NSAIDs and cardiovascular disease: transducing human pharmacology results into clinical read-outs in the general population

doi:10.1016/S1734-1140(10)70310-8

Pharmacological Reports

Volume 62, Issue 3, May–June 2010, Pages 530-535

https://doi.org/10.1016/S1734-1140(10)70310-8 Get rights and content

Abstract

Traditional (t) non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors (coxibs) are important and efficacious drugs for the management of musculoskeletal symptoms. These drugs have both beneficial and adverse effects due to the inhibition of prostanoids. Although the tNSAID and coxib inhibition of COX-2-dependent prostaglandin (PG)E2 production is effective in ameliorating symptoms of inflammation and pain, a small but consistent increased risk of myocardial infarction has been detected in association with their use. Convincing evidence suggests that cardiovascular toxicity associated with the administration of these compounds occurs through a common mechanism involving inhibition of COX-2-dependent prostacyclin. The development of biomarkers that predict the impact of NSAIDs on COX-1 and COX-2 activities in vitro, ex vivo and in vivo has been essential to read-out the clinical consequences of the varying degrees of inhibition of the two COX-isozymes in humans. Whole blood assays for COX-1 and COX-2 might be candidates as surrogate end-points of toxicity and efficacy of NSAIDs. Using a biomarker strategy, we have shown that the degree of inhibition of COX-2 and the functional selectivity with which it is achieved are relevant to the level of cardiovascular hazard from NSAIDs and relate to drug potency (exposure). We propose that the assessment of COX-2 in whole blood ex vivo, either alone or in combination with urinary levels of 2,3–dmor-6–keto-PGF_1a a biomarker of prostacyclin biosynthesis in vivo, may represent a valid surrogate end-point to predict cardiovascular risk for functionally selective COX-2 inhibitors.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are an important and efficacious class of drugs for the management of musculoskeletal symptoms. These compounds cause both beneficial and adverse effects due to the inhibition of prostanoids [12, 37]. Prostanoids are biologically active derivatives of arachidonic acid (AA) released from membrane phospholipids by phospholipases [14]. AA is transformed into prostaglandin (PG)H2, through the activity of cyclooxygenase (COX) enzymes (i.e., COX-1 and COX-2). PGH2 is subsequently metabolized by terminal synthases into the biologically active prostanoids, such as prostacyclin (PGI₂), PGD₂, PGF_2α, PGE₂ and thromboxane (TX)A₂ [14, 17]. In particular, the isomeriza-tion of PGH2 to PGE₂ is catalyzed by three different isomerases: a cytosolic PGE synthase (cPGES) and two membrane-bound PGESs, mPGES-1 and mPGES-2 [22]. Of these isomerases, cPGES and mPGES-2 are constitutive enzymes whereas mPGES-1 is mainly an induced isoform.

COX-1 and COX-2 have the same catalytic activities: cyclooxygenase and peroxidase [34, 38]. However, the two isoforms of COX are the products of different genes. The COX-1 gene is considered a “housekeeping gene” by virtue of the constitutively low levels of expression in most cell types. In contrast, the gene for COX-2 is a primary response gene with multiple regulatory sites. COX-2 expression can be rapidly induced by bacterial endotoxin (LPS), cytokines (such as interleukin (IL)-1β and tumor necrosis factor (TNF)- α), growth factors, and the tumor promoter phorbol myristate acetate (PMA) [19]. COX-1-dependent prostanoids play an essential homeostatic role in gastrointestinal (GI) cytoprotection [20, 30, 39], while COX-2-dependent prostanoids play dominant roles in pathophysiologic processes, such as inflammation [6, 9]. Several lines of evidence suggest that the main mechanism of action for traditional (t)NSAIDs and NSAIDs selective for COX-2 (named coxibs), used for the treatment of pain and inflammatory joint disease, is the inhibition of COX-2-dependent PGE₂ [11]. Inhibition of constitutively expressed COX-1 in the GI tract and presumably in platelets by tNSAIDs seems to play a role in the increased risk of upper GI bleeding/perforation [30]. Proof of concept of this hypothesis came from the finding that reduced incidence of serious GI adverse effects has been shown for two COX-2 inhibitors, such as rofecoxib and lumiracoxib, when compared to tNSAIDs in large randomized clinical trials (RCTs) [3, 33].

Although the inhibition of COX-2-dependent PGE₂ production by tNSAIDs and coxibs is effective in ameliorating symptoms of inflammation and pain, a small but consistent increased risk of myocardial infarction (MI) has been detected in NSAID users [15, 16, 26]. Increased incidences of thrombotic events have been detected in placebo-controlled trials involving the COX-2 inhibitors celecoxib, rofecoxib and valdecoxib [4, 24, 25, 35]. However, the results of observational studies and a meta-analysis of data derived from trials with coxibs have shown that the cardiovascular hazard is also related to some tNSAIDs, such as diclofenac [15, 18, 21]. Convincing evidence suggests that cardiovascular toxicity associated with the administration of NSAIDs selective for COX-2 and some tNSAIDs occurs through a common mechanism involving the inhibition of COX-2-dependent prostacyclin.

Section snippets

Pharmacology of NSAIDs

The biochemical selectivity of COX inhibitors for COX-2 has been assessed in the past using different in vitro assays. These experiments yielded variable results depending on the assay used. In fact, several variables may affect the heterogeneity of the results, including the concentrations of exogenous AA, the lack of plasma proteins, and different types of isolated enzyme [5]. To overcome the variability associated with these assays, the human whole blood assays were developed. They are

Cardiovascular hazard of NSAIDs

It has recently been shown that patients taking NSAIDs, both coxibs and tNSAIDs, had a 35% increased risk of non-fatal MI [relative risk 1.35, (95% CI), 1.23 to 1.48] [15]. This elevation of risk increased with increasing treatment duration and daily dose. Using a translational medicine approach, from proof of concept in cells and experimental animals to studies in humans, it was possible to show that the inhibition of COX-2-dependent prostacyclin is the most plausible mechanism for the

Perspectives

The development of biomarkers capable of predicting the impact of NSAIDs on COX-1 and COX-2 activities in vitro, ex vivo and in vivo has been essential to understanding the clinical consequences of varying degree of inhibition of COX-isozymes in humans.

Whole blood assays for COX-1 and COX-2 might be candidates for monitoring levels of toxicity and efficacy of NSAIDs. Using a biomarker strategy, we have shown that, within the group of functionally COX-2 selective NSAIDs with respect to platelets

Acknowledgments

We would like to thank Dr. Licia Totani, Dr. Virgilio Evangelista, Dr. Luigia Di Francesco and Dr. Annalisa Bruno for their invaluable contributions to the results discussed in this review.

