Prospective follow-up of overactive bladder symptoms in patients with prior SARS-CoV-2 infection.

PURPOSE: SARS-CoV-2 infection can result in genitourinary symptoms, such as frequency, urgency, nocturia, and pain/pressure. In this study, we followed the progression of overactive bladder (OAB) symptoms in patients that reported new or worsening OAB symptoms after coronavirus disease-19 (COVID-19) diagnosis. MATERIALS AND METHODS: Individuals from a COVID-19 serology study were invited to participate in a follow-up study. Respondents were divided into three groups based on prior COVID-19 testing. Patients scored symptoms retrospectively before the pandemic, at study onset, and prospectively during 12-month follow-up. Genitourinary symptoms were assessed using international consultation on incontinence questionaire for OAB (ICIQ-OAB). Change in ICIQ-OAB scores from baseline were calculated. The minimal important difference of one on ICIQ-OAB is considered a significant change. RESULTS: 26.0% of participants previously had positive COVID polymerase chain reaction (PCR) test (PCR+), 5.6% a positive serology test only (Ser+), and 65.5% were COVID naïve (COVID-). 23.8% of participants reported a significant increase in ICIQ-OAB score at study onset compared to prepandemic. ICIQ-OAB scores were similar at prepandemic but significantly higher at study start (p < 0.001) in PCR+ group. During follow-up, change in ICIQ-OAB scores from baseline remained unchanged for COVID- group, but gradually reduced for PCR+, reaching similar levels as COVID- group by 12 months. By 12 months, 71.4% of PCR+, 42.9% of Ser+, and 68.8% of COVID- participants still reported significant increase in ICIQ-OAB scores. CONCLUSIONS: Most COVID-19 patients experienced return of symptoms to baseline, indicative of the potential resolution of COVID-associated cystitis. A subset of cases did not, raising questions about the underlying factors contributing to this outcome. Additional research is needed to assess long COVID on urological health.

Iltamiocel Autologous Cell Therapy for the Treatment of Female Stress Urinary Incontinence: A Double-Blind, Randomized, Stratified, Placebo-Controlled Trial.

AIMS: This study aimed to determine the efficacy and safety of iltamiocel investigational autologous muscle cell therapy in females with stress urinary incontinence (SUI). METHODS: Adult females were randomized 2:1 to iltamiocel (150 × 106 cells) or placebo and stratified by severity and prior SUI surgery. The primary objective was efficacy based on the frequency of stress incontinence episodes (SIE) recorded in a 3-day diary at 12 months posttreatment. After 12 months, placebo participants could elect to receive open-label iltamiocel. Efficacy and safety analyses were performed using all patients as treated populations. RESULTS: The study enrolled 311 patients, 297 were randomized to either iltamiocel (n = 199) or placebo (n = 98). Of the 295 participants that completed 12 months blinded follow-up, the proportion achieving the primary endpoint of ≥ 50% SIE reduction was not statistically different between treatment groups (52% vs. 53.6%; p = 0.798). A significantly greater proportion of iltamiocel participants in the prior SUI surgery stratum group achieved ≥ 75% SIE reduction compared with placebo, (40% vs. 16%; p = 0.037). Treatment response was maintained at 24 months in 78.4% and 64.9% of iltamiocel participants who achieved ≥ 50% and ≥ 75% SIE reduction, respectively, at Month 12. Adverse events related to the treatment were reported in 19 (9.5%) iltamiocel participants and 6 (6.1%) placebo participants. CONCLUSION: The study did not meet its primary endpoint however, iltamiocel cell therapy is safe and may be ideally suited to female patients who have undergone prior surgery for SUI. Additional study in this group of patients with high unmet medical needs is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01893138; EudraCT number: 2014-002919-41.

Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing.

