The development of COX2 inhibitors with improved biochemical selectivity (such as etoricoxib and valdecoxib) over that of commercially available coxibs has been driven by the potential advantage of safety using higher coxib doses for increased efficacy. Etoricoxib has been approved in the UK as a once-daily medicine for symptomatic relief in the treatment of osteoarthritis (OA), rheumatoid arthritis (RA) and acute gouty arthritis. It is currently approved with additional indications (i.e., for relief of acute pain associated with dental surgery, for primary dysmenorrhoea and for chronic musculo-skeletal pain, including chronic lower-back pain) in Mexico, Brazil and Peru. Etoricoxib has an in vitro COX1/COX2 IC(50) ratio of 344, the highest of any coxib. The administration of therapeutic doses of etoricoxib to healthy subjects does not affect COX1 activity in circulating platelets and gastric biopsies. The profound inhibition of monocyte COX2 activity at 24 h after dosing, as predicted by a pharmacological half-life of approximately 22 h, supports a once-daily dosing regimen of etoricoxib. In randomised, well-controlled clinical trials, etoricoxib has been shown to have a comparable clinical efficacy with traditional NSAIDs. Combined analysis of efficacy trials with etoricoxib versus non-selective NSAIDs has shown that the drug halves both investigator-reported upper gastrointestinal perforation, ulcers and bleeds (PUBs) and confirmed PUBs, and reduces the need for gastroprotective agents and gastrointestinal comedications by approximately 40%. The risk of lower extremity oedema and hypertension adverse experiences with etoricoxib was low and generally similar to comparator NSAIDs in a combined analysis of eight Phase III studies in OA, RA, chronic low-back pain and surveillance endoscopy. Large, randomised clinical trials have been planned to confirm the renal, gastrointestinal and cardiovascular safety of etoricoxib.

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The development of nonsteroidal anti-inflammatory drugs (NSAIDs) selective for cyclooxygenase (COX)-2 (named coxibs) has been driven by the aim of reducing the incidence of serious gastrointestinal (GI) adverse events associated with the administration of traditional (t) NSAIDs – mainly dependent on the inhibition of COX-1 in GI tract and platelets. However, their use has unravelled the important protective role of COX-2 for the cardiovascular (CV) system, mainly through the generation of prostacyclin. In a recent nested-case control study, we found that patients taking NSAIDs (both coxibs and tNSAIDs) had a 35% increase risk of myocardial infarction. The increased incidence of thrombotic events associated with profound inhibition of COX-2-dependent prostacyclin by coxibs and tNSAIDs can be mitigated, even if not obliterated, by a complete suppression of platelet COX-1 activity. However, most tNSAIDs and coxibs are functional COX-2 selective for the platelet (ie, they cause a profound suppression of COX-2 associated with insufficient inhibition of platelet COX-1 to translate into inhibition of platelet function), which explains their shared CV toxicity. The development of genetic and biochemical markers will help to identify the responders to NSAIDs or who are uniquely susceptible at developing thrombotic or GI events by COX inhibition. We will describe possible strategies to reduce the side effects of etoricoxib by using biochemical markers of COX inhibition, such as whole blood COX-2 and the assessment of prostacyclin biosynthesis in vivo.

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Cyclooxygenase (COX) ‐2 is a key enzyme in the conversion of arachidonic acid (AA) to prostanoids . Inhibition of COX‐2‐dependent prostanoids by nonsteroidal anti‐inflammatory drugs (NSAIDs) (both traditional(t) and selective for COX‐2, named coxibs) is involved in their efficacy in affecting pain and inflammation and in reducing the recurrence of colorectal polyps. However, the use of tNSAIDs and coxibs is associated with a small but consistent increase of cardiovascular (CV) risk which is believed to be due to the reduction of the biosynthesis of endothelial COX‐2‐dependent prostacyclin (PGI 2 ) . Novel knowledge on the biology of COX‐2 show that endocannabinoids may be the substrate for the COX‐isozyme. Endocannabinoids and endocannabinoid‐derived products of COX‐2‐mediated oxidative metabolism serve a variety of regulatory functions. Interference with endocannabinoid metabolism by NSAIDs might contribute to their pharmacological effects. Key Concepts: COX‐2 is overexpressed in inflammation and cancer mainly through posttranscriptional mechanisms involving stabilisation of its mRNA. Enhanced cytoplasmic levels of RNA stability factors, such as HuR, and reduced levels of microRNAs govern COX‐2 mRNA stability and translational efficiency. The constitutive expression of COX‐2 in endothelial cells plays an important role in cardiovascular homoeostasis through the generation of prostacyclin. COX‐2 is the target of NSAIDs, traditional and coxibs, thus leading to therapeutic effects and cardiovascular hazard, in some individuals. The major mechanism of action of NSAIDs is through the inhibition of the conversion of AA to biologically active prostanoids. Novel knowledge on the biology of COX‐2 shows that the activity of the COX‐isozyme may be involved in the generation of novel biologically active lipid mediators through the metabolism of endocannabionids. COX‐2 might affect endocannabinoid tone by contributing to its reduction. Endocannabinoids activate cannabinoid receptors to serve a variety of regulatory functions. These novel actions of COX‐2 may suggest their contribution to the therapeutic effects of NSAIDs. The (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are inactive to inhibit the metabolism of AA by COX‐2, are potent substrate‐selective inhibitors of endocannabinoid oxygenation. The discovery of these novel effects of (R) enantiomers of NSAIDs opens the way to develop novel analgesic drugs based on this mechanism of action.

Background: Aspirin(acetylsalicylic acid, ASA) is recommended for the secondary prevention of atherothrombotic events and has shown anticancer effects. The current enteric-coated drug formulation may reduce aspirin bioavailability. Liquid formulations could improve aspirin pharmacokinetics and pharmacodynamics. IP1867B is a liquid-aspirin formulation that combines three ingredients, ASA/triacetin/saccharin.Methods: ASA and IP1867B(L-ASA) were assessed in human serum(obtained by allowing to clot human whole blood at 37 °C for 1h), washed platelets, and colonic adenocarcinoma HCA7 cells on eicosanoid generation and COX-isozyme acetylation at Serine529 and 516 by LC-MS/MS.Results: In serum, ASA and L-ASA acted by selectively affecting COX-1-derived eicosanoids, including thromboxane(TX)B2. L-ASA was more potent in inhibiting serum TXB2, a known biomarker of aspirin antiplatelet effect, than ASA. However, ASA and L-ASA were equipotent to acetylate COX-1 in washed platelets and COX-2 in HCA7 cells. In HCA7 cells, ASA and L-ASA acted by inhibiting prostaglandin(PG)E2(the most abundant prostanoid) and TXB2 biosynthesis. In the presence of a high arachidonic acid concentration(100 μM), 15R-hydroxyeicosatetraenoic acid(HETE) was generated at baseline by cancer cell COX-2 and was only slightly enhanced by supratherapeutic concentrations of ASA(1 mM). In whole blood and HCA7 cells treated with ASA or L-ASA, 15-epi-lipoxin(LX)A4 were undetectable.Conclusion: IP1867B was more potent in affecting serum TXB2 generation than ASA. The relevance of this finding deserves evaluation in vivo in humans. In cancer cells, ASA and IP1867B acted by inhibiting PGE2 and TXB2 generation via the acetylation of COX-2. ASA and IP867B at clinically relevant concentrations did not substantially induce the biosynthesis of 15R-HETE and 15-epi-LXA4.

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