary incontinence in women: A systematic review.

AIMS: To perform a systematic review to assess and compare the efficacy and safety of all urethral bulking agents (UBAs) available for the treatment of stress urinary incontinence (SUI) in women. METHODS: This systematic review was conducted in accordance with the PRISMA guideline. A systematic search was conducted using the Ovid Medline, Embase and PubMed databases. Studies were included if they involved women who underwent either Bulkamid®, Macroplastique®, Durasphere®, Coaptite®, or Urolastic® injections for the treatment of SUI. A total of 583 articles were screened with 56 articles included. A qualitative analysis was performed. RESULTS: The newer synthetic UBAs are not inferior to Contigen®, with variable mean success rates of 30%-80% in the short-term. Better long-term success rates were found with Bulkamid® (42%-70%), Coaptite® (60%-75%), and Macroplastique® (21%-80%) on qualitative review. Urinary tract infection rates were similar between bulking agents (4%-10.6%) although temporary acute urinary retention was more commonly associated with Coaptite® (mean: 34.2%), and de novo urgency in Durasphere® (mean: 24.7%). Significant complications such as migration into lymph nodes was reported with Durasphere®. Erosion was reported with Macroplastique®, Coaptite®, and Urolastic®, with a rate as high as 24.6% in one study of Urolastic®. CONCLUSION: Available data support the use of Bulkamid® and Macroplastique®, which has shown a short-term efficacy of 30%-90% and 40%-85% respectively, and long-term efficacy of 42%-70%, and 21%-80%, respectively. Bulkamid® appears to have a more favorable safety profile, with no cases of erosion or migration of product associated with its use. Direct comparisons of UBAs have not been performed.

A feasibility study with a novel, dynamic, and disposable over-the-counter device for the management of stress urinary incontinence.

AIMS: This study aimed to evaluate the initial efficacy, safety, and usability of a novel, dynamic, and disposable intravaginal device in women suffering from stress urinary incontinence (SUI). METHODS: Twenty-six women with SUI were recruited to perform a modified 1-h Pad Weight Gain (PWG) test. In this test, women drank 250-500 ml of water, were given a pre-weighed pad, and asked to perform a set of incontinence-inducing activities. At the end of the activities session, the pad was removed and weighed. This test was performed both with and without the Nolix device. Three efficacy endpoints measured were continuous percent reduction in urine leakage, dryness (defined as pad weight increase by no more than 1 g), and improvement in pad weight (measured as continuous percent reduction in PWG ≥ 50%). Any adverse events, reported by subjects during the device use were recorded. The usability and user's satisfaction were assessed using the Benefit, Satisfaction, and Willingness to Continue and Nolix Satisfaction questionnaires. RESULTS: The average reduction in PWG was 79.4%. The average reduction in urine leakage while using the device was at least 70%. In addition, in 79.5% of tests, the clinically meaningful level of improvement in PWG was achieved. Use of the device produced substantial improvement in the patient's perceived quality of life. No adverse events were reported during the study. CONCLUSION: The Nolix device served as a noninvasive, effective, and well-tolerated treatment option for reducing SUI in a modified 1-h PWG test with a set of incontinence-inducing activities.

Seven-year efficacy and safety outcomes of Bulkamid for the treatment of stress urinary incontinence.

AIMS: Bulking agents are a minimally invasive treatment option for women with stress urinary incontinence (SUI) or stress-predominant mixed urinary incontinence (MUI). The aim of this study was to evaluate long-term efficacy and safety following treatment with Bulkamid as a primary procedure for SUI or stress-predominant MUI. METHODS: This was an Institutional Review Board-approved single-center retrospective study of female patients with SUI or stress-predominant MUI who had undergone injection with Bulkamid since 2005 and had completed 7 years of follow up. The primary endpoint was patient satisfaction measured on a four-point scale as cured, improved, unchanged, or worse. Secondary outcomes included the number of incontinence pads used, International Consultation on Incontinence Questionnaire-Short Form (ICIQ-UI SF) scores, Visual Analog Scale Quality of Life (VAS QoL), reinjection rates, and perioperative and postoperative complications. RESULTS: A total of 1,200 patients were treated with Bulkamid since 2005 and of these, 388 (32.3%) had completed 7 years of follow-up. A total of 67.1% of the patients reported feeling cured or improved if Bulkamid was a primary procedure, 11.1% reported no change, and 2.3% reported worsening of incontinence. A total of 19.5% of patients received a subsequent other incontinence procedure. The ICIQ-UI SF was reduced by 8.6 points. VAS QoL improved by a mean of 4.3 points. Postoperative complications were transient. Prolonged bladder emptying time was reported in 15.3% of patients and urinary tract infection in 3.5%. CONCLUSIONS: Bulkamid injections are an effective and safe first-line treatment option for women with SUI or stress-predominant MUI providing durable outcomes at 7 years.

