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)

Non-steroidal anti-inflammatory compounds can relieve pain and inflammation associated with elevated levels of prostaglandins in the body and are proposed to be the agents responsible for the action of traditional herbal remedies associated with the reduction of pain, fever and inflammation. Primarily the bulbs and in some instances the leaves and roots, of Eucomis L 'Herit. species are widely utilized in South African traditional medicine for this purpose. A measure of the anti-inflammatory activity of plant extracts can be generated using the cyclooxygenase (COX-1) assay. High levels of COX-1 inhibitory activity were detected in crude extracts prepared from the leaves, bulbs and roots of Eucomis species. Of the 11 species tested, 9 species exhibited moderate COX-1 inhibitory activity (40-70%) for the aqueous bulb extracts. All 11 species showed COX-1 inhibitory activity of +/-70% or higher, for the ethanol bulb extracts. The bulb and root extracts (ethanol) showed, in general, the highest levels of COX-1 inhibitory activity, but most species exhibited no significant difference in activity between plant parts. Generally (for 7 of the 11 species), these levels did not differ significantly in specimens harvested in summer and in winter. IC50 values were calculated to be 72 microg ml(-1) for the bulb extract of E. autumnalis autumnalis, and 27 microg ml(-1) for the root extracts. The corresponding IC50 value for the leaf extract was estimated to be 15 microg ml(-1). The COX-1 inhibitors were relatively stable over time, both in solution (ethanol) and in the dried plant material. Extracts tested over a period of three years did not differ significantly in COX-1 inhibitory activity. These experimental results validate the extensive use of this plant in southern African traditional medicine.
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PMID:COX-1 inhibitory activity in extracts from Eucomis L'Herit. species. 1129 60

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase and subsequent downstream synthetases. Two closely related forms of the cyclooxygenase have been identified which are now known as COX-1 and COX-2. Both isoenzymes transform arachidonic acid to prostaglandins, but differ in their distribution and their physiological roles. Meanwhile, the responsible genes and their regulation have been clarified. COX-1, the pre-dominantly constitutive form of the enzyme, is expressed throughout the body and performs a number of homeostatic functions such as maintaining normal gastric mucosa and influencing renal blood flow and platelet aggregation. In contrast, the inducible form is expressed in response to inflammatory and other physiological stimuli and growth factors, and is involved in the production of the prostaglandins that mediate pain and support the inflammatory process. All the classic NSAIDs inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects are based on the inhibition of COX-2, but the gastrointestinal toxicity and the mild bleeding diathesis are a result of the concurrent inhibition of COX-1. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis. Apart from its involvement in inflammatory processes, COX-2 seems to play a role in angiogenesis, colon cancer and Alzheimer's disease, based on the fact that it is expressed during these diseases. The benefits of specific and selective COX-2 inhibitors are currently under discussion and offer a new perspective for a further use of COX-2 inhibitors.
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PMID:Cyclooxygenase inhibitors--current status and future prospects. 1131 43

Aseptic loosening is a major complication of prosthetic joint surgery and is manifested as chronic inflammation, pain, and osteolysis at the bone implant interface. The osteolysis is believed to be driven by a host inflammatory response to wear debris generated from the implant. In our current study, we use a selective inhibitor (celecoxib) of cyclo-oxygenase 2 (COX-2) and mice that lack either COX-1 (COX-1-/-) or COX-2 (COX-2-/-) to show that COX-2, but not COX-1, plays an important role in wear debris-induced osteolysis. Titanium (Ti) wear debris was implanted surgically onto the calvaria of the mice. An intense inflammatory reaction and extensive bone resorption, which closely resembles that observed in patients with aseptic loosening, developed within 10 days of implantation in wild-type and COX-1-/- mice. COX-2 and prostaglandin E2 (PGE2) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/kg per day) significantly reduced the inflammation, the local PGE2 production, and osteolysis. In comparison with wild-type and COX-1-/- mice, COX-2-/- mice implanted with Ti had a significantly reduced calvarial bone resorption response, independent of the inflammatory response, and significantly fewer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX-2 is an important mediator of wear debris-induced osteolysis and suggests that COX-2 inhibitors are potential therapeutic agents for the prevention of wear debris-induced osteolysis.
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PMID:Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis. 1131 93

