Why cox 2 inhibitors

As a result, estimates of absolute event risk drawn from these database studies are likely to reflect more realistically the expectations for the population at large than do event rates drawn from randomized clinical trials.

Several recent epidemiologic studies indicate that the cardiovascular risk associated with COX-2 inhibitors generally is similar to that in patients receiving conventional nonselective NSAIDs, although small but potentially important within-group and between-group variability in cardiovascular risk may exist. Overall, the odds of experiencing a cardiovascular event among patients who were using COX-2 inhibitors was 1.

Another retrospective cohort study using a large state Medicaid database [ 33 ] illustrates the differences in risk that may be associated with usage of individual NSAIDs and COX-2 inhibitors Fig.

In this study the risk for acute MI and fatal coronary heart disease was compared between patients receiving rofecoxib, celecoxib, ibuprofen, and naproxen. Patients aged between 50 and 84 years who did not have life-threatening noncardiovascular illnesses were eligible for inclusion in the analysis. Data from Ray and coworkers [33]. Numbers n are person-years. Reproduced with permission from Elsevier [33]. Among the largest epidemiologic studies was a nested case—control analysis of information from the Kaiser-Permanente database [ 34 ].

This study, involving data from more than 1. Interestingly, in this study celecoxib nominally was associated with a lower event rate than that seen in remote drug users not a statistically significant finding, although the celecoxib event rate was significantly lower than that associated with naproxen, among other conventional NSAIDs. All NSAIDs, conventional and COX-2 selective, have the capacity to increase sodium and water retention and thereby to increase blood pressure and cause or potentiate congestive heart failure.

Blood pressure has an important influence on cardiovascular event rates; hypertension is a primary risk factor for cardiovascular events. Epidemiologic data indicate that an average blood pressure increase of even 2—3 mmHg, which is achievable with some NSAIDs and COX-2 inhibitors, can have a measurable impact on cardiovascular risk. Admission rates for heart failure in elderly patients are substantially higher among those who receive rofecoxib or nonselective NSAIDs than among those not receiving these drugs; however, celecoxib has not been associated with an increase in risk of admission for heart failure [ 35 ].

An early meta-analysis [ 36 ] found that, when data from all nonselective NSAIDs including aspirin were pooled, supine mean blood pressure was increased by 5. This suggests that use of these agents may result in different rates of cardiovascular adverse events.

A more recent meta-analysis of COX-2 inhibitors [ 38 ] found that, overall, these agents were associated with a higher relative risk for hypertension than placebo.

It appears that all NSAIDs — both conventional and COX-2 selective — have the capacity to increase sodium and water retention and to cause or potentiate hypertension and heart failure, although celecoxib appears to have a lower propensity to cause blood pressure elevations than does rofecoxib.

These data suggest that a plausible explanation for the apparent association of NSAIDs and COX-2 inhibitors with cardiovascular risk is the effect of these drugs on blood pressure.

Fortunately, this is a remediable problem because the blood pressure effects of the drugs can usually be reversed with appropriate therapy. Another mechanistic hypothesis has been advanced for the adverse cardiac effects of COX-2 inhibitors [ 39 ].

Prostaglandin I 2 is involved in inhibiting platelet aggregation, in causing vasodilation, and in preventing the proliferation of vascular smooth muscle cells. In contrast, thromboxane A 2 , which is largely produced by the COX-1 enzyme, is involved in platelet aggregation, vasoconstriction, and smooth muscle proliferation. As a result, patients in whom COX-2 is selectively suppressed might be expected to have elevated blood pressure, accelerated atherogenesis, and an exaggerated thrombotic response to plaque rupture.

This attractive hypothesis does not easily account for the observation from clinical trials, discussed above, that aspirin use does not appear to have influenced the relation of cardiovascular event rates observed between COX-2 inhibitors and comparators among patients in randomized trials. In addition, pharmacoepidemiologic studies show approximately similar event rates with the nonselective NSAIDs and with at least some doses of certain COX-2 selective inhibitors.

Thus, any relation between COX-2 inhibition and cardiovascular events is likely to be more complex than can be explained solely by an imbalance between COX-1 and COX-2 inhibition. An additional hypothesis suggests that at least some anti-inflammatory drugs may prevent cardiovascular events at some doses because of salutary effects on vascular endothelium or on the inflammatory components of atherosclerosis.

One study, conducted by Chenevard and colleagues [ 40 ], found that COX-2 inhibition improved endothelium dependent vasodilation and reduced low-grade chronic inflammation and oxidative stress in patients with severe coronary artery disease. Indeed, this may be particularly important in systemic inflammatory conditions, such as adult RA, that appear to enhance the risk for cardiovascular events, presumably by potentiating vascular inflammation.

