Table of Contents
Cox-2 inhibitors: where are we ?
Cox-2 inhibitors: where are we ?
Overview of celecoxib clinical trials
Phase III Pivotal OA Trials : Study Design
PPT Slide
Phase III Pivotal OA Trials Patient’s
Assessment
of Arthritis Pain
Combined WOMAC outcomes from 3 OA Studies
n = ~600
per treatment group
Pain Measure Questionnaire of the
American Pain
Society (APS)
Patient’s assessment of average arthritis
pain
in last 24h
Patient’s Assessment of Pain
Efficacy of celecoxib 200 mg once a day
(qd) in
OA
Phase III RA Trial Design
PPT Slide
Celecoxib (200 mg 2x/d) vs Diclofenac (75
mg SR
2X/d) in RA (6 months)
Number of tender / painful joints 6
Months International
Study in RA
Why do need Cox-2 inhibitors ?
Adverse Effects of common NSAIDs
NSAIDs toxicity
NSAID Ulcers and Ulcer Complications
GI mortality associated with typical
NSAIDs vs
other causes in US (1of 2)
GI mortality associated with typical
NSAIDs vs
other causes in US (2 of 2)
Deaths attributed to anti-rheumatic
medication
(series of 1666 patients with RA)
Most patients are asymptomatic prior to a
serious
NSAID-associated GI event ...
Pharmaco-epidemiological studies in
Europe NSAIDs
and GI events
The Tayside study
The Tayside Record Linkage System
NSAID Induced GI Complications - Constant
Risk
*NSAIDs - Relative Risk of GI
Complications
Upper GI complications in Europe
Meloxicam : clinically significant GI
events
Meloxicam : influence of the dose
This is why ...
PPT Slide
PPT Slide
The Discovery of the role of
cyclooxygenase
Conversion of arachidonic acid to
prostaglandins
Mapping of the cyclooxygenase active site
PPT Slide
All conventional NSAIDs have a similar
mechanism
of action ...
All conventional NSAIDs have a similar
mechanism
of action ...
All conventional NSAIDs have a similar
mechanism
of action ...
PPT Slide
Discovery of two forms of cyclooxygenase
Effect of IL-1 and dexamethasone on human
fibroblast
COX activity
COX-2: a new anti-inflammatory drug target
Structures of COX-1 and COX-2
Conventional NSAIDs inhibit both COX-1
and COX-2
Chemistry and Activity
PPT Slide
Pharmacochemical determinants in “coxibs”
Fitting “coxibs” in cyclooxygenases ...
Why do “coxibs” bind so tightly to
cycoloxygenase-2
?
Why do “coxibs” fail to inhibit
cyclooxygenase-1
?
PPT Slide
Selectivity and specificity of
Cox-inhibitors (Lipsky
et al, Editorial, J. Rheumatol, 1998, 25, 2298-2303)
Specificity of coxibs in real life ...
Categories of COX Inhibitors
Rat Adjuvant Arthritis Model
Reversal of inflammation in rat adjuvant
arthritis
Selectivity of COX Inhibitors in vivo
Specificity of Celecoxib in vivo
Specificity of COX inhibitors In Vivo
Selective cyclooxygenase inhibitors
In vivo Specificity of SC-560
Effect of celecoxib or naproxen on
prostanoid levels
in normal and inflamed tissue (carageenan)
Inhibition of COX-1 is not
anti-inflammatory or
analgesic
Specific COX-1 inhibition does not
inhibit inflammation-induced
PGE2 levels in CSF
Model for COX-1 and COX-2 derived
prostaglandins
in inflammation and pain
Pharmacokinetics
PPT Slide
PPT Slide
Pharmacokinetic profile in special
populations
Potential drug interactions ...
Actual results of drug interaction studies
Celecoxib platelet effects
Gastrointestinal Safety and Tolerability
Celecoxib
vs NSAIDs
Phase III Endoscopy Safety Trials Mucosal
Grading
Scale
Phase III Endoscopy Safety Trials
Baseline Demographics
- Study in OA
Phase III Endoscopy Safety Trials
Baseline Demographics
- Study in RA
Incidence of gastroduodenal ulcers - week
12 Celecoxib
- Phase III RA and OA UGI Safety Trials
Incidence of erosions / ulcers in
patients with
OA
Incidence of Erosions / Ulcers in
Patients with
RA
Cumulative Incidence of Gastric Ulcers
Abdominal Pain Moderate-Severe
Assessment of adverse events in relation
to age
Localization of COX-1 and COX-2 in the
kidneys
Conclusions from Renal Function
Assessments
Shall we have a bright future ?
Shall we have a bright future ?
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