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226Urinary bladder neck blood flow: Comparison of transrectal colour doppler ultrasound to laser doppler flowmetry
226
225 THE EFFECTS OF THE FLAVONOID SMOOTH MUSCLE CONTRACTILITY
ON
URINARY
BLADDER
Dambros M ? , Van Koeveringe G. 2, De Jongh R. 2, Van Kerrebroek p.2, Riccetto C. 1, Fraga R. 1, Thiel M ) , Palms p.1 ~Universidade Estadual de Campinas, Urology, Campinas, Brazil, ZMaastricht University, Pharmacology and Toxicology, Maastricht, The Netherlands I N T R O D U C T I O N & OBJECTIVES: Flavonoids comprise a large group of naturally existing polyphenolic compounds, which possess a wide spectrum of physiological and pharmacological effects. Galangin is a flavonol with several biological activities such as an anti-oxidative effect and an inhibitory effect on vas deferens contractility. The aim of the present study was to investigate the muscle actions of Galangin on the pig bladder smooth muscle and to examine their possible underlying mechanisms. M A T E R I A L & METHODS: Male pig detrusor strips were mounted between stainless steel hooks in 20ml organ. Mechanical responses were recorded using an isometric force transducer. After an initial equilibration time, all strips were stimulated at 32Hz electrical field stimulation (EFS), and subjected to a methacholine concentration curve (MCC), then the incubation medium was changed to one with the following additions for each of the 7 experimental groups: all tissues in group 1 were incubated with normal krehs; those in group 2 with Galangin (30raM); group 3 with Galangin + Propanoloi (lmM); group 4 with Galangin + Verapamil (0.1mM); group 5 with Galangin + Phentolamine (lmM); group 6 with Galangin + Atropine (lmM) and those in group 7 with Galangin + Calcium flee solution. All strips were equilibrated in these buffers for 1.5 hours then stimulation at 32Hz and response curve to methacholine were performed. After that, all strips were washed and incubated with normal krebs solution for 1.5 hours and, at the end of that period, responses to field stimulation at 32Hz and MCC were re-assessed. Student's t - test and one factor ANOVA were used to determine the statistical significance to 0.05 levels.
URINARY BLADDER NECK BLOOD TRANSRECTAL COLOUR DOPPLER DOPPLER FLOWMETRY
FLOW: COMPARISON OF ULTRASOUND TO LASER
P i n g g e r a G.M. t, Gozzi C. t, P a l l w e i n L. 2, F r a u s c h e r F. 2, S t a d l b a u e r K. 3, Strasser H.t, Bartsch G.t, Schuster A. 4 ~Medical University Innsbruck, D e p a r t m e n t o f Urology, lnnsbruck, Austria, 2Medical U n i v e r s i t y I n n s b r u c k , D e p a r t m e n t o f U r n - R a d i o l o g y , I n n s b r u c k , Austria, 3Medical University Innsbruck, Department of Anaesthesiology, lnnsbruck, Austria, 4Medical Hospital Feldkirch, D e p a r t m e n t o f Radiology, Innsbruck, Austria I N T R O D U C T I O N & O B J E C T I V E S : It w a s the aim o f the present study to assess the a c c u r a c y o f c o m p u t e r assisted P o w e r D o p p l e r i m a g e quantification for m e a s u r e m e n t the relative c h a n g e s o f urinary bladder b l o o d flow. F o r this reason, m e a s u r e m e n t s w e r e c o m p a r e d with Laser D o p p l e r f l o w m e t r y (LDF), the ' g o l d s t a n d a r d ' , in a n animal model. M A T E R I A L & M E T H O D S : Transrectal P o w e r D o p p l e r U l t r a s o u n d a n d L D F o f the u r i n a r y bladder n e c k w e r e p e r f o r m e d in three anesthetized pigs during c o m p a r a t i v e cystometry. N o r m a l saline (NaC1) w a s u s e d for the first run, followed b y a second run with 0.2 M p o t a s s i u m chloride (KC1). Standardized m a c h i n e settings ( A c u s o n Sequoia 512®, U S A ) w e r e u s e d for P o w e r Doppler Imaging. C o l o r Pixel density (CPD) w a s calculated with c o m p u t e r assistance f r o m sagital P o w e r D o p p l e r i m a g e m a p s u s i n g Scion I m a g e ® analysis software. Tissue perfusion units (TPU) w e r e m e a s u r e d using a B L F 2 1 L a s e r Doppler F l o w m e t e r (Transonic Systems Inc.®, U S A ) .
RESULTS: Galangin inhibited the maximum contractile response to EFS and metacholine by 60% (p<0.05) and 64% (p<0.05), respectively. The inhibitory effect of galangin was unaffected by a combination of propanolol, phentolamine and capsazepine (p >0.05). However, when verapamil was added to the medium, the response to galangin was significantly reduced (p<0.05). The maximum force of the metacholine-evoked contractions, in calcium-free solution after incubation with Galangin was 32% of the maximum initial force (p < 0.01).
R E S U L T S : In the presence o f NaC1, m e a n C P D increased f r o m 18.65 (+/-1.78) to 37.8 (+/-1.84) at 100 ml a n d to 88.32 (+/-1.35) at full bladder capacity, w h e r e a s with KC1 filling, m e a n C P D increased f r o m 18.65 (+/-1.78) to 59.63 (+/-0.5) at 100 ml a n d 110.82 (+/-2.98) at full capacity. With NaCI filling, bladder n e c k b l o o d f l o w increased f r o m 22 T P U to 46 T P U a n d 62.5 TPU, c o m p a r e d to 50 T P U a n d 102.5 T P U with KC1.
CONCLUSIONS: We have demonstrated that Galangin, at high concentrations, exerts an inhibitory effect on pig bladder smooth muscle contractility. The effect was more profound in association with a reduced availability of extracellular calcium. In a wider perspective, the results of this study indicate that Galangin may provide a new approach to further research into the treatment of detmsor overactivity.
C O N C L U S I O N S : C P D and L D F s h o w e d a c o r r e s p o n d i n g increase o f u r i n a r y bladder n e c k perfusion with increasing bladder distension. B a s e d on the direct positive correlation b e t w e e n C P D a n d LDF, C P D is an objective p a r a m e t e r for the quantitative assessment o f u r i n a r y bladder n e c k b l o o d flow changes.
228 PROPIVERINE HYDROCHLORIDE IMMEDIATE AND EXTENDED R E L E A S E : C O M P A R I S O N O F E F F I C A C Y A N D T O L E R A B I L I T Y IN PATIENTS WITH OVERACTIVE BLADDER
THE EMOTIONAL BURDEN SYMPTOMS ON SUFFERERS
OF
OVERACTIVE
BLADDER
(nAB)
Kelleher C. 1, Westphalen 322,Ellsworth p.3 Juenemann K.P.1, Hessdoerfer E.z, Unamba-Oparah I.s, Berse M.4, Bmanjes R. 5, Madersbacher H.a, Gramatte T.s IUniversity Hospital Kiel, Urology, Kiel, Germany, 2Consultant, Urology, Berlin, Germany, 3Consultant, Urology, Voerde, Germany, 4Consultant, Urology, Duisburg, Germany, 5Apogepha Arzneimittel GmbH, Urology, Dresden, Germany, 6Univeristy Hospital of Innsbmck, Neurourology, lnnsbruck, Austria INTRODUCTION & OBJECTIVES: The primary objective was to evaluate the efficacy of propiverine hydrochloride immediate release (IR) and propiverlne hydrochlorlde extended release (ER) in comparison with placebo in patients with overactive bladder in terms of incontinence episodes/24 hours. Secondary objectives were number of micturitions/24h, urge episodes/24h, volume of micturition, quality of life, adverse events (AEs), blood pressure/pulse rate, ECG, haematology, clinical chemistry and urinalysis, evaluation of efficacy and tolerability by patient and investigatnn MATERIAL & METHODS: The double-blind, double-dummy, randomised study compared 3 parallel groups (IR 15 mg twice daily, ER 30 mg once daily and placebo) at a ratio of 2:2:1. ARer a run-in period of 7 days, the patients were treated for 32 days. The safety population consisted of 988 patients (89.5% females and 10.5% males). Its mean age was 56.1 years and its mean BMI was 26.6 kg/m2 in the males and 27.0 kg/m2 in tile females. The ITT population consisted of 974, and the PP population of 910 patients. RESULTS: Efficacy In the ITT population the baseline values for the incontinence episodes were comparable (IR 3.29, ER 3.38, placebo 3.50). The numbers decreased by 2.26 in the IR group (p<0.0001), by 2.46 in the ER group (p<0.0001), and by 1.75 in the placebo group. The number of micturifions and the number of urge episodes were more reduced in both propiverine groups than with placebo (p<0.05). The mean volume of the single micturitions increased statistically significantly more in both propiverine groups than in the placebo group, although the liquid intake was comparable between groups. The efficacy assessment was statistically significantly better in both propiverine groups than with placebo. The improvement in QoL was less consistent, although propiverine was slightly better than placebo. Safety 38.5% of the patients experienced AEs in the IR group, 34.3% in the ER group, and 20.3% in the placebo group. 