Safety Of Selective COX-2 Inhibitors Research Articles

Efficacy and safety of selective COX-2 inhibitors for pain management after third molar removal: a meta-analysis of randomized clinical trials.

To compare selective COX-2 inhibitors with ibuprofen in terms of analgesia, rescue medication consumption, and adverse effects after impacted third molar removal. Electronic databases were searched. Single dose, double-blind, randomized, and controlled clinical trials comparing the analgesic effect of a selective COX-2 inhibitor versus at least one active control group using ibuprofen after impacted third molar removal were selected. Twelve studies were included for the qualitative synthesis and eight were included in the meta-analysis. No statistically significant differences were found between selective COX-2 inhibitors and ibuprofen in terms of pain relief after 6, 8, and 12h. Rescue analgesia use after 24h was significantly greater in the ibuprofen group than in the selective COX-2 inhibitor group. There were no statistically significant differences in the number of patients presenting one or more adverse events between the two groups, though ibuprofen intake was related with more nausea and vomiting. No statistically significant differences were found in terms of pain relief 6, 8, and 12h post-medication between selective COX-2 inhibitors and ibuprofen following totally or partially impacted third molar removal. The patients who consumed selective COX-2 inhibitors needed less rescue analgesia after 24h. The occurrence of one or more adverse events was similar in both groups, though patients who consumed ibuprofen had more nausea and vomiting. COX-2 inhibitors could be considered a suitable alternative to ibuprofen for pain relief after third molar extraction in patients at risk of developing nausea and vomiting. Also, COX-2 inhibitors seem to slightly reduce the need of rescue medication consumption.

Progress in COX-2 Inhibitors: A Journey So Far

The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899. Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes. Their use is associated with side effects such as gastrointestinal and renal toxicity. A number of selective (second generation) COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Observation of increased cardiovascular risks in APPROVe (Adenomatous Polyp Prevention on Vioxx) study sent tremors and led to voluntary withdrawn of Vioxx (rofecoxib) by Merck from the market in September 2004 followed by Bextra (valdecoxib) in 2005 raising a question on the safety of selective COX-2 inhibitors. This leads to the belief that these effects are mechanism based and may be class effect. However, some studies suggested association of traditional NSAIDs with similar effects requiring a relook into the whole class of NSAIDs rather than simply victimizing the selective COX-2 inhibitors. Recognition of new avenues for selective COX-2 inhibitors such as cancer, Alzheimer's disease, Parkinson's disease, schizophrenia, major depression, ischemic brain injury and diabetic peripheral nephropathy has kindled the interest in these compounds. This review highlights the various structural classes of selective COX-2 inhibitors developed during past seven years (2003-2009) with special emphasis on diaryl-hetero/carbo-cyclic class of compounds. Molecular modeling aspects are also briefly discussed.

Prostanoid receptor antagonists: development strategies and therapeutic applications.

Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP(1), EP(2) ...) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP(1), TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP(2)). While some antagonists are structurally related to the natural agonist, most recent compounds are 'non-prostanoid' (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD(2) (acting on DP(1) and DP(2) receptors) and PGE(2) (on EP(1) and EP(4) receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage.

Expression analysis of the prostaglandin E2 production pathway in human pancreatic cancers.

There is strong evidence for an important role of cyclooxygenase (COX) 2 and COX-2-generated PGE2 during pancreatic tumorigenesis. Cyclooxygenase 2 has therefore become a potential chemotherapeutic target for pancreatic cancer. However, recent studies raised concerns regarding the safety of selective COX-2 inhibitors. Although the benefits of COX-2 inhibition may eventually outweigh the associated cardiovascular risks, there are a number of alternative targets for inhibiting the formation of PGE2 in human tumors that may prove less harmful to the patient. This study aimed at analyzing the expression of various proteins involved in the generation of PGE2 in human pancreatic cancers. Real-time polymerase chain reaction and Western blot analyses demonstrated overexpression of cytoplasmic phospholipase A2, COX-2, cytoplasmic prostaglandin E synthase, and microsomal prostaglandin E synthases 1 and 2 in most human pancreatic cancers when compared with matched normal pancreas. Immunohistochemistry revealed expression of these proteins predominantly by pancreatic cancer cells. Variable expression of these proteins was also confirmed in several human pancreatic cancer cell lines. Our studies demonstrated for the first time that various proteins involved in the generation of PGE2 are overexpressed in human pancreatic cancers. These proteins may represent potentially novel targets for the therapy of pancreatic cancers.

Coxibs and Cardiovascular Side-Effects: From Light to Shadow

Since the discovery of COX-2, a second subtype of cyclooxygenase, selective inhibitors or "coxibs" were developed with the idea that this isoform was inducible at the site of inflammation whereas COX-1 was expressed constitutively in several tissues including gastric epithelium. This new class of non steroidal anti-inflammatory agents was though to be safer for ulcerations of the gastroinstestinal mucosa observed with non selective COX-2 inhibitors. Nevertheless, at the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. This decision raised serious concerns about safety of selective COX-2 inhibitors which are actively marketed today, and the ones currently under development. The mechanism of this cardiovascular toxicity could lie in the inhibition of COX-2 itself, and thus be a class effect. On the other hand, these cardiovascular side effects could be limited on rofecoxib and be dependent on its chemical and/or pharmacological own properties. This hypothesis is undermined by the unexpected findings of one colon cancer study which has shown that celecoxib might also increase the chance of heart attack and stroke in some patients. In this review, we compared the different coxibs marketed to date on the basis of their clinical, pharmacological and chemical properties with the aim of providing some clues in the understanding of their potential or revealed "cardiovascular effects".

LBOVI-A-4Short-term gastrointestinal and cardiovascular safety of selective COX-2 inhibitors and non-selective nsaids: An instrumental variable analysis

BACKGROUND A direct comparison of the gastrointestinal (GI) and cardiac safety of NSAIDs in elderly patients is not possible based on randomized trials since different trials employed non-overlapping patient populations and comparison exposures. We sought to estimate the risk reduction of GI complications and risk increase in acute myocardial infarction (MI) by celecoxib and rofecoxib compared with several non-selective NSAIDs addressing confounding by using instrumental variable methods. METHODS We identified 49,731 Medicare beneficiaries who initiated non-selective NSAIDs or selective COX2 inhibitors between 1/1/99 and 7/31/03. Risk increase of GI complications and MI in 180 days after initiation of NSAID therapy (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) was assessed using instrumental variable analysis adjusting un/measured confounders. RESULTS Compared with celecoxib, a tendency for increased risk of GI complications was observed for ibuprofen (risk difference = 0.93 events per 100 patients; −1.88; 3.73) and diclofenac (RD=5.20; −1.07;11.5). We found a clear increase in the risk of MI for rofecoxib (RD=2.17; 0.12;4.21) and diclofenac (RD=7.63; 0.24;15.0), while naproxen had the lowest risk (RD = −1.59; −4.62;1.44). CONCLUSIONS Diclofenac appears to have the least favorable safety profile among NSAIDs, while naproxen has the lowest risk of MI with no meaningful increase in risk for GI complications, making it a viable alternative to celecoxib. Clinical Pharmacology & Therapeutics (2005) 79, P83–P83; doi: 10.1016/j.clpt.2005.12.296

