PHINCIPLES, PRACTICE AND APPLICATION
`
`Edited by
`
`Mundy Ms FRcs MRcP
`
`Professor of Urology, University of London
`at Guy's Hospital and the Institute of Urology;
`Consultant Urological Surgeon, Guy's Hospital,
`London, UK
`
`P .. Stephenson MSCLondon) FRcs FRCS(Edin)
`
`Consultant Urologist, Cardiff Royal Infirmary, Cardiff, UK
`
`.. J .. Wein ABMDFAcs
`
`Professor and Chairman, Division of Urology, University of
`Pennsylvania School of Medicine, Philadelphia, Pennsylvania,
`USA
`
`SECOND EDITION
`
`I> r::J I>
`i=i r::J r::J
`i=i r::J r::J
`L::::7
`CHURCHILL LIVINGSTONE
`EDINBURGH LONDON MADRID MELBOURNE NEW YORI< AND TOKYO 1994
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2008 - 0001
`
`

`
`CHURCHILL LIVINGSTONE
`Medical Division of Longman Group Limited
`
`Distributed in the United States of America by Churchill
`Livingstone Inc., 650 Avenue of the Americas, New York,
`N.Y. 10011, and by associated companies, branches and
`representatives throughout the world.
`
`© Longman Group Limited 1984
`© Longman Group Limited 1994
`
`All rights reserved. No part of this publication may be
`reproduced, stored in a retrieval system, or transmitted in any
`form or by any means, electronic, mechanical, photocopying,
`recording or otherwise, without either the prior permission of
`the publishers (Churchill Livingstone, Robert Stevenson
`House, 1-3 Baxter's Place, Leith Walk, Edinburgh, EHl
`3AF), or a licence permitting restricted copying in the United
`Kingdom issued by the Copyright Licensing Agency Ltd,
`90 Tottenham Court Road, London, WlP 9HE.
`
`First edition 1984
`Second edition 1994
`ISBN 0-443-04081-8
`
`British Library Cataloguing in publication Data
`A catalogue record for this book is available from the British
`Library.
`
`Library of Congress Cataloguing in publication Data
`A catalog record for this book is available from the Library of
`Congress.
`
`Printed in Hong Kong
`CTPS/01
`
`The
`publisher's
`policy is to use
`paper manufactured
`from sustainable forests
`
`I
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2008 - 0002
`
`

`
`..
`
`A. J. Wein P. A. Longhurst R. M. Levin
`
`INTRODUCTION
`
`Most drugs which affect lower urinaty tract function
`do so by initially combining with specialized functional
`components of cells known as receptors. The drug(cid:173)
`receptor interaction alters the function of a cell compo(cid:173)
`nent and initiates the series of biochemical, physiologic
`and urodynamic changes that we associate with the use
`of that agent. Many such drugs affect accepted neuro(cid:173)
`transmitter mechanisms: by affecting the synthesis,
`transport, storage or release of neurotransmitter, the
`combination of the neurotransmitter with postjunc(cid:173)
`tional receptors, or the inactivation, degradation or re(cid:173)
`uptake of neurotransmitter. Other drugs affect receptor
`mechanisms that are not universally accepted as a part
`of the normal physiology of bladder filling/urine storage
`or lower urinary tract emptying. In any case, the
`complex physiologic and biochemical changes which
`occur after receptor activation are what are ultimately
`responsible for the contraction, relaxation, facilitation
`or inhibition which occurs. These mechanisms, 'meta(cid:173)
`bolically distal' to receptor stimulation and blockade,
`are also potential sites of pharmacologic stimulation,
`inhibition or modulation. The basics of lower urinary
`tract pharmacology have been covered in Chapter 3.
`This chapter will include the relevant pharmacologic
`principles on which drug therapy for voiding dysfunc(cid:173)
`tion is based, making liberal reference to Chapter 3,
`and summarize current data and opinion on the effi(cid:173)
`cacy of various drugs for voiding dysfunction.
