Tomonori Yamanishi md, Department of Urology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. Email: email@example.com
Abstract Aim: The aim of our study was to examine the efficacy of naftopidil in terms of the international prostate symptom score (IPSS) and urodynamic parameters in the treatment of benign prostatic hyperplasia (BPH). Eviprostat was used as a control to study the efficacy of naftopidil.
Methods: Forty-nine patients with BPH (mean age 67.9 ± 7.8 years) were involved in the study. Patients were randomly assigned either to the naftopidil group, which was treated with the α-blocker naftopidil (50–75 mg daily, 36 patients), or the eviprostat group, which was treated with phytotherapy (six tablets of eviprostat daily, 13 patients).
Results: The mean total IPSS, the total storage and voiding symptom scores, and the quality of life score decreased significantly (P < 0.0001 for each variable) in the naftopidil group, but not in the eviprostat group. In the naftopidil group, analyses showed significant increases in average and maximum flow rate and bladder capacity at first desire to void (P < 0.001, P = 0.001 and P = 0.024, respectively), and significant decreases in the postvoid residual, the percent of residual and the Abrams–Griffiths number (P = 0.009, P = 0.008 and P = 0.042, respectively). However, in the eviprostat group, no significant changes were noted in terms of these symptomatic and urodynamic parameters. In the pressure/flow study, an improvement in the International Continence Society nomogram grade was noted in 29% of the naftopidil group, but in only 16% of the eviprostat group. Among the 14 patients in the naftopidil group, detrusor overactivity disappeared in 21% and cystometric capacity increased in 36%, but no improvement in detrusor overactivity was noted in the eviprostat group.
Conclusions: Naftopidil appears to have been effective in this short-term treatment of BPH.
Many options for the treatment of benign prostatic hyperplasia (BPH) exist, including transurethral resection of the prostate and various minimally invasive therapies including holmium:YAG laser prostatectomy and pharmaceutical therapy.1 Among these therapies, medical therapy with α1-adrenoceptor antagonists is widely used as a conservative treatment to relieve bladder outlet obstruction caused by benign prostatic enlargement.2–6 Naftopidil, ([+/–]-1-[4-[2-methoxyphenyl] piperazinyl]-3-[1-naphthyloxy] propan-2-ol), is a newly synthesized α1-blocker that has been found to be effective in the treatment of BPH.4 This drug is highly selective for the α1A-, and α1D-adrenoceptor subtypes, with an affinity for the α1D-adrenoceptor that is 3- and 17-fold higher than that for the α1A- and α1B-adrenoceptors, respectively.7 An in vivo study in dogs showed that the selectivity index (dose ratio required to produce a 50% inhibition of the prostatic pressure and mean blood pressure) was higher for naftopidil (3.76) than for tamsulosin (1.23) and prazosin (0.61).7 Naftopidil also has weak antagonistic activity to post-junctional α2-adrenoceptors.8
Phytotherapeutic drugs including Pygeum africanum, Serenoa repens, β-sitosterol and cernilton have also been widely used in the pharmacological treatment of BPH.9–13 These plant extracts are reported to be the most commonly recommended initial treatment for men with lower urinary tract symptoms in Europe and Japan because of their non-hormonal and non-neuropharmacological characteristics (and, therefore, their non-toxicity).14,15 Boyle et al. reported significant improvements in maximum flow rate (Qmax) and nocturia, compared with placebo, in a meta-analysis of clinical trials of Serenoa repens.16 However, there have been few controlled studies on the urodynamic effects of phytotherapeutic drugs, including pressure/flow studies for the treatment of BPH.13,14
Eviprostat is a mixture of plant extracts from Phila umbellata, Populus tremula, Pulsatilla pratensis mill and wheat-germ oil.11,15 Although eviprostat is the most widely used agent in Japan and is reported to be effective in the treatment of the lower urinary tract symptoms associated with BPH, no published reports indicate that it has any effect on urodynamic parameters. In this study, eviprostat was used as a control to study the efficacy of naftopidil.
The aim of the present study is to compare the efficacy of naftopidil with eviprostat in terms of international prostate symptom score (IPSS) and urodynamic parameters, including pressure/flow study in the treatment of BPH.
A total of 49 patients (mean age 67.9 ± 7.8 years) with voiding dysfunction due to BPH were enrolled in this single-blind, randomized controlled study. The inclusion criteria were: (i) a total IPSS of eight or more; (ii) maximum flow rate of ≤12 mL/s, as evaluated by uroflowmetry; (iii) prostate volume of ≥15 mL, as measured by prostatic ultrasound; and (iv) obstructive (or equivocal) condition on International Continence Society (ICS) nomogram as assessed in a pressure/flow study. Patients that matched the following criteria were excluded from the study: (i) patients with complete urinary retention; (ii) patients with prostatic cancer, prostatitis and urethral stricture; (iii) patients with severe cardiac or cerebrovascular disorders, hepatic disorders, renal dysfunction or orthostatic hypotension; and (iv) patients taking medication with anticholinergics, other alpha-antagonists, beta-agonists or antagonists. Local ethical committee approval and written informed consent from each patient was obtained before entry into the study.
