ORIGINAL ARTICLE. WJ Bang 1,CYOh 1,CYoo 1, JS Cho 1, DY Yang 1,DHLee 2, SH Lee 2 and BH Chung 2

International Journal of Impotence Research (2013) 25, 149 154 & 2013 Macmillan Publishers Limited All rights reserved 0955-9930/13 www.nature.com/ijir ORIGINAL ARTICLE Efficacy and safety of the simultaneous administration of mirodenafil and an a-blocker in men with BPH-LUTS: a multicenter open-label prospective study WJ Bang 1,CYOh 1,CYoo 1, JS Cho 1, DY Yang 1,DHLee 2, SH Lee 2 and BH Chung 2 We evaluated the clinical efficacy and safety of the coadministration of a PDE5 inhibitor and an a-adrenergic blocker in patients with both benign prostatic hyperplasia/lower urinary tract symptoms (BPH-LUTS) and ED using mirodenafil 50 mg (Mvixx) once daily (OD) in patients already receiving stable a-blocker therapy. This study was a prospective, multicenter, open-label trial. We selected 147 patients undergoing stable (longer than 4 weeks) a-blocker therapy for BPH-LUTS as recipients of the additive mirodenafil 50 mg OD for 8 weeks. The coprimary measures were the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF-5). The key secondary measures were peak flow rate (Q max ) and postvoiding residual (PVR) volume. Safety was assessed by evaluating cardiovascular parameters and the participant-reported treatment-emergent adverse events (TEAEs). The additional administration of mirodenafil 50 mg OD significantly improved IPSS results (18.70 14.30 at 4 weeks and 18.70 13.72 at 8 weeks; Po0.001). The IIEF-5 score was improved at 8 weeks (10.94 16.16; Po0.001). There was no significant change in systolic blood pressure/diastolic blood pressure (124.8 mm Hg/78.6 mm Hg 122.0 mm Hg/79.6 mm Hg; P ¼ 0.638) and heart rates (78.8 per min to 80.2 per min; P ¼ 0.452). The most common TEAEs were hot flashes (10.9%) and headache (8.1%). The combination of mirodenafil with an a-blocker did not significantly improve PVR; however, Q max was improved at 8 weeks (14.51 16.80 ml s 1 ; P ¼ 0.026). Mirodenafil 50 mg OD in combination with an a-blocker appeared to have few adverse effects, to improve BPH-LUTS and restore sexual function. International Journal of Impotence Research (2013) 25, 149 154; doi:10.1038/ijir.2012.44; published online 10 January 2013 Keywords: adrenergic a-antagonists; lower urinary tract symptoms; mirodenafil; PDE5 inhibitors; prostatic hyperplasia INTRODUCTION Lower urinary tract symptoms (LUTS), suggestive of benign prostatic hyperplasia (BPH) and ED are medical conditions that can have a negative impact on quality of life. In addition, they commonly coexist in aging men. 1,2 Epidemiological surveys have revealed a high rate of comorbidity between BPH-LUTS and ED. Moreover, and considering the association between these medical conditions and age, it is expected that this rate will increase further because of improved life expectancy. 3 5 Although the pathophysiological link between BPH-LUTS and ED remain unclear and under debate, several studies published recently have identified the pathophysiological relationships between BPH-LUTS and ED. 6 8 a-adrenergic blockers (a-blockers) are highly recommended as the first-line treatment for BPH-LUTS, 9 and PDE5 inhibitors (Is) are thought to provide the most effective pharmacotherapy for patients with ED. 10,11 Recently, several proof-of-concept studies have demonstrated that treatment with PDE5-Is significantly improved BPH-LUTS, and the medical treatment of BPH-LUTS with a-blockers had the additional effect of improving ED. 12 14 The safety and efficacy of both a-blockers and PDE5-Is are wellestablished individually, and these drugs have been used with minimal limitations related to side effects, which is likely owing to the common pathophysiological link and high co-occurrence of ED and BPH-LUTS. However, there is a growing interest in assessing the safety and efficacy of a combined therapy regimen including a-blockers and PDE5-Is for patients with BPH-LUTS and ED. The common potential risks of side effects related to hemodynamic status and the cardiovascular system are practical and ethical concerns of urologists when choosing a combination therapy of a-blockers and PDE5-Is. Several studies have reported a combination therapy using these two agents and