all
`SVIR
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`THE OVERACTIVE BLADDER: PHARMACOLOGIC BASIS OF
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`DRUG TREATMENT
`
`KARL—ERlK ANDERSSON
`
`ABSTRACT
`
`0bjectives.To provide an overview of the basis for drug treatment of the overactive bladder.
`Methods.Published information is evaluated.
`
`Resu|ts.The causes of bladder overactivity are not known, but theoretically, increased afferent activity,
`decreased inhibitory control
`in the central nervous system [CNS] or peripheral ganglia, and increased
`sensitivity of the detrusor to efferent stimulation may be involved. Several CNS transmitters can modulate
`voiding, but few useful drugs with a defined CNS site of action have been developed. Drugs that stimulate
`y-aminobutyric acid receptors are used clinically. Potentially, drugs affecting opioid, 5-hydroxytryptamine,
`norepinephrine, dopamine, and glutamatergic receptors and mechanisms can be developed, but a selective
`action on the lower urinary tract may be difficult to obtain. Traditionally. drugs used for treatment of bladder
`overactivity have had a peripheral site of action, mainly efferent neurotransmission or the detrusor itself.
`Antimuscarinic drugs, B—adrenoceptor agonists, wadrenoceptor antagonists, drugs affecting membrane
`channels. prostaglandin synthetase inhibitors, and several other agents have been used with limited success.
`New information on the at-adrenoceptor and muscarinic receptor subtypes in the human detrusor has
`emerged and may be the basis for the development of new compounds with effects on bladder overactivity.
`Decreasing afferent activity seems an attractive therapeutic approach, and drugs affecting afferent nerves by
`causing release of tachykinins, such as capsaicin and analogs, as well as agents blocking tachykinin
`receptors, may be of therapeutic interst.
`treatment of bladder overactivity,
`the
`Conclusions.New drugs,
`specifically designed for
`desirable. UROLOGY 50 [Suppl 6A]: 74-84, 1997. © 1997, Elsevier Science inc. All rights reserved.
`
`are
`
`I‘ 0 effectively treat the overactive bladder, iden-
`tification of suitable targets for pharmacologic
`intervention is a prerequisite. With the present
`knowledge of the central1 and peripheral2 control
`of mictu rition, sites and drug mechanisms that can
`influence bladder function can easily be identified.
`However, the problem is not only to inhibit blad-
`der contractinn, but to eliminate overactivity with-
`out disturbing normal rnicturition. Even if this
`might be possible, there is also a selectivity prob-
`lem: how to affect bladder function without inter-
`
`fering with the function in other organ systems. In
`many cases of urinary incontinence (U1) associated
`with the overactive detrusor, the clinical therapeu-
`tic problem is twofold: urine leakage and lower
`
`This study was supported by the Swedish Medical Research
`Council (Grant No. 6837)
`From the Department ofclinical Pharmacology, Lund Univer-
`sity Hospital, Lund, Sweden
`Reprint requests: Prof. Karl-Erik Anzlersson, Department of
`Clinical Pharmclcology, Lund University Hospital, 5-221 85
`Lund, Sweden
`
`© i997, ELsEv1t=.R SCIENCI-_ INC.
`74 mi. Rlt'§llT.‘i Rfistzkviain
`
`urinary tract (LUT) symptoms. Overactive detru-
`sor function may or may not be associated with
`LUT symptoms or urine leakage, and the relations
`between these factors are far from clarified.
`
`Below, the pharmacologic basis for some of the
`current therapeutic alternatives for treatment of
`bladder overactivity, and possible future develop-
`ments, are briefly discussed.
`
`IDENTIFICATION OF DRUG TARGETS
`
`As discussed in detail elsewhere} several reflexes
`are involved in the storage of urine and in voiding.
`During storage, at low levels of vesical afferent ac-
`tivity, spinal reflexes are active mediating contrac-
`tion of urethral sphincter mechanisms through so-
`matic (striated muscle) and sympathetic (smooth
`muscle) nerves. Sympathetic nerves may also me-
`diate detrusor and ganglionic inhibition. There is
`no activity in the sacral parasympathetic outflow.
