Combination therapies that inhibit cyclooxygenase-2 and leukotriene synthesis prevent disease in murine collagen induced arthritis.
OBJECTIVE
To determine the effect of combinations of cyclooxygenase (COX) inhibitors and inhibitors of leukotriene (LT) syntheses on collagen induced arthritis (CIA) in mice.


METHODS
The CIA model was evaluated for the presence of eicosanoids in the paw tissue. Several selective cyclooxygenase 2 (COX-2) inhibitors or non-selective non-steroidal anti inflammatory drugs (NSAIDs) were evaluated alone or in combination with leukotriene (LT) synthesis inhibitors in the CIA model.


RESULTS
Arthritic paw tissue showed increased levels of prostaglandins and leukotrienes in comparison to normal paws. Analysis of mRNA levels indicated the inducible form of the COX-2 enzyme to be the source of prostaglandins. NSAIDs, COX-2 or leukotriene synthesis inhibitors administered alone in CIA decreased severity but had little effect on disease incidence. However, the combination of selective COX-2 inhibitors with leukotriene synthesis inhibitors produced significant decreases in both incidence and severity, suggesting an additive or synergistic effect. This effect was reversible with removal of drug. Little decrease in incidence was observed with the NSAID/5-LO inhibitor combinations.


CONCLUSIONS
These results suggest that the induction of the disease in CIA is mediated by products of the COX-2 enzyme and LTB4 production, and that blockade of both pathways is required to prevent CIA.
Anderson
G D
GD
Pfizer Inc. St Louis, MO, USA. gary.d.anderson@pfizer.com
Keys
K L
KL
De Ciechi
P A
PA
Masferrer
J L
JL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011453:Prostaglandins / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D015289:Leukotrienes; D011453:Prostaglandins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; C082739:A 78773; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D004851:Epoxide Hydrolases; D000068579:Celecoxib; C043134:leukotriene A4 hydrolase; D006918:Hydroxyurea