Nitric oxide releasing NSAIDs : are they alive?

A conference on nitric oxide releasing aspirin

Stefano FiorucciUniversity of Perugia

Nitric oxide

N=O

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

Synergism between COX inhibition and nitric oxide formation

Enhance gastrointestinal Safety

Increase anti-inflammatory activity

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

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

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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10

*

*

En

do

sc

op

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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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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

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

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

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

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

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

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

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)