Download Physiological Role for COX-2

Dúvidas
[email protected]
Arquivo
Anti inflamatório
Site
www.gilbertodenucci.com
Medicamentos
•
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•
•
•
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Inibidores de Cox não seletivos
Inibidores de Cox seletivos para Cox-2
Antidepressivos
Anticonvulsivantes
Relaxantes musculares
Opióides
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
•
•
•
•
•
•
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)
Roles of Prostaglandins in the 1970’s
beneficial NSAID effects
•
•
•
•
•
•
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
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 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
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
Schematic overview of the cyclooxygenase and
lipoxygenase pathways
Advances in eicosanoid research, novel therapeutic implications - Biochemical and Biophysical Research Communications 396 (2010) 135–139
The 5-lipoxygenase/leukotriene pathway
Advances in eicosanoid research, novel therapeutic implications - Biochemical and Biophysical Research Communications 396 (2010) 135–139
The leukotriene biosynthetic pathway and transcellular
metabolism of lipoxins.
Advances in eicosanoid research, novel therapeutic implications - Biochemical and Biophysical Research Communications 396 (2010) 135–139
Bulbospinal systems regulate spinal excitation.
Analgesic Pharmacology: I. Neurophysiology - Vol 12, No 4, July/August 2004 – fig 6
Enrollment, Randomization, and Outcomes
3260 Patients assessed for eligibility
674 Did not undergo
randomization to 25 mg of
rofecoxib or placebo
403 Were ineligible
160 Withdrew consent
41 Had adverse clinical events
26 Were given 50 mg of
rofecoxib
44 Had other reasons
1287 Assigned to 25 mg of rofecoxib
1287 Received treatment and included
in safety analysis
410 Discontinued treatment
202 Had adverse clinical events
22 Had adverse laboratory events
112 Withdrew consent
14 Were lost to follow-up
60 Had other reasons
877 Completed 3 yr of treatment
1299 Assigned to placebo
1299 Received treatment and included
in safety analysis
319 Discontinued treatment
145 Had adverse clinical events
9 Had adverse laboratory events
88 Withdrew consent
20 Were lost to follow-up
57 Had other reasons
980 Completed 3 yr of treatment
Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial - n engl j med 352;11 – march 17,2005
The pharmaceutical industry spends more than $5.5 billion to
promote drugs to doctors each year — more than what all U.S.
medical schools spend to educate medical students. Major drug
companies employ about 90,000 sales representatives — one
for every 4.7 doctors in the United States, according to the
American Medical Association.
Roles of the COX isozymes in cardiovascular
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
Roles of the COX isozymes in cardiovascular
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
Roles of the COX isozymes in cardiovascular
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
Illustration of the expected interaction of baseline cardiovascular and thrombotic risk
with components of drug exposure including dose, duration of action, and duration of
treatment with a selective inhibitor of COX-2.
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
The spectrum of
selectivity for
COX inhibition.
Discordant dose-response relationships for inhibition of platelet COX-1
(A) and vascular COX-2 (B).
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
Clinical implications of differences in the dose-response relationships for COX-1 and COX-2 of low-dose
aspirin (A), a selective inhibitor of COX-2 (B), and a tNSAID (C). The area between the dose-response
curves would correspond to benefit (A) and hazard (B and C) and to the size of these effects.
Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation
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
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
Incidence of Hypertension, Edema, and Congestive Heart Failure
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
Incidence of Hypertension, Edema, and Congestive Heart Failure
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
Incidence of Hypertension, Edema, and Congestive Heart Failure
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
Incidence of Hypertension, Edema, and Congestive Heart Failure
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
Incidence of Hypertension, Edema, and Congestive Heart Failure
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
Incidence of Hypertension, Edema, and Congestive Heart Failure
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
Biology and therapy of fibromyalgia New therapies in fibromyalgia - Arthritis Research & Therapy Vol 8 No 4 Arnold
Summary of findings from pharmacological studies in fibromyalgia
1. Serotonin and norepinephrine reuptake inhibitors improve pain, other symptom domains, function, quality of life,
and global wellbeing in patients with fibromyalgia.
2. Selective serotonin and norepinephrine reuptake inhibitors (SNRIs) offer an alternative to cyclic medications (e.g.,
tricyclics) that are associated with safety and tolerability concerns.
3. The effect of SNRIs on reduction in pain associated with fibromyalgia is independent of their effects on mood.
