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Keywords:

  • anticholinergic agent;
  • benign prostatic hyperplasia;
  • naftopidil;
  • storage symptom

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Aim: The aim of this study was to compare the efficacy and safety of α1-adrenoceptor (α1-AR) antagonist monotherapy with combination therapy using α1-AR antagonist and anticholinergic agent for benign prostatic hyperplasia (BPH) with storage symptoms as the chief complaint.

Methods: In this prospective comparative study, either 25–75 mg/day of naftopidil monotherapy (monotherapy group) or combination therapy using 25–75 mg/day of naftopidil and an anticholinergic agent (10–20 mg/day of propiverine hydrochloride or 2–6 mg/day of oxybutynin hydrochloride; cotherapy group) were administered for 12 weeks to 101 BPH patients with storage symptoms.

Results: International prostate symptom score (IPSS) and quality of life (QOL) index improved significantly in both groups, with no marked differences between groups. Maximum flow rate (Qmax) and residual urine volume (RUV) tended to improve in both groups, again with no marked differences between groups. However, median post-therapeutic RUV was significantly worse for the cotherapy group (45.0 mL) than for the monotherapy group (13.5 mL; P = 0.0210). Ratio of patients with increased RUV was also significantly worse for cotherapy (22.9%) than for monotherapy (5.0%; P = 0.038).

Conclusions: Although the anticholinergic dosage was low, the present results suggest that naftopidil monotherapy was as useful as combination therapy of naftopidil and an anticholinergic agent. Therefore, naftopidil is a useful agent as the first choice in BPH patients with storage symptoms.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Benign prostatic hyperplasia (BPH) is a common condition involving enlargement of the prostate, and lower urinary tract symptoms (LUTS) and reduced urinary flow associated with BPH are seen in 43% of men in their 60s.1

Of the various symptoms associated with BPH, storage symptoms are the most bothersome to patients.2 In BPH patients with severe storage symptoms, α1-adrenoceptor (α1-AR) antagonist and anticholinergic agents such as oxybutynin hydrochloride or propiverine hydrochloride have been administered,3–6 but the use of anticholinergic agents in male patients with benign prostatic obstruction (BPO) may exacerbate voiding symptoms.4 Furthermore, few studies have investigated the efficacy and safety of combined therapy using an α1-AR antagonist and an anticholinergic agent, and this combination therapy is currently administered based on the empiric experience of individual physicians.

In order to establish drug therapy for BPH patients displaying severe storage symptoms, we compared the efficacy and safety of naftopidil monotherapy with combination therapy using naftopidil and anticholinergic agent. Naftopidil is an α1-AR antagonist that is effective against storage symptoms, particularly nocturia.7–10

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Patients

Subjects comprised 101 patients who had been clinically diagnosed with BPH (international prostate symptom score [IPSS]: ≥8; quality of life [QOL] index: ≥2) at our institution or one of the affiliated hospitals between August 2001 and March 2003. These patients met the following requirements by IPSS: frequency score of 3 points or higher; and nocturia score of 2 points or higher.

The study protocol was approved by the institutional review board of Juntendo University Urayasu Hospital and informed consent was obtained from all patients.

Protocol

The 101 patients were randomly divided into two groups based on medical chart numbers. Naftopidil monotherapy was administered to the 53 odd-numbered patients (monotherapy group), while combination therapy using naftopidil and an anticholinergic agent (propiverine hydrochloride or oxybutynin hydrochloride) was administered to the 48 even-numbered patients (cotherapy group). In both groups, daily dose of naftopidil was 25–75 mg, representing the recommended dose range in Japan. In the cotherapy group, dosage comprised 10–20 mg/day of propiverine hydrochloride or 2–6 mg/day of oxybutynin hydrochloride. The two therapies were administered for 12 weeks.

