Toward a Scientific Nutritional Supplement Combination for Prostatism and Erectile Dysfunction I: From Known Pharmacology to Clinical Testing.

Prostatism and erectile dysfunction (ED) are highly prevalent and closely comorbid. Prescription treatments are limitingly expensive but robust in mechanisms of action (MoA). Nutritional supplements (NS) are low-cost but inadequately supported by evidence. Do any NS use robust MoA? Could their efficacy be amplified via dosing, concentration of active principles, and/or use in combination? The goal is to develop an effective NS for prostatism and ED using the MoA of prescription treatments. Literature reviews were conducted on dietary supplements for prostatism or ED and MoA of relevant drugs. The most promising NS employing these MoA were chosen. A pilot study of a prototype combination was conducted. A protocol was created for an adequate dose-response trial to test the NS combination in men with ED and prostatism. The main measures were response rates, International Prostate Symptom Score, and International Index of Erectile Function. For drugs, the MoAs best proven for prostatism and ED were nitric oxide augmentation, mild androgen inhibition, and anti-inflammatory effects. The following NS best simulate these MoA and are best supported for efficacy; for prostatism: beta sitosterol; for ED: panax ginseng, arginine, and citrulline. Pilot clinical data provided support. A plan for a formal dose-response clinical trial was approved by a central institutional review board. NS using effective MoA might suffice for prostatism and ED. Pilot testing of a combination NS with the best-supported MoA supported further development. A dose-response trial should be conducted using adequate doses of L-citrulline, beta-sitosterol, ginseng, and vitamin D3.

Penile blood pressure is useful to identify candidates for tadalafil treatment in patients with lower urinary tract symptoms.

OBJECTIVES: To determine whether penile blood pressure (PBP) can be used to identify patients who can benefit from tadalafil treatment, the correlation between PBP at baseline and changes in lower urinary tract symptoms (LUTS) induced by tadalafil treatment was studied prospectively. PATIENTS AND METHODS: Patients with BPH who were poor responders to α1 -blockers and took tadalafil instead of an α1 -blocker were registered between 2014 and 2016. The patients were divided into two groups (low- and high-PBP groups) using the median baseline PBP of 110 mmHg as the threshold. The changes in the International Prostate Symptom Score (IPSS) between before and at 4 and 12 weeks after tadalafil treatment were compared between the low- and high-PBP groups. Multivariate analysis was performed to identify parameters associated with IPSS improvement with tadalafil treatment. RESULTS: In all, 51 patients were investigated. The IPSS in the low-PBP group decreased immediately after the start of treatment, and there was significant improvement in the IPSS from baseline at 4 and 12 weeks after the start of treatment, whilst the IPSS in the high-PBP group did not show significant changes. On multivariate analysis, PBP at baseline, anticholinergic drug use, and IPSS at baseline were significant predictors of a good IPSS response to tadalafil treatment. CONCLUSIONS: This study demonstrated that PBP could reliably identify patients with BPH who could benefit from tadalafil treatment. Patients with low PBP could be better responders to tadalafil.

Effect of tadalafil add-on therapy in patients with persistant storage symptoms refractory to α1 -adrenoceptor antagonist monotherapy for benign prostatic hyperplasia: A randomized pilot trial comparing tadalafil and solifenacin.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of tadalafil add-on therapy with α1 -adrenoceptor antagonists. METHODS: Patients with persistent storage symptoms refractory to α1 -adrenoceptor antagonists for benign prostatic hyperplasia were enrolled in the study. Patients were randomly assigned to either a 5 mg tadalafil or 5 mg solifenacin treatment group for 12 weeks. International Prostate Symptom Score, Overactive Bladder Symptom Score, urinary flow rates, residual urine volume, and blood pressure were measured prospectively before treatment and after 4 and 12 weeks of treatment. Changes from baseline were compared between groups. The rate of treatment discontinuation due to adverse effects was evaluated. RESULTS: Of the 75 patients recruited to the study, 38 and 37 were assigned to the tadalafil and solifenacin groups, respectively. There were no significant difference in baseline characteristics between the two groups. The change in the amount of residual urine volume was significantly larger in the solifenacin- than tadalafil-treated group; other parameters, including lower urinary tract symptoms and uroflowmetry measures, did not differ significantly between the two groups. Seven (18%) and 12 (32%) patients in the tadalafil and solifenacin groups, respectively, discontinued treatment because of adverse events. The main reasons for discontinuation in the tadalafil group were stomach discomfort or nausea and dizziness or vertigo; voiding difficulty and constipation were the main reasons for discontinuation in the solifenacin group. There was no significant difference in blood pressure fluctuations from baseline between the two groups. CONCLUSIONS: Tadalafil add-on therapy was not inferior to solifenacin add-on therapy in terms of effect and safety. Therefore, tadalafil could be an alternative add-on drug for patients with persistent lower urinary tract symptoms refractory to α1 -adrenoceptor antagonists.

Effects of Calcium Oxalate on Expression of Clusterin and Lower Urinary Tract Symptoms in Prostatitis and Benign Prostatic Hyperplasia Patients with Calculi.

BACKGROUND Prostatic calculi are common in urological treatments. Our major purpose in the present study was to explore the occurrence and composition of prostatic calculi, and investigate the effect of calcium oxalate (CaOx) on clusterin expression and lower urinary tract symptom (LUTS) in prostatitis and benign prostatic hyperplasia (BPH) patients with calculi. MATERIAL AND METHODS From December 2016 to January 2017, a total of 79 prostatitis patients aged more than 50 years were enrolled. The patients were divided into 3 groups: group A had small calculi (discrete, small echoes); group B had large calculi (large masses of multiple echoes, much coarser), and group C had no calculi. Immunohistochemical analysis was performed to evaluate the tissue scores. The clusterin expression was detected by quantitative real-time CR (qRT-PCR), Western blot, and immunofluorescence. RESULTS According to multifactor analysis, age was significantly associated with prostatic calculus. The composition of prostatic calculus was an independent factor of LUTS. The clusterin expression was elevated in group B. The mRNA and protein levels of clusterin in prostatitis and BPH patients with stones were obviously higher than those in prostatitis and BPH patients without stones. CaOx enhanced clusterin expression in a dose-dependent manner. CONCLUSIONS Large prostatic calculi were associated with LUST. Furthermore, CaOx enhanced clusterin expression, leading to large prostatic calculi. These results may provide a therapeutic strategy for prostatitis and BPH.

Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease-related complications. Naftopidil is an alpha-blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH. SEARCH METHODS: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross-over design trials. DATA COLLECTION AND ANALYSIS: Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We included 22 RCTs with 2223 randomised participants across four comparisons for short-term follow-up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5-alpha reductase inhibitors (5-ARIs) to combination therapy with other ABs and any 5-ARIs.All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.Naftopidil versus tamsulosinBased on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) -0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI -0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.Naftopidil versus silodosinBased on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI -0.78 to 2.85), QoL (MD 0.21, 95% CI -0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events. AUTHORS' CONCLUSIONS: Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.

Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement.

PURPOSE: These studies were undertaken to determine if fexapotide triflutate 2.5 mg transrectal injectable (FT) has significant long-term (LT) safety and efficacy for the treatment of benign prostatic hyperplasia (BPH). METHODS: Two placebo controlled double-blind randomized parallel group trials with 995 BPH patients at 72 sites treated 3:2 FT:placebo, with open-label FT crossover (CO) re-injection in 2 trials n = 344 and long-term follow-up (LF) 2-6.75 years (mean 3.58 years, median 3.67 years; FT re-injection CO mean 4.27 years, median 4.42 years) were evaluated. 12 months post-treatment patients elected no further treatment, approved oral medications, FT, or interventional treatment. Primary endpoint variable was change in Symptom Score (IPSS) at 12 months and at LF. CO primary co-endpoints were 3-year incidence of (1) surgery for BPH in FT treated CO patients versus patients crossed over to oral BPH medications and (2) surgery or acute urinary retention in FT-treated CO placebo patients versus placebo patients crossed over to oral BPH medications. 28 CO secondary endpoints assessed surgical and symptomatic outcomes in FT reinjected patients versus conventional BPH medication CO and control subgroups at 2 and 3 years. RESULTS: FT injection had no significant safety differences from placebo. LF IPSS change from baseline was higher in FT treated patients compared to placebo (median FT group improvement - 5.2 versus placebo - 3.0, p < 0.0001). LF incidence of AUR (1.08% p = 0.0058) and prostate cancer (PCa) (1.1% p = 0.0116) were both reduced in FT treated patients. LF incidence of intervention for BPH was reduced in the FT group versus oral BPH medications (8.08% versus 27.85% at 3 years, p < 0.0001). LF incidence of intervention or AUR in placebo CO group with FT versus placebo CO group with oral medications was reduced (6.07% versus 33.3% at 3 years, p < 0.0001). 28/28 secondary efficacy endpoints were reached in LF CO re-injection studies. CONCLUSIONS: FT 2.5 mg is a safe and effective transrectal injectable for LT treatment of BPH. FT treated patients also had reduced need for BPH intervention, and reduced incidence of PCa and AUR.

Ultrasound image features of intravesical prostatic protrusion indicated failure of medication therapy of finasteride and doxazosin in patients with benign prostatic hyperplasia (LUTS/BPH).

BACKGROUND: Intravesical prostatic protrusion (IPP) is a type of benign prostatic hyperplasia (BPH) adenoma, and it plays a critical role in the pathogenesis of bladder outlet obstruction in patients with lower urinary tract syndromes (LUTS/BPH). AIMS: The goal of this study was to investigate the effect of a combination therapy with finasteride and doxazosin on IPP in BPU/LUTS patients. METHODS: A total of 322 BPH patients with enlarged prostatic volume as well as moderate to severe symptom scores were enrolled and divided into four groups according to the degree of IPP (IPP > 10 mm, 5-10 mm, <5 mm and no IPP) in this study. Aggravated International Prostatic Symptom Score (IPSS), acute urinary retention or relevant urinary complications were considered as failure of the therapy. The degrees of IPP were recorded before and after 6 months of treatment. Student's t test and χ 2 were performed between the baseline and endpoint of the therapy. RESULTS: The results showed that the total prostate volume (TPV) and transition zone volume (TZV) of the prostate decreased significantly after 6-month combination therapy (P < 0.05), while no significant changes in IPP were observed at that point (P > 0.05). Failure rates of the medication differed significantly among the four groups. CONCLUSIONS: The study indicated that the combination therapy using finasteride and doxazosin could not reduce the degree of IPP. LUTS/BPH patients with IPP which contributes to the failure of medication tend to have a higher risk of progression.

α1-Blockers Improve Benign Prostatic Obstruction in Men with Lower Urinary Tract Symptoms: A Systematic Review and Meta-analysis of Urodynamic Studies.

CONTEXT: The urodynamic outcomes for α1-blockers (ABs) treatment in patients with lower urinary tract symptoms related to benign prostatic enlargement (LUTS/BPE) is a matter of debate. OBJECTIVE: To perform a systematic review and meta-analysis of studies evaluating the ABs urodynamic outcomes in patients with LUTS/BPE. The primary endpoint was variation in bladder outlet obstruction index (BOOI). Secondary endpoints were the maximum urinary flow rate (Qmax) and detrusor pressure at Qmax (PdetQmax). A meta-analysis of placebo-controlled randomized clinical trials (RCTs) was performed to compare ABs with placebo. EVIDENCE ACQUISITION: A systematic review of PubMed/Medline, ISI Web of Knowledge, and Scopus databases was performed in May 2015. Seventeen studies were selected for inclusion. EVIDENCE SYNTHESIS: The overall pooled data showed a mean BOOI change of -14.19 (p<0.0001), a mean PdetQmax change of -11. 39cm H2O (p<0.0001), and a mean Qmax improvement of 2.27ml/s (p<0.0001). Subgroup analysis showed a mean BOOI change of -14.88 (p=0.01) for alfuzosin, -19.41 (p=0.01) for doxazosin, -16.47 (p<0.0001) for naftopidil, -30.45 (p<0.0001) for silodosin, -14.27 (p=0.002) for tamsulosin, and -6.69 (p=0.005) for terazosin. Subanalysis of RCTs containing a placebo arm showed a significant improvement in BOOI in patients undergoing ABs treatment. Meta-regression revealed a significant positive association between the percentage of patients with obstruction at baseline and the improvement in BOOI after treatment with ABs. CONCLUSION: ABs improve BOOI in patients with LUTS/BPE mainly by reducing PdetQmax, and this effect is higher in patients presenting with urodynamic obstruction at baseline. The free Qmax variation underestimates the real effect of ABs on benign prostatic obstruction. PATIENT SUMMARY: Results of this meta-analysis suggest that α1-blockers objectively improve urinary voiding function in patients with benign prostatic obstruction.