reinforced the rationale of the concurrent administration of these drugs to patients with BPH-LUTS concomitant with ED. 15 17 However, to establish the safety and efficacy of this combination therapy, additional data from clinical trials that use various kinds of a-blockers and PDE5-Is are needed. Mirodenafil (5-ethyl-2-{5-[4-(2-hydroxyethyl) piperazine-1-sulfonyl]-2-phenyl-7-propoxypropyl-3,5-dihydropyrrolo-[3,2-d]pyrimidin-4-one; Mvixx; SK Chemicals, Seoul, South Korea) is the most recently developed PDE5-Is and is a novel, potent agent with a clinical efficacy in ED that is similar to that of other PDE5-Is. The Tmax and T1/2 of mirodenafil are 1.25 and 2.5 h, respectively. Preclinical studies revealed that the selectivity of mirodenafil toward PDE5 is ten-fold higher than that of sildenafil, whereas its inhibitory effects on other phosphodiesterases are much lower than those of sildenafil. 18 Although its pharmacological half-life is relatively short, as assessed in an in vitro study, its clinical effects were maintained for at least 12 h in previous studies. Therefore, the Korean Food and Drug Administration (KFDA) approved the daily administration of mirodenafil to patients with ED. Because of 1 Department of Urology, Hallym University College of Medicine, Chuncheon, Korea and 2 Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University Health System, Seoul, Korea. Correspondence: Professor BH Chung, Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University Health System, P.O. BOX 1217, Seoul 135-720, Korea. E-mail: chung646@yuhs.ac Received 18 June 2012; revised 9 October 2012; accepted 26 November 2012; published online 10 January 2013

150 its high selectivity and established stable pharmacological profile, mirodenafil is one of the most widely prescribed PDE5-Is in Korea. 18 20 The aim of the present study was to evaluate the clinical efficacy and safety of PDE5-Is co-administered with an a-blocker to patients with both BPH-LUTS and ED (mirodenafil 50 mg once daily (OD) in patients already receiving stable a-blocker therapy). MATERIALS AND METHODS Study design and methods This study was a prospective, multicenter, open-label trial conducted at three urology centers in Korea: Hallym University Sacred Heart Hospital, Hallym University Kangdong Sacred Heart Hospital, and Gangnam Severance Hospital. The length of the study period was 8 weeks and patients visited their center at least three times. All patients were asked to visit the urology center every 4 weeks through to the end of the study period. Sexually active men who were at least 40 years of age and had a history of BPH-LUTS and ED for 3 months or more were eligible for this trial. In addition to the personal history of BPH-LUTS and ED, the patients enrolled in this trial had been receiving stable a-blocker therapy for at least 4 weeks, although they were not fully satisfied with their current medical treatment. According to these unique enrollment criteria, all patients enrolled in this trial experienced moderate to severe LUTS (International Prostate Symptom Score (IPSS) 412), despite previous a-blocker therapy for BPH-LUTS. Patients who were prescribed 5a-reductase inhibitors (5- ARIs) within the previous 12 weeks were excluded from this trial; however, we set no limitations regarding the kind of a-blocker prescribed previously. The degrees of ED were assessed using the International Index of Erectile Function (IIEF-5). All patients enrolled in this trial suffered from ED with IIEF-5 scores of 21 or less. Patients were excluded if they had a history of hypersensitivity to any kind of PDE5-Is, a history of taking any kind of PDE5-Is within the 12 weeks prior to enrollment, a history of symptomatic hypotension or severe cardiovascular or cerebrovascular disease, and severe renal or liver diseases or uncontrolled hypertension with or without any kind of history of cardiac-related surgery. In cases of concomitant medications that might affect the clinical parameters or might be contraindicated to the concurrent a-blocker or PDE5-Is, such as nitrate, inhibitors or inducers of cytochrome P-450 monooxygenase 3A4, androgens, or 5-ARIs, patients were also excluded from this trial. In addition to maintenance a-blocker