Therapeutic efficacy was analyzed using IPSS, QOL index, maximum flow rate (Qmax) and residual urine volume (RUV; measure by transabdominal ultrasonography). Overall efficacy was determined using the IPSS, QOL index and Qmax according to the criteria proposed by Homma et al. and efficacy grade was evaluated as ‘Excellent’, ‘Good’, ‘Fair’ or ‘Poor/worse’.11 In addition, safety was assessed based on adverse reactions and RUV.

Statistical analysis

Data are expressed in terms of mean ± standard deviation and median (interquartile range). The Wilcoxon signed rank test was used to compare data at the start and end of administration. Unpaired t-tests were used to compare age and estimated prostate volume between groups, and Mann–Whitney’s U-test was used for intergroup comparisons of all other parameters. Differences in symptoms, QOL, function and overall efficacy were analyzed using χ2 tests. Fisher’s exact test was used to analyze safety.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Study population

A total of eight patients in the monotherapy group and seven patients in the cotherapy group were withdrawn from the study because they did not attend scheduled visits. As a result, safety was assessed for 45 patients from the monotherapy group and 41 patients from the cotherapy group. Furthermore, during the study period, one patient in the monotherapy group and two patients in the cotherapy group experienced adverse reactions, one patient in the cotherapy group underwent surgery because drug therapy proved ineffective, and two patients in the cotherapy group discontinued drug therapy due to increases in RUV. Efficacy was thus analyzed in 44 patients from the monotherapy group and 36 patients from the cotherapy group.

No significant intergroup differences in patient baseline characteristics were observed (Table 1). Maximum daily doses of naftopidil in each group, and maximum daily doses of oxybutynin hydrochloride and propiverine hydrochloride in the cotherapy group are shown in Table 2.

Table 1.  Baseline characteristics for the naftopidil monotherapy group and the naftopidil plus anticholinergic agent cotherapy group
CharacteristicNaftopidil monotherapyNaftopidil cotherapyP
nMean ± SDMedian (25%, 75%)nMean ± SDMedian (25%, 75%)
  1. †Unpaired t-test; ‡Mann–Whitney U-test. IPSS, international prostate symptom score; Qmax, maximum flow rate; QOL, quality of life.

Age (years)44 67.0 ± 6.9 66.4 (61.2, 72.2)36 67.6 ± 8.2 67.3 (61.5, 73.6)0.7349
Prostate volume (mL)44 31.4 ± 10.8 29.0 (24.5, 36.6)35 33.8 ± 12.0 33.0 (24.3, 42.8)0.3576
IPSS44 17.5 ± 7.5 16.0 (10.5, 23.0)36 16.6 ± 6.1 15.0 (12.0, 19.0)0.7307
QOL index44  4.4 ± 0.9  4.5 (4.0, 5.0)36  4.4 ± 0.9  4.0 (4.0, 5.0)0.6863
Qmax (mL/s)40 10.5 ± 6.7  8.8 (6.5, 10.0)31 11.8 ± 7.2  9.0 (7.0, 16.3)0.4440
Voided volume (mL)40190.8 ± 152.8129.0 (102.0, 217.0)31238.9 ± 145.8250.0 (131.5, 312.0)0.0542
Residual urine volume (mL)39 45.0 ± 62.0 19.0 (0, 83.0)32 55.8 ± 59.2 35.0 (10.0, 92.5)0.1348
Table 2.  Drug dosages in the naftopidil monotherapy group and the naftopidil plus anticholinergic agent cotherapy group
DrugMaximum daily doseMonotherapyCotherapy
Naftopidil25 mg 1 8
50 mg3925
75 mg 4 3
Oxybutynin hydrochloride 2 mg26
 4 mg  1
 6 mg  2
 8 mg  1
Propiverin hydrochloride10 mg 5
20 mg  1

Efficacy analysis

Changes in each IPSS item between pre- and post-treatment were analyzed, revealing significant improvements in incomplete emptying, urinary frequency, nocturia and weak urinary stream for both groups. Significant improvements in urgency were also seen for the cotherapy group (P = 0.0008), but not for the monotherapy group. Furthermore, straining was significantly improved for the cotherapy group (P = 0.0031), but not for the monotherapy group. Conversely, intermittency was significantly improved for the monotherapy group (P = 0.0186), but not for the cotherapy group (Table 3).

