Drugs 35: 477-494 (1988)
`0012-6667/88/0004-0477/$09.00/0
`O ADIS Press Limited
`All rights reserved.
`
`Current Concepts in the Treatment of Disorders of
`Micturition
`
`Karl-Erik Andersson
`
`Department of Clinical Pharmacology, University Hospital of Lund, Lund
`
`
`Summary ................................................................................................................................... ..477
`I. Failure to Store
`................................................. ..478
`1.1 Urge Incontinence
`................................................. ..478
`1.1.1 Anticholinergic Drugs
`...-179
`1.1.2 Drugs with ‘Direct’ Actions ..................................................................... ..480
`1.1.3 Drugs with Mixed Actions
`............................................................... ..481
`1.1.4 .8-Adrenoceptor Agonists
`...433
`1.1.5 a-Adrenoceptor Antagonists
`......................................... "483
`1.1.6 Prostaglandin Synthesis Inhibitors ..
`......................................... ..484
`1.1.7 Other Drugs ..................................... ..
`...484
`1.2 Stress Incontinence
`......................................................485
`1.2.1 a-Adrenoceptor Agonists
`.................................................... ..485
`1.2.2 ti-Adrenoceptor Antagonists ..
`...486
`1.2.3 Imiprarnine
`......................................... "486
`1.2.4 Oestrogens
`......................................... ..486
`2. Failure to Empty
`...487
`2.1 Drugs Acting on the Bladder ..
`........................................................... ..487
`2.1.1 Parasympathomimetic Drugs
`.................................................... ..487
`2.1.2 Prostaglandins
`".488
`2.2 Drugs Acting on the Urethra
`......................................... ..488
`2.2.1 cu-Adrenoceptor Antagonists ......
`....................................488
`2.2.2 Other Drugs
`...489
`3. Conclusions and Recommendations
`............ ..489
`
`
`
`Contents
`
`
`
`Summary
`
`Disorders of micturition may be divided into disturbances of the storage function of
`the bladder. and disturbances of the emptying function. The main symptoms of disturb-
`ances of storage function are fi-equency. urgency and incontinence. Hyperactivity of the
`bladder may lead to urge incontinence, and incompetence of the urethral closure mech-
`anism to stress incontinence.
`
`There are many drugs available for treating bladder hyperactivity, but their efficacy
`as judged ji-om controlled clinical trials (when available) is often limited. Bladder con-
`traction in man is mediated by stimulation of muscarinic receptors, and when given par-
`enteraily anticltolinergic drugs have been shown to depress bladder hyperactivity irrespec-
`tive of the underlying cause. Clinically, however. treatment of urge incontinence with
`anticnolinergic drugs is often unsatisfactory. Lack ofetfect oforal treatment and systemic
`side eflecrs limit the use ofavailabie agents. Drugs with ‘mixed’ actions (anticlzolinergic
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0001
`
`

`
`478
`Treatment of Disorders of Mieturition
`
`
`and ‘direct’ muscle effects). for example oxybutynin and terodiline, have well-documented
`efiicacy in bladder hyperactivity. Side effects are common with oxybutynin; terodiline seems
`to be well tolerated.
`The aim of drug treatment of stress incontinence is to increase outflow resistance.
`Although there is only limited possibility of improving the condition with drugs. beneficial
`effects can be obtained in some patients by use of orally active a-adrenoceptor agonists
`(e.g. phenylpropanolamine) and/or oestrogens.
`The main symptom of disturbed bladder emptying is urinary retention. Drug therapy
`is aimed at improving the contractile activity of the detrusor or reducing urethral outflow
`resistance. Drugs used for improving bladder contraciility include parasympathomimetic
`agents, e.g. bethanecltol or carbachol, and intravesical instillation ofprostaglandins. Al-
`though the eflicacy of both types of treatment is open to question, bethanechol seems to
`be widely used.
`Increased outflow resistance may be seen in patients with parasympathetic decentral-
`isation of the lower urinary tract or in patients with benign prostatic hypertrophy. These
`patients may respond favourably to a-adrenoceptor blockers such as phenoxybenzamine
`or prazosin.
