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OZARELIX, AN LHRH ANTAGONIST, EXERTS A DIRECT RELAXING EFFECT ON HUMAN PROSTATE IN VITRO
THE JOURNAL OF UROLOGY®
Vol. 181, No. 4, Supplement, Wednesday, April 29, 2009
693
to untreated BOO mice, treatment with solifenacin further increased bladder capacity (216.44±11.4 μl versus 153.5±20.9 μl, p=0.02), and VDO1 (55.0% vs 23.4%, p<0.01). Solifenacin treatment mediated a reduction in bladder mass (36.7±4.0 vs 95.3±5.16 mg, p=0.01), detrusor hypertrophy (median=1.0 vs 3.0, p=0.01) and fibrosis (median=1.0 vs 3.0, p=0.01). CONCLUSIONS: In a mouse model of BOO, treatment with 6 wks of solifenacin resulted in significant urodynamic and histological differences compared to untreated obstructed mice. BOO was associated with a significant increase in detrusor overactivity, bladder weight, hypertrophy, and collagen deposition. Treatment with solifenacin caused improvement in detrusor overactivity and bladder capacity, and partially prevented detrusor hypertrophy and fibrosis. Source of Funding: Astellas
1919 OZARELIX, AN LHRH ANTAGONIST, EXERTS A DIRECT RELAXING EFFECT ON HUMAN PROSTATE IN VITRO
Source of Funding: American Cancer Society Pennsylvania Division – Dr. William and Rita Conrady Mentored Research Scholar Grant (MSRG-07-006-01-CPHPS), American Urological Association Foundation, Astellas Pharma US, Inc., National Cancer Institute (R01 CA098481-01A1)
Benign Prostatic Hyperplasia: Medical & Hormonal Therapy (II) Podium 45 Wednesday, April 29, 2009
8:00 am - 10:00 am
1918 SOLIFENACIN SUCCINATE PREVENTS URODYNAMIC AND DETRUSOR CHANGES ASSOCIATED WITH BLADDER OUTLET OBSTRUCTION - A MOUSE MODEL Simon Kimm, Stanford, CA; Carla Mazar, Mohamad W Salkini, Tucson, AZ; Craig V Comiter*, Stanford, CA INTRODUCTION AND OBJECTIVES: Benign prostatic hyperplasia (BPH) can lead to bladder outlet obstruction (BOO). Increased wall tension can contribute to detrusor hypertrophy and fibrosis, resulting in impaired storage and emptying. While de-obstructive therapy remains the standard treatment, the use of antimuscarinics for treating irritative (storage) symptoms has recently gained popularity. We aim to determine if treatment with solifenacin can prevent the structural and functional changes that occur with BOO in a mouse model. METHODS: We partially obstructed the urethra in 24 Balb/ CAN mice. Mice were survived for 6 wks. Half received oral solifenacin succinate (1mg/kg/d) and half did not. 12 mice served as unobstructed controls. Urodynamics were performed at baseline and after 6 wks. Capacity (C), and volume at first uninhibited bladder contraction as a percent of bladder capacity (VDO1) were recorded. Bladders were harvested, weighed, fixed, and sections were stained wi! th trichrome (fibrosis) and hematoxylin and eosin (H&E, hypertrophy). Trichrome scoring=1 for decreased, 2 for normal, and 3 for increased staining of collagen when compared to our control group. H&E scoring=1 for atrophy, 2 for normal, and 3 for hypertrophy, compared to controls. Histologic scoring was performed in blinded fashion by 2 pathologists and 2 urologists. RESULTS: BOO mediated an increase in C (153.5±20.9 μl vs 57.5±7.4 μl, p=0.004) and a decrease in VDO1 (median=23.4% vs 53.5%, p=0.03). BOO mediated an increase in bladder mass (95.34±5.16 mg vs 30.8±3.5 mg, p<0.01), hypertrophy (median=3.0 vs 2.0, p=0.03), and fibrosis (median=3.0 vs 2.0, p=0.04) compared to controls. Compared
François Giuliano*, Garches, France; Delphine Behr-Roussel, Stéphanie Oger, Orsay, France; Pierre Costa, Nîmes, France; Anne Sautet, Suresnes, France; Bela S Denes, Irvine, CA INTRODUCTION AND OBJECTIVES: Clinical results demonstrated the benefit of LHRH antagonists e.g. ozarelix for the treatment of symptomatic BPH. While the reduction in testosterone levels is transient and incomplete with only a modest effect on the prostate volume, degarelix, tevarelix, cetrorelix and ozarelix have all elicited rapid improvement in symptoms as measured by IPSS and uroflow. Little is known about the mechanism of action supporting this rapid