`Micturition is initiated by distention of the blad-
`der, activating mechanoreceptors in the bladder
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`0090-4295/97/517.00
`PII S0090-4295(97)00595-5
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`Patent Owner, UCB Pharma GmbH — Exhibit 2042 - 0001
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`Conical and
`
`dlencephallc
`
`mechanisms
`l
`
`splnal tract
`neurons
`
`A8-fibers
`
`mschanlsms
`
`spinal emrent
`i»—1
`
`-fl
`
`FIGURE 1.
`
`Micturition reflex pathways. Based on de Croat et at.’
`
`wall. This triggers a high level of activity in small
`myelinated afferent nerves (A8), which via the dor-
`sal root ganglia reaches the lumbosacral spinal
`cord (Fig. 1).‘ The A 8 afferents connect to a spine-
`bulbospinal reflex consisting of an ascending limb
`from the lumbosacral spinal cord, an integration
`center in the rostral brain stem (which is known as
`the pontine micturition center [PMC]), and a de-
`scending limb from the PMC back to the parasym-
`pathetic nucleus in the lumbosacral spinal cord.
`Afferent information may also be conveyed by
`small unmyelinated (C-fiber) vesical afferents,
`which have a high mechanical threshold but may
`be activated by irritation of the bladder mucosa.
`They may also be active in spinal cord injuries.
`Efferent micturition reflex pathways reach the
`bladder through the pelvic nerves.
`
`CAUSES OF BLADDER OVERACTIVITY
`
`There is still no consensus about the reasons for
`
`developing bladder overactivity. Theoretically,
`there may be 1) increased afferent activity, 2) de-
`creased inhibitory control in the central nervous
`system (CNS) or in peripheral ganglia, 3) increased
`sensitivity to efferent stimulation in the detrusor,
`or a combination of these factors. Brading and
`Turner3 proposed that all cases of detrusor overac-
`tivity (idiopathic, neuropathic, and obstructive)
`have a common feature—a change in the proper-
`ties of the smooth muscle of the detrusor, predis-
`posing it to unstable contractions—and that this
`change is caused by a reduction in the functional
`motor innervation of the bladder wall. They also
`stressed that bladder instability, as shown in a pig
`model of obstruction, may occur without partici-
`
`UROLOGY 50 (Supplement EA), Uecember 1997
`
`pation of a micturition reflex. It seems difficult,
`however, to accept that a primary change in the
`detrusor should be the cause of the bladder over-
`
`activity seen in, for example, stroke patients. Even
`if the pathogenesis of bladder overactivity is un-
`known (and most probably is different in patients
`with outflow obstruction, neurogenic bladders,
`and idiopathic detrusor instability [DI]), drug tar-
`gets for treatment of U1 may be found peripherally
`or in the CNS.
`
`CNS TARGETS
`
`Anatomically, several CNS regions may be in-
`volved in micturition control: supraspinal struc-
`tures, such as the cortex and diencephalon, mid-
`brain, and medulla, and also spinal structures}
`Several transmitters are involved in the micturition
`
`reflex pathways and may be targets for drugs aimed
`at control of micturition. However, few drugs with
`a CNS site of action have been developed. Drugs
`that stimulate y—aminobutyric acid (GABA) recep-
`tors are used clinically. The potent inhibitory ef-
`fects by opioids are well known, but have not been
`used therapeutically. Potentially, drugs that affect
`GABA, opioid, 5—hydroxytry“ptamine (serotonin),
`norepinephrine, dopamine, and glutamic acid re-
`ceptors and mechanisms can be developed, but a
`selective action on the LUT may be difficult to ob-
`tain.
`
`GABA
`
`Both GABAA and GABAB receptor agonists sup-
`press spinal and supraspinal Components of the
`micturition reflex, and there are reasons to believe
`that in some species the supraspinal micturition
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`reflex pathway is under a tonic GABA~ergic inhib-
`itory control.‘ The GABAB agonist baclofen is con-
`sidered to depress monosynaptic and polysynaptic
`motor neurons and interneurons in the spinal cord
`and has been used in voiding disorders, including
`detrusor hyperreflexia secondary to lesions of the
`spinal cord.“ The drug may also be an alternative in
`the treatment of idiopathic detrusor overactivity?
