Tamsulosin 0.8 mg daily dose in management of BPH patients with failed tamsulosin 0.4 mg monotherapy and unfit for surgical intervention.

AIM: This study aims to evaluate the effectiveness and safety of administering double-dose tamsulosin (0.8 mg) for treating patients with benign prostatic hyperplasia (BPH) who have not responded to the standard single dose of tamsulosin (0.4 mg) and are deemed unsuitable for transurethral resection (TUR) intervention. MATERIALS AND METHODS: Between November 2022 and July 2023, we prospectively analyzed 111 patients who were experiencing severe BPH symptoms. These patients received a double dose of tamsulosin for one month. We collected baseline characteristics such as age, body mass index, and underlying medical conditions. Various parameters including the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) levels, prostate volume, peak urinary flow rate (Qmax), voided volume, and post-void residual volume were evaluated before and after treatment. RESULTS: All 111 patients completed the study. The mean age, PSA level, and prostate volume were 63.12 ± 4.83 years, 3.42 ± 0.93 ng/ml, and 50.37 ± 19.23 ml, respectively. Of these patients, 93 showed improvement in Qmax, post-void residual volume, and IPSS score (p-value = 0.001). The total IPSS score and total Qmax improved from 24.03 ± 2.49 and 7.72 ± 1.64 ml/sec to 16.41 ± 3.84 and 12.08 ± 2.37 ml/sec, respectively. CONCLUSION: Double-dose 0.8mg tamsulosin as an alpha-blocker therapy appears to be a viable temporary management option for BPH patients who have not responded to the standard single dose 0.4mg tamsulosin and are not suitable candidates for TUR intervention.

Naltrexone augmented with prazosin for alcohol use disorder: results from a randomized controlled proof-of-concept trial.

AIMS: We conducted a proof-of-concept randomized controlled trial of the mu-opioid receptor antagonist, naltrexone, augmented with the alpha-1 adrenergic receptor antagonist, prazosin, for alcohol use disorder in veterans. We sought a signal that the naltrexone plus prazosin combination regimen would be superior to naltrexone alone. METHODS: Thirty-one actively drinking veterans with alcohol use disorder were randomized 1:1:1:1 to naltrexone plus prazosin (NAL-PRAZ [n = 8]), naltrexone plus placebo (NAL-PLAC [n = 7]), prazosin plus placebo (PRAZ-PLAC [n = 7]), or placebo plus placebo (PLAC-PLAC [n = 9]) for 6 weeks. Prazosin was titrated over 2 weeks to a target dose of 4 mg QAM, 4 mg QPM, and 8 mg QHS. Naltrexone was administered at 50 mg QD. Primary outcomes were the Penn Alcohol Craving Scale (PACS), % drinking days (PDD), and % heavy drinking days (PHDD). RESULTS: In the NAL-PRAZ condition, % reductions from baseline for all three primary outcome measures exceeded 50% and were at least twice as large as % reductions in the NAL-PLAC condition (PACS: 57% vs. 26%; PDD: 51% vs. 22%; PHDD: 69% vs. 15%) and in the other two comparator conditions. Standardized effect sizes between NAL-PRAZ and NAL-PLAC for each primary outcome measure were >0.8. All but one participant assigned to the two prazosin containing conditions achieved the target prazosin dose of 16 mg/day and maintained that dose for the duration of the trial. CONCLUSION: These results suggest that prazosin augmentation of naltrexone enhances naltrexone benefit for alcohol use disorder. These results strengthen rationale for an adequately powered definitive randomized controlled trial.

Reassessment of amphetamine- and phencyclidine-induced locomotor hyperactivity as a model of psychosis-like behavior in rats.

Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.

Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans.

BACKGROUND: In randomized trials, prazosin, an α1-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans. METHODS: We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change). RESULTS: A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], -0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo. CONCLUSIONS: In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT ClinicalTrials.gov number, NCT00532493 .).

Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/BPH patients with moderate-to-severe symptoms at risk of disease progression.

PURPOSE: To evaluate the effect of delayed start of combination therapy (CT) with dutasteride 0.5 mg and tamsulosin 0.4 mg on the risk of acute urinary retention or benign prostatic hyperplasia (BPH)-related surgery (AUR/S) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) at risk of disease progression. METHODS: Using a time-to-event model based on pooled data from 10,238 patients from Phase III/IV dutasteride trials, clinical trial simulations (CTS) were performed to assess the risk of AUR/S up to 48 months in moderate-to-severe LUTS/BPH patients following immediate and delayed start of CT for those not responding to tamsulosin monotherapy. Simulation scenarios (1300 subjects/arm) were investigated, including immediate start (reference) and alternative delayed start (six scenarios 1-24 months). AUR/S incidence was described by Kaplan-Meier survival curves and analysed using log-rank test. The cumulative incidence of events as well as the relative and attributable risks were summarised stratified by treatment. RESULTS: Survival curves for patients starting CT at month 1 and 3 did not differ from those who initiated CT immediately. By contrast, significant differences (p < 0.001) were observed when switch to CT occurs ≥ 6 months from the initial treatment. At month 48, AUR/S incidence was 4.6% vs 9.5%, 11.0% and 11.3% in patients receiving immediate CT vs. switchers after 6, 12 and 24 months, respectively. CONCLUSIONS: Start of CT before month 6 appears to significantly reduce the risk of AUR/S compared with delayed start by ≥ 6 months. This has implications for the treatment algorithm for men with LUTS/BPH at risk of disease progression.

Free combination of dutasteride plus tamsulosin for the treatment of benign prostatic hyperplasia in South Korea: analysis of drug utilization and adverse events using the National Health Insurance Review and Assessment Service database.

OBJECTIVE: To assess the use and safety of free combination therapy (dutasteride and tamsulosin), dutasteride monotherapy, or tamsulosin monotherapy in patients with benign prostatic hyperplasia (BPH). METHODS: This non-interventional retrospective cohort study used claims data from the Korea Health Insurance Review and Assessment-National Patient Sample database. Patients with BPH ≥ 40 years of age receiving combination therapy (dutasteride 0.5 mg and tamsulosin 0.4 mg daily) or dutasteride 0.5 mg, or tamsulosin 0.4 mg daily dose between 2012 and 2017 were included. The frequency, duration of treatment and risk of any adverse event (AE) or serious AE (SAE) was compared for combination therapy versus each monotherapy using non-inferiority testing. RESULTS: Of 14,755 eligible patients, 1529 (10.4%) received combination therapy, 6660 (45.1%) dutasteride monotherapy, and 6566 (44.5%) tamsulosin monotherapy. The proportion of patients treated with combination therapy exceeded the pre-specified 3% threshold for 'frequent' use. Safety results indicated a similar risk of any AE and SAE irrespective of treatment group. The adjusted relative risk for any AE over the treatment observation period comparing combination therapy with dutasteride monotherapy was 1.07 (95% confidence interval [CI] 1.03, 1.12), and with tamsulosin monotherapy was 0.98 (95% CI 0.95, 1.02) demonstrating non-inferiority. The adjusted relative risk for any SAE was 1.07 (95% CI 0.66, 1.74) and 0.90 (95% CI 0.56, 1.45), compared with dutasteride and tamsulosin monotherapy, respectively. Although the SAE results did not statistically demonstrate non-inferiority of combination therapy based on pre-specified margins, the 95% CI for the risk ratio estimates included the null with a lower limit below the non-inferiority margins, indicating no meaningful differences in SAE risk between groups. Absolute SAE risks were low. CONCLUSION: Combination therapy with dutasteride and tamsulosin is frequently used in real-world practice in South Korea for treatment of BPH and demonstrates a safety profile similar to either monotherapy.

