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.

Can you name that tablet? A cross-sectional study on recognition of common urology medications.

INTRODUCTION: Clinicians frequently rely on patients to accurately tell them what prescription medications and doses they are taking in outpatient visits. This information is essential to monitor the efficacy of a medication and to determine any adverse interactions. This study aimed to assess urologist and urology trainee's visual recognition of common urology medications. METHODS: An online survey was distributed to urologists and urology trainees in Ireland. Images of 11 commonly prescribed urological medications were presented with free text options for answering. Information was gathered on respondent's role and experience. Data was analysed using STATA version 17. RESULTS: The survey had a 90% response rate from 50 distributions. Respondents' roles were consultant (31.1%), specialist registrar (33.3%), registrar (22.2%), senior house officer (11.1%) and intern (2.2%). Forty six percent had more than six years urology experience. Average rate of correct responses was 39.4% ± 23.9. The most accurate group were consultants (46.1% ± 22.1), followed by specialist registrars (41.2% ± 24.9), registrars (39.1% ± 26.8), senior house officers (21.8% ± 10.4) and interns (9.1% ± 0). The most and least recognised medications were sildenafil (Viagra©) (84.4%) and fesoterodine (Toviaz©) (11.1%), respectively. Just 28.9% of respondents had previously handled any of the medications listed. CONCLUSION: Patients often do not reliably know their own medications other than to describe them or show an unpackaged tablet. Prescribing safety is paramount to ensuring patient safety and reducing the risk of adverse drug reactions. This study shows that even experienced clinicians do not recognise the medications they regularly prescribe, and decisions should not be made without accurate medication reconciliation.

Ressecção anterior do reto vs prostatectomia radical. Existem diferenças na reabilitação sexual? / Anterior resection of the rectum vs radical prostatectomy. Are there any differences in sexual rehabilitation?

RESUMO Objetivo: O objetivo deste estudo foi avaliar o impacto da reabilitação peniana na recuperação da função erétil em pacientes submetidos a ressecção anterior do reto (RAR) ou a prostatectomia radical (PR), comparando os resultados entre esses dois grupos. Materiais e Métodos: Foi realizado estudo de coorte retrospetivo unicêntrico, em pacientes avaliados na nossa consulta multidisciplinar de oncosexologia, entre janeiro de 2015 e janeiro de 2018, submetidos a PR ou RAR (homens) com disfunção sexual. Avaliamos as características oncológicas dos pacientes, idade, estado civil, tipo de disfunção sexual, Índice Internacional de Função Erétil (IIEF-5) na primeira e última consulta e terapêutica utilizada. Foi realizada análise estatística. Resultados: Foram incluídos 55 pacientes, 60% (33) realizaram RAR e 40% (22) PR. Em relação à disfunção sexual após a cirurgia, a disfunção erétil (DE) foi encontrada na maioria dos pacientes (> 95%). Na pontuação inicial do IIEF-5, os pacientes com RAR e PR apresentaram, com maior frequência, DE moderada ou grave (escore 5-11), em 78,8% e 59,1% dos casos, respetivamente. Ao reavaliar a pontuação do IIEF-5 de cada paciente durante o acompanhamento, verificou-se melhoria em 69,7% dos pacientes com RAR e 72,7% dos pacientes com PR (p = 0,81). Quanto à abordagem terapêutica, 84,8% dos pacientes com RAR foram medicados com inibidores da fosfodiesterase-5 (PDE5I) exclusivamente e 3% com injeção de Alprostadil. Os pacientes com PR foram medicados com PDE5I em 63,6% e com injeção de Alprostadil em 31,8% (p <0,05). Conclusões: Apesar das diferenças técnicas destas cirurgias, do ponto de vista sexual, os pacientes se beneficiaram com a reabilitação peniana.