`However, published experience with the drug is
`limited. lntrathecal baclofen may be useful in pa-
`tients with spasticity and bladder dysfunction and
`may increase bladder capacity.‘-*5 The therapeutic
`potential in bladder overactivity of the new gener-
`ation of antiepileptic drugs, which are able to en-
`hance GABA-ergic transmission by, for example,
`inhibition of GABA reuptake or GABA-transami-
`nase," would be worth investigating.
`
`ENKEPHALINS
`
`Enkephalinergic varicosities are prominent in
`the regions of the spinal parasympathetic nucleus
`and the PMC, and enkephalins effectively depress
`micturition and sphincter reflexes by stimulation
`of to-, 5-, and K—receptors.' It is well established
`that morphine and other opioids depress micturi-
`tion, and that this effect can be blocked by nalox—
`one. However, so far drugs with effects o11 opioid
`receptors do not seem to have been developed for
`the treatment of bladder overactivity in humans.
`
`SEROTONIN
`
`The lumbosacral sympathetic and parasympa-
`thetic autonomic as well as sphincter motor nuclei
`receive a dense serotonergic input from the raphe-
`spinal pathway} Drugs interfering with serotonin
`or with serotonin receptors have not been system-
`atically tested as a treatment of the overactive blad-
`der in humans. Whether or not imipramine, which
`among other effects blocks the reuptake of seroto-
`nin, depresses bladder overactivity by this mecha-
`nism,‘‘’ has not been established.
`
`NOREPINEPHRINE
`
`Sympathetic, parasympathetic, and somatic nu-
`clei in the lumbosacral spinal cord receive inputs
`from noradrenergic neurons in the brain stem.
`Bladder activation through these bulbospinal nor-
`adrenergic pathways may involve excitatory a1~ad—
`renoceptors.“ Both in normal rats and in rats with
`bladder hypertrophy secondary to outflow ob-
`struction undergoing continuous cystometry, dox-
`azosin, given intrathecally, decreased micturition
`pressure. '3 The effect was much more pronounced
`in the animals with hypertrophied/overactive blad-
`ders. Doxazosin did not markedly affect the fre-
`quency or amplitude of the unstable contractions
`observed in obstmcted rats. It was suggested that
`doxazosin may have an action at the level of the
`
`76
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`spinal cord and ganglia, thereby reducing activity
`in the parasympathetic nerves to the bladder, and
`that this effect was more pronounced in rats with
`bladder hypertrophy than in normal rats. Whether
`or not a spinal/supraspinal site of action contrib-
`utes to the relief of symptoms, including bladder
`overactivity, produced by ozpadrenoceptor antag-
`onists in patients with benign prostatic hypertro-
`phy (BPH),'3 remains to be established.
`
`DOPAMINE
`
`It is well known that patients with Parkinson‘s
`disease may have detrusor hyperreflexia, possibly
`as a consequence of nigrostriatal dopamine deple-
`tion and failure to activate inhibitory dopamine D1
`receptors.” However, other doparninergic systems
`may activate D2 receptors, facilitating the micturi-
`tion reflex. Thus, Sillen et al.‘5 showed that apo-
`morphine, which activates both D1 and D2 recep-
`tors, induced overactivity in anesthetized rats via
`stimulation of central dopaminergic receptors. The
`effects were abolished by infracollicular transec-
`tion of the brain and by prior intraperitoneal ad-
`ministration of the centrally acting dopamine re-
`ceptor blocker spiroperidol. Kontani et al.‘‘‘-”
`suggested that the bladder overactivity induced by
`apomorphine in anesthetized rats resulted from
`synchronous stimulation of the micturition cen-
`ters in the brain stem and spinal cord, and that the
`response was elicited by stimulation of both dopa-
`mine D1 and D2 receptors. Whether or not drugs
`that block dopamine receptors can be used for
`treatment of bladder overactivity has not been es-
`tablished.