Table 3.  Changes in each international prostate symptom score (IPSS) item from baseline to 12 weeks and intergroup comparisons*
IPSS itemnPre-treatmentAfter 12 weeksP (within group)
Mean ± SDMedian (25%, 75%)Mean ± SDMedian (25%, 75%)
  • *

    P-values: within group, Wilcoxon signed rank test; between groups, Mann–Whitney U-test.

Incomplete emptying
 Monotherapy442.3 ± 1.72.0 (1.0, 3.0)1.3 ± 1.11.0 (1.0, 2.0)0.0001
 Cotherapy362.0 ± 1.52.0 (1.0, 3.0)1.6 ± 1.31.0 (1.0, 2.0)0.0393
 P (between groups) 0.3750 0.2533  
Frequency
 Monotherapy443.0 ± 1.53.0 (2.0, 4.5)1.9 ± 1.61.0 (1.0, 3.0)0.0003
 Cotherapy363.2 ± 1.33.0 (2.0, 4.0)1.9 ± 1.61.0 (1.0, 3.0)<0.0001
 P (between groups) 0.6604 0.9399  
Urgency
 Monotherapy441.9 ± 1.91.0 (0, 3.5)1.4 ± 1.61.0 (0, 2.0)0.1271
 Cotherapy361.9 ± 1.62.0 (0, 3.0)1.3 ± 1.71.0 (0, 2.0)0.0008
 P (between groups) 0.7859 0.4205  
Nocturia
 Monotherapy443.0 ± 1.13.0 (2.0, 4.0)2.0 ± 1.02.0 (1.0, 2.5)<0.0001
 Cotherapy362.9 ± 1.23.0 (2.0, 4.0)1.9 ± 1.22.0 (1.0, 2.5)<0.0001
 P (between groups) 0.7543 0.5940  
Intermittency
 Monotherapy442.2 ± 1.82.0 (0.5, 3.5)1.4 ± 1.61.0 (0, 2.0)0.0186
 Cotherapy361.7 ± 1.51.0 (0.5, 2.0)1.6 ± 1.61.0 (0, 2.5)0.3973
 P (between groups) 0.1622 0.5370  
Weak stream
 Monotherapy443.3 ± 1.84.0 (2.0, 5.0)1.9 ± 1.61.0 (1.0, 3.0)<0.0001
 Cotherapy362.8 ± 1.53.0 (2.0, 4.0)2.0 ± 1.71.5 (1.0, 3.5)0.0016
 P (between groups) 0.1280 0.7363  
Straining
 Monotherapy441.7 ± 1.61.0 (0, 3.0)1.3 ± 1.41.0 (0, 2.0)0.2179
 Cotherapy362.1 ± 1.82.0 (0, 4.0)1.3 ± 1.61.0 (0, 2.0)0.0031
 P (between groups) 0.3950 0.6134  

For both groups, total IPSS was significantly improved between pre- and post-treatment (both P < 0.0001). In addition, QOL index was significantly improved for both groups by the end of treatment (monotherapy group: P = 0.0001; cotherapy group: P < 0.0001). On evaluation of 40 patients in the monotherapy group and 31 patients in the cotherapy group, for whom both pre- and post-treatment values were available, neither group displayed significant improvements in Qmax (Table 4).

Table 4.  Changes in total IPSS, QOL index, and Qmax from baseline to 12 weeks and intergroup comparisons*
ParameternPre-treatmentAfter 12 weeksP (within group)
Mean ± SDMedian (25%, 75%)Mean ± SDMedian (25%, 75%)
  • *

    P-values: within group, Wilcoxon signed rank test; between groups, Mann–Whitney U-test.

  • IPSS, international prostate symptom score; Qmax, maximum flow rate; QOL, quality of life.

