Prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors.
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.
de Gaetano
Giovanni
G
Center for High Technology Research and Education in Biomedical Sciences, Catholic University, 86100, Campobasso, Italy. gdegaetano@rm.unicatt.it
Donati
Maria Benedetta
MB
Cerletti
Chiara
C
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013927:Thrombosis / Q000201:enzymology* / Q000517:prevention & control*; D014657:Vasculitis / Q000201:enzymology* / Q000517:prevention & control*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases