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Overactive Bladder & Incontinence

Future Perspective in Pharmacological Treatment Options for

Overactive Bladder Syndrome
Emilio Sacco1 and Bientinesi Riccardo2

1. Staff Member, Urological Clinic, Department of Surgical Sciences, ‘Agostino Gemelli’ Hospital, Catholic University Medical School,
Rome, Italy; 2. Resident in Urology, Urological Clinic, Department of Surgical Sciences, ‘Agostino Gemelli’
Hospital, Catholic University Medical School, Rome, Italy

Abstract
Antimuscarinic medications dominate the first-line pharmacological treatment of overactive bladder (OAB). However, limitations of
tolerability profiles and efficacy of antimuscarinics, together with the increasing prevalence of OAB and growing knowledge of its
pathophysiology fuelled a huge amount of basic and clinical research in this field of pharmacotherapy. Several exiting hypothesis-driven
pharmacological approaches for the future treatment of OAB have been suggested in the last few years and are discussed in the present
article. Many investigational compounds, mostly ligands of key receptors involved in nervous system and molecular pathways controlling
the micturition reflex, are in the pipeline of several pharmacological companies with promising preliminary results. Nevertheless, only a few
of the novel molecules under investigation have passed the proof-of-concept stage of development and may have a therapeutic potential
for the future treatment of OAB.

Keywords
Detrusor overactivity, overactive bladder, urinary incontinence, overactive bladder future pharmacotherapy

Disclosure: The authors have no conflicts of interest to declare.

Received: 3 April 2012 Accepted: 12 April 2012 Citation: European Urological Review, 2012;7(2):120–6
Correspondence: Emilio Sacco, Clinica Urologica, Policlinico 'Agostino Gemelli', Largo Agostino Gemelli 8, 00168, Roma, Italy. E: emilio.sacco@gmail.com

Overactive bladder (OAB) is a complex of lower urinary tract symptoms
(LUTS) defined by the International Continence Society (ICS) as
urgency with or without urinary incontinence, usually associated with
frequency and nocturia.1 Detrusor overactivity (DO) (neurogenic [NDO]
or idiopathic [IDO]) is often the underlying condition. OAB is highly
prevalent in western countries, increases with age, has a detrimental
effect on quality of life and is associated to significant co-morbidities
and to an increased risk of falls and fractures, of hospitalisation and
of being admitted to nursing homes.2–4
antimuscarinic drugs may have been reached, with the only new
innovation being that of dose flexibility with the newer compounds,
such as darifenacin, solifenacin and fesoterodine.7
Recent advances in the understanding of the physiopathology of OAB
have driven a huge amount of basic and clinical research of novel
pharmacological compounds, mostly reviewed thereafter, targeting
different molecular pathways found to be involved in OAB in the CNS
and in the lower urinary tract (LUT).

Current first-line treatment rely mainly on conservative therapeutic
strategies, such as behavioural therapy (including patient education,
fluid and diet management, bladder retraining, pelvic floor muscle
training and biofeedback), functional electrical stimulation, clean
intermittent catheterisation and pharmacological treatment. Second-line
treatment options in refractory patients are neuromodulation (US
Food and Drug Administration [FDA]-approved), botulinum toxin (BoNT)
and surgery.
