Cyclooxygenase-2 inhibition by rofecoxib reverses naturally occurring fever in humans.
Cyclooxygenase (COX) exists as constitutive (COX-1) and inducible (COX-2) isoforms. Nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and diclofenac inhibit both COX-1 and COX-2. The role of COX-2 in the genesis of fever in monkeys and humans was examined with use of the specific COX-2 inhibitor rofecoxib. Rofecoxib was administered to monkeys made febrile by 6 microg/kg intravenous lipopolysaccharide. Induced pyrexia was followed by oral rofecoxib (1 or 3 mg/kg), diclofenac (3 mg/kg), or vehicle. Rofecoxib and diclofenac rapidly reversed the elevated temperature (P < .05 versus vehicle for 3 mg/kg rofecoxib and diclofenac at 70 to 90 minutes after dosing). A single-dose, parallel-group, double-blind randomized trial was conducted in 94 patients with fever caused by a viral-type illness. Mean baseline temperature was similar for all groups (-38.5 degrees C). Patients received oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib, 400 mg ibuprofen, or placebo and the mean +/- SE change in oral temperature at 4 hours after dosing was -0.97 degrees C +/- 0.11 degrees C, -1.19 degrees C +/- 0.09 degrees C, -1.20 degrees C +/- 0.11 degrees C, and 0.01 C +/- 0.17 C, respectively (P < .001 for active treatments versus placebo). Specific inhibition of COX-2 by rofecoxib results in antipyretic activity in monkeys and humans comparable to dual COX-1/COX-2 inhibitors such as diclofenac or ibuprofen. The data support the hypothesis that it is the COX-2 isoform that is primarily involved in the genesis of fever in humans.
Schwartz
J I
JI
Merck Research Laboratories, Rahway, NJ 07065-0914, USA.
Chan
C C
CC
Mukhopadhyay
S
S
McBride
K J
KJ
Jones
T M
TM
Adcock
S
S
Moritz
C
C
Hedges
J
J
Grasing
K
K
Dobratz
D
D
Cohen
R A
RA
Davidson
M H
MH
Bachmann
K A
KA
Gertz
B J
BJ
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004008:Diclofenac / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005334:Fever / Q000188:drug therapy* / Q000201:enzymology* / Q000209:etiology / Q000821:virology; D007052:Ibuprofen / Q000627:therapeutic use; D007527:Isoenzymes / Q000187:drug effects*; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D012453:Saimiri; D013450:Sulfones; D016896:Treatment Outcome
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008070:Lipopolysaccharides; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen