The effect of leukotriene synthesis inhibitors in models of acute and chronic inflammation

Objective. To assess the efficacy of leukotriene synthesis inhibitors, alone and in combination with a nonsteroidal antiinflammatory drug, as potential treatments for rheumatoid arthritis (RA), using the mouse air pouch model and the collagen-induced arthritis (CIA) model. Methods. Two selective leukotriene synthesis inhibitors, Bay x 1005 and Bay y 1015, were compared with zileuton in terms of their ability to decrease exudate volume, cell infiltration, and leukotriene B-4 (LTB(4)) production in response to zymosan injection in the mouse air pouch model. The mouse CIA model was used to assess the effect of leukotriene synthesis inhibitors in a model of chronic inflammation. Bay y 1015 and Bay x 1005, and the cyclooxygenase inhibitor naproxen, were evaluated individually and in combination, for their antiarthritic potency in the mouse CIA model. Results. The results indicate that neither zileuton, Bay x 1005, nor Bay y 1015 inhibited exudate production. All 3 compounds decreased LTB(4) levels in the air pouch, with Bay y 1015 being the most effective. Cell infiltration was significantly decreased with Bay x 1005, but the degree of this decrease did not appear to correlate with LTB(4) levels. No inhibition of arthritis was observed with any compound administered alone. In contrast, a significant inhibition of CIA was observed in animals that received both naproxen and either Bay y 1015 or Bay x 1005. Conclusion. Inhibitors of both cyclooxygenase and leukotriene synthesis in combination may be a more effective treatment of RA than either class of inhibitors alone.