OBJECTIVE: Antimuscarinics and the β3-adrenoreceptor agonist, mirabegron, are commonly used for treating patients with overactive bladder (OAB) and α1 -adrenoreceptor antagonists (α1 -blockers) are the main pharmacological agents used for treating lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). As these conditions commonly occur together, the aim of this systematic review was to identify publications that compared the use of an α1 -blocker plus mirabegron with an α1 -blocker plus antimuscarinic in men with LUTS secondary to BPH and OAB. A meta-analysis was subsequently conducted to explore the safety and efficacy of these combinations.
METHODS: Included records had to be from a parallel-group, randomized clinical trial that was ≥8 weeks in duration. Participants were male with LUTS secondary to BPH and OAB. The indirect analyses that were identified compared an α1 -blocker plus OAB agent with an α1 -blocker plus placebo. The PubMed/Medical Literature Analysis and Retrieval System Online, the Excerpta Medica Database, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry were searched for relevant records up until March 5, 2020. Safety outcomes included incidences of overall treatment-emergent adverse events (TEAEs) and urinary retention, postvoid residual volume, and maximum urinary flow (Qmax ). Primary efficacy outcomes were micturitions/day, incontinence episodes/day, and urgency episodes/day, and secondary outcomes were Overactive Bladder Symptom Score and International Prostate Symptom Score. A Bayesian network meta-analysis approach was used for the meta-analysis.
RESULTS: Out of a total of 1039 records identified, 24 were eligible for inclusion in the meta-analysis. There were no statistically significant differences between the α1 -blocker plus mirabegron and α1 -blocker plus antimuscarinic groups in terms of the comparisons identified for all the safety and efficacy analyses conducted. Numerically superior results were frequently observed for the α1 -blocker plus mirabegron group compared with the α1 -blocker plus antimuscarinic group for the safety parameters, including TEAEs, urinary retention, and Qmax . For some of the efficacy parameters, most notably micturitions/day, numerically superior results were noted for the α1 -blocker plus antimuscarinic group. Inconsistency in reporting and study variability were noted in the included records, which hindered data interpretation.
CONCLUSIONS: This systematic review and meta-analysis showed that an α1 -blocker plus mirabegron and an α1 -blocker plus antimuscarinic have similar safety and efficacy profiles in male patients with LUTS secondary to BPH and OAB. Patients may, therefore, benefit from the use of either combination within the clinical setting.

Phospholipases A2 (PLA2 ) may be involved in α1 -adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1 -adrenergic contractions of the prostate, is still unknown. While α1 -adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2 . Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues.
Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1 -adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls.
Frequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS-induced contractions, nor contractions by α1 -adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM).
Our findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1 -adrenergic agonists occur PLA2 -independent. Lacking sensitivity to montelukast excludes an involvement of PLA2 -derived leukotrienes in promotion of contractile neurotransmission.

There is emerging evidence that α1-blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1-blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1-blockers as add-on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1-blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1-blockers have to be used under several considerations. Among the currently available agents, only long-acting α1-blockers, such as doxazosin gastrointestinal therapeutic system 4-8 mg daily and terazosin 2-4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1-blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1-blocker with a diuretic.

UNASSIGNED: To evaluate the oncological outcomes and genitourinary and gastrointestinal adverse events in acute and late-phases of iodine-125 low-dose-rate brachytherapy for localized prostate cancer.
UNASSIGNED: We retrospectively evaluated 334 patients treated for localized prostate cancer with low-dose-rate brachytherapy. Bio-chemical relapse-free survival, cause-specific survival, and overall survival were evaluated using Kaplan-Meier method and log-rank test. Incidence of adverse events was calculated using National Cancer Institute common terminology criteria for adverse events, version 5. Logistic regression was used to identify independent predictors of acute and late-phase genitourinary and gastrointestinal adverse events.
UNASSIGNED: National Comprehensive Cancer Network\'s low-, intermediate-, and high-risk groups included 133 (39.8%), 163 (48.8%), and 38 (11.3%) patients, respectively. The 5-year cause-specific survival rate was 100%. The 5-year bio-chemical relapse-free survival rates for the low-, intermediate-, and high-risk groups were 98.3%, 95.8%, and 100%, respectively. One patient had a ≥ grade 3 acute adverse event. The 5-year cumulative ≥ grade 1, ≥ grade 2, and ≥ grade 3 genitourinary adverse event rates were 27.9%, 14.4%, and 0.5%, respectively. The 5-year cumulative ≥ grade 1, ≥ grade 2, and ≥ grade 3 gastrointestinal adverse event rates were 3.1%, 1.5%, and 0.5%, respectively. A high pre-treatment international prostate symptom score and non-use of α1-blockers were associated with an increased risk of acute genitourinary adverse events.
UNASSIGNED: Low-dose-rate brachytherapy had good oncological outcomes, with acceptable adverse event rates. Pre-treatment urinary function and use of α1-blockers may be useful in predicting and preventing acute genitourinary adverse events.

