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Terapia medica dell’IPB:
focus su Silodosina
Dr. Umberto Capitanio
Department of Urology
San Raffaele Scientific Institute, Milan, Italy
Male LUTS
EpiLUTS 14,139 men ≥ 40 years old 71% reported LUTS
46% storage symptoms
Voiding symptoms
only
12.1%
10.4%
24.3%
Voiding + storage
symptoms
Storage symptoms
only
10.3%
Voiding + post micturition
symptoms
Post micturition symptoms
only (3.0%)
Voiding + storage + post
micturition symptoms
9.1%
Post micturition +
storage symptoms
(2.0%)
Adapted from Sexton CC et al. BJU Int. 2009;103(Suppl3):12-23
LUTS: Treatment modality
SURGICAL
TREATMENT
DRUG
TREATMENT
LIFESTYLE
ADVICE
Drug Treatment: Evolution In The ‘90s
30.0
6.0
PHARMACOLOGICAL THERAPY
SURGERY
25.0
5.0
20.0
4.0
15.0
3.0
10.0
2.0
5.0
1.0
0.0
0.0
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Souverein, Eur Urol 43:528, 2003
Alpha-blockers in daily practice
1
2
3
Recommendations
LE
GR
α-blockers should be offered to men with moderate to
severe
LUTS
Recommendations
1a
LE
A
GR
1b
A
1b
B
Combination treatment with α-blocker together with 5αreductase inhibitor should be offered to men with
moderate to severe LUTS, enlarged prostates, and reduced
Qmax (men likely to develop disease progression).
Combination treatment is not recommended for shortterm therapy (< 1 year)
Combination treatment with α-blocker and muscarinic
receptor antagonist might be considered in patients with
moderate to severe LUTS if symptom relief has been
insufficient with the monotherapy of either drug
EAU guidelines 2013 on conservative treatment of non neurogenic male LUTS, available at www.uroweb.org
Alpha-blockers
α1A
α1B
α1D
Primary subtype expressed in
the prostate. Regulates
contraction of the smooth
muscle in the prostate,
bladder base and neck,
urethra, seminal vesicles,
and vas deferens.
Primary subtype expressed in
the blood vessels. Regulates
contraction of arterial blood
vessels in response to
postural redistribution of
blood volume.
Primary subtype expressed in
the bladder, spinal cord, and
nasal passages. Thought to
play a role in bladder
symptoms and nasal
secretions.
Silodosin is an -adrenoceptor
antagonist with high selectivity
for the 1A receptors relative to
1B receptors
α1-Blocker
α1-Receptor Selectivity
Doxazosin1
Terazosin1
Alfuzosin1
Tamsulosin1,2
Silodosin3
α1A = α1D = α1B
α1A = α1D = α1B
α1A = α1D = α1B
α1A = α1D >α1B
α1A >α1D >α1B
1. Schwinn DA, et al. Mayo Clin Proc. 2004;79:1423-1434.
2. Kenny BA, et al. Br J Pharmacol. 1996;118:871-878.
3. Akiyama K, et al. J Pharm Exp Ther. 1999;291:81-91.
Results based on in vitro data
α1-Blocker
Receptor Selectivity
α1A:α1B
Silodosin
Tamsulosin
Alfuzosin
Ratio expressed as the relative concentration.
Tatemichi S, et al. Yakugaku Zasshi. 2006;12:209-216.
Data on file, Watson Laboratories, Inc. KMD-0005 Study Report.
162:1
10:1
1:1
Results based on in vitro studies
IN VITRO DIFFERENCES IN ALPHA-BLOCKER SELECTIVITY MAY NOT
CORRELATE TO DIFFERENCES IN ACTUAL CLINICAL OUTCOMES.
α1A Adrenoreceptor Expression Increases in
BPH vs Non-BPH Prostate Tissue
Non-BPH Tissue
BPH Tissue
α1A
63%
85%
α1D
31%
14%
α1B
6%
1%
Nasu K, et al. Br J Pharmacol. 1996;119:797-803
SILODOSIN
• Efficacy
• Safety data
• Who may benefit the most?
