Nazzareno Suardi - Rimini in Forma

Effetti di Difaprost su sintomatologia
disurica, alterazioni istologiche e
infiammazione in pazienti affetti da
ipertrofia prostatica benigna candidati
ad intervento chirurgico
Nazareno Suardi
Urological Research Institute
Università Vita-Salute San Raffaele
LUTS: prevalenza
INFLAMMATION AND BPH
• A causative role for inflammation in the pathogenesis of BPH was first
proposed in 1937
• BPH nodules frequently occur concurrently with chronic inflammatory
infiltrates (mainly chronically activated T cells)
• These infiltrating cells are responsible for the productions of cytokines
which may initiate, support and maintain the fibromuscolar growth in
BPH.
Kramer and Marberger, Curr Opin Urol 2006, 16:25-9
Steiner et al, J Urol 1994, 151:480-4
Untergasser et al, Exp Gerontol 20052005, 40:121-8
ROLE OF INFLAMMATORY CELLS IN BPH
CELLS
T cells
ROLE IN BPH
REFERENCES
Stimulation of stromal growth
Kramer et al, 2002
Recognition of prostatic antigen
Alexander et al, 2004
Klyushnenkova et al, 2004
Morphogenesis of prostate gland
Theyer et al, 1992
Bierhoff et al, 1997
CD8+ citotoxic T cells
Gland destruction in advanced BPH
Blumenfeld et al, 1992
CD8+ suppressor T cells
Maintainace of peripheral tolerannce
El.Demiry et al, 1985
Vyskhovanets et al, 2005
CD4+ T helper 1
Stimulation of stromal and epithelial cell
proliferation, recruitment of more T cells
Kramer et al, 2002
Deshpande et al, 1989
CD4+ T helper 2
Increased prostatic synthesis of active
androgens
Gingras et al, 1999
T helper 17 cells
Production of IL-17, IL-6 and IL-8
Steiner et al, 2003
Stimulation of secretion of proinflammatory
citokines
McKenzie et al, 2006
B cells, mast cell
Unknown
Ablin et al, 1971
Macrofagi
Antigen presentation or regulation of COX-2
expression in BPH epithelium
Taoka et al, 2004
Wang et al, 2004
DEVELOPMENT OF CHRONIC IMMUNE INFLAMMATION IN ASSOCIATION
WITH BENIGN PROSTATIC GROWTH
UNANSWERED QUESTIONS:
1. Which is the primary stimulus?
2. Is it a response to an abnormal or pathologic environmental stimulus
or an abnormal response to an otherwise “physiologic” stimulus?
Kramer et al, Eur Urol 2007, 51:1202-16
ACUTE INFLAMMATION: 15.4%
97.9% mild
1.9% moderate
0.2% severe
CHRONIC INFLAMMATION: 77.6%
89.0% mild
10.7% moderate
0.3% severe
Nickel JC et al Eur Urol 54:1379–1384,2008
EVIDENCE OF A RELATIONSHIP BETWEEN THE DEGREE
OF LUTS AND THE DEGREE OF CHRONIC INFLAMMATION
Nickel JC et al Eur Urol 54:1379–1384,2008
Obiettivi dello studio
1. Valutare l’efficacia del trattamento con Difaprost sui
parametri clinici dei pazienti affetti da ipertrofia
prostatica candidati ad intervento chirurgico
disostruttivo.
2. Valutare l’impatto della terapia con Difaprost sulle
alterazioni istologiche tipiche dell’infiammazione a
livello prostatico.
Difaprost
•
Serenoa Repens
– Inibizione 5-alfa reduttasi
– Azione miorilassante
– Blocco recettori intraprostatici per gli androgeni
•
Quercetina
– Azione antiproliferativa
– Attività antinfiammatoria (mastociti)
– Azione antiossidante
•
Acido lipoico
– Effetto antiossidante
•
Β-sitosterolo
– Azione antinfiammatoria ed immunomodulante
– Attività antiproliferativa e pro-apoptotica
Materiali e metodi
• Studio prospettico randomizzato
• Criteri di inclusione
– Pazienti affetti da ipertrofia prostatica sintomatica
candidati ad intervento chirurgico
– Età: 50-75 anni
– IPSS > 8
– Flusso massimo < 15 ml/sec.
– Residuo post-minzionale < 350 ml
– Nessun sospetto di tumore prostatico
– Urinocoltura negativa
Disegno dello studio - 1
• Screening:
– PSA, uroflussometria, IPSS, residuo postminzionale, volume prostatico
• Pazienti randomizzati in due gruppi:
– Gruppo 1: Difaprost 1 compressa al giorno per 3
mesi
– Gruppo 2: nessuna terapia
• Dopo tre mesi:
– PSA, uroflussometria, IPSS, residuo postminzionale, volume prostatico
Disegno dello studio - 2
• Successivo intervento disostruttivo (TURP)
• Analisi isto-patologica dei pezzi operatori con
analisi dettagliata dei parametri infiammatori
– Edema
– Flogosi
– Angiectasia
– Atrofia
– MIB
Caratteristische dei pazienti
Age (years)
Mean
Range
Total PSA (ng/ml)
Mean
Prostatic Volume
(ml)
Mean
IPSS score
Mean
Q max (ml/sec.)
Mean
Q med (ml/sec.)
Mean
Group 1 (n=18)
Group 2 (n=18)
P-value
65
53-74
66.2
53-83
0.5
2.01
3.6
0.2
54.1
62.3
0.1
18.6
14
0.02
10.1
11.4
0.4
5.6
7
0.04
Caratteristische dei pazienti trattati
PSA
Mean (median)
Range
IPSS score
Mean (median)
Range
Q max
Mean (median)
Range
Q med
Mean (median)
Range
Post-voiding volume
(ml)
Mean (median)
Range
Pre-treatment
Post-treatment
P-value
2.01 (1.24)
0.6 - 7.5
1.99 (1.32)
0.2 - 1.3
0.9
18.6 (17)
9 - 33
18.6 (17.5)
10 - 33
0.9
10.1 (8.9)
4 - 28
10.2 (9.3)
5.3 - 20
0.9
5.6 (5.65)
2.9 - 9
6.5 (7)
2.5 - 9.5
0.9
46.1 (35)
0 - 200
25.2 (27.5)
0 - 70
0.1
Quantitative analysis of flogosis at histology in patients treated
with Difaprost® (Group 1) and in the control group.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Severe
Moderate
Mild
Difaprost
0
50
50
Control
11,1
55,5
33,3
Quantitative analysis of edema presence at histology in patients
treated with Difaprost® (group 1) and in the control group.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Assente
Presente
Difaprost
55,5
45,5
Control
33,3
66,6
Quantitative analysis of angiectasia presence at histology in patients
treated with Difaprost® (group 1) and in the control group.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Assente
Presente
Difaprost
61,1
38,9
Control
50
50
Quantitative analysis of MIB-1 at hystology in patients treated with
Difaprost® (group 1) and in the control group.
MIB-1
3,94
3,92
Difaprost
Control
Conclusioni
• La terapia con Difaprost in pazienti candidati ad intervento
chirurgico per ipertrofia prostatica riduce il volume postminzionale.
• Difaprost esercita una azione anti-infiammatoria riducendo la
presenza di flogosi, edema ed angiectasia.
• L’inclusione di un numero maggiore di pazienti potrebbe
dimostrare effetti significativi anche su altri parametri clinici
ed infiammatori.

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