After the observation run-in period of 1 week, patients were randomly assigned to either the naftopidil group or the eviprostat group using an envelope indicating one of the two groups. Because eviprostat was used as a control in this study, the ratio of the two groups was set to 3 : 1, that is, 36 patients were included in the group taking naftopidil (50–75 mg daily) and 13 patients were included in the group taking eviprostat (six tablets daily). Naftopidil was administered at a dose of 25 mg once daily for 2 weeks, followed by 50 mg once daily for 2 weeks, and then 75 mg daily for another 2 weeks if the patients were not satisfied with the improvement at the lower dose level.4 The effectiveness of each therapy was assessed by changes in IPSS, uroflowmetry and urodynamic parameters, including a pressure/flow study at 4–6 weeks after the initiation of therapy.
Urinary symptom scores were assessed by the IPSS and quality of life (QOL) scores. A symptom of ‘feeling of incomplete emptying’ is defined as a self-explanatory term for the feeling experienced by the individual after passing urine,17 but was included in the storage symptoms in the present study. Free urinary flow rate and postvoid residual urine volume were evaluated at the end of the observation period and after the therapy. Postvoid residual urine volume (mL) and the percent of residual urine (residual urine volume/[residual urine volume + voided volume] × 100%) were measured by catheterization, and then video-urodynamic studies were performed. A 7F double lumen catheter was inserted transurethrally and a water cystometrogram was recorded at an infusion rate of 50 mL/min in the supine position. At maximum cystometric capacity, patients assumed a standing position, and the pressure/flow study was performed. IPSS and urodynamic studies, including cystometry and the pressure/flow study, were assessed before and after the therapy.
Methods, definitions and units conform to the standards recommended by the International Continence Society, except where specifically noted.17
The efficacy of the treatment was evaluated according to the standard criteria proposed by Homma et al. and the International Consultation on BPH, and graded as ‘excellent’, ‘good’, ‘fair’, and ‘poor’. Efficacy for IPSS was calculated as the ratio to pre to post-treatment scores, and efficacy for the QOL score and Qmax as the difference.18,19
Data were expressed as mean ± SD. Pre- and post-treatment data were analyzed using paired Student's t-tests. Intergroup differences were assessed with the Student's t-test or the Mann–Whitney U-test, applied to the changes from baseline to their post-treatment values. P-values <0.05 were regarded as statistically significant.
All subjects, including the 13 patients (69 ± 6.5 years old) in the eviprostat group and the 36 patients (67.5 ± 8.2 years old) in the naftopidil group, completed the study. Two patients needed 75 mg of naftopidil to relieve their symptoms. No remarkable adverse event was noted in either group. Prostate volume calculated by transrectal ultrasonography was 29.5 ± 15.9 mL and 29.7 ± 14.9 mL in the eviprostat and naftopidil groups, respectively. There were no significant differences between the groups in terms of age, prostatic volume, the sum of IPSS, QOL score and baseline urodynamic parameters (Tables 1–4).
Table 1. Changes in urinary symptom scores before and after the therapy
Eviprostat group n = 13
Naftopidil group n = 36
Intergroup difference P-value (Student's t-test)
Intergroup difference in terms of the change of pre- and post values between each group.
IPSS, international prostate symptom scores; QOL, quality of life.
Changes in lower urinary tract symptoms before and after the therapy are summarized in Table 1. Mean total IPSS, total storage symptom scores, total voiding symptom scores and the QOL score decreased significantly (P < 0.0001 for each variable) in the naftopidil group, but did not change in the eviprostat group. Intergroup differences were noted in terms of changes in these symptom scores (Table 1). The efficacy of naftopidil, as measured by improvement in the IPSS, was judged as excellent (pre–post ratio ≤0.25) in five patients (13.9%), good (ratio ≤0.50) in nine (25%), fair (ratio ≤0.75) in 11 (30.6%) and poor (ratio >0.75) in 11 patients (30.6%). No patient in the eviprostat group was judged as excellent or good; four patients (30.8%) were judged as fair and nine (69.2%) were judged as poor in terms of the efficacy criteria for IPSS.18,19 The efficacy of naftopidil as measured by the QOL score was assessed as excellent (pre–post difference ≥4) in three patients (8.3%), good (difference = 3) in two (5.8%), fair (difference = 2.1) in 24 (66.7%) and poor (difference ≤0) in seven patients (19.4%). However, the equivalent efficacy score for eviprostat was only fair in three patients (23.1%) and poor in 10 patients (76.9%). There were significant intergroup differences in terms of the efficacy as measured by IPSS (P = 0.0046) and QOL scores (P = 0.0003). With respect to specific individual symptom scores in the naftopidil group, scores for feelings of incomplete emptying, urinary frequency, intermittency, urgency, decreased urinary stream and straining were decreased significantly (P = 0.003, P = 0.033, P < 0.001, P = 0.007, P < 0.001 and P < 0.001, respectively). Although the score for nocturia decreased somewhat, the decrease was not statistically significant (P = 0.084). In contrast, there were no significant changes for any of the symptom scores in the eviprostat group (Fig. 1).
