scholarly journals A novel anti-atherogenic role for COX-2—potential mechanism for the cardiovascular side effects of COX-2 inhibitors

2007 ◽  
Vol 84 (1-2) ◽  
pp. 24-33 ◽  
Author(s):  
Ajay Narasimha ◽  
Junji Watanabe ◽  
James A. Lin ◽  
Susan Hama ◽  
Robert Langenbach ◽  
...  
Keyword(s):  
Side Effects ◽  
Potential Mechanism ◽  
Cardiovascular Side Effects ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Natural COX-2 inhibitors as promising anti-inflammatory agents: an update

2020 ◽  
Vol 27 ◽  
Author(s):  
Jiahua Cui ◽  
Jinping Jia
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Cell Injury ◽  
Hot Spot ◽  
Structural Features ◽  
Chemistry Research ◽  
Cardiovascular Side Effects ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

: COX-2, a key enzyme that catalyzed the rate-limiting steps in the conversion of arachidonic acid to prostaglandins, played a pivotal role in inflammatory process. Different from other family members, COX-2 was barely detectable in normal physiological conditions and highly inducible during acute inflammatory response of human bodies to injuries or infections. Therefore, the therapeutic utilization of selective COX-2 inhibitors has already been considered as an effective approach for the treatment of inflammation with diminished side effects. Currently, both traditional and newer NSAIDs are the commonly prescribed medications that treat inflammatory disease by targeting COX-2. However, due to the cardiovascular side-effects of the NSAIDs, finding reasonable alternatives for these frequently prescribed medicines are a hot spot in medicinal chemistry research. Naturally-occurring compounds have been reported to inhibit COX-2, thereby possessing beneficial effects against inflammation and certain cell injury. The review mainly concentrated on recently identified natural products and derivatives as COX-2 inhibitors, the characteristics of their structural core scaffolds, their anti-inflammatory effects, molecular mechanisms for enzymatic inhibition and related structure-activity relationships. According to the structural features, the natural COX-2 inhibitors were mainly divided into the following categories: natural phenols, flavonoids, stilbenes, terpenoids, quinones and alkaloids. Apart from the anti-inflammatory activities, a few dietary COX-2 inhibitors from nature origin also exhibited chemopreventive effects by targeting COX-2-mediated carcinogenesis. The utilization of these natural remedies in future cancer prevention was also discussed. In all, the survey on the characterized COX-2 inhibitors from natural sources paths the further development of more potent and selective COX-2 inhibitors in the future.

scholarly journals COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation

2007 ◽  
Vol 204 (9) ◽  
pp. 2053-2061 ◽  
Author(s):  
Mallika Ghosh ◽  
Haibin Wang ◽  
Youxi Ai ◽  
Elisa Romeo ◽  
James P. Luyendyk ◽  
...  
Keyword(s):  
Side Effects ◽  
Tissue Factor ◽  
Vascular Endothelium ◽  
Cardiovascular Events ◽  
Cardiovascular Side Effects ◽  
Factor Expression ◽  
Cox 2 ◽  
Mechanistic Basis ◽  
Cox 2 Inhibitors

Although cyclooxygenase (COX)-2 inhibitors (coxibs) are effective in controlling inflammation, pain, and tumorigenesis, their use is limited by the recent revelation of increased adverse cardiovascular events. The mechanistic basis of this side effect is not well understood. We show that the metabolism of endocannabinoids by the endothelial cell COX-2 coupled to the prostacyclin (PGI2) synthase (PGIS) activates the nuclear receptor peroxisomal proliferator–activated receptor (PPAR) δ, which negatively regulates the expression of tissue factor (TF), the primary initiator of blood coagulation. Coxibs suppress PPARδ activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPARδ agonists suppress coxib-induced TF expression and decrease circulating TF activity. We provide evidence that COX-2–dependent attenuation of TF expression is abrogated by coxibs, which may explain the prothrombotic side-effects for this class of drugs. Furthermore, PPARδ agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects.

The role of celecoxib as a potential inhibitor in the treatment of inflammatory diseases - a review

2021 ◽  
Vol 28 ◽  
Author(s):  
Josiane Viana Cruz ◽  
Joaquín María Campos Rosa ◽  
Njogu Mark Kimani ◽  
Silvana Giuliatti ◽  
Cleydson Breno Rodrigues dos Santos
Keyword(s):  
Side Effects ◽  
Inflammatory Diseases ◽  
Structural Basis ◽  
Potential Inhibitor ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

: This article presents a simplified view of celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) has, predominantly, two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role that is related to homeostatic effects in renal and platelets, while the latter is mainly responsible for induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and without side effects. To this end, of the generation of non-steroidal anti-inflammatory drugs from “coxibs”, celecoxib is the only potent selective COX-2 inhibitor that is still commercially available. Thus, the compound celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for COX-2 enzyme. In this review, we provide highlights where such inhibition should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs) which act as COX-2 inhibitors with lesser side effects on the human body.

