SEARCH

SEARCH BY CITATION

Keywords:

  • α-adrenoceptor antagonists;
  • prostatic hyperplasia;
  • tamsulosin;
  • naftopidil;
  • randomized controlled trial

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

OBJECTIVES

To compare the efficacy and safety of two α1a1d adrenoceptor (AR) antagonists with different affinity for the α1AR subtypes, tamsulosin and naftopidil, in the treatment of benign prostatic hyperplasia (BPH).

PATIENTS AND METHODS

Patients with BPH were randomized to receive either tamsulosin or naftopidil. The primary efficacy variables were the changes in the total International Prostate Symptom Score (IPSS), maximum flow rate on free uroflowmetry, and residual urine volume. The secondary efficacy variables were average flow rate, changes in the IPSS storage score, IPSS voiding score, and quality-of-life (QoL) Index score, from baseline to endpoint (12 weeks). Data on all randomized patients were included in the safety analyses for adverse effects and changes in blood pressure.

RESULTS

Of the 185 patients enrolled data for 144 who were eligible for inclusion in the efficacy analysis were analysed (75 from the tamsulosin and 69 from the naftopidil group). There was no significant difference in any variable at baseline between the groups. There were satistically significant improvements for all primary and secondary variables in both groups, except for residual urine in the tamsulosin group. However, there was no significant intergroup difference in the improvement of any efficacy variable between the groups. The adverse effects were comparable, with no significant differences in systolic and diastolic blood pressure after treatment in both groups.

CONCLUSIONS

This study suggests that naftopidil is as effective and safe as tamsulosin. Both drugs were effective in improving storage and voiding symptoms. However, there was no difference in clinical efficacy or adverse effects between the α1 AR antagonists with different affinity to α1 subtypes, α1a and α1d.


Abbreviations
AR

adrenoceptor

QoL

quality of life (subscore)

PVR

postvoid residual urine volume

Qmax

(Qave) maximum (average) urinary flow rate.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

LUTS caused by BPH comprise storage and voiding symptoms; in the treatment of BPH, α1-adrenoceptor (AR) antagonists play a primary role and relieve both voiding and storage symptoms [1–3]. Although α1-AR antagonists are considered to relieve voiding symptoms by decreasing the smooth muscle tone of the prostate and bladder neck, the mechanism underlying the relief of storage symptoms is unknown. It was recently suggested that an up-regulation of α1d-AR in the bladder would contribute to the storage symptoms observed in BOO. A remarkable increase in α1d gene expression in the bladder, which might contribute to detrusor overactivity after obstruction, was reported in rats with BOO [4]. In terms of lower urinary tract location of the α1a- and 1d-AR subtypes in humans, the former predominates in the prostate and urethra, while the latter predominates in the bladder [5,6]. Based on these findings, it was suggested that targeting the α1d-AR may provide a new therapeutic approach for controlling the storage symptoms in patients with BPH.

Tamsulosin is a third-generation α1-AR antagonist being used worldwide in the treatment of BPH. Tamsulosin has higher selectivity for the α1a-AR than the α1d-AR subtype [7–9], while naftopidil is an α1-AR antagonist with selectivity for the α1a and α1d subtype, with higher affinity for the latter [9]. It is clinically important to investigate whether the α1-AR antagonists with different subtype affinities would produce different clinical effects in patients with BPH. The present study was designed to compare the efficacy and safety of the α1-AR antagonists with different affinities for the α1a and α1d subtypes, tamsulosin and naftopidil, in the treatment of BPH.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The present study was conducted as a prospective, randomized controlled trial; in all, 17 urologists at 16 investigational sites participated in this multicentre trial. Patients were screened for study eligibility on the basis of a complete medical and medication history, an assessment of urinary symptoms and their impacts on quality of life (QoL) using the IPSS and the QoL Index score, free uroflowmetry, measurement of postvoid residual urine volume (PVR), a detailed history of previous treatments and surgery, complete physical examinations, measurement of prostate volume by ultrasonography, and laboratory studies including PSA levels.

