Prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors

Abstract

Anti-thrombotic therapy with aspirin, which at low doses acts as a selective inhibitor of platelet cyclooxygenase 1 (COX-1) activity, is well established. However, a major limitation of aspirin treatment is its gastrointestinal toxicity, which is thought to be linked to the suppression of COX-1-mediated production of cytoprotective prostaglandins. Selective COX-2 inhibitors are effective anti-inflammatory agents with lower gastrointestinal toxicity than aspirin. These inhibitors might also downregulate vascular and leukocyte inflammatory components that play a major part in atherothrombotic disease. However, some selective COX-2 inhibitors appear to increase cardiovascular risk. Newly developed dual COX–5-lipoxygenase (5-LOX) inhibitors share the anti-inflammatory effect and gastric safety of COX-2 inhibitors, but also inhibit COX-1-mediated platelet function and 5-LOX-mediated synthesis of gastrotoxic leukotrienes. Dual inhibitors might thus be beneficial in the treatment of atherosclerosis, where platelet–leukocyte interaction dominates the underlying inflammatory process.