Relugolix combination therapy in European women with symptomatic uterine fibroids: a subgroup analysis from the randomized phase 3 LIBERTY pivotal trials.

OBJECTIVE: In the 24-week, phase 3 LIBERTY 1 (L1) and LIBERTY 2 (L2) trials, relugolix combination therapy (relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg)) reduced uterine fibroid (UF)-associated symptoms. This post hoc analysis assessed safety and efficacy of relugolix-CT in European women from L1/L2. METHODS: Premenopausal women (aged 18-50 years) with UF-associated heavy menstrual bleeding (HMB) were randomized 1:1:1 in L1 (N = 388) and L2 (N = 382) to relugolix-CT or placebo for 24 weeks, or delayed relugolix-CT (relugolix 40 mg then relugolix-CT; 12 weeks each). Primary endpoint: proportion of responders (menstrual blood loss (MBL) <80 mL and reduction of ≥50% from baseline MBL volume) over the last 35 days of treatment. Secondary endpoints: MBL volume, amenorrhea, UF-associated pain, symptom severity, distress related to bleeding and pelvic discomfort, health-related quality of life (HRQoL). Safety endpoints included adverse event (AE) reporting and bone mineral density (BMD) assessment. RESULTS: In European women from L1/L2 (N = 124, 16%), a significantly greater proportion of treatment responders was observed with relugolix-CT vs. placebo (85.4% vs. 19.1%, respectively; nominal p < .0001). There were statistically significant improvements with relugolix-CT vs. placebo for several secondary endpoints: reduction in MBL volume, amenorrhea rate, proportion achieving mild-to-no pain, reduction in symptom severity and distress from bleeding and pelvic discomfort, and improvement in HRQoL. Incidence of AEs and percentage changes in BMD from baseline to week 24 were similar for relugolix-CT and placebo. CONCLUSIONS: In European women with UF and HMB, once-daily relugolix-CT vs. placebo improved UF-associated symptoms and preserved BMD.

Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.

PURPOSE: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. MATERIALS AND METHODS: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction. RESULTS: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). CONCLUSIONS: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.

Identification of the Urogenital Distress Inventory-6 and the Incontinence Impact Questionnaire-7 cutoff scores in urinary incontinent women.

PURPOSE: Urogenital Distress Inventory-6 (UDI-6), Incontinence Impact Questionnaire-7 (IIQ-7) and The International Consultation on Incontinence (ICIQ-SF) Short Form are used to diagnose individuals with urinary incontinence (UI) and to assess the impact of the dysfunction on patient quality of life. While ICIQ-SF has fixed cutoff values-UDI-6 and IIQ-7 do not. We aimed to find the cutoff scores for UDI-6 and IIQ-7 in women with UI. METHODS: The study involved 205 women aged between 31 and 83 years-155 with, and 50 without UI symptoms. All participants completed all three questionnaires: ICIQ-SF, UDI-6 and IIQ-7. Patients were categorized according to their ICIQ-SF scores, as symptomatic ICIQ-SF ≥ 6 (n = 134) and asymptomatic ICIQ < 6 (n = 60). The Receiver Operating Characteristics (ROC) curve was used to test how well UDI-6 allowed a discrimination between patients suffering from UI and those who do not. Area under Curve (AUC) statistic was calculated to measure the UDI-6 and IIQ-7 Total Score efficiency. RESULTS: The cutoff values were selected. On the basis of the ROC curve analysis, the UDI-6 Total Score of 33.33 and IIQ-7 Total Score of 9.52 were determined to be the optimal cutoff for distinguishing between symptomatic and asymptomatic women (AUC = 0.94-UDI-6 and 0.91-IIQ-7). CONCLUSIONS: For UDI-6 scores more than 33.33 indicate higher distress caused by UI symptoms. Moreover, the higher impact of UI on health- related quality of life is seen in women who scored 9 or more in the IIQ-7 questionnaire, and such women felt impaired quality of life. Trial registration number NCT04433715, 11.06.2020 "retrospectively registered".

An association of circulating Tregs and Th17 cells producing IL-21 and IL-22 with the ROMA in ovarian cancer patients.

The purpose of the present study was to assess the association of regulatory T cells (Tregs; CD4+ FOXP3+) and helper T lymphocytes (Th17) releasing interleukin (IL)-21 and IL-22, with the Risk of Ovarian Malignancy Algorithm (ROMA). Similar association was made with two additional tumour markers, human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) from patients serum. The presence of Tregs and Th17 was determined both in the peripheral blood and in the tissue of epithelial ovarian tumors. Mononuclear cells obtained from patient's peripheral blood (PBMCs) and from ovarian tissue were isolated by density gradient centrifugation. As a control group patients who had undergone surgery for infertility without ovarian pathology were selected. The percentage of Tregs and Th17 releasing IL-21 or IL-22 cells from both peripheral blood and tumor tissue was measured by flow cytometry. No differences in demographic parameters like body mass index, age, or gravidity were observed among the studied groups. However, an increased concentration of marker HE4 and value of ROMA was identified in individuals with ovarian cancer when compared with women with cystadenomas. Furthermore, a negative correlation between the ROMA value in the serum and Tregs from the peripheral blood of patients with cystadenoma ovarian tumors was detected. The presented work documents, for the first time, the negative association between peripheral blood Tregs and ROMA evaluation based on the tumour markers present in the serum of women with ovarian cystadenoma. Such an effect might result from the negative impact of Tregs on the inflammation process and on tumorigenesis caused by the persistent inflammation.

Current trends in urogynecological surgeries in Poland.

INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) treatment has become more common in the world's health care systems, and the demand for pelvic floor disorder rehabilitation has been projected to increase by 35% between 2010 and 2030. Restitution procedures vary, but after the US Food and Drug Administration (FDA) notifications, the global use of mesh in vaginal surgeries has significantly decreased. The aim of this study is to show trends in urogynecological surgeries in Poland. METHODS: Retrospective analysis was performed of data obtained between 2009 and 2017 from the National Health Fund Information Centre website. Vaginal hysterectomies (VH), POP and urinary incontinence (UI) surgeries were considered. RESULTS: In the study, 327,294 hospitalizations between 2009 and 2017 were considered: 29,821 VH, 265,147 POP and 53,328 UI procedures. Between 2009 and 2015, a rapid increase in the number of POP procedures was observed (r2 = 0.94, b = 1711, p < 0.001). The following years, however, were characterized by a marked decline in the number of POP surgeries. In addition, the number of vaginal suspensions with mesh dropped by 24.7%, posterior and anterior repair by 8.5%, and posterior repair by 7.5%, but the number of anterior repair procedures increased slightly by 1.5%. Moreover, between 2015 and 2017, the number of vaginal hysterectomies decreased by 9%. The number of UI surgeries had increased between 2011 and 2015 and then remained at a relatively stable level. A similar trend was observed for tape procedures, whereas the popularity of colposuspension has declined noticeably. CONCLUSIONS: The impact of FDA notifications has been observed in Poland as a decrease in TVM surgeries.

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

AIMS: SYNERGY II was a 12-month phase III trial in patients with overactive bladder (OAB) symptoms that investigated the safety and efficacy of the combination of mirabegron and solifenacin in comparison with each monotherapy. This analysis evaluated the trial findings using four age subgroups (<65, ≥65, <75, and ≥75 years). METHODS: Eligible patients were ≥18 years with symptoms of "wet" OAB (urinary frequency and urgency with incontinence) for ≥3 months. Patients were randomized to receive once-daily solifenacin succinate and mirabegron (5 mg/50 mg; combination), solifenacin succinate, or mirabegron (4:1:1). Safety evaluations: treatment-emergent adverse events (TEAEs), vital signs, and electrocardiogram, post-void residual volume, and laboratory assessments. Primary efficacy variables: change from baseline to end of treatment in number of incontinence episodes/24 h and micturitions/24 h. RESULTS: Of 1794 patients (full analysis set), 614 (34.2%) and 168 (9.4%) were ≥65 and ≥75 years old, respectively. Overall, 856 (47.2%) patients experienced ≥1 TEAE. Higher TEAE incidences were typically observed for the combination versus both monotherapies (eg, constipation) and in the older versus younger age groups (eg, urinary tract infection). Increases in mean pulse rate from baseline of >1 bpm were noted in the combination and mirabegron younger age groups only. No clinically significant findings were observed in the other safety parameters. The efficacy variables improved with all treatments and the greatest improvements were typically observed with combination therapy. CONCLUSIONS: Mirabegron and solifenacin combination therapy was a well-tolerated and effective treatment for patients with OAB symptoms irrespective of their age.

Long-Term Follow-Up of Sexual Dysfunction in Women Following Allogeneic Hematopoietic Stem Cell Transplantation.

Chronic graft-versus-host disease is the most common late complication following allogeneic hematopoietic stem cell transplantation. The aim of this study was to present the outcomes of two successful vaginal reconstructions. Patient 1 received chemotherapy for leukemia and underwent bone marrow transplantation (BMT). The patient was sexually inactive for 9 years. In 2012, she was diagnosed with complete vaginal obliteration and underwent vaginal reconstruction. Patient 2 underwent chemotherapy (myeloablative therapy), was sexually inactive for 3 years and was then diagnosed with complete vaginal obliteration. In January 2013, she had vaginal reconstruction with cervical dilatation. Hormonal replacement therapy was administered to both patients. The results of dedicated questionnaires revealed decent quality-of-life and normal sexual functioning and continence status after surgery. Obliteration of the vagina after BMT can be prevented, but if it occurs, vaginal reconstruction surgery should be offered to any patients suffering from obliteration. Our results show that this therapy enables patients to have normal sexual lives without compromising their continence status.

Analgesic Efficacy and Safety of Intravenous Meloxicam in Subjects With Moderate-to-Severe Pain After Open Abdominal Hysterectomy: A Phase 2 Randomized Clinical Trial.

BACKGROUND: An intravenous (IV) formulation of meloxicam was developed for moderate-to-severe pain management. This study evaluated the safety and efficacy of meloxicam IV after open abdominal hysterectomy. Meloxicam IV is an investigational product not yet approved by the US Food and Drug Administration. METHODS: Women (N = 486) with moderate-to-severe pain after open abdominal hysterectomy were enrolled in this multicenter, randomized, double-blind, placebo- and active-controlled trial. Subjects were randomized to receive a single dose of meloxicam IV (5-60 mg), placebo, or morphine (0.15 mg/kg) in ≤6 hours after morphine dosing on postoperative day 1 and were evaluated for 24 hours. Rescue morphine (≈0.15 mg/kg IV) was available if needed for pain not relieved by the study medication. In an open-label extension (N = 295), meloxicam IV was administered once daily for the remaining hospital stay (or per the investigator's discretion). The coprimary efficacy end points were the summed pain intensity difference (SPID24) and total pain relief (TOTPAR24) from hour 0 to 24 hours after dosing. Effect size, the standardized difference between means reported in standard deviation (SD) units, was calculated to indicate the magnitude of the difference in the mean analgesic effect measured for different intervention groups. RESULTS: Subjects who received morphine or meloxicam IV had a median time to first perceptible pain relief within 6-8 minutes. Morphine and meloxicam IV 5-60 mg produced statistically significant differences than placebo in SPID24 and TOTPAR24. SPID24 (standard error [SE]) for meloxicam IV 5-60 mg ranged from -56276.8 (3926.46) to -33517.1 (3930.1; P < .001); SPID24 (SE) for morphine and placebo were -29615.8 (3869.2; P < .001) and 4555.9 (3807.1), respectively. SPID24 effect sizes (95% confidence intervals) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 1.93 (1.61-2.25), 2.00 (1.65-2.35), 1.70 (1.35-2.05), 1.28 (0.95-1.60), 1.25 (0.90-1.61), and 1.12 (0.77-1.45) SDs, respectively. TOTPAR24 (SE) for meloxicam IV 5-60 mg ranged from 3104.5 (155.28) to 4130.4 (191.17; P < .001); TOTPAR24 (SE) for morphine and placebo were 2723.3 (188.4; P < .001) and 1100.6 (185.4), respectively. TOTPAR24 effect sizes (95% confidence interval) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 2.03 (1.70-2.35), 2.05 (1.70-2.40), 1.78 (1.43-2.13), 1.35 (1.03-1.67), 1.37 (1.01-1.72), and 1.10 (0.75-1.45) SDs, respectively. The mean total opioid consumed (SD) during the double-blind phase was 4.6 (8.17), 5.3 (8.85), 5.9 (7.85), 8.5 (9.67), 9.3 (9.47), 9.6 (8.12), and 16.0 (10.15) mg for patients in the 60, 30, 15, 7.5, and 5 mg meloxicam IV, morphine, and placebo groups, respectively. Generally, meloxicam IV was well tolerated, evidenced by the incidence of adverse events compared to placebo and lack of deaths and treatment-related serious adverse events. CONCLUSIONS: A meloxicam IV dose of 5-60 mg was generally well tolerated and appeared to reduce opioid consumption in subjects with moderate-to-severe pain after open abdominal hysterectomy. Once-daily administration of meloxicam IV produced analgesic effect within 6-8 minutes postdose that was maintained over a 24-hour dosing interval.

Reliability of the Polish version of the Overactive Bladder Symptom Score (OABSS) questionnaire : Correlation of the OABSS with urodynamic study and the UDI-6 and IIQ-7 questionnaires.

INTRODUCTION AND HYPOTHESIS: Overactive bladder (OAB) and mixed urinary incontinence (MUI) are significant problems worldwide. Their broad definition makes them difficult to diagnose; therefore, specialists need a tool to confirm diagnosis. The Overactive Bladder Symptom Score (OABSS) is used in the objective diagnosis of OAB. We aimed to develop and evaluate the effectiveness of OABSS for patients in Poland suffering from OAB and MUI and to correlate it with UDI-6 and IIQ-7. METHODS: A total of 824 women suffering from urinary incontinence (UI) aged between 18 and 75 years were included. SUI (n = 290); OAB (n = 285) and MUI (n = 249) were confirmed by medical history and urodynamic study. Of the subjects, 821 women completed the Polish version of OABSS on two separate visits: weeks 0 and 2. In addition, they undertook UDI-6 and IIQ-7 during Week 2. The Cronbach's alpha (α) was used to estimate the internal consistency. Scores were compared using the intraclass correlation coefficient (ICC). RESULTS: We observed statistically significant differences (p < 0.0005) between mean scores of OABSS among patients from the study groups OAB-SUI and MUI-SUI. We did not observe statistically significant differences between patients from the MUI and OAB groups (p > 0.11). Analysis also did not show statistically significant differences between visits. The internal consistency was very good: α = 0.89 (SUI); = 0.9 (OAB); = 0.82 (MUI). In all groups, test-retest reliability was excellent; ICC was >0.99. CONCLUSIONS: The Polish version of the OABSS is a reliable tool for females suffering from UI. However, OABSS does not distinguish patients with MUI from patients with OAB.

Prevention and treatment of uncomplicated lower urinary tract infections in the era of increasing antimicrobial resistance-non-antibiotic approaches: a systemic review.

PURPOSE: Urinary tract infections (UTIs) are one of the more common infections encountered in everyday clinical practice. They account for 10-20% of all infections treated in primary care units and 30-40% of those treated in hospitals. The risk of UTI in the female population is considered to be 14 times higher than in the male population. The prevalence of bacterial etiology results in a large consumption of broad-spectrum antibiotics, which in turn leads to increased rates of resistant uropathogens. Therefore, non-antibiotic prevention and treatment options are now of great importance. METHODS: A systematic literature search was performed for the last 20 years (1999-2019) and the efficiencies of these eight different non-antibiotic interventions were analysed and discussed. RESULTS: This article provides an overview on non-antibiotic options for management of UTI, including the application of cranberry products, the phytodrug Canephron N, probiotics, nonsteroidal anti-inflammatory drugs (NSAID), D-mannose, estrogens, vitamins, and immunotherapy. CONCLUSIONS: The last 20 years of research on non-antibiotic approaches in UTI have not brought conclusive evidence that antibiotic usage can be replaced completely by non-antibiotic options. Hence, antibiotics still remain a gold standard for UTI treatment and prevention. However, changing the therapeutic strategy by including non-antibiotic measures in the management of UTI could be successful in avoiding antimicrobial resistance at least to some extent.

Serum paraoxonase 1 activity and protein N-homocysteinylation in primary human endometrial cancer.

Paraoxonase 1 plays an important role in protection from oxidative stress and also decomposes homocysteine thiolactone, the toxic metabolite of homocysteine. A limited number of reports evaluated the role of paraoxonase 1 in women affected by female genital tract neoplasms, including endometrial cancer. This study aimed to analyze the paraoxonase activity in the group of endometrial cancer patients (n = 48) who underwent primary surgery and to compare the data available with a well-matched control group (n = 30). Due to the role of paraoxonase 1 in the metabolism of homocysteine (Hcy) thiolactone, the amount of Hcy-thiolactone as well as total serum Hcy concentrations was also measured. Serum paraoxonase 1 activity toward synthetic substrates, paraoxon and phenyl acetate, in the study group was significantly lower compared to the control one. The mean paraoxonase 1 activity toward homocysteine thiolactone tended to be lower in the endometrial cancer group but this difference was not significant. There was no relationship between endometrial cancer and Q192R polymorphism of PON1 assessed by the dual substrate method. No differences in paraoxonase 1 activity between endometrial cancer subgroups according to clinico-pathological features were detected. Total serum homocysteine and protein-bound homocysteine thiolactone did not differ between control and cancer groups. In conclusion, reduced paraoxonase 1 activity suggests diminished important antioxidant mechanisms during the development of primary endometrial cancers in humans. PON1 Q192R polymorphism is not associated with the risk of endometrial cancer. Despite lower paraoxonase 1 activity, homocysteine concentration, and protein N-homocysteinylation in endometrial cancers do not differ from matched controls.

The influence of duloxetine on detrusor overactivity in rats with depression induced by 13-cis-retinoic acid.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression. METHODS: After 6 weeks of 13-cis-retinoic acid administration at a dose of 1 mg/kg/day, rats were given duloxetine at a dose of 1 mg/kg. This was followed by conscious cystometry, a forced swim test, and locomotor activity measurement. The levels of corticotropin-releasing factor (CRF) in the hypothalamus, amygdala and plasma were also determined. RESULTS: Duloxetine treatment led to a reduction in detrusor overactivity symptoms induced by the retinoid. Decreases were observed in cystometric parameters including the detrusor overactivity index, and the amplitude and frequency of nonvoiding contractions, while increases were seen in bladder compliance and the volume threshold to elicit nonvoiding contractions. No statistically significant differences were found in basal pressure, threshold pressure, micturition voiding pressure, postvoid residual , volume threshold, voiding efficiency, intercontraction interval, bladder contraction duration or relaxation time. Duloxetine also reduced the immobility time to that observed in control animals, while it did not affect locomotor activity. Its effects also included lowering of the CRF levels in the hypothalamus, amygdala and plasma, which increased following the prior administration of the retinoid. The plasma level of 13-cis-retinoic acid in rats corresponded to the levels found in humans. CONCLUSIONS: This is the first study showing the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression. Further studies in patients with detrusor overactivity and coexisting depression are warranted to confirm these experimental results.

Transobturator midurethral sling: What should patients expect after surgery?

