Prostate Cancer and Prostatic Diseases (1999) 2, 110±119 ß 1999 Stockton Press All rights reserved 1365±7852/99 $15.00 http://www.stockton-press.co.uk/pc Review Alpha-1-adrenoceptor blockade in the treatment of benign prostatic hyperplasia

F Lowe1* 1Department of Urology, St. Luke's-Roosevelt Hospital Center, 425 West 59th Street, New York, NY 10019

In light of the growing interest in the concept of `uroselectivity' and in the increased worldwide use of alpha-blockers for benign prostatic hyperplasia (BPH), this review evaluates the relative bene®ts of various alpha-blocking agents in the treatment of BPH. The pharmacological and physiological selec- tivity as well as the clinical ef®cacy and safety of alfuzosin, doxazosin (Car- dura1), tamsulosin (Flomax1), and terazosin (Hytrin1) are compared. In reviewing ef®cacy and safety, emphasis is given to 17 placebo-controlled, double- blind trials of these alpha-blockers published in peer-reviewed journals. This review also considers long-term data, effects on blood pressure, costs, and dose ranges.

Keywords: benign prostatic hyperplasia; alfuzosin; doxazosin; tamsulosin; terazosin

Introduction The primary goal of alpha-blocker therapy for BPH is to relieve lower urinary tract symptoms. These symptoms As the management of symptomatic benign prostatic are believed to be caused mainly by bladder outlet hyperplasia (BPH) has evolved, alpha-blockers have obstruction secondary to enlargement of the prostate, to become the ®rst choice for medical therapy. They are a increased smooth muscle tone in the prostate, and to the safe and effective noninvasive alternative to transurethral detrusor response to prolonged voiding against a rela- resection of the prostate (TURP), the traditional `gold- tively obstructed outlet. Recently, however, this view has standard' BPH therapy. Alpha-blockers have been recom- been challenged by evidence that bladder outlet obstruc- mended as a ®rst-line therapy for BPH most recently by tion is a weak predictor of symptom severity, and that the International Consultation on BPH1 and previously in prostate size is a very weak predictor of symptom sever- the American Health Care Policy and Research (AHCPR) ity and bladder outlet obstruction.10 ± 12 guidelines.2 Factors that have led to the increasing popularity of alpha-blockade are patient preference for noninvasive Rationale for the use of alpha-blockers 3 treatment, the signi®cant morbidities and high initial The presumed mechanism of action of alpha-blockade in 2 costs of TURP, accumulating long-term data on the BPH is the relaxation of prostatic smooth muscle, which 4±7 ef®cacy and safety of alpha-blockers, and the superior accounts for 40% of the area density of BPH tissue.13 8,9 ef®cacy of alpha-blockers relative to ®nasteride. Finas- However, in light of the fact that men respond to alpha- teride, a 5-alpha-reductase inhibitor, is now considered an blockers even in the absence of bladder outlet obstruc- appropriate treatment option for the subset of BPH tion,14 and that there is a weak correlation between the patients who have moderate or severe symptoms and severity of lower urinary tract symptoms and bladder very large sized prostates (  40 g). outlet obstruction,15 it has been suggested that other mechanisms such as neurological pathways and sensory *Correspondence: Dr F Lowe, Department of Urology, St. Luke's- innervation of the prostate may be responsible for alpha- Roosevelt Hospital Center, 425 West 59th Street, New York, NY blocker ef®cacy.11,12 Only further elucidation of the patho- 10019 physiology of BPH will help to clarify the mechanism (or Received 4 January 1999; revised 15 February 1999; accepted mechanisms) of action of alpha-blockers. 15 March 1999 Alpha-1-adrenoceptor blockade in BPH F Lowe 111 Alpha-blockers and uroselectivity

In the 20 years since Caine et al16 reported that the prostatic capsule is responsive to alpha adrenergic stimu- lation, developments in alpha-blockers have centered on the facts that alpha-1 adrenoceptors predominate in the prostate17 and are responsible for mediating smooth muscle tone.18 These ®ndings in¯uenced the development of the alpha-blockers indicated for BPH, from the non- selective alpha-1 and alpha-2 antagonist phenoxybenza- mine, to the short-acting selective alpha-1 antagonists alfuzosin, prazosin, and indoramin, to the long-acting Figure 1 Pharmacological selectivity of alfuzosin, doxazosin, tamsulosin, selective alpha-1 antagonists doxazosin (Cardura1), tam- and terazosin.31 sulosin (Flomax1), and terazosin (Hytrin1). In recent years, subtypes of the alpha-1 adrenoceptor have been characterized as alpha-1A, -1B, and -1D.19 In the prostate, the alpha-1A subtype predominates, accounting for 70% of the total mRNA; the alpha-1B and alpha-1D subtypes account for the remaining 30%.20 Outside of the prostate, the alpha-1A subtype has been found to be ubiquitous,21 ± 23 the alpha-1B sub- type is present in the vasculature and spleen,24,25 and the alpha-1D subtype is present in the vasculature and, as recent evidence suggests, in the bladder detrusor (accounting for 60±70% of the total mRNA).26 The predominance of the alpha-1A subtype in the prostate, and indications that this subtype may play a prime role in prostatic contraction, has led to research of alpha-1A-selective compounds and to the concept of Figure 2 Physiological selectivity of alfuzosin, doxazosin, tamsulosin, and terazosin. In vivo derived pseudo pA2 values indicate the relative drug `uroselectivity' or prostate selectivity. In the past few effect on the reduction of intraurethral pressure (IUP) or mean arterial years, there has been ongoing research for uroselective blood pressure (MABP).31 agents that act preferentially on prostate smooth muscle (alpha-1A) with little effect on the vasculature (alpha-1B and -1D) and central nervous system (CNS) in an attempt reported that none of these alpha-blockers produced a to improve clinical ef®cacy and curtail side effects. greater reduction in urethral pressure than in blood Pharmacological selectivity is assessed in vitro by mea- pressure in the anesthetized dog model (Figure 2); this suring the relative af®nities for the alpha-1A vs the -1B was similar to tamsulosin data reported by Shibasaki et and -1D subtypes. Physiological or functional selectivity al.34 Recently, Hancock et al 39 demonstrated in vivo in a is assessed in vivo by measuring the relative phenyleph- conscious dog model that doxazosin, tamsulosin, and rine-induced reductions in urethral pressure versus blood terazosin lowered mean arterial blood pressure in a pressure: An ideal agent that demonstrates pharmacolo- dose-dependent manner. While an early report suggested gical and physiological selectivity would then clinically in that alfuzosin may preferentially reduce urethral pressure BPH patients be expected to provide superior ef®cacy, vs blood pressure,32 there have been no subsequent minimal CNS± and blood-pressure±related side effects, studies to con®rm this. and minimal hypotension. If the agent demonstrates In terms of uroselectivity, simply demonstrating phar- optimal ef®cacy with minimal side effects, then this macological selectivity for only the alpha-1A receptor agent would be considered clinically uroselective. may not be suf®cient for achieving clinical uroselectivity The pharmacological and physiological selectivities of (that is, optimizing ef®cacy and minimizing blood-pres- alfuzosin, doxazosin, tamsulosin, and terazosin have been sure±related effects). Firstly, alpha-1A receptors exist out- reported in a number of published analyses.27 ± 34 While side of the prostate and therefore may contribute to some analyses indicate that tamsulosin is weakly selective undesired nonurologic effects. Secondly, alpha-1B and for the alpha-1A subtype vs alpha-1B,29,33 others report alpha-1D subtypes may be as necessary as the alpha-1A that none of the four agents has subtype selectivity.27,28,31 subtype in achieving optimal ef®cacy;11 these subtypes The consensus opinion of the Alpha-Blocker Committee exist in the prostate, and their presence in other tissues at the 4th International Consultation on BPH was that may also contribute to ef®cacy. The alpha-1D receptor none of these agents has any distinct selectivity for alpha- predominates in the bladder detrusor, and this may help 1-adrenoceptor subtypes nor for the prostate that could be confer optimal ef®cacy. Thirdly, an additional alpha-1 indicative of clinical selectivity.1 Regarding in vitro phar- subtype, alpha-1L, has been de®ned in functional but macological selectivity, data ®rst reported by Kenny et not molecular studies, and has been proposed to mediate al.31 and cited in a recent review of alpha-blockers by contraction of human lower urinary tract tissues.36 Kirby35 demonstrated that none of these alpha-blockers Finally, selectivity observed pharmacologically and was selective for the alpha-1A subtype (Figure 1). Regard- physiologically in preclinical in vitro and animal-model ing in vivo physiological selectivity, Kenny et al 31 also settings will not necessarily play out in humans.21 In fact, Alpha-1-adrenoceptor blockade in BPH F Lowe

112 to date, two compounds demonstrating a high degree of able ef®cacy and safety.38 In a pilot study of doxazosin pharmacological selectivity in vitro for the alpha-1A sub- (4 mg) and terazosin (5 mg) evaluating morning and type failed to produce suf®cient ef®cacy in men with evening dosing regimens, these two alpha-blockers pro- BPH.37 With these unanswered questions, de®nitive con- duced comparable ef®cacy and safety, with evening clusions cannot be made about the particular alpha-1 dosing resulting in fewer side effects than morning subtypes that should and should not be blocked in the dosing for both agents.39 A single-blind study of tamsu- treatment of BPH.1 losin and terazosin ef®cacy and safety has been pub- lished40 but limitations of the study design undermine the conclusions and relevance of the comparison. These limitations include the lack of a double-blind study Ef®cacy and safety comparison of alpha- design, short study duration (8 weeks), low tamsulosin blockers dose (0.2 mg), small numbers of patients (fewer than 40 in each group), and use of a Korean symptom scoring To date, only three comparative trials of the ef®cacy and system. safety of alpha-blockers have been published. In a double- Because of the paucity of head-to-head trials, in order blind study, alfuzosin and tamsulosin produced compar- to compare the ef®cacy and safety of currently available

Table 1 Ef®cacy of alpha-blockers vs placebo

No. of No. of SS at Treatment PFR at Treatment random weeks of baseline= SS % effect baseline= PFR % effect on Study patients therapy SS system Drug (mg=d) a change change on SSb change change PFRb

Alfuzosin Buzelin 1997 [48] 390 12 Boyarsky Alfuzosin (10) 15.0= 5.0 31% 13% 10.4=2.4 29% 15% Placebo 15.9= 3.4 18% 10.1=1.1 14% Jardin 1991 [54] 518 26 Boyarsky Alfuzosin (7.5±10) 9.5= 4.0 42% 10% 12.1=1.8 15% 12% Placebo 9.4= 3.0 32% 12.0=0.3 3% Doxazosin Christensen 1993 [50] 100 NR Doxazosin (4) NR=NR NR NR 7.6=1.8 24% 17% 9 Placebo NR=NR NR 7.5=0.5 7% Fawzy 1995 [52] 100 16 AUAc Doxazosin (2±8) 14.2= 5.7 39% 22% 9.7=2.9 30% 23% Placebo 15.6= 2.5 17% 9.9=0.7 7% Gillenwater 1995 [53] 248 16 Boyarskye Doxazosin (4) 30.0= 5.0 17% 3% NR=2.3 NR NR Doxazosin (8) 30.0= 4.2 14% 5% NR=3.3 NR NR Placebo 28.0= 2.5 9% NR=0.1 NR Roehrborn 1996 [60] 337 16 100-pointd Doxazosin (4±8) 47.2= 16.4 35% 15% 10.0=2.2 22% 13% Placebo 48.2= 9.8 20 10.0=0.9 9% Tamsulosin Abrams 1995 [45] 296 12 Boyarsky Tamsulosin (0.4) 9.5= 3.4 36% 12% 10.7=1.4 13% 9% Placebo 9.3= 2.2 24% 10.4=0.4 4% Abrams 1997 [46] 126 Boyarsky Tamsulosin (0.4) 14.9= 4.1 29% 11% 9.8=2.2 23% 24% 4 Placebo 16.7= 2.9 18% 10.9= 0.1 1% Chapple 1996 [49] 575 12 Boyarsky Tamsulosin (0.4) 9.4= 3.3 35% 9% 10.2=1.6 16% 10% Placebo 9.4= 2.4 26% 10.1=0.6 6% Lepor 1998 [55] 756 13 AUA Tamsulosin (0.4) 19.8= 8.3 42% 14% 9.5=1.8 18% 13% Tamsulosin (0.8) 19.9= 9.6 48% 20% 9.6=1.8 19% 14% Placebo 19.6= 5.5 28% 9.8=0.5 5% Narayan 1998 [58] 735 13 AUA Tamsulosin (0.4) 20.4= 5.1 25% NR 10.1=1.5 15% 6% Tamsulosin (0.8) 23.0= 5.8 25% NR 9.9=1.8 18% 9% Placebo NR= 3.6 NR 10.3=0.9 9% Terazosin Brawer 1993 [47] 160 24 Boyarsky Terazosin (1±10) 10.9= 4.6 42% 31% 8.6=2.6 30% 16% Placebo 10.4= 1.1 11% 8.8=1.2 14% Elhilali 1996 [51] 224 24 Boyarsky Terazosin (1±10) 11.1= 3.5 32% 17% 10.2=1.9 19% 13% Placebo 11.0= 1.7 15% 9.6=0.6 6% Lepor 1996 [9] 1229 52 AUA Terazosin (5±10) 16.2= 6.1 38% 22% 10.5=2.7 26% 13% Placebo 15.8= 2.6 16% 10.4=1.4 13% Lepor 1992 [56] 285 12 Boyarsky Terazosin (2) 10.0= 3.3 33% 9% 8.8=2.1 24% 14% Terazosin (5) 10.7= 3.6 34% 10% 9.3=1.7 18% 8% Terazosin (10) 10.1= 4.5 45% 21% 8.8=3.0 34% 24% Placebo 9.7= 2.3 24% 10.1=1.0 10% Roehrborn 1996 [59] 2084 52 AUA Terazosin (2±10) 20.1= 7.6 38% 20% 9.6=2.2 23% 15% Placebo 20.1= 3.7 18% 9.6=0.8 8%