Patients who satisfied all the inclusion and exclusion criteria were randomized to receive tamsulosin or naftopidil, done by the study centre, which was independent from the investigational sites. Patients randomized to tamsulosin received 0.2 mg/day for 12 weeks, while those randomized to naftopidil received 25 mg/day for 2 weeks, followed by 50 mg/day for 10 weeks. The dose of tamsulosin given in the study, i.e. 0.2 mg/day, was approved by the Japanese Ministry of Health, Labor and Welfare, although it is smaller than the dose generally administered in the USA and European countries. The approved dose of naftopidil to be taken once daily is 25–75 mg with 50 mg being recommended and commonly given as the standard dose. Hence, in the present study, the standard doses of tamsulosin and naftopidil that are commonly used in clinical practice were chosen.

Men who were aged ≥ 50 years and had signs and symptoms of BPH were eligible for the study if they met the following requirements: a total IPSS of ≥ 8, BOO, as defined by a maximum urinary flow rate (Qmax) of < 15 mL/s with a voided volume of ≥ 150 mL, and a prostate volume of ≥ 20 mL, as estimated by ultrasonography.

Exclusion criteria included a history of allergy to α-AR antagonists, treatment with antiandrogen drugs, current therapy with any α-AR antagonist, drugs with anticholinergic activity, a significant history of orthostatic hypotension, concomitant neurological diseases, known or suspected neurogenic bladder dysfunction, carcinoma of the prostate or bladder, previous surgery for BPH or bladder neck obstruction, history of recurrent UTI, or concomitant active UTI.

The evaluation of efficacy was based on symptomatic and urodynamic improvements; the IPSS, QoL Index score, uroflowmetry, and PVR (estimated by transabdominal ultrasonography) were measured at baseline and 2, 4, 8 and 12 weeks after drug administration.

The primary efficacy variables were changes in the total IPSS, Qmax on free uroflowmetry and the PVR, from baseline to the endpoint (12 weeks). The secondary efficacy variables were the average flow rate (Qave), changes in the IPSS storage score (frequent voiding, urgency, and nocturia), IPSS voiding score (sense of residual urine, intermittency, loss of force, and straining on urination), and the IPSS QoL Index score, from baseline to endpoint. In addition to the primary and secondary efficacy variables, changes in each IPSS subscore from baseline to endpoint were also assessed. Data on all randomized patients were included in the safety analyses for adverse effects and change in systolic and diastolic blood pressure.

Summary measures were expressed as the mean (95% CI), with differences in patient characteristics and efficacy variables between the groups at the baseline assessed using an unpaired Student's t-test or Mann–Whitney U-test. Changes within groups for each efficacy variable were analysed using the Wilcoxon signed-rank test. The statistical significance of intergroup differences for each efficacy variable was analysed by the Mann–Whitney U-test. The intra- and intergroup changes in blood pressure were analysed by the paired and unpaired Student's t-test, respectively. The difference in the incidence of adverse effects between the groups was analysed using the chi-square test.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Of the 185 enrolled patients, data for 144 who were eligible for inclusion in the efficacy analysis were analysed (75 in the tamsulosin and 69 in the naftopidil group). The reasons for not evaluating patients included withdrawal from visits during the study period in 30 patients, missing data in four, requiring TURP for urinary retention in one, taking concomitant medication in two, withdrawal for adverse effects in two (eruption and orthostatic hypotension), and withdrawal for other reasons in two (patient's desire to withdraw and development of depression).

There was no significant difference in patient age, prostate volume, or primary and secondary efficacy variables the baseline between the groups (Table 1). There were no significant differences in each IPSS subscore at baseline between the groups, except for intermittency (Table 1).

Table 1.  The patients’ characteristics at baseline
VariableTamsulosin (N = 75)Naftopidil (N = 69)P
  • *

    Unpaired Student's t-test;

  • Mann–Whitney U-test.

