Efficacy of a-Adrenergic Receptor Blockers in the Treatment of Male Lower Urinary Tract Symptoms

Advances in the Pharmacologic Treatment of BPH

4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S1 ADVANCES IN THE PHARMACOLOGIC TREATMENT OF BPH Efficacy of -Adrenergic Receptor Blockers in the Treatment of Male Lower Urinary Tract Symptoms Claus G. Roehrborn, MD, FACS Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX Male lower urinary tract symptoms (LUTS) are one of the most common causes for a consultation with a health care provider, and one of the most common causes of male LUTS is benign prostatic hyperplasia (BPH). In recent decades, medical therapy has established itself as viable and cost effective for the majority of men. For the treatment of male LUTS in the United States, the 5 currently available -adrenergic receptor blockers are alfuzosin, doxazosin, silodosin, terazosin, and tamsulosin. -Blockers remain one of the mainstays in the treatment of male LUTS and clinical BPH. They exhibit an early onset of efficacy (within less than 1 week) with regard to both symptoms and flow rate improvement, maintain such improvements in open-label and controlled trials for up to 5 years, and have been shown to prevent symptomatic progression. [Rev Urol. 2009;11(suppl 1):S1–S8 doi: 10.3909/riu11S1S0003] © 2009 MedReviews®, LLC Key words: -Blocker • Benign prostatic hyperplasia • Lower urinary tract symptoms ale lower urinary tract symptoms (LUTS) are one of the most common causes for a consultation with a health care provider, and their treatment is a significant contributor to the overall health care expenditure in the United States and most developed countries. Male LUTS is commonly stratified into 3 different symptom categories: voiding or obstructive (hesitancy, slow stream, intermittency, incomplete emptying), storage or irritative (frequency, urgency, nocturia, urge urinary incontinence), and postmicturition (postvoid dribbling).1 One of the most common, but by no means the only, cause of male LUTS is benign prostatic hyperplasia (BPH), the stromoglandular hyperplasia of the prostate gland that develops after age 40 in the majority of men, and is present M VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S1 4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S2 -Adrenergic Receptor Blockers in the Treatment of LUTS continued on tissue samples in about 50% of all men over the age of 50 years.2 At least as frequently is the bladder the source of male LUTS; symptoms of overactive bladder (urgency, frequency, nocturia, and urge urinary incontinence) are as common in men as they are in women, although they are less often labeled as such and more often treated as BPH-related symptoms in men.3 Due to the increase in life expectancy worldwide, and the aging of the Baby Boom Generation in the United States, a considerable increase in the population of men seeking care for male LUTS is forecast that will require adjustments on the part of the health care provider and cost-effective management algorithms.4 Whereas in decades past the only available treatment option was a transurethral resection of the prostate, in the past 20 years medical therapy has established itself firmly as a viable and cost-effective alternative for the majority of men.5,6 In addition to the 2 major classes of drugs, the -adrenergic receptor blockers (or -blockers) and the 5-reductase inhibitors, antimuscarinics, phytotherapeutic agents, and combinations thereof are in widespread use. None, Gq/11 family of G proteins that stimulate inositol phosphate (membrane phospholipid) hydrolysis, with each subtype demonstrating different efficacy of coupling to phosphoinositide hydrolysis: 1A > 1B > 1D.10 In addition, 1-AR subtypes can be pharmacologically distinguished on the basis of differential binding to 1-antagonists (blockers),11 as well as differential inactivation by the alkylating agent chloroethylclonidine.10,12 Tissue Distribution of 1-Adrenoceptor Subtypes All 3 1-AR subtypes exist in a wide range of human tissues.13 The 1A-AR subtype shows highest levels of expression in human liver, followed by slightly lower levels in heart, cerebellum, and cerebral cortex; the 1B-AR subtype has highest expression in human spleen, kidney, and fetal brain; 1D-AR has highest levels in the cerebral cortex and human aorta.13 In terms of male LUTS, 1-AR expression in prostate, urethra, spinal cord, and bladder is important. Molecular and contraction studies in human prostate tissue demonstrate the 1A-AR subtype predominance (70%-100%) in prostate stroma.14,15 -Blockers were introduced for the treatment of LUTS in the early 1990s. however, are more often used than blockers, which were introduced for the treatment of male LUTS in the early 1990s.7 1-Adrenergic Receptors Adrenergic receptors (ARs) were originally divided into -AR and -AR categories,8 but application of molecular biologic methods has confirmed 9 total AR subtypes: 1A (formerly named 1C), 1B, 1D, 2A, 2B, 2C, 1, 2, and 3.9 1 ARs generally mediate their actions through members of the S2 VOL. 11 SUPPL. 1 2009 Because baseline tone is present in prostate smooth muscle (due to its rich sympathetic innervation), blockade of prostate 1A-ARs results in relaxation of prostate smooth muscle. Hence, 1-AR blockade is capable of modifying the dynamic (prostate smooth muscle contraction) component in BPH. Another tissue important in LUTS is the urethra. To date, most studies show that all regions of human urethra (including bladder neck and intraprostatic urethra) contain only 1A-ARs. Because of reflex REVIEWS IN UROLOGY arcs, spinal cord 1-AR expression may be important in LUTS.16 Normal detrusor (bladder smooth muscle tissue) obtained from surgical patients expresses predominantly 1DARs, although other subtypes are present to a lesser extent.17 Studies demonstrating increased 1D-AR expression and function in models of bladder hypertrophy provide a mechanistic explanation for increased irritability symptoms associated with LUTS.18,19 1-AR antagonists mediate vasodilation in vasculature; therefore, one of the side effects of treating LUTS with 1-AR antagonists is hypotension. 1A-ARs predominate in human splanchnic (mesenteric, splenic, hepatic, and distal omental) resistance arteries.20 Interestingly, 1-AR expression increases 2-fold in representative (mammary) arteries with aging, with the ratio of 1B:1A increasing, whereas no alteration occurs in veins.20 Studies of pharmacy databases in Europe suggest that the administration of 1-AR blockers increases the incidence of hip fractures (chosen as a surrogate for clinically important orthostatic hypotension)18; further analysis with regard to the precise 1-AR antagonists prescribed suggests that avoidance of 1B-AR blockade may result in fewer overall hip fractures.21 Clinical Use of -Adrenoceptor Antagonists for the Treatment of LUTS Efficacy of -Blockers For the treatment of male LUTS in the United States today, alfuzosin, doxazosin, silodosin, terazosin, and tamsulosin are the 5 available 1-AR antagonists (Table 1). Terazosin, doxazosin, and alfuzosin are non—subtype selective in that they block all 3 1-AR subtypes. In contrast, tamsulosin blocks 1A- and 1D-ARs with 10-fold greater affinity than 1B-ARs, and is 4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S3 -Adrenergic Receptor Blockers in the Treatment of LUTS Table 1 Clinical Pharmacology of Currently Available 1-Blockers Used to Treat Male Lower Urinary Tract Symptoms Alfuzosin Doxazosin Silodosin Tamsulosin Terazosin Non–Subtype Selective Non–Subtype Selective 1A  1D  1B 1A  1D  1B Non–Subtype Selective N N Y Y N Clinical selectivity N N Y Y N Registered for use in hypertension? N Y N N Y 1-AR Subtype Selectivity* Pharmacologic selectivity † Reduces elevated blood pressure? Usual daily dose (mg) Y Y N N Y 7.5-10 1-8 8 mg 0.4 1-10 Regimen (doses/d) 1 1 1 1 1 Modified-release formulation Y Y N Y N AR, adrenergic receptor; N, no; Y, yes. *Alfuzosin, doxazosin, and terazosin demonstrate similar selectivities for all 3 1-AR subtypes. † Differentiation of desired urological and unwanted cardiovascular 1-blockade (data from Richardson et al.11). Modified from Schwinn and Roehrborn.46 therefore considered 1-AR subtype selective. The newest compound, silodosin, blocks 1A with 162-fold greater affinity than 1B-ARs and is also subtype selective (Table 2).22 Many authoritative reviews have been published suggesting that the efficacy of the -blockers alfuzosin, doxazosin, tamsulosin, and terazosin is comparable.7,23,24 Many randomized, placebo-controlled trials, as well as open-label studies, suggest that an improvement in the International Prostate Symptom Score (IPSS) of 4 to 6 points may be expected, as well as an improvement in the single disease-specific quality of life (QoL, scale from 1-6) question of 1 to 1.5 points. Changes in the maximum urinary flow rate (Qmax) of 2 to 3 mL/s are in general the results of -blocker therapy (Table 3). These 4 -blocking agents have been shown to be superior to placebo in pivotal phase III trials leading to their approval by the regulatory agencies worldwide. Table 2 Uroselectivity: Inhibition of Hypogastric Nerve Stimulation in Decerebrate Dogs Urethral Pressure (ID50) (/kg) Intravenous Injection Silodosin Blood Pressure (ED15) (/kg) Uroselectivity (BP/UP) 3.15 8.03 2.55 Tamsulosin 1.73 0.59 0.35 Prazosin 11.8 2.46 0.21 Silodosin 26.4 266.3 10.1 Tamsulosin 5.48 5.95 1.09 — — — Intraduodenal Injection Prazosin BP, blood pressure; ED15, dose required to reduce BP by 15%; ID50, dose required to inhibit the increase in intraurethral pressure by 50%; UP, urethral pressure. Adapted with permission from Akiyama K et al.47 The newest entry in the class is silodosin, a highly selective -blocker for the 1A receptor, which was studied in the United States in 2 pivotal phase III studies of 12 weeks duration followed by a common open-label extension study of 40 weeks duration.25,26 The 2 12-week studies randomized 457 and 466 patients, respectively, to receive placebo versus VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S3 4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S4 -Adrenergic Receptor Blockers in the Treatment of LUTS continued Table 3 Efficacy and Adverse Events of -Blockers Alfuzosin* Doxazosin* Silodosin† Tamsulosin* Terazosin* IPSS 3-9 mo/10-16 mo 4.44 5.10/5.63 6.4/7.8 4.63/7.53 6.22/5.99 Qmax 3-9 mo/10-16 mo 2.05 3.11/2.98 2.6 1.85/1.86‡ 2.51/1.94 QoL 3-9 mo/10-16 mo 1.10 1.25/1.47 1.43 1.70‡/1.37 ‡ 2.0/2.47 BPH II 3-9 mo/10-16 mo 1.45‡/2.09 Asthenia 4 15 NR 7 12 Cardiovascular 1 2 NR 8 2 Dizziness 5 13 3.2 12 15 Gastrointestinal system 10 10 2.6 11 5 Headache 5 8 2.4 12 7 Nasal congestion/rhinitis 6 8 2.1 11 6 Ejaculation problem 0 28.1 10 1 3 4 NR 4 5 Hypotension, asymptomatic NR 5 7 8 Hypotension, symptomatic 1 Erection problem Hypotension, symptomatic postural Hypotension, symptomatic syncope 3 4 1 2.6 0 3 6 1 1 BPH, benign prostatic hyperplasia; IPSS, International Prostate Symptom Score; Qmax, peak urine flow rate. *Based on randomized clinical trials (data from American Urological Association Practice Guidelines Committee48). † From 2 randomized, controlled trials lasting 12 weeks and open-label extension trial of 52 weeks in length (data from Marks et al25). ‡ Data based on single-arm meta-analyses. Adapted from American Urological Association Practice Guidelines Committee.48 silodosin, 8 mg, daily, and enrolled men with an average IPSS score of 21.2 to 21.4 points and a Qmax between 8.4 and 9.0 mL/s. The IPSS improvements were 6.3 and 6.5 points versus 3.4 and 3.6 improvements in the placebo arms, respectively, and the flow rate improvements were 2.2 and 2.9 versus 1.2 and 1.9 mL/s, respectively. The data from these 2 trials were pooled by Marks and colleagues.25 Of the 661 participants in the 40-week open-label extension study, 435 (65.8%) completed the study and experienced an improvement in IPSS of 6.8 (crossover from placebo) and 7.8 (continuation on 8 mg silodosin) points, respectively.26 Early Onset of Efficacy A double-blind, placebo-controlled study was conducted to investigate S4 VOL. 11 SUPPL. 1 2009 whether alfuzosin, 10 mg once daily, improves the Qmax and LUTS from BPH after 1 week and 1 month of treatment. A total of 372 men age 50 years or older with symptomatic BPH received alfuzosin or placebo for 28 days. Qmax increased significantly once daily, exhibits a rapid onset of action, with improvements in Qmax and LUTS maintained through 1 month of treatment.27 Similar studies have been performed using tamsulosin28 and doxazosin gastrointestinal therapeutic system (GITS).29 Early onset of activity using silodosin was assessed by administering the IPSS score 0.5 weeks after initiation of treatment in the 2 12-week trials, resulting in an improvement of 3.9 and 4.4 points, respectively, which proved superior to placebo. from baseline at day 8 with alfuzosin (P  .001 vs placebo); this improvement was evident within 24 hours after the first dose and was maintained at day 29. LUTS improved from baseline with alfuzosin at day 8 (P  .07 vs placebo) and day 29 (P  .003 vs placebo). Alfuzosin, 10 mg REVIEWS IN UROLOGY Early onset of activity using silodosin