Latest Evidence on the Use of Phosphodiesterase Type 5 Inhibitors for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.

CONTEXT: Several preclinical reports, randomized controlled trials, systematic reviews, and posthoc analyses corroborate the role of phosphodiesterase type 5 inhibitors (PDE5-Is) in the treatment of men with lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE). OBJECTIVE: Update of the latest evidence on the mechanisms of action, evaluate the current meta-analyses, and emphasize the results of pooled data analyses of PDE5-Is in LUTS/BPE. EVIDENCE ACQUISITION: Literature analysis of basic researches on PDE5-Is, systematic literature search in PubMed and Scopus until May 2015 on reviews of trials on PDE5-Is, and collection of pooled data available on tadalafil 5mg. EVIDENCE SYNTHESIS: Latest evidences on the pathophysiology of LUTS/BPE has provided the rationale for use of PDE5-Is: (1) improvement of LUT oxygenation, (2) smooth muscle relaxation, (3) negative regulation of proliferation and transdifferentiation of LUT stroma, (4) reduction of bladder afferent nerve activity, and (5) down-regulation of prostate inflammation are the proven mechanisms of action of PDE5-Is. Data from eight systematic reviews demonstrated that PDE5-Is allow to improve LUTS (International Prostate Symptom Score mean difference vs placebo: 2.35-4.21) and erectile function (International Index of Erectile Function mean difference vs placebo: 2.25-5.66), with negligible change in flow rate (Qmax mean difference vs placebo: 0.01-1.43). Pooled data analyses revealed that tadalafil 5mg once daily allows the clinically-meaningful improvement of LUTS and nocturnal voiding frequency independent of both erectile dysfunction severity and improvement. CONCLUSIONS: PDE5-Is are safe and effective in improving both LUTS and erectile function in appropriately selected men with LUTS/BPE. Data on the reduction of disease progression, long-term outcomes, and cost-effectiveness analyses are still lacking. PATIENT SUMMARY: We reviewed recent literature on phosphodiesterase type 5 inhibitors in men with lower urinary tract symptoms associated with prostatic enlargement. We found evidence to confirm that phosphodiesterase type 5 inhibitors are a valid treatment option for men affected by bothersome urinary symptoms with or without erectile dysfunction.

Benign Prostatic Hyperplasia - An economic assessment of fixed combination therapy based on a literature review.

FederAnziani Senior Italia and SIU - Italian Society of Urology - have decided to work together to draft a document focussing on Benign Prostatic Hyperplasia (BPH), and to stress the importance of adherence with pharmacological treatment in this setting, from both a scientific and a patient standpoint. Starting from a literature search, the two associations analysed to what extent an increase in treatment adherence amongst these patients influences hospital savings and to what extent therapy persistence levels are affected by monotherapy rather than free drug combinations. These estimates were performed only on patients taking medicinal products belonging to the 5 α-reductase inhibitors (5ARI) class that, although not indispensable, are the compounds that bring the greatest benefits, especially in the elderly and for which we know that every additional 30 days of therapy reduced the likelihood of acute urinary retention (AUR) and surgery by 14% and 11% respectively *. The results show that the use of fixed combination therapy would involve an increase in persistence due to the lower rate of patients abandoning treatment over time. Each 30 day-increment of 5ARI therapy, i.e. for an expenditure of 10.6 million euros extra per year for 5ARI medication, savings of approximately 24.3 million euros in hospital costs could be achieved.