Total IPSS
 Monotherapy4417.5 ± 7.516.0 (10.5, 23.0)11.2 ± 6.510.0 (7.0, 14.5)<0.0001
 Cotherapy3616.6 ± 6.115.0 (12.0, 19.0)11.6 ± 7.410.0 (5.0, 16.5)<0.0001
 P (between groups) 0.7307 0.9768  
QOL index
 Monotherapy44 4.4 ± 0.9 4.5 (4.0, 5.0) 2.9 ± 1.3 3.0 (2.0, 4.0)<0.0001
 Cotherapy36 4.4 ± 0.9 4.0 (4.0, 5.0) 3.3 ± 1.5 3.0 (2.0, 4.0)0.0001
 P (between groups) 0.6863 0.2792  
Qmax (mL/s)
 Monotherapy4010.5 ± 6.7 8.8 (6.5, 10.0)11.6 ± 8.3 9.0 (6.4, 16.9)0.5423
 Cotherapy3111.8 ± 7.2 9.0 (7.0, 16.3)12.2 ± 6.610.0 (7.2, 17.9)0.3616
 P (between groups) 0.4440 0.4304  

Frequency of overall efficacy (rated at least ‘Fair’) was 55.9% for the monotherapy group and 64.5% for the cotherapy group, and no significant differences between groups were identified (Table 5).

Table 5.  Comparison of overall efficacy between the naftopidil monotherapy group (n = 40) and the naftopidil plus anticholinergic agent cotherapy group (n = 31)
Overall efficacyMonotherapyCotherapy
  1. No significant intergroup differences were identified. †Cumulative %.

  2. A χ2 test was used to compare outcomes of ‘Better than fair’ with ‘Poor/worse’. χ2 test (Better than fair vs Poor/worse): P = 0.4173.

Excellent 3 2
Good 5 2
Fair1416
Better than fair22 (55.0%)20 (64.5%)
Poor/worse1811

Safety analysis

Among the 86 patients for whom safety was analyzed, frequency of adverse events was 4.4% for the monotherapy group (dizziness, n = 1; stomachache n = 1) and 7.3% for the cotherapy group (nausea, n = 2; abdominal fullness, n = 1). All adverse events were mild and improved on discontinuation of drug administration. No significant differences between groups were noted in frequency of adverse events (P = 0.6766).

Among 86 patients, there were 75 patients for whom RUV was measured at pretreatment and post-treatment (or withdrawal); 40 patients in the monotherapy group and 35 patients in the cotherapy group. At the start of treatment, median RUV for the monotherapy group was 19.5 mL (interquartile range, 0–94.0 mL) and for the cotherapy group was 35.0 mL (interquartile range, 10.0–99.5 mL), with no significant intergroup differences. At the end of treatment, median RUV was significantly higher for the cotherapy group (45.0 mL; interquartile range, 6.8–83.8 mL) than for the monotherapy group (13.5 mL; interquartile range, 2.0–35.0 mL; P = 0.0210; Fig. 1). An increase in RUV of >50 mL was confirmed in two (5.0%) of the 40 monotherapy group patients and eight (22.9%) of the 35 cotherapy group patients. This difference was statistically significant (P = 0.0383).

image

Figure 1. Differences in residual urine volume from baseline and between groups before and after treatment. An end of a box is interquartile range 25% and 75%. The horizon of a box is statistical median. The whiskers were the farthest points that are not outliers. Outliers are observations that fall outside the whiskers.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Lower urinary tract symptoms caused by BPH markedly affect QOL, and is referred to as a QOL disease. Storage symptoms such as daytime frequency and nocturia are bothersome to BPH patients.2