ABSTRACT Purpose: The aim of this study was to evaluate the impact of penile rehabilitation in restoring erectile function in patients submitted to anterior resection of the rectum (ARR) or radical prostatectomy (RP), comparing the results between these two groups. Materials and Methods: We performed a unicenter retrospective cohort study, on patients evaluated in our multidisciplinary oncosexology consultation, between January 2015 and January 2018, submitted to RP or ARR (males) and presenting sexual dysfunction. We evaluate the patient and oncologic characteristics, the type of sexual dysfunction, marital status, assessed the International Index of Erectile Function (IIEF-5) on the first and last consultation and the therapeutic approach. A statistical analysis was performed. Results: A total of 55 patients were included, 60% (33) performed ARR and 40% (22) RP. Regarding the sexual dysfunction after surgery, erectile dysfunction (ED) was found in the majority of patients (>95%). On the initial IIEF-5 scoring, ARR and RP patients had, most frequently, severe or moderate ED (score 5-11), 78.8% and 59.1% respectively. When reassessed the IIEF-5 scoring of each patient during follow-up, there was an improvement in 69.7% of ARR patients and 72.7% of RP patients (p=0.81). Regarding the therapeutic approach, 84.8% of ARR patients used phosphodiesterase-5 inhibitors (PDE5I) exclusively, 3% used Alprostadil injection, while RP patients used 63.6% and 31.8%, respectively (p<0.05). Conclusions: Despite the technical differences of these surgeries, from the sexual point of view these patients benefit with a penile rehabilitation.

Effect of co-administration of BRL-37344 and tadalafil on reduction of overactive bladder symptoms after induction of detrusor overactivity in mice

Abstract Purpose: To evaluate the impact of the combination of BRL 37344 and tadalafil (TDF) on the reduction of overactive bladder (OB) symptoms. Methods: Thirty mice were randomized into 5 groups (G) of 6 animals each. L-NAME was used to induce DO. G1: Control; G2: L-NAME; G3: L-NAME + TDF; G4: L-NAME + BRL 37344; G5: L-NAME + TDF + BRL 37344. After 30 days of treatment, the animals were submitted to cystometry to evaluate non-voiding contractions (NVC), threshold pressure (TP), baseline pressure (BP), frequency of micturition (FM) and threshold volume (TV). Differences between the groups were analyzed with ANOVA followed by the Tukey test. Results: NVC increased in G2 (4.33±2.58) in relation to G1 (1.50±0.55). NVC decreased in G3 (2.00±1.10), G4 (1.50±1.52) and G5 (2.00±1.26) compared to G2 (p<0.05). FM decreased in G3 (0.97±0.71), G4 (0.92±0.38) and G5 (1.05±0.44) compared to G2 (p<0.05). However, the combination of TDF and BRL37344 was not more effective at increasing NVC and improving FM than either drug alone. The five groups did not differ significantly with regard to TV. Conclusion: The combination of BRL 37344 and TDF produced no measurable additive effect on reduction of OB symptoms.

Pelvic floor muscle training alone or in combination with oxybutynin in treatment of nonmonosymptomatic enuresis. A randomized controlled trial with 2-year follow up / Exercícios dos músculos do assoalho pélvico exclusivos ou em combinação com oxibutinina no tratamento da enurese não monossintomática. Um estudo randomizado controlado com 2 anos de seguimento

Abstract Objective To compare the results of the standard urotherapy alone and associated with pelvic floor muscle training alone, and in combination with oxybutynin in treatment of nonmonosymptomatic nocturnal enuresis. Methods A total of 38 children aged 5 to 10 years were randomized into three groups: Group I (n=12) that was submitted to standard urotherapy; Group II (n=15), standard urotherapy associated with pelvic floor muscle training; and Group III (n=11), standard urotherapy associated with pelvic floor muscle training and oxybutynin; the treatment lasted 12 weeks. The assessment tools used were playful bladder diary, and a 48-hour bladder diary, before and after treatment. After 2 years, patients were assessed by telephone using a standardized questionnaire. Results The data of children from the three groups were homogeneous at baseline. After 12-week treatment, all children showed improved symptoms and signs of nonmonosymptomatic nocturnal enuresis, but the differences were not significant among the groups. After 2 years, the three groups showed maintenance of treatment results, but no differences among them. Conclusion All treatment modalities were effective regarding improved enuresis and lower urinary tract symptoms, but the sample was not large enough to show differences among groups.

