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Author: Admin | 2025-04-28
Mean COX-1 inhibition was 95% for naproxen, 89% for ibuprofen, 53% for meloxicam, and 50% for diclofenac.6 A more recent study used similar methodology for determining COX-1 and COX-2 inhibition— ie, whole blood samples for LPS-induced PGE2 formation as a measure of COX-2 inhibition and serum thromboxane B2 generation in clotting whole blood for determining COX-1 activity. This study compared the COX inhibition of diclofenac (75 mg twice daily) with celecoxib (200 mg twice daily) and etoricoxib (90 mg daily) and found that, at anti-arthritic doses, diclofenac demonstrated significantly (P NSAID Dose, COX-2 Selectivity, and Anti-Hyperalgesic EffectsDetermining the drug concentration necessary for achieving pain relief is another important consideration when selecting the appropriate NSAID, due to their anti-hyperalgesic effects. IC80 concentrations of NSAIDs for COX-2 have been found to correlate with analgesia.19,28 The ratio of IC50 values for COX-1 to COX-2 inhibition for each NSAID provides some indication of the relative inhibitory activity of each NSAID on the COX-1 and COX-2 isoenzymes.11,15 The selectivity of diclofenac for COX-2 over COX-1 inhibition in vitro is lower than that of celecoxib, but diclofenac provides greater COX-2 selectivity than meloxicam, etodolac, ibuprofen, and naproxen.11 Specifically, the concentration of diclofenac necessary to reduce the activity of COX-1 by 50% is 29 times the concentration of diclofenac needed to reduce the activity of COX-2 by 50%; the same ratio for celecoxib is slightly higher at 30.11,15 In contrast with the selectivity of celecoxib and diclofenac, the IC50 selectivity ratio for meloxicam is 18 (Table 1).15-20The Effect of NSAID Dosing on Adverse EventsThe risks of GI and CV AEs are related to the same mechanisms associated with NSAID benefits—namely, inhibition of COX-dependent prostanoids synthesis.11 For example, COX-1 inhibition has been associated with decreased platelet aggregation and GI toxicity.6,14,20 Prostaglandin I2 (PGI2), a prostanoid with cardioprotective properties, is generated by COX-2 and promotes vasodilation and inhibition of platelet aggregation. The inhibition of PGI2 is thought to be a plausible mechanism for CV risks associated with the use of NSAIDs, such as myocardial infarction.5,11 Available data from observational studies strongly suggest that GI and CV events and renal failure are related to total daily dose in patients treated with NSAIDs.8,9,29,30COX-2 expression appears to be the dominant source of prostaglandin formation in inflammation, and COX-1 inhibition is associated with adverse GI events; consequently, the development of newer NSAIDs has been focused on COX-2 selective agents in order to limit the effects associated with COX-1 inhibition.10 However, outcome trials demonstrated that agents with increased COX-2 selectivity were also associated with increased risks of CV events.13Since the original observation of elevated risks for CV events among patients in clinical studies of rofecoxib, CV risks associated with the use of these agents
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