Aceclofenac
Aceclofenac is an orally administered phenyl acetic acid derivatives with effects on a variety of inflammatory mediators.
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. There is a reduction in the stimulated generation of reactive oxygen species (O2), which may play a role in joint damage.
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.
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. 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.
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.
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.
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.
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.
| IC50 | Cox1 | Cox2 |
| Aceclofenac | >100 | 0.8 |
| 4'-hydroxyaceclofenac | >100 | 36 |
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.
(Efficacy and safety of aceclofenac-cr and aceclofenac in the treatment of knee osteoarthritis: a 6-week, comparative, randomized, multicentric, double-blind study.)
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.
(Single dose oral aceclofenac for postoperative pain in adults.)
Aceclofenac in Dysmenorrhoea
In a more recent noncomparative study in 1338 women with dysmenorrohea treated for first 3 days of 2 consecutive cycles.
(Efficacy and safety of aceclofenac and drotaverine fixed-dose combination in the treatment of primary dysmenorrhoea: a double-blind, double-dummy, randomized comparative study with aceclofenac.)
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.
References
http://www.ncbi.nlm.nih.gov/pubmed
http://www.drugs.com/
http://en.wikipedia.org/wiki/Main_Page
http://flipper.diff.org/