Mean (95% CI)
Age, years68.5 (67.0–70.1)68.0 (66.4–69.8)0.686*
Prostate volume, mL33.6 (29.5–37.7)29.0 (27.2–32.0)0.060*
Total IPSS17.1 (15.7–18.5)15.5 (14.1–16.8)0.088
IPSS storage score 7.9 (6.9–8.8) 7.0 (6.0–7.9)0.113
IPSS voiding score10.1 (8.8–11.3) 8.5 (7.2–9.7)0.070
IPSS subscores:
Sense of residual urine 2.2 (1.7–2.6) 2.1 (1.6–2.5)0.960
Frequent voiding 3.1 (2.7–3.5) 2.4 (2.0–2.9)0.057
Intermittency 2.9 (2.4–3.3) 2.1 (1.6–2.5)0.015
Urgency 2.2 (1.7–2.7) 2.0 (1.5–2.5)0.461
Loss of force 3.2 (2.7–3.6) 2.7 (2.2–3.2)0.193
Straining on urination 1.9 (1.4–2.4) 1.7 (1.2–2.1)0.578
Nocturia 2.6 (2.2–2.9) 2.5 (2.2–2.9)0.474
QoL index 4.4 (4.2–4.7) 4.5 (4.2–4.7)0.900
Qmax, mL/s 8.8 (8.1–9.6) 9.3 (8.4–10.1)0.546
Qave, mL/s 4.3 (3.8–4.7) 4.5 (4.1–4.9)0.381
PVR, mL42.5 (29.3–55.7)46.6 (31.1–62.2)0.743

There were statistically significant improvements in IPSS and Qmax in both groups; although the PVR decreased significantly in the naftopidil group, the decrease in the tamsulosin group was not statistically significant. However, there was no significant intergroup difference in the improvement in any primary efficacy variable between the groups (Table 2).

Table 2.  Changes in the primary and secondary variables, each IPSS subscore, and systolic and diastolic blood pressures, from baseline to endpoint
VariableMean (95% CI) changeIntergroup P
TamsulosinNaftopidil
  1. The intergroup comparison used the Mann–Whitney U-test and comparison of each group of before and after treatment (intragroup) the Wilcoxon signed-rank test.

Total IPSS−8.4 (−10.0, −6.8) −5.9 (−7.3, −4.5)0.060
Intragroup P<0.001<0.001 
Qmax2.1 (0.8, 3.4) 2.1 (1.1, 3.1)0.709
Intragroup P<0.001 0.001 
PVR−9.6 (−20.1, 0.6)−13.6 (−26.8, 0.7)0.218
Intragroup P0.062  0.003 
IPSS voiding score−5.3 (−6.6, 4.0) −3.7 (−4.9, −2.5)0.126
Intragroup P<0.001 <0.001 
IPSS storage score−3.4 (−4.4, −2.5) −2.4 (−3.1, −1.6)0.068
Intragroup P<0.001 <0.001 
Qave1.0 (0.5, 1.6) 1.2 (0.5, 1.8)0.636
Intragroup P0.001 0.001 
QoL index−1.4 (−1.7, −1.1) −1.3 (−1.7, −1.0)0.801
Intragroup P<0.001 <0.001 
IPSS subscores
Sense of residual urine−1.1 (−1.6, −0.6) −1.0 (−1.5, −0.6)0.865
Intragroup P<0.001 <0.001 
Frequent voiding−1.4 (−1.8, −0.9) −0.9 (−1.2, −0.6)0.103
Intragroup P<0.001 <0.001 
Intermittency−1.5 (−1.9, −1.0) −0.7 (−1.2, −0.2)0.052
Intragroup P<0.001 0.009 
Urgency−1.2 (−1.6, −0.7) −0.8 (−1.2, −0.3)0.175
Intragroup P<0.001 0.001 
Loss of force−1.6 (−2.1, −1.1) −1.2 (−1.7, −0.7)0.272
Intragroup P<0.001 <0.001 
Straining on urination−1.2 (−1.6, −0.7) −0.8 (−1.3, −0.4)0.312
Intragroup P<0.001 0.001 
Nocturia−0.9 (−1.2, −0.6) −0.7 (−1.0, −0.4)0.474
Intragroup P<0.001 <0.001 
Blood pressure
N7264 
Systolic−6.6 (−10.9, −2.4) −5.1 (−10.3, 0.1)0.646
Intragroup P0.003 0.061 
Diastolic−3.5 (−6.4, −0.7) −5.2 (−8.3, −2.0)0.453
Intragroup P0.018 0.002 

