BPH-RELATED VOIDING DYSFUNCTION (R LEE, SECTION EDITOR)

Future Pharmacotherapies for Male Lower UrinaryTract Symptoms

Roberto Soler & João F. Neves Neto & Claudius Füllhase &

Rogerio Simonetti

# Springer Science+Business Media New York 2014

Abstract Lower urinary tract symptoms (LUTS) in men are aprevalent condition with complex and multifactorial etiology.Different types of symptoms overlap among them and treat-ment has evolved to a more holistic and individualized ap-proach. Advances in the understanding of LUTS pathophys-iology has led to the development of new drugs and com-pounds to treat male LUTS. Recently, new drugs, such asphosphodiesterase type 5 inhibitors and beta3 adrenergic ag-onists, have been approved for the treatment of LUTS andhave just made it to clinical practice. New agents forintraprostatic injection, for instance PRX302 and NX-1207,are currently under evaluation in clinical trials with promisingresults. Rho-kinase inhibitors, transient receptor potentialchannel blockers and activators of soluble guanylyl cyclaseare examples of compounds targeting different pathways in-volved in the pathophysiology of male LUTS, which havebeen tested in experimental studies. New advances in phar-macotherapy may also allow combination of drugs to achievesynergistic effect.

Keywords Benign prostatic hyperplasia . BPH . Bladder .

Combined drug therapy . Lower urinary tract symptoms .

LUTS . Voiding dysfunction .Male . Pathophysiology .

Pharmacotherapy . Prostate

Introduction

Lower urinary tract symptoms (LUTS) [1] are an increasinglyprevalent condition with advancing age in men, which nega-tively impacts quality of life and can progress to significantcomplications [2]. Historically, LUTS in men was believed tooriginate solely from the prostate. Benign prostatic hyperpla-sia (BPH) and clinical BPHwere terms used to describe LUTSin men, still emphasizing the role of the prostate. Nonetheless,a variety of experimental, epidemiological, and clinical datahave shown that this equation is not that simple [3, 4]. There-fore, a terminology, focusing on symptoms rather than on aspecific organ was proposed. The term BPH should be re-served for histologically-proven typical patterns of the dis-ease. Benign prostatic enlargement (BPE) should be the ap-propriate term when an enlarged prostate is present. Bladderoutlet obstruction (BOO), a urodynamic diagnosis, is charac-terized by increased detrusor pressure and reduced urine flowrate in a pressure-flow study. The term benign prostatic ob-struction (BPO) should be used when the cause of BOO isBPE [1]. Finally LUTS were subdivided into storage, voidingand post-micturition LUTS in order to reflect the stage of themicturition cycle during which they occur.

Both men and women present voiding, storage and postmicturition symptoms, with considerable overlap amongthem. Data from a large epidemiological study (the EpiLUTS)in men and women aged ≥40 years showed that a combinationof the three groups of symptoms was present in 24 % of menand 26 % of women [5]. Using the 2002 ICS definitions, theEPIC study evaluated LUTS in 19,165 individuals ≥18 yearsin five countries. The most common type of LUTS inmen wasstorage (51.3 %), followed by voiding (25.7 %) and post

R. Soler (*) : J. F. N. Neto :R. SimonettiDivision of Urology, Federal University of São Paulo, Divisão deUrologia - R. Napoleão de Barros, 715, 2° andar, São Paulo, Brazile-mail: roberto_soler@hotmail.com

J. F. N. Netoe-mail: joaoneves62@gmail.com

R. Simonettie-mail: drsimonetti@ibest.com.br

C. FüllhaseDepartment of Urology, Klinikum Grosshadern,Ludwig-Maximilians-University, 15, 81377 Munich, Germanye-mail: c.fuellhase@web.de

Curr Bladder Dysfunct RepDOI 10.1007/s11884-014-0231-1

micturition (16.9 %). Where nocturia was present at severityof two or more micturitions per night, i.e., excluding peoplereporting only a single nocturia episode nightly on average,storage symptoms were still the most prevalent, accountingfor 26.9 %. The prevalence of overactive bladder (OAB) inmen and women was 10.8 % and 12.8 %, respectively [6].

These observations show that a particular type of LUTS isnot sex or organ-specific. Voiding symptoms do not alwayspredict the underlying vesico-urethral pathology and storagesymptoms may be accompanied or not by BOO [7]. There-fore, LUTS in men should be approached in a more holisticrather than organ-centered way. From the 1980s, when pros-tatic surgery was the mainstay, until the present time, whenpharmacological treatment represents the primary therapy, theway of treating men with LUTS has definitely changed;however, this significant shift was not followed by consider-able innovations regarding the available drug classes [8, 9].

To the well-established mechanisms involved in maleLUTS, new information has been increasingly added anddifferent pathophysiological processes have been implicatedin the development of such a complex multifactorial condition[4, 10]. Among them, some may represent opportunities forfuture pharmacotherapy development [11••]. The goal of thepresent review is to discuss recently introduced pharmacother-apies and also promising compounds in development for thetreatment of male LUTS.