Combination therapy with botulinum toxin and bulking agent-An efficient, sustainable, and safe method to treat elderly women with mixed urinary incontinence.

AIMS: To evaluate the efficacy, sustainability and safety of combined botulinum toxin and polyacrylamide hydrogel (PAHG) therapy to treat urgency and stress components of therapy-refractory mixed urinary incontinence (MUI) in an elderly study population. METHODS: Fifty-five women with therapy-refractory MUI were treated with botulinum toxin and PAHG in one surgical procedure. Urgency urinary incontinence (UUI) and stress urinary incontinence (SUI) outcomes were separately assessed after 4 and 12 months by objective UUI episodes/24 h and cough test, subjective impact of UUI and SUI on quality of life, and subjective International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). MUI outcome was calculated by combining UUI and SUI outcomes. Complications were monitored throughout the study. RESULTS: At 4 months, objective cure rates were 73%, 53%, and 42%, and subjective cure rates were 71%, 52%, and 50% for SUI, UUI, and MUI. At 12 months, objective cure rates were 73%, 56%, 50% and subjective cure rates were 78%, 42%, and 40% for SUI, UUI, and MUI. The ICIQ-UI SF score decreased by 9.0 and 8.7 points after 4 and 12 months. All complications were transient and included 22% clean intermittent catheterization immediately after surgery, 33% postvoid residual volumes >100 ml at 14 days, and 13% symptomatic urinary tract infection within the first postoperative month. CONCLUSIONS: The combination of botulinum toxin and PAHG is effective, sustainable and safe to treat therapy-refractory MUI, even in an elderly and frail study population. Patients benefit from the short surgical procedure without the need for general anaesthesia or discontinuation of anticoagulation.

A randomized, intervention parallel multicentre study to evaluate duloxetine and innovative pelvic floor muscle training in women with uncomplicated stress urinary incontinence-the DULOXING study.

INTRODUCTION AND HYPOTHESIS: The aim of our study was to evaluate the effect of a combination of innovative pelvic floor muscle training (iPFMT) and duloxetine compared with the use of duloxetine alone on women with stress urinary incontinence (SUI) after 12 weeks of treatment. METHODS: We conducted a parallel multicentre study with randomized intervention in 45 national urological outpatient clinics. Patients with an enrolment ratio of 1:1 were divided into the experimental and control groups. The following were used for evaluation: incontinence episode frequency (IEF)/week, the International Consultation on Incontinence Questionnaire (ICIQ-SF), the Urinary Incontinence Quality of Life Scale (I-QoL) and the Patient Global Impression of Improvement (PGI-I). The experimental group received oral treatment with duloxetine (a daily dose of 40 mg BID) and innovative pelvic floor muscle training (iPFMT). The control group received only oral treatment with duloxetine at a daily dose of 40 mg BID. RESULTS: The number of women who were evaluated was 158. The control group comprised 79 women with an average age of 56.8 ± 13.8 years and the experimental group comprised 79 women with an average age of 53.4 ± 11.9 years. There were no significant differences in pre-treatment parameters. For the intent-to-treat analysis after 12 weeks' treatment, significant differences were observed between the experimental vs. control group (p < 0.001) for the following variables: IEF/week decrease (66.7% vs. 50.0%); ICIQ-UI SF decrease (8.3 ± 3.8 vs. 9.7 ± 4.2); PGI-I (70.8% vs. 65.6%); I-QoL score increase (19.3% vs. 6.6%). CONCLUSION: The addition of iPFMT to duloxetine treatment improves SUI syndrome in women compared with duloxetine treatment alone. REGISTRATION: Clinical Trials.gov NCT04140253.

Efficacy and safety of the noradrenaline reuptake inhibitor, TAS-303, in women with stress urinary incontinence: Results of a double-blind, randomized, placebo-controlled, early phase II trial.

OBJECTIVE: To carry out an exploratory assessment of the efficacy and safety of TAS-303, a noradrenaline reuptake inhibitor, in women with stress urinary incontinence. METHODS: In a double-blind, placebo-controlled, early phase II study, women with stress urinary incontinence and stress urinary incontinence-predominant mixed urinary incontinence were randomized to a placebo or TAS-303 (3 or 6 mg) once daily for 8 weeks. The main efficacy end-points were mean percentage change in incontinence episode frequency per 24 h from baseline to week 8 (the primary end-point) and week 4. RESULTS: At week 8, the mean percentage change in incontinence episode frequency per 24 h was -34.73% in the TAS-303 3 mg group, -35.41% in the TAS-303 6 mg group and -28.07% in the placebo group (differences vs placebo, not significant). In patients with stress urinary incontinence, or incontinence episode frequency less than two episodes per 24 h at baseline, TAS-303 significantly reduced incontinence episode frequency versus placebo after 4 weeks; some secondary end-points also showed a tendency to improve in the same subgroups. No serious adverse events (e.g. central nervous system or cardiovascular effects) were observed; TAS-303 was well tolerated and had a favorable safety profile. CONCLUSION: These findings suggest that TAS-303 is effective for improving stress urinary incontinence symptoms in some subgroups of patients with stress urinary incontinence. Therefore, further research is warranted.

False-negative finding in urodynamic study for the chief complaint. Does it interfere with the clinical outcomes for the treatment of SUI or OAB syndromes?

PURPOSE: False-negative urodynamic findings may mislead or prevent planned treatments due to unmatched findings with the clinical presentation. We hypothesized that the absence of urodynamic demonstration of SUI or OAB on urodynamics would interfere with clinical outcomes. MATERIALS AND METHODS: We prospectively studied 124 women with (94) or without (30) demonstrable SUI after sling operations. Similarly, 64 women with OAB syndrome with (38) or without (26) demonstrable DO were also compared after treatment with anticholinergic agents. Patients were assessed with the UDI-6 and IIQ-7 questionnaires 3 and 6 months after treatment. RESULTS: Only 76% of SUI patients demonstrated urine leakage during urodynamics. The UDI-6 score was higher in the demonstrable-SUI and demonstrable-DO groups, while the IIQ-7 score was comparable within the incontinence or urgency/frequency groups. Demonstrable and non-demonstrable SUI-operated patients showed similar outcomes. Patients with urgency syndromes with or without demonstrable DO had a similar rate of improvement with anticholinergic therapy. CONCLUSIONS: Women with clinical complaints of SUI objectively demonstrated on urodynamics presented the same subjective clinical outcome as those with SUI lacking objective demonstration when measured by the UDI-6 and IIQ-7 questionnaires. Similarly, patients with OAB syndrome with or without demonstrable DO had similar clinical improvement when treated with anticholinergics and measured using the same questionnaires.

Therapeutic potential of muscle growth promoters in a stress urinary incontinence model.

Weakness of urinary sphincter and pelvic floor muscles can cause insufficient urethral closure and lead to stress urinary incontinence. Bimagrumab is a novel myostatin inhibitor that blocks activin type II receptors, inducing skeletal muscle hypertrophy and attenuating muscle weakness. ß2-Adrenergic agonists, such as 5-hydroxybenzothiazolone derivative (5-HOB) and clenbuterol, can enhance muscle growth. We hypothesized that promoting muscle growth would increase leak point pressure (LPP) by facilitating muscle recovery in a dual-injury (DI) stress urinary incontinence model. Rats underwent pudendal nerve crush (PNC) followed by vaginal distension (VD). One week after injury, each rat began subcutaneous (0.3 mL/rat) treatment daily in a blinded fashion with either bimagrumab (DI + Bim), clenbuterol (DI + Clen), 5-HOB (DI + 5-HOB), or PBS (DI + PBS). Sham-injured rats underwent sham PNC + VD and received PBS (sham + PBS). After 2 wk of treatment, rats were anesthetized for LPP and external urethral sphincter electromyography recordings. Hindlimb skeletal muscles and pelvic floor muscles were dissected and stained. At the end of 2 wk of treatment, all three treatment groups had a significant increase in body weight and individual muscle weight compared with both sham-treated and sham-injured rats. LPP in DI + Bim rats was significantly higher than LPP of DI + PBS and DI + Clen rats. There were more consistent urethral striated muscle fibers, elastin fibers in the urethra, and pelvic muscle recovery in DI + Bim rats compared with DI + PBS rats. In conclusion, bimagrumab was the most effective for increasing urethral pressure and continence by promoting injured external urethral sphincter and pelvic floor muscle recovery.