therapy, all patients were prescribed mirodenafil 50 mg OD after enrollment. The interval between the administration of the a-blocker and mirodenafil was 6 h or more. Considering the nature of sexual intercourse, patients were asked to take a-blockers in the morning, whereas mirodenafil was prescribed at night. The study protocol was reviewed and approved by the institutional review board at each site, and this study was conducted in accordance with the ethical principles of the Declaration of Helsinki, good clinical practice, and all applicable laws and regulations. Each patient provided written informed consent before enrollment in the trial (IRB approval number; Hallym University IRB approval no. 2010-1073 and Gangnam Severance Hospital IRB approval no. 2010-0114). Main outcome measures The primary efficacy outcome was the change in IPSS from baseline (prior to initial a-blocker therapy) and enrollment (starting point of a-blocker and mirodenafil combination therapy) to the end point. Change in the IIEF-5 score was another important coprimary end point of this trial. The validity of the Korean versions of the IPSS and IIEF-5 used in this trial was confirmed in previous studies. 12,13 The IPSS is a seven-item questionnaire that evaluates BPH-LUTS: lower scores indicate improved LUTS, whereas a higher score on the IIEF indicates better erectile function. These questionnaires were administered at every visit. The key secondary outcomes were the change in the peak flow rate (Q max ) and postvoiding residual (PVR) urine volume, which are objective parameters related to BPH-LUTS. These parameters were evaluated during every visit, including at baseline, to gather objective evidence of improvement in BPH-LUTS. Subjective parameters, such as those measured using the IPSS and IIEF-5, were also assessed. In this study, safety-related parameters were also evaluated. Systolic blood pressure (SBP)/diastolic blood pressure (DBP) and heart rate (HR) were assessed at baseline in all patients. Electrocardiography was optional in cases with a history of hypertension or any other disease that might be related to the cardiovascular system, such as diabetes mellitus and cerebrovascular disease. To assess the impact and safety of the coadministration regimen on the cardiovascular system, we also evaluated the SBP/DBP and HR at every visit. Safety assessments included treatmentemergent adverse events and serious adverse events. Any patient who took at least one additional mirodenafil and for whom posttreatment safety data were available was eligible for inclusion in the safety evaluation. Statistical analysis Efficacy was analyzed at the end point in the intent-to-treat population. Changes from baseline in the IPSS, IIEF-5, Q max, PVR and each parameter related to the cardiovascular system were analyzed using a paired t-test. The Statistical Package for the Social Sciences (SPSS 18.0, SPSS, Chicago, IL, USA) was used for statistical analysis and data processing. Po0.05 was considered significant. Safety was analyzed in the exposed population. All statistical tests were two-sided. RESULTS Patient population Between September 2010 and August 2011, 147 patients (mean age, 52.61±6.35 years; range, 40.6 68.2 years) were enrolled in this trial. The mean duration of the initial a-blocker monotherapy for BPH-LUTS was 6.7±1.2 months. Demographic and other baseline characteristics, including baseline values for the coprimary and secondary efficacy measures and the agents used prior to the enrollment, are shown in Table 1. Nineteen patients (19/147; 12.9%) dropped out because of adverse events (n ¼ 11), loss to follow-up (n ¼ 3), withdrawal of consent without any adverse events (n ¼ 3) or incomplete clinical data (n ¼ 2). LUTS and erectile function Regarding its efficacy in the treatment of BPH-LUTS, the administration of mirodenafil 50 mg OD together with the a-blocker significantly improved the IPSS. Although the improvement of BPH-LUTS during the initial a-blocker monotherapy was significant (23.70 to 18.70 in IPSS, Po0.001), the results did not meet the patients satisfaction. In this study, the addition of mirodenafil to the a-blocker led to an additional reduction in IPSS Table 1. Patients baseline characteristics (n ¼ 147) Variable Baseline/enroll (s.d.) Mean age (years) 52.6 (6.35) Previous a-blocker used (n) Tamsulosin 64 Alfuzocin 62 Doxazocin 14 Silodosin 7 IPSS Total 23.7 (4.2)/18.7 (6.2) QoL 3.9 (0.9)/3.8 (1.1) Q max (ml s 1 ) 12.8 (3.1)/14.5 (2.7) PVR (ml) 42.6 (9.6)/21.1 (6.8) Prostate volume (ml) 35.4 (4.6)/36.4 (5.4) PSA (ng ml 1 ) 1.65 (1.3)/1.74 (1.2) IIEF-5 NA/10.9 Abbreviations: IIEF-5, International Index of Erectile Function; IPSS, International Prostate Symptom Score; NA, not applicable; PSA, prostate specific antigen; PVR, postvoiding residual volume; Q max, peak flow rate; QoL, Quality of life score. International Journal of Impotence Research (2013), 149 154 & 2013 Macmillan Publishers Limited

after 4 weeks (18.70 14.30; Po0.001), which was also observed at 8 weeks (18.70 13.72; Po0.001) (Figure 1). Considering the initial improvement in IPSS as a result of a-blocker therapy before enrollment, the improvement in BPH-LUTS during the study period supports the significant additional clinical efficacy of comedication using an a-blocker and mirodenafil. In addition to the overall IPSS score, the quality of life subscore of the IPSS was decreased after 8 weeks (3.81 2.94; P ¼ 0.005). We used four different a-blockers in this trial. Because we did not regulate the use of the individual a-blockers during the study period, we also performed a subanalysis of the change in IPSS at 8 weeks according to the individual a-blocker used, which revealed that tamsulosin, alfuzocin and doxazosin also yielded an additional decrease in IPSS (tamsulosin, 4.7; alfuzosin, 5.3; doxazosin, 5.4; Po0.05), whereas silodosin did not achieve additional reduction in the individual analysis (silodosin, 3.7; P ¼ 0.24). Although the additional improvement of IPSS suggests that doxazosin was superior to the other agents, the results of the comparative analyses were not significant (P40.05). In addition to the subjective improvement of BPH-LUTS, as assessed using IPSS, there were significant improvements in objective parameters related to BPH-LUTS. Although additional mirodenafil medication did not reduce the PVR (21.16 24.67 ml; P ¼ 0.138), the maximal flow rate improved at the end of the study period compared with the point of enrollment (14.51 16.80 ml s 1 ; P ¼ 0.026) (Figure 2). Regarding the efficacy in terms of ED at enrollment (V1), the V2 (4 weeks after additional mirodenafil medication), V3 (8 weeks after additional mirodenafil medication) and mean IIEF-5 scores were 10.94±5.70, 16.23±5.80 and 16.16±5.07, respectively (V1 vs V2, Po0.001; V1 vs V3, Po0.001) (Figure 3). DISCUSSION In this study, we found that a combination therapy using an a-blocker and mirodenafil OD improved BPH-LUTS, as well as erectile function. Considering the fact that all patients enrolled in this study were undergoing stable a-blocker therapy for BPH-LUTS before the study period, the improvement of LUTS during the study was interpreted as being an independent effect of the additional mirodenafil medication. Numerous studies have reported the clinical effect of PDE5-Is in terms of the improvement of BPH-LUTS, in addition to erectile function alone. 13,14,21,22 The promising results of several clinical trials were reinforced by their well-designed, double-blinded, placebo-controlled features and large sample size. 13,14,23 Although our study had many limitations, 151 Safety There were no significant changes in SBP/DBP (124.8 mm Hg/ 78.6 mm Hg to 122.0 mm Hg/79.6 mm Hg; P ¼ 0.638) and HR (78.8 per min to 80.2 per min; P ¼ 0.452) during the study period. Adverse events are shown in Table 2. The most common treatment-emergent adverse events were hot flashes and headache. No severe or serious adverse events were reported during the study period. Qmax: Peak flow rate, PVR : post-voiding residual volume V1: Enrollment, V2: 4weeks after additional mirodenafil medication V3: 8weeks after additional mirodenafil medication Figure 2. Changes in the maximal flow rate and postvoiding residual (PVR) urine volume over 8 weeks of treatment with mirodenafil and a-blockers (*Po0.05 vs baseline, w Po0.05 vs enrollment). 