title: More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, and reduction of heart rate by treatment with diclofenac compared with celecoxib and rofecoxib.
abstract: OBJECTIVE
  Recent findings suggest that permanent blockade of cyclooxygenase 2 (COX-2) is one factor contributing to the cardiovascular side effects of selective COX-2 inhibitors (coxibs) and nonsteroidal antiinflammatory drugs (NSAIDs). The present study compared the extent and time course of COX-2 inhibition and the effects on cardiovascular parameters (changes in blood pressure and heart rate) between various antirheumatic doses of diclofenac, celecoxib, and rofecoxib in healthy elderly volunteers.
  
  
  METHODS
  A randomized, parallel-group study was conducted in volunteers receiving 75 mg diclofenac twice daily, 200 mg celecoxib twice daily, or 25 mg rofecoxib once daily for 8 days. Blood samples were obtained predose and at specified time points postdose, on days 1 and 8, for assay of drug plasma concentrations and COX-2 inhibition. Lipopolysaccharide-induced prostaglandin E(2) synthesis was measured ex vivo as an index of COX-2 activity in human whole blood.
  
  
  RESULTS
  COX-2 inhibition was significantly less pronounced after treatment with celecoxib and rofecoxib than with diclofenac. Maximal inhibitions after a single dose and at steady state, respectively, were as follows: 99% and 99% with diclofenac, 70% and 81% with celecoxib, and 56% and 72% with rofecoxib. At steady state, only diclofenac caused virtually complete COX-2 inhibition over the whole dose interval, and this corresponded to the highest increase in systolic blood pressure and greatest reduction in heart rate.
  
  
  CONCLUSIONS
  Diclofenac elicited the most pronounced COX-2 inhibition, blood pressure elevation, and suppression of heart rate. It is assumed that the extent and time course of intravascular COX-2 inhibition may determine the differential profile of cardiovascular side effects associated with NSAIDs and coxibs, but this has to be proven in future studies.
authors.affiliation: Dept. of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany. hinz@pharmaklologie.uni-erlangen.de
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hinz
authors.forename: Harald
authors.initials: H
authors.lastname: Dormann
authors.forename: Kay
authors.initials: K
authors.lastname: Brune
mesh_terms: D001794:Blood Pressure / Q000187:drug effects*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004008:Diclofenac / Q000627:therapeutic use*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007783:Lactones / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D013450:Sulfones / Q000627:therapeutic use*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; D051546:Cyclooxygenase 2; D000068579:Celecoxib