Pelvic cancer survivors who were treated with radiation therapy are at risk for developing (hemorrhagic) radiation cystitis (RC) many years after completion of radiation therapy. Patients with RC suffer from lower urinary tract symptoms, including frequency, nocturia, pelvic pain, and incontinence. In advanced stages, hematuria can occur, potentially escalating to life-threatening levels. Current therapeutic options for RC are limited, partly due to ethical concerns regarding bladder biopsy in patients with fragile bladder tissue. This study aimed to leverage our established preclinical model to elucidate the molecular pathways implicated in radiation-induced tissue changes in the bladder. Female C57Bl/6 mice received a single dose of 40 Gy using CT-guided imaging and a two-beam irradiation approach using the SARRP irradiator. Bladders from irradiated and age-matched littermate controls were harvested at 1 week [n = 5/group] or 6 months [n = 5/group] after irradiation, RNA was harvested, and mRNA sequencing was performed at paired-end 150bp on the Illumina NovaSeq6000 with a target of 30 million reads per sample. Following RNA sequencing, thorough bioinformatics analysis was performed using iPathwayGuide v2012 (ADVAITA Bioinformatics). Findings of the RNA sequencing were validated using qPCR analysis. At 1 week post-irradiation, altered gene expression was detected in genes involved in DNA damage response, apoptosis, and transcriptional regulation. By 6 months post-irradiation, significant changes in gene expression were observed in inflammation, collagen catabolism, and vascular health. Affected pathways included the p53, JAK-STAT, and PI3K-Akt pathways. These findings were validated in vivo in bladder tissues from our preclinical model. This is the first study to determine the molecular changes in the bladder in response to radiation treatment. We have successfully pinpointed several pathways and specific genes that undergo modification, thereby contributing to the progression of radiation cystitis. These insights enhance our understanding of the pathophysiology of radiation cystitis and may ultimately pave the way to the identification of potential new therapeutic targets.

Haemorrhagic cystitis: a review of management strategies and emerging treatments.

Haemorrhagic cystitis (HC) is characterised by persistent haematuria and lower urinary tract symptoms following radiotherapy or chemotherapy. Its pathogenesis is poorly understood but thought to be related to acrolein toxicity following chemotherapy or fibrosis/vascular remodelling after radiotherapy. There is no standard of care for patients with HC, although existing strategies including fulguration, hyperbaric oxygen therapy, botulinum toxin A, and other intravesical therapies have demonstrated short-term efficacy in cohort studies. Novel agents including liposomal tacrolimus are promising targets for further research. This review summarises the incidence and pathogenesis of HC as well as current evidence supporting its different management strategies.

Use of Botulinum Toxin in the Genitourinary System.

Botulinum toxin injection has been widely accepted by the urology and urogynecology medical communities as a safe and effective treatment for refractory urinary incontinence. There are two approved genitourinary indications for botulinum toxin. OnabotulinumtoxinA (onaBoNTA) 200 U for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an anticholinergic medication. In addition, onaBoNTA 100 U is used for the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and frequency, in adult patients who have an inadequate response to or are intolerant of an anticholinergic medication. We will discuss the application of botulinum toxin for genitourinary indications with a focus on bladder injection and on potential use of BoNT use in the prostate and pelvic floor.

Proteomic analysis of bladder biopsies from interstitial cystitis/bladder pain syndrome patients with and without Hunner's lesions reveals differences in expression of inflammatory and structural proteins.

BACKGROUND: Interstitial cystitis/bladder pain syndrome is a bladder disease usually characterized by pain, urgency, and frequency. Interstitial cystitis is currently classified into two subtypes, with and without Hunner's lesions. However, the underlying etiology of interstitial cystitis and its subtypes are largely unknown. METHODS: To better understand the biological changes in the bladder of interstitial cystitis/bladder pain syndrome patients, we directly analyzed bladder tissue of interstitial cystitis patients, both those with Hunner's lesions and those without. Proteins in the bladder biopsies were analyzed using nanoscale high-performance liquid chromatography-tandem mass spectrometry. Disease subgroups were compared and significantly expressed proteins were mapped using STRING to determine protein associations and functions. RESULTS: We found that patients with Hunner's lesions had significant increases in inflammatory and endoplasmic reticulum stress proteins, with a decrease in cellular adhesive proteins, compared to patients without Hunner's lesions. These patients also exhibited a decrease in proteins associated with the Rap1 signaling pathway, which regulates cell proliferation and wound healing. When comparing diseased and non-disease-apparent tissue in patients with Hunner's lesions, diseased tissue exhibited a decrease in ubiquitination proteins. CONCLUSIONS: In summary, there are significant differences in protein expression found in the bladders of interstitial cystitis patients with and without Hunner's lesions, indicating a disturbance in proteins associated with cellular adhesion, proliferation, protein processing, and wound healing.

