Transcript Aceclofenac – a novel NSAID

Changing Face of
NSAID Therapy
Dr. Manish Maladkar
M.D.(BOM), M.S.A.S.M.S., M.C.C.P. (USA)
General Manager - Medical
For all happiness
mankind
can gain is not in
pleasure,
but in rest from pain
- John Dryden
Overpowering pain
No single sickness
comes close to
equaling pain in
terms of the number
of people affected
At any given moment,
one in every six adult
is in pain.
The most widely
prescribed medicine
Every day more than
35 million people
worldwide take non
steroidal
antiinflammatory
drugs
The changing face of
NSAID therapy
The Evolution of NSAIDs
Salicylic acid
derivatives
Aspirin
Propionic acids
Ibuprofen,
Naproxen
Coxibs
Etoricoxib
NSAID
Classification
Para-aminophenol
derivatives
Acetaminophen
Phenyl acetic
acid
• Diclofenac,
Aceclofenac
Others
Nabumetone,
Nimesulide
Fenamates
Mefenamic
acid
Enolic acids
Oxicams
(piroxicam,
meloxicam)
Indole acid
Indomethacin,
sulindac
100 Yrs of Aspirin
Medical historians give
1897 as the year in which
Aspirin® was born -but in
fact the exciting story of
the best-known drug in
human history began more
than 3,500 years ago.
Hippocrates, prescribed a
juice extracted from the
bark of the willow tree for
fever and pain, and also for
labor pains. The active
substance in this juice, is as we know today - salicylic
acid. Latin word for willow:
salix.
The birth of Acetylsalicylic acid (ASA)
In his search for an
effective and better
tolerated antirheumatic for
his father, Bayer chemist
Dr. Felix Hoffmann
synthesised acetylsalicylic
acid (ASA), the active
ingredient in Aspirin®, in a
chemically pure and stable
form for the first time.
Aspirin, - the classic that stays forever
young - is 105 years old.
On March 6th 2004 Aspirin®
celebrated its 105th birthday.
The drug of the century has carved
out a unique career in such diverse
fields as the treatment of pain,
headache, migraine ,fever and limb
pain, and the prevention of
cardiovascular disorders, including
myocardial infarction, stroke and
thrombosis.
It has also embarked on a promising
third career as a chemoprophylactic
substance in the fight against various
types of cancer.
1950s
Corticosteroids introduced
• Demonstrated good
antiinflammatory
properties
• Higher incidences of
side effects
1960s
NSAIDs introduced
• Discovery of the first
NSAID – Indomethacin
by Merck
• Soon a whole range of
NSAIDs followed
( Ibuprofen, Diclofenac,
Ketorolac,etc)
1971
• Mode of action of
NSAIDs explained
on the basis of COX
inhibition
• Sir John Vane was
awarded the Nobel
prize in 1982
The Emergence of the
COX Concept
The Inflammation Cascade
Cell Membrane Damage
Phospholipids
Phospholipase A2
Arachidonic acid
Cyclooxygenase
Prostaglandins
Major mediator of Inflammation
Lipooxygenase
Leukotrienes
Amplifier of inflammatory response
Other chemical mediators involved in the process of inflammation include
cytokines ( interleukins, interferons) , histamine, bradykinin etc
The COX Hypothesis
Arachidonic acid
COX-1
constitutive
Cytoprotective PGs
 GI cytoprotection
 Maintains Platelet functions
 Renal function
(blood flow)
COX-2
inducible
Proinflammatory PGs
 Inflammation
 Fever
 Pain
COX -1
“ The housekeeping” enzyme
Physiological stimulus
COX – 1
Constitutive
TXA2
Platelets
PGI2
Endothelium
Stomach, Mucosa etc
Physiological Functions
PGE2
Kidney
COX -2
The Inflammatory Enzyme
Inflammatory Stimulus
Macrophages / Other Cells
COX – 2 induced
Proinflammatory Prostaglandins
( PGE2, PGI2, PGF2, PG D2)
Inflammation
Pain
Fever
A closer look at the process
of Inflammation
3 Phases of inflammation
• Acute phase, characterized by vasodilation
and increased capillary permeability
• Subacute phase, characterised by
infiltration of leukocytes and macrophages
• Chronic phase, in which tissue
degeneration and fibrosis occur
Acute phase of inflammation
PGE2 - An important
inflammatory mediator
• PGE2 markedly enhances oedema
formation and by promoting blood flow in
the inflamed region.
• It potentiates the pain producing activity
of bradykinin and other autocoids.
Subacute inflammation
Cytokines attract Leukocytes at the
site of inflammation
Release of cytokines
Cytokines
Induces Cox 2
Cell-membrane
phospholipids
Cytokines
•
IL
•
TNF
Arachidonic acid
COX-1 / COX 2
PGH2
HPETE
Lipoxygenase
Tissue-specific synthases
TXA2
PGI2
PGF2a PGD2 PGE2
Leukotrienes
induction
of
Cox - 2
Cytokines
Role in Destruction of Cartilage & Bone
• IL-1 seems to be primarily
responsible for driving the
destruction of cartilage and bone
• Cytokines stimulate fibroblasts to
secrete a proteolytic enzyme - matrix
metalloproteinase (MMP).
Cytokines – Role in destruction
of cartilage and bone
Inhibit GAG synthesis
• Glysoaminoglycan (GAG) is the main
extracellular cartilage matrix
macromolecule
• Cytokines ( IL – 1) inhibit GAG synthesis
• Stimulation of GAG synthesis reflects
maintenance and repair of the matrix.
Conventional NSAIDS –The Concerns
Upper - GI
Dyspepsia
Erosions
Anaemia – GI bleeding
Ulcers – bleeds/perforations
Renal
Renal dysfunction, Increase in
blood pressure
Anti – platelet effects
Contributes to blood loss
GI toxicity of NSAIDs
Alarming statistics
• Worldover, 35 million
people consume
NSAIDs on a daily
basis and about 30%
may develop GI toxicity
of sufficient degree
requiring a physician’s
intervention
• About 1/3 rd of the cost
of treating arthritis
patients relates to
treatment of the side
effects of NSAIDs
Gastrointestinal events
The major complication of NSAIDS
GI intolerability
30%
Endoscopic
ulcers
10%
Perforation or
Haemorrhage
1.7%
Death
0.2%
NSAIDs exhibits
Interindividual Variability
NSAIDs are of approximately equal
efficacy, although there is considerable
variability in patient’s responses.
Consequently, NSAID therapy for
patients with rheumatoid arthritis or
osteoarthritis should be individualised
Newer NSAIDs
What to Look For?
A NSAID with
 Excellent antiinflammatory properties
 Good analgesic and antipyretic
activity
 Proven Gastrointestinal safety
 Additional Chondroprotective effects
 No adverse effect concerns
Aceclofenac
A New -Age NSAID
AceclofenacA Phenyl Acetic Acid Derivative
Aceclofenac, a phenyl
CH2COOCH2COOH
contains an additional
NH
Cl
acetic acid derivative
Cl
esterified acetoxy side
chain as compared with
the structurally related
diclofenac
Aceclofenac
Dual Mechanism of Action
Cell-membrane
phospholipids
Aceclofenac
Arachidonic acid
COX2
Proinflammatory
prostaglandins
PGE2
Cytokines
• IL1 & IL -6
• TNF
Aceclofenac
Potent Antiinflammatory agent
 Aceclofenac decreases the expression or
synthesis of mediators of inflammation,
including
Interleukins (IL -1)
Tumor necrosis Factor (TNF)
Cell adhesion molecules from
neutrophils
PGE2
Drugs, 2001
Aceclofenac
Inhibits PGE2 production
 Aceclofenac selectively inhibits the enzyme
COX-2 & inhibits the production of PGE2.
