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Keywords:

  • α1-adrenoceptor antagonist;
  • benign prostatic hyperplasia;
  • crossover study;
  • silodosin;
  • tamsulosin hydrochloride

Abstract

  1. Top of page
  2. Abstract
  3. 1. INTRODUCTION
  4. 2. METHODS
  5. 3. RESULTS
  6. 4. DISCUSSION
  7. 5. CONCLUSIONS
  8. REFERENCES

Objectives: We assessed the efficacy and safety of two α1-adrenoceptor antagonists, tamsulosin and silodosin, in the treatment of male lower urinary tract symptoms.

Methods: Men aged 50 years or older who had a total International Prostate Symptom Score (IPSS) of 8 or higher were enrolled in this study. Forty-six patients were randomized into two groups. Twenty-three patients were initially prescribed tamsulosin 0.2 mg once daily for 3 months, followed by silodosin 4 mg twice daily for 3 months (group T); the other group of 23 patients were initially prescribed silodosin, followed by tamsulosin (group S). Patients then switched to the alternative treatment after a 1-month clearance period. Evaluations included clinical determination of IPSS, quality-of-life index, maximum flow rate and postvoid residual urine volume before and after treatment.

Results: A total of 46 men, 23 in group T and 23 in group S, were treated and 41 (89.1%) completed the treatment. IPSS, quality-of-life index, maximum flow rate and postvoid residual urine volume were significantly improved in both groups after treatment. The changes in the total IPSS from baseline in groups S and T at 3 months were −6.6 and −7.5, respectively. There were no significant differences between the two groups. After taking both medications, 18 patients preferred silodosin, 11 preferred tamsulosin and others felt they had the same effects. Six and none patients experienced adverse events during silodosin and tamsulosin treatment, respectively.

Conclusion: Two types of α1-adrenoceptor antagonists in the same individuals provide similar efficacy. Profiles and difference of each drug should be considered in making treatment choice.


1. INTRODUCTION

  1. Top of page
  2. Abstract
  3. 1. INTRODUCTION
  4. 2. METHODS
  5. 3. RESULTS
  6. 4. DISCUSSION
  7. 5. CONCLUSIONS
  8. REFERENCES

Benign prostatic hyperplasia (BPH) is a chronic condition associated with lower urinary tract symptoms (LUTS). LUTS are common among elderly men and are therefore previously considered synonymous with BPH. Treatment for BPH aims to relieve two types of urinary tract obstruction: mechanical urinary tract obstruction caused by tissue compression due to an enlarged prostate, and functional urinary tract obstruction caused by constriction of the urinary tract and prostatic smooth muscle via sympathetic α1 adrenoceptors (α1-AR). As a result, α1-AR antagonists are widely recognized as the first-line pharmacotherapy for BPH treatment.1

α1-AR can be pharmacologically distinguished from α1A, α1B and α1D on the basis of differential binding to α1-AR antagonists, as well as differential inactivation by the alkylating agent chloroethylclonidine.2,3

Molecular and contraction studies in human prostate tissue demonstrate α1A-AR subtype predominance (70–100%) in prostate stroma.4

Tamsulosin blocks α1A- and α1D-ARs with a 10-fold greater affinity than α1B-AR.5 The newest compound, silodosin, was approved as a new highly selective α1-AR antagonist to improve LUTS associated with BPH in 2006 in Japan and in 2008 in the United States. The affinities of silodosin toward α1A are about 162 times greater than those toward α1B.6

Many papers have been published showing that the efficacy of the α1-AR antagonists alfuzosin, doxazosin, tamsulosin and terazosin is comparable.7,8 However, there have been few comparative studies between silodosin and tamsulosin.9

We assessed the efficacy and safety of two α1-AR antagonists, tamsulosin hydrochloride and silodosin, in the treatment of male LUTS suggestive of BPH.

2. METHODS

  1. Top of page
  2. Abstract
  3. 1. INTRODUCTION
  4. 2. METHODS
  5. 3. RESULTS
  6. 4. DISCUSSION
  7. 5. CONCLUSIONS
  8. REFERENCES

This study was conducted with the approval of the Institutional Review Board of Kawasaki Medical School. After obtaining written informed consent, subjects were registered and divided according to total International Prostate Symptom Score (IPSS) into the following two groups: (i) Tamsulosin preceding group (Group T), receiving 0.2 mg of tamsulosin hydrochloride once daily, and (ii) Silodosin preceding group (Group S), receiving 4 mg of silodosin twice daily. Subjects comprised 46 consenting males patients with LUTS with BPH who visited Kawasaki Medical University Hospital between June 2008 and March 2010 and satisfied the following conditions: fifty years old or older who had a total IPSS of 8 or higher and a quality-of-life (QOL) index of 3 or higher were enrolled in this study. Patients who had prostate cancer, neurogenic bladder, urethral stricture, active urinary tract infection and other complications considered likely to affect micturition, were excluded. Forty-six patients (mean age 69.5 years, range 56–83) were randomized into two groups. Twenty-three patients were initially prescribed tamsulosin hydrochloride for 3 months, followed by silodosin for 3 months (group T); the other group of 23 patients was initially prescribed silodosin for 3 months, followed by tamsulosin hydrochloride for 3 months (group S). Patients then switched to the alternative treatment after a 1-month clearance period. Evaluations included clinical determination of IPSS, QOL index, maximum flow rate (Qmax) and postvoid residual urine volume (PVR) before and after treatment. PVR was measured by transabdominal ultrasonography. Patients with an elevated serum prostatic specific antigen level more than 4 ng/mL were recommended transrectal ultrasonography guided 12-core biopsy. In this series, two patients received biopsy and confirmed no malignancy. Transabdominal ultrasonography was performed to determine prostate volume.

Based on data characteristics, the mean ± standard deviation was calculated. In terms of statistical analysis, the Wilcoxon signed-rank test was performed to compare data pre- and post-administration in each group. The Mann–Whitney U-test was used for inter-group comparisons. P values of less than 0.05 were considered significant.

3. RESULTS

  1. Top of page
  2. Abstract
  3. 1. INTRODUCTION
  4. 2. METHODS
  5. 3. RESULTS
  6. 4. DISCUSSION
  7. 5. CONCLUSIONS
  8. REFERENCES

3.1. Assessments

Of the 46 patients who registered, 23 patients each were assigned to group T and group S. Two patients who did not make a fifth or sixth visit, and three patients who stopped taking the assigned drug due to adverse events could not be assessed and were excluded. Forty-one (89.1%) completed the treatment. Table 1 shows pre-administration background factors for the 46 patients.

Table 1.  Pre-administration background factors of patients in group T and group S
  Group T (n = 23)Group S (n = 23)Inter-group
  1. Mean ± standard deviation. Pre-administration background factors were compared inter-group by the Mann–Whitney U-test. IPSS, International Prostate Symptom Score; PSA, prostatic specific antigen; QOL, quality of life.

 Age (y)70.0 ± 6.868.9 ± 5.60.552
 Prostate volume (mL)36.1 ± 15.535.0 ± 18.40.553
 PSA (ng/mL)3.5 ± 3.72.5 ± 3.40.087
Subjective symptomIPSS storage symptoms8.6 ± 3.47.7 ± 2.80.506
IPSS voiding symptoms9.7 ± 3.18.7 ± 3.20.207
Total IPSS21.1 ± 6.819.3 ± 4.90.247
IPSS QOL index4.5 ± 1.04.6 ± 0.90.963
Objective symptomVoiding volume (mL)118.2 ± 64.2130.9 ± 95.30.978
Max flow rate (mL/sec)7.6 ± 3.07.2 ± 2.90.601
Postvoid residual urine volume (mL)62.8 ± 80.693.9 ± 1510.445

3.2. Clinical assessment

The total IPSS was significantly improved after treatment in the two groups (Table 2). IPSS storage symptoms and voiding symptoms subscores were also significantly improved in the two groups after treatment. The changes in the total IPSS from the baseline in groups S and T at 3 months were −6.6 and −7.5, respectively. QOL scores were significantly improved after therapy in the two groups. There was no statistically significant difference in almost all subjective items between the two groups. Interestingly, total IPSS and IPSS storage symptoms subscores for group S after 1-month clearance were significantly lower than that of group T (Table 2). The changes in the total IPSS from 3 months after treatment to 1 month clearance in groups S and T were +1.8 and +6.2 (P = 0.0139), respectively. Especially the carry-over effect was significant in IPSS storage symptoms. No significant differences were found in the degree of change in 7 IPSS items among the two groups (data not shown). As for uroflowmetry parameters, Qmax and PVR were significantly improved in both groups after treatment. There were no significant differences between the two groups (Table 3).

Table 2.  Change in IPSS storage symptoms, voiding symptoms, total score, and QOL index from pre- to post-administration and comparisons of the degree of change among the two groups
  Baseline1 month after3 months after1 month clearance1 month after3 months after
  1. *P < 0.05 in inter-group comparison. Mean ± standard deviation. Intra-group: the changes pre- and post-administration were compared by the Wilcoxon singed-rank test. Inter-group: The changes pre- and post-administration were compared in each group by the Mann–Whitney U-test. IPSS, International Prostate Symptom Score; QOL, quality of life.