26 (2.6%) patients dropped out prematurely due to aAE: 14 (3.5%) in the IR group, 11 (2.8%) in the ER group, and 1 (0.5%) in the placebo group. Gastrointestinal disorders and nervous system disorders were the most frequent reasons. The most frequent AE was dry mouth with 22.8 % of the patients of the IR group, 21.7 % of the ER group and 6.4 % of the placebo group. "Eye disorders" were experienced by 6.6% of the patients of the IR group, 7.2% of the ER group and 2.5% of the placebo group. All other system organ classes accounted for less than 5% of the patients each. The overall tolerability was rated very good or good by 85% of the investigators and patients. CONCLUSIONS: Propiverinn IR 15 mg twice daily and propiverine ER 30 mg once daily reduce effectively the number of incontinence episodes/24h within a treatment period of 32 days. They also decrease the number of urge episodes and the number of mieturitious. Both formulations are safe.
1Guy's and St. Thomas' Hospital NHS Trust, Obstetrics and Gynaecology, London, United Kingdom, aNovartis Pharma AG, Integrated Insight and Analytics, Basel, Switzerland, 3U. Massachusetts Memorial Hospital, Urology, Worcester, United States INTRODUCTION & OBJECTIVES: Physicians' perceptions of nAB may not reflect the significant emotional burden experienced by patients. The emotional impact of nAB and urinary incontinence is known to be high but is rarely measured directly. Emotional burden may affect treatment perceptions and limit help-seeking behaviour, a major predictor of treatment outcome. This study examines the emotional burden of nAB sufferers. MATERIAL & METHODS: A population-based, cross-sectional study was conducted in 63 men and women with nAB (treatment-naive and drag-treated) in the US and UK, varying in age (40-75 years), continence and nAB severity (based on symptoms selected in a screening questionnaire). These responses were correlated with patient perception of severity and bother. Respondents were excluded if they bad other conditions potentially affecting emotional status such as clinical depression. RESULTS: Patients were: 45 females (39 with wet and 6 with dry nAB) and 18 men (11 wet, 7 dry). • Overall, patients were resigned to their nAB symptoms, believing them to be of genetic origin, a natural part of aging or resulting from childhood behaviours. This perception was most common amongst women aged 60-75 years. • Emotional effects were of greater concern to patients than urologic symptoms. The most severely emotionally impacted patients tended to be wet type and female. Women, especially those with more severe nAB, felt personal shame; those aged 40-49 and 61-75 years felt trapped, and the older group also had poor self-image (felt degraded). Women aged 50-60 years expressed stronger emotions such as fear, anger, injustice, irritation and being too young for an 'old age' condition to set in. • UK patients expressed stronger emotions than US patients, who were more educated on nAB and felt more empowered to seek treatment (reflecting direct-to-consumer advertising). • nAB (both wet and dry) was associated with severe stigmatization and high patiantjphysician communication barriers. • The most common emotional responses were embarrassment, frustration and anxiety. Fear of a possible 'accident' dominated patients' thinking and behaviour. • Patient expectations from drug therapy centered on increased control over their lives and hope, but patients noted that side effects adversely affected compliance. CONCLUSIONS: The study identified a marked emotional impact from nAB which was of greater concern to patients than the nAB symptoms, and was evident across patient age, gender and nAB type/severity. This was associated with clear expression of patient emotional reactions, which was related to overall patient bother. Increased education and more pro-active discussions by physicians are needed to help relieve the social stigma, allow earlier symptom identification and treatment, and increase the effectiveness and satisfaction with drag therapies.
