Specifics of action• 1 trial studied the in • Although all tested • Considering the vitro effects of NSAIDs caused a above results, it is several (NSAIDs) on statistically reasonable to pro-inflammatory significant propose that the cytokines and PGE2 decrease on IL-6 prophylactic production by and TNF-α levels, treatment with synovial membrane aceclofenac & aceclofenac could from loose tenoxicam were delay the process endoprosthesis of seen to be more of the aseptic hip / knee effective loosening of arthroplasty tissue.
Benefits of action Aceclofenac and its metabolite penetrate the inflammatory cells like neutrophils, monocytes and synovial cells Get hydrolyzed to the active diclofenac & 4`-hydroxydiclofenacInhibits cytokine Suppress release by production of inflammatory PGE 2 at the site cells of inflammation
Benefits of actionSuppression of cytokine mediated proteases & Stimulates the synthesis of the increases production/ cytokine receptor antagonists inrelease of proteoglycan the articular chondrocytes Chondro- Stimulatory effects on cartilage protective matrix synthesis. properties Synthesis of glycosaminoglycan in Inhibition of osteoarthritic cartilage. cytokine release by inflammatory Net result is decrease in cells disease progression & repair
Translation of Benefits of action↓ joint Better outcome Decreases paininflammation intensity Visibility Reduces diseaseImproves of benefits of action severity / progressionmobility ↓ duration of Improves functional morning stiffness capacity of the joints like knee
Pharmacokinetics• Rapidly and completely absorbed after oral administration [Bioavailability = nearly 100%],• Peak plasma concentrations are reached 1-3 hours after an oral dose.• Highly protein bound (approx. 99%).• Presence of food does not alter the extent of absorption but absorption rate is reduced [↑ Tmax].• After multiple dosing, aceclofenac penetrates into the synovial fluid – Concentration = approximately 60% of plasma level
Metabolism• Metabolized to 1. Major metabolite = 4-hydroxyaceclofenac; & 2. Other metabolites = Diclofenac, 4- hydroxydiclofenac & 5-hydroxydiclofenac.• Main route of elimination – Renal, with 70 to 80% of an administered dose found in the urine, mainly as the glucuronides of aceclofenac and its metabolites• Plasma elimination half-life – Approximately 4 hours.
Observation of Selectivity• Inhibition of cox-2 by both aceclofenac and 4-hydroxyaceclofenac but with minimal effects on cox-1. How can we say so?• IC50 values of cox-1 and cox-2 respectively have been observed as follows: Cox-1 Cox-2 Aceclofenac > 100 0.8 4-Hydroxy-aceclofenac > 100 36 Further evidence of cox-2 selectivity of aceclofenac has been shown by an IC50 ratio (cox-2: cox-1) of 0.26
Aceclofenac – clinical efficacy• In large trials of 2 to 6 months duration in various diseases, aceclofenac significantly reduced pain and improves functional capacity and mobility relative to baseline in patients with – osteoarthritis, – rheumatoid arthritis or – ankylosing spondylitis• In addition, reduced inflammation in patients with rheumatoid arthritis. [Disease progression?]
