Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal and human data demonstrate that cyclooxygenase (COX)-2 upregulation in osteoarthritis and rheumatoid arthritis is associated with the pain and inflammation of the disease state. The COX-1 isoform, however, is a constitutive enzyme with homeostatic functions. Unlike conventional nonsteroidal anti-inflammatory drugs, which inhibit both forms of the COX enzyme, celecoxib inhibits COX-2 preferentially to COX-1 in vitro. Celecoxib reversed signs of arthritis and pain in an animal model as effectively as indomethacin. Data from murine studies as well as in vitro and epidemiologic data indicate that COX-2 plays a role in the development of colon cancer, and epidemiologic studies also suggest that COX inhibition can slow the progression of Alzheimer's disease.
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PMID:Role of cyclooxygenase-1 and -2 in health and disease. 1019 97

To investigate the mechanisms of action underlying the anti-inflammatory effects of the nonsteroidal anti-inflammatory drug aceclofenac in humans, we studied the metabolism of aceclofenac in detail in primary cultured synovial cells of 10 patients with rheumatoid arthritis. Aceclofenac and 4'-hydroxyaceclofenac are the major compounds in human blood after the administration of aceclofenac, but they had no inhibitory effects on cyclooxygenase (COX) activity or COX expression in the rheumatoid synovial cells. In contrast, aceclofenac and 4'-hydroxyaceclofenac reduced prostaglandin E2 (PGE2) production by the rheumatoid synovial cells. We also observed that aceclofenac and 4'-hydroxyaceclofenac were hydrolyzed into the COX inhibitors diclofenac and 4'-hydroxydiclofenac, respectively, by the rheumatoid synovial cells. However, the hydrolytic activity differed markedly among the cell preparations. Because the suppressive potency of aceclofenac and 4'-hydroxyaceclofenac against the PGE2 production was proportionally correlated with the hydrolytic activity in rheumatoid synovial cell preparations, we suggest that the suppressive effects of aceclofenac and 4'-hydroxy aceclofenac on PGE2 production are facilitated by the hydrolytic activity in rheumatoid synovial cells.
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PMID:Hydrolytic activity is essential for aceclofenac to inhibit cyclooxygenase in rheumatoid synovial cells. 1021 39

Nonsteroidal antiinflammatory drugs (NSAID) are effective for the relief of pain and inflammation, yet their use is tempered by the development of side effects, primarily in the gastrointestinal (GI) tract. It is now known that inhibition of the enzyme cyclooxygenase (COX) is the principal mechanism for both the efficacy and the toxicity of NSAID. Recent research has shown that COX exists as at least two isoenzymes, COX-1 and COX-2. Compelling evidence suggests that COX-1 synthesizes prostaglandins that are involved in the regulation of normal cell activity (including G1 cytoprotection), whereas COX-2 appears to produce prostaglandins mainly at sites of inflammation. These findings led to the search for compounds that would inhibit COX-2 without affecting COX-1. Several agents are under investigation in this new therapeutic category, including celecoxib (SC-58635). Celecoxib was developed as an antiinflammatory and analgesic agent, and has been studied in preclinical studies and in clinical trials. This paper focuses on the results of 5 key clinical trials of celecoxib: an efficacy trial in dental pain, a 2 week osteoarthritis (OA) efficacy trial, a 4 week rheumatoid arthritis (RA) efficacy trial, a one week endoscopic study of GI mucosal effects, and a 10 day study of effects on platelet function. The arthritis trials identified celecoxib doses that were effective in treating OA and RA and that were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, no ulcers occurred in subjects receiving celecoxib or placebo, whereas 19% of subjects receiving naproxen developed gastric ulcers. In the platelet effects trial, no statistically significant difference from placebo was seen in the effect of celecoxib on platelet aggregation or bleeding time. In contrast, naproxen caused statistically significant reductions in platelet aggregation and a statistically significant increase in bleeding time. These preliminary trials show that celecoxib achieves analgesic and antiinflammatory efficacy in arthritis through specific COX-2 inhibition without showing evidence of two of the toxic effects of COX-1 inhibition associated with NSAID.
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PMID:Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? 1022 38