`
`GLUTAMIC ACID
`
`N-methyl-1)-aspartate (NMDA) and ot-arnino-
`3—hydroxy—5-methyl-4—isoxazole propionic acid
`(AMPA) glutarnatergic receptors seem to play an
`essential role at excitatory synapses in the descend-
`ing pathway from the PMC to the spinal parasym-
`pathetic nucleus.“ In adult anesthetized rats, in-
`hibitors of NMDA or AMPA receptors depress the
`amplitude of reflex bladder contractions and in-
`hibit voiding. In unanesthetized animals, on the
`other hand, NMDA receptor antagonists decrease
`the volume threshold for inducing bladder reflex
`contractions and facilitate micturition. The poten-
`tial role of drugs acting on glutamatergic receptors
`for control of bladder overactivity needs further
`study.
`
`PERIPHERAL TARGETS
`
`Anatomically, drug targets for treatment of blad-
`der overactivity may be the bladder, urethra, pros-
`tate, ganglia, or peripheral nerves. The mecha-
`nisms most often aimed at are receptors or ion
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`UROLOGY 50 (Supplement 6A), December 1997
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`Patent Owner, UCB Pharma GmbH — Exhibit 2042 - 0003
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`channels known to be involved in the control of
`
`bladder contraction, for example, muscarinic re-
`ceptors and L—type calcium channels. Other mech-
`anisms involved in neurotransmission or in the ex-
`
`the detrusor
`citation—c0ntraction coupling of
`smooth muscle may also be targets for pharmaco-
`logic interventions.
`
`MUSCARINIC RECEPTORS
`
`Antimuscarinic drugs are still the most widely
`used treatment of urge, sensory, and motor urge
`incontinence.‘ However, the currently used drugs
`lack selectivity for the bladder,'3 which limits their
`usefulness. Theoretically, agents with selectivity
`for the bladder might be obtained if the subtype(s)
`mediating bladder contraction, and those produc—
`ing the main side effects of antimuscarinic drugs,
`were known.
`
`Several subpopulations of muscarinic receptors
`have been identified, and at least five different sub-
`types (m1—m.,) have been cloned. Pharmacologi-
`cally, four different subtypes (M,—M.,,) have been
`defined,” all with a wide distribution in the body.
`The subtypes that can be demonstrated in the hu-
`man bladder, and those responsible for bladder
`contraction, have been studied using various ap-
`proaches. Cultured human detrusor cells ex-
`pressed M3 receptors linked to phosphoinositide
`hydrolysis,“’ and an important role for M3 recep-
`tors is widely accepted. The M 1, M2, and MT, recep-
`tor subtypes were demonstrated in human detru-
`sor muscle by receptor binding; there was a distinct
`predominance
`of M3
`receptors?“ However,
`Yamaguchi et oil.” were able to demonstrate the
`presence of mRNA encoding the m2 and m3 sub-
`types, but not the m,, m,,, and m_., subtypes, in
`human bladder. Using subtype-specific immuno-
`precipitation, Wang et all.” could demonstrate
`only 1112 and H13 subtypes in human and rabbit de-
`trusor membranes, the ratio of m2 to m3 being 3:1.
`Despite a predominance of mg receptors in rabbit
`and rat detrusor, several investigators have found
`that
`the pharmacologically defined M3 receptor
`mediates contraction.”-23 Recently, however, M1
`receptors were also shown to be able to mediate rat
`bladder contraction in vitro as well as in vivo by
`reversing B—adrenoceptor—mediated relaxation.“
`Future studies with muscarinic receptor antago-
`nists with a selectivity for M3 receptors, such as
`darifenacinlilfi and vamicamide,27~13 will reveal
`whether or not the principle of selective M3 recep-
`tor antagonism offers
`therapeutic advantages.