4. Alpha 2 delta ligands also improve pain, other symptom domains, function, and global well-being in patients with
fibromyalgia.
5. Alpha 2 delta ligands improve slow wave sleep.
6. Drugs associated with high risk of abuse and dependence should be avoided. Opiates may contribute to
hyperalgesia if used chronically.
7. Although studies are limited, combinations of medications (e.g., combination of an SNRI and alpha 2 delta ligand)
may be an option for patients who do not fully respond to a single agent or who have problems with tolerability at
higher doses.
Biology and therapy of fibromyalgia New therapies in fibromyalgia - Arthritis Research & Therapy Vol 8 No 4 Arnold
Schematic representation of the neural patterns involved in the spasm-pain-spasm cycle.
Adapted with permission.
Commonly Used Muscle Relaxant Therapies for Acute Low Back Pain: A Review of Carisoprodol, Cyclobenzaprine Hydrochloride, and Metaxalone - CLINICAL THERAPEUTICS
Commonly Used Muscle Relaxant Therapies for Acute Low Back Pain: A Review of Carisoprodol, Cyclobenzaprine Hydrochloride, and Metaxalone - CLINICAL THERAPEUTICS
Severity of somnolence experienced with cyclobenzaprine hydrochloride 5 mg (David G.
Borenstein, protocols 006 and 008, McNeil Consumer & Specialty Pharmaceuticals, Fort
Washington, Pennsylvania, 2003).
Commonly Used Muscle Relaxant Therapies for Acute Low Back Pain: A Review of Carisoprodol, Cyclobenzaprine Hydrochloride, and Metaxalone - CLINICAL THERAPEUTICS
Commonly Used Muscle Relaxant Therapies for Acute Low Back Pain: A Review of Carisoprodol, Cyclobenzaprine Hydrochloride, and Metaxalone - CLINICAL THERAPEUTICS
Limitações dos ensaios clínicos com drogas em Fibromialgia
1 - Duração curta
2 - Ponto primário dor (pontos secundários são avaliados de maneira inconsistente)
3 - Não há padronização para avaliar os sintomas
4 - Ponto primário é redução da dor frente ao placebo (não necessariamente melhora
do quadro clínico)
5 - Não há consenso sobre conceituação de melhora clínica significativa da dor
6 - Presença de outras patologias (principalmente alterações psiquiátricas)
7 - Maior parte dos pacientes nos estudos são mulheres (extrapolação para homens?)
The rationale for testing a dopamine 3 agonist in fibromyalgia is
based on evidence that excessive adrenergic arousal may
fragment sleep, and enhancement of dopaminergic
neurotransmission at the D3 receptors in the mesolimbic
hippocampus may reduce expression of arousal and improve
sleep.
Compared with the placebo group, those patients receiving
pramipexole titrated over 12 weeks to 4.5 mg every evening had
gradual and significant improvement in pain, fatigue, function,
and global status.
Central sensitization, a possible pathogenic mechanism of the chronic pain
associated with fibromyalgia, is mediated, in part, by the binding of
excitatory amino acids (glutamate and aspartate) to the NMDA receptor.
NMDA antagonists may inhibit or attenuate central sensitization [97] and
potentially reduce pain associated with fibromyalgia. In one clinical study,
48 female patients with fibromyalgia were treated with an open-label
combination of tramadol 200 mg/day and increasing doses of
dextromethorphan (50 to 200 mg/day), titrated to therapeutic effect or
tolerability. Fifty-eight percent(28 of 48) responded to the addition of
dextromethorphan and entered a double-blind phase in which the patients
were randomized to dextromethorphan and tramadol or tramadol and
placebo. A Kaplan-Meier drop-out analysis showed that significantly fewer
patients on dextromethorphan and tramadol discontinued treatment
compared with patients on tramadol alone [98].
Among these possible medications are the 5-HT3 antagonists
(e.g., ondansetron and tropisetron), which have analgesic effects.
A randomized, placebo-controlled, double-blind,10 day trial in
418 patients with fibromyalgia evaluated the short-term efficacy
of tropisetron at doses of 5 mg/day, 10 mg/day, and 15 mg/day.
Significant reduction in pain was noted only in those patients
taking 5 mg/day and 10 mg/day, while the effects of tropisetron 15
mg/day were no different from placebo, suggesting a bell-shaped
dose response curve
Tramadol is a novel analgesic with weak agonist activity at the
mu opiate receptor combined with dual serotonin and
norepinephrine reuptake inhibition that may exert antinociceptive
effects within both the ascending and descending pain pathways.
Recently, fibromyalgia trials have focused on new selective
serotonin and norepinephrine reuptake inhibitors (SNRIs),
which are potent dual reuptake inhibitors but, unlike the
tricyclics, do not interact with adrenergic, cholinergic or
histaminergic receptors, or sodium channels, and, therefore,
lack many side effects of tricyclics.
Fibromyalgia patients often develop an increased response to
painful stimuli (hyperalgesia) and experience pain from
normally non noxious stimuli (allodynia) [6]. Both
hyperalgesia and allodynia reflect an enhanced central nervous
system processing of painful stimuli that is characteristic of
central sensitization [7].
Fibromyalgia is a chronic, musculoskeletal pain condition that
predominately affects women. Although fibromyalgia is
common and associated with substantial morbidity and
disability, there are no US Food and Drug Administrationapproved treatments.
Chronic pain is one of the most common reasons