Although there were statistically significant improvements in all four secondary efficacy variables for both treatment groups, there was no significant difference in the improvement in any secondary efficacy variable between the groups (Table 2).

Additional analysis for the change in each IPSS subscore showed that all improved significantly in both groups at endpoint, but there was no significant intergroup difference (Table 2). The intragroup mean changes from baseline were significant at all visits for both treatment groups, and there was no significant intergroup difference in any primary and secondary variable at any visit, except at 2 weeks. There was an overall trend for the total IPSS, the storage and the voiding score to progressively improve across consecutive visits until the 12-week visit.

Adverse effects were comparable in both treatment groups; they were reported in nine of 95 (9.5%) patients in the tamsulosin and nine of 90 (10%) in the naftopidil group, which was not statistically significant (P = 0.94, chi-square test). The adverse effects reported in the tamsulosin group comprised dizziness on standing in four patients, vertigo in one, heavy-headedness in two, diarrhoea in one, and urinary incontinence in one. Those reported in the naftopidil group comprised dizziness on standing in one, unsteady gait in one, abdominal pain in one, skin eruption in one, numbness of the tongue in four, and sleepiness in one. Changes in blood pressure from baseline to endpoint were assessed in 136 patients (72 tamsulosin, 64 naftopidil); there were no significant differences in systolic (mean 144.2 vs. 141.2 mmHg, P = 0.399) and diastolic blood pressure (mean 83.3 mmHg vs. 84.7, P = 0.563) at baseline between the groups. Systolic blood pressure showed a significant decrease in the tamsulosin but not in the naftopidil group. Diastolic blood pressure significantly decreased in both groups from baseline to endpoint, but there were no significant differences in changes in systolic and diastolic pressures between the groups (Table 2).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

There have been extensive studies on the role of the sympathetic nervous system and α1-ARs in the pathophysiology of BPH, leading to clinical studies on α1-AR antagonists in the treatment of BPH. Subsequent clinical studies showed that α1-AR antagonists relax prostatic smooth muscle, relieving voiding symptoms and improving the objective flow rate on uroflowmetry [1–3]. In addition, α1-AR antagonists also relieve the storage symptoms [1–3].

The IPSS, which was developed and validated to quantify the subjective symptoms in patients with BPH, has been used worldwide in clinical practice as a reliable measure of the changes in subjective symptoms. In addition to the total score, the IPSS is occasionally used to assess the voiding and storage symptom scores, because it is assumed that the mechanism underlying these two symptom groups includes two different causes, i.e. BOO and bladder function. The separation of the symptom questions in the IPSS into these two categories is psychometrically valid [10]. Although the clinical utility of the symptom groupings for distinguishing the responses to any treatment has not been well established, several randomized trials have used the voiding and storage subscales of the IPSS, and have successfully differentiated the effects of treatments on each symptom subscale [2,3]. In the present study, as one of the interests was the possible difference of the effects of two drugs on bladder function, we used the voiding and storage subscales as one of the secondary outcome measures.