Clinical significance of prostatic-urethral angulation on the treatment outcome of patients with symptomatic benign prostatic hyperplasia treated with tamsulosin hydrochloride.

OBJECTIVES: To evaluate the impact of the prostatic-urethral angulation (PUA) on the treatment efficacy of selective alpha-1A receptor blocker in male patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: A total of 80 patients with LUTS/BPH and with mean age 53.3 ± 6.3 (range 47-70) were included in our prospective comparative study. The patients were classified into 2 groups as a consecutive cases 40 in each one depending on the PUA either ≤ 35° (group A) or > 35° (group B). PUA and different prostatic parameters were measured using transrectal ultrasound. Prostate-specific antigen (PSA), the International Prostate Symptom Score and quality of life score (IPSS/QoL score), maximum flow rate (Qmax), and postvoid residual (PVR) volume were compared between the groups. The clinical significance of PUA was evaluated after 8 weeks of medical treatment with tamsulosin hydrochloride 0.4 mg daily. RESULTS: Baseline evaluation (pre-treatment) for both groups were comparable to each other with no clinically significant difference regarding age, PSA, IPSS/QoL score, Q(max) and PVR volume (P-value > 0.05). Comparison of parameters after 8 weeks showed that tamsulosin hydrochloride improved the total IPSS and all subscores (P < 0.001), QoL (P = 0.001), Q(max) (P = 0.002), and PVR (P = 0.04) in group A (Table 1). CONCLUSION: Tamsulosin hydrochloride appears to be less effective in improving IPSS/Qol score, Qmax and PVR in patients with lager PUA. The PUA might be a predictor for the treatment efficacy of α-blockers and more studies are warranted in the future before the final conclusion.

Alpha blocker monotherapy versus combination therapy with antimuscarinics in men with persistent LUTS refractory to alpha-adrenergic treatment: patterns of persistence.

INTRODUCTION: Patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) often present with voiding and storage symptoms, which may require combination therapy with an alpha blocker and an antimuscarinic (AM). This study compared treatment persistence in LUTS/BPH patients on alpha blocker monotherapy with those using combination alpha blocker and AM therapy (AB/AM). MATERIALS AND METHODS: Retrospective analysis of anonymized patient longitudinal prescription reimbursement claims data. All patients who had claims for any of four alpha blocker medications and six AM agents during an index period from April 1, 2011 to March 31, 2012 were included. For the combination therapy group, the effect of adherence with the AM medication on persistence to the alpha blocker was examined. RESULTS: Patients on AB/AM combination therapy remained on alpha blockers for longer than those on alpha blocker monotherapy (p = 0.04); 92.4% were persistent at 3 months versus 89.0%, and at 1 year 50.8% were persistent versus 49.6%, respectively. The highest number of days on therapy was reported for tamsulosin plus solifenacin. As confirmed by multivariate analysis, patients with the highest adherence to AM medication (= 80%) persisted on alpha blockers for longer than those with the lowest (< 50%) adherence (p < 0.05). CONCLUSIONS: Patients taking an AM in combination with an alpha blocker showed greater persistence with alpha blocker treatment over a 1 year period. When an AM is combined with an alpha blocker in patients with LUTS/BPH, the additional medication burden does not have a negative impact on persistence and may even improve it.

Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo.