Antimuscarinic drugs are FDA-approved for OAB and represent the
mainstay of pharmacological treatment. Unfortunately, antimuscarinics
are not definitively and always effective in controlling OAB symptoms,
the associated quality of life improvement is often limited and
rarely ‘cures’ OAB. Furthermore, bothersome side-effects (including
dry-mouth, nausea, constipation and central nervous system [CNS]
adverse effects) due to their lack of bladder selectivity, cause poor
long-term adherence to treatment.5,6 The upper limit of efficacy of
Centrally Acting Drugs
GABAergin Agents
Gamma-aminobutyric acid (GABA) has been showed to play an
inhibitory role on micturition nervous reflex both centrally and
peripherally.8,9 CNS inhibitory actions of GABAB-receptors agonists,
such as baclofen, appear to be useful for controlling micturition
disorders caused by C-fibre activation in the bladder. Thus,
intrathecal baclofen attenuated oxyhaemoglobin-induced DO and,
given subcutaneously, had an inhibitory effect in mice with citric
acid-induced DO. Human clinical studies supported a possible role
for chronic intrathecal baclofen pump infusion in the treatment of
patients with NDO.10,11
Gabapentin was originally designed as an anticonvulsant
GABA-mimetic crossing the blood–brain barrier, although it does not
appear to act via GABA receptors and its mechanism of action, likely
binding a subunit of the alpha-2-delta unit of voltage-dependent

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Future Perspective in Pharmacological Treatment Options for Overactive Bladder Syndrome
calcium channels and inhibiting afferent C-fibres nerve activity, remains
unclear.12,13 In a pilot study, gabapentin improved both symptoms and
urodynamic parameters in NDO patients.14 In antimuscarinics-refractory
patients with OAB and nocturia, oral gabapentin was well tolerated
and improved symptoms in 14 out of 31 patients.15 A randomised
controlled trial (RCT) exploring the use of gabapentin in OAB patients
are currently recruiting participants.
Opioids
Several lines of evidence suggest that opioids influence the
micturition control at both central and peripheral sites.16 Opioids
inhibit detrusor activity, likely via CNS-based mechanisms and delta (δ)
(OP1), kappa (κ) (OP2) and mu (μ) (OP3) opioids receptors.17 A μ- and
δ-receptor-mediated, tonic, inhibitory action was also proposed in
human detrusor.8
Tramadol, an effective and safe analgesic, is a weak μ-agonist, but
its metabolites have a stronger μ-agonist effect and also inhibit the
re-uptake of noradrenaline and 5-hydroxytryptamine (5-HT). Intravenous
tramadol increased threshold pressure and micturition volume in
rat18 and, at doses below or similar to those giving analgesia in rats
and humans, abolished experimentally-induced DO.19,20 Tramadol
sustained-release twice-daily was more effective than placebo in
reducing the number of incontinence episodes and improving
urodynamic parameters in patients with IDO, the main adverse event
having been nausea.21 Given epidurally, tramadol increased bladder
capacity and compliance, and delayed filling sensations without
affecting voiding phase.22
Interestingly, a growing volume of information supports a role for the
δ-receptor in the regulation of bladder activity and animal studies
showed beneficial effects of a novel oral δ-receptor agonist.23
Altogether, the principle of opioids receptors agonism may have a
place in the future therapy of OAB and deserves further investigations.
Opioid receptors demonstrated in the urothelium should be explored
as potential targets for drugs influencing bladder function.
Antidepressants
It has been suggested that there may be a deficiency of monoamine
behind both depression and urinary incontinence/OAB and that the
antidepressants, inhibiting the monoamine re-uptake, may become a
treatment option in OAB patients.16
Several tricyclic antidepressants, such as imipramine, actually
improve storage lower urinary tract symptoms (LUTS) and DO but at
the cost of significant side effects.24–26 Studies are ongoing to establish
if the antidepressants selective serotonin re-uptake inhibitors (SSRIs),
such as escitalopram, are effective in improving LUTS in OAB patients.
Duloxetine is a combined noradrenaline and 5-HT re-uptake inhibitor
that, increasing the neural stimulation to the striated urethral
sphincter via pudendal nerves during the storage phase, improves
stress urinary incontinence.27 Duloxetine also improves bladder
capacity in the animal model. However, the central actions of
duloxetine may explain its beneficial effects observed in two RCTs
on women with mixed incontinence,28,29 and with ‘wet’ and ‘dry’ OAB
associated with DO or reduced bladder capacity.30 These findings
provide evidence for the concept that duloxetine-like drugs may have
potential for OAB treatment.