was assessed by administering the IPSS score 0.5 weeks after initiation of treatment in the 2 12-week trials, resulting in an improvement of 3.9 and 4.4 points, respectively, which proved superior to placebo. Similarly, in a subset of patients, a flow rate 4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S5 -Adrenergic Receptor Blockers in the Treatment of LUTS measurement was performed 2 to 6 hours after the first morning dose, and a 2.8 mL/s improvement was noted, suggesting that the onset of efficacy is indeed quite rapid.25 Urodynamic Effects of -Blockers Urodynamic effects of the compounds were assessed in 2 studies employing invasive pressure flow studies in Japan. Yamanishi and coworkers30 treated 36 patients with LUTS and BPH and performed pressure flow studies at baseline and at 3 months, noting a decrease in the detrusor pressure at maximal flow (pdet @ Qmax) from 80.6 to 48.6 cm H2O and a decrease in the bladder outlet obstruction index (BOOI) from 70.2 to 32.6 (P  .0001 for both). In a similar study, Matsukawa and coauthors31 treated 57 patients with silodosin, 8 mg, for 4 weeks and performed pressure flow studies before and after. Similar to the previous study, they found a decrease in pdetQmax (cm H2O) from 72.5 to 51.4 and in the BOOI from 60.6 to 33.8 (P  .0001). These findings are particularly remarkable as meta-analyses of urodynamic studies using -blocking agents had failed to show a significant effect of the other -blocking agents on these parameters,32,33 raising the possibility that the highly selective effect on the extension studies, often following a placebo-controlled, double-blinded study, in which patients are asked to participate voluntarily. These studies are sometimes criticized because of the so-called responder enrichment bias. This effect implies that only those patients who had good results with the drug are interested in continuing in the open-label extension portion of the study. Despite this potential bias, the resulting data allow at least a comparison between the patients who were originally on placebo and switched to open-label active drug and those who were on active drug (but did not know it) and continued on it. In the case of silodosin, the results of such open-label extension studies suggest that the activeactive patients had a 7.8-point improvement at 1 year as compared with the placebo-active patients who experienced a 6.8-point improvement.26 For the older -blockers, controlled clinical trial data are available that in aggregate suggest that the efficacy in terms of symptom improvement in unselected patient populations with LUTS is maintained. The Veterans Administration Cooperative Study combination medical therapy study34 randomized 1229 patients to placebo versus finasteride versus terazosin versus combination for 12 months. The onset of action of all -blockers is rather quick (ie, within 1 week). 1A receptor at the bladder neck might be responsible for the observed reduction in obstruction, which is nearly commensurate with the effect of a surgical intervention. Long-Term Effects of -Blocker Therapy Although the onset of action of all -blockers is rather quick (ie, within 1 week), controlled long-term efficacy and safety data are not as widely available. There are many open-label The IPSS improvements were 2.6, 3.2, 6.1, and 6.2 points, respectively (P  .001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at 1 year in Qmax rates were increases of 1.4, 1.6, 2.7, and 3.2 mL/s, respectively (P  .001 for the comparisons of both terazosin and combination therapy). The results of a very similar study in 1095 patients randomized in Europe (Prospective European Doxazosin and Combination Therapy [PREDICT])35 to placebo versus finasteride versus doxazosin versus combination were very similar. ALTESS (the Alfuzosin Long-Term Efficacy and Safety Study)36 enrolled more than 1500 men at risk for progression to be randomized to alfuzosin, 10 mg daily, versus placebo. Symptom score and flow rate improvements in the alfuzosin arms were significantly superior to placebo and maintained for 2 years. Tamsulosin was tested in the CombAT (Combination Therapy with Avodart and Tamsulosin) study,37 in which more than 4500 men at risk for progression were randomized to tamsulosin versus dutasteride versus combination for 4 years. The adjusted mean change in IPSS from baseline to year 4 was 6.3 points for combination