Platinum Priority Review Voiding Dysfunction

Editorial by Jean-Nicolas Cornu on pp. 622623 of this issue

Future Direction in Pharmacotherapy for Non-neurogenic Male
Lower Urinary Tract Symptoms
Roberto Soler
a
, Karl-Erik Andersson
b
, Michael B. Chancellor
c
, Christopher R. Chapple
d
,
William C. de Groat
e
, Marcus J. Drake
f
, Christian Gratzke
g
, Richard Lee
h
, Francisco Cruz
i,
*
a
Division of Urology, Federal University of Sao Paulo and Hospital Israelita Albert Einstein, Sao Paulo, Brazil;
b
Institute of Regenerative Medicine, Wake
Forest University School of Medicine and Department of Urology, Wake Forest Baptist Medical Center, Winston Salem, NC, USA;
c
Oakland University William
Beaumont School of Medicine, Royal Oak, MI, USA;
d
Department of Urology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust,
Sheffield, UK;
e
Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA, USA;
f
Bristol Urological Institute
and School of Clinical Sciences, University of Bristol, Bristol, UK;
g
Department of Urology, LMU Munich, Campus Grosshadern, Munich, Germany;
h
James
Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College, New York, NY, USA;
i
Department of Urology, Hospital de S. Joao,
University of Porto, Porto, Portugal
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1
avai l abl e at www. sci encedi r ect . com
j our nal homepage: www. eur opeanur ol ogy. com
Article info
Article history:
Accepted April 29, 2013
Published online ahead of
print on May 7, 2013
Keywords:
Benign prostatic hyperplasia
Bladder
Lower urinary tract symptoms
Male
Pathophysiology
Pharmacotherapy
Prostate
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Abstract
Background: The pathophysiology of male lower urinary tract symptoms (LUTS) is
highly complex and multifactorial. The shift in perception that LUTS are not sex or organ
specific has not been followed by significant innovations regarding the available drug
classes.
Objective: To review pathophysiologic mechanisms and clinical and experimental data
related to the development of new pharmacologic treatments for male LUTS.
Evidence acquisition: The PubMed database was used to identify articles describing
experimental and clinical studies of pathophysiologic mechanisms contributing to male
LUTS and, supported by them, new pharmacotherapies with clinical or experimental
evidence in the eld.
Evidence synthesis: Several pathologic processes (eg, androgen signaling, inammation,
and metabolic factors) and targets (eg, the urothelium, prostate, interstitial cells,
detrusor, neurotransmitters, neuromodulators, and receptors) have been implicated
in male LUTS. Some newly introduced drugs, such as phosphodiesterase type 5 inhibitors
and b3-adrenergic agonists, have just started broad use in clinical practice. Drugs with
potential benet, such as vitamin D3 receptor analogs, gonadotropin-releasing hormone
antagonists, cannabinoids, and drugs injected into the prostate, have been evaluated in
experimental studies and have progressed to clinical trials. However, safety and efcacy
data for these drugs are still scarce. Some compounds with interesting proles have only
been tested in experimental settings (eg, transient receptor potential channel blockers,
Rho-kinase inhibitors, purinergic receptor blockers, and endothelin-converting enzyme
inhibitors).
Conclusions: Newpathophysiologic mechanisms of male LUTS are described that lead to
the continuous development of new pharmacotherapies. To date, few drugs have been
added to the current armamentarium, and several are in various phases of clinical or
experimental investigation.
#2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Hospital de S. Joao, University of Porto, Porto,
Portugal, Alameda Prof. Hernani, 4200-319, Porto, Portugal. Tel. +35 1 91 3231123;
Fax: +35 1 22 5513655.
E-mail address: cruzfjmr@med.up.pt (F. Cruz).
0302-2838/$ see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2013.04.042
1. Introduction
Lower urinary tract symptoms (LUTS) can be subdivided
into storage (overactive bladder [OAB]), voiding, and
postmicturition subtypes, with OAB symptoms generally
the most bothersome [1]. LUTS in men are not disease
specific. Benign prostatic hyperplasia (BPH) as a histologic
diagnosis and clinical BPH are terms best avoided when
describing LUTS in men, due to a bias toward a potential role
of the prostate versus other likely contributory mecha-
nisms. Avariety of experimental, epidemiologic, and clinical
data have shown that LUTS, particularly the storage
component (OAB), are multifactorial in origin [2,3].
BPHis extremely prevalent in the aging male population,
increasing from 42% in men 5059 yr of age to 88% in men
>80 yr [4]. Approximately 50% of men with histologic BPH
develop benign prostatic enlargement (BPE), but only
2550% of men with histologic BPH have LUTS [2,5,6].
Clearly the inverse is also true: The presence of LUTS in men
does not conclusively signify a diagnosis of benign prostatic
obstruction (BPO) or bladder outlet obstruction (BOO). In
series of male patients presenting with LUTS, only 50% were
found to have urodynamically proven BOO [79]. LUTS
suggestive of BOO may actually be due to an underactive
detrusor, regardless of whether BOOis present [10]. Overall,
the direct correlation of BPH, BPE, BOO, and LUTS is poor.
The storage symptom complex (OAB) is defined as
urgency, with or without urge incontinence, usually with
frequency and nocturia [1]. This symptom syndrome was
previously considered to be a female disorder [11].