OBJECTIVES: To report the secondary analyses of treatment satisfaction and clinically meaningful improvements in a randomized study comparing coadministration of tadalafil 5 mg with finasteride 5 mg versus finasteride alone in men with prostatic enlargement secondary to benign prostatic hyperplasia. METHODS: An international, randomized, double-blind, parallel study was carried out in men aged ≥45 years who were 5-alpha reductase inhibitor naïve, and had an International Prostate Symptom Score ≥13 and prostate volume ≥30 mL; 350 men received placebo/finasteride and 345 received tadalafil/finasteride over 26 weeks. Treatment satisfaction was assessed per protocol using the Treatment Satisfaction Scale-Benign Prostatic Hyperplasia. Responder cut-offs, analyzed post-hoc were total International Prostate Symptom Score improvement ≥3 points or ≥25% from randomization. RESULTS: Baseline patient characteristics were generally comparable between responders and non-responders. The proportion of patients with an International Prostate Symptom Score improvement ≥3 points with tadalafil/finasteride and placebo/finasteride, respectively, at week 4 was 57.0% and 47.9% (OR 1.45, 95% confidence interval 1.07-1.97), at week 12 was 68.8% and 60.7% (OR 1.48, 95% confidence interval 1.07-2.05) and at week 26 was 71.4% and 70.2% (OR 1.14, 95% confidence interval 0.81-1.61); for IPSS change ≥25%, the corresponding proportions were 44.8% and 32.9% (OR 1.66, 95% confidence interval 1.21-2.28), 55.5% and 51.9% (OR 1.18, 95% confidence interval 0.87-1.62), and 62.0% and 58.3% (OR 1.23, 95% confidence interval 0.89-1.70). Treatment satisfaction at week 26 was significantly greater with tadalafil/finasteride versus placebo/finasteride for total treatment satisfaction scale score (P=0.031) and satisfaction with efficacy subscore (P = 0.025); scores were not significantly different between treatments for satisfaction with dosing or side-effects (both P ≥ 0.371). CONCLUSIONS: Tadalafil/finasteride results in significantly more patients achieving early clinical meaningful improvements in symptoms, and in greater treatment satisfaction versus placebo/finasteride.

Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies.

OBJECTIVES: Assess the efficacy and safety of tadalafil 5 mg once-daily in Asian men with lower urinary tract symptoms by pooling data from three clinical studies. METHODS: Data on 1199 Japanese, Korean, and Taiwanese men given tadalafil 5 mg (n = 601) or placebo (n = 598) were pooled from three double-blind, placebo-controlled, 12-week studies. Efficacy measures included International Prostate Symptom Score, and Patient and Clinician Global Impressions of Improvement. These measures were also assessed for patient subgroups (age categories, baseline disease severity and/or prostate volume, prior alpha-blocker treatment). Safety measures included adverse events, including those in selected body systems. Efficacy measure changes throughout treatment were assessed by mixed-effect model repeated-measures analysis; baseline to end-point changes for the total population and subgroups were evaluated by analysis of covariance. RESULTS: Tadalafil 5 mg led to significant improvement (vs placebo) in all International Prostate Symptom Scores at all time-points (week 4 P ≤ 0.013 for all measures; week 8 P ≤ 0.005, week 12 P < 0.001). End-point results for both global impressions scales also favored tadalafil (both P < 0.001 vs placebo). Tadalafil efficacy was similar between patient subgroups of varied disease severity (interaction P = 0.097), prior alpha-blocker use (P = 0.580), and prostate volume (P = 0.921). The drug was slightly less effective in older men (interaction P = 0.042). No unexpected adverse events were reported, and no meaningful adverse effects were observed in visual, auditory, or cardiovascular systems. CONCLUSIONS: Tadalafil 5 mg once-daily for 12 weeks is efficacious and safe in Asian men with lower urinary tract symptoms. Tadalafil is also effective in men of different ages, disease severity, prior alpha-blocker exposure, and prostate volumes.

Effect of tadalafil on male lower urinary tract symptoms: an integrated analysis of storage and voiding international prostate symptom subscores from four randomised controlled trials.

