Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rofecoxib (Vioxx, Merck Sharp & Dohme) is a potent and selective inhibitor of the COX-2 isoform of cyclooxygenase which is used as a nonsteroidal anti-inflammatory drug (NSAID). It is indicated in the symptomatic relief of pain due to osteoarthritis. The initial oral dosage of rofecoxib is 12.5 mg once daily in adults, and this dose may be increased up to a maximal dosage of 25 mg once daily if necessary. Its clinical efficacy seems to be similar to that of other NSAIDs at maximal recommended dosages, but its safety profile, especially gastrointestinal tolerance, is much better because of the COX-2 selectivity. Ongoing clinical trials are performed in patients with rheumatoid arthritis.
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PMID:[Pharma-clinics. The drug of the month. Rofecoxib (Vioxx)]. 1101 11

Rofecoxib (Vioxx, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.
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PMID:Rofecoxib. 1124 95

Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies. Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P =.002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P =.04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P =.02 compared with the placebo group of the meta-analysis). The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.
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PMID:Risk of cardiovascular events associated with selective COX-2 inhibitors. 1244 Oct 30

Tumor growth and angiogenesis are interdependent. Cyclooxygenase (COX) catalyzes the synthesis of prostaglandins from arachidonic acid. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit COX-mediated synthesis of prostaglandins. COX-1 is constitutively expressed in a wide range of tissues, whereas COX-2 is cytokine inducible. Enhanced COX-2 expression has been attributed a key role in the development of inflammation and related processes observed in pathologically altered disease states. Two specific COX-2 inhibitors, namely rofecoxib (Vioxx) and celecoxib (Celebrex), both oral agents and U.S. Food and Drug Administration approved, have been shown preclinically and clinically to have efficacy comparable to that of NSAIDs for relief of pain and inflammation in osteoarthritis, with decreased risk of gastrointestinal damage. Little is known about how angiogenesis is affected by the combination of rofecoxib and radiation. We have evaluated the combination of rofecoxib, at various concentrations, and radiation on cytokine-induced angiogenesis in vitro. We have found that rofecoxib inhibited endothelial cell proliferation, migration, and tube formation (differentiation) at clinically relevant doses. In combination with radiation, inhibition of endothelial cell function further increased twofold. The combination of rofecoxib and radiation suggests a complementary strategy with clinical ramifications to target angiogenesis-dependent malignancies.
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PMID:Targeting angiogenic processes by combination rofecoxib and ionizing radiation. 1158 92

Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective inhibitors of cyclooxygenase (COX) isoforms COX-1 and COX-2. NSAIDs have analgesic and anti-inflammatory properties that are proven, and they are extensively used in the treatment of arthritis, pain, and headache. Despite their good efficacy, NSAIDs are associated with significant gastrointestinal (GI) toxicity, which appears to be related to the inhibition of the cytoprotective function of COX-1. Thus, selective COX-2 inhibitors, or coxibs, were designed to inhibit only the production of COX-2-dependent inflammatory prostaglandins, without any effect on COX-1 and its gastroprotective function. This article reviews important evidence on the GI safety of coxibs. Endoscopic studies demonstrated that coxibs, such as celecoxib and rofecoxib, induced significantly fewer ulcers than nonspecific NSAIDs. To analyze whether the incidence of clinical GI events is also lower with coxibs, 2 large controlled clinical trials, the Celecoxib Long-term Arthritis Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research (VIGOR), evaluated the GI safety of celecoxib and rofecoxib, respectively. Based on evidence from the VIGOR trial, it was demonstrated that rofecoxib has already fulfilled the promise and significantly decreases the risk of clinically important and complicated GI events compared with a nonselective NSAID, naproxen. In contrast, the CLASS trial showed that the incidence of ulcer complications in patients treated with celecoxib was similar in patients treated with nonspecific NSAIDs.
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PMID:An evidence-based evaluation of the gastrointestinal safety of coxibs. 1190 55

Aspirin and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory and analgesic effects. In addition, aspirin is documented to reduce cardiovascular events in selected populations, presumably because of inhibition of platelet aggregation. Yet these drugs are not without toxicity, particularly adverse effects on the gastric mucosa. The gastrointestinal toxicity of nonselective NSAIDs and aspirin derives from the inhibition of the cyclooxygenase (COX) enzyme, COX-1, which synthesizes gastroprotective prostaglandins, while the anti-inflammatory and pain-relieving effects are largely derived from inhibition of COX-2-derived prostaglandins. Available data indicate that the harmful gastric effects of nonselective NSAIDs are reduced by substitution of agents that only inhibit the COX-2 protein. The COX-2-selective inhibitors, however, have also been shown to inhibit the production of vascular prostacyclin, which has vasodilatory effects and inhibits platelet aggregation; unlike nonselective NSAIDs, they do not inhibit the production of thromboxane, an eicosanoid that promotes platelet aggregation. Whether these effects could potentially contribute to a prothrombotic environment is the subject of current, intensive debate. In the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, there was a higher incidence of cardiovascular thrombotic events in the rofecoxib- vs the naproxen-treated group: 1.67 vs 0.70 per 100 patient years. However, in a pooled analysis of rofecoxib studies, the risk of sustaining a thrombotic cardiovascular event was similar when comparing patients receiving rofecoxib with those receiving placebo, or when comparing patients receiving rofecoxib with those receiving nonnaproxen nonselective NSAIDs. These findings are likely to result, at least in part, from the antiplatelet action of naproxen, which has been shown to be potent and sustained during a typical dosing regimen (500 mg twice daily in VIGOR). In contrast, the other NSAID comparators effect weaker and/or nonsustained antiplatelet action. In the Celecoxib Long-term Arthritis Safety Study (CLASS) trial, there was no difference between celecoxib and the nonselective NSAIDs explored (which did not include naproxen) in cardiovascular event rates. Unlike those in VIGOR, patients in the CLASS trial were allowed to take low-dose aspirin. Thus, despite concerns raised by results of VIGOR, other existing data, including those pooled from existing placebo-controlled trials, do not support a clinically relevant prothrombotic effect of the COX-2 inhibitors. Additional placebo-controlled data, from patients at both high and low risk for cardiovascular events, are warranted to clarify the cardiovascular effects of this class of agents.
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PMID:Current perspective on the cardiovascular effects of coxibs. 1208 93

Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastritis, gastric and duodenal ulcers, and gastrointestinal (GI) blood loss, as well as alterations in small bowel permeability. Patients at a high risk for these complications include those who are older than 60 years of age, those with a previous history of complicated peptic disease and bleeding, and those who take high dose or multiple NSAIDs, including low dose aspirin, corticosteroids or anticoagulants. The introduction of selective inhibitors of cyclo-oxygenase-2 (COX-2) has provided effective treatment of inflammatory arthritis and musculoskeletal pain, with dramatic reductions in the risk of GI adverse events. The two most widely prescribed coxibs are celecoxib and rofecoxib, and others are being developed. Endoscopic studies have revealed that coxibs are only half as likely to induce upper GI ulceration than are traditional NSAIDs, and are as safe as placebo. Furthermore, the newer drugs do not cause excessive blood loss from the GI tract and do not affect small bowel permeability. The Vioxx Gastrointestinal Outcomes Research Study (VIGOR) revealed that the incidence of myocardial infarction was significantly lower with naproxen than rofecoxib, although this study was not designed to look at this endpoint. Coxibs are an important addition to the pharmacotherapy of inflammatory disease.
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PMID:Motion--Cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs are as safe as placebo for the stomach: arguments for the motion. 1277 9