The changes in free uroflowmetric parameters and postvoid residual before and after the therapy are summarized in Table 2. In the naftopidil group, average and maximum flow rates (Qave and Qmax, respectively) increased significantly (P = 0.0008 and P = 0.0005, respectively) and the postvoid residual and percent of residual both decreased significantly (P = 0.009 and P = 0.008, respectively). The efficacy of naftopidil with regard to Qmax was judged as excellent (post–pre difference ≥10 mL/ s) in seven patients (19.4%), good (difference ≥5) in six (16.7%), fair (difference ≥2.5) in six (16.7%) and poor (difference <2.5) in 17 patients (47.2%). However, the equivalent efficacy for eviprostat was judged as good in only one patient (9.1%), fair in one (9.1%) and poor in nine patients (81.8%).
The changes in urodynamic parameters before and after the therapy are summarized in Table 3. The pressure/flow study could be assessed both before and after the therapy in 12 and 24 patients in the eviprostat and naftopidil group, respectively. In the pressure/flow study, the baseline grade in the ICS nomogram was classed as obstructed and equivocal in 11 patients and one patient, respectively, in the eviprostat group, and in 22 and two patients, respectively, in the naftopidil group. After treatment, seven patients (29%) had improved grades (obstructed to unobstructed in three, obstructed to equivocal in two and equivocal to unobstructed in two) in the naftopidil group, but only two patients (16%) showed improvement (obstructed to equivocal) in the eviprostat group (Fig. 2).
Detrusor overactivity was noted in 14 patients in the naftopidil group and five patients in the eviprostat group Table 4. Overactivity disappeared in three patients (21%) from the naftopidil group but in none of the patients in the eviprostat group. In patients with detrusor overactivity, bladder capacities at first and strong desire to void tended to increase (P = 0.051 and P = 0.092, respectively) in the naftopidil group. Cystometric bladder capacity increased by more than 100 mL in five patients (36%) in the naftopidil group, but no change was noted in terms of cystometric capacity in patients from the eviprostat group. The amplitude of the largest overactive detrusor contraction decreased significantly (P = 0.008) in the naftopidil group.
The overall efficacy, that is, the median of the efficacy grades determined by the IPSS, Qmax and QOL score domains,18,19 was judged as excellent, good, fair and poor in three (10.6%), five (13.9%), 19 (52.8%) and nine patients (25.0%), respectively, in the naftopidil group, but only fair and poor in three (23.1%) and 10 patients (76.9%), respectively, in the eviprostat group. There was a significant difference in terms of the overall efficacy grade between the groups (P = 0.0010). Patients in the naftopidil group judged the treatment as excellent in six cases (17.1%), good in 16 (45.7%), fair in 10 (28.6) and poor in three cases (8.6%). Those in the eviprostat group judged the treatment as good in two (15.4%), fair in two (15.4%) and poor in nine cases (69.2%). There was an intergroup difference in terms of patient assessment.
The mechanism of action of eviprostat in the treatment of BPH has been reported to be due to diuretic, antiseptic and anti-inflammatory effects.15 In animal experiments with rats, oral administration of eviprostat (300 mg/kg) ameliorated the negative impacts induced in urodynamic parameters by the intravesical instillation of mustard oil. In these experiments, negative impacts in urodynamic parameters included decreases in bladder capacity, maximum contraction pressure and voided volume, increases in residual volume, and the inhibition of spontaneous contractions caused by chronic partial obstruction of the urethra.20 Based on the results of these experiments, eviprostat does appear to ameliorate bladder irritability.20 In a non-randomized study with eviprostat, Ishigooka et al. reported subjective improvements as well as a decrease in prostatic volume in 64% of patients assessed by ultrasonography of the prostate; they also reported an increase in flow rate in 22 patients with BPH, and a reduction in the degree of prostatic inflammation, as shown by histological evaluation of resected specimens by transurethral prostatectomy.15 However, in the present study, no significant improvements in free uroflowmetry or urodynamic parameters, except for detrusor opening pressure, were noted in the eviprostat group. Discrepancies in the results between these reports might be due to differences in patient selection, study duration or sample size. However, our results are in agreement with those of Gerber et al., who demonstrated no urodynamic improvements, including urinary flow rate, residual urine, bladder capacity, detrusor pressure at maximum flow and Abrams–Griffiths number in treatment using Serenoa repens.14 They considered the symptomatic improvement by this drug to be a placebo effect.