European Urology Supplements 4 (2005) No. 3, pp. 59
225 THE EFFECTS OF THE FLAVONOID SMOOTH MUSCLE CONTRACTILITY
ON
URINARY
BLADDER
Dambros M ? , Van Koeveringe G. 2, De Jongh R. 2, Van Kerrebroek p.2, Riccetto C. 1, Fraga R. 1, Thiel M ) , Palms p.1 ~Universidade Estadual de Campinas, Urology, Campinas, Brazil, ZMaastricht University, Pharmacology and Toxicology, Maastricht, The Netherlands I N T R O D U C T I O N & OBJECTIVES: Flavonoids comprise a large group of naturally existing polyphenolic compounds, which possess a wide spectrum of physiological and pharmacological effects. Galangin is a flavonol with several biological activities such as an anti-oxidative effect and an inhibitory effect on vas deferens contractility. The aim of the present study was to investigate the muscle actions of Galangin on the pig bladder smooth muscle and to examine their possible underlying mechanisms. M A T E R I A L & METHODS: Male pig detrusor strips were mounted between stainless steel hooks in 20ml organ. Mechanical responses were recorded using an isometric force transducer. After an initial equilibration time, all strips were stimulated at 32Hz electrical field stimulation (EFS), and subjected to a methacholine concentration curve (MCC), then the incubation medium was changed to one with the following additions for each of the 7 experimental groups: all tissues in group 1 were incubated with normal krehs; those in group 2 with Galangin (30raM); group 3 with Galangin + Propanoloi (lmM); group 4 with Galangin + Verapamil (0.1mM); group 5 with Galangin + Phentolamine (lmM); group 6 with Galangin + Atropine (lmM) and those in group 7 with Galangin + Calcium flee solution. All strips were equilibrated in these buffers for 1.5 hours then stimulation at 32Hz and response curve to methacholine were performed. After that, all strips were washed and incubated with normal krebs solution for 1.5 hours and, at the end of that period, responses to field stimulation at 32Hz and MCC were re-assessed. Student's t - test and one factor ANOVA were used to determine the statistical significance to 0.05 levels.
URINARY BLADDER NECK BLOOD TRANSRECTAL COLOUR DOPPLER DOPPLER FLOWMETRY
FLOW: COMPARISON OF ULTRASOUND TO LASER
P i n g g e r a G.M. t, Gozzi C. t, P a l l w e i n L. 2, F r a u s c h e r F. 2, S t a d l b a u e r K. 3, Strasser H.t, Bartsch G.t, Schuster A. 4 ~Medical University Innsbruck, D e p a r t m e n t o f Urology, lnnsbruck, Austria, 2Medical U n i v e r s i t y I n n s b r u c k , D e p a r t m e n t o f U r n - R a d i o l o g y , I n n s b r u c k , Austria, 3Medical University Innsbruck, Department of Anaesthesiology, lnnsbruck, Austria, 4Medical Hospital Feldkirch, D e p a r t m e n t o f Radiology, Innsbruck, Austria I N T R O D U C T I O N & O B J E C T I V E S : It w a s the aim o f the present study to assess the a c c u r a c y o f c o m p u t e r assisted P o w e r D o p p l e r i m a g e quantification for m e a s u r e m e n t the relative c h a n g e s o f urinary bladder b l o o d flow. F o r this reason, m e a s u r e m e n t s w e r e c o m p a r e d with Laser D o p p l e r f l o w m e t r y (LDF), the ' g o l d s t a n d a r d ' , in a n animal model. M A T E R I A L & M E T H O D S : Transrectal P o w e r D o p p l e r U l t r a s o u n d a n d L D F o f the u r i n a r y bladder n e c k w e r e p e r f o r m e d in three anesthetized pigs during c o m p a r a t i v e cystometry. N o r m a l saline (NaC1) w a s u s e d for the first run, followed b y a second run with 0.2 M p o t a s s i u m chloride (KC1). Standardized m a c h i n e settings ( A c u s o n Sequoia 512®, U S A ) w e r e u s e d for P o w e r Doppler Imaging. C o l o r Pixel density (CPD) w a s calculated with c o m p u t e r assistance f r o m sagital P o w e r D o p p l e r i m a g e m a p s u s i n g Scion I m a g e ® analysis software. Tissue perfusion units (TPU) w e r e m e a s u r e d using a B L F 2 1 L a s e r Doppler F l o w m e t e r (Transonic Systems Inc.®, U S A ) .
