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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    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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    • "However, COX-2 inhibitors have been shown to be associated with increased cardiovascular incidence possibly due to the inhibition of prostaglandin I2 [14], [15]. Therefore, long-term treatment of COX-2 inhibitors in diabetic patients is not applicable. "
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    ABSTRACT: Prostaglandin E2 (PGE2) has been implicated to play a pathogenic role in diabetic nephropathy (DN) but its source remains unlcear. To elucidate whether mPGES-1, the best characterized PGE2 synthase, was involved in the development of DN, we examined the renal phenotype of mPGES-1 KO mice subjected to STZ-induced type-1 diabetes. After STZ treatment, mPGES-1 WT and KO mice presented the similar onset of diabetes as shown by similar elevation of blood glucose. Meanwhile, both genotypes of mice exhibited similar increases of urinary and renal PGE2 production. In parallel with this comparable diabetic status, the kidney injury indices including the urinary albumin excretion, kidney weight and the kidney histology (PAS staining) did not show any difference between the two genotypes. By Western-blotting and quantitative qRT-PCR, mPGES-1, mPGES-2, cPGES and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) remain unaltered following six weeks of diabetes. Finally, a selective COX-2 inhibitor celecoxib (50 mg/kg/day) was applied to the STZ-treated KO mice, which resulted in significant reduction of urinary albumin excretion (KO/STZ: 141.5±38.4 vs. KO/STZ + Celebrex: 48.7±20.8 ug/24 h, p<0.05) and the blockade of renal PGE2 induction (kidney: KO/STZ: 588.7±89.2 vs. KO/STZ + Celebrex: 340.8±58.7 ug/24 h, p<0.05; urine: KO/STZ 1667.6±421.4 vs. KO/STZ + Celebrex 813.6±199.9 pg/24 h, p<0.05), without affecting the blood glucose levels and urine volume. Taken together, our data suggests that an as yet unidentified prostaglanind E synthase but not mPGES-1 may couple with COX-2 to mediate increased renal PGE2 sythsesis in DN.
    PLoS ONE 07/2014; 9(7):e93182. DOI:10.1371/journal.pone.0093182 · 3.23 Impact Factor
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    • "Inhibition of urinary prostacyclin metabolites by drugs such as rofecoxib [22] and celecxoib [22] has been used as the main evidence to support the idea that COX-2 drives prostacyclin locally within the vessel wall [8], [23]. Accordingly, inhibition of COX-2 derived prostacyclin release by NSAIDs has been suggested to remove a local protective block on platelet reactivity, vascular inflammation and atherosclerosis [8]. "
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    ABSTRACT: Cyxlo-oxygenase (COX)-2 inhibitors, including traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased cardiovascular side effects, including myocardial infarction. We and others have shown that COX-1 and not COX-2 drives vascular prostacyclin in the healthy cardiovascular system, re-opening the question of how COX-2 might regulate cardiovascular health. In diseased, atherosclerotic vessels, the relative contribution of COX-2 to prostacyclin formation is not clear. Here we have used apoE-/-/COX-2-/- mice to show that, whilst COX-2 profoundly limits atherosclerosis, this protection is independent of local prostacyclin release. These data further illustrate the need to look for new explanations, targets and pathways to define the COX/NSAID/cardiovascular risk axis. Gene expression profiles in tissues from apoE-/-/COX-2-/- mice showed increased lymphocyte pathways that were validated by showing increased T-lymphocytes in plaques and elevated plasma Th1-type cytokines. In addition, we identified a novel target gene, rgl1, whose expression was strongly reduced by COX-2 deletion across all examined tissues. This study is the first to demonstrate that COX-2 protects vessels against atherosclerotic lesions independently of local vascular prostacyclin and uses systems biology approaches to identify new mechanisms relevant to development of next generation NSAIDs.
    PLoS ONE 06/2014; 9(6):e98165. DOI:10.1371/journal.pone.0098165 · 3.23 Impact Factor
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