Silodosin is efficacious within 2 - 6 hours…
…..with sustained efficacy during 12-weeks treatment (8mg
o.d) versus placebo (p<0.0001 – p<0.005) in two phase III
trials in the USA
Marks et al J Urol 181, 2634, 2009
More than 2,500 pts included in 5 RCTs
Silodosin: 68% of responders (delta IPSS ≥25%)
Capitanio et al. Int J Clin Pract, June 2013, 67, 6, 544–551
Pharmacokinetics
and Safety data
SILODOSIN
does not inhibit cytochrome P450 enzyme systems
at normal (8 mg) and supra-therapeutic (24 mg) doses had
no meaningful effects on heart rate, PR, and QRS interval
duration
does not affect cardiac repolarization
Marks et al J Urol 181, 2634, 2009
Silodosin has no effect on ECG parameters
QTc interval
Heart Rate
Time-averaged change (beats / min)
10
5
placebo
0
Silodosin 8 mg od
Silodosin 24 mg od
-5
-10
In 139 healthy male subjects, placebo, silodosin 8 or 24 mg once daily
for 5 days did not affect heart rate, QTc interval, PR-interval or QRScomplex and did not cause any deviations of the ECG morphology
Morganroth et al Clin Pharm Ther 87, 609, 2010
Virtually no effect on blood pressure
Chapple et al. Eur Urol 2011
SILODOSIN: SAFETY & TOLERABILITY
Most common adverse reactions (all studies)
Placebo controlled studies
Preferred Term
All studies
Silodosin 8
mg
(n = 931)
Placebo
(n = 733)
Silodosin
(n = 1,581)
Total No. of patients with
drug related AE
268 (28.8%)
66 (9.0%)
502 (31.8%)
Retrograde ejaculation
200 (21.5%)
6 (0.8%)
373 (23.6%)
Dizziness
17 (1.8%)
6 (0.8%)
33 (2.1%)
Orthostatic hypotension
11 (1.2%)
7 (1.0%)
20 (1.3%)
9 (1.0%)
1 (0.1%)
20 (1.3%)
Headache
10 (1.1%)
9 (1.2%)
20 (1.3%)
Diarrhoea
6 (0.6%)
2 (0.3%)
16 (1.0%)
Nasal congestion
Silodosin Integrated Summary of Safety (September 2008)
SILODOSIN: SAFETY & TOLERABILITY
Discontinuations due to adverse reactions
• In controlled studies 40/931 (4.3%) patients discontinued
with silodosin, as compared to 14/733 (1.9%) patients on
placebo
• Overall (controlled + long term extensions), only 148/1,581
(9.4%) subjects discontinued the study due to TEAE
• The most frequent cause was retrograde ejaculation (3.9%)
SILODOSIN: EFFICACY
Placebo
Sil-EjD
Sil+EjD
Ejaculation disorder was associated with a significantly improved change
in total IPSS at all time points from weeks 1-12 vs no ejaculation disorder
or placebo
Homma Y et al., Urology 2011
DIMINUZIONE DEL VOLUME
DELL’EIACULATO
Forte correlazione tra una importante riduzione nel volume
dell’eiaculato e la gravità dei LUTS
n = 11,063 (uomini con erezioni)
Netta riduzione dell’eiaculato
Aneiaculazione
% 100
88
90
80
70
70
64
63
60
10
0
27
18
16
2
73
58
62
43
31
2
7
50 – 59 anni
2
67
57
44
36
25
2
69
45
38
40
20
50
45
50
30
81
78
6
5
60 - 69 anni
5
9
13 14 19
70 - 79 anni
Rosen et al. Eur.Urol. 44(2003) 637-649
Terapia medica dell’IPB: focus su Silodosina
A
novel alpha blocker: Silodosin
 Who
are the best candidates?
