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