Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX‐1 and COX‐2. COX‐2 is the therapeutic target for the nonsteroidal anti‐inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one of the fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, knowledge that has allowed us, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways, and how they can be used to improve human health. Perhaps, the most important and controversial outstanding question in the field remains; ‘how do NSAIDs produce their much publicized cardiovascular side‐effects?’ This review summarizes the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COX products and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side‐effects of NSAIDs.

Linked Articles

This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc

Related collections

Most cited references 83

Record: found
Abstract: found
Article: not found

Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

C Bombardier, L Laine, A Reicin … (2000)

Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

0 comments Cited 402 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

Robert Bresalier, Robert Sandler, Hui Quan … (2005)

Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk. Copyright 2005 Massachusetts Medical Society.

0 comments Cited 380 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.

Scott Solomon, John J V McMurray, Marc Pfeffer … (2005)

Selective cyclooxygenase-2 (COX-2) inhibitors have come under scrutiny because of reports suggesting an increased cardiovascular risk associated with their use. Experimental research suggesting that these drugs may contribute to a prothrombotic state provides support for this concern. We reviewed all potentially serious cardiovascular events among 2035 patients with a history of colorectal neoplasia who were enrolled in a trial comparing two doses of celecoxib (200 mg or 400 mg twice daily) with placebo for the prevention of colorectal adenomas. All deaths were categorized as cardiovascular or noncardiovascular, and nonfatal cardiovascular events were categorized in a blinded fashion according to a prespecified scheme. For all patients except those who died, 2.8 to 3.1 years of follow-up data were available. A composite cardiovascular end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure was reached in 7 of 679 patients in the placebo group (1.0 percent), as compared with 16 of 685 patients receiving 200 mg of celecoxib twice daily (2.3 percent; hazard ratio, 2.3; 95 percent confidence interval, 0.9 to 5.5) and with 23 of 671 patients receiving 400 mg of celecoxib twice daily (3.4 percent; hazard ratio, 3.4; 95 percent confidence interval, 1.4 to 7.8). Similar trends were observed for other composite end points. On the basis of these observations, the data and safety monitoring board recommended early discontinuation of the study drug. Celecoxib use was associated with a dose-related increase in the composite end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure. In light of recent reports of cardiovascular harm associated with treatment with other agents in this class, these data provide further evidence that the use of COX-2 inhibitors may increase the risk of serious cardiovascular events. Copyright 2005 Massachusetts Medical Society.

0 comments Cited 304 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Jane A Mitchell:

ORCID: http://orcid.org/0000-0001-9879-546X

j.a.mitchell@ic.ac.uk

Nicholas S Kirkby: n.kirkby@ic.ac.uk

Journal

Journal ID (nlm-ta): Br J Pharmacol

Journal ID (iso-abbrev): Br. J. Pharmacol

Journal ID (doi): 10.1111/(ISSN)1476-5381

Journal ID (publisher-id): BPH

Title: British Journal of Pharmacology

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0007-1188

ISSN (Electronic): 1476-5381

Publication date (Electronic): 14 April 2018

Publication date (Print): April 2019

Publication date PMC-release: 14 April 2018

Volume: 176

Issue: 8 , Themed Section: Eicosanoids 35 years from the 1982 Nobel: where are we now? Guest Editors: Roderick J Flower and Timothy D Warner ( doiID: 10.1111/bph.v176.8 )

Pages: 1038-1050

Affiliations

[ ¹ ] Cardiothoracic Pharmacology National Heart and Lung Institute London UK

Author notes

[*] [* ] Correspondence Jane A. Mitchell and Nicholas S. Kirkby, Cardiothoracic Pharmacology, National Heart and Lung Institute, Dovehouse Street, London SW36LY, UK. E‐mail: j.a.mitchell@ 123456ic.ac.uk ; n.kirkby@ 123456ic.ac.uk

Author information

Jane A Mitchell http://orcid.org/0000-0001-9879-546X

Article

Publisher ID: BPH14167 Other ID: 2017-BJP-1500-RCT-G.R1

DOI: 10.1111/bph.14167

PMC ID: 6451069

PubMed ID: 29468666

SO-VID: 75b4bed3-2a18-4047-8774-a1be518e707f

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 08 December 2017

Date revision received : 19 January 2018

Date accepted : 29 January 2018

Page count

Figures: 5, Tables: 0, Pages: 13, Words: 6252

Funding

Funded by: British Heart Foundation

Award ID: FS/16/1/31699

Custom metadata

source-schema-version-number 2.0

component-id bph14167

cover-date April 2019

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:06.04.2019

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

Read this article at

Abstract

Linked Articles

Related collections

RNA drug delivery

Most cited references 83

Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.

Author and article information

Contributors

Journal

Affiliations

Author notes

Author information

Article

History

Page count

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 913

Cited by 74

Most referenced authors 1,462