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`©Adns :[‘ll'Ell'|Gl‘D:"IGl Lin-1-ted All rights reserved
`
`Tolterodine: Selectivity for the Urinary
`Bladder Over the Eye (as Measured by
`Visual Accommodation) in Healthy Volunteers
`
`Christopher R. Chapplel and Lisbeth Nilvebrantz
`
`1 Department of Urology, The Royal Hallarnshire Hospital, Sheffield, UK
`2 Nilvebrant Pharma Consulting AB, Bromma, Sweden
`
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`Objective: Tolterodine exhibits a favourable selectivity for the urinary bladder
`over salivary glands in vivo, in the anaesthetised cat, whereas oxybutynin shows
`the opposite selectivity profile in this model. This study further evaluated the
`selectivity profiles of tolterodine and oxybutynin by comparing the effects on
`bladder function and visual accommodation in the Same individuals.
`
`Methods: in a double-blind, randomised, l'uur—way crossover study, I6 healthy
`volunteers received single oral doses of tolterodinc 5mg and oxybutynin 2.5, 5
`and 7.5mg. Voiding parameters were assessed for 12 hours post-dose, along with
`visual accommodation (near point of vision) at regular intervals.
`Results: A dose-dependent increase in maximum bladder capacity was observed
`for oxybutynin [2.5mg (+35%), 5mg [+450/rt) and 7.5mg (+57%)l. The effect of
`tolterodine 5mg on bladder capacity was approximately twice (+93%) that seen
`after oxybutynin 5mg and the onset of the effect was more rapid with tolterodine.
`Effects on visual accommodation were also dose—dcpendent for oxybutynin
`(maximum changes in near point of vision were 13%, 20% and 29%, respec-
`tively). The maximum change observed after tolterodine Sing was the same as
`after oxybutynin Srng (i .e. 20%).
`
`Conclusions: Tolterodine seems to exhibit selectivity for the bladder over the
`eye. Therefore, these results suggest that the normal dosage of tolterodine (Zmg
`twice daily) may have less effect on visual accommodation than the equivalent
`dosage of oxybutynin (Smg three times daily) in patients with an overactive
`bladder.
`
`Pharmacotherapy with muscarinic receptor ant-
`agonists is the mainstay in the treatment of over-
`active bladder.“*2' Cholinergic muscarinic recep—
`tors are expressed in a wide variety of tissues —
`including smooth muscles, salivary glands, the eye,
`
`heart and central nervous system.'3l Five molecu-
`larly distinct muscarinic receptor subtypes have
`beenidentified(M.,Mg, M_>,,M4 and M5) and many
`tissues contain mixed populations of different sub-
`types.l3‘5l Obviously, this wide and heterogeneous
`
`Patent Owner, |.lCB Pharma GmbH — Exhibit 2065 - 0001
`
`
`
`76
`
`Chapplc 8 Nilvebrtmt
`
`distribution of muscarinic receptor subtypes may
`result in a variety of peripheral and central adverse
`effects during treatment with muscarinic receptor
`antagonists. Dry mouth, which is the most common
`peripheral adverse effect of antimuscarinics, can be
`particularly bothersome for the patient. Thus, this
`adverse effect often results in discontinuation of
`medication.”-7‘
`
`Tolterodine is a pure and potent muscarinic
`receptor antagonist
`that has been specifically
`developed for the treatment of overactive bladder.
