Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity

  title={Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity},
  author={Kathleen M. Knights and Arduino Aleksander Mangoni and John O. Miners},
  journal={Expert Review of Clinical Pharmacology},
  pages={769 - 776}
The hypothesis that the anti-inflammatory activity of NSAIDs derives from COX inhibition is well established. It also underpins the accepted mechanism of the gastrointestinal and renal toxicity of NSAIDs. However, in terms of NSAID-induced cardiovascular toxicity, is COX inhibition then guilty by association? Multiple experimental models of COX-1/COX-2 inhibition have enabled ranking of the relative inhibitory activity of NSAIDs. Inhibition is expressed as an IC50 value and the index of COX… 
Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications.
  • S. HarirforooshWaheed AsgharF. Jamali
  • Medicine
    Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques
  • 2013
The GI toxicity of the NSAIDs is discussed, lower but still therapeutics doses of some NSAIDs may be cardioprotective and their renal and CV adverse effects are assessed.
COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles
The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.
Prostanoid receptor EP2 as a therapeutic target.
  • T. Ganesh
  • Biology, Medicine
    Journal of medicinal chemistry
  • 2014
The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases and future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2.
Evaluation of Selective COX-2 Inhibition and In Silico Study of Kuwanon Derivatives Isolated from Morus alba
Six kuwanon derivatives (A/B/C/E/H/J) extracted from the roots of Morus alba L. were evaluated to determine their cyclooxygenase (COX)-1 and 2 inhibitory effects, showing selective COX-2 inhibitory activity, almost equivalent to that of celecoxib, a known COX inhibitor.
Clinical Pharmacology and Cardiovascular Safety of Naproxen
The balance of evidence suggests that cardiovascular risk correlates with cyclooxygenase (COX)-2 selectivity, and the low COX-2Selectivity of naproxen results in a lower cardiovascular risk than that of other NSAIDs.
NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs
This review is focused on damage caused by NSAIDs in the upper and lower GI tracts, the different mechanisms of damage and the GI-sparing NSAIDs designed to minimize adverse events based on understanding of these mechanisms.
NSAIDs; Safety and Risk Assessment in CVS Events, Comparisons andFacts
While cardiovascular toxicities associated with NSAIDs are mainly related with COX-2 selective inhibitor and primarily dependent on their dose time and duration, variability in therapeutic response and susceptibility to toxicity is well recognized and can be manageable if considerable precautions implement.
Pharmacological evaluation of novel dimers of an arylpropionic acid class of non-selective cyclooxygenase inhibitors
The dimerised lead drug molecules showed significant anti-inflammatory, analgesic, and antipyretic activities in  animals and may further be explored as potential new drug candidates for inflammatory conditions.
Aldosterone glucuronidation inhibition as a potential mechanism for arterial dysfunction associated with chronic celecoxib and diclofenac use in patients with rheumatoid arthritis.
Celecoxib has a greater potency for AGI than diclofenac and its use is associated with a significantly higher AIX%, which supports AGI as a plausible mechanism for the CV toxicity of NSAIDs.


Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.
Questions that remain to be addressed are whether this hazard extends to all or some of the traditional NSAIDs; whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and how to identify individuals most likely to benefit or suffer from such drugs in the future.
Cardiovascular effects of the cyclooxygenase inhibitors.
The impact that the COX inhibitors have on CV events from several recent clinical trials for the treatment of arthritis or for cancer prevention, as well as from selected large observational studies, is discussed.
Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic
  • T. WarnerJ. Mitchell
  • Biology, Medicine
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2004
Clinical use of COX‐2‐selective compounds has ignited strong debates regarding potential side effects, most notably those within the cardiovascular system such as myocardial infarctions, strokes, and elevation in blood pressure, and this review will discuss how the latest studies help to understand the roles ofCOX‐1 and COx‐2 and what clinically proven benefits the newer generation of CO X‐2•selective inhibitors offer.
Experimental models used to investigate the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by non-steroidal anti-inflammatory drugs
Analysis of the ratio of inhibition ofCOX-1 to COX-2 by non-steroidal anti-inflammatory drugs, suggests inhibitors can be classified based on their COX selectivity, and human pharmacology studies concentrating on the inhibition of prostanoid synthesis in target tissues are of paramount importance in determining the clinical relevance of COx-2 selectivity.
Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2.
The International Consensus Meeting on the Mode of Action of COX-2 Inhibition (ICMMAC) brought together 17 international experts in arthritis, gastroenterology and pharmacology to foster a consensus definition on COx-2 specificity and to consider the clinical relevance of COZ-2-specific agents.
Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents
The structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COx-2 inhibitor, determined are explained and some of the conformational changes associated with time-dependent inhibition are demonstrated.
Review: Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema?
The body of literature linking the nsNSAIDs and COX-2 inhibitors with important adverse cardiorenal effects and their putative mechanisms is reviewed.
The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame
Despite initial promising reports that anti-inflammatory properties of cycloxygenase-2 (COX-2) inhibitors may confer anti-atherosclerosis effects and stabilize the atherosclerotic plaque, subsequent
Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.
This full in vitro analysis of COx-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.
Limitation of the in vitro whole blood assay for predicting the COX selectivity of NSAIDs in clinical use.
Assessment of COX-2 selectivity based on in vitro studies and pharmacological modelling has a limited clinical relevance and there is a need to investigate COX selectivity at therapeutic plasma concentrations of NSAIDs using the ex vivo whole blood assay.