Efficacy of Silodosin for Relieving Benign Prostatic Obstruction: Prospective Pressure Flow Study

Efficacy of Silodosin for Relieving Benign Prostatic Obstruction: Prospective Pressure Flow Study Yoshihisa Matsukawa,* Momokazu Gotoh, Tomonori Komatsu, Yasuhito Funahashi, Naoto Sassa and Ryohei Hattori From the Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan Purpose: We investigated the effect of the new sympathetic 1A-adrenoceptor antagonist silodosin for relieving benign prostatic obstruction by pressure flow study. Materials and Methods: In this open, nonblinded, prospective study we administered 8 mg silodosin daily for 4 weeks in 60 patients with lower urinary tract symptoms associated with benign prostatic enlargement. As a primary outcome measure, we assessed changes in bladder function and benign prostatic obstruction using pressure flow study. As secondary outcome measures, changes in subjective symptoms and quality of life were assessed by the International Prostate Symptom Score. Objective changes in urination status were also assessed by free uroflowmetry in terms of maximum flow rate and post-void residual urine volume. Results: A total of 57 patients were enrolled for analysis. In the storage phase of the pressure flow study bladder capacity at first desire to void increased significantly with no significant change in maximum cystometric capacity. Of 24 patients 14 (58.3%) with uninhibited detrusor contractions before administration showed apparent improvement in detrusor overactivity after administration, including 6 in whom uninhibited contractions disappeared. In the voiding phase mean detrusor pressure at maximum flow significantly decreased from 72.5 to 51.4 cm H 2 O. The mean bladder outlet obstruction index decreased significantly from 60.6 to 33.8. Obstruction grade assessed by the Schaefer nomogram improved in all except 1 patient. Total symptom and quality of life scores, maximum flow rate and post-void residual urine volume on free uroflowmetry significantly improved. Conclusions: Silodosin improved lower urinary tract symptoms by improving bladder storage function and relieving benign prostatic obstruction. Key Words: urinary bladder neck obstruction, prostatic hyperplasia, KMD 3213, adrenergic antagonists, urodynamics IN BPO cases various LUTS are caused by mechanical bladder outlet obstruction due to BPE or by functional obstruction due to increased tension of prostatic smooth muscle mediated by sympathetic nerves. 1 Changes in bladder function associated with BPO modify LUTS comprising voiding and storage symptoms. Because prostatic smooth muscle contraction is caused by sympathetic 1-AR stimulation, sympathetic 1-AR antagonists are widely used as first line drug therapy for LUTS associated with BPO. 2 4 Sympathetic 1-ARs, in- Abbreviations and Acronyms AR adrenoceptor BOOI bladder outlet obstruction index BPE benign prostatic enlargement BPH benign prostatic hyperplasia BPO benign prostatic obstruction I-PSS International Prostate Symptom Score LUTS lower urinary tract symptoms pdetqmax detrusor pressure at Qmax PFS pressure flow study PVR post-void residual urine Qmax maximum flow rate QOL quality of life Submitted for publication March 17, 2009. Study received Nagoya University Graduate School of Medicine ethics committee approval. * Correspondence: Department of Urology, Nagoya University Graduate School of Medicine, 65-Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (telephone: 81-52-744-2985; FAX: 81-52- 744-2319; e-mail: yoshi44@med.nagoya-u.ac.jp). For another article on a related topic see page 2964. 0022-5347/13/1891-0117/0 http://dx.doi.org/10.1016/j.juro.2012.11.031 THE JOURNAL OF UROLOGY Vol. 189, S117-S121, January 2013 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A. www.jurology.com S117 Please cite this article as J Urol 2013;189: S117-S121. DOI: http://dx.doi.org/10.1016/j.juro.2012.11.031

S118 SILODOSIN FOR BENIGN PROSTATIC OBSTRUCTION cluding 1A, 1B and 1D-AR subtypes, have been identified with 1A and 1D-AR subtypes localized predominantly in the prostate, urethra and bladder neck, and 1B-AR subtype localized predominantly in blood vessels. 3,5 First-generation 1-AR antagonists such as prazosin and terazosin, which have no selectivity for sympathetic 1-AR subtypes, can cause adverse reactions related to vascular dilatation by inhibiting the 1B-AR subtype. Consequently in recent years second-generation 1-AR antagonists such as tamsulosin and naftopidil, which are selective for the 1A and 1D-AR subtypes, have come into wide use with the aim of decreasing adverse reactions. 6,7 Sympathetic 1-AR antagonists improve LUTS due to BPO, and provide relief of voiding and storage symptoms. 4,8 These drugs are thought to improve functional obstruction by relaxing prostatic smooth muscles, thereby relieving voiding symptoms. The mechanisms of storage symptom improvement are not clear. The beneficial effects of 1-AR antagonists on subjective symptoms have been investigated in detail based on quantitative symptomatic evaluation using questionnaires such as I-PSS. The objective effects of 1-AR antagonists on lower urinary tract function and particularly the beneficial effects on BPO require evaluation by urodynamic testing. PFS is particularly useful to objectively evaluate bladder contractile function and the degree of BPO. Although there have been few reports of the effects of 1-AR antagonists as measured by PFS, the beneficial effects of doxazosin, 9 tamsulosin 10 and alfuzosin 11 on BPO were reported based on PFS findings. Silodosin, which was recently developed as a new 1-AR antagonist, is purely selective for 1A-AR subtypes. This agent demonstrated affinity for the 1A-AR subtype that was 583-fold higher than for the 1B-AR subtype and 55.6-fold higher than for the 1D-AR subtype. 12 A phase III study of silodosin revealed its prominent beneficial effects on subjective symptoms and on the urinary flow rate on uroflowmetry. 13 This drug was launched in 2007 in Japan and in 2009 in the United States. To our knowledge there is no report of the objective effects of this drug on bladder function and BPO based on urodynamic testing. We investigated the effects of silodosin on bladder function and BPO using PFS in patients with LUTS due to BPE. PATIENTS AND METHODS The current investigation was an open, nonrandomized, single center prospective study. The protocol was approved by the ethics committee of Nagoya University Graduate School of Medicine, Nagoya, Japan. Study participants were patients with untreated BPE who visited our hospital from January 2007 to October 2008 complaining of LUTS. Study inclusion criteria were 1) I-PSS total score 8 points or greater, 2) I-PSS-QOL score 3 points or greater, 3) prostate volume 20 ml or greater on transperitoneal or transrectal ultrasonography, 4) urination Qmax greater than 100 ml but less than 15 ml per second on uroflowmetry, 5) PVR less than 100 ml and 6) patient age greater than 50 years. We excluded patients 1) on oral treatment with -antagonists, anticholinergic agents, antidepressants, anti-anxiety agents or antiandrogens, 2) suspected of having prostate cancer, 3) with neurogenic bladder dysfunction, bladder calculus or active urinary tract infection, 4) with serious cardiac complications, 5) with renal complications (serum creatinine 2 mg/dl or greater) and 6) with hepatic dysfunction (aspartate aminotransferase/alanine aminotransferase at least 2-fold higher than reference values). Silodosin as 4 mg capsules was administered orally twice daily for a total of 8 mg daily in 60 patients for 4 weeks. I-PSS and I-PSS-QOL scores, Qmax on free uroflowmetry and PVR were evaluated at baseline and 4 weeks after administration. PFS was performed before and after administration. For PFS bladder capacity at first desire to void, maximum cystometric capacity and the presence (pressure increase magnitude) or absence of uninhibited detrusor contractions in the storage phase were investigated along with Qmax, pdetqmax and PVR in the voiding phase. Apparent improvement in overactive bladder was defined as the disappearance of uninhibited detrusor contractions or a decrease in amplitude of uninhibited contractions of greater than 15 cm H 2 O. On PFS the degree of obstruction was assessed in terms of BOOI 14 according to International Continence Society recommendations before and after silodosin administration. Also, the obstruction grade of 0 to 6 based on the Schaefer nomogram was evaluated and baseline findings were compared with those after silodosin administration. Patients unable to continue oral administration due to adverse reactions and those who could not be evaluated after administration were excluded from analysis. Primary outcome measures were changes in bladder function and BPO on PFS. Secondary outcome measures were changes in subjective symptoms and QOL on I-PSS, and urination status on free uroflowmetry in terms of Qmax and PVR. PFS was performed by one of us (YM) based on standard International Continence Society methods. 