Blood Pressure Control in Acute Stroke: Labetalol or Nicardipine?

PURPOSE: To assess the safety and efficacy of continuous infusion (CIV)-labetalol compared to -nicardipine in controlling blood pressure (BP) in the acute stroke setting. MATERIALS: Patients were eligible if they had a diagnosis of an acute stroke and were administered either CIV-labetalol or CIV-nicardipine. Study outcomes were assessed within the first 24 h of the antihypertensive infusion. RESULTS: A total of 3,093 patients were included with 3,008 patients in the CIV-nicardipine group and 85 in the CIV-labetalol group. No significant difference was observed in percent time at goal BP between the nicardipine (82%) and labetalol (85%) groups (p = 0.351). There was also no difference in BP variability between nicardipine (37%) and labetalol (39%) groups (p = 0.433). Labetalol was found to have a shorter time to goal BP as compared to nicardipine (24 min vs. 40 min; p = 0.021). While CIV-nicardipine did have a higher incidence of tachycardia compared to labetalol (17% vs. 4%; p <0.001), the incidence of hypotension (13% vs. 15%; p = 0.620) and bradycardia (24% vs. 22%; p = 0.797) were similar. CONCLUSIONS: These results indicate that CIV-labetalol and CIV-nicardipine are comparable in safety and efficacy in controlling BP for patients with acute stroke.

The Fall Risk with Alpha blockers Given InitiaL dose or Elderly status (FRAGILE) Study.

Background: α-1 adrenergic antagonists are commonly prescribed, but there is question regarding their safety in patients at increased fall risk. Objective: The purpose of the FRAGILE study was to determine the risk for developing adverse drug events (ADEs) in veterans prescribed α-1 blockers. Methods: A single-center, retrospective, observational cohort analysis was conducted of veterans newly initiated on α-1 antagonists. Veterans were categorized into at-risk (patients who met at least 1 of 2 criteria: age 65 or older or high initial dose of α blockade) or control (veterans without either risk factor) groups. The primary outcome was the composite all-cause ADEs, including hospitalizations or emergency department (ED) visits. Secondary outcomes included number of fall-related ADEs and medication discontinuation rates with follow-up for 12 months. Results: A total of 300 veterans were evaluated. There was no significant difference in the composite outcome of all-cause ED visits between at-risk (n = 169) versus control (n = 131) groups (0.81 vs 1.17, P = 0.09) or all-cause hospitalizations (0.28 vs 0.39, P = 0.25). Seventy-three veterans in the at-risk group experienced an all-cause ADE versus 64 in the control group (P = 0.36). No significant differences in secondary outcomes were found. Fall-related side effects occurred in 8% of the total cohort. Conclusion and Relevance: Rates of all-cause or fall-related ADEs were not significantly different. An 8% discontinuation rate resulting from fall-related ADEs and high rates of coadministered medications that could increase fall risk. Pharmacists can play a key role in optimizing α-1 blocker administration.

Effect of carvedilol on arteriovenous graft primary patency.

BACKGROUND: The major mechanisms of arteriovenous graft (AVG) failure due to intimal hyperplasia (IH) are smooth muscle cell proliferation and inflammation. Therefore, carvedilol may improve AVG primary patency because of its anti-proliferative and anti-inflammatory activities. METHODS: The data of end-stage renal disease patients receiving regular hemodialysis were collected from the National Health Insurance Research database. The end point was the first percutaneous transluminal angioplasty (PTA) for AVG failure or death during a follow-up period of two years or the end of 2013. The analysis was calculated with Cox proportional hazard model. RESULTS: There were 3028 patients treated with carvedilol and 13,704 patients not treated with carvedilol. According to a univariate analysis, the carvedilol group was younger, received more anti-hypertensive medications and platelet aggregation inhibitors, and had higher rates of diabetes mellitus and hyperlipidemia but had lower rates of hypotension and smoking. According to a multivariate analysis, after controlling for covariates, the use of carvedilol for more than 84 days reduced the probability of a first PTA for AVG failure by 9% compared with no use of carvedilol (p = 0.021), but the use of carvedilol for 1 to 84 days did not. CONCLUSION: The results of this study indicate that the use of carvedilol for more than 84 days improves the primary patency of AVGs, but the use of carvedilol for less than 84 days does not.

Post-operative urinary retention after lower extremity arthroplasty and the peri-operative role of selective alpha-1 adrenergic blocking agents in adult male patients: a propensity-matched retrospective cohort study.

PURPOSE: The purpose of this study was to determine whether male patients taking pre-operative selective alpha-1 adrenergic blocking agents have a lower likelihood of developing post-operative urinary retention (POUR) and a shorter length of hospitalization following lower extremity arthroplasty. METHODS: A retrospective cohort study was conducted of patients who underwent primary or revision total hip or knee arthroplasty, or unicompartmental knee arthroplasty at an academic institution from January 2002 to May 2014. A cohort of male patients aged 35 and older who were taking a selective alpha-1 blocker prior to surgery (N = 229) were compared with a control group (N = 330) not taking one of these medications. Propensity score-matched logistic regression was performed to isolate the effect of taking a selective alpha-1 blocker on POUR. RESULTS: When evaluating for the outcome of POUR while controlling for age, hypertension, benign prostatic hyperplasia, urinary tract infections, type of anaesthesia, and procedure, those patients taking an alpha-1 blocker had a 12.1% decreased relative risk (95% CI 3.4 to 20.8%; p = 0.007) of developing POUR compared with patients not taking these medications. Mean length of stay was 3.8 days (95% CI 3.6 to 4.1) in the cohort taking selective alpha-1 blockers compared with 4.7 days (95% CI 4.4 to 4.9) for the control cohort. CONCLUSIONS: After controlling for known risk factors for the development of POUR, the use of selective alpha-1 blockers pre-operatively reduces the risk of developing urinary retention after lower extremity arthroplasty and is associated with a 1-day decreased length of stay.

Alfuzosin hydrochloride-loaded low-density gastroretentive sponges: development, in vitro characterization and gastroretentive monitoring in healthy volunteers via MRI.

The current work aimed to develop low-density gastroretentive sponges loaded with alfuzosin HCl (ALF) to sustain the rate of drug release, improve its oral bioavailability and deliver it to the main site of absorption. Sponges were developed, according to a 23 full factorial design, by compression of the lyophilized ALF-loaded hydroxypropylmethylcellulose (HPMC) or chitosan (CH) solutions. The influences of the polymer type, grade and concentration on the appearance, topography, porosity, density, in vitro ALF release, floating behavior, swelling, erosion, and mucoadhesive potential of the developed sponges were explored. Based on the desirability value, the best achieved system was selected. The gastroretentive potential of this system was evaluated in healthy male volunteers via MRI. Soft and flexible sponges were developed. They were characterized with interconnecting pores and channels and had excellent floating properties with respect to floating lag time and duration. Compared to HPMC-based sponges, CH-based ones exhibited higher porosity, larger pore diameters, lower bulk densities, higher drug release rates, larger swelling ratios, faster erosion rates and better mucoadhesive properties. MRI of magnetite-loaded best-achieved CH-based system (F8) ascertained the development of a promising gastroretentive system; exhibiting a gastric residence period of at least 5 h.

Tamsulosin as a Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: Tamsulosin is widely administered as a medical expulsive therapy to facilitate stone passage in patients with ureteral calculi. Recently several large, multicenter, randomized controlled trials revealed conflicting results, which led to considerable uncertainty about the efficacy of tamsulosin in the management of ureteral stones. The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of tamsulosin in the management of ureteral stones. MATERIALS AND METHODS: We searched MEDLINE®, Embase®, Web of Knowledge, Google Scholar™ and the Cochrane Central Search Library databases up to June 2018. Two reviewers independently evaluated eligible randomized controlled trials of the efficacy of tamsulosin to treat ureteral stones. Study quality was assessed with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Subgroup analyses were performed to explore heterogeneity. RESULTS: Included in study were 56 randomized controlled trials in a total of 9,395 patients. The observed treatment effect indicated that tamsulosin was associated with a higher stone expulsion rate (RR 1.44, 95% CI 1.35-1.55, p <0.01), a shorter stone expulsion time (weighted mean difference -0.73, 95% CI -1.00--0.45, p <0.01), a lesser incidence of ureteral colic (weighted mean difference -0.81, 95% CI -1.24--0.39, p <0.01) and fewer incidences of requiring subsequent intervention (RR 0.68, 95% CI 0.50-0.93, p = 0.017). Treatment with tamsulosin did not differ from a control group in the overall incidence of side effects (RR 1.14, 95% CI 0.86-1.51, p = 0.36). On subgroup analysis we observed a significant benefit in the stone expulsion rate for tamsulosin among patients with stones greater than 5 mm (RR 1.44, 95% CI 1.22-1.68, p <0.01) but no effect for stones 5 mm or less (RR 1.08, 95% CI 0.99-1.68, p <0.01). CONCLUSIONS: Our current meta-analysis results indicate that tamsulosin is effective and relatively safe in patients with ureteral stone as a medical expulsive therapy to facilitate stone passage. It is suggested to administer it selectively in patients with 5 to 10 mm ureteral stones.

Beyond medical expulsive therapy: evolution to supported stone passage for ureteric stones.

OBJECTIVE: To evaluate the impact of removing tamsulosin from standardized ureteric stone clinical protocols on rate of stone surgery. PARTICIPANTS AND METHODS: We conducted a single-centre, comparison of all patients with unilateral, <1 cm ureteric stones presenting to a stone clinic after discharge from the emergency department during consecutive years. In the initial year, patients were initially offered medical expulsive therapy (MET) with tamsulosin. In the subsequent year, the protocol was modified to focus on symptom control without tamsulosin; this was termed 'supported stone passage' (SSP). The primary outcome was rate of stone surgery within 90 days of the initial clinic encounter. RESULTS: Among 723 patients (360 MET, 363 SSP), the rate of attempted stone passage increased from 65% to 74%, between the initial and the subsequent year (P < 0.016). Tamsulosin prescription in patients to attempting stone passage decreased from 84% to 13% (P < 0.001). In patients attempting stone passage, the rate of stone surgery was 26% in the METand 19% in the SSP group (P = 0.066). The overall surgery rate decreased from 51% in the MET group to 40% in the SSP group (P = 0.003). Multivariable analysis, controlling for age, sex and stone burden, did not demonstrate a difference in either rate of attempting to pass stones or in rate of failure of passage according to care protocol. We were unable to demonstrate an independent effect of tamsulosin on failure of passage. Overall, surgical intervention was less likely in the SSP phase than in the MET phase, with an odds ratio of 0.64 (confidence interval) 0.44-0.91; P = 0.013). CONCLUSIONS: Removing tamsulosin from clinical protocols did not impair stone passage in patients attempting to pass stones.

Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review.

We conducted a systematic review to evaluate the efficacy and adverse effects of newer drugs used to treat lower urinary tract symptoms (LUTS). The drugs were either Food and Drug Administration (FDA) approved for benign prostatic hyperplasia (BPH) or not FDA approved for BPH but have been evaluated for treatment of BPH since 2008. We searched bibliographic databases through September 2017. We included randomized controlled trials (RCTs) lasting one month or longer published in English. Outcomes of interest were LUTS assessed by validated measures. Efficacy was interpreted using established thresholds indicating clinical significance that identified the minimal detectable difference. Twenty-three unique, generally short-term, RCTs evaluating over 9000 participants were identified. Alpha-blocker silodosin and phosphodiesterase type 5 inhibitor tadalafil were more effective than placebo in improving LUTS (moderate strength evidence) but these drugs had more adverse effects, including abnormal ejaculation (silodosin). Anticholinergics were only effective versus placebo when combined with an alpha-blocker. Evidence was generally low strength or insufficient for other drugs. Evidence was insufficient to assess long-term efficacy, prevention of symptom progression, need for surgical intervention, or long-term adverse effects. Longer trials are needed to assess the effect of these therapies on response rates using established minimal detectable difference thresholds, disease progression, and harms.

Meta-analysis of the efficacy and safety of combination of tamsulosin plus dutasteride compared with tamsulosin monotherapy in treating benign prostatic hyperplasia.

BACKGROUND: We performed a meta-analysis to confirm the efficacy and safety of the combination of tamsulosin plus dutasteride compared with tamsulosin monotherapy in treating benign prostatic hyperplasia (BPH) during a treatment cycle of at least 1 year. METHODS: Randomized controlled trials were searched by using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. Systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-analyses. The data was evaluated and statistically analyzed by using RevMan version 5.3.0. RESULTS: Five studies including 4348 patients were studied. The analysis found that the combination group was significantly greater effect in international prostate symptom score (mean difference [MD], - 1.43; 95% confidence interval [CI], - 2.20 to - 0.66; P = 0.0003), prostate volume (MD, - 10.13; 95% CI, - 12.38 to - 7.88; P < 0.00001), transitional zone volume (MD, - 3.18; 95% CI, - 3.57 to - 2.79; P<0.0001), maximum urine flow rate (MD, 1.05; 95% CI, 0.82 to 1.29; P < 0.00001), prostate specific antigen (MD, - 0.54; 95% CI, - 0.80 to - 0.29; P < 0.0001) and post-void residual volume (MD, - 3.85; 95% CI, - 4.95 to - 2.76; P < 0.00001) compared with the tamsulosin group. In terms of safety, including adverse events (odds ratio [OR], 2.06; 95% CI, 1.34 to 3.17; P = 0.001), erectile dysfunction (OR, 2.24; 95% CI, 1.73 to 2.92; P < 0.00001), ejaculation disorder (OR, 3.37; 95% CI, 1.97 to 5.79; P < 0.0001), retrograde ejaculation (OR, 2.30; 95% CI, 1.08 to 4.93; P = 0.03), decreased libido (OR, 2.25; 95% CI, 1.53 to 3.31; P < 0.0001) and loss of libido (OR, 3.38; 95% CI, 1.94 to 5.88; P<0.0001), the combination group showed poor tolerance than the tamsulosin group with the exception of dizziness (OR, 1.16; 95% CI, 0.75 to 1.80; P = 0.50). The combination group significantly reduced the risk of clinical progression than the tamsulosin group especially in incidence of BPH-related symptom progression (OR, 0.56; 95% CI, 0.46 to 0.67; P < 0.00001) and acute urinary retention (OR, 0.61; 95% CI, 0.38 to 0.98; P = 0.04). CONCLUSION: The combination of tamsulosin plus dutasteride provides a preferable therapeutic effect for BPH with a higher incidence of sexual side effects, but combination-therapy can markedly reduce risk of BPH-related symptom progression and acute urinary retention relative to tamsulosin monotherapy.

Characteristics of men with untreated LUTS interested in over-the-counter tamsulosin.