2-Substituted Benzoxazoles as Potent Anti-Inflammatory Agents: Synthesis, Molecular Docking and In Vivo Anti-Ulcerogenic Studies

2021 ◽  
Vol 18 ◽  
Author(s):  
Iqra Hamid ◽  
Humaira Nadeem ◽  
Sameen Fatima Ansari ◽  
Sonia Khiljee ◽  
Inzamam Abbasi ◽  
...  
Keyword(s):  
Side Effects ◽  
Therapeutic Interventions ◽  
Binding Potential ◽  
Spectroscopic Techniques ◽  
Standard Drug ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors ◽  
Protein Pocket

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes. Objectives: In the present study, a new series of 2-substituted benzoxazole derivatives 2(a-f) and 3(a-e) were synthesized in our lab as potent anti-inflammatory agents with outstanding gastro-protective potential. The new analogs 2(a-f) and 3(a-e) were designed depending upon the literature review to serve as ligands for the development of selective COX-2 inhibitors. Methods: The synthesized analogs were characterized using different spectroscopic techniques (FTIR, 1HNMR, 13CNMR) and elemental analysis. All synthesized compounds were screened for their binding potential in the protein pocket of COX-2 and evaluated for their anti-inflammatory potential in animals using the carrageenan-induced paw edema method. Further 5 compounds were selected to assess the in vivo anti-ulcerogenic activity in an ethanol-induced anti-ulcer rat model. Results: Five compounds (2a, 2b, 3a, 3b and 3c) exhibited potent anti-inflammatory activity and significant binding potential in the COX-2 protein pocket. Similarly, these five compounds demonstrated a significant gastro-protective effect (p<0.01) in comparison to the standard drug, Omeprazole. Conclusion: Depending upon our results, we hypothesize that 2-substituted benzoxazole derivatives have excellent potential to serve as candidates for the development of selective anti-inflammatory agents (COX-2 inhibitors). However, further assessments are required to delineate their underlying mechanisms.

Is COX-2 a ‘collateral’ target in cancer prevention?

2005 ◽  
Vol 33 (4) ◽  
pp. 724-727 ◽  
Author(s):  
K. Kashfi ◽  
B. Rigas
Keyword(s):  
Cancer Prevention ◽  
Malignant Lesion ◽  
Aberrant Crypt Foci ◽  
Cardiovascular Side Effects ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
In Vitro Data ◽  
Modest Effect

NSAIDs (non-steroidal anti-inflammatory drugs) prevent colon and other cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug-developmental work focusing on COX (cyclo-oxygenase) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, one COX-2 inhibitor has been withdrawn from the market because of cardiovascular side effects, and there are concerns about a class effect. Evidence suggests that COX-2 may not be the only, or the ideal, target for cancer prevention; for example, COX-2 is not expressed in human aberrant crypt foci, the earliest recognizable pre-malignant lesion in the colon; COX-2 is expressed in less than half of the adenomas; in vitro data show that NSAIDs do not require the presence of COX-2 to prevent cancer; in familial adenomatous polyposis, the COX-2 inhibitor, celecoxib, had a modest effect, which was weaker than that of a traditional NSAID; and COX-2-specific inhibitors have several COX-2-independent activities, which may account for part of their cancer-preventive properties. The multiple COX-2-indpendent targets, and the limitations of COX-2 inhibitors, suggest the need to explore targets other than COX-2.

Bayesian approaches to aspects of the Vioxx trials: Non-ignorable dropout and sequential meta-analysis

2018 ◽  
Author(s):  
Jerry Cheng ◽  
David Madigan
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trials ◽  
Side Effects ◽  
Meta Analysis ◽  
Signs And Symptoms ◽  
Bayesian Approaches ◽  
Cardiovascular Side Effects ◽  
Menstrual Symptoms ◽  
Statistical Issues ◽  
Cox 2

This article discusses Bayesian approaches to aspects of the Vioxx trials study, with a focus on non-ignorable dropout and sequential meta-analysis. It first provides a background on Vioxx, a COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) approved by the FDA in May 1999 for the relief of the signs and symptoms of osteoarthritis, the management of acute pain in adults, and for the treatment of menstrual symptoms. However, Vioxx was found to cause an array of cardiovascular side-effects such as myocardial infarction, stroke, and unstable angina. As a result, Vioxx was withdrawn from the market. The article describes an approach to sequential meta-analysis in the context of Vioxx before considering dropouts in the key APPROVe study. It also presents a Bayesian approach to handling dropout and showcases the utility of Bayesian analysis in addressing multiple, challenging statistical issues and questions arising from clinical trials.

Selective COX-2 inhibitors: New insights into mechanisms of side effects?*

2008 ◽  
Vol 36 (9) ◽  
pp. 2694-2695 ◽  
Author(s):  
Suzanne Flier ◽  
Wolfgang Buhre ◽  
Wolfgang Buhre
Keyword(s):  
Side Effects ◽  
Cox 2 ◽  
Cox 2 Inhibitors

scholarly journals Brief Story on Prostaglandins, Inhibitors of their Synthesis, Hematopoiesis, and Acute Radiation Syndrome

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4019
Author(s):  
Hofer ◽  
Hoferová ◽  
Falk
Keyword(s):  
Side Effects ◽  
Significant Role ◽  
Acute Radiation ◽  
Selective Inhibitors ◽  
Acute Radiation Syndrome ◽  
Cox Inhibitors ◽  
Post Irradiation ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Prostaglandins and inhibitors of their synthesis (cyclooxygenase (COX) inhibitors, non-steroidal anti-inflammatory drugs) were shown to play a significant role in the regulation of hematopoiesis. Partly due to their hematopoiesis-modulating effects, both prostaglandins and COX inhibitors were reported to act positively in radiation-exposed mammalian organisms at various pre- and post-irradiation therapeutical settings. Experimental efforts were targeted at finding pharmacological procedures leading to optimization of therapeutical outcomes by minimizing undesirable side effects of the treatments. Progress in these efforts was obtained after discovery of selective inhibitors of inducible selective cyclooxygenase-2 (COX-2) inhibitors. Recent studies have been able to suggest the possibility to find combined therapeutical approaches utilizing joint administration of prostaglandins and inhibitors of their synthesis at optimized timing and dosing of the drugs which could be incorporated into the therapy of patients with acute radiation syndrome.

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