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The Challenge of the Overactive Bladder: From Laboratory
to New Drugs
Massimo Lazzeri a,*, Massimo Porena b
a
b
Department of Urology, Casa di Cura Santa Chiara Firenze (Giomi Group), Italy
Section of Urology and Andrology, Department of Medical-Surgical Specialties and Public Health, University of Perugia, Italy
Article info
Abstract
Keywords:
Antimuscarinics
Drugs
Micturition reflex
Overactive bladder (OAB)
Therapy
Urinary incontinence
Antimuscarinic agents are currently the first-line therapy for overactive
bladder (OAB). Many urologists believe the pharmacologic management
of OAB is not altogether satisfactory. Pharmacologic research is trying to
provide answers to the issues of efficacy, tolerability, and convenience of
new drugs. This paper discusses the rationale underlying the development of new compounds, provides an update of progress in the search
for new therapies for OAB, and tracks their translation into clinical
practice. It offers an insight into the mechanism of action, efficacy,
side-effects, and ‘‘market status’’ of several drug categories targeting
the central nervous system (adrenoceptor modulators, serotonin/norepinephrine reuptake inhibitors, tachykinin modulators, opioids), neuromuscular blocking agents (botulinum toxin A), selective modulators of
the afferent branch of micturition reflex (vanilloid, nociceptin/orphanin
FQ), autonomic nervous system modulators (b3-agonists), potassium
and calcium channel openers, and nonsteroidal anti-inflammatory
drugs.
# 2007 European Association of Urology and European Board of Urology.
Published by Elsevier B.V. All rights reserved.
* Corresponding author. Casa di Cura Santa Chiara, P.zza Indipendenza 11, 50129 Firenze,
Italy. Tel. +39 055 50381; Fax: +39 055 480676.
E-mail address: [email protected] (M. Lazzeri).
1.
Introduction
Overactive bladder (OAB) is a complex clinical
syndrome that the International Continence Society
(ICS) defines as characterised by urgency (sudden,
compelling desire to pass urine, which is difficult to
defer), urinary incontinence (involuntary urine
leakage with or without urgency), frequency, and
nocturia (waking to void more than once at night), in
absence of genitourinary pathologies or metabolic
factors that could explain these symptoms (www.
icsoffice.org). OAB may be associated with, but needs
to be distinguished from, detrusor overactivity (DO),
which refers to an uninhibited, involuntary rise in
detrusor pressure during the filling phase of filling
cystometry during urodynamic assessment in a
conscious cooperative patient.
European and North American surveys reported
that OAB is found in about 16% of the general
population aged 40 yr and over; one third of patients
with a clinical diagnosis of OAB present urgency
urinary incontinence [1]. Interestingly, OAB rates are
1871-2592/$ – see front matter # 2007 European Association of Urology and European Board of Urology. doi:10.1016/j.eeus.2007.08.002
Published by Elsevier B.V. All rights reserved.
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eau-ebu update series 5 (2007) 250–258
similar in men and women. In a cross-sectional
population-based survey of adults (>18 yr old),
Irwing et al reported a 12.2% total prevalence of
OAB in four European countries and confirmed that
it is common in men and women of all adult age
groups [2].
Because OAB-related symptoms are extremely
distressing and have a significant negative impact
on quality of life and health care costs, treatment
and management remain the main challenges
for health care professionals [3]. At present, the
primary pharmacologic treatment for OAB uses
antimuscarinic agents; objective clinical data, systematic reviews, and adjusted indirect comparisons
confer a high level of evidence and strong recommendations [4]. Urologists are, however, aware that
caution should be exercised when evaluating,
interpreting, or prescribing antimuscarinics. Attention should focus on the natural history of OAB,
choice of appropriate study design, trial duration,
restricted population, economic issues, unrealistic
patient expectations, high placebo response rates,
and diverse methods of outcome assessment in
different trials. Currently there is no consensus on
how long patients should be treated, whether
treatment should be continuous, intermittent, or
on demand, and why only relatively few patients
remain on medication for >4–6 mo [5]. Many
urologists are systematically searching for appropriate answers to these open questions and looking
for more efficacious alternatives to antimuscarinic
agents.