`Tolterodine has been shown to exhibit a selectivity
`for the urinary bladder over salivary glands in vivo,
`in the anaesthetised cat."” This favourable selectiv-
`
`ity profile has also been confirmed in humans,
`since the effect of tolterodine on the bladder is
`
`much more pronounced and long lasting than the
`effect on salivation.”-""101 Moreover, in compara-
`tive clinical phase III studies, it was demonstrated
`that tolterodine 2mg twice daily is equivalent to
`oxybutynin 5mg three times daily with regard to
`efficacy on the bladder, whereas tolterodine is
`significantly better tolerated ~ i.e. it causes signif-
`icantly less dry mouth, in terms of both frequency
`and severity — than oxybutynin (Ditropan@ ‘).""'3'
`The urinary bladder contains both M2 and M3
`receptors, constituting about 80% and 20%, re-
`spectively. of the total number of muscarinic recep-
`tors.'”~'5' In contrast. M3 receptors are known to
`predominate in salivary glands, although M. recep-
`tors may also be present.'5=“’=”l Similarly, the
`ciliary muscle in the eye that is responsible for the
`process of accommodation (i.e. the ability of the
`eye to change its refractive power to bring objects
`at different distances into focus) also primarily
`contains M3 receptors.”-13' In general, the M3
`subtype is considered to mediate the muscarinic
`responses in all of these tissues — i.e. the bladder,
`salivary glands and ciliary muscle.l3<4l However,
`evidence suggesting that M; receptors have a func-
`tional role in bladder contraction is accumulat-
`
`-mg_:4,s,19-221
`
`I Use of tradenames is for product identification only and
`does not imply endorsement
`
`The objective ofthe present study was to test the
`hypothesis that tolterodine would exhibit selectiv-
`ity for the urinary bladder over the eye (as mea-
`sured by the effect on maximal bladder capacity
`versus the effect on visual accommodation) com-
`
`pared with oxybutynin. This hypothesis was
`based on: a) the previously demonstrated selectiv-
`ity of tolterodine for the bladder versus salivary
`glands in viva; b) the potential role of M2 recep-
`tors in bladder contraction; C) the predominance
`of M3 receptors in salivary glands and the ciliary
`muscle of the eye; and d) the fact that oxybutynin,
`in contrast to tolterodine, exhibits a selectivity for
`M3 over M2 receptors.l“'33‘25l
`
`Subjects and Methods
`
`Subjects
`
`This was a double-blind, randomised, single-
`dose, four-way crossover study intended to enrol
`16 male subjects between 20 and 45 years of age
`with normal medical history. Subjects were ex-
`cluded if they had a history of alcohol or drug
`abuse, had participated in another study within 1
`month of study start, had a clinically significant
`illness within 2 weeks of study start, were on drug
`therapy, had a baseline residual bladder volume
`exceeding 501111, or had a peak urine flow rate less
`than 10 ml/sec.
`Written informed consent was obtained from all
`
`volunteers before study commencement, the
`protocol having been approved by a local institu-
`tional review board. The study was conducted in
`accordance with the latest version of the Declara-
`
`tion of Helsinki. Blinding was achieved by over-
`encapsulation of the study medication.
`
`Methods
`
`Three doses of oxybutynin (2.5mg, 5mg and
`7.5mg) were used in the study. In addition, a super-
`therapeutic dose of tolterodine (Sing) was tested.
`This high dose of tolterodine was used to ensure
`that some effects on visual accommodation (near
`point of vision) occurred, since accommodation
`disturbances have been reported rarely and at the
`
`Adis International Limited All rights reserved
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`Drugs R&D QED2: 3 (2)
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`
`
`Selectivity of Toltenodine for Bladder over Eye
`
`77
`
`Same level as placebo in clinical studies using the
`recommended normal 2mg twice daily regimen of
`tolterodine.l'3'2"J Subjects were randomly assigned
`to the four treatment sequences using a Latin
`square design. A one-week washout separated each
`study period. Each study period was 2 days in
`duration. On day 1, subjects drank 300ml of water
`hourly for l2 hours. This was done to facilitate
`voiding, gather a baseline maximum bladder capa-
`city, and create consistency between patients and
`treatment periods. On day 2, patients drank fluid
`hourly for 2 hours, were administered the drug, and
`then continued hourly fluid consumption (300 ml]
`hour) for ll hours post~dose. For 12 hours post-
`dose, voiding measurements (flow rate, voided
`volume and post-void residual) were taken after
`each urination. Post-void residual measurements
`
`were made with ultrasound. After each void, ultra-
`
`sound was performed a minimum of three times to
`ensure accurate post-void residual measurement.
`Visual accommodation was measured at baseline
`
`and 75, I35, 255, 375, 495, 615 and 735 minutes
`after drug administration using a convergence
`metre. The ability to accommodate for near vision
`was measured binocularly by moving a card with
`fine print along a graduated pole at eye level and
`recording the nearest point (in mm} at which the
`print could still be read.
`
`Data Analysis and Statistics
`
`Although measurements of both bladder capac-
`ity and visual accommodation were carried out up
`to 12 hours post-dose, calculation of the pharmaa
`cological effects were not performed later than 8
`hours post-dose because of the usual three times
`daily drug administration interval of oxybutynin
`(i.e. compared with the twice daily drug adminis-
`tration with tolterodine).
