New clinical evidence of silodosin, an α(1A) selective adrenoceptor antagonist, in the treatment for lower urinary tract symptoms.

Lower urinary tract symptoms associated with benign prostatic hyperplasia are highly prevalent in older men. Pharmacological treatment is the first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia. The first choice in the pharmacological treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia is the α(1) -adrenoceptor antagonists. Many α(1) -adrenoceptor antagonists are available in the world. Silodosin is an α(1) -adrenoceptor antagonist developed by Kissei Pharmaceutical, and has a specific selectivity for the α(1A-) adrenoceptor subtype. By antagonizing α(1A) -adrenoceptor in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. As a result of the high affinity for the α(1A) -adrenoceptor than for the α(1B) -adrenoceptor, silodosin minimizes the propensity for blood pressure-related adverse effects caused by blockade of α(1B) -adrenoceptor. The efficacy and safety of silodosin for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia was first reported by Japanese investigators in 2006. At present, silodosin is used in many countries. In the present review, we summarize the new clinical evidence for lower urinary tract symptoms associated with benign prostatic hyperplasia and introduce the data supporting the new clinical indications of silodosin.

Safety and efficacy of silodosin for the treatment of benign prostatic hyperplasia.

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are highly prevalent in older men. Medical therapy is the first-line treatment for LUTS associated with BPH. Mainstays in the treatment of male LUTS and clinical BPH are the α(1)-adrenergic receptor antagonists. Silodosin is a new α(1)-adrenergic receptor antagonist that is selective for the α(1A)-adrenergic receptor. By antagonizing α(1A)-adrenergic receptors in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. Since silodosin has greater affinity for the α(1A)-adrenergic receptor than for the α(1B)-adrenergic receptor, it minimizes the propensity for blood pressure-related adverse effects caused by α(1B)-adrenergic receptor blockade. In the clinical studies, patients receiving silodosin at a total daily dose of 8 mg exhibited significant improvements in the International Prostate Symptom Score and maximum urinary flow rate compared with those receiving placebo. Silodosin showed early onset of efficacy for both voiding and storage symptoms. Furthermore, long-term safety of silodosin was also demonstrated. Retrograde or abnormal ejaculation was the most commonly reported adverse effect. The incidence of orthostatic hypotension was low. In conclusion, silodosin, a novel selective α(1A)-adrenergic receptor antagonist, was effective in general and without obtrusive side effects. This review provides clear evidence in support of the clinical usefulness of silodosin in the treatment of LUTS associated with BPH.

Ejaculation disorder is associated with increased efficacy of silodosin for benign prostatic hyperplasia.

OBJECTIVES: To provide clinical evidence that ejaculation disorder caused by selective alpha(1A)-blockers may be associated with larger symptomatic improvements in patients with benign prostatic hyperplasia. METHODS: Post hoc analyses of data from a randomized, double-blind, placebo-controlled clinical trial of silodosin in Japan were performed. Subjects were randomized into 3 treatments: silodosin (4 mg twice daily), tamsulosin (0.2 mg once daily), or placebo. For statistical analysis, subjects receiving silodosin were stratified by the presence or absence of ejaculation disorder. Efficacy was assessed using total International Prostate Symptom Score (IPSS), IPSS subscores, 25% reduction in total IPSS, and quality of life score. Safety was assessed by frequency of adverse drug reactions (ADRs) and silodosin discontinuation. RESULTS: The silodosin subgroup with ejaculation disorder (SIL+EjD) showed larger change in total IPSS than the silodosin subgroup without ejaculation disorder (SIL-EjD) (difference: -4.36 [95% CI: -6.44 to -2.27]) and the placebo group (difference: -6.29 [95% CI: -8.44--4.14]). Remarkable improvement was observed at all time points. The success rate in SIL+EjD was higher than in SIL-EjD and placebo when measured using a 25% reduction in the total IPSS category. There were no significant differences in ADR rates other than ejaculation disorder. Discontinuation rates between SIL+EjD and SIL-EjD were similar. CONCLUSIONS: Our results suggest that ejaculation disorder caused by selective alpha(1A)-blockers is associated with very large improvements in lower urinary tract symptoms. Patients with ejaculation disorder may have larger symptomatic improvements without incremental risk for adverse events.

Silodosin, a novel selective alpha 1A-adrenoceptor selective antagonist for the treatment of benign prostatic hyperplasia.

Silodosin is a novel selective alpha(1A)-adrenoceptor (AR) antagonist generated by Kissei Pharmaceutical Co. Ltd. This drug selectively binds to alpha(1A)-AR, which is widely distributed in the prostate, urethra and bladder trigone, involved in their contraction, located at the lower urinary tract. This high selectivity for alpha(1A)-AR contributes to inhibition of sympathetic nerve stimulation and relaxation of smooth muscle tone of the lower urinary tract tissues, resulting in suppression of increase in intraurethral pressure. Clinical data suggested that silodosin showed significant improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia, as well as in quality of life. The improvements were observed in both voiding and storage symptoms. In addition, the clinical effects occurred in the early treatment phase, and were observed not only in mild cases, but also in cases with severe symptoms. Long-term study revealed that the efficacy and safety was sustained for 1 year. Although silodosin showed relatively high incidence rate of abnormal ejaculation, the adverse events associated with lowering of blood pressure were low. This article reviews preclinical and clinical data of silodosin, and introduces the usefulness of the drug for treatment of benign prostatic hyperplasia patients.

Prediction of alpha1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia.

Alpha1-adrenoceptor antagonists are clinically useful for the improvement of urinary obstruction due to benign prostatic hyperplasia (BPH), and their therapeutic effects are mediated through the blockade of prostatic alpha(1)-adrenoceptors. The present study was undertaken to predict the magnitude and duration of alpha(1)-adrenoceptor occupancy in the human prostate after oral alpha(1)-adrenoceptor antagonists. Prostatic alpha(1)-adrenoceptor-binding parameters of silodosin were estimated by measuring specific [(3)H]prazosin binding in rat prostate after oral administration of this drug. The plasma concentration of silodosin after oral administration in rats and healthy volunteers was measured using a high-performance liquid chromatographic method. The alpha(1)-adrenoceptor-binding affinities (K(i)) of silodosin, tamsulosin, and terazosin in the human prostate and plasma concentrations of tamsulosin and terazosin were obtained from the literature. Using the alpha(1)-adrenoceptor binding parameters of silodosin in rat prostate, alpha(1)-adrenoceptor occupancy in the human prostate was estimated to be around 60-70% at 1-6 h after oral administration of silodosin at doses of 3.0, 8.1, and 16.1 micromol. Thereafter, the receptor occupancy was periodically decreased, to 24% (8.1 micromol) and 54% (16.1 micromol) 24 h later. A similar magnitude and time course of alpha(1)-adrenoceptor occupancy by silodosin in the human prostate were estimated using alpha(1)-adrenoceptor-binding affinities (K(i)) in the human prostate. Despite about two orders of differences in the plasma unbound concentrations after clinically effective oral dosages of silodosin, tamsulosin, and terazosin, there was a comparable magnitude of prostatic alpha(1)-adrenoceptor occupancy by these drugs. In conclusion, the prediction of alpha(1)-adrenoceptor occupancy in the human prostate by alpha(1)-adrenoceptor antagonists may provide the rationale for the optimum dosage regimen of these drugs in the therapy of BPH.

Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men.