This paper discusses the pharmacologic rationale
underlying the development of new compounds,
provides an update of progress in the search for new
therapies for OAB, and tracks their translation into
clinical practice.
2.
Pathophysiology of the micturition reflex
The lower urinary tract (LUT) serves two main
functions: (1) urine storage without leakage (storage
phase) and (2) release of urine (voiding phase). These
two functions depend on central, peripheral autonomic, and somatic neuronal pathways and local
peripheral factors.
During the storage phase afferent impulses,
which reach the central nervous system (CNS) from
the bladder, send information to the pons. In the
pontine tegmentum in animals, positron emission
tomography (PET) studies visualised a medial region
(M-region), corresponding to Barrington’s nucleus or
pontine micturition center, which is involved in
micturition reflex coordination, and a lateral region
(L-region), which suppresses bladder contractions
and improves external sphincter muscle activity
during the storage phase [6]. PET and functional
magnetic resonance imaging (fMRI) recently
detected several suprapontine centers that modulate the micturition reflex in humans [7]. These
areas are under the chemical control of different
ligands (neurotransmitters) and receptors (Table 1).
The micturition reflex involves the parasympathetic, sympathetic, and somatic peripheral neuronal
systems. The parasympathetic system, originating in
the spinal cord sacral area (S2–4) controls bladder
contractions. It provides an excitatory input to the
bladder through post-ganglion nerve terminal
release of acetylcholine (ACh), which excites muscarinic receptors (M2, M3) in the detrusor smooth
muscle and leads to contraction. The sympathetic
system originating in the thoracolumbar cord (Th11–
L2) is involved in bladder relaxation and urethral
closure through, respectively, post-ganglion nerve
terminal release of norepinephrine (NE). NE provides
Table 1 – Central nervous system ligands and receptors involved in the regulation of micturition reflex
Ligands
Receptors
Function
Norepinephrine
ARs (a, b)
Micturition reflex
Excitatory: a1
Inhibitory: a2
b (?)
g-aminobutyric acid (GABA)
Glycine
Opioids
Serotonin
Dopamine
Glutamate
N/OFQ
GABAA and GABAB
GlyR
m, d, k
5-HT1–7
D1 and D2
NMDA and AMPA
NOP
Inhibition of micturition reflex
Inhibition of micturition reflex
Inhibition of micturition reflex
Inhibition of micturition reflex
Inhibition of micturition reflex
Excitatory/inhibitory function
Excitatory/inhibitory function
AR = adrenoreceptor; GlyR = glycine receptor; HT = hydroxytryptamine; NMDA = N-methyl-D-aspartate; AMPA = a-amino-3-hydroxy-5methylisoxazole-4-propionic acid; N/OFQ = heptadecapeptide nociceptin/orphanin FQ; NOP = N/OFQ peptide receptor.
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eau-ebu update series 5 (2007) 250–258
inhibitory input to the bladder, which excites b3receptors in the detrusor body and leads to bladder
relaxation. NE provides excitatory input to urethral
smooth muscle, which excites a1-receptors in the
urethra and leads to a rise in urethral closing
pressure. The somatic system provides excitatory
input to striated urethral muscle. Motor neurons,
located along the lateral ventral horn of the sacral
spinal cord (Onuf’s nucleus), release ACh, which
acts on nicotinic receptors to induce muscle contraction.