`Since M3 receptors are located not only in the blad-
`der, but also in the salivary glands and the intes-
`tine, this could mean that two of the most common
`side effects, dry mouth and constipation, will not
`be avoided. However, selective muscarinic recep-
`tor antagonists, such as zamiienacin, may be able
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`UROLOGY 50 (Supplement ESA), December 1997
`
`to distinguish between M3 receptors in different
`smooth muscles.” Tolterodine” lacks selectivity
`for muscarinic receptor subtypes, but still shows
`selectivity for the bladder over the salivary glands
`in an animal model, and possibly in humans.“
`Muscarinic receptors. which on stimulation in-
`hibit transmitter release, have been demonstrated
`on cholinergic nerves in rat bladder? in this organ,
`three types of cholinergic receptors were demon-
`strated to affect acetylcholine release.3233 M2 in-
`hibitory receptors dominated in untreated prepa-
`rations, whereas in physostigmine-treated bladder
`strips, Where the Concentrations of acetylcholine
`were elevated, facilitatory M, and nicotinic recep-
`tors were also demonstrated. Physostigmine had a
`biphasic effect, causing inhibition of acetylcholine
`release at low (M2) and facilitation at high (M1)
`concentrations. The authors suggested that even if
`muscarinic inhibitory receptors appear to be the
`only type activated by acetylcholine released by
`electrical stimulation under normal conditions, fa-
`cilitatory receptors may be activated by the high-
`frequency parasympathetic nerve discharge that
`occurs during micturition. Particularly in patho-
`logic conditions, such as the neurogenic hyperre-
`flexic bladder, a mechanism like this may contrib-
`ute to changes in bladder function. Antagonism of
`M 1 receptors may contribute to bladder inhibition.
`Detrusor denervation as a consequence of out-
`flow obstruction has been demonstrated in pigs
`and humans.“-35 In detrusor from pigs with exper-
`imental outilow obstruction, Sibley“ found that
`the response to intramural nerve stimulation was
`decreased. There was, however, a supersensitivity
`of the detrusor, including a leftward displacement
`of the concentration-response curve for acetylcho-
`line. Sibley” suggested that this was due to partial
`denervation of the bladder as a result of the ob-
`
`struction, and that one consequence of the super-
`sensitivity might be D1. Further supporting the
`presence of cholinergic denervation in the bladders
`of obstructed patients with bladder instability,
`Harrison et al.” found that in detrusor strips from
`such patients, the acetylcholine concentration-re-
`sponse curve was significantly shifted to the left,
`suggesting an increased sensitivity to acetylcho-
`line. On the other hand, Yokoyama et al.3*‘ found
`that the responses to acetylcholine of detrusor
`strips from patients with bladder instability were
`not significantly different from the responses of
`strips from patients without instability. The rea-
`sons for these conflicting results are unclear.
`It might be assumed that the muscarinic receptor
`functions also change in nonobstructed bladders
`showing overactivity. Kinder and Mundy” com-
`pared detrusor muscle from human normal, idio-
`pathic unstable, and hyperreflexic (neurological
`damage) bladders. They found no significant dif-
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`ferences in the degree of inhibition of electrically
`induced contractions produced by tetrodotoxin
`and atropine between detrusor strips from any of
`these bladders, and no significant differences in the
`concentration—response curves for acetylcholine.
`ln overactive bladders without associated neuro-
`
`logic disorders, a decreased number of muscarinic
`receptors has been demonstrated,“ but its relation
`to overactivity remains unclear. Isolated detrusor
`strips from patients with detrusor hyperreflexia
`were supersensitive to both carbachol and KC], but
`responded like normal controls to intramural
`nerve stimulation. The results were interpreted to
`suggest a state of post] unctional supersensitivity of
`the detrusor secondary to a partial parasympa-
`thetic denervation of the detrusor.“
`
`The muscarinic receptors remain a main target
`for drugs used to treat the overactive bladder.
`However, the complexity of muscarinic receptor
`functions in the bladder and elsewhere in the body
`makes it difficult to predict the optimal profile of
`subtype selectivity of antimuscarinic drugs meant
`for treatment of bladder overactivity.
`
`ADRENOCEPTOR5
`
`The role of the sympathetic nervous system in
`human bladder function has been much discussed,
`partly because of the paucity of the adrenergic in-
`nervation of human detrusor muscle. There is no
`
`doubt, however, that norepinephrine is released on
`electrical stimulation of human bladder tissue. in
`
`detrusor muscle from several species, including
`humans, B-adrenoceptors have been shown to
`dominate over a—adrenoceptors, and the normal
`response to released norepinephrine is relax-
`ation.““*3
`
`cx-Aclrenoceptors. The predominating postjunc—
`tional wadrenoceptor subtype in the human LUT
`seems to be ot1.‘*‘*~‘*5 Recently, Walden et al.‘‘5 re-
`ported a predominance of 0:1,,-adrenoceptor pro-
`tein in the human bladder dome, trigone, and blad-
`der base, but which aradrenoceptor Subtype
`predominates functionally has not been clarified.