Prostanoids, which consist of prostaglandins (PGs) and thromboxane, are produced from arachidonic acid by cyclooxygenases (COXs) as a rate-limiting step, and they exert various biological actions. Classically, prostanoids are suspected to be closely related to female reproductive processes such as ovulation, luteolysis and uterine contraction, as well as pathological processes such as fever generation and pain modulation. Recently the cDNA cloning of a series of prostaglandin-synthesizing enzymes and receptors enabled us to clarify which isoform or subtype is involved in each reproductive process by generating individual gene-deficient mice. In late pregnancy, PGF2 alpha synthesized by COX-1 is essential for induction of parturition via luteolysis. Furthermore, impaired induction of COX-2 in the myometrium of PGF2 alpha receptor-deficient mice is accompanied with loss of parturition, suggesting that COX-2 is presumably responsible for producing uterotonic PGs. In early pregnancy, PGE2 synthesized by COX-2 induces the expansion of cumulus cells through EP2 receptor and contributes to ovulation and fertilization. These results may be useful in not only developing novel drugs in the reproductive area but also understanding and overcoming harmful reproductive side effects of classical and novel drugs in non-reproductive areas.
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PMID:[Reproduction physiology and prostanoids]. 1133 76

Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment.
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PMID:Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. 1139 14

NSAIDs are used throughout the World Health Organization three-step analgesic ladder, and are indicated for pain in all stages of malignancy. Side-effects are common with NSAIDs. Much has been written about NSAIDs and COX, since the discovery of COX-1 and COX-2 isoforms. How do you choose the appropriate NSAID? The choice of NSAID continues to be dependent upon associated gastroduodenal toxicity and the related risk factors of individual patients. Choosing the appropriate NSAID should minimize the likelihood of needing additional medications to manage adverse effects and symptoms caused by the NSAID therapy itself.
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PMID:Ibuprofen to rofecoxib: what does it all mean and what do I do now? 1146 2

Non-steroidal anti-inflammatory drugs (NSAID) induce their action by inhibiting prostaglandin synthesis via the cyclooxygenase enzymes (COX). COX has recently been shown to have at least two isoforms, termed COX-1 and COX-2. The life-threatening gastrointestinal side effects of NSAID are caused by their inhibition of COX-1, which results in increased gastrointestinal bleeding and decreased ability to induce platelet aggregation. Highly specific COX-2 inhibitors are now available. These have the same ability to relieve pain, but do not cause gastrointestinal bleeding or prolong bleeding time. However, many other side effects caused by NSAID are due to COX-2 inhibition and COX-2 inhibitors should still be used with caution when patients suffer from lung, heart, or kidney diseases.
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PMID:[NSAID--COX-2-inhibitors, where is the difference? Focus on the modes of action]. 1151 Feb 35

Cyclooxygenase (COX), the key enzyme for synthesis of prostaglandins, exists in two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed in the gastrointestinal tract in large quantities and has been suggested to maintain mucosal integrity through continuous generation of prostaglandins. COX-2 is induced predominantly during inflammation. On this premise selective COX-2 inhibitors not affecting COX-1 in the gastrointestinal tract mucosa have been developed as gastrointestinal sparing anti-inflammatory drugs. They appear to be well tolerated by experimental animals and humans following acute and chronic (three or more months) administration. However, there is increasing evidence that COX-2 has a greater physiological role than merely mediating pain and inflammation. Thus gastric and intestinal lesions do not develop when COX-1 is inhibited but only when the activity of both COX-1 and COX-2 is suppressed. Selective COX-2 inhibitors delay the healing of experimental gastric ulcers to the same extent as non-COX-2 specific non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, when given chronically to experimental animals, they can activate experimental colitis and cause intestinal perforation. The direct involvement of COX-2 in ulcer healing has been supported by observations that expression of COX-2 mRNA and protein is upregulated at the ulcer margin in a temporal and spatial relation to enhanced epithelial cell proliferation and increased expression of growth factors. Moreover, there is increasing evidence that upregulation of COX-2 mRNA and protein occurs during exposure of the gastric mucosa to noxious agents or to ischaemia-reperfusion. These observations support the concept that COX-2 represents (in addition to COX-1) a further line of defence for the gastrointestinal mucosa necessary for maintenance of mucosal integrity and ulcer healing.
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PMID:Cyclooxygenase 2-implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives. 1151 70

