Dexamethasone Impairs the Gastric Mucosal Integrity in Rats Treated with a Cyclooxygenase-1 but Not with a Cyclooxygenase-2 Inhibitor
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In rats, neither the cyclooxygenase-1 inhibitor SC-560 nor the cyclooxygenase-2 inhibitor rofecoxib damages the gastric mucosa. Coadministration of dexamethasone induced injury in SC-560- but not in rofecoxib-treated rats. High levels of cyclooxygenase-1 protein occurred in the gastric mucosa of control rats, with no change after administration of SC-560. In contrast, the gastric cyclooxygenase-2 protein levels were low in control rats, but increased in a time-dependent manner after administration of SC-560. Dexamethasone prevented the increase in cyclooxygenase-2 protein levels. Our findings show that inhibition of cyclooxygenase-1 upregulates cyclooxygenase-2. When the upregulation is prevented by dexamethasone, gastric damage develops, suggesting that induction of cyclooxygenase-2 represents a compensatory mechanism that counteracts the injurious effect of cyclooxygenase-1 inhibition.Objective To compare the effects of two cyclooxygenase-2 inhibitors,celecoxib and rofecoxib on the growth of human osteosarcoma (HOS-8603) and lung cancer cell (A-549) lines. Methods The anti-proliferation effects were determined by methabenzthiazuron (MTT) method. The cell growing cycle and the cell apoptosis were analyzed by flow cytometry. Results Cyclooxygenase-2 inhibitors, celecoxib and rofecoxib had inhibitory and apoptosis-inducting effect on the growth of the two tumor cell lines. The inhibitions of celecoxib and rofecoxib to the two tumor cell lines were dose-dependent and time-dependent. The cells treated with the two drugs showed a G_2/M arrest which was the peak time of apoptosis. There was a significant difference between rofecoxib and celecoxib groups ( P 0.05). And celecoxib had a stronger inhibition to HOS-8603 than rofecoxib. Conclusion Cyclooxygenase-2 inhibitors, celecoxib and rofecoxib have significant effect on the growth of the two tumor cell lines, and may become useful medicines in tumor treatment.
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Objective: To study the clinical safety of selective cyclooxygenase-2 inhibitors which mainly include rofecoxib,celecoxib,valdecoxib and lumiracoxib.Methods: The related literatures were searched for and analyzed retrospectively with clinical practice.Results: The selective cyclooxygenase-2 inhibitors including rofecoxib,celecoxib,valdecoxib and lumiracoxib could increase the risk of cardiovascular event and the risk of rofecoxib was higher than celecoxib.Conclusion: Cardiovascular risk is of class effect of the selective cyclooxygenase-2 inhibitors.Supervision of them in clinical use should be intensified and the cardiovascular safety of these drugs should be investigated further.
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Sulindac
Celecoxib
Prostaglandin H2
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Specific inhibitors of cyclooxygenase-2 were introduced into widespread clinical use in 1999. Since that time, celecoxib and rofecoxib have become two of the most commonly prescribed medications in the United States. Clinical trials using these medications for arthritis and pain have uniformly demonstrated efficacy superior to that of placebo and similar to that of nonsteroidal anti-inflammatory drugs. However, controversy surrounding the proper place of cyclooxygenase-2 inhibitors in the hierarchy of treatment for arthritis continues, based primarily on their higher cost compared with that of acetaminophen and nonsteroidal anti-inflammatory drugs. A decreased risk of gastrointestinal toxicity remains the primary justification for using the more expensive cyclooxygenase-2 inhibitors in preference to nonsteroidal anti-inflammatory drugs. The renal and cardiovascular effects of rofecoxib and celecoxib have been investigated in relation to nonsteroidal anti-inflammatory drugs and to one another. The data with respect to alteration in renal function, lower extremity edema, and hypertension indicates that cyclooxygenase-2 inhibitors affect the kidney in a manner similar to that of nonsteroidal anti-inflammatory drugs. The data comparing the cyclooxygenase-2 inhibitors is difficult to interpret because it is not clear that comparable doses have been used in clinical trials. The potential thrombogenic risk of cyclooxygenase-2 inhibitors remains controversial, and conflicting data exist. It remains important to increase our understanding of the place of these agents in clinical practice from the perspective of efficacy, toxicity, and cost.
