Dr. Manish Maladkar M.D.(BOM), M.S.A.S.M.S., M.C.C.P. (USA) General Manager - Medical Changing Face...
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Transcript of Dr. Manish Maladkar M.D.(BOM), M.S.A.S.M.S., M.C.C.P. (USA) General Manager - Medical Changing Face...
Dr. Manish MaladkarM.D.(BOM), M.S.A.S.M.S., M.C.C.P. (USA)
General Manager - Medical
Changing Face of NSAID Therapy
For all happiness mankind
can gain is not in pleasure,
but in rest from pain
- John Dryden
For all happiness mankind
can gain is not in pleasure,
but in rest from pain
- John Dryden
Overpowering painOverpowering 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.
Every day more than
35 million people
worldwide take non
steroidal
antiinflammatory
drugs
The most widely prescribed medicine
The most widely prescribed medicine
The changing face of NSAID therapy
The changing face of NSAID therapy
The Evolution of NSAIDsThe Evolution of NSAIDs
NSAIDClassification
Salicylic acid derivatives
Aspirin
Para-aminophenol
derivatives
Acetaminophen
Indole acid
Indomethacin, sulindac
Phenyl acetic
acid• Diclofenac,
Aceclofenac
Propionic acids
Ibuprofen, Naproxen
Fenamates
Mefenamic acid
Enolic acids
Oxicams (piroxicam,meloxicam)
Others
Nabumetone, Nimesulide
Coxibs
Etoricoxib
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.
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.
The birth of Acetylsalicylic acid (ASA)The birth of Acetylsalicylic acid (ASA)
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.
Aspirin, - the classic that stays forever young - is 105 years old.
Aspirin, - the classic that stays forever young - is 105 years old.
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
Phospholipids
Arachidonic acid
Prostaglandins Leukotrienes
Cyclooxygenase Lipooxygenase
Major mediator of Inflammation Amplifier of inflammatory response
Other chemical mediators involved in the process of inflammation include cytokines ( interleukins, interferons) , histamine, bradykinin etc
Phospholipase A2
Cell Membrane Damage
The COX Hypothesis
Proinflammatory PGsCytoprotective PGs
COX-1constitutive
COX-2inducible
Inflammation Fever Pain
GI cytoprotection Maintains Platelet functions Renal function
(blood flow)
Arachidonic acid
COX -1 “ The housekeeping” enzyme
Physiological stimulus
COX – 1Constitutive
TXA2 Platelets
PGI2EndotheliumStomach, Mucosa etc
PGE2Kidney
Physiological Functions
COX -2 The Inflammatory Enzyme
Inflammatory Stimulus
Macrophages / Other Cells
COX – 2 inducedProinflammatory Prostaglandins( PGE2, PGI2, PGF2, PG D2)
InflammationPainFever
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
CytokinesInduces Cox 2
Cell-membrane phospholipids
Cytokines• IL• TNF
Arachidonic acid
PGH2
COX-1 / COX 2
HPETE
Leukotrienes
Lipoxygenase
Tissue-specific synthases
PGE2PGD2PGI2TXA2 PGF2
inductionof 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.
Contributes to blood loss
Renal dysfunction, Increase in blood pressure
Ulcers – bleeds/perforations
Anaemia – GI bleeding
Erosions
Dyspepsia
Upper - GI
Renal
Anti – platelet effects
Conventional NSAIDS –The Concerns
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 eventsThe major complication of NSAIDS
GI intolerability30%
Endoscopic ulcers
10%
Perforation orHaemorrhage
1.7%Death0.2%
NSAIDs exhibits Interindividual Variability
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?
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 NSAIDAceclofenac
A New -Age NSAID
Aceclofenac- A Phenyl Acetic Acid Derivative
Aceclofenac- A Phenyl Acetic Acid Derivative
CH2COOCH2COOH
NH
Cl Cl
Aceclofenac, a phenyl
acetic acid derivative
contains an additional
esterified acetoxy side
chain as compared with
the structurally related
diclofenac
Cell-membrane phospholipids
Cytokines• IL1 & IL -6• TNF
Arachidonic acid
PGE2
Aceclofenac
Aceclofenac Dual Mechanism of Action
Aceclofenac Dual Mechanism of Action
COX2
Proinflammatory prostaglandins
Aceclofenac Potent Antiinflammatory agent
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 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
Aceclofenac – Better inhibition of synovial PGE2 levels than
Diclofenac
Diclofenac
- 41%
- 21%
PG
E2
Aceclofenac
Drugs, 2001
AceclofenacAnalgesic Potency similar to
Diclofenac
AceclofenacAnalgesic 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
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)
AceclofenacStimulatory effects on cartilage matrix synthesis
AceclofenacStimulatory 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
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
AceclofenacEffects 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)
AceclofenacInhibits Promatrix metalloproteinase
production
AceclofenacInhibits 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
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)
AceclofenacWeaker ulcerogenic effect than other NSAIDS
AceclofenacWeaker ulcerogenic effect than other NSAIDS
UD50/ED50
0 2 4 6 8
Aceclofenac
Phenylbutazone
Naproxen
Diclofenac
Indometacin Drug Res 41(11), 1991
AceclofenacIncreases Cytoprotectant
Hexosamine Levels
AceclofenacIncreases 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)
AceclofenacUnlike Diclofenac Increases Hexosamine
levels
AceclofenacUnlike Diclofenac Increases Hexosamine
levels
Diclofenac significantly reduced gastric
mucosal levels of cytoprotectant
hexosamine (from 58 to 27 mg/g) & gastro-
duodenal 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
Aceclofenac – Fewer Adverse Effects than Diclofenac
Aceclofenac vs Diclofenac
0
Aceclofenac
Diclofenac
15.2
5
10
15
20
25
30
%
10.5
14.1
18.7
27.1
22.4
GI Adverse events*Adverse events* Discontinuation dueto adverse event*
SAMM Study, European J Rheumatol. & Inflamm. Vol. 17, Issue 1, 2000
No. of Patients - 10142
AceclofenacDemonstrates better GI safety on
endoscopy
AceclofenacDemonstrates better GI safety on
endoscopy
20%
50% 50%
% o
f p
atie
nts
wit
h
gas
tric
dam
age
Aceclofenac Diclofenac Naproxen
AcelofenacSafety demonstrated in more than 1 lakh
patients
AcelofenacSafety 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)
AceclofenacFewer Adverse Effects than Diclofenac
AceclofenacFewer Adverse Effects than Diclofenac
Nature of adverse Aceclofenac Diclofenac P value
event (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
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
Aceclofenac improves patient status
Physician’s opinion Patient opinion
Visit 2 Visit 3 Visit 4 Visit 5
20% 35% 21% 36%
64%50% 63%
49.5%
100%
0%
GreatlyImprovedImprovedUnchanged
Worse13%16% 15% 18%
1% 2% 1% 1.5%
As judged by both patient and physician for all indications
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac Improves Patient status in Low Back Pain
Aceclofenac Improves Patient status in Low Back Pain
19% 37% 27% 35%
Physician’s opinion Patient opinion
67%46%
55%
Visit 2 Visit 3 Visit 2 Visit 3
100%
0%
44%
1%
13% 16% 16% 16%
1% 2% 1%
GreatlyImprovedImprovedUnchanged
Worse
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac Improves Patient status in Post traumatic painAceclofenac Improves Patient status in Post traumatic pain
Physician’s opinion
Visit 2 Visit 3 Visit 2 Visit 3
100%
0% 0.5%
10.5%
Patient opinion
55%
34% 44% 34%
45.5% 54.5%
10%9%
1.5% 1.5%
46%
45.5%