Phosphodiesterase Type 5 Inhibitors

Originally used in urology for the treatment of erectile dys-function (ED), phosphodiesterase type 5 inhibitors (PDE5-I)coincidentally proved to be beneficial also to men with LUTS.Taking together the association between LUTS and erectiledysfunction (ED) [12], these drugs seemed a viable alternativefor men with both conditions. Several clinical trials followed,and currently tadalafil is approved for the treatment of maleLUTS [13]. The mechanism(s) of action of PDE-Is on LUTSis not completely understood, but may involve upregulation ofnitric oxide/cyclic GMP, modulation of autonomic nervoussystem overactivity, downregulation of Rho-kinase activity,reduction of inflammation, modulation of bladder and prostateafference and increase of pelvic blood perfusion [10].

A recent systematic review and meta-analysis includedstudies comparing PDE5-Is with placebo and studies on thecombination of PDE5-Is with α-blockers versus α-blockersalone. The use of PDE5-Is compared with placebo led tosignificant improvement of the International Index of ErectileFunction (IIEF) score (+5.5 points) and also of the IPSS (−2.8points). However, there was no effect on maximum urinaryflow (Qmax). The association of PDE5-Is withα-blockers, onthe other hand, besides improving subjective assessments,improved Qmax (+ 1.5 mL/s). The authors concluded that

PDE5-Is seem to be a promising treatment option for menwith LUTS/BPH with or without DE.

Following the first reports of the efficacy of PDE5-Is intreating LUTS/BPH, questions were raised concerning theindirect effects on the treatment response. Psychological ben-efits of improved erectile function might have influenced thesubjective response for LUTS, especially because most of thestudies did not show improvement in Qmax. A study wasdesigned to answer this query using integrated data from fourtadalafil randomized clinical trials (RCTs) and unidirectionaland bidirectional path analysis models to determine direct andindirect treatment effects. The analysis tested whether I-PSSimprovement with tadalafil was due to improvement in IIEF-erectile function domain score. A total of 77 % of the menenrolled in those trials had ED and LUTS and the rest, onlyLUTS. The authors concluded that self-reported ED did notinfluence tadalafil treatment response in men withLUTS/BPH. This result supports the direct treatment effectof tadalafil on LUTS/BPH [14].

Beta3 Adrenergic Agonists

Based on the relaxing effect of norepinephrine on the bladderthrough activation of β adrenergic receptors (ARs), a newclass of drugs for the treatment of overactive bladder symp-toms was developed. In vitro and in vivo studies have proventhat β3-ARs are the predominant subtype in the bladder, bothin concentration and in activity [15, 16]. The activation of β3-ARs relaxes the detrusor, improving bladder compliance andthus, increases bladder capacity, without changing micturitionpressure or post void residual (PVR) [17]. Different selectiveβ3-AR agonists have been tested preclinically and clinically.Solabegron has been evaluated in a phase II RCT, which onlyenrolled women with overactive bladder (OAB) [18].Ritobegron failed to reach primary efficacy end point in phaseIII RCT [19] and TRK-380 is under preclinical evaluation[20]. To date, mirabegron is the onlyβ3-AR agonist approvedfor OAB treatment [19].

Mirabegron was tested in several animal models of bladderdysfunction, leading to reduction of non-voiding activity,without interfering with the amplitude of voiding contraction.Furthermore, mirabegron seems to reduce bladder afferentactivity during filling [17, 21]. Thus, the selective β3-ARagonist acts on spontaneous contractile activity, which occursduring bladder filling, while the voiding contraction, whichdepends on parasympathetic output from the sacral spinalcord, is not affected. Urinary retention is, therefore, an unlike-ly adverse event [19].

Three large phase III RCTs were conducted to evaluate theefficacy and safety of mirabegron for the treatment of OAB.Both men and women were included. Mirabegron 50 mg (allthree studies), 100 mg (two studies), 25 mg (one study) and

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tolterodine ER 4 mg (active control arm in one study) werecompared with placebo. Mirabegron at doses of 50 and100 mg led to significant improvement in reducing the num-ber of incontinence episodes and number of micturitions per24 h at week 4 and 12. Moreover, level of urgency, nocturia,urgency and urgency incontinence episodes were also signif-icantly improved with both 50 and 100 mg mirabegron doses.Mirabegron was well tolerated, with a good safety profile. Themost common adverse events were hypertension,nasopharyngitis, and urinary tract infection. The incidence ofdry mouth with mirabegron was at placebo level and lowerthan with tolterodine [22•]. In a post-hoc analysis, mirabegron50 and 100 mg demonstrated similar efficacy in bothantimuscarinics-naïve OAB patients and in patients whodiscontinued prior antimuscarinic therapy (due to insufficientefficacy or poor tolerability). Tolterodine had an effect similarto placebo in patients who had discontinued antimuscarinicsdue to insufficient efficacy [23]. In a long-term clinical trial,mirabegron demonstrated sustained safety, tolerability, andefficacy over 12 months [24•].

A phase II safety RCT was conducted to evaluateurodynamic parameters in men with LUTS and BOO treatedwith mirabegron 50 or 100 mg daily versus placebo. Thisassessment is particularly interesting considering that pre-scribing antimuscarinics for men with storage and voidingLUTS still represents a matter of concern. A total of 200men 45 years or older, with a maximum urinary flow(Qmax) rate ≤12 mL/s, a IPSS score ≥8 and a bladder outletobstruction index ≥20 were randomized to receivemirabegron 50 mg or 100 mg, or placebo for 12 weeks.Urodynamics was performed at screening and at week 12.At treatment end, mean Qmax and detrusor pressure at Qmaxand the mean change in those parameters from baseline wereof similar magnitude among treatment groups. PVR volumewas statistically higher at treatment end only in themirabegron 100 mg group, which was not considered clini-cally meaningful. Likewise, bladder contractility index andbladder voiding efficiency were not affected by the treatment[25••]. These results support the safety of mirabegron inobstructed patients.

Anti-inflammatory Drugs

The role of inflammation in the pathophysiology of LUTS andBPH has been reported in experimental and clinical studies.Chronic inflammation is a common finding in pathologicalspecimens from BPE surgeries [26]. Moreover, inflammationwas correlated with prostate volume, overall clinical progres-sion and increased incidence of acute urinary retention (AUR)[27]. Higher levels of prostaglandins were associated withbladder hypertrophy and detrusor overactivity in rats [28]and in men with OAB [29]. This association led to studies

evaluating the effect of anti-inflammatory drugs onLUTS/BPH.

A recent systematic review andmeta-analysis assessed datafrom three RCTs, with follow-up of 4 to 24weeks. The studiesincluded comparisons of rofecoxib plus finasteride versusfinasteride alone, celecoxib versus placebo and tenoxicamplus doxazosin versus doxazosin alone. The anti-inflammatory drugs improved symptoms and urinary flow.The weighted mean difference for IPSS was – 2.89 pointsand for Qmax, 0.89 mL/s, both statistically significant. Theincidence of adverse events did not increase with the use of theanti-inflammatory drugs [30••]. The main concern regardingthese studies is the small sample of patients, so larger trials areneeded to achieve more robust conclusions. Even thoughadverse events were not a problem, there are general safetyconcerns regarding cycloxygenase 2 inhibitors. Nevertheless,it seems that the inflammatory cascade may provide interest-ing targets for LUTS treatment in the future.

Agents for Intraprostatic Injection

The injection of drugs into the prostate may be an alternativeto medical and surgical treatments for LUTS/BPH, especiallyin those patients with insufficient response to or who do nottolerate pharmacotherapies and who are poor candidates tosurgery. Those agents may act on both the dynamic and staticcomponents of BPO, through apoptosis and tissue necrosis,and on the urethral afferent neurotransmission, which maymodulate detrusor overactivity [31••]. Novel drugs underevaluation have renovated the interest on this therapeuticmodality; however, a higher level of evidence is needed toestablish them as a real option for the treatment ofLUTS/BPH.

NX-1207

NX-1207 is a protein with selective proapoptotic properties,which is currently under investigation in a multicentric phaseIII RCT. When injected into the transition zone of the prostateit causes cell loss and shrinkage of the prostate. This phenom-enon was first demonstrated in experimental studies with ratsand dogs. Two phase II RCTs showed improvement in theAmerican Urological Association Symptom Index (AUA-SI).In one of them 175 men were enrolled and the mean AUA-SIreduction was 11 points. The other was a non-inferiority studywith finasteride as an active open-label comparator. The in-jection of NX-1207 led to a mean improvement in AUA-SI of9.7 points vs 4.1 points for finasteride after 90 days. The non-inferiority was sustained through the 180 day endpoint.Despite the good initial results, data from phase III RCTs

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are needed to assess its feasibility in future clinicalpractice [32, 33].

PRX302

PRX302 is a proaerolysin (pore-forming protoxin) geneticallymodified, which is specifically activated by enzimaticallyactive PSA, present only in the prostate tissue. Following itsactivation, PRX 302 forms a stable transmembraneheptameric pore that leads to cell death. When injected intothe transition zone, it may lead to tissue ablation and relief ofobstruction [34••]. In phase IIb RCT, 61 men untreated with,non-responders to or intolerant of pharmacotherapy forLUTS/BPH were injected with PRX302 at a volume equiva-lent to 20 % of the prostate volume at a fixed concentration of3.0 μg/mL for a fixed dose of 0.6 μg/g prostate, while 31subjects (control group) were injected with the same volumeof vehicle (2 % human albumin). Patients were followed for12 months. In the PRX302 group, there was a mean reductionof 9 points in IPSS and a mean increase of 3 mL/s in Qmax,which were statistically significant compared with vehicle.Efficacy was sustained for 12 months. Adverse events asso-ciated with PRX302 were mild and transitory, including per-ineal discomfort/pain and irritative urinary symptoms, with nooccurrence of ED. The injection route used was transperineal,and a study is currently ongoing to assess the safety andefficacy of the transrectal administration of PRX302. Futurephase III studies are needed to confirm the efficacy, safety andfeasibility of repeated injections of PRX302 for the treatmentof LUTS/BPH [34••].