Prostanoids sensitize sensory afferents during inflammation. However, their role in neuropathic pain is still unclear. We analyzed the actions of prostanoids, non-selective (indomethacin) or selective (celecoxib and NS-398) cyclooxygenase-2 (COX or COX-2) inhibitors, on the ectopic activity of dorsal root ganglia (DRG) and dorsal horn (DH) neurons in a model of neuropathic injury. Extracellular recordings of DRG and DH neurons and cardiovascular measurements were performed on anesthetized, paralyzed and artificially ventilated adult male Sprague-Dawley rats whose sciatic nerve had been transected. PGD(2), PGE(2), PGF(2alpha), carbaprostacyclin (cPGI(2); a stable prostacyclin analog), and carbocyclic thromboxane (cTXA(2)) were administered at cumulative doses (0.0001-5 mg/kg, i.p.) at 5 or 10 min intervals. Only cPGI(2) significantly increased the DRG and DH activity in a dose-dependent manner, with ED(50) values of 0.05 (0.01-0.96) and 0.69 (0.11-1.04) mg/kg, respectively. The other prostanoids did not significantly increase activity, although they reduced heart rate for up to 5 min following administration. Time course experiments with single doses of cPGI(2) (1 mg/kg, i.v.) increased DH discharge rate 3-17 min after injection. Indomethacin (3 mg/kg, s.c.), but not celecoxib or NS-398 (both at 6 mg/kg, s.c.), reduced both DRG and DH activity. Our results indicate that cPGI(2) excites DRG and DH neurons of neuropathic rats, and may suggest a role for IP prostanoid receptors in pain episodes associated with nerve injury. The inhibitory effect of indomethacin, but not celecoxib or NS-398, on ectopic activity may suggest that a tonic generation of PGI(2) by COX-1 could contribute to neuropathic pain.
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PMID:A stable prostacyclin analog enhances ectopic activity in rat sensory neurons following neuropathic injury. 1151 14

The oxygenating enzyme cyclooxygenase (COX) catalysis the conversion of arachidonic acid to proinflammatory prostaglandins. For many years it was thought that COX is a single enzyme that is present constitutively in most tissues. But in the late 80ies COX activity was found to be increased in inflammatory states with cytokines and bacterial lipopolysaccharides as inducing agents. The expression of the induced COX is inhibited by glucocorticoids which is not the case with the COX known up to then. According to these findings COX exists in two forms, the aminoacid sequences of which are known. The expression of COX-1 is not or only poorly regulated, the prostaglandins produced by it are responsible for the protection of the gastric mucosa, maintenance of normal kidney function and platelet aggregation. COX-2, in contrast, is highly regulated, the prostaglandins produced by this isoenzyme are involved in inflammation, fever and pain but also in the regulation of kidney function. Conventional non-steroidal antiinflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2. The analgesic, antipyretic and antiinflammatory effects of these agents are accounted for by COX-2 inhibition, whereas the toxic effects on the stomach as well as the inhibition of platelet aggregation are attributed to COX-1 inhibition. In search for selective blockers of COX-2, celecoxib and rofecoxib were developed which have an analgetic and antirheumatic potency similar to that of conventional NSAIDs but are associated with significantly fewer adverse gastroduodenal events. The renal toxicity of the selective COX-2 inhibitors is not better than that of the non-selective NSAIDs.
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PMID:[Coxibs: cyclooxygenase-2 inhibitors]. 1157 32


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