Total IPSSS-T19.3 ± 4.913.5 ± 5.512.7 ± 5.314.5 ± 5.313.2 ± 5.813.7 ± 5.0
Intra-group0.00020.00020.0210.00090.011
T-S21.1 ± 6.815.3 ± 6.013.6 ± 6.519.8 ± 6.014.0 ± 6.712.5 ± 6.8
Intra-group<0.0001<0.00010.078<0.00010.0002
Inter-group0.2470.3490.8780.0139*0.6740.409
IPSS storage symptomsS-T7.7 ± 2.85.6 ± 2.55.4 ± 2.95.5 ± 2.65.4 ± 3.35.5 ± 2.6
Intra-group0.00060.00040.01360.00340.013
T-S8.6 ± 3.46.9 ± 2.95.8 ± 2.68.1 ± 2.65.7 ± 2.65.1 ± 2.5
Intra-group0.0031<0.00010.0113<0.00010.002
Inter-group0.5060.9340.6830.0283*0.6060.409
IPSS voiding symptomsS-T8.7 ± 3.26.4 ± 3.15.9 ± 2.77.3 ± 3.56.1 ± 2.86.5 ± 2.7
Intra-group0.0050.00380.01870.000520.0127
T-S9.7 ± 3.16.6 ± 3.36.0 ± 3.79.2 ± 3.26.5 ± 3.85.8 ± 3.7
Intra-group0.00010.00020.03070.00020.0006
Inter-group0.2070.8080.8950.1360.8010.445
IPSS QOL indexS-T4.6 ± 0.93.3 ± 1.43.2 ± 1.24.1 ± 0.93.3 ± 1.13.3 ± 1.0
Intra-group0.00030.00040.03480.00130.0004
T-S4.5 ± 1.03.5 ± 1.13.2 ± 1.03.8 ± 1.03.0 ± 1.02.7 ± 1.1
Intra-group0.0180.00010.0080.00020.0003
Inter-group0.9630.6070.8640.7010.5930.0692
Table 3.  Change in uroflowmetry parameters and postvoid residual urine volume from pre- to post-administration and comparisons of the degree among the two groups
  Baseline1 month after3 months after1 month clearance1 month after3 months after
  1. *P < 0.05 in inter-group comparison. Mean ± standard deviation. Intra-group: the changes pre- and post-administration were compared by the Wilcoxon singed rank test, Inter-group: The changes pre- and post-administration were compared in each group by the Mann–Whitney U-test.

Maximum flow rate (mL/sec)S-T7.2 ± 2.911.2 ± 6.29.4 ± 5.19.3 ± 3.110.2 ± 4.58.7 ± 5.1
Intra-group0.01340.1220.2090.0280.332
T-S7.6 ± 3.09.9 ± 3.710.7 ± 4.57.6 ± 3.09.3 ± 4.47.5 ± 4.0
Intra-group0.0030.00440.6780.05260.717
Inter-group0.6010.9440.3690.1240.5490.445
Residual urine volume (mL)S-T93.9 ± 15137.9 ± 33.639.2 ± 34.860.5 ± 60.664.2 ± 65.836.5 ± 37.6
Intra-group0.00710.01570.1360.5520.0442
T-S62.8 ± 80.634.8 ± 33.936.5 ± 35.766.5 ± 81.225.5 ± 31.332.0 ± 35.1
Intra-group0.01080.05800.1910.00150.0028
Inter-group0.4450.6460.7450.8980.0326*0.608

Out of 46 patients who took both medications, 18 (39.1%) preferred silodosin, 11 (23.9%) preferred tamsulosin and others (37%) felt they had the same effects after taking both types of drug.

Responders were defined on the basis of IPSS by a reduction of >25% from the baseline. Group T showed six non-responders (26%) during tamsulosin treatment, and two of the six (33.3%) showed a response after changing to silodosin treatment. On the contrary, Group S showed eight non-responders (30.8%) during silodosin treatment, and two of the eight (25%) showed a response after changing to tamsulosin treatment.

3.3. Safety

Six patients experienced adverse events during silodosin treatment. Four patients complained of ejaculatory dysfunction and three of them stopped taking the medication. Two patients complained of nasal congestion or a dry mouth. They continued administration without withdrawal. None of the patients experienced adverse events during tamsulosin treatment.