However, using the 2002 International Incontinence Society
definitions, the Extended Prostate Cancer Index Composite
study evaluated LUTS in 19 165 individuals 18 yr of age in
five countries and reported a similar prevalence of OAB in
men and women10.8% and 12.8%, respectively [12].
To date, the first-line medical therapy for men with LUTS
is a
1
-adrenergic receptor antagonists (a-blockers) and 5a-
reductase inhibitors (5-ARIs) [5,13]. Despite the high
prevalence of OAB symptoms in men, antimuscarinics are
not commonly used. Clinical trials have been conducted to
assess the efficacy of combination therapy with existing
drugs: a-blocker plus 5-ARI, a-blocker plus antimuscarinics,
and 5-ARI plus antimuscarinics [1416]. In addition, new
information on different pathophysiologic processes related
to LUTS has been reported [3,17]. The present paper
considers pathophysiologic mechanisms and possible
targets for drug therapy, and it reviews the clinical and
experimental data related to the development of these new
treatments for male LUTS.
2. Evidence acquisition
Aliterature search was performed via the PubMed database.
Articles describing experimental or clinical data on
pathophysiologic mechanisms of male LUTS were selected.
Based on the targets and mechanisms included in the first
section, articles about new pharmacotherapies for male
LUTS were chosen. For this section, newly introduced drugs,
drugs in the phase of clinical trials, and drugs in the phase of
experimental investigation were included. Only studies
published in English were included. Nocturia was not
included in the search. A recent review covered this topic
comprehensively [18].
3. Evidence synthesis
3.1. Pathophysiologic mechanisms and targets for future
therapies (Fig. 1)
3.1.1. Androgen and estrogen receptor signaling in prostatic tissue
remodeling
Androgens play a key role in the growth and development of
the prostate as well as in the pathogenesis of BPH. Subjects
castrated before puberty do not develop BPH [19].
Testosterone is converted to dihydrotestosterone (DHT)
by 5a-reductases (5-ARs) predominantly in the stromal
tissue. DHT is more potent than testosterone and also has a
higher affinity for the androgen receptor (AR), allowing it to
accumulate in the prostate even when circulating testos-
terone levels are low. Intracellular ARs are activated by
androgen binding and/or through interactions with growth
factor (GF) signaling and protein kinase A pathways [20].
Androgen deprivation, either surgically or chemically with
finasteride, a 5-AR type1 inhibitor, or dutasteride, a 5-AR
type1 and 2 inhibitor, reduce both circulating and
intraprostatic DHT, and prostate volume by 20% [21,22].
Conversely, a few recent studies have pointed out the
effect of low androgen levels on urinary functions. Late-
onset hypogonadism has been associated not only with
erectile dysfunction but also with LUTS. A definitive
pathophysiologic explanation is not clear, but the basis
for this association relies on the distribution of ARs
throughout the LUTS, the impact of androgens on the
autonomic nervous system, nitric oxide synthase, phos-
phodiesterase type 5 (PDE5), RhoA/Rho kinase (ROK)
activity, and pelvic blood flow [23]. In a cohort of
community-dwelling older men, the ones with higher
midlife levels of testosterone to DHT and bioavailable
testosterone had a decreased 20-yr risk of LUTS [24]. Male
hypogonadismhas recently been associated with metabolic
syndrome, probably via increased aromatase activity,
hypogonadotropic hypogonadism, and increased activity
of the hypothalamicpituitaryadrenal axis [25].
Estrogen and estrogen-mimicking compounds may also
have a role in prostate biology because estrogen receptor
(ER)-a is associated with proliferation and ER-b is
associated with regulation of proliferation and induction
of apoptosis [26]. In the aging man, there is a progressive
decrease in the ratio of circulating levels of androgens to
estrogens. This is believed to contribute to BPH develop-
ment through a mitogenic effect on ER-a. Aromatase, which
converts androgen precursors to aromatic estrogens, has
been identified in the prostatic stroma [21].
3.1.2. Urothelium
The urothelium represents more than a barrier in the
bladder. Urothelial cells express nociceptors and mechan-
oreceptors and when stimulated release several substances
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1 611
such as adenosine triphosphate (ATP), nitric oxide (NO),
acetylcholine (ACh), cytokines, prostanoids, and nerve
growth factor (NGF), among others. During the storage
phase in patients with detrusor overactivity (DO), possible
release of ACh from the urothelium may initiate spontane-
ous localized contractile activity of the detrusor and trigger
afferent noise [27].
ATP acts on purinergic receptors: P2X (ligand-gated
cation channel) and P2Y (G protein-coupled). Several
purinergic receptors are expressed in the urothelium: All
seven P2X receptors subunits (17) and P2Y subunits 1, 2,
and 4. P2X
3
receptors were detected on pelvic afferent
nerves, dorsal root ganglia, bladder wall, and in a
suburothelial plexus of afferent nerves [2831].
3.1.3. Interstitial cells
Interstitial cells (ICs) occur in the lamina propria and within
and adjacent to smooth muscle bundles. ICs in the lamina
propria respond to ATP by firing Ca
2+
transients, suggesting
the existence of a sensory transduction signaling system. In
the detrusor, ICs respond to cholinergic agonists, preferen-
tially mediated by M3 receptors [32]. ICs may directly
generate detrusor contractile activity during filling and be
involved in ACh-mediated voiding contractions [32,33]. In a
rat model of partial BOO, there was an increase of ICs in the
suburothelial and muscle layers expressing endothelial
nitric oxide synthase and neuronal nitric oxide synthase
[34]. Imatinib mesylate, a selective inhibitor of c-kit
receptor tyrosine kinase, inhibited evoked smooth muscle
contraction and spontaneous activity in human OAB but not
in normal detrusor. Systemic administration of imatinib
mesylate improved bladder capacity, compliance, voided
volume, and urinary frequency, and it reduced contraction
thresholds and spontaneous activity during guinea pig
cystometry [35].