Resumo Objetivo Comparar os resultados da uroterapia padrão isolada e associada ao treinamento dos músculos do assoalho pélvico isoladamente e em combinação com a oxibutinina no tratamento da enurese noturna não monossintomática. Métodos Trinta e oito crianças entre 5 e 10 anos de idade foram randomizadas em três grupos: Grupo I (n=12) realizou uroterapia padrão; Grupo II (n=15) realizou uroterapia padrão associada ao treinamento muscular do assoalho pélvico; e Grupo III (n=11) realizou uroterapia padrão associada ao treinamento muscular do assoalho pélvico e oxibutinina. O tratamento teve duração de 12 semanas. Os instrumentos de avaliação foram diário miccional lúdico e diário miccional de 48 horas, antes e depois do tratamento. Após 2 anos, os pacientes foram avaliados por telefone, usando um questionário padronizado. Resultados Os dados das crianças dos três grupos eram homogêneos no início do estudo. Após 12 semanas de tratamento, todas as crianças apresentaram melhora em relação aos sinais e sintomas de enurese noturna não monossintomática, mas as diferenças não foram significativas entre os grupos. Depois de 2 anos, os resultados do tratamento se mantiveram nos três grupos, mas não houve diferenças entre os grupos. Conclusão As três modalidades de tratamento foram eficazes na melhora da enurese e dos sintomas do trato urinário inferior, mas o tamanho da amostra não foi grande o suficiente para mostrar diferenças entre os grupos.

Effectiveness and durability of solifenacin versus percutaneous tibial nerve stimulation versus their combination for the treatment of women with overactive bladder syndrome: a randomized controlled study with a follow-up of ten months

ABSTRACT Purpose To assess effectiveness and durability of Solifenacin (SS) versus tibial nerve stimulation (PTNS) versus combination therapy (PTNS + SS) in women with overactive bladder syndrome (OAB). Materials and Methods 105 women with OAB were divided randomly into three groups of 35 patients each. In group A women received SS, in group B women underwent PTNS, in group C women underwent combination of PTNS + SS. Improvements in OAB symptoms were assessed with OABSS questionnaire; patients' quality of life was assessed with OAB-q SF questionnaire. Evaluation of effectiveness of treatments was performed with PGI-I questionnaire. OABSS and PGI-I were also assessed monthly for ten months. Results All treatments were effective on symptoms. PTNS showed a greater effectiveness than SS, but PTNS + SS was more effective than SS and PTNS. Furthermore, PTNS + SS showed a greater duration of effectiveness than PTNS and SS. Conclusions Combination of PTNS with SS showed more effectiveness and more durability than PTNS and SS alone.

The effect of extended release tolterodine used for overactive bladder treatment on female sexual function

ABSTRACT Introduction Overactive bladder (OAB) is a common condition, especially in middle aged women, requiring long term therapy with anticholinergics to maintain symptoms relief. The aim of the study was to determine the effect of tolterodine extended release (ER) used for OAB treatment on the sexual function of women. Materials and Methods Between August 2010 and August 2014, 220 women with confirmed OAB, attended Urogynecology Outpatient Clinic and were prospectively enrolled in this study. 158 women were evaluated, with a comprehensive history, physical examination, urodynamic studies and Female Sexual Function Index (FSFI) questionnaire. 73 patients of group A (control group) received no treatment and 85 patients of group B received an anticholinergic regimen - tolterodine ER 4mg once daily. Data were evaluated again in accordance with FSFI after three months, using SPSS software. Results A statistically significant increase was noted in group B in domains of desire (pre-treatment 2.5±0.2 to 4.5±0.2 post-treatment), arousal (3.1±0.2 to 3.1±0.2 respectively), lubrication (3.4±0.3 to 4.3±0.3 respectively), orgasm (3.5±0.3 to 4.5±0.3 respectively), satisfaction (2.6±0.2 to 4.2±0.3 respectively) and pain (2.4±0.2 to 4.6±0.4 respectively) after three months treatment with tolterodine ER. In group A there were no statistically significant changes in pre and post treatment values (p>0.05). Total FSFI score for group B was significantly higher after tolterodine treatment (26.5±1.5) compared to pre-treatment values (17.4±1.4, p<0.01) and to control group A (17.7±1.2 and 17.9±1.5, p>0,05) respectively. Conclusions This preliminary study demonstrates that treatment of OAB with tolterodine ER was found to have positive effect on sexual function of patients with OAB.