`Effect variables in the study were maximum
`bladder capacity (volume voided plus residual
`volume), maximum effect on accommodation, ac-
`commodation area under the curve (AUC), mean
`flow rate, and onset of bladder effect (as measured
`by the change in bladder capacity as a function of
`time). For both the maximum bladder capacity and
`
`maximum effect on accommodation, the greatest
`change noted on day 2 of each treatment period was
`identified from each patient and percentage change
`from baseline was determined from the maximum
`
`bladder capacity recorded from day l and from
`accommodation recorded prior to drug administra-
`tion on day 2, respectively. Accommodation AUC
`was determined using a linear trapezoidal rule and
`expressed as percentage of the baseline value
`(baseline value = 100%). The percentage change in
`mean flow rate was determined by comparing
`mean flow rates from day 2 with those recorded on
`clay I. Data for the effect variables were normally
`distributed, therefore parametric tests were con-
`ducted and means :l: standard error were reported.
`Onset of bladder effect was calculated by taking
`the mean percentage change from baseline in
`bladder capacity at hourly intervals after drug ad-
`ministration. Safety was measured by monitoring
`adverse events.
`
`Results
`
`A total of 16 subjects were enrolled and 15 com-
`pleted the study. One patient discontinued for per-
`sonal reasons after completing the first treatment
`period. The mean age of included subjects was 31
`years (range 20 to 45 years). Eight Caucasian,
`seven black and one Hispanic subject participated
`in the study. Subjects had a mean weight of 80kg
`(range 65 to l06kg) and height of 175cm (range
`163 to 188cm}.
`Oxybutynin induced a dose-dependent increase
`in accommodation AUC [expressed as percentage
`(%) change from predose-hour]. The AUC values
`observed after oxybutynin 2.5, 5 and 7.5mg were:
`737, 787 and 855, respectively. In comparison,
`tolterodine 5mg resulted in an AUC value of
`811 %0hour — i.e. a value between those observed
`
`for the 5 and 7.5mg doses of oxybutynin (table I,
`figure 1). Effects on accommodation, as measured
`by the maximum change from baseline, also
`linearly increased with the dose of oxybutynin.
`Maximum changes in near point of vision were
`13%, 20% and 29% for the three oxybutynin
`doses, respectively, while the maximum change
`
`(9 Ads International Limited Atl rights reserved.
`
`Drugs R&D 2002: 3 (2)
`
`Pafiht O\ivner,'UCB Pharma GmbH — Exhibit 2065 - 0003
`
`
`
`78
`
`Chapplc 5‘ Nilvcbrant
`
`Table I. Mean percentage change and standard error (SE) in visual and bladder variables from baseline as a function of treatment
`
`
` Variable Oxybutynin 2.5mg Oxybutynin 5mg Oxybutynin 7.5mg Tolterodine 5mg
`
`
`Accommodation AUC“
`736.8 (53.0)
`737 3 (70.0)
`855.2 (?5.3)
`311.1 (36.7)
`Maximum accommodation
`12.? (14.2)
`19.5 (18.8)
`29.1 (12.0)
`20.1 (6.6)
`Maximum bladder capacity
`34.9 (3.3)
`45.4 (4.7)
`56.9 (5.1)
`92.8 (5.7)
`Urine flow rate
`-5.7 (9.2)
`+3.5 (9.0)
`+4.3 (8.6)
`-153 (11.4)
`
`a "/a-hour.
`
`
`
`I Oxyhutynm
`Toiterodnna
`
`860
`840
`
`820
`800
`780
`
`"rt.ChangefrompredoseIh 740
`
`2.5 mg
`
`50mg
`Dose
`
`7.5 mg
`
`Fig. 1. Change in accommodation area under the curve (AUG).
`
`I Oxybutynin
`
`E Toiterodine
`
`30
`
`20
`
`10
`
`
`
`%Changefrombaseline
`
`2.5 mg
`
`5.0 mg
`Dose
`
`7.5 mg
`
`Fig. 2. Change in maximal effect on accommodation.
`
`after tolterodine 5mg (20%) was the same as that
`after oxybutynin 5mg (table I, figure 2).