18 16 16.2* 16.1* Total IIEF-5 score 14 12 10 8 6 4 2 10.9 IPSS : International prostate symptom score V1 : Enrollment V2 : 4weeks after additional mirodenafil medication V3 : 8weeks after additional mirodenafil medication Figure 1. Changes in the International Prostate Symptom Score (IPSS) over 8 weeks of treatment with mirodenafil and a-blockers (*Po0.05 vs baseline, w Po0.05 vs enrollment). 0 V1 V2 V3 IIEF-5 : International index of erectile function V1 : Enrollment V2 : 4weeks after additional mirodenafil medication V3 : 8weeks after additional mirodenafil medication Figure 3. Changes in the International Index of Erectile Function (IIEF-5) score over 8 weeks of treatment with PDE5 inhibitors and a-blockers (*Po0.001). & 2013 Macmillan Publishers Limited International Journal of Impotence Research (2013), 149 154

152 Table 2. Adverse events Summary of recorded adverse events Number of events (multiple choice) Hot flush 16 9 Headache 12 6 Dizziness 5 1 Fever sense 9 6 Dry mouth 2 1 Nasal congestion 6 3 Hyperemia 3 1 Dyspepsia 2 1 Chest discomfort 1 0 Total 56 (n ¼ 31) 28 (n ¼ 16) V2: 4 weeks after additional mirodenafil medication. V3: 8 weeks after additional mirodenafil medication. V2 such as the lack of a placebo control group, a relatively short-term follow-up period, and a small patient sample, the unique enrollment criteria placed our results on a par with the findings of those well-designed previous studies. If this trial had included newly diagnosed patients without a medication history, we would not have been able to confirm the effect of mirodenafil medication in BPH-LUTS because of the original effect of the a-blocker on BPH-LUTS. The unique enrollment criteria of this study represented an effort to overcome this limitation and ensure the rational interpretation of our results. Two previous studies employed a study design and enrollment criteria similar to ours. 15,17 One used mirodenafil 50 mg and the other used udenafil 100 g per 200 mg, as the PDE5-Is administered in addition to the stable a-blocker therapy. However, these trials had a common limitation related to the regularity of the medication. The design of these studies did not require daily medication; rather, it provided for on-demand medication regulated by the needs of the patients themselves. These previous studies also found an additive and positive effect of PDE5-Is on BPH-LUTS; the results should be interpreted cautiously because of the limitations mentioned above. The unique enrollment criteria and the daily medication schedule used in our study reinforced the positive results and suggestions stemming from previous studies. To our knowledge, there is paucity of well-designed placebocontrolled studies dealing with the effectiveness of PED5-Is on BPH-LUTS. To overcome the limitation of our study and to reinforce positive results, a comparisonal study composed of three arms; PDE5-Is plus a-blocker versus a-blocker versus placebo is needed. For patients with BPH-LUTS, a-blockers are considered to be the initial drug of choice because of their novel and rapid onset efficacy. 10,24 In addition, PDE5-Is are the first-line treatment modality for patients with ED. 11 Because of the high incidence of comorbid BPH-LUTS and ED, urologists frequently encounter patients who want to be treated simultaneously for these two medical conditions. Considering the characteristics of aging patients with a high prevalence of comorbidity with other cardiovascular risk factors, practicing urologists must acknowledge the well-established safety profiles of combination treatments that use these two agents. Both agents can affect hemodynamic parameters, such as SBP/DBP and HR; thus, urologists have to be careful when prescribing a combination therapy using these two kinds of drugs. Moreover, controversy exists regarding the coadministration of a-blockers and PDE5-Is to patients with concomitant BPH-LUTS and ED. The guidelines of the European Association of Urology regarding ED recommend V3 that a-blockers should not be administered within 4 h of sildenafil administration; they do not recommend the use of tadalafil in patients with BPH-LUTS who were prescribed an a-blocker. 