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)

The non-steroidal anti-inflammatory drug (NSAID) meloxicam is a preferential cyclooxygenase-2 (COX-2) antagonist. The UV protective potential of this drug was studied to compare it with the reported beneficial effects of such preferentially COX-1 specific NSAIDs as indomethacin and acetylsalicylic acid in the literature. In a pilot study (open-label, non-randomized, non-controlled, unblinded), 10 patients received UV irradiation with the minimal erythema dose (MED), first with meloxicam (7.5 mg/die) to reduce post-operative pain and second without ingestion of meloxicam. The factor of UV protection was evaluated. In six of ten patients meloxicam showed no benefit, whereas four of ten patients had a 1.3- up to 3-fold UV protection. In this study, the benefit in UV protection of meloxicam as a preferential COX-2 antagonist was not above the reported benefit of the "old" COX-1 inhibiting NSAIDS.
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PMID:Meloxicam in acute UV dermatitis--a pilot study. 982 88

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce their therapeutic activities through inhibition of cyclooxygenase (COX), the enzyme that makes prostaglandins (PGs). They share, to a greater or lesser degree, the same side effects, including gastric and renal toxicity. Recent research has shown that there are at least two COX isoenzymes. COX-1 is constitutive and makes PGs that protect the stomach and kidney from damage. COX-2 is induced by inflammatory stimuli, such as cytokines, and produces PGs that contribute to the pain and swelling of inflammation. Thus, selective COX-2 inhibitors should be anti-inflammatory without side effects on the kidney and stomach. Of course, selective COX-2 inhibitors may have other side effects and perhaps other therapeutic potential. For instance, COX-2 (and not COX-1) is thought to be involved in ovulation and in labor. In addition, the well-known protective action of aspirin on colon cancer may be through an action on COX-2, which is expressed in this disease. Moreover, NSAIDs delay the progress of Alzheimer's disease. Thus, selective COX-2 inhibitors may demonstrate new important therapeutic benefits as anticancer agents, as well as in preventing premature labor and perhaps even retarding the progression of Alzheimer's disease.
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PMID:Anti-inflammatory drugs and their mechanism of action. 983 28

Cyclooxygenase (COX)-2 is the predominant COX isoform present at sites of inflammation, and produces prostaglandins (PG) that cause swelling and pain. However, in situations where the release of protective PGs by COX-1 has been lost, the induction of COX-2 may compensate and reduce inflammatory responses. This is particularly likely in large blood vessels, where, under physiological conditions, the release of prostacyclin by COX-1, present in the endothelium, is an important component of cardiovascular homeostasis. We, and others, have recently shown that COX-2 can be induced by proinflammatory cytokines in human blood vessels, and also in human airway cells. Moreover, recent data from our group have suggested that in these structures, COX-2 is anti-inflammatory at the level of cellular proliferation, adhesion receptor expression, and cytokine release.
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PMID:Cyclooxygenase-2 as a therapeutic target. 983 29

Cyclooxygenases (COX) are prostaglandin synthases and are the main therapeutic targets for non-steroidal anti-inflammatory drugs. Recently it has been established that apart from the constitutive isoform, an inducible isoform of this enzyme is upregulated after injurious stimuli. The structures of the genes encoding these enzymes and protein structures have been determined, and with the utilization of knockout mice, the physiological properties of each isozyme are being revealed. COX-1 is responsible for the production of physiological levels of prostanoids, whereas COX-2 is upregulated during inflammatory states and produces prostanoids responsible for the generation of fever, pain or other inflammatory responses. Selective COX-2 blockers may be a safe and useful alternative in the treatment of inflammatory disorders, pain, and fever.
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PMID:[Current topics in the regulation of prostanoids-1. Inducible cyclooxygenase COX-2 and selective blockers]. 985 96

