Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

BACKGROUND: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. OBJECTIVES: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. RESULTS: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. CONCLUSIONS: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS.

Possible Involvement of Muscarinic Receptor Blockade in Mirabegron Therapy for Patients with Overactive Bladder.

The selective ß 3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 µM) inhibited specific [N-methyl-3H]scopolamine methyl chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart and significantly higher than those in the submaxillary gland and brain. Mirabegron induced the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high- and low-affinity components for mirabegron were 44.5% and 55.5%, respectively. Respective pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of mirabegron, muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg mirabegron was 37%-76%. The present results demonstrate for the first time that mirabegron may relax the detrusor smooth muscle not only by ß 3-adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective ß 3-adrenoceptor agonist, represents an alternative to antimuscarinic agents for management of overactive bladder (OAB). The present study aimed to clarify whether mirabegron directly binds to muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder and to predict muscarinic receptor occupancy in human bladder after oral administration of mirabegron. The results demonstrated that mirabegron therapy for patients with OAB may be due not only to ß 3-adrenoceptor activation but also muscarinic receptor blockade.

Alternative Treatment for Erectile Dysfunction: a Growing Arsenal in Men's Health.

PURPOSE OF REVIEW: To highlight and review encouraging preliminary studies behind several alternative products and interventions for erectile dysfunction (ED). RECENT FINDINGS: Alternative treatments for ED are becoming more prevalent with increased consumer interest. "Natural" products are sold online, and numerous clinics offer various off-label and investigational interventions. These alternative treatments have demonstrated varying degrees of efficacy in randomized trials and meta-analyses, but none of these interventions has robust enough evidence to be considered first-line therapy. These treatments may find a role in combination with guideline treatments or may be used in novel penile rehabilitation research protocols. With growing interest in alternative treatment for men's health, an awareness of the literature is imperative for patient counsel. Alternative treatments, like L-arginine, have a growing body of evidence for efficacy in combination with PDE5i, and low-intensity shock wave therapy and stem cell therapy continue to demonstrate encouraging outcomes in ED trials.

Conservative Therapy for Peyronie's Disease: a Contemporary Review of the Literature.

PURPOSE OF REVIEW: To analyze the literature on current conservative treatment options for Peyronie's disease (PD). RECENT FINDINGS: Conservative therapy with intralesional collagenase clostridium histolyticum (CCH) is safe and efficacious in either the acute or chronic phases of PD. Combination treatment with penile traction therapy (PTT) can produce even better results. While most PTT devices require extended periods of therapy up to 8 h per day, the RestoreX® device can be effective at 30-90 min per day. A variety of conservative therapies are available for treatment of PD. The available literature does not reveal any treatment benefit of oral therapies. Intralesional therapy is the mainstay conservative treatment of PD. Intralesional CCH therapy is the first Food and Drug Administration-approved intralesional therapy and represents the authors' preference for medical therapy. The most effective conservative management of PD likely requires a combination of therapies.

The Management of Penile Fracture: a Review of the Literature with Special Consideration for Patients Undergoing Collagenase Clostridium Histolyticum Injection Therapy.

PURPOSE OF REVIEW: To review the current literature on acute management of traumatic penile fracture, with a specific discussion of those injuries following collagenase clostridium histolyticum (CCH) injections for the treatment of Peyronie's disease. RECENT FINDINGS: The immediate repair of traumatic penile fracture injury is associated with significantly better prognosis for long-term sexual health. Corporal disruption following CCH administration has several distinct features, and the trend is to manage these patients conservatively in the absence of urethral injury. Traumatic penile fracture repair continues to have excellent results when performed immediately following injury. The post-CCH treatment setting portends increased difficulty during surgical management and can be successfully managed in most cases by conservative measures.

Effect of Early Oxybutynin Treatment on Posterior Urethral Valve Outcomes in Infants: A Randomized Controlled Trial.