`A linear dose—effect relationship was also seen
`for the effect of oxybutynin on the urinary bladder.
`As compared with baseline, the maximum bladder
`capacity increased by 35%, 45% and 57% after
`
`©Adis international Limited. Ail rights reserved.
`
`Drugs J?&D 2002: 3 (2)
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2065 - 0004
`
`oxybutynin 2.5mg, 5mg and 7.5mg, respectively.
`The effect of tolterodine (Smg) on the bladder was
`approximately double that of oxybutynin 5mg —
`i.e.
`the bladder capacity was increased 93% by
`tolterodine, as compared with the 45% seen after
`oxybutynin Smg (table I, figure 3). Interestingly.
`the change in mean flow rate during the drug
`administration interval was not affected to any
`degree by any of the doses of oxybutynin or
`tolterodine. However. the onset of the effect (as
`measured by the percentage change in bladder
`capacity as a function oftime) occurred earlier with
`tolterodine than with oxybutynin (figure 4). In
`addition, the duration of the effect of tolterodine
`
`was longer lasting than that of oxybutynin. Thus.
`the present results confirm the previous reports that
`tolterodine exerts a pronounced and long-lusting
`effect on the hladder,‘9-'”' and Support the rationale
`for the simpte twice-daily dosage regimen for
`tolterodine.
`
`No tolerahility concerns were noted in the study.
`Seven subjects reported a total of 12 adverse
`
`1'00
`
`I Oxybulynin
`El Toiterodlne
`
`frombaseline
`“A.Change
`
`2.5 mg
`
`5.0 mg
`Dose
`
`7.5 mg
`
`Fig. 3. Change in maximum bladder capacity.
`
`
`
`
`
`760
`
`720
`
`
`
`79
`Selectivity of Tolterodine for Bladder over Eye
`
`lence, dizziness, cognitive impairment), and vi-
`sion (e.g. blurred vision) that should not be ne-
`glected. Indeed, the classical effect ofantimuscari-
`nic agents on vision (cf.
`the ‘belladonna effect’
`after topical administration of atropine to the eye)
`is well known. The impact of these effects in pa-
`tients who are receiving systemic antimuscarinic
`drugs has not yet been properly investigated or
`evaluated. However, it is obvious that changes in
`accommodation brought about by antimuscarinic
`agents could also have a negative effect (e.g. cause
`difficulty with reading or perfonning close work),
`and in some cases also be dangerous (e.g. when
`driving an automobile), and impact on patients‘
`lives.
`
`The circular fibres of the ciliary muscle control
`visual accommodation ofthe eye, which occurs by
`alteration of the shape of the lens. In essence, con-
`traction of the ciliary muscle reduces the tension
`on Suspensory ligaments of the lens. When this
`occurs, the lens assumes a more spherical shape,
`which results in an increase in refractive power of
`the eye. Contraction ofthe ciliary muscle is medi-
`ated via activation of M3 muscarinic recep-
`tors.“3-2"'3”l Thus, ifthe M3 receptor is blocked by
`an antimuscarinic drug, the accommodation reflex
`will become impaired as a result of inhibition of
`the contraction of the ciliary muscle.
`The fact that the M3 receptor subtype predomi-
`nates in the ciliary muscle of the eye likely explains
`the results shown in this study — i.e. that tolterodinc
`(as compared with oxybutynin) has a more pro-
`nounced effect on the urinary bladder (maximum
`bladder capacity) than on the eye (visual accom-
`modation). in the urinary bladder, the predominant
`muscarinic receptor is M2 (30%), with lower
`quantities of M3 (20%). Although it is generally
`assumed that bladder contraction is mediated only
`by the M3 subtype. a body of emerging evidence
`clearly suggests that both the M3 and M2 subtypes
`may work in concert in the bladder.”-‘9’22l
`As in the ciliary muscle, M3 receptors are
`known to predominate in salivary glands.‘-1’-5‘
`Tolterodine and oxybutynin have,
`in radioligand
`binding studies, been shown to exhibit equal
`
`7D
`60
`
`‘D
`50
`$3
`S 40
`
`A Oxybutynin 2.5 mg
`I Oxybutynin 5.0 mg
`V Oxybutymn 7.5 mg
`O Toltarodine 5.0 mg
`
`IF ~ - — .