Nitric oxide (NO) and prostaglandin E2 (PGE2) are two pleiotropic inflammatory mediators overproduced in arthritis-affected joints. The inducible isoform of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) are found both in the synovial tissue and in the cartilage. Their expression is regulated by catabolic cytokines, such as interleukin-1beta and tumor necrosis factor-alpha. These inflammatory mediators play a profound role in the pathogenic processes that arise in the pannus of rheumatoid arthritis and also interfere with cartilage homeostasis in osteoarthritis. Several drugs, including nonsteroidal anti-inflammatory drugs, immunosuppressive agents, and tetracyclines, attenuate the activity of NO and PGE2. These pleiotropic mediators are targets for pharmacologic intervention and gene therapy.
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PMID:Nitric oxide synthase and cyclooxygenases: distribution, regulation, and intervention in arthritis. 1032 80

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase (COX) and subsequent downstream synthetases. Recently, it has been found that there are two closely related forms of COX, which are now known as COX-1 and COX-2. Although both isoforms of this enzyme convert arachidonate to prostaglandins, there are significant differences in their distribution in the body and their roles in health and disease. The basis for these important differences lies in the genes for COX-1 and COX-2 and the regulation of these genes. COX-1, the predominantly constitutive form of the enzyme, is expressed throughout the body and provides certain homeostatic functions, such as maintaining normal gastric mucosa, influencing renal blood flow, and aiding in blood clotting by abetting platelet aggregation. In contrast, COX-2, the inducible form, is expressed in response to inflammatory and other physiologic stimuli and growth factors and is involved in the production of those prostaglandins that mediate pain and support the inflammatory process. All conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects occur through the inhibition of COX-2, but the gastrointestinal toxicities and the mild bleeding diathesis occur as a result of concurrent inhibition of COX-1. It is important that physicians fully understand the pharmacologic basis for the differential actions of NSAIDs when prescribing them for pain and inflammation. This understanding is also important so that physicians can critically evaluate the basis for, and the emerging data on, COX-2-specific inhibitors and their potential role in clinical medicine. Agents that would inhibit COX-2 while sparing COX-1 represent an attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis, as well as a diverse array of other conditions.
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PMID:Role and regulation of cyclooxygenase-2 during inflammation. 1039 Jan 26

The cyclooxygenase isoenzymes (COX-1 and -2) catalyze the rate-limiting steps in prostanoid biosynthesis. COX-1 and -2 genes encode two isoenzymes with overlapping yet distinct expression patterns and functions. Physiologically, various extracellular stimuli such as growth factors, cytokines and tumor promoters regulate the expression of COX-1 and -2 genes at both transcriptional and post-transcriptional levels. COX-2 is overexpressed in rheumatoid arthritis, colorectal and breast cancer. Prostanoids produced by the COX pathway signal via plasma membrane-localized, G-protein-coupled receptors as well as via nuclear receptors. Currently, several COX-2-selective inhibitors are developed to control the anti-inflammatory and anti-neoplastic activities of the COX-2 isoenzyme. Inhibition of the COX isoenzyme activity and/or expression may be the basis of future generation of anti-inflammatory and anti-neoplastic drugs.
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PMID:Cyclooxygenase-1 and -2 isoenzymes. 1039 16

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.
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PMID:Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. 1041 62

An inhibitor of cyclooxygenase (COX)-1 activity of prostaglandin H2 synthase was isolated from aerial parts of Celastrus orbiculatus Thunb. (Celastraceae), an oriental folk medicine for rheumatoid arthritis by activity-guided column chromatographic methods. The COX inhibitor was identified as (-)-epiafzelechin, a member of flavan-3-ols by the structural analysis with HR-EI-mass, 1H-NMR and 13C-NMR spectral data. The compound exhibited a dose-dependent inhibition on the COX activity with an IC50 value of 15 microM. (-)-Epiafzelechin exhibited about 3-fold weaker inhibitory potency on the enzyme activity than indomethacin as a positive control. (-)-Epiafzelechin exhibited significant anti-inflammatory activity on carrageenin-induced mouse paw edema when the compound (100 mg/kg) was orally administrated at 1 h before carrageenin treatment.
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PMID:(-)-Epiafzelechin: cyclooxygenase-1 inhibitor and anti-inflammatory agent from aerial parts of Celastrus orbiculatus. 1041 38

