A Randomized Study Comparing Once-Daily and Thrice-Daily Naftopidil 75 Mg/Day for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia

Elmer Press Original Article World J Nephrol Urol. 2014;3(2):72-82

A Randomized Study Comparing Once-Daily and Thrice-Daily Naftopidil 75 mg/Day for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia

Akiou Okumuraa, e, Shinji Tsuritania, b, Tetsuo Nozakia, c, Hitomi Kimurad, Taizo Kazamad

Abstract Conclusions: The overall efficacy of naftopidil 75 mg/day given OD was approximately equal to that of 75 mg/day TID, but OD Background: The efficacy and tolerability of naftopidil 75 mg ad- therapy was objectively more effective. LUTS/BPH patients with ministered once daily (OD) in the evening (group O) were com- large prostate volume should be given OD therapy because the pared to those of naftopidil 25 mg thrice daily (TID), given in the therapy is not affected by the severity of subjective symptoms or morning, afternoon and evening (group T), for lower urinary tract prostate volume. symptoms associated with benign prostatic hyperplasia (LUTS/ BPH). The factors predicting the efficacy of each dosage regimen were also examined. Keywords: Benign prostatic hyperplasia; Dosage method; Naftopi- dil; Predictive factor Methods: The participants were 101 patients with LUTS/BPH who were randomly administered naftopidil for 8 weeks in either group O or group T. Inclusion criteria were international prostate symptom score (IPSS) ≥ 8 and IPSS quality of life (IPSS-QoL) ≥ 3. Introduction

Results: IPSS total score, IPSS-QoL and the BPH impact index Benign prostatic hyperplasia (BPH) decreases quality of life were all significantly improved compared to baseline for both (QoL) because of lower urinary tract symptoms (LUTS) and groups at 8 weeks after treatment. Voided volume, maximum flow bladder outlet obstruction (BOO). rate and average flow rate were significantly improved compared to Naftopidil has higher selectivity for the lower urinary baseline only for group O at 8 weeks after treatment. The effective- tract, because it is an α1D/A-adrenoceptor (α1D/A-AR) an- ness rate based on the criteria for treatment efficacy of the Japanese clinical practice guideline for voiding dysfunction was not signifi- tagonist that has higher affinity for the α1D-adrenoceptor cantly different between the two groups. There was no - indepen (α1D-AR) subtype. Therefore, it shows fewer adverse ef- dent predictive factor for the efficacy of naftopidil in group O, but fects related to blood pressure [1]. The effects of naftopidil prostate volume and symptom severity were identified as predictive are dose-dependent, and the optimal dosage for the treatment factors in group T. The rate of adverse events was not significantly of LUTS associated with BPH (LUTS/BPH) in Japan is rec- different between the two groups. ommended to be from 25 mg/day to 75 mg/day [2]. Recently, the dosage regimen of the drug has been changed to once daily (OD) to improve compliance. Similar- ly, the tolerability of naftopidil 75 mg given OD has been reported [3, 4]. However, combination therapy with a drug giv- Manuscript accepted for publication May 21, 2014 en OD and drugs given twice (or more than twice) in divided doses is complicated for patients who already take drugs in aDepartment of Urology, Kurobe City Hospital, Toyama, Japan b divided doses. It has been reported that a decrease in the (Present) Department of Urology, Asahi General Hospital, Toyama, number of combination drugs and changing to a simple dos- Japan c(Present) Department of Urology, Graduate School of Medicine and age regimen improves compliance [5]. Since a complicated Pharmaceutical Sciences for Research, University of Toyama, Toyama, dosage regimen affects compliance, it is necessary to consid- Japan er the most suitable dosage regimen for each patient. In addi- dDepartment of Urology, Saiseikai Toyama Hospital, Toyama, Japan e tion, cases of patients in whom a thrice-daily (TID) regimen Corresponding Author: Akiou Okumura, Department of Urology, of naftopidil had to be considered because the patients were Kurobe City Hospital, 1108-1 Mikkaichi, Kurobe City, Toyama 938-8502, Japan. Email: [email protected] taking other drugs on a TID basis also arose. However, the kind of patient who would have a good response with each doi: http://dx.doi.org/10.14740/wjnu169e regimen (OD and TID) has not been considered.