Until recently, all these factors—the complex
neurology of the voiding reflex, the simple, ‘‘easy-toaccept’’ idea of antagonistic, parasympathetic cholinergic, and sympathetic adrenergic, control of the
LUT, the interrelationship between voluntary
somatic and involuntary control of micturition
reflex—discouraged extensive research into new
drugs for the treatment of OAB. However, in the last
two decades LUT neuropharmacology has progressed. Immunohistochemical and morphologic
studies of the bladder wall showed that many
neuronal terminal endings do not correspond to
cholinergic and adrenergic innervation [8]. These
nonadrenergic, noncholinergic (NANC) nerves are
peptide-containing fibres that are thought to be
‘‘silent’’ in normal conditions but that might play a
major role in regulating LUT functions in pathologic
conditions [9]. In the neurogenic bladder the NANC
primary sensory nerves are up-regulated and they
play the main role in the regulation of the micturition reflex in these patients [9]. The NANC-muscular
junction is not a ‘‘fixed synapse junction,’’ with
prejunctional and postjunctional specialisation [10].
Observing the synthesis and release of multiple
neurotransmitters such as monoamines, purines,
amino acid, peptides, and nitric oxide was another
step forward in understanding the micturitional
reflex [8]. Further achievements included accepting
the principles of cotransmission (axons release
more than one transmitter for each action potential)
[11], neuromodulation (locally released agents may
modulate the amount of neurotransmitters released
prejunctionally) [12], and recognition that a subset of
sensory nerves, which are selectively sensitive to
capsaicin, the pungent ingredient in red chilli, are of
primary importance because they have both afferent and efferent functions [13]. New varieties of
receptors in neuronal and nonneuronal tissues were
identified as being involved in regulating sensoryafferent nerve conduction [14]. Finally, autonomic
nervous system plasticity during development,
ageing, and chronic inflammation and after trauma
(neuroplasticity) was another fundamental factor in
the development of new drugs [15].
Data from several laboratories have recently
shown the urothelium and some suburothelial cells
have several novel properties. The urothelium is
involved in sensory mechanisms (ie, the ability to
express sensor molecules or to respond to thermal,
mechanical, and chemical stimuli), expresses many
different receptor families, and can release neurotransmitters on stretch during the filling phase of
the micturition reflex (Table 2). Birder and de Groat
suggested urothelial cells might be targets for
neurotransmitters released from bladder nerves or
that chemicals released by urothelial cells could
alter afferent nerve excitability [16]. Finally, some
authors have addressed the presence of interstitial
cells of Kajal in the bladder as important components of peripheral modulation of the micturition
reflex.
Consequently, OAB may result from increased
bladder afferent activity, decreased capacity to
handle afferent information, or decreased suprapontine inhibition in the CNS and increased peripheral sensibility to mediating transmitters. The
CNS as well as the periphery may be targets for a
new class of medications against OAB.
3.
Emerging therapies
In recent years several clinical trials have reported
the relative benefits and weaknesses of new drugs
for the treatment of OAB. The potential place of
many of these drugs within OAB therapy and the
probability of their reaching the market in the near
future are addressed in the following sections.
3.1.
Drugs targeting the CNS
CNS transmitter/receptor systems have been investigated as potential targets of new drugs. Table 1 lists
the main ligands and receptors involved in regulating micturition control.
In vitro and in vivo evidence confirmed expression of several adrenoreceptors in the brain and
spinal cord. Naftopidil, an a-adrenergic receptor
blocker, may inhibit bladder activity in rats by
targeting the lumbosacral cord. When associated
with tamsulosin in an 8-wk crossover study in 96
patients with benign prostatic hyperplasia (BPH), it
seemed to improve storage and voiding symptoms
[17]. The antidepressant reboxetine [18], a selective
NE reuptake inhibitor (selective NRI), which has
minimal affinity for muscarinic ACh receptors and
therefore causes less dry mouth, is being tested in a
phase 2 trial for mixed urinary incontinence by
Pfizer and it might be another alternative agent.
