Diapositiva 1 - Società Urologia Nuova

Fisiopatologia
comune e
terapia dei
LUTS/IPB e DE
Vincenzo Gentile
Sapienza Università di Roma
Associazione BPH-LUTS e
Disfunzioni Sessuali
Indagine su 14.000 soggetti di sesso maschile di età
compresa fra 50 e 80 anni in USA, UK, Francia,
Germania, Italia, Spagna e Paesi Bassi sulle
correlazioni fra Sintomi delle Basse Vie Urinarie
e Disfunzioni Sessuali
Board scientifico:P. Rosen, M. o'Leary, J. Altwein,
F. Giuliano, R. Kirby, E Meuleman
MSAM - 7
Circa il 90% degli over 50 soffre di LUTS
Base : campione totale
I-PSS>0
% 90
89
90
90
91
86
92
85
10
11
10
10
9
14
8
15
100
75
+
92
8
+
59
60
56
65
62
54
-
I-PSS>0
61
61
61
19
24
50
25
25
0
23
27
6
6
7
Tot.C Tot.EU USA
12815 10900 1915
+
21
23
25
26
4
Fr
1896
6
Ger
2012
7
It
1772
5
Nl
2103
Never
Mild
Moderate
Severe
5
7
Uk
Sp
1305 1812
Gravità di LUTS (IPSS) e DE (DAN-PSS-Sex):
MSAM-7 Survey
Rosen et al, Eur Urol 2003
E’ ampiamente riconosciuta una associazione
significativa tra LUTS e disfunzioni sessuali
In particolare:
La gravità dei LUTS è risultata (analisi di regressione logistica)
un predittore indipendente di problemi sia erettili che eiaculatori
“Paz con LUTS moderati o gravi dovrebbero essere
indagati rutinariamente sulla loro funzione erettile
ed eiaculatoria, e a questo riguardo dovrebbero
essere informati sui potenziali effetti in queste aree
del trattamento”
MSAM-7,Rosen et al, Eur Urol 2003
Leliefeld et al, BJU Int, 2002
UrEpik St, Boyle et al, BJU Int, 2003
ALF-ONE St., Vallencien et al, J Urol, 2003
MTOPS St., McConnell et al, N Eng J M, 2003
Cologne Survey
LUTS & Sexual Dysfunction
ED°
(n=853)
No ED°
(n=3581)
Diabetes
20.2%
3.2%
Hypertension
32.0%
13.6%
Pelvic surgery
18.8%
2.4%
LUTS
72.2%
37.7%
Smoker
29.6%
34.6%
Regular alcohol
37.5%
42.4%
°Erectile dysfunction
Braun M et al. Int J Impot Res 2000; 12: 305-311
Patologie croniche più frequenti nella terza età
- Disfunzione Erettile (DE)
- Depressione
- Patologie Cardiovascolari
- LUTS/BPH
*
Sono le 4 principali patologie croniche che impattano
negativamente sulla salute degli uomini sopra i 50 anni,
secondo il Columbia Male Aging Project *
*Zakaria et al, Int Urol Nephrol, 2001
Inoltre: il TUMORE PROSTATICO ha una prevalenza
maggiore nelle fasce di età più avanzata, con:
• 179.300 nuovi casi all’anno (USA)
• 32.000 decessi all’anno (USA) Stanford JL et al. JAMA 2000
Principali fattori di rischio di Disfunzione Endoteliale
età
fumo
diabete
ipertensione
Malattia
coronarica
Disfunzione
erettile
Disfunzione
endoteliale
LUTS/BPH e DE: associazione o causalità?
4 leading theories for
causal association
McVary KT. Eur Urol, 47:838-845, 2005
Andersson KE, et al. NeuroUrol Urodyn, 30:292-301, 2011
Ipertono adrenergico
Obesity-BMI
Hypertension
Hyperinsulinemia
Age
INCREASED SYMPATHETIC TONE
Physical inactivity
Other factors?
BPH
BOO, BPH
Erectile dysfunction?
McVary, AUA 2003
I SOGGETTI DIABETICI HANNO UN RISCHIO DI DE
TRIPLICATO RISPETTO ALLA POPOLAZIONE GENERALE
PER LA DE
30
MMAS
(Massachussets Male Aging Study
1290 soggetti, 40-70 anni)
28
25
% 20
15
10
9,6
5
0
Popolazione
1 generale
Diabete mellito
tipo I e II
2
Feldman et al J Urol 151: 54, 1994
Glycemic
Variability
Erectile Dysfunction in Diabetes Mellitus Lasantha L Malavige J Sex Med 2009; 6:1232-1237
LUTS/BPH e DE: associazione o
causalità?
