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


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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    ABSTRACT: Abstract In the presented study, we synthesized a novel series of 18 diphenylthiazole derivatives and tested their anti-inflammatory properties. They showed significant antiinflammatory properties in inflamed mice paws animal model. Docking-based analysis suggested that they act as COX enzyme inhibitors. The most potent compound 9e is significantly more active in reducing inflamed animal paws compared to diclofenac. Accordingly, we believe these compounds are good leads for further development into potent anti-inflammatory drugs.
    Medicinal Chemistry Research 07/2015; 24(10). DOI:10.1007/s00044-015-1418-5 · 1.40 Impact Factor
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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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    ABSTRACT: In this review, we present the relation between power generation capabilities and pulmonary oxygen uptake during incremental cycling exercise in humans and the effect of exercise intensity on the oxygen cost of work. We also discuss the importance of oxygen delivery to the working muscles as a factor determining maximal oxygen uptake in humans. Subsequently, we outline the importance of coronary blood flow, myocardial oxygen uptake and myocardial metabolic stability for exercise tolerance. Finally, we describe mechanisms of endothelium-dependent regulation of coronary and skeletal muscle blood flow, dysregulation of which may impair exercise capacity and increase the cardiovascular risk of exercise. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. All rights reserved.
    Pharmacological reports: PR 06/2015; 67(4). DOI:10.1016/j.pharep.2015.06.002 · 1.93 Impact Factor
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    • "However, COX-2, often referred to as the inducible or rate-limiting isoform, is usually undetectable in most normal tissues, being responsible for most of the prostanoid production during inflammation and markedly upregulated in various types of cancer, as well as in other diseases [1] [17] [31]. COX-2 gene can also be constitutively expressed in some tissues, such as the endothelium, kidney, gastrointestinal mucosa, and brain [32] [33] [34], and the constitutive expression of COX-2 gene may be a contributing factor promoting tumoral pathologies, such as colorectal cancer [35]. "
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    ABSTRACT: The potential relevance of prostanoid signaling in immunity and immunological disorders, or disease susceptibility and individual variations in drug responses, is an important area for investigation. The deregulation of Cyclooxygenase- (COX-) derived prostanoids has been reported in several immunoinflammatory disorders such as asthma, rheumatoid arthritis, cancer, and autoimmune diseases. In addition to the environmental factors and the genetic background to diseases, epigenetic mechanisms involved in the fine regulation of prostanoid biosynthesis and/or receptor signaling appeared to be an additional level of complexity in the understanding of prostanoid biology and crucial in controlling the different components of the COX pathways. Epigenetic alterations targeting inflammatory components of prostanoid biosynthesis and signaling pathways may be important in the process of neoplasia, depending on the tissue microenvironment and target genes. Here, we focused on the epigenetic modifications of inflammatory prostanoids in physiological immune response and immunological disorders. We described how major prostanoids and their receptors can be functionally regulated epigenetically and consequently the impact of these processes in the pathogenesis inflammatory diseases and the development of therapeutic approaches that may have important clinical applications.
    Mediators of Inflammation 05/2015; 2015:1-9. DOI:10.1155/2015/841097 · 3.24 Impact Factor
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