7.5%2%
GreatlyImprovedImprovedUnchanged
Worse
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac Improves Patient status in Osteoarthritis
Aceclofenac Improves Patient status in Osteoarthritis
14% 28% 17% 30%
Physician’s opinion Patient opinion
68% 54% 63%49.5%
16%
Visit 2 Visit 3 Visit 4 Visit 5
100%
0%
53%
16%
GreatlyImprovedImprovedUnchanged
Worse
18%14.5%
1% 2% 2% 2.5%
Curr. Med. Res. Opin. 2002; 18(3):146-53
Greater than 90% patients satisfied with AceclofenacGreater than 90% patients satisfied with Aceclofenac
13%13%
Not satisfied/poor
Satisfied/good
Visit 2
6.5%6.5%
Visit 3
Curr. Med. Res. Opin. 2002; 18(3):146-53
Aceclofenac vs Diclofenac in patients with acute low back
pain
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)
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
90
80
70
60
50
40
30
20
10
0V1 V2 V3
VA
S S
core
(m
m)
Aceclofenac (n=100)
Diclofenac (n= 105)
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
Visual analogue (VAS) pain scores at rest at baseline {time 0 hours} and during the first
6 h after intake of aceclofenac & diclofenac
90
0
80
70
60
50
40
VA
S (
mm
)
0.5 1 3 6
Time after treatment (hours)
Aceclofenac (n=100)
Diclofenac (n= 105)
Clin. Rheumatol. (2003) 22: 127-135
Quebec Back Pain Disability Score (QBPDS), at baseline (V1) and during treatment
(Intermediate visit v2 & final visit, V3) with aceclofenac & diclofenac
Quebec Back Pain Disability Score (QBPDS), at baseline (V1) and during treatment
(Intermediate visit v2 & final visit, V3) with aceclofenac & diclofenac
90
80
70
60
% o
f M
axim
um
po
ssib
le Q
BP
DS
sco
re
0
V3V2V1
50
100
40
30
20
10
Aceclofenac (n=100)
Diclofenac (n= 105)
Clin. Rheumatol. (2003) 22: 127-135
in
Indian Populations
Aceclofenac
Comparison of changes in the average pain score (VAS)
between the groups
Comparison of changes in the average pain score (VAS)
between the groups
Duration in days
6.14 6.26 6.17
2.412.88 2.9
0.54 0.73 0.8
0
1
2
3
4
5
6
7
Aceclofenac Diclofenac Ibuprofen
Basal37
Me
an
Pa
in S
co
re (
VA
S)
Overall global evaluation of treatment by patients
Overall global evaluation of treatment by patients
Groups
Pe
rce
nta
ge
of
cas
es
120
100
80
60
40
20
0Diclofenac IbuprofenAceclofenac
Poor
Moderate
Good
Excellent
Overall assessment of treatment by investigators
Overall assessment of treatment by investigators
Groups
Pe
rce
nta
ge
of
cas
es
120
100
80
60
40
20
0Diclofenac IbuprofenAceclofenac
Poor
Moderate
Good
Excellent
Fewer Adverse EventsFewer Adverse Events
Events
1.8
0
3.7 3.7
0
1.8
3.6
1.8
5.4 5.4
0
1.8
5.9
3.9
5.9 5.9
0 00
1
2
3
4
5
6
7
Nausea Vomiting Heart Burn Gastritis ExudationErythema
Others
Aceclofenac
Diclofenac
Ibuprofen
Per
cen
tag
e o
f C
ases
Aceclofenac
Pharmacokinetic Profile
Aceclofenac – Pharmacokinetic Profile Absorption
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 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 Distribution
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 Metabolism
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 – Pharmacokinetic Profile Elimination
Aceclofenac Dosage Recommendations
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 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%)
AceclofenacHighlights
AceclofenacHighlights
Aceclofenac is a highly selective COX 2 inhibitor
Aceclofenac increases cytoprotective hexosamine levels
Gastrointestinal safety proven in several multicentre clinical trials
Aceclofenac exerts chondroprotective action
Aceclofenac stimulates GAG synthesis, helps in maintenance & repair of matrix
Aceclofenac inhibits PMP production & proteoglycan release
Aceclofenac Highlights
Aceclofenac Highlights
Aceclofenac The New – Age NSAID
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 SummarizeTo 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 youCan make you feel betterOnly the one that inflicts painCan take it away
Madonna
Dr.Vinay Saraf