`Despite disagreements on some details, all 'experts'
`would doubtless agree that, for the purposes of descrip(cid:173)
`tion and teaching, two phases of micturition exist from
`a conceptual point of view and can be succinctly
`summarized as follows (Wein 1981, Wein et al 1991).
`Bladder filling and urine storage require:
`
`1. accommodation of increasing volumes of urine at a
`low intravesical pressure and with appropriate
`sensation
`2. a bladder outlet which is closed at rest and remains
`so during increases in intraabdominal pressure
`
`3. absence of involuntary bladder contractions
`(detrusor instability or detrusor hyperreflexia).
`
`Lower urinary tract emptying requires:
`
`1. a coordinated contraction by the bladder smooth
`musculature of adequate magnitude and duration
`2. concomitant lowering of resistance at the level of
`the smooth sphincter (the smooth muscle of the
`bladder neck and proximal urethra) and of the
`striated sphincter (the periurethral and intramural
`urethral striated musculature)
`3. absence of anatomic obstruction.
`
`This very simple overview implies that any type of
`voiding dysfunction must result from an abnormality of
`one or more of the factors listed above. This descrip(cid:173)
`tion, with its implied subdivisions under each category,
`provides a logical framework for the discussion and
`classification of all types of voiding dysfunction. There
`are indeed some types of voiding dysfunction which
`represent combinations of filling/storage and emptying
`these
`abnormalities. Within this scheme, however,
`become readily understandable and their detection and
`treatment can be logically described. All aspects of
`urodynamic, radiologic and videourodynamic evalua(cid:173)
`tion can be conceptualized as to exactly what they
`evaluate in terms of either bladder or outlet activity
`during filling/storage or emptying within this scheme.
`Likewise, one can easily classify all known treatments
`for voiding dysfunction under the broad categories of
`whether they facilitate filling/storage or emptying and
`whether they do so by an action that is primarily on the
`bladder or on one or more of the components of the
`bladder outlet. We will use this classification (Tables
`4.1 and 4.2) as the framework for discussion. As an
`apology to others in the field whose works have not
`been specifically cited, it should be noted that refer(cid:173)
`ences have generally been chosen because of their
`review or informational content and are not meant to
`imply originality or initial publication on a particular
`subject.
`
`43
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2008 - 0003
`
`

`
`44 URODYNAMTCS
`
`Table 4.1 Therapy to facilitate bladder emptying
`
`Table 4.2 Therapy to facilitate bladder filling/urine storage
`
`A. Increasing intravesical pressure/bladder contractility
`1. External compression, Valsalva
`2. Promotion or initiation of reflex contractions
`a. Trigger zones or manoeuvres
`b. Bladder training, tidal drainage
`3. Pharmacologic therapy
`a. Parasympathomimetic agents
`b. Prostaglandins
`c. Blockers of inhibition
`( 1) alpha-adrenergic antagonists
`(2) Opioid antagonists
`4. Electrical stimulation
`a. Directly to the bladder or spinal cord
`b. To the nerve roots
`c. Transurethral intravesical electrotherapy
`5. Reduction cystoplasty
`
`B. Decreasing outlet resistance
`1. At a site of anatomic obstruction
`a. Prostatectomy
`b. Balloon dilatation
`c. Intraurethral stent
`d. Decrease prostate size/tone
`(1) LHRH agonists
`(2) Antiandrogens
`(3) 5-cx reductase inhibitors
`( 4) Alpha-adrenergic antagonists
`e. Urethral stricture repair/dilatation