INTRODUCTION AND HYPOTHESIS: Midurethral sling (MUS) surgeries are minimally invasive procedures; however, they are not free of postoperative complications. The aim of the study was to assess the occurrence of lower urinary tract symptoms (LUTS) (urgency, nocturia, frequency, splitting/spraying, hesitancy, terminal dribbling, and subjective feeling of postvoid residual) in patients suffering from stress (SUI) or mixed (MUI) urinary incontinence with a predominant SUI component before and after transobturator MUS placement. METHODS: The study group consisted of 88 women with SUI and 18 with MUI who underwent transobturator MUS. All participants were questioned with a self-developed questionnaire before and after surgery regarding the presence of LUTS. RESULTS: Seven days after surgery, 62 patients (58.5%) noted voiding and postmicturition symptoms, whereas 67 (63.2%) reported problems in storage. The more commonly reported LUTS at week 1 after surgery were urgency (52.8%), splitting/spraying (41.5%), and feeling of incomplete bladder emptying (34.0%). Patients perceived that splitting/spraying was the most bothersome. After 6 months, the most common LUTS reported were hesitancy (14.1%), terminal dribbling (10.4%), and splitting/spraying (9.4%). We noticed a decrease in the number of urgency episodes >2.7 times (p < 0.001) compared with baseline. After 6 months, 97 (91.5%) patients reported the lack of incontinence episodes. CONCLUSIONS: A vast majority of patients after MUS suffer from LUTS in the early postoperative period; however, the majority of undesired symptoms resolve spontaneously within the first 6 months postsurgery.

Candida lusitaniae - a case report of an intraperitoneal infection.

Candida lusitaniae is a rare opportunistic yeast which is known for its resistance to amphotericin B (AmB). It is responsible for about 19.3% of all infections caused by non-Candida albicans species, and for about 1.7% of all cases of genitourinary candidiasis brought about by the entire spectrum of Candida species. Most commonly it occurs in patients with hematologic malignancies, especially when a patient is receiving chemotherapy. Candida lusitaniae infection usually presents with fungemia; however, only 7.3% of all patients will develop peritonitis. This case study describes an immunocompetent female patient with an intraperitoneal infection caused by C. lusitaniae after laparoscopic hydrosalpinx surgery. The patient was treated with fluconazole according to susceptibility testing. Fluconazole was implemented both orally and by transvaginal injection into the space after the evacuated pseudocyst. Conservative treatment resulted in a temporary improvement of the patient's condition and a reduction of the pseudocyst. Candida lusitaniae is very similar to other Candida species in generating systemic and local infections - mainly in compromised patients. It is also unique in its ability to develop resistance to AmB. Proper identification and quick implementation of selective therapy with the right anti-fungal drug are crucial for successfully treating infected patients. Surgery should always be considered as a final treatment option.

The effect of combined treatment with a ß3 AR agonist and a ROCK inhibitor on detrusor overactivity.

AIMS: The objective of the study was to evaluate the efficacy and safety of the combined treatment with the ß3 AR agonist and ROCK inhibitor in the rat model of detrusor overactivity induced by retinyl acetate instillation. METHODS: The ROCK inhibitor (GSK 269962) and/or the ß3 AR agonist (BRL 37344) were administered in single doses and a cystometry was carried out, along with a 24 hr measurement of cardiovascular parameters and diuresis. RESULTS: The combined use of GSK 269962 and BRL 37344 in doses ineffective in monotherapies, ameliorated DO. An increase was found in voided volume, voiding efficiency, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions, accompanied by a decrease in basal pressure, threshold pressure, detrusor overactivity index, nonvoiding contractions amplitude, and frequency. The combination therapy in question proved to have no effect on micturition voiding pressure, post-void residual, bladder contraction duration, or relaxation time. A 24 hr observation of female rats who received GSK 269962 and/or BRL 37344 did not show any significant changes in urine production. BRL 37344 increased heart rate and blood pressure proportionately to the applied dose. The assessment of the combined treatment with GSK 269962 and BRL 37344 revealed a significant drop of cardiovascular parameters when compared to the rats which only received BRL 37344. DISCUSSION: The combined use of ß3 AR agonists and ROCK inhibitors may improve overactive bladder treatment efficacy and minimize side effects. CONCLUSION: This polytherapy appears to improve urine storage with no impairment of voiding function. Neurourol. Urodynam. 36:580-588, 2017. © 2016 Wiley Periodicals, Inc.