Adverse drug reactions to NSAIDs

Whilst the debate on the safety of selective COX-2 inhibitors continues, articles such as the paper presented by Titchen et al. [1] do little to allay public fears about NSAIDs in general. This hospital based study of adverse drug reactions (ADRs) was effectively a retrospective audit of reactions suffered by children attending one paediatric facility in Australia. The authors’ conclusion that NSAIDs as a class are a significant cause of morbidity in children is without foundation. Firstly, no data are given about numbers of children who received NSAIDs without adverse effect. Secondly, from their data, 19/754 children suffered a probable or possible ADR to NSAIDs (2.5%). Of these, only 10/754 (1.3%) children had an ADR to ibuprofen alone. In comparison, the paracetamol ADR was 0.8%, which given the small sample size is in my view a comparable figure. Interestingly, of the 10 children who had a reaction to ibuprofen, haematemesis occurred in three cases, all in adolescents taking between 1600 and 1800 mg day−1 of the drug. This dose is in excess of UK recommendations for this age group, where the dose for juvenile rheumatoid arthritis is a maximum of 15 mg kg−1, so that even a 70 kg teenager would not receive a dose greater than 1050 mg under normal circumstances. Finally, the authors report one tragic case of a death with respiratory complications in a 10 year old girl on one tablet a day rofecoxib, and in whom the likelihood of an ADR was probable (Naranjo scale). Whilst I agree with the authors that we should develop better guidelines and carry out vigilant surveillance of ADRs in the paediatric population there is a risk that data such as those presented in this study could be misinterpreted by the media, the lay press and the public at large, causing further confusion and anxiety.

To the Heart of the Matter

When cyclooxygenase (COX)-2–selective inhibitors (coxibs) first entered the market about 5 years ago, the major concern with regard to cardiovascular side effects related to their potential to increase blood pressure and cause salt and water retention, in a manner similar to conventional (nonselective) nonsteroidal antiinflammatory drugs (NSAIDs). In the short time since, wariness about these side effects has grown into widespread alarm about putative prothrombotic actions and generation of excess major cardiovascular events with these agents. See p 1024 In September 2004, safety findings of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study indicated an increase in risk for myocardial infarction and stroke among subjects randomized to rofecoxib compared with those randomized to placebo. This study had been designed to examine recurrent colonic polyps rather than cardiovascular disease end points and therefore could only be considered hypothesis generating. Subsequent data from a number of observational studies further implicated the drug’s association with arterial thromboembolic disease. As with APPROVe, no single study generated sufficiently robust attestation by itself, but they provided concordant signals, and the accumulating evidence eventually reached a critical mass. As the data on rofecoxib emerged, concerns about other COX-2–selective agents on the market also grew. This was based on the assumption of a “class effect” for an increase in risk of cardiovascular disease related to preferential inhibition of prostacyclin over thromboxane and thus a tendency toward prothrombosis. The results presented by McAdam and colleagues in this issue of Circulation 1 challenge our view with regard to this prostanoid hypothesis and raise new questions about the mechanisms underlying the potential cardiovascular side effects of coxibs and traditional NSAIDs. The authors hypothesized that the enhanced systemic biosynthesis of prostacyclin in smokers was dependent on COX-2 activity. They also sought to determine the functional importance of COX2–derived prostacyclin (PGI2) in limiting platelet activation in smokers in vivo. Contrary to the conventional wisdom of an expected increase in the biosynthesis of TxA2 (related to increased platelet activation via COX-1), the authors demonstrated the opposite finding—ie, that COX-2 contributed to, and a COX-2 inhibitor reduced, TxA2 biosynthesis in smokers.

Selective COX-2 Inhibitors and Renal Injury in Salt-Sensitive Hypertension

In view of the ongoing controversy of cardiorenal safety of selective COX-2 inhibitors (coxibs), the present study was designed to examine the effects of 2 different coxibs, celecoxib and rofecoxib, compared with a traditional NSAID, diclofenac, and placebo on renal morphology and function in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl-enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib), or placebo was added to chow from weeks 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. Renal cortex mRNA was isolated for determination of COX-2, eNOS, and CRP mRNA by real-time reverse-transcriptase polymerase chain reaction. Untreated hypertensive animals showed glomerular injury including collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops, and an especially high grade of glomerulosclerosis (P<0.05 versus DR-placebo) and CD8-positive and ED1-positive cells (P<0.01 versus DR-placebo), which was improved by celecoxib but not by diclofenac and rofecoxib. C-reactive protein mRNA in renal cortex was increased in DS-placebo animals (P<0.05 versus DR-placebo) and normalized by celecoxib (P<0.05 versus DS-placebo), whereas eNOS mRNA was decreased in the DS-rofecoxib group (P<0.05 versus DR-placebo, DS-celecoxib, and DS-diclofenac). Proteinuria was observed in hypertensive animals (P<0.0001 versus DR-placebo), increased by rofecoxib (P<0.05 versus DS-placebo), and normalized by celecoxib (P=0.0015 versus DS-placebo). This head-to-head comparison of selective and nonselective COX inhibitors demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertension.