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Besipirdine, a combined inhibitor of serotonin and noradrenaline
re-uptake (SNRI), is a potential novel first-in-class oral treatment for OAB
currently in Phase III development after promising preclinical results.31
Luteinising Hormone-releasing Hormone Antagonists
Based on the favourable effects on LUTS with the clinical use of
5-aplha-reductase inhibitors, other antiandrogens such as antagonists
of luteinising hormone-releasing hormone (LHRH) have been
studied in patients with benign prostatic hyperplasia (BPH). The LHRH
antagonist cetrorelix, given subcutaneously at submaximal noncastrating
doses, rapidly improved LUTS in male patients.32 Preclinical data using
ganirelix showed that both systemic and intravesical administration
counteracted experimental DO in rats, leading to the conclusion that a
peripheral site of action of these class of drugs in the bladder cannot be
excluded.33 Whether or not this new pharmacological way of treatment
of OAB is a valid alternative to existing therapies is still to be established.
Peripherally Acting Drugs
Beta-Adrenoceptors Agonists
Beta-adrenoreceptors (ARs) mediate the noradrenaline-induced
activation of the cyclic adenosine monophosphate (cAMP) pathway
resulting in detrusor relaxation.16 Beta (β)3-ARs are by far predominant
in the human detrusor muscle and significant evidence has been
accumulated about the peripheral inhibitory effects of β3-AR agonists
on detrusor contractility, NDO and experimentally-induced or bladder
outlet obstruction (BOO)-associated OAB.8,34–36 Several β3-AR agonists
are currently been evaluated as possible treatment for OAB patients,
such as mirabegron, ritobegron (KUC-7483) and solabegron.
Mirabegron is a novel, once-daily orally active, first-in-class, potent
β3-AR agonist at the late stages of clinical development.36 An important
proof-of-concept study suggesting possible efficacy of mirabegron in a
clinical trial setting of OAB patients has been published.37 Recently, two
large-scale Phase III trials, one conducted in the US and Canada,38 and
one conducted in Europe and Australia,39 have confirmed its efficacy
and tolerability for up to 12 weeks of therapy. Post-hoc analysis of
these trials showed that both mirabegron doses (50 and 100 mg
once-daily) were effective in antimuscarinic-treatment-naïve patients
and in patients who failed prior OAB antimuscarinic therapy.40
Another multinational Phase III RCT assessed the long-term (12 months)
safety and efficacy of the drug, reporting that for both doses the
incidence and severity of treatment-emergent and serious adverse
effects were similar with established OAB therapy, as well as the
improvement in OAB symptoms, while the incidence of dry mouth was
>3-fold lower compared with tolterodine slow release (SR) 4 milligram
(mg) group.41 As soon as regulatory authorities approve its clinical
use, mirabegron may be an alternative option for OAB patients in the
near future.
Phosphodiesterase Inhibitors
Phosphodiesterase (PDE) enzymes degrade cyclic nucleotides and it
has been shown that PDE inhibitors (PDE-Is) can reverse the
antimuscarinic-induced tension of human detrusor and enhance
intracellular cAMP-mediated and cyclic guanosine monophosphate
(cGMP)-mediated relaxation of LUT smooth muscle.42 Amongst six PDE
families identified in human detrusor, PDE1–5 have been described to
be involved in the regulation of the detrusorial activity.43–48
Preclinical data and a RCT suggested that vinpocetine, a PDE1-I, could
be effective in patients with refractory OAB.42,45 PDE4-Is, such as
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Overactive Bladder & Incontinence
rolipram and IC485, have been showed to inhibit detrusor phasic
contractile activity as well.47,49
Preclinical findings on PDE5-Is,46 together with the observation that
patients treated for erectile dysfunction with sildenafil reported
improvement of their LUTS,50 prompted interest in the use of these
compounds in the treatment of BPH, LUTS and OAB. McVary et al.51
reported on the beneficial effects on urinary symptoms score of the
treatment with sildenafil (50–100 mg daily for 12 weeks) in men of 45
years or older affected by erectile dysfunction and LUTS. Similar results
were reported in RCTs using tadalafil or vardenafil.48,52,53 Interestingly, it
does not appear that these drugs act by improving flow rate.
Although promising, PDE-Is require further evaluations in order to
define their mechanism and site of action in LUT, and their role and
optimal dosage in the management of patients with LUTS/OAB.
Neurokinin Receptors Antagonists
Numerous neuropeptide/receptor systems are expressed in the LUT in
both neural and non-neural (e.g. urothelium) components.54 Substance P
(SP) and neurokinin A (NKA) possess the highest affinity for NK1 and NK2
receptors, respectively. Many experimental observations are available
indicating that spinal and supraspinal NK receptors may modulate the
micturition reflex55–59 and that NK-receptors selective antagonists
counteract NDO.60
Aprepitant is a CNS-penetrating NK1-receptor antagonist used to
treat chemotherapy-induced nausea. A pilot, proof-of-concept
RCT including 125 post-menopausal women with urge or mixed
(urge-predominant) incontinence reported that aprepitant was well
tolerated and significantly decreased OAB symptoms compared with
placebo. 61 Another NK1 antagonist, serlopitant, significantly
decreased the primary endpoint of daily micturitions but not the
secondary endpoints compared with placebo and did not offer
advantages in efficacy compared with tolterodine in a RCT.62 Several
other NK1 antagonists are under evaluation in Phase II trials.
Nociceptin Opioid Peptide Receptor Agonists
Nociceptin or orphanin FQ (N/OFQ) is an endogenous ligand of
opioid-like receptor-4 (or NOP receptor). Several studies suggested that
N/OFQ inhibits the micturition reflex in rats by acting on the afferent
bladder signalling and on supraspinal micturition sites,8,63 although a
peripheral excitatory effect was also detected.63 A RCT including 14 NDO
patients found that intravesical N/OFQ, but not placebo, increased
significantly bladder capacity and reflex volume,64 and the results were
replicated in a multicentre study.65 As a result, selective NOP receptor
agonists have been suggested as a prospective alternative for the
treatment of OAB worthy of further investigation.
Antiserotoninergic Agents
The peripheral excitatory function of serotonin (5-HT) was
demonstrated in animal and human detrusor and appears to be
increased in disorders known to be associated with DO, such as BOO
and diabetes.66–70 Symptomatic benefit was reported in patients with
diabetes and refractory OAB treated with the 5-HT2 antagonist
sarpogrelate.71 Selective 5-HT4 and 5-HT1A receptor antagonists such
as piboserod and ketanserin, respectively, potently inhibited the
micturition reflex in animal models and the human detrusor
contractile response.67,68,72,73 As a result, 5-HT receptor inhibitors have
been suggested as promising drugs for the treatment of OAB.
122
Purinergic Receptors Antagonists
Several studies suggested that the adenosine 5’-triphosphate (ATP)
and purinergic ionotropic (P2X) receptors are involved in OAB. This is
not surprising taking into account that purinergic transmission has
been found on both afferent and efferent signalling pathways within
the LUT and appears to be abnormally enhanced with ageing and
DO.74 Preclinical evidences support a possible role of purinergic
antagonist in the management of LUT dysfunctions75 and novel
compounds in this class possess attributes that offer the potential for
optimisation into candidate drug molecules.76
Vanilloids and Transient Receptor
Potential Vanilloids Agents
‘Transient receptor potential vanilloids 1’ (TRPV1) is the principal
transduction channel for nociception and is expressed by the urothelial
cells and the sensory unmyelinated C-fibres from the bladder.77,78 Its
accepted that abnormal activity of C-fibre afferent neurons may trigger
neurogenic and non-neurogenic DO.79–81 ‘Vanilloids’ such as capsaicin
are the best known natural TRPV1 agonists and several trials showed
that, given intravesically, they can cause a sustained activation of the
TRPV1 receptor resulting in a desensitisation of C-fibres with beneficial
effects in patients with NDO/IDO, but at the cost of non-negligible
side effects.82–84 Resiniferatoxin is at least as effective as capsaicin,
without the local side-effect but formal RCT are needed to determine its
precise use and dosage.85–87
The cloning of the TRPV1 receptor has accelerated the search for
novel ultra-potent ‘capsaicinoid’ that are likely to represent a safer
way to treat OAB by avoiding the need for desensitisation.88–90
Although promising, published clinical data on TRPV1 antagonists
remain sparse and the potential to cause hyperthermia could be a
possible dose-limiting effect.
