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Characterization of rofecoxib as a cyclooxygenase‐2 isoform inhibitor and demonstration of analgesia in the dental pain model
Author(s) -
Ehrich Elliot W.,
Dallob Aimee,
De Lepeleire Inge,
Van Hecken Anne,
Riendeau Denis,
Yuan Weiying,
Porras Arturo,
Wittreich Johanna,
Seibold James R.,
De Schepper Paul,
Mehlisch Donald R.,
Gertz Barry J.
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(99)70113-x
Subject(s) - rofecoxib , cyclooxygenase , ibuprofen , pharmacology , aspirin , medicine , analgesic , prostaglandin e2 , indometacin , prostaglandin , thromboxane b2 , celecoxib , placebo , chemistry , prostaglandin endoperoxide synthase , biochemistry , platelet , enzyme , alternative medicine , pathology
Background Nonsteroidal anti‐inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX‐1) and inducible (COX‐2) isoforms of cyclooxygenase. The induction of COX‐2 after inflammatory stimuli has led to the hypothesis that COX‐2 inhibition primarily accounts for the therapeutic properties of NSAIDs. Methods Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX‐isoform specific assays (serum thromboxane B 2 [TXB 2 ] and lipopolysaccharide [LPS]‐stimulated whole blood prostaglandin E 2 and assays of COX‐1 and COX‐2 activity, respectively). A double‐blind, parallel‐group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain. Results Rofecoxib showed a >800‐fold COX‐2 selectivity with use of CHO cells that express human COX‐1 and COX‐2. In subjects, dose‐ and concentration‐dependent inhibition of LPS‐stimulated prostaglandin E 2 was observed with both rofecoxib (IC 50 [the concentration estimated to produce 50% inhibition], 0.77 μmol/L) and indomethacin (IC 50 , 0.33 μmol/L). Whereas indomethacin inhibited TXB 2 , (IC 50 , 0.14 μmol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen ( P > .20). All active treatments showed greater improvement than placebo ( P < .001) Conclusions Rofecoxib inhibited COX‐2 without evidence of COX‐1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform‐selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX‐2. Clinical Pharmacology & Therapeutics (1999) 65 , 336–347; doi: