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

Abstract

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. 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 B4 (LTB4) 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. The results indicate that neither zileuton, Bay x 1005, nor Bay y 1015 inhibited exudate production. All 3 compounds decreased LTB4 levels in be 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 LTB4 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. Inhibitors of both cyclooxygenase and leukotriene synthesis in combination may be a more effective treatment of RA than either class of inhibitors alone.