Therapeutic Treatment for Benign Prostatic Hyperplasia

Therapeutic Treatment forBenign ProstaticHyperplasia

Therapeutic Treatment forBenign ProstaticHyperplasiaEdited byRoger S Kirby MA MD FRCS (Urol) FEBUVisiting Professor of UrologySt. George’s Hospital, London, UKJohn D McConnell MDProfessor of UrologyUniversity of Texas Southwestern Medical Center, Dallas, Texas, USAJohn M Fitzpatrick MCh FRCSI FC Urol (SA) FRCSGlas FRCSConsultant Urologist and Professor of SurgeryMater Misericordiae Hospital, and University College Dublin, Dublin, IrelandClaus G Roehrborn MDProfessor of UrologyUniversity of Texas Southwestern Medical Center, Dallas, Texas, USAMichael G Wyllie BSc PhDManaging DirectorUrodoc Limited, Herne Bay, UKPeter Boyle PhDDirectorDivision of Epidemiology and Biostatistics, European Institute of Oncology, Milan, ItalyLONDON AND NEW YORK

© 2005 Taylor & Francis, an imprint of the Taylor & Francis GroupFirst published in the United Kingdom in 2005by Taylor & Francis,an imprint of the Taylor & Francis Group,2 Park Square, Milton ParkAbingdon, Oxon OX14 4RN, UKTel.: +44 (0) 20 7017 6000Fax.: +44 (0) 20 7017 6699Website: www.tandf.co.ukAll rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any formor by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of thepublisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of anylicence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P0LP.Although every effort has been made to ensure that all owners of copyright material have been acknowledged in thispublication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention.British Library Cataloguing in Publication DataData available on applicationLibrary of Congress Cataloging-in-Publication DataData available on applicationISBN 1-84184-601-5Distributed in North and South America byTaylor & Francis2000 NW Corporate BlvdBoca Raton, FL 33431, USAWithin Continental USATel.: 800 272 7737; Fax.: 800 374 3401Outside Continental USATel.: 561 994 0555; Fax.: 561 361 6018E-mail: orders@crcpress.comDistributed in the rest of the world byThomson Publishing ServicesCheriton HouseNorth WayAndover, Hampshire SP10 5BE, UKTel.: +44 (0) 1264 332424E-mail: salesorder.tandf@thomsonpublishingservices.co.ukComposition by Parthenon PublishingPrinted and bound by T. G. Hostench S.A., Spain

ContentsList of Contributorsvii1. Medical management – watchful waiting 1P Hegarty, J M Fitzpatrick, R C Bruskewitz2. The placebo effect in the treatment of benign prostatic hyperplasia 11C G Roehrborn3. Dutasteride in the treatment of the BPH patient 41J D McConnell, C G Roehrborn4. Finasteride in the treatment of benign prostatic hyperplasia 53J D McConnell5. Combination therapy in the treatment of BPH 67C G Roehrborn6. The differential effects of adrenoceptor antagonists on prostate tissue growth 83N Kyprianou7. Terazosin in the treatment of obstruction of the lower urinary tract 91M K Brawer, J M Fitzpatrick8. Doxazosin in the treatment of benign prostatic hyperplasia 103R S Kirby9. Alfuzosin 119A Jardin10. Tamsulosin 139C R Chapple11. Phytotherapeutic agents in the treatment of LUTS and BPH 167K Dreikorn, J M Fitzpatrick12. Uroselectivity revisited 185K-E Andersson, M G WyllieIndex 197v

List of ContributorsKarl-Erik AnderssonDepartment of Clinical PharmacologyLund University Hospital221 85 Lund, SwedenKurt DreikornUrology ClinicSt. Jurgen Str.28205 Bremen, GermanyPeter BoyleDirector, Division of Epidemiology andBiostatisticsEuropean Institute of Oncologyvia Ripamonte 43520141 Milan, ItalyMichael K Brawer MDDirector of Northwest Prostate InstituteNorthwest HospitalSeattle, WA 98133, USAJohn M Fitzpatrick MCh FRCSI FC Urol (SA)FRCSGlas FRCSConsultant Urologist and Professor of SurgeryMater Misericordiae Hospital and UniversityCollege Dublin47 Eccles StreetDublin 7, IrelandPaul HegartyUniversity College HospitalGalway, IrelandReginald C Bruskewitz MDProfessor of Surgery, Department of SurgeryDivision of UrologyClinical Science Center600 Highland AvenueMadison, WI 53792, USAChristopher R Chapple MD FRCS(Urol) FEBUConsultant Urological SurgeonDepartment of UrologyRoyal Hallamshire HospitalGlossop RoadSheffield S10 2JF, UKAlain Jardin MDChef du Service D’UrologieUniversité Paris SudCentre Hospitalier de BicêtreSecteur P. Broca78 rue Général Leclerc94275 Le Kremlin-Bicêtre, Cedex, FranceRoger S Kirby MA MD FRCS (Urol) FEBUProfessor of Urology145 Harley StreetLondon W1G 6BJ, UKvii

viiiTHERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIANatasha Kyprianou MD PhDProfessor, Division of UrologyDepartment of SurgeryUniversity of Kentucky Medical Center800 Rose StreetLexington, KY 40536, USAClaus G Roehrborn MDProfessor and Chairman, Department of UrologyThe University of Texas Southwestern MedicalCenter5323 Harry Hines Boulevard, J8.142Dallas, TX 75390-9110, USAJohn D McConnell MDProfessor of Urology, Department of UrologyUniversity of Texas Southwestern Medical Center5323 Harry Hines Boulevard, B11.300Dallas, TX 75390-9131, USAMichael G Wyllie BSc, PhDManaging DirectorUrodoc LimitedHerne Bay, UK

Medical management – watchful waitingP Hegarty J M Fitzpatrick R C Bruskewitz1INTRODUCTIONThe spectrum of treatment options for benignprostatic hyperplasia (BPH) is matched by thespectrum of disease severity. New medicationsand minimally invasive modalities offer a greaterrange of choices to the urologist and the patient.This does not make treatment planning anyeasier. Despite these innovations the naturalhistory of the condition with or withoutintervention is still unclear and can only beinferred from a number of studies. As BPH israrely life-threatening, management is focused onquality of life. Provided it is safe to avoid surgery,watchful waiting (WW) can be offered to patientswho are not bothered much by their symptoms.WW is an active process of patientmonitoring, which allows for change to medicalor surgical intervention as required. The patientmust understand that it is not a passive processand that compliance with follow-upappointments is essential. This chapter describesWW as an active treatment option.The natural history of BPH appears to be oneof waxing and waning. Only through knowingthe natural history of the disease can we ascribenet benefit to any treatment. While the incidenceof symptomatic BPH increases with age, it doesnot follow that the disease is not progressive inany one individual. Cohorts of untreated BPHare useful in describing the heterogeneity of thedisease. As the studies have been carried out asthe classification of the disease has evolved, it isdifficult to compare results. Much of the work todate has compared WW to transurethralresection of the prostate (TURP), however theadvent of novel medical and minimally invasivetherapies has offered a ‘middle ground’, whichmust now be explored. Not only may thesetreatments improve symptoms, but there is alsoevidence that they may retard diseaseprogression. The rate of TURP has droppedsignificantly with the introduction of α-adrenergic antagonists and finasteride. This mayreflect the lack of strong indications for TURP inthe majority of patients, or indeed that theseagents are in some way disease modifying.Although current guidelines recommend WWfor patients with mild symptoms, 1 or patientswith more severe symptoms who are notbothered by them, medical management is alsoreducing the number of patients being assigned toWW, even for mildly symptomatic BPH. 2 Large,randomized, controlled prospective trials usingthe American Urological Association (AUA)symptom score, urinary flow rates, and postvoidresidual are necessary to allow valid comparisonbetween the many treatments, including WW.Based on the available evidence, the indicationsfor and logistics of WW are outlined.BALTIMORE LONGITUDINAL STUDY OFAGINGA large epidemiological study by Arrighi et al.was published in 1991. 3 A cohort of 1371volunteers was followed from 1958 with physical1

2THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAexamination, digital rectal examination (DRE),and a self-administered questionnaire. Thosewith a history of prostate cancer or prostatectomywere excluded, leaving 1057 in the final analysis.The risk of prostatectomy increased with age. Aman aged between 50 and 59 years had a 24%probability of undergoing prostatectomy in thesubsequent 20 years. This risk increased to 39%for men over 60 years. Change in prostate size(determined on DRE) and obstructive symptomsincreased the chance of prostatectomy.The increase in prostatectomy rates with agein this cohort may not reflect progression of thedisease as historical comparison is skewed byprevailing attitudes of practicing urologists.Transrectal ultrasonography would improve thesensitivity of measuring changes in prostate size.PROSPECTIVE STUDY OF PATIENTS WITHVOIDING SYMPTOMSCraigen et al. prospectively followed 251 patientswith lower urinary tract symptoms (LUTS) for4–6 years. 4 Initially 39 patients had prostatecancer, 89 were in acute urinary retention, and123 had prostatism. Of these 123 patients, 6.5%developed urinary retention and 39% requiredprostate surgery. Of the 67 patients who did notrequire surgery, 48% became symptom free.There was no difference in baseline symptoms,general health or age in those who did or did notrequire surgery.This study was limited by its nonspecificurinary symptoms and patient selection.However, it illustrates that of patients who do notrequire surgery, symptoms resolve in 48% ofcases. In a more recent study, of 50 patients withan International Prostate Symptom Score (I-PSS)score of less than 7, 81.2% were clinically stable ata mean follow-up of 17 months. 5NATURAL HISTORY OF UNTREATED‘PROSTATISM’ OVER 5 YEARSBall et al. described the 5-year follow-up of acohort of 107 symptomatic patients for whomsurgery was not indicated. 6 Ten patients requiredsurgery in the interim, two for acute retentionand eight for worsening symptoms. Of the 97untreated, 31 were subjectively improved, 50unchanged, and 16 felt worse. This studyincluded detailed urodynamic testing. Theannual decrease in maximal flow rates of 1.2 ml/swas the same as that due to aging in the generalpopulation. Voiding pressure could safely remainabove 70 cmH 2O, though it tended to fall over the5-year period. On average, the ten patients whorequired surgery had lower initial flow rates andincreased prostatic length of profilometry. All tenwere classified as obstructed on pressure–flowstudies. On review of the initial assessmentparameters, it was not possible to predict thosewho would subsequently require surgery. Thesimplest and least invasive test, the urinary flowrate, was as good a screening parameter as anyother. This study demonstrated the safety of WWover a 5-year period.In an examination of the urodynamics ofpatients with bladder outlet obstruction (BOO)who underwent WW, it was possible to predictfailure rate on the basis of obstruction grade,however. 7 Treatment failure was defined aspatients who did not wish to continue WW.Pressure–flow studies were conducted at baselineand again after 1 and 4 years. After 1 year, I-PSShad fallen at unchanged Q maxand postvoidresidual (PVR), and this did not change at 4 years.LUTS severity and failure rate increased overtime in patients with severe BOO. The resultsindicate that prediction of failure is possible,which may allow a more precise prognosis for

MEDICAL MANAGEMENT – WATCHFUL WAITING 3individual patients who prefer WW. Theselection of patients for TURP, minimallyinvasive therapy, or WW on the basis ofpressure–flow studies has also been shown toyield good symptomatic effects in terms of Q max,PVR, and I-PSS with less risk of complications. 8TURP WAITING LISTBarham et al. reported in 1993 a study evaluating118 patients on a waiting list for TURP. 9 Surgerywas indicated for symptoms of BPH incombination with an enlarged prostate on DRE.Patient mean age was 70 years (55–89 years), witha mean time on the waiting list of 3 years. Elevenof the original 118 patients were excluded becausethey had died, refused surgery, or had theprocedure elsewhere, 107 patients wereevaluated. Of these, 65% said symptoms wereunchanged, 12% improved, and 22%deteriorated. Twenty-nine patients (27%) werekept on the waiting list for severe symptoms anda peak flow rate of less than 6 ml/s. Theremaining 78 were re-evaluated. Of these, 51(65%) were discharged from the waiting list dueto mild symptoms, nine patients (12%) were keptunder review for mild symptoms with objectiveevidence of severe obstruction (flow rate between6 and 15 ml/s and residual volumes greater than150 ml) and 18 (23%) stayed on the waiting listdue to bothersome symptoms.In summary, of the original 107 patientsevaluated, 47 (44%) were kept on the waiting list,nine (8%) remained under review, and 51 (48%)were discharged. This study demonstrated thefluctuations in BPH symptoms. The authorsconcluded that patients will opt to avoid surgeryif reassured of the natural history of BPH. Likeother studies, this study is limited by its definitionof symptoms and indications for surgery.PROSPECTIVE TRIAL OF TURP VERSUSCONSERVATIVE MANAGEMENTKadow et al reported a randomized prospectivetrial of 38 patients with LUTS in 1988. 10 Twentyonepatients were randomized to undergo TURP,and 17 WW. Patients were assessed byurodynamics and symptoms at baseline and 6months after treatment.Of the WW group, 56% of patients wereeither symptom free or improved, compared to71% following TURP. Irritative symptomsdecreased in both groups, with 79% of the TURPgroup and 50% of the WW group demonstratingimprovement in detrusor instability onurodynamics. Peak flow increased from 8.5 to19.0 ml/s in the TURP group, with little changein the WW group (9.8–11.2 ml/s). Thisdemonstrates that, in a nonstratified group ofpatients, TURP is superior to WW in itsurodynamic outcome and that with conservativemanagement about half the patients improveover 6 months.DEPARTMENT OF VETERANS’ AFFAIRSCOOPERATIVE STUDYThe Department of Veterans’ Affairs (DVA)Cooperative Study compared TURP with WWin 556 men with moderate symptoms of BPH. 11Symptoms were assessed using the Madsensymptom score and bother to patients wasmeasured by a qualify of life score. Exclusioncriteria were age less than 55, previous prostatesurgery, bladder or prostate cancer, residualvolume greater than 350 ml, or evidence of aneurogenic bladder; 280 patients wererandomized to TURP and 276 to WW. Medianage was 65, and there was no difference in thegroups in their findings on examination, peak

4THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAflow, residual volume, serum creatinine, orurinalysis at baseline. The follow-up period was 3years. Flow rates and residual volumes weremeasured every 6 months, whereas symptomscores and quality of life scores were repeatedannually. All patients were advised aboutaggravating factors such as medication, coffee,and alcohol. Treatment failure was defined as anyof the following: death, urinary retention,residual urine more than 350 ml, development ofa bladder calculus, new-onset persistentincontinence, or a Madsen symptom score ofmore than 24, or more than 21 on two consecutivevisits.The values at baseline and after 3 years’follow-up are listed in Table 1.1. The objectivemeasurement of flow rate improved with TURPand was unchanged in the WW group. Postvoidresidual volumes decreased to a greater extent inthe TURP group over the WW cohort. Botherwas ameliorated in both arms, however to agreater degree following TURP. General healthand sexual performance remained stable in bothgroups. The treatment failures were greater inthe WW group (17%) than in the TURP group(8%). Successful outcome with WW was morelikely in those with high urinary flow rate, a lowpostvoid residual volume, and low bother score,whereas the only identifiable predictor of successin the TURP group was a high baseline botherscore.This study demonstrates that TURP achievesbetter objective and subjective outcomes thanWW in patients with moderate symptoms ofBPH. However, patients with minimal bothercan be managed safely by WW, as 82% do notexperience treatment failure.WATCHFUL WAITING VERSUS MEDICALTHERAPYThe studies discussed so far have comparedTURP to WW. A clinically more relevantquestion is the difference between medicalmanagement and WW. Direct comparison ofoutcomes of α-adrenergic blockade, finasteride,or WW showed improvement in symptoms andpeak flow rates for all three approaches. 12However the actual degree of symptomTABLE 1.1 Baseline and 3-year follow-up values for patients in the DVA Cooperative Study.WWTURPParameter Baseline 3-year follow-up Baseline 3-year follow-upPeak urinary flow rate (ml/s)* 12.3 12.7 11.6 17.8Residual urine volume (ml)* 113 72 110 51Symptom score (points)* 14.6 9.1 14.5 4.9Bother from urinary difficulties (points † )* 48.0 57.6 46.4 75.7Sexual performance (points † ) 38.6 35.6 40.0 36.0General well-being (points † ) 71.3 71.4 73.2 76.2*Changes on transurethral resection of the prostate (TURP) significantly different (p

MEDICAL MANAGEMENT – WATCHFUL WAITING 5improvement was greatest for the α-blockadegroup. In the Veterans’ Affairs CooperativeStudies published by Lepor et al. in 1996, thedegree of improvement in AUA symptom scoreand peak flow rates was greatest among those onan α-adrenergic antagonist. 13In an examination of the effect of a variety ofBPH treatments on sexual function, finasteride,α-blockers, and TURP were associated withlevels of improvement and deterioration in sexualfunction similar to WW. 14 Although surgicalintervention has been more closely associatedwith negative sexual effects in the past, thesefindings suggest that other factors, such as age,may be more influential. 14,15CURRENT TREATMENT PATTERNS GLOBALLYThe variation between countries on patterns oftreatment was the subject of six articles in aEuropean Urology supplement in 1999. 1,16–20 Thedifferent approaches to treating patients are quitestriking. In particular, phytotherapeuticscommand 40% of the market share in France andGermany. 17,18 This is despite the lack of evidenceof their efficacy over placebo. 21 These papers alsodescribe the widening range of physicians caringfor men with BPH. This has occurred with theadvent of medical management and the fall-off inthe TURP rate occurring in most countries(except the UK). 20 The prescribing of α-adrenergic antagonists in combination withfinasteride is still prevalent, and may increasefollowing recent positive findings regarding thecombination of doxazosin and finasteride; 22however, there is also evidence showing nobenefit over α-adrenergic antagonist alone. 13 In atelephone survey of 502 American urologists, 20%said they favored medical management over WWin patients with only mild LUTS. 23 Thus it isevident that in recent years medical managementhas reduced both the TURP and WW rates.TREATMENT PREFERENCESThe influence of urologist preference is welldescribed in a paper published in 1999 byStoevelaar et al. 24 The preferences of 39 urologistswere evaluated in treating 670 consecutivepatients, in 13 Dutch hospitals. The majority ofpatients (67.8%) belonged to the gray area forwhich, according to the study guidelines,management should be based on patient choiceand urologist preference. Patients with highurinary flow rate, low residual volume, or mildirritative symptoms were more likely to undergoWW. Controling for patient characteristics, theurologist’s preference could more than double thelikelihood of surgery. The number of years’experience also influenced treatment choice, inthat younger urologists were less likely torecommend WW.Patient preference should predominate indeciding treatment. 25,26 However, 27,28 since theadvent of medical and minimally invasivetherapies, this decision has become more difficult.When patients were shown an educational videoprogram, those who had previously chosen aninvasive therapy changed to a less invasiveoption. 29 Based on AUA symptom scores, 35% ofpatients with severe symptoms preferred WW tomedical or surgical intervention. 12 This indicatesthat factors other than disease severity areimportant in the decision-making process.INDICATIONSWhen TURP was introduced over 70 years ago,the mortality and morbidity were high. 30 The

6THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAprocedure was reserved for life-threateningconditions such as hemorrhage, uremia andsepsis. With the gradual reduction in mortality,the indications for TURP have greatlyexpanded. 31 The availability of medical andminimally invasive therapies has also alteredindications for treatment. 32–36STRONG INDICATIONS FOR TREATMENTOR WATCHFUL WAITINGThe absolute indications for intervention are easyto define. Surgery is recommended for (1)refractory urinary retention, patients who have atleast one trial without catheter with or without α-adrenergic blockade, (2) recurrent urinary tractinfection caused by bacterial prostatitis, refractoryto medical treatment, (3) bladder calculi, (4) renalinsufficiency due to BOO, (5) severe hematuriafrom BPH. Other indications for TURP arerelative. There is no strong indication for WW,however a strategy of WW is recommended forpatients with mild symptoms of BPH. 1BotherTwo patients with the same AUA symptom scoremight be bothered by their symptoms to differentdegrees. Bother is ameliorated to a greater extentby TURP than by WW. 11 The interference by thedisease in the day-to-day activities of patients canbe measured using the BPH impact index. 37Postvoid residualPatients with higher residual volumes fare lesswell with a WW strategy than with TURP. 10There is no strict cut-off volume at whichintervention is recommended.UroflowmetryObjective evidence of obstruction is gained withuroflowmetry, with the maximal flow rate beingthe best predictor of surgical outcome. 38–40Patients with a flow rate greater than 15 ml/sdemonstrate poorer outcomes following TURPthan those with maximal flow rates less than15 ml/s. 40,41ConclusionsMODERATE INDICATIONS FOR TREATMENTOR WATCHFUL WAITINGManagement of patients with moderatesymptoms of BPH is controversial. Such patientsneed to be informed of the current evidenceregarding the available treatments, so thatpotential side-effects can be weighed against thenatural history of the disease. Many patients,however, seek the opinion of a specialist, in whichcase it is appropriate to select the optimaltreatment. This is based on clinical findings and anumber of tests. For WW these include (1) thepatient’s bother from urinary symptoms, (2)postvoid residual volume, and (3) uroflowmetry.Low bother score, high urinary flow rates, andlow postvoid residual volumes favormanagement by WW, but the decision should notbe based on these factors alone. The indicationsfor WW versus other intervention are listed inTable 1.2. 5STRATEGYPatients being followed in a strategy of WW mustunderstand that this is an active program. Thepatient’s symptoms and clinical course aremonitored, usually on an annual basis. More (orless) frequent review periods have yet to be

MEDICAL MANAGEMENT – WATCHFUL WAITING 7TABLE 1.2 Indications for therapeutic intervention vs watchful waiting in BPH.Strength ofStrategyindication Watchful waiting Therapeutic interventionStrong Mild symptoms (AUA score ≤ 7) Recurrent urinary retention (more than a single episode)Recurrent urinary tract infectionsRecurrent gross hematuriaBladder stonesRenal insufficiency due to BPHModerate Moderate symptoms (AUA score ≥8 Moderate to severe symptoms (AUA score ≥8) andand ≤ 19) but not bothersomebothersome (high BPH Impact Score)(low BPH Impact Score)Higher peak urinary flow rateHigh post-voiding residual and low peak urinary flow rate(rate not specified)(volume and rate not specified)Low post-void urinary residual(volume not specified)defined by research. Patients should receiveadvice with regard to aggravating factors such asdiuretic dose scheduling and coffee and alcoholconsumption. On review, the patient should beasked about his satisfaction with this approach.Symptoms should be reassessed, along withphysical examination and routine laboratorytesting (serum creatinine, urinalysis). Repeat ofuroflowmetry and residual urine measurementshould be considered. Medical or surgicaltreatment can be offered to those who deteriorateor those substantially bothered by a lack ofimprovement. The WW program can bedelivered in a shared care setting, provided thesystem is based on good information and mutualconfidence. 42CONCLUSIONSUrologists tend to measure outcome by means ofsymptom score and urinary flow rates. This isbalanced against the side-effect profile of anytreatment. A minor risk of even a serious sideeffectsuch as incontinence is consideredacceptable if the chance of success (as measuredby symptom score or urinary flow) is high. Fromthe patient’s aspect, the prime factor is whetherthe degree of bother is worth risking themorbidity of undergoing treatment. The risk ofharm may outweigh the anticipatedimprovement.Guidelines recently issued by the AUArecommend that patients with mild symptoms(AUA score ≤ 7), or moderate to severe symptomswho are not significantly bothered by them, be‘treated’ with WW.From the evidence in this chapter, it isappropriate to recommend WW for patients withmild symptoms. Patients with moderate or severesymptoms can be considered for WW, if theirsymptoms do not interfere with their activities ofdaily living. Large, prospective, randomizedcontrolled studies of WW versus medical andsurgical treatments are necessary to developclearer indications for each modality. Furtherresearch is necessary to outline precise follow-upschedules, the need for repeated renal functiontests, and how much postvoid residual isexcessive. Allowing patients with BPH to

8THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAparticipate in the decision process makes forbetter compliance and optimal care.REFERENCES1. de la Rosette J J, Alivizatos G, Madersbacher S etal. European Association of Urology. EAUGuidelines on benign prostatic hyperplasia (BPH).Eur Urol 2001; 40: 256–263; discussion 2642. Bruskewitz R C. Management of symptomaticBPH in the US: who is treated and how? Eur Urol1999; 36 (Suppl 3): 7–133. Arrighi H M, Metler E J, Guess H A et al. Naturalhistory of benign prostatic hyperplasia and risk ofprostatectomy. Urology 1991; 38: 4–84. Craigen A A, Hickling J B, Saunders C R et al.Natural history of prostatic obstruction. J R CollGen Pract 1969; 18: 226–2325. Netto N R Jr, Lima M L, Netto M R, D’Ancona CA L. Evaluation of patients with bladder outletobstruction and mild international prostatesymptom score followed up by watchful waiting.Urology 1999; 53: 314–3166. Ball A J, Feneley R C L, Abrahams P H. Thenatural history of untreated ‘prostatism’. Br J Urol1981; 53: 613–6167. Knutson T, Schafer W, Fall M et al. Canurodynamic assessment of outflow obstructionpredict outcome from watchful waiting?—a fouryearfollow-up study. Scand J Urol Nephrol 2001;35: 463–4698. Knutson T, Pettersson S, Dahlstrand C.Pressure–flow studies for patient selection in thetreatment of symptomatic BPH—a one-yearfollow-up study. Scand J Urol Nephrol 2001; 35:470–4759. Barham C P, Pocock R D, Jamed E D. Who needsa prostatectomy? Review of a waiting list. Br J Urol1993; 72: 314–31710. Kadow C, Feneley R C L, Abrahms P H.Prostatectomy or conservative management in thetreatment of benign prostatic hypertrophy? Br JUrol 1988; 61: 432–43411. Wasson J H, Reda D J, Bruskewitz R C et al.Comparison of transurethral surgery withwatchful waiting for moderate symptoms of benignprostatic hyperplasia. N Engl J Med 1995; 332:75–7912. McConnell J D, Barry M J, Bruskewitz R C et al.Benign prostatic hyperplasia diagnosis andtreatment. Clinical practice guideline No 8AHCPR publication No 94-0582. Rockville:Agency for Health Care Policy and Research,Public Health Service, US Department of Healthand Human Services, 199413. Lepor H, Williford W O, Barry M L et al. Theimpact of medical therapy on bother due tosymptoms, quality of life and global outcome, andfactors predicting response. Veterans AffairsCooperative Studies Benign Prostatic HyperplasiaStudy Group. J Urol 1998; 160: 1358–136714. Leliefeld H H, Stoevelaar H J, McDonnell J.Sexual function before and after various treatmentsfor symptomatic benign prostatic hyperplasia. BJUInt 2002; 89: 208–21315. Kassabian V S. Sexual function in patients treatedfor benign prostatic hyperplasia. Lancet 2003; 361:60–6216. Speakman M J. Who should be treated and how?Evidence based medicine in symptomatic BPH.Eur Urol 1999; 36 (Suppl 3): 40–5117. Lukacs B. Management of symptomatic BPH inFrance: who is treated and how? Eur Urol 1999; 36(Suppl 3): 14–2018. Berges R R, Pientka L. Management ofsymptomatic BPH in Germany: who is treated andhow? Eur Urol 1999; 36 (Suppl 3): 21–2719. Tubaro A, Montanari E. Management ofsymptomatic BPH in Italy: who is treated andhow? Eur Urol 1999; 36 (Suppl 3): 28–3220. McNicholas T. Management of symptomatic BPHin the UK: who is treated and how? Eur Urol 1999;36 (Suppl 3): 33–3921. Fitzpatrick J M, Lynch T H. Phytotherapeuticagents in the management of symptomatic benignprostatic hyperplasia. Urol Clin North Am 1996;22: 407–412

MEDICAL MANAGEMENT – WATCHFUL WAITING 922. McConnell J D and the MTOPS SteeringCommittee. The impact of medical therapy on theclinical progression of BPH: results of the MTOPStrial. J Urol 2002; 167 (Suppl 4): abstract 1042(updated)23. Gee W F, Holgrewe H L, Albertsen P C et al. 1997American Urological Association Gallup Survey:changes in diagnosis and management of prostatecancer and benign prostatic hyperplasia, and otherpractice trends from 1994–1997. J Urol 1998; 160:1804–180724. Stoevelaar H J, Van De Beek C, Casparie A F et al.Treatment choice for benign prostatic hyperplasia:a matter of urologist preference? J Urol 1999; 161:133–13825. Barry M J, Mulley A G Jr, Fowler F J et al.Watchful waiting vs immediate transurethralresection for symptomatic prostatism: theimportance of patient preferences. J Am Med Assoc1988; 259: 3010–301726. Kaplan S A, Golubluff E T, Olsson C A et al. Effectof demographic factors, urinary peak flow rates,and Boyarsky symptom scores on patient treatmentchoice in benign prostatic hyperplasia. Urology1995; 45: 398–40527. Speakman M J. Initial choices and final outcomesin lower urinary tract symptoms. Eur Urol 2001; 40(Suppl 4): 21–3028. Teillac P. Benign prostatic hyperplasia: patients’perception of medical treatment and theirexpectations. Results of a French survey involvingpatients treated with finasteride [in French].Therapie 2002; 57: 473–48329. Kasper J F, Mulley A G Jr, Wennberg J E.Developing shared decision-making programs toimprove the quality of health care. Qual Rev Bull1992; 18: 183–19030. Perrin P, Barnes R, Hedley H et al. Forty years oftransurethral resections. J Urol 1976; 16: 757–75831. Mebust W K, Holtgrewe H L, Cockett A T K et al.Immediate and postoperative complications. Acooperative study of 13 participating institutionsevaluating 3,885 patients. J Urol 1989; 141: 243–24732. Fitzpatrick J M. Current management and futuretrends in benign prostatic hyperplasia (BPH). IrMed J 1997; 90: 256–25833. Debruyne F M, Witjes W P, Fitzpatrick J M et al.The international terazosin trial: a multicentrestudy of the long-term efficacy and safety ofterazosin in the treatment of benign prostatichyperplasia. The ITT group. Eur Urol 1996; 30:369–37634. Fitzpatrick J M. Alternative instrumentaltreatments in BPH. Introduction. Eur Urol 1999;35: 117–11835. Hegarty N J, Fitzpatrick J M. High intensityfocused ultrasound in benign prostatic hyperplasia.Eur J Ultrasound 1999; 9: 55–6036. Ramon J, Lynch T H, Eardley I et al. Transurethralablation of the prostate for the treatment of benignprostatic hyperplasia: a collaborative multicentrestudy. Br J Urol 1997; 80: 128–13437. Barry M J, Fowler F J, O’Leary M P et al.Measuring disease-specific health status in menwith benign prostatic hyperplasia. Med Care 1995;33: AS145–AS15538. Jensen K M E, Bruskewitz R C, Iversen P et al.Spontaneous uroflowmetry in prostatism. Urology1984; 24: 403–40939. Jensen K M E, Jorgensen J B, Morgensen P.Urodynamics in prostatism I. Prognostic value ofuroflowmetry. Scand J Urol Nephrol 1988; 22:109–11740. Abrahms P H. Prostatism and prostatectomy: thevalue of urine flow rate measurement in thepreoperative assessment for operation. J Urol 1977;117: 70–71

The placebo effect in the treatment ofbenign prostatic hyperplasiaC G Roehrborn2‘The principal quality of a physician, as wellas of a poet (for Apollo is the God of physicsand poetry), is that of fine lying, or flatteringthe patient ... And it is doubtless as well forthe patient to be cured by the working of hisimagination, or a reliance upon the promiseof his doctor, as by repeated doses of physics.’ 1‘Is it ethical to use a placebo? The answer tothis question will depend, I suggest, uponwhether there is already available an orthodoxtreatment of proven or accepted value. Ifthere is such an orthodox treatment the questionwill hardly arise, for the doctor will wishto know whether a new treatment is more, orless, effective than the old, not that it is moreeffective than nothing.’ 2PLACEBO AND PLACEBO EFFECT:DEFINITIONS AND THEORETICALCONSIDERATIONSIt has long been recognized by practicing physiciansthat procedures that offer patients reassuranceor the expectation of help may lead tomarked improvement in their clinical status, 3 andmany doctors believe that placebo interventionhas an ethically acceptable place in clinical practice.4 The Latin-derived term ‘placebo’ originallyappears in the Bible (placebo domino in regionevivorum, Psalm 116, Verse 9), where it may be literallytranslated as ‘I shall please’. This originalmeaning of please is still found in the first medicaldefinition of the term in Hooper’s medicaldictionary in the early nineteenth century: ‘qualityascribed to any drug prescribed to please thepatient rather than being useful’. The first articlededicated to the placebo effect did not appearuntil 1945: ‘A note on placebo’ by Pepper. 5 Thepotency of belief and expectation in affectinghealth is also underscored by such dramaticharmful effects as voodoo death, which in contrastcan be referred to as a ‘nocebo’ (‘I shallharm’) effect. 6In clinical context, placebo has come to denotea deceptive practice, a view that originates fromthe practice of singing vespers for pay. This negativeconnotation of placebo has come to dominatecontemporary thinking due to the emergence ofdouble-blind, placebo-controlled drug studies, inwhich the differentiation of effects due to thepharmacologic action of a compound from otherunspecified effects is a primary consideration.Placebo effects are so omnipresent that if they arenot controlled for in therapeutic studies, the findingsare considered unreliable. Conditions inwhich placebo effects have been described includecough, mood changes, angina pectoris, headache,anxiety, hypertension, asthma, depression,lymphosarcoma, gastric motility, dermatitis, andpain from a variety of sources. 7A prevalent view of placebo is that its use ismandatory in clinical trials, but unethical in clinicalpractice, a view that may be challenged onboth accounts. 7One of the most influential writers in the fieldof placebo research is Arthur K. Shapiro whooffers the following definition:11

12THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA‘A placebo is defined as any therapy or componentof therapy that is deliberately used forits nonspecific, psychological, or psychophysiologicaleffect, or that is used for its presumedspecific effect, but is without specificactivity for the conditions being treated. Aplacebo effect is defined as the psychologicalor psychophysiological effect produced byplacebos.’ 8Others have suggested definitions differentfrom the one quoted above, 9 or further deliberatedon Shapiro’s theory. Grünbaum developed adiagram to illustrate his definition of placebo(Figure 2.1). 10 If a therapeutic theory recommendsa therapy ‘t’ for a condition, this treatmentusually consists of a spectrum of factors, namelycharacteristic factors ‘F’ and incidental treatmentfactors ‘C’. These incidental treatment factorsmay be known or unknown. The patient’s lifeactivities and functions are subdivided into twoparts: the target disorder ‘D’, e.g. BPH, and otheraspects of the patient’s life functions or health.The arrows in Figure 2.1 illustrate the possiblecausations (effects). The characteristic factors ‘F’may have a positive or a negative effect on thetarget disorder (or it may have no effect whatsoever).Similarly, the factors ‘F’ may have similarinfluences, good or bad, on other aspects of thepatient’s life, which are known as side-effects.The incidental treatment factors ‘C’ may haveside-effects, but they may also affect the targetdisorder, in which case it is referred to as a placeboeffect.For example, let the target disorder be BPHand the therapeutic theory the administration ofα-blocking drugs by a physician who evaluatesthe patient at regular intervals. The relaxation ofthe smooth muscle in the bladder neck andprostate positively affects the symptoms of BPH(nonplacebo effect), but it also causes side-effects,namely a lowering of the blood pressure (positive)and asthenia (negative). An incidental treatmentfactor is the dispensation of the drug by the physician.If he expresses his confidence in the medicationit may result in a positive placebo effect, if heis neutral or makes a comment like: ‘We mighttry this for a while before we have to do somethingmore serious’, it may result in a negativeplacebo effect. Obviously, the frequent visits tothe physician’s office have an impact on thepatient’s life functions as well by forcing him tomake time for the visits, etc. (negative side-effectof incidental treatment factors).Recent research has suggested that thedopaminergic reward mechanisms of the brainTherapy tPatient's life processesSpectrumof factorsCharacteristic factorsFnonplacebo effectside-effectsTarget disorderDIncidental treatmentfactorsCplacebo effectside-effectsOther aspects of patient'slife functions orhealthFIGURE 2.1 Illustration of a therapeutic theory used to clarify the definition of ‘placebo’. For further explanation seetext. (Adapted from reference 10.)

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 13are responsible for mediating the placebo effect. 11Brody listed three possibilities to explain why apatient improves after a certain therapy is instituted:12• The patient got better due to the natural historyof the condition in an organism withintact healing and recuperative powers.• The patient got better due to the symboliceffect of the treatment, that is its impact on hisor her imagination, beliefs, and/or emotions.• The patient got better due to some specific orcharacteristic feature of the treatment that canbe studied, isolated, and predicted within thecontext of contemporary medical theory.A positive placebo effect (the second of the abovelist) is most likely to occur when three factors arepresent: 12• The meaning of the illness experience for thepatient is altered in a positive manner, giventhe patient’s belief system and world view.• The patient is supported by a caring group.• The patient’s sense of mastery or control overthe illness is restored or enhanced.This theory, emphasizing the importance of thepatient’s belief system and his or her expectations,highlights the cultural dimension of the placebophenomenon and the importance of cross-culturalstudies in placebo research.White et al. 7 pointed out that there is no singleplacebo effect with a single mechanism and efficacy,but rather a multiplicity of effects with differentialefficacy and mechanisms, and they providea list of placebogenic variables or determinantsof a placebo response (Table 2.1). Turner etal., 13 in a review of the importance of the placeboeffect in pain treatment and research, listed similarfactors influencing the placebo response.Among the patients’ factors contributing to aTABLE 2.1 Biopsychosocial determinants of placeboresponse. (Reproduced with permission from White etal. 7 )Cultural contextBelief systemFaithEnvironmental milieuInstructionSuggestionPreparation characteristicsDoctor–patient relationshipPatient’s expectations and beliefsPatient’s personalityPsychological stateSymptom severityDiscomfort severityAnxiety and stressCentral evaluative processesCognitive processesCognitive schemaSelf-schemaSelf-controlExpectancyOutcome expectancyEfficacy expectationsOperant behaviorSymbolic processesImaginationCovert rehearsalEmotionsCentral nervous system influences upon physiologyImmune systemStress mechanismEndogenous opiatesClassical conditioningSpontaneous remissions

14THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAhigh placebo response rate were anticipation andexpectations, a positive attitude toward providerand treatment, anxiousness and compliance withthe prescribed treatment. As an example for thelatter, a randomized trial to evaluate the efficacyof a lipid-lowering drug in the therapy of coronaryheart disease may be mentioned. Patients inthe placebo arm were stratified by whether theytook more or less than 80% of the placebotablets. 14 Even after controling for 40 known orsuspected risk factors, the noncompliers had a57% higher 5-year mortality rate than the compliantpatients. Either the placebo lowered mortality,or patients’ compliance related to other characteristicsassociated with mortality, which wasnot assessed in this study. Among the providers’factors they listed warmth, friendliness, interest,sympathy, empathy, prestige, and, again, a positiveattitude towards the patient and the treatment.These considerations all address the issue of a‘placebo treatment’ and the ‘placebo effect’ in theusually understood sense of a medical treatmentwith a drug. Placebo effects, however, are equallyimportant to consider when the treatment consistsof a procedure or surgical therapy. Instead ofusing an inactive preparation, a procedure or surgeryis performed which is similar in all respectsto the active procedure or surgery, but different inthat the key aspect of the procedure, which isbelieved to convey the main therapeutic benefit, isomitted. Such procedures are referred to as ‘shamtreatment’ and the incidental causes or effects as‘sham effects’. Throughout this chapter, the term‘placebo/sham’ will be used to indicate the pertinenceof the observation to both medical (drug)treatments and procedural (surgical) interventions.RATIONALE FOR PLACEBO/SHAMCONTROLLED TRIALSThe value of controlled clinical trials in the determinationof the safety and effectiveness of a newintervention is largely undisputed. The US Foodand Drug Administration (FDA) recognizes fourtypes of comparative trials:• No treatment, which involves a comparison ofthe results in comparable concurrent groupsof treated and untreated patients. This type ofcontrol is utilized when objective measurementsof effectiveness are available and placeboeffect or spontaneous improvement of thecondition is negligible.• Placebo control, which involves a comparisonof the results of a particular therapy with aninactive preparation or a sham procedure.• Active treatment control, which involves acomparison of the results from the new interventionwith those from a treatment known tobe effective.• Historical control, which involves comparisonof the results from a new intervention withprior experience obtained in a comparablegroup of patients receiving no therapy or aknown effective regimen.The caveat listed in the first paragraph is of greatrelevance in BPH treatment trials. While betterobjective outcome measures are being developedand utilized, there is certainly a placebo effect andthe natural history of the disease is such thatspontaneous remissions are quite common. Thus,in clinical BPH research the only alternatives areplacebo/sham-controlled trials, or active treatment-controlledtrials. Active control trials mightsubstitute for placebo-controlled trials (1) whenthere is reasonable certainty that a new treatmentwill be more effective than other agents known to

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 15be effective; (2) when the effectiveness of the newtreatment is self-evident; or (3) where the natureof the therapy or procedure is such that it is notpossible to blind the patients or the observers. 15While the first two arguments rarely are true inBPH treatment trials, the third argumentdemands a closer look. Experience has shownthat it is feasible to blind both patients andobservers responsible for outcome assessmentregarding the randomization in a trial comparingballoon dilatation of the prostate with a shamprocedure (cystoscopy). 16 As will be discussedbelow, blinding is also possible in treatment trialsusing microwave-induced heat and other minimallyinvasive treatments. Whether or not trueblinding could be achieved in a trial comparingtransurethral resection of the prostate (TURP)with a sham procedure is more questionablebecause of the need for catheterization, the bleeding,and the irrigation necessary following theTURP. Despite the absence of any such trial,TURP is currently considered the gold standardof BPH treatments, and, in fact, it serves occasionallyas an active-treatment control for otherinvasive treatment modalities.Despite the general acceptance ofplacebo/sham controls in medical research, 17 othershave warned against the ‘continuing unethicaluse of placebo controls’, 18 stating that in manycases the use of placebo control groups is in directviolation of the Declaration of Helsinki. TheDeclaration states that:‘The benefits, risks, burdens and effectivenessof a new method should be tested against those ofthe best current prophylactic, diagnostic, andtherapeutic methods. This does not exclude theuse of placebo, or no treatment, in studies whereno proven prophylactic, diagnostic or therapeuticmethod exists.’ 19Thus, Rothman and Michels argue that theuse of a placebo is unethical whenever there is aproven therapy available according to theDeclaration of Helsinki. 18 The two ethical counterarguments which can be made are the notionthat withholding of active treatment may not leadto any harm on the part of the patient dependingon the underlying condition, and second, thatpatients in fact give their informed consent, afterbeing fully informed, to participate in a placebo/shamcontrolled trial.In the field of clinical BPH research, theAmerican Urological Association (AUA), the USFDA, and the World Health Organization(WHO) advocate rather strictly the use of placebocontrols.The AUA BPH Clinical Trials Subcommitteeis currently preparing a blueprint for the designand reporting of clinical trials in BPH. It is notedthat BPH is a disease characterized by a somewhatunpredictable natural history. A significantminority of patients experience stabilization ofsymptoms or actual improvement. Moreover,improvements in symptoms and uroflow are seenin patients treated with placebo. This makes arandomized, placebo- (or sham-) controlleddesign mandatory. New surgical technologiesshould be compared to standard surgical treatments,such as TURP or transurethral incision ofprostate (TUIP), utilizing a randomized design.For BPH medical therapies and minimally invasivetechnologies, efficacy relative to placebo orsham must be established (J. D. McConnell, personalcommunication). The document furthermorestipulates that patients have to be blindedtowards the assigned treatment, and that preferentiallythe treating physician should also beblinded (double-blind).The FDA circulated a draft guidance for theclinical investigation of hyperthermia devices

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 17for one of four consultations: a positive consultationwith therapy (thiamine hydrochloride 3 mgtablets) or without treatment, or a negative consultationwith or without treatment. 23 In a positiveconsultation the patient was given a firmdiagnosis and told that he would be better in afew days. If no treatment was given, he was toldhe needed none. If treatment was given, he wastold that the treatment would make him betterwith certainty. In a negative consultation the doctorstated that he could not be sure about thediagnosis, and that therefore no treatment wasgiven (no treatment group), or that a treatmentwould be tried without assuring that it wouldhelp (treatment group). During the follow-upvisit, 64% of patients in the positive consultationgroup got better versus 39% in the negative consultationgroup (p = 0.001). However, there wasno significant difference between the treated(53%) and the not treated (50%) patients (p =0.5).In this example the physician-related placeboeffect was clearly stronger than the effect conveyedby the medication given.The largest body of literature regardingplacebo effects exists in the area of pain treatment.Turner et al. 13 identified over 150 articlesdescribing placebo effects in pain treatment andresearch. They found that placebo response ratesvary greatly. Frequently they were found to behigher than the widely accepted one-third placeboresponse rate based on the classic article byBeecher. 24 Placebos have time–effect curves, andpeak, cumulative, and carry-over effects similarto those of active medications. A certain placeboresponderpersonality could not be identified, andthe role of anxiety, expectations, and learningwere emphasized. The authors concluded thatplacebo effects plus natural history and regressionto the mean 25 may result in high rates of goodoutcomes in pain treatment, which may be misattributedto specific treatment effects. The importantrole of the physician as administrator of thetreatment for pain, be it active or placebo, wasemphasized by Gracely et al. 26 Dental patientswere told that they would receive either a placebo,a narcotic analgesic, or a narcotic antagonist,and that this treatment might increase, decrease,or have no effect on their pain. The physiciansadministering the drugs knew, however, that onegroup of patients would receive either placebo orthe narcotic antagonist but not the narcotic analgesic(group A), while another group wouldreceive any one of the three agents (group B).Thus, the two groups of placebo-treated patientsin groups A and B did only differ in the clinician’sknowledge of the range of possible double-blindtreatments, including the knowledge thatpatients in the group A had no chance of receivingactive pain medication. Nonetheless, theplacebo-treated patients in group B had significantlyless pain than those in group A. Thisexperiment shows clearly that analgesia does notonly depend on the action of the administeredtreatment, but also on the expectations of thepatient and, most surprisingly, on those of thephysician, who may influence the patient’sresponsiveness by a subtle behavioral change.This phenomenon of expectation and anticipationof analgesia must be taken into account whendesigning a cross-over study, as the patient’s pastexperience of pain relief (i.e. during phase I of across-over trial) may influence his/her subsequent(i.e. during phase II of a cross-over trial) responseto treatment. 27Surgical procedures may also have a verystrong placebo effect as described earlier byBeecher. 28 A most striking and classic example isthe history of internal mammary artery ligationfor the treatment of angina pectoris, which waspopular in the first half of the twentieth century

18THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAas a means to increase blood flow to the coronarycirculation. Beecher analyzed the early experienceand divided the reports into those written by‘enthusiasts’ versus ‘sceptics’. The former groupfound complete relief of chest pain in 71/213patients (38%) while the latter in only 6/56(10%). 28 Cobb et al. 29 and Diamond et al. 30 performeda double-blinded study (the cardiologistwas blinded as to the procedure performed by thecardiac surgeon) of internal mammary artery ligationversus a sham procedure, namely skin incisiononly, and published remarkably similarresults. Cobb et al. reported a 63% significantimprovement and 34% decrease in the use ofnitroglycerine in the ligation group versus a 56%improvement and 42% decrease in nitroglycerineuse in the sham group. Diamond et al. reported a100% improvement in both groups regardingexercise tolerance, nitroglycerine use, and anginapain. During the year after surgery, 69% ofpatients reported over 50% improvement in painin the ligation group versus 100% who experiencedgreater than 50% improvement in the shamgroup. In a review, Johnson 31 discussed the possibleplacebo effect of extracorporeal shock wavelithotripsy (ESWL) for gallstones. In a randomizedtrial comparing ESWL with open cholecystectomythe symptomatic response was similar inboth groups but, surprisingly, the symptomaticresponse in the ESWL group was identicalwhether or not the stones had actually beencleared. Thus, the symptomatic response might atleast partially be triggered by a placebo effect.Comparatively little is known about the placeboeffects on healthy volunteers in clinical pharmacologytrials. Rosenzweig et al. 27 reviewedadverse events reported during placebo administrationin 109 double-blind, placebo-controlledstudies involving 1228 volunteers. The overallincidence of adverse events was 19%, and complaintswere more frequent after repeated dosing(28%) and in elderly subjects (26%). The most frequentadverse events were headache (7%),drowsiness (5%), and asthenia (4%). The overallincidence and distribution of adverse events alsoappeared to depend on the nature of the activeinvestigational drug in the young volunteers insingle-dose studies. The highest incidence for alladverse events was noted when the active drughad a central nervous system effect (16.7%). Theincidence was lower when the active drug hadmiscellaneous effects (16.2%) or a cardiovascularsystem effect (6.1%).NATURAL HISTORY, WATCHFUL WAITING,VERSUS PLACEBO EFFECTThe importance of placebo/sham-controlled trialsin BPH research is emphasized by the highlyvariable natural history of the disease, and thetendency towards spontaneous improvement andregression documented in several watchful waitingstudies, and, to a lesser degree in longitudinalstudies of the natural history of the disease. Whilenatural history studies refer to the longitudinalstudy of a cohort of men with signs and symptomsof BPH over time without any kind of treatmentintervention, the watchful waiting studiesusually entail at least a yearly follow-up visit witha ‘treating’ physician. According to the discussionabove, this consultation may have a profoundimpact on the ‘natural history’ of the diseaseprocess depending on the attitude and behavior ofthe physician. It is probably reasonable to expectthat at the end of each visit the physician wouldtell the patient that ‘he is doing well and does notneed any [additional or active] treatment’, a statementthat carries with it a considerable placeboeffect. Even in a natural history study the mem-

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 19bers of the study population have to be seen,interviewed, and examined at regular intervals,thus providing for the possibility of a placeboeffect. Longitudinal natural history studies mayprovide nonetheless the best information aboutthe ‘background activity’ of the disease process.Watchful waiting studies add at least one knownand powerful placebo effect, and they carry withthem the possibility of ‘treatment failure’ andconversion to a presumably more active treatment.Lastly, placebo/sham control groups addadditional nonspecific effects and, thus, their outcomestheoretically should be superior to watchfulwaiting and natural history studies.Regression to the meanPlacebo control arms differ in at least one othervery important characteristic from natural historystudies. In general, patients are selected to participatein studies based on inclusion/exclusioncriteria, usually eliminating patients perceived tobe less symptomatic, i.e. those with lower symptomscores and higher peak flow rates. By theprinciple of trial conduct, patients then repeat thesymptom and flow rate assessment during andafter therapy in both active and placebo groups.However, the same inclusion/exclusion criteriaare not applied to those measurements. To determinethe effect that the stringency of pretrialscreening has on the outcome of placebo treatment,a cohort of 145 volunteers were invited tofill in the I-PSS score and perform a flow raterecording twice within a month without receivingany therapy or instructions whatsoever. 32Although many patients experienced either anincrease or a decrease in both parameters, themean values did not change significantly (I-PSS12.1 vs 11.7 points, peak flow rate 17.7 vs17.4 ml/s; not significant). However, when typicalBPH trial conditions were applied and only thosepatients considered for analyses who had an I-PSS score above (>7, >10, >15) and a flow ratebelow a certain threshold (

20THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIATABLE 2.2 Mean ± SD and range for AUA symptom index for tests 1 and 2, mean difference between the two tests andthe 95% confidence interval (CI) for the difference, for all subjects, and for subjects censored based on test 1 > 7 points,> 10 points, and > 15 points. Statistical comparison between tests 1 and 2 by t-test. Note the reduction in the number ofpatients available for follow-up due to censoring which affects the power of the statistical test.Selection Mean ± SD Range Mean difference 95% CI t-Test nAll subjects 1 12.1 ± 8.8 0–32 –0.392 11.7 ± 9.0 0–32 –1.1 to 0.29 0.133 145>7 at 1 1 17.8 ± 6.5 9–32 –0.972 16.8 ± 7.7 0–32 –2.0 to 0.08 0.035* 88> 10 at 1 1 19.9 ± 5.6 11–32 –1.12 18.9 ± 6.9 0–32 –2.2 to 0.1 0.036* 70> 15 at 1 1 22.0 ± 4.6 16–32 –1.42 20.6 ± 6.6 0–32 –2.8 to 0.01 0.026* 54*p < 0.05.TABLE 2.3 Mean ± SD and range for peak flow rate for tests 1 and 2, mean difference between the two tests and the95% confidence interval (CI) for the difference, for all subjects, and for subjects censored based on test 1

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 21score slope and variability in slope increased withpatient age at baseline from a mean of 0.05 ± 1.06(standard deviation) per year among men in theirforties to 0.44 ± 1.35 per year for men in their sixties,and decreased to 0.14 ± 1.42 per year for menin their seventies. 43 More recently, 92 months’data showed an annual change of 0.34 points/year,with 31% of all men reporting at least a 3-pointincrease. The greatest annualized increase wasobserved in men in their sixties with 0.6points/year. 44In addition, 6-year follow-up data on peakflow rate measurements in a subset of about 500men showed a median peak urinary flow rateslope decrease of –2.1% per year (25th centile–4.0, 75th centile –0.6). Peak urinary flow ratedeclined more rapidly with decreasing baselinerate, and increasing baseline age, prostate volume,and symptom severity (all p = 0.001). Whenthe variables were simultaneously adjusted foreach other, a rapid decline (negative slope 4.5% orgreater per year) was more likely in men 70 yearsold or older and in those with a rate less than10 ml/s at baseline compared to those 40 to 49years old and those with a rate of 15 ml/s orgreater, respectively. Prostate volume and symptomseverity were not statistically significant predictorsof a rapid decline in peak urinary flowrate when variables were considered simultaneously.45Based on transrectal ultrasonography(TRUS), the growth of the prostate in the menaged 40–79 years was estimated to be about 0.6 mlper year or 6 ml per decade of life. However,prostate growth followed an exponential growthpattern, with a slope estimate of 0.4 ml per yearfor men aged 40–59 years at baseline and of 1.2 mlper year for those aged 60–79 years at baseline. 46An updated analysis revealed a median growthrate of about 1.9%/year independent of age andsymptoms. However, a higher baseline serumPSA and larger prostate volume predictedgreater annualized volume increases (Figure2.2). 47Diokno et al. 48 provided estimates of theprevalence, incidence, and remission of lower urinarytract symptoms in 803 community-dwellingmen aged 60 years or older. The annual incidenceof prostate surgery was 2.6% and 3.3% duringyears 1 and 2 of follow-up. The prevalence of atleast one symptom was 35%, with annual incidencerates during years 1 and 2 of follow-upbeing 16.4% and 16.1%. Remission was also notedin that 22.9% of those having severe symptoms atbaseline were asymptomatic at follow-up. Table2.4 details the changes in symptom severity fromone survey to the next. The tendency for fluctuationand spontaneous remission of symptoms aswell as the regression to the mean become evidentfrom an analysis of these data.Watchful waiting studiesIn the absence of other longitudinal natural historystudies, several watchful waiting studies areavailable for review. Most of these studies havesignificant shortcomings. Inclusion and exclusioncriteria are poorly defined, follow-up is loose,assessment instruments are either not defined orinsufficient, and patient accounting is incomplete.Five such studies, reported between 1919 and1988 and totaling 456 patients with follow-upranging from 3 to 6 years, 49–53 were analyzed forthe AHCPR BPH Guidelines. 54 A change insymptom status was reported for all 456 patients,while none of the studies utilized a quantitativesymptom severity scale. Data on urinary flow rateand residual urine were available for 223 and 197patients, respectively. The peak urinary flow ratedeteriorated in 66% and improved in 20%.Residual urine increased (35%), decreased (37%),

22THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA(a)Annual % increaseAnnual % increase4.543.532.521.510–0.54.543.532.521.510–0.5Spearman r = 0.59, p < 0.00010 10 20 30 40 50 60 70 80 90 100Baseline prostate volume (ml)(b)Spearman r = 0.34, p < 0.00010 1 2 3 4 5 6 7 8 9 10PSA (ng/ml)FIGURE 2.2 Per cent annual increase in prostate volume by baseline prostate volume (a) and baseline serum PSA (b) inparticipants of Olmsted County study of urinary symptoms in men. (Adapted from reference 47.)and remained unchanged (28%) in about thesame number of all patients. The mean change inpeak flow rate (in those patients for whom dataare available) was 2.2 (from a mean of 9.0 to11.2) ml/s or 24%, while the mean change inresidual urine was +37 (from a mean of 115 to152) ml or 32%. The data on symptom improvementwere dichotomized (improved versus notimproved). The probability for symptomimprovement was then calculated using the confidenceprofile method (CPM) described byDavid Eddy 55 (Figure 2.3). The mean probabilityfor improvement in symptom severity was estimatedto be 42.5% (90% CI 30.8 to 54.8), surprisinglysimilar to the probability for improvementnoted in the placebo arms, and in a carefullydesigned, prospective study to be discussed below.It must, however, be recognized that, because oflimitations of the dataset, the magnitude of theimprovement cannot be estimated. In updated

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 23TABLE 2.4 Changes in status of obstruction severity from one survey to the next (adapted from reference 48). Patientswho underwent prostatectomy in the preceding year were excluded from the next survey.Severity in following year (%)Severity Year No None Mild Moderate SevereNone Baseline 293 83.6 12.3 2.7 1.4Year 1 223 83.9 9.0 2.2 4.9Mild Baseline 88 18.2 55.7 11.4 14.8Year 1 84 33.3 52.4 8.3 6.0Moderate Baseline 38 7.9 31.6 26.3 34.2Year 1 27 3.7 33.3 22.2 40.7Severe Baseline 35 22.9 17.1 11.4 48.6Year 1 31 9.7 22.6 12.9 54.8Probability of improvement (%)45.2% 42.5%10098.4%9088.1%8070605080.2%74.1%56.6%403020100Placebo Dilatation Open surgeryWatchful waiting TUIPα-BlockerTURPFIGURE 2.3 Probability of achieving symptom improvementfollowing various treatment interventions. Meanprobability and 90% confidence interval calculated withthe confidence profile method 55 using hierarchical Bayes’.guidelines for the management of BPH,published by the AUA, 56 watchful waiting is recommendedfor patients with mild symptoms(AUA symptom score ≤ 7) or moderate to severeBPH in patients who are not bothered by theirsymptoms. Watchful waiting is therefore anappropriate early treatment strategy for mostmen with BPH.A randomized study with a 3-year follow-upwas reported comparing watchful waiting withTURP in 556 men with symptoms of BPH 57 .Inclusion criteria included a Madsen–Iversensymptom score between 10 and 20 points (0–27point scale), thus limiting the informational valueof the watchful waiting arm of the study topatients with moderate lower urinary tract symptoms.There were 47 treatment failures (definedas death, recurrent infection, residual urine volumeover 350 ml, development of bladder calculus,incontinence, a symptom score of 24 or higher,or a doubling of serum creatinine from baseline)in the watchful waiting arm (n = 276) versus23 in the surgery arm (n = 280) over 3 years of follow-up(relative risk 0.48; 95% CI 0.3–0.77).Sixty-five (24%) men assigned to watchful waitingunderwent surgery during follow-up, 20 ofthem for treatment failure. The majority of thesemen were classified as more bothered at baseline(Figure 2.4). It should be noted that about 40% ofpatients in this category experienced improvementin the degree of bother from urinary difficulties(Figure 2.4). The changes from baselinefor the watchful waiting patients are shown in

24THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAPercentage of patients100755025Table 2.5. It should be noted that the meanchanges represented in almost all categories animprovement for those men who were followedin the assigned treatment arm (watchful waiting)over 3 years. The magnitude of the improvement,however, was less than that realized by surgery inalmost all categories (p values in Table 2.5).Furthermore, this analysis obviously excludesthose men who were categorized as treatmentfailures, underwent surgery (cross-over), or werelost to follow-up.0Surgery WatchfulwaitingMore botheredat baselineSurgeryWatchfulwaitingLess botheredat baselineFIGURE 2.4 Degree of bother from urinary difficultiesafter 3 years of follow-up among men with LUTS andBPH managed with TURP or watchful waiting stratifiedby more or less bother at baseline. 57 , Improved; ,worse or no change; , cross-over to surgery.Placebo arms of controlled medical treatmenttrials for BPHFor the AHCPR BPH guidelines, data on 1417patients treated in 45 placebo arms of placebocontrolledtrials were analyzed. 54 Table 2.6 andFigure 2.3 allow a direct comparison between thewatchful waiting and the placebo studies. A significantdifference between the two treatmentmodalities cannot be identified for any of theTABLE 2.5 Changes from baseline for men followed over 3 years in a watchful-waiting protocol. (Adapted from reference57.)Outcome Baseline* Follow-up** Mean change ± SD p Value †Symptom Score (0–27) 14.6 9.1 –5.5 ± 5.2 < 0.001Residual urine (ml) 113 72 –41 ± 90 0.015Peak flow rate (ml/s) 12.5 12.7 0.4 ± 9.2 < 0.001Bother from urinary difficulties ‡ 46.3 57.6 9.6 ± 29.7 < 0.001Sexual performance ‡ 42.5 35.6 –3.2 ± 26.6 0.92Activities of daily living ‡ 69.0 75.6 6.4 ± 30.3 < 0.001General well-being ‡ 71.2 71.4 0.1 ± 28.3 0.217Social activities ‡ 74.2 73.1 –1.7 ± 23.5 0.945*n = 276; **only patients who were followed over 3 years excluding cross-overs, failures etc.; † for difference betweentreatment groups (surgery versus watchful waiting); ‡ on a scale from 0 (greatest impairment) to 100 (least impairment).

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 25TABLE 2.6 Comparison of outcomes following watchful waiting and placebo treatment. (Adapted from reference 54.)Outcomes Watchful waiting PlaceboTotal number of patients in database 456 1417Peak flow rateProbability for flow rate increase 19.7% 35.8%Probability for no change in flow rate 14.2% 41.1%Probability for flow rate decrease 66.1% 23.1%Mean pretreatment flow rate (ml/s) 9.0 9.1Mean posttreatment flow rate (ml/s) 11.2 9.7Difference (ml/s) +2.2 +0.6Per cent change in peak flow rate +24.4% +6.6%Residual urineProbability for decrease in residual urine 35.0% 38.0%Probability for residual urine to remain unchanged 28.0% 26.1%Probability for increase in residual urine 37.0% 35.9%Mean pretreatment residual urine (ml) 115 87Mean posttreatment residual urine (ml) 152 76Difference (ml) +37 –11Per cent change in residual urine +32.2% –12.6%Symptom improvementProbability for symptom improvement 41.7% 41.7%Probability for symptoms to remain unchanged 25.8% 53.5%Probability for symptom worsening 32.4% 4.7%Mean probability for symptom improvement* 41.7% 41.7%90% Confidence interval for symptom improvement* 30.8 to 54.8% 26.3 to 65.1%* Calculated by confidence profile method using hierarchical Bayes’. 55examined parameters. However, several pointsdeserve discussion. As opposed to the long-termfollow-up in the watchful waiting studies, theplacebo studies are part of short- to mid-termmedical treatment trials ranging from 3 days to52 weeks in duration (mean 13 weeks). In allthese studies the patients are blinded as to thetreatment arm, and thus have in most cases atleast a 50 : 50 (or better in case of 2 : 1 or 3 : 1 randomization)chance of receiving active drug.Dropping out of such studies because of failuredoes not have the same ramification as it does inwatchful waiting studies where the patients willinglyassume a conservative treatment approachknowing that it might fail (i.e. they might fail andgo on to active treatments). In contrast, in someplacebo-controlled studies a promise—either tacitor openly—is made stating that following theconclusion of the trial the patient would be eligiblefor either ‘free’ active treatment or he wouldbe ‘moved up’ on the surgical waiting list (thisphenomenon is unique to those studies conductedin the UK). The inactive preparation givenshould theoretically add to the placebo effect and,thus, improve the outcome above those noted forwatchful waiting studies. The probability for apatient to experience improvement, however, isestimated to be about 40% in the uncontrolled

26THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAwatchful waiting studies, the randomized watchfulwaiting versus TURP study, and the combinedplacebo arms. The changes in peak flowrate and residual urine are similar, and similarlysmall, for these three groups as well (see Tables2.5 and 2.6). Figure 2.5 shows a comparison of thepercentage changes in peak flow rate and residualurine as well as the percentage of patients experiencingsymptom improvement between varioustreatment modalities. It becomes evident that a40% rate of patients reporting improvement andthe minimal fluctuation of peak flow rate andresidual urine represent the ‘placebo effect’ backgroundagainst which the more substantialchanges in these parameters achieved by activetreatment modalities must be seen.With the advent of symptom severity assessmenttools or symptom scores it is possible toquantitatively describe the response of patientstreated by a variety of treatment interventionsincluding placebo and watchful waiting (seeChapter 1). Unfortunately, the different symptom-scoringinstruments differ regarding theirfoot points (0 or different from 0), their scale, andoccasionally even their direction (increasing ordecreasing severity of symptoms with increasingscore). While currently the AUASI orInternational Prostate Symptom Score(I–PSS), 58–63 with its scale from 0 to 35 points, isthe most widely utilized instrument, thus facilitatingdirect comparisons between studies, in theyears past different scores with different scaleswere used. The only way to compare symptomimprovement in different trials quantitatively insuch cases is to rescale the individual scales to a100% scale, and to express the changes as the dropin percentage symptom score from before to aftertreatment. Using this technique, seven placebo-200100Percentage changes in peak flow rateand residual urine150100500–507040Percentage of patients reporting improvementin symptoms–1001 2 3 4 5 6 710FIGURE 2.5 Percentage changes in peak flow rate and residual urine (left y-axis), and percentage of patientsreporting improvement in symptoms (right y-axis) following various treatment interventions. (Adapted from reference54.)

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 27controlled trials were reanalyzed and comparedto the most significant watchful waiting study 57(Figure 2.6). These seven trials enrolled between11 and 267 subjects per arm, lasted from 4 to 24weeks, and utilized an injectable steroid hormone(norprogesterone), 64 a prolactin inhibitor(bromocriptine), 65 an H 2blocker (cimetidine), 66an α-blocker (alfuzosin), 67 or candicin 68–70 as the‘active’ drug. Each study is represented by itsactive and the placebo arm side by side. Severalpoints are noteworthy. The pretreatment symptomseverity score expressed as percentage ofachievable score on a 100% scale ranges from 35%to almost 60%, and the drop in symptom severityfrom 7% to 33% for the placebo arms. Moreover,the pre- to posttreatment symptom score rangedoes not even overlap between some of the trialslisted, indicating that vastly different patient populationswere treated. Specifically addressing thethree placebo-controlled, double-blinded trialsusing candicin as the active drug, the drops insymptom score were 9, 15, and 33% (placebo), and6, 26, and 22% (candicin). With the exception ofthe bromocriptine trial, the baseline symptomseverity was reasonably similar between theplacebo and the active treatment arm, and in allsuch cases the placebo response closely matchedthe active drug response.These observations allow several conclusions:• There is a strong placebo response noted inmedical treatment trials for BPH when quantitativesymptom severity scores are used.• The placebo response in medical treatmenttrials for BPH depends largely on the pretreatmentcharacteristics of the treated cohort.70Symptom score (0–100% scale)605040302020%11% 15% 27% 23%8%17%7% 8%9% 6%15%26%33%22%10Watchful waitingPlaceboα-BlockerPlaceboNorprogesteronePlaceboBromocriptinePlaceboTreatmentCimetidinePlaceboCandicinPlaceboCandicinPlaceboCandicinFIGURE 2.6 Improvements noted using a quantitative symptom score in seven placebo-controlled trials and a watchfulwaiting study. Due to the different scales used, all scores were rescaled to a 100% scale and the reported changes expressedas mean pretreatment and mean posttreatment per cent symptom score. The number above the vertical bar indicates thechange noted following treatment (expressed as per cent).

28THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA• Even when the baseline symptom severity issimilar between two trials (A and B), theresponse of the placebo group in trial Amatches more closely its actively treatedcohort than the placebo group in trial B.• The latter fact indicates that factors other thanthe active drug or placebo are most responsiblefor the placebo effect.These factors may include patient selection criteria(solicitation, advertising), design and durationof study, incentives offered to patients (financialor otherwise), conduct and attitude of treatingphysician or research coordinator (sympatheticversus unsympathetic, friendly versus unfriendly,positive versus negative), and other unrecognizedfactors. In fact, given the parallel changes in bothtreatment groups in most trials, the latter factors,which are provider factors, are more likely to beresponsible than the previously mentionedpatient factors.It could be reasoned that placebo-treatedpatients enrolled with similar inclusion andexclusion criteria into clinical trials using thesame class of active drugs might have a similarplacebo response. A comparison of three α 1-receptor-blocker trials allows this hypothesis to betested. Eighty-two patients were treated withdoxazosin versus placebo over 16 weeks, 71 2064patients with terazosin versus placebo over 52weeks, 72 and 296 patients with tamsulosin versusplacebo over 12 weeks. 73 In all three trials a differentsymptom score was used. In the doxazosintrial, the scale ranged from 0 to 30 points, in theterazosin trials from 0 to 35 points (AUASI), andin the tamsulosin trial from 0 to 27 (Boyarskyscore). In Figure 2.7 all scores are rescaled to a100% scale and the pre- and posttreatment meanscores are expressed as a percentage of the 100%scale. Although the pretreatment symptom severityis different in the three trials, the placebo70Symptom score (0–100% scale)605040302047.328.352.043.757.435.757.446.935.222.234.426.31019.0% 8.3% 21.7% 10.6% 13.0% 8.1%Doxazosin Placebo Terazosin Placebo Tamsulosin PlaceboTreatmentFIGURE 2.7 Pre- and posttreatment mean symptom scores (upper and lower tickmark of vertical bar, respectively)rescaled to 100% for active-drug- and placebo-treated cohorts in three randomized α-blocker trials (for details see text).The number at the bottom of the graph represents the per cent improvement achieved.

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 29responses are very similar, ranging from 8.1 to10.6% on the 100% scale, roughly half of theactive drug cohort in each trial.Improvements in peak urinary flow rates arealso similar between these three drug trials, rangingfrom 0.4 to 0.8 ml/s in the three placebogroups, despite the fact that the baseline meanpeak flow rates are rather different (Figure 2.8).It should be noted that this improvement in peakflow rate is very similar to the mean changesnoted in the combined placebo arm analysis of theAHCPR guidelines (0.6 ml/s) and the watchfulwaiting study (0.4 ml/s) by Wasson et al. 57 Thepercentage improvement calculated for the combinedplacebo arms (6.6%) falls also in the rangeof improvements seen in these three α-blockertrials (3.8 to 8.3%).Sham arms of controlled-device treatmenttrials for BPHIn recent years a multitude of minimally invasivedevice treatments for BPH have been developedand tested in randomized, sham-controlled, open,single-, or even double-blinded trials. While themajority of these trials compare various types ofheat treatments (transrectal or transurethralhyperthermia or thermotherapy) with a shamtreatment, one investigator compared balloondilatation with ‘sham’ cystoscopy alone in a randomized,double-blinded trial involving 33 menwith BPH. 74 Blinding of the patients was effectivein that an equal number of patients in eacharm thought they had undergone balloon dilatation.After 3 months, 40% of balloon dilatedpatients noted marked improvement, while 27%noted no change. After cystoscopy, 63% hadmarked improvement and 12% no change. Thechanges in symptom score were significant at 3months in both groups, while the peak urinaryflow rate changes were not significant from baselinein either group (Table 2.7). Most importantly,there was no difference in the symptom score orpeak flow rate data at 3 months between the‘active’ and the ‘sham’ treatment. This study iswidely used to support the notion that balloondilatation has no role in the treatment of BPH,and is not better than placebo/sham treatment.Figures 2.9 and 2.10 analyze the outcomes ofthe balloon dilatation versus cystoscopy trial, onemulticenter trial using transrectal ortransurethral hyperthermia in comparison with asham control, 75 and five transurethral microwavethermotherapy (TUMT) trials and their respectivesham-control arms. 76–79 The following observationscan be made. The baseline or pretreatmentmean symptom severity expressed as a percentageof total achievable severity (rescaled to100%) is different from trial to trial. The meanimprovements in symptom severity in the shamgroups ranged from 5.2 to 15.6% (on a 100%scale), while the active thermotherapy-treatedpatients had improvements ranging from 27.0 to37.8%, or in most cases twice the improvementcompared to the sham control. The multicenterhyperthermia trial represents the exception, inthat the actively treated cohort has an improvementsimilar to the sham control, which is wellwithin the range of the other sham control trials.The changes in peak urinary flow rate follow asimilar pattern (Figure 2.10). With the exceptionof TUMT trials 2 and 4, the changes in peak flowrate are either very modest improvements ordeteriorations (0.5, 0.6, –0.2, –1.0 ml/s), while theactive-treatment arms report substantialimprovements, with the exception of the hyperthermiatrial. The changes noted in the shamarms (and the largely ineffective hyperthermiatreatment arm) are very similar to those observedafter α-blocker therapy (see Figures 2.7 and 2.8).Both thermotherapy trial 5 and the terazosin trial

30THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA1312.51211.5Q max (ml/s)1110.5109.529.9%7.1%22.9% 8.3%12.1%3.8%98.582.9 ml/s 0.7 ml/s 2.2 ml/s 0.8 ml/s 1.4 ml/s 0.4 ml/sDoxazosin Placebo Terazosin Placebo Tamsulosin PlaceboTreatmentFIGURE 2.8 Pre- and posttreatment mean peak flow rates (Q max) (lower and upper tickmark of vertical bar) for activedrug-and placebo-treated cohorts in three randomized α-blocker trials (for details see text). The number at the bottomat the vertical line indicates the per cent improvement in mean peak flow rate, while the number at the bottom of thegraph represents the absolute mean improvement.TABLE 2.7 Outcomes at 3 months following balloon dilatation or cystoscopy in a randomized, double-blinded study.(Reproduced with permission from Lepor et al. 74 )p Value: baseline p Value: cystoscopy versus balloonBaseline 3 months versus 3 months dilatation at 3 monthsPeak flow rateCystoscopy 10.5 12.9 NSBalloon dilatation 9.2 11.5 NS p =0.48Symptom scoreCystoscopy 11.9 8.8 < 0.01Balloon dilatation 12.4 7.5 < 0.05 p =0.33have similar entry criteria and baseline meansymptom severity. The improvements noted inthe placebo and sham arms were 3.3 points(10.6%) and 2.6 points (6.4%), respectively, whilein the active-treatment arms the improvementswere 7.6 points (21.7%) and 12.1 points (34.6%),respectively.Placebo/sham effect and baseline symptomseverityAn area of considerable interest is the question towhat degree the placebo/sham effect depends onthe baseline status of the patients. This could pertainto baseline symptom severity, baseline bother,

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 316015.6%37.8%5.2%28.1%15.6% 34.6%7.4%18.1%5028.1%27.0%Symptom score (0–100% scale)403015.9%13.0%14.4%11.5%2010HyperthermiaShamTUMT-1Sham-1TUMT-2Sham-2TUMT-3Sham-3TreatmentTUMT-4Sham-4TUMT-5Sham-5BalloonCystoscopyFIGURE 2.9 Pre- and posttreatment (3 months) mean symptom scores (upper and lower tickmark of vertical bar)rescaled to 100% for active-treated and sham-treated patients in a multicenter hyperthermia trial, five transurethralmicrowave thermotherapy (TUMT) trials, and a balloon dilatation versus cystoscopy trial. The improvement in per centis noted above the horizontal tickmark.quality of life, baseline flow rate, and all otherimaginable parameters. Although very few investigatorshave thus far reported data stratified bybaseline parameters, results from a multicenter,placebo-controlled, 12-month α-blocker trial(terazosin) can be analyzed. 80 Figure 2.11 showsthe absolute and percentage improvement inAUA symptom score for the placebo- and drugtreatedpatients stratified in six strata by symptomseverity. While the active drug-treated cohort hasalmost twice the improvement within each stratum,the placebo-treated patients had improvementsranging from 1.4 points (4.6%) to 7.5 points(21.4%). The placebo improvements for theentire placebo cohort were 3.3 points (10.6%).A similar increase in the placebo effect withincreasing baseline symptom severity has beenreported for patients treated with finasteride inthe phase III trials. 81 It might be speculated thatthe baseline symptom severity may also affect thesham effect seen in device trials. This phenomenonmight be due to increased expectations inpatients with more severe baseline symptoms, orsimply due to a regression to the mean.Natural history of disease progression inlong-term placebo armsThe distinction between placebo response in controlledstudies versus the natural history of thedisease itself observed in population-based studiesbecomes blurred when the placebo control is carriedout over a period of time long enough toallow natural history changes to take place and

32THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA154.0%14134.0%4.0%4.0%124.0%4.0%4.0%Q max (ml/s)111094.0%4.0%4.0%4.0%4.0%4.0%4.0%87650.4 0.5 4.2 2.1 3.4 –0.2 4.5 0.6 4.5 2.1 2.3 –1.0 2.3 2.4TreatmentHyperthermiaShamTUMT-1Sham-1TUMT-2Sham-2TUMT-3Sham-3TUMT-4Sham-4TUMT-5Sham-5BalloonCystoscopyFIGURE 2.10 Pre- and posttreatment (3 months) mean peak urinary flow rates (lower and upper tickmark of verticalbar) for active-treated and sham-treated patients in a multicenter hyperthermia trial, five transurethral microwave thermotherapy(TUMT) trials, and a balloon dilatation versus cystoscopy trial. The changes in per cent are noted below thehorizontal tickmark and the absolute improvement (deterioration) at the bottom of the graph.confound the situation. The Proscar Long TermEfficacy and Safety Study (PLESS) followed acohort of over 3000 men with moderate symptomsand enlarged prostate glands randomized totreatment with finasteride 5 mg daily versusplacebo over 4 years. 82,83 While in most placeboarms of controlled trials lasting 12 months or lessthe combined placebo effect is maintained for theentire duration of the study, in this trial, both themean symptom score and peak flow rate slowlydrifted back to baseline after a typical initialplacebo response, without quite reaching baselinelevels, however. 83The almost 1500 men in the placebo arm ofthis trial allowed for a detailed analysis of theplacebo response and the subsequent natural historystratified by baseline parameters. By far themost powerful of these parameters proved to beunexpectedly the baseline serum PSA level.When stratifying the population by serum PSAinto tertiles or thirds of patients with PSA levelsfrom 0–1.3, 1.4–3.2, and 3.3–10 ng/ml, three distinctlydifferent patterns emerged (Figure 2.12). 82While the initial placebo response in the lowestPSA tertile for both symptom and flow rate wasmaintained over the entire 4 years of follow-up,the middle tertile experienced a slow deteriorationof symptoms back to baseline and in essencethe natural history and progression of diseaseeliminated any flow rate gains. In the highestPSA tertile the symptom score increased steadilyover time following an initial placebo response by–1.5 points. Over the subsequent years, the scoreincreased by 0.5 points/year, bringing it at the end

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 33353019.4% 31.4% 21.4% 36.9%2520.0% 30.0%AUASI (0–35 points)20154.6% 13.7%6.9% 17.4%11.7% 25.1%1051.6 4.8 2.4 6.1 4.1 8.8 7.0 10.5 6.8 11.0 7.5 12.913–15P 13–15T 16–19P 16–19T 20–23P 20–23T 24–27P 24–27T 28–31P 28–31T 32–35P 32–35TBaseline symptom scoreFIGURE 2.11 Improvements in symptom score expressed recorded in a placebo-controlled, 12-month α-blocker treatmenttrial for patients stratified in six baseline symptom severity strata (along x-axis labeled as P = placebo- and T = terazosin-treated).The per cent improvement (100% scale) and the absolute changes (at bottom of graph) are shown.of the study back to the original baseline level.The initial response in terms of flow rateimprovement was completely negated by the progression/naturalhistory after 2 years, and at theend of the study, this group of patients registereda net worsening of the flow rate by a mean of–1.0 ml/s (Figure 2.12b).For the first time, the PLESS study and itsplacebo control group allowed the study of naturalhistory and disease progression in a cohortselected for moderate symptoms and other evidenceof disease (in contrast to a population-basedstudy) on the background of the initial combinedplacebo responses.Relationship between placebo/sham effect andperception of improvementBarry et al. reported an important observation byassessing the relationship between changes in theAUASI and patients’ global rating of improvementin over 1200 men treated in a medical treatmenttrial for BPH. 84 They noted that a meandecrease in AUASI of 3.1 points was associatedwith a slight improvement; however, this relationshipwas strictly dependent on the baselineAUASI (Figure 2.13). For patients to perceive aslight, moderate, or marked improvement,increasing drops in AUASI were required withincreasing baseline symptom severity. In Figure2.13 this relationship is illustrated graphically forslight, moderate, and marked improvement. Thesymbols indicate the improvement in AUASInoted in the already-mentioned α-blocker trialactive-drug and placebo arms. 72 It is evident, thatfor every symptom severity stratum, the improvementin the placebo arm fell roughly on the‘slight’ improvement line, which is the minimumimprovement noticeable to patients. Thus, for

34THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA(a)0Months0 4 8 12 16 20 24 28 32 36 40 44 48–0.5I-PSS–1–1.5–23.2–2.5–3(b)1.50 4 8 12 16 20 24 28 32 36 40 44 481.5Peak flow rate10.50–0.510–1.21.2–3.20.53.2–100-0.50 - 1.21.2 - 3.23.2 - 10–1-1–1.5-1.5FIGURE 2.12 Mean ± 95% CI for symptom (a) and peak flow rate (b) in placebo-treated patients in PLESS study stratifiedby baseline serum PSA levels.each baseline symptom severity level, patientstreated with placebo would have a noticeablesymptom improvement. However, the patientstreated with active drug experienced in all strataanalyzed at least a ‘moderate’ improvement.SUMMARY AND CONCLUSIONSThe data discussed demonstrate rather convincinglythat in both medical and minimally invasive-devicetreatment trials for BPH, aplacebo/sham effect must be expected, in additionto a regression to the mean effect, the magnitudeof which depends on the chosen thresholds forinclusion and exclusion (i.e. the more restrictive,the greater the effect). The combined regressionto the mean and placebo/sham effect is surprisinglystable across different trials and differenttreatment modalities. About 40% of patientsexperience some unspecified degree of improvement,albeit marginal, in watchful waiting andplacebo/sham control cohorts. Improvements insymptom severity scores range from 5 to 15%

THE PLACEBO EFFECT IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 355AUA symptom score improvement0–5–10–15slightmoderatemarked–200 5 10 15 20 25 30 35AUA symptom scoreFIGURE 2.13 Relationship between baseline (x-axis) symptom score and absolute changes in scores for subjects ratingglobal improvement as slight, moderate, or marked (adapted from reference 85). The symbols indicate the absolute dropsin symptom scores from baseline for patients treated in a placebo-controlled, 12-month α-blocker treatment trial stratifiedin six strata by baseline symptom severity (placebo = triangle; α-blocker = circle).(about 2 to 5 points using the AUASI rangingfrom 0 to 35 points) for placebo/sham-treatedcohorts, while changes in peak urinary flow rateare in general more modest, ranging from actualdeterioration to improvements of 1.0 ml/s withfew exceptions. The magnitude of this effect issimilar to that seen in watchful waiting studies.Of great importance is the observation that themagnitude of the improvement correlates directlywith the baseline symptom severity. Patients’perception of improvement also correlates withbaseline symptom severity and, in general, a largerdrop in symptom score is associated with aglobal rating of a slight, moderate, or markedimprovement with increasing baseline symptomscore. In the limited datasets available the placeboeffect for each symptom severity stratum is of amagnitude associated with a global perception ofslight improvement.The statement that treatment for BPH is associatedwith a ‘40% placebo/sham effect’ is clearlyan inadequate oversimplification. More detailedand sophisticated analyses of responses in placebo/sham-treatedcohorts of men with BPH areneeded to further our understanding of the complexrelationship between patients’ expectations,baseline symptom severity, bother, quality of life,nature and invasiveness of the active treatmentarm, and the responses noted in regards to symptom,bother, quality of life, and indirect outcomessuch as urinary flow rates. Only once a matrix ofthese responses and their predictors has beenestablished will we be able to judge newly developedtreatments for BPH against the backdrop oftheir associated placebo/sham effects.

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Dutasteride in the treatmentof the BPH patientJ D McConnell C G Roehrborn3INTRODUCTIONBenign prostatic hyperplasia (BPH) and thelower urinary tract symptoms (LUTS) associatedwith the condition are becoming increasinglyprevalent as the Western male population agesand healthcare provision worldwide improves.The need for new and improved treatments forthe condition is therefore ongoing and likely toincrease.BPH develops due to a combination of testicularandrogens and aging. The main androgenpresent in the prostate is dihydrotestosterone(DHT). The role of DHT and the enzymeresponsible for its reduction, 5α-reductase, in thedevelopment of BPH has long been established,and the clinical potential of inhibitors of theenzyme has been proven.Limitations of inhibitors with a selectiveaction on one of the isoforms of 5α-reductasehave been described, however. Inhibition of both5α-reductase isozymes has therefore been suggestedas a means of increasing clinical responsein terms of reducing prostate volume and therebyimproving urinary symptoms and limiting risk ofacute urinary retention (AUR) and BPH-relatedsurgery.The selective 5α-reductase type II inhibitorfinasteride has been available for the treatment ofBPH for over 10 years, and this is testament to itsefficacy in reducing symptoms of the condition inpatients over an extended period of time.However, dual inhibition of 5α-reductase hasbeen predicted to expand and enhance responsein both finasteride responders and nonresponders.DEVELOPMENT OF BPH AND ROLE OF DHTThe prevalence of BPH increases in a linear fashionalongside age. At the age of 40, approximately23% of men suffer from BPH, while 88% ofmen in their nineties are thought to have the condition.1Androgen stimulation is necessary for the initialgrowth and development of the prostate andfor the maintenance of its integrity, as well as thedevelopment of the obstructive urinary symptomsassociated with BPH. 2 Although the mechanismsunderlying the development of BPH havenot been fully established, testicular androgens,particularly DHT, are recognized as integral tothe process. The influence of DHT in initial prostaticdevelopment has been determined, with thehormone found to be responsible for the embryonicdifferentiation of the prostate and the formationof external genitalia in the male. 3 Fetal castrationresults in inhibited formation of thegland, 4 and the continued role of testicular androgensin later life is evidenced by the lack of BPHdevelopment among men who have undergonecastration prior to puberty. 5DHT, which is reduced by 5α-reductase fromtestosterone (Figure 3.1), has been identified asthe predominant androgen contained in theprostate, 2 and its permissive if not causative role41

42THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAOHType 1 and type 2type 1 and type5α-reductaseOHOONADPHNADP+TestosteroneFIGURE 3.1 Reduction of testosterone to dihydrotestosterone by 5α-reductase.HDihydrotestosteroneein hyperplastic prostatic growth has been outlinedin several studies. 6,7DHT binds to androgen receptors containedwithin the epithelium of the prostate. 6,7 Thesereceptors are upregulated during puberty, leadingto increased androgen sensitivity and, althoughthe receptors may also bind testosterone, DHThas much greater affinity, indicating that thishormone is the main driver of subsequent geneticmodulation in the prostate. 8 Although downregulationof many androgen receptors occursafter puberty at other sites, this does not occur inthe prostatic epithelium. Coupled with the factthat DHT levels remain constant after puberty,when testosterone levels fall, this explains thecontinued growth-promoting influence of DHTand the DHT–receptor complex in the prostate.The formation of this complex stimulates theexpression of a range of growth factor promoters,such as epidermal growth factor (EGF), basicfibroblast growth factor, keratinocyte growth factor(KGF), and insulin-like growth factor (IGF),leading to cellular proliferation, 9,10 and inhibitors,such as transforming growth factor-β (TGF-β),which increases levels of apoptosis. 11–13Homeostasis is therefore achieved by the normallyfunctioning prostate. Increased stimulation byDHT leads to increased expression of growth factorpromoters and hyperplastic growth. Removalof the stimulus, through surgical or chemicalmeans, leads to the opposite scenario, with a generalmove towards increased expression of cellgrowth inhibitors, such as TGF-β.A lack of DHT, due to deficiency of theenzyme responsible for its formation from testosterone,i.e. 5α-reductase, has been identified inmen with pseudohermaphroditism. 14,15 The clinicaland pathologic sequelae observed in theseindividuals provide further evidence of the role ofandrogens, specifically DHT, in the prostate.Men affected by 5α-reductase deficiency experiencenormal or partial virilization at puberty, dueto the action of testosterone; however, the prostateitself remains underdeveloped, small, and unpalpableon digital rectal examination.The normal development of the prostate, andits hyperplastic growth during BPH, are thereforepredominantly attributed to the reduction oftestosterone to DHT by 5α-reductase.5α-REDUCTASEThe increased cell proliferation that takes placeduring hyperplastic prostatic growth mainlyoccurs in the stroma of the prostate and a strong

DUTASTERIDE IN THE TREATMENT OF THE BPH PATIENT 43positive association of 5α-reductase activity withstroma and a negative correlation with epitheliumhas been recently identified. 16Two isozymes of the highly lipophilic enzyme5α-reductase have been identified to date. Theseproteins are encoded by different genes, that fortype I being located on chromosome 5 and thatfor type II on chromosome 2. 17 The distributionof the 5α-reductase isozymes differs significantly,with type I predominating in the liver, scalp, andskin, with low levels found in the prostate, whiletype II mainly occurs in the prostate and othergenital tissues and is found to a lesser extent elsewhere.2The 5α-reductase deficiency observed inpseudohermaphroditic men involves type II 5αreductasealone; type I 5α-reductase deficiencyhas not been identified to date in humans. In 5αreductasedeficient men, virilization at puberty isaccompanied by increased expression of 5αreductasetype I in the skin, 18 suggesting thatDHT has paracrine effects, and that dual inhibitionis necessary for complete control of the hormone.It may also explain why finasteride, whichinhibits the action of type II 5α-reductase alone,only succeeds in reducing prostatic DHT by85–90% and often fails to significantly reduce theurinary symptoms of BPH. 19,20THE NEED FOR A DUAL 5α-REDUCTASEINHIBITORThe efficacy of the type II 5α-reductase inhibitor,finasteride, has been described in several shortandlong-term clinical trials. 21–25 Mainly througha reduction in prostate volume, the drug has beenshown to significantly reduce risk of AUR andBPH-related surgery and improve urinary symptomsand peak urinary flow (Q max) in bothyounger and older men, with positive consequencesfor quality of life scores. Since its launchin 1992, the drug has been used to treat millionsof men worldwide, with good reported success inresponders.Stratification of the results of clinical trials hassuggested that men with larger prostates aremore likely to respond to finasteride therapy thanthose with smaller glands. 26 A meta-analysis ofsix clinical trials indicated that significantlygreater improvements in Q maxand symptom scorewere experienced by men with prostates largerthan 60 ml compared to those with prostates of20 ml or smaller. The authors concluded thatfinasteride was most appropriate for men withprostates of 40 ml or greater. Severity of symptomsdoes not necessarily correlate with prostatevolume, however, 27 and the effects of a greaterreduction in prostate volume than that seen withfinasteride have yet to be determined.It has been suggested that finasteride fallsshort of initial expectations due to the simultaneousoccurrence of BPH with symptoms unrelatedto prostatic growth, 28 heterogeneity of the disease,29 and the effect of the increase in levels oftestosterone 8 as well as the influence of the DHTthat continues to circulate despite 5α-reductasetype II inhibition, i.e. that originating from type Ireduction. Between 20 and 40% of baseline DHTremains in men treated with finasteride. 30–32The exact role of DHT reduced by type I 5αreductaseis not known and the level of entry ofthis protein to the prostate has not been established.Therefore, even though finasteride successfullyreduces levels of DHT in the prostate, itcan be postulated that systemic DHT maintainslevels high enough to allow continued cell proliferationor negate the normal ongoing apoptosis ofprostatic cells. On this basis, obstructive urinarysymptoms may therefore persist, particularly in

44THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAmen with smaller prostates. A dual inhibitor ofboth 5α-reductase isoforms, producing greaterreductions in prostatic and circulating DHT,would reduce this possibility.Over the last decade, the principle of 5αreductaseinhibition in terms of reducing prostatevolume and thereby alleviating symptoms hasbeen shown to have considerable clinical benefit;however, selective inhibition of one isozyme alonemay limit the magnitude of the clinical response.PRECLINICAL DEVELOPMENT OFDUTASTERIDEThe assumption that inhibition of both type I andtype II 5α-reductase could improve the urinarysymptoms of BPH over and above mono-inhibitionwith finasteride led to the development ofthe 6-azasteroid molecule 17β-N-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-aza-5α-androst-1-en-3one (dutasteride, Figure 3.2).A range of dual 5α-reductase inhibitors wasdeveloped simultaneously; 33 however, dutasteridewas found to have a particularly high affinity forboth 5α-reductase isozymes. In vitro, the compoundwas 60 times more powerful at inhibitingONHFIGURE 3.2 Structure of dutasteride.HHHONFFFFFFtype I 5α-reductase and 10 times more powerfulat inhibiting type II 5α-reductase than finasteride.34 Trials of the drug in humans revealedtype I inhibition to be 100-fold higher and type IIinhibition 3-fold higher than finasteride. 35Investigation of dutasteride’s mechanism ofinhibition in rats revealed that the drug affectstype I 5α-reductase differently to type II. 36 Thedrug inhibits type I 5α-reductase in a classicallycompetitive manner, forming a dissociable complexwith this isozyme. In contrast, the inhibitionof type II 5α-reductase is time-dependent. In thisanalysis, which compared the actions of finasterideand dutasteride in rats, the latter was foundto be 20 times as powerful an inhibitor as finasterideof 5α-reductase type I, and 10 times aspowerful with type II.Previous studies in rats have indicated thatfinasteride acts as a dual inhibitor of 5α-reductasein these animals, so the beneficial effects of thedrug may in fact be overestimated. 37 However,this model allows the direct comparison of finasterideand dutasteride in terms of overall potency.An additional animal study of dutasterideindicated that its half-life is considerably longerthan that of finasteride. Examination of the pharmacokineticand pharmacodynamic properties ofdutasteride revealed a greater terminal half-lifecompared to finasteride, at 14 hours versus 1 hourin the rat, and 65 hours versus 4 hours in the dog.Total body clearance in the dog was found to be0.5 mg/min per kg and volume of distributionwas high, at 3 liters/kg. In man, a single dose wasfound to have a terminal half-life of around 240hours. Levels of DHT were found to be reducedto a significantly greater level after a 10 mg doseof dutasteride compared to a 5 mg dose of finasteride.38The extended half-life of dutasteride, in additionto its dual-inhibitor nature and decreased

DUTASTERIDE IN THE TREATMENT OF THE BPH PATIENT 45total body clearance, is considered to underpinthe greater inherent potency of this drug comparedto selective 5α-reductase inhibitors. 38CLINICAL EXPERIENCE WITH DUTASTERIDEClinical experience involving dutasteride is relativelylimited due to its recent availability on themarket, and comparison studies are lacking.What evidence there is, however, indicates thatthe drug consistently reduces prostate volume,improves urinary symptoms and Q max, andreduces risk of AUR and BPH-related surgery. 39The pooled analysis of three phase III randomized,placebo-controlled studies of dutasteride,each lasting 24 months, has substantiatedthe potential of the drug in the treatment ofLUTS in BPH patients.A total of 4325 men aged over 50 with moderateto severe symptoms of BPH (AmericanUrological Association symptom index(AUASI) ≥ 12, Q max≤ 15 ml/s, prostate volume≥ 30 ml, as measured using transurethral ultrasound)took part in the trials, which took place at400 sites in 19 countries. After a 1-month placeborun-in period, participants were randomized toreceive 0.5 mg dutasteride or placebo.Assessment, involving AUASI, Q max, and PSAmeasurement, took place at 1, 3, 6, 12, 18, and 24months and testosterone and DHT levels weremeasured at 12 and 24 months. Total prostate volumewas assessed at regular intervals and transitionzone volume was determined in two of thetrials.In total, 68% (2951) of participants completedthe 24-month study period, with discontinuationrates similar between the active and placebogroups (n = 657 and n = 717, respectively). DHTlevels fell by a mean of 90.2% in the active groupcompared to a mean increase of 9.6% in theplacebo group (Figure 3.3).Prostate volume fell significantly compared toplacebo after just 1 month and this differenceincreased over the course of the study period.Total prostate volume fell by a mean of 25.7%and transition zone volume by 20.4% from baselinein the active groups; AUASI fell by 4.5 points FIGURE 3.3 Changes in efficacy parameters at 24 months (expressed as a percentage change of baseline measurements,all changes for dutasteride are statistically significant (p

46THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAcompared to 2.3 points with placebo, reachingsignificance in the pooled results after 6 months;Q maxincreased by 2.2 ml/s compared to 0.6 ml/swith placebo, with a significant differencebetween active and placebo arms after 3 months;PSA increased by 15.8% in the placebo group anddecreased by 52.4% with dutasteride.AUR occurred in less than half the number ofdutasteride-treated patients compared to placebo(39 versus 90), representing a reduction in risk of57% (p = 0.001). BPH-related surgery was performedin 47 and 89 patients, respectively, indicatinga reduction in risk of 48% (p =0.001) withdutasteride.Adverse event rates were similar betweengroups, at 77% for dutasteride-treated patientsand 75% in those receiving placebo. Drug-relatedadverse event rates were 14% and 19%, respectively,with sexual dysfunction being the mostcommonly reported in both groups (Figure 3.4).Prostate cancer was identified in 1.9% and 1.1%of the groups, respectively.The results indicate that impressive clinicalbenefits are associated with dual 5α-reductaseinhibition. Comparison of these results with thosereported for other types of medical therapy forBPH indicates that the improvement in symptomscore for dutasteride described here comparesfavorably with that reported for finasteride andmany α-blockers. 20,40 A review of the differentmedical treatments available for the managementof BPH revealed symptom improvements comparedto placebo of 9–40% for alfuzosin, 2–34%for terazosin, 3–19% for doxazosin, and 2–20%for tamsulosin. 41 In the study described above, animprovement of 13% over placebo was observed,indicating similar results compared to these alternativetherapies.The decrease in risk of AUR and BPH-relatedsurgery adds an additional dimension to thebenefits of dutasteride; 23% of men surviving to80 years are likely to suffer AUR and BPH-relatedsurgery is needed in 29% of all men. 42,43 Thereduction in risk observed here is thereforeextremely significant. Similar results have beenshown for finasteride, 22 indicating the influenceof 5α-reductase inhibitors on this aspect of BPH. FIGURE 3.4 Sexual dysfunction adverse events: incidence (percentage of patients) over the entire study (2 years).Statistically significant for all disorders (p

DUTASTERIDE IN THE TREATMENT OF THE BPH PATIENT 47Direct clinical comparisons of dutasteridewith finasteride are lacking, due to the recentrelease of the former drug. However, a phase IIclinical trial, involving 399 BPH patients (meanage 62.6–65.6 across treatment group, meanprostate volume 41.9–47.3 ml) did compare avariety of doses of dutasteride (0.01, 0.05, 0.5, 2.5,and 5.0 mg) to 5 mg finasteride or placebo over aperiod of 24 weeks. 44 A clear dose–response relationshipwas observed with dutasteride, with98.4 ± 1.2% DHT reduction observed with thehighest dose compared to a mean decrease of70.8 ± 18.3% with 5.0 mg finasteride (Figure 3.5).Significantly greater decreases in DHT wereobserved at dutasteride doses of 0.5, 2.5 and5.0 mg compared to both placebo (p =0.001) andfinasteride (p = 0.001). If, as thought, the reductionin DHT is the mechanism responsible for theimprovement in symptoms seen with finasteride,it may be expected that a greater fall in DHTwould be accompanied by greater improvementsin symptomatology.OTHER CONSIDERATIONSProstate-specific antigenThe reductions in prostate-specific antigen (PSA)levels observed with finasteride therapy havebeen mirrored in clinical trials of dutasteride, 39and it has been suggested that this may haveimplications for prostate cancer screening.However, in vivo studies have shown that complexed-to-totaland free-to-total ratios remainconstant with finasteride treatment, indicatingthat proportional reduction in all molecularforms of PSA occurs with 5α-reductase inhibition.45–47 If similar results are found for dutasteride,measurement of these PSA forms couldpotentially be used to screen for prostate cancerand the use of PSA in cancer screening would notbe compromised.In addition, investigation of PSA levels inmen included in phase III trials of dutasteriderevealed reductions in PSA of around 50%.Multiplication of these scores by 2 showed levelsFIGURE 3.5 Comparative changes in serum DHT and testosterone following 24 weeks’ treatment with dutasteride(0.5 mg), finasteride (5 mg), or placebo (serum DHT suppression significant for dutasteride versus finasteride, p

48THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAof PSA that were superimposable on curvesobserved at baseline, suggesting that this simplemethod could allow continued screening usingtotal PSA levels. Again, free-to-total ratio did notchange in these patients.HematuriaFinasteride and other anti-androgens have beenshown to have potential clinical applications inthe prevention of hematuria, 48–50 possibly due todecreased expression of vascular endothelialgrowth factor (VEGF), which lowers microvesseldensity in the prostatic suburethra. 51,52 It may bepostulated that the decrease in VEGF will begreater following dutasteride treatment, indicatingan even greater anti-hematuric effect; however,such aspects remain to be investigated.Combination therapyThe combination of 5α-reductase inhibitors andα-blockers has recently been investigated, 53 andthe addition of doxazosin to 5α-reductase therapywas found to result in significantly greaterbenefits in terms of disease progression andsymptom score than either treatment alone. Thegreater efficacy of dutasteride in terms of DHTreduction suggests that the combination of an α-blocker with this drug may hold even morepromise. However, long-term, randomized,placebo-controlled trials are needed to investigatethis theory.CONCLUSIONSThe results of pharmacokinetic, pharmacodynamic,and clinical studies have indicated thatdutasteride is the most powerful suppressor ofDHT on the market. The drug effectivelyinhibits type II 5α-reductase activity to a greaterextent than finasteride, with the additional benefitof completely inhibiting type I 5α-reductase.The net effect is a reduction in prostatic and circulatingDHT to virtually zero. Greater reductionsin prostate volume may therefore be expectedwith dual 5α-reductase inhibition than withselective inhibition, with positive clinical consequenceswith respect to urinary symptoms, AUR,BPH-related surgery risk and quality of life.Dutasteride therefore builds on the welldocumentedlong-term safety and tolerance of5α-reductase inhibitors, but potentially couldprovide additional clinical benefit to thatobserved with finasteride due to more effectiveDHT suppression.However, a direct comparison of finasterideand dutasteride is now needed to determine therelative clinical benefits of selective and dualisozyme inhibitors as monotherapy or in combinationwith other classes of drug.REFERENCES1. Berry S J, Coffey D S, Walsh P C, Ewing L L. Thedevelopment of human benign prostatic hyperplasiawith age. J Urol 1984; 132: 474–4792. Lee C, Kozlowski J M, Grayhack J T. Aetiology ofbenign prostatic hyperplasia. Urol Clin N Am1995; 22: 237–2463. Wilson J D. Androgens. In: Hardman J G,Limbird L E (eds). Goodman & Gilman’s Thepharmacological basis of therapeutics, 10th edn.New York: McGraw-Hill, 2001: 1441–14584. Cunha G R, Donjacour A M, Cooke P S et al. Theendocrinology and developmental biology of theprostate. Endocr Rev 1987; 8: 338–3625. Wu C P, Gu F L. The prostate in eunuchs. EORTCGenitourinary Group Monograph 10. Urologiconcology: reconstructive surgery, organ preservation

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DUTASTERIDE IN THE TREATMENT OF THE BPH PATIENT 5146. Brawer M K, Lin D W, Williford W O et al. Effectsof finasteride and/or terazosin on serum PSA:results of VA Cooperative Study #359. Prostate1999; 39: 234–23947. Tarle M, Kraus O, Trnski D et al. Early diagnosisof prostate cancer in finasteride treated BPHpatients. Anticancer Res 2003; 23: 693–69648. Kashif K M, Foley S J, Basketter V, Holmes S A.Haematuria associated with BPH—natural historyand a new treatment option. Prostate CancerProstatic Dis 1998; 1: 154–15649. Perimenis P, Gyftopoulos K, Markou S, BarbaliasG. Effects of finasteride and cyproterone acetate onhematuria associated with benign prostatic hyperplasia:a prospective, randomized, controlled study.Urology 2002; 59: 373–37750. Kearney M C, Bingham J B, Bergland R et al.Clinical predictors in the use of finasteride for controlof gross hematuria due to benign prostatichyperplasia. J Urol 2002; 167: 2489–249151. Pareek G, Shevchuk M, Armenakas N A et al. Theeffect of finasteride on the expression of vascularendothelial growth factor and microvessel density:a possible mechanism for decreased prostatic bleedingin treated patients. J Urol 2003; 169: 20–2352. Haggstrom S, Torring N, Moller K et al. Effects offinasteride on vascular endothelial growth factor.Scand J Urol Nephrol 2002; 36: 182–18753. McConnell JD, Roehrborn CG, Bautista OM et al.Medical Therapy of Prostatic Symptoms (MTOPS)Research Group. The long-term effect of doxazosin,finasteride, and combination therapy on theclinical progression of benign prostatic hyperplasia.N Engl J Med 2003; 18; 349: 2387–2398

Finasteride in the treatment ofbenign prostatic hyperplasiaJ D McConnell4INTRODUCTIONThe androgen dependency of the prostate isresponsible both for the development of benignprostatic hyperplasia (BPH) in older men and thereduction in symptoms associated with finasteridetherapy. Dihydrotestosterone (DHT),which is converted from testosterone by two 5αreductaseisozymes, accounts for around 90% ofall intraprostatic androgens. Finasteride is aninhibitor of the type II isozyme of 5α-reductase,which effectively reduces testosterone conversionto DHT in the prostate and thereby improves theurinary symptoms associated with BPH.The use of finasteride since its approval over adecade ago is supported by a wealth of clinicalexperience, with long-term studies indicatingthat the drug not only prevents acute urinaryretention (AUR) but may delay the need for invasivetherapy indefinitely or negate it altogether inresponders.It has been suggested that men with largerprostates are more likely to respond to treatmentwith finasteride than those with smaller glands.Reductions in libido and other sexual effects havealso been reported in a minority of patients, andthe reduction in prostate-specific antigen (PSA)levels may also have a bearing on the use of thedrug. The clinical relevance of these assumptionswill be examined in this chapter.BPH affects the majority of older Westernmen and, as the age of the general populationincreases and improvements in healthcare provisionoccur in the developing world, the prevalenceof this disease will grow. Pharmacologictreatments with a range of mechanisms of actionare therefore desirable. Effective patient selectionand the use of finasteride as monotherapy or incombination with other preparations also ensurethe continued place of the drug in the armory ofanti-BPH agents.DHT AND 5α-REDUCTASEThe prostate is highly dependent on testicularandrogens for its development and functionalintegrity. BPH develops in older men as a functionof sensitivity to these testicular androgens,specifically DHT. 1 Serum and prostatic DHTlevels remain stable, unlike testosterone, whichfalls over time.The role that androgens play in hyperplasticand normal prostatic growth is governed by thelevels of DHT that bind to androgen receptorswithin the epithelium of the prostate. This complexplays a critical role in stimulating androgenmediatedprostatic growth. 2,3 The characteristicreduction in androgen-dependent growthobserved with aging in some other tissues doesnot occur in the prostate. 4Testosterone is reduced to DHT through theaction of 5α-reductase. Two forms of this enzymehave been identified: type I, which is found ingreater proportions in the skin and liver, and typeII, which is the predominant isozyme containedin the prostate. 153

54THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAThe role of DHT and, by definition, the proteinresponsible for its reduction, in the developmentof BPH was determined following the identificationof 5α-reductase deficiency in a group ofindividuals with pseudohermaphroditism 5–7 .Virilization occurred at puberty in these individuals,although their prostates remained nonpalpable,and male sexuality was in evidencealongside normal muscular composition. This,plus the observation that men with castrate levelsof testosterone do not develop BPH and havevery low levels of DHT, indicated that blockadeof prostate-specific androgens could reduce thesize of the prostate, thereby relieving obstructiveurinary symptoms with limited adverse sexual orphysical implications.THE DEVELOPMENT OF FINASTERIDEThe above observations led to the development ofsynthetic 4-azasteroid α-reductase inhibitors.These agents were designed to reduce levels oftype II 5α-reductase, the isozyme that predominatesin the prostate (Figure 4.1).One compound, N-(2-methyl-2-propyl)-3-oxo-4-aza-5-α-androst-1-ene-17-β-carboxamide(finasteride), was found to reduce levels of DHTin the canine prostate and reduce prostatic volumeby up to 64%. 8 Further studies showed thattestosterone levels were unaffected by the drug,indicating that sexual function should bemaintained. 9,10As anticipated, intraprostatic testosterone levelswere elevated, however, and serum and prostaticDHT were not completely inhibited, due toformation via the uninhibited type I 5α-reductase.11MODE OF ACTIONFinasteride, which reduces serum DHT byaround 70% and prostatic DHT by 85–90%(Figure 4.2), 12 is thought to act predominantly onthe epithelium of the prostate, exerting its beneficialclinical effect by altering prostatic tissue compositionand inhibiting cell proliferation. 13–16 ATTARTFinasteride5αDHTARDHTONHt-BUHDNAH HONHFIGURE 4.1 Structure of finasteride.FIGURE 4.2 Action of finasteride. Free testosterone (T),predominantly manufactured by the testes, enters theprostate where it binds to an androgen receptor (AR) or isconverted to dihydrotestosterone (DHT) by 5α-reductase(5α). DHT will also bind to the androgen receptor, with agreater affinity than testosterone. T or DHT then influencesDNA transcription.