Botulinum Toxin
Seven serotypes of BoNT are known, but only types A and B have been
used in urology. The light chain of BoNT, with protease activity, degrades
the Soluble N-ethylmaleimide-sensitive factor Attachment Protein
REceptor (SNARE)-complex protein synaptosomal-associated protein 25
(SNAP-25), thus preventing neurosecretory vesicles from docking/fusing
and releasing acetylcholine (Ach) and other neurotransmitters from
the axon endings; this results in a long-lasting neuronal blockade
leading to decreased muscle contractility and chemical denervation at
the injection site.91 The process is site-specific, dose-dependent and
reversible with return to muscular function in about 3–6 months. The
clinical efficacy in the OAB setting may be largely dependent on
the inhibition of release of several signalatory molecules (e.g. ACh,
ATP, SP, nerve growth factor [NGF]), the downregulation of purinergic
(P2X3) and TRPV1 receptors expression on afferent neurons, and
the reduction of the contractile and gap junction proteins in the
suburothelial layer.92
From the first study by Schurch et al.93 in 2000, many other reports
have provided level one evidence on the long-term efficacy and
safety of intradetrusor injection of BoNT type A and B in patients
with NDO and short/medium-term efficacy and safety in patients with
idiopathic OAB.94–98 As a result, BoNT-A has recently emerged as
novel treatment for OAB refractory to antimuscarinics and has been
recently approved for the treatment of NDO in patients with spinal
cord lesion or multiple sclerosis in several countries. Even though it
promises to become a major future treatment for the OAB, urologists
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Future Perspective in Pharmacological Treatment Options for Overactive Bladder Syndrome
have to be aware that BoNT has a narrow therapeutic window, can
cause acute urinary retention and large post-void residual, remains
off-label in many countries and further investigations are needed to
define better long-term effects of chronic treatment, the optimal
doses and dilution, site of injection and patient population.
Interestingly, in order to offer patients with OAB a less invasive
treatment, RCTs are ongoing exploring the efficacy of simple
intravesical catheter-based instillation of BoNT-A and of liposome
encapsulated BoNT-A or lipotoxin that are liquid liposome delivering
BoNT-A through the urothelium to the suburothelial space, but not
into the detrusor layer, thus preventing urinary retention and avoiding
cystoscopic-guided needle injection.99
Non-steroidal Anti-inflammatory Drugs and
Prostaglandins Receptor Antagonists
Prostanoids (prostaglandins [PGs] and thromboxanes) are synthesised
in both detrusor and mucosa of human bladder by constitutive (COX-1)
and inducible (COX-2) cyclo-oxygenase.100 Some PGs contract isolated
animal and human detrusor and may have a role in the maintenance of
detrusor tone and in the modulation of efferent and afferent
neurotransmission.101–103 Preclinical studies suggested a role of PGE2,
which acts via mainly EP receptors, in the pathophysiology of DO.103–105
Non-steroidal anti-inflammatory drugs (NSAIDs) such as indometacin,
flurbiprofen, ketoprofen and loxoprofen, which act as COX-inhibitors,
were found to be able to increase bladder capacity in rats and prolong
micturition interval without impairing voiding phase, with favourable
effects on urinary symptoms reported also in humans.106–110 Other
preclinical findings have also indicated COX-2 selective inhibitors as
potential drugs aimed to treat OAB, also by intravesical instillation.111,112
However, clinical evidence of efficacy of COX-inhibitors in the setting
of OAB remains scarce and gastrointestinal side effects and effects on
endothelial and renal COX-2 activities represent important issues.113,114
The most promising future therapy could be the use of selective agents
that target specific PG receptor subtypes. Recently EP1 receptors have
been demonstrated in the urothelium where they may elicit bladder
afferent activity during inflammation, probably through TRPV1. An
involvement in BOO-related DO was suggested based on experiments in
EP1 knockout mice.115 Based also on early observations116 and promising
preclinical results with novel EP1 antagonists, it was suggested that EP
receptors antagonism may have potential as a treatment of OAB.117
Nitric Oxide-releasing Drugs
Nitric oxide (NO) has been identified as an important neurotransmitter
involved in the control of the human urinary tract. It has been suggested
that NO has a key role in the detrusor relaxation during the storage
phase.8 This function might be mediated by the NO-induced elevation of
intracellular cGMP. Nitroflurbiprofen fits in a new class of NO-releasing
drugs (NO-donating NSAIDs) which, combining both antiphlogistic and
NO-donating activity, are being investigated for the treatment of OAB.118
Drugs Active on Ion Channels
Calcium Channels Inhibitors
Several preclinical studies suggested a role for calcium channel,
especially for voltage-gated L-type channels, in the activity of detrusor
muscle of mammalian species and humans.119 Inhibitors of L-type
channels have been shown to inhibit detrusor contraction,120 however,
clinical evidence is very scarce,121 and available information does not
EUROPEAN UROLOGICAL REVIEW
indicate that oral therapy with these drugs is effective, possibly owing
to the use of low doses to limit cardiovascular side effects.