`2. At the level of the smooth sphincter
`a. Pharmacologic therapy
`(1) Alpha-adrenergic antagonists
`(2) Beta-adrenergic agonists
`b. Transurethral resection or incision of the bladder
`neck
`c. Y-V plasty of the bladder neck
`3. At the level of the striated sphincter
`a. Pharmacologic therapy
`(1) Skeletal muscle relaxants
`(a) Benzodiazepines
`(b) Baclofen
`(c) Dantrolene
`(2) Alpha-adrenergic antagonists
`b. Surgical sphincterotomy, injection of botulinum A
`toxin
`c. Urethral overdilatation
`d. Urethral stent
`e. Pudenda! nerve interruption
`f. Psychotherapy, biofeedback
`
`C. Circumventing problem
`1. Intermittent catheterization
`2. Continuous catheterization
`3. Urinary diversion
`
`SPECIFIC METHODS OF
`PHARMACOLOGICAL THERAPY
`
`THERAPY TO FACILITATE BLADDER
`EMPTYING
`
`Absolute or relative failure to empty results from
`decreased bladder contractility, increased outlet resist-
`
`A. Inhibiting bladder contracility/decreasing sensory input/
`increasing bladder capacity
`I. Timed bladder emptying; habit training; prompted
`voiding
`2. Pharmacologic therapy
`a. Anticholinergic agents
`b. Musculotropic relaxants
`c. Calcium antagonists
`d. Potassium channel openers
`e. Prostaglandin inhibitors
`f. Beta-adrenergic agonists
`g. Tricyclic antidepressants
`h. Dimethyl sulphoxide
`i. Polysynaptic inhibitors
`3. Biofeedback, bladder retraining
`4. Bladder overdistension
`5. Electrical stimulation (reflex inhibition)
`6. Acupuncture
`7. Interruption of innervation
`a. Central (subarachnoid block)
`b. Peripheral (sacral rhizotomy, selective sacral
`rhizotomy)
`c. Perivesical (peripheral bladder denervation)
`8. Augmentation cystoplasty
`
`B. Increasing outlet resistance
`1. Physiotherapy, biofeedback
`2. Electrical stimulation of the pelvic floor
`3. Pharmacologic therapy
`a. Alpha-adrenergic agonists
`b. Tricyclic antidepressants
`c. Beta-adrenergic antagonists
`d. Oestrogens
`4. Vesicourethral suspension (SUI)
`5. Bladder outlet reconstruction
`6. Surgical mechanical compression
`a. Sling procedures
`b. Artificial sphincter
`7. Non-surgical mechanical compression
`a. Periurethral polytef
`b. Periurethral collagen, fat
`c. Occlusive devices
`
`C. Circumventing problem
`1. Antidiuretic hormonelike agents
`2. Intermittent catheterization
`3. Continuous catheterization
`4. Urinary diversion
`5. External collecting devices
`6. Absorbent products
`
`ance or both (Barrett & Wein 1991). Absolute or rela(cid:173)
`tive failure of adequate bladder contractility may result
`from temporary or permanent alteration in any one of
`the neuromuscular mechanisms necessary for initiating
`and maintaining a normal detrusor contraction. In(cid:173)
`hibition of the micturition reflex may also occur in a
`neurologically normal individual secondary to painful
`stimuli, especially from the pelvic and perinea! areas, or
`may be psychogenic. Drug therapy may also inhibit
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2008 - 0004
`
`

`
`PHARl'vli\CUl,OGIC TREATMENT OF VOlDING DYSFUNCTION 45
`
`bladder contractility, through either neurologic or myo(cid:173)
`genic mechanisms. Non-neurogenic causes, including
`intrinsic impairment of bladder smooth muscle func··
`tion, may result from overdistension, severe infection
`or fibrosis. Increased outlet resistance is generally sec(cid:173)
`ondary to anatomic obstruction, but may be secondary
`to a failure of coordination of the smooth or striated
`sphincter during bladder contraction. Treatment for
`failure to empty generally consists of attempts to in(cid:173)
`crease intravesical pressure or facilitate the micturition
`reflex, decrease outlet resistance or both.
