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 From Aspirin to New - Age NSAIDs

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

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 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

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.

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

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

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

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 Ulcers – bleeds/perforations Anaemia – GI bleeding Erosions Dyspepsia Upper - GI 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

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

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

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 - 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 36 Drugs 2001; 61 (9)

Aceclofenac Weaker ulcerogenic effect than other NSAIDS UD50/ED50 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) & 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 No. of Patients - 10142 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

Aceclofenac Demonstrates better GI safety on endoscopy % of patients with gastric damage 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 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 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 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

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

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

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

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 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: 127-135

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: 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 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: 127-135

Aceclofenac in Indian Populations

Comparison of changes in the average pain score (VAS) between the groups 7 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

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

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

Fewer Adverse Events Events Percentage of Cases 5.9 5.9 5.9 5.4 5.4 7 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

Pharmacokinetic Profile 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

Thank you Dr.Vinay Saraf