Cyclooxygenase-2 Inhibitors: A Painful Lesson

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.

Stimulatory Role of Lysophosphatidic Acid in Cyclooxygenase-2 Induction by Synovial Fluid of Patients with Rheumatoid Arthritis in Fibroblast-Like Synovial Cells

“…The lipid mediator PGE 2 is produced during inflammatory responses and is thought to be a major PG species working in RA pathogenesis, since a high level of PGE 2 is detected in the synovial fluid of RA patients (4,5) and PGE 2 exhibits pleiotropic biological actions: for example, PGE 2 mediates pain and inflammatory responses (1,6,7). Actually, COX-2 inhibitors are effective for decreasing pain in RA with less gastrointestinal side effects (6,8), although some concerns of risk of cardiovascular events have recently been expressed (9,10). In contrast, several studies suggest that PGE 2 also mediates antiinflammatory effects as well by suppressing the production of proinflammatory cytokine and stimulating the synthesis of antiinflammatory cytokines (11,12).…”

Nutrition and Age‐Associated Inflammation: Implications for Disease Prevention

“…Although anti-inflammatory drugs that inhibit COX-1 and/or COX-2 activity and thereby reduce PGE 2 synthesis have shown some clinical benefits in several age-related diseases, their utility may be limited by concerns of unwanted effects. [34][35][36] This has led to investigation of alternate therapies such as dietary/nutrition interventions that may reduce COX-2 activity and/or PGE 2 production. 37,38 One nutritional compound that appears to have some efficacy is vitamin E supplementation, which diminishes the increased PGE 2 production in Mφ of old mice by inhibiting COX activity, with negligible effects in young mice.…”

Differential expression of E‐prostanoid receptors in human hepatocellular carcinoma

“…This is especially necessary as there is growing evidence that selective COX-2 inhibitors are not free of unwanted side effects, particularly on renal and cardiovascular systems. 18 The PGE 2 synthases (e.g. mPGES-1 and -2) represent such targets downstream of COX.…”