PURPOSE: We studied the effect of oxybutynin on bladder and upper urinary tract outcomes in infants following posterior urethral valve ablation. MATERIALS AND METHODS: Patients younger than 12 months old who had undergone primary endoscopic valve ablation for posterior urethral valves were screened for eligibility. Patients who had undergone urinary diversion or had other conditions that could affect lower urinary tract function were excluded. Study patients were randomized to either oxybutynin (0.2 mg/kg 3 times daily) until toilet training or active observation. The study end points were serum creatinine, estimated glomerular filtration rate, hydronephrosis improvement, vesicoureteral reflux resolution, febrile urinary tract infection and toilet training. RESULTS: A total of 49 infants (24 receiving oxybutynin and 25 undergoing observation) were enrolled between December 2013 and September 2015 and completed at least 1 year of followup. Oxybutynin was discontinued before toilet training in 5 patients due to facial flushing in 2, bladder and upper tract dilatation in 2, and cognitive changes in 1. After a median followup of 44.2 months (range 12 to 57.6) median serum creatinine and estimated glomerular filtration rate were not significantly different between the groups (p=0.823 and p=0.722, respectively). Renal units in the oxybutynin group had a greater likelihood of hydronephrosis improvement (61.9% vs 34.8%, p=0.011) and resolution of vesicoureteral reflux (62.5% vs 25%, p=0.023). Febrile urinary tract infection (29.2% vs 40%, p=0.404), completion of toilet training (70.8% vs 76%, p=0.748) and age at toilet training (p=0.247) did not differ significantly between the oxybutynin and observation groups. CONCLUSIONS: Oxybutynin enhances hydronephrosis improvement and vesicoureteral reflux resolution following primary endoscopic valve ablation in infants but periodic monitoring is warranted.

New targets for overactive bladder-ICI-RS 2109.

AIM: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. METHODS: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. RESULTS: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide-dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for ß3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1 , TRPV4 , TRPA1 , and TRPM4 ) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+ -activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-ß pathway-the canonical fibrosis pathway. CONCLUSIONS: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.

Alkalinized lidocaine solution as a first-line local anesthesia protocol for intradetrusor injection of onabotulinum toxin A: Results from a double-blinded randomized controlled trial.

AIMS: Local anesthesia protocols for intradetrusor onabotulinum toxin A (BoNTA) injection lack standardization. We aimed to determine if an alkalinized lidocaine solution is more effective than lidocaine only. METHODS: Patients of both genders aged 18 or above enlisted for intradetrusor BoNTA injection (idiopathic, neurogenic, and bladder pain syndrome) were included in a double-blinded randomized controlled trial after obtaining their informed consent. All participants filled a bladder diary and a urine culture was performed. Subjects were randomized 1:1 to Protocol A (20 ml 2% lidocaine + 10 ml 8.4% sodium bicarbonate) or Protocol B (20 ml 2% lidocaine + 10 ml 0.9% saline solution). A Numeric Rating Scale (0-10) was used to assess the level of pain immediately after the procedure (primary endpoint). Secondary endpoints included pain after 1 h, urinary tract infection, acute urinary retention, and hematuria related to the procedure. RESULTS: A total of 116 patients were randomized. Baseline characteristics (age, sex, indication, and bladder diary parameters) of patients in Group A and B were similar. Pain scores at the end of the procedure were significantly lower with the alkalinized solution (Protocol A and B, respectively, 2.37 ± 0.31 vs. 4.44 ± 0.36, p < .01). No differences were observed 1 h after treatment (Protocol A and B, respectively, 0.54 ± 0.17 vs. 0.69 ± 0.19, p = .487). The only adverse event reported was mild-to-moderate self-limited hematuria in 15.4% of patients. CONCLUSIONS: The use of an alkalinized lidocaine solution has proven to be significantly superior to lidocaine only as local anesthesia before intradetrusor BoNTA injection, suggesting that this may be considered a first-line option.

Low energy shock wave-delivered intravesical botulinum neurotoxin-A potentiates antioxidant genes and inhibits proinflammatory cytokines in rat model of overactive bladder.

PURPOSE: To study the effect of intravesical instillation of botulinum neurotoxin-A (BoNT-A) combined with low energy shock wave (LESW) for treatment of overactive bladder (OAB) in a rat model and to investigate its effect on the associated inflammatory and oxidative stress process. MATERIAL AND METHODS: Forty rats were subdivided into four equal groups: normal control group, OAB group, LESW group, and BoNT-A plus LESW group. Cystometrogram (CMG) changes and histopathological changes in the bladder mucosa were assessed in the different groups. Oxidative stress markers (malondialdehyde [MDA] and superoxide dismutase [SOD]) and proinflammatory cytokines (tumor necrotic factor-α [TNF-α] and interleukin-6 [IL-6]) were compared among groups. RESULTS: BoNT-A plus LESW group showed statistically significant lower amplitude (p = .001) and lower frequency of detrusor contractions (p = .01) compared to LESW, which showed no statistically significant difference in comparison to the OAB group. Also, the combined group significantly reduced submucosal edema and inflammatory cell infiltrate scores compared to all groups (p < .05). LESW was associated with 42% reduction of MDA expression while, LESW plus BoNT-A decreased it by 68% (p < .001). Also, LESW and LESW plus BoNT-A increased SOD expression by 43% and 75%, respectively (p < .001). LESW plus BoNT-A was associated with statistically significant lower expression of TNF-α and IL-6 expression by 37% and 66% in comparison to LESW group (p = .001). CONCLUSION: Intravesical instillation of BoNT-A plus LESW is an effective method for increasing the urothelial permeability to BoNT-A and enhancing its therapeutic effect against OAB in rat model through the expression of a substantial anti-inflammatory and antioxidative stress effect.

Endoscopic treatment of symptomatic VUR disease after the renal transplantation: analysis of 49 cases.

BACKGROUND: To evaluate the outcome of endoscopic treatment for symptomatic vesicoureteral reflux (VUR) disease in renal transplantation patients and to determine the factors that were associated with the success rate of the treatment. METHODS: A total of 121 symptomatic VUR diseases diagnosed between 2014 and 2018 in 3560 renal transplant patients. The results of 49 VUR cases that presented with febrile urinary tract infection (UTI) and were hospitalized for antibiotic treatment were included in the study. Reflux was detected by voiding cystourethrogram and treatment was performed by endoscopic Deflux® injection. The result of endoscopic treatment was evaluated clinically by 3 months periods. RESULTS: The mean time between transplantation and endoscopic treatment was 59.6 (5-132) months, and the mean follow-up period after the endoscopic treatment was 14 (6-48) months, respectively. The success rate after the first injection was 59.1% (n = 29) and 67.3% (n = 33) after the second injection. One patient developed anuria, one patient febrile UTI and four patients developed minimal macroscopic hematuria after the procedure. CONCLUSIONS: Endoscopic treatment of symptomatic VUR in transplanted kidney is a safe and feasible procedure. The amount of bulking agent or duration between the transplantation and diagnosis of VUR does not have any impact on the success of the treatment. However, the younger age of the patients and the female gender seem to have a positive effect on the outcome of the procedure.

In vivo effects of Rauvolfia vomitoria (Apocynaceae) ethanolic extract on sexual performance and reproductive activity in male rats.