Based on the analysis of the role of α1-ARs and the accumulated evidence of the clinical effectiveness of α1-AR antagonists, it is a commonly accepted consensus that the α1-AR antagonist is the first choice of treatment for symptomatic BPH. To date, sympathetic α1-ARs are subdivided into three groups of receptors, i.e. α1a, α1b and α1d[11]. The α1b-ARs are widely distributed in the smooth muscle of the blood vessels [5]. In terms of lower urinary tract location of the ARs in humans, the α1 subtype predominates in the smooth muscle of the prostate [12,13]. Concerning the quantity of each of the α1 subtypes in the human prostate, a recent study [13] showed that 69%, 3.3%, and 27% of the α1-ARs are subtypes of α1a, α1b and α1d, respectively. In patients with BPH it was reported that α1a subtypes increased to 85%, α1d decreased to 14% and the amount of α1b was negligible [14,15]. α1-AR antagonists that are not subtype selective were reported to be effective in relieving symptoms of BPH, but despite their clinical efficacy, the use of such α1-AR antagonists was associated with adverse effects secondary to vasodilatation and noradrenaline release, e.g. light-headedness, dizziness, postural hypotension, and syncope, which were considered to relate to α1b-mediated vasodilatation [16,17]. Because of the side-effects of such α1-AR antagonists, subtype-selective agents have been explored for clinical use, based on the knowledge of α1 AR subtypes distribution in the prostate. Subtype-selective agents, particularly α1a-AR antagonists, are currently most widely used in the treatment of BPH, with confirmed efficacy in relieving BOO and with a low incidence of side-effects [2].

The mechanism underlying the relief of storage symptoms by α1-AR antagonists in patients with BPH is yet to be elucidated. Recently, attention was focused on the α1-AR in the bladder, which may play a role in the developing storage symptoms of BOO. In terms of α1-AR distribution in the human bladder, in contrast to the bladder trigone that contains only α1a-AR, the detrusor mainly contains α1d subtypes (66%) and, to a lesser extent, the α1a subtypes (34%) but no α1b subtypes [6]. Hampel et al.[4] investigated the changes in mRNA and protein expression in α1 subtypes in the rat bladder with BOO. In the control, 70% of α1 mRNA was of the α1a subtype, 5% was α1b and 25% was α1d, whereas in the obstructed rat bladder, AR expression changed to 23%α1a, 2%α1b and 75%α1d. Parallel changes were also evident at the protein level. They indicated a remarkable increase in bladder α1d mRNA and protein expression after BOO. Along with the data that α1d-AR has a 10- to 100-fold higher affinity for the endogenous neurotransmitter, noradrenaline, than the α1a or α1b subtypes [11], they suggested that up-regulation of α1d in the detrusor may be responsible for bladder overactivity in BOO. These observations lead to the hypothesis that α1d-AR in the bladder might be responsible for bladder overactivity and related storage symptoms in BOO, and that targeting α1d-AR may provide a new therapeutic approach for controlling storage symptoms in patients with BPH. On the other hand, Nomiya et al.[18] compared the expression level of α1 subtype mRNA to that of the β-AR subtype mRNA in control and obstructed human bladders, and examined whether α1-mediated contraction and β-AR-mediated relaxation of human detrusor muscle are altered by BOO. In the urodynamically normal bladder, the expression of β3 AR mRNA was extremely high, being ≈ 94% of the overall α1 and β-AR messages, while the mRNA of all other subtypes (α1a, α1b, α1d, β1 and β2) was expressed at a low level. In contrast to the report of Hampel et al.[4] in rat obstructed bladder, mRNA expression of all three α1 subtypes was unchanged in the human obstructed bladder. As the β-AR subtype mRNA also did not change, the predominant expression of β3-AR mRNA (≈ 96% of the overall α1- and β-AR messages) was not altered by BOO in human bladders. Also, the contractile responses to α-AR agonist were not significantly increased in detrusor preparations from obstructed bladders. Nomiya et al.[18] reported that there is neither up-regulation of α1-ARs nor down-regulation of β3-ARs in the human obstructed bladder, denying the hypothesis that bladder α1d-AR is responsible for storage symptoms in patients with BOO. Other studies suggested a different mechanism for the role of α1d-AR in the relief of storage symptoms by α1-AR antagonists. It was reported that the α1d subtype predominates in the sacral spinal cord [19] and suggested that α1d-AR may be associated with the pathogenesis of storage symptoms [20]. In addition, a recent study [21] suggested that increased bladder blood flow induced by α1-AR antagonist leads to improvement of bladder dysfunction, after BOO in rats.