Potassium Channels Openers
Potassium channels opening (KCO) drugs reduce intracellular calcium
concentration inducing detrusor relaxation in various mammalian
species.122,123 It has been suggested that KCO drugs inhibit also
capsaicin-sensitive bladder afferent nerves activity. Several drug
companies are developing bladder-selective KCO drugs aimed at
OAB treatment without adverse effects on the heart or vascular
system. Although promising preclinical data have been published with
first generation ATP-dependent potassium channels (KATP) openers
(cromakalim, pinacidil and nicorandil) and with the most interesting
novel agent, ZD0947, a Phase II RCT failed to demonstrate superiority
of ZD0947 compared with placebo for the treatment of OAB.124 Other
agents of this class in preliminary developmental stages, such as
ZD6169, have shown favourable profiles in animal models.125
The big calcium-activated potassium channel (BKCa) also appear to
play a key role in smooth bladder muscle excitability126 and BKCa channel
openers, such as NS-8, suppress the micturition reflex in rats127 and
might have the potential for treating OAB patients. Apamin, a selective
blocker of small (SKCa) potassium channels, the new NS309 acting on
both SKCa and intermediate (IKCa) potassium channels128 and, finally,
A-type voltage-dependent (KV) potassium channel openers, such as
retigabine and KV-7158, also showed favourable preclinical effects.129,130
Although no KCO drugs have thus far passed the proof-of-concept stage
and clinical use of KCO drugs is limited by significant cardiovascular side
effects, potassium channels may be promising targets for OAB treatment
and deserve future studies in that they may alleviate OAB symptoms
without dry mouth or without increasing post-void residual urine.
Mechanosensitive Sodium Channels Blockers
There is increasing evidence that mechanosensitive ion channels,
such as degenerin/epithelial sodium channel (ENaC) and TRP channel
families, play key roles in the mechanosensory transduction of the
urinary bladder.131 The subgroup of ENaCs, which are proton-gated
and often found in the urothelium and detrusor muscles, is acid-sensing
ion channels (ASIC). ENaC and ASIC are responsive to hydrostatic
pressure and an increase in intrabladder pressure may activate
these channels and trigger afferent signalling. Consistently, in
human bladder the expression of ENaC increases in patients with
BOO or OAB. As a result, pharmacological interventions targeting
ENaC/ASIC mechanosensitive ion channels may provide a new
approach for the treatment of OAB.131,132
Rho-kinase Inhibitors
The small guanosine triphosphate hydrolase (GTPase) named Ras
homologue family member A (RhoA) and one of its downstream
effectors, Rho-kinase (ROCK, type I and type 2), have been shown to
play an important role in calcium-independent pathway of smooth
muscle contraction.133 RhoA pathway upregulation is associated with
bladder changes occurring in patients with diabetes, BOO and DO.134,135
As a result, ROCK-inhibitors may prove to be therapeutically useful in
the treatment of LUT disorders and preclinical findings with Y-27632
are promising.136 Many novel ROCK-inhibitors have been identified but
without selectivity for the detrusor muscle; selective inhibitors of
hypothetic detrusor-specific ROCKs might allow to disassociate the
unwanted hypotensive effects of these drugs.