Plants and plant-derived products have a long history in the treatment of sexual disorders. Rauvolfia vomitoria is one of such plant used traditionally for the enhancement of male sexual and reproductive activity. This study was carried out to elucidate the potential activity of R. vomitoria ethanolic extract on sexual behaviour and male reproductive function. Twenty-five male rats were assigned to five groups and orally treated with distilled water (control), sildenafil citrate (standard) and R. vomitoria ethanolic extract (50, 100 and 200 mg/kg BW) for 22 days. Sexual behaviour parameters such as mount latency (ML), intromission latency (IL), ejaculation latency (EL), mount frequency (MF), intromission frequency (IF), ejaculation frequency (IF) and post-ejaculatory interval (PEI) were recorded at day 0, 1, 8, 15 and 22. The reproductive function including reproductive organ weights, testicular histology and sperm parameters was also assessed. Results showed enhancement in sexual behaviour through significant reduction (p < .01) in ML, IL and PEI and significant increase (p < .01) in EL, MF IF and EF. The extract also caused an increase in sperm count, motility and transit. Present findings demonstrate the ability of R. vomitoria ethanolic extract to improve male sexual behaviour and reproductive activity in rats.

Outcome of Botulinum Toxin-A intraprostatic injection for benign prostatic hyperplasia induced lower urinary tract symptoms: A prospective multicenter study.

INTRODUCTION: Our aim was to determine the factors predicting the outcome of intraprostatic injection of Botulinum Toxin-A (BTX-A) in the treatment of benign prostatic hyperplasia (BPH)-induced lower urinary tract symptoms (LUTS) and to evaluate its efficacy and safety. METHODS: Between September 2016 and May 2018, 45 Egyptian patients, with BPH-induced LUTS were included; the indication was a failure of medical treatment, unfit, or refusing surgical intervention. Measurements of prostate size by TRUS, total PSA level before and 12 weeks after injection. IPSS, uroflow, and postvoiding residual urine (PVR) were measured before injection, 2, 4, 8 and 12 weeks postinjection. 100 U BTX-A vial was diluted with 10 mL of saline then injected into the transition zone at base and midzone of the prostate by TRUS. RESULTS: The mean patients' age was 64.4 ± 6.6 years. Mean baseline IPSS 24.06 decreased to 18.75 at 2 weeks and progressively decreased to 16.37 at 12 weeks (P < 0.001), Q max of 9.08 mL/s. increased to 10.44 at 2 weeks and 11.44 at 12 weeks (P < 0.001), mean prostate volume was 67.44cc; decreased to 66.06cc (P < 0.001) at 12 weeks and mean residual urine was 82.62 mL and decreased to 57.66 mL at 12 weeks. DISCUSSION: Intraprostatic injection of BTX-A as modality treatment of LUTS/BPH significantly improve IPSS, Q max , PVR, and decrease prostate volume. We can suspect better results with this line of treatment in patients with IPSS ≤ 22 and Q max ≤ 10 mL/min and prostate volume ≤ 56.5cc.

Do Patients Discontinue Overactive Bladder Medications after Sacral Neuromodulation?

PURPOSE: Overactive bladder medications often have poor tolerability or lack of efficacy with many patients progressing to third line therapy such as sacral neuromodulation. Those treated with sacral neuromodulation may avoid the potential side effects of overactive bladder medications while achieving symptom improvement. We evaluated the postoperative rate of discontinuing overactive bladder medications in patients who underwent sacral neuromodulation of refractory overactive bladder. MATERIALS AND METHODS: We queried a prospectively collected, institutional review board approved database for patients who underwent sacral neuromodulation. Patients were excluded from analysis if the surgical indication was urinary retention or a sacral neuromodulation device was removed 1 year or less postoperatively. We assessed clinical characteristics, urodynamic parameters and filled overactive bladder medications using an external prescription database. Patient perceived postoperative outcomes were examined. Groups were compared by the Student t-test and the chi-square test. RESULTS: Of the 78 patients who met inclusion criteria 82.1% stopped and never restarted overactive bladder medications (the sacral neuromodulation only group). Of the patients 14.1% consecutively continued filling overactive bladder medications 1 year or more following surgery (the concurrent group). There was no difference between the groups in body mass index, gender, sacral neuromodulation revision, urodynamic parameters, the PGI-I (Patient Global Impression of Improvement) or patient perceived percent improvement. However, concurrent patients were significantly older than those who received sacral neuromodulation only (p = 0.002). CONCLUSIONS: More than 80% of patients who progressed to sacral neuromodulation discontinued overactive bladder medications and received sacral neuromodulation as the sole treatment. A small portion of patients concurrently used overactive bladder medications following sacral neuromodulation for 1 year or more. However, outcomes were similar in the 2 groups. Sacral neuromodulation is a strategy to provide a successful outcome in refractory cases and yet avoid the potentially detrimental side effects related to overactive bladder medications.