3.1.4. Detrusor and prostatic smooth muscle
Bladder hypertrophy is a consistent response following
obstruction in animal models and men [3638]. Alterations
in the smooth muscle structure, in the extracellular matrix,
and in the neuronal control and blood flow/ischemia have
been associated with the pathophysiology of LUTS [39].
Contractile proteins, such as desmin, actin, and myosin,
were shown to be altered in rats with partial urethral
obstruction (PUO) and in men with BOO [39]. An increase in
collagen deposition was observed in rats with PUO.

Fig. 1 Pathophysiologic mechanisms and targets for pharmacotherapy for male lower urinary tract symptoms. Ach = acetylcholine; ANS = autonomic
nervous system; ATP = adenosine triphosphate; CB-R = cannabinoid receptors; M3-R = M3 muscarinic receptor; NGF = nerve growth factor; NO = nitric
oxide; P-R = purinergic receptors; TRP = transient receptor potential (channels); a
1
a-AR = a
1
A-adrenoreceptor; a
1
D-AR = a
1
D-adrenoreceptor; b3-AR =
b3-adrenoreceptor.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1 612
Increased levels of basic fibroblast growth factor, epidermal
growth factor (EGF), heparin-binding EGF-like growth
factor, insuline-like growth factor 1, NGF, and connective
tissue growth factor were demonstrated [39,40]. Growth
and phenotypic differentiation of sensory afferents and
sympathetic efferents in hypertrophied bladders has been
attributed to NGF, which may also influence spinal
micturition pathways, modulating voiding reflexes, and
pain sensation in pathologic conditions [41]. Ischemia may
also play a role in bladder hypertrophy. BOO models are
associated with a decrease in bladder blood flow [42], and
prevention of ischemia decreases bladder hypertrophy and
improves detrusor contractility [43].
An abnormally upregulated ROK pathway may alter
muscle relaxation in the prostate, urethra, and bladder neck
in male LUTS. RhoA/ROK inhibits myosin light chain
phosphatase and increases the Ca
2+
sensitivity of smooth
muscle contraction [44]. RhoA expression was intense in
prostatic smooth muscle cells of spontaneously hyperten-
sive rats [44]. In rats with PUO, bladder hypertrophy was
accompanied by higher expression of RhoA and ROK, lower
myosin phosphatase activity, and enhanced relaxant effects
of Y27632, a ROK inhibitor [45]. Pelvic ischemia and/or
atherosclerosis have also been associated with upregulation
of the ROK pathway [46].
3.1.5. Neurotransmitters, neuromodulators, receptors, and neural
pathways
3.1.5.1. Norepinephrine and adrenergic receptors. Prostatic stromal
cells express a
1
receptors, more specifically a
1
A, which
provide the prostatic muscle tone. This concept led to the
development of a-blockers for the treatment of LUTS
associated with BPO. However, the mechanism of action of
these drugs has recently been questioned, given their small
effect on urodynamically proven BOO and the poor correla-
tion after treatment between the improvement of LUTS and
obstruction. There is discussionabout the effect of a-blockers
on extraprostatic a-ARs, such as those in the bladder and
spinal cord, andonother ARsubtypes, especiallya
1
D-AR[47].
There is experimental evidence that BOO, although not
changing the relative expressionof a
1
-AR subtypes [48], may
enhance the response of a
1
A-AR to adrenergic agonists [49].
Naftopidil, an a
1
D/a
1
A-AR selective antagonist (rather a
1
D-
AR selective), increased the volume at first desire to void and
the volume at maximumdesire to void while decreasing DO,
whichmight implyaroleat least inpartinsensoryafferent
nerve activity [50].
In the bladder, b-ARs predominate over a-ARs, and the
response of the normal detrusor to norepinephrine is
relaxation. In human bladder smooth muscle, b3-ARs are
the predominant subtype, both in concentration and in
physiologic importance. b3-AR agonists have relaxant
effects in vitro and in animal models of DO [51,52].
b3-ARs are also expressed in the rat sacral spinal cord.
PUO upregulates these adrenoceptors; intrathecal injection
of a b3-AR agonist improved bladder function in obstructed
animals with no effect on sham-operated animals, indicat-
ing that b3-AR containing central nervous pathways may be
relevant [53].
3.1.5.2. Acetylcholine and muscarinic receptors. The detrusor
muscle contains muscarinic receptors (MRs), mainly M2
and M3. M3 receptors are mainly responsible for normal
micturition contractions, which depend on Ca
2+
mobiliza-
tion through the activation of the PLC-IP3 pathway, Ca
2+
entry through nifedipine-sensitive channels, and activation
of the ROK pathway [27,51]. The antimuscarinics are
generally assumed to deliver their beneficial effects by
blocking MRs on the detrusor muscle. However, increasing
evidence now indicates that additional effects involve M3
within the urothelium/suburothelium including bladder
afferent nerves [54]. Because antimuscarinics in clinical
doses have comparatively modest effects on voiding
contractions, their clinical efficacy may reflect influences
on the abnormal leak of ACh, from nerve endings or non-
neuronal sources during the storage phase that may cause
focal myogenic activity or urothelium-sensory fiber stimu-
lation [27].