Low Energy Shock Wave Therapy Inhibits Inflammatory Molecules and Suppresses Prostatic Pain and Hypersensitivity in a Capsaicin Induced Prostatitis Model in Rats.

The effect of low energy shock wave (LESW) therapy on the changes of inflammatory molecules and pain reaction was studied in a capsaicin (10 mM, 0.1 cc) induced prostatitis model in rats. Intraprostatic capsaicin injection induced a pain reaction, including closing of the eyes, hypolocomotion, and tactile allodynia, which effects were ameliorated by LESW treatment. LESW therapy (2Hz, energy flux density of 0.12 mJ/mm2) at 200 and 300 shocks significantly decreased capsaicin-induced inflammatory reactions, reflected by a reduction of tissue edema and inflammatory cells, COX-2 and TNF-α stained positive cells, however, the therapeutic effects were not observed at 100 shocks treated group. Capsaicin-induced IL-1ß, COX-2, IL-6, caspase-1, and NGF upregulation on day 3 and 7, while NALP1 and TNF-α upregulation was observed on day 7. LESW significantly suppressed the expression of IL-1ß, COX-2, caspase-1, NGF on day 3 and IL-1ß, TNF-α, COX-2, NALP1, caspase-1, NGF expression on day 7 in a dose-dependent fashion. LESW has no significant effect on IL-6 expression. Intraprostatic capsaicin injection activates inflammatory molecules and induces prostatic pain and hypersensitivity, which effects were suppressed by LESW. These findings might be the potential mechanisms of LESW therapy for nonbacterial prostatitis in humans.

Crowdsourcing Disease Biomarker Discovery Research: The IP4IC Study.

PURPOSE: Biomarker discovery is limited by readily assessable, cost efficient human samples available in large numbers that represent the entire heterogeneity of the disease. We developed a novel, active participation crowdsourcing method to determine BP-RS (Bladder Permeability Defect Risk Score). It is based on noninvasive urinary cytokines to discriminate patients with interstitial cystitis/bladder pain syndrome who had Hunner lesions from controls and patients with interstitial cystitis/bladder pain syndrome but without Hunner lesions. MATERIALS AND METHODS: We performed a national crowdsourcing study in cooperation with the Interstitial Cystitis Association. Patients answered demographic, symptom severity and urinary frequency questionnaires on a HIPAA (Health Insurance Portability and Accountability Act) compliant website. Urine samples were collected at home, stabilized with a preservative and sent to Beaumont Hospital for analysis. The expression of 3 urinary cytokines was used in a machine learning algorithm to develop BP-RS. RESULTS: The IP4IC study collected a total of 448 urine samples, representing 153 patients (147 females and 6 males) with interstitial cystitis/bladder pain syndrome, of whom 54 (50 females and 4 males) had Hunner lesions. A total of 159 female and 136 male controls also participated, who were age matched. A defined BP-RS was calculated to predict interstitial cystitis/bladder pain syndrome with Hunner lesions or a bladder permeability defect etiology with 89% validity. CONCLUSIONS: In this novel participation crowdsourcing study we obtained a large number of urine samples from 46 states, which were collected at home, shipped and stored at room temperature. Using a machine learning algorithm we developed BP-RS to quantify the risk of interstitial cystitis/bladder pain syndrome with Hunner lesions, which is indicative of a bladder permeability defect etiology. To our knowledge BP-RS is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome and one of the first biomarker assays to be developed using crowdsourcing.

Urodynamic and molecular characteristics of detrusor underactivity in a rat cryoinjury model and effects of low energy shock wave therapy.

