Transcript Physiological Role for COX-2

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Anti inflamatório
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History of inflammation and NSAIDs
For 3,500 years inflammation has been treated with
preparations originating from plants containing salicylates.
• myrtle leaves (Myrtus)
• willow bark (Salix)
• poplar bark (Populus)
• meadowsweet (Spiraea)
• wintergreen oil (Gaultheria)
Aspirin
On 6th March 1899, ‘ Aspirin ’ was
registered as a trademark with the
Imperial Patent Office in Berlin.
WORLDWIDE
Production - 36,000 tons / year
Use - 70 tablets / person / year
acetyl
‘A’
Spiraea
‘SPIRIN’
Cyclo-oxygenase Hypothesis - 1970’s
membrane phospholipids
(-)
Phospholipase A2
glucocorticoids
arachidonic acid
Classical
(-)
NSAIDs
COX
Stomach
Kidney
Endothelium
Platelets
PGE2/PGI2
PGE2/PGI2
PGI2
TXA2
gastric
cytoprotection
renal blood
flow
haemostasis
Physiological Effects
Inflammatory Sites
PGE2
inflammatory
mediators
Inflammation
Roles of Prostaglandins in the 1970’s
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•
Pyretic (Feldberg & Gupta, 1973; Milton & Wendlandt, 1973)
Pro-inflammatory (Willis, 1969)
Hyperalgesic (Ferreira, 1972)
Inhibit gastric acid secretion (Whittle, 1976)
Contract the uterus (Bergstrom et al .,1968)
Increase renal blood flow (Lonigro et al., 1973)
Cyclooxygenase inhibitors: From pharmacology to clinical read-outs
Biochimica et Biophysica Acta 1851 (2015) 422–432 – Fig 04
Long-term effects of low-dose aspirin (0.45 mg/kg per day) on
platelet TXB2 and renal PGI2 synthesis.
Roles of Prostaglandins in the 1970’s
beneficial NSAID effects
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•
•
•
•
•
Pyretic (Feldberg & Gupta, 1973; Milton & Wendlandt, 1973)
Pro-inflammatory (Willis, 1969)
Hyperalgesic (Ferreira, 1972)
Inhibit gastric acid secretion (Whittle, 1976)
Contract the uterus (Bergstrom et al .,1968)
Increase renal blood flow (Lonigro et al., 1973)
harmful NSAID effects
Increasing COX-2
selectivity*
Comparative upper GI toxicity and COX-2 selectivity
naproxen
10
9
8
7
6
5
4
3
2
1
0
nabumetone
/
6MNA
flurbiprofen
tolmetin
aspirin
indomethacin
ketoprofen
ibuprofen
diclofenac
sulindac
r2 0.71; p < 0.03
etodolac
1
*WHRI blood/A549 assay
2
3 4 5 6 7 8 9
Increasing upper GI toxicity
10 11
Cyclo-oxygenase Hypothesis - 1990’s
membrane phospholipids
(-)
Phospholipase A2
glucocorticoids
(-)
arachidonic acid
COX-1
constitutive
(-)
Classical
NSAIDS
COX-2
(-)
inducible
Stomach
Kidney
Endothelium
Platelets
PGE2/PGI2
PGE2/PGI2
PGI2
TXA2
gastric
cytoprotection
renal blood
flow
haemostasis
Physiological Effects
INDUCTION:
mitogens
endotoxins
cytokines
(-)
selective
COX-2
inhibitors
Inflammatory Sites
PGE2
inflammatory
mediators
Inflammation
Schematic depiction of the structural differences between the substrate-binding channels of COX-1 and
COX-2 that allowed the design of selective inhibitors. The amino acid residues Val434, Arg513, and
Val532 form a side pocket in COX-2 that is absent in COX-1.
Nonselective inhibitors have access to the binding channels of both isoforms.
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical
Schematic depiction of the structural differences between the substrate-binding channels of COX-1 and
COX-2 that allowed the design of selective inhibitors. The amino acid residues Val434, Arg513, and
Val523 form a side pocket in COX-2 that is absent in COX-1.
The more voluminous residues in COX-1, Ile434, His513, and Ile532, obstruct access of the bulky side
chains of COX-2 inhibitors.
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
Distribution of COX-2
Present under ‘basal’ conditions:
CNS (cortex, hippocampus and amygdala), stomach (small amount in
superficial mucosa), kidney.