therapy versus 3.8 points (P  .001) for tamsulosin and 5.3 points (P  .001) for dutasteride. At month 48, the adjusted mean increase in Qmax from baseline was 2.4 mL/s for combination therapy versus 0.7 mL/s (P  .001) for tamsulosin and 2.0 mL/s (P  .05) for dutasteride. Lastly, the MTOPS (Medical Therapy of Prostatic Symptoms) study38,39 enrolled more than 3000 patients randomized to placebo versus doxazosin versus finasteride versus combination therapy in a progression prevention study over 5 years. The 4-year mean reduction in symptom score was 4.9 in the placebo group, 6.6 in the doxazosin group, 5.6 in the finasteride group, and 7.4 in the combination therapy group. The mean improvement in flow rate was 4.0 mL/s in the doxazosin group, 3.2 mL/s in the finasteride group, and 5.1 mL/s in the combination therapy group. Acute Urinary Retention and Trial Without Catheter Several randomized trials have studied whether the administration of -blockers at the time of an acute urinary retention (AUR) event would VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S5 4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S6 -Adrenergic Receptor Blockers in the Treatment of LUTS continued be beneficial and improve the outcome of a trial without catheter (TWOC). Two studies performed randomizing patients in AUR to placebo versus alfuzosin suggest that the success rates may be improved from 47.9% to 61.9% and from 29% to 55%, respectively.40,41 Similar success was found by others using tamsulosin with an improvement from 26% to 48% of successful voiding.42 A Cochran meta-analysis concluded that “the limited available evidence suggests that alpha-blockers increase success rates of TWOC.”43 It may be assumed that this represents a class effect and applies to all -blockers. Prevention of Progression of LUTS/BPH Three controlled studies focused on the prevention of certain elements of progression of LUTS and clinical BPH using medical therapy, which are the 2-year ALTESS study (placebo vs alfuzosin),36 the 4-year CombAT study (tamsulosin vs dutasteride vs combination),37 and the 5-5.5 year MTOPS study (placebo vs doxazosin vs finasteride vs combination).40 These 3 studies use 3 different -blocking agents, are of different duration (2 vs 4 vs 5 years), and enroll different patient populations (MTOPS enrolled patients independent of prostate size and serum prostate-specific antigen, whereas ALTESS and CombAT enrolled patients at risk for progression based on prostate size and/or serum prostate-specific antigen). The findings are remarkably consistent among the studies. In the ALTESS trial, alfuzosin did not reduce the risk of AUR (alfuzosin 2.1% vs placebo 1.8%; P  .82) but tended to reduce the risk of surgery (5.1% vs 6.5%; P  .18); the reduction in risk (RR) and 95% confidence interval with alfuzosin was 22% (18-48); and significantly reduced S6 VOL. 11 SUPPL. 1 2009 the risk of symptom deterioration (11.7% vs 16.8%; P  .0013); the RR was 30% (10-46). The overall clinical progression of BPH was significantly lower with alfuzosin than with placebo (16.3% vs 22.1%; P  .001); RR 26% (9-40).36 In the CombAT trial, the time to first AUR or BPH-related surgery was significantly lower with combination stones is beyond the scope of this review. However, likely due to the presence of  receptors in the upper urinary tract, stone passage appears facilitated by the use of -blocking agents.44,45 Safety and Adverse Events Safety issues and adverse events spectra differ considerably between Due to the presence of  receptors in the upper urinary tract, stone passage appears facilitated by the use of -blocking agents. therapy when compared with tamsulosin (P  .001); there was no significant difference between combination therapy and dutasteride (P  .18).37 Time to first BPH clinical progression was significantly different in favor of combination therapy versus tamsulosin and dutasteride (P  .001 for both comparisons). Combination therapy reduced the relative risk of BPH clinical progression by 44.1% compared with tamsulosin and 31.2% compared with dutasteride. In the MTOPS trial, the rate of overall clinical progression among men in the placebo group was 4.5 per 100 person-years. As compared with placebo, doxazosin reduced the risk of progression by 39%, to 2.7 per 100 person-years (P  .001), and finasteride by 34%, to 2.9 per 100 personyears (P  .002). Treatment with finasteride