The influence of Rho-kinase inhibition on acetic acid-induced detrusor overactivity.

AIMS: Accumulating evidence has shown that Rho-kinase (ROCK) is involved in the regulation of bladder contraction. Our objective was to examine whether the ROCK inhibitor, GSK 269962, could prevent acetic acid (AA)-induced detrusor overactivity and to assess its influence on urine production (UP) and mean arterial pressure (MAP). METHODS: The bladder was catheterized from the external urethral orifice. 0.25 % (AA) solution was infused into the bladder for 5 min. In the same session a catheter was inserted into the apex of the bladder dome. In order to measure the blood pressure, the carotid artery was cannulated. Three days after the intravesical instillation of AA, the ROCK-GSK 269962 inhibitor was administered in a single dose of 10 mg/kg and a cystometry was carried out, along with a 24 hr measurement of UP and MAP. RESULTS: GSK 269962 reversed the changes induced by AA causing a drop in basal pressure, threshold pressure, micturition voiding pressure, bladder contraction duration, relaxation time, detrusor overactivity index, amplitude, and frequency of nonvoiding contractions while an increase in voided volume, post-void residual, volume threshold, voiding efficiency, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions. ROCK inhibition did not show any significant changes in UP and MAP. DISCUSSION: The results obtained indicate that ROCK inhibition may ameliorate AA-induced bladder overactivity. CONCLUSION: ROCK inhibitors appear to represent a potentially attractive pharmacological option for the treatment of lower urinary tract disorders associated with changes in detrusor contractility. Neurourol. Urodynam. 36:263-270, 2017. © 2015 Wiley Periodicals, Inc.

Use of uroflow parameters in diagnosing an overactive bladder-Back to the drawing board.

AIMS: The aim of our study was to analyze whether uroflowmetry parameters are helpful in diagnosing overactive bladder (OAB). The working hypothesis was that the flow curves of patients with OAB symptoms would appear as a sharp peak flow rate with a short duration and high amplitude, lasting only for a short period during urgency sensation, followed by reduced urine flow. We introduced a new parameter called flow index (FI) defined as an average divided by maximal urine flow rates as a potential marker for diagnosing OAB. METHODS: We conducted a retrospective study analyzing 757 urodynamic studies performed in women with lower urinary tract symptoms between 2007-2014. Based on subjective clinical symptoms patients were divided into four groups (pure OAB, mixed urinary incontinence with predominant OAB [MUI-OAB], mixed urinary incontinence with predominant SUI [MUI-SUI], and pure SUI patients). RESULTS: When comparing FI between pure OAB and pure SUI patients, a strong statistically significant difference was found (mean 0.45 ± 0.08 vs. 0.53 ± 0.09, respectively; P < 0.001). Similar results were found when comparing the patients with pure OAB and MUI-OAB versus patients with pure SUI and MUI-SUI (mean 0.47 ± 0.11 vs. 0.53 ± 0.09, respectively; P < 0.001). On the other hand, we did not find a statistically significant difference in the FI value between mixed urinary incontinence where SUI is the predominant factor and pure SUI groups (median 0.51 ± 0.09 vs. 0.53 ± 0.09, respectively; P > 0.5). CONCLUSIONS: FI may be used as an additional marker for OAB diagnosis. Neurourol. Urodynam. 36:198-202, 2017. © 2015 Wiley Periodicals, Inc.

Can botox improve night-time overactive bladder symptoms in women?