AIMS: Low energy shock wave (LESW) has been shown to facilitate tissue regeneration and reduce inflammation. We investigated the effects of LESW in an underactive (DU) model induced by cryoinjury of rat detrusor. METHODS: Forty-six female Sprague-Dawley rats were divided into sham, cryoinjury with or without LESW (0.12 mJ/mm2 ; 200 pulses). Under halothane anesthesia, a low midline incision was made and a cryoinjury of detrusor was induced by placing an aluminum rod (chilled with dry ice) for 30 s on the serosal side of the bladder filled with 1 mL sterile saline bilaterally. Awake cystometrogram (CMG), molecular and histopathology studies were performed on Day 8 or 15 after cryoinjury. RESULTS: Significant urodynamic, histological, and molecular changes induced by cryoinjury of rat detrusor were detected on Day 8 and decrease in the contraction amplitude (54.3%), a significant increase in wet bladder weight (64.1%), edematous changes, muscle thinning and downregulation of α-SMA, IL-6, and upregulation of COX-2. LESW reversed the cryoinjury induced histological and COX-2 expression to cause a 49.0% increase in the contraction amplitude (P < 0.05). LESW induced cell proliferation was revealed by increased CD31 and Ki67 immunostaining. The effect of cryoinjury on urodynamic and histological changes was maintained till Day 15. CONCLUSION: The cryoinjury of rat detrusor models myogenic DU, which is partially reversed by LESW. LESW may afford a simple, non-invasive modality to facilitate tissue regeneration and improve voiding function in myogenic detrusor underactivity.

New technology assessment and current and upcoming therapies for underactive bladder.

BACKGROUND AND AIMS: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder. METHODS: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB. RESULTS: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria. 2) Should residual urine volume be the primary outcome parameter and how often should it be measured? 3) Are there secondary measures that should have a place in UAB trials, such as change in the number of catheterizations, quality of life measures, etc.? 4) Use and format of bladder voiding and catheterization diary for trials. 5) Define role and technique of urodynamics in UAB trials. Are urodynamics required to monitor, and possibly exclude, individuals with high pressure voiding induced by bladder prokinetic therapies? 6) Development and use of UAB questionnaires. DISCUSSION AND CONCLUSION: The UAB regulatory working group recognizes the path forward should include engaging the FDA and other regulatory organizations that may harmonize and formalize guidance for regulatory trial designs for therapeutics for UAB.

Patient characteristics for different therapeutic strategies in the management ketamine cystitis.

AIMS: Long-term ketamine abuse results in severely inflamed bladder and intractable bladder pain. Currently there is no guideline for clinician to follow how to manage patients with ketamine cystitis (KC). This study analyzed the KC patient characteristics between who received conservative management and augmentation enterocystoplasty (AE). METHODS: A total of 53 patients with chronic ketamine abuse and lower urinary tract symptoms were included in this study. All of the patients have been initially treated conservatively but fail. They were admitted for detailed urological examinations. Patients were classified according to their maximal bladder capacity (MBC). The patients with extremely small MBC (<100 ml) with or without upper urinary tract damage and very small MBC with upper urinary tract damage were recommended to receive AE. The patient characteristics and treatment outcome are compared between patients with AE and conservative treatment. RESULTS: Among them, 28 patients underwent AE and 25 were managed with conservative treatment. The only significant difference between groups was more patients with urgency urinary incontinence underwent AE. Patients underwent AE had significantly smaller MBC, thicker bladder wall, and higher incidence of vesicoureteral reflux. Patients underwent AE reported a good outcome. Most of patients received conservative treatment had a fair result. CONCLUSIONS: KC patients who already developed a contracted bladder with extremely small bladder capacity (<300 ml) with irreversible urinary tract change, partial cystectomy, and AE seems necessary for early restoration of a normal lower urinary tract function. The treatment outcome of AE is better than patients with conservative treatment. Neurourol. Urodynam. 36:687-691, 2017. © 2016 Wiley Periodicals, Inc.

Role of the Anterior Cingulate Cortex in the Control of Micturition Reflex in a Rat Model of Parkinson's Disease.

