Long-term administration of alpha-1 blocker can reverse the micturition pattern in a bladder outlet obstruction murine model.

OBJECTIVE: To investigate the effect of chronic administration of an alpha-1 blocker on micturition patterns in long-term partial bladder outlet obstruction. METHODS: Mice were divided into three groups: a normal group, in which animals were fed a standard diet; a partial bladder outlet obstruction group, in which the proximal urethra was tied and animals were fed a standard diet; and a partial bladder outlet obstruction + naftopidil group, in which the proximal urethra was tied and animals were fed a standard diet containing naftopidil. Micturition behavior was evaluated in all groups for 6 months after partial bladder outlet obstruction surgery. The parameters evaluated included voided volume, time per void, urination frequency and total urine volume. Quantitative assessment of gene expression was also carried out. RESULTS: Total urine volume, as well as total and average voided volume during night, was significantly decreased in partial bladder outlet obstruction + naftopidil mice compared with partial bladder outlet obstruction animals. The levels of transcripts encoding 5-hydroxytryptamine 2A and tissue inhibitor of metalloproteinase 2 were significantly decreased in the partial bladder outlet obstruction + naftopidil group compared with the partial bladder outlet obstruction group. CONCLUSIONS: Long-term administration of an alpha-1 blocker seems to reverse the disturbance of the micturition pattern caused by partial bladder outlet obstruction. Mechanistically, this effect might be mediated by changes in the expression of a serotonin receptor and/or in the activity of the fibrogenesis pathway.

What Are Factors Contributing to Improvement of Overactive Bladder Symptoms after Alpha-1 Blocker Treatment in Patients with Both Storage and Voiding Symptoms?

INTRODUCTION: To determine the pre-treatment factors related to the improvement of overactive bladder (OAB) symptom after alpha-1 blocker monotherapy in patients with benign prostatic hyperplasia complicated by OAB (BPH/OAB). METHODS: Post-hoc analysis of a prospective study in patients with BPH/OAB, randomized to receive silodosin 8 mg (n = 157) or naftopidil 75 mg (n = 157) treatment for 12 weeks, was performed. At 12 weeks post-administration, patients were divided into 2 groups (good responder [GR] group and poor responder [PR] group), according to the improvement in the OAB symptom score (OABSS). We compared the pre-administration parameters between both groups and evaluated the factors related to OAB improvement. RESULTS: Of 314 patients, 159 patients (50.6%) were classified into the GR and 155 (49.4%) into the PR. International Prostate Symptom score, total OABSS, OABSS urgency-score, OABSS urgency urinary incontinence (UUI)-score, post-void residual urine volume (PVR), and selection rate of naftopidil were significantly higher in the PR than in the GR. On multivariate logistic regression analysis, larger PVR, higher OABSS-UUI-score, and the choice of naftopidil were significant risk factors for insufficient improvement of OAB symptoms. CONCLUSIONS: Pre-treatment PVR, UUI severity, and the choice of treatment agent are predicting factors related to OAB improvement after alpha-1 blocker monotherapy in patients with BPH/OAB.

Long-term efficacy of a combination therapy with an anticholinergic agent and an α1-blocker for patients with benign prostatic enlargement complaining both voiding and overactive bladder symptoms: A randomized, prospective, comparative trial using a urodynamic study.

AIMS: We evaluated long-term efficacy and safety of a combination therapy (CT) with an anticholinergic agent and an α1-blocker for patients with benign prostatic enlargement (BPE) complaining of voiding and overactive bladder (OAB) symptoms, in comparison with those of α1-blocker monotherapy (MT), by conducting a urodynamic study (UDS). METHODS: This was a randomized prospective study involving 120 outpatients with untreated BPE associated with urinary urgency at least once per week and OABSS of ≥3. The patients were randomly assigned to receive MT with silodosin at 8 mg/day or CT with silodosin at 8 mg/day and propiverine at 20 mg/day. Changes in parameters from baseline to 12 weeks and 1 year after administration were assessed based on IPSS, IPSS-QOL, OABSS, and voiding and storage functions as measured by UDS. RESULTS: In efficacy analysis, 53 patients with MT and 51 with CT were included. Although mean IPSS and OABSS significantly improved in both groups, the CT group showed statistically significant improvement in OABSS (-3.4 in CT, -2.4 in MT, P = 0.04), IPSS-QOL (-1.9, -1.2, P = 0.01), and OAB-urgency score (-1.8, -1.2, P < 0.01) at the long-term evaluation. In storage function, both groups showed significant improvements, but the CT group demonstrated a greater improvement in terms of disappearance rate of detrusor overactivity (54.5% in CT, 34.2% in MT, P = 0.07) and bladder capacity (+61 mL, +33 mL, P = 0.02). CONCLUSIONS: Long-term combination treatment with silodosin and propiverine was effective and safe for BPE patients with voiding and OAB symptoms. Neurourol. Urodynam. 36:748-754, 2017. © 2016 Wiley Periodicals, Inc.