 It inhibits the synthesis of cytokines & thus
stops the induction of enzyme COX-2 and
this prevents formation of PGE2
 Causes significant reduction in the synovial
PGE2 levels from 113 to 67 ng/L
Aceclofenac – Better inhibition of
synovial PGE2 levels than Diclofenac
Diclofenac
PGE2
Aceclofenac
- 21%
- 41%
Drugs, 2001
Aceclofenac
Analgesic Potency similar to
Diclofenac
The analgesic potency of the drug,
expressed as a dose required for a 50%
reduction relative to control animals in
response to various stimuli was similar to
diclofenac.
Drugs – 2002; 61(9)
Aceclofenac
Chondroprotective Effects
In contrast to other NSAIDs
( eg Diclofenac and naproxen),
aceclofenac has shown
stimulatory effects on
cartilage matrix synthesis.
This may be linked to the
ability of the drug to inhibit the
suppression of various growth
factors by IL - 1.
Drugs 2001; 61 (9)
Aceclofenac
Stimulatory effects on cartilage matrix synthesis

Glycosaminoglycan (GAG) is
the main extracellular cartilage
matrix macromolecule.

Stimulation of GAG synthesis
reflects maintainence and repair
of the matrix

In vitro data shows stimulation
of GAG synthesis by
Aceclofenac
Drugs 2001; 61 (9)
Aceclofenac stimulates GAG synthesis
In contrast to some other NSAIDs, Aceclofenac has
shown stimulatory effects on cartilage matrix synthesis.
NSAID
Effect on GAG synthesis
Aceclofenac
Stimulate
Diclofenac
Neutral
Piroxicam
Neutral
Aspirin
Neutral
Naproxen
Inhibition
Ibuprofen
Inhibition
Indomethacin
Inhibition
Aceclofenac
Effects superior to Meloxicam
• Aceclofenac and Meloxicam increase
hyaluron synthesis and reduce the loss of
newly synthesized hyaluron molecules
from the articular tissue.
• The action of Aceclofenac is stronger than
Meloxicam
British Journal of Pharmacology Vol 131 (7)
Aceclofenac
Inhibits Promatrix metalloproteinase
production
Aceclofenac and 4 –
hydroxyaceclofenac
supresses IL -1
mediated promatrix
metalloproteinase
production and
proteoglycan release
Drugs, 2001
Aceclofenac
A selective COX 2 Inhibitor
IC 50
COX -1
COX-2
Aceclofenac
>100
0.8
4- Hydroxy aceclofenac
>100
36
Drugs 2001; 61 (9)
Aceclofenac
Weaker ulcerogenic effect than other NSAIDS
UD50/ED50
0
2
4
6
8
Aceclofenac
Phenylbutazone
Naproxen
Diclofenac
Indometacin
Drug Res 41(11), 1991
Aceclofenac
Increases Cytoprotectant
Hexosamine Levels
 Aceclofenac
significantly increased
hexosamine levels
(from 33 to 53 mg/g)
and did not alter
gastroduodenal blood
flow. (Measured by
laser Doppler Analysis)
Aceclofenac
Unlike Diclofenac Increases Hexosamine levels
 Diclofenac significantly reduced gastric
mucosal levels of cytoprotectant
hexosamine (from 58 to 27 mg/g) & gastroduodenal blood flow
 Whereas, Aceclofenac significantly
increased hexosamine levels (from 33 to
53 mg/g) & did not alter blood flow)
Aceclofenac – Fewer Adverse
Effects than Diclofenac
27.1
30
25
%
Diclofenac
22.4
18.7
20
15
Aceclofenac
No. of Patients - 10142
15.2
14.1
10.5
10
5
0
Adverse events* GI Adverse events* Discontinuation due
to adverse event*
Aceclofenac vs Diclofenac
SAMM Study, European J Rheumatol. & Inflamm. Vol. 17, Issue 1, 2000
Aceclofenac
% of patients with
gastric damage
Demonstrates better GI safety on endoscopy
50%
50%
20%
Aceclofenac
Diclofenac
Naproxen
Acelofenac
Safety demonstrated in more than 1 lakh patients
 Data from 142776 Spanish patients have
suggested that aceclofenac is associated