Effect of a 5-HT2c receptor agonist on urethral closure mechanism in healthy women.

AIMS: To evaluate the effect of ASP2205, a selective serotonin 5-HT2c receptor agonist, and Duloxetine on the urethral pressure in healthy female subjects. METHODS: Healthy females aged 18 to 55 years were recruited for this phase 1, single site, placebo-controlled, randomized, four-period, cross-over study. The interventions were single oral doses of 10 and 60 mg ASP2205, 80 mg duloxetine, and placebo. As a pharmacodynamics endpoint, opening urethral pressure (OUP), corrected for placebo, was measured using urethral pressure reflectometry under both resting and squeezing condition of the pelvic floor at predose and 3, 6, 12, and 24 hours after dosing. Safety and tolerability of ASP2205 were also compared with duloxetine and placebo. RESULTS: Eighteen healthy women signed informed consent, however, one dropped out before dosing and one dropped out after the first period, therefore, 16 subjects completed the study. Duloxetine significantly increased the OUP during both resting and squeezing condition (maximal increase 18.1 and 16.8 cmH2 O, respectively). Both doses of ASP2205 did not increase OUP at any time point. During squeezing OUP decreased significantly in the ASP2205 60 mg group from 6 to 24 hours after dosing. All subjects experienced predominantly central nervous system-related side effects (eg, dizziness and nausea) during ASP2205 treatment, which was most pronounced at 60 mg. CONCLUSIONS: ASP2205, a serotonin 5-HT2c receptor agonist, does not increase the urethral pressure and it is therefore unlikely that 5-HT 2c receptor agonists can be used as a treatment for stress urinary incontinence. ASP2205 was less well tolerated than the high dose of duloxetine.

Effect of imipramine on urethral opening pressure: A randomized, double-blind, placebo-controlled crossover study in healthy women.

AIMS: In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry. METHODS: A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department. RESULTS: There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06. CONCLUSIONS: In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.

TAS-303, a Novel Selective Norepinephrine Reuptake Inhibitor that Increases Urethral Pressure in Rats, Indicating Its Potential as a Therapeutic Agent for Stress Urinary Incontinence.

Stress urinary incontinence (SUI) is characterized by involuntary leakage associated with exertion, effort, sneezing, coughing, or lifting. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is approved for the treatment of patients with SUI in some European countries, but not in the United States. There is currently no globally approved pharmacological drug for the treatment of patients with SUI. Therefore, a new pharmacological treatment option is required. TAS-303 [4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-day7 )acetate hydrochloride] is a novel small-molecule selective norepinephrine reuptake inhibitor that displays significant norepinephrine transporter (NET) inhibitory activity toward the serotonin or dopamine transporters. In this report, we describe the pharmacological properties of TAS-303 and its effects on urethral function, using preclinical in vitro and in vivo studies. Radioligand-binding studies showed that TAS-303 selectively and potently inhibited [3H]norepinephrine binding to the human NET. Oral administration of TAS-303 (3 mg/kg) significantly increased norepinephrine levels in the plasma, whereas it did not significantly affect epinephrine, dopamine, and serotonin levels. TAS-303 (0.3, 1, and 3 mg/kg) dose-dependently increased basal urethral pressure in normal rats and leak point pressure in vaginal distention rats, exhibiting a maximal effect comparable to duloxetine. In the forced swimming test, TAS-303 (100 mg/kg) showed no significant effects on immobility time in rats, raising the possibility that this agent would have minimal central nervous system side effects at an effective dose for urethral function. These results demonstrate that TAS-303 has therapeutic potential for the treatment of patients with SUI.

Controlled release of insulin-like growth factor 1 enhances urethral sphincter function and histological structure in the treatment of female stress urinary incontinence in a rat model.

