Celecoxib

The first two selective COX-2 inhibitors to be marketed and subjected to in depth clinical trials were celecoxib and rofecoxib. Both compounds are as effective as standard NSAIDs in rheumatoid arthritis, osteoarthritis and for pain following orthopaedic or dental surgery. Gastrointestinal side effects were far fewer than with comparator diugs and in fact were no... 

However, already in an early clinical trial, rofecoxib was found to produce four times the number of myocardial infarctions than its comparator drug, naproxen. A subsequent trial of rofecoxib compared to placebo in colorectal cancer prevention demonstrated, after 18 months of study, that a greater number of myocardial infarctions occulted in the rofecoxib group. In 2004 the manufacturers of rofecoxib withdrew the diug from the market. A similar study of celecoxib compared to placebo in cancer prevention, showed that celecoxib also increased the risk of cardiovascular embolisms [3]. 

Celecoxib, which has a low selectivity for COX-2 compared to COX-1, is still available, although its more selective successor, valdecoxib has been withdrawn. Etoricoxib, the successor to rofecoxib, is marketed in Europe but not in the USA. In a large multinational clinical trial, etoricoxib caused no more thromboembolic events than diclofenac, but after 18 months the incidence of gastrointestinal ulcers and bleeding was the same for both drugs [4]. 

It follows that drugs that selectively inhibit COX-2 should cause fewer side effects than those that inhibit both COX-1 and COX-2. At therapeutic doses, all currently available NSAIDs, with the excqrtion of celecoxib, etoricoxib, lumiracoxib and parecoxib (the prodrug of valdecoxib), are non-selective and inhibit both COX isoforms. 

The development of the COXIBs has been based on the hypothesis COX-1 is the physiological COX and COX-2, the pathophysiological isoenzyme. Inhibition of the pathophysiological COX-2 only is assumed to result in fewer side effects as compared to non-selective inhibition of both COX isoenzymes (Fig. 2). Celecoxib, etoricoxib and lumiracoxib (in some countries also parecoxib) are the only COXIBs currently approved. 

The anti-inflammatory effects of the NSAIDs are carried out by inhibition of COX-2. The gastrointestinal adverse reactions are caused by inhibition of COX-1. The newer NSAIDs (celecoxib and rofecoxib) appear to work by specifically inhibiting the COX-2 enzyme, without inhibiting the COX-1 enzyme. Celecoxib and rofecoxib relieve pain and inflammation with less potential for gastrointestinal adverse... 

Nausea, vomiting, diarrhea, drowsiness, gastric or duodenal ulcer formation, Gl bleeding Same as celecoxib... 

The most common adverse reactions seen with celecoxib include dyspepsia, abdominal pain, diarrhea, nausea, and headache Like other NSAIDs, celecoxib may compromise renal function. Elevation of aminotransferase levels also occurs. 

Celecoxib is contraindicated in patients who are allergic to die drug itself, die sulfonamides, odier NSAIDs, or aspirin it also is contraindicated during pregnancy (Category C) and lactation. 

Organ et al. from York University demonstrated that a diarylated IH-pyrazole-based library, based on the structure of the potent COX II inhibitor Celecoxib [4-(3-trifluoromethyl-5-(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide], could be rapidly prepared using MAOS [59]. Microwave-accelerated Suzuki reaction on 4-(5-iodo-3-methyl-lH-pyrazol-l-yl)-benzenesulfonamide using heterogeneous Pd/C was the principal diversification step investigated (Scheme 41). The interest of the team in microwave... 

C4H5F3O2 383-63-1) see Celecoxib Efavirenz Lisinopril ethyl 7,7,7-trifluoroacetoacetate (QH7F30, 372-31-6) see Mefloquine l-ethyl-6,7,8-trilluoro-l,4-dibydro-4-oxa-3-quinoIinecarb-oxylic acid... 

C9H10O 122-00-9) see Celecoxib Moperone Triprolidine methyl 2-acetoxyacrylate (QHj04 686-46-4) see Vincamine 16a-methyl-21-acetoxy-llp,17-a-dihydroxypregna-l,4,6-triene-3,20-dione... 

Highly selective COX-2 inhibitors - coxibs (rofecoxib, celecoxib, or less popular - valdecoxib, etoricoxib parecoxiband lumiracoxib) - were found to be well tolerated in a series of placebo-controlled clinical trials [8]. However, rofecoxib and valdecoxib have been withdrawn from the market because of an increased incidence... 

Jenkins C, Costello J, Hodge L Systematic review of prevalence of aspirin-induced asthma and its implications for clinical practice. BMJ 2004 328 434-437. Baldassarre S, Schandene L, Choufani G, Michils A Asthma attacks induced by low doses of celecoxib, aspirin and acetaminophen. J Allergy Clin Immunol 2006 117 215-217. 

Schuster C, Wuthrich B Anaphylactic drug reaction to celecoxib and sulfamethoxazole cross-reactivity or coincidence Allergy 2003 58 1072. 

Recent data suggest that COX-2 inhibitors, including rofe-coxib, valdecoxib, and celecoxib, may increase the risk for MI and stroke.47 There is also some evidence that the non-selective NSAIDs may increase the risk for cardiovascular events.47,48 Rofecoxib was withdrawn from the market in late 2004 because of safety concerns. The FDA requested the withdrawal of valdecoxib from the market in 2005. The FDA also asked the manufacturers of celecoxib and non-selective NSAIDs (prescription and over-the-counter) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.48 Patients with cardiovascular disease should consult a clinician before using over-the-counter NSAIDs. 

Two large trials, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study and the Celecoxib Long-term Arthritis Safety Study (CLASS), compared selective COX-2 inhibitors and traditional, non-selective NSAID therapy in terms of their ability to prevent clinical PUD (i.e., symptomatic ulcers and ulcer complications). VIGOR (9-month median follow-up) demonstrated that rofecoxib (50 mg daily) therapy was significantly more efficacious than naproxen.28 The CLASS study (6-month median follow-up) found that high-dose celecoxib (400 mg twice daily) was superior to non-selective NSAID therapy (either ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily).29... 

Selective COX-2 inhibitors are not superior to PPIs in preventing NSAID-related PUD. One randomized, place-bo-controlled trial that included 267 patients at high risk for ulceration (arthritic patients with a previously healed bleeding ulcer) compared celecoxib 200 mg twice daily to the combination of diclofenac 75 mg twice daily plus omeprazole 20 mg daily.32 After 6 months, the risk for recurrent bleeding was found to be similar between groups (celecoxib, 4.9% and diclofenac/omeprazole, 6.4%) the authors concluded that neither of these therapies can completely prevent recurrent ulcer complications. 

CLASS Celecoxib Long-term Arthritis Safety Study... 

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