aTable includes common therapeutic doses reported in the publications. bTreatment effect represents the difference in percent change between active drug and placebo. cAUA-derived scale, 0 ± 30 points. d100-point scale, 0 ± 100 points. eModi®ed Boyarsky, 7 ± 39 points. SS ˆ symptom score. PFR ˆ peak ¯ow rate. NR ˆ not reported or not available. Alpha-1-adrenoceptor blockade in BPH F Lowe alpha-blockers, the results of published double-blind, score and peak ¯ow rate; these were reported in the 16 113 placebo-controlled studies of alfuzosin, doxazosin, tam- trials and therefore allowed for a comparison of mean sulosin, and terazosin must be reviewed. Previous changes for the alpha-blockers in relation to placebo. reviews have suggested that among these alpha-blockers For each of the 16 trials, Table 1 and Figures 3 and 4 there are no apparent differences in overall ef®cacy, and summarize available data for baseline, mean change, and some quantitative but not qualitative differences in over- percent change in symptom score and peak ¯ow rate for all safety.1,35,41 ± 44 This present analysis includes the most alfuzosin, doxazosin, tamsulosin, and terazosin in rela- recent studies to date. There are some limitations in tion to placebo. To allow further comparisons among assessing the results of different studies together, for these trials, Table 1 also reports the number of rando- example differences in study design, study duration, mized patients, number of weeks of therapy, symptom number of patients, method of data analysis, etc.; how- scoring system used, and common therapeutic doses ever, this is the best approach available. To minimize used. potential biases in the following analysis, only placebo- The trials used in this analysis employed a number of controlled, double-blind trials published as full papers in different symptom scoring systems: the International peer-reviewed journals were selected. Trials published Prostate Scoring System (IPSS), the American Urological only as abstracts or supplements were excluded from Association (AUA), the Boyarsky, and adaptations of this part of the review. All treatment effects reported in these. Additionally, the baseline symptom scores can this analysisÐ both ef®cacy and safetyÐ are expressed in in¯uence the mean changes in symptom scores; larger relation to placebo (drug effect). This review comprises 17 reductions in symptom scores tend to occur with higher published reports representative of the literature on alfu- baselines, whereas smaller reductions occur with lower zosin, doxazosin, tamsulosin, and terazosin, involving baselines. more than 8000 patients.9,45 ± 60 One of these reports Table 1 and Figures 3 and 4 indicate overall that evaluated only safety data57 and is therefore excluded alfuzosin, doxazosin, tamsulosin, and terazosin provide from the ef®cacy sections below. a comparable range of improvement over placebo in symptom score (5±31%) and peak ¯ow rate (9±24%). There is some suggestion that terazosin (9±31%) may have a slightly better effect on symptom scores than Effect on symptom score and peak ¯ow doxazosin (5±22%), tamsulosin (9±20%), or alfuzosin (10±13%). Regarding urinary ¯ow, there is considerable rate overlap in the magnitude of improvement in peak ¯ow While a variety of ef®cacy endpoints (for example, rates of doxazosin (13±23%), tamsulosin (6±24%), and changes in symptom score, peak ¯ow rate, mean ¯ow terazosin (8±24%), while it appears that alfuzosin (12± rate, residual volume, sexual function score, nocturia 15%) might produce slightly less improvement. score, and proportion of patients responding) are Variances in the degree of the placebo effect can in¯uence the degree of drug-effect improvement. Firstly, reported in trials of medical therapy for BPH, the two 47 most common primary ef®cacy endpoints are symptom in the Brawer et al study, placebo produced an 11%

Figure 3 Percent change in symptom score (SS) from baseline for alfuzosin, doxazosin, tamsulosin, and terazosin minus placebo.9,45 ± 60 Alpha-1-adrenoceptor blockade in BPH F Lowe 114

Figure 4 Percent change in peak ¯ow rate (PFR) from baseline for alfuzosin, doxazosin, tamsulosin, and terazosin minus placebo.9,45 ± 60