Tamsulosin is the third generation of α1-AR antagonists and the selectivity of tamsulosin has generally been found to be α1a > α1d >> α1b, although the degree of selectivity is a matter of debate. In radioligand-binding studies, the variation in estimates of the selectivity of tamsulosin for the α1a over α1d range from three-fold [7] to 20-fold [8]. Using cloned human α1 subtypes, the affinity of tamsulosin for the α1a over the α1d was reported to be 3.3-fold [9]. On the other hand, in functional studies, it was reported that tamsulosin has equal affinity for the α1a and the α1d subtypes [22]. Naftopidil is a novel α1-AR antagonist and has a higher affinity for the α1d subtype, showing 3–17-fold higher potency for this subtype than for the α1a and α1b subtypes, respectively. The mean Ki values (nmol/L) of the drugs at the cloned human α1-AR for tamsulosin are; α1a (0.019) > α1d (0.063) >> α1b (0.29), and for naftopidil, α1d (1.2) > α1a (3.7) >> α1b(20.0) [9].

Naftopidil is clinically available for treating BPH only in Japan. Although several clinical comparative studies on the efficacy of naftopidil and tamsulosin are available, only two trials were randomized. Two randomized crossover clinical studies showed that naftopidil was better than tamsulosin in relieving storage symptoms. Nishino et al.[23] compared the efficacy of tamsulosin (0.2 mg/day) and naftopidil (50 mg/day) in 36 patients, by a randomized crossover trial. Both drugs significantly improved the IPSS and the objective variables of Qmax, Qave and PVR, with no intergroup difference. However, naftopidil was better than tamsulosin in reducing the number of episodes of nocturia per night. Ikemoto et al.[24] reported that tamsulosin (0.2 mg/day) was better for relieving voiding symptoms and naftopidil (50 mg/day) for relieving storage symptoms, with no significant intergroup differences, on the basis of a randomized crossover trial on 66 evaluable patients. However, no study is available to compare the efficacy of the two drugs by a standard direct randomized controlled trial; the present study is the first to do so, and there was no difference in clinical efficacy reflecting the difference in the affinity to α1 subtypes. Both drugs are effective and safe for treating BPH, but despite pharmacological interest in the different affinities of both these drugs on α1 subtypes, neither showed clinical selectivity. In addition to the above factors discussed on the role of the α1-AR in the storage function of the bladder, the reason for failure to detect any significant difference in storage symptoms could be because there is insufficient difference in pharmacological selectivity. Although the selectivity of naftopidil for the α1d-AR is three times its selectivity for the α1a, this difference in pharmacological selectivity may be insufficient to show clinical selectivity. Also the present study had limited power to detect subtle differences between the effects on the voiding and storage symptoms. A large-scale study involving more patients may detect any clinical difference corresponding to the pharmacological selectivity of these drugs, but it is unclear whether such subtle differences have any clinical value.