RESULTS: Galangin inhibited the maximum contractile response to EFS and metacholine by 60% (p<0.05) and 64% (p<0.05), respectively. The inhibitory effect of galangin was unaffected by a combination of propanolol, phentolamine and capsazepine (p >0.05). However, when verapamil was added to the medium, the response to galangin was significantly reduced (p<0.05). The maximum force of the metacholine-evoked contractions, in calcium-free solution after incubation with Galangin was 32% of the maximum initial force (p < 0.01).
R E S U L T S : In the presence o f NaC1, m e a n C P D increased f r o m 18.65 (+/-1.78) to 37.8 (+/-1.84) at 100 ml a n d to 88.32 (+/-1.35) at full bladder capacity, w h e r e a s with KC1 filling, m e a n C P D increased f r o m 18.65 (+/-1.78) to 59.63 (+/-0.5) at 100 ml a n d 110.82 (+/-2.98) at full capacity. With NaCI filling, bladder n e c k b l o o d f l o w increased f r o m 22 T P U to 46 T P U a n d 62.5 TPU, c o m p a r e d to 50 T P U a n d 102.5 T P U with KC1.
CONCLUSIONS: We have demonstrated that Galangin, at high concentrations, exerts an inhibitory effect on pig bladder smooth muscle contractility. The effect was more profound in association with a reduced availability of extracellular calcium. In a wider perspective, the results of this study indicate that Galangin may provide a new approach to further research into the treatment of detmsor overactivity.
C O N C L U S I O N S : C P D and L D F s h o w e d a c o r r e s p o n d i n g increase o f u r i n a r y bladder n e c k perfusion with increasing bladder distension. B a s e d on the direct positive correlation b e t w e e n C P D a n d LDF, C P D is an objective p a r a m e t e r for the quantitative assessment o f u r i n a r y bladder n e c k b l o o d flow changes.
228 PROPIVERINE HYDROCHLORIDE IMMEDIATE AND EXTENDED R E L E A S E : C O M P A R I S O N O F E F F I C A C Y A N D T O L E R A B I L I T Y IN PATIENTS WITH OVERACTIVE BLADDER
THE EMOTIONAL BURDEN SYMPTOMS ON SUFFERERS
OF
OVERACTIVE
BLADDER
(nAB)
Kelleher C. 1, Westphalen 322,Ellsworth p.3 Juenemann K.P.1, Hessdoerfer E.z, Unamba-Oparah I.s, Berse M.4, Bmanjes R. 5, Madersbacher H.a, Gramatte T.s IUniversity Hospital Kiel, Urology, Kiel, Germany, 2Consultant, Urology, Berlin, Germany, 3Consultant, Urology, Voerde, Germany, 4Consultant, Urology, Duisburg, Germany, 5Apogepha Arzneimittel GmbH, Urology, Dresden, Germany, 6Univeristy Hospital of Innsbmck, Neurourology, lnnsbruck, Austria INTRODUCTION & OBJECTIVES: The primary objective was to evaluate the efficacy of propiverine hydrochloride immediate release (IR) and propiverlne hydrochlorlde extended release (ER) in comparison with placebo in patients with overactive bladder in terms of incontinence episodes/24 hours. Secondary objectives were number of micturitions/24h, urge episodes/24h, volume of micturition, quality of life, adverse events (AEs), blood pressure/pulse rate, ECG, haematology, clinical chemistry and urinalysis, evaluation of efficacy and tolerability by patient and investigatnn MATERIAL & METHODS: The double-blind, double-dummy, randomised study compared 3 parallel groups (IR 15 mg twice daily, ER 30 mg once daily and placebo) at a ratio of 2:2:1. ARer a run-in period of 7 days, the patients were treated for 32 days. The safety population consisted of 988 patients (89.5% females and 10.5% males). Its mean age was 56.1 years and its mean BMI was 26.6 kg/m2 in the males and 27.0 kg/m2 in tile females. The ITT population consisted of 974, and the PP population of 910 patients. RESULTS: Efficacy In the ITT population the baseline values for the incontinence episodes were comparable (IR 3.29, ER 3.38, placebo 3.50). The numbers decreased by 2.26 in the IR group (p<0.0001), by 2.46 in the ER group (p<0.0001), and by 1.75 in the placebo group. The number of micturifions and the number of urge episodes were more reduced in both propiverine groups than with placebo (p<0.05). The mean volume of the single micturitions increased statistically significantly more in both propiverine groups than in the placebo group, although the liquid intake was comparable between groups. The efficacy assessment was statistically significantly better in both propiverine groups than with placebo. The improvement in QoL was less consistent, although propiverine was slightly better than placebo. Safety 38.5% of the patients experienced AEs in the IR group, 34.3% in the ER group, and 20.3% in the placebo group. 