The biochemical selectivity of novel COX-2 inhibitors in whole blood assays of COX-isozyme activity.
We have evaluated the biochemical selectivity of novel cyclo-oxygenase (COX)-2 inhibitors, etoricoxib, valdecoxib, DFU and DFP, vs rofecoxib and celecoxib, using the human whole blood assays of COX-isozyme activity, in vitro. Compounds were incubated with human whole blood samples, allowed to clot for 1 h at 37 degrees C, or stimulated with lipopolysaccharide (10 microg/ml) for 24 h at 37 degrees C. Serum thromboxane (TX) B2 and plasma prostaglandin (PG) E2 levels were measured by specific radioimmunoassays as indices of platelet COX-1 and monocyte COX-2 activity, respectively. Valdecoxib, etoricoxib, DFU and DFP inhibited platelet COX-1 and monocyte COX-2 with the following COX-1/COX-2 IC50 ratios: 61.5, 344, 660 and 1918, respectively. The reference compounds, celecoxib and rofecoxib had corresponding values of 29.6 and 272. In conclusion, a second wave of COX-2 inhibitors with higher biochemical selectivity than the existing coxibs has been developed. Whether their administration will be associated with improved clinical efficacy and/or safety vis-à-vis celecoxib and rofecoxib remains to be established.
Tacconelli
Stefania
S
Division of Pharmacology, Department of Medicine and Center of Excellence on Aging, G. D'Annunzio University School of Medicine, 66013 Chieti, Italy.
Capone
Marta L
ML
Sciulli
Maria G
MG
Ricciotti
Emanuela
E
Patrignani
Paola
P
D000328:Adult; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000097:blood*; D000077613:Etoricoxib; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000187:drug effects*; D007555:Isoxazoles / Q000097:blood*; D007558:Italy; D007783:Lactones / Q000097:blood*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011725:Pyridines / Q000097:blood*; D013449:Sulfonamides / Q000097:blood*; D013450:Sulfones / Q000097:blood*; D000096926:Benzenesulfonamides
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D000077613:Etoricoxib; D007527:Isoenzymes; D007555:Isoxazoles; D007783:Lactones; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011725:Pyridines; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; C406224:valdecoxib; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human