We recently demonstrated that silodosin, a selective α1-blocker often prescribed for the symptomatic treatment of benign prostatic hyperplasia (BPH), could inactivate a c-fos proto-oncogene regulator ELK1 in bladder cancer cells possessing a functional androgen receptor (AR). However, the clinical impact of α1-blockers on the development and progression of bladder cancer remained poorly understood. In the present study, we investigated if α1-blockers clinically used, including silodosin, tamsulosin, and naftopidil, could prevent the neoplastic/malignant transformation and cell growth, using non-neoplastic urothelial SVHUC sublines with carcinogen/MCA challenge and bladder cancer lines, respectively. Bladder cancers in men treated with silodosin, tamsulosin, or naftopidil for their BPH were then compared. Silodosin at 1-10 µM significantly inhibited the neoplastic transformation of MCA-SVHUC-AR cells, but not that of AR-negative MCA-SVHUC-control cells. In MCA-SVHUC-AR, silodosin significantly reduced the expression levels of oncogenes (c-fos/NF-κB1) and induced those of tumor suppressors (p27/PTEN). However, tamsulosin (up to 1 µM) or naftopidil (up to 10 µM) failed to significantly inhibit the neoplastic transformation of AR-positive or AR-negative urothelial cells. Similarly, cell proliferation/migration of AR-positive bladder cancer lines was considerably inhibited only by silodosin. Meanwhile, the incidence of bladder cancer in patients with silodosin [49/540 (9.1%)] was marginally lower, compared to those with tamsulosin [64/523 (12.2%); P=0.094] or tamsulosin or naftopidil [64+28/523+236 (12.1%); P=0.082]. There were no significant differences in tumor grade/stage among the 3 cohorts. Outcome analysis revealed lower risks for disease progression of non-muscle-invasive bladder tumors in the silodosin group than in the naftopidil group (P=0.011) or tamsulosin+naftopidil groups (P=0.035). Similarly, silodosin patients with muscle-invasive tumor had lower risks for disease progression, compared with tamsulosin (P=0.006) or tamsulosin+naftopidil (P=0.028) patients. Multivariate analysis further showed that silodosin treatment in those with non-muscle-invasive tumor was associated with improved progression-free survival, compared with naftopidil (hazard ratio=0.086; 95% confidence interval=0.008-0.905; P=0.041) or tamsulosin/naftopidil (hazard ratio=0.128; 95% confidence interval=0.016-1.036; P=0.054) treatment. Our in vitro studies thus indicate that both urothelial tumorigenesis and tumor growth are inhibited by silodosin, but not by tamsulosin or naftopidil. Clinical data further suggest that even pharmacological doses (e.g. 0.1 µM) of silodosin contribute to preventing bladder cancer progression.

Urinary measurement of fractionated metanephrines is one of the best available biochemical tests for the diagnosis of pheochromocytoma and paraganglioma; however, false-positive results remain an issue. In addition, despite their convenience, there is no evidence to suggest that spot urine samples should replace the standard 24-h urine collection method. The objective of this study is to elucidate clinical variables that may influence the levels of spot urine fractionated metanephrines and to examine their instability. The study is a retrospective review of prospectively collected data from 949 patients whose spot urine fractionated metanephrines were measured under suspicion of pheochromocytoma or paraganglioma at our institution from January 2011 to June 2017. The effects of clinical factors such as age, sex, renal function, and medications on the level of spot urine fractionated metanephrines were evaluated. Urinary fractionated metanephrines were significantly higher in female subjects. They correlated with age but not with estimated glomerular filtration rate (eGFR). A multivariate regression model for urinary fractionated metanephrine levels revealed that age, female sex, eGFR, and the presence of α1-blocker medication were significantly positively correlated with urinary metanephrine (M) levels. Age, female sex, eGFR, and presence of α1-blockers and antidepressant and antipsychotic medications positively correlated with urinary normetanephrine (NM). In addition, age, female sex, eGFR, and presence of α1-blockers and antidepressant and antipsychotic medications were positively correlated with urinary M + NM. In conclusion, sex, age, eGFR, and treatment with α1-blockers, antidepressants, and antipsychotics may affect the levels of urinary fractionated metanephrines. When assessing urinary fractionated metanephrines in patients with suspected PPGLs, we must consider these factors.

Background: Prostate smooth muscle contraction plays an important role for pathophysiology and treatment of male lower urinary tract symptoms (LUTS) but is incompletely understood. Because the efficacy of available medication is limited, novel options and improved understanding of prostate smooth muscle contraction are of high demand. Recently, a possible role of polo-like kinase 1 (PLK1) has been suggested for smooth muscle contraction outside the lower urinary tract. Here, we examined effects of PLK inhibitors on contraction of human prostate tissue. Methods: Prostate tissues were obtained from radical prostatectomy. RT-PCR, Western blot and immunofluorescence were performed to detect PLK expression and phosphorylated PLK. Smooth muscle contractions were induced by electric field stimulation (EFS), α1-agonists, endothelin-1, or the thromboxane A2 analog U46619 in organ bath. Results: RT-PCR, Western blot, and immunofluorescence suggested expression of PLK1 in the human prostate, which may be located and active in smooth muscle cells. EFS-induced contractions of prostate strips were reduced by SBE 13 (1 μM), cyclapolin 9 (3 μM), TAK 960 (100 nM), and Ro 3280 (100 nM). SBE 13 and cyclapolin 9 inhibited contractions by the α1-agonists methoxamine, phenylephrine, and noradrenaline. In contrast, no effects of SBE 13 or cyclapolin 9 on endothelin-1- or U46619-induced contractions were observed. Conclusion: Alpha1-adrenergic smooth muscle contraction in the human prostate can be inhibited by PLK inhibitors. PLK-dependent signaling may be a new pathway, which promotes α1-adrenergic contraction of prostate smooth muscle cells. As contractions by endothelin and U46619 are not susceptible to PLK inhibition, this reflects divergent regulation of adrenergic and non-adrenergic prostate smooth muscle contraction.

Ideal therapy for lower urinary tract dysfunction in patients with spinal cord injury (SCI) should decrease detrusor overactivity, thereby promoting urine storage at low intravesical pressure and promoting efficient voiding at low pressure by decreasing detrusor-sphincter dyssynergia. Here we investigated blockade of various α-adrenoceptors to determine the subtype that was principally responsible for improving the voiding dysfunction. The effects of the intravenous α-blocker naftopidil, the α-blocker BMY 7378, and the α-blocker silodosin were evaluated using cystometrography and external urethral sphincter-electromyography (EMG) in decerebrated, unanesthetized female Sprague-Dawley rats with chronic SCI following transection at Th8. Parameters measured included the voided volume, residual volume, voiding efficiency, and burst and silent periods on EMG. Compared with values in decerebrated non-SCI rats, EMG of decerebrated SCI rats revealed more prominent tonic activity, significantly shorter periods of bursting activity, and a reduced ratio of the silent to active period during bursting. Compared with the value before drug administration (control), the voiding efficiency was significantly increased by naftopidil (1 and 3 mg/kg) (<0.05 each), and the burst (<0.01 and <0.05, respectively) and silent periods (<0.01 each) on EMG were significantly lengthened. BMY 7378 (1 mg/kg) significantly increased voiding efficiency and lengthened the burst periods (<0.05 each). Silodosin did not affect any parameters. These results suggest that α-blockade reduces the urethral resistance associated with detrusor-sphincter dyssynergia, thus improving voiding efficiency in SCI rats.

Background Regression of meningioma has been reported after hemorrhage or hormonal withdrawal. Here, we report a case of an incidentally diagnosed meningioma that regressed in association with α1-adrenoceptor antagonist. Case report A 59-year old male patient with an incidentally diagnosed lateral sphenoid wing meningioma was followed with serial magnetic resonance imaging. The tumor with a maximum diameter of 43 mm showed progressive regression, and after 3 years the size was reduced to 22% of the initial volume. During follow-up the patient was treated with an α1-adrenoceptor antagonist (tamsulosin) for benign prostatic hyperplasia. Possible mechanisms are discussed, including our main hypothesis of reduced mitogenic effects through phospholipase C-signal transduction. Conclusion This is the first report of regression of an incidentally diagnosed meningioma associated with α1-adrenoceptor antagonist treatment.

To prospectively investigate the association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective α1 -blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms (BPH/LUTS), as nitric oxide has recently gained increasing recognition as an important neurotransmitter of functions in the lower urinary tract.
In all, 136 men with BPH/LUTS were recruited from urology outpatient clinics in a university hospital. Oral therapy with doxazosin gastrointestinal therapeutic system (GITS) 4 mg once-daily was given for 12 weeks. The drug efficacy was assessed by the changes from baseline in the total International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ) and post-void residual urine volume (PVR) at 12 weeks of treatment. The \'responders\' to doxazosin GITS were defined as those who had a total IPSS decrease of >4 points from baseline. eNOS G894T polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism method.
Patients had statistically significant improvements in total IPSS, quality of life score, and Qmax (P < 0.01) after a 12-week period of treatment. Using multiple logistic regression analysis adjusted for age and IPSS, our results showed that being a eNOS 894T allele carrier was an independent risk factor for being a drug non-responder (P = 0.03, odds ratio 4.19). Moreover, a decreased responder rate (P = 0.01), as well as the lower improvements in IPSS (P = 0.02) and Qmax (P = 0.03) were significantly associated with increment in the T allele number.
The presence of the eNOS 894T allele had a significantly negative impact on responsiveness to a selective α1 -blocker in BPH/LUTS treatment, suggesting that eNOS G894T gene polymorphism may be a genetic susceptibility factor for α1 -blocker efficacy in men with BPH/LUTS.