1. 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

2. For all happiness mankind can gain is not in pleasure, but in rest from pain - John Dryden

3. 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.

4. The most widely prescribed medicine
Every day more than 35 million people worldwide take non steroidal antiinflammatory drugs

5. The changing face of NSAID therapy
From Aspirin to New - Age NSAIDs

6. The Evolution of NSAIDs
Propionic acids
Ibuprofen, Naproxen
Salicylic acid
derivatives
Aspirin
Para-aminophenol
derivatives
Acetaminophen
Coxibs
Etoricoxib
Phenyl acetic
acid
Diclofenac, Aceclofenac
NSAID Classification
Others
Nabumetone, Nimesulide
Indole acid
Indomethacin, sulindac
Enolic acids
Oxicams (piroxicam, meloxicam)
Fenamates
Mefenamic acid

7. 100 Yrs of Aspirin

8. 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.

9. 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.

10. 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.

11. 1950s Corticosteroids introduced
Demonstrated good antiinflammatory properties
Higher incidences of side effects

12. 1960s NSAIDs introduced
Discovery of the first NSAID – Indomethacin by Merck
Soon a whole range of NSAIDs followed
( Ibuprofen, Diclofenac, Ketorolac,etc)

13. 1971 Mode of action of NSAIDs explained on the basis of COX inhibition
Sir John Vane was awarded the Nobel prize in 1982

14. The Emergence of the COX Concept

15. The Inflammation Cascade
Cell Membrane Damage
Phospholipids
Phospholipase A2
Arachidonic acid
Cyclooxygenase
Lipooxygenase
Prostaglandins
Arachidonic acid is mobilized from membrane-bound phospholipids in a reaction catalyzed by the enzyme phospholipase A2. The isozymes cyclooxygenase (COX)-1 and -2 convert arachidonic acid to unstable intermediate prostaglandins (PGs) G2 and H2. Then, tissue-specific isomerases are involved in the production of stable prostanoids such as PGD2, PGE2, PGF2, prostacyclin (PGI2), and thromboxane A2 (TxA2).
Prostanoids are bioactive lipids that act through specific cell-membrane receptors to mediate key cellular responses. Each class of prostanoids is involved in a specific set of functions.
Whereas aspirin irreversibly inhibits COX-1 in platelets, nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 activity. Coxibs are selective COX-2 inhibitors.
Leukotrienes
Major mediator of Inflammation
Amplifier of inflammatory response
Other chemical mediators involved in the process of inflammation include
cytokines ( interleukins, interferons) , histamine, bradykinin etc

16. The COX Hypothesis Arachidonic acid COX-1 constitutive COX-2 inducible
Cytoprotective PGs
Proinflammatory PGs
GI cytoprotection
Maintains Platelet functions
Renal function (blood flow)
Inflammation
Fever
Pain
COX-1, considered a “housekeeping” enzyme, is expressed constitutively in almost all tissues, particularly in the GI tract, platelets, endothelial cells, and kidneys.
COX-1 appears to be responsible for the production of PGs that are important for homeostatic functions, such as maintaining the integrity of GI mucosa, mediating platelet function, and regulating renal blood flow.
COX-2 expression increases dramatically during inflammation and in carcinogenesis. For example, synovial tissue in patients with rheumatoid arthritis (RA) and osteoarthritis (OA), as well as colorectal carcinomas and adenomas, express increased amounts of COX-2.
NSAIDs are widely used drugs that nonselectively inhibit inducible COX-2, which results in a beneficial anti-inflammatory effect, and constitutive COX-1, which may cause GI toxicity. Therefore, it was hypothesized that selective COX-2 inhibition, such as that provided by coxibs, would maintain anti-inflammatory efficacy and avoid GI toxicity.

17. COX -1 “ The housekeeping” enzyme
Physiological stimulus
COX – 1
Constitutive
PGI2
Endothelium
Stomach, Mucosa etc
TXA2
Platelets
PGE2
Kidney
Physiological Functions

18. COX -2 The Inflammatory Enzyme
Inflammatory Stimulus
Macrophages / Other Cells
COX – 2 induced
Proinflammatory Prostaglandins
( PGE2, PGI2, PGF2, PG D2)
Inflammation
Pain
Fever

19. A closer look at the process of Inflammation

20. 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

21. Acute phase of inflammation

22. 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.