`
`Increasing intravesical pressure
`
`Paras:ympathomimetic agents
`
`Since at least a major portion of the final common
`pathway in physiologic bladder contraction is stimula(cid:173)
`tion of parasympathetic postganglionic muscarinic
`cholinergic receptor sites (see Chapter 3, Wein et al
`1991), agents that imitate the actions of acetylcholine
`(ACh) might be expected to be useful to treat patients
`who cannot empty because of inadequate bladder
`contractility. ACh itself cannot be used for therapeutic
`purposes because of actions at central and ganglionic
`levels and because of its rapid hydrolysis by acetyl(cid:173)
`cholinesterase and by butyrylcholinesterase (Taylor
`1990). Many acetylcholine-like drugs exist. Bethanechol
`chloride (BC) exhibits a relatively selective action on
`the urinary bladder and gut with little or no nicotinic
`action (Taylor 1990). It is cholinesterase-resistant and
`causes an in vitro contraction of smooth muscle from
`all areas of the bladder (Raezer et al 1973, Barrett &
`Wein 1991). Agents similar to BC have long been rec(cid:173)
`ommended (Starr & Ferguson 1940) for the treatment
`of postoperative or postpartum urinary retention. In
`this instance, BC should be used only if the patient is
`awake and alert and if there is no outlet obstruction.
`The dose is 5-10 mg subcutaneously. For over 30 years
`BC has been used in the treatment of the atonic or
`hypotonic bladder (Lee 1949) and has been reported
`as effective in achieving 'rehabilitation' of the chroni(cid:173)
`cally a tonic or hypo tonic detrusor (Sonda et al 1979).
`Bethanechol has also been used to stimulate or facili(cid:173)
`tate the development of reflex bladder contractions
`in patients with suprasacral spinal cord injury (Perkash
`1975).
`Although BC has been reported to increase gastro(cid:173)
`intestinal motility and has been used in the treatment
`of gastrooesophageal reflux, and although anecdotal
`success in specific patients with voiding dysfunction
`seems to occur, attempts to facilitate bladder emptying
`in series of patients where BC was the only variable
`have been disappointing (Finkbeiner 1985). A pharma-
`
`cologically active subcutaneous dose (5 mg) did nol
`demonstrate significant changes in flow parameters or
`residual urine volume in a group of women with a
`residual urine volume equal to or greater than 20% of
`bladder capacity, but no evidence of neurologic disease
`or outlet obstruction in a group of 27 'normal' women
`of approximately the same age or in a group of patients
`with a positive bethanechol supersensitivity test (Wein
`et al 1980). This dose did increase intravesical pressure
`at all points along the filling cystometrogram and also
`decreased bladder capacity threshold, findings previ(cid:173)
`ously described by others (Sonda et al 1979). Although
`BC is capable of eliciting an increase in bladder smooth
`muscle tension, as would be expected from in vitro
`studies, its ability to stimulate or facilitate a physio(cid:173)
`logiclike bladder contraction in patients with voiding
`dysfunction has been unimpressive (Finkbeiner 1985).
`Similar sentiments have been expressed by Andersson
`(1988) and others (see Barrett & Wein 1991).
`It is difficult to find reproducible urodynamic data
`that support recommendations for the usage of BC in
`any specific category of patients. Most, if not all, 'long
`term' reports in such patients are neither prospective
`nor double blind and do not exclude the effects of other
`simultaneous regimens (such as treatment of urinary
`infection, bladder decompression or timed emptying
`and other types of treatment affecting the bladder or
`outlet), an important observation to consider when de(cid:173)
`signing such drug studies. Short term studies in which
`the drug was the only variable have generally failed to
`demonstrate significant efficacy in terms of flow and
`residual urine volume data (Barrett 1981). Whether
`repeated doses of BC or any cholinergic agonist can
`achieve a clinical effect that a single dose cannot is
`speculative, as are suggestions that BC has a different
`mode of action or effect on atonic or decompensated
`bladder muscle than on normal tissue. BC, adminis(cid:173)
`tered subcutaneously, does cause an increased aware(cid:173)
`ness of a distended bladder (Downie 1984). In the
`laboratory, a functioning micturition reflex
`is an
`absolute requirement for the production of a sustained
`bladder contraction by a subcutaneous injection of
`drug (Downie 1984). Clinically, there is little logic
`for its use in patients with detrusor hyperreflexia, who
`already have bladder contractions, though the contrac(cid:173)
`tions are uncontrollable. Patients with incomplete
`lower motor neuron lesions seem to constitute the most
`reasonable group for a trial of BC (Awad 1985),
`although subcutaneous administration may be re(cid:173)
`quired. It is generally agreed that, at least in a 'dener(cid:173)
`vated' bladder, an oral dose of 200 mg is required to
`produce the same urodynamic effects as a subcutane(cid:173)
`ous dose of 5 mg (Diokno & Lapid es 1977).