improvement in symptom score (which is lower than that varied according to the de®nition of response. Some trials reported in most other alpha-blocker studies), while de®ned response as a  25% improvement in symptom terazosin produced a 42% improvement. Therefore, the score from baseline,45,49,55,58 while others used more low placebo effect in this study enhanced the resulting stringent thresholds of  30%,51,56  35%,59 or  50%.47 treatment effect (the difference between active drug and One trial de®ned response as a successive range of placebo); the symptom-score treatment effect of 31% is improvement in symptom score from baseline of  10% notably higher than in any of the other trials in Table 1 up through  50%.60 In other studies, response was and Figures 3 and 4. Secondly, in a study by Abrams et de®ned subjectively by the patient or investiga- al,46 patients receiving placebo had a 1% decrease in peak tor.46,50,54,58 Three studies did not de®ne or report symp- ¯ow rate, which is lower than that reported in all other tomatic response.9,52,53 alpha-blocker studies, while tamsulosin produced a 23% Because of the varying de®nitions of symptomatic increase. Therefore, the low placebo effect in this study response used in these 16 studies, it is impossible to produced an attributable drug effect on peak ¯ow rate of conclude that one agent produces better responder rates 24%; this is markedly higher than that reported in the than another agent. Overall, however, while there is no other four tamsulosin trials.45,49,55,58 clear de®nition of responder, a markedly greater propor- There is con¯icting evidence as to whether tamsulosin tion of alpha-blocker patients (approximately 10±30% 0.4 and 0.8 mg produce different magnitudes of symptom greater) than placebo patients achieved a symptomatic relief. While the 0.4 mg dose produced a 9±14% improve- response in these studies by either their own or their ment over placebo in symptom score in four stu- investigator's de®nition. dies,45,46,49,55 in one study the 0.8 mg produced a 20% improvement over placebo.55 The recent Narayan study, however, suggests that there is no difference between the two dose levels in relieving symptoms.58 This raises Long-term ef®cacy questions as to whether 0.4 mg or 0.8 mg is the optimal dose for symptom relief. BPH is a chronic disease; therefore, long-term data on alpha-blockers are needed to establish their durability. While there are no double-blind, placebo-controlled trials of alpha-blockers longer than 1 y, open-label studies have Proportion of patients responding demonstrated the ef®cacy of these agents in BPH for 14 months up to 54 months. The longest-term alpha-blocker Beyond improvements in symptom score and peak ¯ow data have been published on terazosin and doxazosin. rate, another measure of ef®cacy is the proportion of Terazosin has been shown to improve Boyarsky symptom patients achieving a symptomatic response to treatment. scores 38±51% (4.0±5.4 units) from baseline (10.5 units) In these 16 trials, the proportion of patients considered to and peak ¯ow rates 23±40% (2.3±4.0 mL=s) from baseline be symptomatically responding to alpha-blocker therapy (10.0 mL=s) for up to 42 months of treatment (n ˆ 494 at Alpha-1-adrenoceptor blockade in BPH F Lowe entry; n ˆ 47 at 42 months).5 Similar results have been (n ˆ 2488), alfuzosin (n ˆ 908), and doxazosin (n ˆ 785). 115 reported in an extension of these terazosin data to 54 (These n values represent the total number of randomized months (n ˆ 140 at 48 months; n ˆ 54 at 54 months).61 patients in trials listed for each agent in Table 2. The total Doxazosin has been shown to improve AUA and mod- number for terazosin excludes patients from the McKier- i®ed Boyarsky symptom scores for severity and bother- nan and Lowe survey57 who are represented in three someness 14±31% from baseline and peak ¯ow rates 19% other terazosin studies).47,56,59 Study durations were gen- (1.9 mL=s) from baseline (10.0 mL=s) for up to 48 months erally longer in terazosin studies (8±52 weeks) than in (n ˆ 450 at entry; n ˆ 28 at 48 months).6 Tamsulosin has trials of alfuzosin (12±26 weeks), doxazosin (9±16 been shown to improve Boyarsky symptom scores 36% weeks), and tamsulosin (4±13 weeks). (3.4 units) from baseline (9.4 units) and peak ¯ow rates Although the overall side-effect pro®les of alpha-block- 13.7% (1.4 mL=s) from baseline (10.2 mL=s) for up to 14 ers are similar, there are marked differences in the inci- months (n ˆ 240 at entry; n ˆ 181 at 14 months).7 A dence of speci®c side effects among studies of the same preliminary report has indicated that tamsulosin main- drug. For example, for doxazosin, two separate studies tains improved symptom scores and ¯ow rates for up to report that the attributable risk of headache is 8%52 and 36 months.62 Alfuzosin has been shown to improve 0%.53 For terazosin, two separate studies report that the Boyarsky symptom scores 40% (3.5 units) from baseline attributable risk of dizziness is 19%9 and 5.3%.57 For (8.7 units) for up to 24 months (n ˆ 50) and ¯ow rates 7% tamsulosin, two separate studies report that the attribu- (1.0 mL=s) from baseline (13.6 mL=s) for up to 12 months table risk of abnormal ejaculation is 10%58 and 0%.46 Also, (n ˆ 46); alfuzosin, however, failed to maintain improve- there is a marked difference in the incidence of side effects ments in ¯ow at 24 months (n ˆ 20), when ¯ow rates reported in the two US tamsulosin trials55,58 vs the three decreased 6% ( 0.9 mL=s) from baseline (15.0 mL=s).4 European tamsulosin trials.45,46,49 It is uncertain whether Despite these studies, the long-term durability of these this is due to cultural differences, to the methodologies of agents is still unknown and uncertain. It should be noted the reporting of side effects, or to other factors. that the results of open-label studies may be somewhat The development of slow-release alpha-blocker formu- enhanced because responding patients are included in the lations might affect the incidence of side effects. Doxazo- results and those withdrawing are not. sin and terazosin are currently available as standard- release formulations; for these agents, bedtime dosing and judicious stepwise titration of dose levels tend to minimize hypotensive side effects.63 Alfuzosin and tam- Safety sulosin are sustained-or modi®ed-release formulations that allow for a gradual onset of action to help minimize While there are differences in the incidence rates of hypotensive side effects. A slow-release formulation of speci®c side effects among alfuzosin, doxazosin, tamsu- doxazosin has now been developed, and initial reports losin, and terazosin, the overall side-effect pro®les of suggest that it improves the side effect pro®le vs standard these agents have been characterized as `very similar' doxazosin.64 by the Alpha-Blocker Committee at the 4th International Attributable drug effects (vs placebo) for discontinua- Consultation on BPH.1 Seventeen double-blind, placebo- tion due to side effects in Table 2 suggest that doxazosin controlled trials of these four agents are reviewed herein. (5.8±11.9%) and terazosin (2.5±6.1%) may be associated Table 2 reports the incidence of selected side effects in with somewhat higher withdrawal rates than tamsulosin these trials for each agent and placebo, as well as the (0±3%) and alfuzosin (0±2%). Unfortunately, disconti- respective attributable risks. nuation data were not available for all 17 studies. One There are many variables that can in¯uence the inci- doxazosin50 and one tamsulosin publication55 each did dence of side effects: the de®nition of side effects, how not report these rates. While there may be slight differ- actively the investigators elicited side effects, the degree ences in the side-effect pro®les of the four agents, from of bother needed to register a particular side effect, the these data it can be concluded that alpha-blocker therapy registering of transient side effects, the titration regimen, is well tolerated, and that the majority of side effects with and the length of time patients were exposed to active alpha-blockers are mild to moderate, seldom causing a drug. The incidence of side effects for the alpha-blockers patient to prematurely discontinue therapy. must be judged against the respective placebo control Most of these 17 trials did not report side effects by arms to assess the attributable risk of the drugs. dose level, so it is impossible to conclude from these data The data in Table 2 suggests that the overall side-effect whether side effects increase with increased doses. Two pro®les of doxazosin, tamsulosin, and terazosin are simi- tamsulosin trials55,58 and one terazosin trial56 did list side lar. Speci®c side effects that are notably higher than effects by dose level. In these three studies, the only placebo are dizziness, asthenia, and headache with dox- clearly dose-related side effect was abnormal ejaculation azosin; abnormal ejaculation, rhinitis, and dizziness with in the tamsulosin trials (6±10% at 0.4 mg vs 17±18% at tamsulosin; and dizziness, postural hypotension, and 0.8 mg). A recent doxazosin report indicated that the asthenia with terazosin. While alfuzosin appears to be incidence of side effects at 4 mg and 8 mg is similar.65 associated with lower rates of these side effects than the other agents, alfuzosin has not been as extensively inves- tigated in double-blind, placebo-controlled trials. Table 2 Long-term safety is based on six such trials of terazosin, ®ve of tamsulosin, four of doxazosin, and two of alfuzosin. The terazosin Data on the long-term safety of alpha-blockers in BPH has trials investigated a greater number of randomized been obtained only in open-label studies for 12±54 patients (n ˆ 4506) than the trials of tamsulosin months' duration. In general, the side effects with the Alpha-1-adrenoceptor blockade in BPH F Lowe 116 Table 2 Safety of alpha-blockers vs placebo

Postural No. of No. of hypo- Abnormal random weeks of Druga Discontin. Dizziness Headache Asthenia tension Rhinitis ejaculation Study patients therapy (mg=day) due to AE (AR)b (AR)b (AR)b (AR)b (AR)b (AR)b