25 There are no official guidelines or legal regulations regarding the use of mirodenafil together with other a-blockers in Korea. However, the KFDA recommends a combination therapy using these two kinds of agents with careful observation of hemodynamic parameters and, if possible, at least a 6-h interval between the administration of a-blockers and mirodenafil. An interval of at least 6 h between the administration of these two drugs was recommended in this study, to ensure the safety of the clinical trials and adhere to the KFDA guidelines. The favorable safety results of this trial were likely partially related to the regulation of the drug-to-drug administration interval. In this trial, the coadministration of the two agents did not affect cardiovascular parameters, such as SBP/DBP and HR. None of the enrolled patients dropped out because of any severe side effects related to the cardiovascular system, such as syncope or postural hypotension. Several previous studies examined the safety profile of combined oral medication in relation to cardiovascular parameters. According to a report by Chung et al. 15 SBP/DBP and HR were not influenced by combination treatment using udenafil and a-blockers. Lee et al. also reported minimal changes after a combination treatment using mirodenafil and a-blockers. 17 However, these previous studies had a common limitation in the interpretation of results because the PDE5-Is were administered intermittently by the patients, as needed, before sexual intercourse. The results of our study using a continuous medication design support the safety of the PDE5-Is/a-blocker combination therapy. The positive safety results regarding cardiovascular parameters may also result from the pharmacological characteristics of mirodenafil itself. An animal study showed that the selectivity of mirodenafil was 10 times higher than that of sildenafil, and its inhibitory effects on other PDE5-Is were very small. 26 In addition to the safety assessment in terms of BP and HR, the patients reported adverse events during the study period, which were also tolerable. The most common adverse events were hot flashes and headache. The incidence of adverse events was not significantly higher than that observed in previous studies that were performed to assess the safety of individual PDE5-Is or of the PDE5-Is/a-blocker combination therapy. 13,14,16,17,22 The high selectivity of mirodenafil might be responsible for the favorable safety results obtained in our study, suggesting that the selectivity of the individual PDE5-Is should be considered when choosing a combination therapy of PDE5-Is/a-blockers. Although mirodenafil is advantageous in terms of its selectivity, it is disadvantageous regarding its action time. The pharmacological profile of mirodenafil is similar to that of sildenafil and vardenafil; thus, mirodenafil has the advantage of a rapid onset, whereas the maintenance of its serum level for 24 h is difficult. 26 Because of its maintenance in the serum over 24 h and its stable pharmacological profile, tadalafil is considered by many to be appropriate for the treatment of BPH-LUTS, in conjunction with PDE5-Is. 13,14,27 However, the use of PDE5-Is not as a monotherapy, but in combination with an a-blocker, may provide increased safety to patients as well as efficacy maintenance. In this respect, mirodenafil has additional benefits when used in combination with a-blockers for the improvement of BPH-LUTS. In our study, a combination therapy using mirodenafil and a-blockers significantly improved not only the subjective parameters, such as IPSS and IIEF, but also the change in Q max. When considering the design of our open-label study lacking a placebo control group, the improvement in the subjective symptoms of patients should be interpreted cautiously with psychological effects taken into consideration. Although many authors have reported positive results regarding the potential efficacy of PDE5- Is in the treatment of patients with BPH-LUTS, the psychological International Journal of Impotence Research (2013), 149 154 & 2013 Macmillan Publishers Limited