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2008 - 0005
`
`

`
`46 URODYNAMICS
`
`Other methods of achieving a cholinergic effect are
`seldom used in the United States. Philp et al 1980)
`reported that a 4 mg oral dose of carbachol, a choliner(cid:173)
`gic agonist which also possesses some ganglionic stimu(cid:173)
`lating properties, had a much greater favourable effect
`on urodynamic parameters in patients with super(cid:173)
`sensitivity than a 50 mg oral dose of BC, without an
`apparent increase in side effects. Voided volumes were
`reduced, detrusor pressures increased and the length of
`contraction shortened. Hedlund and Andersson (1988)
`treated patients with BPH with 2-4 mg TID of carba(cid:173)
`chol. Though GI side effects were experienced, there
`were no changes in urodynamic variables. Taylor
`(1990) states that carbachol is 'no longer available'
`because of its nicotinic action. Anticholinesterase
`agents also have the net effect of producing or enhanc(cid:173)
`ing cholinergic stimulation. Philp and Thomas (1980)
`have reported that parenteral, but not oral, distigmine
`improved voiding efficiency in patients with neurogenic
`bladder dysfunction with reflex detrusor activity.
`Shah et al (1983) reported a double blind study which
`showed that parenteral distigmine produced no statisti(cid:173)
`cally significant differences in voiding effectiveness
`after prostatectomy in patients with large preoperative
`residual urine volumes.
`No agreement exists as to whether cholinergic stimu(cid:173)
`lation produces an increase in urethral resistance (Wein
`et al 1980). It would appear that pharmacologically
`active doses do in fact increase urethral closure pres(cid:173)
`sure, at least in patients with detrusor hyperreflexia
`(Sporer et al 1978). As to whether cholinergic agonists
`could be combined with agents to decrease outlet re(cid:173)
`sistance to facilitate emptying, Khanna (1976) reported
`that a combination of a total daily oral BC dose of
`50-100 mg with 20-30 mg of oral phenoxybenzamine
`produced 'satisfact01y' results in a group of patients
`with an atonic bladder and functional outlet obstruc(cid:173)
`tion. Our own experience with such therapy, utilizing
`even 200 mg of oral bethanechol daily, has been ex(cid:173)
`tremely disappointing. Certainly, most clinicians would
`agree that a total divided daily dose of 50-100 mg
`rarely affects any urodynamic parameter at all. The
`potential side effects of cholinomimetic drugs include
`flushing, nausea, vomiting, diarrhoea, gastrointestinal
`cramps, bronchospasm, headache, salivation, sweating
`and difficulty with visual accommodation (Taylor
`1990). Intramuscular or intravenous use is contraindi(cid:173)
`cated, as this can precipitate acute and severe side
`effects, resulting in acute circulatory failure and cardiac
`arrest. Contraindications to the use of this general
`category of drug include bronchial asthma, peptic
`ulcer, bowel obstruction, enteritis, history of recent
`gastrointestinal surgery, cardiac arrhythmia, hyper(cid:173)
`thyroidism and any type of bladder outlet obstruction.
`
`Metoclopramide (Reglan) is a dopamine antagonist
`with cholinergic properties. It has an antiemetic effect
`centrally in the chemoreceptor trigger zone and peri(cid:173)
`pherally increases the tone of the lower oesophageal
`sphincter, promoting gastric emptying. Its effects seem
`to be related w its ability to antagonize the inhibitory
`action of dopamine, to augment acetylcholine release
`and to sensitize the muscarinic receptors of gastro(cid:173)
`intestinal smooth muscle (Albibi & McCallum 1983).
`Preliminary data in the dog suggests that this agent can
`increase detrusor contractility (Mitchell & Venable
`1985) and there is one case report of improvement of
`bladder function in a diabetic patient treated originally
`with this agent for gastroparesis (Nestler et al 1983).
`This seems a reasonable area for further study of the
`effects of the drug either alone or in combination witl1
`other parasympathomimetic agents.