At present, LUTS caused by BPH is predominantly treated using second-generation α1-AR antagonists that are selective against the prostate and have a low incidence of causing orthostatic hypotension. Naftopidil is a second-generation α1-AR antagonist with a relatively high affinity towards the α1d-adrenoceptor (α1d-AR) subtype.12 In human detrusor muscle, α1d-ARs outnumber α1a adrenoceptor (α1a-AR),13 and increased bladder weight, up-regulation of the α1a-AR subtype and increased urinary frequency have been reported in bladder outlet obstruction (BOO) in rats.14 The relationship between storage symptoms and distribution and function of the α1d-AR subtype has thus been examined. Furthermore, when naftopidil was administered intrathecally to rats, isovolumetric bladder contraction ceased transiently, suggesting that naftopidil might also act on the lumbosacral cord.15 Many studies have reported naftopidil to be effective for improving storage symptoms.7–9

The effects of oxybutynin hydrochloride and propiverine hydrochloride on bladder smooth muscle are said to be anticholinergic or calcium antagonistic actions.16,17 These anticholinergic agents have occasionally been administered to BPH patients with severe storage symptoms, but they can exacerbate prostatic obstruction or increase RUV.4 As a result, an α1-AR antagonist is often administered.3–6 However, only a few studies have examined therapies combining anticholinergic agents and α1-AR antagonists, and no general consensus has been reached regarding efficacy and safety.

The present study administered naftopidil monotherapy or anticholinergic agent and naftopidil combination therapy in BPH patients with severe storage symptoms, to compare safety and efficacy between the two therapies.

There were no significant differences between the groups regarding changes in IPSS, QOL and Qmax. Athanasopoulos et al. conducted a study comparing tamsulosin hydrochloride monotherapy against tamsulosin hydrochloride and tolterodine combination therapy, in BPH patients with mild/moderate BOO according to Schafer’s nomogram and concomitant detrusor instability (DI), and reported the QOL score for combination therapy to be significantly higher than that for monotherapy. Moreover, Lee et al. reported combination therapy of doxazosin and tolterodine to be effective in 73% of the symptomatic BOO with OAB.6 These reports were different from our results. Recently, the function of the lower urinary tract in α1d-AR knockout (α1d-KO) and its wild-type mice was reported. As a result, bladder capacity and voided volume were significantly larger for the α1d-KO mice compared with the wild type. This is theoretically supported in a clinical finding that α1-AR antagonists with high affinity for α1d-AR, such as naftopidil, were effective for storage symptoms.18 Moreover, in the present study, anticholinergic dosage was low; 26 out of 30 patients received 2 mg/day of oxybutynin hydrochloride, and 5 of 6 patients received 10 mg/day of propiverine hydrochloride. In terms of the reason for no significant difference between the groups, naftopidil was effective for storage symptoms, and anticholinergic dosage was low.

The two therapies were thus effective against different symptoms: combination therapy was less effective against intermittency, but more effective against urgency, according to within-group comparison. If naftopidil is not effective in urgency, combination therapy with anticholinergic agent could be considered as a therapeutic strategy. However, suitable doses for anticholinergic agents for combined therapies were not fully investigated in this study.

Saito et al. compared tamsulosin hydrochloride monotherapy against combination therapy using propiverine hydrochloride and tamsulosin hydrochloride in BPH patients with daytime frequency and/or urinary incontinence, and reported that while monotherapy was more effective against intermittency, combination therapy was more effective against nocturia.4 The same results were thus obtained regarding intermittency. This is somewhat expected considering the mechanism of an anticholinergic agent on the bladder.

However, the causes of nocturia vary greatly and include reduced functional bladder volume caused by bladder hyperactivity; in the elderly, age-related reduction in renal concentrating ability; decreased levels of antidiuretic hormone; and polyuria by excessive water intake. In this study, we did not examine storage symptoms using a frequency volume chart. Therefore, the effectiveness for nocturia needs more detailed examination.