Effects of carvedilol on human prostate tissue contractility and stromal cell growth pointing to potential clinical implications.

BACKGROUND: Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α1-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly used antihypertensive and α1-adrenoceptors are essential for the treatment of voiding symptoms in benign prostatic hyperplasia, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on stromal cell growth. METHODS: Contractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α1-agonists. Growth-related functions were examined in cultured stromal cells. RESULTS: Concentration-response curves for phenylephrine, methoxamine and noradrenaline were right shifted by carvedilol (0.1-10 µM), around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes with 10 µM. Right shifts were reflected by increased EC50 values for agonists, with unchanged Emax values. EFS-induced contractions were reduced by 21-54% with 0.01-1 µM carvedilol, and by 94% by 10 µM. Colony numbers of stromal cells were increased by 500 nM, but reduced by 1-10 µM carvedilol, while all concentrations reduced colony size. Decreases in viability were time-dependent with 0.1-0.3 µM, but complete with 10 µM. Proliferation was slightly increased by 0.1-0.5 µM, but reduced with 1-10 µM. CONCLUSIONS: Carvedilol antagonizes α1-adrenoceptors in the human prostate, starting with concentrations in ranges of known plasma levels. In vitro, effect sizes resemble those of α1-blockers used for the treatment of voiding symptoms, which requires concentrations beyond plasma levels. Bidirectional and dynamic effects on the growth of stromal cells may be attributed to "biased agonism".

A non-randomized pilot trial of the use of prazosin in the prevention of transition from acute stress disorder to post-traumatic stress disorder.

BACKGROUND: Following a traumatic event, 40-80% of the patients with acute stress disorder (ASD) will develop post-traumatic stress disorder (PTSD), 67% at 6 months. Alpha1-blockers are effective in treating some symptoms of PTSD but their usefulness in acute stress situations remains unclear. We hypothesized that reducing noradrenergic hyperactivity with an alpha1-blocker during the acute phase after a traumatic event could prevent the transition to PTSD in patients with ASD. OBJECTIVE: To investigate the efficacy and safety of a 1-month course of alpha1-blocker (prazosin) to prevent the transition to PTSD in patients with ASD at 6 months. METHOD: In a monocentric open-label prospective pilot study, 15 patients with ASD were included within 3-7 days of exposure to a traumatic event. After enrolment, they received prazosin LP at home at bedtime at 2.5 mg/day for 7 days and then 5 mg/day for 21 days. Incidence of PTSD was assessed at 6 months using the Clinician Administrated PTSD Scale (CAPS). RESULTS: At 6 months, 22% of patients who completed the study (2/9) met the diagnostic criteria for PTSD. This rate was significantly lower than that observed in previous studies (67%; p = .047). The treatment was well tolerated and there were no serious adverse events. CONCLUSIONS: These preliminary findings indicating the safety of prazosin and suggesting its potential to prevent the development of PTSD in ASD require to be replicated in large-scale randomized placebo-controlled studies.Trial registration: The study was pre-registered on a public database (www.clinicalTrials.gov identifier: NCT03045016).

Alpha1-blockers are safe and well tolerated in patients with acute stress disorder.The use of alpha1-blockers 3­7 days after traumatic exposure is worthy of study.Alpha1-blockers could prevent the transition to PTSD in ASD patients at 6 months.

Management of benign prostate hyperplasia (BPH) by combinatorial approach using alpha-1-adrenergic antagonists and 5-alpha-reductase inhibitors.