`
`
`The bladder and urethra constitute a functional
`
`unit which is controlled by a complex interplay be-
`tween the central and peripheral nervous systems
`and local regulatory factors (Andersson & Sjogren
`1982; Wein et al. 1987). Disturbances at various
`levels may result in disorders of the 2 main func-
`
`tions of this unit, storage and emptying. Failure to
`store urine may lead to various forms of incontin-
`ence, and failure to empty results in urinary reten-
`tion. Pharmacological interventions have been used
`in attempts to treat these disorders, although often
`with limited success. To improve a disturbed stor-
`
`age function the treatment should aim at decreas-
`ing detrusor activity, increasing bladder capacity
`and/or increasing outlet resistance. To facilitate
`bladder emptying the agents given should increase
`the intravesical pressure, and/or decrease the ure-
`thral resistance.
`
`1. Failure to Store
`
`1.! Urge Incontinence
`
`Urge incontinence is defined as involuntary loss
`of urine associated with a strong desire to void
`(Bates et al. 1976). It may be subdivided into mo-
`tor urge incontinence and sensory urge incontin-
`ence. Motor, but not sensory, urge incontinence is
`
`bladder, either in the form of uninhibited (invol-
`untary) bladder contractions and/or decreased
`
`compliance. Uncontrolled bladder contractions may
`occur in connection with neurological diseases or
`lesions, but can also be associated with outflow ob-
`struction, inflammation and irritative processes in
`the bladder muscle, or they may be idiopathic.
`In man, normal bladder contraction is mediated
`
`mainly through muscarinic receptors in the detru-
`
`sor muscle. Atropine resistance, i.e. contraction of
`isolated bladder muscle in response to electrical
`nerve stimulation after pretreatment with atropine,
`has been demonstrated in most animal species (see
`Andersson & Sjogren 1982), but does not seem to
`occur in normal human bladder muscle (Kinder &
`
`Mundy 1985; Sibley 1984; Sjogren et al. 1982). It
`appears that bladder hyperactivity may be the re-
`sult of several different mechanisms and it is un-
`
`likely that the hyperactivity which occurs in pri-
`mary instability without morphological changes is
`mediated by the same mechanism as hyperactivity
`in a morphologically changed bladder, such as may
`occur secondary to prostatic hypertrophy (Anders-
`son 1986).
`There is an abundance of drugs available for
`
`treatment of the overactive detrusor (table I).
`However, for many of them, estimations of elli-
`
`associated with an increased contractile activity in
`the detrusor muscle during the filling phase of the
`
`cacy are based on the results of preliminary, open
`studies rather than controlled clinical
`trials.
`It
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0002
`
`

`
`479
`Treatment of Disorders of Micturition
`
`
`Table I. Drugs used In the therapy of bladder hyperactivity
`
`Anflehellnerule drugs
`Propanthellne bromide
`Emepronium bromide
`
`Drugs with ‘direct’ eflocta
`Flavoxato
`
`Calcium antagonists
`
`Dmge with mixed actions
`Oxybulynin
`Dlcyclornlne
`Terodlline
`Irnlprarnine
`
`.6-Adrenoeeptor egonlstu
`Terbutallne
`Clenbuterol
`
`a-Adrenoceptor antagonists
`Phenoxybenzamlne
`Prazosin
`
`Proetaglnndin synthelaae Inhibitors
`Inclomathacin
`
`Fiurbiprofen
`
`Other drugs
`Baclofen
`
`Desrnopressin
`Bromoeriptlne
`
`should be stressed that in many trials on detrusor
`instability there has been such a high placebo re-
`
`sponse that meaningful differences between pla-
`cebo and active drug cannot be demonstrated.
`
`However, drug effects in individual patients may
`be useful and important.
`
`l'.I.1 Anticholinergic Drugs
`There are reasons to believe that muscarinic re-
`
`ceptors mediate not only normal bladder contra ‘-
`tions but also the main part of contractions in
`hyperactive bladders. Atropine and other anti-
`cholinergic drugs are known to produce an almost
`complete paralysis of the normal bladder when in-
`
`jected intravenously. Several studies suggest that
`blockade of detrusor contractions can also be
`
`achieved in patients with bladder hyperactivity
`(Cardozo & Stanton 1979; Low 1977; Naglo et al.