72 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 73 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Okumura et al World J Nephrol Urol. 2014;3(2):72-82 a a b b b b b b b NS NS NS NS NS NS NS NS Intergroup P value P Intergroup NS 24.7 ± 12.9 (48) 16.3 ± 6.7 (50) 4.4 ± 1.0 (50) 5.1 ± 2.8 (50) (35) 181.2 ± 117.5 10.9 ± 6.3 (35) 5.7 ± 3.1 (35) 62.9 ± 69.3 (36) Group T T (n) Group 70.4 ± 8.0 (50) 27.3 ± 14.7 (50) 14.7 ± 5.2 (51) 4.5 ± 0.9 (51) 5.1 ± 2.7 (50) (35) 159.5 ± 115.7 10.3 ± 5.7 (35) 5.8 ± 3.3 (34) 70.1 ± 85.7 (34) Group O (n) Group 68.5 ± 8.3 (51) 26.0 ± 13.8 (98) 15.5 ± 6.0 (101) 4.5 ± 0.9 (101) 5.1 ± 2.7 (100) (70) 170.4 ± 116.3 10.6 ± 6.0 (70) 5.8 ± 3.2 (69) 66.4 ± 77.2 (70) Total (n) Total 69.4 ± 8.2 (101) Mann-Whitney U test. b t -test; Unpaired a Prostate volume (mL) IPSS total score IPSS-QoL BPH impact index volume (mL) Voided Max flow rate (mL/s) flow rate (mL/s) Average Post void residual urine (mL) Age (years) Baseline Characteristics of the Two Groups Two 1. Baseline Characteristics of the Table Mean ± SD.

72 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 73 Dosage Method for 75 mg/Day Naftopidil World J Nephrol Urol. 2014;3(2):72-82

The present study compared the efficacy and tolerability Values of P < 0.05 were considered significant. of naftopidil given as 75 mg/day OD and given as 75 mg/day TID for LUTS/BPH and investigated the predictive factors for efficacy of each dosage regimen. Results