OBJECTIVE: To verify the efficacy and safety of the new alpha1A-adrenoceptor-selective antagonist silodosin compared with tamsulosin and placebo in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled study was conducted at 88 centres in Japan. Men aged > or = 50 years with an International Prostate Symptom Score (IPSS) of > or = 8, a quality-of-life (QoL) score of > or = 3, a maximum urinary flow rate (Qmax) of < 15 mL/s, a prostate volume of > or = 20 mL and a postvoid residual urine volume of < 100 mL were eligible for enrolment. Patients were randomized to receive silodosin 4 mg twice daily, tamsulosin 0.2 mg once daily, or placebo, for 12 weeks. The primary endpoint was the change in IPSS from baseline. Safety was assessed by adverse events, physical examination, vital signs and laboratory tests. RESULTS: In all, 457 patients were randomized (silodosin 176, tamsulosin 192 and placebo 89). The change in the total IPSS from baseline in the silodosin, tamsulosin and placebo groups was -8.3, -6.8 and -5.3, respectively. There was a significant decrease in the IPSS vs placebo in the silodosin group from 1 week. In the early-stage comparison, silodosin showed a significant decrease in IPSS vs tamsulosin at 2 weeks. The change in QoL from baseline was -1.7, -1.4 and -1.1 in the silodosin, tamsulosin and placebo groups, respectively; silodosin showed a significant improvement in the QoL score vs placebo. In the subgroup of patients with severe symptoms (IPSS > or = 20) silodosin also gave a significantly better improvement than placebo (-12.4 vs -8.7). The incidence rates of adverse events and drug-related adverse events were, respectively, 88.6%, 82.3% and 71.6% and 69.7%, 47.4% and 36.4%, respectively. The most common adverse event in the silodosin group was abnormal ejaculation, which occurred more often in the silodosin than in the tamsulosin group (22.3% vs 1.6%). However, only five men (2.9%) discontinued treatment for abnormal ejaculation. CONCLUSION: Silodosin was generally effective in the absence of obtrusive side-effects. This study suggests that silodosin is clinically useful for treating LUTS associated with BPH.

[Latest frontiers in pharmacotherapy for benign prostatic hyperplasia].

Alpha(1)-adrenoceptor antagonists, called alpha(1)-blockers, are the first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Nonselective alpha(1)-blockers like prazosin were mainly used in the past, but prostate-specific alpha(1)-blockers such as tamsulosin or naftopidil are now the mainstream agents for the management of BPH, based on the function of alpha(1)-adrenoceptor subtypes. Recent studies on voiding dysfunction have clarified the association between BPH and overactive bladder (OAB), underlining the use of OAB treatment in the management of BPH, inducing the simultaneous administration of antimuscarinic agents. Every aspect of diversified BPH symptom can be controlled individually in a short period.

How frequent are invasive therapies required in patients receiving tamsulosin for benign prostatic hyperplasia? A retrospective long-term study.

Three hundred Japanese patients with benign prostatic hyperplasia (BPH) who started an alpha1-adrenoceptor blocker, tamsulosin, between 1993 and 1996 were followed for 3.0+/-3.3 years (mean+/-SD) to determine whether an association existed between the disease severities measured prior to the tamsulosin treatment and the timing at which the invasive therapy was implemented. Patients with a lower quality of life (QOL) index or maximum urinary flow rate (Qmax) were transferred for invasive therapy earlier than those with less severe BPH. The International Prostate Symptom Score (I-PSS) was also associated, but apparently to a lesser extent, with the timing of the invasive therapy. Finally, the overall severity evaluated using all of the above three indices, I-PSS, QOL index, and Qmax, in accordance with the 'Severity Criteria for BPH' issued by the Japanese Urological Association, was found to be a good measure for predicting the prognosis of patients with BPH treated with tamsulosin.

A clinical study of PMCJ-9 (Bacillus Calmette-Guérin Connaught strain) treatment of superficial bladder cancer and carcinoma in situ of the bladder.