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eau-ebu update series 5 (2007) 250–258
Table 2 – Ligands and receptors in bladder urothelium
Ligands released by the urothelium
Receptors expressed in the urothelium
ATP
P2X, P2Y
NO
ACh
M1-M5 (muscarinic receptors)
Catecholamine (norepinephrine)
ARs (a, b)
NGF
P75, TrK-A
Bradykinin
H+ (heat/vanilloids)
B1 and B2
TRPV1
Antiproliferative factor
Cytokines
Prostanoids
Anandamide (?)
CB1 and CB2
Functions
Autocrine/paracrine signalling
Activation primary afferents
Regulation micturition reflex
Nociceptive transmission
Activation/inhibition micturition reflex
Release of ATP
Activation micturition reflex
Release of ATP and NO
Regulation of sensory functions
Paracrine signalling
Development of sympathic and sensory nerves
Cell growth
Nociception/inflammation
Modulation of micturition reflex
(afferent and efferent functions)
Nociception
Inhibition of epithelial proliferation
Micturition reflex
Nociception
Cell growth
ATP = adenosine triphosphate; NO = nitric oxide; ACh = acetylcholine; AR = adrenoreceptor; NGF = nerve growth factor; TRPV1 = transient
receptor potential vanilloid-1.
The CNS opioid receptor system is a potential
target of pharmacologic research because morphine
and analogues have profound inhibitory effects on
the micturition reflex. Tramadol, a opioid receptor
ligand, which inhibits NE and serotonin reuptake,
has promising effects on micturition in preclinical
studies [19]. In rats it inhibits cerebral infarctioninduced detrusor overactivity and counteracts the
excitatory effects of apomorphine in other animals
[20].
Evidence from laboratory studies on the potential
of drugs acting on the serotonin receptor system is
controversial. In humans, exposure to selective
serotonin reuptake inhibitors (SSRIs) is associated
with increased risk of urinary incontinence especially in elderly users of sertraline [21]. Fluoxetine, a
widely prescribed SSRI for depression, seems to
inhibit detrusor activity. Capeserod hydrochloride, a
5-hydroxytriptamine 4 (5-HT4) receptor agonist,
which has been tested as treatment for Alzheimer’s
disease, is under investigation by Sanofi-Aventis as
therapy for urgency urinary incontinence in
humans. To date, no convincing evidence exists to
show SSRIs are effective in the treatment of OAB.
Duloxetine, a serotonin-NRI, which is approved
by the European Medicine Evaluation Authority
(EMEA) for the treatment of female stress urinary
incontinence (SUI), was tested in a randomised
controlled trial in 306 women with symptoms
of OAB. Patients randomised to duloxetine had
significant decreases in voiding frequency and
incontinence episodes and improvements in incontinence quality-of-life scores compared with
patients receiving placebo. The most common
adverse events (nausea, dry mouth, dizziness,
constipation, insomnia, and fatigue) were the same
as those reported by women with SUI and were
significantly more common with duloxetine than
placebo [22].
Several studies have focused on g-aminobutyric
acid (GABA) and its receptors, mainly in the CNS, as
specific targets to inhibit micturition. Baclofen, a
GABA agonist, which is used orally and intrathecally
to treat spasticity and DO in humans, attenuates
oxyhaemoglobin-induced DO, suggesting the inhibitory actions of GABAB receptor agonists in the
spinal cord. It may help control micturitional
disorders caused by C-fibre activation in the
urothelium or suburothelium [23]. However, even
if its effect on the LUT has been demonstrated some
decades ago, this has not been successful enough to
introduce it into the treatment of OAB. Experimental
studies demonstrated that exogenous GABA has an
inhibitory effect on micturition. In preclinical
studies tigabine, a GABA reuptake inhibitor, blocked
the micturition reflex and could be used in refractory DO in humans [24].
Finally, some pilot studies have proposed anticonvulsants such, as gabapentin and retigabine for
the treatments of OAB. Kim et al found gabapentin
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eau-ebu update series 5 (2007) 250–258
improved clinical parameters in 14 of 31 patients
with refractory OAB [25] and was generally well
tolerated. Gabapentin could be considered as an
alternative to antimuscarinic agents in selected
patients and some evidence has indicated that there
may be synergism with oxybutynin.
3.2.
Tachykinins
Experimental studies in animals have suggested
tachykinins may play a role in the micturition reflex
by acting at the level of CNS as well as peripherally
[26]. Mammalian tachykinins, such as substance P,
neurokinin A (NKA), and NKB, function as sensory
neurotransmitters by the activation of specific
receptors (NK-1, NK-2). NK-1 receptor antagonists
may inhibit sensorial bladder–spinal cord input,
thus increasing the threshold for initiating micturition and increasing bladder capacity without
blocking the voiding phase. In a double-blind,
randomised, placebo-controlled, parallel group pilot
study, postmenopausal women with a history of
urge urinary incontinence were assigned to receive a
160 mg capsule of aprepitant, an NK-1 receptor
antagonist, or placebo once daily for 8 wk [27]. At
8 wk aprepitant significantly decreased the average
daily micturitions and episodes of urgency. The
average daily episodes of urgency urinary incontinence and total urinary incontinence were also
reduced, although not significantly. Aprepitant was
generally well tolerated and adverse experiences
were generally mild. Although this study by Green
et al seems to demonstrate the potential efficacy of
an NK-1 receptor antagonist in the management of
OAB, results need to be confirmed in powered
follow-up studies. New NK-1 antagonists such as
casopitant, Sanofi-Aventis SSR 240600, and tanabe
TA-5538 are under clinical investigation (phase 2)
and preliminary results are expected by the end of
2007 or early in 2008.
3.3.
Acute exposure to capsaicin depolarises and excites
the sensory fibres expressing TRPV1 receptors.
Because excitation is followed by a refractory period,
repeated, long-term, high-dose exposure to capsaicin desensitises, defunctionalises, and ultimately
damages peripheral terminals, which become unresponsive. In other words, capsaicin exerts longlasting reversible suppression of sensory nerve
activity, which is dependent on dose, exposure
time, and interval between instillations. Intravesical
instillation of repeated low doses of capsaicin [28]
showed inhibitory modulation of urinary bladder
afferent nerves and had therapeutic benefit in OAB.
At the turn of the century, several independent and
sponsored trials were started using resiniferatoxin
(RTX), the ultrapotent capsaicin analogue, to treat
LUT disorders. The clinical trials were discontinued
because a study about the effects of intravesical RTX
for the treatment of incontinent patients failed to
show a significant improvement of symptoms when
data were compared with placebo and because there
were problems with the agent sticking to plastic
when being given, so variable amounts were
administered, negating the accuracy of the studies.
Recent papers on the role of TRPV1 in the LUT
reported the benefits of intravesical vanilloid instillation as treatment for the painful bladder syndrome and neurogenic and nonneurogenic OAB [29–
31]. In an interesting study 54 patients with DO
refractory to anticholinergics were randomly treated with 4 weekly intravesical instillations of 10 nM
RTX [32] or vehicle. Three months after the treatment cycle, a significantly higher percentage of
patients receiving RTX had excellent and improved
results; treatment remained effective at 6 mo in 50%
of patients. The authors concluded that multiple
intravesical instillations of 10 nM RTX improved
incontinence in patients with OAB. Interest in these
drugs was rekindled, but to date no natural or
synthetic TRPV1 agonist/antagonists are available
on the market.
Vanilloid agents
3.4.
As a potential alternative to current drug therapies,
urologists are placing their trust in afferent blockade
by targeting afferent nerves that control the micturition reflex because preventing the micturition reflex
that initiates OAB seems more desirable than
inhibiting detrusor smooth muscle contractions.