23. Subacute inflammation

24. Cytokines attract Leukocytes at the site of inflammation
Release of cytokines

25. Cell-membrane phospholipids Tissue-specific synthases
Cytokines Induces Cox 2
Cell-membrane phospholipids
Cytokines IL
TNF
Arachidonic acid
COX-1 / COX 2
induction of
Cox - 2
PGH2
HPETE
Leukotrienes
Lipoxygenase
Tissue-specific synthases
TXA2
PGI2
PGF2a
PGD2
PGE2

26. 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).

27. 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.

28. Conventional NSAIDS –The Concerns
Ulcers – bleeds/perforations
Anaemia – GI bleeding
Erosions
Dyspepsia
Upper - GI
Renal
Renal dysfunction, Increase in
blood pressure
Anti – platelet effects
Contributes to blood loss

29. 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

30. Gastrointestinal events The major complication of NSAIDS
GI intolerability
30%
Endoscopic
ulcers
10%
Perforation or
Haemorrhage
1.7%
Death
0.2%

31. 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

32. 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

33. Aceclofenac A New -Age NSAID

34. Aceclofenac- A Phenyl Acetic Acid Derivative
Aceclofenac, a phenyl acetic acid derivative contains an additional esterified acetoxy side chain as compared with the structurally related diclofenac
CH2COOCH2COOH NH Cl Cl

35. Aceclofenac Dual Mechanism of Action
Cell-membrane phospholipids
Cytokines
IL1 & IL -6
TNF
Aceclofenac
Arachidonic acid
COX2
Proinflammatory prostaglandins
PGE2

36. 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

37. 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

38. Aceclofenac – Better inhibition of synovial PGE2 levels than Diclofenac
- 21%
- 41%
Drugs, 2001

39. 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)

40. 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)

41. 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)

42. 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

43. 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)

44. Aceclofenac Inhibits Promatrix metalloproteinase production
Aceclofenac and 4 – hydroxyaceclofenac supresses IL -1 mediated promatrix metalloproteinase production and proteoglycan release
Drugs, 2001

45. Aceclofenac A selective COX 2 Inhibitor
IC 50
COX -1
COX-2
Aceclofenac
>100
0.8
4- Hydroxy aceclofenac 36
Drugs 2001; 61 (9)

46. Aceclofenac Weaker ulcerogenic effect than other NSAIDS
UD50/ED50 2 4 6 8
Aceclofenac
Phenylbutazone
Naproxen
Diclofenac
Indometacin
Drug Res 41(11), 1991

47. 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)

48. Aceclofenac Unlike 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)

49. Aceclofenac – Fewer Adverse Effects than Diclofenac
No. of Patients 30
27.1
22.4 25
18.7 20 %
15.2
14.1 15
10.5 10 5
Adverse events*
GI Adverse events*
Discontinuation due
to adverse event*
Aceclofenac vs Diclofenac
SAMM Study, European J Rheumatol. & Inflamm. Vol. 17, Issue 1, 2000

50. Aceclofenac Demonstrates better GI safety on endoscopy
% of patients with
gastric damage
50%
50%
20%
Aceclofenac
Diclofenac
Naproxen

51. Acelofenac Safety demonstrated in more than 1 lakh patients
Data from 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)

52. Aceclofenac Fewer Adverse Effects than Diclofenac
Nature of adverse Aceclofenac Diclofenac P value
event (n = 7890) (n = 2252)
Dyspepsia
Abdominal pain < 0.001
Diarrhoea < 0.001
Nausea
Dizziness
SAMM Study, European J Rheumatol. & Inflamm. Vol. 17, Issue 1, 2000

53. 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)

54. Aceclofenac improves patient status
As judged by both patient and physician for all indications
Physician’s opinion
Patient opinion
Visit 2
Visit 3
Visit 4
Visit 5
20%
35%
21%
36%
64%
50%
63%
49.5%
100% 0%
Greatly
Improved
Unchanged
Worse
13%
16%
15%
18% 1% 2%
1.5%
Curr. Med. Res. Opin. 2002; 18(3):146-53

55. Aceclofenac Improves Patient status in Low Back Pain
Physician’s opinion
Patient opinion
Greatly
Improved
Unchanged
Worse
100%
19%
37%
27%
35%
67%
55%
44%
46%
16%
16%
16%
13% 1% 1% 2% 1% 0%
Visit 2
Visit 3
Visit 2
Visit 3
Curr. Med. Res. Opin. 2002; 18(3):146-53

