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Aceclofenac: A Potent Non-Steroidal Anti-Inflammatory Drug

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Prof. S. Saraf

The pain management is always a problem for a physician and the search for a safe and effective option is still on.

Although cyclooxygenase-2 selective inhibitors (coxibs) represent a new class of analgesic and anti-inflammatory drugs that exhibits preference for inhibition of cyclooxygenase-2, its cardiovascular safety is controversial, since trial showed increased incidence of cardiovascular events in patients receiving coxibs. There is a need of a drug, which has high efficacy like traditional NSAIDs, shows high GI tolerability like selective cox-2 inhibitors but have no adverse cardiovascular effects.

Aceclofenac has been shown to have potent analgesic and anti-inflammatory activities, similar to indomethacin and diclofenac and due to its preferential cox-2 blockade it has better safety than conventional NSAIDs with respect to adverse effects on gastrointestinal and cardiovascular system.

INTRODUCTION

The pain is symptomatic of some form of dysfunction and resultant inflammatory processes in the body. A survey conducted for the WHO reported that one adult in five suffers from chronic non-malignant pain, which mostly occurs in the back, head, joints and limbs. More than 15% of the worldwide population suffers for instance from some form of osteoarthritis, and this incidence is even higher in the elderly. As the world population is grows older, this incidence will continue to rise.

The pain has been defined as a characteristic sensation arising from a noxious stimulus, which includes its neurophysiological aspect. Sherrington, in his classic definition has further included the reactive component of pain, i.e. the "psychical adjuvant of an imperative protective reflex". This indicates that pain also has a survival value for the species. There are two main classes of pain superficial and deep. Some pain receptors in the body are probably chemoreceptors, as a wide variety of compounds, including autacoids like bradykinin, and several of the prostaglandins, can elicit the pain. Drugs can alter the pain experience in three ways (Pain reception, perception, and reaction) the first that can be intercepted is peripheral pain reception at the nerve endings. This modality is susceptible to non-narcotic analgesic and local anesthesia. The second step, which can be modified, is pain perception at the level of the CNS. Both, narcotic and non-narcotic analgesics interfere with this level of pain integration. The third step, which can be influenced, is pain reaction.

Mechanism of pain & Inflammation:

Prostaglandins are implicated in the inflammatory response and are sensitizing nociceptors to the actions of other Mediators, occurring during acute and chronic inflammatory illness, prostaglandins are produced at the site of inflammation where it is believed that they mediate many of symptoms of inflammation such as oedema and pain.

Arachidonic acid is released from cell membranes by phospholipases, cyclooxygenases catalyze the addition of molecular oxygen to arachidonic acid to form in initially the endoperoxide intermediate prostaglandin G2. The same enzymes also process peroxidase activity, which catalyzes the reduction of these prostaglandins to form PGH2. PGH 2 may then react with a number of enzymes sometimes called isomerases to become one of the prostaglandins or thromboxanes.

Role of Non-Steroidal Anti inflammatory drugs in pain (NSAIDs)

Orally administered NSAIDS play an important role in symptomatic management of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and other acute pain conditions. In general, they produce their anti-inflammatory and analgesic effects by inhibiting cyclooxygenase and this preventing the production of prostaglandins from arachidonic acid. It has been suggested that some NSAIDS inhibit leukotriene production via lipooxygenase inhibition.

ACECLOFENAC

Aceclofenac is an orally administered phenyl acetic acid derivatives with effects on a variety of inflammatory mediators.

Aceclofenac chemical structure

Aceclofenac contains not less than 99.0% and not more than the equivalent of 101.0 percent of 2-[[2-[2-[(2, 6-dichlorophenyl) amino] phenyl] acetyl] oxy] acetic acid.

It is a white or almost white crystalline powder. It is an effective analgesic and anti-inflammatory agent with a good tolerability profile. Through its analgesic and anti-inflammatory properties, aceclofenac provides symptomatic relief in a variety of painful conditions. A reduction in the stimulated generation of reactive oxygen species (O2), which may play a role in joint damage, was observed after 15 days in these patients, but after 180 days. At day 180, O2 release was similar to that seen in a group of 41 healthy untreated individuals.

Structure Activity Relationship

Structure-activity relationship in this series, have not been extensively studied. It does appear that the function of the two o-chloro groups is to force the anilino-phenyl ring out of the plane of the phenylacetic acid portion, this twisting effect being important in the binding of NSAIDs to the active site of the cyclooxygenase enzyme.

Pharmacology

The mode of action of aceclofenac is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclooxygenase, which is involved in the production of prostaglandins.

The Drugs inhibits synthesis of the inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor and prostaglandin E2 (PGE2) production. Effects on cell adhesion molecular from neurophils have also been noted. In vitro data indicate inhibition of cyclooxygenase (Cox)-1 and 2 by aceclofenac in whole blood assays, with selectivity for Cox-2 being evident.

Aceclofenac has shown stimulatory effects on cartilage matrix synthesis that may be linked to the ability of the drug to inhibit IL-1 activity. In vitro data indicate stimulation by the drug of synthesis of glycosaminoglycan in osteoarthritic cartilage. There is also evidence that aceclofenac stimulates the synthesis of IL-1 receptor antagonist in human articular chondrocytes subjected to inflammatory stimuli and that 4'-hydroxyacelofenac has chondroprotective properties attributable to suppression of IL-1 mediated promatrix metalloproteinase production and proteoglycan release.

In patients with osteoarthritis of the knee, aceclofenac decrease pain reduces disease severity and improves the functional capacity of the knee. It reduces joint inflammation, pain intensity and the duration of morning stiffness in patients with rheumatoid arthritis. The duration of morning stiffness and pain intensity are reduced and spinal mobility improved, by aceclofenac in patients with ankylosing spondylitis.

PHARMACOKINETICS

Aceclofenac is rapidly and completely absorbed after oral administration, peak plasma concentrations are reached 1 to 3 hours after an oral dose. The drug is highly protein bound (7.99%). The presence of food does alter the extent of absorption of aceclofenac but the absorption rate is reduced. The plasma concentration of aceclofenac was approximately twice that in synovial fluid after multiple doses of the drug in-patient with knee pain and synovial fluid effusion. Aceclofenac is metabolized to a major metabolite, 4'-hydroxyaceclofenac and to a number of other metabolites including 5-hydroxyaceclofenac, 4'-hydroxydiclofenac, diclofenac and 5-hydroxydiclofenac. Renal excretion is the main route of elimination of aceclofenac with 70 to 80% of an administered dose found in the urine, mainly as the glucuronides of aceclofenac and its metabolites of each dose of aceclofenac, 20% is excreted in the faeces. The plasma elimination half-life of the drug is approximately 4 hours.

Drug Interactions

Aceclofenac may increase plasma concentrations of lithium, digoxin and methotrexate, increase the activity of anticoagulant, inhibits the activity of diuretics, enhance cyclosporin nephrotoxicity and precipitate convulsions when co-administered with quinolone antibiotics.       Furthermore, hypo or hyperglycaemia may result from the concomitant administration of aceclofenac and antidiabetic drugs, although this is rare. The co administration of aceclofenac with other NSAIDS of corticosteroids may results in increased frequency of adverse event.

Adverse Drug Reaction

Aceclofenac is well tolerated, with most adverse events being minor and reversible and affecting mainly the GI system. Most common events include dyspepsia (7.5%), abdominal pain (6.2%), nausea (1.5%), diarrhea (1.5%), flatulence (0.8%), gastritis (0.6%), constipation (0.5%), vomiting (0.5%), ulcerative stomatitis (0.1%), pancreatitis (0.1%).

Although the incidence of gastro intestinal adverse events with aceclofenac was similar to those of comparator NSAIDS in individual clinical trials, withdrawal rates due to these events were significantly lower aceclofenac than with ketoprofen and tenoxicam.

Other adverse effect, which is not common such as dizziness (1%), vertigo (0.3%), and rare cases: par aesthesia and tremor.