`1981). On the other hand, there are several reports
`of insufiicient efficacy of anticholinergic drugs given
`
`orally to patients with unstable detrusor contrac-
`tions (see, for example, Bonnesen et al. 1984; Ritch
`et al. 1977; Walter et al. 1982; Zorzitto et al. 1986).
`It is unclear to what extent this can be attributed
`
`to low bioavailability (making it difficult to achieve
`
`sufficient drug concentrations in the effector or-
`gan), or to side effects (limiting the dose that can
`be given), or if atropine resistance really occurs in
`some cases of unstable bladder.
`
`In the treatment of the unstable bladder, pro-
`pantheline bromide and emepronium bromide are
`probably the most widely used drugs. These drugs
`have pronounced effects on bladder function when
`given parenterally (Blaivas et al. 1980; Boman &
`von Garrelts 1973; Cardozo & Stanton 1979; Low
`1977; Syversen et al. 1976; Ulmsten & Andersson
`1977). However, intramuscular emepronium bro-
`mide (0.l5 mg/kg) was not found to have any ef-
`fect in 6 elderly subjects suffering from urinary in-
`
`continence due to small capacity, hyper-reflexic
`bladders (Perera et al. 1982). This raises the ques-
`tion of whether or not atropine-resistant activation
`may occur in some cases.
`Both propantheline bromide (Vose et al. 1979)
`
`and emepronium bromide (Sundwall et al. 1973)
`possess low biological availabilities (S to 10%)
`which vary markedly between individuals. Pro-
`
`pantheline bromide is usually given in a dose of
`15 to 30mg 4 times daily, while the emepronium
`bromide dosage must be kept in the range 200mg
`3 to 4 times daily or higher. To obtain an optimal
`
`effect individual titration of the drugs is necessary:
`the dose is increased until incontinence is elimi-
`
`nated or until untoward side effects preclude fur-
`ther increase. Using this approach in 26 patients
`with uninhibited detrusor contraction Blaivas et al.
`
`(1980) obtained a complete clinical response in all
`
`but 1, who did not tolerate more than propanthc-
`line 15mg 4 times daily. The range of dosages var-
`ied from 7.5 to 60mg 4 times daily. In 72 women
`
`with detrusor instability, Massey & Abrams (1986)
`studied emepronium canageenate in a double-blind,
`placebo-controlled,
`randomised crossover
`trial.
`
`Dosages were individually titrated. Out of 72
`patients entering the study, 5 were withdrawn dur-
`ing the titration phase, 24 were treated with a low
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0003
`
`

`
`Treatment of Disorders of Micturition
`480
`
`
`dose (I200mg daily), and 43 with a medium/high
`(1600/2000mg daily) dose. A dose-dependent im-
`provement, both of symptoms and of micturition
`parameters, was found.
`
`Emepronium bromide has often been attributed
`
`a ganglionic blocking action, and it has been sug-
`gested that such an effect would contribute to a
`favourable and selective effect on the bladder
`
`muscle. However, this has never been documented
`
`clinically and there is no experimental evidence that
`anticholinergic drugs have a selective effect on
`
`bladder muscle. Muscarinic receptors in detrusor
`muscle do not exhibit characteristics which dis-
`
`tinctly separate them from muscarinic receptors in
`other organs (Nilvebrant et al. 1985). The available
`anticholinergic drugs will,
`therefore, cause sys-
`temic side effects independent of which drug is
`used.
`
`As atropine and related anticholinergics are ter-
`tiary amines, they are well absorbed from the gas-
`trointestinal tract, and penetrate the central nerv-
`ous system (CNS) well. CNS side effects will,
`
`therefore, often limit their use." Quarternary am-
`monium compounds have a lower incidence of
`
`CNS side effects, but produce well-known peri-
`pheral anticholinergic side effects such as accom-
`
`tachycardia and dryness of
`modation paralysis,
`mouth. Emepronium bromide has been reported to
`cause oesophageal damage (Johnsen et al. 1982;
`Kavin I977; Kobler et al. 1978) and this prompted
`
`the development of emepronium carrageenate
`(Bagger et al. 1985; Massey & Abrams I986), from
`which active substance is released only in the pres-
`ence of excess hydrogen or sodium ions. No oeso-
`phageal damage has so far been reported with this
`preparation.
`
`1.1.2 Drugs with ‘Direct’ Actions
`
`Flavoxate
`
`The mechanism of flavoxate's effect on smooth
`
`muscle has not been established (Cazzulani et al.
`1984; Fredericks et al. I978). Cazzulani et al. (I984)
`found the drug to have moderate calcium antag-
`onistic activity and an ability to inhibit phospho-
`diesterase; no anticholinergic effect was found
`
`(CazzuIani et al. 1985). Local analgesic properties
`have also been reported (Bradley & Cazort I970;
`
`Kohler & Morales 1968). In vivo an active metab-
`olite may contribute to its effects (Pietra et al. 1986).
`The clinical effects of flavoxate in patients with
`detrusor instability and frequency, urge and incon-
`tinence have been studied in both open and con-
`
`trolled investigations but with varying rates of suc-
`cess (Delaere et al. 1977; Griineberger 1984; Jonas
`et al. 1979; Stanton 1973). Stanton (1973) com-
`pared emepronium bromide and flavoxate in a
`
`double-blind crossover study of patients with de-
`trusor instability and reported improvement rates
`of 83% and 66% after flavoxate or emepronium
`
`bromide, respectively, both administered as 200mg
`3 times daily. In another double-blind randomised
`crossover study, Robinson and Broclclehurst (1983)
`
`investigated the combined effects of 4 times daily
`administration of flavoxatc l00mg and emepron-
`ium bromide 200mg in elderly women with detru-
`
`sor instability. Despite evidence of a pharmaco-
`logical effect on the bladder, the therapeutic efficacy
`of the combination was disappointing.
`Other investigators have not been able to show
`any beneficial effect of flavoxate at the usually rec-
`ommended dosage of I00 to 200mg 3 to 4 times
`
`daily (Briggs et al. 1980). No effect was observed
`in women with detrusor instability administered
`
`flavoxate 200mg intravenously (Cardozo & Stan-
`ton 1979).
`In general, few side effects have been reported
`during treatment with flavoxate. On the other hand
`its efficacy, compared to other therapeutic altem-
`atives, is not well documented.
`
`Calcium Antagonists
`Influx of extracellular calcium is important for
`
`detrusor muscle contractions (Andersson & For-
`man 1986) and this can be blocked by calcium ant-
`agonists. Forman et al.
`(1978) showed that
`in
`isolated human bladder muscle nifedipine pretreat-
`ment effectively suppressed contractions induced
`
`by several agonists and also caused relaxation when
`administered after the agonist. Nifedipine and other
`calcium antagonists also inhibit contractions in-
`duced by electrical stimulation in bladder muscle
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0004
`
`

`
`481
`Treatment of Disorders of Micturition
`
`
`from animals and from man (Andersson 8:. For-
`man 1986).
`There have been few clinical studies of the ef-
`
`fects of calcium antagonists in patients with un-
`stable bladders (Andersson & Forman 1986). Rud
`
`et al. (1979) found that nifedipine reduced the fre-
`quency and amplitude of unstable detrusor con-
`
`tractions, increased bladder capacity and also gave
`symptomatic relief. These results could not be con-
`
`firmed by Laval and Lutzeyer (1980) who found
`
`that nifedipine had no significant effect on un-
`stable detrusor contractions.
`
`In a double-blind placebo-controlled study,
`
`Palmer et al. (1981) found that flunaiizine caused
`both symptomatic and urodynamic improvement
`
`in women with urge incontinence. Unfortunately,
`their results could not be confirmed by several other
`
`investigators {Anderson & Murray 1984; Fanciul-
`
`laeci et al. I985; Ferrari et al. 1985).
`
`Intravesical administration of verapamil was re-
`ported to depress detrusor activity in rabbits (Go-
`toh etal. 1986). Preliminary data in man suggest
`
`that intravesical instillation of verapamil increases
`
`bladder capacity and decreases the degree of leak-
`
`age during cystometry in patients with detrusor
`hyper-reflexia. The effect was less pronounced in
`
`patients with non-neurogenic hyperactivity (Mat-
`tiasson et al. 1987).
`
`The available information does not suggest that
`
`systemic therapy with calcium antagonists is an ef-
`
`fective way to treat bladder hyperactivity. How-
`ever, the possibility that intravesical therapy with
`
`these drugs will be useful cannot be excluded, nor
`the fact that calcium antagonists may enhance the
`
`effects of anticholinetgic agents (Andersson et al.
`1987a).
`
`1.1.3 Drugs With Mixed Actions
`
`Some drugs used to block bladder hyperactivity
`have been shown to have more than 1 mechanism
`
`of action. They all have a more or less pronounced
`anticholinergic effect and,
`in addition, an often
`
`poorly defined ‘direct’ action on bladder muscle.
`
`Oxybutynin
`Oxybutynin has been attributed with a pro-
`nounced direct muscle relaxant effect, whereas its
`anticholinergic‘ action was considered moderate
`(Anderson & Fredericks 1977; Lish et al. 1965).
`However, investigations in vitro on human bladder
`tissue revealed that oxybutynin was a potent anti-
`cholinergic drug with high affinity for muscarinic
`receptors in human bladder tissue and that it ef-
`fectively blocked carbachol-induced contractions
`(Nilvebrant et al. 1985).
`Several studies have shown that oxybutynin is
`effective
`in controlling bladder hyperactivity
`(Brooks & Braf 1980; Diol-mo & Lapides 1972; Ga-
`
`jewski & Awad 1986; Homsy et al. 1985; Moisey
`et al. 1980; Paulson 1978; Riva & Casolati 1984).
`In a ‘randomised, double-blind, crossover trial of
`
`30 patients with detrusor instability, Moisey et al.
`(1980) compared oxybutynin 5mg 3 times daily
`with placebo. The study was completed by 23
`patients; 5 withdrew because of severe side effects.
`Of the patients who completed the trial, 17 (69%)
`
`had symptomatic improvement and nine had im-
`provement on urodynamic assessment. The effect
`of oxybutynin in the management of idiopathic de-
`trusor instability in women was studied by Car-
`dozo et al. (1987) in a double-blind, fixed-dose,
`
`placebo-controlled trial. Oxybutynin was signifi-
`cantly better than placebo in improving lower ur-
`inary tract symptoms and urodynamic parameters.
`However, 8 of 20 women receiving oxybutynin
`stopped medication because of side effects and of
`those completing active therapy 30% suffered sig-
`nificant side effects, of dry mouth or dry skin.
`Oxybutynin has a well-documented therapeutic
`effect in bladder hyperactivity, although it is also
`associated with a high incidence of side effects.
`These are typically anticholinergic in nature and
`are often dose-limiting. It might,
`therefore, be
`questioned whether oxybutynin in the dosage usu-
`ally used clinically (Sing 3 times daily) has other
`than anticholinergic actions.
`
`Dicyclomine
`In addition to a direct relaxant effect on smooth
`
`muscle dicyclomine also has an anticholinergic ac-
`tion (Downie et al. 1977; Johns et al. 1976; Khanna
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0005
`
`

`
`482
`Treatment of Disorders of Micturition
`
`
`et al. 1979). It relaxed carbachol-contracted iso-
`lated human bladder muscle and displaced 3H-QNB
`(3-quinuclidinyl benzilate) fi‘om muscarinic bind-
`ing sites in homogenates of human bladder muscle,
`but was less potent than oxybutynin (Nilvebrant et
`
`al. 1985). Beck et al. ([976) compared the effects
`of 3 times daily administration of dicyclomine
`
`10mg, propantheline 15mg or placebo for 3 weeks
`in 43 patients with detrusor overactivity. They
`i found that in the placebo group 20% were cured or
`improved. Corresponding figures for propantheline
`bromide and dicylomine were 73% and 62%, re-
`spectively. Awad et al. (1977) reported, in a pre-
`liminary study, that dicyclomine 20mg 3 times daily
`
`caused a resolution or significant improvement of
`symptoms in 24 of 27 patients with uninhibited
`bladder contractions. Side effects were few, mainly
`
`anticholinergic in nature, and did not necessitate
`withdrawal from the study. In another preliminary
`study of 14 patients with uninhibited neurogenic
`bladder, Fischer et al.
`(1978) reported that ii
`patients showed a significant blockade of uninhi-
`bited bladder contractions when given dicyclomine
`as a single 20mg oral dose.
`Published experiences on the effect of dicyclom-
`inc on uninhibited bladder contractions are fa-
`
`vourable. However, controlled clinical trials docu-
`
`menting its efficacy and side effects are scarce.