Silodosin: who are the best candidates
1- Patients suffering from moderate-severe nocturia
Post-hoc analyses: statistically
significant superiority vs placebo,
while tamsulosin not, in a subgroup
of patients with at least 2 episodes
of nocturia at baseline
Michel et al. EAU Annual Meeting Vienna 2011
Montorsi et al. Eur Urol Suppl 2010; 9: 491-5
Silodosin: who are the best candidates
1- Patients suffering from moderate-severe nocturia
1. Nocturia
2. Frequency
3. Incomplete emptying
Statistically significant superiority
vs tamsulosin and placebo on the
simultaneous improvement of
nocturia,
frequency
and
incomplete emptying
Michel et al. EAU Annual Meeting Vienna 2011
Montorsi et al. Eur Urol Suppl 2010; 9: 491-5
Silodosin: who are the best candidates
2 – Patients with low blood pressure levels and
patients concomitantly treated with antihypertensive
medications
• One third of the patients included in clinical trials received
concomitant antihypertensive agents
• Dizziness was cause of discontinuation in
8/1,581 pts (0.5%) and orthostatic
hypotension in only 3/1,581 pts (0.2%)
• Virtually no risk of orthostatic hypotension
Agency EM. CHMP ASSESSMENT REPORT FOR Silodyx. Doc.Ref.: EMA/72316/2010. Procedure No.
EMEA/H/C/001209.
2010.
http://www.ema.
europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/001209/WC500074188.
Silodosin: who are the best candidates
3 – Patients concomitantly treated with PDE5-I
Heart-rate
Systolic BP
Diastolic BP
MacDiarmid et24a Urology 75;l, 520, 2010
Silodosin: who are the best candidates
4 – Patients with ureteral stone
EAU Guidelines 2014
Silodosin: who are the best candidates
4 – Patients with ureteral stone
The density of α1 receptors (especially α1A and α1D) in the ureteral smooth
muscle has been shown to be greater than other adrenoceptors
Park et al. Urol Res 2007
55 male Sprague-Dawley rats (250-300gr)
Saline infusion in the ureter through a PE-10 catheter at a speed 0.4ml/hour
The psoas muscle was sutured around the distal part of the ureter to cause
a partial distal obstruction.
Carotid artery and femoral vein were cannulated in order to register mean
arterial pressure and to administer drugs, respectively.
α – BLOCKERS EFFECT IN VIVO
α – BLOCKERS EFFECT IN VITRO
- Silodosin reduces ureteral pressure with less systemic side effects than tamsulosin
and prazosin
- Silodosin exhibits better inhibitory efficacy on EFS-induced contraction of human
and rat isolated ureters than tamsulosin and prazosin
Villa et al. BJP 2013
Silodosin: who are the best candidates
5 – Chronic prostatitis/chronic pelvic syndrome-related
symptoms
Nickel JC et al. J Urol 2011. 186: 125-31
6 – Patients not satisfied (for efficacy or tolerability) with
previous treatment with other alpha-blokers
Miyakita et al. IJU 2010; 17: 869-75
7 – Brachytherapy-related symptoms
Tsumura H et al. IJROBP 2011; 81: e385-92
8 – After Acute Urinary Retention for TWOC success
Kumar et al. Urology 2013
CONCLUSIONI - 1
 I LUTS sono molto frequenti nella popolazione generale
 I farmaci antagonisti dei recettori α1A-adrenergici
rappresentano la terapia di prima linea nel trattamento dei
LUTS
 La Silodosina ha dimostrato una selettività mai riscontrata
per i recettori adrenergici α1A rispetto a α1B e α1D in studi
di legame e funzionali.
CONCLUSIONI - 2
 La Silodosina ha un’efficacia pari a quella della tamsulosina,
addirittura superiore in alcuni scenari clinici (e.g. nocturia)
 Grazie alla sua elevata uroselettività gli effetti collaterali a livello
dell‘apparato cardiovascolare sono risultati minimi.
 Silodosina puo’ essere somministrata in concomitanza di PDE5-I
 Dati preliminari suggeriscono un ruolo determinante di silodosina
nell’espulsione di calcoli ureterali, nei sintomi secondari a
brachiterapia e nella CP/CPPS