`
`Prostaglandins
`
`The use of prostaglandins (PG) to facilitate emptying
`is based upon the hypothesis that these substances con(cid:173)
`tribute to the maintenance of bladder tone and bladder
`contractile activity (Wein et al (1991) for a complete
`discussion). PGE2 and F2a; cause in vitro and in vivo
`bladder contractile responses. E 2 seems to cause a net
`decrease in urethral smooth muscle tone, while F2a;
`causes an increase. Bultitude et al (1976) reported that
`instillation o'f 0.5 mg E 2 into the bladders of females
`with varying degrees of urinary retention resulted in
`acute emptying and in improvement of longer term
`emptying
`in
`two
`thirds of the patients studied.
`Desmond et al (1980) reported results with intravesical
`use of 1.5 mg of this agent (diluted with 20 cc of
`0.2% neomycin solution) in patients whose bladders
`exhibited no contractile activity or in whom bladder
`contractility was relatively impaired. Twenty of 36
`patients showed a strongly positive and six showed a
`weakly positive immediate response. Fourteen patients
`were reported to show prolonged beneficial effects,
`all but one of whom had shown a strongly positive im(cid:173)
`mediate response. Stratification of the data revealed
`that an intact sacral reflex arc was a prerequisite for
`any type of positive response. The authors noted
`additionally that the effects of PGE2 appeared to be
`additive or synergistic in some patients with cholinergic
`stimulation. Vaidyanathan et al (1981b) reported that
`intravesical instillation of 7 .5 mg prostaglandin F 2a;
`produced reflex voiding in some patients with incom(cid:173)
`plete suprasacral spinal cord lesions. The favourable
`response to a single dose of drug, when present, lasted
`from 1.0 to 2.5 months.
`Tammela et al (1978) reported that 10 mg of F 2a;
`administered once intravesically facilitated voiding in
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2008 - 0006
`
`

`
`PHARMACOLOGlC TREATMENT Of' VOIDING DYSFUNCTION 47
`
`women who were in retention three days after surgery
`for stress urinary incontinence. The drug was adminis(cid:173)
`tered in 50 cc of saline as a single dose and retained for
`two hours. It should be noted that the data show that,
`in these successfully treated patients, the average maxi(cid:173)
`mum flow rate was 10.6 cc per second with a mean
`residual urine volume of i07 cc and also that the
`authors state that 'bladder emptying deteriorated in
`most patients on the day after treatment'. Jaschevatsky
`et al (1985) reported that 16 mg of F 2a in 40 cc of
`saline given intravesically reduced the frequency of
`urinary retention in a group of women undergoing
`gynaecological surgery but, inexplicably, only in women
`undergoing vaginal hysterectomy with vaginal repair
`and not in women undergoing vaginal repair with
`urethral plication or vaginal repair alone. Koonings et
`al ( 1990) reported that daily intravesical PGF2a and
`intravaginal E 2 reduced the number of days required
`for catheterization after stress incontinence surgery
`when compared to a control group receiving intravesi(cid:173)
`cal saline. Stanton et al (1979) and Delaere et al (1981)
`have reported no success utilizing E 2 in doses similar
`to those reported above, and Delaere et al (1981) have
`reported no success using F 2a in a group of women
`with emptying difficulties of various aetiologies, although
`it should be noted that they used lower doses than
`those reported above. Wagner et al (1985) utilized E 2
`in doses of 0.75 to 2.25 mg and reported no effect on
`urinary retention in a group of patients after anterior
`colporrhaphy. Prostaglandins have a relatively short
`half life and it is difficult to understand how any effects
`after a single application can last up to even several
`months. If such does occur, it must be the result of a
`'triggering effect' on some as yet unknown physiologic
`or metabolic mechanism. Potential side effects of pros(cid:173)
`taglandin usage include vomiting, diarrhoea, pyrexia,
`hypertension and hypo tension (Rall 1990).
`
`Blockers of inhibition
`
`De Groat and coworkers (de Groat & Booth 1984,
`Wein et al 1991) have demonstrated a sympathetic
`reflex during bladder filling which, at least in the cat,
`promotes urine storage by exerting an a-adrenergic
`inhibitory effect on pelvic parasympathetic ganglionic
`transmission. Some have suggested that a-adrenergic
`blockade, in addition to decreasing outlet resistance,
`may in fact facilitate transmission through these ganglia
`and thereby enhance bladder contractility. On this
`basis, Raz & Smith (1976) advocated a trial of an a-.
`adrenergic blocking agent for the treatment of non(cid:173)
`obstructive urinary retention. Tammela (1986) reported
`that phenoxybenzamine was more effective in prevent(cid:173)
`ing recurrent retention after initial catheterization in a
`
`group of postoperative patiento than was either carba(cid:173)
`chol or placebo. It may be that CY,··adrenergic blockade
`can, under certain circumstances, facilitate the detrusor
`reflex. Although we and others have had occasional an(cid:173)
`ecdotal success using this or another 'exotic' approach,
`healthy scepticism is warranted against accepting the
`assumption that, under such circumstances, improve(cid:173)
`ment during administration of the drug occurs solely
`because of it.
`Recent advances in the field of neuropeptide physiol(cid:173)
`ogy and pharmacology have also provided new insights
`into lower urinary tract function and its potential phar(cid:173)
`macologic alteration. Endogenous opioids are thought
`to exert a tonic inhibitory effect on the micturition re(cid:173)
`flex at various levels (Chapter 2; see Wein et al 1991)
`and agents such as narcotic antagonists therefore may
`offer possibilities for stimulating reflex bladder activity.
`Thor et al (1983) were able to stimulate a micturition
`contraction with naloxone, an opiate antagonist, in
`unanaesthetized chronic spinal cats. The effects, how(cid:173)
`ever, were
`transient and
`tachyphylaxis developed.
`Vaidyanathan et al (1981a) reported that an intra(cid:173)
`venous injection of 0.4 mg of naloxone enhanced de(cid:173)
`trusor reflex activity in five of seven patients with
`neuropathic bladder dysfunction caused by incomplete
`suprasacral spinal cord lesions. The maximum effect
`occurred within 1-2 minutes after intravenous injection
`and was gone by 5 minutes. Murray & Feneley (1982)
`reported that the same dose of naloxone caused, in a
`group of patients with idiopathic detrusor instability,
`an increase in detrusor pressure at zero volume and
`at first desire to void, a decrease in the maximum
`cystometric capacity and a worsening of the degree of
`instability. Galeano et al (1986) reported that nalo(cid:173)
`xone, although it increased bladder contractility in the
`chronic spinal cat, also aggravated striated sphincter
`dyssynergia and spasticity. Wheeler et al (1987) noted
`no significant cystometric changes in a group of spinal
`cord injury patients following intravenous naloxone.
`
`Decreasing outlet resistance
`
`At the level of the smooth sphincter
`
`Whether or not one believes there is significant inner(cid:173)
`vation of the bladder and proximal urethral smooth
`musculature by postganglionic fibres of the sympa(cid:173)
`thetic nervous system, one must acknowledge the exist(cid:173)
`ence of a- and ~-adrenergic receptor sites in these areas
`(see Chapter 3). The smooth muscle of the bladder
`base and proximal urethra contains predominantly a(cid:173)
`adrenergic receptors. The bladder body contains both
`varieties of adrenergic receptors, with the ~ variety
`being more common. The implication that a-adrener-
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2008 - 0007
`
`

`
`48 URODYNA!vlICS
`
`gic blockade could be useful in certain patients with a
`failure to empty was actually first made by Kleeman in
`1970. Krane & Olsson (1973a, 1973b) endorsed the
`concept of a physiologic internal sphincter partially
`controlled by tonic sympathetic stimulation of contrac(cid:173)
`tile ex-adrenergic receptors in the smooth musculature
`of the bladder neck and proximal urethra. Further, they
`hypothesized that some obstructions that occur at this
`level during detrusor contraction are a result of an
`inadequate opening of the bladder neck and/or an
`inadequate decrease in resistance in the area of the
`proximal urethra. They also theorized and presented
`evidence that ex-adrenergic blockade could be useful in
`promoting bladder emptying in such a patient - one
`with an adequate detrusor contraction but without
`anatomic obstruction or detrusor striated sphincter
`dyssynergia. Abel et al (1974) called attention to the
`fact that such a functional obstruction, which they too
`presumed to be mediated by the sympathetic nervous
`system, could be maximal at a urethral level rather than
`at the bladder neck and coined the term 'neuropathic
`urethra'. Many others have subsequently confirmed the
`utility of ex blockade in the treatment of what we now
`usually call smooth sphincter or bladder neck dys(cid:173)
`synergia or dysfunction (see Barrett & Wein 1991 for
`references), Successful results, usually defined as an
`increase in flow rate, decrease in residual urine and
`improvement in upper tract appearance (where patho(cid:173)
`logical), can often be correlated with an objective
`decrease in urethral profile closure pressures.