clinical response. We postulated that ozarelix could provide rapid relief to patients with symptomatic BPH by exerting a direct relaxing effect on the prostate. In order to investigate the effects of ozarelix, a 4th generation LHRH antagonist, isometric tissue tension studies were performed on human prostate strips. METHODS: Twelve human prostate samples were obtained from 12 patients (65 ± 3 years old), undergoing cystoprostatectomy for infiltrating bladder cancer. Then, 8 strips (6 mm long x 3 mm wide on average) were excised from the prostatic sample of each donor. Prostatic strips were mounted isometrically at a resting tension of 500 mg in 5 ml organ bath filled with Krebs-HEPES buffer maintained at 37°C and continuously bubbled with 95% O2 and 5% CO2 at pH 7.4. Indomethacin (10-5 M) and dexamethasone (10-5 M) were also added to the organ bath throughout the experiments to eliminate possible interferences of cyclooxygenase products or induction of NO-synthase, as previously reported. Concentration-response curves (CRC) to phenylephrine (PHE) were constructed in semi-log increments from 10-8 to 3.10-5M. Then, after a 20-minute incubation period with either ozarelix (at two different clinically meaningful concentrations: 16 ng/ ml and 32 ng/ml) or vehicle, CRC to PHE were repeated. RESULTS: At 32 ng/ml, ozarelix induced a significant inhibition of the PHE-induced contractions (vehicle versus ozarelix 32 ng/ml, p < 0.01, two-way ANOVA) whereas at 16 ng/ml, ozarelix did not exert any significant effect on PHE-induced contractions (vehicle versus ozarelix 16 ng/ml, p = ns, two-way ANOVA). CONCLUSIONS: Ozarelix at 32ng/ml significantly inhibited contractions induced by PHE on human prostatic strips. This study provides the first evidence for a direct relaxant effect of an LH-RH antagonist on human prostate. This direct relaxant effect of ozarelix on pre-contracted human prostate strips may explain in part the reported rapid relief in symptoms when administered to men with LUTS/BPH. This study supports the development of ozarelix in the treatment of BPH. Source of Funding: Spectrum Pharmaceuticals
Vol. 181, No. 4, Supplement, Wednesday, April 29, 2009
693
to untreated BOO mice, treatment with solifenacin further increased bladder capacity (216.44±11.4 μl versus 153.5±20.9 μl, p=0.02), and VDO1 (55.0% vs 23.4%, p<0.01). Solifenacin treatment mediated a reduction in bladder mass (36.7±4.0 vs 95.3±5.16 mg, p=0.01), detrusor hypertrophy (median=1.0 vs 3.0, p=0.01) and fibrosis (median=1.0 vs 3.0, p=0.01). CONCLUSIONS: In a mouse model of BOO, treatment with 6 wks of solifenacin resulted in significant urodynamic and histological differences compared to untreated obstructed mice. BOO was associated with a significant increase in detrusor overactivity, bladder weight, hypertrophy, and collagen deposition. Treatment with solifenacin caused improvement in detrusor overactivity and bladder capacity, and partially prevented detrusor hypertrophy and fibrosis. Source of Funding: Astellas
1919 OZARELIX, AN LHRH ANTAGONIST, EXERTS A DIRECT RELAXING EFFECT ON HUMAN PROSTATE IN VITRO
Source of Funding: American Cancer Society Pennsylvania Division – Dr. William and Rita Conrady Mentored Research Scholar Grant (MSRG-07-006-01-CPHPS), American Urological Association Foundation, Astellas Pharma US, Inc., National Cancer Institute (R01 CA098481-01A1)
Benign Prostatic Hyperplasia: Medical & Hormonal Therapy (II) Podium 45 Wednesday, April 29, 2009
8:00 am - 10:00 am
1918 SOLIFENACIN SUCCINATE PREVENTS URODYNAMIC AND DETRUSOR CHANGES ASSOCIATED WITH BLADDER OUTLET OBSTRUCTION - A MOUSE MODEL Simon Kimm, Stanford, CA; Carla Mazar, Mohamad W Salkini, Tucson, AZ; Craig V Comiter*, Stanford, CA INTRODUCTION AND OBJECTIVES: Benign prostatic hyperplasia (BPH) can lead to bladder outlet obstruction (BOO). Increased wall tension can contribute to detrusor hypertrophy and fibrosis, resulting in impaired storage and emptying. While de-obstructive therapy remains the standard treatment, the use of antimuscarinics for treating irritative (storage) symptoms has recently gained popularity. We aim to determine if treatment with solifenacin can prevent the structural and functional changes that occur with BOO in a mouse model. METHODS: We partially obstructed the urethra in 24 Balb/ CAN mice. Mice were survived for 6 wks. Half received oral solifenacin succinate (1mg/kg/d) and half did not. 12 mice served as unobstructed controls. Urodynamics were performed at baseline and after 6 wks. Capacity (C), and volume at first uninhibited bladder contraction as a percent of bladder capacity (VDO1) were recorded. Bladders were harvested, weighed, fixed, and sections were stained wi! th trichrome (fibrosis) and hematoxylin and eosin (H&E, hypertrophy). Trichrome scoring=1 for decreased, 2 for normal, and 3 for increased staining of collagen when compared to our control group. H&E scoring=1 for atrophy, 2 for normal, and 3 for hypertrophy, compared to controls. Histologic scoring was performed in blinded fashion by 2 pathologists and 2 urologists. RESULTS: BOO mediated an increase in C (153.5±20.9 μl vs 57.5±7.4 μl, p=0.004) and a decrease in VDO1 (median=23.4% vs 53.5%, p=0.03). BOO mediated an increase in bladder mass (95.34±5.16 mg vs 30.8±3.5 mg, p<0.01), hypertrophy (median=3.0 vs 2.0, p=0.03), and fibrosis (median=3.0 vs 2.0, p=0.04) compared to controls. Compared
François Giuliano*, Garches, France; Delphine Behr-Roussel, Stéphanie Oger, Orsay, France; Pierre Costa, Nîmes, France; Anne Sautet, Suresnes, France; Bela S Denes, Irvine, CA INTRODUCTION AND OBJECTIVES: Clinical results demonstrated the benefit of LHRH antagonists e.g. ozarelix for the treatment of symptomatic BPH. While the reduction in testosterone levels is transient and incomplete with only a modest effect on the prostate volume, degarelix, tevarelix, cetrorelix and ozarelix have all elicited rapid improvement in symptoms as measured by IPSS and uroflow. Little is known about the mechanism of action supporting this rapid clinical response. We postulated that ozarelix could provide rapid relief to patients with symptomatic BPH by exerting a direct relaxing effect on the prostate. In order to investigate the effects of ozarelix, a 4th generation LHRH antagonist, isometric tissue tension studies were performed on human prostate strips. METHODS: Twelve human prostate samples were obtained from 12 patients (65 ± 3 years old), undergoing cystoprostatectomy for infiltrating bladder cancer. Then, 8 strips (6 mm long x 3 mm wide on average) were excised from the prostatic sample of each donor. Prostatic strips were mounted isometrically at a resting tension of 500 mg in 5 ml organ bath filled with Krebs-HEPES buffer maintained at 37°C and continuously bubbled with 95% O2 and 5% CO2 at pH 7.4. Indomethacin (10-5 M) and dexamethasone (10-5 M) were also added to the organ bath throughout the experiments to eliminate possible interferences of cyclooxygenase products or induction of NO-synthase, as previously reported. Concentration-response curves (CRC) to phenylephrine (PHE) were constructed in semi-log increments from 10-8 to 3.10-5M. Then, after a 20-minute incubation period with either ozarelix (at two different clinically meaningful concentrations: 16 ng/ ml and 32 ng/ml) or vehicle, CRC to PHE were repeated. RESULTS: At 32 ng/ml, ozarelix induced a significant inhibition of the PHE-induced contractions (vehicle versus ozarelix 32 ng/ml, p < 0.01, two-way ANOVA) whereas at 16 ng/ml, ozarelix did not exert any significant effect on PHE-induced contractions (vehicle versus ozarelix 16 ng/ml, p = ns, two-way ANOVA). CONCLUSIONS: Ozarelix at 32ng/ml significantly inhibited contractions induced by PHE on human prostatic strips. This study provides the first evidence for a direct relaxant effect of an LH-RH antagonist on human prostate. This direct relaxant effect of ozarelix on pre-contracted human prostate strips may explain in part the reported rapid relief in symptoms when administered to men with LUTS/BPH. This study supports the development of ozarelix in the treatment of BPH. Source of Funding: Spectrum Pharmaceuticals