with a lower incidence of upper GI bleeding
events than 10 other NSAIDs
Drugs 2001 ;61(9)
Aceclofenac
Fewer Adverse Effects than Diclofenac
Nature of adverse Aceclofenac Diclofenac
event
P value
(n = 7890)
(n = 2252)
Dyspepsia
5.4
6.7
0.017
Abdominal pain
2.5
4.4
< 0.001
Diarrhoea
1.5
3.6
< 0.001
Nausea
1.6
2.4
0.01
Dizziness
1.1
0.7
0.073
SAMM Study, European J Rheumatol. & Inflamm. Vol. 17, Issue 1, 2000
European Observational
Cohort Study
 23574 patients
 Results collected during 1999 & 2000
 Data from Austria, Belgium , Germany and Greece
 International cohort data (OA & low back pain And
post traumatic conditions)
Aceclofenac improves patient status
As judged by both patient and physician for all indications
Physician’s opinion
Patient opinion
100%
20%
35%
21%
50%
63%
16%
13%
15%
18%
1%
2%
1%
1.5%
Visit 3
Visit 4
Visit 5
36%
64%
0%
Visit 2
49.5%
Greatly
Improved
Improved
Unchanged
Worse
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac Improves Patient status
in Low Back Pain
Physician’s opinion
Patient opinion
100%
19%
67%
0%
37%
46%
27%
35%
55%
44%
13%
16%
16%
16%
1%
1%
2%
1%
Visit 2
Visit 3
Visit 2
Visit 3
Greatly
Improved
Improved
Unchanged
Worse
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac Improves Patient status
in Post traumatic pain
Physician’s opinion
Patient opinion
100%
34%
44%
34%
55%
45.5%
54.5%
10.5%
0%
10%
46%
Greatly
Improved
Improved
Unchanged
Worse
45.5%
0.5%
9%
1.5%
1.5%
7.5%
2%
Visit 2
Visit 3
Visit 2
Visit 3
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac Improves Patient status
in Osteoarthritis
Physician’s opinion
Patient opinion
100%
0%
14%
28%
17%
30%
68%
54%
63%
53%
49.5%
16%
1%
16%
2%
18%
Visit 2
Visit 3
2%
Visit 4
Greatly
Improved
Improved
Unchanged
Worse
14.5%
2.5%
Visit 5
Curr. Med. Res. Opin. 2002; 18(3):146-53
Greater than 90% patients
satisfied with Aceclofenac
Not satisfied/poor
Satisfied/good
6.5%
13%
Visit 2
Visit 3
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac vs Diclofenac in
patients with acute low back pain
 15 German centres
 2 x 100 mg daily
Aceclofenac compared with
3 x 75 mg daily diclofenac
Clin. Rheumatol. (2003) 22: 127-135
Visual analogue (VAS) pain scores at rest (mean +SE) at
baseline (visit 1, VI) and during treatment (intermediate
visit V2 and inal visit V3) with aceclofenac and diclofenac
(per-protocol population)
100
Aceclofenac
(n=100)
VAS Score (mm)
90
Diclofenac (n= 105)
80
70
60
50
40
30
20
10
0
V1
V2
V3
Clin. Rheumatol. (2003) 22: 127-135
Visual analogue (VAS) pain scores at rest
at baseline {time 0 hours} and during the first 6 h
after intake of aceclofenac & diclofenac
90
Aceclofenac
(n=100)
VAS (mm)
80
Diclofenac (n= 105)
70
60
50
40
0 0.5 1
3
6
Time after treatment (hours)
Clin. Rheumatol. (2003) 22: 127-135
% of Maximum possible QBPDS score
Quebec Back Pain Disability Score (QBPDS), at
baseline (V1) and during treatment (Intermediate visit
v2 & final visit, V3) with aceclofenac & diclofenac
100
90
Aceclofenac
(n=100)
80
Diclofenac (n= 105)
70
60
50
40
30
20
10
0
V1
V2
V3
Clin. Rheumatol. (2003) 22: 127-135
Aceclofenac
in
Indian Populations
Comparison of changes in the average
pain score (VAS) between the groups
7
6.26
Mean Pain Score (VAS)
6.14
Basal
3
7
6.17
6
5
4
3
2.9
2.88
2.41
2
1
0.54
0.73
0.8
0
Aceclofenac
Diclofenac
Duration in days
Ibuprofen
Overall global evaluation of
