This document discusses nitric oxide-releasing NSAIDs, which combine nonsteroidal anti-inflammatory drug (NSAID) properties with nitric oxide (NO) release. NO supports gastric mucosal defenses and reduces injury when combined with aspirin or other NSAIDs. Studies show that an NO-releasing aspirin derivative called NCX-4016 has synergistic effects, reducing platelet aggregation, and protecting the gastric mucosa more than aspirin alone as demonstrated by reduced endoscopic injury scores and better preservation of blood flow.

1. Nitric oxide releasing NSAIDs :
are they alive?
A conference on nitric oxide releasing
aspirin
Stefano Fiorucci
University of Perugia

2. Nitric oxide
N=O

3. 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
O
ONO2

4. Synergism between COX inhibition
and nitric oxide formation
Enhance gastrointestinal
Safety
Increase anti-inflammatory activity

5.  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

6. Reduces mucosal blood flow
Loss of mucosal barrier integrity
Aspirin
Gastric mucosal injury
COX-1
Anti-thrombotic
Analgesic
Anti-pyretic
Anti-inflammatory
Fiorucci S., et al Gastroenterology 1999, 116: 1089
Gastric mucosal protection
NO
Spares mucosa
blood flow

7. 0
2
4
6
8
10
12
14
16
18
*
*
Endoscopicscore
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

8. 0
1
2
3
4
5
6
7
8
9
10
*
*
Endoscopicscore
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

9. 0
1
2
3
4
5
6
7
8
9
10
*
*
Endoscopicscore
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

10. 0
10
20
30
40
50
60
70
80
90
100
PercentofAA-induced
aggregation
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

11. 0
200
400
600
800
1000
Pre-treatment Post-treatment
TxB2serum
concentration
(ng/ml)
*
* * *
Placebo NCX-4016 ASA
400 800 200 450
mg/b.i.d.
Serum TxB2
Fiorucci et al. , Gastroenterology. 2003 Mar;124(3):600-7

12. 0
1000
2000
3000
4000
5000
Pre-treatment Post-treatment
TxB2production
(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

13. 1.0 2.0 3.0 4.0
0
2
4
6
8
10
12
Alone + celecoxib Alone + celecoxib
NCX-4016 Aspirin
Meantotalendoscopic
score
P<0.001
Fiorucci S., et al. Proc Natl Acad Science USA 2003 100(19):10937-41

14. 1.0 2.0 3.0 4.0
0
2
4
6
8
10
12
Alone + celecoxib Alone + celecoxib
NCX-4016 Aspirin
Meantotalendoscopic
score
P<0.0001
P>0.05
Fiorucci S., et al. Proc Natl Acad Science USA 2003 100(19):10937-41

15. 0.0 8.0 15.0
0
50
100
150
NCX4016 NCX4016 + celecoxib
Aspirin Aspirin + celecoxib
Day 0 Day 8 Day 15
* *
* * * * *
*
Time
TxB2plasmalevels
(ng/ml)
Fiorucci S., et al. Proc Natl Acad Science USA 2003 100(19):10937-41

16. 0
2
4
6
8
10
12
14
16 *
**
Placebo ASA NCX-4016 ASA+ NCX-4016
**
MeangastricInjuryscore
NCX-4016 protects against injury caused by ASA
Fiorucci S.,Minuz P. et al. J. American College of Cardiology, 2004 (in pres)