INTRODUCTION: Treatment for lower urinary tract symptoms (LUTS) is often delayed, as it is considered a natural progression of aging. We described baseline demographic and clinical characteristics of men currently not using prescription medications for benign prostatic hyperplasia (BPH) but interested in self-directed use of over-the-counter (OTC) tamsulosin and who had participated in OTC tamsulosin-simulated studies. MATERIALS AND METHODS: Pooled baseline data from four OTC tamsulosin-simulated studies were analyzed for men who were currently not using BPH prescription medication and who believed that OTC tamsulosin was appropriate for use or were interested in purchasing it. Data from the OTC-simulated studies for men using BPH prescription medication and from the BPH registry, which included men diagnosed with BPH, were used for comparison. RESULTS: Overall, 3285 non-prescription-using men (mean age +/- standard deviation [SD], 60.6 +/- 11.6 years) were included. Average American Urological Association Symptom Index (AUA-SI) total score was 17.6; 25.5% reported urinary symptoms for > 5 years. Overall, 46.7% of these men had > 1 visit/year with their physicians. Baseline characteristics of prescription users from the OTC-simulated studies (n = 364; mean age ± SD, 68.3 +/- 9.1 years; mean AUA-SI score, 18.5) and of men from the BPH registry (n = 5042; 64.8 +/- 10 years; 11.6) were similar to those of non-prescription users. CONCLUSIONS: Non-prescription users had long term moderate-to-severe male LUTS, yet remained untreated; self-management may be a viable alternative strategy for this population. Disease characteristics of men not using BPH prescription medication and interested in using OTC tamsulosin were similar to those using BPH medication or diagnosed with BPH.

Murine breast cancer feed arteries are thin-walled with reduced α1A-adrenoceptor expression and attenuated sympathetic vasocontraction.

BACKGROUND: Perfusion of breast cancer tissue limits oxygen availability and metabolism but angiogenesis inhibitors have hitherto been unsuccessful for breast cancer therapy. In order to identify abnormalities and possible therapeutic targets in mature cancer arteries, we here characterize the structure and function of cancer feed arteries and corresponding control arteries from female FVB/N mice with ErbB2-induced breast cancer. METHODS: We investigated the contractile function of breast cancer feed arteries and matched control arteries by isometric myography and evaluated membrane potentials and intracellular [Ca2+] using sharp electrodes and fluorescence microscopy, respectively. Arterial wall structure is assessed by transmission light microscopy of arteries mounted in wire myographs and by evaluation of histological sections using the unbiased stereological disector technique. We determined the expression of messenger RNA by reverse transcription and quantitative polymerase chain reaction and studied receptor expression by confocal microscopy of arteries labelled with the BODIPY-tagged α1-adrenoceptor antagonist prazosin. RESULTS: Breast cancer feed arteries are thin-walled and produce lower tension than control arteries of similar diameter in response to norepinephrine, thromboxane-analog U46619, endothelin-1, and depolarization with elevated [K+]. Fewer layers of similarly-sized vascular smooth muscle cells explain the reduced media thickness of breast cancer arteries. Evidenced by lower media stress, norepinephrine-induced and thromboxane-induced tension development of breast cancer arteries is reduced more than is explained by the thinner media. Conversely, media stress during stimulation with endothelin-1 and elevated [K+] is similar between breast cancer and control arteries. Correspondingly, vascular smooth muscle cell depolarizations and intracellular Ca2+ responses are attenuated in breast cancer feed arteries during norepinephrine but not during endothelin-1 stimulation. Protein expression of α1-adrenoceptors and messenger RNA levels for α1A-adrenoceptors are lower in breast cancer arteries than control arteries. Sympathetic vasocontraction elicited by electrical field stimulation is inhibited by α1-adrenoceptor blockade and reduced in breast cancer feed arteries compared to control arteries. CONCLUSION: Thinner media and lower α1-adrenoceptor expression weaken contractions of breast cancer feed arteries in response to sympathetic activity. We propose that abnormalities in breast cancer arteries can be exploited to modify tumor perfusion and thereby either starve cancer cells or facilitate drug and oxygen delivery during chemotherapy or radiotherapy.

A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial.

BACKGROUND: Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials. METHODS/DESIGN: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred. CONCLUSIONS: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501).