New concepts in regenerative medicine approaches to the treatment of female stress urinary incontinence.

PURPOSE OF REVIEW: Update on recent regenerative medicine approaches to the treatment of stress urinary incontinence (SUI) caused by intrinsic sphincter deficiency (ISD). RECENT FINDINGS: In the treatment of female SUI/ISD, results using different types of cellular therapy have been disappointing, and new approaches are desirable. To advance our regenerative medicine approaches to SUI/ISD, it is critical to utilize animal models that best parallel the pathophysiology of this disease in women. Many current animal models mimic acute SUI/ISD. However, SUI/ISD in women is usually a chronic condition resulting from previous muscle and nerve sphincter damage during parturition or muscle loss during aging. Similar to women, a nonhuman primate (NHP) model of chronic SUI/ISD has demonstrated only modest response to cell therapy. However, treatment with stromal cell-derived factor 1 (SDF1), also known as C-X-C motif chemokine 12 (CXCL12) restored continence in this model. SUMMARY: As a potential therapeutic approach, the use of a well characterized chemokine, such as CXCL12, may by-pass the lengthy and expensive process of cell isolation, expansion, and injection. Recent findings in this new NHP model of chronic SUI/ISD may open up the field for noncell-based treatments.

Mirabegron as a treatment for overactive bladder symptoms in men (MIRACLE study): Efficacy and safety results from a multicenter, randomized, double-blind, placebo-controlled, parallel comparison phase IV study.

AIMS: To evaluate the efficacy and safety of mirabegron in males with overactive bladder (OAB) symptoms. METHODS: In total, 464 males with OAB symptoms were enrolled from 14 institutes and were sorted into either the mirabegron 50 mg (n = 310) or placebo (n = 154) groups. The change in (i) the mean number of 24-h micturition episodes; (ii) OAB Symptom Scale (OABSS); and (iii) International Prostate Symptom Score (IPSS) from baseline to 12 weeks of treatment were compared between the two groups. Safety assessments included treatment-emergent adverse events, blood pressure, pulse rate, postvoid residual volume, and maximum urinary flow rate. After 12 weeks, the study was extended for 14 additional weeks by administering mirabegron 50 mg to both groups. RESULTS: The reduction in the mean number of 24-h micturition episodes from baseline to 12 weeks of treatment was similar between the two groups. However, significantly greater changes from baseline to 12 weeks were observed in total OABSS, OABSS urgency incontinence score (Q4), IPSS storage subscore (Q2 + Q4 + Q7), and IPSS urgency score (Q4) in the mirabegron group (P = 0.01 for all). According to the extended study, the changes of all efficacy variables from baseline to 26 weeks were similar between both groups. The safety assessment results were also similar between the two groups at 12 and 26 weeks. CONCLUSION: A daily 50 mg dose of mirabegron for 12 weeks reduced OAB symptoms in men, and no significant adverse events compared to the placebo group were noted.

A prospective randomized clinical trial comparing two doses of AbobotulinumtoxinA for idiopathic overactive bladder.