FINASTERIDE IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 5524- to 30-month open-label extension study offinasteride in a group of 19 men whose prostateswere assessed by magnetic resonance imaging(MRI) and biopsy revealed a reduction in symptoms,PSA, DHT, and prostate volume after 6months. 14 The percentage of prostate volumeattributed to epithelium shrank significantlyfrom 19.2% to 12.5% at intermediate follow-upand to 6.4% at long-term follow-up. Changes inthe transforming growth factor beta (TGFβ) signalingsystem, in terms of upregulation of TGFβsignaling receptors and a subsequent increase inepithelial apoptosis, may be instrumental in thisprocess.The inhibition of prostatic cell proliferationhas been demonstrated in several studies. 15,16Stromal and epithelial prostate cells from hyperplasticand normal glands treated in vitro withfinasteride in the presence of labeled thymidinerevealed that normal stromal cells incorporatedmore thymidine than epithelial cells. Finasteridetreatment resulted in 80 ± 3% and 55 ± 10%thymidine incorporation in stromal and epithelialcells, respectively, while rates of 70 ± 4% and74 ± 4% were observed in hyperplastic tissue.Measurement of 5α-reductase activity showedthat type II activity was reduced 100-fold whiletype I activity was reduced 5-fold, demonstratingthe selectivity of finasteride for the formerisozyme. 16 The incomplete inhibition of cell proliferationobserved indicates the action of factorsother than DHT in prostate cell proliferation,however. 15Locally produced growth factors, such as basicfibroblast growth factor (bFGF), insulin-likegrowth factor (IGF), and keratinocyte growthfactor (KGF), may also have an impact on prostaticenlargement, 17,18 stimulating an increase inlevels of mitosis in the prostatic stroma (Figure4.3). Analysis of bFGF expression and that offibroblast growth factor receptor types 1 and 2(FGFR1, FGFR2) in finasteride-treated anduntreated BPH patients revealed strong bFGFimmunoreactivity in the stroma and weakerimmunoreactivity in the epithelium of theuntreated patients, and virtually no immunoreactivityin the epithelium and lower stromalimmunoreactivity in finasteride-treated patients.This suggests that finasteride treatment leads todownregulation of bFGF activity, thereby limit-SecretoryEpithelialcompartmentParacrine interactions:stimulation/inhibitionbFGFKGFIGFDHTBasalTGFβ…StromalcompartmentFIGURE 4.3 Locally produced growth factors influence prostatic cell proliferation and apoptosis.

56THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAing the growth-stimulating action of this protein.Epidermal growth factor (EGF) appears to beunaffected by finasteride treatment, however,with only small changes observed in levels ofTGF-α and EGF receptors after treatment, indicatinga potential means of continued growth ofandrogen-independent basal prostatic epithelialcells. 19CLINICAL EXPERIENCE WITH FINASTERIDEFinasteride was first launched in 1992 and is currentlyprescribed in developed countries worldwide.The duration of its clinical usage meansthat a range of long-term studies and meta-analysesare available as evidence of its safety and efficacy(Table 4.1). Men treated with 5 mg finasteridehave been consistently shown to exhibitsignificant improvements in peak urinary flow(Q max) and reductions in obstructive symptomsand prostatic volume in both older and youngermen. 20–28 Incidence of sexual dysfunction, interms of lower libido, ejaculatory dysfunction,and impotence, is greater in men who receive thedrug, although the majority of patients remainunaffected.The Proscar (finasteride) Long-term Efficacyand Safety Study (PLESS) investigated the effectsof finasteride relative to placebo over a 4-yearperiod. 22 Over 3000 men aged 45–78 with moderateto severe BPH were randomized to receiveeither 5 mg finasteride or placebo. Risk of acuteurinary retention (AUR) or BPH-related surgerywas significantly lower (–55–57% relative risk) inthe finasteride group compared to placebo overthe study period (Figure 4.4). Quasi-AUA symptomscore improved in this group (3.3 versus 1.3points) and prostate volume fell (–18% versus+14% for placebo). In 4 years, 6.6% of the placebogroup experienced AUR compared to 2.8% of thefinasteride group (p = 0.001). 23 As a result ofAUR, surgery was then performed in 75% of theformer and 40% of the latter group (p =0.01).Prostate volume and PSA level were powerfulpredictors of risk of AUR or BPH-related surgeryin this patient group. 27 Risk of AUR or surgeryranged from 8.9% to 22%, depending onprostate volume, and from 7.8% to 19.9%depending on PSA level.In PLESS, only three drug-related sideeffectsoccurred within the first year with an incidenceof > 1%: impotence (8.1% versus placebo3.7%); decreased libido (6.4% versus 3.4%), anddecreased ejaculate volume (3.7% versus 0.8%).Further analysis of PLESS data showed thatfinasteride was effective and safe in both older(≥65 years) and younger (45–64 years) patients,with no additional risk of drug-related adverseevents in the older cohort. 24 Spine bone mineraldensity, for example, was unaffected by 4-yearfinasteride administration. 29Longer-term studies indicate that the efficacyof finasteride is durable and that, in responders,the drug negates the need for prostatic surgeryaltogether. 25–27 Men prescribed open-label finasteridefor a 7- to 8-year period (n = 71) after takingpart in two short-term phase II trials werefound to maintain the reductions in Boyarskysymptom score seen after 1 year over the following6 years. 25 Baseline DHT fell by 85% over thestudy period while serum PSA fell by 45%.Prostate volume fell by 25% from average baseline61.2 g after 1 year and this was sustained after7 years. Sexual side-effects (impotence, abnormalejaculation, and low libido) occurred most oftenduring the first year of extension and decreasedover the extension period. Discontinuation due tosuch effects was 1.9% in year 1 and 0% after year4. Likewise, only minor reductions in sexual

FINASTERIDE IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 57TABLE 4.1 Long-term finasteride trials.Reduction in Reduction in BPH- Prostate SymptomStudy Duration Regimen AUR risk related surgery risk volume Q maxscore Side-effectsRoehrborn et al. 23 4 years 5 mg FIN/day 57% 55% –18% +1.9 ml/s –3.3 ED 8.1%or placebo L LIB 6.4%EJD 3.7%Vaughan et al. 25 7–8 years 5 mg FIN/day — — –25% +20% 1-year 1st year, ED 6.4%(or 10 mg 1st year) improvement L LIB 10.9%maintained EJD 5.8%few new casesthereafterEkman et al. 26 6 years 5 mg FIN/day — — –21% +2.2 ml 30% 0.6–1.7% drop-outimprovement to SD each yearLam et al. 27 10 years 5 mg FIN/day — — — — 55.8% Treatment durationtreatment not linked to sidesuccesseffectsBoyle et al. 43 N/A — — — — 0.89–1.84 ml* + 1.8–2.8* —meta-analysis* Depending on prostate volume; larger prostates linked to greater improvement. ED, erectile dysfunction; FIN, finasteride; L LIB, lowered libido; EJD, ejaculatorydysfunction; SD, sexual dysfunction.

58THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA1210FinasteridePlacebo86420AUR (%) Surgery (%) Decrease in symptomscore (points)FIGURE 4.4 Reduced risk of acute urinary retention (AUR) and BPH-related surgery with finasteride.function were observed in a 6-year extensionstudy of the drug. 26A 10-year follow-up study suggested thatappropriately selected patients, often with largerprostates, could be effectively treated for BPHsymptoms with finasteride over this extendedtime period. 27 Of an original 43 patients whoentered phase III 12-month double-blind trials,41 completed the year and 30 continued to takethe drug for a further 4 years. Twenty-two continuedtreatment for a further 10 years, indicatinga 48.8% overall discontinuation rate, but only26.7% between 5 and 10 years. In total, 24 (56%)were judged to be successfully treated over the10-year follow-up. The majority of withdrawalsdue to treatment failure occurred in the first 1 or2 years, suggesting continued therapeutic successin initial responders.The adverse event profiles in the 1-year,placebo-controlled, phase III studies, the 5-yearopen extension study, and PLESS are similar.Overall, therefore, there is no evidence ofincreased side-effects with increased duration oftreatment.Adverse treatment effects are, by and large,limited to sexual dysfunction; 25,26 however, fewpatients report such effects overall and superficialanalysis would appear to indicate that numbersare similar across alternative treatment options 30(Figure 4.5). A study of 670 BPH patients treatedwith a range of medical and surgical options andwatchful waiting (n = 90 (α-blocker 43, finasteride47), 207, and 234, respectively involvedassessment of sexual effects by questionnaire 9months after surgery or the initiation of therapy.Libido, sexual activity, potency, and penile rigiditywere determined. An improvement of between7 and 14% was reported for libido for all treatments(α-blocker 3%, finasteride 8%) and deteriorationin libido was reported by between 7 and14% (α-blocker 14%, finasteride 8%) of all participants.Similar results were observed for sexualactivity and erectile capacity; however, completeresults for rigidity were not available for finasteride-treatedpatients.A similar degree of improvement in urinarysymptoms and quality of life has been reported insome studies of 5α-reductase inhibitors and α-blockers. For example, a randomized study oftamsulosin (0.2 mg) and finasteride (5 mg)showed both drugs to result in similar improvementsin a group of Korean BPH patients

FINASTERIDE IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 59Rigidity Erection Sexual activity Libido* No data availableWatchfulwaiting*Finasterideα-BlockersSurgery–20 –15 –10 –5 00 5 10 15Deterioration (%) Improvement (%)FIGURE 4.5 Percentage of patients with improved and reduced sexual function following BPH treatment.(n = 205) after a period of 24 weeks. I-PSS, Q max,and quality of life improved in both groups withno significant difference between scores at endpoint;however, analysis at 4 weeks showed tamsulosinto have a swifter time to onset. 31COMBINATION STUDIESThe different mode of action of 5α-reductaseinhibitors and α-blockers has led to the assumptionthat a combination of both drug types mayincrease clinical improvement in BPH patients,due to the dual effects of inhibiting cell proliferationand altering the smooth muscle tone of theprostatic stroma and detrusor.The most comprehensive evaluation of theclinical potential of combination therapy hasbeen the Medical Therapy Of ProstaticSymptoms (MTOPS) study. This trial indicatedthat the combination of finasteride with doxazosinboth slows the progression of BPH andreduces risk of AUR to a greater extent thaneither type of therapy alone. 32 This studyinvolved a total of 3047 BPH patients whoreceived monotherapy, placebo, or combinationtherapy for an average of 5 years. Finasteride ordoxazosin monotherapy brought about reductionsin risk of disease progression of 34% and39%, respectively, while combination therapy wasassociated with a 67% reduction in risk (Figure4.6). AUR risk was cut by 79% in this group comparedto 67% in the finasteride group and 31% inthe doxazosin group. Reductions in risk of BPHsurgery were 69%, 64%, and 8% relative to placeboin each group, respectively. No increase inside-effects was observed with combination treatment.The results suggest that enlargement of theprostate is slowed by finasteride while the symptomsof BPH are reduced by doxazosin.Interestingly, the combination of the two drugsreduces the risk of clinical progression even in

60THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA0Progression AUR Surgery–20% Reduction–40–60–80–100Finasteride Doxazosin CombinationFIGURE 4.6 MTOPS—reductions in disease progression with combination treatment. AUR, acute urinary retention.men with only modest prostate enlargement(25–40 cc). 33Investigation of baseline characteristics andsubsequent progression of the men in theMTOPS placebo group (n = 737) indicated thateasily obtainable measures, such as PSA level,Q max, postvoid residual urine, and prostate volume,correlate significantly with disease progressionand the need for surgery. 34 Such an approachmay allow improved patient selection to ensureoptimum clinical results.Additional research has suggested that it maybe possible to discontinue combination therapyafter 1 year with no compromise in clinical benefit.35 A group of BPH patients (n = 270) were prescribed2, 4, or 8 mg doxazosin alongside 5 mgfinasteride for a period of 3, 6, 9, or 12 months,after which the α-blocker was discontinued. Ofthose who discontinued doxazosin at 12 months,84% of the 2 mg group, 85% of the 4 mg group,and 87% of the 8 mg group experienced noincrease in AUA symptom score and reported nodesire to resume taking doxazosin 1 month later.In studies of generally shorter duration andreduced patient numbers the results with combinationshave not been as conclusive. The additionof finasteride to terazosin in the Veterans’ AffairsCooperative Studies BPH Study Group, whichinvolved 1229 patients, conveyed no additionalbenefit compared to terazosin monotherapy after1 year. 36 The relatively low average prostate volumeof the men involved in this study(36.2–38.4 ml) could explain the limited improvementobserved in patients treated with finasteridealone, due to the correlation between gland sizeand clinical response observed in several studies.37,38 Pharmacokinetic interactions betweenfinasteride and terazosin, but not doxazosin mayalso have a bearing on clinical response to differentcombination therapy regimens. 39A 6-month trial of sustained-release alfuzosin(5 mg), finasteride (5 mg), or both drugs in 1051men yielded similar findings to the VACooperative trial, with higher symptom improvementobserved in patients who received α-blockadeor combination therapy. 40 The short-termnature of this trial precludes any definitive conclusions,however.An additional 1-year randomized placebocontrolledstudy involved 1007 men who received

FINASTERIDE IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 61finasteride (5 mg) or doxazosin (1–8 mg, titrated)monotherapy, combination therapy, or placebo.Results indicated no additional benefit of finasterideto doxazosin therapy. 41 Again, meanprostate size was relatively small, at 36.3 g, whichmay explain the lack of observed efficacy of finasteride.No stratified analysis based on prostatevolume was performed.The role of prostate volume is illustrated by afurther trial of finasteride, alfuzosin, or a combinationof both in a group of 138 men with I-PSS> 13 and prostate volume of at least 60 ml.Overall, 96% of patients in the combinationgroup showed improved Q maxand I-PSS, comparedto 84% in the α-blocker alone group and74% in the finasteride group. 42Meta-analysis of six randomized clinical trialsinvolving finasteride (Table 4.2) provides furtherevidence of the role of prostate volume inresponse to therapy, with men with largerprostates showing particularly good response totreatment with finasteride. 43,44 Over 2600 individualswere included in this study, which includedall finasteride studies and phase III trials plus anumber of other trials including the VACooperative Study. Men with prostates smallerthan 20 g were less likely to show clinicalimprovement in quasi-I-PSS symptom score andQ maxcompared to those with prostates larger than60 g (1.8 versus 2.8 points and 0.89 ml versus1.84 ml, respectively). Improvements werejudged to become significant in men withprostates greater than 40 ml, i.e. 50% of the entirepopulation, and the results indicate that prostatevolume is a significant predictor of response totherapy.ADDITIONAL CONSIDERATIONSHematuriaHematuria, which often emerges secondary toBPH, is associated with significant morbidity,including anemia and clot retention. Recentresearch has shown that the condition may besuccessfully treated with finasteride and otheranti-androgens. 45–47 Although the exact mechanismis not understood, histochemical studieshave suggested that this is due to decreasedexpression of vascular endothelial growth factor(VEGF) following finasteride treatment which,as a consequence, lowers microvessel density inthe prostatic suburethra. 48,49 Such mechanismscould explain the reduction in hematuria andTABLE 4.2 Studies included in meta-analysis of finasteride.Patients Age Prostate volume Peak flow Quasi-I-PSSStudy (n) (mean) (mean ml) (mean ml) (mean)Gormley et al. 20 567 64.1 59.9 9.6 12.1The Finasteride Study Group 60 447 65.5 48.1 8.9 11.8Andersen et al. 60 384 65.3 41.3 10.2 10.1Lepor et al. 36 601 65.7 37.5 10.4 13.4Nickel et al. 62 554 63.3 45.9 11.0 12.4Bonilla et al. 63 188 56.4 41.6 15.8 9.3

62THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAintraoperative blood loss observed when patientsdue to undergo transurethral resection of theprostate (TURP) receive finasteride treatmentpreoperatively. 50,51Investigation of potential predictors of clinicalresponse to finasteride treatment in patients withgross hematuria revealed that 94% responded totreatment and that 77% suffered no furtherbleeding while taking the drug. 47 Treatment waseffective in patients taking a range of anticoagulants.Recurrent but lower-grade bleeding andslower response time were identified in men withlarger prostates. Men with smaller prostates andthose who had undergone previous prostatectomyhad more rapid responses to treatment (2.7days in men with glands < 40 g versus 45 days inthose with glands 100–150 g and 5.5 days in menwho had undergone prostatectomy versus 18.6days in those who had not).PSAPSA levels have been found to fall followingapplication of finasteride to prostate cells treatedin vitro with testosterone. 52 In vivo studies haveshown that plasma and serum complexed-to-totaland free-to-total ratios remain constant withfinasteride treatment, indicating that proportionalreduction in all molecular forms of PSA occurswith finasteride treatment. 53–55 Measurement ofthese PSA forms could potentially be used toscreen for prostate cancer in men receiving finasteride,but this requires further investigation. 55,56The effect of finasteride on overall PSA levelshas implications for prostate cancer screening butmay also impact upon actual risk of prostate cancer.A case–control study of the medication use in639 men with prostate cancer and 659 tumor-freecontrols indicated that, after adjustment for confounders,finasteride has a protective role againstprostate cancer while nonaspirin nonsteroidalanti-inflammatory drugs (NSAIDs) have no protectiveinfluence. 57Further evidence of the potential preventativerole of finasteride has been recently highlightedin a large-scale study of the incidence of prostatecancer among men aged ≥55 years prescribedfinasteride or placebo over 7 years. 58 Men whoreceived the active agent were significantly lesslikely to develop prostate cancer during the studythan those prescribed placebo (p = 0.001),although when cancer did develop in this group,it was more likely to be of a higher Gleason gradethan in the placebo group. Whether the benefitsof reduced likelihood of prostate cancer developmentand urinary symptoms outweigh the risksof higher-grade tumor development and sexualside-effects requires further investigation.CONCLUSIONSPatient perception of finasteride has been shownto be excellent. In a survey of French BPHpatients, the primary preoccupations were reportedas a reduced risk for urological complicationsand need for surgery, with improved symptomsand quality of life of secondary importance.These expectations were easily met by finasteridein the majority of cases, and 89% of participantsreported good or extremely good improvementof symptoms, with very few tolerabilityissues. 59The studies outlined here indicate that finasterideis an effective long-term treatment optionfor BPH. The benefit of finasteride over placebohas been repeatedly proven in well-designedlarge-scale clinical trials and comparison studieshave shown the drug to be of similar efficacy interms of AUR prevention and necessity for BPHsurgery to α-blockers in well-chosen patientgroups. Men with larger prostates appear to ben-

FINASTERIDE IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 63efit particularly from finasteride therapy.Response to therapy has been shown to haveexceptionally long duration in responders,exceeding 10 years in many cases. The data fromthe MTOPS study indicate that the drug has furtherpotential when used in combination with α-blockers. On this basis, future treatment algorithmscould include both a 5α-reductaseinhibitor and α-receptor antagonist, dependingon the initial clinical presentations.The effects of finasteride on PSA level havebeen frequently documented; however, recentfindings regarding the lack of effect of the drugon free-to-total PSA ratio may mean that suggestionsthat prostate cancer detection may be compromisedcan largely be dismissed. Further investigationof this aspect is required, however.REFERENCES1. Lee C, Kozlowski J M, Grayhack J T. Aetiology ofbenign prostatic hyperplasia. Urol Clin North Am1995; 22: 237–2462. Walsh P C, Hutchins G M, Ewing L L. Tissue contentof dihydrotestosterone in human prostatichyperplasia is not supranormal. J Clin Invest 1983;72: 1772–17773. Traish A M, Wotiz H H. Prostatic epidermalgrowth factor receptors and their regulation byandrogens. Endocrinology 1987; 121:1461–14674. Wilson J D. The pathogenesis of benign prostatichyperplasia. Am J Med 1980; 68: 745–7565. Walsh P C, Madden J D, Harrod M J et al. Familialincomplete male pseudohermaphroditism, type 2:decreased dihydrotestosterone formation inpseudovaginal perineoscrotal hypospadias. N EnglJ Med 1974; 291: 944–9496. Imperato-McGinley J, Guerrero L, Gautier T,Peterson R E. Steroid 5a-reductase deficiency inman: an inherited form of male pseudohermaphroditism.Science 1974; 186: 1213–12157. Thigpen A E, Davis D L, Milatovich A et al.Molecular genetics of steroid 5α-reductase 2 deficiency.J Clin Invest 1992; 90: 799–8098. Brooks J R, Berman C, Garnes D et al. Prostaticeffects induced in dogs by chronic or acute oraladministration of 5 alpha-reductase inhibitors.Prostate 1986; 9: 65–759. Rittmaster R S, Stoner E, Thompson D L et al.Effect of MK-906, a specific 5α-reductase inhibitor,on serum androgens and androgen conjugates innormal men. J Androl 1989; 10: 259–26210. Vermeulen A, Giagulli C A, Schepper P D et al.Hormonal effects of an orally active 4-azasteroidinhibitor of 5α-reductase in humans. Prostate 1989;14: 45–5311. Thigpen A E, Silver R I, Guileyardo J M et al.Tissue distribution and ontogeny of steroid 5alpha-reductase isozyme expression. J Clin Invest1993; 92: 903–91012. Bartsch G, Rittmaster R S, Klocker H. Dihydrotestosteroneand the concept of 5 alpha-reductaseinhibitors in human benign prostatic hyperplasia.Eur Urol 2000; 37: 367–38013. Marks L S, Partin A W, Dorey F J et al. Long-termeffects of finasteride on prostate tissue composition.Urology 1999; 53: 574–58014. Saez C, Gonzalez-Baena A C, Japon M A et al.Regressive changes in finasteride-treated humanhyperplastic prostates correlate with an upregulationof TGF-beta receptor expression. Prostate1998; 37: 84–9015. Lobaccaro J M, Boudon C, Lechevallier E et al.Effect of finasteride (Proscar) on the proliferationof cultured epithelial and stromal cells from normaland hyperplastic human prostates. Cell MolBiol (Noisy-le-grand) 1996; 42: 511–51816. Feneley M R, Span P N, Schalken J A et al. Aprospective randomized trial evaluating tissueeffects of finasteride therapy in benign prostatichyperplasia. Prostate Cancer Prostatic Dis 1999; 2:277–28117. Saez C, Gonzalez-Baena A C, Japon M A et al.Expression of basic fibroblast growth factor and itsreceptors FGFR1 and FGFR2 in human benign

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66THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA55. Tarle M, Kraus O, Trnski D et al. Early diagnosisof prostate cancer in finasteride treated BPHpatients. Anticancer Res 2003; 23: 693–69656. Keetch D W, Andriole G L, Ratliff T L, CatalonaW J. Comparison of percent free prostate-specificantigen levels in men with benign prostatic hyperplasiatreated with finasteride, terazosin or watchfulwaiting. Urology 1997; 50: 901–90557. Irani J, Ravery V, Pariente J L et al. Effect of nonsteroidalanti-inflammatory agents and finasterideon prostate cancer risk. J Urol 2002; 168: 1985–198858. Thompson I M, Goodman P J, Tangen C M et al.The influence of finasteride on the development ofprostate cancer. Published at www.nejm.org 24June, 2003 (doi: 10.1056/NEJMoa030660)59. Teillac P. Benign prostatic hyperplasia: patients’perception of medical treatment and their expectations.Results of a French survey involving patientstreated with finasteride [in French]. Therapie 2002;57: 473–48360. The Finasteride Study Group. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia.Prostate 1993; 22: 291–29961. Andersen J T, Ekman P, Wolf H et al. and theScandinavian BPH Study Group. Can finasteridereverse the progress of benign prostatic hyperplasia?A two-year placebo-controlled study. Urology1995; 46: 631–63762. Nickel J C, Fradet Y, Boake R C et al. Efficacy andsafety of finasteride therapy for benign prostatichyperplasia: results of a 2-year randomized controlledtrial (the PROSPECT study). PROscarSafety Plus Efficacy Canadian Two year Study.CMAJ 1996; 155: 1251–125963. Bonilla J, Stoner E, Grino P et al. Intra- and interobservervariability of MRI prostate volume measurements.Prostate 1997; 31: 98–102

Combination therapy in thetreatment of BPHC G Roehrborn5INTRODUCTIONTreatment for benign prostatic hyperplasia(BPH) in recent years has been characterized by afall in the use of surgical procedures, mainlytransurethral resection of the prostate (TURP),and a rise in the use of minimally invasive treatmentsand, particularly, medical therapy. 1–3Up to 90% of men in their eighties are estimatedto suffer from BPH to some extent andprevalence of the disease is growing. 4Development of the associated symptomatologyis androgen-dependent, and castration before orduring puberty prevents its occurrence. Lowerurinary tract symptoms (LUTS) secondary toBPH occur due to increased sensitivity to circulatingandrogens in the prostate. Increased cellproliferation, mainly in the transition zone of theprostate, occurs alongside a rise in the smoothmuscle tone of both the prostate and bladderneck. Symptoms of reduced urinary flow and urinaryretention, increased urinary frequency, andnocturia are particularly common. 5Pharmacologic therapies available for thetreatment of LUTS include α-adrenoceptorantagonists (α-blockers), such as terazosin, doxazosin,alfuzosin, and tamsulosin, and the 5αreductaseinhibitors, finasteride and dutasteride.Other strategies, such as plant-derived medicationor watchful waiting, are applied to varyingextents.Alpha-blockers act on the α-adrenoceptors ofthe prostate and bladder neck, thereby reducingthe sympathetic nervous system controlled tone ofthe smooth muscle. Many placebo-controlled trialsof α-blockers have shown them to increaseurinary flow and relieve irritative and obstructivesymptoms, often within as little as 2 weeks oftreatment. 6–11In contrast, 5α-reductase inhibitors reducethe formation of dihydrotestosterone (DHT)from testosterone in the prostate and therebyincrease rates of apoptosis and reduce rates of cellproliferation. Enlarged prostate glands thereforeshrink, causing alleviation of BPH symptoms andurinary flow in the process, 12–14 as proven byplacebo-controlled trials. 15–17 More recently, it hasbeen shown that the risks of acute urinary retention(AUR) and BPH-related surgery are reducedin men receiving finasteride by 55% and 57%, 15respectively. However, symptom improvementmay only be observed after up to 6 months oftreatment 15,16 and, indeed, it has been suggestedthat the clinical benefit is limited to men withlarger prostates. 16,18The recent development of diverse formulationsof pharmacologic therapies, such as the doxazosingastrointestinal therapeutic system (GITS)and doxazosin XL, has increased patient andphysician treatment choice. 10 Further alterationsin the pharmacokinetic profiles of available drugsare possible, however such avenues may be limited.In real terms we may have reached the limit ofclinical benefit that can be achieved by monotherapy.Alternative pharmacologic treatment strategiesfor targeting BPH are therefore desirable.Given the different mechanisms of action ofα-blockers and 5α-reductase inhibitors, a67

68THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAcombination of each of the drug classes in a singledrug regimen might logically be expected to conveycumulative benefit to BPH patients. 19 Severallarge-scale studies have been performed in recentyears to determine whether the administration ofan α-blocker in combination with a 5α-reductaseinhibitor leads to greater improvement in BPHsymptoms than either one individually andwhether the side-effects documented with eachdrug class occur with greater frequency in combination.The following represents a summary of thesalient findings from the most important combinationstudies that have been completed.TERAZOSIN AND FINASTERIDEVA Cooperative StudyThe first large-scale trial established to examinethe potential benefits of combining an α-blockerwith a 5α-reductase inhibitor was the Veterans’Affairs (VA) Cooperative Study. 6 This multicentertrial compared the use of terazosin and finasterideindividually and in combination.The double-blind, placebo-controlled trialinvolved 1229 men (87% white, 11% black, 1%Asian/Pacific Islanders, 0.5% Native Americans)aged 45–80 suffering from symptomatic BPH.Baseline measures were obtained during an initial1-month wash-out period and includedAmerican Urological Association (AUA) symptomscore, peak urinary flow (Q max), and volumeof postvoid residual urine (PVR). Prostate-specificantigen (PSA) levels were recorded andtransurethral ultrasound examination of theprostate was also performed.Participants had an AUA symptom score of≥8, Q maxof 4–15 ml/s, minimal voided volume of125 ml and PVR of < 300 ml. After the wash-outperiod, they were randomized to receive 5 mgfinasteride, terazosin titrated to 10 mg, a combinationof both drugs, or placebo for a period of 1year.Clinical evaluation, in terms of uroflowmetry,symptom score, PVR, and adverse effects, tookplace at 2, 4, 13, 26, 39, and 52 weeks. Transrectalultrasound examination took place at the halfwaypoint and on completion of the study. PSAwas recorded at the end of the study period.Drop-out rates were similar between groupsafter 1 year, although discontinuation due toadverse effects was less common in the placebogroup (p < 0.05). Overall, men receiving terazosineither alone or in combination were more likelyto suffer dizziness and men receiving finasteridealone or in combination were more likely to experienceerectile dysfunction (ED) or loweredlibido. Ejaculatory dysfunction was significantlymore common in men receiving combinationtherapy. Compliance was similar between all fourtreatment groups, however.Examination of symptom scores revealed thatmen receiving terazosin alone or in combinationwith finasteride had improved symptoms comparedto both the finasteride and placebo groups(p < 0.001), with respective point reductions of6.1, 6.2, 3.2, and 2.6 (Figure 5.1). Peak improvementlevels were attained in the terazosinexposedgroups by 13 weeks and did not differsignificantly between this point and completionof the study. The improvements in symptomscore were accompanied by significant increasesin Q max(p < 0.001 for terazosin and combinationtherapy compared to finasteride alone and placebo),which were greatest after 4 weeks. Meanincreases in Q maxat 52 weeks were 3.2, 2.7, 1.6,and 1.4 ml/s, respectively.Significant reductions in prostatic volumewere observed in the finasteride and combination

COMBINATION THERAPY IN THE TREATMENT OF BPH 69Reduction in AUA symptom scoreIncrease in Q maxterazosinterazosin + finasteridefinasterideplacebo****0 2 4 6 8 0 2 4 6Pointsml/s*p < 0.001 for comparisons with placebo or finasteride aloneFIGURE 5.1 VA Cooperative Study: symptom improvement at 1 year according to treatment group. AUA, AmericanUrological Association; Q max, peak urinary flow.therapy groups (–61 ml and –70 ml, respectively)but no significant change was observed in thisvalue in the other two groups. PSA was also significantlyreduced in the finasteride and combinationgroups (p < 0.001) while increases werenoted in men who received terazosin alone orplacebo (p

70THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAwith terazosin. 26 The pharmacokinetic profile ofterazosin was not altered, however. Whether thisrelationship is significant in terms of drug efficacyis as yet unknown.ALFUZOSIN AND FINASTERIDEALFIN studyThe α-blocker alfuzosin is a uroselective preparationthat targets the α 1-adrenoceptors of theprostate. Animal studies have shown alfuzosin toexert its effect at doses below the threshold ofinfluence on the cardiovascular system. 28–30 Itdoes not require titration to its optimum dosage.A 6-month evaluation of the effects of combining5 mg twice-daily (sustained-release alfuzosin)with 5 mg once-daily finasteride (theALFIN study) showed similar effects to the VAstudy described above. 31 Again, the α-blockerwas shown to improve symptoms of LUTS secondaryto BPH to a greater extent alone or incombination compared to finasteride.The ALFIN study involved 1051 BPHpatients aged between 50 and 75 from 11European countries. Participants had anInternational Prostate Symptom Score (I-PSS)>7 and Q maxof between 5 and 15 ml/s. Theyunderwent a 2-week wash-out period prior torandomization to alfuzosin, finasteride, or a combinationof both.Clinical assessment took place at baseline andthen after 1, 3, and 6 months of therapy. I-PSSwas recorded alongside uroflowmetry, bloodpressure, and heart rate during these sessions,while prostate volume, measured usingtransurethral ultrasound, and PSA level wereassessed at baseline and on completion of thestudy. Adverse events were reported throughoutthe entire trial.All three patient groups were found to showimprovement over the study period (Figure 5.2).Mean I-PSS fell by 6.3 points in the alfuzosinalone group, 6.1 in the combination group, and5.2 in the finasteride alone group, but a significantlygreater improvement in the alfuzosin andReduction in I-PSSIncrease in Q maxalfuzosin*alfuzosin + finasteride†finasteride0 2 4 6 8 0 2 4 6Pointsml/s*p < 0.01 for alfuzosin vs finasteride† p < 0.03 for combination vs finasterideFIGURE 5.2 ALFIN Study: symptom improvement at 6 months according to treatment group. I-PPS, InternationalProstate Symptom Score; Q max, peak urinary flow.

COMBINATION THERAPY IN THE TREATMENT OF BPH 71combination groups compared to finasteride wasrecorded (p =0.01 and 0.03, respectively).Improvement of at least 50% was observed in 43,42, and 33% of the men in each group, respectively.Q maxincreased by similar degrees at 6 months(alfuzosin 1.8 ± 3.8 ml/s; combination2.3 ± 4.7 ml/s; finasteride 1.8 ± 4.5 ml/s); however,at 3 months, men in the alfuzosin and combinationgroups had greater Q maxthan those in thefinasteride alone group. Patients with a baselineQ maxof < 10 ml/s had a significantly greater Q maxat the end of the study period if they were treatedwith alfuzosin or combination therapy ratherthan finasteride alone, however (p = 0.05).Prostate volume and PSA level fell significantlyin the finasteride and combination therapygroups, but no significant change was observed inmen treated with alfuzosin alone.Similar numbers of adverse events wereobserved in all patient groups; however, sexualdysfunction, in the form of erectile dysfunction(ED) and ejaculatory disorders, was more commonamong finasteride-treated patients. Levels ofvasodilatory events, potentially linked to α-blockade, were similar between all three groups,as was incidence of AUR. This is in accordancewith previous reports of both drugs. 15,32The improvements observed with finasteridein this study are higher than those of the VAstudy, but are significantly lower than those seenwith α-blockade by alfuzosin. Patients were notselected or stratified according to prostate sizeand so the potential effects of this variable on outcomecould not be analyzed.A longer-term, but smaller-scale study indicatedthat the combination of alfuzosin and finasteridebrought about greater improvements in I-PSS and urinary flow. 33 One hundred and thirtyeightBPH patients with prostates ≥ 60 ml andI–PSS > 13 were treated with alfuzosin, finasteride,or both for 3 years. Improved urinary flowand I-PSS results were observed in 84%, 74%, and96% of patients, respectively. These findings haveyet to be confirmed by larger-scale trials, however.DOXAZOSIN AND FINASTERIDEPREDICTA large-scale, placebo-controlled study designedto evaluate the potential benefits of combining anα-blocker with a 5α-reductase inhibitor was conductedusing the α 1-selective adrenoceptor antagonistdoxazosin in the Prospective EuropeanDoxazosin and Combination Therapy (PRE-DICT) Trial. 34The 1-year trial took place at 90 centers inEurope. Following a 2-week run-in period, 1095men aged 50–80 with an I-PSS ≥12 and Q max≥ 5ml/s but ≤ 15 ml/s in a total void of 150 ml ormore, were randomized to receive doxazosinalone, finasteride alone, a combination of bothdrugs, or placebo for 52 weeks. Patients receivingdoxazosin underwent a 10-week titration period,while the dose was increased from 1 mg to 8 mgon the basis of treatment response as judged byI–PSS and Q max, as part of their regimen.Participants were assessed at baseline forI–PSS and Q maxand then at regular intervals (10,14, 26, 39, and 52 weeks) throughout the studyperiod. Blood pressure, heart rate, and adverseevents were also recorded regularly over the 12-month period, while PSA, electrocardiography,and standard blood tests were performed at baselineand then again on conclusion of the trial.Prostate volume was estimated using DRE.In total, 1007 patients were included in theintention to treat analysis. Mean doxazosin dose

72THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAwas 6.4 mg/day in the monotherapy group and6.1 mg/day in the combination group.Men who received doxazosin alone or in combinationhad significantly improved I-PSS resultscompared to those who received finasteride alone(p ≤ 0.0001) or placebo (p

COMBINATION THERAPY IN THE TREATMENT OF BPH 73trial, which progressed in parallel to these studies,has generated important new information onboth the clinical potential of 5α-reductaseinhibitors as monotherapy and the potential ofdrug combinations.The Medical Therapy of Prostatic Symptoms(MTOPS) trial, a prospective, randomized, double-blind,multicenter, placebo-controlled trial,was established to determine whether medicaltherapy can prevent or delay the progression ofBPH in the long term. 40 Further elucidation ofthe natural history of BPH, determining baselinefactors associated with more rapid disease progression,was a secondary aim of the study.In 18 academic centers across the US a total of3 047 patients were recruited and randomized toreceive doxazosin, finasteride, a combination ofboth, or placebo. 41 Mean age of participants was62.6 years, most were white (82.6%), with 8.8%black and 7.2% Hispanic participants. The inclusion/exclusioncriteria allowed men with allprostate sizes to be enrolled, as long as the serumPSA was less than 10 ng/ml. This resulted in awide distribution of prostate sizes and serumPSA values allowing for stratified analyses ofsubsets based on these criteria.Disease progression was defined as a worseningof BPH symptoms according to the AUAsymptom index (AUASI). 42 Progression wasdeemed to have occurred in the case of one of thefollowing: a 4-point rise in AUASI, confirmed bya second visit within 4 weeks; a 50% increase increatinine relative to baseline levels; AUR; two ormore urinary tract infections (UTIs) within 1year or a single episode of urosepsis due to bladderoutlet obstruction (BOO); socially unacceptableincontinence. The first occurrence of any ofthe above events indicated BPH progression.Progression as an endpoint represented a novelconcept at the time of the initiation of theMTOPS study, although the PLESS study as wellas the dutasteride studies later on utilized AURand surgery as endpoints in their study design. 15,17Entirely novel was the concept of utilizing athreshold to define symptom progression. Basedon data from the VA Cooperative study, in whichmen perceived general improvement in theirsymptom status once the AUASI improved bymore than 3 points, a threshold of 4 points waschosen — to be confirmed within 4 weeks — toindicate global subjective worsening of symptomstatus. 43To assess the natural history of BPH, Q max,prostate volume, sexual function, and quality oflife were regularly recorded with respect to BPHsymptoms. Transrectal ultrasound and DREwere used to evaluate prostate volume, the SexualFunction Inventory Questionnaire evaluated sexualityand the Short Form-36 Health Surveyinstrument recorded quality of life scores.Prostatic biopsies were obtained at baseline and at5 years (or at primary endpoint) in 37% of studyparticipants who volunteered to take part in abiopsy substudy.Patients were randomized to receive 5 mgfinasteride and doxazosin placebo, 5 mg finasterideand doxazosin titrated to up to 8 mg, titrateddoxazosin and finasteride placebo, or twoplacebo drugs.The results of the trial suggest that the combinationof doxazosin and finasteride exerts a clinicallyrelevant, positive effect on rates of diseaseprogression 44 (Figure 5.4). Men who receivedcombination therapy were significantly less likelyto experience BPH progression than those receivingeither monotherapy or placebo, with riskreduction rates of 39% for doxazosin, 34% forfinasteride, and 67% for combination therapycompared to placebo. Overall rates of BPH progressionevents are shown in Figure 5.5.

74THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA% risk reduction compared to placebo100806040200Doxazosin Combination FinasterideBPH progression Invasive therapy Acute urinary retentionFIGURE 5.4 MTOPS Study: risk reduction of BPH clinical progression, BPH-related invasive surgery, and acute urinaryretention in treated patients in comparison to placebo.Renal insufficiency (0%)AUR (12%)Incontinence (9%)UTI/urosepsis (1%)4 point AUA (78%)FIGURE 5.5 MTOPS Study: distribution of BPH progression events, all groups. AUR, acute urinary retention; UTI,urinary tract infection; AUA, American Urological Association.Invasive therapy and AUR risk were significantlyreduced by finasteride and combinationtherapy (by 69 and 64%, and by 79 and 67%,respectively), while all treatment regimens (placebo,doxazosin, finasteride, and combination)brought about a significant improvement inAUA symptom score (4.0, 6.0, 5.0, and 7.0, respectively)and Q max(1.4, 2.5, 2.2, and 3.7 ml/s, respectively)at 4 years.AUA symptom score and Q maximproved significantlymore in the combination therapy groupcompared to the monotherapy groups, whileadverse events were similar to previously reportedstudies.In addition to indicating the potential benefitsof combination therapy, MTOPS providedimportant data regarding the natural history ofuntreated BPH and the prediction of BPHpatients who will respond most effectively tomedical treatment 45–47 (Figure 5.6). While thepatients receiving finasteride alone or in combinationexperienced the expected decrease inprostate volume, patients on placebo or doxazosinalone experienced an increase in prostate volume

COMBINATION THERAPY IN THE TREATMENT OF BPH 7510Baseline PSA (ng/ml) < 1.2 1.2–2.5 > 2.5Risk (rate per 100 patient years)8642BPH progression Invasive therapy Acute urinary retentionFIGURE 5.6 MTOPS Study: prediction of future risk of BPH clinical progression, BPH-related invasive surgery, andacute urinary retention from baseline prostate-specific antigen (PSA) measures in placebo-treated patients.from a baseline of 34.0 ml by 9.3 (30.3%) (placebo)and from 36.4 ml by 9.9 (31.4%) (doxazosin),respectively. 47 Stratified by PSA quartiles, totalprostate volume in both placebo- and doxazosintreatedpatients increased from 4.9 ml (24.9%) to16.2 ml (34.5%) from the lowest to the highestquartile for an annualized growth of 1.1 to3.6 ml/year. These findings suggest that doxazosindespite its apoptotic effect does not interferewith the natural growth tendency of the prostategland, and that baseline PSA is a useful predictorof future prostate growth in men with LUTS andBPH. 25Examination of baseline measures and thedisease outcomes of 737 patients treated withplacebo revealed that PSA, Q max, PVR, andprostate volume at baseline correlated with clinicalprogression of the disease and the need forBPH-related surgery (p = 0.03 to < 0.001). 45 Agewas linked to clinical progression (p 4.0 ng/ml, however, the NNT was 4.7,and for those with a prostate volume over 40 ml itwas 4.9, suggesting that in fact combination therapybecomes an economically viable option inpatients at higher risk for progression (unpublishedMTOPS data, personal communication DrClaus Roehrborn).The link between sexual dysfunction andseverity of LUTS was also confirmed by the

76THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAMTOPS data. 48 A correlation was observedbetween LUTS and five domains of sexual dysfunction(libido, sexual function, ejaculatoryfunction, the patient’s assessment of his sexualproblems, and overall satisfaction). In addition,men with larger prostates were more likely tohave low libido, low overall sexual functioning,reduced ejaculatory function, and greater sexualproblems.ADDITIONAL COMBINATION STUDIESAnticholinergic plus α-blockerThe anticholinergic agent tolterodine is used forthe treatment of incontinence related to detrusorinstability, while the α-blocker tamsulosin iscommonly used for the treatment of BOO.Patients may present with concomitant BOO anddetrusor instability. Investigation of the efficacyof a combination of 2 mg tolterodine twice dailyand 0.4 mg tamsulosin once daily was performedto determine whether patient quality of lifeimproved as a result. 49Fifty patients took part in the study, and allinitially received tamsulosin for 1 week. Afterthis point, the patients were randomized to continuewith this regimen or to receive tolterodinein addition to tamsulosin. Baseline urodynamicsand quality of life were recorded and these measureswere repeated after 3 months of treatment.Quality of life scores were found to increasesignificantly in patients who received combinationtherapy (p = 0.0003), while no increase wasobserved in patients who received tamsulosinalone. In addition, a significant difference inmaximum detrusor pressure and unstable contractionpressure was observed in the combinationgroup. Q maxand volume at first contractionimproved significantly in both groups and noAUR was reported. The results suggest that thiscombination is a safe and effective treatmentoption for this patient group.Combined ‘natural’ productsThe role of plant-derived therapy in the treatmentof BPH has been, and still is, consideredcontroversial, 50–52 and the combination of productssuch as Serenoa repens, β-sitosterol, andPygeum africanum is even more debatable.One trial comparing a combination of cernitin,Serenoa repens, β-sitosterol, and vitamin Eto placebo indicated potential benefits for patientsreceiving the active agents. 53 In total, 127 BPHpatients with a Q maxof 5–15 ml/s took part in thestudy and were randomized to receive either thecombined therapy or placebo for 3 months.AUASI, Q max, PSA, and PVR were assessed atbaseline and on conclusion of the trial.Significant reductions in nocturia (p

COMBINATION THERAPY IN THE TREATMENT OF BPH 77value to α-blockade alone. 6,31,34 However, thelarger and longer-term MTOPS study wouldappear to be at variance with these findings 44(Table 5.1). In this trial, participants were followedup for 4.5 years on average and those whowere involved in the pilot phase were followed upfor an average of 6 years. This is considerablylonger than previous trials of combination therapyfor BPH. The VA and PREDICT studies hada duration of 1 year, while the ALFIN study lastedjust 6 months.Although earlier trials indicated no benefitover and above α-blockade with the addition offinasteride treatment, the evidence provided byMTOPS has shown that combination therapymay be appropriate for many patients, particularlythose with larger glands and higher baselineserum PSA values. This observation is reflectedin the recently published AUA Guidelines on theManagement of BPH state, on the basis of panelconsensus, that the combination of an α-blockerand a 5α-reductase inhibitor may be appropriatein LUTS patients with demonstrable enlargementof the prostate. 55Any reduction in risk of AUR and BPHrelatedsurgery associated with combination therapydescribed in the MTOPS study should beweighed up against cost and other factors on anindividual basis, however. 55 The panel stated thatthose most likely to benefit are men at greatestrisk of disease progression, i.e. those with largerprostates and higher PSA levels. Although thebest-tested combination to date is doxazosin andfinasteride, and the safety of other combinationshas not been fully assessed, the panel assumes thatany combination of these drug classes would leadto a similar degree of clinical benefit.Additional factors should also be consideredin the combination therapy debate. Cost issues areof primary importance, as dual therapy is obviouslymore expensive than monotherapy alone. Ithas been suggested that dual therapy need not becontinued indefinitely, however, which may havea bearing on associated costs.Baldwin et al. found that BPH patients treatedinitially with finasteride plus an α-blocker tolerateddiscontinuation of combination therapyafter 1 year with no compromise in clinical benefit.56 A group of BPH patients (n = 270) were prescribed2, 4, or 8 mg doxazosin alongside 5 mgfinasteride for a period of 3, 6, 9, or 12 months,after which doxazosin was discontinued. Of thosewho discontinued combination therapy at 12months, 84% of the 2 mg group, 85% of the 4 mggroup, and 87% of the 8 mg group experienced noincrease in AUA symptom score and reported nodesire to resume taking doxazosin 1 month later.Similarly high tolerance levels were reported inpatients with BOO and moderately enlargedprostates who discontinued combination therapyafter 9 months. 57Other factors, such as the difference in theeffects of 5α-reductase inhibitors and α-blockerson PSA levels, 58 and the recently discovered relationshipbetween the use of finasteride and areduction in risk of prostate cancer, 59 may alsoinfluence the use of combination therapy.It has been suggested that prostate volumeinfluences the outcome of patients treated withfinasteride, and that men with larger prostateswill benefit more from treatment with 5α-reductaseinhibitors. 16,17 The VA, ALFIN, and PRE-DICT studies all included BPH patients with relativelysmall prostates (36.2–38.4 ml, mean41.2 ml, and mean 36.3 g, respectively). Men withlarger glands may therefore benefit more fromcombination treatment than those with smallerglands, who might be better treated with an α-blocker alone. 60 The ongoing subset stratification

78THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIATABLE 5.1 Comparison of large-scale combination studies of BPH treatments.Mean age Mean baseline Regimen Symptom score* Q maxProstate volumeDuration (years) prostate volume (ml) n (daily dose) % improvement % improvement % changeVA Cooperative Study 6 1 year 65 36.2–38.4 305 Terazosin (10 mg) 38 26 +1310 Finasteride (5 mg) 20 15 –17309 Combination 39 31 –19305 Placebo 16 13 +1ALFIN 31 6 months 63 41.2 358 Alfuzosin (10 mg) 41 19 –0.5344 Finasteride (5 mg) 36 18 –11349 Combination 39 23 –12PREDICT 34 1 year 63 36.3 g 275 Doxazosin (< 8 mg) 49 35 —264 Finasteride (5 mg) 39 18 —286 Combination 49 37 —270 Placebo 33 10 —MTOPS 44 4 years 62 31.0 756 Doxazosin (4/8 mg) 35 24 +18768 Finasteride (5 mg) 30 21 –16786 Combination 41 35 –13737 Placebo 24 13 +18*Evaluation tools: for VA, PREDICT, and MTOPS = American Urological Association symptom score; for ALFIN = International Prostate Symptom Score.

COMBINATION THERAPY IN THE TREATMENT OF BPH 79of the MTOPS data may provide further insightinto this area.CONCLUSIONSThe reduction in frequency of TURP for thetreatment of BPH and the rise in use of medicaltherapy suggest high levels of patient and physiciansatisfaction with pharmacologic options.However, future advances in available drugpreparations may be limited. Dual therapy,involving preparations from different drug classes,may represent a further potential avenue formedical BPH therapy.The efficacy of the α-blockers doxazosin, terazosin,alfuzosin, and tamsulosin and the 5αreductaseinhibitors finasteride and dutasteridehas been proven in many large, well-controlledclinical trials. However, the combination of thetwo drug classes has produced variable clinicalresults. Until recently, the benefits that might logicallybe expected from therapy targeting twoseparate elements of BPH pathology—namely,prostatic enlargement and an increase in smoothmuscle tone—had not been described in largerscalestudies.The results of the MTOPS trial, however,indicate that symptomatic improvements in BPHoccur to a greater extent in men receiving doxazosinand finasteride in combination compared toeither agent alone. Disease progression, asassessed mainly by a four-point rise in theAUASI, was significantly less likely in patients inthe combination group, while AUR and BPHsurgery were also less common in this group.The strength of the findings has led to theinclusion of recommendations for combinationtherapy in suitable patients in the AUA BPHmanagement guidelines. Further trials assessingthe safety and efficacy of other types of α-blockerand 5α-reductase inhibitor in combination maybe expected to follow.The value of different types of combinationtherapy, involving plant-derived preparations orthe use of anticholinergics for example, remainsto be determined.REFERENCES1. Holtgrewe H L, Bay-Nielsen H, Carlsson P et al.The economics of the management of lower urinarytract symptoms and benign prostatic hyperplasia.In: Denis L, Griffiths K, Khoury S et al.(eds). The fourth international consultation onbenign prostatic hyperplasia (BPH), Paris, 2–5 July,1997. Plymouth, UK: Health Publications, 1998:63–812. Baine W, Yu W, Summe J P, Weis K A.Epidemiologic trends in the evaluation and treatmentof lower urinary tract symptoms in elderlymale Medicare patients from 1991 to 1995. J Urol1998; 160: 816–8203. McVary K T. Medical therapy for benign prostatichyperplasia progression. Curr Urol Rep 2002; 3:269–2754. Berry S J, Coffey D S, Walsh P C, Ewing L L. Thedevelopment of human benign prostatic hyperplasiawith age. J Urol 1984; 132: 474–4795. Madsen F A, Bruskewitz R C. Clinical manifestationsof benign prostatic hyperplasia. Urol ClinNorth Am 1995; 22: 291–2986. Lepor H, Williford W O, Barry M J et al. for theVeterans’ Affairs Cooperative Studies BenignProstatic Hyperplasia Study Group. The efficacy ofterazosin, finasteride or both in benign prostatichyperplasia. N Engl J Med 1996; 335: 533–5397. Chapple C R, Baert L, Thind P et al. and TheEuropean Tamsulosin Study Group. Tamsulosin0.4 mg once daily: tolerability in older and youngerpatients with lower urinary tract symptoms suggestiveof benign prostatic obstruction (symptomaticBPH). Eur Urol 1997; 32: 462–470

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82THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA46. Kaplan S A, Roehrborn C G, McConnell J D et al.Baseline symptoms, uroflow and post-void residualurine as predictors of BPH clinical progression inthe medically treated arms of the MTOPS trial. JUrol 2003; 169 (Suppl 4): abstract 128947. Roehrborn C G, McConnell J D, Jacobs S C et al.Baseline prostate volume and serum PSA predictrate of prostate growth: analysis of the MTOPSdata. J Urol 2003; 169 (Suppl 4): abstract 136148. McVary K, Foley J, Bautista O, Kusek J.Association of lower urinary tract symptoms(LUTS) with sexual function in men participatingin a clinical trial of medical therapy for benign prostatichyperplasia. J Urol 2003; 169 (Suppl 4):abstract 125249. Athanasopoulos A, Gyftopoulos K, Giannitsas K etal. Combination treatment with an alpha-blockerplus an anticholinergic for bladder outlet obstruction:a prospective, randomized, controlled study. JUrol 2003; 169: 2253–225650. Gerber G S. Phytotherapy for benign prostatichyperplasia. Curr Urol Rep 2002; 3: 285–29151. Dreikorn K. The role of phytotherapy in treatinglower urinary tract symptoms and benign prostatichyperplasia. World J Urol 2002; 19: 426–43552. Levin R M, Das A K. A scientific basis for the therapeuticeffects of Pygeum africanum and Serenoarepens. Urol Res 2000; 28: 201–20953. Preuss H G, Marcusen C, Regan J et al.Randomized trial of a combination of naturalproducts (cernitin, saw palmetto, β-sitosterol, vitaminE) on symptoms of benign prostatic hyperplasia(BPH). Int Urol Nephrol 2001; 33: 217–22554. T Aoki A, Naito K, Hashimoto O et al. Clinicalevaluation of the effect of tamsulosin hydrochlorideand cernitin pollen extract on urinary disturbanceassociated with benign prostatic hyperplasia in amulticentered study [In Japanese]. Hinyokika Kiyo2002; 48: 259–26755. AUA BPH Guideline Update Panel. The managementof BPH, 2003. https://shop.auanet.org/timssnet/products/guidelines/bph_management.cfm56. Baldwin K C, Ginsberg P C, Roehrborn C G,Harkaway R C. Discontinuation of alpha-blockadeafter initial treatment with finasteride and doxazosinin men with lower urinary tract symptomsand clinical evidence of benign prostatic hyperplasia.Urology 2001; 58: 203–20957. Baldwin K C, Ginsberg P C, Harkaway R C.Discontinuation of alpha-blockade after initialtreatment with finasteride and doxazosin for bladderoutlet obstruction. Urol Int 2001; 66: 84–8858. Keetch D W, Andriole G L, Ratliff T L, CatalonaW J. Comparison of percent free prostate-specificantigen levels in men with benign prostatic hyperplasiatreated with finasteride, terazosin or watchfulwaiting. Urology 1997; 50: 901–90559. Thompson I M, Goodman P J, Tangen C M et al.The influence of finasteride on the development ofprostate cancer. Published at www.nejm.org June24, 2003 (doi: 10.1056/NEJMoa030660)60. Horninger W, Bartsch G. Drug therapy of benignprostatic hyperplasia. Is combination therapy with5 alpha-reductase inhibitors and alpha-receptorblockers effective? [in German]. Urologe A 2002;41: 442–446

The differential effects of adrenoceptorantagonists on prostate tissue growthN Kyprianou6INTRODUCTIONBenign prostatic hyperplasia (BPH) is the mostfrequently diagnosed neoplastic disease in theaging male, affecting approximately 85% of allmen over 50 years of age. By the ninth decade oflife, 50% of all American men require treatmentfor symptomatic relief of the lower urinary tractsymptoms (LUTS) associated with BPH.Clinically, BPH is characterized by prostaticenlargement and the accompanying symptoms ofprogressive bladder outlet obstruction.Histologically, BPH can present as hyperplasiain both the stromal and glandular componentsof the gland and arises in the periurethral andtransition zones. 1 It has been hypothesized thatthis abnormal proliferation arises because of theability of the prostate stroma to retain an embryonicgrowth potential that is ‘reawakened’ in theaging gland. 2 Although aging and the presence ofa functional testis have become established asmajor factors causally related to the developmentof the disease, 3,4 the molecular processes involvedin the pathogenesis of BPH remain poorly understood.In this chapter we review some recent clinicaldata 5 that may provide additional insight into thepathophysiology of BPH and facilitate the developmentof more effective pharmacologic therapy.MEDICAL MANAGEMENT OF BPH: AHISTORICAL PERSPECTIVEThe development of LUTS secondary to prostaticenlargement is thought to be caused by static(mechanical) and dynamic components of urethralrestriction. The mechanical component arisesfrom the physical obstruction of urinary outflowcaused by urethral constriction, induced bythe mass of the enlarged gland. The dynamiccomponent is related to the variations in smoothmuscle tone in the fibromuscular stroma, prostatecapsule, and bladder neck. 6 Treatment modalitiestherefore aim either to reduce the mechanicalobstruction, or to induce relaxation of the periurethralprostatic smooth muscle.A critical level of androgen is required tomaintain the benign growth pattern and androgendeprivation results in significant involutionof the glandular epithelial component of theprostate, 7 without affecting stromal growth.Androgen ablation/deprivation undoubtedlyleads to a favorable ‘therapeutic’ response incanine BPH, 4 a species where the bulk of thehyperplasia is androgen-dependent epithelialproliferation. In man, however, the maximaltherapeutic effect of androgen deprivationappears to be limited by both the substantial stromalcomponent of the proliferation 1,8 and byintrinsic resistance of stromal cells to androgenmodulation. 8Given that at least 40% of the cellular volumeof the enlarged prostate is composed of stromalsmooth muscle, it is not surprising that pharmacologicintervention at this level has proved highlysuccessful. In this context, α 1-adrenoceptorantagonists (α-blockers) are widely used to produceacute symptomatic relief. The classic beliefis that α-blockers reduce the tone of the prostatesmooth muscle and thereby inhibit the dynamiccomponent of the obstruction. 9,10 The pharmacol-83

84THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAogy of α-blockers is described in detail elsewhere.11 The following represents a summary ofthe key features.Periurethral smooth muscle tone, and thereforeurethral resistance, varies according to thedegree of sympathetic nervous system activationof the α 1-adrenoceptors in the prostate andprostate capsule. 12,13 Therefore, pharmacologicblockade of the α 1-adrenoceptors would reducethe actions of noradrenaline (the endogenousneurotransmitter), resulting in tissue relaxation.This provided the impetus for the developmentof several α 1-blockers and has resulted in widespreaduse of this class of drugs as first-line interventionin BPH.Currently, four native α 1-adrenoceptor subtypes—α1A, α 1B, α 1D, and α 1L—have been identifiedand are known to be located in the prostate. 11The best correlation between prostate tissue contractionand binding with any α 1-adrenoceptorrecognition site is with the α 1Asubtype. 14,15 Manyinvestigators consider this evidence to be consistentwith a primary role of this adrenoceptor subtypein the control of prostate tone and urethralresistance. However, when considering the treatmentof BPH symptoms, extraprostatic actions ofα 1-blockers must also be taken into account 11 . Inparticular, α 1-adrenoceptors in the bladder andbladder neck, 16,17 and spinal cord, 18,19 and onefferent pathways 19,20 may make an importantcontribution to the overall improvements in urodynamicand symptom profiles that are observedshortly after the onset of therapy.Although the immediate and short-term therapeuticbenefit of α-blockers is believed to arisefrom the prostatic and extraprostatic physiologicactions listed above, it has become apparent thatin the long term other factors or loci may make anequally important contribution. 5THE α-BLOCKER PARADOXConsistent with their actions as α-blockers onperiurethral stromal smooth muscle, the acuteclinical benefit of terazosin and doxazosin inBPH is well documented 22 .In the early days of use in the management ofBPH, there was a general expectation that α-blockers might serve as clinical ‘sticking plaster’in the face of ongoing glandular hyperplasia;tachyphylaxis (tolerance) to the drug action wasanticipated. Although this may undoubtedlyoccur in individual patients, the effects of doxazosinand terazosin in BPH have been maintained(Figure 6.1), in some cases for up to 7years, 22–24 a period over which the prostate masswould be expected to increase by up to 50%. 1 Theequivalent long-term data for doxazosin similarlyshow no overall evidence of tachyphylaxis. Onthe assumption that the increase in prostate bulk(the static component of obstruction) would resultin a corresponding increase in urethra resistance,considerable diminution in benefit might beanticipated over an equivalent time period.Boyarsky score, mean changefrom baseline0–1–2–3–4–5–6–76 12 18 24 30 36 42 48 54 60MonthsFIGURE 6.1 Long-term terazosin efficacy data. Datawere generated in open-label uncontrolled clinical trials.From 1 month onwards all points were significantly differentfrom baseline and there was no evidence of tachyphylaxis.

ADRENOCEPTOR ANTAGONIST EFFECTS ON PROSTATE TISSUE GROWTH 85Several clinical papers now offer a partialexplanation of the well-documented, but unexpectedlongevity of the α-blocker response. 5,23,25These were retrospective, placebo-controlledstudies involving a total of 134 BPH patients andwere designed to determine the effects of α-blockers on apoptosis and the interrelationshipwith symptom improvement. Importantly, eachpatient acted as his own control: LUTS and histochemicalparameters were measured at baselineand at one other time point in the study after thepatient had been assigned to either placebo or α-blocker.In three other studies, cell proliferation andapoptosis were evaluated in BPH patients, whocomprised an untreated control group and twocohorts treated with either terazosin or doxazosinat doses designed to provide symptom relief. 26–28The treatment period varied from 1 week to 3years. Terazosin was used at 1–10 mg/day anddoxazosin at 2–8 mg/day. Proliferation and apoptosisof the stromal and epithelial cell componentsof the prostate, obtained by initial biopsy or atprostatectomy, were quantified by Ki 67immunostaining and TUNEL (terminal transferaseUTP-end labeling) assay, respectively.Both terazosin and doxazosin induced epithelialand stromal cell apoptosis within the firstmonth of treatment (Figure 6.2) when comparedwith the untreated controls (p

86THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAwithin the first month of treatment, which correlatedwith morphologic stromal regression andthe improvement in LUTS. There was no effecton cell proliferation. The data indicate that terazosininduced apoptosis in the glandular epitheliumand stroma but has no effect on the cellulardynamics of normal (i.e. nonBPH) tissue. 22,23There is an excellent correlation between thedegree of apoptosis and improvement of symptoms(Figure 6.4). One interpretation of thesephenomena is that α-blockers can affect abnormalprostate growth such as that observed inBPH and potential prostate carcinoma. Thiscould reflect a direct effect on cellular dynamicsor may arise secondary to an action on cellularproliferative factors. As in the case of the vasculature,androgenic and estrogenic factors alter theexpression of α 1-adrenoceptors in prostate tissue.28,29 Catecholamines have been shown to haveproliferative (promitogenic) action in several vasculartissues. 30 Should this translate to theprostate, the observed effects could merely reflectthe drug-induced attenuation of endogenous catecholamines.A model of the potential interventionpoints for terazosin is shown in Figure 6.5.Symptom improvement10Apoptosis inductionr = 0.79FIGURE 6.4 Correlation between induction of apoptosisand improvement in BPH/LUTS.5The most obvious explanation of the proapoptoticphenomenon is that this is directly related toblockade of α 1-adrenoceptor subtypes. A goodcorrelation is known to exist between activity atthe α 1Asubtype and prostate smooth muscle contraction.11 However, prostate tissue contains otherα 1-adrenoceptor subtypes (α 1Aand α 1B) and it istempting to speculate that an action at one ofthese could underpin the cellular effects of the α-blockers. It is likely that an action additional toblockade of the proliferative effects of endogenouscatecholamines, and independent of α-adrenoceptors, is involved. 5,30The clinical evidence for a proapoptotic actionof doxazosin and terazosin is supported by cellbiology and in vivo animal experiments. 31,32 In amouse prostatic reconstruction model, α-blockershad a proapoptotic action and reduced oncogeneinducedgrowth hormone without affecting normalcellular growth patterns 31 . This proapoptoticeffect does not appear to be restricted to themouse, at least in vitro; a similar profile of activityis observed in cancer cell lines 33–35 at drug concentrationssimilar to those found therapeutically.33 The effect was apparent in both hormonedependentand hormone-independent celllines, 32,34 and as such could indicate a potentialbeneficial effect in prostate carcinoma, in additionto prevention of BPH/LUTS. Intriguingly,these actions are not found with tamsulosin. 34Tamsulosin is a sulfonamide that is structurallydissimilar to the quinazoline α-adrenoceptorantagonists (Figure 6.6). This indicates that theproapoptotic actions are not a class effect, and areindependent of the α 1-adrenoceptor. 5,32,34The effects of terazosin on prostatic apoptosismay also help in the interpretation of clinical datagenerated by the Veterans’ Affairs study 36 and thePREDICT study 37 using a combination of finasteridewith terazosin and doxazosin, respectively.

ADRENOCEPTOR ANTAGONIST EFFECTS ON PROSTATE TISSUE GROWTH 87CellproliferationAndrogens(DHT)Cell–proliferation+ +NoradrenalineNoradrenalineProstate hyperplasiaProKGFEGFIGFsImbalancedTGF-βAntiApoptosisṡTerazosinProTerazosin-treatedKGFEGFIGFsAndrogens(DHT)BalancedAntiTGF-βApoptosis–TerazosinTerazosin+ṡNoradrenalineNoradrenalineFIGURE 6.5 Representation of some of the major factors controling tissue proliferation and apoptosis. DHT, dihydrotestosterone;EGF, endothelial growth factor; IGF, insulin-like growth factor; KGF, keratinocyte growth factor; TGF-β,transforming growth factor β.These studies showed that the combination offinasteride and an α-blocker does not provide anytherapeutic benefit within the first 2 years overterazosin alone, at least with respect to symptomimprovement. Potentially, doxazosin and terazosinin their own right can affect prostategrowth by inducing both epithelial and stromalapoptosis; by comparison, the anti-androgeniceffect of finasteride is likely to be restricted toinduction only of glandular epithelial apoptosis. 38Thus, it could be argued that the apoptosisinducingprofile of quinazolines provides themolecular basis for the inability of finasteride toenhance the therapeutic effect of doxazosinand/or terazosin therapy in the short to mediumterm.However, considering the multifactorialpathogenesis, there is logic in the use of therapiesthat target different cellular components. Thecombination of a 5α-reductase inhibitor with aquinazoline-type α-blocker should potentiallyTerazosinCH 3 OTamsulosinNH 2CH 3 O N N N CNCH 3 O CH 2 CH 2 NO 2 SCH 3H•HCl•2H 2 Ocombine the clinical benefit resulting from theanti-growth effects of androgen deprivationinducedapoptosis in the epithelium with theapoptosis induced by the quinazolines in the stroma.In the long-term MTOPS study over 7 yearssuch synergy was observed. 24 At least with respectONHCH 2 CH 2 OOOCH 2 CH3•HClFIGURE 6.6 Structures of quinazoline (terazosin) andsulfonamide (tamsulosin) α-adrenoceptor antagonists.

88THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAto delaying clinical progression, the combinationwas more effective than either component.Intriguingly, doxazosin alone was found to delayprogression only over the first 3 years or so. Thusthe long-term data are consistent with the data inthe combination studies described above, of 2years’ duration. 36,37SUMMARYThere is now considerable evidence that α-blockershave a proapoptotic effect in prostate tissue.Although such an action may not underlie theshort-term therapeutic benefit observed withthese agents, it could make an important contributionto the longer-term durability of theresponse. The proapoptotic effect of doxazosinand terazosin in both stromal and epithelial componentscould offer an explanation of the inabilityof finasteride (which has effects on epithelialcomponents) to augment the response of these α-blockers in clinical studies of up to 2 years’ duration.The finding that tamsulosin does not havethese properties raises the possibility that theproapoptotic action is not a class effect, and maybe independent of the α 1-adrenoceptor.REFERENCES1. Oesterling J E. Benign prostatic hyperplasia: areview of its histogenesis and natural history.Prostate Suppl 1996; 6: 67–732. McNeal J E. Origin and evolution of benign prostaticenlargement. Invest Urol 1978; 15: 340–3453. Berry S J, Coffey D S, Walsh P C, Ewing L L. Thedevelopment of human benign prostatic hyperplasiawith age. J Urol 1984; 132: 474–4794. Issacs J T, Coffey D A. Etiology and disease processof benign prostatic hyperplasia. Prostate 1989; 2(Suppl): 33–505. Kyprianou N. Doxazosin and terazosin suppressprostate growth by inducing apoptosis: clinical significance.J Urol 2003; 169: 1520–15256. Caine M. Alpha-adrenergic mechanisms indynamics of benign prostatic hypertrophy. Urology1988; 32: 16–207. McConnell J D. Medical management of benignprostatic hyperplasia with androgen suppression.Prostate Suppl 1990; 3: 49–598. Peters C A, Walsh P C. The effect of nafarelinacetate, a luteinizing-hormone-releasing hormoneagonist on benign prostatic hyperplasia. N Engl JMed 1987; 317: 599–6049. Caine M, Raz S, Zeigler M. Adrenergic and cholinergicreceptors in the human prostate, prostate capsuleand bladder neck. Br J Urol 1975; 47: 193–20210. Lepor H. Role of long-acting selective alpha-1blockers in the treatment of benign prostatic hyperplasia.Urol Clin North Am 1990; 17: 651–65711. Andersson K E, Lepor H, Wyllie M G. Prostaticalpha 1-adrenoceptors and uroselectivity. Prostate1997; 30: 202–21512. Lepor H, Tang R, Shapiro E. The alpha-adrenoceptorsubtype mediating the tension of humanprostatic smooth muscle. Prostate 1993; 22: 301–30713. Caine M, Pfau A, Perlberg S. The use of alphaadrenergicblockers in benign prostatic obstruction.Br J Urol 1976; 48: 255–26314. Marshall I, Burt R P, Andersson P O et al. Humanalpha 1c-adrenoceptor, functional characterizationin the prostate. Br J Pharmacol 1992; 107: 327P15. Lepor H, Tang R, Meretyk S, Shaprio E. Alpha 1-adrenoceptor subtypes in the human prostate. JUrol 1993; 149: 640–64216. Perlberg S, Caine M. Adrenergic response of bladdermuscle in prostatic contraction. Urology 1982;20: 524–52717. Yoshimura N, Sasa M, Yoshida O, Takaori S. a 1-Adrenergic receptor-mediated excitation from thelocus coeruleus of the sacral parasympathetic preganglionicneurone. Life Sci 1990; 47: 789–79718. Ishizuka O, Persson K, Mattiasson A et al.Micturition in conscious rats with and without out-

ADRENOCEPTOR ANTAGONIST EFFECTS ON PROSTATE TISSUE GROWTH 89let obstruction: role of spinal α 1-adrenoceptors. BrJ Pharmacol 1996; 117: 962–96619. Ramage A G, Wyllie M G. Effects of doxazosinand terazosin on inferior mesenteric nerve activity,spontaneous bladder contraction and blood pressurein anaesthetized cats. Br J Pharmacol 1994;112: 526P20. Danuser H, Thor K. Inhibition of central sympatheticand somatic outflow to the lower urinarytract of the cat by the α 1-adrenergic receptor antagonistprazosin. J Urol 1995; 153: 1308–131221. Eri L M, Tveter K J. α-Blockade in the treatmentof symptomatic benign prostatic hyperplasia. J Urol1995; 75: 265–27022. Kyprianou K, Litvak J P, Borkowski A et al.Induction of prostate apoptosis by doxazosin inbenign prostatic hyperplasia. J Urol 1998; 159:1810–181523. Chon J K, Borkowski A, Partin A W et al. α 1-Adrenoceptor antagonists terazosin and doxazosininduce prostatic apoptosis without affecting cellproliferation in patients with benign prostatichyperplasia. J Urol 1999; 166: 2002–200524. McConnell J D. For the MTOPS steering committee:the long term effects of medical therapy on theprogression of BPH: results from the MTOPS trial.J Urol 2002; 167: 265, abstract 104225. Lepor H and the Terazosin Research Group.Long-term efficacy and safety of terazosin inpatients with benign prostatic hyperplasia. Urology1995; 45: 406–41326. Kirby R S. Doxazosin in benign prostatic hyperplasia:effects on blood pressure and urinary flow innormotensive and hypertensive men. Urology1995; 46: 182–18627. Lepor H, Kaplan S A, Klimberg I et al. Doxazosinfor benign prostatic hyperplasia; long-term efficacyand safety in hypertensive and normotensivepatients. The Multicenter Study Group. J Urol1997; 157: 525–53028. Zhang J, Hess M, Hittmair A et al. Human prostaticsmooth muscle cells in culture: estradiolenhances expression of smooth muscle cell-specificmarkers. J Urol 1994; 153: 341A29. Benaim E A, Lin V K, McConnell J D.Quantitation of alpha 1 c-adrenergic receptorexpression in minute quantities of prostate tissue. JUrol 1995; 153: 343A30. Wyllie M G. Does doxazosin affect prostaticgrowth? Prostate 1998; 35: 152–15331. Yang G, Timme T L, Park S H et al. Transforminggrowth factor beta 1 transduced mouse prostatereconstitutions: II. Induction of apoptosis by doxazosin.Prostate 1997; 33: 157–16332. Kyprianou N, Allen L F, Wyllie M G. Induction ofprostate apoptosis by doxazosin; alpha1-adrenoceptor-dependentand -independent actions? Br JPharmacol 1997; 22: 283P33. Kirby R S. Doxazosin in the treatment of obstructionof the lower urinary tract. In: Kirby R S,McConnell J D, Fitzpatrick J M, Roehrborn C G,Boyle P (eds). Textbook of benign prostatic hyperplasia.Oxford: Isis Medical Media 1996: 287–29334. Benning CM, Kyprianou N. Quinazoline-derivedalpha1-adrenoceptor antagonists induce prostatecancer via an alpha1-adrenoceptor-independentaction. Cancer Res 2002; 62: 597–60235. Kyprianou N, Benning CM. Suppression of humanprostate cancer cell growth by alpha1-adrenoceptorantagonists, doxazosin and terazosin, via inductionof apoptosis. Cancer Res 2000; 60: 4550–4555.36. Lepor H, Williford W O, Barry M J et al. The efficacyof terazosin, finasteride, or both in benign prostatichyperplasia. Veterans’ Affairs CooperativeStudies Benign Prostatic Hyperplasia Study Group[see comments]. N Engl J Med 1996; 335: 533–53937. Kirby RS, Roehrborn C, Boyle P, et al. Efficacy andtolerability of doxazosin and finasteride, alone or incombination, in the treatment of symptomaticbenign prostatic hyperplasia: the prospectiveEuropean doxazosin and combination therapy(PREDICT) trial. Urology 2003; 61: 119–126.38. Peters C A, Walsh P C. The effect of nafarelinacetate, a luteinizing-hormone-releasing-hormoneagonist on benign prostatic hyperplasia. N Engl JMed 1987; 317: 599

Terazosin in the treatment of obstructionof the lower urinary tractM K Brawer J M Fitzpatrick7INTRODUCTIONThe treatment of the lower urinary tract symptoms(LUTS) associated with benign prostatichyperplasia (BPH) with α-adrenoceptor antagonists(blockers) has evolved considerably since thepioneering clinical work of Marco Caine 1 usingphenoxybenzamine. Initially, only two types of α-adrenoceptor (α 1and α 2) were identified.Phenoxybenzamine has antagonist activity atboth α 1- and α 2-adrenoceptors and is therefore anonselective antagonist. Subsequently, it wasfound that prostate tissue contraction relied primarilyon activation of the α 1-adrenoceptor. 2This led to the development and clinical evaluationof the prototype selective α 1-adrenoceptorantagonist, prazosin, in an attempt to reduce theside-effects associated with phenoxybenzamine.The proposed mechanism for the efficacy ofselective α 1-blockade in BPH is via relaxation ofprostate smooth muscle. It therefore follows thatthe magnitude of the clinical response to selectiveα 1-blockade in BPH should be related directly tothe proportion of the hyperplasia that is smoothmuscle. Shapiro et al. 3 evaluated the relationshipbetween the percentage area density of prostatesmooth muscle and the clinical response to theselective long-acting α 1-antagonist, terazosin.Before starting terazosin therapy, prostate biopsyspecimens were obtained from 26 men. The doseof terazosin was titrated to 5 mg, provided thatserious adverse events were not observed. Thepercentage area density of smooth muscle in thebiopsy specimens was quantified using doubleimmunoenzymatic staining and color-assistedcomputer image analysis. A direct relationshipbetween the increase in peak urinary flow rate(Q max) and the percentage area density of smoothmuscle was observed. This correlation stronglysupports the hypothesis that a component of thedevelopment of bladder outlet obstruction ismediated by an increase in prostate smooth muscletone. Certainly the classical belief is that α-antagonists act by reducing the tone of theprostate smooth muscle, decreasing urethralresistance, and thereby the dynamic componentof the obstruction. 4,5 However, increasingly this isbeing challenged and it is probable that extraprostaticactions of α-antagonists are of considerableimportance. 6Although bladder outlet obstruction in agingmen is often mediated by prostate smooth muscleproliferation, there is increasing evidence that theseverity of urinary symptoms is not exclusivelythe result of bladder outlet obstruction. The correlationbetween symptom severity captured bythe American Urological Association (AUA)symptom index and Q maxis poor 7 and, unlikeQ max, the density of prostate smooth muscle is notdirectly correlated with symptom severity. 3 Theseobservations suggest that urinary symptoms inthe aging male are probably multifactorial. It isalso conceivable that symptom improvement inmen with prostatism is achieved via nonprostatesmooth muscle events mediated by the α 1-adrenoceptor.91

92THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAOur understanding of adrenoceptor pharmacologyhas increased considerably. Four nativeα 1-adrenoceptor subtypes have now been identifiedand are known to be located in the prostate:the α 1A, α 1B, and α 1Dsubtypes are high-affinityreceptors for prazosin; the α 1Lis a low-affinityreceptor. The evolution of this nomenclature hasbeen confusing and has changed over the last fewyears, as reviewed by Bylund et al. 8 The best correlationbetween prostate tissue contraction andbinding with any of the α 1-adrenoceptor recognitionsites is with the α 1Asubtype (Figure 7.1). 9,10On the basis of this and other evidence, manyinvestigators consider that the α 1Asubtype withinthe periurethral stroma is the prime determinantof prostatic tone. However, the extraprostaticactions of α-antagonists may make importantcontributions to the overall urodynamic andsymptom score that is observed soon after therapyis initiated. 6Considerably less is known about the role ofthe prostate α 1Band α 1Dsubtypes. However,these could be linked to the effects of terazosin onglandular growth and apoptosis (see Chapter 10),described in more detail below. 11The α-antagonists that have been used clinicallyin the treatment of LUTS/BPH can be subgroupedaccording to their selectivity for differentreceptor subtypes and their pharmacokinetichalf-lives. Phenoxybenzamine is a non-selectiveα-antagonist with equal affinity for α 1- and α 2-adrenoceptors. Drugs with selectivity for the α 1-adrenoceptor, including prazosin, alfuzosin,indoramin, terazosin, doxazosin, and tamsulosin,were subsequently developed. The primaryadvantage of these selective α 1-antagonists is thatthe incidence and severity of adverse events is significantlyless than with the nonselective α-blocker,phenoxybenzamine. There is no evidencefrom in vitro or whole-animal experiments thatany of the established agents is selective for anyone α 1-adrenoceptor subtype (Figure 7.2), 6 orpossesses any degree of clinical uroselectivity asdefined by the α-blocker subcommittee of theInternational Consultation on BPH. 12101010Prostate pA 2987632 4 257Prostate pA 29875347621Prostate pA 29873475261a66 7 8 9 10pK ib66 7 8 9 10pK ic66 7 8 9 10pK iFIGURE 7.1 Correlation plots of the potency of prazosin (1), terazosin (2), indoramin (3), SNAP 1069 (4), 5-methylurapidil(5), SKF104856 (6), and RS 17053 (7) for cloned human and animal (RS 17053) α 1A- (a), α 1B- (b), and α 1D- (c)adrenoceptors versus their potency at inhibiting α 1-mediated contraction of the human prostate in vitro. There is a goodcorrelation between functional α 1-adrenoceptor affinity (pA 2) on human prostate and binding affinity (pK i) for most, butnot all, α 1-adrenoceptor antagonists at the cloned α 1Asubtype. (Adapted from references 32 and 49.)

TERAZOSIN IN LOWER URINARY TRACT OBSTRUCTION 93pK iDoxazosin7.07.58.08.59.09.5TerazosinAlfuzosinLowAffinityHighFIGURE 7.2 Affinities of doxazosin, terazosin, alfuzosin,tamsulosin, and 5-methylurapidil (5-MU) for thecloned α 1A- ( ), α 1B- ( ), and α 1D-( ) adrenoceptor subtypes.Tamsulosin5-methylurapidilclinical advantages for patient, primary-carephysician, and urologist alike.HISTORIC BACKGROUNDTerazosin is a potent quinazoline α-adrenoceptorantagonist that is extremely selective for the α 1versus the α 2subtype. 2 There is little evidencefrom isolated-tissue studies or whole-animalexperiments that terazosin has higher affinity forany one of the α 1-adrenoceptor subtypes. 14 Theplasma half-life (16 hours) is consistent with oncedailydosing. The contribution of metabolites tothe overall profile of terazosin is unknown.As a class, α 1-adrenoceptor antagonists havebeen shown to be safe and effective in the treatmentof obstruction-related LUTS. 13 Obstructiveand irritative symptoms are improved, andchanges in urinary flow and residual volume areconsistent with a reduction in urethral resistance.Prazosin has been used in this context for severalyears, but its clinical use is limited by its dosingregimen and the orthostatic hypotension that followsrapid absorption. Terazosin was the firstselective α 1-antagonist specifically developed toovercome these shortcomings. It has similar affinityfor the α 1A-, α 1B-, and α 1D-adrenoceptor subtypes(Figure 7.2), 14 and is therefore considered tohave a balanced profile. In addition, terazosin canbe distinguished from prazosin on the basis ofphysicochemical differences that result in a moregradual onset of action and a much longer plasmahalf-life (16 hours compared with about 3 hours).In this chapter we review the clinical data onterazosin and discuss how the balanced action ofterazosin across the three high-affinity α 1-adrenoceptor subtypes translates into potentialSAFETY AND EFFICACY IN THEMANAGEMENT OF BPHShort-term efficacyAt least 11 double-blind placebo-controlled studiesin patients with BPH/LUTS have been completed,and a rigorous meta-analysis of the findingshas been reported. 15The data from a large (285 patients) representativestudy 16 are shown in Figure 7.3. Statisticallysignificant decreases from baseline were observedfor obstructive, irritative, and total symptomscores, for all terazosin groups; the higher dosesproduced statistically significant improvementsover placebo, with up to 70% of patients achievingmore than a 30% improvement in symptomscores. Changes in symptoms were mirrored bydose-related improvements in peak and meanurinary flow (Figure 7.4).The LUTS symptoms associated with BPHwere also improved to a statistically significantextent in most of the studies included in the metaanalysis.15 Irrespective of the different symptom

94THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA% of patients706050403020100Placebo 2 mg 5 mg 10 mgTerazosinFIGURE 7.3 Percentage of patients experiencing greaterthan 30% improvement in total symptoms scores ( ) andpeak urinary flow ( ) in a randomized double-blindcomparison of placebo and terazosin once daily (n = 285).scores used in these studies, consistently greaterresponses were recorded in patients treated withterazosin than in those receiving placebo and,when assessed, the degree of symptom bothersomenesswas reduced significantly. The usualeffective dose was either 2 mg or 5 mg per day,although additional benefits were observed insome patients with doses up to 10 mg per day.The beneficial effects of terazosin on irritativeand obstructive symptoms and urinary flow areseen within the first few weeks of treatment,often before the dose of terazosin has been titratedto its optimum (Figure 7.4). This has considerableclinical implications, in that patients may bemore likely to comply with treatment if theyexperience an early improvement in symptoms.Systematic reviews of the effectiveness of terazosinin the treatment of LUTS have confirmedthat the drug is superior to both placebo andfinasteride. 15,17,18 In these analyses, terazosintreatment was associated with increases in peakMean change peak flow rate (ml/s)3.53.02.52.01.51.00flow of 1.4 ml/s compared to placebo and with anaverage reduction in symptom score of 2.2 pointsbeyond that observed with placebo.Long-term efficacyn = 473 n = 457Baseline1 2 3Month of treatmentFIGURE 7.4 Mean change in peak flow rate betweenbaseline and 3 months in terazosin-treated patients. The nvalues indicate the number of patients at each time interval.All data points were significantly different from baseline(p ≤ 0.05).Any treatment for LUTS/BPH must achieve adurable clinical response in order to assume ameaningful role in patient management. Thedurability of the terazosin response has beenreported in one open-label study of almost 500men over a 4-year period. 19 In this study, terazosinwas started at 1 mg per day and the dosewas titrated upwards at the investigators’ discretion,to a maximum of 20 mg per day. The primaryefficacy variables were Q maxand Boyarskysymptom score. At the follow-up visits, Q maxwassignificantly higher than baseline; a 30%improvement over the course of the follow-upwas observed in 40–59% of patients. Similarly, theirritative, obstructive, and total Boyarsky symptomscores were significantly lower than at baselineat all follow-up intervals (Figure 7.5); 30% or

TERAZOSIN IN LOWER URINARY TRACT OBSTRUCTION 95Mean change peak flow rate (ml/s)n = 473 457 429 380 352 292 274 254 233 135 99 473.53.02.52.01.51.003 6 9 12 15 18 21 24 30 36 42BaselineMonth of treatmentFIGURE 7.5 Mean change in peak flow rate betweenbaseline and 24 months in terazosin-treated patients. Then values indicate the number of patients at each timeinterval. All data points were significantly different frombaseline (p ≤ 0.05).Symptom problem score12111098765Entry 2 4 13 26 39 52Week of studyFIGURE 7.6 Group mean symptom problem scores inpatients receiving placebo ( ), or treated with finasteride( ), terazosin ( ), or a combination of terazosinand finasteride ( ).greater improvement was noted in 62–77% ofpatients.A similar durability of response was observedin another long-term study involving over 1200patients in whom the response to terazosin wascompared with that of placebo, finasteride (a 5αreductaseinhibitor), and a combination of finasterideplus terazosin (Figure 7.6). 20 In this study,finasteride and placebo were equally effective,producing only marginal improvements in symptoms.By contrast, terazosin and the combinationtherapy were significantly more effective; terazosinalone reduced the AUA symptom score by6 units and increased Q maxby 3.6 ml/s. Thus,improvements in symptoms and urinary flowwere equivalent to those observed in the shorterdouble-blind studies described above.These data certainly refute the expectations ofearlier years that α-antagonists may only providetemporary benefit in BPH/LUTS. In the face ofongoing glandular proliferation, it was anticipatedthat tachyphylaxis (tolerance) would occur.However, the long-term data show that the effectof terazosin in BPH is maintained over a 5-yearperiod, over which time the prostatic mass wouldbe expected to increase by up to 50%. 21 On thebasis that the increased prostatic bulk wouldresult in a corresponding increase in urethralresistance, considerable diminution of benefitcould have been expected over this time course.Two clinical studies (described in more detailbelow) suggest that the unanticipated longevity ofthe response could be due to induction of apoptosiswithin the prostate (see Chapter 10). 11,22Safety profileThe clinical database for terazosin in the treatmentof LUTS/BPH and hypertension extends tomore than 3 billion patient days and shows thatthe drug is well tolerated. In double-blind studiesin BPH, overall 15% of terazosin-treated patientsdiscontinued therapy, compared with 9% ofplacebo recipients (representing only a 6% reductionin compliance compared with placebo). Themost frequently reported side-effects in bothgroups were dizziness, vertigo, headache, andfatigue; cardiovascular events such as posturalhypotension were infrequent. Most side-effects

96THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAwere mild in severity and did not warrant treatmentor discontinuation of therapy.Terazosin was equally well tolerated overmuch longer periods. In the long-term studydescribed above, 21 the incidence of adverse eventswas similar to that observed in the initial doubleblindstudies.Overall, the side-effect profile of terazosin atdoses that are fully effective in providing relief ofLUTS/BPH appears to be characteristic of theclass. 13OVERALL CLINICAL PROFILEEffects on blood pressureThe role of α 1-adrenoceptors in the control of thehemodynamic baseline is of potential clinical consequenceto both normotensive and hypertensiveBPH patients. Epidemiologic studies have shownthat up to 40% of men with BPH have hypertension(controlled or uncontrolled).Although (as described above) there is someconsensus that the α 1A-adrenoceptor is the primedeterminant of prostate tissue contraction, muchless is known about the subtype involved in cardiovascularregulation. Perhaps not surprisingly,as blood pressure is the algebraic summation ofmany cardiac and vascular processes, the ‘bloodpressure receptor subtype’ has not been identified.6 Although there may be differential distributionswithin the vasculature, all three subtypes(α 1A, α 1B, and α 1D) are ubiquitous. 8,23 On this basisit can be assumed that these three subtypes areinvolved in cardiovascular homeostasis and thateffective blood pressure control will thereforeoccur only with a balanced α 1-adrenoceptorantagonist, such as terazosin. Equally, a ‘uroselective’antagonist will not provide effective bloodpressure control in the many LUTS/BPHpatients who also have hypertension.It is well documented that the changes inblood pressure observed with α 1-blockers arehighly dependent on the hemodynamic baseline.Terazosin lowers blood pressure when the sympathetictone is high, for example in BPH/LUTSpatients with hypertension (Figure 7.7), 17,24 buthas much less effect on resistance vessels innormotensive patients, in whom only clinicallyinsignificant changes in blood pressure areobserved (Figure 7.7). 17,24,25 Terazosin has noeffect on the hemodynamic baseline, irrespectiveof whether the BPH/LUTS patients are physiologicallynormotensive or are stabilized on hypertensivetherapy. 24,25Overall, therefore, the potential antihypertensiveeffect of terazosin could be of considerableadvantage to the relatively high proportion (40%)of BPH/LUTS patients who have uncontrolledor poorly controlled hypertension. Similarly, thelong-term effects of terazosin in normotensivepatients are of little clinical concern, although thepotential to produce first-dose postural hypotensionmust always be considered.Blood pressure (mmHg)170160150140130120110100908070aTerazosin PlacebobTerazosin PlaceboFIGURE 7.7 Effect of terazosin on blood pressure in (a)hypertensive and (b) normotensive patients. Data showblood pressure at baseline ( ) and after treatment ( ).(Adapted from reference 17.)

TERAZOSIN IN LOWER URINARY TRACT OBSTRUCTION 97Tamsulosin does not appear to lower bloodpressure consistently or markedly in hypertensivepatients. 26 This profile is claimed to arise from theintrinsic ‘uroselectivity’ of the drug; however, thisclaim has been disputed, 6 and the ‘uroselectivity’may simply reflect incomplete α-blockade at thedose used in clinical practice (0.4 mg). 27Cardiovascular risk factorsMost of the risk factors for hypertension are commonto congestive heart failure and atherosclerosis.28 Particularly relevant are an abnormal lipidprofile and abnormal insulin resistance/glucosetolerance. The metabolic effects of terazosin andother antihypertensive agents have been reviewedby Pool. 28,29 Terazosin has potentially beneficialactions on several of the risk factors (abnormallipids, fibrinolysis, platelet aggregation) thatcould have important implications in the preventionof hypertension, coronary heart disease(CHD), and atherosclerosis. 30–32Extensive studies of almost 17 000 hypertensivepatients in primary care and communityfacilities suggest that the blood-pressure-loweringactions of terazosin, coupled with its beneficialeffects on associated cardiovascular risk factors,should significantly reduce CHD. 30 On thebasis of the Framingham model, 33 a reduction inthe incidence of CHD of approximately 20%would be predicted from these changes in CHDrisk factors. However, the recent results from theALLHAT study, 34 and the conclusions of JNC-7, 35 indicate that terazosin and other α-blockersshould not be considered as front-line monotherapyin the treatment of cardiovascular disease.However, bearing in mind that manyBPH/LUTS patients have several associated cardiovascularrisk factors, these data provide supportfor the use of terazosin in any holisticapproach to the management of the BPH/LUTSpatient as a whole.Effects on the urogenital tractThe clinical improvement in BPH/LUTSobserved with any α-antagonist depends on avariety of actions within the urogenital tract. 6,12Although actions on prostate smooth muscleundoubtedly contribute to these effects, it isimportant to remember that there is no directcorrelation between changes in urethral resistanceand flow rates on the one hand and symptomimprovement on the other. Furthermore, itshould be remembered that patients usually presentbecause of symptoms and bothersomeness,not because of reduced urinary flow. Thus, theextraprostatic actions of terazosin on the bladder,bladder neck, spinal cord, and efferent pathways6,36 may be just as important as the changesinduced in periurethral prostate smooth muscletone.Effects on glandular growthAlthough (as described above) the immediate andshort-term therapeutic benefits of α-antagonistsundoubtedly arise from direct and indirectactions on prostate smooth muscle, it is becomingapparent that other factors are important in thelong term.In the early days of the use of α-blockers inBPH/LUTS, tachyphylaxis (tolerance) to thedrug was expected, and, because of the continuedglandular hyperplasia, it was thought that α-antagonists might act only as clinical ‘stickingplasters’, with the effect reducing with time.Clearly, long-term studies with terazosin (Figure7.5) show a durability of response beyond theoriginal expectations.

98THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAThe findings of at least two recent clinicalstudies may offer some insight into this apparentlyparadoxical longevity of response with terazosin.11,20,37 In one study cell proliferation andapoptosis were evaluated in BPH patients whoeither received no treatment (control group) orwere treated with terazosin at the normal clinicaldose range (1–10 mg); the treatment period wasbetween 1 week and 3 years. Compared with theuntreated controls, terazosin induced epithelialand stromal cellular apoptosis within the firstmonth of treatment (Figure 7.8), and there was aparallel increase in the expression of smooth muscleα-actin. The loss of prostate smooth musclecells correlated with morphologic stromal regressionand the improvement in LUTS. There wasno effect on cell proliferation. The data indicatethat terazosin treatment (over the normal doserange) results in a substantial induction of apoptosisin the glandular epithelium and stroma.Apoptotic index (%)302520151050Control < 1 1–5 6–11 12–36(n = 31) (n = 12) (n = 12) (n = 9) (n = 9)Treatment period (months)FIGURE 7.8 Effect of terazosin on prostate apoptosis inpatients with BPH. The apoptotic index of glandularepithelial ( ) and stromal ( ) smooth muscle cells inbiopsy sections is expressed as mean percentage ofTUNEL-positive cells/total number of cells after variousperiods of terazosin therapy (1–10 mg/day). (Adaptedfrom reference 11.)However, there was no effect on the cellulardynamics of normal (i.e. nonBPH) tissue. Onepotential interpretation is that terazosin can affectabnormal prostate growth, such as that observedin BPH or prostate carcinoma. Theoretically thiscould account for the durability of the response toterazosin in long-term studies.The effects of terazosin on prostate apoptosismay also help in the interpretation of the clinicaldata generated in the Veterans’ Affairs study(Figure 7.6). 20 This study showed that the combinationof finasteride and terazosin did not provideany therapeutic benefit over terazosin alone,at least with respect to symptom improvement.Terazosin potentially affects prostate growth byinducing apoptosis in both epithelial and stromalcomponents. Should this be the case, it is perhapsnot surprising that finasteride (which affects onlyepithelial tissue) cannot augment the response toterazosin. However, further clinical evaluation ofthis hypothesis is required. The overall profile ofterazosin and the possibility that the induction ofapoptosis is independent of the α 1-adrenoceptorand is not a class effect is explored in Chapter 30.CONCLUSIONSTerazosin has a balanced pharmacologic actionacross the three high-affinity receptor subtypes ofthe α 1-adrenoceptor, which is reflected clinicallyin the drug’s utility in the holistic approach to themanagement of the patient with BPH/LUTS. Atthe level of the prostate, the potent action of terazosinon the α 1A-adrenoceptor subtype undoubtedlyaccounts for the rapid changes seen in urinaryflow rate and voiding pressure, secondary tochanges in urethral resistance. However, in additionto these prostatic actions, the extraprostaticactions of terazosin on the bladder, bladder neck,

TERAZOSIN IN LOWER URINARY TRACT OBSTRUCTION 99and higher centers also contribute to the significantchanges in symptoms and bothersomeness.In addition there is increasing evidence thatterazosin may have an additional action on apoptosiswithin prostate tissue. Intriguingly, thisaction, which could underpin the durability of theclinical benefit seen with terazosin, may notinvolve an action at adrenoceptors and may notbe a class effect.Terazosin produces clinically beneficialreductions in blood pressure in patients withBPH/LUTS who are also hypertensive, viaactions at all three high-affinity α 1-adrenoceptorsubtypes. However, in patients who are normotensiveor whose hypertension is controlled,only minor, clinically insignificant reductions inblood pressure are observed. Terazosin also hasbeneficial effects on several cardiovascular riskfactors (e.g. lipid profiles, glucose metabolism)which, when coupled with the blood-pressureloweringeffect seen in hypertensive BPHpatients, could translate into a reduction in CHDrisk.In addition to the balanced pharmacologicaction across all three high-affinity α 1-adrenoceptorsubtypes, the physicochemical properties ofterazosin offer considerable advantages over mostother α-antagonists. Terazosin has a long plasmahalf-life, which makes it suitable for once-dailyadministration. The relatively slow absorptionand gradual onset of action associated with thislong plasma half-life underpin the reducedpropensity for postural effects and general sideeffects.Importantly, the pharmacokinetics areunchanged in the elderly or in patients with renalfailure.Terazosin is well tolerated in both old andyoung patients. Most side-effects are mild ormoderate and do not require treatment or discontinuationof therapy.Overall, therefore, terazosin has a desirableclinical profile for the treatment of BPH/LUTS.Any theoretic advantage that could be achievedwith a genuinely ‘uroselective’ agent will ultimatelyhave to be weighed against the deficits ofsuch therapy with respect to the treatment of thewhole patient.REFERENCES1. Caine M, Pfau A, Perlberg S. The use of alphaadrenergic blockers in benign prostatic obstruction.Br J Urol 1976; 48: 255–2632. Lepor H, Gup D I, Bauman M, Shapiro E.Laboratory assessment of terazosin and alpha 1-blockade in prostatic hyperplasia. Urology 1988; 32(Suppl): 21–263. Shapiro H, Hartatano V, Lepor H. The response toalpha blockade in benign prostatic hyperplasia isrelated to the percent density of prostate smoothmuscle. Prostate 1992; 21: 297–3074. Caine M, Raz S, Ziegler M. Adrenergic and cholinergicreceptors in the human prostate, prostaticcapsule and bladder neck. Br J Urol 1975; 27:193–2025. Lepor H. Role of long-acting selective alpha 1-blockers in the treatment of benign prostatic hyperplasia.Urol Clin North Am 1990; 17: 651–6576. Andersson K -E, Lepor H, Wyllie M G. Prostaticalpha 1-adrenoceptors and uroselectivity. Prostate1997; 30: 202–2057. Barry M J, Cockett A T K, Holtgrewe H L et al.Relationship of symptoms of prostatism to commonlyused physiological and anatomical measuresof severity of benign prostatic hyperplasia. J Urol1993; 150: 351–3588. Bylund B D, Eikenberg D C, Hieble J -P et al.International Union of Pharmacology nomenclatureof adrenoceptors. Pharmacol Rev 1994; 46:121–136

100THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA9. Marshall I, Burt R P, Andersson P -O et al. Humanalpha 1c-adrenoceptor, functional characterisation inthe prostate. Br J Pharmacol 1992; 107: 327P10. Lepor H, Tang R, Shapiro E. The alpha-adrenoceptorsubtype mediating the tension of humanprostatic smooth muscle. Prostate 1993; 22: 301–30711. Chon J K, Borkowski A, Partin A W et al. Alpha 1-adrenoceptor antagonists, doxazosin and terazosininduce prostate apoptosis without affecting cellproliferation in patients with benign prostatichyperplasia. J Urol 1999; 161: 2002–200812. Jardin A, Andersson K -E, Bono V A et al. Alphablockersin the treatment of BPH. In: Denis L,Griffiths K, Khoury S et al. (eds). Proceedings ofthe fourth international consultation on benignprostatic hyperplasia (BPH). Plymouth: SCI, 1998:599–63213. Eri L M, Tveter K J. Alpha-blockade in the treatmentof symptomatic benign prostatic hyperplasia.J Urol 1995; 154: 923–93414. Kenny B, Naylor A M, Carte A J et al. Effect ofalpha 1-adrenoceptor antagonists on prostatic pressureand blood pressure in the anaesthetised dog.Urology 1994; 44: 52–5715. Boyle P, Robertson C, Manski R et al. Meta-analysisof randomized trials of terazosin in the treatmentof benign prostatic hyperplasia. Urology2001; 58: 717–72216. Lepor H, Aurbach S, Puras-Baez A et al. A randomisedmulti-centre placebo controlled study ofthe efficacy and safety of terazosin in benign prostatichyperplasia. J Urol 1992; 148: 1467–147417. Wilt T J, Howe R W, Rutks I R, MacDonald R.Terazosin for benign prostatic hyperplasia.Cochrane Database Syst Rev 2002; CD00385118. Kaplan S A. Terazosin for treating symptomaticbenign prostatic obstruction: a systematic review ofefficacy and adverse events. J Urol 2002; 168:1657–165819. Lepor H. Long-term efficacy and safety of terazosinin patients with benign prostatic hyperplasia.Terazosin Research Group. Urology 1995; 45:406–41320. Lepor H, Williford W O, Barry M J et al. Theimpact of medical therapy on bother due to symptoms,quality of life and global outcome, and factorspredicting response. Veterans’ AffairsCooperative Studies Benign Prostatic HyperplasiaStudy Group. J Urol 1998; 160: 1358–136421. Oesterling J E. Benign prostatic hyperplasia: areview of its histogenesis and natural history.Prostate Suppl 1996; 6: 67–7322. Kyprianou N, Litvak J P, Borkowski A et al.Induction of prostate apoptosis by doxazosin inbenign prostatic hyperplasia. J Urol 1998; 159:1308–131223. Hoffman B B, Hu Z -H. Regulation of responsesmediated by alpha 1-adrenergic receptors in smoothmuscle cultures. Pharmacol Commun 1995; 6: 1–324. Kirby R S. Terazosin in benign prostatic hyperplasia:effects on blood pressure in normotensive andhypertensive men. Br J Urol 1998; 82: 373–37925. Lowe F C, Olson P J, Padley R J. Effects of terazosintherapy on blood pressure in men withbenign prostatic hyperplasia concurrently treatedwith other antihypertensive medications. Urology1999; 54: 81–8526. Chapple C R. Tamsulosin. In: Kirby R, McConnellJ D, Fitzpatrick J M et al. (eds). Textbook of benignprostatic hyperplasia, 2nd edn. London: Taylor andFrancis, 200527. Wyllie M G. Alpha 1-adrenoceptor selectivity: theNorth American experience. Urology 1999; 36(Suppl): 59–6328. Pool J L. Effects of doxazosin on coronary heartdisease risk factors in hypertensive patients. Br JClin Pract Symp Suppl 1994; 74: 8–1229. Pool J L. Effects of doxazosin on serum lipids. Areview of the clinical data and the molecular basisfor altered lipid metabolism. Am Heart J 1991; 121:251–26030. Itskovitz H D. Alpha 1-blockade for the treatmentof hypertension: a megastudy of terazosin in 2214clinical practice settings. Clin Ther 1994; 16:490–50431. Shinori H, Gotoh E, Ito T et al. Long-term therapywith terazosin may improve glucose and lipid

TERAZOSIN IN LOWER URINARY TRACT OBSTRUCTION 101metabolism in hypertensives: a multicenterprospective study. Am J Med Sci 1994; 307 (Suppl):91–9532. Hernandez R, Angeli-Greaves M, Carvajal A R etal. Terazosin: ex vivo platelet aggregation effects inpatients with arterial hypertension. Am JHypertens 1996; 9: 437–44433. Levy D, Wilson P W F, Anderson K M, Castelli WP. Stratifying patients at risk from coronary heartdisease; new insights from the Framingham HeartStudy. Am Heart J 1990; 119: 712–71734. Flack J M, Nasser S A. The antihypertensive andlipid-lowering treatment to prevent heart attacktrial (ALLHAT). Major outcomes in high-riskhypertensive patients randomized to angiotensinconvertingenzyme inhibitor or calcium channelblocker versus diuretic. Curr Hypertens Rep 2003;5: 189–19135. JNC-7. The seventh report of the Joint NationalCommittee on Prevention, Detection, Evaluationand Treatment of High Blood Pressure. May 2003:NIH Publication No 03-523336. Ramage A G, Wyllie M G. A comparison of effectsof doxazosin and terazosin on the spontaneoussympathetic drive to the bladder and related organsin anaesthetised cats. Eur J Pharmacol 1996; 117:962–96637. Kyprianou N. Doxazosin and terazosin suppressprostate growth by inducing apoptosis. Clinical significance.J Urol 2003; 169: 1520–1525

Doxazosin in the treatment ofbenign prostatic hyperplasiaR S Kirby8INTRODUCTIONThe treatment with α 1-adrenoceptor antagonistsof the benign prostatic hyperplasia (BPH) symptomcomplex associated with obstruction of thelower urinary tract has evolved substantially fromthe original observations of Caine with phenoxybenzamine.Initially, only two types of α-adrenoceptor(α 1and α 2) were identified. Phenoxybenzamine,an antagonist at both α-adrenoceptors,was classified as a nonselective α-adrenoceptorantagonist. Subsequently, the prime determinantof periurethral smooth muscle tone wasfound to be the α 1-adrenoceptor, which led to theclinical evaluation of the first α 1-selective antagonist,prazosin, in an attempt to improve the sideeffectprofile of phenoxybenzamine. Understandinghas increased further, to an extent wherethree major subtypes of the α 1-adrenoceptor havebeen cloned and characterized, namely α 1A, α 1B,and α 1D. A fourth receptor subtype, the α 1L-adrenoceptor, has also been defined pharmacologically,but neither fully characterized norcloned. 1 The evolution of the nomenclature,which has been confusing and has undergonechange over the last few years, is described in areview by Bylund et al. 2As a class, α 1-adrenoceptor antagonists arewell tolerated and effective in the treatment ofobstruction-related lower urinary tract symptoms.3 Both obstructive and irritative symptomsare improved, and there are changes in urinaryflow and residual volume consistent with a reductionin urethral resistance. Prazosin has been usedin this context for several years, but its therapeuticpotential has been limited owing to the dosingregimen and the side-effects associated with therapidity of onset of action. Doxazosin, a selectiveα 1-adrenoceptor antagonist, was developed toovercome these shortcomings. It has similar affinityfor all α 1-adrenoceptor subtypes and, therefore,can be considered to have a balanced pharmacologicprofile. 4 In addition, doxazosin can bedistinguished from prazosin on the basis of physiochemicaldifferences, which result in a moregradual onset of action and an extended plasmahalf-life (22 hours), consistent with utility as aonce-a-day agent (Figure 8.1). 5,6 Doxazosin hashad a wide exposure in BPH and hypertensivepatients, and also in the high proportion ofpatients with concomitant disease. 7Change in standing systolic BP (mmHg)0–10–20–30–40–500 2 4 6 8Time (h)FIGURE 28.1 Onset of action of doxazosin ( ; meandose 0.95 mg i.v.) and prazosin ( ; mean dose 1 mg i.v.):effect on standing systolic blood pressure (BP). (FromElliot et al., 5 with permission.)103

104THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAThis chapter reviews the available data ondoxazosin, and analyzes whether the balancedaction of doxazosin on α 1-adrenoceptor subtypestranslates into clinical advantages for patient, primary-carephysician, and urologist, alike.α 1-ADRENOCEPTOR HETEROGENEITYTo understand the clinical profile of doxazosin itis necessary to consider briefly the pathophysiologicroles of α 1-adrenoceptor subtypes. A comprehensivereview of the literature is not withinthe scope of this chapter, but the salient featuresare summarized below. For a more detailedreview of the potential role of the different α 1-adrenoceptor subtypes throughout the urogenital,cardiovascular, and central nervous system, consultKirby et al. 8All three high-affinity α 1-adrenoceptor subtypesα 1A, α 1B, and α 1Dare present in the prostate.The α 1-receptor predominates, in both hyperplasticand normal prostate tissue, and its presenceis correlated with the prostatic contractileresponse. 9–11 α-Blockers were first thought torelieve the symptoms of BPH by inhibiting theα 1A-adrenoceptors of the prostatic smooth muscle.Any associated side-effects were assumed tobe mediated via α 1-adrenoceptors in the vasculature.However, more recent evidence suggeststhat both the efficacy and tolerability of α-blockersin BPH may have a centrally mediated component.8 The α 1D-receptor subtype, for example,is predominant in CNS structures involved withmicturition. Side-effects such as asthenia anddizziness may be due to a central rather than avascular effect. As such, although an α 1-adrenoceptorsubtype probably cannot preferentially betargeted as a treatment for BPH, reducing activityat the α 1Bsubtype may reduce cardiovascularcomplications. 8SAFETY AND EFFICACY OF DOXAZOSIN INBPH TREATMENTShort-term efficacyA number of double-blind, placebo-controlledclinical studies of doxazosin in patients with BPHhave been completed, and reported in the literature.12–19 Patients enrolled in the studies havebeen men aged between 50 and 80 years with clinicalevidence of BPH and maximum flow ratesbelow 15 ml/s. In general, patients receivingtreatment with other α 1-adrenoceptor antagonists,and patients with urinary tract infections orother serious illnesses, were excluded from thesestudies. A wash-out phase of at least 1 week wasfollowed by a double-blind treatment period ofbetween 1 and 6 months. Patients were randomizedeither to doxazosin (at an initial dose of1 mg/day and increased sequentially according toprotocol) or to placebo. Both normotensive andhypertensive patients were included in thesestudies.Treatment with doxazosin increased bothmaximum and average urinary flow rates inalmost all studies. The changes achieved statisticalsignificance compared with placebo in themajority of patients. Doxazosin also produced aconsistently reduced residual urine volume, albeitsmall and variable, compared with placebo.BPH-associated symptoms were also improved toa statistically significant extent in the majority ofstudies. Irrespective of the different symptomscores used in these studies, consistently greaterresponses were recorded in patients treated withdoxazosin than in those given placebo.

DOXAZOSIN IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 105In the studies reported above, the beneficialeffects of doxazosin on symptoms and uroflowwere seen within the first few weeks of treatment,often before doxazosin had been titrated to theoptimum dose (Figure 8.2). This has importantclinical implications, in that patients may beencouraged to continue to comply with treatmentif they experience an early improvement in symptoms.Doxazosin has a beneficial effect on symptomsand urinary flow rates, irrespective of thebaseline severity of disease. In a pooled analysis ofthree of the double-blind, placebo-controlledstudies reported above, doxazosin was seen toproduce a significantly greater improvementcompared to placebo in peak urinary flow rate,symptom severity, and symptom bother. 20Stratification by severity of symptoms at baselinedemonstrated that the greatest improvementwith doxazosin was seen in patients with the mostsevere symptoms (p = 0.0001); age did not impacton the capacity to benefit from treatment. Thus,it can be concluded that treatment with doxazosinis effective in patients with mild, moderate,and severe BPH, not just those with only mild ormoderate symptoms.Pooled analysis also allowed a more in-depthassessment of urodynamic changes with doxazosinversus placebo. 21 Doxazosin significantlyimproved free urinary flow rate versus placebo,and reduced detrusor pressure, leading to adecreased voiding time and increased voided volume.Urethral resistance was also reduced withdoxazosin.While the majority of studies have been concludedin men between 50 and 80 years of age, theefficacy and safety of α 1-adrenoceptor antagonistshas also been investigated in men over the age of80 years. 22 In a study of doxazosin and terazosin,both agents were seen to produce a significantincrease in peak urinary flow rate and asignificant improvement in American UrologicalAssociation (AUA) symptom score. Importantly,doxazosin or terazosin could be introduced forthe treatment of BPH in patients who werealready receiving antihypertensive treatment.abMean change (score)0–1–2–3–4–5–6†****** *0 2 4 6 7 8 10 12 14Duration of treatment (weeks)Mean change (ml/s)43210–1*** ** ***0 2 4 6 7 8 10 12 14Duration of treatment (weeks)FIGURE 8.2 Effect of doxazosin ( ) versus placebo ( ) on (a) symptom score and (b) peak uroflow. Asterisks indicatesignificant differences from placebo (*p

106THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIALong-term efficacyThe longest double-blind study with doxazosinwas conducted by Holme et al., 15 with a durationof 29 weeks. This study demonstrated that efficacywas maintained throughout the treatmentperiod. These double-blind data are supported bydata from an open-label extension study ofpatients who completed three of the doubleblind,placebo-controlled studies listed above. 23 Atotal of 450 men entered the long-term study, anddata are available for up to 48 months of followup.Results show that doxazosin, over the courseof 4 years, produces a clinically and statisticallysignificant increase in maximum and average urinaryflow rate (Figure 8.3), as well as a clinicallyand statistically significant improvement in total,obstructive, and irritative BPH symptoms(Figure 8.4).In a further analysis of only those patientswith concurrent hypertension and BPH, treatmentwith doxazosin over 48 months resulted ina sustained improvement in the severity andbothersomeness of BPH symptoms, and anincrease in maximum urinary flow rate. 24 Therewas also a significant and sustained reduction indiastolic blood pressure.The efficacy and tolerability of doxazosin incombination with finasteride has also been evaluatedin the Prospective European Doxazosin andCombination therapy (PREDICT) trial. 25 In thisstudy of 1095 men, doxazosin was effective inimproving symptoms and flow and was moreeffective that finasteride or placebo. Addition offinasteride did not provide further benefit to thatobserved with doxazosin alone. Therefore, overallthe results were similar to combination studiesinvolving other α-blockers. 26The PREDICT study and the MedicalTherapy of Prostatic Symptoms (MTOPS) 27study have also provided further evidence of thedurability of the response to doxazosin with littleevidence of tachyphylaxis.Q max mean changes vs baseline (ml/s)n = 449 438 402 372 352 321 297 257 131 592.5***2.0***** **1.51.00.500 < 60 3 6 9 12 15–18 21–24 27–30 33–36 39–42daysMonthsFIGURE 8.3 Maximum urinary flow rates (Q max) during the 4-year open-label extension study with doxazosin.Decreased patient numbers at successive time points are not because patients withdrew from the study, but primarilybecause patients were enrolled as they completed each double-blind study, which spanned many months. Asterisks indicatep

DOXAZOSIN IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 107n = 407 416 373 365 347 316 290 252 124 57Months0 < 60 3 6 9 12 15–18 21–24 27–30 33–36 39–42days0Mean change from baseline–1–2–3–4–5–6******* * * * * * * ***** ************–7FIGURE 8.4 Effect of doxazosin on obstructive ( ), irritative ( ), and Boyarsky total ( ) symptom bothersomenessscore during the 4-year open-label extension study with doxazosin. Decreased patient numbers at successive timepoints are not because patients withdrew from the study, but primarily because patients were enrolled as they completedeach double-blind study, which spanned many months. Asterisks indicate p

108THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAtinued therapy with doxazosin due to adverseevents did so within the first 9 months of therapy(Figure 8.5).TREATMENT OF THE WHOLE PATIENTEffects on blood pressure controlThe involvement of α 1-adrenoceptor subtypes incardiovascular control is of prime importance innormotensive and hypertensive patients. Not surprisingly,as blood pressure regulation is the algebraicsum of many cardiac and vascular processes,the ‘blood pressure subtype’ of the α 1-adrenoceptorhas not been identified. Although there maybe differential distributions within the vasculature,and distribution may be species and vesseldependent, all subtypes appear to play a role inthe contractile response of vascular tissue. 8,9,30The human α 1A-adrenoceptor appears to be thepredominant α-adrenoceptor subtype in arterialsmooth muscle, but this does not mean that it necessarilycontrols systemic blood pressure andorthostasis. It is more reasonable to assume thatcardiovascular homeostasis depends on all subtypes,and effective blood pressure control will beachieved only with a balanced α 1-adrenoceptorantagonist. Equally, a prostate-selective antagonistmay be incapable of providing effective bloodpressure control in BPH patients with associatedhypertension.It is well documented that the blood pressureloweringeffects of α 1-adrenoceptor antagonistsare highly dependent on the hemodynamic baseline.Doxazosin lowers blood pressure when sympatheticdrive is high, for example in hypertension.In contrast, doxazosin has less effect onresistance vessel tone in normotensive patients,and clinically insignificant changes in blood pressureare observed (Figure 8.6). 31,32 Interestingly,there is no effect on the hemodynamic baseline,irrespective of whether BPH patients are physiologicallynormotensive or are stabilized on antihypertensivetherapy. 31Hypertension and BPH are often encounteredconcomitantly in primary care practice. It isimportant, therefore, that an agent used to treatBPH can be used effectively and safely in patients100Cumulative discontinuation (%)806040200< 60 3 6 9 12 15 18 21 24 27 30 33 36 39 42daysDuration of treatment (months)FIGURE 8.5 Reverse Kaplan–Meier plot of discontinuations from long-term doxazosin therapy because of adverseevents (upper curve) or inadequate clinical response (lower curve). (From Lepor et al., 23 with permission.)

DOXAZOSIN IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 109receiving additional antihypertensive treatment.The Hypertension and BPH Intervention Study(HABIT) evaluated the efficacy and safety ofdoxazosin in patients with concomitant hypertensionand BPH, in a community-based setting. 33There were four groups in the study: patientstreated with antihypertensives who were wellcontrolled; patients treated and poorly controlled;untreated, hypertensive patients; and untreatednormotensive patients. Treatment with doxazosinwas effective in all groups of patients; therewas significant improvement in symptom scoresas well as BPH-specific indices of health status(p

110THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAproliferation in the vasculature via an α 1-adrenoceptormechanism. 38,39 α 1-Adrenoceptor-antagonistattenuation of a proliferative vascularresponse could have important implications in theprevention of hypertension, coronary heart disease(CHD), and atherosclerosis. Doxazosin hasalso been shown to have a favorable effect onother cardiovascular risk factors, includingincreased fibrinolysis, inhibition of platelet aggregation,attenuation of the adverse hemodynamicand hemostatic effects of smoking, and regressionof left ventricular hypertrophy. 34,35Extensive studies of almost 5000 hypertensivepatients in general practice show a beneficialeffect of doxazosin in significantly reducingCHD. 40 On the basis of the Framingham Studyequation, 41 an approximate 20% reduction inCHD incidence would be predicted to resultfrom these changes in CHD risk factors. In theHypertension and Lipid Trial (HALT), a studyenrolling over 800 patients with hypertension in aclinical practice setting, treatment with doxazosinproduced a significant reduction in mean totalcholesterol levels, LDL cholesterol, and triglycerides;levels of HDL cholesterol were essentiallyunchanged. In previously untreated patients,these doxazosin-induced changes in serum lipidprofile, together with a significant reduction inblood pressure, resulted in a reduction in mean 5-year coronary disease risk of 15%. 42 The effects ofdoxazosin on predicted coronary disease risk arein contrast to other antihypertensive agents, e.g.β-blockers. In a 5-year comparison of doxazosinand the β-blocker atenolol, doxazosin significantlyreduced the predicted 10-year risk of CHD byapproximately 12%, whereas atenolol had essentiallyno effect (0.2% increase). While both agentswere effective antihypertensives, and both werewell tolerated, only doxazosin had favorableeffects on the serum lipid profile. 43More recently, the Antihypertensive Lipid-Lowering Treatment to Prevent Heart AttackTrial (ALLHAT) was completed. 44 Although theinterpretation of data has created considerabledebate, careful analysis confirms that it does notaffect the management of BPH patients withdoxazosin. 45Thus, the beneficial effects of doxazosin oncardiovascular risk further support the use of abalanced agent in the treatment of the BPHpatient as a whole.Sexual functionFor several years there has been indirect evidencethat doxazosin has a positive effect in males witherectile dysfunction (ED). In the 4-year TOMHSstudy, 36,46 a much reduced incidence of ED wasreported in the doxazosin group compared withplacebo (Figure 8.7). In contrast, other antihypertensiveagents (e.g. diuretics) appeared to increasethe incidence. Throughout the duration of thestudy, erection problems disappeared in 88% ofmen randomized to doxazosin, compared with55% of men in all other groups combined.More recently, in an Italian multicenter studyin BPH patients, doxazosin was found to improveerectile function, independent of any improvementin LUTS. 47 The positive effect is consistentwith the well-documented role of α 1-adrenoceptorsin the control of corpus cavernosal tone 48 andthe clinical benefit observed with intracavernosalinjection of α 1-adrenoceptor antagonists.Although doxazosin may not necessarily representeffective monotherapy for ED per se, thereis some suggestion that it could form part of acombination strategy in the management of EDrefractory to other agents. In one study of menwith moderate to severe ED, oral doxazosinimproved the response to intracavernosalalprostadil injection. There was an 18% improve-

DOXAZOSIN IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 111100Percentage of patients2520151050Doxazosin Enalapril Placebo Amilodipine Acebutolol Chlorthalidone(n = 71) (n = 61) (n = 118) (n = 59) (n = 72) (n = 70)Treatment groupFIGURE 8.7 Treatment of Mild Hypertension Study: incidence of men reporting inability to maintain an erection.(From Neaton et al., 36 with permission.)ment in International Index of Erectile Function(IIEF) with alprostadil alone, compared with a52% improvement over 12 weeks with the additionof doxazosin (p

112THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIADOXAZOSIN: THE NEW GITSFORMULATIONA new formulation of doxazosin, the doxazosingastrointestinal therapeutic system (GITS), hasbeen developed to enhance the pharmacokineticprofile of the drug. It employs controlled-releasetechnology to allow more gradual drug deliverywith the first dose, and precise, sustained serumlevels with long-term, once-daily administration.It is as effective and well tolerated as the standardformulation. For example, in a study of patientswith mild hypertension, both doxazosin standardand doxazosin GITS produced significant reductionsin blood pressure compared to placebo(p < 0.001). The most commonly reported sideeffectswere headaches, dizziness, and asthenia. 57The GITS formulation appears to eliminate theneed for doxazosin dose titration in most patients.In a combined analysis of two randomized, double-blindstudies in hypertension, approximately60% of patients achieved goal blood pressureresponse at the 4 mg starting dose. 58 The simplifieddosing regimen is likely to result in feweroffice visits for patients.Studies with doxazosin GITS have also beencarried out in patients with BPH. 18,19,59 Resultshave shown that doxazosin GITS provides effectiverelief from the signs and symptoms of BPH,with an efficacy comparable to that of the standardformulation. In a combined analysis of twodouble-blind, placebo-controlled studies, a similarincrease in urinary flow rate and a similarimprovement in symptoms were seen with doxazosinGITS and doxazosin standard (Figure 8.8).Fewer titration steps were needed with doxazosinGITS, and almost 50% of patients achievedsymptom relief at the starting dose of 4 mg/day.Tolerability was also enhanced with doxazosinGITS. In the same combined analysis, the overallincidence of adverse events was similar in doxazosinGITS and placebo groups, and lower thanthat with standard doxazosin treatment (Table8.1)Intriguingly, in a ‘gold standard’ double-blindstudy, the doxazosin GITS (4 mg, 8 mg) wasMean total I-PSS2018161412108a* †§ * † b14* †*10****13* †§ *† * †** †12* ‡*11* †* †* †9* †Mean Q max (ml/s)800 1 2 3 4 5 6 7 8 9 10 11 12 13Week00 1 2 3 4 5 6 7 8 9 10 11 12 13WeekFIGURE 8.8 Effect of doxazosin gastrointestinal therapeutic system (GITS) ( ), doxazosin standard ( ), and placebo( ) on (a) total International Prostate Symptom Score (I-PSS) and (b) maximum urinary flow rate. (From Kirby et al., 59with permission.)

DOXAZOSIN IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 113TABLE 8.1 Incidence of adverse events in patients with BPH treated with doxazosin GITS, doxazosin standard, andplacebo. (Adapted from Kirby et al. 59 )Doxazosin GITS (%) Doxazosin standard (%) Placebo (%)(n = 666) (n = 651) (n = 156)All adverse events 41.1 53.6 39.1Treatment-related adverse events 16.1 25.3 7.7Discontinuations due to 3.3 4.8 0.6treatment-related adverse eventsGITS, gastrointestinal therapeutic system.found to be more effective than tamsulosin(0.4 mg, 0.8 mg) in improving LUTS symptoms.60 This could represent the first evidencefrom a carefully controlled study that α-blockersmay have different effects.CONCLUSIONSDoxazosin has a balanced pharmacologic actionat all subtypes of the α 1-adrenoceptor, which isreflected clinically in a beneficial effect on thewhole patient. It improves both symptoms andmeasures of urinary flow in the patient withBPH, as well as producing clinically importantblood pressure reductions in BPH patients withhypertension. It is likely that an action on alladrenoceptor subtypes is required to produce thisprofile. In subjects with physiologic or drug-controllednormotension, only minor, clinicallyinsignificant changes in blood pressure areobserved.Doxazosin appears to have a beneficial effecton several risk factors (e.g. lipid profile, glucosemetabolism) associated with hypertension, CHD,and atherosclerosis. The α 1-adrenoceptor subtypeinvolved has not been identified, and there maybe a contribution from receptor-independentevents.In addition to these pharmacologic actions,the physiochemical properties of the drug offerconsiderable advantages. In particular, doxazosin,compared with other α 1-adrenoceptor antagonists,has a long plasma half-life consistent withonce-daily dosing. The associated gradual onsetof action also underpins the reduced propensityfor side-effects. Importantly, the pharmacokineticsare unchanged in the elderly and in renal failure.The new GITS formulation extends theestablished benefits of standard doxazosin therapy.Doxazosin GITS has an efficacy and tolerabilityprofile similar to that of the standard formulation,with the additional advantages of anenhanced pharmacokinetic profile and simplifieddosing regimen.Doxazosin is very well tolerated in both oldand young patients. Most adverse events are mildor moderate in severity and do not require discontinuationof therapy. There is no suggestion ofa deleterious impact on sexual function—in fact,there is evidence of a positive effect of doxazosinon erectile dysfunction.Overall, the balanced action of doxazosin onα 1-adrenoceptor subtypes is associated with ahighly desirable clinical profile for the BPHpatient. Any advantages arising from a genuinelyprostate-selective antagonist will ultimately have

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AlfuzosinA Jardin9INTRODUCTIONAlfuzosin, a quinazoline derivative, acts as aselective antagonist of α 1-adrenoceptor-mediatedcontraction of bladder neck, proximal urethral,and prostatic smooth muscle. Bladder outletresistance resulting from benign prostatic hyperplasia(BPH) is consequently reduced. Alfuzosinis approved in Europe for the treatment of symptomaticBPH.PHARMACOLOGIC PROFILE OF ALFUZOSINAT α 1-ADRENOCEPTOR SUBTYPESThe human prostatic smooth muscle containshigh densities of α 1-adrenoceptors. 1,2 Several α 1-adrenoceptor subtypes have been identified andtheir heterogeneity revealed both pharmacologicallyand by molecular cloning. 3,4 The three α 1-adrenoceptor subtypes with high affinity for prazosin(grouped under the α 1Hheading), so faridentified, i.e. α 1A-, α 1B-, and α 1D-adrenoceptors,have been cloned (α 1a, α 1b, and α 1d). Anotheradrenoceptor subtype has been identified and ischaracterized by a low affinity for prazosin andfor that reason entitled α 1L. 5,7,8 Table 9.1 summarizesthe affinity for the three cloned α 1-adrenoceptorsof the major α 1-adrenoceptor antagonistsavailable today. As shown with doxazosin, terazosin,and prazosin, alfuzosin has no distinctselectivity for any of the receptor subtypes.Uroselectivity has been shown to result from thepharmacodynamic properties of agents withoutspecificity for any particular subtype, however. 9In addition, uroselectivity does not appear to berelated to receptor subtype affinity. 10AFFINITY OF ALFUZOSIN FORα-ADRENOCEPTORS IN THE HUMANPROSTATEThe cranial region of the human prostatic adenomapossesses high affinity [ 3 H]-prazosin bindingsites. 11,12 These sites display the pharmacologiccharacteristics of α 1-adrenoceptors. As shown inTable 9.2, [ 3 H]-prazosin binding is potently displacedby alfuzosin and phentolamine, with IC 50values in the low nanomolar range, while the α 2-adrenoceptor antagonists idazoxan and yohimbine,and the β-adrenoceptor antagonist propranolol,only affect [ 3 H]-prazosin binding with IC 50values in the micromolar range. Thus, alfuzosinTABLE 9.1 Affinity of various α 1-adrenoceptor antagonistsfor the human cloned α 1-adrenoceptors.AffinityCompound α 1aα 1bα 1dAlfuzosin 8.20 8.53 8.40Doxazosin 8.56 8.98 8.78Prazosin 9.70 9.60 9.50Tamsulosin 9.70 8.90 9.80Terazosin 8.16 8.71 8.465-ME-Urapidil 8.68 6.76 7.91Adapted from Forray C et al. 6 and Kenny et al. 7119

120THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAshows high affinity for α 1-adrenoceptors in thehuman prostate, which represents the pharmacologictarget in BPH. In support of this view, it hasbeen reported that alfuzosin-displaceable [ 125 I]-HEAT (iodo-4-hydroxyphenyl-ethyl-aminomethyl-tetralone)binding sites, which have thepharmacologic characteristics of α 1-adrenoceptors,are exclusively associated with muscularstroma of the prostate and are markedly elevatedin sections from prostatic adenomas as comparedwith nonhypertrophic tissue. 13As far as α 1-adrenoceptor subtypes are concerned,Faure et al. 14 have shown that the humanprostate expresses at the level of the apex, base,periurethral, and lateral lobe, mRNA transcriptscorresponding to α 1a-, α 1b-, and α 1d-adrenoceptors.In addition, these authors have shown that areconstituted partial sequence (349 amino acids)of the human prostatic α 1α-adrenoceptor shares94% identity with the bovine brain α 1a-adrenoceptor,and that this receptor represents the predominantα 1-adrenoceptor subtype in this tissue.FUNCTIONAL UROSELECTIVITY OFALFUZOSINEffects on elevated urethral and blood pressureInhibition of urethral responses to stimulation ofhypogastric sympathetic nerves in the cat is consideredto represent an animal model of thedynamic sympathetic constriction of urethralsmooth muscle, which is regarded as a contributoryfactor in the obstructive disorders whichcharacterize BPH. 15 On the other hand, α 1-adrenoceptor antagonist reduction of blood pressurein spontaneous hypertensive rats is acceptedas a model to assess antihypertensive drugs actingat receptors physiologically stimulated by anincreased sympathetic tone. Thus a relationshipTABLE 9.2 Affinity of alfuzosin for α 1-adrenoceptors incranial human prostatic adenoma labeled with 3 H-prazosin.DrugIC 50* (µM)Alfuzosin 0.035 ± 0.008Phenoxybenzamine 0.038 ± 0.016Idazoxan 3.5 ± 1.0Yohimbine 6.0 ± 2.0Propranolol 37 ± 9*IC 50values represent drug concentrations producing50% inhibition of specific 3 H-prazosin binding. Values aretaken from Pimoule et al. 11 and Lefevre-Borg et al. 12between the ability of alfuzosin to inhibit sympatheticallymediated increases in urethral tone inthe cat and sympathetically mediated hypertensionin the spontaneously hypertensive rat can beconsidered as a relevant way to evaluate the therapeuticmargin in BPH with respect to unwantedvascular effects (e.g. orthostatic hypotension). 15Studies conducted in the anesthetized cat andin conscious spontaneously hypertensive rats confirmthe α 1-antagonist properties of alfuzosin.The compound produces a dose-related as well asa complete and prolonged inhibition of the rise inurethral pressure resulting from postganglionicstimulation of hypogastric sympathetic nerves inthe cat. As shown in Table 9.3, alfuzosin decreasesthe urethral resistance induced by hypogastricnerve stimulation in the cat at doses 11 timeslower than those which reduce blood pressure inspontaneously hypertensive rats. 15Effects on normal urethral and arterial bloodpressureIn recent years, attempts have been made to evaluate,in the same animal, the respective effects ofα 1-adrenoceptor antagonists on prostatic tissue

ALFUZOSIN 121TABLE 9.3 Effects of alfuzosin on urethral pressure (UP) in the cat and on mean arterial blood pressure (AP) in thespontaneously hypertensive rat.Dose producing a 50% reduction Dose producing a 20% reductionin urethral pressure in arterial blood pressure Uroselectivity ratioCompound (ID 50UP) (mg/kg, id) (ID 20AP) (mg/kg, po) (ID 20AP/ID 50UP)Alfuzosin 0.36 4.0 11Terazosin 0.12 0.42 3.5Prazosin 0.12 0.13 1The doses of each compound producing a 50% reduction in urethral pressure (UP 50) in anesthetized cats and a 20% reductionin blood pressure (UP 20) in spontaneously hypertensive rats are shown. Values are taken from Lefevre-Borg et al. 15compared to side-effects, most particularly theeffects on blood pressure. In the most recentlydeveloped model, which allows the simultaneousmeasurement of urethral and arterial pressures inconscious male rats, 16 a direct estimation of thefunctional uroselectivity of alfuzosin was performed.At clinically relevant doses (10–30 µg/kg,intravenous route), alfuzosin decreased urethralpressure without noticeable effects on blood pressure(Figure 9.1). In a comparative investigation,using the same experimental model, the functionaluroselectivity of alfuzosin has been shown to besuperior to that of other α 1-adrenoceptor antagonists.17 These results are further evidence thatfunctional uroselectivity may be achieved in theabsence of pharmacologic selectivity for one ofthe α 1-adrenoceptor subtypes.TISSUE DISTRIBUTIONThe role of tissue distribution of α 1-adrenoceptorantagonists and its possible effect on functionaluroselectivity has been less rigorously examined.However, a direct measurement of plasma andprostate distribution of alfuzosin, related to measurementof its pharmacologic activity on arterialUrethral pressure (% inhibition)0–20–40–60–80–1000.001 0.010 0.100 1Dose (mg/kg. i.v.)FIGURE 9.1 Effect of alfuzosin (triangle) comparedwith vehicle control (circle) on an increase in urethralpressure in the anesthetized cat. Doses of alfuzosin correspondto cumulative i.v. bolus administration of the drug.Increased urethral pressure was elicited by electrical stimulationof sympathetic hypogastric nerves. (From ref. 5with permission.)blood pressure and urethral pressure, has broughtnew and useful information. 18 One hour followingoral administration of 10 mg/kg of alfuzosin

122THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAin rats, plasma and prostate levels, respectively,reached 88.0 ng/ml and 335 ng/ml, leading to aprostate/plasma concentration ratio of 3.8. At 6hours, the plasma concentration decreased to20 ng/ml, whereas prostatic tissue concentrationwas still about nine times higher than plasmaconcentration. Moreover, in the same study, anindex of the antagonistic activity of alfuzosinagainst phenylephrine-induced urethral contractionswas directly correlated with prostatic tissueconcentrations. This study, by demonstrating thatalfuzosin concentrates in the prostate at levels4–9-fold above the plasma levels, may thus providea basis for its preferential activity in thelower urinary tract compared to vascular effects.High prostatic diffusion of alfuzosin has alsobeen observed in orally treated patients. 19ConclusionsIn conclusion, alfuzosin is a potent selective α 1-adrenoceptor antagonist which displays functionaluroselectivity in animal models. These pharmacologicproperties lend support to the theorythat alfuzosin alleviates the dynamic componentof urinary obstruction attributable to sympathetictone in BPH. These pharmacologic properties arelikely to underlie the clinical profile of alfuzosin.PHARMACOKINETIC PROPERTIESThe pharmacokinetics of alfuzosin are linear andnonsaturable. Absorption of the immediaterelease (IR) formulation of alfuzosin is relativelyrapid, with a maximum plasma concentrationoccurring after a mean of 1.5 hours. Its bioavailabilityis 64%, with a negligible effect of concomitantadministration of food on its absorption.Alfuzosin is approximately 90% protein bound inplasma. It is extensively metabolized by the liverand the metabolites are inactive. Its main route ofelimination is fecal. The mean plasma eliminationhalf life of IR alfuzosin is 4.8 hours. Becauseof this pharmacokinetic profile, the IR of alfuzosinhas to be administered three times daily(7.5 mg/day). The slow release (SR) formulationof alfuzosin (5 mg daily), currently available inEurope, has been developed in order to improvecompliance with the treatment by reducing thenumber of daily doses from three to two. The relativebioavailability of this formulation is 15%lower than for the IR formulation of alfuzosin.The time to reach the peak is longer, approximately3 hours instead of 1.5 hours, confirmingthat the absorption is delayed as well as its apparentelimination half-life, which is 8 hours. Theusual recommended daily dose is 5 mg twicedaily, i.e. 10 mg/day. This higher daily dosagecompares with the usual daily dose of 7.5 mg forthe IR formulation, compensating for the relativeloss of bioavailability.A once-daily formulation of alfuzosin is nowavailable and, although the absorption characteristicsare different from the IR and SR formulations,the metabolism of the drug is similar. 20,21Inactive barrier layers ensure that the active elementis released over 20 hours. The dissolutionrate is almost constant between 2 and 12 hoursand the area under the plasma concentration–timecurve is similar over 24 hours to that observed for2.5 mg thrice-daily and 5 mg twice-daily formulations.The plasma elimination half-life of theprolonged-release 10 mg formulation was 9.1hours compared to 7 hours for the IR formulation.19 The pharmacokinetic properties of 10 mgalfuzosin once-daily were not significantly differentin patients with renal impairment or in olderadults compared to the IR formulation. 22,23The overall pharmacokinetic profile of alfuzosinis not significantly changed in patients with

ALFUZOSIN 123renal insufficiency, in contrast to what is observedin patients with hepatic insufficiency, wheredosage modifications appear to be necessary.PHARMACODYNAMIC EFFECTS IN HUMANSUrodynamic effectsIntravenous alfuzosin significantly reduced highurethral pressure arising from neurologic causes.One hundred and sixty-three patients with neurogenicbladder disease (NBD) and a mean maximalurethral pressure of 108 cmH 2O wereincluded in a randomized, double-blind, placebocontrolledstudy assessing the effect of a single i.v.injection of alfuzosin (0.5, 1, or 2 mg) or placebo.Alfuzosin significantly and dose-dependentlydecreased urethral pressure, with a meandecrease of 44% for the 2 mg dose. 24 A single i.v.test dose of 5 mg alfuzosin had previously beenused to determine which patients with spinal cordinjury (n = 21) were likely to benefit from alfuzosintherapy. Response was assessed in terms ofchange in micturition, residual urine, and posteriorurethral pressure and diameter. 25Furthermore, in a placebo-controlled study conductedin 66 patients with NBD, this decreasewas maintained with oral alfuzosin for 12 weeksand associated with a significant improvement ofvoiding symptoms (–45%) and residual urine volume(–39%) compared with placebo. 26 Theseactions appear to be correlated with the α 1-adrenoceptor antagonism produced by alfuzosin.In patients with BPH, orally administered IRalfuzosin significantly and dose-dependentlyincreased urinary flow rates from the first dose. 27At 90 minutes after a single alfuzosin dose, peakflow rate (PFR) was significantly increased by 23and 34% with 1.25 and 2.5 mg, respectively, comparedwith placebo in 93 patients with initial PFRvalues of less than 15 ml/s. In patients with PFRvalues of less than 10 ml/s (n = 47), mean increasesin PFR with 1.25 or 2.5 mg alfuzosin or placebowere even greater: 26, 55, and 17%, respectively.27 Similar results were observed with SR alfuzosin.At 180 minutes after a single SR alfuzosindose, PFR was significantly increased by 29 and36% with 3 and 5 mg doses compared with placebo(+17%) in elderly patients (≥65 years) with initialPFR values of less than 15 ml/s. 28The 30% increase in flow rates, which is therate of improvement expected with α 1-blockertherapy in patients with BPH, is maintained aftermultiple-dose administration of alfuzosin. 28–32Furthermore, this is of the same order of magnitudeas that of prazosin 4 mg per day 33,34 and tamsulosin0.4 mg per day. 31 In those patients with anincrease in PFR of at least 25% (i.e. 45–50% ofpatients), the mean increase with alfuzosin isapproximately 5 ml/s.Residual urine volume is a parameter reflectingnot only the decrease in urinary flow resistance,but also the bladder contractility which mayshow wide intra-individual variability betweenserial examinations. 35 Alfuzosin has been shownto decrease significantly the volume of residualurine by 38% after 6 months of treatment comparedwith 9% in placebo recipients. 29A pooled analysis of 11 double-blind, placebocontrolledtrials involving 1470 LUTS patientsshowed that immediate- and sustained-releasealfuzosin effectively reduced postvoid residualurine volume. 36 Significant differences wereobserved between patients treated with alfuzosinand those who received placebo. The analysisshowed that acute urinary retention (AUR) wasmore common in men with residual urine greaterthan 100 ml. Patients receiving alfuzosin wereless likely to suffer AUR than those receivingplacebo.

124THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIASeveral more complex urodynamic assessmentshave been carried out in patients underalfuzosin treatment. In a 3-month, double-blind,placebo-controlled study performed in 31 patientswith urodynamically proven bladder outflowobstruction treated with alfuzosin, there was asignificant increase in the volume that produced astrong desire to void, which reflected the increaseof bladder capacity. 37 A pressure–flow, placebocontrolledstudy carried out in 52 patients withBPH treated with alfuzosin (7.5 mg/day for 4weeks followed by a 5–8-week single-blindextension) showed that alfuzosin significantlydecreases detrusor pressure compared with placebo(opening pressure, –39%; pressure at maximumflow, –30%; and maximum pressure, –29%;p < 0.05 for all parameters). These improvementsgradually increased up to 12 weeks. 38It can be concluded that the urodynamic effectof alfuzosin is characterized by a decrease in urethralpressure of about 45%, an increase in flowrate in patients with BPH of 30%, i.e. the expectedbenefit from α 1-blocker therapy in BPH, 39 anda beneficial effect on bladder capacity and pressure.Hemodynamic effectsAt doses used in the treatment of BPH, as wouldbe predicted from the uroselectivity describedabove, alfuzosin produces only minor changes inblood pressure. After single oral doses of IR alfuzosin(1.25 mg (n = 31) and 2.5 mg (n = 31))administered to BPH patients, mean supine andstanding systolic and diastolic blood pressureswere not significantly changed by alfuzosin comparedwith placebo. 29 The effects of SR alfuzosinon supine blood pressure following medium termadministration are likewise minimal, as shown ina large placebo-controlled study conducted on390 patients who received SR alfuzosin 10 mg perday or placebo for 3 months. The mean reductionsin systolic and diastolic blood pressures didnot differ statistically from those observed withplacebo in the whole population as well as in thesubgroups of normotensive and hypertensivepatients. 30 Similar results were observed in a large6-month double-blind study comparing SR alfuzosin(5 mg once daily), and the combination ofboth: mean changes in blood pressure were comparablein the three treatment groups (Figure9.2). 32However, supine blood pressure effects do notentirely represent the potential risk associatedwith α 1-blockers, which is mainly related toorthostatic changes in blood pressure, particularlyin the elderly and/or hypertensive patients. 40Urethral pressure (% inhibition)0–20–40–60–80–1000 1 2 3Time (h)FIGURE 9.2 Effect of alfuzosin (circle, 0.1 mg/kg;square, 1 mg/kg; triangle, 3 mg/kg) or vehicle control(hollow circle) on an increase in urethral pressure in theanesthetized cat. Doses of alfuzosin correspond to cumulativei.v. bolus administration of the drug. Increased urethralpressure was elicited by electrical stimulation ofsympathetic hypogastric nerves. (From ref. 5 with permission.)

ALFUZOSIN 125Thus, in order to address this potential riskspecifically in patients receiving SR alfuzosin, acombined analysis of two clinical studies conductedwith SR alfuzosin (10 mg/day) was performedwith special attention to orthostatic blood pressurechanges during the first month of treatment.41 Blood pressure was measured at peakplasma concentrations. Asymptomatic orthostatichypotension (AOH) was defined as a decrease insystolic blood pressure of at least 20 mmHg whenstanding. The cumulative incidence of AOH wasslightly more frequent with alfuzosin than withplacebo, but the difference was not statisticallysignificant. SR alfuzosin moderately increasedthe incidence of AOH in elderly and hypertensivepatients, during the first month of treatment.This effect was transient and was not associatedwith an increased incidence of related adverseevents (i.e. postural side-effects) in this subgroupof frail patients. In addition, orthostatic bloodpressure changes were assessed in the large(n = 1051 patients) 6-month study comparing SRalfuzosin (5 mg twice daily), finasteride (5 mgonce a day (od)) and the combination of both. 32The incidence of AOH was comparable in thethree treatment groups, regardless of age or preexistinghypertension (Figure 9.3).THERAPEUTIC POTENTIALMore than 33 000 BPH patients have been evaluatedin reported European clinical studies assessingthe efficacy and/or safety of alfuzosin or theimprovement in quality of life after administrationof alfuzosin. These studies were conductedwith the IR formulation of alfuzosin (7.5 to 10 mgper day given in three divided doses), the SR for-20–2Supine systolic BPSupine diastolic BPChanges in BP (mmHg)–4–6–8–10–12–14Between-group p = 0.80–16–18Between-group p = 0.50FIGURE 9.3 Maximum changes in blood pressure (BP) from baseline following a single i.v. injection of alfuzosin of 0.5( ), 1 ( ), or 2 ( ) mg in comparison with placebo ( ).

126THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAmulation (SR alfuzosin 5 mg bid), and, morerecently, the once-a-day formulation (alfuzosin10 mg od) for the treatment of symptomaticBPH.Clinical efficacyJardin et al. 29 reported the efficacy of alfuzosin ina large multicenter placebo-controlled study of518 patients with symptoms of BPH whoreceived either alfuzosin 7.5 or 10 mg/day orplacebo for 6 months. Patients were evaluatedusing the Boyarsky symptom scoring system, urinaryflow rates, and postvoid residual urine volume.Obstructive and irritative symptoms,assessed according to the Boyarsky scale,improved significantly in the alfuzosin groupcompared with the placebo group (p =0.004).Fewer patients in the alfuzosin group than in theplacebo group dropped out due to lack of efficacy(6.8 vs 14.6%, p = 0.0004) and the prevalence ofspontaneous acute urine retention (AUR) waslower in the alfuzosin group (0.4% vs 2.6%,p = 0.04). By 6 months, mean urinary flow rateshad increased (p

ALFUZOSIN 127urinary symptoms in comparison with placebo(Figure 9.5). A clinical improvement in LUTSwas observed whatever their initial severity, withan overall improvement in total I-PSS score of30% as a mean. 30 The clinical efficacy wasobserved from the first month. Maximum flowrate increased significantly with SR alfuzosin(+2.4 ml/s, i.e. +29%) compared with placebo(+1.1 ml/s, i.e. +14%, p =0.006). Residual urinewas also significantly reduced with SR alfuzosin.In those patients with baseline Q max≤ 12 ml/s andI-PSS score ≥13, the total I-PSS score decreasedby 6.7 points (36%) (comparison versus placebo:p =0.002) (Table 9.4).The efficacy of the once-daily formulation,administered at a dose of 10 mg per day withoutinitial titration, has been compared to that of theIR formulation (2.5 mg thrice daily) and placeboin a 3-month study which involved 436 patients:symptomatic improvement with the od formulationwas significantly higher than placebo andsimilar to that of the IR formulation, with I-PSSimprovements of 6.9 points in the od group and6.4 points in the 2.5 mg tid group (p =0.002 and0.02 vs placebo, respectively). The bothersomenessof these symptoms, assessed using the qualityof life index, was also significantly improvedwith both formulations compared with placebo(Table 9.5) (the ALFORTI study 44 ). Followingtreatment with alfuzosin od, Q max(measured attrough plasma levels) also significantly increasedin comparison with placebo (mean SD values:10987Score6***5*400 0.5 1 1.5 2 2.5Length of study (years)FIGURE 9.5 Total BPH symptom score improvement with alfuzosin: maintenance of symptomatic efficacy in the longterm. Part 1: 6-month placebo-controlled study (circle; n = 251); part 2: 1-year open extension (triangle; n = 131); part 3:1-year (additional) open extension (square; n = 50). *p

128THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIATABLE 9.4 Lower urinary tract symptoms (LUTS) and peak urinary flow (Q max) improvement in patients with baselineQ max≤ 12 ml/s and I-PSS ≥13*Parameter SR alfuzosin 10 mg/day Placebo p †I-PSS score ‡ n = 104 n = 110Baseline 17.8 (3.9) 18.3 (4.1)Final 11.2 (6.5) 14.4 (6.5)Change vs baseline –6.7 (–36%) –4.0 (–22%) 0.002Q max(ml/s) ‡ n = 91 n = 91Baseline 9.3 (2.1) 8.9 (2.2)Final 12.5 (5.1) 10.1 (3.8)Change vs baseline +3.2 (+39%) +1.1 (+16%) 0.0006% Patients with Q maxchange >30% 53 26*Adapted from Buzelin et al. 30 ; † intergroup comparison; ‡ mean (SD). SR, slow release.TABLE 9.5 Symptomatic improvement after 3 months of treatment with the once daily formulation of alfuzosin (10 mgod): comparison with immediate release (IR) alfuzosin and placebo. 44AlfuzozinAlfuzosinPlacebo 10 mg od 2.5 mg tid(n = 154) (n = 143) (n = 150) p*I-PSS scoreBaseline † 17.7 (4.1) 17.3 (3.5) 16.8 (3.7) 0.13Change vs. baseline † –4.9 (5.9) –6.9 (4.9) –6.4 (5.6) 0.005% of patients with a 26 37 42clearance of at least 50%Quality of life indexBaseline † 3.3 (1.0) 3.3 (1.0) 3.3 (0.9) 0.96Change vs. baseline † –0.6 (1.2) –0.1 (1.1) –1.1 (1.1) 0.002*Intergroup comparison; † mean (SD). Data from van Kerrebroeck et al. 44+2.3 (3.6) ml/s and +1.6 (3.2) ml/s, respectively;p = 0.03), demonstrating the therapeutic coverageover a 24-hour period.In a 9-month, non-blinded extension of thisstudy, the long-term efficacy of 10 mg od alfuzosinwas assessed over 12 months. 45 In total, 311of the original 436 patients took part in the extensionphase. At the start of the extension phase,mean I-PSS was 10.9 and did not change over thesubsequent 9 months, with mean I-PSS 9.3 atendpoint. Significant improvements wereobserved in patients who had originally receivedplacebo as part of the double-blind study(p = 0.0001). Peak flow, which was 11.5 ml/s atmonth 3, remained at its improved rate at month12 (p = 0.0001 compared to baseline).In addition, the 10 mg od formulation hasbeen compared to 15 mg od over 3 months. 46 Asin the ALFORTI study, the ALFUS studyincluded a wash-out period of 1 month before

ALFUZOSIN 129treatment with nontitrated alfuzosin or placebo.I-PSS, uroflowmetry, and quality of life wereassessed at baseline and then regularly throughoutthe studies. The men who took part in thetrial were aged 50 or over, had a history of LUTSsuggestive of BPH, an I-PSS of 13 or greater, apeak flow of 5–12 ml/s, a voided volume of150 ml or greater, and a PVR volume of 350 ml orless.Patients were stratified in each study accordingto whether they were < 65 or ≥65 and alsoaccording to blood pressure (< 90 or ≥90 mmHg).The primary efficacy outcome was mean changein I-PSS.The 3-month trial indicated that 15 mg odalfuzosin and 10 mg od both improved I-PSS significantlycompared to placebo. 46 In the ALFUSstudy, endpoint I-PSS scores improved frombaseline by 3.6 points in the 10 mg od group and3.4 points in the 15 mg od group (p =0.001 and0.004, respectively). As in the ALFORTI study,improvements were observed in the I-PSS fillingand voiding subscores.Peak urinary flow increased by 1.7 ml/s (17%,p =0.0004) in the 10 mg od group and by 0.9 ml/s(10%) in the 15 mg od group.Quality of life is now becoming accepted as animportant criterion in the evaluation of treatmentsfor BPH. 47 Results from a study involvingover 7000 outpatients treated with alfuzosin for 3months in general practice showed quality of lifescores to improve by 43% and to correlate significantlywith symptom scores. 48 These symptomaticand quality of life improvements weremaintained in those patients who continued thetreatment for 2 years (> 4500) 49 and 3 years(> 3200). 50 In this population, the rate of spontaneousAUR and of prostate surgery was low,respectively 0.3% and 3.7%, 50 confirming the beneficialeffect of alfuzosin on the risk of AURdemonstrated in the medium term. 29In the ALFUS and ALFORTI trials, 44,46 qualityof life scores were significantly better in theactive treatment groups compared to placebo. Inthe ALFORTI trial, the quality of life index fellby 33%, 30%, and 18% in the 10 mg od, 2.5 mgtid, and placebo groups, respectively 44 (p =0.0008and 0.005 for the active groups vs placebo, respectively).In the ALFUS study, quality of life indeximproved by 18% in both active groups comparedto 8% with placebo (p = 0.002 vs placebo). Theextension of the ALFORTI trial 45 saw animprovement from 2.3 at month 3 to 2.1 at endpoint(35% improvement from baseline).The potential additive benefit of combiningthe α 1-blocker alfuzosin and the 5α 1-reductaseinhibitor finasteride was assessed in a European,randomized double-blind, multicenter trialwhich involved 1051 patients with lower urinarytract symptoms associated with BPH. 26 Patients(n = 358) received SR alfuzosin 5 mg twice dailywithout dose titration, finasteride (n = 344) 5 mgonce daily, or both drugs (n = 349) for 6 months.Symptomatic improvement was significantlyhigher from the first month of treatment with SRalfuzosin, alone or in combination; mean changesin I-PSS versus baseline at endpoint were –6.3and –6.1, respectively, compared with –5.2 withfinasteride alone (SR alfuzosin vs finasteride,p = 0.01; combination vs finasteride p = 0.03).More than 40% of patients who received alfuzosinalone or in combination with finasteridehad a 50% reduction of their urinary symptoms(Figure 9.6). In the overall population, increasesin Q maxwere greater with SR alfuzosin and thecombination compared with finasteride aloneafter 1 month of therapy, but changes at endpointwere similar in the three treatment groups. Inthose 47% of patients likely to be obstructed

130THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA75AlfuzosinPlacebo70Percentage of patients improved6560555045406 weeks 3 months 6 months 6 weeks 3 months 6 monthsLength of studyFIGURE 9.6 Maintenance in the long term (up to 6 months) of at least 25% improvement in BPH symptoms (circles,obstructive scores; squares, irritative scores; triangles, total scores) in patients given alfuzosin or placebo.(baseline Q max

ALFUZOSIN 13140%. The relief is prompt, more pronounced thanwith finasteride, and can be maintained over 3years. In the medium term, alfuzosin reduced theincidence of AUR and, in long-term treatment, itis associated with a low incidence of AUR andprostate surgery.Side-effects and toleranceOral IR alfuzosin (7.5–10 mg/day) is generallywell tolerated in clinical studies of up to 30months’ duration. 29,42,43 The overall incidence ofside-effects with alfuzosin appears to be similar tothat seen with placebo, and the incidence of posturalside-effects potentially related to the pharmacodynamicproperties of alfuzosin appears tobe lower than that with prazosin (up to 2 mg bid)and similar to that observed with the SR formulationof tamsulosin 0.4 mg od. Reported adverseeffects with alfuzosin are usually transitory: themajority occur within the first 4 weeks of treatmentand resolve spontaneously after drug withdrawal.Furthermore, both the SR and the od formulationsof alfuzosin are at least as well toleratedas the immediate formulation.In the 6-month placebo-controlled study, 29 theoverall incidence of adverse events was similar inalfuzosin-treated patients (36%) and in the placebogroup (36%), with a similar rate of drop-outfor adverse events (10 and 9%, respectively). Inaddition, the number of patients reporting at leastone vasodilatation-related adverse effect was alsosimilar in alfuzosin and placebo groups (11 and10%, respectively). A lower incidence of impotencewith alfuzosin (< 1%) compared with placebo(3%) may reflect the beneficial effect of α 1-adrenoceptor antagonists in this condition (Table9.6). Alfuzosin appears to be well tolerated in thelong term, 42,43 which is of particular interestbecause BPH patients are likely to require longtermtreatment.In support of these data were the results of anoncomparative, nonblinded, multicenter postmarketinggeneral practice survey, involving over13 000 evaluable BPH patients who received alfuzosin2.5 mg three times daily for 3 months. Thisstudy showed that the overall discontinuationrate was low (3.7%) and that two-thirds ofpatients’ withdrawals due to side-effects werecaused by vasodilatation-related adverse events:vertigo/dizziness (1.4%), malaise (0.6%), posturalhypotension (0.6%), and headache (0.4%). Most ofthese side-effects occurred during the first weekof treatment and in fewer than 0.3% of patientsafter the first dose. 53 As expected, postural sideeffectswere more common in the elderly and inpatients receiving concomitant antihypertensivetreatment. In this survey, which was extended upto 3 years, the incidence of side-effects leading toTABLE 9.6 Adverse effects reported by patients withbenign prostatic hyperplasia during 6 months’ treatmentwith alfuzosin 7.5–10 mg/day (n = 251) or placebo(n = 267). (Adapted from Jardin et al. 29 )Adverse Alfuzosin Placeboeffect recipients (%) recipients (%)Vasodilatoryadverse effectsDizziness 7.2 5.2Headache 6.4 4.9Postural hypotension 1.9 1.2Drowsiness 1.6 < 1Tachycardia 1.6 < 1Other adverse effectsSkin rash 4.4 5.2Dry mouth 4.4 2.6Diarrhea 2.8 < 1Nausea 2.4 < 1Vomiting 1.6 1.9Asthenia 2.0 3.8Chest pain 2.0 < 1Hypertension 1.6 2.3Bad taste < 1 3.4Impotence < 1 2.3

132THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAdrug discontinuation was 2.3% and 4.2% duringthe 1-year and 3-year survey, respectively. 48–50,53These figures confirm the good safety profile inlong-term administration. Alfuzosin was bettertolerated than prazosin in terms of posturalsymptoms in patients with BPH. 33,34 The IR formulationof alfuzosin (2.5 mg tid) was as well toleratedas the marketed formulation of tamsulosin(0.4 mg od) in a 12-week study conducted inBPH. 31 Decreases in supine and standing bloodpressure were slightly greater in patients receivingalfuzosin than with tamsulosin. However,these changes were not associated with anincreased incidence of side-effects, confirmingthat they were not clinically relevant. The numberof drop-outs for adverse events was twice aslow with alfuzosin than with tamsulosin (4% and8%, respectively). The incidence of posturalhypotension was low, i.e. 1% with alfuzosin and3% with tamsulosin.The safety profile of SR alfuzosin was specificallyaddressed in a pooled analysis of two placebo-controlledstudies involving 588 patients (292receiving SR alfuzosin 5 mg twice daily and 296 aplacebo). 41 Fifty-one per cent of the patients were≥65 years of age and 43% had associated cardiovasculardisease including hypertension and/orwere receiving concomitant antihypertensivedrugs. SR alfuzosin administered without initialtitration was very well tolerated, with an overallincidence of adverse events similar to that ofplacebo (18.5% and 15.8% of patients, respectively)and an overall incidence of withdrawal fromtherapy for adverse events lower than that ofplacebo (3.4% and 5.7%, respectively). Adverseevents potentially related to vasodilatation wereinfrequent with SR alfuzosin (the same incidenceas with placebo, i.e. 2.7% of patients) and theseadverse events occurred mainly during the firstmonth of alfuzosin treatment.The safety profile of SR alfuzosin was alsocompared to that of a standard dose of finasteride(5 mg od) and the combination of both drugs. 32The incidence of postural symptoms was notincreased in those patients who received alfuzosin(Table 9.7). Conversely, impotence and ejaculatorydisorders were significantly more frequentwith finasteride, alone or in combination, thanwith alfuzosin alone. No ejaculatory disorderswere reported with alfuzosin monotherapy.The safety profile of the od SR formulation ofalfuzosin assessed in the ALFORTI study wasalso very satisfactory. Alfuzosin od 10 mg wasadministered without dose titration. No first-dayeffect was observed. The incidence of adverseevents related to vasodilatation was low (dizziness/vertigo2.8%, headache 1.4%, malaise 1.4%,asymptomatic hypotension 0.7%). No case of syncopewas recorded. In addition, no sexual dysfunctionwas observed. 44An additional 3-month study showed similarlylow rates of patient withdrawal and adverseevents. 46 At least one serious adverse event wasexperienced by 4.5, 3.4, and 2.9% of the 10 mg,15 mg, and placebo groups, respectively, withpotentially drug-related negative effects reportedby 52, 43, and 43% of each group. Dizziness wasreported by 7.4% of patients in the active group.Again, clinically relevant blood-pressure orheart-rate changes did not occur. Althoughsupine systolic and diastolic blood pressure fell inthe active groups, levels did not differ significantlyfrom the placebo groups (–1.1, 2.3, and2.7 mmHg and 0.8, 1.5, and 2.1 mmHg, respectively).Orthostatic hypotension rates were alsosimilar between active groups and placebo.Again, ejaculatory disorders did not occur.In a 9-month extension of the 10 mg od formulationof alfuzosin, no specific events occurredthat were not observed during the 3-month

ALFUZOSIN 133TABLE 9.7 Comparative safety profile of alfuzosin (slow release (SR) 5 mg twice daily), finasteride (5 mg once daily),and the combination of both drugs: incidence of adverse effects.Alfuzosin Finasteride Combination Intergroup(n = 358) (n = 344) (n = 349) pVasodilatory events (%)Vertigo/dizziness 1.7 1.2 2.3 NSHeadache 2.0 1.2 1.4 NSPostural hypotension/hypotension 0.6 0.9 0.6 NSMalaise 0.3 0.3 0.3 NSSexual disorders (%)Impotence 2.2 6.7 7.4 < 0.002Ejaculation failure 0.0 1.5 0.9 0.04Decreased libido 0.6 1.7 2.0 NSOthers (%)Somnolence 0.0 0.3 0.6 NSAsthenia/fatigue 1.1 0.6 0.0 NSMyocardial infarction 0.0 0.3 0.3 NSAcute urinary retention 0.6 0.3 0.3 NSdouble-blind phase. 45 Discontinuation due toadverse effects occurred in 5.6% of patients;vasodilatory effects were reported by 4.4% ofpatients, but were not due to first-day or ageeffects. Hypertensive patients reported morevasodilatory-related effects. No clinically relevantchanges in systolic or diastolic blood pressureoccurred (–2.6 and –2.8 mmHg compared tobaseline, respectively). Nonclinically relevantorthostatic hypotension affected 2.8% of patientsand risk was low in patients with mild and moderaterenal impairment. Only 0.6% of patientsreported ejaculatory disorders.Apart from the intrinsic functional uroselectivityof alfuzosin, the low incidence of posturalevents observed with the new formulation ofalfuzosin could be related to its pharmacokineticproperties, i.e. delayed peak plasma concentrationsdue to both a slowing and a prolongation ofthe rate of release of the active drug. The lack ofCNS-related side-effects such as asthenia or somnolencecould also be related to its low brain barrierpenetration. Overall, consistent with thegood tolerability of the drug, alfuzosin is not associatedwith impairment of sexual function.PLACE OF ALFUZOSIN IN THERAPYAlthough it is unlikely that a drug would abolishboth the static and dynamic components of BPHas effectively as surgery, pharmacologicapproaches to the symptomatic treatment of BPHhave attracted increasing interest and havebecome the mainstay of patient management.α 1-Blockers such as alfuzosin 54 and 5α-reductaseinhibitors 55 are now considered first-line therapyfor BPH. 5α-Reductase inhibitors can reduce thesize of the prostate, but may take months to havesuch an effect and in the overall study population,

134THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAthe magnitude of benefit is relatively modest. 55The potential benefits of the combination ofalfuzosin and finasteride have yet to be demonstratedin the medium term. 32The potential clinical advantage of alfuzosinover some other α 1-adrenoceptor antagonists isthat it selectively blocks contraction mediated byα 1-adrenoceptors in the genitourinary tract comparedto its action on receptors in the vasculature.Therefore, as described above, alfuzosin may beeffective in BPH at doses that produce minimaladverse effects related to vascular α 1blockade,especially postural symptoms. In addition, theincidence of CNS-related adverse events (i.e.asthenia, somnolence) is not markedly increasedwith alfuzosin compared to placebo and no deleteriouseffects on sexual function have beenreported. With increased realization of theimportance of maintained sexual function inolder adults, this factor is likely to be of significantvalue to BPH patients. Both the SR and IRformulations of alfuzosin offer patient-friendlydaily dosings. These are convenient for the normalroutine of daily life, as once-a-day and twicea-dayregimens are associated with better compliance(73 and 70%, respectively) than are thricedailyregimens (52%). 56 There is new evidenceregarding the od formulation, indicating that it isas effective as SR and IR formulations, withfewer vasodilatory effects. 44The beneficial effect of alfuzosin as an adjuvanttreatment of AUR is promising, as is thereported low incidence of AUR in patients treatedin the medium and long term with alfuzosin.Although the predictive criteria of those patientswith BPH who are likely to respond to α 1-blockershave not yet been identified, the α 1-blockeralfuzosin is a first-line and safe agent in patientswith symptomatic BPH.ACKNOWLEDGMENTSThe author would like to thank S. Arbilla, M. C.Delauche and D. Martin for their fruitful collaborationin the writing of this chapter.REFERENCES1. Muramatsu I, Oshita M, Ohmura T et al.Pharmacological characterization of α 1-adrenoceptorsubtypes in the human prostate: functional andbinding studies. Br J Urol 1994; 74: 572–5782. Hieble J P, Caine M, Zalaznik E. In vitro characterizationof the α-adrenoceptors in humanprostate. Eur J Pharmacol 1985; 107: 111–1173. Michel M C, Büscher R, Kerker J et al. α-Adrenoceptor subtypes affinities of drugs for thetreatment of prostatic hypertrophy. Evidence forheterogeneity of chloroethylclonidine-resistant ratrenal α 1-adrenoceptor. Naun Schmied ArchPharmacol 1993; 348: 385–3954. Price D T, Schwinn D A, Lomasney J W et al.Identification, quantification and localization ofmRNA for three distinct alpha1 adrenergic subtypesin human prostate. J Urol 1993; 150: 546–5515. Ford A P D W, Arredondo N F, Blue D R Jr et al.RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)-ethyl]-5-chloro-α, α-dimethyl-1H-indole-3-ethanaminehydrochloride), a selective α 1A-adrenoceptorantagonist, displays low affinity for functional α 1-adrenoceptors in human prostate: implications foradrenoceptor classification. Eur J Pharmacol 1996;49: 209–2156. Forray C, Bard J A, Wetzel J M et al. The alpha 1-adrenergic receptor that mediates smooth musclecontraction in human prostate has the pharmacologicalproperties of the cloned alpha 1csubtype. MolPharmacol 1994; 45: 703–7087. Kenny B A, Miller A M, Williamson I J R et al.Evaluation of the pharmacological selectivity profileof α 1-adrenoceptors: binding, functional and invivo studies. Br J Pharmacol 1996; 118: 871–878

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136THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA29. Jardin A, Bensadoun H, Delauche-Cavallier M C,Attali and the BPH-ALF Group. Alfuzosin fortreatment of benign prostatic hypertrophy. Lancet1991; 337: 1457–146130. Buzelin J M, Roth S, Geffriaud-Ricouard C,Delauche-Cavallier M C and the ALGEBI StudyGroup. Efficacy and safety of sustained-releasealfuzosin 5 mg in patients with benign prostatichyperplasia. Eur Urol 1997; 31: 190–19831. Buzelin J M, Fonteyne E, Kontturi M et al.Comparison of tamsulosin with alfuzosin in thetreatment of patients with lower urinary tractsymptoms suggestive of bladder outlet obstruction(symptomatic benign prostatic hyperplasia). Br JUrol 1997; 80: 597–60532. Debruyne F M K, Jardin A, Colloi D et al. SR-alfuzosin,finasteride and the combination of both inthe treatment of benign prostatic hyperplasia. EurUrol 1998; 34: 169–17533. Buzelin J M, Hebert M, Blondin P and thePRAZALF Group. Alpha-blocking treatmentwith alfuzosin in symptomatic benign prostatichyperplasia: comparative study with prazosin. Br JUrol 1993; 72: 922–92734. Stephenson T P, Jensen R D and the PRANALFGroup. A placebo-controlled study of the efficacyand tolerability of alfuzosin and prazosin, for thetreatment of benign prostatic hypertrophy (BPH).Proceedings of the 11th Congress of the EuropeanAssociation of Urology, Berlin, Germany, 1994; 25:abstract 4835. Birsch N E, Hurst G, Doyle P T. Serial residualurine volumes in men with prostatic hypertrophy.Br J Urol 1988; 62: 571–57536. McNeill S A, Hargreave T B, Geffriaud-RicouardC et al. Postvoid residual urine in patients withlower urinary tract symptoms suggestive of benignprostatic hyperplasia: pooled analysis of eleven controlledstudies with alfuzosin. Urology 2001; 57:459–46537. Ramsay J W A, Scott G I, Whitfield H N. A double-blindcontrolled trial of a new α 1blocking drugin the treatment of bladder outflow obstruction. BrJ Urol 1985; 57: 657–65938. Martorana G, Gilberti C, Di Silverio F et al. Effectsof short-term treatment with α 1-blocker alfuzosinon urodynamic pressure/flow parameters inpatients with benign prostatic hyperplasia. EurUrol 1997; 32: 47–5339. Eri L M, Tveter K J. α-Blockade in the treatmentof symptomatic benign prostatic hyperplasia. J Urol1995; 154: 923–93440. Lipsitz L A. Orthostatic hypotension in the elderly.N Engl J Med 1989; 321: 952–95641. Buzelin J M, Delauche-Cavallier M C, Roth S et al.Clinical uroselectivity: evidence from patientstreated with SR alfuzosin for symptomatic benignprostatic obstruction. Br J Urol 1997; 79: 898–90642. Jardin A, Bensadoun H, Delauche-Cavallier M C,Attali P and the BPH-ALF Group. Long termtreatment of benign prostatic hypertrophy withalfuzosin: a 12–18 month assessment. Br J Urol1993; 72: 615–62043. Jardin A, Bensadoun H, Delauche-Cavallier M Cet al. and the BPHALF Group. Long term treatmentof benign prostatic hyperplasia alfuzosin: a24–30 month survey. Br J Urol 1994; 74: 579–58444. van Kerrebroeck P, Jardin A, Laval KU et al.Efficacy and safety of a new prolonged release formulationof alfuzosin 10 mg once daily versus alfuzosin2.5 mg thrice daily and placebo in patientswith symptomatic benign prostatic hyperplasia.ALFORTI Study Group. Eur Urol 2000; 37:306–31345. van Kerrebroeck P, Jardin A, van Cangh P et al.Long-term safety and efficacy of a once-daily formulationof alfuzosin 10 mg in patients with symptomaticbenign prostatic hyperplasia: open labelextension study. Eur Urol 2002; 41: 54–6146. Roehrborn G C. Efficacy and safety of once dailyalfuzosin in the treatment of lower urinary tractsymptoms and clinical benign prostatic hyperplasia:a randomized placebo-controlled trial. ALFUSStudy Group. Urology 2001; 58: 953–95947. Fowler F J, Barry M J. Quality of life assessmentfor evaluating benign prostatic hyperplasia treatments.Eur Urol 1993; 24 (Suppl 1): 24–27

ALFUZOSIN 13748. Lukacs B, Leplège A, Thibault P, Jardin A.Prospective study in men with clinical benign prostatichyperplasia treated with alfuzosin by generalpractitioners: 1-year results. Urology 1996; 48:731–74049. Lukacs B, Comet D, Doublet D et al. Health relatedquality of life in benign prostatic hyperplasiapatients treated for 2 years with alfuzosin. JEpidemiol Bio 1997; 2: 203–21150. Lukacs B, Grange J C, Comet B, McCarthy C andthe BPH group in General Practice. Three yearprospective study of 3228 BPH patients treatedwith alfuzosin in General Practice. Prostate CancerProstatic Dis 1998; 5: 276–28351. McNeill S A, Donat R, Pillai M K et al.Prospective, multicentre randomized, placebo controlled,double-blind study of the effects of alfuzosinon the outcome of trial removal of catheterfollowing acute urinary retention. J Urol 1998; 159:abstract 98052. McNeill S A, Daruwala P D, Mitchell I D C et al.Sustained-release alfuzosin and trial withoutcatheter after acute urinary retention: a prospective,placebo-controlled trial. BJU Int 1999; 84:622–62753. Lukacs B, Blondin P, McCarthy C et al. Safety profileof 3 months’ therapy with alfuzosin in 13 389patients suffering from benign prostatic hypertrophy.Eur Urol 1996; 29: 29–3554. Wilde M J, Fitton A, McTavish D. Alfuzosin: areview of its pharmacodynamic and pharmacokineticproperties and therapeutic potential in benignprostatic hyperplasia. Drugs 1993; 45: 410–42955. Gormley G J, Stonnerr E, Bruskewitz R C et al.The effect of finasteride in men with benign prostatichyperplasia. N Engl J Med 1992; 327:1185–119156. Greenberg R N. Overview of patient compliancewith medication dosing: a literature review. ClinTher 1986; 6: 592–599

TamsulosinC R Chapple10INTRODUCTIONIntroduction to α 1-adrenoceptor antagonistsα 1-Adrenoceptor antagonists were originallydeveloped for the treatment of hypertension.Blockade of postsynaptic α 1-adrenoceptors in theblood vessels by these agents results in vasodilatation.As a consequence, the peripheral vascularresistance and blood pressure are reduced.Examples of α 1-adrenoceptor antagonists thathave been developed for and/or are still used forthe treatment of hypertension are alfuzosin, doxazosin,prazosin, and terazosin.In 1976, Caine et al. proposed a hypothesis forthe use of α 1-adrenoceptor antagonists in lowerurinary tract symptoms (LUTS) suggestive ofbenign prostatic obstruction (BPO), also referredto as symptomatic benign prostatic hyperplasia(BPH). 1 By inhibiting the effect of noradrenaline—theneurotransmitter of the sympatheticnervous system—at α 1-adrenoceptors in the bladderneck, prostatic urethra, and prostate capsuleand stroma, α 1-adrenoceptor antagonists reducethe dynamic component of BPH. 1–3 Today, α 1-adrenoceptor antagonists are one of the mostwidely used medical therapies for this condition.3–5 They improve symptoms and urinaryflow quickly (within a few weeks) and have afavorable clinical response in about 70% ofpatients. Total symptom score is in generalimproved by 30–40% and maximum urinary flowrate (Q max) is increased by 16–25%. 3–4The 5α-reductase inhibitor (5αRI) finasterideis another medical treatment option for LUTSsuggestive of BPH accepted by the 4th and 5thInternational Consultations on BPH. 6,7 It reducesthe prostatic mass and therefore the mechanicalor static component of BPH. Several direct comparativestudies between α 1-adrenoceptor antagonistsand finasteride have been published or presented.8–10 The initial trial demonstrated superiorefficacy of α 1-adrenoceptor antagonists overfinasteride in terms of improvement in BPHsymptoms and peak flows. More recently, theMTOPS study has demonstrated greater efficacyfor a combination of α 1-adrenoceptor antagonist+ 5αRI, although the extrapolation of these findingsto clinical practice still remains the subject ofdebate 11 . Comparison of an alternative 5αRI,dutasteride, to α 1-adrenoceptor suggests thatthere are no major therapeutic differences.There is evidence that the efficacy of α 1-adrenoceptor antagonists is independent ofprostate size at baseline. 12 Finasteride in contrastacross the whole spectrum of patients has modestefficacy compared with placebo and is most effectivein patients with an enlarged prostate(> 40 g). 6,13Finally, α 1-adrenoceptor antagonists workmuch faster (within a few weeks) than finasteride(up to 6 months) and, in contrast to 5αRIs are notassociated with erectile dysfunction or loss in sexualinterest and do not reduce prostate-specificantigen (PSA). 14 These facts together will reinforcethe use of α 1-adrenoceptor antagonists asfirst-choice medical therapy for LUTS suggestiveof BPH. The most important drawback of theclassical α 1-adrenoceptor antagonists remains,139

140THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAhowever, adverse events attributed to the bloodpressure-lowering potential such as dizziness,orthostatic hypotension, and syncope. In addition,in order to reduce the occurrence of the first doseeffect (i.e. excessive blood pressure reduction withsubsequent symptomatic orthostatic hypotension),they are recommended to be initiated at alow, subtherapeutic dose with gradual titration tothe optimal therapeutic dose.Introduction to tamsulosinTamsulosin hydrochloride (YM-617) has beenspecifically developed by the YamanouchiPharmaceutical Company for the treatment ofLUTS suggestive of BPH. The chemical structureof tamsulosin, a methoxybenzenesulfonamide,differs from that of the other clinicallyavailable short-acting (alfuzosin and prazosin)and long-acting (doxazosin and terazosin) α 1-adrenoceptor antagonists which are quinazolinederivatives. 15 This may have consequences fordrug–receptor interaction.In the late 1980s and the 1990s, it became clearthat part from α 1- and α 2-adrenoceptors, thereexist several subtypes of the α 1-adrenoceptor. TheInternational Union of Pharmacology(IUPHAR) has accepted the existence of three α 1-adrenoceptor subtypes (with high affinity for prazosin):α 1A, α 1B, and α 1D, (quoted in lower casewhen referring to the cloned entities). 16 Anotherα 1-adrenoceptor subtype has been describedpharmacologically, which is a low-affinity prazosinadrenoceptor, termed α 1L. 12 Although themolecular identify of this fourth α 1-adrenoceptorsubtype is not fully established, recent evidencesuggests that the α 1Lsubtype may represent a particularconformational state of the α 1-adrenoceptor.17 It has been demonstrated that the α 1Aandα 1L-adrenoceptor subtypes are the predominantfunctional α 1-adrenoceptors in the humanprostate. 17–22 Research indicates that α 1-adrenoceptorsin the human detrusor are of the α 1Dandto a lesser extent of the α 1Asubtypes and it hasbeen suggested that inhibition of these subtypesleads to improvement of irritative symptoms byα 1-adrenoceptor antagonists. 23 It is not completeclear which subtype is involved in blood pressureregulation in humans, since receptor binding andmolecular biological techniques do not provideconsistent data on this matter. 24–26 However, clinicalpharmacology studies with doxazosin, terazosin,and tamsulosin suggest that α 1B-adrenoceptorsare more prominently involved in vasoconstrictionthan α 1-adrenoceptors. 27,28At present, tamsulosin is the only clinicallyavailable α 1-adrenoceptor antagonist that displaysselectivity for α 1A- and, to a slightly lesserextent, α 1D, over α 1B-adrenoceptors. 29–31 In addition,tamsulosin has 12 times greater affinity forα 1-adrenoceptors in the human prostate than inthe aorta in contrast to prazosin which has similaraffinity for those in the prostate and aorta. 32This can be referred to as receptor pharmacologicuroselectivity. 33 Other available α 1-adrenoceptorantagonists (alfuzosin, doxazosin, prazosin,and terazosin) do not display selectivity for any ofthe α 1-adrenoceptor subtypes. 29–31Tamsulosin hydrochloride is available worldwideas a modified-release formulation. Due tothe long half-life (about 10–13 hours in elderlysubjects), tamsulosin can be classified as a longactingα 1-adrenoceptor antagonist that can betaken once daily (after a meal). In Japan it wasintroduced by Yamanouchi in 1993 under thetradename Harnal ® . In Europe it was first introducedin The Netherlands in 1995 and has sincebeen marketed in most countries by YamanouchiEurope (tradenames Omnic ® , Omic ® , Omix ® ,and Flomax ® ) and/or Boehringer Ingelheim(Alna ® , Pradif ® , Josir ® , or Urolosin ® ).

TAMSULOSIN 141Tamsulosin is also available in many LatinAmerican countries (Flomax ® and Secotex ® ) andwas approved by the FDA in the US in 1997(Flomax ® ).PHYSIOLOGIC UROSELECTIVITYPhysiologically, an α 1-adrenoceptor antagonistcan be considered uroselective if it inhibits to alesser extent than other α 1-adrenoceptor antagoniststhe α 1-adrenoceptors in the vascular system.Considerable species differences for tissue distributionand functionality of α 1-adrenoceptor subtypesexist. Therefore, α 1-adrenoceptor antagonistscan only be differentiated from a physiologicuroselectivity point of view based on resultsobtained in human beings.Two such experimental studies have been performedwith tamsulosin and a hemodynamicallyactive α 1-adrenoceptor antagonist to evaluate theinhibition of phenylephrine or cold-inducedvasoconstriction. 27,28 One placebo-controlled trialcompared a single dose of tamsulosin (modifiedreleaseformulation) 0.2 mg and doxazosin 1 mgin eight Japanese healthy subjects in a cross-overdesign. 27 The other placebo-controlled trial comparedequi-effective single doses of tamsulosin(modified release) 0.4 mg with terazosin 5 mg inten healthy Caucasian volunteers in a cross-oversetting. 28 Figure 10.1a shows that the number ofpatients who had an increase in diastolic bloodpressure of 7.6 mmHg after phenylephrine infusionwas reduced to a lesser extent in tamsulosintreatedthan in terazosin-treated patients. Inaddition, the inhibition of phenylephrineinducedincreases in diastolic blood pressure relativeto placebo was less with tamsulosin than terazosin(Figure 10.1b).There is evidence from in vivo studies inhuman volunteers that tamsulosin causes lessinhibition of vasoconstriction and therefore haslower affinity for vascular α 1-adrenoceptors thandoxazosin and terazosin. 27,28CLINICAL UROSELECTIVITYClinical uroselectivity has been defined as‘desired effects on obstruction and LUTS relatedto adverse events’ in patients with LUTS suggestiveof BPH. 33 This implies that the α 1-adrenoceptorantagonist should have at least comparableefficacy to other α 1-adrenoceptor antagonistswith an improved side-effect profile (i.e. lowerpotential to induce excessive blood pressurereductions with subsequent dizziness, symptomaticorthostatic hypotension, and syncope).Japanese clinical placebo-controlled dataA randomized, double-blind, placebo-controlled,parallel-group, phase II, dose-ranging study wasperformed in 270 Japanese patients with LUTSsuggestive of BPH, using 0.1, 0.2, or 0.4 mg tamsulosinonce daily for 4 weeks, after a 2-weekplacebo run-in period. 34The Q maxfor the placebo, 0.2 mg, and 0.4 mggroups improved by 1.4 ml/s (15%), 4.0 ml/s(44%), and 3.6 ml/s (35%), respectively (nonsignificantvs placebo; Table 10.1). With respect to averageurinary flow rate (Q ave), there were statisticallysignificant differences between 0.2 and 0.4 mgtamsulosin once daily (increases of 26% and 41%,respectively) and placebo (decrease of 4%). Inaddition, global subjective improvement was similarin the 0.2 mg and the 0.4 mg dosing groupsand significantly better in comparison with placebo(p < 0.01). Approximately 80% of patients

142THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA FIGURE 10.1 (a) Number of responders (increase diastolic blood pressure (DBP) > 7.6 mmHg) during treatment withplacebo, tamsulosin, or terazosin and (b) percentage inhibition of phenylephrine (PE)-induced increase in diastolic bloodpressure during treatment with tamsulosin or terazosin relative to placebo. 28 *p < 0.05.reported that their condition had (slightly, moderately,or markedly) improved.Tamsulosin was very well tolerated. Neitherorthostatic hypotension nor a significant decreasein blood pressure were observed.In conclusion, both 0.2 and 0.4 mg tamsulosinonce daily are effective and well-tolerateddosages in the treatment of Japanese patients withLUTS suggestive of BPH. Tamsulosin 0.2 mg isthe recommended dose in Japan.European clinical placebo-controlled dataA randomized, double-blind, placebo-controlled,parallel group, phase II dose-ranging study wasperformed in the UK. 35 After a 3-week placeborun-in period, 126 patients with LUTS due to

TAMSULOSIN 143BPH (Q max 100 ml; urethral resistance: detrusor pressure(P det) at Q max(P detQ max)/Q max2≥ 0.5) were randomizedto placebo or tamsulosin (0.2, 0.4, or0.6 mg) once daily for 4 weeks. Efficacy was evaluatedby free-flow and pressure–flow parametersand by a modified Boyarsky symptom score(eight symptoms to be rated from 0 to 5; totalscore range 0–40).Table 10.1 and Figure 10.2a show that boththe 0.4 and 0.6 mg dose increased mean Q max(2.2 ml/s or 22.6% and 1.8 ml/s or 20.2%, respectively)statistically significantly compared withplacebo (–0.1 ml/s or –0.9%, p < 0.05). The 0.4 mgdose produced the greatest decrease in meanP detQ max(–26.6 cmH 2O or –28.2%) comparedwith an increase of 4.9 cmH 2O (+5.7%) withplacebo (Figure 10.2b). The decrease in meantotal symptom score was comparable for the 0.4(–4.1 or –28.7%) and 0.6 mg dose (–4.4 or –28.2%)and was superior to the decrease in the placebogroup (–2.9 or –17.7%: Table 10.2 and Figure10.2c). The difference versus placebo did notreach statistical significance, probably due to thesmall sample size and the relatively short durationof treatment (4 weeks). The percentage ofpatients who experienced slight or muchimprovement in their condition was also greatestin the 0.4 mg group (Figure 10.2d).It can be concluded that optimal improvementin all efficacy parameters was achieved withthe 0.4 mg dose of tamsulosin. This dose was alsowell tolerated and did not induce statistically significantlygreater blood pressure changes duringthe first 8 hours after the first dose. Therefore, the0.4 mg dose was further evaluated in phase IIIclinical trials in Europe.Two multinational, multicenter, doubleblind,randomized, placebo-controlled phase IIIstudies were performed in Europe. The Boyarskysymptom score was used to assess the effect onLUTS (nine symptoms, each to be rated from 0 to3; total score range 0–27). 36 Both studies enrolledmore than 300 patients with mild–moderateLUTS (total Boyarsky score > 6) suggestive ofBPH (free flow Q max4–12 ml/s for a voided volume≥120 ml). They were randomized to 12weeks of treatment with placebo or tamsulosin0.4 mg once daily in a 1 : 2 ratio (after a 2-weekplacebo run-in period). 37 As the design, assessments,and results (Tables 10.1. and 10.2) of bothstudies were comparable, a meta-analysis thatinvolved 193 placebo and 381 tamsulosin patientswas carried out. 38Tamsulosin increased mean peak flow Q maxby1.6 ml/s (16%). Although there was a considerableplacebo-effect (0.6 ml/s or 6%), the difference wasstatistically significant (p = 0.002: see Table 10.1).The same applied for the percentage of patientswith a clinically significant improvement in Q max(defined as an increase from baseline of ≥ 30%) 39 :32% of tamsulosin- and 20% of placebo-treatedpatients (p = 0.003). Mean total Boyarsky symptomscore was decreased to a statistically significantextent in the tamsulosin (–3.3 or –35.1%)versus the placebo group (–2.4 or –25.5%,p = 0.002). The same applied for the decrease intotal voiding (p =0.008) and filling (p =0.017)scores. A decrease in total Boyarsky symptomscore from baseline ≥ 25% was considered to be aclinically significant response. 40 This wasachieved in 66% of patients in the tamsulosin and49% of patients in the placebo group (p

144THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIATABLE 10.1 Effect of placebo or tamsulosin on mean free flow Q maxin placebo-controlled studies in Japan, Europe, and the US.Tamsulosin PlaceboFirst author Duration (weeks) Dose (mg) Baseline End-point Change Change (%) Baseline Change Change (%) p ValueKawabe 34 4 0.2 9.1 13.1 4.0 44 9.4 1.4 15 NS0.4 10.4 14.0 3.6 35 NSAbrams 35 4 0.2 9.6 10.7 1.2 13 10.9 –0.1 –1 NS0.4 9.8 12.1 2.2 23 0.030.6 9.1 10.9 1.8 20 NSAbrams 37 12 0.4 10.7 12.0 1.4 13 10.4 0.4 4 0.028Chapple 38 12 0.4 10.2 11.8 1.6 16 10.1 0.6 6 0.002Lepor 43 13 0.4 9.5 — 1.8 18 9.8 0.5 5 < 0.0010.8 9.6 — 1.8 19 < 0.001Narayan 44 13 0.4 — — 1.5 — — 0.9 — 0.0640.8 — — 1.8 — 0.007Lepor 46 53 0.4 9.5 — 1.7 18 9.9 0.4 4 —0.8 9.5 — 2.1 22

TAMSULOSIN 145 FIGURE 10.2 Effect of placebo or tamsulosin (0.2, 0.4, or 0.6 mg) once daily on (a) mean free flow Q max, (b) meanP detQ max, (c) mean total modified Boyarsky symptom score, and (d) percentage of patients who had slight or muchimprovement in their condition after 4 weeks of therapy in the phase II dose-ranging study in the UK. 354 weeks, the symptom score continued to improvefor the last 8 weeks of the trial when the effectwas (nearly) optimal (Figure 10.3b). At 4 weeks,about 70% of the total effect seen after 12 weekswas achieved.Tamsulosin 0.4 mg was very well tolerated. Ithad minimal effects on blood pressure. In comparisonwith placebo there were no clinically significantchanges in supine or standing systolic ordiastolic blood pressure at end-point. Except forthe change in standing diastolic blood pressure(–2.5 mmHg), the differences were also not statisticallysignificant (Table 10.3). Approximately20% of patients were hypertensive. In both thenormotensive and hypertensive subgroups, tamsulosin0.4 mg did not affect blood pressure to aclinically significantly greater extent than placebo.The decrease in standing diastolic blood pressurein normotensive patients was statistically significantlygreater than in the placebo group butthe reduction was minimal (–0.8 mmHg;p = 0.049: Table 10.4).In addition, tamsulosin did not induce moreadverse events than placebo, be it treatmentemergent adverse events (36% vs 32%, p =0.290)or possibly/probably drug-related adverse eventsaccording to the investigator (13% vs 12%,p = 0.802). The same applied for the percentage

146THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIATABLE 10.2 Effect of placebo or tamsulosin on mean total symptom score in placebo-controlled studies in Japan, Europe, and the US.Tamsulosin PlaceboFirst author Duration(symptom score) (weeks) Dose (mg) Baseline End-point Change Change (%) Baseline Change Change (%) p ValueAbrams 35 4 0.2 16.9 13.6 –3.4 –20 16.7 –2.9 –18 NS(modified 0.4 14.9 10.2 –4.1 –29 NSBoyarsky) 0.6 15.8 10.9 –4.4 –28 NSAbrams 37 12 0.4 9.5 6.0 –3.4 –36 9.3 –2.2 –24 0.002(Boyarsky)Chapple 38 12 0.4 9.4 6.1 –3.3 –35 9.4 –2.4 –26 0.002(Boyarksy)Abrams 42 12 0.4 17.7 — –8.8 –50 17.4 –4.7 –27 ≤ 0.01(I-PSS)Lepor 43 13 0.4 19.8 — –8.3 –42 19.6 –5.5 –28 < 0.001(I-PSS) 0.8 19.9 — –9.6 –48 < 0.001Narayan 44 13 0.4 — — –5.1 — — –3.6 — 0.01(I-PSS) 0.8 — — –5.8 — 0.01Lepor 46 53 0.4 19.7 — –9.4 –48 19.1 –6.5 –34 —0.8 20.0 — –9.7 –49

TAMSULOSIN 147 FIGURE 10.3 Effect of placebo or tamsulosin 0.4 mg once daily on (a) mean Q maxand (b) mean total Boyarsky symptomscore over time in the meta-analysis of the two European phase III placebo-controlled studies. 38of patients that discontinued due to adverseevents (4.5% vs 3.6%). Adverse events commonlyattributed to hemodynamically active α 1-adrenoceptorantagonists such as dizziness, orthostatichypotension, and syncope occurred at a comparableincidence in the tamsulosin and placebogroups (Table 10.5). This also applied for otheradverse events associated with α 1-adrenoceptorantagonists (asthenia, somnolence, rhinitis/nasalcongestion). The only adverse event that wasreported by significantly more tamsulosin thanplacebo patients was abnormal ejaculation (4.5%vs 1%, p = 0.045). This adverse event was, however,very well tolerated by the patients, because fewtamsulosin patients (0.8%) withdrew from thestudy for this reason. 38,41 Other sexual function-

148THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIATABLE 10.3 Change in mean systolic and diastolic bloodpressure (SBP/DBP) at end-point with placebo or tamsulosin0.4 mg in meta-analysis of two European phase IIIplacebo-controlled studies: all patients. 38Placebo Tamsulosin(n = 189) (n = 373)Supine SBP (mmHg)Baseline 144.3 143.1Change –3.5 –3.1Supine DBP (mmHg)Baseline 85.4 85.4Change –0.9 –1.6Standing SBP (mmHg)Baseline 142.9 141.8Change –1.7 –3.3Standing DBP (mmHg)Baseline 86.4 86.8Change –0.4 –2.5**p =0.018 vs placebo.related adverse events (impotence and decreasedlibido) were reported to the same extent in thetamsulosin and placebo groups (Table 10.5). 41Another randomized, double-blind, placebocontrolledphase IV, 12-week study has been performedwith tamsulosin 0.4 mg once daily inEuropean patients with LUTS (I-PSS ≥ 13) suggestiveof BPH (Q max

TAMSULOSIN 149TABLE 10.5 Incidence of adverse events (AEs) withplacebo or tamsulosin 0.4 mg in the meta-analysis of thetwo European placebo-controlled phase III studies. 38,41Values are numbers of patients with percentages in parentheses.Placebo Tamsulosin(n = 193) (n = 381)Any AE 61 (32) 137 (36)Any drug-related* AE 24 (12) 50 (13)Discontinued due toadverse events 7 (3.6) 17 (4.5)Dizziness 6 (3.1) 13 (3.4)Headache 4 (2.1) 8 (2.1)Tachycardia/palpitation 3 (1.6) 5 (1.3)Postural hypotension 1 (0.5) 0 (0)Syncope 1 (0.5) 1 (0.3)Asthenia 2 (1.0) 4 (1.0)Somnolence 2 (1.0) 1 (0.3)Rhinitis (nasal congestion) 1 (0.5) 1 (0.3)Abnormal ejaculation 2 (1.0) 17 (4.5) †Impotence 3 (1.6) 3 (0.8)Libido decreased 0 (0) 4 (1.0)Discontinued due to 1 (0.5) 3 (0.8)sexual function-relatedadverse events*Possibly or probably drug-related according to the investigator;† p =0.045 vs placebo.treated patients. The AG number was reduced by10.3 (–19%) on tamsulosin and increased by 1.2(2%) on placebo (p = 0.014). Clinical improvementin total I-PSS occurred within 1 week withcontinuing improvement up to 12 weeks(decrease 8.8 or –50% vs –4.7 (–27%) with placebo;p ≤ 0.01).It can be concluded that tamsulosin 0.4 mgonce daily is the optimal dose for EuropeanTABLE 10.6 Effect on pressure–flow parameters andtotal I-PSS after 12 weeks of therapy with tamsulosin0.4 mg or placebo in the European ESPRIT study. 42Placebo Tamsulosin(n = 54) (n = 106)P detQ max(cmH 2O)Baseline 68.0 69.2Change (%) at 12 weeks 2.0 (3%) –7.2 (–10%)*Pressure flow Q max(ml/s)Baseline 6.4 7.1Change (%) at 12 weeks 0.4 (6%) 1.5 (21%) †AG numberBaseline 55.2 55.1Change 1.2 (2%) –10.3 (–19%) ‡Total I-PSS scoreBaseline 17.4 17.7Change –4.7 (–27%) –8.8 (–50%)**n = 193 instead of 160 for total I-PSS. *p = 0.038;†p =0.020; ‡ p =0.014; **p ≤ 0.01.patients with LUTS suggestion of BPH. It has arapid onset of action: Q maxis maximally increasedat the first assessment after 4 weeks and totalsymptom score within 1 week. It is extremelywell tolerated, even without the need for dosetitration. It has no clinically significant effect onblood pressure in normotensive or hypertensivepatients and no increased potential to inducesymptomatic orthostatic hypotension comparedwith placebo. Abnormal ejaculation is the onlyadverse event that occurs to a greater extent thanwith placebo.US clinical placebo-controlled dataTwo randomized, double-blind, placebo-controlledphase III short-term (13-week) studieswere performed in the US with tamsulosin0.4 mg or 0.8 mg once daily. 43,44 The AmericanUrological Association (AUA) symptom index,which is identical to the International Prostate

150THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIASymptom Score (I-PSS), was used in these studiesto assess the effect on LUTS (seven symptoms,each to be rated from 0 to 5; total score range0–35). 45 In each study, approximately 750 patientswith moderate–severe LUTS (totalI-PSS ≥ 13) suggestive of BPH (Q max4–15 ml/s)were randomized to one of the three groups aftera placebo run-in of 4 weeks. There were four primaryefficacy parameters in each study (at endpoint):(a) mean change in total I-PSS, (b) meanchange in Q max, (c) number of symptom scoreresponders (decrease total I-PSS ≥ 25%), and (d)number of Q maxresponders (increase Q max≥ 30%). FIGURE 10.4 Percentage of (a) Q maxresponders and (b) total symptom score responders at end-point in the placebo andtamsulosin groups of two short-term US studies: study 1 43 and study 2. 44

TAMSULOSIN 151In both studies, tamsulosin 0.4 mg and 0.8 mgonce daily were statistically significantly superiorto placebo (see Tables 10.1 and 10.2, and Figure10.4a and b). The only parameter that did notreach but approached statistical significance overplacebo in the 0.4 mg group (p = 0.064) was meanQ max(measured at through plasma concentration)in one of the studies. 40 Tamsulosin 0.4 mg and0.8 mg had comparable efficacy in both studies,only the change in total I-PSS at end-point wasgreater in the 0.8 mg than in the 0.4 mg group(p = 0.020). However, the difference between thetwo treatment groups was already partly apparentafter 1 week of therapy when both the FIGURE 10.5 Effect of tamsulosin (0.4 or 0.8 mg) and placebo on (a) mean Q maxand (b) mean total I-PSS score over timein one of the US short-term studies. 43

152THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIApatients in the 0.4 and 0.8 mg groups had received0.4 mg (Figure 10.5b). This shows that the greatereffect of the 0.8 mg dose with regard to change intotal I-PSS at end-point was probably caused by adifference in response between treatment/patientgroups and not by a difference in response to tamsulosindose.Tamsulosin 0.4 mg had a very fast onset ofaction in both studies. In one of the studies, Q maxwas measured 4–8 hours after intake of the firstdose. 43 At that time point, Q maxwas already significantlyand maximally increased comparedwith placebo (Figure 10.5a). In addition, the differencein improvement in total I-PSS scorebetween tamsulosin and placebo was significantat the first assessment after 1 week (Figure10.5b). 43,44 The symptom score continued toimprove up to 13 weeks when the optimal effecton LUTS was achieved. At week 1, approximately50% of the total reduction was observed.Tamsulosin 0.4 mg and 0.8 mg had no clinicallysignificant effects on blood pressure, eitherin normotensive or (controlled or uncontrolled)hypertensive patients. Multiple and rigorousorthostatic stress testing was performed at everyvisit in both studies. Despite this, the number ofpatients that developed symptomatic orthostatichypotension with tamsulosin 0.4 mg or 0.8 mg inboth studies was comparable to that with placebo:1 (0.2%), 2 (0.4%), and 0 (0%), respectively. Othersymptoms of orthostatic hypotension reportedduring the multiple and rigorous orthostaticstress tests (such as dizziness, lightheadedness,and faintness/syncope) were also included in theadverse events listing (Table 10.7). The onlyadverse event that was reported consistently andsignificantly more frequently with the 0.4 mgdose in both studies was abnormal ejaculation(6% and 11%) vs

TAMSULOSIN 153it was reported by significantly more patients on0.8 mg (18%) than 0.4 mg in both studies. Thereporting of other adverse events such as dizziness,rhinitis/nasal congestion, and somnolencealso increased with the higher tamsulosin doseand they were experienced by significantly morepatients on tamsulosin 0.8 mg than placebo.Discontinuation due to adverse events occurredin about 8% of patients in both the placebo andtamsulosin 0.4 mg groups and in 12–13% ofpatients on 0.8 mg. 43,44A total of 418 patients who completed one ofthe 13-week placebo-controlled US studies 43 continuedwith a 40-week, placebo-controlled extensionstudy in which they remained on the samedouble-blind medication as in the short-termstudy. 46The efficacy and good tolerability of tamsulosin(0.4 mg and 0.8 mg) in comparison withplacebo was sustained during the 40-week extensionphase. Both tamsulosin doses had comparableefficacy (Figure 10.6). The number of patients FIGURE 10.6 Change in (a) mean Q maxand (b) mean total I-PSS score after 53 weeks of treatment with placebo ortamsulosin (0.4 mg or 0.8 mg) once daily in a long-term US study. 46

154THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAthat discontinued due to adverse events remainedlow and comparable in the placebo (6%) and tamsulosin0.4 mg (5%) groups. A total of 16% ofpatients on 0.8 mg discontinued due to adverseevents.It can be concluded that tamsulosin 0.4 mg isthe optimal dose in the treatment in Americanpatients with LUTS suggestive of BPH with avery good safety profile. 44 It has a fast onset ofaction with significant improvements in Q maxwithin 24 hours and a symptomatic score within1 week. It does not lower blood pressure to a clinicallysignificant extent, even in uncontrolledhypertensives. It has no increased potential forsymptomatic orthostatic hypotension comparedwith placebo, even when administered withoutdose titration and when exposed to multiple andrigorous orthostatic stress testing. Only abnormalejaculation occurred consistently and significantlymore often with tamsulosin 0.4 mg than placebo.Therefore, 0.4 mg is the recommended tamsulosindosage in the US. If patients fail torespond after 2–4 weeks, the dose may beincreased to 0.8 mg.Long-term open-label extension studiesAll patients (be it tamsulosin- or placebo-treated)who completed the two European placebo-controlledphase III studies could be enrolled in along-term extension study with open-label tamsulosinfor up to 4 years. In an interim analysis,355 patients were treated with tamsulosin for upto 3 years. 47 The significant improvements inQ max, total Boyarsky symptom score, Q maxresponders,and symptom score responders observed inthe 12-week placebo-controlled studies were sustainedfor up to 3 years in the patients whoremained in the study. The increase in mean Q maxfrom baseline ranged from 0.7 to 1.8 ml/s(p < 0.05) and remained between 11.5 and 12 ml/sthroughout the follow-up period (Figure 10.7a).Total Boyarsky symptom score was improvedfrom baseline by 3.7 to 4.1 (or –39% to –44%:p

TAMSULOSIN 155 FIGURE 10.7 Effect of tamsulosin over time on (a) mean Q maxand (b) mean total Boyarsky symptom score in patientsfollowed for up to 3 years in an extension of the two European placebo-controlled studies. 47Direct comparative clinical studies vs otherα 1-adrenoceptor antagonistsThree direct comparative clinical studies havebeen performed. 51–53 One was a European phaseIII, double-blind, randomized, comparativestudy between alfuzosin (2.5 mg twice daily for 2weeks and 2.5 mg three times daily for 10 weeks)and tamsulosin (0.4 mg once daily after breakfastthroughout). It involved 256 patients with LUTS(total Boyarsky score > 6) suggestive of BPH(Q max4–12 ml/s). 51 The other single-blind, randomizedtrial compared terazosin (dose titratedfrom 1 to 5 mg once daily) and tamsulosin (0.2 mgonce daily throughout) for 8 weeks in 98 Koreanpatients with LUTS (total I-PSS ≥ 8) suggestive

156THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA FIGURE 10.8 Effect of tamsulosin over time on (a) Q maxresponders and (b) total Boyarsky symptom score respondersin patients followed for up to 3 years in an extension of the two European placebo-controlled studies. 47of BPH (Q max5–15 ml/s). 52 The results show thattamsulosin had comparable efficacy to both alfuzosinand terazosin. They all increased Q maxby1.6–2.1 ml/s (16–22%: Figure 10.9a) and reducedtotal symptom score by 36–40% (Figure 10.9b).Both tamsulosin and alfuzosin were very welltolerated. The incidence of abnormal ejaculationwas also comparable in both groups (one patientwith tamsulosin and none with alfuzosin).Terazosin was, however, associated with significantlymore drug-related adverse events (37% ofpatients) than tamsulosin (2% of patients;p =0.001). In particular, dry mouth (16% vs 0%)

TAMSULOSIN 157 FIGURE 10.9 Percentage improvement in (a) total symptom score and (b) Q maxin two direct comparative clinical trialsbetween tamsulosin and alfuzosin 51 or tamsulosin and terazosin. 52and dizziness (12% vs 0%) were reported morefrequently with terazosin. None of the patientson tamsulosin or terazosin experienced (drugrelated)abnormal ejaculation. Alfuzosin and terazosinproduces significant decreases in bloodpressure compared with baseline whereas thiswas not the case with tamsulosin (Figure 10.10).In addition, the blood pressure reductions withalfuzosin were statistically significantly greaterthan those with tamsulosin, especially in elderlypatients. 51

158THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA FIGURE 10.10 Effect on blood pressure (BP) in direct comparative clinical study between (a) tamsulosin and alfuzosin 51and (b) tamsulosin and terazosin. 52 S, systolic; D, diastolic.A third double-blind, randomized study comparedthe potential of tamsulosin and terazosin toinduce orthostatic hypotension during earlymorning and nocturnal orthostatic stress testingin 50 normotensive elderly subjects (more than50% had LUTS). 53 Tamsulosin and terazosinwere administered for 15 days according to theirrecommended dosage regimen in daily practice:tamsulosin 0.4 mg once daily after breakfastwithout dose titration, terazosin dose titratedfrom 1 to 5 mg once daily in the evening. Theresults show that tamsulosin caused significantly

TAMSULOSIN 159FIGURE 10.11 Number of patients with symptomatic orthostatic hypotension during orthostatic stress testing in directcomparative trial between tamsulosin and terazosin. 53less symptomatic orthostatic hypotension (4% ofpatients) than terazosin (36% of patients;p = 0.011: Figure 10.11). The patient with symptomaticorthostatic hypotension on tamsulosinhad pre-study vertigo, which was an exclusioncriterion for the study.It can be concluded that α 1-adrenoceptorantagonists have similar efficacy in the treatmentof LUTS suggestive of BPH. It is their potentialto lower blood pressure and produce cardiovascular-relatedadverse events such as symptomaticorthostatic hypotension that differentiatesbetween α 1-adrenoceptor antagonists. 3,4 Tamsulosin0.4 mg has the lowest potential to reduceblood pressure and causes less symptomaticorthostatic hypotension than terazosin. This maybe clinically important as orthostatic hypotensionand syncope are risk factors for falling. Falls arethe sixth largest cause of death in the elderly andthe cost of fall-related fractures in the elderlyamounts to US $10 billion/year. 54 Tamsulosin,furthermore, is easy to use as it does not requiredose titration and can be taken once a day.Tolerability in elderly patients and patientswith co-morbidity or co-medicationTamsulosin has been repeatedly shown to be welltolerated. 51–53,55 A subgroup analysis of younger(< 65 years) and older (≥ 65 years) patientsenrolled in the two European phase III placebocontrolledtrials 38 revealed that tamsulosin 0.4 mgonce daily had comparable effects on blood pressureand was as well tolerated in both youngerand older patients, compared with placebo. 56In two observational surveys, in which almost20 000 German patients with LUTS suggestive ofBPH received tamsulosin 0.4 mg once daily for 4or 12 weeks, approximately 40–50% of patientshad concomitant hypertension, other cardiovascular(CV) diseases, or diabetes. 57 It appeared thatoverall about 95% of patients rated the global tolerabilityof tamsulosin as good or very good.Concomitant hypertension, other CV diseases, ordiabetes had only a minor effect on global tolerability,which became significant due to the largepatient numbers. It was still rated as good or very

160THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAα α βα βα FIGURE 10.12 Percentage of patients that perceived (a) the global efficacy and (b) the global tolerability as better thanthat of previous treatment with β-sitosterol, other phytotherapy, finasteride, or other α 1-adrenoceptor antagonists. 59good in more than 90% and 95% of cases in thetwo surveys. A multivariate analysis showed thathypertension did not contribute to changes inglobal tolerability. Diabetes and other CV diseasescontributed significantly. This may be dueto the reduced quality of life associated with theseconditions and the large patient numbers andmay therefore not be clinically significant for themajority of these patients. Many patients in thesetrials also took concomitant CV medication

TAMSULOSIN 161(diuretics, β-blockers, angiotensin-convertingenzyme (ACE) inhibitors, or calcium antagonists).Global tolerability in these patientsremained good to very good in 95% of patientsand the CV co-medication did not contribute tochanges in global tolerability in a multivariateanalysis. Blood pressure changes in patients withco-morbidity or co-medication were minimal andcomparable to those reported for tamsulosin andplacebo in placebo-controlled trials. In patientswith co-morbidity or co-medication, additionalblood pressure reductions were not more than2 mmHg. This did not significantly contribute toblood pressure changes in a multivariate analysis.In three clinical interaction studies, tamsulosinwas administered to the hypertensivepatients controlled with the β-blocker atenolol,the ACE inhibitor enalapril, or the calciumantagonist nifedipine. The results confirm thattamsulosin has no clinically significant additionaleffects on blood pressure or an increased potentialto produce orthostatic hypotension in hypertensivepatients treated with antihypertensive medication.58It can be concluded that in such elderlypatients and the majority of patients with cardiovascularco-morbidity or co-medication, tamsulosinis well tolerated and has minimal effects onblood pressure.USE IN PATIENTS PRETREATED WITH OTHERMEDICAL THERAPYIn two large German observational surveys,patients pretreated with other medical therapies,such as phytotherapy, finasteride, or other α 1-adrenoceptor antagonists, were asked to rate theglobal efficacy and tolerability of tamsulosin incomparison with their previous treatment (i.e.worse, similar, better). 59 It appeared that relativeto patients pretreated with other α 1-adrenoceptorantagonists, the global efficacy of tamsulosin wasperceived better than that of previous treatmentin about 25% of phytotherapy- and 15% of finasteride-pretreatedpatients (Figure 10.12a).Relative to previous treatment with phytotherapy,the global tolerability of tamsulosin wasperceived better than that of previous treatmentin about 25% of other α 1-adrenoceptor antagonistsand 13% of finasteride pretreated patients(Figure 10.12b).META-ANALYSISIn addition to the two meta-analyses mentionedpreviously 38,41 two systematic reviews of tamsulosinin the treatment of BPH have been performedin recent years. 60,61 The latest of theseincluded 14 studies with a total of 4122 participants,mean age 64, with moderate LUTS.Patients were treated with a range of doses oftamsulosin per day. The weighted mean difference(WMD) for mean change in Boyarsky symptomscore from baseline showed a 12% improvementwith 0.4 mg/day and a 16% improvementwith 0.8 mg/day, relative to placebo.Improvements in Q maxwere 1.1 ml/s for bothdosages. Lower doses of tamsulosin(0.2–0.4 mg/day) were found to be as effective asalternative α-antagonists.Rates of adverse events, which were generallymild, included dizziness, rhinitis, and abnormalejaculation. These increased in a dose-dependentmanner, with discontinuations due to such effectssimilar to placebo at the 0.2 mg/day dose, butincreasing to 16% with 0.8 mg/day. Efficacyincreased only slightly with higher doses.

162THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAANCILLARY PROPERTIESEffect on PSAIn contrast to finasteride, which reduces meanPSA plasma levels by 50%, tamsulosin (0.4 or0.8 mg once daily), in comparison with placebo,had no clinically significant effect on PSA plasmalevels, either in the phase III placebo-controlledEuropean 54 (Figure 10.13) or US studies. 43,44Effect on lipidsModest positive effects on lipid plasma levels havebeen described in hypertensive patients treatedwith hemodynamically active α 1-adrenoceptorantagonists. In one of the US placebo-controlledstudies, tamsulosin also reduced serum triglyceridelevels by 9% compared with < 1% on placebo. 44SUMMARYα 1-Adrenoceptor antagonists have superior efficacyover finasteride and phytotherapy (at least inthe short term), work independent of prostatesize, are not associated with erectile dysfunction,and do not affect PSA plasma levels. Therefore,they are a very good first-choice medical therapyfor patients with LUTS suggestive of BPH. Themajor disadvantages of the classical α 1-adrenoceptorantagonists that were originally developedfor hypertension (prazosin, doxazosin, terazosin,and alfuzosin) are their blood pressure-loweringpotential with subsequent risk of (first-dose)orthostatic hypotension and associated need fordose titration. The reduction of the occurrence oforthostatic hypotension is clinically importantbecause it is one of the risk factors for falling.Falls may lead to major injuries such as fracturesand are the sixth leading cause of death in the elderly.Tamsulosin is an α 1-adrenoceptor antagonistthat displays selectivity for α 1A- and α 1D-adrenoceptors.In human volunteers, tamsulosin (modified-releaseformulation) caused less inhibition ofexperimentally induced vasoconstriction thanhemodynamically active α 1-adrenoceptor antagonistssuch as doxazosin and terazosin and it was FIGURE 10.13 Percentage of patients with specific changes in PSA from baseline on placebo or tamsulosin 0.4 mg oncedaily in the meta-analysis of the two European phase III placebo-controlled studies. 62

TAMSULOSIN 163therefore specifically developed to treat LUTSsuggestive of BPH. It is available in Japan, mostEuropean countries, many Latin American countries,and the US. The recommended dosage forCaucasian patients is 0.4 mg once daily (after ameal). Tamsulosin 0.4 mg can be administered asits therapeutic dose from the start of therapy withno need for dose titration. As such it has superiorefficacy to placebo and is as effective as otherα 1-adrenoceptor antagonists such as alfuzosinand terazosin. It has, however, a negligible potentialfor blood pressure lowering compared withother α 1-adrenoceptor antagonists such as alfuzosinand terazosin, and induces less symptomaticorthostatic hypotension than terazosin. Theonly adverse event that was reported consistentlyand significantly more often with tamsulosin0.4 mg than placebo was abnormal ejaculation.There was no difference in reporting of abnormalejaculation on tamsulosin, alfuzosin, or terazosinin comparative trials. The very good tolerabilityand minimal effects on blood pressure of tamsulosinare maintained in elderly patients and thevast majority of patients with cardiovascular comorbidityand co-medication. The global efficacyof tamsulosin 0.4 mg was perceived better thanthat of previous treatment with finasteride orphytotherapy. The global tolerability was perceivedbetter than that of previous treatment withother α 1-adrenoceptor antagonists or finasteride.Tamsulosin 0.4 mg once daily is therefore a verygood first-choice medical therapy for Caucasianpatients with LUTS suggestive of BPH.REFERENCES1. Caine M, Pfau A, Perlberg S. The use of alphaadrenergicblockers in benign prostatic obstruction.Br J Urol 1976; 48: 255–2632. Chapple C R. Medical therapy and quality of life.Eur Urol 1998; 34 (Suppl 2): 10–173. Chapple C R. Pharmacotherapy for benign prostatichyperplasia—the potential for α 1-adrenoceptorsubtype-specific blockade. Br J Urol 1998; 81(Suppl 1): 34–474. Djavan B, Marberger M. A meta-analysis on theefficacy and tolerability of α 1-adrenoceptor antagonistsin patients with lower urinary tract symptomssuggestive of benign prostatic obstruction. EurUrol 1999; 36: 1–135. McVary K T. Medical therapy for benign prostatichyperplasia progression. Curr Urol Rep 2002; 3:269–2756. Denis L, McConnell J, Yoshida O et al. and TheMembers of the Committees. 4th InternationalConsultation on BPH. Recommendations of theInternational Scientific Committee: the evaluationand treatment of lower urinary tract symptoms(LUTS) suggestive of benign prostatic obstruction.In: Denis L, Griffiths K, Khoury S et al. (eds).Proceedings 4th international consultation onbenign prostatic hyperplasia (BPH). Paris, 2–5 July,1997. Plymouth: Plymbridge Distributors, 1998:669–6847. Focus on lower urinary tract symptoms: nomenclature,diagnosis, and treatment options. Highlightsfrom the 5th international consultation on benignprostatic hyperplasia, June 25–27, 2000, Paris,France. Rev Urol 2001; 3: 139–1458. Lepor H, Williford W O, Barry M J et al. The efficacyof terazosin, finasteride, or both in benign prostatichyperplasia. N Engl J Med 1996; 335: 533–5399. Debruyne F M J, Jardin A, Colloi D et al. on behalfof the European ALFIN study group. Sustainedreleasealfuzosin, finasteride and the combinationof both in the treatment of benign prostatic hyperplasia.Eur Urol 1998; 34: 169–17510. Kirby R S, Roehrborn C, Boyle P et al. for thePREDICT Study Investigators. Efficacy and tolerabilityof doxazosin and finasteride, alone or incombination, in treatment of symptomatic benignprostatic hyperplasia: the Prospective EuropeanDoxazosin and Combination Therapy (PREDICT)Trial. Urology 2003; 61: 119–126

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TAMSULOSIN 165selectivity of drugs for the treatment of prostatichypertrophy. Eur J Pharmacol 1995; 288: 201–20730. Michel M C, Grubbel B, Taguchi K et al. Drugs fortreatment of benign prostatic hyperplasia: affinitycomparison at cloned α 1-adrenoceptor subtypesand in human prostate. J Auton Pharmacol 1996;16: 21–2831. Richardson C D, Donatussi C F, Page S O et al.Pharmacology of tamsulosin: saturation-bindingisotherms and competition analysis using clonedα 1-adrenergic receptor subtypes. Prostate 1997; 33:55–5932. Yamada S, Suzuki M, Tanaka C et al. Comparativestudy on α 1-adrenoceptor antagonist binding inhuman prostate and aorta. Clin Exp PharmacolPhysiol 1994; 21: 405–41133. Andersson K E. Uroselectivity. In: Cockett A T,Khoury S, Aso Y et al. (eds). Proceedings of the 3rdinternational consultation on benign prostatichyperplasia (BPH). Jersey: Scientific CommunicationsInternational, 1996: 541–54234. Kawabe K, Ueno A, Takimoto Y et al. and theYM617 Clinical Study Group. Use of an α 1-blocker,YM617, in the treatment of benign prostatichypertrophy. J Urol 1990; 144: 908–91235. Abrams P, Speakman M, Stott M et al. A doserangingstudy of the efficacy and safety of tamsulosin,the first prostate-selective α 1A-adrenoceptorantagonist, in patients with benign prostaticobstruction (symptomatic benign prostatic hyperplasia).Br J Urol 1997; 80: 587–59636. Boyarsky S, Jones G, Paulson D F, Prout G R. Anew look at bladder neck obstruction by the Foodand Drug Administration regulators: guide linesfor investigation of benign prostatic hypertrophy.Trans Am Assoc Genitourin Surg 1977; 68: 29–3137. Abrams P, Schulman C C, Vaage S and theEuropean Tamsulosin Study Group. Tamsulosin, aselective α 1C-adrenoceptor antagonist: a randomized,controlled trial in patients with benign prostatic‘obstruction’ (symptomatic BPH). Br J Urol1995; 76: 325–33638. Chapple C R, Wyndaele J J, Nordling J et al. onbehalf of the European Tamsulosin Study Group.Tamsulosin, the first prostate-selective α 1A-adrenoceptorantagonist. A meta-analysis of two randomized,placebo-controlled, multicentre studies inpatients with benign prostatic obstruction (symptomaticBPH). Eur Urol 1996; 29: 155–16739. Lepor H, Auerbach S, Puras-Baez et al. A randomized,placebo-controlled multicenter study ofthe efficacy and safety of terazosin in the treatmentof BPH. J Urol 1992; 148: 1467–147440. Aso Y, Boccon-Gibod L, Da Silva F C et al.Subjective response, objective response, impact onquality of life. In: Cocket A T K, Aso Y, Denis L,Khoury S (eds). Proceedings of the internationalconsultation on benign prostatic hyperplasia(BPH), Paris, 26–27 June. SCI, 1991: 85–9041. Hofner K for the European Tamsulosin StudyGroup. Tamsulosin: effect on sexual function inpatients with LUTS suggestive of BPO (symptomaticBPH). Eur Urol 1998; 33 (Suppl 1): 129(abstract 515)42. Abrams P, Tammela T L, Hellstrom P et al. for theESPIRIT Group. European pressure–flow investigationof tamsulosin in men with lower urinarytract symptoms (LUTS) suggestive of benign prostaticobstruction (BPO) – ESPRIT study. J Urol1998; 159 (Suppl 5): 256 (abstract 982)43. Lepor H for the Tamsulosin Investigator Group.Phase III multicenter placebo-controlled study oftamsulosin in benign prostatic hyperplasia.Urology 1998; 51: 892–90044. Narayan P, Tewari A and Members of UnitedStates 93–01 Study Group. A second phase III multicenterplacebo controlled study of 2 dosages ofmodified release tamsulosin in patients with symptomsof benign prostatic hyperplasia. J Urol 1998;160: 1701–170645. Barry M J, Fowler F J, O’Leary M P et al. and theMeasurement Committee of the AmericanUrological Association. The American UrologicalAssociation symptom index for benign prostatichyperplasia. J Urol 1992; 148: 1549–155746. Lepor H for the Tamsulosin Investigator Group.Long-term evaluation of tamsulosin in benign prostatichyperplasia: placebo-controlled, double-blindextension of phase III trial. Urology 1998; 51:901–906

166THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA47. Schulman C C, Cortvriend J, Jonas U et al. onbehalf of the European Tamsulosin Study Group.Tamsulosin: 3-year long-term efficacy and safety inpatients with lower urinary tract symptoms suggestiveof benign prostatic obstruction: analysis of aEuropean, multinational, multicenter, openlabeledstudy. Eur Urol 1999; 36: 609–62048. Schulman C C, Buzelin J-M, Lock T M T W.Tamsulosin: 3-year follow-up of efficacy and safetyin 516 patients with LUTS suggestive of BPO. JUrol 1998; 159 (Suppl 5): 256 (abstract 983)49. Lepor H and the Tamsulosin Investigator Group.Tamsulosin, long-term, open-label, extension studyto evaluate response and efficacy. J Urol 1997; 157(Suppl 4): 331 (abstract 293)50. Narayan P, Evans C P, Moon T. Long-term safetyand efficacy of tamsulosin for the treatment oflower urinary tract symptoms associated withbenign prostatic hyperplasia. J Urol 2003; 170:498–50251. Buzelin J M, Fonteyne E, Kontturi M et al. for theEuropean Tamsulosin Study Group. Comparisonof tamsulosin with alfuzosin in the treatment ofpatients with lower urinary tract symptoms suggestiveof bladder outlet obstruction (symptomaticbenign prostatic hyperplasia). Br J Urol 1997; 80:597–60552. Lee E, Lee C. Clinical comparison of selective andnon-selective α 1A-adrenoceptor antagonists inbenign prostatic hyperplasia: studies on tamsulosinin a fixed dose and terazosin in increasing doses. BrJ Urol 1997; 80: 606–61153. De Mey C, Michel M C, McEwen J, Moreland T. Adouble-blind comparison of terazosin and tamsulosinon their differential effects on ambulatoryblood pressure and nocturnal orthostatic stress testing.Eur Urol 1998; 33: 481–48854. Coffey D S. Controversies in the management oflower urinary tract symptoms: an overview. Br JUrol 1998; 81 (Suppl 1): 1–555. Michel M C, Bressel H U, Goepel M, Rubben H. A6-month large-scale study into the safety of tamsulosin.Br J Clin Pharmacol 2001; 51: 609–61456. Chapple C R, Baert L, Thind P et al. on behalf ofthe European Tamsulosin Study Group.Tamsulosin 0.4 mg once daily: tolerability in olderand younger patients with lower urinary tractsymptoms suggestive of benign prostatic obstruction(symptomatic BPH). Eur Urol 1997; 32:462–47057. Michel M C, Mehlburger L, Bressel H-U et al.Tamsulosin treatment of 19,365 patients with lowerurinary tract symptoms: does co-morbidity altertolerability? J Urol 1998; 160: 784–79158. Lowe F C. Coadministration of tamsulosin andthree antihypertensive agents in patients withbenign prostatic hyperplasia: pharmacodynamiceffect. Clin Ther 1997; 19: 730–74259. Michel M C, Bressel H -U, Mehlburger L, GoepelM. Tamsulosin: real life clinical experience in 19365 patients. Eur Urol 1998; 34 (Suppl 2): 37–4560. Wilt T J, MacDonald R, Rutks I. Tamsulosin forbenign prostatic hyperplasia. Cochrane DatabaseSyst Rev 2003; 1: CD00208161. Wilt T J, MacDonald R, Nelson D. Tamsulosin fortreating lower urinary tract symptoms compatiblewith benign prostatic obstruction: a systematicreview of efficacy and adverse effects. J Urol 2002;167: 177–18362. Denis L for the European Tamsulosin StudyGroup. Tamsulosin: effect on PSA levels in 3-month placebo-controlled studies and long-termfollow-up of these studies. Eur Urol 1998; 33 (Suppl1): 130 (abstract 517)

Phytotherapeutic agents in the treatmentof LUTS and BPHK Dreikorn J M Fitzpatrick11INTRODUCTIONThe spectrum of synthetic pharmaceutical treatmentoptions for patients presenting with lowerurinary tract symptoms (LUTS) secondary tobenign prostatic hyperplasia (BPH) has expandedconsiderably over the last decade and this hasbeen accompanied by an increase in the use ofplant-derived therapies. 1,2 At the same time, aworldwide decrease in classical operative procedureshas been reported, with rates oftransurethral resection of the prostate (TURP)and open prostatectomy falling by up to 50% insome countries. 3While there is at least some agreement concerningthe scientific rationale and indications forthe use of α-adrenoceptor blockers and 5αreductaseinhibitors, the role of phytotherapeuticagents in the treatment of LUTS and BPH hastraditionally been less clear and has been continuouslydebated. 4–22 The use of plant extracts is longestablished in France and Germany, and so productscontaining extracts of Serenoa repens andPygeum africanum, among others, have a marketshare of up to 50% of all preparations used for thetreatment of symptomatic BPH. In these countries,plant extracts are prescribable drugs, theircosts being totally or partly reimbursed by theheathcare system, in contrast to the UK, forexample, where they are neither approved norreimbursed. 23In the US, plant-derived medications are soldas nonreimbursable nonprescription dietary supplements,mostly in natural health food stores.Some preparations which are available by prescriptiononly in Europe, such as the lipidosterolicextract of Serenoa repens (LSESr)Permixon ® , are not available at all in the US. 1 In2000, US sales of dietary supplements werereported to have reached $17.1 billion, 24 andaround $1.5 billion are reportedly spent on theself-medication of LUTS. 25According to some US urologists, 50–90% ofnewly referred patients with LUTS secondary toBPH have already tried or are using some form ofalternative or complementary medication at thetime of their presentation. 13–15,26 The suggestionthat ‘natural agents’, commonly supposed to bewithout side-effects, might be as efficacious assynthetic and chemical products, seems attractivefor patients who prefer such an approach. 17,26 Weas treating physicians have to face this development.This widespread and increasing patientpreference, however, has to be balanced againstthe need for increased awareness of the importanceand necessity to select treatment options onevidence-based rationales. 27,28ORIGIN OF PLANT EXTRACTSIn Europe alone, more than 100 botanic preparationsare available for the treatment of LUTS secondaryto BPH. 5,6,29 Although extracts from morethan 30 different plants are being used for theseproducts, the most popular phytotherapeuticagents originate from the roots, seeds, barks, orfruits of the plants listed in Table 11.1.167

168THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIATABLE 11.1 Origin of phytotherapeutic agents for the treatment of LUTS secondary to BPHCommon term Element utilized Latin termAmerican dwarf palm, saw palmetto Fruit Serenoa repens, Sabal serrulataSouth African star grass Root Hypoxis rooperiPine Root PinusSpruce Root PiceaAfrican plum tree Bark Pygeum africanumStinging nettle Root Urtica dioicaRye Pollen Secale cerealePumpkin Seeds Cucurbita pepoSome preparations are produced from a singleplant, others contain extracts from two or moresources. The extraction procedures differ fromcompany to company. Therefore, the compositionand components of one individual product maybe significantly different to those of another manufacturer,even if the product originates from thesame plant(s). As a consequence, the results ofbasic research studies or clinical trials involving aspecific product cannot automatically be appliedto another preparation.Several active components of plant extractshave been identified (Table 11.2). However,whether these elements represent all the mostactive and important elements of the preparationsfor the beneficial in vitro and in vivo effectsdescribed (Table 11.3) is still not known. 6,8–12,29,30The precise mechanism of action of manyproducts has also yet to be elucidated, althoughantiestrogenic and proapoptotic effects have beenreported for some preparations, alongside inhibitionof 5α-reductase activity. 31,32As the extraction methods of products derivedfrom the same source could lead to differing levelsof efficacy, bioavailability, and pharmacodynamics,it has been recommended that individualTABLE 11.2 Proposed active constituents of plantextracts.Phytosterols (β-sitosterol)Phyto-estrogensFree fatty acids (lauric and myristic acid)LectinsFlavonoidsPlant oilsPolysaccharidesproducts be evaluated separately. 29 In addition,both synthetic and natural products should besubjected to identical analytic, biological, andclinical evaluations.PHYTOTHERAPEUTIC COMPOUNDSSerenoa repensThe extracts from the berries of the Americandwarf palm (Serenoa repens, saw palmetto, Sabalserrulata) are the most popular plant-based

PHYTOTHERAPEUTIC AGENTS IN THE TREATMENT OF LUTS AND BPH 169TABLE 11.3 Proposed mode of action of plant extracts.Mechanism of actionInhibition of 5α-reductase I and II activityAnti-estrogenic effectAnti-androgenic effectAnti-inflammatory effectInduction of apoptosisInterference with prostaglandin metabolismInhibition of phospholipase A2 and 5-lipoxygenase enzymesSuppression of prostate cell metabolism and growthInhibition of proliferative growth factorsDecrease of sex hormone-binding globulinProtection/strengthening of detrusor muscleAlteration of cholesterol metabolismFree radical scavengers/membrane stabilizationInhibition of aromatase activityReduction of prostatic urethral resistanceAction on α-adrenergic receptorsExtractSerenoa repens, Secale cereale, cactus flowerSerenoa repens, Pygeum africanumSerenoa repens, Cucurbita pepoSerenoa repens, β-sitosterol, Pygeum africanum,Cucurbita pepoβ-Sitosterol, Serenoa repensβ-Sitosterol, Pygeum africanumβ-SitosterolUrtica dioica, Serenoa repensUrtica dioica, Serenoa repensUrtica dioicaPygeum africanumPygeum africanumPygeum africanumCactus flowerSecale cerealeSecale cereale, Serenoa repensproducts used in the treatment of symptomaticBPH. 4–6,13–16,29 In Germany alone, more than 30different products contain Serenoa repens, 6,29while numerous similar products are also availablein the US. Many of them contain extractsfrom other plants (Pygeum africanum, pumpkinseeds, etc.) and minerals, such as zinc. The differentextracts contain mainly free and esterifiedfatty acids, phytosterols, and long-chain alcohols.More recently, free fatty acids have been proposedto be the active components of Serenoa repensextracts, primarily responsible for their beneficialeffects on the prostate. On this basis the precisecomposition could critically influence both biologicaland clinical activity.The most extensively investigated preparationis Permixon, an n-hexane LSESr and a complexmixture of free fatty acids, phytosterols, aliphaticalcohols, and various polyphrenic compounds.6,29,33 A number of potential mechanismsof action have been attributed to Permixon,including anti-androgenic and anti-inflammatoryactivity, inhibition of cell proliferation, andpromotion of apoptosis. 31,33–38The action of Permixon is now considered tobe predominantly attributable to uncompetitive5α-reductase type I and type II inhibition, resultingin lower levels of dihydrotestosterone (DHT)formation from testosterone in the prostate. 31,39Although Rhodes et al., 40 in 1993, did not

170THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAsubscribe to this, the theory that Permixon is aneffective inhibitor of 5α-reductase type I and typeII has been substantiated by in vitro studies byBayne et al. 31,39 In a specially developed clinicallyrelevant model, 5 days’ treatment of co-culturedhuman prostate cells with 10 µg/ml Permixonresulted in significant inhibition of 5α-reductasetype I and type II; the dose utilized was estimatedto correspond to the concentration reached inplasma and prostate at the recommended clinicaldose.The hypothesis promulgated is that lauric andmyristic acid, which comprise a subfraction of thefree fatty acids contained in the preparation,modulate the cell-membrane environment in away that reduces the activity of the nuclear membrane-bound5α-reductase. 41 The observationthat no decrease of prostate-specific antigen(PSA) is observed in vivo 42 is explained by theassumption that Permixon, in contrast to finasteride,does not interfere with PSA productionand has little or no effect on other androgendependentprocesses which rely on the binding ofandrogens to their receptor. Subsequent studiesalso suggested that Permixon specifically decreasescell proliferation and increases the apoptoticindex of the prostatic stromal and epithelialcells. 38 Studies involving alternative sources ofSerenoa repens have suggested that it has antiestrogenicor anti-inflammatory effects. 32,43Lower levels of DHT and higher levels oftestosterone have been identified in the prostatesof Permixon-treated BPH patients; 44 however,superficially at variance with an action as a 5αreductaseinhibitor, no significant effect on serumlevels of PSA and prostate volume has beendemonstrated in several studies. 6,29,33,42 Indeed,the data on several potential mechanisms ofaction of Serenoa repens are often confusing andcontradictory and many of the effects describedhave only been demonstrated in vitro, often withconsiderably higher dosages of the extract thanare recommended for clinical treatment.The commonly recommended dose of Serenoarepens is 320 mg daily, often divided into twodoses. A dose of 160 mg Permixon twice dailyseems to be as efficacious as two capsules of160 mg once daily. 45 Aside from occasional gastrointestinaldiscomforts, no significant sideeffectshave been reported with the extract, incontrast to most other medical or surgicalapproaches.The numerous published clinical trials involvingSerenoa repens extracts have been criticallyreviewed by a committee during the 4th (1997)and 5th (2000) International Consultations onBPH, 6,29 and in two articles by one of the committeemembers. 15,16 These Consultations recommendedthat extracts of Serenoa repens producedby different manufacturers be evaluated separatelyand regarded as discrete entities, due to variancebetween products associated with differentextraction processes and other factors. They alsohighlighted the need for placebo-controlled trialsof such products, as are conducted for traditionalsynthetic pharmaceuticals.Although it is accepted that uncontrolled trialsand comparative trials without placebo controlsare of only limited value in the quantificationof the clinical efficacy of Serenoa repens in thetreatment of LUTS and BPH, 6,29 several trialsinvolving the extract have taken place that indicatethat significant improvements in LUTSsymptomatology occur. However, the results aredependent on the product (and presumably thecomposition).A recent long-term trial examined the efficacyof twice-daily Permixon (160 mg) in 130 BPHpatients over 2 years. 46 Prostatic symptoms wereassessed using validated instruments such as the

PHYTOTHERAPEUTIC AGENTS IN THE TREATMENT OF LUTS AND BPH 171International Prostate Symptom Score (I-PSS)and sexual function using the Male SexualFunction (MSF-4) questionnaire. PSA, peak urinaryflow (Q max), and quality of life were alsoevaluated every 6 months. Significant improvementswere observed for I-PSS, Q max, and qualityof life, while prostate size fell by 5.9 ml by the endof the study period. MSF-4 scores rose significantlyin the second year of treatment and totalPSA and hormonal levels did not change.A further, longer-term study of Permixon inmen with mild to moderate BPH (n = 26)revealed that twice-daily administration of320 mg of the drug decreased meanI-PSS by 8.8 ± 0.18, increased Q maxby4.13 ± 0.51 ml/s on average, and improved qualityof life after 5 years, providing further evidenceof the long-term efficacy of the drug. 47It has been suggested that a ‘placebo effect’may contribute to the improvements observed inmen receiving some extracts of Serenoa repens. Ina study of 50 men with LUTS, who were treatedfor 6 months with a Serenoa repens preparation, asignificant improvement in I-PSS from 19.5 to12.5 was noted (p = 0.001). 48 No significantchanges in PSA levels or improvement in Q max,postvoid residual volume (PVR), bladder capacity,or detrusor pressure at peak urinary flow ratewere observed, however. The authors accept thatthis subjective improvement in voiding symptomsthat occurred without demonstrable objectivechange in any of the measure urodynamicparameters may be attributable in part to theplacebo effect and conclude that further studies,including placebo-controlled trials, are needed. 48Other studies have suggested that the benefitdoes not only arise from a placebo effect. A trialexcluding patients who had previously respondedto placebo medication revealed that, when treatedwith Permixon, these nonresponders showed significantreductions in both daytime and nocturnalurinary frequency and improvement in Q max. 49Some data have proven inconclusive. 6,16,29Thus, although it was shown in the 30-day studydescribed above 49 that dysuria, daytime frequency,nocturia, and Q maxwere all significantlyimproved in Permixon-treated patients comparedwith baseline values and placebo-treatedpatients, the study did not show any real perceivedclinically relevant benefit of the drug overplacebo by the patients or their physicians. Whenthe patients and physicians were asked to assessthe global efficacy of the treatment at the end ofthe trial, the rates of satisfaction were 68% and47%, respectively, for the placebo group versus71% and 57%, respectively, for the Serenoa repenstreatedpatients. The short-term nature of thistrial limits the interpretation of the data.In an attempt to quantify the benefit moreprecisely, double-blind randomized clinical trialshave been undertaken on some Serenoa repenscontainingproducts. In a 6-month, double-blind,randomized comparative trial with finasteride in1098 patients, the efficacy of Permixon was foundto be equivalent to that of the 5α-reductaseinhibitor 50 . The decrease in I-PSS was 37% and39% and the increase in Q maxwas 2.7 ml/s (25%)and 3.2 ml/s (30%) in the Serenoa repens and finasteridegroups, respectively. Greater drug-relatedside-effects, particularly in terms of loweredlibido and increased erectile dysfunction wereobserved in the finasteride group.Unfortunately, this study did not include aplacebo group and the volumes of the prostateswere rather small (baseline volumes 43 ml and44 ml, respectively, for the two groups). As weknow today, the effect of finasteride may be limitedin small prostates. 51 Therefore, in analogy tothe VA study, 52 the comparison between Serenoarepens and finasteride in this study might simply

172THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAshow equivalency of both agents to placebo,although Hamdy et al. postulated that prostaticvolume does not correlate with the efficacy oftreatment using either finasteride orphytotherapy. 53Comparison of Serenoa repens to ‘conventional’therapy is not limited to finasteride, however.A comparison of the α-blocker tamsulosin toPermixon took place over a period of 12 monthsand involved 811 BPH patients from 11 differentcountries. 54 I-PSS fell by 4.4 in each group andQ maxalso improved to a similar extent. A secondtrial, involving alfuzosin and Permixon, alsorevealed the latter drug to be equally effective forthe treatment of urinary symptoms. Sixty-threemen with mild to moderate BPH who did notrespond to placebo were randomized to receiveeither 320 mg Permixon daily or 2.5 mg alfuzosinthree times a day for 3 weeks. 55 Symptom scoresimproved significantly from baseline with no significantdifference between treatment groups.Overall, therefore, Permixon has been shownto produce clinical efficacy equivalent to thatobserved with both α-blockers and finasteride;this would tend to indicate that the action ofPermixon does not arise from a placebo effectalone.Phytosterols/β-sitosterolAlthough β-sitosterol and various other phytosterolsare contained in many plant extracts usedfor the treatment of symptomatic BPH, somemanufacturers presume that β-sitosterol is themajor active component and therefore classifytheir preparation by the content of this element.Most preparations available derive from thespecies Hypoxis rooperi, Pinus, or Picea.β-Sitosterol is claimed to be both a cyclo-oxygenaseand a lipoxygenase inhibitor, interferingwith prostaglandin metabolism and therebyexerting anti-inflammatory effects. 30 A stimulatoryeffect on transforming growth factor(TGFβ), which induces apoptosis, and translocationprotein kinase Cα has also been discussed.6,56,57In a German study the β-sitosterol preparationHarzol ® was evaluated in a 6-month, double-blind,placebo-controlled study of 200patients. 56,58 While the placebo group showedonly mild improvements, statistically significantimprovements were noted for I-PSS, quality oflife, Q max, and PVR in the β-sitosterol-treatedpatients who received 20 mg of the product, threetimes daily. The I-PSS improved by 2.3 points forplacebo and 7.4 for β-sitosterol; Q maxincreased by1.1 ml/s for placebo and 5.2 ml/s for the testgroup. Follow-up observations (up to 18 months)have shown that those patients who continuedtreatment and even those who stopped the medicationmaintained their benefit, while placebotreatedpatients improved with a similar responseonce started on β-sitosterol. 56Another preparation, also containing mainlyβ-sitosterol (Azuprostat ® , 65 mg twice daily) wasevaluated in a 6-month, randomized, placebocontrolledtrial of 177 patients. 59 The magnitudeof the statistically significant improvement in thisstudy was great: the I-PSS improved by 2.8 in theplacebo group compared to 8.2 in the treatmentgroup and Q maxincreased by 4.4 ml/s and8.8 ml/s, respectively. The results of both studieswith phytosterols, although exciting, await confirmationby other groups.African plum treeExtracts from the bark of the African plum tree(Pygeum africanum) are widely used in Franceand the US. Almost all basic research and clinicalstudies have been performed with the productTadenan ® . 6,15,16 The chloroform extract contains

PHYTOTHERAPEUTIC AGENTS IN THE TREATMENT OF LUTS AND BPH 173phytosterols, short-chain (lauric and myristic)and unsaturated long-chain (oleic and linolic)fatty acids.The extract is thought to inhibit fibroblastproliferation and to exert an anti-inflammatoryand anti-estrogenic effect. 6,60,61 Eleven constituentshave been identified in the crude extract,including high levels of myristic acid, which isthought to affect membrane fluidity directly andto reduce the contact between propagating freeradicals and unsaturated lipid substances, therebyslowing the process of hydrolysis and membranedegradation. 61 Moreover, in a rabbit model, theagent is thought to protect the bladder musculaturefrom contractile dysfunction caused by outletobstruction, improving bladder ultrastructure,bladder compliance, and contractileresponses. 62–67According to Levin et al. 65 and Hass et al., 61obstruction induces ischemic muscular membranedamage, which might be caused by lipidperoxidation. High levels of myristic acid foundin the Pygeum extract may make the bladder cellmembranes less susceptible to lipid peroxidationand thereby exert their protective effect on thebladder. However, in the experimental studiesdemonstrating this effect, highly supraclinicaldoses were used. Therefore, the applicability ofthese findings to clinical BPH remains questionable.Although there are numerous open andshort-term placebo-controlled studies suggestingclinical efficacy, 68–70 the trials do not meet theguidelines recommended by the InternationalConsultation conferences. 6Breza et al. 71 reported a multicenter openlabeltrial involving 85 patients, treated over 2months with Tadenan, followed by 1 monthwithout treatment. Improvement in I-PSS was40%, reduction of nocturia 32%, improvement ofquality of life 31%, and increase in Q max19%,without any reduction of prostate volume.Significantly, the improvements were maintainedduring the 1-month no-treatment phase. Overall,the data are not conclusive, however, and longertermdata are not available.Stinging nettleExtracts from the roots of the stinging nettle(Urtica dioica) are widely used in Germany. Theycontain a complex mixture of water- and alcoholsolublecompounds, including lectins, phenols,and sterols. 5,6,30Whether the suggested modes of action,which include inhibition of prostatic growth factorinteraction, suppression of prostatic cellmetabolism and modulation of the binding of sexhormone-binding globulin, have any relevance inclinical BPH is uncertain. Studies performedmore than 10 years ago are inconclusive becauseof small patient numbers and short trial duration.72,73 In a randomized, placebo-controlled, 3-month study of 41 patients, a liquid preparationshowed superiority over placebo, but was notmarketed because its taste was not accepted bypatients. 74Extracts of stinging nettle are often combinedwith one or more alternative plant-derived therapy,as discussed later in the chapter.Rye grass pollen extractA product deriving from the pollen of someselected plants growing in southern Sweden ismarketed as a registered pharmaceutical(Cernilton ® ) in some European countries, Japan,Korea, and Argentina. The extract consists of awater- and fat-soluble fraction combined into atablet or capsule.In vitro studies suggest that pollen extractsexert an effect on α-adrenergic receptors, relax

174THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAthe sphincteric musculature, increase prostaticand serum zinc levels, and 5α-reductase activity.30,75 Moreover, the growth of immortal cancercell lines was inhibited and in rats atrophy of theprostatic lobes was observed. 76In a German 3-month, multicenter, doubleblind,placebo-controlled study of 103 patients,nocturia and diurnal frequency were significantlyreduced by 69 and 66%, respectively, in thetreatment group, compared to 37% and 44% inthe placebo group. 77 A 6-month, double-blind,placebo-controlled study of 60 patients reportedan overall significant symptomatic improvementof 69% in the pollen extract group compared to29% in the placebo group. 78In a comparative trial of 89 patients over 4months with a Pygeum africanum extract(Tadenan), the pollen extract showed betterresults with regard to improvement of irritativeand obstructive symptom scores, Q max, and residualurine. 75 However, comparison of Cernilton totamsulosin and a combination of both revealedthe combination and tamsulosin alone to be moreeffective than Cernilton alone. 79Pumpkin seedsExtracts from pumpkin seeds (Cucurbita pepo) areused to treat symptomatic BPH in several countries,such as Germany. The seeds contain asweet-tasting, oily substance, mainly composed oflinolic acid, ∆5 and ∆7 sterols, tocopherol, selenium,magnesium, and carotenoid. The extract isthought to have an anti-androgenic and antiphlogisticaction.A randomized, placebo-controlled, doubleblindtrial of 476 men with BPH showed a significantlygreater reduction in I-PSS (–6.8) comparedto the placebo group (–5.6) over a period of12 months. The other parameters (Q max, qualityof life, prostate volume, PVR) did not change ineither of the groups, however. 80Cactus flower extractsCactus flower extract, known as opuntia, isincluded in the British herbal pharmacopoeia asindicated for prostatic hypertrophy and is a commonlyused herbal remedy for BPH in Israel.Aqueous and organic solvent extracts of driedcactus flower powder have been described as havinga broad spectrum of activity, including inhibitionof both type I and type II 5α-reductase activityand inhibition of aromatase and antioxidantactivity. 81 The authors postulate that as cactusflower has simultaneous 5α-reductase and aromataseinhibitory activity it possesses a uniquelydual advantage in the treatment of BPH; however,there are no reports of any controlled clinicaltrials with cactus flower products.COMBINATION PRODUCTSAlthough there is no scientific evidence showingthat the efficacy of phytotherapeutic preparationsis enhanced by the combination of extracts fromseveral plants, many companies offer mixtures ofplant extracts, claiming that the possible effectsdemonstrated for extracts from individual plantsmay be additive in combination products.In a 3-month, randomized, double-blindstudy of 53 patients given extracts from pumpkinseeds and Serenoa repens, urinary flow rates, micturitiontime, residual urine, frequency of micturition,and a subjective assessment of the treatmenteffect were all significantly improved whilethe changes in the placebo group were not. 82A combination product of Serenoa repens andstinging nettle (Prostagutt ® forte) was used in arandomized, placebo-controlled study of 40

PHYTOTHERAPEUTIC AGENTS IN THE TREATMENT OF LUTS AND BPH 175patients (6-month double-blind treatment phasefollowed by 6 months of open treatment). Greaterimprovement in both I-PSS and Q maxwasobserved with treatment than with placebo: I-PSSdecreased from 18.6 to 11.1 in the treatmentgroup during the 6 months of double-blind treatment,compared to a decrease from 19 to 17.6(p = 0.002) with placebo. During the open-labelextension phase, the initially placebo-treatedpatients decreased in I-PSS from 17.6 to 13.3 andthe treatment group continued to improve from11.1 to 9.8. Q maxincreased by 2.3 ml/s over thefirst phase in the verum group and by an additional1.15 ml/s over the open-label second 6-month phase, while an increase of only 0.45 ml/swas observed in the placebo group over the initialplacebo phase with a 2 ml/s increase during thesubsequent active treatment phase. 83The same preparation was also comparedwith finasteride in 489 patients randomized andobserved for 48 weeks. 84 There was a statisticallysignificant improvement in each group, with adrop in I-PSS from 11.3 to 6.5 for the patientstreated with the plant extract, compared with adecrease from 12.6 to 6.9 in finasteride-treatedpatients. Q maxincreased by 1.9 ml/s in the plantextract group and 2.7 ml/s in the finasteridegroup; however, there was no statistical significancebetween the treatment groups. Prostate volumeand PSA decreased in the finasteride grouponly. The mean baseline prostate volume was42 ml in the plant extract group versus 44 ml inthe finasteride group.META-ANALYSES OF PHYTOTHERAPEUTICAGENTSIf adequate (gold-standard) randomized, placebocontrolledstudies are lacking, confirmation ofefficacy of a drug is often sought through metaanalysis.There are some potential limitations inthis approach, however, as it has been shown thatthe agreement between meta-analyses and subsequentlarge clinical trials can be discordant. Metaanalyseshave a positive predictive value of 68%and a negative predictive value of 67%. 85 Thismeans that up to one-third of meta-analyses maynot accurately predict subsequent clinical trialresults. Further, when the studies pooled in ameta-analysis are of poor quality, the meta-analysisitself can be compromised and the impact ofthe conclusions diluted. Overall, however, there isan increasingly widespread use of meta-analysesin the health-care environment.Several meta-analyses involving plant-derivedBPH treatments have been published, four onSerenoa repens extracts, 86–89 two on β-sitosterols,90,91 one on Pygeum africanum, 92 and two onrye grass pollen (Cernilton). 93,94 In general, themeta-analyses support the hypothesis that phytotherapeuticagents are beneficial in the treatmentof LUTS in BPH patients.In the original meta-analysis published byWilt et al. 86 on Serenoa repens, 18 randomizedstudies were included, involving 2939 men withBPH. The mean weighted difference in comparisonto placebo was an improvement in symptomscore of 1.41 points, an increase in Q maxof1.93 ml/s and a reduction in nocturia episodes of0.76 per night. A follow-up analysis conducted 4years later, with an additional three trials and atotal of 3139 patients, revealed quantitatively andqualitatively similar results. 57 Overall, urinarysymptom score fell by 1.41 points (range 0–19),nocturia rates fell by 0.76/night, and Q maxincreased by 1.86 ml/s.Despite the benefit observed in these analyses,the inclusion of products from 11 different manufacturersobtained by different extraction

176THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAprocesses partially compromised the interpretationof the data and thereby potential extrapolationto general clinical use.On the basis of the evidence, it was thereforeconcluded that Serenoa repens improves urologicsymptoms and flow parameters, but that furtherclinical profiling is needed. In particular, the clinicalactivity of individual standardized preparationsshould be determined.It has been emphasized by an expert committeeat the ICUD BPH Consultations, 6 and evenrecently by Wilt himself, 18 that comparisonbetween various manufacturers’ preparations ofthe same plant extract is problematic. Data analysiscan be hindered because of variations in theextraction processes, absence of precise analyticalinformation on composition, lack of certainty thatthe same supposedly active component(s) of theextract are included in the final product, andvariability in batch preparation. Moreover, onlyone of the 18 studies included in the first metaanalysisby Wilt et al. fulfilled the three main criteriaof being placebo-controlled, utilizing standardsymptom score evaluations, and being of atleast 3 months’ duration.In an attempt to address some of the issuesraised in previous analyses, another meta-analysison a single Serenoa repens product (Permixon) waspublished by Boyle et al. 87 Eleven placebo-controlledrandomized trials and two open-label trialswere pooled. Eleven trials had informationregarding Q maxand nocturia. The additionalPermixon effect, beyond that observed on placebo,on Q maxwas 1.87 ml/s and the additionaleffect on nocturia was a decrease of 0.55 episodesper night. A further meta-analysis conducted bythe same team of all contemporary publisheddata available on Permixon involved a further1963 men from four randomized studies. 89 Theadditional data allowed examination of the effectof Permixon on I-PSS and revealed that, in additionto improving peak flow (2.28 ± 0.29 aboveplacebo) and nocturia (1.01 ± 0.13 above placebo),the drug caused a significant fall in I-PSS(–4.7 ± 0.41). Such changes are at least as great asthose described in equivalent meta-analyses forterazosin 95 and finasteride 96 (Figure 11.1).Wilt et al. 90 also published a review of β-sitosterolstudies, including four double-blind trials of519 men, with a duration of 4–26 weeks. Theweighted mean difference (WMD) of β-sitosterolversus placebo was –4.9 points on the I-PSS (35%improvement versus placebo) in two studies.When a study which did not show pure β-sitosterol-β-D-glucosideto be superior to placebo wasexcluded, the WMD for the Q maxwas 5.13 ml/s(53% improvement). The authors state that β-sitosterols improve symptom scores by 35%, Q maxby 34%, and reduced PVR by 24%. Nevertheless,the necessity of additional studies of sufficientsize and duration, with known concentrations ofβ-sitosterol, is emphasized in order to assess thelong-term efficacy of β-sitosterols and their abilityto prevent complications from BPH. Threedifferent preparations were used in the four studies,and as it is uncertain whether the doses arecomparable, no definite conclusions can be drawnfrom this review.MacDonald et al. 93 published a review of fourold studies with the rye pollen extract Cernilton.Two placebo-controlled and two comparative trialsinvolving 444 men were included. None of thestudies would have fulfilled the quality criteria ofthe recommendations of the InternationalConsultation, because of short trial duration,insufficient and incomplete outcome data, and nocontrols in two studies. The conclusion of thereview was that Cernilton is well tolerated andmodestly improves subjective urologic symptoms.Cernilton was not shown to improve urinary flow

PHYTOTHERAPEUTIC AGENTS IN THE TREATMENT OF LUTS AND BPH 17732*10–1–2–3**–4–5Q max (ml/s)I-PSS (points)Permixon Terazosin Finasteride* For prostates larger than 60 ml** Quasi-I-PSS scoreFIGURE 11.1 Comparison of Permixon, terazosin, and finasteride meta-analytical data for peak urinary flow (Q max) andInternational Prostate Symptom Score (I-PSS) improvement above placebo.compared with placebo. The most important conclusion,however, could be anticipated by lookingat the studies included, namely, that randomized,placebo-controlled studies are needed to evaluatethe clinical effectiveness and safety of Cerniltonand its ability to prevent complications fromBPH.After a critical evaluation of the four publishedmeta-analyses available at the time, theexpert committee (‘Other Medical Therapies’) ofthe 5th International Consultation on BPH(Paris, 2000) 29 came to the following conclusions:‘Although there is uniformity in the results ofthese meta-analyses to suggest clinical efficacy ofphytotherapeutic products, it is the opinion of thecommittee that the hypothesis and claim of phytotherapiesto be beneficial in the management ofLUTS/BPH can not be confirmed conclusivelywithout large, appropriately randomised clinical trialsof adequate duration that meet the GCPGuidelines resp. recommendations of theInternational Consultation on BPH’.On this basis the more recent analyses byBoyle et al. 89 would appear to indicate that, of theproducts evaluated, only Permixon would comeclose to satisfying these criteria.CONCLUSIONSWhile there has always been at least basic consensuson the rationale and indications for α-blockersand finasteride in the treatment of LUTS secondaryto BPH, there has been much controversyconcerning the place and efficacy of plant extractsin these patients. As clinical evidence gathers, atleast for some preparations, this picture is slowlychanging, however. As evidence of their efficacy,plant-derived agents have been used for manyyears, especially in some European countries, and

178THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAtheir use is increasing in the US, where a 100%rise in the sale of botanic products has been notedsince 1994. Moreover, there is an increasing trendof patients and even physicians in many countriesto turn away from chemical and synthetic drugsto ‘natural’ preparations and paramedical formsof therapy. Additionally, an increasing number ofpatients prefer self-medication and treatment,which is supported by the marketing strategies ofcompanies producing such products.On the other hand, the medical profession isincreasingly aware of the importance of the needto make treatment selections on the basis of goodevidence of benefit : risk from carefully controlledclinical trials. 27,28 For novel therapies,potentially this may lead to conflicts when guidelinesare established according to the principles ofevidence-based medicine.It is astonishing that, although a tremendousamount of literature concerning the use of phytotherapyin LUTS and BPH exists, many importantquestions remain at least partially unanswered:• Which are the active components of thepreparations?• How do they exert their claimed effects?• What is their bioavailability?• Is there a dose dependency?• How can the products be standardized andcompared?The International Consultations on BPH haverepeatedly called for phytotherapeutic preparationsto be subjected to the same critical evaluationswhich are applied to the treatment of LUTSand BPH with drugs designed by medicinalchemists, such as α-blockers and 5α-reductaseinhibitors. 6–8,11,29,97 Ony a few companies have sofar taken up this challenge. Reasons for others nothaving done this might include that the costs ofsuch evaluations would be difficult to recoupbecause these products are not patentable.Overall, it can reasonably be concluded thatphytotherapeutic products are generally well toleratedand, in some countries, less expensive thanα-blockers and 5α-reductase inhibitors.Although both objective and subjective clinicalimprovements have been shown in carefully controlledclinical trials, these evaluations have beenrestricted to only a few products/brands and haveyet to be mirrored with the majority of plantbasedpreparations.It is pertinent to note that most plant extractsare complex mixtures and a product from onecompany is, in real terms, unique, as the extractionprocedures differ from producer to producerand the exact compositions of the preparationsmay vary between batches. In the majority ofcases they are also only partly chemically defined.Therefore, the products of the different companiesmay not be comparable with regard to thecomponents contributing to the overall biologicaland clinical profile, even if the extracts originatefrom the same plant. As a consequence, metaanalysescontaining extracts from different companiesare only of limited use in evaluation of theefficacy of plant extracts, even if the productsstem from the same species.In addition, it may be assumed that an extractfrom one type of plant has different mechanismsof action, efficacy, bioavailability, and pharmacodynamics,compared to an extract from anotherplant species. For this reason, meta-analyseswhich include studies with products from differentcompanies and different plant species maycarry a substantial risk of ‘inborn errors’ if generalconclusions are drawn. Further, meta-analyticaldata from one brand will not be directly translatableto another with a different composition.