Current approaches to prevent NSAID‐induced gastropathy – COX selectivity and beyond

Gastrointestinal (GI) toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) is still an important medical and socio-economic problem--despite recent pharmaceutical advances. To prevent NSAID-induced gastropathy, three strategies are followed in clinical routine: (i) coprescription of a gastroprotective drug, (ii) use of selective COX-2 inhibitors, and (iii) eradication of Helicobacter pylori. Proton pump inhibitors are the comedication of choice as they effectively reduce gastrointestinal adverse events of NSAIDs and are safe even in long-term use. Co-medication with vitamin C has only been little studied in the prevention of NSAID-induced gastropathy. Apart from scavenging free radicals it is able to induce haeme-oxgenase 1 in gastric cells, a protective enzyme with antioxidant and vasodilative properties. Final results of the celecoxib outcome study (CLASS study) attenuated the initial enthusiasm about the GI safety of selective COX-2 inhibitors, especially in patients concomitantly taking aspirin for cardiovascular prophylaxis. Helicobacter pylori increases the risk for ulcers particularly in NSAID-naive patients and therefore eradication is recommended prior to long-term NSAID therapy at least in patients at high risk. New classes of COX-inhibitors are currently evaluated in clinical studies with very promising results: NSAIDs combined with a nitric oxide releasing moiety (NO-NSAID) and dual inhibitors of COX and 5-LOX. These drugs offer extended anti-inflammatory potency while sparing gastric mucosa.

Differential effects of selective cyclooxygenase-2 inhibitors on endothelial function in salt-induced hypertension

P-576 Key Words: Inflammation, Nitric Oxide, Oxidative Stress

Cyclooxygenase-2 inhibitors: are they really atherothrombotic, and if not, why not?

BACKGROUND AND SUMMARY: Selective cyclooxygenase (COX)-2 inhibitors are increasingly being used in place of "conventional" nonsteroidal anti-inflammatory drugs (NSAIDs). This is because they are just as effective as NSAIDs in relieving arthritic pain and yet less gastrotoxic. However, the cardiovascular safety of selective COX-2 inhibitors has been questioned because they selectively reduce prostacyclin production, thus disrupting the normal homeostatic balance and promoting a prothrombotic state. These theoretical concerns appear to be supported by the results of clinical trials demonstrating an increased risk of myocardial infarction with COX-2 inhibitors compared with a conventional NSAID, and indirect comparisons of the rates of myocardial infarction among patients treated with a selective COX-2 inhibitor compared with aspirin in different trials. However, emerging data from animal, experimental and clinical studies suggest that COX-2 is atherogenic and thrombogenic, and that selective COX-2 inhibitors may be cardioprotective. Meta-analyses of randomized trials of selective COX-2 inhibitors compared with placebo have demonstrated no excess of cardiovascular events among patients allocated COX-2 inhibitors, and preliminary data from a randomized controlled trial of the selective COX-2 inhibitor meloxicam, in patients with acute coronary syndrome who were treated with aspirin, demonstrated a reduction in cardiovascular events among patients allocated the COX-2 inhibitor. Continuing uncertainty regarding the direction and magnitude of any cardiovascular effects of selective COX-2 inhibitors, coupled with their widespread and increasing use, mandates prospective randomized evaluation of their efficacy and safety in patients at increased risk of future cardiovascular events.