effects of PDE5-Is on the perception of improvement in patients with BPH-LUTS remain unclear. 28 Many previous studies have suggested the subjective improvement of BPH-LUTS through PDE5-Is or a combination of PDE5-Is and a-blockers, whereas objective parameters, such as Q max and PVR, did not improve in other studies. 14,15,17,21,22 The change in IPSS during the course of our study period was 18.70 13.72. Although the improvement was significant, the degree of change was relatively small compared with that observed in previous studies. The change in Q max observed in our study was also significant, but inferior to improvements reported in other recent studies. 3,5,10,24 The unique inclusion criteria used in our study may have contributed to our observation of relatively small improvements. All patients enrolled in this trial were undergoing stable a-blocker therapy for BPH-LUTS. Therefore, the initial improvement related to the a-blocker monotherapy may not have been reflected in the results. The improvement during the study period might have been the independent effect of mirodenafil-related BPH-LUTS. We did not regulate the individual type of a-blocker previously chosen for stable a-blocker therapy in BPH-LUTS patients. The individual selectivity of the a-blocker might affect safety regarding hemodynamic parameters. Although our study had some limitations, its promising subjective and objective results provide additional evidence of the possible efficacy of PDE5-Is in the treatment of patients with BPH-LUTS. The subanalysis of the individual a-blocker and the decrease in IPSS at the end of the study revealed the absence of significant differences according to the type of a-blocker used. Although the results showed a tendency for the superiority of doxazosin and alfuzosin, the interpretation of these results must be made with caution because of the small scale of the study and uneven distribution of the individual agents. Monotherapy using a-blockers is widely accepted as the initial medical treatment for patients with BPH-LUTS, especially for relatively younger patients with mild to moderate LUTS. Most urologists prefer a-blocker monotherapy to 5-ARIs monotherapy or combination therapy using both drugs, considering the rapid onset efficacy and avoidance of possible adverse events associated with polypharmacy. 21 However, regardless of the nature of the initial medication, in patients with unsatisfactory improvement (especially those with large prostate volumes or disease progression), urologists have to consider combination therapy using a-blockers and 5-ARIs. Although the combination therapy using 5-ARIs has been proven to be efficacious for BPH- LUTS, these therapies may have side effects related to sexual function. 10,29 There is a paucity of choice for urologists treating patients with severe BPH-LUTS who want to preserve or restore their sexual function. The results of our study suggest one additional treatment option for these patients. Although the establishment of a concrete rationale for a combination treatment that includes both a-blockers and PDE5-Is for patients with BPH- LUTS and ED faces many hurdles, recent consistent results from various trials, including our study, suggest a high possibility of advancement in the medical treatment of male sexual dysfunction and BPH-LUTS. In conclusion, mirodenafil 50 mg OD in combination with an a-blocker appeared to have few adverse effects on the cardiovascular system, to improve BPH-LUTS, and restore sexual function. However, further studies are needed to determine the long-term outcomes of this therapy and compare this synergic effect to conventional individual therapy. CONFLICT OF INTEREST The authors declare no conflict of interest. ACKNOWLEDGEMENTS This study was funded by SK chemicals Korea. REFERENCES 1 Hoesl CE, Woll EM, Burkart M, Altwein JE. Erectile dysfunction (ED) is prevalent, bothersome and underdiagnosed in patients consulting urologists for benign prostatic syndrome (BPS). Eur Urol 2005; 47: 511 517. 2 Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003; 44: 637 649. 3 Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: results of the Cologne Male Survey. Int J Impot Res 2000; 12: 305 311. 4 Kohler TS, McVary KT. The relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. Eur Urol 2009; 55: 38 48. 5 Lewis RW, Fugl-Meyer KS, Corona G, Hayes RD, Laumann EO, Moreira Jr ED et al. Definitions/epidemiology/risk factors for sexual dysfunction. J Sex Med 2010; 7: 1598 1607. 6 Deedwania PC. Mechanisms of endothelial dysfunction in the metabolic syndrome. Curr Diab Rep 2003; 3: 289 292. 