Alfuzosin Buzelin 1997 [48] 390 12 Alfuzosin (10) 4.6 2.6 (0.6) 0.5 NR 0.5(0.5) NR NR Placebo 7.1 2.0 1.0 NR 0.0 NR NR Jardin 1991 [54] 518 26 Alfuzosin (7.5±10) 11. 7.2 (2.0) 6.4 (1.5) 2.0 1.9(0.7) NR NR Placebo 9 5.2 4.9 3.8 1.2 NR NR Doxazosin Christensen 1993 [50] 100 9 Doxazosin (4) NR NR NR NR NR NR NR Placebo NR NR NR NR NR NR NR Fawzy 1995 [52] 100 16 Doxazosin (2±8) 14. 24.(20) 12.(8) 12.(8) NR NR NR Placebo 2.1 4. 4. 4. NR NR NR Gillenwater 1995 [53] 248 16 Doxazosin (4±8) 11.1 19.(15) 14. 10.(10) NR NR NR Placebo 4.1 4. 18. 0. NR NR NR Roehrborn 1996 [60] 337 16 Doxazosin (4±8) 10. 17.(10.7) 11.(1.2) 11.(8.2) NR NR NR Placebo 4.2 6.3 9.8 2.8 NR NR NR Tamsulosin Abrams 1995 [45] 296 12 Tamsulosin (0.4) 4.1 2.5 (0.5) 3.0 (2.0) NR 0. NR 4.(3) Placebo 3.1 2.0 1.0 NR 1.0 NR 1. Abrams 1997 [46] 126 4 Tamsulosin (0.4) 3. 7.(7) 3. 0. NR NR 0.(0) Placebo 7. 0. 4. 7. NR NR 0. Chapple 1996 [49] 575 12 Tamsulosin (0.4) 4.5 3.4 (0.3) 2.1 1.(0) 0. 0.3 4.5 (3.5) Placebo 3.6 3.1 2.1 1. 0.5 0.5 1. Lepor 1998 [55] 756 13 Tamsulosin (0.4) NR 10.(5) 19.(1) 5.(3) NR 12.(6) 6.(6) Tamsulosin (0.8) NR 11.(6) 18. 5.(3) NR 15.(9) 18.(18) Placebo NR 5. 18. 2. NR 6. 0. Narayan 1998 [58] 735 13 Tamsulosin (0.4) 9. 20.(5) 20. 11.(2) NR 14.(3) 11 (10) Tamsulosin (0.8) 12. 23.(8) 24.(2) 12.(3) NR 20.(9) 18 (17) Placebo 8. 15. 22. 9. NR 11. 1. Terazosin Brawer 1993 [47] 160 24 Terazosin (1±10) 15. 19.(14) 6. 7.(4) NR NR NR Placebo 8.9 5. 9. 3. NR NR NR Elhilali 1996 [51] 224 24 Terazosin (1±10) 8.6 19.8 (8.8) 7.4 (3.7) 12.3 (3.8) 2.5 (2.5) 9.9 (1.4) NR Placebo 4.8 11.0 3.7 8.5 0.0 8.5 NR Lepor 1996 [9] 1229c 52 Terazosin (5±10) 5.9 26.(19) 6.(3) 14.(7) 8.(7) 7.(2) 0.3 Placebo 1.6 7. 3. 7. 1. 5. 1.0 Lepor 1992 [56] 285 12 Terazosin (2) 6.8 8.1 (5.2) 5.4 6.8 (3.9) 2.7 (2.7) NR NR Terazosin (5) 6.9 2.8 1.4 5.6 (2.7) 8.3 (8.3) NR NR Terazosin (10) 7.1 10.0 (7.1) 2.9 10.0 (7.1) 5.7 (5.7) NR NR Placebo 4.3 2.9 5.8 2.9 0. NR NR McKiernan 1997 [57] 3080 8±52 Terazosin (1±20) 14.5 10.7 (5.3) NR 7.5 (4.5) 2.7 (2.1) NR 1.0 (0.7) Placebo 11.4 5.4 NR 3.0 0.6 NR 0.3 Roehrborn 1996 [59] 2084 52 Terazosin (2±10) 16. 12.(6.2) NR 7.5 (4.6) 1.9 (1.4) NR 1.4 (1.2) Placebo 11. 5.8 NR 2.9 0.5 NR 0.2

aTable includes common therapeutic doses reported in the publications. bAR ˆ attributable risk (the difference in incidence between active drug and placebo). cThe number of patients randomized to terazosin or placebo was 610; the other 619 patients were randomized to ®nasteride or combination therapy (terazosin plus ®nasteride). NR ˆ not reported or not available.

highest incidence in short-term placebo-controlled studies increased risk of dizziness or hypotension-related side (see Table 2) were also the most common in these long- effects. However, accumulating evidence to date suggests term studies. In a 42-month study of terazosin5 that has that alpha-blockade with doxazosin, tamsulosin, or ter- now been extended to 54 months,61 and in a 48-month azosin is equally well tolerated in both older and younger study of doxazosin,6 the side effects with the highest BPH patients.66 ± 70 incidence were dizziness, asthenia, headache, and som- nolence. In a 14-month study of tamsulosin,7 the side effects with the highest incidence were abnormal ejacula- Blood-pressure effects tion, dizziness, headache, and postural hypotension. In a Alpha-blockers were originally developed for the treat- 24±30-month study of alfuzosin, the side effects with the ment of hypertension and are now well established as highest incidence were dizziness, headache, and malaise= safe and effective, although usually not as ®rst-line anti- postural hypotension.4 hypertensive therapy.71 In BPH patients, alpha-blockers have been shown to bene®cially reduce blood pressure in Safety in the elderly men with hypertension, but produce little or no reduction in normotensive patients.55,72 ± 75 Evidence indicates that it There are concerns that the hemodynamically active is safe to co-administer alpha-blockade for BPH with pre- alpha-blockers may cause elderly BPH patients to be at existing antihypertensive treatment. The addition of Alpha-1-adrenoceptor blockade in BPH F Lowe doxazosin or terazosin to pre-existing antihypertensive doubles its cost. At the lowest common therapeutic 117 treatment has been shown to produce a bene®cial and doses, doxazosin and tamsulosin are less expensive than safe reduction in blood pressure in noncontrolled hyper- terazosin; at the highest doses, tamsulosin is the most tensive patients while producing little or no reduction in expensive. blood pressure in pharmacologically normotensive patients.73,75,76 While some studies have suggested that tamsulosin produces a minimal effect on blood pressure in BPH Conclusions patients,45,46 data from other studies suggest that tamsu- losin may produce some reductions in men who have This present review indicates that, based on the results of elevated blood pressure. In men with elevated blood 17 placebo-controlled, double-blind trials, there are no pressure at baseline, tamsulosin's effect on supine diasto- dramatic differences in the overall ef®cacy and safety of lic blood pressure (mmHg) was 9.1 (101.6 baseline, currently available alpha-blocking agents. While the data 0.4 mg),49 8.1 (101.2, 0.4 mg),38 7.2 and 8.5 mmHg suggest that terazosin may provide some minor advan- (baselines not reported, 0.4 and 0.8 mg),55 and 6.6 (89.4, tage in symptom relief over the other agents, and that 0.2 mg).40 While the blood-pressure changes for tamsulo- there are some differences in the incidence of speci®c side sin were not different from placebo in two of these effects, only a properly conducted, double-blind, com- studies,49,55 the magnitude of the changes (range 6.6 parative trial will reveal meaningful differences between to 9.1 mmHg) approaches that reported for doxazosin72 agents. Such a trial must also include a placebo arm to and terazosin73 in hypertensive men with BPH (range properly elicit the degree of drug effects. Until such head- 10.0 to 11.5 mmHg). Additionally, in two comparative to-head trials are conducted, clinicians need to determine, trials of the blood-pressure effects of tamsulosin versus with each individual patient, what clinical features of a doxazosin77 and vs terazosin,78 tamsulosin was similar to particular agent are best suited for the patient. Besides the comparative agents. The latter study indicated that ef®cacy, safety, blood-pressure effects, therapeutic dose tamsulosin was associated with a lower level of nocturnal range, and cost, other considerations of alpha-blockers orthostatic hypotension. should include their effects on plasma lipids,80 apopto- sis,81,82 erectile function,83,84 and prostatitis.85 In the future, the development of a true subtype- selective alpha-1 antagonist may lead to signi®cant advances in the medical treatment of BPH. It remains to Dose ranges and cost be seen whether a subtype-selective agent will be able to In light of the fact that there are no marked differences in reduce side effects while maintaining ef®cacy. overall ef®cacy and safety among current alpha-blockers, for the practicing clinician the considerations of ease of administration and cost become important. Tamsulosin and alfuzosin do not need to be titrated; References therefore, the therapeutic dose may be reached on the ®rst 1 Jardin A et al. Alpha-blockers in the treatment of BPH. In: Denis day of therapy. Tamsulosin is available as a once-daily L, Grif®ths K, Khoury S, Cockett ATK, McConnell J, Chatelain C, 0.4 mg dose. In the US, if a patient fails to achieve a Murphy G and Yoshida O (eds). 4th International Consultation on suf®cient clinical response after a trial of tamsulosin Benign Prostatic Hyperplasia (BPH). Health Publication Ltd: Ply- 0.4 mg, the dose may be doubled to 0.8 mg (two 0.4 mg mouth, United Kingdom, 1998, 599±632. 2 McConnell JD et al. Benign Prostatic Hyperplasia: Diagnosis and doses). Alfuzosin, which is only available outside of the Treatment. Quick Reference Guide for Clinicians. AHCPR Publication US, is administered at a dose of 7.5±10 mg per day in No. 94-0583. Agency for Health Care Policy and Research, Public three divided doses. Recently a sustained-release (SR) Health Service, US Department of Health and Human Services: formulation of alfuzosin, 5 mg administered twice daily, Rockville, MD, February 1994. has been developed. 3 Kaplan SA et al. Effect of demographic factors, urinary peak ¯ow Doxazosin (1±8 mg) and terazosin (1±10 mg) are avail- rates, and Boyarsky symptom scores on patient treatment choice able in escalating once-daily doses in both the US and in in benign prostatic hyperplasia. Urology 1995; 45: 398±405. 4 Jardin A et al. Long-term treatment of benign prostatic hyperpla- Europe. A clinical bene®t of doxazosin and terazosin sia with alfuzosin: a 24±30 month survey. Br J Urol 1994; 74: 579± therapy is that a wider range of therapeutic doses is 584. available, whereby the dose can be increased until the 5 Lepor H for the Terazosin Research Group. Long-term ef®cacy optimal therapeutic response is achieved, or reduced if and safety of terazosin in patients with benign prostatic hyper- necessary to balance effectiveness with optimal tolerabil- plasia. Urology 1995; 45: 406±413. ity for individual patients. BPH symptom severity varies 6 Lepor H et al. Doxazosin for benign prostatic hyperplasia: long- term ef®cacy and safety in hypertensive and normotensive from patient to patient, and thus one dose level of patients. The Multicenter Study Group. J Urol 1997; 157: 525±530. tamsulosin may not provide adequate symptomatic 7 Schulman CC et al. Tamsulosin, the ®rst prostate-selective alpha- relief for many patients. 1A-adrenoceptor antagonist. Eur Urol 1996; 29: 145±154. In the US, monthly (30 d) costs of these alpha-blockers 8 Debruyne FM et al. Sustained-release alfuzosin, ®nasteride and at common therapeutic doses are as follows: doxazosin 4 the combination of both in the treatment of benign prostatic and 8 mg, $31 and $32; tamsulosin 0.4 and 0.8 mg, $39 hyperplasia. Eur Urol 1998; 34: 169±175. and $78; and terazosin 5 and 10 mg $46 and $46.79 9 Lepor H et al. The ef®cacy of terazosin, ®nasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996; 335: 533±539. (Alfuzosin is not available in the US). Increasing the 10 Girman CJ et al. Natural history of prostatism: relationship dose with doxazosin and terazosin does not increase the among symptoms, prostate volume and peak urinary ¯ow rate. cost, whereas increasing the dose with tamsulosin J Urol 1995; 153: 1510±1515. Alpha-1-adrenoceptor blockade in BPH F Lowe