The frequency of adverse reactions was not significantly different between the groups. However, the ratio of patients with increased RUV was significantly worse for the cotherapy group compared with the monotherapy group. Further, post-therapeutic RUV was significantly higher for the cotherapy group than for the monotherapy group, but it did not pose a problem clinically. Yoshino et al. reported that the frequency of urinary tract infections was significantly higher among patients with RUV ≥148 mL compared with those with RUV <148 mL.19 Athanasopoulos et al. found no marked changes in RUV in a combined therapy group.5 Suzu et al. administered propiverine hydrochloride to patients with voiding disorders and reported that Qmax was ≤10 mL/s before therapy in all of the patients that had increased by the end of therapy.20 For an anticholinergic agent to be added to the treatment of a male patient with BPO, the risk of RUV increase is not high, if attention is paid to Qmax, and RUV may not need to receive the concern it is conventionally given.

According to Saito et al. the exacerbation of voiding symptoms such as acute urinary retention (AUR; characteristic adverse reactions associated with anticholinergic agent) was 3.0%.4 Lee et al. found temporary AUR in 3.3% of patients treated with combined therapy.6 In the present study, no patients experienced AUR, but it is necessary for an anticholinergic agent to be added to treatment with consideration of AUR for BPO in a male patient.

In BPH patients with storage symptoms as the chief complaint, naftopidil monotherapy was equally effective compared with combination therapy using naftopidil and an anticholinergic agent, and it was more tolerable. Therefore, naftopidil was useful as the first choice in BPH patients with storage symptoms.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
    Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338: 46971.
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    Saitoh H, Yamada T, Oshima H et al. A comparative study of the efficacy and safety of tamsulosin hydrochloride alone and combination of propiverine hydrochloride and tamsulosin hydrochloride in the benign prostatic hypertrophy with pollakisuria and/or urinary incontinence. Jpn. J. Urol. Surg. 1999; 12: 52536.
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    Athanasopoulos A, Gyftopoulos K, Giannitsas K, Fisfis J, Perimenis P, Barbalias G. Combination treatment with an α-blocker plus an anticholinergic agents for bladder outlet obstruction: a prospective randomized, controlled study. J. Urol. 2003; 169: 22536.
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    Ikemoto I, Kiyota H, Ohishi Y et al. Usefulness of tamsulosin hydrochloride and naftopidil in patients with urinary disturbances caused by benign prostatic hyperplasia: a comparative, randomized, two-drug crossover study. Int. J. Urol. 2003; 10: 58794.
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    Takei R, Ikegaki I, Shibata K et al. Naftopidil, a novel α1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human α1-adrenoceptors. Jpn. J. Pharmacol. 1999; 79: 44754.
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    Hampel C, Dolber PC, Smith MP et al. Modulation of bladder α1-adrenergic receptor subtype expression by bladder outlet obstruction. J. Urol. 2002; 167: 151321.
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    Sugaya K, Nishijima S, Miyazato M, Ashitomi K, Hatano T, Ogawa Y. Effects of intrathecal injection of tamsulosin and naftopidil, alpha-1A and -1D adrenergic receptor antagonists, on bladder activity in rats. Neurosci. Lett. 2002; 328: 746.
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    Fredericks CM, Anderson GF, Kreulen DL. A study of the anticholinergic and antispasmodic activity of oxybutynin (dipropan) on rabbit detrusor. Invest. Urol. 1975; 12: 31719.
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    Riotte J, Mutschler E. [The spasmolytic activity of propiverine and some of its structural analogs.] Arzneimittelforschung 1987; 37: 3002 (in German).
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    Chen Q, Takahashi S, Zhong S et al. Function of the lower urinary tract in mice lacking α1d-adrenoceptor J. Urol. 2005; 174: 3704.
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    Yoshino Y, Oishi Y, Onodera S et al. Clinical study of the relationship between residual urine and urinary tract infection in patients with voiding disorders. Rinsyo Hinyokika 2000; 54: 4557.
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    Suzu H, Saito Y. Clinical efficacy of propiverine hydrochloride in patients with pollakisuria or urinary incontinence: effect on lower urinary tract function. Nishinihon J. Urol. 1999; 61: 68995.