Dosage and Administration

The usual dose of aceclofenac is 100 mg given twice daily by mouth, one tablet in the morning and one in the evening. There is no evidence that the dosage of aceclofenac needs to be modified in patients with mild renal impairment, but as with other NSAIDS caution should be exercised.

Aceclofenac Balanced Cox Inhibitor

It has been suggested that aceclofenac blocks PGE2 production via cyclo-oxygenase (cox)-1 and cox-2 inhibition after intracellular metabolism to 4'-hydroxyaceclofenac and diclofenac in human rheumatoid synovial and other inflammatory cells.

However data from human whole blood assays show inhibition of cox-2 (with minimal effects on cox-1) by both the parent compound and 4'-hydroxyaceclofenac. IC50 values of cox-1 and cox-2 respectively were > 100 and 0.8 for aceclofenac and > 100 and 36 for 4'-hydroxyaceclofenac.

IC 50

 

Cox-1

Cox-2

Aceclofenac

> 100

0.8

4'-hydroxyaceclofenac

> 100

36

Further evidence of cox-2 selectivity of aceclofenac has been shown by an IC50 ratio (cox-2: cox-1) of 0.26, which fell between IC50 ratios of 0.7 and 0.12 for the cox-2 inhibitors celecoxib and rofecoxib, respectively in other study. Most recent data have shown aceclofenac to have the highest cox-1: cox-2 IC 50 ratio of a range of agents, including rofecoxib, celecoxib, nimesulide, diclofenac and tenoxicam.

Drugs

IC50

Aceclofenac

0.26

Celecoxib

0.7

Rofecoxib

0.12

Aceclofenac may prevent the degradation of articular connective tissue in patients with rheumatoid arthritis and osteoarthritis and this should be classified as unique NSAIDs.

Aceclofenac - Clinical Efficacy

In large trials of 2 to 6 months duration, aceclofenac significantly reduced pain and improves functional capacity and mobility relative to baseline in patients with osteoarthritis, rheumatoid arthritis or ankylosing spondylitis and reduces inflammation in patients with rheumatoid arthritis. No head to head comparison between aceclofenac and coxibs have been performed, nor for efficacy neither for tolerance.

Aceclofenac in osteoarthritis

In patients with osteoarthritis of the knee, aceclofenac decreases pain, reduces disease severity and improves the functional capacity of the knee to a similar extent to diclofenac, piroxicam, and naproxen.

Aceclofenac in rheumatoid arthritis

The anti-inflammatory and analgesic efficacy of aceclofenac is similar to that of ketoprofen, indomethacin, tenoxicam and diclofenac in patients with rheumatoid arthritis. In randomized, double blind trials in 169 to 261 patients, aceclofenac (100 mg twice daily for 3 or 6 months) significantly reduced relative to baseline joint inflammation, pain intensity and the duration of morning stiffness and improved handgrip strength.

Aceclofenac in ankylosing spondylitis

The duration of morning stiffness and pain intensity are reduced and spinal mobility improved, by aceclofenac in patients with ankylosing spondylitis, with improvements being similar to those observed with indomethacin, naproxen or tenoxicam. These effects were observed after aceclofenac 100 mg twice daily for 3 months in randomized, double blind trials involving 104 to 308 patients.

Aceclofenac in dental pain

The analgesic efficacy as single doses of aceclofenac has been assessed in patients with moderate to severe tooth pain and in extraction of impacted third molars. The analgesic efficacy of single doses of aceclofenac 50, 100 and 150 mg was greater than that of placebo in patients with moderate to severe tooth pain or pain caused by extraction of impacted third molars.

Aceclofenac in postoperative pain

The analgesic efficacy of aceclofenac has been shown in comparisons with paracetamol in women undergoing episiotomy. Aceclofenac 100 mg was superior to paracetamol 650 mg in providing relief from postepisiotomy pain, particularly 3 to 5 hours after ingestion.

Aceclofenac in Dysmenorrhoea

In a more recent noncomparative study in 1338 women with dysmenorrohea treated for first 3 days of 2 consecutive cycles.