prompting visits to healthcare providers; collectively, it
possibly disables more people annually than heart disease
and cancer combined.
Applied topically as a gel or as a cream, NSAIDs have
been widely studied as topical agents for sports injury
pain, osteoarthritis, postoperative pain, and eye pain;
these agents include diclofenac (patch/gel), ibuprofen
(cream), ketoprofen (gel), piroxicam (gel), eltenac(gel),
and aspirin.
Mean concentration vs. time profiles of diclofenac in plasma (closed circles), subcutaneous adipose (open triangles)
and skeletal muscle tissue (closed squares) after the final dose of a 3-day regimen of either MIKA Diclofenac Spray Gel
4% applied to the skin of the thigh (left panel) or with VOLTAREN® 50 mg enteric coated tablets given orally (right
panel) in 12 healthy males. Results are presented as mean ± SE. Plasma (●), subcutaneous tissue (▲), skeletal
muscle tissue (■)
Main pharmacokinetic parameters for diclofenac obtained in plasma (total drug) and
subcutaneous and skeletal muscle tissue (free drug) of the thigh in 12 healthy males after
the final dose of a 3-day multiple dose regimen of either topical application of MIKA
Diclofenac Spray Gel 4% or oral administration of VOLTAREN® 50 mg enteric coated
tablets
Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation - Br J Clin Pharmacol 60 :5 573–577 573
Inhibitor ratios of NSAIDs in human blood/A549 cells
IC50s
COX-1 COX-2
COX-2
selectivity
1
<<0.01
>>100x
L745,337
1
0.1
10x
nimesulide, NS398, meloxicam,
celecoxib
1
1
1x
etodolac, diclofenac, sulindac
1
10
0.1x
ibuprofen, ketoprofen, diflunisal,
indomethacin, aspirin, tolmetin
1
10
0.1x
flurbiprofen, naproxen,
nabumetone/6MNA?
Human whole blood assay
• Predictive for GI damage?
Rank
11
10
9
8
7
6
5
4
3
2
1
0
indomethacin
flurbiprofen
tolmetin
naproxen
aspirin
ketoprofen
ibuprofen
sulindac
diclofenac
etodolac
nabumetone
Comparative upper GI toxicity - ARAMIS database
(Singh et al., 1998)
Meloxicam: Expected concentration in
whole blood (15 mg, once daily)
1.8
1.8
COX-1
1.6
1.4
1.4
1.2
1.2
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
COX-2
0.2
168
0.0
192
0.0
0
24
48
72
96
120
Time (hours)
144
Estimated IC50 for COX
Drug Concentration [µg/mL]
1.6
Effect of meloxicam on platelet COX-1
and monocyte COX-2
% inhibition ± SE
100
90
80
70
J1
J
1 COX-1
J
1
COX-2
60
J
1
50
40
1
30
20
15 mg, ss: Cmin -Cmax:
0.46 - 1.10 µg/mL
10
0
-10
0.01
J
1
1
0.1
1
10
Concentration in whole blood (µg/mL)
20
Importance of Drug Plasma Levels
Meloxicam
Naproxen
7.5 mg / day
Cmin - Cmax : 0.23 - 0.55 µgml-1
2 x 500 mg / day
Cmin - Cmax : 23 - 50 µgml-1
% Inhibition
100
80
COX-1
COX-2
60
40
20
0
0.01
0.1
1
10
100
concentration in whole blood µgml-1
0.01
0.1
1
10
100
concentration in whole blood µgml-1
Nimesulide: Expected
concentration in whole blood (100
mg, twice daily)
4.0
3.0
COX-1
3.0
2.0
2.0
1.0
1.0
COX-2
0.0
0
24
48
72
96
120
Time (hours)
144
168
0.0
192
Estimated IC50 for COX
Drug Concentration [µg/mL]
4.0
Nimesulide: Expected concentration in
whole blood (200 mg, twice daily)
4.0
4.0
3.0
COX-1
3.0
2.5
2.0
2.0
1.5
1.0
1.0
COX-2
0.5
0.0
0
24
48
72
96
120
Time (hours)
144
168
0.0
192
Estimated IC50 for COX
Drug Concentration [µg/mL]
3.5
Meloxicam
•
•
•
•
Selective COX-2 inhibitor in vitro.
Preferential inhibitor of PG release at inflammatory sites.
Potent anti-inflammatory drug in vivo.
Superior therapeutic margin.
“A potent anti-inflammatory agent
with reduced risk of side-effects”
Structures of COX-2-selective
compounds
O
O
Meloxicam
Nimesulide
CH3
N
O
OH
CH3
NH
DuP 697
S
O
S
NO2
Br
S
S
O
H
N
N
CH3
F
O
CH3
S
O
F
O
Etodolac
Flosulide
NS-398
F
H3C
H
N
COOH
CH3
O
O
O
O
H
H
N
N
CH3
NO2
S
O
CH3
S
O
O
O
Structures of COX-2-selective compounds
F
SC 58125
O
O
MK 966
S
CI 1004
F
CH3
N
O
S
N
CF3
O
(CH3) C
N
Na
H
N
NH2
C (CH3)
CH3
F
S
O
O
Celecoxib
(SC58635)
H2NSO2
N
RS 57067000
O
N
N
CF3
CH2
Cl
CH3
CH3
N
NH
CH3
O
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)
Relationship between dose and GI toxicity
Relative risk of toxicity
(+ 95% confidence limits)
12
Ibuprofen
Naproxen
Indomethacin
6
0
low/medium
high
Dose
(Garcia Rodriguez, 1997)
Relative risk of toxicity
(+ 95% confidence limits)
Comparative upper GI toxicity of NSAIDs at high
doses
36.4
20
10
0
(Garcia Rodriguez, 1997)
Ibuprofen
>1500 mg
Naproxen Diclofenac Indomethacin
>750 mg >100 mg
>75 mg
Celecoxib in RA patients
• RA patients withdrawn from NSAID therapy and those with
disease flare up used for study
• subjects given placebo or celecoxib (40, 200 or 400 mg b.i.d.)
for 4 weeks
• relative to placebo, improvements in:
• patient global assessment
• duration morning stiffness
• number of tender or painful joints
• no increase in adverse events relative to placebo
• at 400 mg b.i.d. no effect on platelet function
(Lipsky & Isakson, 1997)
Celecoxib in short term pain
• subjects had >2 molars removed
• given placebo, aspirin (650 mg) or celecoxib (100 or 400 mg)
• pain assessed for up to 8 h; endpoint being requirement for
rescue medication (RM)
• placebo takers: 60% required RM within 1h, 90% within 3 h.
• aspirin takers: 60% required RM within 4 h.
• celecoxib takers: 50% required RM within 4 h.
(Lane, 1997)
Celecoxib in medium term pain
subjects with painful knee osteoarthritis studied for 2 weeks
 given placebo, or celecoxib (40, 100 or 200 mg, b.i.d.)
 placebo takers

