Inibitori della Cox-2 in gastroenterologia: attualità ed evidenze cliniche

1. Inibitori della Cox-2 in
gastroenterologia:
attualità ed evidenze cliniche
Stefano Fiorucci
Università di Perugia

2. Figure 7
Biosynthesis of the Products of Arachidonic Acid
Various Stimuli:
ESTERIFIED ACID Chemical Arachidonic Acid Dexamethasone
ESSENTIAL IN CELL LIPID and Mechanical
FATTY ACID
COOH
Cytokines
e.g., Phospholipids of Cell
Growth Factors
IN DIET Membrane ? Activation of Endotoxin
? Also Triglyceride Phospholipase A2 or Cyclooxygenase-2 or
Other Acylhydrolases Cyclooxygenase-1
Lipoxygenases X X
False substrates: e.g.
COOH
Antiinflammatory Drugs: .
COOH
e.g., Aspirin and
O O
O O .
5, 8, 11, 14- Indomethacin O COOH
Eicosatetraynoic Acid
Dazoxiben, Pirmagrel O
thase
clin Syn
O COOH O COOH
Prostacy
HOOC
X Thromboxane Sy
O O
O
OH PGH2 nthase OOH
PGG2
Isomerases
OH OH
PGI2
Active COOH
Metabolites HYDROLYSIS O HO HO O
COOH COOH COOH COOH O
O
HO OH
TXA2
HO
OH PGE2 HO
OH PGF2α O
OH PGD2 HYDROLYSIS
OH
OH PGDH PGDH
OH
6-keto O HO
COOH
Inactive PGF1α COOH COOH HO O
Metabolites β OXIDATION
OH
TXB2
HO OH
HO O O
OH β OXIDATION
O COOH ∆13 REDUCTION ∆13 REDUCTION COOH
HO β OXIDATION β OXIDATION COOH
ω OXIDATION ω OXIDATION O O
O HO HO O
COOH COOH OH
OH
Urinary OH OH COOH
Metabolites 2,3-Dinor- HO HO
COOH
11-Dehydro-TXB2 2,3-Dinor-TXB2
6-keto-PGF1α
O
PGE-M O PGF-M
40% of original ISIS draw

3. The Nobel Prize in Physiology or Medicine 1982
Sune K. Bergström Bengt I. Samuelsson John R. Vane
Sweden Sweden United Kingdom
Karolinska Institutet Karolinska Institutet The Wellcome
Stockholm, Sweden Stockholm, Sweden Research
Laboratories
Beckenham, United
Kingdom

6. Garavito et al. Ann Rev Pharmacol 1998

7. The COX
pathway
Membrane Lip
ase Arachidonic Acid Lipoxins,
Lipid Storage re COOH
leas Leukotrienes
e 13
Lipoxygenases
HETEs
p450
11 15 EETs
Cyclooxygenase
COX-1
COX-1 PGH Synthase 15-R oxygenation COX-2
COX-2
X
SH HR SH HR
ASPIRIN
13 13
15 15
NSAIDs
NSAIDs
Prostaglandins Aspirin-Triggered Lipid Mediators
Parturition Renal Function Anti-inflammation
Inflammation Hemodynamics
15-epi-LXA
15-epi-LXA

8. COX- 1 and COX-2
ARACHIDONIC ACID
COX-1 COX-2
TxA PGI2 PGE2 PGI2
Platelets CNS Endothelium
Kidney
PGE2 PGE2
Stomach Macrophages
Sinovial cells
Chondrocytes

9. COX-3, a cyclooxygenase-1 variant
inhibited by acetaminophen and
other analgesic/antipyretic drugs:
Cloning, structure, and expression
N. V. Chandrasekharan, Hu Dai, K. Lamar Turepu Roos, Nathan K.
Evanson, Joshua Tomsik, Terry S. Elton, and Daniel L. Simmons
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 21, 13926-13931, October 15, 2002

10. COX-1 and COX-2 Protein
Expression in Human GI Tract
700
600
ng/mg Protein
500
400 COX-1
300 COX-2
200
100
0
Body Antr Duo Jejun Ileum Colon
Kargman et al. Gastroenterology, 1996

11. Warner TD and Mitchel J. PNAS 2002

12. COX-2

13. Aspirin
Celecoxib

14. Struttura schematica di COX-1 e COX-2
COX-1 COX-2
sito catalitico sito catalitico
dell’enzima dell’enzima
Valina523,
o Isoleucina523,
n ic o
ido nic
PGH2 ac
h ido
Ar PGH2 ac
h
ido Ar
Ac ido
Ac
Arginina120 “tasca laterale”
Arginina120

15. FANS tradizionali: si legano a COX-1 e COX-2
COX-1 COX-2
sito attivo sito attivo
“ponte salino”
con
Arginina120
“ponte salino”
o
nic
con o
ido Arginina120 onic
rac
h h id
ac
o
A Ar
cid ido
A Ac

16. Coxib: interazione specifica solo con COX-2
COX-1 COX-2
sito attivo
sito attivo
coxib
PGH2 “tasca laterale”
co
o ni
id
a ch
o Ar
id co Arg 120
Ac
Arg
o ni 513
Arg 120 id hido
Ac rac
Hist
90
A
coxib

17. COX-2/COX-1
100
Platelets PGE2
80
TXA2
Percent of
inhibition
60
40 TxA2 Aspirin
TBX2
20
Macrophages 0
0
100 0.01 0.1 1.0 10 100
80
TxA
TBX2 2
Percent of
PGE2
inhibition
60
40 Rofecoxib
PGE2
LPS 20
0
Warner et al. PNAS 99 0 0.01 0.1 1.0 10 100

18. COX-2 selectivity of NSAIDs
Percent inhibition of COX-1 when COX-2 is inhibited by 80%
100
80
60
40
20
0
ox b
e
es m
en
L- DFP
clo ib
xic c
7
na am
xi
id
rin
na
ni ica
33
di cox
ox
ul
co
pi
fe
5,
pr
as
fe
le
74
ro
m
el
ce
ro
m
pi
Warner et al, PNAS 1999

19. NSAIDs SELECTIVITIES FOR COX-1/COX-2
specific
Rofecoxib
> 50-fold
Etodolac
Meloxicam selective
Celecoxib
Nimesulide 5 to 50-fold
Diclofenac < 5-fold COX-2 selective
Piroxicam
Ibuprofen
Naproxen Non selective
Aspirin
Indomethacin
Ketoprofen
-3 0
-2 -1 1 2 3
Log[IC ratio(COX-2/COX-1)]
80 Warner et al, PNAS 1999

20. COX-1 Activity: PGE2 Synthesis in GI Biopsies
Rofecoxib vs. Naproxen x 5 Days
170
160
PGE2 Synthesis ng/gm • min
150
140
130
120
110
100
90
80
70
60
50
40
30
Placebo Rofecoxib Placebo Naproxen
25 mg qd 500 mg bid
Hawkey CJ, Gastroenterology 2001

21. Gastric and intestinal injury
related to NSAIDs

22. Gastrointestinal Lesions induced by NSAIDs
1. Acute Mucosal Lesions:
•Petequia
•Erosions
•Acute Ulcers
2. Chronic/Deep GD Ulcers
3. Complications:
• GI Bleeding
•Perforation
•Obstruction

23. NSAIDs related GI side effects
Chronic users in Italy ≈2 million
30-40% of patients taking an NSAID
develops dyspepsia
1-3% develop serious GI side effects
with an overall mortality of 2000
patients/year

24. Number of
deaths
25.000
USA 1997
20187
NUMBER OF DEATH
20.000 16685 16500
15.000
10503
10.000
5338 4441
5000
1437
0
Leukemia AIDS NSAIDs Multiple Asthma Cervical Hodgking
myeloma cancer disease
Wolfe MM et al. NEJM 1999

25. Gastropatia da FANS: fattori di rischio
Fattori di richio definiti
1. Eta’>65
2. Storia di ulcera duodenale o sanguinamento GI
3. Alte dosi di FANS
4. Uso simultaneo di 2 FANS
5. Uso concomitante di corticosteroidi
6. Uso di anticoagulanti
7. Malattie sistemiche severe (cardiovascolari)
Fattori di rischio possibili
• Infezione da H.pylori
• Consumo di alcolici

26. Upper GI lesions: risk
factor and NSAID
structrure
Drug R.R. (I.C. 95%)
Ibuprofen 2.0
Aspirin 2.6 (1.3-2.5)
Diclofenac 2.8 (1.4-2.3)
Sulindac 3.1 (1.6-2.7)
Naproxen 3.2 (1.7-2.9)
Indomethacin 3.4 (1.9-3.1)
Piroxicam 4.8 (2.7-5.2)
Ketoprofen 5.2 (2.7-6.4)
Garcia Rodriguez et al 1995