3.1.5.3. Transient receptor potential channel superfamily. Members
of the transient receptor potential (TRP) family channels
may respond to stretch and/or chemical irritation, and they
participate in urothelialafferent interactions that underlie
sensory perception and overall bladder function. Several
members of this receptor family have been implicated in
LUTS pathophysiology [55]. In a subgroup of patients with
idiopathic DO responding to intravesical resiniferatoxin
treatment, bladder TRPV1 messenger RNA (mRNA) expres-
sion was higher than in nonresponders and controls [56]. In
addition, patients with increased filling sensation exhibited
upregulation of TRPV1 mRNA in the trigonal mucosa, which
was inversely correlated with the bladder volume at first
sensation during filling cystometry [57]. Urothelial TRPV1
and TRPV4 activation increases ATP release, which may
contribute to DO and OAB pathophysiology [58].
3.1.5.4. Cannabinoids and cannabinoid receptors. The interest in
the modulatory effect of cannabinoid (CB) receptor agonists
on voiding function started with the report of improvement
of LUTS in patients with multiple sclerosis (MS) using
smoked cannabis [59]. CBs act on at least two types of
receptors: CB1 and CB2 expressed in several structures of
the bladder including urothelium and sensory fibers
[60,61]. Sensitization of bladder afferents by inflammation
can be partly suppressed by activation of CB receptors, an
effect that appears to be mediated by CB1 [62]. Fatty acid
amide hydrolase (FAAH), the key enzyme for the degrada-
tion of the endogenous cannabinoid agonist anandamide, is
expressed in human, mouse, and rat bladder mucosa. FAAH
increases anandamide in the bladder tissues and activates
CB2 expressed in the urotheliumand bladder afferents [63].
In addition to modulating afferent signaling, CB2 receptors
also seem to influence cholinergic nerve activity [60].
3.1.5.5. Adenosine triphosphate and purinergic receptors. Although
negligible in normal human detrusor neuromuscular
excitation, ATP participation in detrusor contraction is
prominent in other species and in pathologic conditions in
humans, particularly with DO. In vitro bladder preparations
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1 613
from patients with OAB and BOO showed a greater
contractile response to ATP compared with specimens from
normal bladders. In addition, ecto-adenosine triphospha-
tase activity was lower in overactive bladders, which may
lead to greater access to ATP and enhanced contractile
activity, contributing to DO[64]. In another study, P2X
1
was
the main purinoceptor in male human bladder, and its
mRNA expression was higher in BOO [65]. In an in vitro
study with porcine detrusor strips, detrusor motor drive
was enhanced by excitatory muscular P2X
1
and by neural
P2X
3
subunits, facilitating the release of ACh. The experi-
mentally induced downregulation of purine breakdown
produced smooth muscle hyperactivity that was reduced by
the P2X
1,3
blockade [66].
3.1.5.6. Nitric oxide/cyclic guanosine monophosphate activity. NO
acts as a nonadrenergic, noncholinergic inhibitory factor
responsible for urethral relaxation during voiding and
possibly for bladder relaxation during the filling phase [51].
NO has an inhibitory effect on afferent nerve activity [17].
Expression of all the key enzymes of the NO/cyclic
guanosine monophosphate (cGMP) signal has been dem-
onstrated in the human prostate. The PDE5 isoenzymes are
highly expressed in the bladder, prostate, and their
supporting vasculature [67]. In the bladder, NOS-containing
nerves are present. Furthermore, the NO/cGMP pathway
can modulate smooth muscle cell proliferation, through
protein kinase C inhibition [68].
3.1.6. Inflammation
The observation of chronic inflammation coexisting with
BPH histologic changes in pathologic specimens led to the
suspicionthat inflammation plays a role in the development
of prostate enlargement and LUTS/BPH [69]. In a retrospec-
tive analysis of 1700 BPH patients, chronic inflammation
and prostate volume were correlated [70]. Prostatic
inflammation was associated with overall clinical progres-
sion and increased incidence of acute urinary retention
(AUR) [71]. A positive association between high plasma
C-reactive protein levels and the odds of reporting
moderate to severe LUTS (American Urological Association
Symptom Index [AUA-SI] 8) was reported [72].
Local inflammation may be triggered by a viral or
bacterial infection, which would lead to the secretion of
cytokines, chemokines, and growth factors involved in the
inflammatory response with consequent growth of epithe-
lial and stromal prostatic cells. It has been hypothesized
that the inflammatory response is perpetuated by the
release of prostatic self-antigens following tissue damage,
which would sensitize the immune system and start
autoimmune responses. Important factors in this process
are the prostatic stromal cells, which activate CD4
+
lymphocytes and proinflammatory cytokines and chemo-
kines, such as stromal-derived interleukin-8 [73].
Prostanoids (prostaglandins [PGs] and thromboxanes)
are synthesized by cyclo-oxygenases (COX-1 and -2)
in the bladder after different physiologic stimuli, injuries,
and nerve stimulation, and by agents such as ATP and
mediators of inflammation. In rats, intravesical instillation
of prostaglandin E 2 (PGE2) was shown to cause DO[74,75].
BOO in rats was associated with a higher expression of
COX-2, suggesting that PGs may be involved in the
development of bladder hypertrophy and DO [76,77].