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. These drugs tend to cause significant side effects, however, including gastric and intestinal toxicity. The mechanism of action of NSAIDs is through their inhibition of the key enzyme of prostaglandin biosynthesis, the cyclooxygenase. Recently, two forms of cyclooxygenase have been found to exist: COX-1 and COX-2, the constitutive and inducible forms, respectively. COX-1 exists in the stomach, intestine, kidneys and platelets, while COX-2, the inducible form, is expressed during inflammation. The therapeutic effects of NSAIDs are largely the result of inhibition of the enzyme cyclooxygenase-2 (COX-2), whereas the toxic effects (e.g., gastrointestinal, renal and platelet effects) are primarily due to the inhibition of COX-1. Individual NSAIDs show different potencies against COX-1 compared with COX-2 and this explains the variations in the side effects of NSAIDs at their anti-inflammatory doses. Drugs with high potency against COX-2 and a better COX-2-/COX-1 activity ratio will have anti-inflammatory activity with fewer gastrointestinal side effects. In contrast piroxicam and indomethacin, which drugs have a much higher potency against COX-1 than against COX-2, are amongst those with the highest gastrointestinal toxicity. Based on these findings, COX-2 seems to be an ideal target for the development of new anti-inflammatory drugs. Several compounds with preferential or specific COX-2 inhibiting properties have been synthesized and evaluated in pre-clinical and clinical studies i.e. Meloxicam, Celecoxib, MK-966, Flusolid and L-745, 337. The COX-2 selectivity of these novel NSAIDs relate well to their favorable gastrointestinal tolerability profile. Clinical trials have shown meloxicam and celecoxib to be as effective as currently available NSAIDs, but with an improved gastrointestinal tolerability profile. Further clinical trials and large-scale postmarketing surveillance programs are needed, however, to confirm the potential therapeutic benefits of these novel preferential or specific COX-2 inhibitors.
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PMID:[Preferential COX-2 inhibition: its clinical relevance for gastrointestinal non-steroidal anti-inflammatory rheumatic drug toxicity]. 1009 Dec 84

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, thereby suppressing the synthesis of proinflammatory prostaglandins. The identification and molecular-biological characterization of an inducible COX isoform (COX-2) in inflammatory cells led to the hypothesis that a selective inhibition of COX-2 would result in relief of inflammation and pain without causing the COX-1-dependent side effects (gastrointestinal ulceration, platelet dysfunction, kidney damage) of conventional NSAIDs. On the basis of data obtained in several laboratories by means of the "human whole blood assay" there is now convincing evidence that none of the currently available NSAIDs is a selective COX-2 inhibitor. Meanwhile, the specific COX-2 inhibitors celecoxib and rofecoxib are being tested worldwide in phase III clinical trials on patients with rheumatoid arthritis and osteoarthritis. However, the simple concept of COX-2 being an exclusively proinflammatory inducible enzyme cannot be upheld any longer. In addition, COX-2 is expressed constitutively in brain, spinal cord and kidney, as well as in numerous other organs. In the present review the perspectives and possible risks of specific COX-2 inhibitors are discussed, as well as additional indications for their implementation (e.g. colon cancer).
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PMID:[Specific COX-2 inhibitors: prospects of therapy with new analgesic and anti-inflammatory substances]. 1009 92

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

Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.
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PMID:2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors. 1019 70

The existence of two distinct isoforms of cyclooxygenase (COX), which convert arachidonic acid to prostanoids, is now well established. COX-1, which is constitutively expressed in many tissues (including the gastrointestinal tract, platelets, and kidney) is responsible for producing prostanoids that regulate normal housekeeping or physiologic functions. In contrast, COX-2 is the inducible form responsible for the production of prostanoids in response to a variety of evoking stimuli in different tissues and for mediation of inflammation and pain in certain diseases. Since the identification of COX-2, a great deal of research has been devoted to elucidating and understanding its molecular and physiologic characteristics. As a result of research into the differences between COX-1 and COX-2, new insights into the role of each isoform in normal homeostasis and in their responses to exogenous stimuli have emerged. Besides its induction in cells at inflammatory sites, COX-2 is known to be induced in the kidney in response to sodium depletion or in hyperfiltration states; in postsynaptic excitatory neurons in the brain after electroconvulsive stimulation, in the ovary and uterus during ovulation and implantation; in intestinal epithelium after bacterial infection; as well as in colon adenoma and carcinoma cells. These findings, largely from animal studies, have suggested a broader spectrum of biologic activity of COX-2 and potential alterations of specific physiologic or protective mechanisms by inhibition of COX-2, as well as potential new clinical targets of therapy with COX-2 inhibitors. As COX-2 appears to play an important role in pathologic processes other than pain and inflammation, ongoing research is investigating the potential utility of COX-2 inhibitors in other conditions, such as colonic polyposis, colorectal cancer, and Alzheimer's disease.
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PMID:Specific COX-2 inhibitors in arthritis, oncology, and beyond: where is the science headed? 1022 37

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


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