After treatment with hormones or other regulatory factors:
Ovaries, kidney (macula densa).
After treatment with LPS, cytokines etc.:
Monocytes,
macrophages,
endothelial
cells,
synoviocytes,
chondrocytes, osteoblasts, amnion, CNS, pulmonary epithelial cells,
smooth muscle cells.
Regulation of COX-2 Expression
The COX-2 promoter contains binding sites for NFkB,
glucocorticoids, IL-6 and other cytokines.
COX-2 is upregulated by LPS, IL-1, TNF, EGF, PDGF, TPA
and serum.
Induction has been seen in macrophages, endothelial cells,
fibroblasts,
amnion cells, glomerular mesangial cells and osteoclasts.
COX-2 down-regulated by glucocorticoids, cycloheximide
and anti-sense agents.
Inflammatory Role for COX-1 ?
In rat peritoneal and alveolar macrophages COX-1 contributes to
PG synthesis in basal and stimulated states.
(Wilborn et al., 1995)
Positive feedback between PGE2 and COX-2:
PGs generated from endogenous COX-1 may be involved in the
initial induction of COX-2.
(Mertz et al., 1994)
Overall increase of COX-1 levels in rheumatoid synovial tissue
is likely due to markedly increased cellularity.
(Crofford, 1996)
Physiological Role for COX-2 ?
Levels of COX-2 mRNA (similar to COX-1mRNA)
High
- prostate, lung
Medium - stomach, small intestine, uterus and mammary gland
Low
- kidney, liver, pancreas, testis, thymus, brain
(O’Neill & Ford-Hutchinson, 1994)
STOMACH
Under basal conditions COX-2 is present in the surface mucous
cells of the fundic and pyloric regions of the stomach.
(Iseki et al., 1995)
COX enzyme effects
COX-2 Inhibitors and Cardiovascular Risk -
VOL 336 SCIENCE - Fig 01
Cyclooxygenase inhibitors: From pharmacology to clinical read-outs
Biochimica et Biophysica Acta 1851 (2015) 422–432 – Fig 01
Chemical structures
of NSAIDs
Cumulative Incidence of the Primary End Point of a Confirmed Upper Gastrointestinal Event
among All Randomized Patients.
COMPARISON OF UPPER GASTROINTESTINAL TOXICITY OF ROFECOXIB AND NAPROXEN IN PATIENTS WITH RHEUMATOID ARTHRITIS - The New England Journal of Medicine – fig 01
Kaplan–Meier Estimates of the Cumulative Incidence of Confirmed
Serious Thrombotic Events.
Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial - n engl j med 352;11 – march 17,2005
Kaplan–Meier Estimates of the Cumulative Incidence of Investigator- Reported
Congestive Heart Failure (CHF), Pulmonary Edema (PE), or Cardiac Failure (CF).
Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial - n engl j med 352;11 – march 17,2005
Disposition of
patients
N = 3987
Celecoxib 400mg BID
N = 1779
Completed Study
N = 2208
Withdrawn
Lost to follow-up: 0
Preexisting violation: 27
Protocol noncompliance: 585
Treatment failure:691
Adverse event:905
N = 8059
Patients Randomized
N = 7968
Patients Taking Study Medication
N = 1996
Diclofenac 75mg BID
N = 939
Completed Study
N = 1057
Withdrawn
Lost to follow-up: 0
Preexisting violation: 11
Protocol noncompliance: 197
Treatment failure: 309
Adverse event: 540
N = 1985
Ibubrofen 800mg TID
N = 691
Completed Study
N = 1294
Withdrawn
Lost to follow-up: 0
Preexisting violation: 12
Protocol noncompliance: 365
Treatment failure: 456
Adverse event: 461
N = 3409
Patients Completing Study
Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002
Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002
Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002
Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002
Kaplan-Meier analyses of time to thromboembolic events in patients not taking aspirin
from the CLASS trial.
A, celecoxib versus the combined nonsteroidal antiflammatory agents (NSAIDs) ibuprofen and
diclofenac combined (p 0.973 celecoxib vs NSAIDs).
Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002
Kaplan-Meier analyses of time to thromboembolic events in patients not taking aspirin
from the CLASS trial.
B, celecoxib versus the individual NSAIDs (p 0.379 and 0.236, celecoxib vs diclofenac
and vs ibuprofen, respectively).
Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002
Duration of use of tNSAIDs and individual tNSAIDs among current users
(use within a month) and risk of myocardial infarction.