Higher levels of PGE2 and of PGE2 and prostaglandin F2a
(PGF2a) were found in the urine of men and women with
OAB, respectively [78,79]. PGs have been shown to
sensitize bladder afferent nerves via different prostanoid
receptors [32].
3.1.7. Metabolic factors
Body weight, body mass index (BMI), and waist circumfer-
ence have all been positively associated with prostate
volume in multiple study populations [80]. In the Baltimore
Longitudinal Study of Aging cohort, each 1 kg/m
2
increase in
BMI corresponded to a 0.41-ml increase in prostate volume.
Obese (BMI 35 kg/m
2
) participants had a 3.5-fold increased
risk of prostate enlargement compared with nonobese (BMI
<25 kg/m
2
) participants [81]. Most establishedaspects of the
metabolic syndrome are linked to BPH. The presence of
metabolic syndrome is associated with a higher annual BPH
growth rate, increased sympathetic activity, and LUTS [25].
Diabetes, increased serum insulin, and elevated fasting
plasma glucose have beenassociatedwithincreasedprostate
sizeandincreasedrisks of prostateenlargement, clinical BPH,
BPH surgery, and LUTS. The underlying pathophysiologic
mechanisms involved in the association of metabolic factors
and LUTS/PBH are not completely understood, but systemic
inflammation, pelvic ischemia, and increased sympathetic
activity may play a role [8082].
3.2. New advances in pharmacotherapy (according to the
identified targets) (Table 1)
3.2.1. Hormonal
The use of antiandrogens or gonadotropin-releasing hor-
mone (GnRH) agonists, widely used for the treatment of
prostate cancer, is not warranted for the treatment of male
LUTS due to the unacceptable side effects of medical
castration. However, GnRH antagonists may lead to an
intermediate level of testosterone suppression, achieving
therapeutic benefits while avoiding the adverse events
(AEs) associated with medical castration [83]. The luteiniz-
ing hormone-releasing hormone antagonist cetrorelix,
given intramuscularly, caused a 4-point improvement in
the International Prostate SymptomScore (IPSS) in excess of
the changes observed in the placebo group in a phase 2
randomized controlled trial (RCT) [84]. However, those
results were not confirmed in phase 3 clinical trials [85].
Because male hypogonadism is also associated with
LUTS, the effect of androgen-replacement therapy (ART)
was tested in men with both conditions. In a small RCT, the
use of ART led to improvements in IPSS, maximumflowrate
(Q
max
), and voided volume compared with untreated
controls [86].
3.2.2. Antimuscarinics
Antimuscarinics are often neglected in men with only
storage symptoms before some kind of prostate-driven
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1 614
treatment because many urologists believe that male LUTS
are always secondary to the prostate. There is also the
common perception that these drugs may impair the
detrusor contraction and therefore be detrimental in a
presumed obstructed patient [11,87]. To address this issue,
several RCTs evaluated the effect of the combination of
antimuscarinics and a-blockers. The combination was more
effective at reducing male LUTS than a
1
-AR antagonists
alone in men with OAB and coexisting BPO. Moreover, the
combination was safe because the increase in postvoid
residual (PVR) and the incidence of AUR were, in general,
clinically negligible. It is important to note, however, that
most of the studies defined an upper limit of PVR of 200 ml
and a lower limit of Q
max
of 5 ml/s in their inclusion criteria
[8893].
3.2.3. The b3 adrenergic agonists
The b3 selective agonists, which include mirabegron and
solabegron, are currently being evaluated or used for the
treatment of OAB. Currently, clinical trials with solabegron
have only enrolled women, which has not been the case
with mirabegron [94]. In a phase 3 North American RCT,
1328 patients (25.7% men) were randomized to received
placebo or mirabegron 50 or 100 mg once daily for 12 mo.
In the European-Australian phase 3 trial, 1978 patients
(27.8% men) were randomized to receive placebo, mirabe-
gron 50 or 100 mg, or tolterodine sustained release (SR)
4 mg once daily for 12 wk. Both doses of mirabegron
showed significant improvement in incontinence, frequen-
cy, urgency, nocturia, and voided volume per micturition at
week 12. Improvements in incontinence and frequency
were evident at the first measured time point (4 wk). The
global incidence of AEs was similar across the four study
groups with the exception of dry mouth that was higher in
the tolterodine SR group [95]. Unfortunately, a post hoc
analysis of the two phase 3 trials with mirabegron to
analyze the effect of the compound exclusively in men is
not available. Nevertheless, the safety of mirabegron was
urodynamically evaluated in 200 men with LUTS and BOO.
Patients were randomized to receive mirabegron 50 mg,
mirabegron 100 mg, or placebo once daily for 12 wk.
Mirabegron at both doses had no effect on urinary flow,
detrusor pressure at maximum flow, or bladder contractil-
ity. PVR was marginally increased by mirabegron 100 mg
but not 50 mg [96].
3.2.4. Phosphodiesterase inhibitors
Based on the relaxant effects of drugs on smooth muscle
(prostate, urethra, detrusor) and on the association between
LUTS and erectile dysfunction, the use of PDE5 inhibitors
(PDE5-Is) has been investigated in the treatment of male
LUTS [97]. The precise mechanism(s) of action of PDE5-I on
LUTS, however, remains to be elucidated. As discussed by
Andersson et al, PDE5-Is may act on several pathways
including upregulating NO/cGMP activity, downregulating
Rho-kinase activity, modulating autonomic nervous system
overactivity and bladder and prostate afferent nerves,
increasing pelvic blood perfusion, and reducing inflamma-
tion [17].