The characteristics of the 101 patients enrolled in this study Materials and Methods (group O, n = 51; group T, n = 50) are shown in Table 1. No significant differences were apparent between the groups. The participants in this study were 101 patients who had been Adverse events were evaluated in these 101 patients. Among clinically diagnosed with LUTS/BPH in the Department of the 101 patients, four (group O, n = 2; group T, n = 2) with Urology at Kurobe City Hospital and Saiseikai Toyama Hos- IPSS < 8, three (group O, n = 2; group T, n = 1) with IPSS- pital between September 2005 and April 2009. QoL < 3, three (group O, n = 1; group T, n = 2) for whom The inclusion criteria were international prostate symp- baseline PV was not measured and one patient (group O, n = tom score (IPSS) ≥ 8 and IPSS-QoL ≥ 3. The exclusion crite- 1) for whom baseline BII was not measured were excluded. ria included presence of urinary retention, post-void residual Efficacy was thus evaluated in 90 patients and compared be- urine volume (PVR) ≥ 200 mL, hydronephrosis and/or renal tween 45 patients in group O and 45 patients in group T. impairment caused by BOO, intractable hematuria, prostate Overall severity using the criteria for treatment efficacy cancer, history of prostatic surgery, neurogenic bladder, ure- in BPH proposed by the Japanese Urological Association is thral stricture, or chronic bacterial prostatitis. The enrolled shown in Table 2. These parameters showed no significant patients were randomly divided into two groups based on differences between groups O and T. medical chart numbers after their informed consent was ob- Differences in IPSS total score, IPSS-QoL and BII total tained, and characteristics such as age, complications and score are shown in Table 3. All parameters were significantly estimated prostate volume (PV) by transabdominal ultraso- improved at 8 weeks compared with baseline in groups O nography (TRUS) were investigated. Naftopidil 75 mg/day and T. The changes of these parameters at 8 weeks com- OD in the evening was administered to the 51 odd-numbered pared to baseline showed no significant differences between patients (group O), while naftopidil 75 mg/day TID (25 mg groups O and T. once in the morning, afternoon and evening) was admin- Differences in objective findings are shown in Table 4. istered to the 50 even-numbered patients (group T) for 8 VV, MFR and AFR were significantly improved at 8 weeks weeks. compared with baseline in group O, but not significantly At baseline and 8 weeks after treatment, subjective improved in group T. The changes of these parameters at 8 symptoms and objective findings were assessed using the weeks compared to baseline showed no significant differ- IPSS, IPSS-QoL, BPH impact index (BII), voided volume ences between groups O and T. (VV), maximum flow rate (MFR), average flow rate (AFR) Treatment efficacy using the criteria for treatment effica- and PVR as measured by TRUS. In addition, overall severity cy in BPH proposed by the Japanese Urological Association and treatment efficacy using the criteria for treatment effi- is shown in Table 5. The patients judged to be “excellent”, cacy in BPH proposed by the Japanese Urological Associa- “good” and “fair” were defined as effective cases, and the tion in 1997 [6] were evaluated. All study protocols were ap- patients judged to be “poor/worse” were defined as insuf- proved by the Institutional Review Board for Clinical Study ficient effect cases. The efficacy rates are shown inTable at Saiseikai Toyama Hospital. 5. The efficacy rates for symptoms, QoL and function were 62.2%/62.2%, 88.9%/80.0% and 45.5%/42.4%, respectively Statistical analysis (group O/group T). The overall efficacy rate was 67.6% in group O and 64.1% in group T. These parameters showed no Results are expressed as means ± standard deviation (SD). significant differences between groups O and T. Paired t-tests were used to compare blood pressures between Logistic regression analysis was used to identify pre- baseline and 8 weeks. Unpaired t-tests were used to com- dictive factors for efficacy with each dosage method. The pare age, estimated PV and blood pressure between groups. dependent variable was the effective and insufficient effect For all other parameters, the Wilcoxon signed-rank test was cases, and the independent variables were age, PV, symptom used for comparisons between baseline and 8 weeks, while severity, severity of QoL, severity of dysfunction and BII at the Mann-Whitney U test was used for comparisons between baseline. The results are shown in Table 6. No factor related groups. The effectiveness rate using the criteria for treatment to efficacy was identified in group O, while PV (odds ratio: efficacy in BPH proposed by the Japanese Urological As- 1.13) and symptom severity (odds ratio: 0.06) were identi- sociation and adverse events were compared used the Chi- fied in group T. square test. Logistic regression analysis was used to identify An adverse event was encountered in only one patient predictive factors for the efficacy of each dosage method. in group O (dryness of the mouth, 2.0%), and no significant

74 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 75 Okumura et al World J Nephrol Urol. 2014;3(2):72-82 Intergroup P val ue P Intergroup NS NS NS NS (%) (20.0) (28.9) (51.1) (44.4) (9.3) (7.0) (17.8) (23.3) Severe n 9 13 23 20 4 3 8 10 Association. Chi-square test. (%) (80.0) (71.1) (48.9) (55.6) (69.8) (72.1) (80.0) (72.1) Moderate n 36 32 22 25 30 31 36 31 (%) (0.0) (0.0) (0.0) (0.0) (20.9) (20.9) (2.2) (4.7) Mild n 0 0 0 0 9 9 1 2 Group Group O Group T Group Group O Group T Group Group O Group T Group Group O Group T Group Criteria for overall severity Criteria for Symptom (IPSS) QoL (IPSS-QoL) QoL Function (Qmax) Overall severity Table 2. Overall Severity Table Overall severity was evaluated by the criteria for treatment efficacy in BPH proposed Japanese Urological