OBJECTIVES: To determine the effects of controlled release of insulin-like growth factor 1 (IGF-1) from alginate-poly-L-ornithine-gelatine (A-PLO-G) microbeads on external urethral sphincter (EUS) tissue regeneration in a rat model of stress urinary incontinence (SUI), as SUI diminishes the quality of life of millions, particularly women who have delivered vaginally, which can injure the urethral sphincter. Despite several well-established treatments for SUI, growth factor therapy might provide an alternative to promote urethral sphincter repair. MATERIALS AND METHODS: In all, 44 female Sprague-Dawley rats were randomised into four groups: vaginal distension (VD) followed by periurethral injection of IGF-1-A-PLO-G microbeads (VD + IGF-1 microbeads; 1 × 104 microbeads/1 mL normal saline); VD + empty microbeads; VD + saline; or sham-VD + saline (sham). RESULTS: Urethral function (leak-point pressure, LPP) was significantly lesser 1 week after VD + saline [mean (sem) 23.9 (1.3) cmH2 O] or VD + empty microbeads [mean (sem) 21.7 (0.8) cmH2 O) compared to the sham group [mean (sem) 44.4 (3.4) cmH2 O; P < 0.05), indicating that the microbeads themselves do not create a bulking or obstructive effect in the urethra. The LPP was significantly higher 1 week after VD + IGF-1 microbeads [mean (sem) 28.4 (1.2) cmH2 O] compared to VD + empty microbeads (P < 0.05), and was not significantly different from the LPP in sham rats, demonstrating an initiation of a reparative effect even at 1 week after VD. Histological analysis showed well-organised skeletal muscle fibres and vascular development in the EUS at 1 week after VD + IGF-1 microbeads, compared to substantial muscle fibre attenuation and disorganisation, and less vascular formation at 1 week after VD + saline or VD + empty microbeads. CONCLUSION: Periurethral administration of IGF-1-A-PLO-G microbeads facilitates recovery from SUI by promoting skeletal myogenesis and revascularisation. This therapy is promising, but detailed and longer term studies in animal models and humans are needed.

Results of an innovative bulking agent in patients with stress urinary incontinence who are not optimal candidates for mid-urethral sling surgery.

AIMS: To assess the efficacy and safety of peri-urethral bulking injections (PBI) with an innovative bulking material (PDMS-U) in women with stress-urinary incontinence (SUI) who are not optimal candidates for mid-urethral sling surgery. METHODS: A prospective study was performed in women with SUI who, for several reasons, have a relative contraindication for a mid-urethral sling procedure. These reasons include: (i) recurrent SUI after a prior SUI surgical procedure; (ii) a history of oncologic gynaecological surgery; (iii) a history of neurologic disease resulting in voiding problems; (iv) a maximal flow rate of less than 15 mL per second or; (v) women with a contraindication for surgery with general or regional anaesthesia. All women were treated with PBI consisting of PDMS-U, a bulking agent that polymerizes in situ. The primary outcome was subjective improvement, defined as "a little better" to "very much better" on the PGI-I. Secondary outcomes included objective cure, disease specific quality of life and adverse events. RESULTS: Subjective improvement was reported by 18 (90%) of the 20 included patients. The subjective cure rate was 56% and the objective cure rate was 65%. There was a statistically significant improvement of all domain scores of the UDI-6, IIQ-7, and PISQ-12 at 6 months follow up. Abnormal post voiding residual volume (>150 mL) was the most common adverse event (40%), but persisted in only one patient, based on the patient's preference for a catheter. CONCLUSIONS: PBI with PDMS-U is a viable treatment option in women with a relative contra-indication for mid-urethral sling surgery.

Does assessing urethral function allow the selection of the optimal therapy for recurrent SUI? Report from the ICI-RS 2017.

AIMS: The management of recurrent stress urinary incontinence following failed previous continence surgery remains challenging. Whilst the role of urodynamic investigations has been questioned in the management of primary stress incontinence there is a widely held view that women with recurrent symptoms require further investigation although there is no agreement regarding which tests are required. We sought to understand what testing is recommended prior to managing this difficult cohort of patients. METHOD: This research proposal was presented at the International Consultation on Incontinence Research Society (ICI-RS) in order to clarify our current knowledge regarding the assessment of urethral function and to set research priorities for the future. RESULTS: Whilst the majority of clinicians would advocate urodynamic evaluation of women with recurrent stress incontinence following previous surgery there is no consensus of opinion as to which tests should be performed, on whom or where. The available evidence to date suggests that urethral function tests do have a role with regard to prognosis following surgery and also in planning the most appropriate surgical intervention. CONCLUSION: The ICI-RS developed a list of research questions which may be able to assist in improving the investigation and management of women with recurrent SUI. Questions included whether patients felt the information gained via urethral function tests had an important role in their counseling regarding outcome of repeat SUI surgery.