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Overactive Bladder & Incontinence

Vitamin D3 Receptor Agonists
Vitamin D3 receptors have been found in rat and human bladder
and vitamin D3 receptor agonists, such as elocalcitol, inhibit the
RhoA/Rho kinase pathway and has also been showed to inhibit
the androgen-dependent and androgen-independent proliferation
of BPH cells more potently than finasteride. 137 In a Phase IIb trial in
patients with BPH, treatment with elocalcitol significantly reduced
prostate volume compared with placebo; storage urinary symptoms
and urodynamic parameters were comparable to the tamsulosin. 138
Unfortunately, in a Phase IIb trial, elocalcitol given to OAB patients
failed to meet the primary endpoint leading BioXell to decide to
terminate all further clinical development of elocalcitol, including
an uncompleted Phase IIa trial in patients with male infertility.
However, given the novel mechanism of action, efficacy profile
and improved tolerability of elocalcitol, the compound deserves
further investigation. 139
Vasopressin Analogues
Vasopressin (also called antidiuretic hormone) induces contraction
of vascular smooth muscle and water reabsorbtion in the renal
medulla via V1 and V2 receptor. A relative deficiency in vasopressin
production is considered a common cause of nocturnal polyuria.140
Desmopressin is a synthetic vasopressin receptor agonist with
strong antidiuretic effects, currently licensed for the treatment of
children and adults with nocturia. Favourable effects have been
reported in patients with nocturia associated to BPH and OAB.141,142,143
Antidiuresis with desmopressin, by decreasing renal urine production,
would prolong bladder filling-time thereby increasing the time to
reach maximum capacity, thus reducing OAB symptoms and
especially nocturia and its negative effects on sleeping well. A
multicentre, proof-of-concept, Phase II RCT demonstrated that oral
desmopressin can be considered a novel, feasible and safe method of
treatment for adults with OAB.143 Caution must be used before
considering desmopressin in patient with cardiovascular risk factors,
and monitoring of sodium plasma level is recommended in order to
prevent a dangerous hyponatraemia especially in the elderly.
Urothelium-targeting Therapies
Urothelial cells exhibit specialised sensory and signalling properties
that allow them to respond to chemical, thermal or mechanical stimuli
and engage in reciprocal communication with neighbouring nerves and
interstitial cells.78 These properties include:
• expression of receptors for Ach, noradrenalin, neuropeptides
and vanilloids;
• responsiveness to transmitters (ATP, SP) released from
sensory nerves;
• close physical association with afferent nerves; and
• ability to release several signalling molecules (ATP, ACh,
cAMP, PGs, NO, detrusor-relaxing factors).78
It is supposed that urothelium could mediate, totally or partly, the
effect of many drugs, such as vanilloids, BoNT, PDE inhibitors and
anticholinergics.78,144 A non-neuronal cholinergic system, composed
by urothelial Ach, muscarinic receptors and specific molecular
components, has been recently described and it has been suggested
to mediate partly the effects of antimuscarinics.144 In the future
non-neuronal and neuronal systems might be differentially targeted
by pharmacological approaches.133,144
Based on the apparent complexity and relevance of the urothelial
functions in normal and pathological bladder, it seems reasonable to
foresee future major advances in the field of intravesical therapies,
especially if intravesical drug delivery systems under development will
become available in the clinical practice.145
Conclusions
Although antimuscarinic agents will continue to represent the gold
standard for the first-line pharmacological treatment of OAB in the
near future, their limitations urge the necessity of novel compounds
in this field of pharmacotherapy. In the last years a huge amount of
research shed light on the pathophysiology and molecular bases
of OAB indicating a number of potential pharmacological targets
for the development of future agents that may ultimately provide
alternative treatment options for OAB patients. While some of
the novel compounds, such as β3-adrenoceptors agonists and
botulinum toxin, promise to become major future treatment options
for the OAB, several other investigational agents in the pipeline are
in different stages of development with some of them (such as
NK1-antagonist) having already entered proof-of-concept studies
with promising results. n

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