`Although one would expect success with ex-adrener(cid:173)
`gic blockade to be most evident in patients without
`detrusor striated sphincter dyssynergia as reported by
`Hachen (1980), Mobley (1976) reported a startling
`86% success rate in 21 patients with a reflex neuro(cid:173)
`genic bladder, with a corresponding success rate of
`66% in what was termed 'flaccid' and 57% of what was
`termed 'autonomous' neurogenic bladder dysfunction,
`success being defined as a postvoid residual urine vol(cid:173)
`ume consistently less than 100 ml. Scott & Morrow
`(1978), on the other hand, noted excellent results with
`phenoxybenzamine therapy in nine of 10 patients
`with a flaccid bladder and a flaccid external sphincter,
`a single patient with an upper motor neuron bladder
`with intact sympathetic innervation, but only eight of
`21 patients with hyperreflexia and autonomic dys(cid:173)
`reflexia and none of six patients with an upper motor
`neuron bladder and sympathetic denervation (lesion
`between TlO and L2).
`Although most would agree that ex blockers exert
`their favourable effects on voiding dysfunction prima(cid:173)
`rily by affecting the smooth muscle of the bladder neck
`and proximal urethra, there is information which sug-
`
`gests that they may affect striated sphincter tone as
`well. Other data suggest that they may exert: some
`effects on the symptorns of voiding dysfunction by de(cid:173)
`creasing bladder contractility. Much of the confusion
`relative to whether or not ex blockers have a direct (as
`opposed to indirect) inhibitory effect on the striated
`sphincter relates to the interpretation of observations
`referrable to their effect on urethral pressure in the
`region of the urogenirnl diaphragm and on electro(cid:173)
`myographic (EMG) activity in the periurethral striated
`muscle of this area. One cannot tell by pressure trac(cid:173)
`ings alone whether decreased resistance in one area
`of the urethra is secondary to a decrease in smooth or
`striated muscle activity. Nanninga et al (1977) found
`that
`the EMG activity of the external sphincter
`decreased after phentolamine administration in three
`paraplegic patients and attributed this to a direct inhi(cid:173)
`bition of a sympathetic action on the striated sphincter.
`Nordling et al (1981 b) demonstrated that clonidine
`and phenoxybenzamine (both of which pass the blood(cid:173)
`brain barrier) decreased urethral pressure and EMG
`activity from the area of the striated sphincter in five
`normal women; phentolamine (which does not pass the
`blood-brain barrier) also decreased urethral pressure in
`this area, but had no effect on EMG activity. They
`concluded that the effect of phentolamine was due
`to smooth muscle relaxation alone, while the effect
`of clonidine, and possibly phenoxybenzamine, was
`elicited mostly through centrally induced changes in
`striated urethral sphincter tonus, but that these agents
`also had an effect on the smooth muscle component of
`urethral pressure. None of the three drugs, however,
`affected the reflex rise in either urethral pressure or
`EMG activity seen during bladder filling and none
`decreased
`the urethral pressure or EMG activity
`response to voluntary contraction of the pelvic floor
`striated musculature. Pedersen et al (1980) showed
`that thymoxami