Modulation of the afferent arm of the micturition
reflex emerged from studies on the effect of
capsaicin on sensory nerves. Capsaicin targets the
transient receptor potential vanilloid-1 (TRPV1),
which is expressed on small-to-medium–sized
afferent neurons (C-type and, partially, A-d type).
b3-agonists
Two b3-agonists have been under clinical investigation: GlaxoSmithKline solabegron (GW427353) and
Astellas YM178. GlaxoSmithKline tested the safety
and efficacy of 125 mg and 50 mg solabegron
administered twice daily against placebo in reducing OAB symptoms in women.
In North America and Europe, Astellas will
develop a phase 2 study for YM178, a b3-agonist
with activity against OD in rats [33]. The compound had relaxant effects on rat and human
bladder strips. An in vivo study demonstrated it
eau-ebu update series 5 (2007) 250–258
decreased the frequency of rhythmic bladder
contractions induced by intravesical filling with
saline.
3.5.
Nociceptin/orphanin FQ–NOP receptor system
About 10 yr ago, naturally occurring heptadecapeptide nociceptin/orphanin FQ (N/OFQ) was identified
as the endogenous ligand of a previously orphan G
protein-coupled receptor now named N/OFQ peptide (NOP) receptor. At peripheral levels N/OFQ
exerts potent inhibitory effects on primary afferent
bladder fibres.
A preliminary report and a subsequent randomised, placebo-controlled, double-blinded study
demonstrated that intravesical instillation of 1 mM
N/OFQ solution produces an acute inhibitory effect
on the micturition reflex in humans. In patients
with neurogenic DO, Lazzeri et al observed daily
intravesical instillation of 1 mg N/OFQ (but not
placebo) is associated throughout the 10-d instillation period with less frequent incontinence episodes, increased bladder capacity, and improved
urodynamic parameters [34]. Malagutti et al performed the neurophysiologic assessment of the
nociceptive flexion reflex (NFR-RIII) in four healthy
subjects and in five patients with LUT symptoms
(LUTS) to investigate the N/OFQ neuronal site and
functional mechanism of action. N/OFQ seems to
selectively inhibit vesical sensory innervation in
patients with LUTS [35] as it exerts a tonic inhibitory
modulation of the nociceptive reflex, which is
mediated by descending pathways. In healthy
subjects N/OFQ modulation of the nociceptive
reflex is not functionally active. These findings
seem to provide evidence that N/OFQ and C-fibres
are involved in the pathophysiology of LUTS and
make them attractive targets for new therapies.
3.6.
Botulinum toxin
Botulinum toxin (BTX) is a complex protein produced by the anaerobic bacterium Clostridium botulinum and was originally known only to cause
serious, often fatal paralysis after ingestion in
contaminated food. The BTX-linked neuromuscular
blocking effect is thought to alleviate muscle spasm
due to excessive neural activity of central origin.
Local BTX injections are effective in the treatment of
muscular disorders and unlicensed BTX has been
used to treat LUTS.
BTX is thought to cleave SNAP-25, a synaptosome-associated protein, thereby blocking presynaptic ACh release at the neuromuscular junction.
This leads to temporary chemical denervation and
255
muscle relaxation. In animal models, BTX inhibits
abnormal urothelial release of adenosine triphosphate (ATP) and calcitonin gene-related peptide
(CGRP), reduces capsaicin-evoked detrusor contractions, and inhibits mucosal release of CGRP. Parasympathetic transmission inhibition is not the only
mechanism of action of BTX. It also inhibits
substance P release and induces a blockade of
mechanisms involved in TRPV1 axonal expression.
Apostolidis et al investigated the effect of BTX
therapy on human bladder afferent pathways and
found a progressive decrease in suburothelial fibres
expressing P2X3 and TRPV1, which correlated with
clinical improvement but no change in urothelial
sensory-receptor immunoreactivity [36].