Currently, the main available treatments for benign prostate hyperplasia (BPH) are alpha-1 adrenergic receptor antagonists (ARAs), 5-alpha reductase inhibitors (5-αRI), anticholinergics, and Phosphodiesterase-5 inhibitors. Recent studies support the combined therapy approach using ARAs with 5-αRI for lower urinary tract symptoms (LUTS) in BPH patients at risk of clinical progression. We aimed to review BPH management in select group of randomized controlled trials by combination therapy with ARAs and 5-αRIs compared to monotherapy with either drug with respect to the safety and efficacy. A total of 6 randomized controlled trials (RCTs) involving comparison of combination therapy with monotherapy using ARAs and 5-αRIs were retrieved from PubMed Central and reviewed for international prostate symptom score (IPSS), quality of life (QoL), post-residual urinary flow rate (PUF), and clinical progression. The results significantly favour the treatment group that received the combination therapy in comparison with the groups receiving monotherapy. However, outcome with regard to prostate volume showed insignificant improvement when the combination therapy is compared with 5- αRIs alone, rather than ARAs. In conclusion, combination therapy using ARAs and 5-αRI is better than monotherapy in the patients of BPH. Fixed dose combination (FDC), a type of combination, is also cost-effective and its side-effects profile resembles to that of monotherapy.

Effect of perioperative selective alpha-1 blockers in non-stented ureteroscopic laser lithotripsy for ureteric stones: a randomized controlled trial.

INTRODUCTION: The aim of this studywas to assess the efficacy of perioperative alpha-1 blockers on improving the success rate and decreasing complications of non-stented ureteroscopic laser lithotripsy for ureteric stones. MATERIAL AND METHODS: A randomized control trial was conducted at two high volume urological centers from September 2017 to December 2018. We enrolled 150 patients with lower ureteric stones. They were randomly divided into two groups. Patients in group A, underwent non-stented ureteroscopy using Ho-YAG laser for stone disintegration and received alpha-1 blockers for one week preoperatively and another two weeks postoperatively. Patients in group B, underwent non-stented ureteroscopy and laser and received a placebo. RESULTS: One hundred and twenty patients were available for analysis at the end of our study. There was no statistically significant difference found between both groups regarding demographic data and stone parameters. The need for intraoperative ureteric dilatation was 32.7% and 51.6% for both groups A and B respectively with a statistically significant difference. The incidence of lower urinary tract symptoms (LUTS) and the need for analgesics were higher in group B with a statistically significant difference. CONCLUSIONS: Administration of perioperative tamsulosin seems to not only to significantly decrease the need for intra-operative dilatation and hence operative time, but also leads to a significant decrease in the development of postoperative LUTs, postoperative pain and the need for analgesia and hospital stay.

Do alpha-1 antagonist medications affect the success of semi-rigid ureteroscopy? A prospective, randomised, single-blind, multicentric study.

The objective of this study is to assess the efficacy of adjunctive silodosin therapy in improving the success rate of semi-rigid ureteroscopy for removing ureteral stones. Prospective randomised controlled clinical trial performed between July 2016 and September 2016. All the patients underwent ureteroscopic holmium lithotripsy with a YAG laser. The patients were randomised into one of three groups: those who did not use an alpha-1 blocker (AB) (Group 1, n = 50), those who used an AB for one day (Group 2, n = 50), and those who used an AB for three days (Group 3, n = 47). The following information was recorded for each patient: the side, location, and surface area of the stone; successful access; operative success; complications; and operative time. There were no significant differences between the three groups in terms of demographics, stone location or size, and number of doses of an analgesic drug used. Access to the stone and the stone-free rate were significantly higher in group 3 (95.7, 93.6%) than in group 1 (76, 74%) and group 2 (78, 74%) (p = 0.018, p = 0.021), respectively. Balloon dilatation and complication rates were significantly lower in group 3 (12.8, 0%) than in group 1 (34, 12%) and group 2 (22, 4%) (p = 0.045, p = 0.029), respectively. The use of silodosin for 3 days before ureteroscopy for ureteral stones increased the rate of access to all ureter stones and decreased the complication rate.

Two-year follow up of silodosin on lower urinary tract functions and symptoms in patients with benign prostatic hyperplasia based on prostate size: a prospective investigation using urodynamics.