BACKGROUND: Intravesical Bacillus Calmette-Guérin (BCG) is now a standard treatment for Ta, T1 carcinoma and carcinoma in situ (CIS) of the urinary bladder. In Japan, however, only BCG Tokyo 172 strain is commercially available. We therefore designed a clinical study of PMCJ-9 (BCG Connaught strain) for obtaining approval from Japanese Ministry of Health, Labor and Welfare. METHODS: In the phase I-II study, PMCJ-9 40.5, 81 (standard dose overseas) or 121.5 mg in saline was instilled into the bladder of patients with Ta, T1 or CIS once weekly for 8 weeks. The recommended dose was decided and similarly administered in the late phase II study. RESULTS: In the phase I-II study, 49 patients were evaluable for efficacy. The complete response (CR) rates were 60.0% (9/15), 68.2% (15/22) and 75.0% (9/12) in the 40.5, 81 and 121.5 mg groups. The incidence of adverse drug reactions (ADRs) was similar in all groups, but four 121.5 mg group patients developed severe ADRs. Thus, 81 mg was the recommended dose for the late phase II study. In that study, 39 patients were evaluable, showing CR rates of 71.8% (28/39) overall and 61.5% (16/26) and 92.3% (12/13) for the Ta, T1 and CIS cases. The safety was assessed in 42 patients and three (7.1%) were discontinued owing to ADRs. CONCLUSION: The recommended dose for the BCG Connaught strain was decided as 81 mg. PMCJ-9 administration at this dose level weekly for 8 weeks showed a clear antitumor effect and good safety profile against Ta, T1 and CIS transitional cell carcinoma of the bladder.

Habitual intake of lactic acid bacteria and risk reduction of bladder cancer.

INTRODUCTION: A kind of lactic acid bacteria, Lactobacillus casei strain Shirota, shows antitumor activity in experimental animals. One clinical trial using L. casei showed a significant decrease in the recurrence of superficial bladder cancer. So, to assess the preventive effect of the intake of L. casei, widely taken as fermented milk products in Japan, against bladder cancer, we conducted a case-control study. METHODS: A total of 180 cases (mean age: 67 years, SD 10) were selected from 7 hospitals, and 445 population-based controls matched by gender and age were also selected. Interviewers asked them 81 items. The conditional logistic regression was used to estimate adjusted odds ratios (OR). RESULTS: The OR of smoking was 1.61 (95% confidence interval: 1.10-2.36). Those of previous (10-15 years ago) intake of fermented milk products were 0.46 (0.27-0.79) for 1-2 times/week and 0.61 (0.38-0.99) for 3-4 or more times/week, respectively. CONCLUSION: It was strongly suggested that the habitual intake of lactic acid bacteria reduces the risk of bladder cancer.

Treatment of patients with superficial bladder cancer by intravesical instillation of anticancer drugs plus oral chemotherapy following TUR-Bt: a randomized controlled trial.

We conducted a randomized controlled trial to compare local recurrence rate after transurethral resection of superficial bladder cancer treated by either intravesical instillation of an anticancer drug alone (method A) and the intravesical instillation plus oral chemotherapy (doxifluridine, 5'-DFUR, an intermediate metabolite of capecitabine) (method B). Results between groups showed no difference in recurrence-free survival curves in 196 patients subjected to primary analysis. However, patients subjected to secondary analysis (method B, over 3 months administration of 5'-DFUR) showed a significantly better prognosis than method A (p=0.0244, Wilcoxon). Regarding correlation between thymidine phosphorylase (TP, an enzyme to convert 5'-DFUR to 5-fluorouracil) level and prognosis, method A patients showed poorer prognosis in higher TP level cases than in lower TP levels. However, there was no significant difference in prognosis between those with higher and lower TP levels. In method B patients, there was no difference in prognosis between those with higher and lower TP levels. Method A patients tended to show a slightly better prognosis than those with lower TP levels, while method B patients tended to have a slightly better prognosis with higher TP levels, but no significant difference was observed. These findings suggested 5'-DFUR showed a mild efficacy in patients with higher TP levels and that patients with higher TP levels resulted in poorer prognosis.