`
`'
`
`i,
`
`.
`
`J.‘
`
`so
`20
`10
`
`0-10
`
`-20
`
`5
`in
`2'«cs
`
`5a
`
`s
`
`Preduse 0-1
`
`1-2
`
`4-5
`3-4
`2-3
`Time after dose (h)
`
`5-6
`
`6-7
`
`7-3
`
`Fig. 4. Change in maximum bladder capacity as a function oi
`time after drug administration.
`
`events. The numbers of events per treatment were:
`three (oxybutynin 2.5mg), one (oxybutynin 5mg),
`three (oxybutynin 7.5mg) and five (tolterodine
`5mg). The most common adverse event was head-
`ache, reported for oxybutynin in three subjects and
`tolterodine in one subject. Only one case of dry
`mouth was reported (tolterodine 5mg). The lack of
`reports of dry mouth in this study may be a result
`of the large fluid intake that was required of all
`study subjects.
`
`Discussion
`
`Overactive bladder is known to have a signifi-
`cantly negative impact on patients’ lives.l3"'J This
`is coupled with the problems that patients encoun-
`ter in trying to control their condition by a variety
`of coping actions. e.g. timed voiding, toilet map-
`ping and restricting their fluid intake. The diffi-
`culty with older antimuscarinic drugs (e.g. oxy-
`butynin) for this condition is that adverse effects
`often confound the positive effects of treatment.
`For the majority of patients, dry mouth is the most
`frequent and bothersome adverse effect, which often
`results in discontinuation of drug treatment."’~7l
`However,
`there is also a potential risk of anti-
`muscarinic adverse effects associated with the
`
`gastrointestinal system (eg. dyspepsia, constipa-
`tion, nausea), central nervous system (e.g. somno-
`
`© Adis international LilTIil'Ed. All rights reserved.
`
`Drugs RSLD 2032: 3 (2)
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2065 - 0005
`
`
`
`BU
`
`Clmpple £7 Nilvcbranr
`
`affinity at bladder muscarinic receptors, whereas
`tolterodine has an 8-fold lower affinity than oxy-
`butynin at muscarinic receptors in the parotid
`gland.l3l In viva, tolterodine exhibits a selectivity
`for the bladder over salivary glands. This selectiv-
`ity profile cannot be explained by selectivity of
`tolterodine for a specific subtype, because tolterod-
`ine essentially exhibits an equal affinity across the
`five muscarinic receptor types.'”»2" However, it has
`also been shown that drugs that exhibit a selectivity
`for M3 over M2 receptors (e.g. oxybutynin and
`darifenacin) are more potent inhibitors of saliva-
`tion than of bladder contractions in viv0.l2l*22l
`
`Taken together, along with the fact that tolterodine
`and its active metabolite are specific for muscarinic
`receptors and do not exhibit secondary pharmaco-
`logical actions, these findings suggest both that the
`M2 receptors are involved in bladder contraction
`and that the propensity of M3-selective drugs (e.g.
`oxybutynin) to cause dry mouth may be a result of
`their selectivity for the M3 over M2 receptors.'“‘22l
`In analogy, the findings in the present study — i.e.
`that a single dose of tolterodine (Smg) had about
`the same effect on visual accommodation as oxy-
`butynin (Sing), while tolterodine was about twice
`as effective on the bladder, may also be explained
`by the selectivity of oxybutynin for the M3 versus
`M2 receptors.
`A few limitations in this study are worth noting.
`While single-dose effects of the medications were
`evaluated in healthy volunteers, it would have been
`more clinically interesting if the study were con-
`ducted in patients with overactive bladder. How-
`ever. the ability to standardise study procedures
`would have been extremely difficult in patients
`with different levels of frequency and urgency.
`Furthermore, competitive inhibitors like tolterod-
`ine and oxybutynin were expected to have the same
`overall effect (i.e. increasing bladder capacity) in
`healthy volunteers as would be seen in patients.
`The change in maximum accommodation was
`quite variable in this study, consistent with other
`work where accommodation measurements had a
`
`great amount ofvariability.'3” This did not have an
`impact on the results since the accommodation
`
`AUC results were not highly variable and were
`consistent with the results seen in maximum
`
`accommodation effect. In this study, maximum
`bladder capacity as an endpoint was not a limita-
`tion, since it has been shown previously to signi-
`ficantly positively correlate with cystometric
`bladder capacity}-‘zl The immediate—release formu-
`lations of tolterodine and oxybutynin were used in
`this study. Further work is required to determine
`whether the selectivity noted for tolterodine in this
`study is also noted with the once-daily formula-
`tions of these medications.
`
`In Conclusion, the hypothesis of the present
`study seemed to be proven correct, even though it
`did not encompass the full role of muscarinic re-
`ceptors involved in bladder contraction or accom-
`modation. In this study, measurements of the
`effects on the bladder and visual accommodation
`
`changes were made up to I2 hours post-dose. How-
`ever, in order to coincide with the three times daily
`administration of oxybutynin compared with the
`twice daily administration of tolterodine, calcula-
`tions of drug effects were limited to data collected
`up to 8 hours post-dose. While this may not be
`optimal with regard to tolterodine, the effects of
`this drug on both the bladder and visual accommo-
`dation reached their maximums during the first
`8 hours after drug administration. Therefore, these
`comparisons were valid whether 8 or 12 hours was
`used for the calculations.
`
`Conclusion
`
`This study shows that a single super-therapeutic
`5mg dose of tolterodine causes approximately the
`same effect on visual accommodation as a single
`standard Smg dose of oxybutynin. At these doses,
`however, tolterodine has twice the effect on blad-
`
`der capacity. Therefore, these results suggest that
`the normal dosage of tolterodine (Zmg twice daily)
`may have less effect on visual accommodation than
`the equivalent dosage of oxybutynin (Sing three
`times daily) in patients with overactive bladder.
`
`Acknowledgements
`
`This study was sponsored by Pharmacia Corporation
`
`© Aclis International Limited. Ali rights reserved
`
`Drugs i<‘&D 2032: 3 (2)
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2065 - 0006
`
`
`
`Selectivity of Tolterocline for Bladder over Eye
`
`S1
`
`References
`. Wein AJ. Rovner ES. The overactive bladder: an overview for
`primary care health providers. lntl I-‘ertil Womens Med 1999;
`44; 56-66
`. Nilvebrant L. The mechanism of action of tolterodine. Rev
`
`logy. XVII. Classification of rnuscarinic acetylcholine recep-
`tors. Pharmacol Rev I998; 50: 279-90
`Yarker YE, Goa KL, Fitton A. Oxybutynin. A review of its
`phannaeodynamic and pharmacokinetic properties, and its
`therapeutic use in detrusur instability. Drugs Aging 1995; 6:
`243-62
`Kelleher Cl. Cardozo LD. Khullar V. et al. A medium term
`analysis of the subjective elficacy of treatment for women
`with detrusor instability and low bladder compliance. Br J
`Obstet Gynaecol I997; 104: 988-93
`Nilvebrant L. Andersson K-E. Gillberg P—G, et al. Toltcroditre
`-a new bladder selective antimuscarinic agent. Earl Pharm-
`acol I997; 327: 195-207
`. Stahl MM, Ekstrom B, Sparf B, et al. Urodynamic and other
`effects of tollerodiner a novel antimuscarinic drug for the
`treatment of detrusor overactivity. Neurouroi Urodyn I995;
`14; 647-55
`Brynne N. Slahl MMS, Hallén B, et al. Pharmacokinetics and
`pharmacodynamics of tolterodine in man: a new drug for the
`treatment 0|" urinary bladder overactivity. Int J Clin Phar-
`macol Ther I997‘. 35: 287-95
`Appell RA, Clinical ctlicacy and safety of tolterodine in the
`treatment of overactive bladder: a pooled analysis. Urology
`I997: 50 (6A Suppl): 90-6
`Abrams P, Freeman R, Anderstrorn C, et al. Tolterodine, a new
`antimuscarinic agent: as effective but better tolerated than
`oxybutynin in patients with an overactive bladder. Br] Urol
`l998;8l: 80l—|tl
`Drutz ll. Appell RA, Gleason D. et al. Clinical cflicacy and
`safety of tolterodine compared to oxybutynin and placebo in
`patients with overactive bladder. Int Urugynecol J Pelvic
`Floor Dysfuncl I999; I0: 283-9
`Ya maguclti U, Shisda K, Tamura K, et. al. Evaluation of mRNAs
`encoding for muscarinic receptor subtypes in human dctrusor
`muscle. J Urol I996; 56'. 1208-13
`Wang P, Luthin GR, Ruggieri MR. Muscarinic acetylcholine
`receptor subtypes mediating urinary bladder contractility and
`coupling to UTP binding proteins. J Phamtacol Exp Ther
`I995; 273: 959-66
`Vanderheyden P, Gies JP. Ebinger G. et al. Human Ml-, M2-
`and M3—muscarinic cholinergic receptors binding charac-
`teristics of agonists and antagonists. J Neurol Sci 1990; 97:
`67-80
`
`10.