`
`Terodiline
`
`Terodiline has been shown to possess both anti-
`
`cholinergic and calcium antagonistic properties
`within the same concentration range (Husted et al.
`1980; Larsson-Backstrom et al. 1985; flstergaard et
`
`al. 1980). Several controlled trials have demon-
`strated beneficial effects of the drug in patients with
`motor urge incontinence (for example, Ekman et
`
`al. 1980; Gerstenberg et al. 1986; Lukkarinen et al.
`1987; Macfarlane & Tolley 1984; Peters et al. 1984;
`Sole & Arkell 1984; Tapp el al. 1987; Ulmsten et
`al. 1985).
`Tapp et al. (1987) perfonned a double-blind,
`randomised multicentre study of 91 women with
`
`detrusor instability. The dosage of the drug was in-
`dividually titrated (25 to 50 to 75mg daily). Com-
`pared with the placebo group, significant improve-
`
`ments were found in total
`frequency, daytime
`frequency, daytime and total
`incontinence epi-
`sodes and the voided volumes in the treated group.
`
`Significantly more patients (62%) in the treated
`group considered themselves slightly or markedly
`improved than in the control group (42%). There
`was no difference in the total number of side ef-
`
`fects between the 2 groups. These results are in
`
`agreement with those obtained in another multi-
`centre study of 89 women with urinary frequency
`
`and motor urge incontinence (Peters et al. 1984).
`The eifects of terodiline (37.5 to 75mg daily)
`were evaluated in 24 women with motor urge in-
`continence,
`l2 in a double-blind crossover study
`
`and [2 in a subsequent long term study (6 months
`
`to 3 years). All but 2 patients in the double-blind
`study and all in the long term study reported im-
`provement when on terodiline treatment (Ulmsten
`
`et al. 1985). Side effects (mainly dryness of mouth),
`
`not necessitating discontinuation of treatment, were
`
`reported by 4 patients in the double-blind study
`
`and by 6 in the long term study. Gerstenberg et al.
`(1986) treated 18 females with detrusor instability
`with terodiline 25mg twice daily or placebo in a
`double-blind crossover study. Patient preference for
`
`terodiline was statistically significant. The 24-hour
`micturition frequency was significantly reduced,
`volume at first sensation increased and volume at
`
`first contraction increased. No serious side effects
`
`occurred. 25 geriatric patients (17 women and 8
`men) with severe motor urge incontinence were
`treated with terodiline and the polysynaptic inhib-
`itor meladrazin, separately and in combination
`
`(Beisland & Fossberg 1985). Urodynamically sig-
`nificant improvement was found only with tero-
`
`diline, there being no further improvement with
`added meladrazin. Because meladrazin caused a
`
`high incidence of side effects, treatment with ter-
`odiline separately was recommended.
`The clinical effectiveness of terodiline in patients
`
`with motor urge incontinence is well documented
`and, in the usual dose range (25 to 75mg daily), it
`is well tolerated (Fischer-Rasmussen et al. 1984).
`
`Clinically, the anticholinergic properties of tero-
`diline seem to dominate (Andersson 1984).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0006
`
`

`
`483
`Treatment of Disorders of Micturition
`
`
`Imipramine
`The complex pharmacological effects of imipra-
`
`tions, but favourable effects were reported in open
`studies with terbutaline (Lindholm & Lose 1986;
`
`mine include marked systemic anticholinergic ac-
`tions (Baldessarini 1985). However, the mechan-
`ism behind its effect on the bladder has not been
`
`established. Imipramine exerts a marked direct in-
`hibitory effect on the detrusor; its antimuscarinic
`effect on bladder muscle seems rather weak (Ben-
`son et al. 1977; Dhattiwala 1976; Fredericks et al.
`
`1978; Olubadewo 1980; Tulloch & Creed 1979).
`Although other tricyclic antidepressants have
`been reported to be effective in bladder instability
`(Martin & Schiif 1984; Nissenkorn et al. 1986) im-
`
`ipramine is the only drug that has been widely used
`clinically to treat this disorder.
`No effect was found when imipramine 25 to
`
`75mg was given intmrnuscularly to l l patients with
`uncontrolled detrusor contractions (Diokno et al.