treatment by patients
Percentage of cases
120
100
Poor
Moderate
Good
Excellent
80
60
40
20
0
Aceclofenac
Diclofenac
Groups
Ibuprofen
Overall assessment of treatment
by investigators
Percentage of cases
120
100
Poor
Moderate
Good
Excellent
80
60
40
20
0
Aceclofenac
Diclofenac
Groups
Ibuprofen
Fewer Adverse Events
7
5.9
Percentage of Cases
6
5.9
Aceclofenac
Diclofenac
Ibuprofen
5.9
5.4
5.4
5
3.9
3.6
4
3.7
3.7
3
2
1.8
1.8
1.8 1.8
1
0
0
0
0
0
0
Nausea
Vomiting
Heart Burn
Events
Gastritis
Exudation
Erythema
Others
Aceclofenac
Pharmacokinetic
Profile
Aceclofenac – Pharmacokinetic Profile
Absorption
 After oral administration, aceclofenac is
rapidly absorbed and the bioavailability is
almost 100%
 Peak plasma concentrations are reached
approximately 1.25 to 3 hours following
ingestion
 Tmax is delayed with concomitant food
intake whereas the degree of absorption is
not influenced
Aceclofenac – Pharmacokinetic Profile
Distribution
 Aceclofenac is highly protein-bound
(>99.7%).
 Aceclofenac penetrates into the synovial
fluid, where the concentrations reach
approximately 60% of those in plasma.
Aceclofenac – Pharmacokinetic Profile
Metabolism
Aceclofenac is metabolised to a major
metabolite, 4 – hydroxyaceclofenac, and to a
number of other metabolites including
5 – hydroxyaceclofenac, diclofenac, 4
hydroxydiclofenac and 5 hydroxydiclofenac.
These other metabolites account for the fate of
approximately 20% of each dose of
aceclofenac
Aceclofenac – Pharmacokinetic Profile
Elimination
 The mean plasma elimination half-life is
4 – 4.3 hours.
 Approximately two-thirds of the
administered dose is excreted via the
urine, mainly as conjugated
hydroxymetabolites. Only 1% of an oral
single dose is excreted unchanged.
Aceclofenac
Dosage Recommendations
 The recommended dosage of
aceclofenac is 100 mg twice
daily
 Dosage reduction generally
not needed in elderly patients
and those with mild renal
impairment.
 A dosage reduction to 100 mg
daily is suggested in patients
with hepatic impairment
Aceclofenac
Highlights
 Aceclofenac is effective as an analgesic &
antiinflammatory agent in both acute and
Chronic conditions
 Aceclofenac blocks the production of various
inflammatory mediators including
Interleukins, tumor necrosis factors, and
PGE2
 Aceclofenac acheives greater reduction of
PGE2 levels than Diclofenac ( 21% vs 41%)
Aceclofenac
Highlights
 Aceclofenac is a highly
selective COX 2
inhibitor
 Aceclofenac increases
cytoprotective
hexosamine levels
 Gastrointestinal safety
proven in several
multicentre clinical
trials
Aceclofenac
Highlights
 Aceclofenac exerts
chondroprotective action
 Aceclofenac stimulates
GAG synthesis, helps in
maintenance & repair of
matrix
 Aceclofenac inhibits
PMP production &
proteoglycan release
Aceclofenac
The New – Age NSAID
Available in 63 countries including
UK/Europe
Originator – Almiral Prodesfarma
Brand – Airtal
One of the most preferred NSAIDs in
Europe
To Summarize
Aceclofenac is a novel compound with
potent anti inflammatory, anti arthritic
analgesic and antipyretic activities which
showed improved gastric tolerance and
consequently offered greater potential
security than other highly active NSAIDs
currently used in clinical practice.
Only the one that hurts you
Can make you feel better
Only the one that inflicts pain
Can take it away
Madonna
Dr.Vinay Saraf