A prospective randomized controlled multicentre trial comparing intravesical DMSO and chondroïtin sulphate 2% for painful bladder syndrome/interstitial cystitis

ABSTRACT Objective To compare effectiveness of intravesical chondroïtin sulphate (CS) 2% and dimethyl sulphoxide (DMSO) 50% in patients with painful bladder syndrome/interstitial cystitis (PBS/IC). Materials and methods Patients were randomized to receive either 6 weekly instillations of CS 2% or 50% DMSO. Primary endpoint was difference in proportion of patients achieving score 6 (moderately improved) or 7 (markedly improved) in both groups using the Global Response Assessment (GRA) scale. Secondary parameters were mean 24-hours frequency and nocturia on a 3-day micturition dairy, changes from baseline in O’Leary-Sant questionnaire score and visual analog scale (VAS) for suprapubic pain. Results Thirty-six patients were the intention to treat population (22 in CS and 14 in DMSO group). In DMSO group, 57% withdrew consent and only 6 concluded the trial. Major reasons were pain during and after instillation, intolerable garlic odor and lack of efficacy. In CS group, 27% withdrew consent. Compared with DMSO group, more patients in CS group (72.7% vs. 14%) reported moderate or marked improvement (P=0.002, 95% CI 0.05-0.72) and achieved a reduction in VAS scores (20% vs. 8.3%). CS group performed significantly better in pain reduction (-1.2 vs. -0.6) and nocturia (-2.4 vs. -0.7) and better in total O’Leary reduction (-9.8 vs. -7.2). CS was better tolerated. The trial was stopped due to high number of drop-outs with DMSO. Conclusions Intravesical CS 2% is viable treatment for PBS/IC with minimal side effects. DMSO should be used with caution and with active monitoring of side effects. More randomized controlled studies on intravesical treatments are needed.

Efficacy of Tamsulosin, Oxybutynin, and their combination in the control of double-j stent-related lower urinary tract symptoms

ABSTRACT Introduction and objective Indwelling double J ureteral stents are used routinely in the resolution of ureteral obstruction caused by different etiologies. Evaluation of urinary symptoms related to double-J stent, indicate that these affect 73-90% of patients. We conducted a prospective, randomized study, to evaluate the efficacy of tamsulosin, oxybutinin and combination therapy in improving the urinary symptoms. Methods Patients who underwent ureteral stent placement after ureterolithotripsy (total 51), were randomized into three groups: Group I: Tamsulosin 0.4 mg. once per day(17 patients), Group II: Oxybutinin 5 mg. once per day (17 patients), Group III: Tamsulosin+ oxybutynin once per day (17 patients). All the groups received the drugs for three weeks and completed a Spanish validated Ureteral Stent Symptom Questionnaire (USSQ) at day 7 and 21. Results Repeated measures ANOVA showed mean urinary symptom index score was 22.3 vs. 15.5 in group three (p<0.001) at day 7 and 21 respectively. The mean work performance index was 6.6 vs 8.1 (p=0.049) favoring tamsulosin group, the mean sexual score was 0.5 vs 1.5 (p=0.03). Among additional problems the mean was 7.2 vs 6.2 (p=0.03). No significant difference was noted among pain and general health index. No side effects were reported. Conclusions Combination therapy with tamsulosin and oxybutynin improved irritative symptoms and work performance as well as sexual matters. Combination therapy should be considered for patients who complained of stent related symptoms.

Effects of chronic administration of tamsulosin and tadalafil, alone or in combination, in rats with bladder outlet obstruction induced by chronic nitric oxide deficiency

Purpose The aim of this study was to define if tadalafil causes detrusor muscle impairment and to observe the effect of combination of tadalafil with tamsulosin on the lower urinary tract of rats with bladder outlet obstruction (BOO) induced by chronic nitric oxide deficiency. Materials and Methods Thirty-one male rats were randomized to following groups: 1 - control; 2 - L-Nitroarginine methyl ester (L-NAME); 3 - Tamsulosin + L-NAME, 4 Tadalafil+L-NAME; and 5 - Tamsulosin + Tadalafil + L-NAME. At the end of the treatment period (30 days), all animals were submitted to urodynamic study. Results The administration of L-NAME increased the number of non-voiding contractions (NVC) (1.04 ± 0.22), volume threshold (VT) (1.86 ± 0.35), and micturition cycle (MC) (1.34 ± 0.11) compared with control (0.52 ± 0.06, 0.62 ± 0.06, and 0.67 ± 0.30), respectively. The administration of tamsulosin reduced the number of NVC (0.57 ± 0.42) and VT (0.76 ± 0.24 ) compared with L-NAME group. Co-treatment with tadalafil decreased the number of VT (0.85 ± 0.53) and MC (0.76 ± 0.22) compared with L-NAME group. The combination of tamsulosin with tadalafil improved the number of NVC (0.56 ± 0.18), VT (0.97 ± 0.52) and MC (0.68 ± 0.30) compared with L-NAME group. Conclusion In rats with BOO induced by chronic nitric oxide deficiency, tadalafil did not cause impairment in detrusor muscle and seems to have an addictive effect to tamsulosin because the combination decreased non voiding contractions as well the number of micturition cycles. .