AIMS: To compare 300 U versus 500 U of abobotulinumtoxinA (ABO) intravesical injections for the treatment of idiopathic overactive bladder (OAB) refractory to first and second-line treatments. METHODS: A prospective, randomized, single blind study was performed in female patients with symptoms of OAB, who had failed conservative treatment. Patients were treated with 300 or 500 U of ABO injected into 30 sites, avoiding the trigone. All treatments were evaluated by voiding diary, ICIQ-OAB questionnaire, urodynamic test, visual analogue scale (VAS) for treatment satisfaction and patient global impression of improvement (PGI-I). The primary outcome was change in maximum cistometric capacity (MCC). Secondary outcome included changes in urgency, complete continence, subjective success (VAS and PGI-I), and adverse events (urinary retention, UTI, and CIC). RESULTS: Twenty-one patients were included. MCC has increased from 185.0 to 270.9 mL (300 U) and from 240.8 to 311.7 mL (500 U), comparing the baseline with 12 weeks, without statistical difference between the groups (P = 0.270). At 12 weeks, 91% of patients were dry in both groups. At 24 weeks, episodes of incontinence had returned in 50% (300 U) and 0% (500 U) (P = 0.013). Patients were better or much better (PGI-I) in70% (300 U) and 88.9% (500 U) at 12 w; and 50% (300 U) and 100% (500 U), at 24 w (P = 0.027). The peak of PVR was at 4 w, being 71.7 mL (300 U) and 96.5 mL (500 U). General UTI incidence was 35.7%. One patient (500 U) required CIC for 2 weeks. CONCLUSIONS: Intravesical ABO injection at 500 U improves symptoms and quality of life for longer period of time than 300 U for idiopathic OAB.

Adjustment of Conditions for Combining Oxybutynin Transdermal Patch with Heparinoid Cream in Mice by Analyzing Blood Concentrations of Oxybutynin Hydrochloride.

The combination of skin external preparation and transdermal patch is influenced by drug absorption through the skin. We investigated the effect of heparinoid cream on the transdermal absorption of oxybutynin hydrochloride using an oxybutynin transdermal patch and determined the combined effect of these medications. Normal skin and dry dorsal skin in hairless mice were treated with heparinoid cream, followed by the application of the oxybutynin transdermal patch. A blood sample was collected from the mouse tail vein and the blood concentration of oxybutynin hydrochloride was analyzed by LC-MS/MS. Transepidermal water loss, the hydration level of the stratum corneum, and the stratum corneum thickness in the dorsal skin were measured. The blood concentration and area under the curve (AUC)0→24 of oxybutynin hydrochloride increased when the 4.0-cm2 oxybutynin transdermal patch was applied 1 h after the application of the moisturizer, compared to the values without moisturizer. Normal skin and dry skin did not affect this result. As the hydration level of the stratum corneum and stratum corneum thickness increased before patch application by pre-treatment with moisturizer, it was suggested that transdermal absorption of oxybutynin hydrochloride was increased by skin hydration. The increased blood concentration of oxybutynin hydrochloride was regulated by changing the effective area of the patch and applying additional moisturizer at intervals. The pharmacokinetics of oxybutynin hydrochloride under the regulation of combination treatment was similar to that of treatment without moisturizer. These findings indicate that the application conditions of the oxybutynin transdermal patch and heparinoid cream influence the proper use of the patch.

Do patient characteristics predict which patients with overactive bladder benefit from a higher fesoterodine dose?

INTRODUCTION AND HYPOTHESIS: We sought to determine whether baseline characteristics predict which overactive bladder (OAB) patients benefit from fesoterodine 8 mg versus 4 mg. METHODS: In double-blind, placebo-controlled, flexible-dose trials, baseline characteristics of OAB patients with ≥ 1 urgency urinary incontinence (UUI) episodes/24 h who escalated from fesoterodine 4 mg to 8 mg were evaluated. Possible dose-escalation predictors (age; sex; previous antimuscarinic use; UUI, micturitions, and urgency episodes/24 h; race; body mass index; time to dose escalation; OAB duration) were compared in escalators versus non-escalators. Patients from fixed-dose trials with dose-escalator characteristics were identified (matched dose-escalator sample) to assess changes from baseline with fesoterodine 4 mg, 8 mg, and placebo. RESULTS: In flexible-dose trials, significant predictors of fesoterodine dose escalation were younger age (≤ 65.8 years), greater number of baseline micturitions (≥ 13.1) and urgency episodes/24 h (≥ 10.9), greater OAB duration (≥ 9.1 years), and more frequent previous antimuscarinic use (58.3%), but not baseline UUI episodes/24 h. In the matched dose-escalator sample (fesoterodine 4 mg: n = 215; 8 mg: n = 198; placebo: n = 217), change from baseline in UUI episodes significantly improved with fesoterodine 8 mg versus 4 mg (P = 0.043) and with both doses versus placebo (P < 0.001). Dry mouth and constipation rates were higher with fesoterodine 8 mg. CONCLUSIONS: Dose-escalator patients had a significantly greater UUI response with fesoterodine 8 mg versus 4 mg. Given the potential for adverse events, fesoterodine 4 mg is recommended to start; however, patients with UUI and identified predictors may benefit from initial treatment with fesoterodine 8 mg or rapid dose escalation.

Real-Life Data on Mirabegron in Neurogenic Bladder Dysfunction.

AIMS: To determine factors for treatment persistence in a real-life cohort of adult neurogenic lower urinary tract dysfunction. METHODS: We reviewed records of patients with neurogenic lower urinary tract dysfunction and mirabegron prescriptions. Exclusion criteria were indwelling urethral or suprapubic catheters and implanted neurostimulators. We extracted demographic data, indication for prescription, concomitant use of other agents with possible anticholinergic effect, beta blockers, duration of treatment and reason of discontinuation. RESULTS: We included 110 subjects in this study. Neurologic diagnoses included multiple sclerosis, Parkinson's disease, and other diagnoses (dementia, paraplegia, and tetraplegia). Previous usage of antimuscarinics was found in 78 patients (71%). Mirabegron was combined with antimuscarinics in 15 patients (14%). Drugs with any anticholinergic activity were taken by 94 subjects (86%). Mirabegron was taken for a median of 497 days and 60 patients discontinued the medication within the study period. Main reasons of discontinuation were lack of effect (44/110), side effects (10/110), and non-reimbursement (6/110). There were no differences in mirabegron discontinuation by neurological disease, beta blocker usage, or anticholinergic burden. CONCLUSIONS: Mirabegron is continued in more than half of patients with neurogenic lower urinary tract dysfunction for more than 6 months. Further research is needed to identify eventual predictive factors.

Is there a role for bilateral peak systolic velocity readings in a penile duplex ultrasound?

The penile duplex ultrasound (PDU) has been used as a diagnostic tool in erectile dysfunction (ED) management. It is currently recommended that peak systolic velocity (PSV) and end-diastolic flow (EDF) should be recorded on both the right and left cavernosal arteries. However, the clinical utility of bilateral recordings is unknown. Our primary objective is to assess the clinical utility of bilateral recordings in ED treatment with sildenafil. A total of 77 patients were included. All patients had a standardised PDU and also completed the IIEF-5 and started on-demand treatment with sildenafil at 100 mg at baseline. The IIEF-5 and EDITS were completed at the 6-month follow-up. The Spearman test was used to assess correlation. Receiver operating characteristic (ROC) curves were drawn, and the area under the curve (AUC) was calculated. Improvement, cure and satisfaction were high (77.9%, 64.9% and 67.5%, respectively), and the median IIEF-5 and EDITS were 25(22; 25) and 81.81(63.63; 88.63) respectively. The lowest PSV had the highest positive correlation with IIEF-5 and EDITS (p = 0.436 and 0.379, respectively), and it could predict improvement, cure and satisfaction with a fair-to-good accuracy (AUC = 0.837, 0.750 and 0.749 respectively). The present study shows bilateral penile blood-flow assessment is important, and attention should be focused on the lowest bilateral PSV.