In conclusion, comparing the efficacy of two α1-AR antagonists, tamsulosin and naftopidil, with different affinities to α1 subtypes (α1a and α1d) for treating symptomatic BPH showed that, despite pharmacological interest in the different affinities of these drugs to α1 subtypes, this randomized comparative trial suggested that both drugs are equally effective and safe for treating BPH, and failed to show any difference in clinical selectivity reflecting differences in the affinity to α1 subtypes.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This trial was completed in collaboration with the following urologists participating in the Tokai Urological Clinical Trial Group: Kumiko Kato, Yoshimasa Hashimoto, Seiji Ohmura, Tamio Fujita, Satoshi Hirabayashi, Tatsuya Nagai, Takanori Kato, Takashi Kurokawa, Kikuo Okamura, Yasuhiro Aota, Kuniaki Tanaka, and Shin Yamada.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES
  • 1
    Lepor H, Nieder A, Feser J, O'Connell C, Dixon C. Effect of terazosin on prostatism in men with normal and abnormal peak urinary flow rates. Urology 1997; 49: 47680
  • 2
    Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology 1998; 51: 892900
  • 3
    Elhilali MM, Ramsey EW, Barkin J et al. A multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of terazosin in the treatment of benign prostatic hyperplasia. Urology 1996; 47: 33542
  • 4
    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
  • 5
    Schwinn DA. The role of α1 adrenergic receptor subtypes in lower urinary tract symptoms. BJU Int 2001; 88: 2734
  • 6
    Malloy BJ, Price DT, Price RR et al. α1 adrenergic receptor subtypes in human bladder. J Urol 1998; 160: 93743
  • 7
    Michel MC, Buscher R, Kerker J et al. α1-Adrenoceptor subtype affinities of drugs for the treatment of prostatic hypertrophy. Naunyn-Schmiedeberg's Arch Pharmacol 1993; 348: 38595
  • 8
    Testa R, Poggesi E, Taddei C, Guarnei L, Ibba M, Leonardi A. A new α1-antagonist selective for the lower urinary tract: in vitro studies. Neurourol Urodynam 1994a; 13: 4734
  • 9
    Takei R, Ikegaki I, Shibata K, Tsujimoto G, Asano T. 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
  • 10
    Welch G, Kawachi I, Barry MJ, Giovannucci E, Colditz GA, Willett WC. Distribution between symptoms of voiding and filling in benign prostatic hyperplasia: findings from the health professionals follow-up study. Urology 1998; 51: 4227
  • 11
    Schwinn DA, Johnston GI, Page SO et al. Cloning and pharmacological characterization of human alpha-adrenergic receptors: sequence corrections and direct comparison with other species homologues. J Pharmacol Exper Ther 1995; 272: 13442
  • 12
    Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 1975; 47: 193202
  • 13
    Price DT, Schwinn DA, Lomasney JW, Allen LF, Caron MG, Lefkowitz RJ. Identification, quantification, and localization of mRNA for three distinct α1–adrenergic receptor subtypes in human prostate. J Urol 1993; 150: 54651
  • 14
    Nasu K, Moriyama N, Kawabe K et al. Quantification and distribution of alpha 1-adrenergic subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and non hypertrophied tissue. Br J Pharmacol 1996; 119: 797803
  • 15
    Kawabe K. Current status of research on prostate-selective alpha 1-antagonists. Br J Urol 1998; 81: 4850
  • 16
    Gregorini L, Marco J, Kozakova M et al. Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation 1999; 99: 48290
  • 17
    Rudner XL, Berkowitz DE, Booth JV et al. Subtype specific regulation of human vascular alpha 1-adrenergic receptors by vessel bed and age. Circulation 1999; 100: 233643
  • 18
    Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of α1 and β-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol 2003; 170: 64953
  • 19
    Smith MS, Schambra UB, Wilson KH, Page SO, Schwinn DA. Alpha-1 adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding alpha 1-adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res 1999; 63: 25461
  • 20
    Persson K, Pandita RK, Spitsbergen J, Steers WD, Tuttle JB, Andersson KE. Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 1998; 275: R 1366–73
  • 21
    Das AK, Leggett RE, Whitbeck C, Eagen G, Levin RM. Effect of doxazosin on rat urinary bladder function after partial outlet obstruction. Neurourol Urodyn 2002; 21: 1606
  • 22
    Noble AJ, Chess-Williams R, Couldwell C et al. The effects of tamsulosin, a high affinity antagonist at functional α1A- and α1D-adrenoceptor subtypes. Br J Pharmacol 1997; 120: 2318
  • 23
    Nishino Y, Ogura T, Yamada T, Ishihawa S, Deguchi T. Assessment of two α1 adrenoceptor antagonists, naftopidil and tamsulosin hydrochloride, on voiding disturbance in benign prostatic hyperplasia, a randomized cross-over study. ICS Proceedings 2002: 116
  • 24
    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