Cyclooxygenase Inhibition and Atherothrombosis

Abstract

Cyclooxygenases represent a major target of pharmaceutical therapy. Cyclooxygenase inhibitors are applied in order to reduce inflammation, to relieve from pain, or to prevent atherothrombotic complications in cardiovascular disease. Inhibition of platelet aggregation by aspirin, which is due to inhibition of platelet cyclooxygenase-dependent formation of thromboxane A2, is a cheap, safe and effective strategy to prevent myocardial infarction or stroke and is thus the most established strategy of secondary prevention of atherothrombotic disease. However, the existence of several isoforms of the cyclooxygenase enzyme, their tissue-specific expression patterns, their spatial and functional association with enzymes that further degrade the major cyclooxygenase products and the specific pharmacological properties of substances that have the potential of inhibiting cyclooxygenase make the ultimate physiological effects of a specific cyclooxygenase inhibitor a highly sophisticated pharmacological question. Specific inhibitors of the cyclooxygenase-2 isoform (COX-2) have at first promised to represent a major improvement of pharmaceutical therapy, but later have been suggested to enhance the risk of atherothrombotic events in vivo. This has led to the withdrawal of some of these substances from global markets and also initiated a discussion as to whether some non-selective cyclooxygenase inhibitors (non-steroidal anti-inflammatory drugs, NSAID), such as naproxen would also have an antithrombotic effect in vivo. This review summarizes current pathophysiological and clinical knowledge about the effects on atherothrombosis of drugs that target cyclooxygenases either as specific inhibitors of a cyclooxygenase isoform, or as non-specific cyclooxygenase inhibitors. It specifically discusses the question, whether all selective COX-2 inhibitors may have an intrinsic risk of enhancing the risk of atherothrombosis.

Anti-inflammatory, anti-hyperalgesic, antiplatelet and antiulcer activities of Byrsonima japurensis A. Juss. (Malpighiaceae)

“…However, these agents have been associated with undesirable effects on the cardiovascular system, such as heart attacks and strokes, since that they do not inhibit thrombosis associated with release of thromboxane A 2 , a powerful inductor of platelet aggregation, produced by COX-1 constitutively present in all platelets, after platelet activation by collagen, adenosine diphosphate (ADP), epinephrine, platelet activating factor, arachidonic acid metabolites, polycations, serotonin and thrombin, among other substances involved in inflammatory response (Weyrich et al, 2003;Sohn and Krötz, 2006).…”

Preserving vascular prostacyclin levels by microsomal prostaglandin E2 synthase isoform 1 inhibition: a new strategy for vasoprotection?

“…In this way, the authors provide data that support the concept that COX-2 is the most important cyclooxygenase isoform for vascular PGI 2 production, a concept that has been supported by preclinical, clinical and experimental studies for some years now [12][13][14][15]. Unfortunately, in the study by Camacho and colleagues, PGI 2 synthase was not knocked down in those experiments performed to assess the pathophysiological importance of this concept.…”

QSAR of 2-(4-methylsulphonylphenyl)pyrimidine derivatives as cyclooxygenase-2 inhibitors: simple structural fragments as potential modulators of activity

“…valdecoxib 19,20 and etoricoxib [21][22][23] . The follow-up studies of this class of compounds [24][25][26][27][28][29] have pointed out that the mechanism of action as probable cause of adverse effects 30,31 . Moreover, the traditional NSAIDs are not devoid of toxic effects on cardiovascular system 32,33 .…”