Nitric oxide releasing nsai ds
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Transcript of Nitric oxide releasing nsai ds
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Nitric oxide releasing NSAIDs : are they alive?
A conference on nitric oxide releasing aspirin
Stefano FiorucciUniversity of Perugia
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Nitric oxide
N=O
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Nitric Oxide ( NO) -releasing derivative of aspirin
Wallace JL, Ignarro JL, S. Fiorucci. Nature Reviews: Drug Discovery 1, 375-382 (2002)
NCX-4016
Aspirin
O
O
O
OONO2
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Synergism between COX inhibition and nitric oxide formation
Enhance gastrointestinal Safety
Increase anti-inflammatory activity
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Gastric mucosal blood flow + + Mucus secretion + + Cytoprotection + + Mucosal barrier integrity + +
NO PGE2
NO: Gastric and duodenal functions
Wallace JL, Miller MJ. Nitric oxide in mucosal defense.
Gastroenterology. 2000;119: 512-520
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Reduces mucosal blood flowLoss of mucosal barrier integrity
Aspirin
Gastric mucosal injury
COX-1Anti-thromboticAnalgesicAnti-pyreticAnti-inflammatory
Fiorucci S., et al Gastroenterology 1999, 116: 1089
Gastric mucosal protection
NO
Spares mucosa blood flow
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02468
1012141618
*
*E
nd
osc
op
ic s
core
Placebo NCX-4016 ASA
400 800 200 450
mg/b.i.d.
Total score
92.9%
95.2%
Fiorucci et al. , Gastroenterology. 2003 Mar;124(3):600-7
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0123456789
10
*
*
En
do
sc
op
ic s
co
re
Placebo NCX-4016 ASA
400 800 200 450
mg/b.i.d.
Erosions: stomach and duodenum
98%
87%
Fiorucci et al. , Gastroenterology. 2003 Mar;124(3):600-7
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0123456789
10
*
*
En
do
sc
op
ic s
co
re
Placebo NCX-4016 ASA
400 800 200 450
mg/b.i.d.
Hemorrhagic lesions:stomach and duodenum
85%
99%
Fiorucci et al. , Gastroenterology. 2003 Mar;124(3):600-7
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0102030405060708090
100
Per
cen
t o
f A
A-i
nd
uce
dag
gre
gat
ion
Placebo NCX-4016 ASA
400 800 200 450
mg/b.i.d.
Inhibition of platelets aggregation
Fiorucci et al. , Gastroenterology. 2003 Mar;124(3):600-7
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0
200
400
600
800
1000
Pre-treatment Post-treatmentT
xB2 s
eru
mco
nce
ntr
atio
n(n
g/m
l)
** * *
Placebo NCX-4016 ASA
400 800 200 450
mg/b.i.d.
Serum TxB2
Fiorucci et al. , Gastroenterology. 2003 Mar;124(3):600-7
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0
1000
2000
3000
4000
5000
Pre-treatment Post-treatmentT
xB2 p
rod
uct
ion
(ng
/ml)
Placebo NCX-4016 ASA
400 800 200 450
mg/b.i.d.
* * * *
TxB2 generation
Fiorucci et al. , Gastroenterology. 2003 Mar;124(3):600-7
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1.0 2.0 3.0 4.00
2
4
6
8
10
12
Alone + celecoxib Alone + celecoxib
NCX-4016 Aspirin
Mea
n to
tal e
ndos
copi
csc
ore
P<0.001
Fiorucci S., et al. Proc Natl Acad Science USA 2003 100(19):10937-41
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1.0 2.0 3.0 4.00
2
4
6
8
10
12
Alone + celecoxib Alone + celecoxib
NCX-4016 Aspirin
Mea
n to
tal e
ndos
copi
csc
ore
P<0.0001
P>0.05
Fiorucci S., et al. Proc Natl Acad Science USA 2003 100(19):10937-41
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0.0 8.0 15.00
50
100
150
NCX4016 NCX4016 + celecoxib
Aspirin Aspirin + celecoxib
Day 0 Day 8 Day 15
* * * * * * **
Time
TxB
2 p
lasm
a le
vels
(ng/
ml)
Fiorucci S., et al. Proc Natl Acad Science USA 2003 100(19):10937-41
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0
2
4
6
8
10
12
14
16 *
**
Placebo ASA NCX-4016 ASA+ NCX-4016
**Mea
n ga
stri
c In
jury
sco
reNCX-4016 protects against injury caused by ASA
Fiorucci S.,Minuz P. et al. J. American College of Cardiology, 2004 (in pres)