Botulinum Toxin

Botulinum toxin (BoNT) is produced by Clostridiumbotulinum, and comprises seven different subtypes. The mostused one in the urinary tract is the subtype A [31••]. Thisneurotoxin acts on cholinergic nerve endings by binding tosynaptic vesicle protein type 2 and preventing release ofacetylcholine in the neuromuscular junction [35]. The mech-anisms of action of BoNT in the prostate are not fully under-stood. Some studies demonstrated apoptosis of the stromaland glandular components of the prostate, down-regulation ofα1A-AR [4, 31••] and reduction of prostatic afferent signaling[31••, 36]. Following animal studies interest was raised in thepossible clinical application of BoNT for the treatment ofLUTS/BPH. The first small non-controlled studies demon-strated positive results [37, 38]. Other studies showed thebeneficial effects of intraprostatic BoNT injection in men withLUTS/BPH, but the limited number of subjects and lack of aplacebo group were consistently a drawback [36, 39]. In 2013,Marberger et al. reported the results of a phase II dose ranging

trial comparing 100, 200 and 300 U onabotulinumtoxinAwithplacebo. After 12 weeks there was significant improvement inIPSS, Qmax, PVR and transition zone prostatic volume in allgroups, including placebo. The only significant improvementover placebo was seen in patients receiving 200 U BoNTwhowere previously treated with α-blockers [40••]. In a recentsystematic review, it was concluded that the evidence is con-tradictory, and onabotulinumtoxinA should not be used rou-tinely in clinical practice. Further studies with high level ofevidence are required to draw more concrete conclusions[41•].

Ethanol

Ethanol is one of the most widely studied agents forintraprostatic injection. Upon injection, ethanol causes inflam-mation and coagulative necrosis with cavity formation. Fur-thermore, it may also destroy afferent nerves [31••]. Most ofthe studies with intra-prostatic ethanol injection have shownsignificant improvements in symptoms, PVR, Qmax, qualityof life reduction in prostate volume. One concern with ethanolis that controlling its distribution throughout the gland isdifficult. Also, there is risk of inadvertent bladder injectionleading to necrosis [42]. A proposed solution for this problemwas using anhydrous ethanol in gel form. Preliminary resultswith this compound showed significant improvements inQmax (mean change at 3 months: 3.51; and at 12 months:2.79 mL/s), IPSS (mean change at 3 months: − 11.12; and at12 months: − 9.36), and quality of life (mean change at3 months: − 1.95; and at 12 months: − 1.75). There were noextraprostatic adverse events [43]. Despite the good initialresults, however, further studies did not follow. A recentexperimental study proposed a new injection technique. Usinga microporous hollow fiber catheter to inject ethanol intocanine prostates the authors achieved greater tissue changesand improved distribution compared with injection with astandard needle. Backflow did not occur in either method,probably because of the use of an infusion pump [44]. In along-term non-controlled study, 56 patients with LUTS/BPHunderwent transurethral ethanol prostate ablation and werefollowed for 54 months. Patients had multiple comorbiditiesand were considered at high surgical risk. Response wasconsidered satisfactory in 73 % of the patients, while the other23 % required another type of treatment [45]. However, therewas a high rate of loss to follow-up, and data on sexualfunction and continence were not well described. Despitereports of efficacy in some patients, the description of casesof bladder necrosis may also have slowed down the enthusi-asm with this therapy [46]. Considering the lack of a highlevel of evidence, intraprostatic injection of ethanol for thetreatment of LUTS/BPH remains as experimental as it waswhen first described 15 years ago [47].

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Compounds Tested only in the Experimental Field

Based on specific pathophysiological mechanisms and attrac-tive effects, some compounds have been tested in experimen-tal settings. Clinical data for these drugs are not available, andsome (or all) of them may never make it to the clinical trials;nonetheless, their profiles are interesting and promising.

Rho-kinase Inhibitors

The RhoA/Rho kinase (ROK) is a Ca2+ independent pathwayof regulation of the smooth muscle tone. An abnormallyupregulated ROK pathway has been described in the prostateand bladder in experimental models of bladder dysfunctionand has been associated with pelvic ischemia and/or athero-sclerosis [48–50].

Fasudil, a specific Rho-kinase inhibitor, was given orally toobstructed male rats for 6 weeks. Treatment partly but signif-icantly reduced detrusor overactivity and decreased the ex-pression of RhoA protein in the detrusor muscle [51].Hydroxyfasudil, a nonselective Rho-kinase inhibitor, reducedmicturition frequency and increased single voided volume andintercontraction interval in male spontaneous hypertensiverats (SHR) compared with non-treated ones [52].Hydroxyfasudil also had beneficial effects on bladder dys-function induced by cyclophosphamide in rats, significantlyincreasing voided volume and decreasing maximum detrusorpressure [53].

Transient Receptor Potential Channel Blockers

Transient receptor potential (TRP) channels are highlyexpressed in the bladder, especially in afferent nerves andurothelium. They are involved in the transmission of sensorysignals in physiological and pathological conditions [54].

In animal models of cystitis induced by capsaicin, aceticacid or lipopolysaccharide, GRC 6211, an orally activeTRPV1 antagonist, ameliorated bladder hyperactivity. Thesame dose did not alter bladder function in sham animals,but at a high dose the bladder contraction was suppressed [55].The TRPV4 antagonist HC-067047 had beneficial effects onvoiding function in a dose-dependent manner of mice withcyclophosphamide-induced cystitis. At a high dose the sameeffects were seen in sham animals, in a lower magnitude [56].Systemic co-administration of TRPV1 and TRPV4 antago-nists showed an interesting synergistic effect in reducinglipopolysaccharide-induced bladder hyperactivity. This effectwas achieved at very low doses of both drugs, which had noeffect when applied isolated. This finding might be relevant toovercome eventual adverse events related with the use ofsome of these antagonists [57].

Activators of soluble guanylyl cyclase

In the human prostate the presence and activity of enzymes ofthe nitric oxide/cyclic guanosine monophospahate (NO/cGMP)pathway has been documented. In the bladder, NO synthase-containing nerves are present. NO has an inhibitory effect onion channels in afferent nerves and on afferent nerve activity[10]. Conditions of low bioavailability of NO can lead tobladder/urethra dysfunction [58]. NO is an important neuro-transmitter and mediator in the LUT, involved in urethral re-laxation during voiding and possibly in bladder relaxationduring filling, though the latter is still debated. NO stimulatessoluble guanylyl cyclase (sGC), leading to an increase incGMP, which acts as its second messenger [15]. Treatmentfor two weeks with BAY 58–2667, an activator of sGC, nor-malized detrusor contractile responses in vitro, and normalizedmicturition and non-voiding contractions frequency comparedwith obese mice treated with vehicle. Treatment with BAY 58–2667 increased the concentration of cGMP in the bladder, whileit did not prevent local reactive oxygen species generation [59].

Combination of Drugs

Recently, combination of drugs for the treatment ofLUTS/BPH has been established as standard for a subtypeof men. This strategy had already been used in clinical prac-tice, but it was after the publication of pivotal studies, such asMTOPS and CombAT, that the combination of α-blockersand 5-ARI has become a standard therapy for men at risk ofBPH clinical progression [60, 61]. They combine the effect ofboth drugs, targeting different pathophysiological mecha-nisms, which may lead to better outcomes.

Following the same strategy, the combination of drugsmay be beneficial for men with mixed LUTS. For in-stance, using the efficacy of an α-blocker and anantimuscarinic to achieve synergistic effect is a suggestedtherapy for men with persistent storage LUTS despitetreatment with an α-blocker, or as an initial treatmentfor men with mixed LUTS with moderate to severe stor-age symptoms [62•, 63••]. Most of the studies on thiscombination are add-on studies, in which antimuscarinicswere added to baseline α-blocker therapy. In general, thecombination therapy was more efficacious in reducingstorage symptoms than the α-blocker alone [63••]. In-crease in PVR volume with antimuscarinics was not ho-mogeneously significant in all studies and when presentwas not considered clinically meaningful. Some studiesreported a higher frequency of AUR in patients treatedwith antimuscarinics add-on compared with placebo add-on, ranging from 1.9 % to 3 % versus 0 %. However, theincidence of AUR in the placebo group of other studieswas approximately 1.8 %. It is important to note that

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PVR >200 mL and Qmax <5 mL/s were exclusioncriteria in these studies [63••].

Recently, a fixed dose combination of solifenacin and anoral controlled absorption system (OCAS) formulation oftamsulosin (TOCAS) was evaluated as an initial therapy formenwith LUTS. A phase II RCTshowed that the combinationwas more efficacious in a subset of men with moderate tosevere storage symptoms (≥ 2 urgency episodes per 24 h(PPIUS grade 3 or 4) and ≥8 micturitions per 24 h). Thissubgroup had clear improvements in storage parameters withsolifenacin + TOCAS over TOCAS alone. Increases in PVRvolume were not considered to be clinically relevant and werenot accompanied by an increase in the incidence of AUR. Theincidence of AUR was low [64]. A phase III RCT followedincluding only men with voiding symptoms and moderate tosevere storage symptoms to evaluate the efficacy and safety ofthe combination solifenacin and TOCAS (6 mg+0.4 mg or9 mg+0.4 mg) in a single tablet. Both doses improved signif-icantly total IPSS and total urgency and frequency score(TUFS) (solifenacin 6 mg + TOCAS: −7.0 and −8.1, respec-tively) (solifenacin 9 mg + TOCAS: −6.5 and −7.6, respec-tively) compared with TOCAS alone (−6.2 and −6.7, respec-tively) and placebo (−5.4 and −4.4, respectively). Urinaryretention occurred in 0.3 % of the patients with TOCAS +solifenacin 6 mg and in 0.9 % with TOCAS + solifenacin9 mg. Small increases in PVR volume were observed with theuse of solifenacin 6 mg (3.8 mL) and solifenacin 9 mg(12.3 mL) and were considered clinically irrelevant [65•].

Use of combinations of drugs appears to be a current trend,which may allow a broader way of treating patients withLUTS/BPH [62•]. Future development and introduction ofnew drugs into clinical practice may open new possibilitiesfor combinations, which may fulfill different patients’ needsin a more individualized basis.

Conclusions

The treatment of LUTS/BPH has been evolving and differentalternatives have been added to the drug armamentarium.Some of these drugs, such as PDE5-Is (tadalafil) and β3agonists, mirabegron, have recently become available forclinical practice. Still under clinical evaluation in RCTs, somecompounds may represent interesting alternatives. Theintraprostatic agents PRX302 and NX-1207 have renewedthe interest in this kind of therapy and anti-inflammatory drugsmay provide evidence for new target pathways in the patho-physiology of LUTS/BPH. Based on the complexity of theetiology of LUTS new compounds have been proposed andevaluated in the experimental setting and may represent prom-ising alternatives for a more future individualized treatment ofmale LUTS.

