Development of Cyclooxygenase-2 Inhibitors

The first step in the clinical development of rofecoxib was to determine the degree of selectivity when the drug was administered to humans. As outlined above, the assessment of selectivity of Cox inhibitors for the two isoforms is dependent on the systems used and in vitro systems may not reflect the degree of selectivity of the enzyme inhibitors in vivo. Two clinical models were used to assess the selectivity of rofecoxib in humans. For both tests, tissues were obtained from patients or volunteers receiving either rofecoxib or NSAIDs, and the ability of these tissues to synthesize prostanoids ex vivo was determined. The simplest of these models is the whole blood assay, which was mentioned earlier in this chapter as one of the tests than can be used for evaluation of Cox selectivity (Patrignani et al, 1994). To use this test in the clinical setting, two samples of blood are drawn from individuals receiving a Cox inhibitor. One sample is allowed 

These assays for selectivity indicate that rofecoxib has a sufficiently low affinity for Cox-1 that no inhibition of this enzyme is detectable in humans at concentrations achievable with any dose tested up to 1,000 mg, 80 times the starting dose for osteoarthritis. Thus, rofecoxib maintains a high 

The Cox-2 inhibitors, rofecoxib and celecoxib, are as elfective as the NSAIDs in the treatment of osteoarthritis. Rofecoxib 12.5-25 mg once daily showed efficacy statistically equivalent to diclofenac 50 mg three times daily and ibuprofen 800 mg three times daily (Saag et al., 1998 Cannon et al., 1998). Celecoxib 200 mg daily showed elfects similar to naproxen 500 mg twice daily in the treatment of osteoarthritis. 

Celecoxib is approved for the treatment of rheumatoid arthritis at doses up to 200 mg twice daily. These doses produced elfects that were similar to naproxen 500 mg twice a day. In clinical development, rofecoxib has shown efficacy in the therapy of rheumatoid arthritis. Rofecoxib is currently in phase III for the therapy of rheumatoid arthritis. 

Rofecoxib is approved for the treatment of acute pain and dysmenorrhea at a dose of 50 mg for up to 5 days. The clinical studies indicate that rofecoxib shows efficacy similar to that produced by the maximum analgesic doses of naproxen and ibuprofen (Ehrich et al., 1999). The pain settings in which rofecoxib has been tested include acute postoperative dental pain, the pain of dysmenorrhea for up to 3 days, and postoperative pain for 5 days following surgical replacement of the knee or hip. In contrast, celecoxib is not approved in the United States for the treatment of acute pain, and it appears to be less effective when given acutely than rofecoxib, ibuprofen, or naproxen. The explanation for the differences between rofecoxib and celecoxib in acute pain is not known. 

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Vosooghi M, Amini M. The discovery and development of cyclooxygenase-2 inhibitors as potential anticancer therapies. Expat Opin Drug Discov. 2014 9 255-67. doi 10.1517/ 17460441.2014.883377. 

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