26 (2.6%) patients dropped out prematurely due to aAE: 14 (3.5%) in the IR group, 11 (2.8%) in the ER group, and 1 (0.5%) in the placebo group. Gastrointestinal disorders and nervous system disorders were the most frequent reasons. The most frequent AE was dry mouth with 22.8 % of the patients of the IR group, 21.7 % of the ER group and 6.4 % of the placebo group. "Eye disorders" were experienced by 6.6% of the patients of the IR group, 7.2% of the ER group and 2.5% of the placebo group. All other system organ classes accounted for less than 5% of the patients each. The overall tolerability was rated very good or good by 85% of the investigators and patients. CONCLUSIONS: Propiverinn IR 15 mg twice daily and propiverine ER 30 mg once daily reduce effectively the number of incontinence episodes/24h within a treatment period of 32 days. They also decrease the number of urge episodes and the number of mieturitious. Both formulations are safe.
1Guy's and St. Thomas' Hospital NHS Trust, Obstetrics and Gynaecology, London, United Kingdom, aNovartis Pharma AG, Integrated Insight and Analytics, Basel, Switzerland, 3U. Massachusetts Memorial Hospital, Urology, Worcester, United States INTRODUCTION & OBJECTIVES: Physicians' perceptions of nAB may not reflect the significant emotional burden experienced by patients. The emotional impact of nAB and urinary incontinence is known to be high but is rarely measured directly. Emotional burden may affect treatment perceptions and limit help-seeking behaviour, a major predictor of treatment outcome. This study examines the emotional burden of nAB sufferers. MATERIAL & METHODS: A population-based, cross-sectional study was conducted in 63 men and women with nAB (treatment-naive and drag-treated) in the US and UK, varying in age (40-75 years), continence and nAB severity (based on symptoms selected in a screening questionnaire). These responses were correlated with patient perception of severity and bother. Respondents were excluded if they bad other conditions potentially affecting emotional status such as clinical depression. RESULTS: Patients were: 45 females (39 with wet and 6 with dry nAB) and 18 men (11 wet, 7 dry). • Overall, patients were resigned to their nAB symptoms, believing them to be of genetic origin, a natural part of aging or resulting from childhood behaviours. This perception was most common amongst women aged 60-75 years. • Emotional effects were of greater concern to patients than urologic symptoms. The most severely emotionally impacted patients tended to be wet type and female. Women, especially those with more severe nAB, felt personal shame; those aged 40-49 and 61-75 years felt trapped, and the older group also had poor self-image (felt degraded). Women aged 50-60 years expressed stronger emotions such as fear, anger, injustice, irritation and being too young for an 'old age' condition to set in. • UK patients expressed stronger emotions than US patients, who were more educated on nAB and felt more empowered to seek treatment (reflecting direct-to-consumer advertising). • nAB (both wet and dry) was associated with severe stigmatization and high patiantjphysician communication barriers. • The most common emotional responses were embarrassment, frustration and anxiety. Fear of a possible 'accident' dominated patients' thinking and behaviour. • Patient expectations from drug therapy centered on increased control over their lives and hope, but patients noted that side effects adversely affected compliance. CONCLUSIONS: The study identified a marked emotional impact from nAB which was of greater concern to patients than the nAB symptoms, and was evident across patient age, gender and nAB type/severity. This was associated with clear expression of patient emotional reactions, which was related to overall patient bother. Increased education and more pro-active discussions by physicians are needed to help relieve the social stigma, allow earlier symptom identification and treatment, and increase the effectiveness and satisfaction with drag therapies.
European Urology Supplements 4 (2005) No. 3, pp. 59