PHYTOTHERAPEUTIC AGENTS IN THE TREATMENT OF LUTS AND BPH 179In conclusion, as long as the components ofplant extracts are not chemically defined or standardizedfor all products, separate scientific studieshave to be performed with each extract/mixturein order to assess its individual efficacy. If theprinciples of evidence-based medicine are appliedto the evaluation of the current data on phytotherapeuticagents in the treatment of LUTSand BPH, clear-cut evidence for their efficacyuntil recently has been difficult to establish.Although there is increasing evidence of efficacyfor some products this is not true of all extracts byany means. More proof is needed for other plantbasedmedications, particularly if the prescriptioncosts are to be reimbursed by the public healthcare system.If patients buy phytotherapeutic agentsbecause of their preferences for ‘natural’ productsas dietary supplements at their own expense theyshould not be discouraged because they will, atleast, enjoy a placebo effect. However, it must bestressed that a sole symptom relief may mask theprogression of a disease.Uncontrolled studies with low patient numbersand of short duration, not performed accordingto accepted standards and guidelines, are ofquestionable value. Likewise, meta-analyses areonly acceptable if the quality of the studiesincluded is assessed and shown to be appropriate.Due to the widely controversial and partly insufficient‘hard’ data about the efficacy of phytotherapyfor the treatment of symptomatic BPH, theInternational Consultations on BPH were reluctantto recommend phytotherapy as a therapeuticoption. 98 The same opinion was developed by anexpert committee which established the guidelinesfor the German urologists according to theprinciples of evidence-based medicine. 99 Moreevidence has become available, from gold-standardclinical trials and rigorous meta-analysis, 87,89however, suggesting that a review of the role ofphytotherapy in the management of the BPH isrequired.REFERENCES1. Gerber G S. Phytotherapy for benign prostatichyperplasia. Curr Urol Rep 2002; 3: 285–2912. Vallancien G, Pariente P. Treatment of lower urinarytract symptoms suggestive of benign prostaticobstruction in real life practice in France. ProstateCancer Prostatic Dis 2001; 4: 124–1313. Bruskewitz R. Management of symptomatic BPHin the US: who is treated and how? Eur Urol 1999;36 (Suppl 3) 7–134. Dreikorn K, Richter R. Conservative nonhormonaltreatment of patients with benign prostatichyperplasia. N Develop Biosci 1989; 5: 109–1215. Dreikorn K, Schönhöfer P S. Stellenwert vonPhytotherapeutika bei der Behandlung der benignenProstatahyperlasie (BPH). Urologe A 1995; 34:119–1296. Dreikorn K, Borkowsi A, Braeckman J et al. Othermedical therapies. In: Denis L, Griffiths K, KhouryS et al. (eds). Proceedings of the 4th internationalconsultation on benign prostatic hyperplasia (BPH)1997. Plymouth: Plymbridge Distributors, 1998:633–6597. Fitzpatrick J M, Dreikorn K, Khoury S et al. Themedical management of BPH with agents otherthan hormones or alpha-blockers. In: Cocket A TK, Aso Y, Chatelain C et al. (eds). Proceedings ofthe 2nd international consultation on benign prostatichyperplasia (BPH), Paris 26–27 June 1991SCI. 1991: 195–1998. Fitzpatrick J M, Dreikorn K, Khoury S et al. Themedical management of BPH with agents otherthan hormones or alpha-blockers. In: Cocket A TK, Aso Y, Chatelain C et al. (eds). Proceedings ofthe 2nd international consultation of benign prostatichyperplasia (BPH), Paris 27–30 June 1993 SCI.1993: 445–450

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PHYTOTHERAPEUTIC AGENTS IN THE TREATMENT OF LUTS AND BPH 18370. Yablonsky F, Riffaud J P. Pygeum africanum forthe treatment of patients with BPH: a review of 25years of published experience. Curr Therap Res1995; 56: 796–81771. Breza J, Dziurny O, Borowka A et al. Efficacy andacceptability of Tadenan (Pygeum africanumextract) in the treatment of benign prostatic hyperplasia(BPH): a multicentre trial in Central Europe.Curr Med Res Opin 1998; 143: 127–13972. Dathe G, Schmid H. Phytotherapie der benignenProstatahyperplasie: Doppelblindstudie mitExtractum Radicis Urticae (ERU). Urologe [B]1987; 27: 233–23673. Vontobel H P, Herzog R, Rutishauser G H.Ergebnisse einer Doppelblindstudie über dieWirksamkeit von ERU-Kapseln in der konservativenBehandlung der benignen Prostatahyperplasie.Urologe [A] 1985; 24: 49–5174. Engelmann U, Boos G, Kres H. Therapie derbenignen Prostatahyperplasie mit BazotonLiquidum. Urologe [B] 1996; 36: 287–29175. Dutkiewicz S. Usefulness of Cernilton in the treatmentof benign prostatic hyperplasia. Int UrolNephrol 1996; 28: 49–5376. Habib F K, Ross M, Lewenstein A et al. The identificationof a prostate inhibitory substance in apollen extract. Prostate 1995; 26: 133–13977. Becker H, Ebeling L. Konservative Therapie derbenignen Prostatahyperplasie (BPH) mitCernilton. Urologe [B] 1988; 28: 301–30678. Buck A C, Cox R, Rees R W M et al. Treatment ofoutflow tract obstructive due to benign prostatichyperplasia with the pollen extract Cernilton. Br JUrol 1990; 66: 398–40479. Aoki A, Naito K, Hashimoto O et al. Clinical evaluationof the effect of tamsulosin hydrochlorideand cernitin pollen extract on urinary disturbanceassociated with benign prostatic hyperplasia in amulticentered study [in Japanese]. Hinyokika Kiyo2002; 48: 259–26780. Bach D. Phytopharmaka. In: Höfner K, Stief C G,Jonas U (eds). Benigne Prostatahyperplasie. Berlin,Heidelberg: Springer, 2000: 238–26081. Jonas A, Rosenblut G, Krapf D et al. Cactus flowerextracts may prove beneficial in benign prostatichyperplasia due to inhibition of 5-alpha-reductaseactivity, aromatase activity and lipid peroxidation.Urol Res 1998; 26: 265–27082. Carbin B E, Larsson B, Lindahl O. Treatment ofbenign prostatic hyperplasia with phytosterols. Br JUrol 1990; 66: 639–64183. Metzker M, Kieser M, Hölscher U. Wirksamkeiteines Sabal-Urtica-Kombinationspräparates bei derBehandlung der benignen Prostatahyperplasie(BPH). Urologe [B] 1996; 36: 292–30084. Sökeland J, Albrecht J. Kombination aus SabalundUrticaextrakt mit Finasterid bei BPH (Styad.Ibis II nach Alken). Urologe [A] 1997; 36: 327–33385. LeLorier J, Grégoire G, Benhaddad A et al.Discrepancies between meta-analyses and subsequentlarge randomised controlled trials. N Engl JMed 1997; 337: 536–54286. Wilt T J, Ishani A, Stark G et al. Saw palmettoextracts for treatment of benign prostatic hyperplasia:a systematic review. J Am Med Assoc 1998; 280:1604–160987. Boyle P, Lowe F, Robertson C, Roehrborn C G.Meta-analysis of clinical trials of Permixon ® in thetreatment of symptomatic benign prostatic hyperplasia.Urology 2000; 55: 533–53988. Wilt T, Ishani A, MacDonald R. Serenoa repens forbenign prostatic hyperplasia. Cochrane DatabaseSyst Rev 2002; (3): CD00142389. Boyle P, Robertson C, Lowe F, Roehrborn C G.Meta-analysis of Permixon in treatment of symptomaticbenign prostatic hyperplasia: an update[abstract]. J Urol 2003; 169 (Suppl 4): 129790. Wilt T J, McDonald R, Ishani A. b-sitosterol forthe treatment of benign prostatic hyperplasia: systematicreview. BJU Int 1999; 83: 976–98391. Wilt T, Ishani A, MacDonald R et al. Beta-sitosterolsfor benign prostatic hyperplasia. CochraneDatabase Syst Rev 2000; (2): CD00104392. Wilt T, Ishani A, MacDonald R et al. Pygeumafricanum for benign prostatic hyperplasia.Cochrane Database Syst Rev 2002; (1): CD001044

184THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA93. MacDonald R, Ishani A, Rutks I et al. A systematicreview of Cernilton for the treatment of benignprostatic hyperpasia. BJU Int 2000; 85: 836–84194. Wilt T, MacDonald R, Ishani A et al. Cernilton forbenign prostatic hyperplasia. Cochrane DatabaseSyst Rev 2000; (2): CD00104295. Boyle P, Robertson C, Manski R et al. Meta-analysisof randomized trials of terazosin in the treatmentof benign prostatic hyperplasia. Urology2001; 58: 717–72296. Boyle P, Gould L, Roehrborn C G. Prostate volumepredicts outcome of treatment of benign prostatichyperplasia with finasteride: meta-analysis of randomizedclinical trials. Urology 1996; 48: 398–40597. Roehrborn C G, Boyle P, Nickel J C et al. on behalfof the ARIA3001, ARIA3002, and ARIA3003study investigators. Efficacy and safety of a dualinhibitor of 5 alpha-reductase types 1 and 2 (dutasteride)in men with benign prostatic hyperplasia.Urology 2002; 60: 434–44198. Denis L, McConnell J, Yoshida O et al. 4th internationalconsultation of BPH. Recommendations ofthe international scientific committee: the evaluationand treatment of lower urinary tract syndromes(LUTS) suggestive of benign prostaticobstruction. In: Denis L, Griffiths K, Khoury S etal. (eds). Proceedings of the 4th international consultationof benign prostatic hyperplasia (BPH).Plymouth: Plymbridge Distributors, 1998; 669–98499. Altwein J, Aumüller G, Berges R et al. Leitliniender Deutschen Urologen zur Therapie des BPH-Syndromes. Urologe [A] 1999; 38: 529–536

Uroselectivity revisitedK-E Andersson M G Wyllie12BACKGROUNDThe two major components of lower urinarytract symptoms (LUTS)—voiding (obstructive)and storage (irritative) symptoms—associatedwith benign prostatic hyperplasia (BPH) havetraditionally been linked directly or indirectly topathophysiologic changes in the prostate. 1Voiding symptoms have been attributed to twofacets of prostate function: the physical mass ofthe enlarged gland (the static component) and thetone of the smooth muscle of the prostate stroma(the dynamic component). 2 Storage symptoms,however, have been more closely associated withthe bladder dysfunction produced secondary tothe increased outflow resistance, arising fromprostate-dependent urethral obstruction. Theprecise interrelationship between morphologicBPH, bladder outflow obstruction, and profile ofsymptoms produced is, however, unclear 3 andthere are several paradoxes. In particular, bothvoiding and storage symptoms are common inwomen. 3,4 Furthermore, many patients who haveundergone prostatectomy to relieve obstructionstill experience persistent storage symptoms.Several studies have also now shown that there islittle or no correlation between drug-inducedchanges in flow and symptom improvement 5,6 .The use of LUTS as a clinical descriptor is a neutralway to describe the symptoms, and makes noassumption about their link to the prostate.On the basis of our knowledge of the controlof periurethral, stromal prostate smooth muscletone it is logical to assume that prostate α-adrenoceptorsshould be responsible for at least part ofthe LUTS associated with BPH (Figure 12.1).However, the welldocumented beneficial effectsFIGURE 12.1 Sympathetic innervation of the human prostate showing the location of α 1- and α 2-adrenoceptors.185

186THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAof α 1-adrenoceptor antagonists on the symptomsof BPH 7–11 occur even in the absence of outflowobstruction. This indicates that extraprostatic α 1-adrenoceptors may also be fundamentallyinvolved in the pathogenesis of LUTS. 10 The lackof correlation between α-antagonist-inducedimprovements in urine flow and symptomimprovement 6,12 could also be explained on thebasis of an action via extraprostatic α 1-adrenoceptors(Figure 12.1).The extraprostatic α 1-adrenoceptors may belocated in the bladder, ganglia, and nerves innervatingthe lower urinary tract and at spinal orsupraspinal levels within the central nervous system.Indeed, there is evidence for involvement ofα 1-adrenoceptors in the spinal control of bothsympathetic and somatic (filling), as well as parasympathetic(voiding), efferent activity of thelower urinary tract. 10,13In approximately 10% of patients, the use ofα 1-adrenoceptor antagonists in common clinicaluse (alfuzosin, doxazosin, tamsulosin, terazosin)has been limited by side-effects, particularlydizziness, headache, asthenia, nasal congestion,and orthostatic hypotension, that may be attributedto action on nonprostatic α 1-adrenoceptors.It is likely that most of the common side-effectsare characteristic of a direct action on the vasculature.To circumvent these side-effects, the pharmaceuticalindustry has attempted to find α 1-adrenoceptor antagonists that are selective for theprostate α 1-adrenoceptors. The underlyingassumption is that these should be ‘uroselective’agents. It should be noted, however, that the definitionof uroselectivity is ambiguous because thecriteria were not established at the outset. Notsurprisingly, therefore, the term has been used invarious contexts which are often confusing andcontradictory. In this chapter we attempt to putsome degree of definition on the criteria to beused in the definitive designation of a drug asuroselective as it relates to management of thepatient with LUTS/BPH.In theory, the selectivity of drugs can bedefined using a variety of parameters, includingpharmacologic or physiologic uroselectivity, ormay be defined from a clinical perspective. 9,14Ultimately, however, only clinical uroselectivity isrelevant to patient and physician.PHARMACOLOGIC UROSELECTIVITYα 1-AdrenoceptorsMultiple α 1-adrenoceptor subtypes have beenidentified, 15–17 and may offer the opportunity totarget the prostate selectively. Receptor cloningand pharmacologic studies of the human prostatehave revealed the existence of both high-affinity(α 1A, α 1B, and α 1D) and low-affinity (α 1L) receptorsfor prazosin.α 1-Adrenoceptors in the prostateNerves that contain adrenergic, cholinergic, andnonadrenergic, noncholinergic neurotransmittersor mediator-producing enzymes supply thesmooth muscles of the prostate capsule and thetrabecular tissue around the ducts. 18,19 The adrenergicnerves are considered to be responsible forprostate smooth muscle tone by releasing noradrenaline,which stimulates contraction via α-adrenoceptors. 20 Although both α 1- and α 2-adrenoceptors can be identified in the humanprostate, the contractile effects of noradrenalineare mediated primarily by α 1-adrenoceptors. 10All three high-affinity α 1-adrenoceptor subtypeshave been identified in prostate stromal tissueusing molecular techniques. The α 1asubtypepredominates, representing 60–85% of the

UROSELECTIVITY REVISITED 187α 1adrenoceptor population. However, the α 1-adrenoceptor subtype responsible for prostaticsmooth muscle contraction has not been establishedunequivocally, although it is likely to beclosely related to the α 1A-adrenoceptor.α 1-Adrenoceptors in the urethraUrodynamic studies in humans have suggestedthat up to about 50% of intraurethral pressure ismaintained by stimulation of α-adrenoceptors, asjudged from results obtained with α 1-adrenoceptorantagonists. 21,22 In human male urethralsmooth muscle, functional and receptor-bindingstudies have suggested that the predominatingpostjunctional α-adrenoceptor is α 1. 23,24 UsingRNase protection assays and in situ hybridization,Nasu et al. 25 quantified and studied the distributionof α 1-adrenoceptor subtypes in thehuman proximal urethra. They found (in bothmales and females) that mRNA for the α 1asubtypewas predominant; the ratio of mRNA forα 1a, α 1b, α 1din the male urethra was 100 :0:0.Fukasawa et al. 26 found that in man the α 1L-adrenoreceptor subtype was more prominent inthe male urethra than in the prostate.α 1-Adrenoceptors in the bladderIn detrusor muscle from most species, includinghumans, β-adrenoceptors, which mediate relaxation,normally dominate over α-adrenoceptors,which mediate contraction; the normal responseto noradrenaline is β-adrenoceptor-mediatedrelaxation. However, this may change in outflowobstruction. Perlberg and Caine 27 assessed theresponse to noradrenaline in the hypertrophicbladder and found that, in strips taken fromhypertrophic bladders, noradrenaline caused α-adrenoceptor-mediated contraction in almostone-quarter of patients. This change was alsoreflected in the symptoms: patients whose bladdersresponded to noradrenaline by contractinghad symptoms of bladder overactivity. Thisobservation suggests that a change in the responseto noradrenaline may play a role in producingboth obstructive and irritative symptoms.However, Smith and Chapple 28 studied α 1-adrenoceptor function in strips from obstructedbladders and found that only five of 72 stripsresponded to phenylephrine; these results are notin agreement with the view that α-adrenoceptorstimulation during storage contributes to bladdercontraction and thereby to symptoms. Most probably,the balance between β- and α-adrenoceptorfunctions in the bladder changes in BPH, but it isnot known what this really means for the pathophysiologyof LUTS, particularly storage symptoms.The predominating postjunctional α-adrenoceptorsubtype in the human lower urinary tractseems to be α 1; however, the number of α 1-adrenoceptors in the detrusor is very low. 29 Innormal human isolated detrusor muscle, drugsthat selectively stimulate isolated α-adrenoceptors,particularly those acting on α 1-adrenoceptors,produce a small and variable contractileeffect. 23 It is not clear which α 1-adrenoceptor subtypepredominates in the detrusor, trigone, andbladder base.Walden et al. 30 reported a predominance ofα 1a-adrenoceptor mRNA in the human bladderdome, trigone and bladder base. This contrastswith the findings of Malloy et al., 31 who foundthat among the high-affinity receptors for prazosin,only α 1a- and α 1d-adrenoceptor mRNAwas expressed in the human bladder. The totalα 1-adrenoceptor expression was low(6.3 ± 1.0 femtomol/mg), but was highly reproducible.The relationship between the differentsubtypes was 66% α 1dand 34% α 1a; α 1bwas not

188THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAexpressed. This is in contrast to findings in thehuman prostate. 32 The fact that drugs that actselectively on prostate α 1-adrenoceptors mayhave little effect on LUTS could, in theory, beexplained if they did not block the α 1-adrenoceptors(α 1D) of the bladder. 33 Considering thedoubtful functional importance of the bladderα 1-adrenoceptors, this mechanism seems unlikely,but cannot be discounted completely.α 1-Adrenoceptors in peripheral and centralnervous system structures (Figure 12.2)In animal experiments, facilitatory α 1-adrenoceptorshave been identified in ganglia and oncholinergic terminals in the bladder. 34–37 Aneffect of α 1-adrenoceptor antagonists at the ganglionicand/or prejunctional level, leading to adecrease in acetylcholine release, is also possible.Descending spinal pathways involved in micturitioninclude noradrenaline-containing projectionsfrom the locus coeruleus. 38 From the locuscoeruleus, the noradrenergic neurones supplysympathetic and parasympathetic nuclei in thelumbosacral spinal cord. Bladder activationthrough these bulbospinal noradrenergic pathwaysmay well involve excitatory α 1-adrenoceptors.39 Thus, in the anesthetized cat, electricalstimulation of the locus coeruleus induced bladdercontractions that were antagonized byintrathecal administration of prazosin. 39–42 Inaddition, destruction of noradrenergic cell bodiesin the locus coeruleus by microinjection of 6-hydroxydopamine produced a hypoactive bladder,which could be partly reversed by intrathecalinjection of prazosin or phentolamine in cats,depressed the external urethral sphincter activity,and reduced reflex firing in pudendal nerve efferentpathways by a presumed central site ofaction. 43 In the conscious cat, however, Downie etal. 44 found that the intrathecal prazosin did notalter the micturition reflex. The reasons for theseapparently conflicting results are unclear, butmost of the evidence supports a key central rolefor central α 1-adrenoceptors.Pontine micturitioncenterLumbar cord(T10–L2)Sacral micturitioncenter (S2–S4)BladderafferentUrethraCortexPelvicnerveDetrusorPelvic floorHypogastricnervePudendal nerveFIGURE 12.2 The micturition reflex. The afferentbranch of the micturition reflex runs in the spinal cord viathe dorsal root ganglia to the pontine micturition center,which is under voluntary control. The efferent branchruns from the pontine micturition center to the sacralmicturition center, from which the preganglionic nervesrun to the pelvic plexus and then to the bladder to causecontraction. At the same time, the efferent branch inhibitsthe hypogastric and pudendal nerves, leading to relaxationof the outflow region and the pelvic floor.

UROSELECTIVITY REVISITED 189In the central nervous system, facilitatory α 1-adrenoceptors, tonically active in both the sympatheticand somatic neural control of the lower urinarytract, were identified in the cat. 45,46Intrathecal doxazosin decreased micturition pressure,both in normal rats and in animals with postobstructionbladder hypertrophy. 47 The effectwas much more pronounced in the animals withhypertrophied/overactive bladders. Doxazosindid not markedly affect the frequency or amplitudeof the unstable contractions observed in ratswith obstructed bladders. It was suggested thatdoxazosin may have an action at the level of thespinal cord and ganglia, thereby reducing activityin the parasympathetic nerves to the bladder, andthat this effect was more pronounced in rats withbladder hypertrophy than in normal rats. 47Urodynamic studies revealed that spontaneouslyhypertensive rats (SHRs) have pronouncedbladder overactivity. 48 These animalsalso have an increased noradrenergic bladderinnervation and an increased voiding frequency. 49Whereas the control rats (Wistar Kyoto rats) havea regular contraction frequency during continuouscystometry, the SHRs show both micturitionand nonmicturition contractions. To investigatewhether the peripheral adrenergic system wasinvolved in the pathogenesis of the bladder overactivity,SHRs were treated with 6-hydroxydopaminein order to destroy the noradrenergicnerves chemically. Under these conditions, bladderoveractivity was maintained (as demonstratedby continuous cystometry). 50 Furthermore, α 1-adrenoceptor antagonists, injected intra-arteriallynear the bladder, did not abolish the bladderoveractivity. On the other hand, when givenintrathecally, the same dose of α 1-adrenoceptorantagonist normalized micturition. Although therelevance of these findings to man is not known,it is probable that spinal α 1-adrenoceptors maycontribute to the overall clinical improvement inLUTS seen with α 1-adrenoceptor antagonists.The neuronal localization of α 1-adrenoceptorsubtypes (α 1a, α 1b, α 1d) in the human spinal cordwas investigated. 51 In situ hybridization studiesrevealed that α 1-adrenoceptor mRNA was presentin ventral gray matter only (ventral > dorsal;sacral > lumbar = thoracic > cervical). Signalingcell bodies were detected in anterior horn motorneurones at all levels, in the dorsal nucleus ofClark, and in intermediolateral columns in cervicalenlargement, in thoracic and lumbar spinalcord regions, and in the parasympathetic nucleusin the sacral spinal cord. Although all three highaffinityα 1-adrenoceptor subtypes were presentthroughout the human spinal cord, α 1d-adrenoceptormRNA predominated. Whether this hasany clinical significance in the treatment ofLUTS remains to be established. It is pertinent,however, to note that the distribution of α 1-adrenoceptor mRNA subtypes in the rat spinalcord is different from that in humans; 52 thisshould be borne in mind when discussing theclinical relevance of data obtained in rats.Overall, there is good evidence in severalspecies that α 1-adrenoceptors at spinal andsupraspinal levels can profoundly influence themicturition reflex. The possibility that they maycontribute to the overall clinical improvement inLUTS cannot be discounted.α 1-Adrenoceptors in the cardiovascular systemThe involvement of α 1-adrenoceptor subtypes invascular control is of particular relevance to anydiscussion of uroselectivity. Species- and vesseldependentα 1A-, α 1B-, α 1D-, and α 1L-adrenoceptorsall seem to subserve the contractile responsein vascular tissue. 53–57 On this basis, one couldassume that cardiovascular homeostasis dependson all of the different subtypes, albeit to varying

190THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAextents. Equally, no one α 1-adrenoceptor subtypecan be considered to be the ‘blood pressureadrenoceptor’.Summary of pharmacologic uroselectivityThere is good evidence to suggest that an agentselective for the α 1A-adrenoceptor subtype willinfluence periurethral smooth muscle tone, urethralresistance, and thereby urinary flow.However, there is some degree of uncertainty asto whether the use of α 1A-adrenoceptor antagonistswould improve symptoms. Indeed, shouldan extraprostatic action on the other subtypes berequired to optimize symptom improvement, anα 1A-adrenoceptor-selective antagonist may havelower efficacy than existing agents. Equally, aselective action at α 1A-adrenoceptors may notnecessarily translate into a reduction in cardiovascularside-effects. Thus, although several agentswith considerable pharmacologic (α 1A-adrenoceptor)‘uroselectivity’ have been synthesized, 58,59there is no guarantee that this will translate intoclinical benefit.PHYSIOLOGIC UROSELECTIVITYObviously the response in the whole animal and,indeed, in man represents an integrated responsethat is much more complicated than can be predictedfrom analysis at the pharmacologic orreceptor level in isolation. In the whole animal,homeostatic mechanisms tend to counteractTABLE 12.1 Binding affinities (pK I) for compounds at cloned human α 1-adrenoceptors.Compound α 1Aα 1Bα 1DBMY 7378 6.2 ± 0.10 6.7 ± 0.11 8.2 ± 0.10Prazosin 9.7 ± 0.20 9.6 ± 0.14 9.5 ± 0.10Doxazosin 8.5 ± 0.20 9.0 ± 0.20 8.4 ± 0.12WB 4101 9.3 ± 0.10 8.2 ± 0.16 9.2 ± 0.065-Methylurapidil 8.5 ± 0.09 6.8 ± 0.13 7.8 ± 0.09Tamsulosin 10.3 ± 0.21 9.5 ± 0.17 10.1 ± 0.22Phentolamine 8.1 ± 0.09 7.1 ± 0.15 7.8 ± 0.03SNAP 1069 7.8 ± 0.19 7.6 ± 0.18 6.8 ± 0.20Indoramin 8.3 ± 0.03 8.0 ± 0.12 7.3 ± 0.15Alfuzosin 8.0 ± 0.20 8.0 ± 0.13 8.5 ± 0.07Spiperone 7.6 ± 0.12 8.5 ± 0.16 8.1 ± 0.03Terazosin 8.6 ± 0.22 8.7 ± 0.08 8.3 ± 0.13Affinities were determined by displacement of 0.2 nM [ 3 H]prazosin from rat-1 fibroblasts stably expressing cloned α 1-adrenoceptor subtypes by 12 concentrations of competing drug. Values represent mean ± SEM for three to five separatedeterminations. Hill slopes for displacement curves were not significantly different from unity. (Data from reference 67with permission.)pK I

UROSELECTIVITY REVISITED 191many of the effects produced by any drug,particularly under normal conditions. However,in disease or in situations of abnormal pathophysiology,homeostatic compensation may haveoccurred to the maximum extent. Thus, theresponse to the drug under these conditions maybe substantially different—either exaggerated orattenuated.In terms of LUTS and in the context of uroselectivity,an agent that decreases outflow resistancewithout affecting the blood pressure wouldobviously be of considerable interest. Manygroups have reported that α 1-adrenoceptorantagonists decrease urethral resistance in animalmodels. 60–66 Indeed, such animal models are usedroutinely within the pharmaceutical industry todetermine the relative potency and selectivity ofα 1-adrenoceptor antagonists for prostate functionover other parameters such as blood-pressurelowering. The rank order of potency of the effectsof various α 1-adrenoceptor antagonists on urethralpressure has been defined in several animalmodels, and has then been related to blood pressurechanges in the same animal. 11,65 The ratio ofthese effects could therefore be considered as apotential index of uroselectivity. Although suchmodels may have some predictive value, they alsohave limitations, and the results may be bothspecies- and assay-dependent. 67,68 Thus, resultsobtained in one animal species may differ fromthose obtained in another, and it has not beenestablished which animal model is the most predictiveof effects in humans.Side-effects that may be dose limiting clinicallyare not always cardiovascular (or directly relatedto hemodynamic changes), but may arise fromthe central nervous system, for example drowsinessand dizziness. Also, because such effects cannotalways be studied in animals, animal modelsmay not adequately predict benefit–risk profilesor provide a reliable index of clinical uroselectivityas it would impact on patient management.The use of animal models has, however, producedencouraging results. All establishedagents—alfuzosin, doxazosin, prazosin, tamsulosin,and terazosin—affect urethral pressure inanimals over the same dose range that producesvascular effects (see Table 12.1 and Figure 12.3).The relative lack of uroselectivity seen in wholeanimalstudies is entirely consistent with thereceptor-binding profile of these α 1-adrenoceptorantagonists (i.e. the pharmacologic ‘uroselectivity’,as defined by the selectivity for the α 1A-adrenoceptor subtype over the other subtypes)(Figure 12.3). Thus, none of these agents can beconsidered to demonstrate significant physiologicuroselectivity in the whole animal. Although it ispossible to carry out similar evaluations inman, 69,70 ultimately we need to define clinicaluroselectivity 9,71 .CLINICAL UROSELECTIVITYA clinically relevant definition of uroselectivitycan be made only in relation to man. It is knownthat α 1-adrenoceptor antagonists have more pronouncedeffects on blood pressure in hypertensivepatients than in normotensive patients. For example,it is well documented that doxazosin and terazosineffectively reduce blood pressure in hypertensiveBPH patients but have only relativelymodest effects in normotensive men (Figure12.4). 72,73 Assuming that this occurs at doses thataffect urinary flow, both drugs could be consideredto demonstrate clinical uroselectivity, at leastin normotensive BPH patients. Ironically, however,using this definition neither agent would beclassified as uroselective in hypertensive BPHpatients. The blood pressure-lowering effect is of

192THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIA(a)7.07.5(b)Dox Ter Alf Tam 5-MU Dox Ter Alf Tam 5-MULow7.07.5pKi8.08.59.0AffinityPseudo pA 28.08.59.5High9.0alpha 1A alpha 1B alpha 1D Prostate pressure Blood pressureFIGURE 12.3 (a) Selectivity profile of doxazosin (Dox), terazosin (Ter), alfuzosin (Alf), tamsulosin (Tam), and 5-methylurapidil (5-MU)for the cloned α 1A-, α 1B, and α 1D-adrenoceptor subtypes. 5-MU is the only compound that showsselectivity for the cloned human α 1A-adrenoceptor. (b) Selectivity profile of the same compounds in the anesthetized dog.All compounds are equi-active on prostate pressure and blood pressure, except the α 1A-selective 5-MU, which is about 30-fold prostate selective.benefit in the large number of BPH patients whoare hypertensive. Thus, in theory, a drug couldaffect blood pressure in a hypertensive subjectbefore it has any noticeable effects on the urethra(i.e. the drug has no uroselectivity or indeed hasvascular selectivity). The same drug may reduceoutflow resistance in a normotensive patient butwithout having any effects on blood pressure (i.e.the drug is uroselective in this situation). The situationis complicated further by the fact thatpharmacokinetic properties may contribute toapparent differences between drugs in the effectson different organ systems.In the context of managing patients withBPH, it is therefore both obvious and essential tohave an all-encompassing but precise definitionof clinical uroselectivity. This has to take intoaccount the fact that the clinical endpoints of outflowobstruction (as defined urodynamically) andLUTS, and adverse effects may vary independently.Thus, uroselectivity (as for any clinicaltherapeutic index) may be defined by describingthe ratio between the dose required for thedesired therapeutic action and the dose that producesside-effects. Such a definition of uroselectivityis the one recommended in 1995 by theFourth international consultation on benign prostatichyperplasia: ‘desired effects on obstructionand lower urinary tract symptoms related toadverse effects’. 9 It should be noted that clinicaluroselectivity defined in this way is not an all-ornothingphenomenon but is merely a qualitativedescriptor.The clinical definition should be borne inmind when considering the profiles described forthe α 1-adrenoceptor antagonists. It is obviousthat, although animal studies have greatlyincreased our understanding of the control of thelower urinary tract, they may be of relatively littlevalue in the prediction of clinical uroselectivity.

UROSELECTIVITY REVISITED 193Blood pressure (mmHg)170160150140130120110100908070HypertensiveNormotensiveTerazosin Placebo Terazosin PlaceboBaselineTreatmentFIGURE 12.4 Effect of terazosin on blood pressure in hypertensive and normotensive patients. Data show blood pressureat baseline and after treatment. (Adapted from reference 70.)CONCLUSIONSA drug may be uroselective in the sense that it hasa preference for the α-adrenoceptors in theprostate, or that in an animal model it can affectthe prostate and urethra without affecting bloodpressure, for example. There are α 1-adrenoceptorsin the urethra, trigone, detrusor, spinal cord,supraspinal structures, and peripheral ganglia,the contributions of which to the symptoms ofBPH remain unknown, and whose subtypes havenot been determined. Thus, such a definition ofuroselectivity may not be meaningful from a clinicalpoint of view. A clinically meaningful definitionof uroselectivity can be made only withrespect to findings in man, and considers desiredeffects on obstruction and LUTS relative toadverse effects. Clinical uroselectivity can be usedas a guideline for selecting drugs for the managementof BPH that are cost-effective and safe, andwhich can improve the individual patient’s qualityof life. It is possible, however, that the pharmaceuticalindustry may have exhausted both thepharmacologic and pharmacokinetic options forachieving uroselectivity 74 .REFERENCES1. Abrams P. New words for old; urinary tract symptomsfor ‘prostatism’. Br Med J 1994; 308: 929–9302. Caine M. The present role of alpha-adrenergicblockers in the treatment of benign prostatic hypertrophy.J Urol 1986; 136: 1–43. Shapiro E, Lepo H. Pathophysiology of clinicalbenign prostatic hyperplasia. Urol Clin North Am1995; 22: 285–2904. Jollys J V, Jollys J C, Wilson J et al. Does sexualequality extend to urinary symptoms? NeurourolUrodyn 1993; 12: 391–3925. Lepor H, Machi G. Comparison of the AUA symptomindex in unselected males and females between55 and 79 years of age. Urology 1993; 42: 36–406. Barry M J, Cockett A T K, Holtgrewe H L et al.Relationship of symptoms of prostatism to commonlyused physiological measures of the severityof benign prostatic hyperplasia. J Urol 1993; 150:351–3587. Eri L M, Tveter K J. α-Blockade in the treatmentof symptomatic benign prostatic hyperplasia. J Urol1995; 154: 923–9348. Chapple C R. Selective α 1-adrenoceptor antagonistsin benign prostatic hyperplasia: rationale andclinical experience. Eur Urol 1996; 29: 129–144

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Indexadrenoceptors 185–91subtypes 92, 93, 103–4adrenoceptor antagonists 91–2apoptosis induction 85–6blood pressure effects 193differential effects on prostate tissue growth83–9physiologic uroselectivity 190–1, 192–3serum lipids 109vs watchful waiting 4–5African plum tree (Pygeum africanum) 172–3ALFIN study 70–1, 77–8ALFORTI study, alfuzosin 128–9, 132ALFUS study, alfuzosin 129alfuzosin 119–37acute urinary retention 123alpha-adrenoceptor affinity 119–20blood pressure 120, 122–4vs tamsulosin 157–8clinical studies 125–31ALFORTI 128–9, 132ALFUS 129combination therapy, finasteride 129, 131, 133efficacy 126–34vs placebo 27, 46formulation, comparisons 122hemodynamic effects 124–5pharmacodynamic effects 122–3pharmacokinetic properties 122pharmacologic profile 119prostate/plasma concentrations 122safety and adverse events 132, 133therapeutic applications 133–4urodynamic effects 123urethral pressure 121vs tamsulosin 157–8ALLHAT (Antihypertensive Lipid-LoweringTreatment to Prevent Heart Attack Trial)110alpha-1 adrenoceptorsbinding affinities 186, 190in bladder 187–8in cardiovascular system 189–90contractile role 186and LUTS 93in peripheral and CNS structures 188–9pharmacologic uroselectivity 186–90in prostate 186–7subtypes 84in urethra 187alpha-adrenoceptor antagonists 91–2with 5-alpha reductase inhibitor, MTOPStrial 76–7apoptosis 85–6see also alfuzosin; doxazosin; tamsulosin:terazocin5-alpha-reductase (5-AR) 42–3deficiency, pseudohermaphroditism 4, 43types I and II 43type II see finasteride5-alpha-reductase inhibitors (5-ARI)and alpha-blockers 48combination therapy 48DHT 41–2DHT reduction 47dual isoforms 43–4, 46phytotherapeutic agents 178see also dutasteride; finasteride197

198THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAAmerican dwarf palm (Serenoa repens) 76,168–72American Urological Association (AUA)AUASI scale 26, 73bother score 6, 24combination therapy guidelines 77watchful waiting treatment guidelines 5–7androgen ablation/deprivation 83angina, surgical procedures, placebo effects17–18apoptosis, alpha-adrenoceptor antagonists 85–6balloon dilatation vs cystoscopy, placebo/shamcontrolled trials 29–33Baltimore longitudinal study of aging, watchfulwaiting 1–2bladderalpha-1 adrenoceptors 187–8smooth muscle, alpha-blockers 83bladder outlet obstruction (BOO) 185tolterodine/tamsulosin combination therapy76watchful waiting 2blood pressure effectsadrenoceptor antagonists 193alfuzosin 122–4, 120doxazosin 108–9tamsulosin 148vs alfuzosin 157–8, 158vs terazosin 157–8terazosin 96, 99BMY-7378, binding affinities 190bother score 6, 24Boyarsky symptom scores 145, 147, 154BPH (benign prostatic hyperplasia)historical perspective 83–6natural history, placebo effects 18–34treatment preferences 5bromocriptine, efficacy, vs placebo 27cactus flower extracts 174candicin, efficacy, vs placebo 27cardiovascular system, alpha-1 adrenoceptors189–90cernitin, combination therapy 76cimetidine, efficacy, vs placebo 27combination studiesALFIN study 70–1MTOPS trial 72–6phytotherapy 76Veterans’ Affairs (VA) Cooperative Study68–70confidence profile method (CPM), symptomimprovement 22controlled clinical trials, placebo/sham effect14–16coronary heart disease (CHD), doxazosin 109–10Cucurbita pepo (pumpkin) 174cystoscopy vs balloon dilatation, placebo/shamcontrolled trials 29–33Declaration of Helsinki, rationale forplacebo/sham controlled trials 15detrusor overactivity (DO),tolterodine/tamsulosin combination therapy76DHT (dihydrotestosterone)5-alpha-reductase inhibitors (5-ARI) 47BPH development 41–2dual inhibition, dutasteride treatment 44formation 42doxazosin 103–17affinity for adrenoceptor subtypes 93ALLHAT trial 110antihypertensive effects 108–9binding affinities 190efficacy 46with finasteride 5GITS formulation 112–13adverse events 113

INDEX 199HABIT 109HALT 110MTOPS 59, 72–6, 77–8, 106PREDICT 71–2, 77–8, 106prostate apoptosis effect 85–6safety and efficacyadverse events 107–8long-term 84–5, 106safety profile 107short-term 104–5sexual dysfunction 110–11TOMHS 109uroselectivity 192drugs, meta-analyses 61, 161dutasteride 41–51adverse events 46clinical experience 45–7combination studies 48preclinical development 44–5and PSA (prostate-specific antigen) 45, 47–8structure 44vs finasteride 47–8ESPIRIT (European Standardized PressureFlow Investigation Trial) 148–9FDA, rationale for placebo/sham controlledtrials 14–15finasteride 53–66adverse events 58ALFIN study 70–1, 77–8clinical studies 56–9combination studies 59–61with alfuzosin 129, 131, 133with alpha-adrenoceptors 5with doxazosin 5terazosin, interactions 60development 54DHT and 5-alpha-reductase 53–4hematuria prevention 48, 61meta-analysis 61mode of action 54MTOPS study 59–60, 72–6, 77–8PREDICT study 71–2, 77–8, 106PSA effects 62safety profile 133structure 54VA Cooperative Study 60vs dutasteride 47–8France and Germany, phytotherapeutic agents 5growth factorsDHT-receptor complex 42and finasteride 553H-prazosin, binding sites 120HABIT (Hypertension and BPH Interventionstudy), doxazosin evaluation 109HALT (Hypertension and Lipid Trial),doxazosin 110hematuria prevention, finasteride treatment 48,61hermaphroditism, pseudohermaphroditism, 5-AR deficiency 43hyperplasia, adrenoceptor antagonist differentialeffects 83–7hypertension, TOMHS 109hyperthermia devices see TUMThypotension, tamsulosin 147, 149, 159, 161Hypoxis rooperi (South African star grass) 168124I-HEAT, binding sites 120I-PSS (International Prostate Symptom Score)26tamsulosin 149, 150–2indoraminbinding affinities 190efficacy, and potency 92Ki 67 immunostaining 85

200THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAlipids, alpha-blocker effects 109–10LUTS (lower urinary tract symptoms)alpha-adrenoceptor antagonist therapy 93dutasteride treatment 45effects of alpha-1 adrenoceptors 93terazosin therapy 91–6watchful waiting prospective study 35-methylurapidilaffinity for adrenoceptor subtypes 93binding affinities 190uroselectivity 192micturition reflex 188MTOPS (Medical Therapy of ProstaticSymptoms) trial 59–60, 72–6, 77–8doxazosin 106norprogesterone, efficacy, vs placebo 2, 27Olmsted County Study of Urinary Symptomsand Health Status Among Men 19–21orthostatic hypotension, tamsulosin 147, 149,159, 161pain treatment, placebo effects 17patientsmonitoring see watchful waitingtreatment preferences 5peripheral NS, alpha-1 adrenoceptors 188–9phenoxybenzamine 103phentolamine, binding affinities 190phytotherapeutic agents 167–845-alpha-reductase inhibition 168–9active constituents 168combination preparations 174–5combination therapy 76France and Germany 5meta-analyses 175–7mode of action 169origin 167–8phytosterols/beta-sitosterol 172Picea (spruce) 168Pinus (pine) 168placebo/sham effect 11–39balloon dilatation vs cystoscopy studies 29–33biopsychosocial determinants 13controlled trials, cystoscopy vs balloondilatation 29–33definitions and theoretical considerations11–13ethical considerations 15hyperthermia treatment studies 15–16, 29–32improvement perception 33–4long-term natural history of diseaseprogression 31–3medical treatment studies 24–9natural history studies 18–34, 31–3regression to mean 19watchful waiting studies 21–4Olmsted County study 19–21pain control 17phytotherapeutic agents, Serenoa repens 170quantitative symptom scores 30–3surgical procedure studies 17–18therapeutic theory 12watchful waiting studies 21–4plants, phytotherapeutic agents 167–84PLESS (Proscar Long-term Efficacy and SafetyStudy) 32–3, 56–8postvoid residual urine (PVR), treatmentindications 6prazosinbinding affinities 190efficacy, and potency 923H-prazosin, binding sites 120PREDICT (Prospective European Doxazosinand Combination Therapy) study 71–2,77–8finasteride 106terazosin 86–7

INDEX 201prostate, innervation 185prostatic growth/developmentcell proliferation control 86–7finasteride 54–6growth rate (40–79 y) 21prostatic size/volumedoxazosin 111dutasteride 45, 77finasteride 56, 61, 77terazosin growth effects 97–8prostatism, watchful waiting over 5 years 2–3PSA (prostate-specific antigen)dutasteride treatment 45, 47–8and finasteride 62pseudohermaphroditism, deficiency of 5-alphareductase43pumpkin (Cucurbita pepo) 174Pygeum africanum 172–3rye (Secale cereale) 168, 173meta-analyses 175–7Sabal serrulata (saw palmetto) see Serenoa repensSecale cereale (rye) 168, 173Serenoa repens (American dwarf palm) 168–72cernitin, beta-sitosterol and vitamin Ecombination therapy 76combination therapy 174–5meta-analyses 175sexual function/dysfunctiondoxazosin 110–11dutasteride 46ejaculation abnormalities 147, 147–9MTOPS data 75–6tamsulosin 147–8beta-sitosterolmeta-analysis 175–7phytotherapeutic agents 172Serenoa repens, cernitin and vitamin Ecombination therapy 76smooth muscle, alpha-blockers 83SNAP 1069binding affinities 190efficacy, and potency 92South African star grass (Hypoxis rooperi) 168spiperone, binding affinities 190spruce (Picea) 168stinging nettle (Urtica dioica) 173surgical proceduresplacebo effects 17–18risk, MTOPS data 72–6symptom improvement, confidence profilemethod (CPM) 22tamsulosin 139–70adverse events 149affinity for adrenoceptor subtypes 93ancillary properties 162binding affinities 190blood pressure effects 148chemical structure 87clinical studiesdirect comparative studies 155–9European phase II 142–3European phase III 143, 147European phase IV 148Japanese phase II 141–2, 144long-term 154–5US phase III 149–52co-medication 159–60dosages and formulations 140–1, 158–9efficacy and tolerability 46, 146, 159–61, 160vs placebo 28elderly patients 159–60ESPIRIT 148–9meta-analysis 161onset of action 143, 152previous treatment comparisons 161tolterodine combination therapy 76uroselectivity 192

202THERAPEUTIC TREATMENT FOR BENIGN PROSTATIC HYPERPLASIAvs alfuzosin, blood pressure effects 157–8vs terazosin, blood pressure effects 157–8terazosin 91–101affinity for adrenoceptor subtypes 93binding affinities 190blood pressure effects 96, 193cardiovascular risk factors 97chemical structure 87effects on urogenital tract 97efficacy 46long-term 84–5, 93–4and potency 92short-term 93vs placebo 28finasteride interactions 60historic background 92LUT obstruction 91–2prostate apoptosis effect 85–6prostate gland growth 97–8safety profile 95–6uroselectivity 192VA Cooperative Study 60testosteronedutasteride treatment 47formation of DHT 42tolterodine, tamsulosin combination therapy 76TOMHS (Treatment of Mild HypertensionStudy), doxazosin evaluation 109–11TUMT (transurethral microwavethermotherapy)efficacy, vs sham control 29placebo/sham controlled trials 15–16, 29–32TUNEL assay 85TURP (transurethral resection of prostate) 1indications 4, 5–6vs conservative management 3WW, waiting list 3urethra, alpha-1 adrenoceptors 187urethral pressure, alfuzosin 120–1urinary flow rate Q maxand density of smooth muscle 91ESPIRIT study 148–9treatment indications 6urinary retention, acutealfuzosin 123MTOPS data 74, 75urinary tract symptoms see LUTSurodynamic studies, doxazosin 104–5urologists, treatment preferences 5uroselectivity 185–96clinical, defined 191pharmacologic 186–90physiologic 190–1, 192–3summary 190Urtica dioica (stinging nettle) 173Veterans’ Affairs (VA) Cooperative Study 3–4baseline and 3-year follow-up 3–4terazosin 86–7terazosin vs finasteride 60, 68–70vitamin E, beta-sitosterol, Serenoa repens andcernitin combination therapy 76watchful waiting (WW, patient monitoring) 1–9placebo/sham effect 21–4strategy 6–7treatment indications 6vs medical therapy 6–7vs placebo, comparison of outcomes 25WB-4101, binding affinities 190WHO, on placebo/sham control groups 16YM-617 see tamsulosin