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For about two years, selective inhibitors of cyclooxygenase-2 have been hailed as powerful additions to the armamentarium of nonsteroidal anti-inflammatory drugs (NSAIDs). Predicted by financial analysts to become among the pharmaceutical industry's greatest-ever blockbusters, two so-called coxibs are now widely utilized clinically: rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Monsanto). The clinical advantages of the coxibs over traditional NSAIDs are related to the distinct roles played by cyclooxygenase-2 in comparison to its earlier described isoform, cyclooxygenase-1. Ongoing research into the disparate roles of the two isoforms will have implications not only for the pharmaceutical use of coxibs, but also for our basic appreciation of inflammation, cardiovascular diseases, Alzheimer's disease, cancer, and more.
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Selective cyclooxygenase-2 inhibitors represent a significant advance in the management of inflammatory disorders. They have similar efficacy to nonselective ‘conventional’ nonsteroidal anti-inflammatory drugs, but a superior gastrointestinal safety profile. However, a significant caveat is the perceived potential of cyclooxygenase-2 inhibitors to cause adverse cardiovascular effects, an issue first raised by the Vioxx Gastrointestinal Outcomes Research (VIGOR) study of rofecoxib (Vioxx®, Merck & Co. Inc.). Mechanisms by which cyclooxygenase-2 inhibitors may increase cardiovascular risk are selective inhibition of prostaglandin I2 over thromboxane A2 within the eicosanoid pathway, which promotes thrombosis, and inhibition of prostaglandins E2 and I2 within the kidney, which leads to sodium and water retention and blood pressure elevation. In spite of this, the cardiovascular findings from VIGOR are not firmly supported by observations from large cohort studies and other clinical trials of selective cyclooxygenase-2 inhibitors, including the Celecoxib Long-term Arthritis Safety Study. The two main theories that explain the VIGOR findings are that the comparator used (naproxen; Naprosyn®, Roche) is cardioprotective and that very high doses of rofecoxib were used, but at present neither is backed by firm evidence. Indeed, there is now early evidence that selective cyclooxygenase-2 inhibition with celecoxib may even protect against the progression of cardiovascular disease, on the basis that cyclooxygenase-2 mediates key processes in atherothrombosis. Currently, it is not clear what the net cardiovascular effects of cyclooxygenase-2 inhibitors are. The data are inconsistent and at best, speculative. It may be also that celecoxib and rofecoxib differ in their cardiovascular effects. Clarification of these issues is of vital importance given the vast number of patients presently taking both types of cyclooxygenase-2 inhibitors. Therefore, what is clear in this situation is the urgent need for randomized clinical trials designed specifically to examine the impact of selective cyclooxygenase-2 inhibitors on cardiovascular risk.
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OBJECTIVE To establish the assay model of cyclooxygenase-2 activity and provide the screening method of NSAIDs.METHODS Observations were made that cyclooxygenase-2 was induced in the exist of FCS.The inhibitory potency of the compounds was evaluated by determining the concentration of PGE 2.Rofecoxib employed as the reference drug was used to evaluate whether this method was available to determine the inhibitory potency of cyclooxygenase-2.RESULTS The results proved that rofecoxib can inhibit the activity of cyclooxygenase-2.CONCLUSION The in vitro method can be used to screen the cyclooxygenase-2 inhibitor.