27. Rofecoxib and Acute Gastroduodenal
Mucosal Lesions after 7 days of
Treatment
% patients with Lanza score > 2
100 94
* †
80 71
* †
60
40
20
8 12
0
Placebo Rofecoxib 250 Ibuprofen 800 Aspirin 650
mg/day mg/8h mg/6h
* P<0.05 vs. placebo.
†
P<0.001 vs. rofecoxib. Lanza et al. Aliment Pharmacol Ther 1999; 13: 761-7

28. Investigator-Reported Thrombotic
Cardiovascular Events in the VIGOR Study
Compared with Phase IIb/III OA Study
3.5
3.0
Cumulative Incidence %
Rofecoxib (VIGOR)
2.5
2.0
1.5
1.0 Naproxen (VIGOR)
0.5
0.0
0 2 4 6 8 10 12 14
Months of Follow-up
CARDIOVASCULAR SAFETY PROFILE OF ROFECOXIB: A META-ANALYSIS:
A. Reicin, E. Barr, D. Shapiro - EULAR ORAL PRESENTATION, SAT. JUNE 16: 12:00 -

29. The CLASS study:
RESULTS
P = 0.02
6
Annualized incidence
P = 0.09 49/1384
3.5%
(%)
3
30/1441
20/1384 2.0%
11/1441 1.5%
0.76%
0
Celecoxib NSAIDS Celecoxib NSAIDS
Ulcer Symptomatic and
complications complicated ulcers

30. The CLASS study:
RESULTS
P = 0.49
17/293
6.0%
6 P = 0.02 14/298
Annualized incidence
4.6%
32/1101
3.0%
(%)
3
16/1143
1.3%
0
Celecoxib NSAIDS Celecoxib NSAIDS
Patients not Patients
taking aspirin taking aspirin

31. The CLASS study
(Celecoxib Long-term Arthritis Safety
Study)
• 8059 patients
6 12
Juni et al., BJM 2002;324:1287

32. Effects of NSAIDs on
Thromboxane and Prostacyclin
Endothelial
Platelet Cell
Nonselective
COX-1 NSAIDs/ASA COX-1
COX-2 Inhibitor COX-2
Thromboxane (TxA2) Prostacyclin (PGI2)
Promotes Platelet Aggregation Inhibits Platelet Aggregation
Hemostasis Thrombosis
McAdam et al. Proc. Natl. Acad Sci. USA . 1999;96:272.

33. VIGOR
Confirmed Thrombotic Cardiovascular
Events
RA Patients with Events (Rates per 100 Patient-Years)
Rofecoxib Naproxen Relative Risk
Event Category N=4047 N=4029 (95% CI)
Confirmed 45 (1.7) 19 (0.7) 0.42
CV events (0.25, 0.72)
Cardiac 28 (1.0) 10 (0.4) 0.36
events (0.17, 0.74)
Cerebrovascular 11 (0.4) 8 (0.3) 0.73
events (0.29, 1.80)
Peripheral 6 (0.2) 1 (0.04) 0.17
vascular events (0.00, 1.37)
Bombardier et al. N Engl J Med. 2000;343:1520-1528

36. A randomised, double blind, placebo controlled study
of celecoxib, a selective cyclooxygenase 2 inhibitor
on duodenal polyposis in familial adenomatous polyposis
R K S Phillips and The Fap Study Group7
Gut 2002;50:857-860

37. A randomised, double blind, placebo controlled study
of celecoxib, a selective cyclooxygenase 2 inhibitor
, on duodenal polyposis in familial adenomatous polyposis
R K S Phillips and The Fap Study Group7
Gut 2002;50:857-860

38. The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor,
in Familial Adenomatous Polyposis
Steinbach et al. 342 (26): 1946, Table 2 June 29, 2000

39. Steinbach et al. 342 (26): 1946, Table 2 June 29, 2000

40. Primary Chemoprevention of Familial Adenomatous Polyposis with Sulindac.
. Giardiello FM et al. , NEJM, Volume 346:1054-1059 April 4, 2002

41. NAG-1
Expression and regulation of nonsteroidal anti-inflammatory drug–activated gene
(NAG-1) in human and mouse tissue. KIm et al. May 2002

42. Dual Function of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
Inhibition of Cyclooxygenase and Induction of NSAID-Activated Gene
Seung Joon Baek, Leigh C. Wilson, Chang-Ho Lee1 and Thomas E. Eling
JPET 2002 301(3):1126-31

44. Rofecoxib inhibits cyclooxygenase 2 expression and activity and
reduces cell proliferation in Barrett's esophagus. Baljeet S. Kaur et al
Gastroenterology 2002 Jul;123(1):60-7