and combination therapy significantly reduced the risk of receiving invasive therapy by 64% (P  .001) and 67% (P  .001), respectively, as compared with placebo. In contrast, doxazosin did not significantly reduce the cumulative incidence of invasive therapy.39 Medical Expulsive Therapy for Ureteral Stones An interesting use of -blockers in medical expulsive therapy for ureteral REVIEWS IN UROLOGY the available -blockers and are discussed in another contribution in this supplement [Kaplan SA. Side effects of -blocker use: retrograde ejaculation. Rev Urol. 2009;11(suppl 1): S14–S18]. Conclusions -Blockers remain a mainstay in the treatment of male LUTS and clinical BPH. They exhibit an early onset of efficacy (within less than 1 week) with regard to both symptoms and flow rate improvement, maintain such improvements in open-label and controlled trials for up to 5 years, are useful adjuncts in the management of patients in AUR prior to a TWOC and in the management of ureteral stones, and have been shown to prevent symptomatic progression (although not progression to AUR and subsequent surgery, which appears to be driven by prostate volume increases and the natural history of BPH, which is not affected by -blockers). The efficacy appears to be similar across all -blockers, although some drugs simply have not been tested in certain situations. The new compound silodosin has excellent early efficacy and distinguishes itself by a strong effect not only on symptoms but on obstruction as measured by pressure 4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S7 -Adrenergic Receptor Blockers in the Treatment of LUTS flow studies, a finding perhaps explained by the strong selectivity to the 1A receptor. 10. References 1. 2. 3. 4. 5. 6. 7. 8. 9. Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol. 2006;49: 651-659. Roehrborn C, McConnell J. Etiology, pathophysiology, epidemiology and natural history of benign prostatic hyperplasia. In: Walsh P, Retik A, Vaughan E, et al, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders; 2002:1297-1336. Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006;50:1306-1315. Jacobsen SJ, Girman CJ, Guess HA, et al. New diagnostic and treatment guidelines for benign prostatic hyperplasia. Potential impact in the United States. Arch Intern Med. 1995;155:477-481. McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign Prostatic Hyperplasia: Diagnosis and Treatment. Quick Reference Guide for Clinicians. AHCPR Publication No. 95-0583. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services; 1994. McConnell J, Abrams P, Denis L, et al. Male Lower Urinary Tract Symptoms: Evaluation and Management. 6th ed. Paris, France: Health Publications; 2006. Clifford GM, Farmer RD. Medical therapy for benign prostatic hyperplasia: a review of the literature. Eur Urol. 2000;38:2-19. Docherty JR. Subtypes of functional alpha1- and alpha2-adrenoceptors. Eur J Pharmacol. 1998; 361:1-15. Hieble JP, Bylund DB, Clarke DE, et al. International Union of Pharmacology. X. Recommenda- 11. 12. 13. 14. 15. 16. 17. 18. tion for nomenclature of alpha 1-adrenoceptors: consensus update. Pharmacol Rev. 1995;47: 267-270. Hawrylyshyn KA, Michelotti GA, Coge F, et al. Update on human alpha1-adrenoceptor subtype signaling and genomic organization. Trends Pharmacol Sci. 2004;25:449-455. Richardson CD, Donatucci CF, Page SO, et al. Pharmacology of tamsulosin: saturation-binding isotherms and competition analysis using cloned alpha 1-adrenergic receptor subtypes. Prostate. 1997;33:55-59. Schwinn DA, Johnston GI, Page SO, et al. Cloning and pharmacological characterization of human alpha-1 adrenergic receptors: sequence corrections and direct comparison with other species homologues. J Pharmacol Exp Ther. 1995;272:134-142. Price DT, Lefkowitz RJ, Caron MG, et al. Localization of mRNA for three distinct alpha 1adrenergic receptor subtypes in human tissues: implications for human alpha-adrenergic physiology. Mol Pharmacol. 1994;45:171-175. Price DT, Schwinn DA, Lomasney JW, et al. Identification, quantification, and localization of mRNA for three distinct alpha 1 adrenergic receptor subtypes in human prostate. J Urol. 1993; 150:546-551. Andersson KE, Lepor H, Wyllie MG. Prostatic alpha 1-adrenoceptors and uroselectivity. Prostate. 