4. DISCUSSION

  1. Top of page
  2. Abstract
  3. 1. INTRODUCTION
  4. 2. METHODS
  5. 3. RESULTS
  6. 4. DISCUSSION
  7. 5. CONCLUSIONS
  8. REFERENCES

In the treatment of LUTS suggestive of BPH, α1-AR antagonists are widely recognized as the first-line pharmacotherapy in the treatment of BPH.1 A basic study investigating the affinity of human α1-AR subtypes (α1A, α1B and α1D) showed that α1B was mainly involved in vasoconstriction and blood pressure control.10 First generation α1-AR antagonists such as doxazosin have the potential to cause orthostatic hypotension. Therefore, agents with high selectivity for α1A-AR should have beneficial effects on LUTS, fewer effects on blood pressure and fewer cardiovascular side effects.11 The affinity of tamsulosin and silodosin for α1A is about 10 and 160 times greater than that towards α1B-AR.5,6 Tamsulosin and silodosin have been shown to improve urinary flow rates and LUTS in a variety of clinical trials.12–15 The onset of silodosin associated effects was rapid. A phase 2 study of silodosin in the Unites States demonstrated an average IPSS and Qmax improvement of 6.5 points and 2.9 mL/sec respectively.14 The first randomized double-blind, placebo-controlled study between tamsulosin and silodosin was reported in 2006.15 Patients received silodosin 4 mg twice daily, tamsulosin 0.2 mg once daily, or a placebo for 12 weeks. The changes in the total IPSS from the baseline in the silodosin, tamsulosin, and placebo groups were −8.3, −6.8, and −5.3 respectively. The results showed silodosin was better than the placebo and not inferior to tamsulosin. Yu et al. also demonstrated non-inferiority of silodosin to tamsulosin in Asian patients.16 In our study, the changes in the total IPSS from the baseline in groups S and T at 3 months were −6.6 and −7.5, respectively, and no significant difference was found among the two groups, which is the same as the previous study.16 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 because of abnormal ejaculation.15 Miyakita et al.9 performed a crossover trial with tamsulosin hydrochloride and silodosin for 97 patients. After the trial, they found that silodosin showed a significant improvement in terms of straining and nocturia with first and crossover treatments. In the present study, no significant differences were found in the degree of change in 7 IPSS items among the two groups.

It has been suggested that the subtype selectivity of α1−AR antagonists may limit their effect on LUTS compared to non-selective α1−AR antagonists.7,8 Adverse events commonly reported with α1A-selective antagonists involve sexual dysfunction. Tamsulosin and silodosin are associated with higher incidences of ejaculatory disorders than placebos. In this study, none of patients complained of de novo ejaculatory discomfort after tamsulosin (0.2 mg daily). However, 4 of 46 (8.7%) patients treated with silodosin complained of ejaculatory disorder. The discontinuation rate due to ejaculatory disorder (6.5%, 3 out of 46) was relatively low. Recently Homma et al.17 suggested that ejaculation disorder caused by silodosin was associated with a very large improvement in LUTS. Also we reported the highly α1A-selectiveness of silodosin to the prostate and seminal vesicles using color Doppler ultrasonography during ejaculation.18 Although silodosin administration caused more adverse events, more patients preferred silodosin administration in the present study.

Interestingly, in the silodosin preceding group, even after stopping medication, the subjective symptoms remained better than that of group T. Kaplan et al.19 and Yanardag et al.20 suggested that complete cessation of α1-AR antagonists led to relapse of both symptoms and impairment of urinary flow within 3 months, while, it is reported that some populations of male LUTS patients demonstrated a carry-over effect after cessation of medication.21 The reason for the differences is unknown. However, Kobayashi et al. also reported that 80% patients who discontinued α1-AR antagonists maintained same condition after 4 weeks.22 More data will be needed to clarify this evidence.

In the present study, even with a low number of patients and no placebo group, the efficacy was almost the same with both drugs. In both groups, IPSS, Qmax, and PVR improved significantly. Moreover, in both groups, there were some no responders in the first line therapy who felt a positive effect after switching to other medication. When a favorable effect in the treatment of LUTS cannot be obtained with one drug, there may be some benefit in changing to another one.

5. CONCLUSIONS

  1. Top of page
  2. Abstract
  3. 1. INTRODUCTION
  4. 2. METHODS
  5. 3. RESULTS
  6. 4. DISCUSSION
  7. 5. CONCLUSIONS
  8. REFERENCES

Two types of α1A-selective AR antagonists in the same individuals provided similar efficacy. Subjective improvement can be sustained even after the cessation of silodosin. Profiles and difference of each drug should be considered in making treatment choice. More cases are needed to compare the two drugs more carefully in the future.

Disclosure

There are no financial or commercial interests concerned for the authors of the present paper.

REFERENCES

  1. Top of page
  2. Abstract
  3. 1. INTRODUCTION
  4. 2. METHODS
  5. 3. RESULTS
  6. 4. DISCUSSION
  7. 5. CONCLUSIONS
  8. REFERENCES