7 Khan MA, Thompson CS, Dashwood MR, Mumtaz FH, Morgan RJ, Mikhailidis DP. Endothelin-1 and nitric oxide in the pathogenesis of urinary tract disorders secondary to bladder outlet obstruction. Curr Vasc Pharmacol 2003; 1: 27 31. 8 Uckert S, Oelke M, Stief CG, Andersson KE, Jonas U, Hedlund P. Immunohistochemical distribution of camp- and cgmp-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 2006; 49: 740 745. 9 McVary KT, Roehrborn CG, Avins AL, Barry MJ, Bruskewitz RC, Donnell RF et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol 2011; 185: 1793 1803. 10 American Urological Association. AUA Guideline. Management of erectile dysfunction. Arch Esp Urol 2011; 64: 4. 11 Wespes E, Amar E, Hatzichristou D, Hatzimouratidis K, Montorsi F, Pryor J et al. EAU Guidelines on erectile dysfunction: an update. Eur Urol 2006; 49: 806 815. 12 Chung BH, Lee JY, Kim CI, Kim CS, Oh CY, Lee SW et al. Sexuality and the management of BPH with alfuzosin (SAMBA) trial. Int J Impot Res 2009; 21: 68 73. 13 Egerdie RB, Auerbach S, Roehrborn CG, Costa P, Garza MS, Esler AL et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. J Sex Med 2012; 9: 271 281. 14 Tamimi NA, Mincik I, Haughie S, Lamb J, Crossland A, Ellis P. A placebo-controlled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. BJU Int 2010; 106: 674 680. 15 Chung BH, Lee JY, Lee SH, Yoo SJ, Lee SW, Oh CY. Safety and efficacy of the simultaneous administration of udenafil and an alpha-blocker in men with erectile dysfunction concomitant with BPH-LUTS. Int J Impot Res 2009; 21: 122 128. 16 Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 2007; 51: 1717 1723. 17 Lee JY, Cho SY, Oh CY, Ha US, Lee SH, Park SY et al. Efficacy and safety of combination therapy with mirodenafil and alpha1-blocker for benign prostatic hyperplasia-induced lower urinary tract symptoms accompanied by erectile dysfunction: a multicenter, open-label, prospective study. Int J Impot Res 2011; 23: 249 256. 18 Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC et al. Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction. J Sex Med 2008; 5: 2672 2680. 19 Lee YS, Choi YH, Kim TK, Ryu KH, Lee BY, Lee MG. Pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, after intravenous and oral administration of mirodenafil to streptozotocin-induced diabetes mellitus rats. Xenobiotica 2010; 40: 129 137. 20 Yang CS, Kim SC. The Influence of Treatment-emergent Adverse Reactions on Selecting Phosphodiesterase Type 5 Inhibitors. Korean J Urol AID 2006; 47: 272 278. 21 Andersson KE, de Groat WC, McVary KT, Lue TF, Maggi M, Roehrborn CG et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol Urodyn 2011; 30: 292 301. 22 Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology 2010; 75: 1452 1458. 23 Porst H, Kim ED, Casabe AR, Mirone V, Secrest RJ, Xu L et al. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms 153 & 2013 Macmillan Publishers Limited International Journal of Impotence Research (2013), 149 154

154 suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 2011; 60: 1105 1113. 24 Oh CY, Lee SH, Yoo SJ, Chung BH. Korean urologist s view of practice patterns in diagnosis and management of benign prostatic hyperplasia: a nationwide survey. Yonsei Med J 2010; 51: 248 252. 25 Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010; 57: 804 814. 26 Lee J, Yoo HH, Rhim KJ, Sohn DR, Kim DH. Metabolism and excretion of 5-ethyl-2- {5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl-3,5- dihydropyrrolo[3,2-d]-pyrimidin-4-one (SK3530) in rats. Rapid Commun Mass Spectrom 2007; 21: 1139 1149. 27 Warde N. Therapy: Two birds, one stone: tadalafil is an effective treatment for men with both BPH-LUTS and ED. Nat Rev Urol 2011; 8: 643. 28 Martinez-Salamanca JI, Carballido J, Eardley I, Giuliano F, Gratzke C, Rosen R et al. Phosphodiesterase type 5 inhibitors in the management of non-neurogenic male lower urinary tract symptoms: critical analysis of current evidence. Eur Urol 2011; 60: 527 535. 29 van Dijk MM, de la Rosette JJ, Michel MC. Effects of alpha(1)-adrenoceptor antagonists on male sexual function. Drugs 2006; 66: 287 301. International Journal of Impotence Research (2013), 149 154 & 2013 Macmillan Publishers Limited