Article

Grosser, T., Fries, S. & FitzGerald, G. A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 116, 4-15

Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 02/2006; 116(1):4-15. DOI: 10.1172/JCI27291
Source: PubMed

ABSTRACT

Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs--adverse effects attributed to suppression of COX-1-derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2-derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a "balance" between COX-2-derived PGI2 and COX-1-derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.

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    • "Inflammation is a physiological reaction which involves cellular and biochemical responses that cause symptoms for common diseases and even an early phase for some serious ailments such as Alzheimer's disease, cancer, heart vascular diseases (Fitzgerald, 2004; Grosser et al., 2006). Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketoprofen, ibuprofen and aceclofenac, which are currently in clinical use for the treatment of inflammatory disorders (Fitzgerald, 2004; Grosser et al., 2006), are associated with major drawbacks related to gastrointestinal disorders such as dyspepsia, gastric ulcers and so forth. These side effects are due to the direct contact of their free carboxylic groups with the gastric mucosa and due to decreased production of prostaglandins in the GIT (Fries and Grosser, 2005; Sauzem et al., 2008). "
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    • "Furthermore, PGI 2 or PGI 2 analogs enhance the exercise capacity not only in patients with pulmonary hypertension [105] [106] [107], but also in patients with stable angina pectoris [108]. Importantly, PGI 2 possesses antiplatelet , vasculoprotective, cardioprotective and anti-atherogenic activity [109] [110] [111], which can limit the cardiovascular risk of exercise and be of importance in mediating the beneficial effects of exercise. It has been shown that 1-methylnicotinamide (MNA), a major metabolite of nicotinamide, which displayed antithrombotic effects mediated by COX-2/PGI 2 [112], has proven to be effective in improving the endurance exercise capacity in diabetic mice and to limit post-exercise leukocytosis, and that both could be linked to PGI 2 mediated mechanisms [Przyborowski et al., PLoS One 2015, in press]. "
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