Several clinical trials on the effect of PDE5-Is on
male LUTS have been published. In these studies, different
PDE5-Is (sildenafil, vardenafil, tadalafil, and UK-369003) and
combinations of an a-blocker (alfuzosin or tamsulosin) and
PDE5-I were compared with placebo or to a-blocker alone.
According to a recent meta-analysis, the use of PDE5-I alone
was associated with a significant improvement of IPSS at
the end of the studies compared with placebo [98].
The association of an a-blocker and PDE5-I significantly
improved IPSS and Q
max
at the end of the studies compared
with a-blockers alone [97,98]. Tadalafil is now approved
by the US Food and Drug Administration for male LUTS
management.
Table 1 Future pharmacotherapy for non-neurogenic male lower urinary tract symptoms, their respective targets, and phase of studies
Class of drugs Target Phase of studies References
Antimuscarinics M3 muscarinic receptors Clinical practice [8893]
Phosphodiesterase inhibitors NO/cGMP Clinical practice [97,98]
ROK
Autonomic nervous system
Afferent nerves
Blood perfusion
Inammation
b3-agonists b3-adrenergic receptor Phase 2 (completed) [9496]
Clinical practice
Botulinum toxin Acetylcholine release Clinical practice [125,127]
Prostate tissue Phase 3 (currently)
LHRH antagonists Testosterone Phase 3 (completed) [84,85]
Cannabinoids Cannabinoid receptors Phase 3 (completed) [115,116]
NX-1207 Prostate tissue Phase 3 (currently) [122]
PRX-302 Prostate tissue Phase 2 (completed) [124]
Vitamin D3 receptor analogs Vitamin D3 receptors Phase 2 (completed) [110]
Anti-inammatory drugs Inammation Phase 1 [100,101]
Transient receptor potential channel blockers Transient receptor potential channels Experimental [111113]
Rho-kinase inhibitors ROK Experimental [117119]
Purinergic receptor blockers Purinergic receptors Experimental [120]
Endothelin-converting enzyme inhibitors Detrusor muscle Experimental [121]
cGMP = cyclic guanosine triphosphate; LHRH = luteinizing hormone-releasing hormone; NO = nitric oxide; ROK = RhoA/Rho kinase.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1 615
3.2.5. Anti-inflammatory drugs
In an experimental model of BPH in rats treated with
flavocoxid, a dual inhibitor of COX-2 and 5-lipoxygenase
(5-LOX), reduced prostate weight and hyperplasia was
observed, and inducible expression of COX-2 and 5-LOX
andthe productionof PGE2andleukotriene B4were blunted.
The drug also enhanced apoptosis pathways and decreased
GF expression [99]. The combination of rofecoxib and
finasteride caused a significantly higher improvement in
IPSS and Q
max
than finasteride alone at 4 wk but not at 24 wk
[100]. The combination of tenoxicam and doxazosin had a
superior effect onthe IPSS, IPSS-quality of life (QoL), andOAB
SymptomScorethandoxazosinaloneat 6wk, inparticular on
storagesymptoms [101]. However, nolargeRCTs followed, so
the results should be interpreted with caution.
3.2.6. Vitamin D3 receptor analogs
Human prostatic urethra, prostate, and bladder exhibit
vitamin D3 receptors (VDRs) [102]. Elocalcitol, a VDR
agonist, may decrease stromal prostate cell proliferation,
even in the presence of GFs, and induce apoptosis without
interfering with AR signaling [103]. In human and rat
bladder smooth muscle, elocalcitol also inhibited RhoA/ROK
signaling [104] and limited the COX2/PGE2 pathway [105].
In a rat model of BOO, daily treatment with elocalcitol for
14 d, in a nonhypercalcemic dose, did not prevent bladder
hypertrophy, but it reduced the occurrence of spontaneous
contractions and the decrease in contractility of the
detrusor that occurred with increasing bladder weight,
both in vivo and in vitro [106]. Previous treatment with
elocalcitol enhanced the effects of tolterodine on bladder
compliance of rats with partial BOO [107].
A phase 2 RCT could not demonstrate differences in Q
max
and symptoms between elocalcitol and placebo, however,
despite the capacity to arrest prostate growth in men 50 yr
of age with prostatic volume 40 ml [108,109]. A recent
phase 2b RCT caused a revival of interest in elocalcitol after
showing a significant reduction in incontinence episodes
and improvement of the Patients Perception of Bladder
Condition in women with OAB. Unfortunately, male
patients were not included [110].
3.2.7. Transient receptor potential channel blockers
Experimental data on the effect of drugs interacting with
TRP channels in regard to LUTS have been published;
however, no proof-of-concept studies in humans are avail-
able. Most of the data onTRP channel blockers originate from
inflammation models. In animal models of cystitis or spinal
cord transection GRC 6211, anorally active TRPV1 antagonist
counteracted bladder hyperactivity and noxious input. At the
same doses, the compound had no effect on bladder function
in sham animals [111]. Likewise, the TRPV4 antagonist
HC-067047 also dose-dependently decreased the voiding
frequency and increased the voided volume. However, at the
same doses the TRPV4 antagonist also affected shamanimals
[112]. Systemic coadministration of TRPV1 and TRPV4
antagonists showed an interesting synergistic effect in DO
[113]. No studies are available in humans due to the
hyperthermic effect of these drugs in pilot studies.
3.2.8. Cannabinoids
Clinical studies with the use of cannabinoids on LUTS are
scarce and essentially restricted to MS patients. The efficacy
of whole plant extracts of Cannabis sativa was demonstrated
in MS patients with LUTS, who experienced significant
improvement in urgency, incontinence, frequency, and
nocturia [114]. In the multicenter trial of the Cannabinoids
in Multiple Sclerosis study, patients who used cannabis
extract or D
9
-tetrahydrocannabinol achieved a significant
reduction in incontinence episodes over matched placebos
[115]. In contrast, Sativex (nabiximols), an endocannabi-
noid system modulator, failed to reach statistical signifi-
cance in the primary end point, reduction in the daily
number of incontinence episodes. The number of daytime
voids, total voids per day, and nocturia, however, were
significantly reduced in the Sativex group [116].
3.2.9. Rho-kinase inhibitors
Treatment with hydroxyfasudil, a nonselective Rho-kinase
inhibitor, ameliorated the bladder dysfunction in male
spontaneous hypertensive rats (SHRs). Micturition frequen-
cy, single voided volume, and intercontraction interval
improved in hydroxyfasudil-treated animals compared
with nontreated ones. Bladder blood flow and NGF content
in the bladders of the treated animals were similar to those
of healthy control animals. The authors theorized that
bladder ischemia may be responsible for NGF overexpres-
sion in the bladder of SHRs and that hydroxyfasudil
ameliorates bladder dysfunction by improving bladder
blood flow and ischemia-induced bladder damage [117].
In another experimental study with cyclophosphamide-
induced cystitis in rats, hydroxyfasudil significantly in-
creased voided volume and decreased maximum detrusor
pressure, whereas the intercontraction interval was not
significantly affected. In vitro, the maximum contraction of
the concentration-response curves to carbachol was signif-
icantly lower in the hydroxyfasudil group [118]. Likewise,
another Rho-kinase inhibitor, Y-27632, attenuated the
phasic and sustained contraction induced by carbachol in
both control and obstructed bladders from rats. The
inhibitory effect of Y-27632 was enhanced on the sustained
responses to carbachol in the obstructed bladders [119].
3.2.10. Purinergic receptor blockers
In an experimental model of neurogenic bladder induced by
spinal cord injury (SCI) in female rats, the P2X3/P2X2/3
antagonist AF-353 reduced the field potential in the dorsal
horn in response to sudden increase in intravesical pressure.
In addition, during cystometry the frequency of nonvoiding
contractions was significantly reduced in SCI animals [120].
3.2.11. Endothelin-converting enzyme inhibitors
Endothelin (ET)-1 is a potent vasoconstrictor that has been
shown to contract human detrusor and is overexpressed in
the detrusor muscle in a rabbit BOO model. Endothelin-
converting enzyme (ECE) is responsible for the generation
of ET-1. It was hypothesized that the inhibition of ECE
could prevent some bladder changes following BOO; thus
WO-03028719, an oral ECE inhibitor, was given to
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1 616
obstructed female rats, leading to a reduction in the
incidence of nonvoiding contractions and in the amplitude
of normal voiding contractions. The drug has not been
tested in humans [121].
3.2.12. Drugs injected into the prostate
3.2.12.1. NX-1207. NX-1207 is an investigational drug for the
treatment of LUTS/BPH, currently in phase 3 clinical trials. It
is a new therapeutic protein of proprietary composition
with selective proapoptotic properties. The drug is injected
under transrectal ultrasound guidance into the transition
zone of the prostate. The drug produces focal cell loss
through apoptosis, leading to prostate tissue shrinkage. In
the first US phase 2 clinical trial, three doses of NX-1207
(2.5, 5.0, and 10 mg) were evaluated in a multicenter RCT
involving 175 men. The dose of 2.5 mg was selected as the
smallest dose showing clinically significant efficacy (mean
improvement in AUA-SI: 11.0). The second trial, a multi-
center randomized noninferiority study, evaluated two
doses (2.5 and 0.125 mg) and an active open-label
comparator (finasteride). The mean AUA-SI improvement
after 90 d in the intent-to-treat group was 9.71 points for
2.5 mg NX-1207 versus 4.13 points for finasteride
( p = 0.001) and 4.29 for 0.125 mg NX-1207 ( p = 0.034).
The 180-d results also were positive (NX-1207 2.5 mg
noninferior to open-label finasteride). None of the clinical
studies identified safety issues relating to NX-1207 itself or
sexual side effects. The drug is currently under investigation
in phase 3 clinical trials in the United States [122].
3.2.12.2. PRX302. PRX302 is a prostate-specific antigen (PSA)-
activated protoxin produced via a modified proaerolysin,
the inactive precursor of a bacterial cytolytic pore-forming
protein. Interestingly, the protoxin requires proteolytic
processing by PSA for activation. When injected into the
nonPSA-producing dog prostate, PRX302 was inactive,
whereas its ability to ablate prostate tissue was observed in
the PSA-producing monkey prostate [123].
PRX302 was injected transperineally under transrectal
ultrasound guidance into the right and left transition zone
in a study of 33 patients with BPH[124]. In phase 1 (n = 15),
subjects received increasing concentrations of PRX302 at a
fixed volume. In phase 2 (n = 18), the concentration was
fixed and the volumes varied. In both phases, a decrease in
total IPSS was observed in all cohorts. In phase 1, no
relationship between IPSS response and dose was observed.