Clinical results have shown BTX is remarkably
efficacious in neurogenic DO and OAB [37,38] when
given as a single injection dose of 100–300 U Botox1
and of 500–1000 U Dysport1 (toxin equivalence is 1 U
Botox to 3.5–5 U Dysport) in an injection volume
ranging from 0.1 to 0.5 ml/injection site. BTX
injection is usually performed using 20–40 evenly
distributed intramural injection sites, sparing the
trigone. However, two recent studies reported
successful outcomes using a Botox injection with
trigone inclusion. Most studies used 300 U Botox,
with isolated studies reporting the effects of 100,
150, or 200 U. Despite similar outcomes the optimal
dose has not yet been defined. The clinical benefit of
BTX injection seem to last for a mean of 6–9 mo,
apparently independently of population and dose.
Side-effects have been rare to date. Botox injections
were repeated at different intervals of time in almost
all studies and efficacy was reported to continue in
the majority of patients undergoing repeated injections.
Haematuria and pain are the most frequent
symptoms soon after injection. Systemic symptoms
such as respiratory muscle weakness, extremity
weakness, and hyposthenia have occasionally been
reported, but disappear within 4–5 wk. Urinary
retention is a main concern when BTX is given to
patients with OAB because several authors reported
different percentages of urinary retention over
different periods of time. Although many studies
were small, overwhelming evidence supports the
efficacy, safety, and tolerability of BTX, specifically
serotype A, in the management OAB. At present BTX
is being tested in phase 3 trials in North America and
in phase 2 studies in Europe.
3.7.
Others
Chapple et al recently reported the first randomised,
double-blind, placebo-controlled phase 2 clinical
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study administering ZD0947, a potassium channel
opener, to patients with OAB [39]. After 12 wk of
treatment with 25 mg/d ZD0947 did not emerge as
better than placebo in changing frequency and
incontinence episodes even though it was generally
safe and well tolerated.
Although past clinical studies showed nonsteroid
anti-inflammatory drugs (NSAIDs) have potential
benefits in treating urinary symptoms associated
with OAB, prolonged use is limited by undesired
gastrointestinal and cardiovascular effects. NSAIDs
inhibit synthesis of prostaglandin/prostaglandin E2,
reduce peripheral sensory fibre afferent activation,
and decrease glutamate release, thereby reducing
afferent signal transmission to the spinal cord and
excitability of neurons involved in the micturition
reflex. Chemically modified NSAIDs with enhanced
safety for gastrointestinal and cardiovascular effects
or combining NSAIDs with other compounds for the
treatment of OAB will be under clinical study in the
coming year.
4.
Conclusion
Several implications should be considered when
translating basic science into clinical practice. One is
creation of potentially unrealistic expectations in
patients and clinicians, of the likely benefits of new
treatments. The clinical researcher should try to
estimate the probability, on average, of a proposed
new treatment for OAB being better than antimuscarinic agents. Unfortunately, antimuscarinics
remain the only ‘‘on-label’’ medication on the
market, and no significant comparison study with
new drugs is available even though several have
been tested as alternatives for OAB in the past few
years. Most urologists have been optimistic about
their efficacy and safety but need to be aware that
optimism is usually both unwarranted and counterproductive when uncertainty about the long-term
effects of treatments can only be resolved in postmarketing phase 4 surveys.
Conflicts of interest
The authors have nothing to disclose.
Acknowledgement
We thank Geraldine Boyd, at the University of
Perugia (Italy), who performed the English revision
of the manuscript.
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CME questions
Please visit www.eu-acme.org/europeanurology
to answer these CME questions on-line. The CME
credits will then be attributed automatically.
1. Overactive bladder syndrome is:
A. A medical condition more prevalent in people
<18 yr old.
B. A common condition in men and women
across all adult age groups.
C. A uncommon condition in women aged 40 yr
and older.
D. A uncommon condition in men aged 40 yr and
older.
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
257
with piperine, a new TRPV1 agonist. Neurourol Urodyn
2007;26:440–50.