74 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 75 Dosage Method for 75 mg/Day Naftopidil World J Nephrol Urol. 2014;3(2):72-82 NS -2.2 ± 2.8 -2.6 ± 2.0 NS -1.5 ± 1.2 -1.8 ± 1.2 NS -5.5 ± 5.6 -5.3 ± 4.7 Difference < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 Intragroup P value P Intragroup NS 3.2 ± 2.3 2.7 ± 2.1 NS 3.1 ± 1.2 2.9 ± 1.0 NS 11.3 ± 5.0 11.3 9.7 ± 5.0 8 weeks NS 5.4 ± 2.6 5.3 ± 2.7 NS 4.5 ± 0.8 4.6 ± 0.7 NS 16.8 ± 6.4 15.0 ± 5.2 Baseline 45 45 45 45 45 45 N Intergroup P value P Intergroup Group T Group Group O Intergroup P value P Intergroup Group T Group Group O Intergroup P value P Intergroup Group T Group Group O Group BII total score IPSS-QoL IPSS total score Differences in IPSS, IPSS-QoL and BII 3. Differences in IPSS, IPSS-QoL Table Mean ± SD (range). Intragroup: Wilcoxon signed-rank test; intergroup: Mann-Whitney U test.

76 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 77 Okumura et al World J Nephrol Urol. 2014;3(2):72-82 -28.0 ± 66.9 NS -5.7 ± 52.3 0.8 ± 2.8 NS 1.8 ± 3.0 1.5 ± 6.0 NS 2.5 ± 4.9 11.8 ± 151.6 11.8 NS 46.6 ± 105.6 Difference NS NS NS 0.003 NS 0.003 NS 0.017 Intragroup P value P Intragroup NS 38.2 ± 43.2 NS 54.5 ± 91.0 6.5 ± 3.7 NS 7.6 ± 4.1 12.3 ± 6.1 NS 13.0 ± 6.1 196.7 ± 109.4 209.4 ± 142.5 8 weeks NS 66.2 ± 69.9 60.2 ± 78.0 NS 5.7 ± 3.0 5.8 ± 3.4 NS 10.8 ± 6.3 10.4 ± 5.8 NS 184.8 ± 119.3 162.8 ± 118.3 Baseline 34 32 33 32 33 33 33 33 N Intergroup P value P Intergroup Group T Group Group O Intergroup P value P Intergroup Group T Group Group O Intergroup P value P Intergroup Group T Group Group O Intergroup P value P Intergroup Group T Group Group O Group Post void residual urine (mL) Average flow rate (mL/s) Average Max flow rate (mL/s) Voided volume (mL) Voided Table 4. Differences in Objective Findings Table Mean ± SD (range). Intragroup: Wilcoxon signed-rank test; intergroup: Mann-Whitney U test.

76 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 77 Dosage Method for 75 mg/Day Naftopidil World J Nephrol Urol. 2014;3(2):72-82 Intergroup P P Intergroup value NS NS NS NS (%) (37.8) (37.8) (11.1) (20.0) (54.5) (57.6) (32.4) (35.9) Poor n 17 17 5 9 18 19 12 14 (%) (31.1) (42.2) (64.4) (62.2) (15.2) (12.1) (43.2) (51.3) Fair n 14 19 29 28 5 4 16 20 (%) (22.2) (17.8) (15.6) (15.6) (30.3) (27.3) (21.6) (12.8) Good n 10 8 7 7 10 9 8 5 (%) (8.9) (2.2) (8.9) (2.2) (0.0) (3.0) (2.7) (0.0) Excellent n 4 1 4 1 0 1 1 0 Group (n) Group Group O (45) Group T (45) T Group Group O (45) Group T (45) T Group Group O (33) Group T (33) T Group Group O (37) Group T (39) T Group Symptom (IPSS) QoL (IPSS-QoL) QoL Function (Qmax) Overall efficacy Criteria for Treatment Efficacy Treatment 5. Criteria for Table efficacy wasTreatment evaluated by the criteria for treatment efficacy in BPH proposed Association. by Overallthe Japanese efficacy Urological was the median of the efficacy grades and function. Chi-square test. of three items: symptoms, QoL

78 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 79 Okumura et al World J Nephrol Urol. 2014;3(2):72-82

Group T T Group (n = 39) NS 0.021 0.029 NS NS NS P value P NS NS NS NS NS NS Group O Group (n = 37)

oiding Dysfunction 0.99 - 1.33 1.02 - 1.25 0.01 - 0.75 0.70 - 70.72 0.18 - 8.70 0.51 - 1.32 Group T T Group (n = 39) 95% Confidence limits 0.98 - 1.19 0.93 - 1.13 0.20 - 3.33 0.09 - 3.67 0.06 - 1.51 0.73 - 1.57 Group O Group (n = 37)

1.14 1.13 0.06 7.02 1.26 0.82 Group T T Group (n = 39) 1.077 1.03 0.26 0.59 0.30 0.07 Group O Group (n = 37) Odds ratio Age PV Severity of symptoms Severity of QoL Severity of dysfunction Baseline BII Table 6. Predictive Factors for Efficacy Using the Japanese Clinical Practice Guideline V Table Logistic regression analysis.

78 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 79 Dosage Method for 75 mg/Day Naftopidil World J Nephrol Urol. 2014;3(2):72-82 difference in adverse events between the groups was iden- who show no improvements in objective findings with 75 tified. Diastolic blood pressure and systolic blood pressure mg/day TID. were not significantly decreased in either group O or T, and No independent predictive factors that affected effec- the degree of change at 8 weeks in comparison to baseline tiveness were identified in group O, but PV and severity of showed no significant difference between the groups. symptoms were identified in group T. In other words, 75 mg/ day TID of naftopidil was associated with an increased risk of lack of efficacy with large PV and slight symptoms. De la Discussion Rosette et al examined the re-treatment rate using follow-up data for up to 3 years for 316 of LUTS/BPH patients treated Naftopidil was approved at an OD dosage [2]. Generally, with an α1-blocker. They found that the re-treatment rate OD dosing contributes to improved drug compliance. How- was significantly higher in patients with a PV > 40 mL at ever, for elderly patients with many combination drugs, it is baseline, and tended to be high in patients with severe of complicated to use TID and OD drugs together. Lipton et al subjective symptom [14]. It has been reported that IPSS and compared a group that consulted a clinical pharmacist about IPSS-QoL at baseline in the 3,514 LUTS/BPH patients given their own medical treatment every 3 months and a group that an α1-blocker for 6 months could not be used to predict the did not. They reported that compliance was significantly im- risk of acute urinary retention or re-treatment by operation proved in the group that consulted a clinical pharmacist, as [15]. In this way, there is no consensus about whether the they had fewer medications and less complex regimens [5]. severity of subjective symptoms at baseline is a predictive Naftopidil may be administered in divided doses de- factor for the efficacy of α-1 blocker therapy. Some reports pending on the drug regimen of the individual patient, in- have described various α1-blockers as markedly more effec- cluding the number of doses of concomitant drugs, to avoid tive when subjective symptoms are severe at baseline, but a complicated dosage regimen. However, a difference in the the efficacy of α1-blockers might not be apparent with mod- dosage regimen may affect efficacy and tolerability. There- erate symptoms at baseline [16, 17]. Further examination is fore, the efficacy and tolerability of naftopidil 75 mg/day OD necessary to determine whether the severity of subjective and 75 mg/day TID for LUTS/BPH were compared, and the symptoms affects the effectiveness of α1 blockers. factors predictive of efficacy with each dosage regimen were On the other hand, PV at baseline is a predictive factor evaluated. for the efficacy of α1-blockers [14, 18, 19]. PV was a predic- Naftopidil is an α1D/A-AR antagonist with higher selective factor of the efficacy of naftopidil only in the 75 mg/day tivity for the α1D-AR subtype than for the α1A-adrenoceptor TID group, not in the 75 mg OD group in the present study. (α1A-AR) subtype [1]. Some reports have suggested that the Nakashima et al reported that the concentration max (Cmax) α1D-AR subtype plays an important role in the regulation of of a single dose of naftopidil was dose-dependent, with a bladder function [7-9]. Therefore, naftopidil is highly valued higher value seen with once-daily than with BID dosage for the relief of storage symptoms, particularly nocturia [10]. [20]; this suggests that naftopidil OD allowed the achieve- For these reasons, group O was given the drug in the evening ment of a higher Cmax than the TID regimen. In addition, it and group T was given the drug in the morning, afternoon was reported that maximal inhibition by the α1-blocker of the and evening. intraurethral pressure response correlated well with Cmax In this study, the subjective symptoms showed no signif- in anesthetized male dogs [21]. It was thought that only 75 icant differences between the two different dosage regimens, mg/day OD might inhibit BOO regardless of PV based on similar to our previous report [11]. However, VV, MFR and these reports. However, it is a limitation of this study that AFR were significantly improved between baseline and 8 the blood concentration of naftopidil was not measured, and weeks only in group O. The OD regimen was approximately future studies of the dosage regimen and relationships with equal in overall efficacy to the TID regimen. Extended-re- factors predictive of the efficacy of naftopidil are needed. lease alfuzosin 10 mg OD showed almost the same efficacy The dosage method is often chosen from the viewpoint as 2.5 mg TID, although the dosage regimen was different of compliance. However, it was thought that the dosage [12]. In a comparative study of naftopidil 50 mg/day dosage method affected the effectiveness based on the individual regimens with OD administration in the morning and twice- characteristics of patients in the present study. Therefore, the daily (BID) administration in the morning and evening, the dosage regimen must be chosen based on the characteristics efficacy for subjective symptoms was approximately equal, of the patients from the viewpoint of individual medical care. but MFR showed that the effectiveness of the OD regimen Based on the results of the present study, patients with a large started earlier than that of the BID regimen [13]. These re- PV should be given naftopidil with an OD dosage regimen. ports were similar to the present results. Therefore, it was thought that the choice of 75 mg/day OD or 75 mg/day TID Conclusions might be considered as combination therapy. However, it is necessary to consider a change to 75 mg/day OD for patients Naftopidil 75 mg/day OD offered superior efficacy to 75 mg/