Use in OA• One trial was a controlled, comparative, randomized, and double-blind study that included 247 patients suffering from osteoarthritis.• Patients were randomized to receive either aceclofenac (100 mg twice daily) or diclofenac (75 mg twice daily).• Clinical assessment was done at screening, randomization, and at 2 weeks, 4 weeks and 8 weeks of treatment by calculating – Western Ontario MacMaster (WOMAC) scores, – time taken to walk 100 feet, – visual analogue scores for pain, – investigators assessment on a Likert scale and – joint tenderness.• Tolerability assessment was based on adverse events.• Patient compliance was also assessed. Curr Med Res Opin. 2006; 22(5):977-88
Use in OA• Aceclofenac was found to be statistically superior to diclofenac in efficacy parameters of – WOMAC scores, – investigators assessment and – joint tenderness.• Aceclofenac was found to be statistically superior to diclofenac in terms of GI tolerance.• Patient compliance was also better with better acceptance.• The overall response of patients osteoarthritis to aceclofenac was found to be statistically superior to diclofenac by both physician and patient. Curr Med Res Opin. 2006; 22(5):977-88
Use in RA• In randomized, double blind comparative trial in 170 patients in each group, aceclofenac (100 mg twice daily for 3 or 6 months) was compared wioth diclofenac 50 mg. tid – Although both treatment groups showed significant improvement in all evaluations of pain and inflammation & a progressive reduction in morning stiffness, there were no significant differences between the groups. – But, greater improvement in hand grip strength was seen with aceclofenac (22% improvement) than diclofenac (17% improvement). Adverse GI events were less with aceclofenac (13%) than with diclofenac (17%). Curr Med Res Opin. 1995;13(6):305-15
Use in ankylosing spondylitis• In randomized, double blind trials involving 104 to 308 patients after aceclofenac 100 mg twice daily for 3 months, Improvements were observed similar to those observed with indomethacin, naproxen or tenoxicam. 1. Reduced duration of morning stiffness and pain intensity and 2. Improved spinal mobility. J Rheumatol. 1996 Jul;23(7):1194-9.
Use in acute lumbago• In a comparative study, Aceclofenac (100 mg orally, twice daily) was superior to diclofenac in alleviating functional impairment in a 7 days study in 100 patients with acute lumbago.• In a non-comparative study in 67 patients, aceclofenac 100 mg twice daily was associated with symptomatic relief of acute low back pain.
Use in dental pain• The analgesic efficacy as single doses of aceclofenac 100 mg has been assessed in patients with moderate to severe tooth pain and in extraction of impacted third molars and found to be greater than that of placebo.• Aceclofenac was more efficient in controlling pain when administered before the surgery as maximum impact of activity for this condition was evident at 6h after surgery, which is the time of maximum pain for this surgical procedure. Int J Oral Maxillofac Surg. 2006 Jun;35(6):518-21
Other uses Post Operative Dysmenorrhoea Musculoskeletal trauma In various studies, In a more recent Aceclofenac 100 mgaceclofenac 100 mg has noncomparative study in twice daily has also been been superior to 1338 women with assessed in patients with paracetamol 650 mg in dysmenorrohea treated musculoskeletal trauma, providing relief from for first 3 days of 2 although only non- postepisiotomy pain, consecutive cycles, comparative studies areparticularly 3 to 5 hours aceclofenac appeared to available. after ingestion. be effective as other NSAIDs with lesser side effects.
Drug interactions• Concomitant administration of aceclofenac and antidiabetic drugs = hypo or hyperglycaemia• Co-administration with other NSAIDS of corticosteroids may result in increased frequency of adverse event.• ↓ the activity of diuretics, but ↑ the activity of anticoagulants and also ↑ cyclosporin nephrotoxicity• May ↑ plasma concentrations of lithium, digoxin and methotrexate.
ADRs• Most adverse events affect mainly the GI system; are minor, reversible and include – dyspepsia (7.5%), 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%).• Rare adverse effect – dizziness (1%), vertigo (0.3%), paraesthesia and tremor.• Withdrawal rates significantly lower than other NSAIDS in relation to incidence of GI adverse events.
Dosage• 100 mg given twice daily by mouth, one tablet in the morning and one in the evening.• In patients with mild renal impairment, there is no evidence to suggest dosage modification but caution should be exercised as with other NSAIDS.
Summary Faster, safer onset of action Pain control + More potent effect with 2. Repair, and selectivity for Cox-2 3. ↓ in disease progression Protection ofchondrocytes against Aceclofenac Well tolerated andROS and breakdown better GI tolerability Classical inhibition of Stimulatory effects on prostaglandins E2 matrix component synthesis Decrease in the expression of cytokines like IL-1 & TNF-α
Summary Osteoarthritis Ankylosing RA Spondylitis Dental pain Dysmenorrhoea