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Gastrointestinal erosions, ulcerations and bleeding have, for long, been the most commonly reported ADRs, with a 15–30% incidence rate of peptic ulcers among NSAID users (Butt et al., 1988; SE Burke and FitzGerald, 2006). Furthermore, cardiovascular complications of NSAIDS were reported to be correlated with doses used and potency of cyclooxygenase 2 (COX-2) inhibition of individual agents (García Rodríguez et al., 2008; Capone et al., 2010). Attempts of preserving the analgesic and anti-inflammatory effects of NSAIDs while eliminating ADRs have led to the development of selective COX-2 inhibitors.
The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital importance to patients suffering from chronic course pain and inflammatory conditions. This study aims at evaluating the therapeutic activity and adverse drug reactions associated with the use of the newly synthesized pyrazole derivative, compound AD732, E-4-[3-(4-methylphenyl)-5-hydroxyliminomethyl-1H-pyrazol-1-yl]benzenesulfonamide, as compared to indomethacin and celecoxib as standard agents. Anti-inflammatory activity was assessed using carrageenan-induced rat paw edema and cotton pellet granuloma tests; formalin-induced hyperalgesia and hot plate tests were done to study analgesic activity. In vitro tests to determine COX-1/COX-2 selectivity and assessment of renal and gastric toxicity upon acute exposure to AD732 were also conducted. Compound AD732 exhibited promising results; higher anti-inflammatory and analgesic effects compared to standard agents, coupled with the absence of ulcerogenic effects and minimal detrimental effects on renal function. Additionally, compound AD732 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It may be concluded that compound AD732 appears to be a safer and more effective molecule with promising potential for the management of pain and inflammation.
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Cilostazol exerts potent anti-inflammatory effects and celecoxib, a COX-2 specific inhibitor, improves the unsatisfactory profile of NSAIDs. It was aimed to assess the anti-arthritic potential of celecoxib add-on for cilostazol therapy in collagen induced arthritis (CIA), and to elucidate the implication of interleukin (IL)-10 in the action of cilostazol and celecoxib cotreatment. Cotreatment of RAW 264.7 cells with 10 μM cilostazol and 0.3 μM celecoxib synergistically suppressed RANKL-induced increases in RANK mRNA and protein levels. When cultured in the presence of RANKL for 5 days, RANKL-stimulated expressions of osteoclastogenic genes (OSCAR, DC-STAMP, and cathepsin K mRNA) and the expression of RANK mRNA were markedly elevated. Furthermore, these gene expressions, including that of RANK, were significantly suppressed by cotreatment with cilostazol (10 μM) and celecoxib (0.3 μM). In addition, this co-treatment strongly down-regulated RANKL-induced NFATc1 protein and TRAP activity (key osteoclastogenic factors), and these down-regulations were significantly prevented by pretreating cells with IL-10 neutralizing antibody. Furthermore, increased osteoclast formation and extensive resorption pit formation by bone marrow-derived monocytes obtained from C57BL/6 mice cultured in the presence of M-CSF/RANKL were markedly suppressed by cilostazol and celecoxib cotreatment. Consequently, hindlimb paw thicknesses in DBA/1J CIA mice were significantly reduced by cilostazol (10 mg/kg/d) and celecoxib (5 mg/kg/d) cotreatment. These results were accompanied by synergistic suppression of cartilage depletion and bone erosion and reductions in arthritis scores in the CIA mice. In conclusion, serum IL-10 levels in these mice were markedly increased by cilostazol and celecoxib cotreatment, whereas elevated serum IL-1β levels were markedly reduced. Cotreatment with low-dose cilostazol and celecoxib may ensure the synergistic anti-arthritic potential.
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This problem was addressed by the development of COX-2–selective inhibitors that preserved COX-1–dependent gastrointestinal PGE2 production. These drugs exhibit good anti-inflammatory activity with reduced gastrointestinal side effects; however, subsequent clinical trials uncovered adverse cardiovascular side effects associated with inhibition of COX-2 (10, 11). An alternative approach to NSAID-mediated gastrointestinal toxicity is to increase the levels of AEA and other fatty acyl ethanolamides (FAEs), such as palmitoylethanolamide, in individuals receiving NSAID therapy.
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Citation Excerpt :
A review of the available safety data demonstrated that diclofenac use was associated with the highest cardiovascular risk among nonselective NSAIDs (Farkouh and Greenberg, 2009). The inhibition of COX2-mediated prostacyclin synthesis is proposed as the cause for the poor cardiovascular outcomes (Capone et al., 2010). In addition, prostaglandin F-2α, a product of COX activity, contributes to myocardial fibrosis in a manner that is dependent on ROCK activity (Ding et al., 2012) offering a potential for crosstalk between CSA- and NSAID/COX inhibition-mediated cardiotoxicity.
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NSAIDs and cardiovascular disease: transducing human pharmacology results into clinical read-outs in the general population

Abstract

Introduction

Section snippets

Pharmacology of NSAIDs

Cardiovascular hazard of NSAIDs

Perspectives

Acknowledgments

Gastroenterology

J Am Coll Cardiol

Prog Lipid Res

Gastroenterology

J Thorac Cardiovasc Surg

Chest

Thromb Res

J Thromb Haemost

Blood

Lancet

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

BMJ

Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition

Circ Res

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

N Engl J Med

Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial

N Engl J Med

Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2

Rheumatology

Many actions of cyclooxygenase-2 in cellular dynamics and in cancer

J Cell Physiol

Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects

Circulation

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

J Clin Invest

COX-1 and COX-2 tissue expression: implications and predictions

J Rheumatol