1997;30:202-215. Smith MS, Schambra UB, Wilson KH, et al. Alpha1-adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding alpha1-adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res. 1999;63:254-261. Malloy BJ, Price DT, Price RR, et al. Alpha1adrenergic receptor subtypes in human detrusor. J Urol. 1998;160:937-943. Ishizuka O, Persson K, Mattiasson A, et al. Micturition in conscious rats with and without bladder outlet obstruction: role of spinal alpha 1-adrenoceptors. Br J Pharmacol. 1996;117: 962-966. 19. 20. 21. 22. 23. 24. 25. 26. 27. Bouchelouche K, Andersen L, Alvarez S, et al. Increased contractile response to phenylephrine in detrusor of patients with bladder outlet obstruction: effect of the alpha1A and alpha1Dadrenergic receptor antagonist tamsulosin. J Urol. 2005;173:657-661. Lee E, Lee C. Clinical comparison of selective and non-selective alpha 1A-adrenoreceptor antagonists in benign prostatic hyperplasia: studies on tamsulosin in a fixed dose and terazosin in increasing doses. Br J Urol. 1997;80:606-611. de Mey C, Michel MC, McEwen J, et al. A doubleblind comparison of terazosin and tamsulosin on their differential effects on ambulatory blood pressure and nocturnal orthostatic stress testing. Eur Urol. 1998;33:481-488. Tatemichi S, Kobayashi K, Maezawa A, et al. [Alpha1-adrenoceptor subtype selectivity and organ specificity of silodosin (KMD-3213).] Yakugaku Zasshi. 2006;126(Spec no):209-216. Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999;36:1-13. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170: 530-547. Marks LS, Gittelman MC, Hill LA, et al. Rapid efficacy of the highly selective alpha1Aadrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol. 2009; 181:2634-2640. Marks LS, Gittelman MC, Hill LA, et al. Silodosin in the treatment of the signs and symptoms of benign prostatic hyperplasia: a 9-month, openlabel extension study [published online ahead of print October 8, 2009]. Urology. doi:10.1016/j .urology.2009.06.072. Resnick MI, Roehrborn CG. Rapid onset of action with alfuzosin 10 mg once daily in men with benign prostatic hyperplasia: a randomized, Main Points • Male lower urinary tract symptoms (LUTS) are commonly stratified into 3 different symptom categories: voiding or obstructive, storage or irritative, and postmicturition. One of the most common causes of male LUTS is benign prostatic hyperplasia (BPH). • In the past 20 years medical therapy has established itself firmly as viable and cost effective in the treatment of LUTS due to BPH. In addition to the 2 major classes of drugs, the -adrenergic receptor blocker (or -blocker), and the 5-reductase inhibitors, antimuscarinics, phytotherapeutic agents, and combinations thereof are in widespread use. • 1-Adrenoceptor blockade is capable of modifying the dynamic (prostate smooth muscle contraction) component in BPH. • Many randomized placebo-controlled trials, as well as open-label studies, suggest that an improvement in the International Prostate Symptom Score and changes in the peak urinary flow rate are in general the results of -blocker therapy. • -Blockers exhibit an early onset of efficacy (within  1 week) with regard to both symptoms and flow rate improvement, and maintain such improvements in open-label and controlled trials for up to 5 years. • -Blockers are useful adjuncts in the management of patients with acute urinary retention and in the management of ureteral stones, and have been shown to prevent symptomatic progression. VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S7 4. RIU0_S0003_12-14.qxd 12/14/09 4:09 PM Page S8 -Adrenergic Receptor Blockers in the Treatment of LUTS continued 28. 29. 30. 31. 32. 33. 34. S8 placebo-controlled trial. Prostate Cancer Prostatic Dis. 2007;10:155-159. Dunn CJ, Matheson A, Faulds DM. Tamsulosin: a review of its pharmacology and therapeutic efficacy in the management of lower urinary tract symptoms. Drugs Aging. 2002;19:135-161. Roehrborn CG, Prajsner A, Kirby R, et al. A double-blind placebo-controlled study evaluating the onset of action of doxazosin gastrointestinal therapeutic system in the treatment of benign prostatic hyperplasia. Eur Urol. 2005;48: 445-452. Yamanishi T, Mizuno T, Tatsumiya K, et al. Urodynamic effects of silodosin, a new alpha(1A)adrenoceptor selective antagonist, for the treatment of benign prostatic hyperplasia [published online ahead of print August 19, 2009]. Neurourol Urodyn. doi: 10.1002/nau.20802. Matsukawa Y, Gotoh M, Komatsu T, et al. 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