Taken together, data from clinical trials and epidemiologic studies suggest that NSAIDs as a group may potentiate cardiovascular risk at some doses, whether they are selective for COX-2 or not. The data also suggest some interdrug variability in these effects, and a potentially important relation of cardiovascular effects and dose with at least some of these drugs. Among the COX-2 agents tested thus far at their labeled doses, cardiovascular and gastrointestinal safety profiles generally have been similar, although studies suggest that celecoxib may have a slightly better safety profile than other COX-2 inhibitors or NSAIDs.

A possible basis for this is suggested by the study conducted by Whelton and colleagues [ 41 ], in which elderly patients with OA and hypertension were randomly assigned to therapy with once daily celecoxib mg or rofecoxib 25 mg. Nearly twice as many patients who received rofecoxib experienced edema compared with those who received celecoxib. Mean blood pressure after 6 weeks of therapy was increased by 2.

The gastroprotective benefit of COX-2 inhibitors is partially or, in some patients, totally ameliorated if aspirin is used for cardiovascular prophylaxis. In a study conducted by Schnitzer and colleagues [ 44 ] 18, patients aged 50 years or older were randomly assigned to lumiracoxib mg once daily, naproxen mg twice daily, or ibuprofen mg three times daily for 1 year.

Patients were stratified by low dose aspirin use and age. Recent evidence suggests that gastrointestinal benefits may also be lost in patients who receive warfarin together with anti-inflammatory drugs. In a nested case—control analysis, Battistella and colleagues [ 45 ] quantified the gastrointestinal risk in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors.

During the study period, 0. These patients were 1. Paradoxically, the introduction of COX-2 inhibitors has been associated with an increase in hospitalization rates for upper gastrointestinal hemorrhage. In an epidemiologic study conducted by Mamdani and colleagues [ 46 ], billing records for more than 1. Moreover, it cannot be inferred that hospitalization rates directly reflect the impact of COX-2 inhibitor introduction; increased NSAID use and increasing use of aspirin for cardiovascular prophylaxis occurred during the same interval and might have importantly influenced the hospitalization data.

Data from Mamdani and coworkers [46]. NSAID, nonsteroidal anti-inflammatory drug. The article also examines recent research and explains the recommendations given by the U. See Potential Risks and Complications of Celecoxib. The studies tested new uses of the drugs and have shown an increased risk for cardiovascular problems among certain groups of patients.

For example, elderly patients and those who take the drugs for long periods of time tend to be more susceptible to known side effects such as gastrointestinal, kidney, and liver problems. The most important thing to remember is that each patient should meet with his or her physician to determine the best course of action based on individual risk factors, treatment needs, and previous experience with NSAIDs.

Ongoing trials are expected to answer — at least partly — the remaining questions concerning COX-2 and cancer. Here, we focus on the rationale for using selective COX-2 inhibitors as anti-cancer agents.

Increased amounts of COX-2 are found commonly in both premalignant and malignant tissues Overexpression of COX-2 appears to be a consequence of both increased transcription and enhanced mRNA stability 44 , Regulation of cyclooxygenase 2 COX-2 in cancer. By contrast, wild-type p53 suppresses transcription of COX COX-2 is also regulated by post-transcriptional mechanisms. In addition, prostaglandin E2 PGE2 induces COX-2 by activating the tyrosine kinase activity of the EGF receptor, but it is not known whether this positive feedback mechanism is relevant in human tumors.

Although many factors enhance COX-2 transcription, much less is known about negative modulators. Wild-type, but not mutant, p53 markedly suppresses the transcription of COX These findings suggest that the balance between activation of oncogenes and inactivation of tumor suppressor genes affects expression of COX-2 There is growing evidence that post-transcriptional mechanisms also determine COX-2 levels in neoplastic tissues.

Oncogenes, cytokines, growth factors and tumor promoters induce COX-2 by enhancing mRNA stability in addition to the stimulating transcription. In human colon cancers, overexpression of COX-2 is a consequence of both increased transcription and decreased mRNA turnover. COX-2 affects many processes that have been implicated in different stages of carcinogenesis. These include xenobiotic metabolism, cell proliferation, angiogenesis, apoptosis, immune function and tumor invasiveness 15 , 42 Figure 7.

Different mechanisms through which the COXderived prostaglandins are involved in the carcinogenesis derived from The peroxidase part of COX can convert the procarcinogens to carcinogens and thus initiate tumor formation. Substantial amounts of xenobiotics natural non-human organic compounds can be co-oxidized into mutagens by the peroxidase activity of COX This reaction could be relevant at organ sites that are exposed to tobacco carcinogens such as lung, oral cavity and bladder.