Effects of Terazosin and Tolterodine on Ureteral Stent Related Symptoms: A Double-Blind Placebo-Controlled Randomized Clinical Trial

Objective To evaluate the effects of terazosin and tolterodine on ureteral stent discomfort. Materials and Methods Of 163 patients assessed for eligibility, 104 patients were randomly assigned to receive placebo, 2 mg of terazosin twice daily, 2 mg of tolterodine daily, or both terazosin plus tolterodine during the stenting period. Prior to stenting and at stent removal, the International Prostate Symptom Score (IPSS), the IPSS quality of life (QoL) subscore and the Visual Analog Scale for Pain were determined. The patients also reported their analgesic use during the stenting period. Results Ninety-four patients completed the study. We noted significant decreases in the total IPSS scores (p = 0.002), irritative subscore (p = 0.039), QoL (p = 0.001), flank pain (p = 0.013), voiding pain (p = 0.01) and amount of analgesics used (p = 0.02) in the groups. However, neither the obstructive subscore nor the suprapubic pain improved significantly (p = 0.251 and p = 0.522, respectively). The patients receiving terazosin plus tolterodine experienced significant reductions in the total IPSS, irritative symptoms, QoL, flank pain, voiding pain and decreased analgesics use compared with those patients receiving placebo. However, compared with placebo, terazosin monotherapy did not affect pain levels, and tolterodine monotherapy did not improve QoL, flank pain or analgesics use. Conclusions Terazosin plus tolterodine improves ureteral stent-related complications, including irritative symptoms, the amount of analgesics used, QoL, flank pain and voiding pain but does not decrease obstructive symptoms or suprapubic pain. This trial was registered at www.clinicaltrials.gov as NCT01530243. .

Synergistic effect of iontophoresis and chemical enhancers on transdermal permeation of tolterodine tartrate for the treatment of overactive bladder

Purpose The objective of the study was to evaluate the synergistic transdermal permeation effect of chemical enhancers and iontophoresis technique on tolterodine tartrate (TT) transdermal gel and to evaluate its pharmacokinetic properties. Materials and Methods Taguchi robust design was used for optimization of formulations. Skin permeation rates were evaluated using the Keshary-chein type diffusion cells in order to optimize the gel formulation. In-vivo studies of the optimized formulation were performed in a rabbit model and histopathology studies of optimized formulation were performed on rats. Results Transdermal gels were formulated successfully using Taguchi robust design method. The type of penetration enhancer, concentration of penetration enhancer, current density and pulse on/off ratio were chosen as independent variables. Type of penetration enhancer was found to be the significant factor for all the responses. Permeation parameters were evaluated when maximum cumulative amount permeated in 24 hours (Q24) was 145.71 ± 2.00µg/cm2 by CIT4 formulation over control (91.89 ± 2.30µg/cm2). Permeation was enhanced by 1.75 fold by CIT4 formulation. Formulation CIT4 containing nerolidol (5%) and iontophoretic variables applied (0.5mA/cm2 and pulse on/off ratio 3:1) was optimized. In vivo studies with optimized formulation CIT4 showed increase in AUC and T1/2 when compared to oral suspension in rabbits. The histological studies showed changes in dermis indicating the effect of penetration enhancers and as iontophoresis was continued only for two cycles in periodic fashion so it did not cause any skin damage observed in the slides. Conclusion Results indicated that iontophoresis in combination with chemical enhancers is an effective method for transdermal administration of TT in the treatment of overactive bladder. .