PURPOSE: In the current study we examined dynamic changes in neural activity of the anterior cingulate cortex and the midbrain periaqueductal gray during the micturition reflex in a Parkinson's disease model as well as the effects of direct stimulation of the anterior cingulate cortex on the micturition reflex. MATERIALS AND METHODS: Electrodes were inserted in the anterior cingulate cortex or the periaqueductal gray. The effects of intravenous administration of the adenosine A2A receptor antagonist ZM24138 on pelvic nerve evoked field potentials were examined. The effect of electrical stimulation of the anterior cingulate cortex was also examined. RESULTS: Rats with Parkinson's disease showed bladder overactivity as evidenced by a significant decrease in the intercontraction interval compared with sham operated rats. Intravenous administration of ZM24138 increased the intercontraction interval in both groups with the inhibitory effects greater in rats with Parkinson's disease. It dose dependently increased the amplitude of evoked potentials in the anterior cingulate cortex of rats with Parkinson's disease but not in sham operated rats. Intravenous administration of ZM24138 decreased evoked potential amplitude in the periaqueductal gray of both groups with the inhibitory effects greater in Parkinson's disease vs sham operated rats. Electrical stimulation of the anterior cingulate cortex significantly increased the intercontraction interval. CONCLUSIONS: These results suggest that anterior cingulate cortex neurons have an inhibitory role in bladder control. Neural activity in the anterior cingulate cortex was significantly increased along with suppression of bladder overactivity after ZM241385 administration in the Parkinson's disease model and the stimulation of the anterior cingulate cortex inhibited the micturition reflex. Understanding the roles of the anterior cingulate cortex in the modulation of micturition could provide further insights into the pathophysiology of overactive bladder.

Liposome Based Intravesical Therapy Targeting Nerve Growth Factor Ameliorates Bladder Hypersensitivity in Rats with Experimental Colitis.

PURPOSE: Pelvic organ cross sensitization is considered to contribute to overlapping symptoms in chronic pelvic pain syndrome. Nerve growth factor over expression in the bladder is reportedly involved in the symptom development of bladder pain syndrome/interstitial cystitis. We examined whether a reduction of over expressed nerve growth factor in the bladder by intravesical treatment with liposome and oligonucleotide conjugates would ameliorate bladder hypersensitivity in a rat colitis model. MATERIALS AND METHODS: Adult female rats were divided into 1) a control group, 2) a colitis-oligonucleotide group with intracolonic TNBS (2,4,6-trinitrobenzene sulfonic acid) enema and intravesical liposome-oligonucleotide treatments, 2) a colitis-saline group with intracolonic TNBS and intravesical saline treatments, 4) a sham oligonucleotide group with intravesical liposome-oligonucleotide treatment without colitis and 5) a sham-saline group with intravesical saline treatment without colitis. Liposomes conjugated with nerve growth factor antisense oligonucleotide or saline solution were instilled in the bladder and 24 hours later colitis was induced by TNBS enema. Effects of nerve growth factor antisense treatment were evaluated by pain behavior, cystometry, molecular analyses and immunohistochemistry 10 days after TNBS treatment. RESULTS: In colitis-oligonucleotide rats nerve growth factor antisense treatment ameliorated pain behavior and decreased a reduction in the intercontraction interval in response to acetic acid stimulation as well as nerve growth factor expression in the bladder mucosa. All were enhanced in colitis-saline rats compared to sham rats. CONCLUSIONS: Nerve growth factor over expression in the bladder mucosa and bladder hypersensitivity induced after colitis were decreased by intravesical application of liposome-oligonucleotide targeting nerve growth factor. This suggests that local antinerve growth factor therapy could be effective treatment of bladder symptoms in chronic pelvic pain syndrome.

Botulinum Toxin to Treat Neurogenic Bladder.

Alteration in neural control from suprapontine areas to the nerves innervating the bladder can lead to bladder dysfunction and the development of a neurogenic bladder (NGB). Patients with NGB often suffer from urinary incontinence, which can lead to adverse events such as urinary tract infections and decubiti, in addition to creating a large care burden for family members or healthcare providers and significantly impairing patient quality of life. The common failure of anticholinergic medications has spurned the development of second-line treatments, including the use of botulinum toxin. OnabotulinumtoxinA (onaBoNT-A; BOTOX, Allergan, Inc.) was approved by the U.S. Food and Drug Administration (FDA) in 2011 to treat neurogenic detrusor overactivity in patients with urinary incontinence resulting from a NGB. In this review the authors summarize pertinent results from key trials leading to FDA approval of onaBoNT-A as well as more recent long-term data.