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Abstract Pain-induced functional impairment in the rat (PIFIR) is a model of inflammatory and arthritic pain similar to that of clinical gout. Nociception is induced by the intra-articular injection of uric acid into the right hind limb, inducing its dysfunction. Animals then receive analgesic drugs and the recovery of functionality over time is assessed as an expression of antinociception. We have examined the role of peripheral prostaglandins synthesized by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in inflammatory pain using the PIFIR model. Rofecoxib (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor) both produced dose-dependent effects. When the inhibitors were administered before uric acid, they showed similar potency, but the antinociceptive efficacy of SC-560 was lower than rofecoxib; the best antinociceptive effects were obtained with the dose of 100 μ g/articulation of each inhibitor (pre-treatment). In post-treatment (inhibitors administered after the uric acid), rofecoxib showed the least antinociceptive effect and SC-560 was more potentthan rofecoxib. The inhibition of both COX-1 and COX-2 produced a more profound analgesic effect than the inhibition of either COX-1 or COX-2 alone. The present data support the idea that both COX isoforms contribute to the development and maintenance of local inflammatory nociception. Thus, it could be expected that inhibition of both COX-1 and COX-2 is required for non-steroidal anti-inflammatory drugs (NSAID)-induced antinociception in the rat. These findings suggest that the therapeutic effects of NSAIDs may involve, at least in part, inhibition of COX-1 and COX-2.
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Etoricoxib
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The purpose of this review is to summarize new information regarding the use of selective inhibitors of the cyclooxygenase-2 enzyme, emphasizing recent developments regarding cardiovascular risk.Selective cyclooxygenase-2 inhibitors are as effective as nonselective nonsteroidal antiinflammatory drugs in relieving pain and inflammation but are associated with significantly fewer gastric, duodenal, and intestinal ulcers and ulcer complications. Cyclooxygenase-2 inhibitors may also reduce colorectal polyp development or recurrence as well as reduce the risk of colorectal and esophageal cancer. Some, but not all, studies have suggested increased myocardial infarction with certain cyclooxygenase-2 inhibitors, in particular rofecoxib. It is unclear whether this is a class effect because there are inconclusive data to incriminate celecoxib despite a relatively large number of clinical trials enrolling a large number of patients. Rofecoxib was voluntarily withdrawn by the manufacturer. The European Medicines Agency concluded that cyclooxygenase-2 inhibitors are contraindicated in patients with established cardiovascular disease, should be used with caution in patients with risk factors, and were justified in patients at risk for serious gastrointestinal adverse events.Rofecoxib, but perhaps not all cyclooxygenase-2 inhibitors, may be associated with increased risk for myocardial infarction. It is unclear whether nonselective nonsteroidal antiinflammatory drugs increase or decrease the rate of myocardial infarction. The final truth awaits further studies.
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This review describes the biology underpinning the development of selective cyclooxygenase-2 inhibitors, documenting the clinical experience from the pivotal gastrointestinal safety trials to their eventual withdrawal or labelling with cardiovascular safety warnings.The elucidation of differences between the active sites of cyclooxygenase-1 and cyclooxygenase-2 allowed the targeted design of the selective cyclooxygenase-2 inhibitors known as coxibs. These were developed and marketed as non-steroidal anti-inflammatory drugs (NSAIDs) that had improved upper gastrointestinal safety compared with older non-selective NSAIDs. A large-scale study with arthritis patients to evaluate upper gastrointestinal safety, however, demonstrated that celecoxib was not superior in terms of upper gastrointestinal safety compared with the older non-selective NSAIDs that were used as comparators. In an equally large study with arthritis patients, a more selective cyclooxygenase-2 inhibitor, rofecoxib, did have improved upper gastrointestinal safety compared with the non-selective non-steroidal anti-inflammatory drug naproxen. Although concomitant clinical trial evidence emerged that rofecoxib increased cardiovascular risk, this was discounted by its pharmaceutical company owner. Despite the lack of improved upper gastrointestinal safety with celecoxib and the evidence of cardiovascular risk with rofecoxib, both agents had widespread clinical use for 4-5 years. This was not diminished by the publication of plausible eicosanoid-based biological mechanisms whereby selective cyclooxygenase-2 inhibition could increase cardiovascular risk. Finally, clinical trials involving patients with colorectal cancer and post-operative pain revealed increased cardiovascular risk with all members of this class of drug.These events provide a case study of a failure of the medical journal literature to guide drug usage.
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