15 A 6Fr single pigtail catheter was placed in the bladder transurethrally to measure intravesical pressure and an additional 8Fr catheter was inserted in the bladder to inject physiological (0.9%) saline solution. A balloon catheter was inserted from the anus to measure abdominal pressure. The test was done with the patient standing. Physiological saline solution was injected into the bladder at 50 ml per minute after evacuating the bladder. Intravesical pressure, abdominal pressure and detrusor pressure in the storage phase were simultaneously measured and recorded. After the patient expressed the maximum desire to urinate the catheter for injection was removed, leaving the 6Fr catheter to measure intravesical pressure, abdominal pressure, detrusor pressure and urinary flow in the voiding phase, which were recorded simultaneously. Statistical analysis was done with the paired or nonpaired

SILODOSIN FOR BENIGN PROSTATIC OBSTRUCTION S119 Student t and Wilcoxon rank tests with p 0.05 considered significant. Values at baseline and 4 weeks after silodosin administration Mean SD Baseline Mean SD 4 Wks p Value I-PSS 18.2 6.4 12.0 6.1 0.0001 I-PSS-QOL 4.8 0.8 3.3 0.8 0.0001 Uroflowmetry: Qmax (ml/sec) 8.4 3.8 11.5 4.7 0.0007 Voided vol (ml) 140 79.3 158 71.6 0.26 PVR (ml) 63 48.8 33 27.6 0.0004 Bladder capacity at first void 113 50.2 140 49.6 0.009 desire (ml) Max cystometric capacity (ml) 239 99.2 275 90.1 0.07 pdetqmax (cm H 2 O) 72.5 26.6 51.4 17.9 0.0001 Qmax (ml/sec) 5.9 2.8 8.8 3.0 0.0001 PVR (ml) 67 54.4 34 33.0 0.0009 BOOI 60.6 28.9 33.8 20.4 0.0001 RESULTS Two patients could not continue administration due to adverse reactions and 1 was unable to undergo PFS after administration. The 57 patients who completed the investigation were 51 to 84 years old (mean age 68.5) with a prostate volume of 25 to 120 ml (mean 42.0). Total I-PSS and I-PSS-QOL scores were significantly improved after drug administration. On free uroflowmetry Qmax and PVR were significantly improved without a significant change in voided volume (see table). The table shows changes in parameters measured by PFS from baseline to after administration. Bladder volume at first desire to void significantly increased but maximum cystometric capacity showed no significant change. Uninhibited detrusor contraction was observed in 24 patients (42.1%) before silodosin administration. After drug administration 14 of the 24 patients (58.3%) had apparent improvement in detrusor overactivity and in 6 (25%) uninhibited detrusor contraction disappeared. In 8 patients (33.3%) in whom uninhibited detrusor contraction amplitude showed a remarkable decrease of greater than 15 cm H 2 O the mean amplitude of uninhibited detrusor contraction decreased from 51.6 to 11.5 cm H 2 O. None of the 33 patients who were free from uninhibited detrusor contraction before administration showed uninhibited contraction upon testing after administration. Qmax and PVR significantly improved after silodosin administration, similar to findings on free uroflowmetry. After administration pdetqmax significantly decreased from 72.5 to 51.4 cm H 2 O for a mean decrease of 21.1 cm H 2 O. BOOI decreased in all patients and mean BOOI significantly decreased from 60.6 to 33.8 after administration (p 0.0001). As evaluated by the Schaefer nomogram, the degree of obstruction improved by 3 levels in 8 patients, by 2 in 20 and by 1 in 28, and was unchanged in only 1. DISCUSSION Investigation of the ratio of mrna expression to 1-AR subtypes in human prostate tissue showed that 1A-AR up-regulation occurs in patients with BPH, in whom mrna expression of the 1A-AR subtype is about 9-fold higher than in normal individuals. 16 Therefore, 1A-ARs are considered important factors in functional bladder outlet obstruction in BPH cases. Based on such findings second-generation 1-AR antagonists such as tamsulosin, which act selectively on 1A-ARs, have come into broad use as first line drug treatment for this condition worldwide. 2,6,7 Silodosin is a new, unique 1-AR antagonist that is purely selective for 1A-ARs. In a randomized comparative study of silodosin vs tamsulosin and placebo the superiority of silodosin vs placebo and the noninferiority of this drug vs tamsulosin were demonstrated by I-PSS and I-PSS-QOL scores, and Qmax on free uroflowmetry. 13 In regard to subjective symptoms silodosin significantly improves not only I-PSS total score but also voiding and storage symptom scores. 