Tumor growth and angiogenesis are interdependent. Cyclooxygenase (COX) catalyzes the synthesis of prostaglandins (PGs) from arachidonic acid. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit COX-mediated synthesis of PGs. Although COX-1 is constitutively expressed in a wide range of tissues, COX-2 is cytokine inducible. Enhanced COX-2 expression has been attributed a key role in the development of inflammation and related processes observed in pathologically altered disease states. Two specific COX-2 inhibitors, namely, rofecoxib (Vioxx) and celecoxib (Celebrex), both oral agents and FDA approved, have been shown preclinically and clinically to have efficacy comparable to that of NSAIDs for relief of pain and inflammation in osteoarthritis, with decreased risk of gastrointestinal damage. Significant preclinical evidence strongly supports the potential role for these inhibitors for the treatment of cancer. On June 29, 2001, the Radiation Therapy Oncology Group (www.rtog.org), a National Cancer Institute-sponsored cooperative group, held a 1-day symposium focusing on the potential role of inhibitors of COX-2 in the treatment of cancer. This issue of the American Journal of Clinical Oncology contains the summary of those presentations.
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PMID:COX-2 inhibitors and cancer therapeutics: potential roles for inhibitors of COX-2 in combination with cytotoxic therapy: reports from a symposium held in conjunction with the Radiation Therapy Oncology Group June 2001 Meeting. 1290 55

The ApcDelta716 knockout mouse develops hundreds of intestinal polyps and smaller numbers in the colon because of the truncation of the suppressor protein Apc. We show inhibition of polyposis in the ApcDelta716 mouse by rofecoxib (Vioxx), a specific cyclooxygenase-2 (COX-2) inhibitor. Both the number and size of polyps in the ApcDelta716 mouse were markedly reduced by rofecoxib (Vioxx) treatment at plasma concentrations similar to those achieved in humans with antiinflammatory concentrations of Vioxx. Sulindac, a dual cyclooxygenase-1/2 inhibitor, also diminished size and number of polyps but to a lesser extent than rofecoxib. The protein expression of COX-1 or COX-2 was unchanged by treatment with rofecoxib or sulindac because these agents inhibit enzyme activity and prostaglandin product formation rather than transcription of the COX genes. The proangiogenic protein vascular derived endothelial growth factor was decreased in polyps treated with rofecoxib, whereas membrane-associated beta-catenin increased in rofecoxib-treated polyps. DNA proliferation was decreased in polyps by both rofecoxib and sulindac treatment. Rofecoxib (Vioxx) is used clinically for osteoarthritis and pain, and in addition the results described here suggest that Vioxx may be useful as a chemopreventive in humans at risk for colorectal neoplasia.
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PMID:Rofecoxib (Vioxx), a specific cyclooxygenase-2 inhibitor, is chemopreventive in a mouse model of colon cancer. 1290 58

NSAIDs have been the mainstay of treatment in the management of pain and inflammation associated with chronic inflammatory disorders. They are effective. However, complications arising from chronic NSAID use are common and are primarily due to gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulceration and GI bleeds. GI toxicity has been attributed to the blockade of the cyclo-oxygenase (COX)-1-mediated generation of the cytoprotective prostanoids, such as prostaglandin (PG) E2 and PGI2 (prostacyclin). More recently, selective COX-2 inhibitors ('coxibs') were designed to inhibit the production of COX-2-dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products. The coxibs, while exhibiting similar efficacy to traditional NSAIDs in controlled clinical trials of their efficacy in chronic inflammatory conditions, such as osteoarthritis and rheumatoid arthritis, have been associated with a reduced incidence of surrogate or actual indices of GI toxicity. However, concerns regarding cardiovascular safety in high-risk patients have evolved. These concerns were driven initially by the concept that inhibition of COX-2-derived endothelial PGI2 without concomitant inhibition of platelet thromboxane A2 would result in increased cardiovascular risk. This was borne out in the Vioxx Gastrointestinal Outcomes Research study of rofecoxib, but not demonstrated in the Celecoxib Long Term Arthritis Safety Study trial. Further elucidation of the relative roles of COX-1- and COX-2-generated prostanoids has enabled a greater understanding of the biology of these pathways. However, it is still not completely clear how this understanding may be appropriately translated into clinical medicine.
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PMID:Balancing gastroprotection and cardioprotection with selective cyclo-oxygenase-2 inhibitors: clinical implications. 1458 67


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