BACKGROUND: The international prostate symptom score (IPSS) evaluates lower urinary tract symptoms (LUTS) in men with suspected benign prostatic hyperplasia (BPH); the total score does not differentiate between storage and voiding and is unevenly weighted (four questions [57%] on voiding, three questions [43%] on storage). OBJECTIVE: To evaluate the relative contributions of storage and voiding IPSS subscores to total IPSS at baseline and in response to treatment with tadalafil. DESIGN, SETTING, AND PARTICIPANTS: Integrated analysis of data from four placebo-controlled, 12-wk studies of tadalafil (5mg once daily) in 1499 men with LUTS/BPH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships between total IPSS and the storage and voiding subscores were assessed using graphical exploration and linear regression modelling. Linear modelling was performed for the baseline and endpoint and for changes in subscores. The optimal storage subscore to total IPSS (S:T) ratio for IPSS improvement was identified using nonparametric regression and gradient-descent optimisation. RESULTS AND LIMITATIONS: The contribution of storage and voiding subscores at baseline and endpoint was 38.8% and 61.2%, and 39.2% and 60.7%, respectively. This intuitive 40:60 storage-to-voiding ratio was similar at baseline and endpoint by treatment group and for changes in subscores, but spanned the entire range for individuals. Changes in total IPSS were greatest for a storage subscore percentage contribution to total IPSS of 42.7%. There was no statistical association between S:T ratio (≥ 40% vs < 40%) at baseline and response to tadalafil. The main limitation was the use of unvalidated storage and voiding IPSS subscores. CONCLUSIONS: A constant S:T ratio of 4:10 was observed at baseline and endpoint. The greatest effect on total IPSS was noted for an S:T percentage contribution of 42.7%. Tadalafil efficacy was unaffected by the level of storage dysfunction at baseline. PATIENT SUMMARY: This analysis shows that for men with BPH, improvements during treatment with tadalafil apply to both storage and voiding symptoms at a constant ratio. The extent of storage dysfunction before treatment did not affect the response to treatment.

Impact of alpha blockers, 5-alpha reductase inhibitors and combination therapy on sexual function.

Medical treatments for lower urinary tract symptoms due to benign prostatic hyperplasia are frequently associated with changes in sexual function. While these medications are generally well-tolerated and have both reduced and delayed more invasive surgical options, the ramifications of long-term chronic use are largely unknown. Sexual side effects of these medications are frequently either reported as part of a short-term initial drug study or have inflexible endpoints that are not able to gauge more subtle changes in sexual performance. This review will delineate the currently known effects of these medications on sexual function and will consider mechanisms of dysfunction.

An updated systematic review and statistical comparison of standardised mean outcomes for the use of botulinum toxin in the management of lower urinary tract disorders.

CONTEXT: Botulinum toxin A (BoNTA) has received regulatory approval for use in neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), but it remains unlicensed in other lower urinary tract symptoms (LUTS) indications such as nonneurogenic LUTS in men with benign prostatic enlargement (LUTS/BPE), bladder pain syndrome (BPS), and detrusor sphincter dyssynergia (DSD). OBJECTIVE: To compare statistically the outcomes of high level of evidence (LE) studies with placebo using BoNTA for LUTS indications; NDO, OAB, LUTS/BPE, BPS and DSD. EVIDENCE ACQUISITION: We conducted a systematic review of the published literature on PubMed, Scopus, and Embase reporting on BoNTA use in LUTS dysfunction. Statistical comparison was made between high LE studies with placebo and low LE studies. EVIDENCE SYNTHESIS: In adult NDO, there are significantly greater improvements with BoNTA in daily incontinence and catheterisation episodes (-63% and -18%, respectively; p<0.01), and the urodynamic parameters of maximum cystometric capacity (MCC), reflex volume, and maximum detrusor pressure (MDP) (68%, 61%, and -42%, respectively; all p<0.01). In OAB, BoNTA leads to significant improvements in bladder diary parameters such as daily frequency (-29%), daily urgency (-38%), and daily incontinence (-59%) (all p<0.02). The urodynamic parameters of MCC and MDP improved by 58% (p=0.04) and -29% (p=0.002), respectively. The risk of urinary tract infection was significantly increased from placebo at 21% versus 7% (p<0.001), respectively; the risk of intermittent self-catherisation increased from 0% to 12% (p<0.001). Men with LUTS/BPE showed no significant improvements in International Prostate Symptom Score, maximum flow rate, or prostate volume. There were insufficient data for statistical analysis in DSD, BPS, and paediatric studies. Low LE studies were found to overestimate the effects of BoNTA in all indications, but differences from high LE studies were significant in only a few parameters. CONCLUSIONS: BoNTA significantly improves all symptoms and urodynamic parameters in NDO and OAB. The effect of BoNTA in treating LUTS dysfunction appears to be overestimated in lower as opposed to higher LE studies.