Published reports have shown the efficacy of α-blockers in improving urodynamics and producing symptomatic improvement in the treatment of BPH. In treatment with terazosin for BPH, Gleason and Bottaccini reported a significant reduction in both the number of voidings per 24 h and in the number of overactive contractions. They also reported a significant increase in Qmax, and a tendency towards an increase in bladder capacity and opening pressure, but no changes in IPSS were noted.21 Arnold demonstrated a significant reduction in IPSS, detrusor pressure at maximum flow and Abrams–Griffiths number (by 15.5), and a significant increase in Qmax (by 1.4 mL/s) in treatment with tamsulosin for BPH patients.2 In our study, lower urinary symptom scores were improved significantly, urinary flow rates increased significantly, and postvoid residual urine volume decreased significantly in the naftopidil group. Urodynamically, in the naftopidil group, bladder capacity at first desire to void increased, and Abrams–Griffiths number decreased significantly. In our pressure/flow study, seven naftopidil patients (29%) showed improvements in terms of obstruction grade in the ICS nomogram. The effects of naftopidil appear to be comparable to those of tamsulosin as reported by Arnold.2
Furthermore, detrusor overactivity was abolished in three (21%) and cystometric bladder capacity increased in five (36%) of 14 patients with detrusor overactivity in the naftopidil group. Similar improvements in detrusor overactivity by other α-blockers have also been reported.5,21 These improvements in detrusor overactivity might be partly due to relief of bladder outlet obstruction by naftopidil, and might also be due to direct relaxation of the overactive detrusor by the antagonist activity of this drug against the α1D-adrenoceptor. Predominant distribution of α1D-adrenoceptors over α1A-adrenoceptors at the mRNA expression, and at a protein level, have been reported in human detrusor.22 Recently, Hampel et al. reported a remarkable increase in α1D-adrenoceptor mRNA and protein expression in obstructed and hypertrophied rat bladder, and suggested that targeting the α1D-adrenoceptor might provide a new therapeutic approach for controlling bladder storage symptoms and detrusor overactivity associated with bladder outlet obstruction.23 Clinical studies have also shown that selective α1A-adrenoceptor antagonists relieve bladder outlet obstruction and increase urinary flow, but fail to relieve storage symptoms, whereas non-selective α1-adrenoceptor antagonists were effective for both storage and voiding symptoms. Another possible mechanism of naftopidil for relieving detrusor overactivity might be that it inhibits the micturition reflex by acting on α1D- or α1A-adrenoceptors in the lumbosacral spinal cord.24–26 Therefore, it has been suggested that the α1D-adrenoceptor can be a target for treating detrusor overactivity associated with bladder outlet obstruction.24,27
In a randomized study comparing phytotherapy and α-blockers, Abbou et al. reported that alfuzosin was more effective than Pygeum africanum with regard to Qmax, residual urine and storage symptoms.28 However, Debuyne et al. reported that the phytotherapeutic agent (Permixion) and α-blocker (tamsulosin) were equivalent in terms of IPSS and Qmax improvements in a 12-month, double-blind randomized trial.29 The duration of the present study was set at 4–6 weeks, because it was thought that a shorter duration was less likely to lead to withdrawal. In a long-term use study for tamsulosin, a maximum increase in Qmax was achieved after 4 weeks and sustained for up to 4 years.24 Therefore, the duration of 4–6 weeks was thought to be sufficient to evaluate the urodynamic effects of α-blockers. However, there remains a possibility that eviprostat produces significant effects if the drug is used for longer periods. Interestingly, detrusor opening pressure decreased in the eviprostat group and detrusor pressure at maximum flow decreased in the naftopidil group, although these decreases were not statistically significant.
In the present study, clinically and statistically significant improvements in symptomatic, as well as urodynamic parameters were found in the naftopidil group, but no significant improvement was noted in the eviprostat group. Intergroup differences were noted in the IPSS and uroflowmetric parameters. Detrusor overactivity disappeared in 21%, and cystometric capacity increased in 36% of the 14 patients in the naftopidil group, but no improvement in detrusor overactivity was noted in the eviprostat group. Based on the above results, we can conclude that naftopidil appears to be effective, whereas no significant changes were found following eviprostat administration in this short-term treatment of BPH. A long-term study might be necessary to verify the efficacy of eviprostat.