`
`_11,
`
`I2.
`
`I3.
`
`14.
`
`I5.
`
`I6.
`
`17
`
`I8
`
`2]
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`2‘).
`
`30.
`
`31.
`
`32.
`
`lzutsu KT, et al. Characterization of
`. Mei L. Rocske WR.
`muscarinic acetylcholine receptors in human labial salivary
`glands. Eur] Pharmacnl 1990; I76: 367-70
`. Gil DW, Brsen TS, Bugardus AM. et al. Muscarinic receptors
`in human ciliary muscle identified by polymerase chain re-
`st‘-l"r9-5%-’.“ri5+‘.'2tt'§viZtl“"""“""”"“'“"“" ’”'"""“'“" “‘ '
`. Nilvebrant 1.. Hallen B, Larsson G. Toltemdine -a new bladder
`selective musearinic receptor antagonist: preclinical pharma-
`cological and clinical data. Life Sci 1997; 60: I129-36
`, Gillberg P-(E, Sundquisl 3. Nilvebranl L, Comparison of the in
`vitro and Ill vivo profiles of tolterodine and those of subtype-
`seleetive muscarinic receptor antagonists. Eur J Pharmacol
`1998'. 349: 285-92
`Nilvebmnt L. On the muscarinic receptors in the urinary bladder
`and the putative subclassification of muscarinic receptors.
`Acta Pharmacol Toxicol 1986; 59 Suppl I: I-45
`Nagao M, Kaneko S, Hirota T, et al. Effects of propiverine
`hydrochloride (propiverine) on the muscarinic receptor bind-
`ing aflinity in guinea pig tissues and on salivation in the eun-
`scious dog. Folia Pharmaeologica Jpn I999; ll3: 157-66
`Waldeek K. Larssurt N. Anderssun K-li. Comparison of oxy-
`butynin and its active metabolite in the human detrusor and
`parotid glILI'l[l..l Urol I997; I57: 1093-7
`Physician Desk Reference, 54th ed. Montville (NJ): Detrol
`product information. Medical Economics Company. Inc-.,
`2000: 2439-41
`Jackson S. The patient with an overactive bladder -symptoms
`andquallty ot‘lil'e issues. Urology l997;5U(6ASuppl): I8-22
`Gupta N, Drance SM. McAllister R, et al. Localization of M3
`Il'lt.lSL‘ZIl'lI'Il.L‘ receptor subtype and mRNA in the human eye.
`Ophthalmic Res I994; 26: 207-13
`Zhang X. Hcmandez MR, Yang H, et al. Expression of tr1usL:a—
`rinic receptor subtype mRNA in the human ciliary muscle.
`Invest Uphthalmol Vis Sci 1995; 36: 1645-57
`Pang lH, Matsumoto S. Tamm E. et al. Characterization ofmus—
`carinic receptor involvement in human ciliary muscle cell
`function.J Ocul Pharnracol. I997; I0: 125-36
`Zetterstrom C. l-'_-'t'fects of adrenergie drugs on accommodation
`and distant refraction in daylight and darkness. Acta Op-
`hthalmol (Copenh) I988; 66: 58-64
`Diokno AC, Wells Tl. Brink CA. Comparison of self—reported
`voided volume with cystornetrie bladder capacity. J Urol
`I987; l37: 693-700
`
`Correspondencie and offprints: Dr Christopher R. Chupple,
`Urology Research, The Royal I-lallamshire Hospital, I Floor,
`Glossop Road, Sheffield, S10 ZJF, UK.
`E—mail: c.r.chapplp@she=f.nc.ttl<
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