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low dose resiniferatoxin in the treatment of refractory
interstitial cystitis. Urol Int 2007;78:78–81.
Takasu T, Ukai M, Sato S, et al. Effect of (R)-2-(2-aminothiazol-4-yl)-40 -{2-[(2-hydroxy-2-phenylethyl)amino]
ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp
Ther 2007;321:642–7.
Lazzeri M, Calo G, Spinelli M, et al. Daily intravesical
instillation of 1 mg nociceptin/orphanin FQ for the control
of neurogenic detrusor overactivity: a multicenter, placebo controlled, randomized exploratory study. J Urol
2006;176:2098–102.
Malagutti S, Spinelli M, Citeri M, Lazzeri M. Neurophysiological evidence of nociceptin/orphanin FQ (N/OFQ)/NOP
receptor system involvement in patients with lower urinary tract symptoms (LUTS). Assessment of nociceptive
flexion (RIII) reflex (NFR). Eur Urol Suppl 2007;6:167
(abstract no. 579).
Apostolidis A, Popat R, Yiangou Y, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve
fibers following intradetrusor injections of botulinum
toxin for human detrusor overactivity. J Urol 2005;174:
977–83.
Patel AK, Patterson JM, Chapple CR. Botulinum toxin
injections for neurogenic and idiopathic detrusor overactivity: a critical analysis of results. Eur Urol 2006;50:684–
709.
Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ,
Dasgupta P. Quality of life changes in patients with
neurogenic versus idiopathic detrusor overactivity after
intradetrusor injections of botulinum neurotoxin type
A and correlations with lower urinary tract symptoms
and urodynamic changes. Eur Urol 2006;49: 528–35.
Chapple CR, Patroneva A, Raines SR. Effect of an ATPsensitive potassium channel opener in subjects with
overactive bladder: a randomized, double-blind, placebo-controlled study (ZD0947IL/0004). Eur Urol 2006;49:
879–86.
2. The bladder urothelium:
A. Is an inert physical barrier between urine and
blood.
B. Is capable of releasing mediators that regulate
the striated urethral sphincter.
C. Regulates the renal function by the release of
neurotransmitters.
D. Expresses many different receptor families and can release several chemical ligands.
3. The concept of neuromodulation refers to:
A. The locally released agents that may modulate
the amount of neurotransmitters released
prejunctionally and the effect of postjunctional receptors activation.
258
eau-ebu update series 5 (2007) 250–258
B. The recognition of capacity of autonomic
nervous system to change during development, ageing, and chronic inflammation and
after trauma.
C. The recognition of synthesis and release of a
multiplicity of neurotransmitters such as
monoamines, purines, amino acid, peptides,
and nitric oxide.
D. The interrelationship between the voluntary
somatic control of micturition reflex and the
involuntary components.
4. Desensitisation, which is a mechanism of action
of vanilloid agents, results in:
A. Activation of a G-coupled receptor and block
of second messenger chain reaction.
B. A long-lasting reversible suppression of sensory nerve activity.
C. A nonreversible block all the primary sensory
nerves of the bladder.
D. A long-lasting reversible suppression of parasympathetic activity.
5. Aprepitant, a neurokinin 1 receptor antagonist:
A. Decreases the average daily number of micturitions compared with placebo at 8 wk as
well as the average daily number of urgency.
B. Increases the average daily number of micturitions compared with placebo at 8 wk as
well as the average daily number of urgency.
C. Increases the daily number of urge urinary
incontinence and total urinary incontinence
episodes.
D. Improves the cystometric bladder capacity at
urodynamic assessment.
6. The mechanism of action of botulinum toxin
consists of:
A. Blocking the presynaptic release of acetylcholine at the neuromuscular junction.
B. Inhibiting the abnormal urothelial release of
neurotransmitters.
C. Inhibiting the primary afferents nerves of the
bladder.
D. All the previous answers.