 12%
decrease in joint pain after 1 week
 14% dropout rate over 2 weeks

celecoxib takers
 20-30%
decrease in joint pain after 1 week
 1% dropout at 100 mg dose; 4% dropout at 200 mg dose
(Lane, 1997)
DFU in primate pyresis
I.p. temperature monitored in conscious monkeys given LPS
(6 µg/kg, i.v.) followed 120 min later by vehicle, diclofenac
(3 mg/kg, p.o.) or DFU (1 or 3 mg/kg, p.o.).
 Body temperature increased by max. of 2.07±0.07 °C after
140 min and remained elevated for up to 240 min.
 At 240 min body temperatures were

1.77±0.13 °C
 DFU: 1 mg/kg, 1.15±0.07 °C; 3 mg/kg, 0.10±0.10 °C
 diclofenac: 0.32±0.20 °C
 vehicle:

conclude that pyresis is entirely dependent upon COX-2 activity
(Chan et al., 1997)
DFU in primate pyresis

I.p. temperature monitored in conscious monkeys given
LPS (6 µg/kg, i.v.) followed 120 min later by vehicle,
diclofenac (3 mg/kg, p.o.) or DFU (1 or 3 mg/kg, p.o.).

Body temperature increased by max. of 2.07±0.07 °C
after 140 min and remained elevated for up to
240 min.
(Chan et al., 1997)
Eleveation in body temperature
(°C)
DFU in primate pyresis
2
1
0
vehicle
(Chan et al., 1997)
DFU
(1 mg/kg)
DFU
(3 mg/kg)
Diclofenac
(3 mg/kg)