Age-related changes in bladder function with altered angiotensin II receptor mechanisms in rats.

AIMS: To examine alterations in expression of angiotensin II type 1 receptors (AT1R) which induce organ tissue remodeling, angiotensin II type 2 receptors (AT2R) which protect against it, and related molecules in the bladder of matured rats with bladder dysfunction. METHODS: Female SD rats of three different ages were used: 8 weeks old (8W; n = 5), 9 months old (9M; n = 5), and 15 months old (15M; n = 5). After cystometry, the expression levels of AT1R, connexin43 (Cx43), MAP kinase (MAPK), collagen1, AT2R, PPAR-γ, adiponectin (Adipo), and adiponectin receptor (Adipo-R) were investigated in the bladder. RESULTS: Pressure threshold, post-void residual volume and the number of non-voiding contractions were significantly increased in 15M versus 8W rats (P < 0.01). Maximum voiding pressure was significantly decreased in 15M versus 8W rats (P < 0.05). There was no significant difference in CMG parameters between 8W and 9M rats. In the bladder, the mRNA expression of AT1R, Cx43, MAPK, collagen 1, AT2R, PPAR-γ, Adipo, and Adipo-R were significantly higher in 15M than in 8W rats. The relative expression ratio of AT1R protein against AT2R protein in the mucosa and detrusor was significantly increased in 15M versus 8W rats. CONCLUSIONS: These results indicate that matured rats exhibit not only bladder overactivity but also impaired voiding, which are associated with upregulation of AT1R. The upregulation of AT2R also may play a significant role in the suppressing of AT1R induced remodelling. However, because AT1R upregulation is more dominant than AT2R increases, AT2R activation may not be sufficient to suppress AT1R stimulation in matured rats. Neurourol. Urodynam. 35:908-913, 2016. © 2015 Wiley Periodicals, Inc.

Intravesical Liposomal Tacrolimus Protects against Radiation Cystitis Induced by 3-Beam Targeted Bladder Radiation.

PURPOSE: We primarily determined whether the small animal radiation research platform could create a rat radiation cystitis model via targeted bladder irradiation (phase I). The response to treating early phase radiation cystitis in rats with transurethral catheter instillation of liposomal tacrolimus was also examined (phase II). MATERIALS AND METHODS: In phase I 16 adult female Sprague Dawley® rats were used. Metabolic urination patterns were analyzed before and after exposure to 20, 30 or 40 Gy radiation. In phase II irradiated rats were randomly assigned to receive a single instillation of saline or liposomal tacrolimus. RESULTS: The 40 Gy radiation dose induced statistically significant reductions in the intermicturition interval compared to the lower radiation doses. By approximately 20 minutes 40 Gy radiation caused a significant decrease in the mean intermicturition interval (p < 0.0001). Histological analysis revealed degenerative epithelial changes and urothelial swelling with evidence of pseudocarcinomatous epithelial hyperplasia. Therefore, 40 Gy were chosen for the phase II efficacy study. There was no measurable change in total voided urine volume after irradiation, or after liposomal tacrolimus or saline instillation. Liposomal tacrolimus significantly increased the post-irradiation intermicturition interval by approximately 30 minutes back to baseline (p < 0.001). CONCLUSIONS: The radiation cystitis rat model showed a dose dependent decrease in the intermicturition interval without inducing short-term skin or gastrointestinal damage. This study demonstrates that liposomal tacrolimus may be a promising new intravesical therapy for the rare, serious condition of radiation cystitis.

Effects of Duloxetine on Urethral Continence Reflex and Bladder Activity in Rats with Cerebral Infarction.