Aceclofenac in acute lumbago

Aceclofenac (150 mg intramuscularly for 2 days, then 100 mg orally, both twice daily) was superior to diclofenac in alleviating functional impairment in a 7 days study in 100 patients with acute lumbago. Aceclofenac 100 mg twice daily was associated with symptomatic relief of acute low back pain in a non-comparative study in 67 pateints.

Aceclofenac in musculoskeletal trauma

Aceclofenac 100 mg twice daily has also been assessed in patients with musculoskeletal trauma, although only non-comparative studies are available.

Aceclofenac Gonalgia (Knee pain)

A controlled double blind study was performed with aceclofenac comparing it with diclofenac in 40 patients with acute or chronic gonalgia. The results of the trial indicate slightly superior activity, although there was no statistically significant difference between two drugs.

CONCLUSION

Aceclofenac is superior form other NSAIDs as it has selectivity for cox-2, a beneficial cox inhibitor, well tolerated, better GI tolerability and improved cardiovascular safety when compared to other selective cox-2 inhibitors. It also shows Increased matrix component synthesis and protection of chondrocytes against apoptosis. Aceclofenac has a faster and more potent effect than the other NSAIDs. It efficiently interferes with Neutrophils adhesion to endothelium and this effect may represent an additional relevant mechanism in its anti-inflammatory activity. Aceclofenac has an outstanding anti-inflammatory profile, involving a classical inhibition of prostaglandins E2, a decrease in the expression of several cytokines including interleukin and tumor necrosis factor. It also inhibits activated oxygen species production and influences cell adhesion. Thus it can be concluded that Aceclofenac may be a better option for the management of pain.

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About Authors

G. Garg, Deependra Singh, Swarnlata Saraf and S. Saraf*

Institute of  Pharmacy, Pt. Ravishankar Shukla University, Raipur, 492 010 C.G.E-mail: shailendrasaraf@rediffmail.com

Gopal Garg

Mr. Gopal Garg has nearly 2 years of research and teaching experience. He is a hard working researcher. Mr. Garg did his masters degree from Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. He has over 7 publications to his credit published in international and national journals. His research interest extends from Analytical technique to phytochemical estimation. Presently, he is working as a Lecturer at Institute of pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.)

Mr. Deependra Singh
Mr. Deependra Singh has nearly 6 years of research and teaching experience. He is a hard working researcher. Mr . Singh did his masters degree from Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR., He has over 20 publications to his credit published in international and national journals. He is a founder secretary of IPA Chhattisgarh branch. His research interest extends from Noble topical delivery systems, Delivery Systems for biologicals to Plant tissue culture. Presently, he is working as a Lecturer at Institute of Pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.)

Dr. (Mrs). Swarnlata Saraf

Dr. (Mrs). Swarnlata Saraf has nearly 14 years of research and teaching experience. She is a leading scientist and well-known in the field of herbal Cosmetics. Dr. (Mrs.) Saraf did her doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. She has over 45 publications to her credit published in international and national journals. She is an active member of IPA ,APTI and ISTE. Her research interest extends from Herbal Cosmetics to transdermal drug delivery (Iontophoresis), New Drug Delivery Systems for biological therapeutic agents. She has Co-authored 1 books, (in press). Presently she is working as a Reader at Institute of pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.)

Prof. S. Saraf

* Prof. S. Saraf has nearly 17 years of research and teaching experience at U.G. and P.G. level. He is a leading scientist and well-known academician . Prof. Saraf did his doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. He has over 55 research publications to his credit published in international and national journals. He has delivered invited lectures and chaired many sessions in several National Conferences and Symposia in India. His research interest extends from Herbal Cosmetics to Herbal drug standardization Modern analytical techniques, New Drug Delivery Systems with biotechnology bias. He has authored 1 book, in press. Presently, he is Professor and Director Institute of pharmacy and Dean, Faculty of Technology, Pt. Ravishankar Shukla University , Raipur , (C.G.)

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