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective for the relief of pain and inflammation, yet their use is tempered by the development of side effects, primarily in the gastrointestinal (GI) tract. It is now known that inhibition of the enzyme cyclooxygenase (COX) is the principal mechanism for both the efficacy and the toxicity of NSAIDs. Recent research has shown that COX exists as at least two isoenzymes, COX-1 and COX-2. Compelling evidence suggests that COX-1 synthesizes prostaglandins that are involved in the regulation of normal cell activity (including GI cytoprotection), whereas COX-2 appears to produce prostaglandins mainly at sites of inflammation. These findings led to the search for compounds that would inhibit COX-2 without affecting COX-1. Several agents are under investigation in this new therapeutic category, including celecoxib (SC-58635). Celecoxib was developed as an anti-inflammatory and analgesic agent, and has been studied in preclinical studies and in clinical trials. This paper focuses on the results of five key clinical trials of celecoxib: an efficacy trial in dental pain, a 2-week osteoarthritis (OA) efficacy trial, a 4-week rheumatoid arthritis (RA) efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 10-day study of effects on platelet function. The arthritis trials identified celecoxib doses that were effective in treating OA and RA and that were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, no ulcers occurred in subjects receiving celecoxib or placebo, whereas 19% of subjects receiving naproxen developed gastric ulcers. In the platelet effects trial, no statistically significant difference from placebo was seen in the effect of celecoxib on platelet aggregation or bleeding time. In contrast, naproxen caused statistically significant reductions in platelet aggregation and a statistically significant increase in bleeding time. These preliminary trials show that celecoxib achieves analgesic and anti-inflammatory efficacy in arthritis through specific COX-2 inhibition without showing evidence of two of the toxic effects of COX-1 inhibition associated with NSAIDs.
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PMID:Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? 1042 44

The purpose of this paper is to review the rationale for a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) known as selective cyclooxygenase (COX)-2 inhibitors and to present preliminary clinical data on 2 COX-2 inhibitors that are approved for use in the United States. The primary mechanism of NSAIDs in the treatment of inflammation is the inhibition of COX, which exists in 2 forms. COX-I appears to regulate many normal physiologic functions, and COX-2 mediates the inflammatory response. Theoretically, an NSAID that inhibits COX-2 selectively should decrease inflammation but not influence normal physiologic functions and thus should cause fewer gastrointestinal side effects. Preliminary data suggest that celecoxib, a highly selective COX-2 inhibitor, is superior to placebo and similar to traditional NSAIDs in the short-term treatment of pain due to osteoarthritis, although it has been associated with adverse effects such as headache, change in bowel habits, abdominal discomfort, and dizziness. Celecoxib also has been shown to be as effective as traditional NSAIDs in the treatment of rheumatoid arthritis, but it may cause fewer adverse effects, including endoscopically documented ulcers. Celecoxib is metabolized in the liver by the cytochrome P-450 isozyme CYP2C9, and thus serious drug interactions are possible. In the treatment of osteoarthritis, rofecoxib has been shown to be as effective as traditional NSAIDs and may cause fewer endoscopically documented ulcers, but its complete adverse-effect profile is not known. Until the selective COX-2 inhibitors are widely used and more clinical as well as pharmacoeconomic studies are published, the exact role of COX-2 therapy cannot be determined. words: cyclooxygenase, celecoxib, rofecoxib, rheumatoid arthritis, osteoarthritis.
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PMID:Selective cyclooxygenase-2 inhibitors for the treatment of arthritis. 1046 13


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