13,17 The beneficial effects of silodosin on subjective symptoms and on Qmax on uroflowmetry were similarly confirmed in our study. Although uroflowmetry reflects voiding function, uroflowmetry parameters are determined by urethral resistance and bladder contractile force, making it difficult to evaluate the degree of lower urinary tract obstruction only by uroflowmetry parameters. PFS is the only method that can accurately evaluate the presence and extent of BPO. Because to our knowledge there have been no reports of the effects of silodosin as measured by PFS, we used PFS to objectively evaluate the beneficial effects of silodosin on BPO. Our results showed significant improvements in parameters related to voiding function on PFS after silodosin administration. This drug improved subjective symptoms in patients with BPH with LUTS and provided beneficial effects on voiding function by decreasing BPO. Mean BOOI before administration was as high as 60.6, suggesting apparent obstruction, but it significantly decreased to 30.8 after administration. When we evaluated findings using the Schaefer nomogram, the degree of obstruction improved in all except 1 patient. A few groups have used PFS to assess the effects of 1-AR antagonists. In randomized, controlled studies comparing 1-AR antagonists and placebo the decrease in pdetqmax was significantly greater after administering alfuzo-

S120 SILODOSIN FOR BENIGN PROSTATIC OBSTRUCTION sin 9 or doxazosin 11 than after placebo, and tamsulosin showed a remarkable decrease in pdetqmax compared with that in the placebo group, although this decrease was not significant. 10 Tatemichi et al reported the suppressive effects of silodosin on detrusor overactivity in rats 18 but to our knowledge such effects have not been reported in humans. The increase in bladder capacity at first desire to void and the suppression of uninhibited detrusor contraction observed on PFS in our study objectively suggest that this drug beneficially affects storage function. Improvement in storage symptoms is associated with terazosin 19 (not selective for 1-AR subtypes), tamsulosin 6 (selective for 1A 1D 1B-ARs) and naftopidil 20 (selective for 1D 1A 1B-ARs). These findings clearly suggest that 1-AR antagonists improve not only voiding symptoms but also storage symptoms regardless of selectivity for 1-AR subtypes. The mechanisms of the beneficial effects of 1-AR antagonists on storage function are not well characterized and several hypotheses have been proposed. Up-regulation of 1D-ARs occurs in the obstructed rat bladder 21 and 1D-ARs are localized predominantly in the human bladder. 5 This suggests that the involvement of bladder 1D-ARs in storage symptoms and the beneficial effects of 1-AR antagonists on storage function occur via 1D-ARs. Several experimental series support the role of 1D-ARs in regulating bladder storage function. 7,22 25 This hypothesis is negated by the observations that 1-AR expression is extremely sparse in human bladder smooth muscle and 3-ARs account for 96% of sympathetic receptors. 26 Also, a randomized clinical study comparing tamsulosin and naftopidil revealed no difference between these 2 drugs in regard to improvement in storage symptoms. 7 Our results indicate that the 1A-AR subtype is also associated with storage symptoms but to our knowledge mechanisms to improve bladder storage function by suppressing 1A-ARs remain unknown. Mechanical stimulation of urethral afferent nerves causes bladder contraction and uninhibited detrusor contractions have been suppressed by mucosal anesthesia of the prostatic urethra with lidocaine in patients with BPH. 27 Relaxing the prostate gland and urethral smooth muscle by 1A-AR antagonists may suppress afferent stimulation and improve storage symptoms. The role of 1A-ARs in terms of the storage function is poorly understood and is an interesting area for future investigation. Our series has some limitations. Since this study was open and nonblinded, several factors are open to bias. Observer bias when analyzing PFS would be possible but we believe that this would not have caused a serious impact on the study outcome since at least 2 of us read the PFS tracing and assessed the data. Another limitation is a leaning bias in patients when urodynamics were repeated in the same patients. The change in pdetqmax and obstruction grade were highly significant in our series but in previous randomized, controlled studies comparing other 1-AR antagonists and placebo pdetqmax decreases were observed to a certain degree, although they were not significant. 9,10,11 CONCLUSIONS Silodosin is a novel 1-AR antagonist that is purely selective for 1A-AR subtypes. It improved voiding and storage symptoms in patients with BPH. Objective findings based on PFS storage and voiding phases show that this agent improves bladder storage function and BPO. REFERENCES 1. Shapiro E, Becich MJ, Hartanto V et al: The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia. J Urol 1992; 147: 1293. 