56. Aceclofenac Improves Patient status in Post traumatic pain
Physician’s opinion
Patient opinion
Greatly
Improved
Unchanged
Worse
100%
34%
44%
34%
46%
55%
45.5%
54.5%
45.5%
10.5% 9%
10%
7.5% 0%
0.5%
1.5%
1.5% 2%
Visit 2
Visit 3
Visit 2
Visit 3
Curr. Med. Res. Opin. 2002; 18(3):146-53

57. Aceclofenac Improves Patient status in Osteoarthritis
Physician’s opinion
Patient opinion
Greatly
Improved
Unchanged
Worse
100%
14%
28%
17%
30%
68%
54%
63%
53%
49.5%
14.5%
18%
16%
16% 0% 1% 2% 2%
2.5%
Visit 2
Visit 3
Visit 4
Visit 5
Curr. Med. Res. Opin. 2002; 18(3):146-53

58. 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

59. 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:

60. 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 V1 V2 V3
VAS Score (mm)
Aceclofenac (n=100)
Diclofenac (n= 105)
Clin. Rheumatol. (2003) 22:

61. Time after treatment (hours)
Visual analogue (VAS) pain scores at rest at baseline {time 0 hours} and during the first 6 h after intake of aceclofenac & diclofenac 90 80 70 60 50 40
VAS (mm)
0.5 1 3 6
Time after treatment (hours)
Aceclofenac (n=100)
Diclofenac (n= 105)
Clin. Rheumatol. (2003) 22:

62. % 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 90 80 70 60
% of Maximum possible QBPDS score V3 V2 V1 50
100 40 30 20 10
Aceclofenac (n=100)
Diclofenac (n= 105)
Clin. Rheumatol. (2003) 22:

63. Aceclofenac
in Indian Populations

64. Comparison of changes in the average pain score (VAS) between the groups7
6.26
Basal
6.14
6.17 3 6 7 5 4
Mean Pain Score (VAS)
2.88
2.9 3
2.41 2
0.73
0.8 1
0.54
Aceclofenac
Diclofenac
Ibuprofen
Duration in days

65. Overall global evaluation of treatment by patients
120
100 80 60 40 20
Poor
Moderate
Good
Excellent
Percentage of cases
Aceclofenac
Diclofenac
Ibuprofen
Groups

66. Overall assessment of treatment by investigators
120
100 80 60 40 20
Poor
Moderate
Good
Excellent
Percentage of cases
Aceclofenac
Diclofenac
Ibuprofen
Groups

67. Fewer Adverse Events Events Percentage of Cases 5.9 5.9 5.9 5.4 5.47
Aceclofenac
Diclofenac
5.9
5.9
5.9 6
Ibuprofen
5.4
5.4 5
3.9 4
3.6
3.7
3.7
Percentage of Cases 3
1.8
1.8
1.8
1.8 2 1
Nausea
Vomiting
Heart Burn
Gastritis
Exudation
Others
Erythema
Events

68. Pharmacokinetic Profile
Aceclofenac
Pharmacokinetic Profile

69. 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

70. 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.

71. Aceclofenac – Pharmacokinetic Profile Metabolism
Aceclofenac is metabolised to a major metabolite, 4 – hydroxyaceclofenac, and to a number of other metabolites including – hydroxyaceclofenac, diclofenac, 4 hydroxydiclofenac and 5 hydroxydiclofenac.
These other metabolites account for the fate of approximately 20% of each dose of aceclofenac

72. 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.

73. 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

74. 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%)

75. Aceclofenac Highlights
Aceclofenac is a highly selective COX 2 inhibitor
Aceclofenac increases cytoprotective hexosamine levels
Gastrointestinal safety proven in several multicentre clinical trials

76. Aceclofenac Highlights
Aceclofenac exerts chondroprotective action
Aceclofenac stimulates GAG synthesis, helps in maintenance & repair of matrix
Aceclofenac inhibits PMP production & proteoglycan release

77. 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

78. 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.

79. Only the one that hurts you Can make you feel better Only the one that inflicts pain Can take it away
Madonna

80. Thank you
Dr.Vinay Saraf