Similarly, estrogens, oxidized to diethylstilbestrol demonstrate transforming and genotoxic activity. Moreover, the metabolism of the arachidonic acid itself produces mutagens. Some by-products of the oxidation of arachidonic acid, like malondialdehyde are chemically highly reactive and form adducts with DNA Previous studies have demonstrated that PGs stimulate proliferation of different cell lines derived from gastrointestinal tract such as colonic, intestinal, gastric and esophageal cell lines.

Therefore, it is not surprising that NSAIDs and selective COX-2 inhibitors as inhibitors of PG synthesis exert the inhibitory effect on the proliferation of malignant cell lines derived from gastrointestinal tract in-vitro studies and on tumor growth in-vivo.

Studying downstream mechanisms can also support the role of COX-2 in carcinogenesis 15 , Their association with COX-2 inhibitors could therefore be interesting in treating cancer Apoptosis, the morphologically defined form of programmed cell death, plays a crucial role in the carcinogenesis. The disegulation of this process can lead to abnormal survival of cells and the increased risk of mutagenesis and oncogenesis COXderived PGs regulate programmed cell-death and reduce the apoptotic rate via inhibition of the mitochondrial apoptotic pathway characterized through reduced cytochrome c release, attenuated caspase-9 and -3 activation and upregulation of bcl-2 15 , Additionally, increased prostanoid generation due to the COX-2 overexpression specifically inhibits Fas-mediated apoptosis Another evidence supporting the role of PGs in the regulation of apoptotic rate of tumor cells is the studies demonstrating that COX-2 overexpression in these cells increases their resistance to apoptosis Conversely, COX-inhibitors trigger both the mitochondrial and death receptor-mediated apoptotic pathways with resultant cytochrome c release.

Tumor cell invasion is an extremely important factor for the formation of solid tumors and necessary for their spread to distant organs. Matrix degradation and cell motility are essential in this process. Matrix metalloproteinases MMPs are a family of matrix degradation enzymes. Their expression is associated with tumor cell invasion of the basement membrane and stroma, bloodvessel penetration and metastasis It has been demonstrated that COX-2 induces MMP expression in human colon cancer cells and therefore promotes metastasis COXderived PGs play an important role in the increased invasiveness of cancer cells.

One of the important mechanisms through which coxibs suppress the tumor invasiveness is the inhibition of matrix metalloproteinases MMP-2 and MM-9 which are known to facilitate cell invasion and migration with degrading the extracellular matrix Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is an essential process in the carcinogenesis and metastasis.

Neovascularization is regulated by the balance between pro-angiogenic factors and angiogenesis inhibitors in the local tissue environment. The link between the COXderived PGs and angiogenesis is suggested through studies showing a correlation between COX-2 gene expression and angiogenesis in premalignant tissues and cancer. Based on these observations, it is hypothesized that tumor-derived growth factors promote angiogenesis by inducing the production of COXderived PGE2 15 , PGs have ability to regulate the immune system.

This is of great clinical importance since immunosuppression correlates with the progression of the neoplastic diseases. Macrophages are activated and produce PG E2 which in turn inhibits the production of regulatory cytokines, the B and T-cell proliferation, and decreases the cytotoxic activity of natural killer NK cells.

Interestingly, the induction of IL and its immunosuppressive effects are related to PG E2 production. Thus, the overproduction of COXderived PGs could result in the inhibition of cell-mediated antitumor response MDR-1 or P-glycoprotein , is an efflux pump for chemotherapeutic drugs and thereby contributes to multidrug resistance. Overexpression of COX-2 has been found to increase the production and function of MDR-1 in cells in culture, an effect that was prevented by treatment with a selective COX-2 inhibitor.

Although much work is required to establish the clinical significance of this interaction, it is appealing to speculate that selective COX-2 inhibitors will enhance the anti-tumor activity of cancer chemotherapy by reducing the multidrug resistance Estrogen deprivation is an effective therapy for the prevention and treatment of hormone-dependent breast cancer. The final step in estrogen biosynthesis is catalyzed by aromatase.

PGE2 increases the aromatase activity in cells in culture and, thus, should stimulate cell proliferation indirectly by increasing the estrogen biosynthesis. This implies that inhibiting the production of estrogen in breast tissue using a selective COX-2 inhibitor might be useful for either preventing or treating breast cancer It can be concluded that: 1 COXderived PGs play a key role in the tumorogenesis; 2 The tumor-promoting effect of PGs may be attributed to their ability to stimulate the cell proliferation and migration, to inhibit the apoptosis and to increase angiogenesis and invasiveness; 3 in accordance to the proposed major role of COX-2 in cancerogenesis, selective COX-2 inhibitors have been shown in numerous studies to exhibit strong chemopreventive effect on the development of cancers.