AIMS: Despite the efficacy of intravesical onabotulinumtoxinA (Botox) therapy for urgency, urgency incontinence, and daytime frequency, its value in treatment of nocturia remains unclear. The aim of the prospective observational study was to assess the effect of onabotulinumtoxinA on night-time symptoms in women with overactive bladder (OAB), including nocturia, night-time urgency incontinence, and nocturnal voided volume as end-points. METHODS: Women with idiopathic OAB (with at least one episode of urgency urinary incontinence (UUI) per day, ≥8 micturitions per 24 hr, and ≥2 nocturia episodes per night) were enrolled. Patients with nocturnal polyuria were excluded. Botox (100 U) was administered in 20 intra-detrusor injections. Post-void residual volumes (PVR) were checked at 2, 4, and 12 weeks. Participants completed a 3-day bladder diary and the King's Health Questionnaire (KHQ) before and 12 weeks after treatment, and reported the efficacy of the treatment on visual analog scale (VAS) at the final follow-up visit. RESULTS: Seventy-six women completed the study. Botox injections were effective in the reduction of nocturia episodes (mean -0.98; P < 0.001) and night-time UUI episodes (-0.37; P < 0.001) compared to the baseline. The increase of mean voided volume of the night-time micturitions was 92.6 ml (P < 0.001). Patients reported a mean 58 points of improvement on the VAS. Urinary retention, which required self-catheterization, was observed in three patients. CONCLUSIONS: Intravesical Botox injection provides significant benefit for night-time symptoms in OAB patients. Our results are applicable for women without nocturnal polyuria, and should prove useful when counseling patients about the risks and benefits of Botox. Neurourol. Urodynam. 36:648-652, 2017. © 2016 Wiley Periodicals, Inc.

Impact of intravesical onabotulinumtoxinA on sexual function in women with OAB.

AIMS: Urgency urinary incontinence (UUI), and the symptoms of overactive bladder (OAB) have a negative impact on female sexual function. The aim of this study was to investigate the effect of intravesical onabotulinumtoxinA (Botox) injection on sexual function in women with OAB, using the multi domain Female Sexual Function Index (FSFI) questionnaire. METHODS: Sixty-eight sexually active women with idiopathic OAB with at least one episode of UUI and ≥8 micturitions per 24 h were recruited. Patients completed the FSFI questionnaire before and 12 weeks after treatment with intravesical onabotulinumtoxinA injections. Baseline scores were compared with a control group of age-matched healthy women. RESULTS: Fifty-six women completed the study. At baseline OAB patients reported decreased quality of sexual function in all domains measured with FSFI, in comparison to healthy women (median 21.8 vs. 26.3, P < 0.001). Over 90% of participants reported clinically relevant improvements in sexual function, with statistically significant changes in mean scores in all six domains. CONCLUSIONS: Intravesical Botox injections provide improvement in sexual function in women with OAB. Neurourol. Urodynam. 9999:XX-XX, 2016. © 2016 Wiley Periodicals, Inc.

Urinary retention in female OAB after intravesical Botox injection: who is really at risk?

INTRODUCTION AND HYPOTHESIS: Intravesical onabotulinumtoxinA (Botox) injections are effective for the treatment of idiopathic overactive bladder (OAB) symptoms. The aim of our study was to assess the predisposing factors for urinary retention in women with OAB after intravesical Botox injection. METHODS: All participants were women of European descent with idiopathic OAB. OnabotulinumtoxinA (100 U) was administered in 20 intra-detrusor injections. Analysis was performed based on the results of safety assessments made during follow-up (FU) visits on weeks 2, 4 and 12, in 208 women who were treated with Botox injections for refractory OAB and who completed all FU visits. RESULTS: Women who required clean intermittent self-catheterisation (CISC) and those with post-void residual (PVR) greater than 200 ml were older in comparison with patients with PVR between 50 and 200 ml. Patients who required CISC were also characterised by higher parity and particularly by a higher number of vaginal deliveries. Other factors such as body mass index or comorbidities did not significantly influence PVR and the risk of CISC. CONCLUSIONS: Elderly and/or multiparous women are at increased risk of urinary retention after intravesical 100-U Botox injections. The risk of new onset urine retention in our study has completely disappeared 2 weeks after Botox injections. Based on our results of the way in which the PVRs have changed over time, we can conclude that OAB patients should be optimally assessed during the first 2 weeks after Botox injections.