`
`1972). However, in elderly patients with detrusor
`instability who received oral imipramine in doses
`up to 150mg daily good effects were reported (Cas-
`tleden et al. 1981). Raezer et al. (1977) found that
`a combination of propantheline and imipramine
`
`was particularly useful. It has also been known for
`a long time that imipramine can have favourable
`effects in the treatmentof nocturnal enuresis in
`
`children (Kunin et al. 1970; Noack 1964).
`It is well established that therapeutic doses of
`
`tricyclic antidepressants including imipramine may
`cause serious toxic effects on the cardiovascular
`
`system (orthostatic hypotension, ventricular ar-
`
`rhythmias). Children seem particularly sensitive to
`their cardiotoxic action (see Baldessarini 1985). This
`should be taken into consideration when prescrib-
`
`ing these drugs as a treatment for bladder instab-
`ility and enuresis.
`
`1.1.4 ,6’~AdrenocepIor Agonists
`Isolated human bladder muscle contracted by
`means of acctylcholine, for example, can be effec-
`tively relaxed by .8-adrenoceptor agonists (Larsen
`
`1979; Nergeirdh et al. 1977). In vivo it has been
`shown that administration offi-adrenoceptor agon-
`ists can increase bladder capacity in man (Norlén
`
`et al. 1978). Few investigations have been per-
`formed in patients with unstable detrusor contrac-
`
`Norton et al. 1978) and in a controlled trial with
`clenbuterol (Griineberger 1984). In a double-blind
`
`investigation clenbuterol 0.0lmg 3 times daily was
`shown to have a good therapeutic effect in l5 of
`20 women with motor urge incontinence (Grime-
`
`berger 1984). Four patients reported trembling of
`fingers and tachycardia and 3 complained of nerv-
`ousness. None had to stop treatment.
`
`Other investigators, however, have not been able
`
`to confirm that B-adrenoceptor agonists represent
`an effective therapeutic principle.
`In 6 elderly
`patients with unstable bladder, Castleden and Mor-
`
`gan (1980) found no beneficial effects of intraven-
`ous salbutamol (albuterol) [4 pg/kg]. In addition,
`oral therapy (4mg 3 times daily) for 2 weeks in 2
`patients had no clinically detectable effect. Naglo
`et al. (1981) gave isoprenaline (isoproterenol) sub-
`cutaneously (0.2 to l.0rng) to 9 patients (aged 3 to
`
`17 years) with myelodysplasia and detrusor hyper-
`activity. No effect on the detrusor activity was ob-
`served.
`
`The therapeutic efficacy of 3-adrenoceptor
`
`agonists for the inhibition of bladder hyperactivity
`has not been established, but available information
`
`does not exclude the possibility that they may pro-
`
`vidc a therapeutic alternative in some patient
`groups.
`
`1.1.5 a-A drenoceptor Antagonists
`Stimulation of as-adrenoeeptors in isolated hu-
`man bladder muscle produces no or a weak con-
`
`tractile effect (Awad et al. 1974). Noradrenaline in-
`hibits the response to electrical stimulation in
`human detrusor muscle, probably by effects on both
`a- and B-adrenoceptors (/lmarlt et al. I986). Stimu-
`lation of at-adrenoceptors on cholinergic neurons
`may lead to a decreased release of aoetylcholine,
`and stimulation of postjunctional 5-adrenooeptors
`to relaxation of the detrusor muscle. Normal dog
`bladder reacts to noradrenaline with relaxation, but
`
`after outflow obstruction has been established, nor-
`adrenaline produces contraction (Rohner et al.
`1978). In 11 of 47 patients with benign prostatic
`hypertrophy and outflow obstniction, Perlberg and
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0007
`
`

`
`484
`Treatment of Disorders of Micturition
`
`
`Caine (1982) found a contractile effect of noradren-
`aline mediated by stimulation of as-adrenoceptors
`on the detrusor muscle. In some patients with be-
`
`nign prostatic hypertrophy, treated with phenoxy-
`benzamine or prazosin for improving outflow re-
`sistance (see section 2.2.1), simultaneous bladder
`instability was reduced or abolished (Gerstenberg
`et al. 1980-, Hedlund et al. I983; Reuther & Aa-
`
`gaard 1984). In both short term and long term
`treatment of 9 patients with uninhibited detrusor
`contractions secondary to multiple sclerosis and
`
`myelopathy, Jensen (1981) found prazosin to be
`effective.
