Thromboxane

Abstract: There is abundant evidence that changes in diet and various types of vessel wall injury can independently induce the growth of arterial lesions in experimental animals. These lesions closely resemble those found in humans with atherosclerosis. Whether endothelial injury or accumulation of lipoprotein in the arterial intima is the initial event, the progression of the disease is characterized by changes in the neointima that favor the deposition of lipid. The metabolism of proteoglycans may be especially important in this process; this is relevant to diabetes because changes in proteoglycan metabolism are associated with this disease. Insulin and growth hormone may favor the proliferation of smooth muscle cells in the arteries of diabetic patients. Many agents, which are potentially injurious to the endothelium, accentuate the response of the vessel wall to injury. Modifications of the thrombotic process, such as increased production of thromboxane by platelets, decreased production of prostacyclin by the endothelium, and increased production of von Willebrand factor further enhance the thrombotic process and may be important in the initiation and subsequent progression of atherosclerosis in diabetics. Alterations in lipoprotein metabolism may also facilitate the development of endothelial injury.

Abstract: Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory diseases, but significant side effects such as gastrointestinal erosion and renal damage limit their use. NSAIDs inhibit the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostaglandins (PGs) and thromboxane. Two forms of COX have been identified--COX-1, which is constitutively expressed in most tissues and organs, and the inducible enzyme, COX-2, which has been localized primarily to inflammatory cells and tissues. In an animal model of acute inflammation (injection of carrageenan into the footpad), edema was produced that was associated with marked accumulation of COX-2 mRNA and thromboxane. A selective inhibitor of COX-2 (SC-58125) inhibited edema at the inflammatory site and was analgesic but had no effect on PG production in the stomach and did not cause gastric toxicity. These data suggest that selective inhibition of COX-2 may produce superior antiinflammatory drugs with substantial safety advantages over existing NSAIDs.

Abstract: Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; (ii) comparable COX-2 inhibition is attained by celecoxib (100-800 mg) and ibuprofen (800 mg) after acute dosing; and (iii) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.