Compliance with Ethics Guidelines

Conflict of Interest Claudius Füllhase, João Neves Neto and RogérioSimonetti declare they do not have a conflict of interest. Roberto Solerreports personal fees from Astellas, outside the submitted work.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Abrams P, Cardozo L, Fall M, et al. The standardisation of termi-nology of lower urinary tract function: report from theStandardisation Sub-committee of the International ContinenceSociety. Neurourol Urodyn. 2002;21:167–78.

2. Roehrborn CG. Male lower urinary tract symptoms (LUTS) andbenign prostatic hyperplasia (BPH). Med Clin N Am. 2011;95:87–100.

3. Chapple CR, Roehrborn CG. A shifted paradigm for the furtherunderstanding, evaluation, and treatment of lower urinary tractsymptoms in men: focus on the bladder. Eur Urol. 2006;49:651–8.

4. Roosen A, Chapple CR, Dmochowski RR, et al. A refocus on thebladder as the originator of storage lower urinary tract symptoms: asystematic review of the latest literature. Eur Urol. 2009;56:810–9.

5. Sexton CC, Coyne KS, Kopp ZS, et al. The overlap of storage,voiding and postmicturition symptoms and implications for treat-ment seeking in the USA, UK and Sweden: EpiLUTS. BJU Int.2009;103 Suppl 3:12–23.

6. Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey ofurinary incontinence, overactive bladder, and other lower urinarytract symptoms in five countries: results of the EPIC study. EurUrol. 2006;50:1306–14. discussion 14–5.

7. Abdel-Aziz KF, Lemack GE. Overactive bladder in the male pa-tient: bladder, outlet, or both? Curr Urol Rep. 2002;3:445–51.

8. Wei JT, Calhoun E, Jacobsen SJ. Urologic diseases in americaproject: benign prostatic hyperplasia. J Urol. 2008;179:S75–80.

9. Andersson KE. LUTS treatment: future treatment options.Neurourol Urodyn. 2007;26:934–47.

10. Andersson KE, de Groat WC, McVary KT, et al. Tadalafil for thetreatment of lower urinary tract symptoms secondary to benignprostatic hyperplasia: pathophysiology and mechanism(s) of action.Neurourol Urodyn. 2011;30:292–301.

11.•• Soler R, Andersson KE, Chancellor MB, et al. Future direction inpharmacotherapy for non-neurogenic male lower urinary tractsymptoms. Eur Urol. 2013;64:610–21. This review comprehensive-ly discuss pathophysiological mechanisms involved in male LUTSand respective advances in pharmacotherapy.

12. Gacci M, Eardley I, Giuliano F, et al. Critical analysis of therelationship between sexual dysfunctions and lower urinary tractsymptoms due to benign prostatic hyperplasia. Eur Urol. 2011;60:809–25.

13. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or incombination with alpha-blockers for lower urinary tract symptomsdue to benign prostatic hyperplasia. Eur Urol. 2012;61:994–1003.

Curr Bladder Dysfunct Rep

14. Brock GB, McVary KT, Roehrborn CG, et al. Direct effects oftadalafil on lower urinary tract symptoms versus indirect effectsmediated through erectile dysfunction symptom improvement: in-tegrated data analyses from 4 placebo controlled clinical studies. JUrol. 2013;191:405–11.

15. Andersson KE, Arner A. Urinary bladder contraction and relaxa-tion: physiology and pathophysiology. Physiol Rev. 2004;84:935–86.

16. Takasu T, Ukai M, Sato S, et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide(YM178), a novel selective beta3-adrenoceptor agonist, on bladderfunction. J Pharmacol Exp Ther. 2007;321:642–7.

17. Andersson KE. New developments in the management of overac-tive bladder: focus on mirabegron and onabotulinumtoxinA. TherClin Risk Manag. 2013;9:161–70.

18. Ohlstein EH, von Keitz A, Michel MC. A multicenter, double-blind, randomized, placebo-controlled trial of the beta3-adrenoceptor agonist solabegron for overactive bladder. Eur Urol.2012;62(5):834–40.

19. Andersson KE, Martin N, Nitti V. Selective beta(3)-adrenoceptoragonists for the treatment of overactive bladder. J Urol. 2013;190:1173–80.

20. Kanie S, Otsuka A, Yoshikawa S, et al. TRK-380, a novel selectivehuman beta3-adrenoceptor agonist, ameliorates formalin-inducedpollakiuria in rats and carbachol-induced bladder contraction indogs. Urology. 2013;82:975 e7–e12.

21. Gras J. Mirabegron for the treatment of overactive bladder. DrugsToday (Barc). 2012;48:25–32.

22.• Nitti VW, Khullar V, van Kerrebroeck P, et al. Mirabegron for thetreatment of overactive bladder: a prespecified pooled efficacyanalysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract.2013;67:619–32. Pooled results of phase III clinical trials withmirabegron for the treatment of overactive bladder.

23. Khullar V, Cambronero J, Angulo JC, et al. Efficacy of mirabegronin patients with and without prior antimuscarinic therapy for over-active bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial. BMC Urol. 2013;13:45.

24.• Chapple CR, Kaplan SA, Mitcheson D, et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety andefficacy of mirabegron, a beta(3)-adrenoceptor agonist, in overac-tive bladder. Eur Urol. 2013;63:296–305. Long-term study showingsustained efficay and safety of mirabegron.

25.•• Nitti VW, Rosenberg S, Mitcheson DH, HeW, Fakhoury A, MartinNE. Urodynamics and safety of the beta3-adrenoceptor agonistmirabegron inmales with lower urinary tract symptoms and bladderoutlet obstruction. J Urol. 2013;190:1320–7. This is the first studyreporting the urodynamic safety of mirabegron in obstructed men.

26. Fibbi B, Penna G, Morelli A, Adorini L, Maggi M. Chronicinflammation in the pathogenesis of benign prostatic hyperplasia.Int J Androl. 2010;33:475–88.

27. Roehrborn CG. Definition of at-risk patients: baseline variables.BJU Int. 2006;97 Suppl 2:7–11. discussion 21–2.

28. Park JM, Yang T, Arend LJ, Smart AM, Schnermann JB, Briggs JP.Cyclooxygenase-2 is expressed in bladder during fetal developmentand stimulated by outlet obstruction. Am J Physiol. 1997;273:F538–44.

29. Kim JC, Park EY, Hong SH, Seo SI, Park YH, Hwang TK. Changesof urinary nerve growth factor and prostaglandins in male patientswith overactive bladder symptom. Int J Urol. 2005;12:875–80.

30.•• Kahokehr A, Vather R, Nixon A, Hill AG. Non-steroidal anti-inflammatory drugs for lower urinary tract symptoms in benignprostatic hyperplasia: systematic review and meta-analysis of ran-domized controlled trials. BJU Int. 2013;111:304–11. Systematicreview and meta-analysis showing the efficay of anti-inflammatorydrugs for the treatment of LUTS/BPH.

31.•• Andersson KE. Treatment of lower urinary tract symptoms: agentsfor intraprostatic injection. Scand J Urol. 2013;47:83–90. Reviewdiscussing results and controversies about injection ofintraprostatic agents for the treatment of BPH.

32. Shore N, Cowan B. The potential for NX-1207 in benign prostatichyperplasia: an update for clinicians. Ther Adv Chronic Dis.2011;2:377–83.

33. Fullhase C, Soler R, Gratzke C. New strategies in treating malelower urinary tract symptoms. Curr Opin Urol. 2014;24:29–35.

34.•• Elhilali MM, Pommerville P, Yocum RC, Merchant R, RoehrbornCG, Denmeade SR. Prospective, randomized, double-blind, vehiclecontrolled, multicenter phase IIb clinical trial of the pore formingprotein PRX302 for targeted treatment of symptomatic benignprostatic hyperplasia. J Urol. 2013;189:1421–6. Randomized con-trolled clinical trial showing the efficacy of intraprostatic injectionof PRX302.

35. Ikeda Y, Zabbarova IV, Birder LA, et al. Botulinum neurotoxinserotype A suppresses neurotransmitter release from afferent as wellas efferent nerves in the urinary bladder. Eur Urol. 2012;62:1157–64.

36. Oeconomou A, Madersbacher H. Botulinum neurotoxin A forbenign prostatic hyperplasia. Curr Opin Urol. 2010;20:28–36.

37. Chuang YC, Chiang PH, Yoshimura N, De Miguel F, ChancellorMB. Sustained beneficial effects of intraprostatic botulinum toxintype A on lower urinary tract symptoms and quality of life in menwith benign prostatic hyperplasia. BJU Int. 2006;98:1033–7. dis-cussion 337.

38. Chuang YC, Tu CH, Huang CC, et al. Intraprostatic injection ofbotulinum toxin type-A relieves bladder outlet obstruction in humanand induces prostate apoptosis in dogs. BMC Urol. 2006;6:12.

39. Crawford ED,Hirst K, Kusek JW, et al. Effects of 100 and 300 unitsof onabotulinum toxin A on lower urinary tract symptoms of benignprostatic hyperplasia: a phase II randomized clinical trial. J Urol.2011;186:965–70.

40.•• Marberger M, Chartier-Kastler E, Egerdie B, et al. A randomizeddouble-blind placebo-controlled phase 2 dose-ranging study ofonabotulinumtoxinA in men with benign prostatic hyperplasia.Eur Urol. 2013;63:496–503. Randomized controlled trial showingthat intraprostatic injection of onabotulinumtoxinA has similarefficacy than placebo for the treatment of BPH.

41.• Mangera A, Apostolidis A, Andersson KE, et al. An updatedsystematic review and statistical comparison of standardised meanoutcomes for the use of botulinum toxin in the management oflower urinary tract disorders. Eur Urol. 2013. doi:10.1016/j.eururo.2013.10.033. Comprehensive review about the use of botulinumtoxin for LUT diseases.

42. Chung A, Woo HH. What's truly minimally invasive in benignprostatic hyperplasia surgery? Curr Opin Urol. 2014;24:36–41.

43. Larson BT, Netto N, Huidobro C, et al. Intraprostatic injection ofalcohol gel for the treatment of benign prostatic hyperplasia: prelim-inary clinical results. ScientificWorldJournal. 2006;6:2474–80.