80 Articles © The authors | Journal compilation © World J Nephrol Urol and Elmer Press Inc™ | www.wjnu.elmerpress.com 81 Okumura et al World J Nephrol Urol. 2014;3(2):72-82

day TID in terms of objective findings, but the overall effica- nary tract in mice lacking alpha1d-adrenoceptor. J Urol. cy rate using criteria for treatment efficacy in BPH proposed 2005;174(1):370-374. by the Japanese Urological Association showed no signifi- 8. Ishihama H, Momota Y, Yanase H, Wang X, de Groat cant difference between the two dosage regimens. Therefore, WC, Kawatani M. Activation of alpha1D adrenergic re- the dosage regimen of naftopidil can be chosen based on op- ceptors in the rat urothelium facilitates the micturition timizing compliance. However, it is necessary to consider a reflex. J Urol. 2006;175(1):358-364. change to the OD regimen for patients whose objective find- 9. Kurizaki Y, Ishizuka O, Imamura T, Ichino M, Ogawa T, ings show no improvement with the TID regimen. In addi- Igawa Y, Nishizawa O, et al. Relation between expres- tion, in patients with a large prostate, the OD regimen should sion of alpha(1)-adrenoceptor mRNAs in bladder mu- be chosen because its efficacy is not affected by PV. cosa and urodynamic findings in men with lower urinary tract symptoms. Scand J Urol Nephrol. 2011;45(1):15- 19. Grant Support 10. Yokoyama O, Aoki Y, Tsujimura A, Takao T, Namiki M, Okuyama A. alpha(1)-adrenoceptor blocker naftopidil None. improves sleep disturbance with reduction in nocturnal urine volume. World J Urol. 2011;29(2):233-238. 11. Tsuritani S, Nozaki T, Okumura A, Kimura H, Kazama Conflict of Interest T. A prospective, randomized, controlled, multicenter study of naftopidil for treatment of male lower urinary We certify that there is no conflict of interest with any fi- tract symptoms associated with benign prostatic hyper- nancial organization regarding the material discussed in the plasia: 75 mg once daily in the evening compared to 25 manuscript. mg thrice daily. Urol Int. 2010;85(1):80-87. 12. van Kerrebroeck P, Jardin A, Laval KU, van Cangh P. Efficacy and safety of a new prolonged release formula- tion of alfuzosin 10 mg once daily versus alfuzosin 2.5 References mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. 1. Takei R, Ikegaki I, Shibata K, Tsujimoto G, Asano T. Eur Urol. 2000;37(3):306-313. Naftopidil, a novel alpha1-adrenoceptor antagonist, dis- 13. Yamanaka N, Yamaguchi O, Kameoka H, Fukaya Y, Yo- plays selective inhibition of canine prostatic pressure kota T, Shiraiwa Y, Yokoyama J, et al. [Effect of KT-611 and high affinity binding to cloned human alpha1-adre- (Naftopidil) on the contraction of human prostatic tissue noceptors. Jpn J Pharmacol. 1999;79(4):447-454. and its use in benign prostatic obstruction]. Hinyokika 2. Masumori N. Naftopidil for the treatment of urinary Kiyo. 1991;37(12):1759-1772. symptoms in patients with benign prostatic hyperplasia. 14. de la Rosette JJ, Kortmann BB, Rossi C, Sonke GS, Flo- Ther Clin Risk Manag. 2011;7:227-238. ratos DL, Kiemeney LA. Long-term risk of re-treatment 3. Yokoyama T, Kumon H, Nasu Y, Takamoto H, Watanabe of patients using alpha-blockers for lower urinary tract T. Comparison of 25 and 75 mg/day naftopidil for lower symptoms. J Urol. 2002;167(4):1734-1739. urinary tract symptoms associated with benign prostatic 15. Emberton M, Elhilali M, Matzkin H, Harving N, van hyperplasia: a prospective, randomized controlled study. Moorselaar J, Hartung R, Alcaraz A, et al. Symptom de- Int J Urol. 2006;13(7):932-938. terioration during treatment and history of AUR are the 4. Funahashi Y, Hattori R, Matsukawa Y, Komatsu T, Sas- strongest predictors for AUR and BPH-related surgery sa N, Gotoh M. Clinical efficacy of a loading dose of in men with LUTS treated with alfuzosin 10 mg once naftopidil for patients with benign prostate hyperplasia. daily. Urology. 2005;66(2):316-322. World J Urol. 2011;29(2):225-231. 16. Kumamoto Y, Tsukamoto T, Tsuchida S, Nishizawa O, 5. Lipton HL, Bird JA. The impact of clinical pharmacists’ Aso Y, Koshiba K, Miyake K, et al. Clinical evaluation consultations on geriatric patients’ compliance and med- of terazosin hydrochloride on urinary obstruction caused ical care use: a randomized controlled trial. Gerontolo- by benign prostatic hypertrophy (I) Dose finding study. gist. 1994;34(3):307-315. Jpn J Urol Surg. 1992;5(8):721-734. 6. Homma Y, Gotoh M, Yokoyama O, Masumori N, 17. Park YC, Nishioka T, Arai Y, Tomoyoshi T, Kurita T, Kawauchi A, Yamanishi T, Ishizuka O, et al. Outline of Hayashida H, Nagai N, et al. [A multicenter, fixed-flex- JUA clinical guidelines for benign prostatic hyperplasia. ible dose study of terazosin hydrochloride in the treat- Int J Urol. 2011;18(11):741-756. ment of symptomatic benign prostatic hypertrophy]. 7. Chen Q, Takahashi S, Zhong S, Hosoda C, Zheng HY, Hinyokika Kiyo. 1992;38(7):857-868. Ogushi T, Fujimura T, et al. Function of the lower uri- 18. Masumori N, Hashimoto J, Itoh N, Tsukamoto T, The

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