BACKGROUND: The aim of this research was to investigate intermediate-term effects of silodosin on lower urinary tract functions and symptoms in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) according to prostate size, using urodynamics. METHODS: A total of 70 untreated outpatients with a prostate volume <40 ml [small prostate (SP) group] and 70 with prostate volume ⩾40 ml [large prostate (LP) group] were prospectively enrolled and treated by monotherapy with silodosin for 24 months. Changes in parameters from baseline to 3 months and 24 months after silodosin administration were assessed based on LUTS, voiding and storage function. In addition, withdrawal rates of silodosin due to insufficient effects were compared between the two groups and factors to influence the withdrawal were investigated. RESULTS: The International Prostate Symptom Score (IPSS), bladder outlet obstruction index (BOOI), and detrusor overactivity (DO) improved significantly for the 2-year follow up in both groups as compared with the baseline. IPSS, BOOI and DO improved by 40.4%, 41.3%, and 48.1% in the SP group, 32.7%, 35.9%, and 34.4% in the LP group at 3 months, while, 44.3%, 43.5%, and 63.0% in the SP group, 22.6%, 21.1%, and 34.4% in the LP group at 24 months, respectively. Improvement rates in the IPSS and BOOI at 3 months were maintained until 24 months in the SP group, but decreased in the LP group. Storage function improvements continued in both groups for 2 years. Dropout rate due to unsatisfactory effects was significantly higher in the LP group (20% versus 8.6%). Maximum flow rate, BOOI, and intravesical prostatic protrusion had a significant influence on the withdrawal of silodosin treatment in the LP group. CONCLUSIONS: Silodosin significantly improved lower urinary tract functions for 2 years in patients with LUTS/BPH, regardless of prostate size. However, LUTS and BOO improvements tended to decrease in patients with a large prostate (>40 ml) in the intermediate term.

Evaluation of Anterior Segment Changes of Patients Taking Alpha1-Blockers by Ultrasound Biomicroscopy in the Drug-free Period.

OBJECTIVES: To evaluate and compare anterior segment changes in patients taking alpha-1 (α1) blockers (tamsulosin, terazosin, doxazosin, alfuzosin) for benign prostatic hypertrophy, during drug intake and drug-free period, using ultrasound biomicroscopy (UBM). MATERIALS AND METHODS: In this prospective study, UBM was done before and after pupil dilatation in 31 phakic eyes of 19 male patients taking α1-blockers. Undilated and dilated UBM was repeated before cataract extraction, after stopping the drug for 10 days. On ideal images, pupil diameter (PD), anterior chamber depth (ACD), anterior chamber angle (ACA), and angle opening distances at points 500 µm and 250 µm from the scleral spur (AOD500 and AOD250) values were noted and changes in parameters were evaluated to reveal any changes that occurred after discontinuing the drug. No patient in the study was previously or currently using any other α1-adrenergic antagonist medication. Exclusion criteria for all patients included a history of diabetes mellitus, systemic hypertension, glaucoma, pseudoexfoliation syndrome, chronic use of medicated eye drops, and previous ocular surgery. RESULTS: PD, ACD, ACA, AOD500 and AOD250 values measured before pupil dilatation in the drug-free period were not significantly different from those measured during α-blocker intake (p>0.05). In dilated eyes, the mean value of AOD500 was 0.35±0.08 mm during drug usage and 0.39±0.08 mm in the drug-free period. The mean value of AOD250 was 0.23±0.06 mm during drug usage and 0.26±0.07 mm after discontinuation. These increments were statistically significant (p<0.05, z=-3.699, z=-2.984). On the other hand, there were no significant differences in ACD, ACA, or PD values in dilated eyes after discontinuing α1-blockers (p>0.05). CONCLUSION: The interruption of taking α1-blockers in patients who have benign prostatic hypertrophy does not seem to influence anterior segment parameters generally. However, further investigation is needed.

The drug treatment of premature ejaculation.

The management recommendation for both acquired premature ejaculation (APE) and lifelong PE (LPE) are similar, such as a behavioral/psychotherapy, a pharmacotherapy and a combination of these treatments. For the drug treatment for PE, gold standard is selective serotonin reuptake inhibitors (SSRIs) including dapoxetine or paroxetine. The drug treatment for PE is still developing and some new promising therapeutic options have been proposed. Topical anesthetics, tramadol, and alpha-1 blockers will be the next strategies of the drug treatment for PE in the future.

Three-year outcome analysis of alpha 1-blocker naftopidil for patients with benign prostatic hyperplasia in a prospective multicenter study in Japan.

PURPOSE: Our aim was to prospectively analyze the 3-year outcomes of naftopidil treatment for patients with benign prostatic hyperplasia (BPH), including those who dropped out during follow-up and had retreatment for BPH after termination of the drug within 3 years. PATIENTS AND METHODS: Naftopidil, 50 mg/d or 75 mg/d, was given to 117 patients having BPH aged 50 years and older who had international prostate symptom scores (IPSS) ≥8. They were prospectively followed for 3 years with periodic evaluation. If naftopidil was terminated, the reason was determined. For patients with termination, an outcome survey was done to evaluate the status of retreatment for BPH at 3 years. RESULTS: Twenty-five patients (21.4%) continued the same medication for 3 years. The total IPSS, quality of life index, BPH problem index, and maximum flow rate were significantly improved during 3 years. Treatment failure defined as symptomatic progression (an increase in the IPSS of ≥4 points compared to the baseline value), development of acute urinary retention, conversion to other α1-blockers, add-on of a 5α-reductase inhibitor, or conversion to surgery was observed in 41 patients (35.0%). In the univariate analysis, age, prostate volume, and serum prostate-specific antigen were predictors of treatment failure. Of the 50 patients who discontinued naftopidil during the follow-up, only 13 (26%) patients reported that they needed retreatment with α1-blockers and/or surgery within 3 years. CONCLUSION: Long-term efficacy of naftopidil was observed, although older age, increased prostate volume, and elevated prostate-specific antigen at baseline were highly likely to result in treatment failure. Even after termination for various reasons, only a small portion of the patients needed retreatment for BPH within 3 years.

Alfuzosin: a clinically uroselective α1-blocker.

A once-daily (o.d.) formulation of alfuzosin has recently been developed in order to improve the convenience of dosing and to provide optimal pharmacokinetic coverage over a 24-h period. The results of two double-blind, placebo-controlled phase III studies of similar design that included 983 patients with LUTS that suggested BPH have confirmed that alfuzosin 10 mg o.d. is a 24-h effective treatment for both symptoms and flow rates, and that there is no additional benefit in using a higher dosage. In addition, alfuzosin is the only α1-blocker that has demonstrated a significant decrease in post-void residual urine, a known risk factor for acute urinary retention, as well as the incidence of acute urinary retention in comparison with a placebo. Administered without an initial dose titration, alfuzosin 10 mg o.d. is well tolerated, with a low incidence of postural hypotension (<1%) and no significant changes in blood pressure compared with a placebo, even in elderly and hypertensive patients. Ejaculation disorders were rarely reported and did not show an evident causal relationship to treatment. Alfuzosin 10 mg o.d. also exhibits an excellent sexual side-effect profile, with no deleterious impact on this important aspect of quality of life for BPH patients.

Does Baseline Prostate Volume Affect the Short-Term Outcome of Tamsulosin?

OBJECTIVE: To investigate the short-term efficacy of tamsulosin treatment for patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) according to baseline prostate volume (PV). METHODS: Tamsulosin, 0.2 mg/day, was prospectively given to 112 patients aged 50 years or older who had International Prostate Symptom Scores (IPSS) ≥ 8. The short-term efficacy was analyzed using the IPSS, quality of life (QOL) index, BPH problem index (BPI), maximum flow rate (Qmax ) and postvoid residual urine volume (PVR) at 4 weeks and 3 months after treatment considering the estimated PV at baseline. RESULTS: Of the 112 patients, 81 and 31 had PV of < 35 and ≥ 35 mL, respectively. The IPSS was significantly improved in patients with PV of < 35 mL (17.8 ± 5.9 at baseline, 13.5 ± 7.0 at 4 weeks, 11.9 ± 6.1 at 3 months) and in those with PV of ≥ 35 mL (17.4 ± 6.7 at baseline, 13.1 ± 7.0 at 4 weeks, 13.4 ± 6.2 at 3 months). There was no significant difference in the changes of the IPSS between the groups in a combined analysis model (P = 0.559). In addition, the model revealed no significant differences in changes in the QOL index, BPI, Qmax and PVR. CONCLUSION: The short-term efficacy of tamsulosin is observed irrespective of baseline PV. Thus, α1-blocker monotherapy should be considered for all patients with BPH/LUTS to rapidly relieve symptoms, although the long-term outcome is not promising for patients with a large PV at baseline.