Ipotesi della riduzione della Ossido Nitrico sintetasi (NOS)/Ossido Nitrico (NO)
Ipertensione Fumo
Ipercolesterolemia
Diabete
Riduzione NOS/NO
Aterosclerosi
Stenosi Arteriosa
Fibrosi
Riduzione della
funzione dei nervi e
dell’endotelio
Insufficienza Arteriosa
e
mancato rilassamento della muscolatura liscia
McVary and McKenna. Curr Urol Reports 2004;5:251-257
Biologic Link Between BOO and ED?
Atherosclerosis-induced chronic ischemia causes bladder
and penile fibrosis
Tarcan et al, BJU Int, 82 (Suppl 1): 26-33, 1998
Ipotesi della riduzione della Ossido Nitrico
sintetasi (NOS)/Ossido Nitrico (NO)
• Analisi Biochimiche hanno dimostrato l’attività della NOS nella
zona periferica e di transizione nella prostata umana1
• La produzione di NOS/NO è ridotta nella prostata con IPB
rispetto alla prostata sana 2,3
• Con il progredire dell’ IPB i livelli tissutali di NOS/NO
potrebbero ridursi ulteriormente, il che comporta una riduzione
del rilassamento del tono prostatico 2,3
Riduzione di NOS influenza la minzione  LUTS
1. Burnett AL, et al. Urology 1995;45:435-439.
2. Bloch W, et al. Prostate 1997;33:1-8.
3. Klotz T, et al. Urology 1997;36:316-322.
Localizzazione delle PDE nella prostata umana
PDE5
prostatic
smooth muscle
PDE11
glandular epithelium
Loughney K et al. Int J Impot Res. 2005;17(4):320-5.
Localization of PDE5-isoenzymes in the Lower
Urinary Tract
PDE5-isoenzymes in the LUT
Localization of PDE5-isoenzymes
 Smooth muscle cells
–
–
–
–
–
Vasculature
Bladder
Urethra
Prostate
Corpus cavernosum
 Striated muscle cells
– External urethral sphincter
Andersson et al. Neurourol Urodyn 2011;30(3):292-301.
PDE5 Inibitori nella IPB: Razionale
• Il collo vescicale e la prostata hanno innervazione
nitrossidergica e contengono PDE5
• PDE5 inibitori potenziano l’ effetto rilassante NO-mediato
in questi tessuti
• PDE5 inibitori potrebbero ridurre i sintomi ostruttivi e
migliorare il LUTS
Tadalafil Once
Daily for the
Treatment
of
LUTS/BPH
12 Months Extension Trial:Study Design1,2
Screening/ Placebo
Washout Run-in
Period
Period
Placebo-controlled
Treatment Period
Open-label Extension (OLE) Period
Placebo QD
N = 92
Tadalafil 2.5 mg QD
N = 96
Tadalafil 5 mg QD
428 men entered:
44 centers in US, and
Canada
Tadalafil 5 mg QD, N = 427
N = 83
Tadalafil 10 mg QD
N = 85
Tadalafil 20 mg QD
N = 71
Baseline & Randomization
Week -8
Visit 1
-4
2
0
3
4
4
8
5
12 16
6/7a 8
24
9
38
10
51
11
This12-month extension trial was an extension of the dose-finding study
aA total of 428 patients elected to continue for an additional 52 weeks in the open-label
extension; 427 received treatment and 299 (69.9%) completed the open-label extension
1. Roehrborn et al. J Urol 2008;180(4):1228-34.
2. Donatucci et al. BJU Int 2011;107(7):1110-6.
64
12
12 Months Extension Trial:Study Design1,2
Mean
Total IPSS
20
19
OLE to Endpoint Change
(LOCF, n = 416)
mean (SD)
18
17
Placebo
→ 5 mg
-2.2 (5.3)
16
5 mg → 5 mg
15
0.2 (5.4)
14
13
12
11
Placebocontrolled,
doubleblind
period
Open-label extension, all on 5 mg
10
Week 0
Visit 3
12
16
24
38
51
64
6
8
9
10
11
12
Long-term once daily treatment with 5 mg tadalafil was effective in maintaining reduction in LUTS/BPH
This12-month extension trial was an extension of the dose-finding study
1. Donatucci et al. BJU Int 2011;107(7):1110-6.
2. Data on file, Eli Lilly and Company.
LUTS/BPH and ED Comorbidity Study: Results
***p .001
12-week Endpoint LS Mean Change (ANCOVA, LOCF)
IPSS and IIEF-EF:
Coprimary objectives
IPSS
IIEF-EF
SEP Q3
Baseline
18.218.5
15.716.6
36.342.7
Placebo
-3.8
1.8
12.0
Tadalafil 2.5 mg
-4.6
5.2***
24.6***
-6.1***
6.5***
31.7***
Tadalafil 5 mg
SEP Q3: Key secondary
objective
Only the dose of 5 mg Tadalafil once daily showed an improvement in both ED as well as LUTS/BPH
Egerdie et al. J Sex Med 2011;9(1):271-81.