This inflammatory response may damage neurons and exacerbate the pathological processes underlying the disease. Since COX-2 expression in the brain and PGE2 content in the cerebrospinal fluid have been reported to be elevated in AD together with the finding that COX-2 protein levels in the brain correlate with the severity of amyloidosis and clinical dementia, it has been suggested that COX-2 inhibition by NSAIDs might be involved in the apparent protection in this setting.

However, the results of a recent randomized, double-blind clinical trial of rofecoxib vs. Several factors might have contributed to the failure of this trial. In particular, the selection of patients with advanced neuropathology and the short period of exposure to treatment may have played a role. However, it should be pointed out that no evidence is available to correlate these alternative mechanisms of NSAIDs with their clinical benefit reported inpopulation-based studies.

COX-2 is constitutively expressed at high levels in brain and is specifically concentrated in pyramidal neurons which are vulnerable to AD pathology. On the other hand, COX-1 is not constitutively expressed in brain at high levels but is upregulated in reactive microglia, the target for inflammatory suppression.

It would be anticipated, therefore, that NSAIDs 1 rather than selective COX-2 inhibitors would be more likely to reduce the brain inflammation selectively 41 , 59 , However, it has been shown that COX-2 is up-regulated in brain dopaminergic neurons of both PD postmortem specimens and 1-methylphenyl-1,2,3,6-tertrahydropyridine MPTP mouse model of PD, and COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone involved in the pathogenesis of PD, suggesting that the inhibition of COX-2 may be a valuable target for the development of new therapies for PD aimed at slowing the progression of the neurodegenerative process Within the last two decades, the volume of literature on the structural types introduced as selective COX-2 inhibitors is enormous.

In this review, we have chosen to focus on the structure-activity relationship SAR and also various structural families of compounds, which have emerged within the last years. The chemical structures of COX-2 inhibitors are heterogenic so that a further classification of this group will be made in the following chapter.

Contrary to the classic NSAIDs Figure 8 , this new class of enzyme inhibitors is lacking a carboxylic group, thus effecting COX-2 affinity by a different orientation within the enzyme without formation of a salt bridge in the hydrophobic channel of the enzyme.

In general classification, selective COX-2 inhibitors belong to two major structural classes: 1 Tricyclics also known as ortho-diarylheterocycles or carbocycles ; 2 Non-tricyclics. All of the compounds in this class possess 1,2-diarylsubstitution on a central hetero or carbocyclic ring system with a characteristic methanesulfonyl, sulfonamido, azido, methanesulfonamide or pharmacophore-based tetrazole group on one of the aryl rings that plays a crucial role on COX-2 selectivity.

Coxibs such as Celecoxib, Rofecoxib, Valdecoxib and etc , belong to this common structural class 62 Figure 9. Compounds belonging to this class can be sub-classified based on the size and type of the central heterocyclic or carbocyclic ring system core.

Ring contraction to smaller carbocycles such as cyclobutenes also leads to potent COX-2 inhibitors as well as insertion of 5- and 6-membered carbocyclic or heterocyclic groups Figure A wide variety of 5-membered heterocycles can serve as a template for COX-2 inhibitors Figure 13 , i.

Knaus et al. Zarghi et al. Compounds [14] and [15] were potent COX-2 inhibitors which showed higher selectivity than celecoxib Besides, a group of 2-aryl, 3-benzyl- 1,3-oxazolidine or 1,3-thiazolidine ones possessing a SO2Me pharmacophore at the para-position of C-2 phenyl ring were reported by Zarghi et al.

New series of 2,4,5-triarylimidazoles possessing a SO 2 CH 3 pharmacophore at thepara position of C-4 phenyl ring has also been reported by Zarghi et al.

Structure-activity relationship of this group showed that COX-2 inhibitory potency and selectivity is dependent on the nature of the substituent on the C-2 phenyl ring. Compound [18] possessing OH group at the para-position of the C-2 phenyl ring is the most potent and selective COX-2 inhibitor in this group 76 Figure One of the first structural types emerged in this category were pyridine series. Li et al. Various n -substituted analogues were initially prepared to evaluate the effect of n -substitution in this category.

It was very clear that n -substitution was absolutely required for a good in-vitro COX-2 inhibitory potency since the unsubstituted analogues were not potent. Vioxx rofecoxib was recalled worldwide in due to concerns about adverse cardiovascular effects, like heart attacks and strokes.

Bextra valdecoxib was withdrawn from U. Prexige lumiracoxib was withdrawn from much of the world market because of concerns about severe liver damage. Arcoxia etoricoxib is available in many countries, but not in the United States.