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)

Cyclooxygenase-2 (COX-2), the inducible isoform of COX, has been identified as the key enzyme to regulate prostaglandin E2 synthesis in inflammatory conditions. Although it has been reported that COX-2 is present in herniated disc samples obtained from patients, little is known concerning the relationships between COX-2 and painful radiculopathy. The purpose of this study was to evaluate whether epidural injection of COX-2 inhibitor abolishes hyperalgesia induced by nucleus pulposus, which is a pain-related behavior in the rat. Rats, in which nucleus pulposus was relocated on the nerve root, exhibited evidence of mechanical hyperalgesia. Epidural injection of COX-2 inhibitor resulted in decrease in mechanical hyperalgesia 1 h, 3 and 7 days after the epidural injection of COX-2 inhibitor (0.1 mg/kg SC-'236 dissolved in the vehicle). There were no significant differences in sensitivity to thermal noxious stimuli after either application of the nucleus pulposus or epidural injections. These results suggest that prostaglandins and thromboxane, which are produced by COX-2 in inflammatory cells, appear to be related to the inflammatory process produced by application of nucleus pulposus to the nerve root. It is possible that COX-2 plays a significant role in painful radiculopathy following herniated nucleus pulposus.
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PMID:Epidural injection of cyclooxygenase-2 inhibitor attenuates pain-related behavior following application of nucleus pulposus to the nerve root in the rat. 1191 20

The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.
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PMID:Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. 1199 Dec 54

Cyclooxygenase-2 (COX-2) is the enzyme that normally synthesizes prostaglandins during an inflammatory response. Many primary and metastatic cancers express COX-2, and its presence is correlated with tumor angiogenesis, more invasive tumor phenotype, resistance to apoptosis, and systemic immunosuppression. The expression of COX-2 is associated with a worse prognosis. Inhibition of prostaglandin synthesis may be beneficial in human malignancy. Regular consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of, and mortality rate resulting from, a number of types of gastrointestinal cancers. Premalignant colonic lesions regress following the administration of nonspecific COX inhibitors, such as sulindac (Clinoril). Advanced solid tumor patients treated with indomethacin (Indocin) survive twice as long as do such patients who receive supportive care alone. The U.S. Food and Drug Administration has approved specific COX-2 inhibitors for the treatment of arthritis, pain, and familial adenomatous polyposis. Preclinical studies show that these drugs block angiogenesis, suppress solid tumor metastases, and slow the growth of implanted gastrointestinal cancer cell lines. The COX-2 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies. Ongoing clinical trials are currently assessing the potential therapeutic role of COX-2 inhibitors in both prevention and treatment of a diverse range of human cancers.
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PMID:Celecoxib with chemotherapy in colorectal cancer. 1201 63

Anti-inflammatory agents have been used for centuries, but only in the last few decades has medical science gained insight into the complex biologic roles of the primary mediators of inflammation, the eicosanoids and their derivatives. Detailed understanding of the prostaglandins and leukotrienes provides a framework for the treatment of pain, inflammation, and fever with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), but these agents have exacted a substantial side effect burden. The discovery of cyclooxygenase-2 (COX-2) has guided development of rationally designed therapeutic agents that have the benefits of older NSAIDs with reduced gastrointestinal toxicity. Elucidation of the structure of COX isoenzymes has been key in the development of coxibs, the COX-2-selective subset of NSAIDs. Methods to determine the degree of COX-2 selectivity have been refined and are indispensable for comparing the relative selectivity of these agents. This review summarizes some of the key aspects of COX biochemistry, structure, and function and the evolution of understanding the mechanism of action of COX-2-selective inhibitors. The clinical relevance of COX-1 compared with COX-2 inhibition is discussed to provide a framework upon which clinicians can better appreciate current and future therapeutic applications of coxibs.
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PMID:Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. 1208 89

Prostaglandin E(2) (PGE(2)) is the major prostaglandin produced both centrally and in the periphery in models of acute and chronic inflammation, and its formation in both locations is blocked by cyclooxygenase-2 (COX-2) inhibitors such as celecoxib. In animal models of inflammation, PGE(2) inhibition in the brain may occur secondarily to a peripheral action by inhibiting local PG formation that elicits increased firing of pain fibers and consequent activation of PG synthesis in the central nervous system (CNS). Celecoxib was studied in the kainate-induced seizure model in the rat, a model of direct central prostaglandin induction, to determine whether it can act directly in the CNS. In the kainate-treated rat brain there was increased PGE(2), PGF(2alpha), and PGD(2) production, with COX activity and PGE(2) formation increased about 7-fold over normal. We quantitated mRNA levels for enzymes involved in the prostaglandin biosynthetic pathways and found that both COX-2 and PGE synthase (PGEs) mRNA levels were increased in the brain; no changes were found for expression of COX-1 or PGD synthase mRNA. By Western blot analysis, COX-2 and PGEs were induced in total brain, hippocampus, and cortex, but not in the spinal cord. Immunohistological studies showed that COX-2 protein expression was enhanced in neurons. Dexamethasone treatment reduced the expression of both COX-2 and PGEs in kainate-treated animals. Celecoxib reduced the elevated PGE(2) levels in brain of kainate-treated rats and inhibited induced COX activity, demonstrating the ability of this compound to act on COX-2 in CNS. Doses of celecoxib that inhibited brain COX-2 were lower than those needed for anti-inflammatory activity in adjuvant arthritis, demonstrating a potent direct central action of the compound.
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PMID:Pharmacology of celecoxib in rat brain after kainate administration. 1218 39

Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal antiinflammatory drugs. Here we describe a third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins). COX-3 and one of the PCOX-1 proteins (PCOX-1a) are made from the COX-1 gene but retain intron 1 in their mRNAs. PCOX-1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX-1 mRNA. COX-3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In human, COX-3 mRNA is expressed as an approximately 5.2-kb transcript and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX-1 genes. This intron contains an ORF that introduces an insertion of 30-34 aa, depending on the mammalian species, into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX-3 and PCOX-1a are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX-3, but not PCOX-1a, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
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PMID:COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. 1260 Jul 54

Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling.
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PMID:Multiple mtDNA deletions with features of MNGIE. 1229 82

Cyclooxygenases-1 and -2 (COX-1 and COX-2, also known as prostaglandin H2 synthases-1 and -2) catalyze the committed step in prostaglandin synthesis. COX-1 and -2 are of particular interest because they are the major targets of nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2-selective inhibitors. Inhibition of the COXs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces the incidence of fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of COXs relate mechanistically to cyclooxygenase and peroxidase catalysis and how alternative fatty acid substrates bind within the COX active site. We further examine how NSAIDs interact with COXs and how differences in the structure of COX-2 result in enhanced selectivity toward COX-2 inhibitors.
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PMID:The structure of mammalian cyclooxygenases. 1257 66

Studies performed on drug therapy in regional musculoskeletal pain conditions are of varying quality, and this is related to several methodological problems. The efficacy of analgesic medications is well established from clinical practice. However, both weak and especially strong opioid analgesics are associated with adverse reactions and also with dependency and abuse. The use of anti-depressants and skeletal muscle relaxants is only weakly supported by results from controlled clinical trials. The efficacy of both systemic and topical non-steroidal anti-inflammatory drugs (NSAIDs) has been examined in several Cochrane reviews of various regional musculoskeletal pain conditions. Studies of COX-2 selective NSAIDs have not been performed in conditions with regional musculoskeletal pain, but it is assumed that COX-2 selective inhibitors will not differ from dual COX inhibitors regarding efficacy. Therefore, some of the recent controversies related to gastrointestinal safety and possible risk of myocardial infarctions are also discussed.
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PMID:Pharmacotherapy for regional musculoskeletal pain. 1265 25

Neurogenic inflammation of the meninges, expressed in plasma extravasation and vasodilatation, putatively contributes to certain types of headache. Both, non-steroidal antiinflammatory drugs (NSAIDs) and serotonin-1 (5-HT1) receptor agonists are similarly effective antimigraine drugs but their mechanism of action is unclear. The clinical observation that sumatriptan lowered plasma levels of calcitonin gene-related peptide (CGRP), found increased during migraine attacks, drew attention to a possible inhibition of pro-inflammatory neuropeptide release from trigeminal afferents. An isolated preparation of fluid-filled rat skull cavities was used to study effects of NSAIDs and 5-HT(1B/D) agonists on the dura stimulated by inflammatory mediators (bradykinin, histamine and serotonin, 10(-5)M each). The release of immunoreactive CGRP (iCGRP) and immunoreactive PGE(2) (iPGE(2)) was measured in 5-min samples of superfusates using enzyme immunoassays. S(+)-flurbiprofen (10(-6)M) strongly reduced the basal and stimulated iCGRP release and abolished iPGE(2) release; R(-)-flurbiprofen showed much less effect on iPGE(2) liberation and did not influence iCGRP release. The 5-HT(1B/D) agonists naratriptan and CP93,129 were ineffective on both iCGRP and iPGE(2) release. Inspite of its weak COX blocking effect, R(-)-flurbiprofen is reported to exert antinociceptive effects, although it has not been tested in migraine. Only the potent COX blocker S(+)-flurbiprofen also suppressed iCGRP release while the 5-HT(1B/D) agonists were ineffective. Thus, inhibition of meningeal neuropeptide secretion is not a common action principle of the drugs that could be essential for their antimigraine effects.
Pain 2003 Jun
PMID:S+ -flurbiprofen but not 5-HT1 agonists suppress basal and stimulated CGRP and PGE2 release from isolated rat dura mater. 1279 37


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