118 11 Lepor H. Prostate selectivity of alpha-blockers: from receptor 34 Shibasaki M et al. Effect of the optical isomers of YM-12617 on biology to clinical medicine. Eur Urol 1996; 29 (Suppl): 12±16. increased intra-urethral pressure induced by phenylephrine in 12 Lepor H. The pathophysiology of lower urinary tract symptoms anaesthetised dogs. J Autonom Pharmacol 1992; 12: 263±268. in the ageing male population. Br J Urol 1998; 81 (Suppl 1): 35 Kirby RS, Pool JL. Alpha adrenoceptor blockade in the treatment 29±33. of benign prostatic hyperplasia: past, present and future. Br J Urol 13 Shapiro E, Hartanto V, Lepor H. Quantifying the smooth muscle 1997; 80: 521±532. content of the prostate using double-immunoenzymatic staining 36 Ford AP et al. Pharmacological pleiotropism of the human and color assisted image analysis. J Urol 1992; 147: 1167±1170. recombinant alpha1 A-adrenoceptor: implications for alpha-1- 14 Witjes WPJ et al. Urodynamic and clinical effects of terazosin adrenoceptor classi®cation. Br J Pharmacol 1997; 121: 1127±1135. therapy in symptomatic patients with and without bladder outlet 37 Recordati's urologicals disappoint. Scrip. May 13, 1996. obstruction: a strati®ed analysis. Urology 1997; 49: 197±206. 38 Buzelin JM et al. Comparison of tamsulosin with alfuzosin in the 15 Nitti V, Kim Y, Combs AJ. Correlation of the AUA symptom treatment of patients with lower urinary tract symptoms sugges- index with urodynamics in patients with suspected benign pro- tive of bladder outlet obstruction (symptomatic benign prostatic static hyperplasia. Neurourol Urodyn 1994; 13: 521±529. hyperplasia). Br J Urol 1997; 80: 597±605. 16 Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors 39 Kaplan SA, Soldo KA, Olsson CA. Terazosin and doxazosin in in the human prostate, prostatic capsule and bladder neck. Br J normotensive men with symptomatic prostatism: a pilot study to Urol 1975; 47: 193±201. determine the effect of dosing regimen on ef®cacy and safety. Eur 17 Chapple CR et al. Characterisation of human prostatic adreno- Urol 1995; 28: 223±228. ceptors using pharmacology receptor binding and localisation. Br 40 Lee F, Lee C. Clinical comparison of selective and non-selective J Urol 1989; 63: 487±496. alpha-1A-adrenoceptor antagonists in benign prostatic hyperpla- 18 Gup DI, Shapiro E, Bauman M, Lepor H. Autonomic receptors in sia: studies on tamsulosin in a ®xed dose and terazosin in asymptomatic and symptomatic BPH. J Urol 1990; 143: 179±185. increasing doses. Br J Urol 1997; 80: 606±611. 19 Ford APDW, Wiliams TJ, Blue DR, Clarke DE. Alpha-1 adreno- 41 Beduschi MC, Beduschi R, Oesterling JE. Alpha-blockade therapy ceptor classi®cation: Sharpening Occam's razor. Trends Pharmacol for benign prostatic hyperplasia: from a nonselective to a Sci 1994; 15: 167±170. more selective alpha-1A-adrenergic antagonist. Urology 1998; 20 Price DT et al. Identi®cation, quanti®cation, and localization of 51: 861±872. mRNA for three distinct alpha-1-adrenergic receptor subtypes in 42 Chapple CR. Selective alpha-1 adrenoceptor antagonists in human prostate. J Urol 1993; 150: 546±551. benign prostatic hyperplasia: rationale and clinical experience. 21 Andersson K-E, Lepor H, Wyllie MG. Prostatic alpha-1-adreno- Eur Urol 1996; 29: 129±144. ceptors and uroselectivity. Prostate 1997; 30: 202±215. 43 Eri LM, Tveter KJ. Alpha-blockade in the treatment of sympto- 22 Ford APDW et al. (N-[2-(2-Cyclopropylmethoxyphenoxy) ethyl-5- matic benign prostatic hyperplasia. J Urol 1995; 154: 923±934. chloro-alpha, alpha-dimethyl-1H-indole-3-ethanamine hyp- 44 Heimbach D, Muller SC. Treatment of benign prostatic hyperpla- drochloride), a selective alpha-1A-adrenoceptor antagonist, dis- sia with alpha-1-adrenoceptor antagonists. Urologe A 1997; 36: plays low af®nity for functional alpha-1 adrenoceptors in human 18±34. prostate: implications for adrenoceptor classi®cation. Mol Phar- 45 Abrams P, Schulman CC, Vaage S, European Tamsulosin Study macol 1996; 49: 209±215. Group. Tamsulosin, a selective alpha-1c-adrenoceptor antagonist: 23 Ford APDW et al. Do alpha-1A (alpha-1C)-adrenoceptors (AR) a randomized, controlled trial in patients with benign prostatic mediate prostatic smooth muscle contraction in man? Studies `obstruction' (symptomatic BPH). Br J Urol 1995; 7: 325±336. with a novel, selective alpha-1A-AR antagonist, RS 17053. Br J 46 Abrams P et al. A dose-ranging study of the ef®cacy and safety of Pharmacol 1995; 114: 579p. tamsulosin, the ®rst prostate-selective alpha-1A-adrenoceptor 24 Hatano A et al. Pharmacological evidence of distinct alpha-1- antagonist, in patients with benign prostatic obstruction adrenoceptor subtypes mediating the contraction of human pro- (symptomatic benign prostatic hyperplasia). Br J Urol 1997; 80: static urethra and peripheral artery. Br J Pharmacol 1994; 113: 723± 587±596. 728. 47 Brawer MK, Adams G, Epstein H. Terazosin in the treatment of 25 Ruffolo RR Jr, Nichols AJ, Stadel JM, Hieble JP. Structure benign prostatic hyperplasia. Terazosin Benign Prostatic Hyper- and function of alpha adrenoceptors. Pharmacol Rev 1991; 43: plasia Study Group. Arch Fam Med 1993; 2: 929±935. 475±505. 48 Buzelin JM et al. Ef®cacy safety of sustained-release alfuzosin 26 Malloy BJ et al. Alpha-1 adrenoceptor subtypes in human bladder 5 mg in patients with benign prostatic hyperplasia. Eur Urol 1997; detrusor. J Urol 1998; 159 (Suppl): 329. Abstract 1263. 31: 190±198. 27 Brune ME et al. Pharmacological antagonism of alpha-adrenergic 49 Chapple CR et al. Tamsulosin, the ®rst prostate-selective alpha- agonist induced increases in canine intraurethral pressure in vivo. 1A-adrenoceptor antagonist. Eur Urol 1996; 29: 155±167. Drug Dev Res 1995; 34: 267±275. 50 Christensen MM et al. Doxazosin treatment in patients with 28 Brune ME et al. Effects of selective and nonselective alpha-1- prostatic obstruction. A double-blind placebo-controlled study. adrenoceptor antagonists on intraurethral and arterial pressures Scand J Urol Nephrol 1993; 27: 39±44. in intact conscious dogs. Drug Dev Res 1996; 53: 356±368. 51 Elhilali MM et al. A multicenter, randomized, double-blind, 29 Foglar R et al. Use of recombinant alpha-1-adrenoceptors to placebo-controlled study to evaluate the safety and ef®cacy of characterize subtype selectivity of drugs for the treatment of terazosin in the treatment of benign prostatic hyperplasia. Urol- prostatic hypertrophy. Eur J Pharmacol 1995; 288: 201±207. ogy 1996; 47: 335±342. 30 Hancock AA et al. Actions of A-131701, a novel, selective antago- 52 Fawzy A et al. Doxazosin in the treatment of benign prostatic nist for alpha-1A compared with alpha-1B adrenoceptors on hyperplasia in normotensive patients: a multicenter study. J Urol intraurethral and blood pressure responses in conscious dogs 1995; 154: 105±109. and a pharmacodynamic assessment of in vivo prostatic selectiv- 53 Gillenwater JY et al. Doxazosin for the treatment of benign ity. JPET 1998; 285: 628±642. prostatic hyperplasia in patients with mild to moderate essential 31 Kenny BA et al. Effect of alpha-1 adrenoceptor antagonists on hypertension: a double-blind, placebo-controlled, dose-response prostatic pressure and blood pressure in the anesthetized dog. multicenter study. J Urol 1995; 154: 110±115. Urology 1994; 44: 52±56. 54 Jardin A et al. Alfuzosin for treatment of benign prostatic hyper- 32 Lefevre-Borg F, Lechaire J, O'Connor S. In vivo uroselectivity of plasia. Lancet 1991; 337: 1457±1461. alfuzosin compared to prazosin and terazosin. Br J Pharmacol 55 Lepor H for the Tamsulosin Investigator Group. Phase III multi- 1992; 106: 84. center placebo-controlled study of tamsulosin in benign prostatic 33 Michel MC et al. Drugs for treatment of benign prostatic hyper- hyperplasia. Urology 1998; 51: 892±900. plasia: af®nity comparison at cloned alpha-1-adrenoceptor sub- 56 Lepor H et al. A randomized, placebo-controlled multicenter types and in human prostate. J Auton Pharmacol 1996; 16: study of the ef®cacy and safety of terazosin in the treatment of 21±28. benign prostatic hyperplasia. J Urol 1992; 148: 1467±1474. Alpha-1-adrenoceptor blockade in BPH F Lowe