PURPOSE: We investigated the effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on the sneeze induced continence reflex and on bladder function in rats with cerebral infarction. MATERIALS AND METHODS: Using urethane anesthesia the effect of duloxetine (1 mg/kg intravenously) on the amplitude of urethral responses during sneezing as well as urethral baseline pressure at the mid urethra was evaluated in normal female adult rats and cerebral infarction rats. Tilt leak point pressure was also measured. In normal and cerebral infarction rats continuous cystometry was evaluated before and after duloxetine injection. RESULTS: In cerebral infarction rats urethral baseline pressure was 43% lower than in normal rats but the amplitude of urethral responses during sneezing did not differ in the 2 groups. Duloxetine increased the amplitude of urethral responses during sneezing and urethral baseline pressure by 31% and 21%, respectively, in normal rats but did not affect either in cerebral infarction rats. Also, in cerebral infarction rats leak point pressure was 29% lower compared with normal rats. Duloxetine increased leak point pressure in normal rats but not in cerebral infarction rats. Cerebral infarction reduced intercontraction intervals without affecting the amplitude of bladder contractions compared with normal rats. Duloxetine prolonged intercontraction intervals in cerebral infarction rats but not in normal rats. CONCLUSIONS: These results suggest that cerebral infarction induces not only bladder overactivity but also stress urinary incontinence, which may account for mixed incontinence in patients with cerebral infarction. After cerebral infarction duloxetine reduced bladder overactivity but failed to enhance active urethral closure mechanisms during sneezing, suggesting that disorganization of the brain network after cerebral infarction might influence the effect of duloxetine on lower urinary tract function.

Current and emerging drugs for interstitial cystitis/bladder pain syndrome (IC/BPS).

INTRODUCTION: Interstitial cystitis or bladder pain syndrome (IC/BPS) is a debilitating chronic disease characterized by suprapubic pain and lower urinary tract symptoms: however, the etiology is still unknown. Therefore, the long-lasting, effective treatments of IC/BPS are still not established, and the treatment is sometimes empirically selected depending on practitioners' experience and preference. AREA COVERED: In this review we focus on the current treatments, ongoing clinical trials, and several potential new drugs based on the results of basic and clinical research studies. First, we discuss the potential etiologies of IC/BPS that include altered barrier lining, afferent and/or central nervous system abnormalities, possible contribution of inflammation or infection and abnormal urothelial signaling. Then, the current therapies of IC/BPS, either systemic or local, are reviewed by critical evaluation of the efficacy and shortcomings of each treatment. Finally, based on proposed etiologies of the disease, potential emerging drugs and treatments are discussed. EXPERT OPINION: Current therapies often fail to control the symptoms of IC/BPS. Several interventions including sustained drug release and retaining techniques, and drugs that act on afferent neural pathways are emerging and may be promising. In addition, phenotyping of IC/BPS patients based on cystoscopic findings (e.g., Hunner vs. non-Hunner lesion) or patients' symptoms would be important for further investigation of IC/BPS etiology and the evaluation of efficacy of new treatments.

Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium.

AIMS: Botulinum neurotoxin serotype A (BoNT/A) has emerged as an effective treatment of urinary bladder overactivity. Intravesical lipotoxin (BoNT/A delivery using liposomes), which may target the urothelium, is effective in blocking acetic acid induced hyperactivity in animals. The objective of this study was to assess the possible site of toxin action within the urothelium. METHODS: We examined expression of the toxin receptor (SV2) and its cleavage targets (SNAP-25 and SNAP-23) within urothelium as well as effects of the toxin on mechanically evoked release of ATP from cultured rat urothelial cells. ATP release was measured using the luciferin-luciferase assay; we examined expression of SNAP-23 and -25 in urothelial cells and mucosa of rat and human bladders. RESULTS: BoNT/A (1.5 U; 1-3 hr) blocked hypotonic evoked release of urothelial ATP, without affecting morphology. The expression of protein targets for BoNT/A binding (SV2) was detected in human and rat bladder mucosa and catalytic action (SNAP-23, -25) in urothelial cells and mucosa (differed in intensity) from rat and human bladder. Incubation of cultured (rat) urothelial cells with BoNT/A decreased expression levels of both SNAP-23 (44%) and SNAP-25 (80%). CONCLUSIONS: Our findings reveal that the bladder urothelium expresses the intracellular targets and the binding protein for cellular uptake of BoNT/A; and that the toxin is able to suppress the levels of these targets as well as hypotonic-evoked ATP release. These data raise the possibility that intravesical treatment with BoNT/A suppresses bladder reflex and sensory mechanisms by affecting a number of urothelial functions including release of transmitters.