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.

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.

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.

OBJECTIVE: Both the presence of lower urinary tract symptom (LUTS) and that of hypertension (HT) increase with age. We investigated the associations between male LUTS and HT, and also whether α1-blockers could allow for the alteration of symptoms.
METHODS: The subjects comprised 10 744 men with LUTS in a multicenter Japan-Tamsulosin International Prostate Symptom Score (IPSS) Survey to assess the long-term effects of α1-blockers. A total of 4828 men (mean age, 68.5 years) who received a 12-week administration of tamsulosin (0.2 mg/day) were assessed using IPSS and quality of life (QOL) surveys before and after tamsulosin administration. Data were collected by self-administered questionnaires including age, complete history and IPSS at the initial visit.
RESULTS: HT was a more common comorbidity (25.9%) than diabetes mellitus (9.9%) or cardiac disease (7.2%). The presence of HT increased significantly with the degree of frequency (mild, 21%; severe, 29%) and nocturia (mild, 23%; severe, 28%), but did not increase with the degree of urgency. Tamsulosin significantly improved all storage and voiding symptoms in every age group above 40 years. The effect of tamsulosin on storage symptoms was more prominent in patients with HT than in patients without it. Concerning voiding symptoms, however, tamsulosin was as effective in patients with HT as it was in patients without HT.
CONCLUSIONS: HT represents a risk factor for the increased frequency and severity of storage symptoms and it also influences the efficacy of α1-blockers.

OBJECTIVE: The clinical efficacy and safety of 75 mg/day of naftopidil, an α1-adrenargic receptor antagonist, was assessed in patients with benign prostatic hyperplasia (BPH).
METHODS: A total of 28 patients (mean age, 71.1 years; range, 46-86 years) with BPH were studied. Inclusion criteria were: (i) International Prostate Symptom Score (IPSS) ≥8; and (ii) quality of life (QOL) index ≥3. IPSS, QOL index, Overactive Bladder Symptom Score (OABSS), and bladder diary (urinary frequency in daytime and nighttime, frequency of urinary incontinence and urgency) were evaluated before and 4 weeks after treatment with naftopidil at 75 mg/day.
RESULTS: Total IPSS and QOL index were significantly decreased after treatment. Total OABSS tended to decrease after treatment, with significant improvements in the \"urgency\" parameter. From the bladder diary, urinary frequency in daytime and nighttime and frequency of urgency were significantly decreased after treatment. Total IPSS and QOL index in patients with previous treatment were significantly improved after treatment, with significant improvements in the \"incomplete emptying,\"\"poor flow\" and \"nocturia\" parameters of IPSS. One case with a mild adverse effect of dizziness was encountered.
CONCLUSIONS: These results suggest that administration of naftopidil at 75 mg/day was safe and effective for patients with BPH, regardless of the presence of previous treatment. This study indicates the feasibility of naftopidil at 75 mg/day as a first-line treatment for men with BPH, or a second-line treatment in cases with symptoms of incomplete emptying, poor flow and nocturia.

Prostatic α1 -adrenoceptors are known to be involved in the pathophysiology of lower urinary tract symptoms (LUTS) in patients with benign prostate obstruction (BPO). It is widely accepted that enhanced α1 -adrenergic smooth muscle contraction can contribute to bladder outlet obstruction; α1 -adrenoceptor antagonists still represent a gold standard in the treatment of LUTS. Accordingly, expression and function of α1 -adrenoceptors in the prostate have attracted large attention over the last three decades. However, recent preclinical studies have challenged our understanding of prostatic α1 -adrenoceptors. In the current review article, we summarize \"modern\" concepts of prostatic α1 -adrenoceptors which include novel intracellular mediators of contraction as well as non-contractile signaling and post-translational receptor regulation. Configuration of α1 -adrenoceptors with binding partners may determine its function, leading to a dynamic receptor with high functional plasticity. Cooperative regulation of different intracellular effectors (MAPK, Akt, transcription factors) by α1 -adrenoceptors, hormones or growth factors has been suggested. The prostatic α1 -adrenoceptor is no longer being regarded as an isolated, static receptor exclusively mediating prostatic smooth muscle contraction by G proteins, but a dynamic receptor interacting with other receptors within a complex network of mediators.

Naftopidil, approved only in Japan, is an α1-adrenergic receptor antagonist (α1-blocker) used to treat lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Different from tamsulosin hydrochloride and silodosin, in that it has higher and extremely higher affinity respectively, for the α1A-adrenergic receptor subtype than for the α1D type, naftopidil has distinct characteristics because it has a three times greater affinity for the α1D-adrenergic receptor subtype than for the α1A subtype. Although well-designed large-scale randomized controlled studies are lacking and the optimal dosage of naftopidil is not always completely determined, previous reports from Japan have shown that naftopidil has superior efficacy to a placebo and comparable efficacy to other α1-blockers such as tamsulosin. On the other hand, the incidences of ejaculatory disorders and intraoperative floppy iris syndrome induced by naftopidil may be lower than for tamsulosin and silodosin having high affinity for the α1A-adrenergic receptor subtype. However, it remains unknown if the efficacy and safety of naftopidil in Japanese is applicable to white, black and Hispanic men having LUTS/BPH in western countries.