Rofecoxib selective toxicity

Celecoxib (Celebrex) and rofecoxib (Vioxx) are highly selective COX-2 inhibitors. Because of this, they produce less erosion of the GI mucosa and cause less inhibition of platelet aggregation than do the nonselective COX inhibitors. Short-term (6 months-to a year) clinical trials have shown that celecoxib and rofecoxib produce less GI toxicity than nonselective NSAIDs. However, serious GI bleeding and ulceration have occurred in patients taking these drugs, and long-term prospective studies of their safety have yet to be completed. Like the nonselective NSAIDs, the selective COX-2 inhibitors can produce renal side effects such as hypertension and edema. 

Post-2000 Renal rhabdomyolysis with the statin, cerivastin cardio-toxicity with the COX-2 inhibitor, rofecoxib and liver damage with the selective serotonin and norepinephrine reuptake inhibitor, atomoxetine. 

Rofecoxib, a furanose derivative, is a potent, selective COX-2 inhibitor (Table 36-1). In the USA, rofecoxib is approved for osteoarthritis and rheumatoid arthritis, and it also appears to be analgesic and antipyretic—in common with other NSAIDs. This drug does not inhibit platelet aggregation and appears to have little effect on gastric mucosal prostaglandins or lower gastrointestinal tract permeability. At high doses it is associated with occasional edema and hypertension. Other toxicities are similar to those of other coxibs. 

Selective inhibition of COX-2 has the objective of preserving anti-inflammatory activity whilst avoiding gastric mucosal toxicity. Rofecoxib, celecoxib and meloxicam vary in their selectivity for COX-2. The incidence of peptic ulcers and their complications with rofecoxib is similar to that seen when proton pump inhibitors are co-administered with nonselective NSAIDs. The adverse effect profile of these drugs remains fully to be evaluated. 

Two other aspects of gastrointestinal toxicity have yet to be studied. First, the use of COX-2 inhibitors in patients with inflammatory bowel disease, in whom it is likely that COX-2 activity is upregulated (92) and in whom traditional NSAIDs may exacerbate the disease. Experimental colitis has been induced both in COX-2-deficient mice and in rats treated with COX-2-selective inhibitors (93). However, in healthy volunteers, rofecoxib did not alter intestinal permeability, in contrast to indometacin, which increased it (94). Studies in patients with inflammatory bowel disease are necessary before considering COX-2 selective inhibitors to be safe in these patients (95). 

In conclusion, clinical trials have shown that COX-2-selective NSAIDs seem to be less toxic to the gastrointestinal mucosa than traditional ones. However, life-threatening ulcer complications have been reported in patients taking both celecoxib (81,96,97) and rofe-coxib (79). The FDA and other regulatory authorities require that drug information sheets for celecoxib and rofecoxib carry gastrointestinal ulcer warnings similar to those for older NSAIDs. 

Selective COX-2 inhibitor acts mainly on enzymes of cells involved in inflammation. Used in rheumatoid arthritis and other inflammatory disorders. Tox GI toxicity, but less than that of aspirin and other NSAIDs. Rofecoxib is similar. 

NSAIDs can be classified on the basis of their COX inhibitory and selective properties. Most NSAIDs inhibit both COX-1 and COX-2 to some extent. Most are mainly COX-1 inhibitory, e.g., aspirin, ibuprofen, diclofenac, naproxen, while some are COX-2 inhibitory, e.g., celecoxib, rofecoxib, and lumiracoxib. Vane et al. established the relative inhibitory potencies of NSAID COX-1 and COX-2 inhibitors. NSAIDs with the highest gastrointestinal toxicity have the highest COX-1 selectivity. 

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