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
Comparison of major gastrointestinal events between COX-2 inhibitors and NSAID plus PPI and
subgroup analysis stratified by the risk for NSAID- related GI complications
Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors:
a systematic review and meta-analysis - J Gastroenterol (2013) 48:830–838 – Fig 03
Comparison of major gastrointestinal events between COX-2 inhibitors and NSAID plus PPI and
subgroup analysis stratified by the risk for NSAID- related GI complications
Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors:
a systematic review and meta-analysis - J Gastroenterol (2013) 48:830–838 – Fig 03
Flow of selection and censoring of ankylosing spondy- litis (AS)/spondyloarthritis (SpA) patients prior to
and during the study period (January 1, 2006 through December 31, 2009).
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – fig 01
Patient demographics, medications, and comorbidities at baseline (n 5 21,872)
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 01
Events, number of patient-years
(PYs) at risk, and unadjusted
and adjusted incidence rates
(IRs) for the outcomes of interest
for etoricoxib, nonselective
NSAIDs, celecoxib, and those
totally unexposed to any NSAID
for ankylosing spondylitis/
spondyloarthritis patients
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 02
Events, number of patientyears (PYs) at risk, and
unadjusted and adjusted
incidence rates (IRs) for the
outcomes of interest for
etoricoxib, nonselective
NSAIDs, celecoxib, and those
totally unexposed to any
NSAID for ankylosing
spondylitis/ spondyloarthritis
patients (cont’d)
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 02
vents, number of patient-years (PYs) at risk, and unadjusted and adjusted incidence rates (IRs) for the
outcomes of interest for etoricoxib, nonselective NSAIDs, celecoxib, and those totally unexposed to any
NSAID for AS patients
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 03
Events, number of patient-years (PYs) at risk, and unadjusted and adjusted incidence rates (IRs) for the outcomes of interest for etoricoxib,
nonselective NSAIDs, celecoxib, and those totally unexposed to any NSAID for other SpA patients
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 04
Events, number of patient-years (PYs) at risk, unadjusted incidence rates (IRs), and adjusted relative risks (RRs) for
the outcomes of interest for the subgroups of most used nonselective NSAIDs (diclofenac, ketoprofen, naproxen,
ibuprofen, and indomethacin) and patients not exposed to any NSAID for AS/SpA patients
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 05
Events, number of patient-years (PYs) at risk, unadjusted incidence rates (IRs), and adjusted relative risks (RRs) for
the outcomes of interest for the subgroups of most used nonselective NSAIDs (diclofenac, ketoprofen, naproxen,
ibuprofen, and indomethacin) and patients not exposed to any NSAID for AS/SpA patients (cont’d)
Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study
Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 05
the risks for
adverse outcome events related to nonselective NSAIDs, etoricoxib,
and celecoxib exposure in AS and SpA patients in Sweden are not
statistically different. No significantly increased risks were identified in this
In conclusion, the results of this study suggest that in regular care,
population of AS and SpA patients for etoricoxib compared to nonselective NSAIDs and
celecoxib. Unexposed patients had considerably more baseline comorbidities and a
higher RR for atherosclerotic events and congestive heart failure, suggesting that
confounding by indication significantly affects the observed AE rates associated with
NSAIDs in clinical practice.
The lessons from the “COX-2 debacle” will likely continue to increase in
number and be reevaluated for years to come. Looking at the above
information though, we can at least conclude that:
1) NSAIDs, whether c2sNSAID or nsNSAID, have detrimental CV effects that become more
apparent the longer they are given. Hence, the lowest dose, least frequent dosing, and shortest
duration use are always advised (similar to opioids);
2) The severity of these CV effects relates more to the individual agent than the COX-2
selectivity of the drug;
3) The mechanisms of such CV effects are not fully known but is not the result of a
prothrombotic state, and so this theory should be disre- garded in future reviews;
The lessons from the “COX-2 debacle” will likely continue to increase in
number and be reevaluated for years to come. Looking at the above
information though, we can at least conclude that:
4) The currently proven GI ben- efits of c2sNSAIDs are no different than a combination of
PPI/nsNSAID, assuming patient compliance with the PPI, but there may be benefit in highly atrisk patients needing to use a combination PPI/c2sNSAID;
5) The lack of plate- let inhibition by c2SNSAIDs remains a clear factor in their use in the
perioperative period over nsNSAIDs.