In the phase 1 and 2 studies, respectively, a decrease 30%
in IPSS was observed in 73% and 67% at day 90, and 64% and
67% in 1 yr. Patients also experienced improvement in QoL
and reduction in prostate volume out to day 360. A
statistically significant decrease in mean Q
max
was observed
at day 90 in the phase 1 study, which was not sustained out
to 1 yr. In the phase 2 study, a 2.8 ml/s improvement was
noted out to 1 yr. PRX302 injection decreased prostate
mass, with most patients showing a 20% reduction in
prostate volume after 1 yr. The injection >1 ml had the best
overall results. Erectile function was not altered by the
treatment. AEs were mild to moderate and transient in
nature. The small sample of the studies, however, is a major
limitation, particularly because repeated dosing of the toxin
may lead to an antibody response [124]. Nonetheless, the
preliminary safety and efficacy data make PRX302 a
promising minimally invasive targeted treatment for LUTS
associated with BPH.
3.2.12.3. Botulinum toxin. Botulinum neurotoxin (BoNT) pre-
vents exocytosis of ACh vesicles at the nerve terminal,
thereby inhibiting neurotransmission and muscle contrac-
tion. The action of BoNT is not permanent because neuronal
death does not occur, and eventually the toxin is inactivated
and removed. BoNT subtype A (BoNTA) is the most relevant
clinically. OnabotulinumtoxinA (BoNT-ONA), abobotuli-
numtoxinA, and incobotulinumtoxinA are available BoNTAs
[125,126]. Recently, the use of BoNT-ONA in LUTS was
comprehensively reviewed. Its efficacy in the treatment of
idiopathic DO was demonstrated in several studies includ-
ing one RCT and a dose-ranging trial. It seems that the dose
of 100 U may be the one that appropriately balances the
symptoms benefits with the safety profile [125]. Improve-
ment of LUTS associated with BPE has been reported with
the use of intraprostatic injection of BoNT-ONA in clinical
studies; however, the lack of placebo arms was always a
drawback. Recently, intraprostatic injection of BoNT-ONA
100 U, 200 U, and 300 U was tested versus placebo injection
in a phase 2 dose-ranging study. IPSS, Q
max
, and prostate
volume significantly improved in all groups, owing to
a large placebo effect from the injectable therapy. A
post hoc analysis revealed a significant reduction with
BoNT-ONA 100 Uin prior a-blocker users at week 12, which
will be explored in further studies [127].
4. Conclusions
The pathophysiology of male LUTS is highly complex and
multifactorial. Changes in the bladder and prostate as well
as in related structures, such as the pelvic vasculature and
innervation, account for alterations in the normal physiol-
ogy of the male lower urinary tract. Derangements at the
structural, molecular, and cellular levels have been identi-
fied, and newpathophysiologic mechanisms are continually
described. Different categories of symptoms usually over-
lap, making it difficult to pinpoint one guilty organ, leading
to a broader and more symptom-driven approach to the
condition. In this scenario, new drugs have been suggested
either as standalone or as add-on treatments to currently
established treatments for male LUTS. Some of these drugs
are currently being used in clinical practice with short-term
results; others are still in clinical or experimental evalua-
tion. Even though some of the new treatments may be
promising alternatives, there is still a long way to go until
patients can benefit from them.
Author contributions: Francisco Cruz had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Soler, Gratzke, Cruz.
Acquisition of data: Soler, Cruz.
Analysis and interpretation of data: Soler, Cruz, Chapple, Andersson.
E UR OP E AN UR OL OGY 6 4 ( 2 0 1 3 ) 6 1 0 6 2 1 617
Drafting of the manuscript: Soler, Cruz.
Critical revision of the manuscript for important intellectual content:
Chapple, Andersson, Drake, Gratzke, de Groat, Chancellor, Lee.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: Soler
Supervision: Cruz.
Other (specify): None.
Financial disclosures: Francisco Cruz certies that all conicts of interest,
including specic nancial interests and relationships and afliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/afliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents led,
received, or pending), are the following: Roberto Soler is a consultant for
Astellas. Karl-Erik Andersson is a consultant for Astellas, Allergan, Pzer,
Ferring, and TheraVida. Michael Chancellor is a consultant for Allergan,
Astellas, Cook, Lipella, Merck, Pzer, and Targacept. He is an investigator
for Allergan, Cook, Lipella, and Medtronic. Christopher Chapple is a
speaker for Ranbaxy; a consultant for AMS and Lilly; a consultant and
researcher for ONO; and a consultant, researcher, and speaker for
Allergan, Astellas, Pzer, and Recordati. William de Groat is a consultant
for Medtronic, Ethicon, Eli Lilly, Amphora Medical, Endo Pharmaceutical,
and Circuit Therapeutics; he receives speaker honoraria for Medtronic
and Astellas and research grants fromAstellas and Eli Lilly. Marcus Drake
is a consultant, researcher, and speaker for Allergan, Atellas, Ferring, and
Pzer. Christian Gratzke is a consultant, researcher, or speaker for
Astellas, Recordati, Rottapharm Madaus, Lilly, AMS, Bayer Healthcare,
and GSK. Richard Lee has nothing to disclose. Francisco Cruz is a
consultant for Allergan, Astellas, Recordati, and Janssen, and an
investigator or speaker for Allergan, Astellas, and Janssen.
Funding/Support and role of the sponsor: None.
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