57 McKiernan JM, Lowe FC. Side effects of terazosin in the treat- 72 Kirby RS. Doxazosin in benign prostatic hyperplasia: effects on 119 ment of symptomatic benign prostatic hyperplasia. South Med J blood pressure and urinary ¯ow in normotensive and hyperten- 1997; 90: 509±513. sive men. Urology 1995; 46: 182±186. 58 Narayan P, Tewari A, and Members of United States 93-01 Study 73 Kirby R. Terazosin in benign prostatic hyperplasia: effects on Group. A second phase III multicenter placebo controlled study of 2 blood pressure in normotensive and hypertensive men. Br J Urol dosages of modi®ed release tamsulosin in patients with symptoms 1998; 82: 373±379. of benign prostatic hyperplasia. J Urol 1998; 160: 1701±1706. 74 Lowe FC, Olson PJ, Padley RJ. Terazosin treatment of concomi- 59 Roehrborn CG et al. The Hytrin Community Assessment Trial tant symptomatic benign prostatic hyperplasia (BPH) and iso- study: a one-year study of terazosin versus placebo in the lated systolic hypertension (ISH). Br J Urol 1997; 80 (Suppl 2): 206. treatment of men with symptomatic benign prostatic hyperplasia. Abstract 806. Urology 1996; 47: 159±168. 75 Lowe F et al. Blood pressure effects of men with prostatism 60 Roehrborn CG, Siegel R. Safety and ef®cacy of doxazosin in concurrently treated with antihypertensives and terazosin. benign prostatic hyperplasia: a pooled analysis of three double- J Urol 1995; 153: 579A. Abstract 176. blind, placebo-controlled studies. Urology 1996; 48: 406±415. 76 Kaplan SA et al. Doxazosin in physiologically and pharmacolo- 61 Stromberg L. 54-month safety and ef®cacy of terazosin in the gically normotensive men with benign prostatic hyperplasia. treatment of symptomatic BPH. Eur Urol 1998; 33 (Suppl 1): 128. Urology 1995; 46: 512±517. Abstract 510. 77 Sultana SR, Leaker BR, Wyllie MG. A comparison of 62 Schulman CC, Lock TMTW, Buzelin J-M. Tamsulosin: 3-year doxazosin and tamsulosin on mean arterial blood pressure: follow-up of ef®cacy and safety in 516 patients with LUTS attenuation of phenylephrine-induced pressor responses in nor- suggestive of BPO. J Urol 1998; 159 (Suppl): 256. Abstract 983. motensive volunteers. Eur Urol 1998; 33 (Suppl 1): 128. Abstract 63 Lowe FC. Safety assessment of terazosin in the treatment of 512. patients with benign prostatic hyperplasia: a combined analysis. 78 de Mey C, Michel MC, McEwen J, Moreland T. A Urology 1994; 44: 46±51. double-blind comparison of terazosin and tamsulosin on 64 Andersen M et al. Doxazosin gastrointestinal therapeutic system their differential effects on ambulatory blood pressure and (GITS) versus standard doxazosin in patients with symptomatic nocturnal orthostatic stress testing. Eur Urol 1998; 33: benign prostatic hyperplasia (BPH): results of a study in Scandi- 481±488. navia. J Urol 1998; 159 (Suppl): 256. Abstract 981. 79 First DataBank. PriceProbe. software support for drug price 65 MacDiarmid SA et al. A randomized double-blind study assessing analysis. Available at: http:==www.®rstdatabank.com=drug= the optimal dosage of doxazosin in treating patients with benign index.html. Accessed June 30, 1998. prostatic hyperplasia. J Urol 1998; 159 (Suppl): 330. Abstract 1269. 80 Titmarsh S, Monk JP. Terazosin: a review of its pharmaco- 66 Chapple CR et al. Tamsulosin 0.4 mg once daily: tolerability in dynamic and pharmacokinetic properties, and therapeutic older and younger patients with lower urinary tract symptoms ef®cacy in essential hypertension. Drugs 1987; 33: 461± suggestive of benign prostatic obstruction (symptomatic BPH). 477. Eur Urol 1997; 32: 462±470. 81 Chon JK et al. Effect of terazosin on prostate cell proliferation and 67 Jardin A et al. Doxazosin is equally well tolerated by older and apoptosis in patients with benign prostatic hyperplasia (BPH). younger normotensive men. J Urol 1995; 153: 579A. Abstract 179. J Urol 1998; 159 (Suppl): 106. Abstract 406. 68 Kaplan SA, D'Alisera PM. Tolerability of alpha-blockade with 82 Kyprianou N et al. Induction of prostate apoptosis by doxazosin as a therapeutic option for symptomatic benign pro- doxazosin in benign prostatic hyperplasia. J Urol 1998; 159: static hyperplasia in the elderly patient: a pooled analysis of 1810±1815. seven double-blind, placebo-controlled studies. J Gerontol A Biol 83 Neaton JD et al. Treatment of mild hypertension study: ®nal Sci Med Sci 1998; 53: M201±M206. results. JAMA 1993; 270: 713±724. 69 Kaplan SA, Te AE, Ikeguchi E, Santarosa RP. The treatment of 84 Jardin A, Debruyne F. Sexual function in men with BPH treated benign prostatic hyperplasia with alpha-blockers in men over the either with an alpha-adrenergic blocker, alfuzosin, or the 5-alpha age of 80 years. Br J Urol 1997; 80: 875±879. reductase inhibitor, ®nasteride, or the combination: a European 70 Zhang ZJ, Manski RP. Pooled analysis of hypotension-related randomized study in 1051 patients. J Urol 1998; 159 (Suppl): 331. adverse events in six placebo-controlled trials of terazosin. J Urol Abstract 1270. 1998; 159 (Suppl): 331. Abstract 1273. 85 Barbalias GA, Nikiforidis G, Liatsikos E. Alpha-blockers for the 71 Joint National Committee on Prevention, Detection, Evaluation, treatment of chronic prostatitis in combination with antibiotics. and Treatment of High Blood Pressure. The sixth report of the J Urol 1998; 159: 883±887. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI), National Heart, Lung, and Blood Institute: Bethesda, MD, 1997.