`Possibly, the otU_—adrenoceptor subtype is the one
`mediating contractile responses.“
`Drugs stimulating oz—adrenoceptors have hardly
`any contractile effects in isolated, normal human
`detrusor muscle. However, even if the or-adreno—
`ceptors have no significant role in normal bladder
`contraction, there is evidence that this may change
`in bladder overactivity associated with, for exam-
`ple, outflow obstruction, neurogenic bladders, and
`idiopathic bladder instability.
`Perlberg and Caine“ found that norepinephrine
`caused contraction instead of the normal relaxant
`
`response in bladder strips from 11 of 47 patients
`with benign prostatic obstruction. They proposed
`that there was a correlation between the response
`
`78
`
`to stimulation on one hand, and bladder instability
`and irritative symptoms on the other. it has been
`observed that in patients with BPH treated with
`cx-adrenoceptor blockers, bladder overactivity
`(bladder
`instability) disappears during treat-
`ment.” Taken together, these observations would
`suggest that there may be an increased a-adreno-
`ceptor function associated with the morphologic
`changes occurring in bladder hypertrophy. On the
`other hand, Smith and Chapple“ could not com
`firm the occurrence of an increased a-adrenocep-
`tor function in the unstable, obstructed human
`bladder.
`
`A change in the at-adrenoceptor function of the
`detrusor and outflow region associated with out-
`flow obstruction secondary to BPH cannot be ex-
`cluded. On the other hand, the importance of such
`a change for the clinical response to a-adrenocep-
`tor antagonists is difficult to assess. It cannot be
`excluded that an effect of the ct—adrenoceptor
`blockers on the CNS contributed to these actions.
`
`There are clinical observations in agreement with
`the view that neurologic damage may be associated
`with a change in at-adrenoceptor functions of rele-
`vance to detrusor function. In a study of patients
`with bladder hyperreflexia, Jensen” found that
`treatment with prazosin decreased the overactivity
`and increased bladder capacity. This was con-
`firmed by other investigators,'’‘’ but
`the results
`were not impressive. In children with n1yelome-
`ningocele and detrusor hyperreflexia, phentol—
`amine injected intramuscularly decreased tone and
`bladder overactivity.“ Detrusor tissue from pa-
`tients with bladder overactivity (without neuro-
`logic disorders) had an almost fourfold increase in
`the density of wadrenoceptors compared to the
`density in patients with normal bladder activity.“
`The importance of this finding for bladder overac-
`tivity is, however, unclear.
`The oi,-adrenoceptor subtypes of the LUT and
`those involved in the central control of the rnicturi-
`tion reflexes deserve further attention. Whether or
`
`not drugs with a selective effect on au_—adrenocep-
`tors can eliminate bladder overactivity should be
`investigated.
`B-Adrenoceptors. In isolated human bladder,
`non—subtype—selective and B-adrenoceptor ago-
`nists, such as isoprenaline, have a pronounced in-
`hibitory effect} It was speculated that. in bladder
`overactiviry, there is a lack of an inhibitory [3-ad-
`renoceptomnediated norepinephrine response.
`However, detrusor muscle from patients with blad-
`der instability was reported to show a similar de-
`gree of inhibition in response to isoprenaline as
`normal detrusor,“ even if the inhibitory effect of
`isoprenaline on the response to electrical stimula-
`tion was less in unstable muscle. However, the [3-
`adrenoceptors of the human bladder were shown
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`to have functional characteristics typical of neither
`31- nor B2-adrenoceptors, since they could be
`blocked by propranolol, but not by practolol or
`metoprolol (B_Z).53"'5'5 On the other hand, receptor
`binding studies using subtype—selective ligands
`suggested that the B-adrenoceptors of the human
`detrusor are primarily of the B2 subtype, and favor-
`able effects on bladder overactivity were reported
`with selective Byadrenoceptor agonists, such as
`terbutaline and clenbuterolfi-“"° Treatment with
`
`these agents has been limited by side effects.
`Atypical, B—adrenoceptor—mediated responses that
`were reported repeatedly in early studies of B-adre-
`noceptor antagonists have recently been sh own to be
`mediated by a [3-adrenoceptor that has been cloned,
`sequenced, expressed in a model system, and exten-
`sively characterized functionally.57'5“ Both normal
`and neurogenic human detrusors were shown to ex-
`press (3 1-, 32-, and B3-adrenoceptor mRNA, and
`CGP-12177A, a 3-adrenoceptor partial agonist with
`B1/B2-adrenoceptor antagonist activity, effectively re-
`laxed both types of detrusor muscle.” Thus, it seems
`as if the atypical fl-adrenoceptor of the human blad-
`der may be the l33—adrenoceptor.
`Experiments in rats” have demonstrated an age-
`related decrease in the responsiveness of the blad-
`der to ,8-adrenoceptor stimulation, possibly related
`to a decreased density of _8—adrenoceptors and de-
`creased production of cyclic adenosine monophos-
`phate. Whether or not this is of importance in hu-
`mans and whether Byadrenoceptor stimulation
`will be an effective way of treating the overactive
`bladder remains to be shown in controlled clinical
`trials.
`
`TACHYKININ AND VANILLOID RECEPTORS
`
`The importance of afferent nerve activity in the
`pathogenesis of detrusor overactivity has been em-
`phasized by several investigators. Local release of
`tachykinins (substance P, neurokinin A, neuroki—
`nin B) and other peptides from sensory nerves in
`the bladder wall has been shown to produce di-
`verse biological effects. such as smooth muscle
`contraction, facilitation of transmitter release from
`nerves, vasodilatation, and increased plasma per-
`meability.“ The actions of the tachykinins are me-
`diated by activation of three distinct receptor types
`termed NK-1, NK-2, and NK-3.5‘ Specific tachyki-
`nin receptors are present in the smooth muscle of
`the urinary bladder of several species, including
`humans. Whereas the rat and guinea-pig detrusors
`contain both NK—l and NK-2 receptors, the NK—2
`receptor seems to be the only mediator of contrac-
`tile responses to tachykinins in human bladder
`smooth muscle.°2*°“
`
`As mentioned previously, the sensation of blad-
`der filling and initiation of the micturition reflex
`are caused by activation of mechanoreceptors in
`
`UROLOGY 50 (Supplement 6.4), December‘ 1997
`
`the bladder wall, and the responsible afferents are
`small, slowly conducting myelinated A5 fibers. Af-
`ferents mediating painful sensations are slowly
`conducting, unmyelinated C-fibers. Experimental
`studies suggested that the voiding reflex in animals
`with spinal cord injury is mediated by unmyeli-
`nated C-fibers and that
`this pathway can be
`blocked by capsaicin.” Capsaicin is believed to act
`on vanilloid receptors,“ causing desensitization of
`C-fiber sensory afferents by an initial release and
`emptying of the stores of neuropeptides and then
`blocking further release, thereby suppressing sen-
`sory neuron activity. Cystometric evidence that
`capsaicin-sensitive nerves may modulate the affer-
`ent branch of the micturition reflex in humans was
`
`originally presented by Maggi et al.,"7 who instilled
`capsaicin (0.1 to 10 ,u.mol/L) intravesically in pa-
`tients with hypersensitivity disorders. These inves-
`tigators found a concentration-related reduction of
`the volume required to elicit the first desire to void,
`of bladder capacity, and of pressure threshold for
`micturition, suggesting release of tachykinins. All
`patients reported disappearance or marked attenu-
`ation of their symptoms a few days after adminis-
`tration of capsaicin. Intravesical capsaicin, given in
`considerably higher concentrations
`(1
`to
`2
`mmol/L) than those administered by Maggi et al.,‘”’
`has since been used with success in patients with
`bladder overactivity due to neurologic disorders,
`such as multiple sclerosis or traumatic chronic spi-
`nal lesions. The effect of treatment may last for 2 to
`T months.“-7“ These positive effects have been ex-
`plained by the blocking of C—fiber afferents. lt has
`also been suggested that the ice—water test could be
`used to determine the dose of capsaicin needed to
`influence bladder C-fiber afferents adequately.“
`Resiniferatoxin was shown to be approxi-
`mately 1,000 times more potent than capsaicin
`in stimulating bladder activity.“-72 However,
`resiniferatoxin was relatively less potent in pro-
`ducing tissue inflammation“ and seemed to be
`able to desensitize bladder sensory fibers with
`less C—fos expression in the rat spinal cord than
`capsaicin.” Resiniferatoxin may therefore be an
`interesting therapeutic alternative to capsaicin.
`Supporting this, Lazzeri et al.“ reported that
`when instilled intravesically in humans (concen-
`tration, 10-3 mol/L), resiniferatoxin did not
`produce a warm and burning sensation at the
`suprapubic/urethral level, an effect that is com-
`monly found with capsaicin. If tachykinins, re-
`leased from sensory nerves, produce bladder
`overactivity and hypersensitivity disorders, an-
`tagonism of NK—receptors with selective drugs
`seems to be an interesting, novel way of treating
`these disorders.
`
`79
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2042 - 0006
`
`

`
`PROSTANOIDS
`
`Human bladder mucosa has the ability to synthe-
`size eicosanoids” and these agents can be liberated
`from both bladder muscle and mucosa in response
`to stimuli, such as stretch of the detrusor smooth
`muscle, injuries of the vesical mucosa, nerve stim-
`ulation, and agents such as adenosine triphosphate
`(ATP) and mediators of inflammation (see Maggi”
`and Anderssonl). Even if prostaglandins cause
`contraction of human bladder muscle, it is still un-
`clear whether they contribute to the pathogenesis
`of unstable detrusor contractions. More important
`than direct effects on the bladder muscle may be
`sensitization of sensory afferent nerves, increasing
`the afferent input produced by a given degree of
`bladder filling. Capsaicin—sensitive afferents in the
`bladder are chemosensitive and can be activated by
`prostanoids to increase the afferent input pro-
`duced by a given degree of bladder filling. Maggi“
`suggested that prostanoids may be the link be-
`tween detrusor muscle stretch produced by blad-
`der filling and activation of capsaicin-sensitive af-
`ferents by bladder distention. Evidence of this was
`produced in the rat urinary bladder, where intra~
`vesical instillation of prostaglandin E2 (PGE2) low-
`ered the threshold for reflex rnicturition, and top-
`ical application of PGE2 and thromboxane B2 on
`the serosal surface activated reflex micturition.
`
`Both effects were prevented by systemic capsaicin
`desensitization.
`lndomethacin pretreatment and
`systemic
`capsaicin increased the micturition
`threshold without affecting the amplitude of the
`rnicturition contraction. Since intravesical PGEZ
`did not reduce the residual urine volume in capsa—
`icin-pretreated animals, it was suggested that en-
`dogenous prostanoids enhance voiding efficiency
`through an action, direct or indirect, on sensory
`nerves.”
`
`If prostaglandins generated by the bladder in-
`crease the afferent input produced by filling, invol-
`untary bladder contractions can then be triggered
`at a small bladder volume. If this is an important
`mechanism, treatment with prostaglandin synthe-
`sis inhibitors could be expected to be an effective
`treatment of bladder overactivity. However, clini-
`cal evidence for this is scarce. For example, in a
`double-blind, controlled study of 30 women with
`DI using the prostaglandin synthesis inhibitor flur-
`biprofen, the drug was shown to have favorable
`effects, although it did not completely abolish de-
`trusor overactivity." There was a high incidence of
`side effects (43%),
`including nausea, vomiting,
`headache, and gastrointestinal symptoms. Cyclo-
`oxygenase (COX) is the pivotal enzyme in prosta-
`glandin biosynthesis. The constitutive COX-1 is
`considered responsible for the physiologic func-
`tions of the prostaglandins, whereas the inducible
`COX-2 is involved in inflammation.75\79 If prosta-
`
`80
`
`glandins generated by inflammation are contribut-
`ing to bladder overactivity, it would theoretically
`be possible to obtain maximal antiinflammatory
`efficacy combined with less toxicity if the COX-2
`was inhibited selectively. Whether or not available
`selective COX-2