2. American Urological Association guideline on management of benign prostatic hyperplasia (2003). Chapter 1: diagnosis and treatment recommendations. J Urol 2003; 170: 530. 3. Schwinn DA and Roehrborn CG: Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol 2008; 15: 193. 4. Andersson KF: Alpha-adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with alpha-adrenoceptor antagonists. World J Urol 2002; 19: 390. 5. Malloy BJ, Price DT, Price RR et al: Alpha1- adrenergic receptor subtypes in human detrusor. J Urol 1998; 160: 937. 6. Lepor H: Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic. hyperplasia. Urology 1998; 51: 892. 7. Gotoh M, Kamihira O, Kinukawa T et al: Comparison of tamsulosin and naftopidil for efficacy and safety in the treatment of benign prostatic hyperplasia: a randomized controlled trial. BJU Int 2005; 96: 581. 8. Cooper KL, McKiernan JM and Kaplan SA: Alphaadrenoceptor antagonists in the treatment of benign prostatic hyperplasia. Drugs 1999; 57: 9. 9. Martorana G, Giberti C, Di Silverio F et al: Effects of short-term treatment with the alpha 1-blocker alfuzosin on urodynamic pressure/flow parameters in patients with benign prostatic hyperplasia. Eur Urol 1997; 32: 47. 10. Abrams P, Speakman M, Stott M et al: A dose-ranging study of the efficacy and safety of tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist, in patients with benign prostatic obstruction (symptomatic benign prostatic hyperplasia). Br J Urol 1997; 80: 587. 11. Ozbey I, Aksoy Y, Polat O et al: Effects of doxazosin in men with benign prostatic hyperplasia: urodynamic assessment. Int Urol Nephrol 1999; 31: 471. 12. Shibata K, Foglar R, Horie K et al: KMD-3213, a novel, potent, 1A adrenoceptor-selective antagonist: characterization using recombinant

SILODOSIN FOR BENIGN PROSTATIC OBSTRUCTION S121 human 1-adrenoceptors and native tissues. Mol Pharmacol 1995; 48: 250. 13. Kawabe K, Yoshida M and Homma Y: 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. BJU Int 2006; 98: 1019. 14. Abrams P: Bladder outlet obstruction index, bladder contractility index and bladder voiding efficacy: three simple indices to define bladder voiding function. BJU Int 1999; 84: 14. 15. Abrams P, Cardozo L, Fall M et al: The standardisation of terminology in lower urinary tract function: report from the Standardisation Subcommittee of the International Continence Society. Urology 2003; 61: 37. 16. Nasu K, Moriyama N, Fukasawa R et al: Quantification and distribution of alpha1-adrenoceptor subtype mrnas in human proximal urethra. Br J Pharmacol 1998; 123: 1289. 17. Takao T, Tsujimura A, Kiuchi H et al: Early efficacy of silodosin in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Int J Urol 2008; 15: 992. 18. Tatemichi S, Akiyama K, Kobayashi M et al: A selective alpha1a-adrenoceptor antagonist inhibits detrusor overactivity in a rat model of benign prostatic hyperplasia. J Urol 2006; 176: 1236. 19. Elhilali MM, Ramsey EW, Barkin J et al: A multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of terazosin in the treatment of benign prostatic hyperplasia. Urology 1996; 47: 335. 20. Yamanishi T, Yasuda K, Kamai T et al: Singleblind, randomized controlled study of the clinical and urodynamic effects of an alpha-blocker (naftopidil) and phytotherapy (eviprostat) in the treatment of benign prostatic hyperplasia. Int J Urol 2004; 11: 501. 21. Hampel C, Dolber PC, Smith MP et al: Modulation of bladder 1 adrenergic receptor subtype expression by bladder outlet obstruction. J Urol 2002; 167: 1513. 22. Smith MS, Schambra UB, Wilson KH et al: Alpha 1-adrenergic receptors in human spinal cord: specific localized expression of mrna encoding alpha 1-adrenergic subtypes at four distinct levels. Brain Res Mol Brain Res 1999; 63: 254. 23. Persson K, Pandita RK, Spitsbergen JM et al: Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 1998; 275: 1366. 24. Chen Q, Takahashi S, Zhong S et al: Function of the lower urinary tract in mice lacking alpha 1d-adrenoceptor. J Urol 2005; 174: 370. 25. Ishihama H, Momota Y, Yanase H et al: Activation of alpha 1D adrenergic receptors in the rat urothelium facilitates the micturition reflex. J Urol 2006; 175: 358. 26. Nomiya M and Yamaguchi O: A quantitative analysis of mrna expression of alpha 1 and betaadrenergic subtypes and their functional roles in human normal and obstructed bladders. J Urol 2003; 170: 649. 27. Yokoyama O, Nagano K, Kawaguchi K et al: The influence of prostatic urethral anesthesia in overactive detrusor in patients with benign prostatic hyperplasia. J Urol 1994; 151: 1554.