44. King BJ, Plante MK, Kida M, Mann-Gow TK, Odland R, Zvara P.Comparison of intraprostatic ethanol diffusion using a microporoushollow fiber catheter versus a standard needle. J Urol. 2012;187:1898–902.

45. El-Husseiny T, Buchholz N. Transurethral ethanol ablation of theprostate for symptomatic benign prostatic hyperplasia: long-termfollow-up. J Endourol. 2011;25:477–80.

46. Kaplan SA. Re: Transurethral ethanol ablation of the prostate forsymptomatic benign prostatic hyperplasia: long-term follow-up. JUrol. 2012;187:211–2.

47. Goya N, Ishikawa N, Ito F, et al. Ethanol injection therapy of theprostate for benign prostatic hyperplasia: preliminary report onapplication of a new technique. J Urol. 1999;162:383–6.

48. Christ GJ, Andersson KE. Rho-kinase and effects of Rho-kinaseinhibition on the lower urinary tract. Neurourol Urodyn. 2007;26:948–54.

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49. Bing W, Chang S, Hypolite JA, et al. Obstruction-induced changesin urinary bladder smooth muscle contractility: a role for Rhokinase. Am J Physiol Ren Physiol. 2003;285:F990–7.

50. Kohler TS, McVary KT. The relationship between erectile dysfunc-tion and lower urinary tract symptoms and the role of phosphodi-esterase type 5 inhibitors. Eur Urol. 2009;55:38–48.

51. Kim JY, Han JY, Kwon TG, Choo MS. Effects of oral Rho kinaseinhibitor fasudil on detrusor overactivity after bladder outlet ob-struction in rats. LUTS. 2013;5:96–100.

52. Inoue S, Saito M, Takenaka A. Hydroxyfasudil ameliorates bladderdysfunction in male spontaneously hypertensive rats. Urology.2012;79:1186 e9–14.

53. Masago T, Watanabe T, Saito M, Kinoshita Y, Sato K, Miyagawa I.Effect of the rho-kinase inhibitor hydroxyfasudil on bladder over-activity: an experimental rat model. Int J Urol. 2009;16:842–7.

54. Avelino A, Charrua A, Frias B, et al. Transient receptor potentialchannels in bladder function. Acta Physiol (Oxf). 2013;207:110–22.

55. Charrua A, Cruz CD, Narayanan S, et al. GRC-6211, a new oralspecific TRPV1 antagonist, decreases bladder overactivity andnoxious bladder input in cystitis animal models. J Urol. 2009;181:379–86.

56. Everaerts W, Zhen X, Ghosh D, et al. Inhibition of the cationchannel TRPV4 improves bladder function in mice and rats withcyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A.2010;107:19084–9.

57. Charrua A, Cruz CD, Cruz F. TRPV1 and TRPV4 antagonists havesynergistic effect for treating bladder overactivity in rats. Eur UrolSuppl. 2012;11:e365.

58. Soler R, Fullhase C, Lu B, Bishop CE, Andersson KE. Bladderdysfunction in a new mutant mouse model with increased superox-ide–lack of nitric oxide? J Urol. 2010;183:780–5.

59. Leiria LO, Silva FH, Davel AP, et al. The soluble guanylyl cyclaseactivator BAY 60–2770 ameliorates overactive bladder in obesemice. J Urol. 2013;191:539–47.

60. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-termeffect of doxazosin, finasteride, and combination therapy on theclinical progression of benign prostatic hyperplasia. N Engl J Med.2003;349:2387–98.

61. Roehrborn CG, Siami P, Barkin J, et al. The effects of combinationtherapy with dutasteride and tamsulosin on clinical outcomes inmen with symptomatic benign prostatic hyperplasia: 4-year resultsfrom the CombAT study. Eur Urol. 2010;57:123–31.

62.• Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on thetreatment and follow-up of non-neurogenic male lower urinary tractsymptoms including benign prostatic obstruction. Eur Urol. 2013;64:118–40. Excellent current guideline on the treatment of male LUTS.

63.•• Fullhase C, Chapple C, Cornu JN, et al. Systematic review ofcombination drug therapy for non-neurogenic male lower urinarytract symptoms. Eur Urol. 2013;64:228–43. Excellent systematicreview on combination drug therapy for the treatment of maleLUTS, discussing objective and subjective efficacy and safety.

64. Van Kerrebroeck P, Haab F, Angulo JC, et al. Efficacy and safety ofsolifenacin plus tamsulosin OCAS in men with voiding and storagelower urinary tract symptoms: results from a phase 2, dose-findingstudy (SATURN). Eur Urol. 2013;64:398–407.

65.• van Kerrebroeck P, Chapple C, Drogendijk T, et al. Combinationtherapy with solifenacin and tamsulosin oral controlled absorptionsystem in a single tablet for lower urinary tract symptoms in men:efficacy and safety results from the randomised controlledNEPTUNE trial. Eur Urol. 2013. doi:10.1016/j.eururo.2013.07.034. Clinical trial showing that the fixed dose combination ofsolifenacin and tamsulosin OCAS is beneficial for patients withmixed LUTS and moderate to severe storage symptoms.

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