`
`The value of n:-adrenoceptor antagonists in the
`
`treatment of bladder hyperactivity is still to be es-
`tablished and further clinical investigations of dif-
`ferent patient groups are necessary.
`
`1.1.6 Prostaglandin Synthesis Inhibitors
`It has been demonstrated that human bladder
`
`mucosa has the ability to synthesise eicosanoids
`
`(Jeremy et al. 1987), and that these agents can be
`liberated from bladder muscle and mucosa in re-
`
`sponse to different types of trauma (Downie &
`Karmazyn 1984; Leslie et al. 1934). Even if pros-
`
`taglandins cause contraction of human bladder
`muscle (Andersson & Forman 1978) it is still un-
`clear whether prostaglandins contribute to the
`
`ported to give symptomatic relief in patients with
`detrusor instability (Cardozo & Stanton 1980). The
`incidence of side effects was high, occurring in 19
`of 32 patients. However, no patient had to stop
`treatment because of side effects.
`
`There have been few clinical trials on the effects
`
`of prostaglandin synthesis inhibitors in the treat-
`ment of unstable detrusor contractions, and their
`therapeutic value has not been established.
`
`1.1.7 Other Drugs
`
`Baclofen
`Baclofen has been shown to have favourable ef-
`
`fects on detrusor hyper-reflexia secondary to le-
`sions of the spinal cord (Kiesswetter & Schober
`1975; Roussan et al. 1975). The drug may also be
`an alternative in the treatment of idiopathic detru-
`sor hyperactivity (Taylor & Bates 1979). However,
`published experience with the drug is limited.
`
`Desmopressin
`
`Desmopressin (1-desamino-8-D-arginine vaso-
`pressin; DDAVP) is a synthetic vasopressin ana-
`logue with a pronounced antidiuretic effect but
`practically lacking vasopressor actions (Andersson
`et al. 1988). It has for several years been used in
`the treatment of diabetes insipidus and also in in-
`
`pathogenesis of unstable detrusor contractions.
`More important than direct effects on the bladder
`
`vestigations of the renal concentration capacity.
`Desmopressin has a longer duration of action than
`
`muscle may be sensitisation of sensory afferent
`nerves, increasing the afferent input produced by
`a given degree of bladder filling. Involuntary blad-
`der contractions can then be triggered at a small
`bladder volume. If this is an important mechan-
`ism, treatment with prostaglandin synthesis inhib-
`itors could be expected to be effective.
`
`In a double-blind controlled study of 30 women
`with detrusor instability the prostaglandin synthe-
`sis inhibitor flurbiprofen at a dosage of 50mg 3
`times daily was shown to have favourable effects,
`although it did not completely abolish detrusor hy-
`peractivity (Cardozo et al. 1980). There was a high
`
`incidence of side effects (43%) including nausea,
`vomiting, headache and gastrointestinal symp-
`toms. Indomethacin S0 to 100mg daily was re-
`
`atgipressin (arginine vasopressin) or lypressin (lys-
`ine vasopressin) and at a clinical dosage there are
`practically no side effects. By decreasing the noc-
`turnal production of urine, beneficial effects may
`be obtained in enuresis and nocturia. Several con-
`
`trolled double-blind investigations have shown the
`drug to be effective in the treatment of enuresis in
`
`children (Aiadjem et al. 1982; Birkasova et al. 1978;
`Post et al. 1983), and also in adults (Delaere &
`
`Strijbos 1987; Hilton & Stanton 1982; Ramsden et
`al. 1982). The dose used in most studies has been
`20,ug desmopressin intranasally at bedtime.
`
`A controlled study in malepatients with benign
`prostatic hypertrophy and significant nocturia
`showed that desmopressin reduced the number of
`nocturnal urinations, but the change was hardly
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2068 - 0008
`
`

`
`485
`Treatment of Disorders of Micturition
`
`
`clinically relevant (Ménsson et al. 1980). Noctur-
`nal frequency and enuresis due to bladder instab-
`
`ility responded favourably to intranasal desmo-
`pressin therapy even when previous treatment with
`‘antispasmodics' had been unsuccessful (Hilton &
`Stanton 1982;