Tadalafil vs. Placebo and Tamsulosin vs. Placebo
An Active Control Trial: Study Design
Screening/
Washout
Period
511 men randomized
Germany, Italy,
France, Austria,
Netherlands, Belgium,
Greece, Poland,
Australia, Mexico,
Treatment Period
Placebo
Lead-in
Period
Placebo QD, N = 172
Tadalafil 5 mg QD, N = 171
No Study Drug Placebo QD
Tamsulosin 0.4 mg QD, N = 168
Baseline & Randomization
Week -8
-4
0
1
4
8
12
Visit 1
2
3
4
5
6
7
Oelke et al. Eur Urol 2012;61(5):917-25.
Tadalafil vs. Placebo and Tamsulosin vs. Placebo
An Active Control Trial: IPSS Change from Baseline
Total IPSS
LS Mean Change from Baseline
(LOCF)
Baseline
Week1#
12-week endpoint LS mean
change (ANCOVA, LOCF)
*p<.05 vs. placebo (ANCOVA)
# Values based on modified IPSS
Week 4
Week 12
(EP)
0
IPSS1
Qmax1
IIEF-EF2
16.817.4
9.410.5
14.016.1
-1
-2
Baseline
-3
*
*
-4
Placebo
- 4.2
1.2
2.1
-5
Tadalafil 5 mg
- 6.3*
2.4*
6.0*
-6
-4.2
*
*
*-5.7
*
-7
Tamsulosin 0.4 mg
- 5.7*
2.2*
1.7
Placebo
Tadalafil 5mg
-6.3
Tamsulosin 0.4 mg
The LS mean change in total IPSS was statistically significant compared to placebo, as well as similar for both
tadalafil and tamsulosin, already at Week 1 and through Week 12
The LS mean change in IIEF-EF in sexually active men with ED was significant for tadalafil, but not for tamsulosin
1. Oelke et al. Eur Urol 2012;61(5):917-25.
2. Giuliano et al. Eur Urol Suppl 2012;11(2):e705(Abstract).
Tadalafil vs. Placebo and Tamsulosin vs. Placebo
An Active Control Trial: Qmax Change from Baseline
mL/s
3
p = .009
p = .014
2.5
2.4
2.2
2
1.5
1.2
1
0.5
0
Placebo
Oelke et al. Eur Urol 2012;61(5):917-25.
Tamsulosin 0.4mg
Tadalafil 5mg
Tadalafil vs. Placebo and Tamsulosin vs. Placebo
An Active Control Trial: Conclusions
 Tadalafil 5 mg once daily and tamsulosin 0.4 mg once daily resulted
in significant improvement in IPSS
 Significant increases in peak urinary flow (Qmax) compared with
placebo were observed in both the tadalafil and tamsulosin groups
 Only tadalafil improved LUTS/BPH-related quality of life, treatment
satisfaction, and erectile dysfunction
 The adverse event profile was similar to that in previous reports of
once daily tadalafil use in men with BPH or men with ED
Oelke et al. Eur Urol 2012;61(5):917-25.
2012
Conclusioni: once daily tadalafil was more efficacious in treating both ED and LUTS than
on-demand dosing. The side effects were insignificant for both dosing schedules.
2012
Conclusioni: the association of tamsulosin/tadalafil reduces detrusor pressure at
maximum flow without changing the maximum flow rate during micturition and
significantly improves lower urinary tract symptoms compared with the isolated use of
tamsulosin.
2012
Conclusioni: tadalafil enhances cGMP accumulation and potentiates prostate relaxation,
tadalafil combined with tamsulosin results in enhanced inhibition of neurogenic
contractions of human peripheral prostate (HPP) and human bladder neck (HBN)
2012
Conclusioni: tadalafil once daily represents an effective and well tolerated medical
treatment for Asian men presenting with LUTS suggestive of BPH.
I PDE5i potrebbero agire rilassando
la muscolatura liscia della vescica ?
PDE5i
NO
(2)
←cGMP←NO
NOcGMP 
(1)
1)
2)
Hedlund P et al. Nitric oxide/cGMP-mediated effects in the outflow region of the lower urinary tract - is there a basis for pharmacological targeting of cGMP?
(2005) World J Urol 23: 362–367
Oger S et al. Signalling pathways involved in sildenafil-induced relaxation of human bladder dome smooth muscle. Br J Pharmacol. 2010 Jul;160(5):1135-43.
PDE5i
CSE
L-Cysteine
CBS
H2S
Spontaneous
contractions
Afferent
firing
Storage
LUTS
LUTS
improvement
PDE5i
NO
↓
cGMP
ED
L-Cys
↓
H 2S
LUTS