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)

Pain-induced functional impairment in the rat (PIFIR) is a model of inflammatory and arthritic pain similar to that of clinical gout. Nociception is induced by the intra-articular injection of uric acid into the right hind limb, inducing its dysfunction. Animals then receive analgesic drugs and the recovery of functionality over time is assessed as an expression of antinociception. We have examined the role of peripheral prostaglandins synthesized by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in inflammatory pain using the PIFIR model. Rofecoxib (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor) both produced dose-dependent effects. When the inhibitors were administered before uric acid, they showed similar potency, but the antinociceptive efficacy of SC-560 was lower than rofecoxib; the best antinociceptive effects were obtained with the dose of 100 microg/articulation of each inhibitor (pre-treatment). In post-treatment (inhibitors administered after the uric acid), rofecoxib showed the least antinociceptive effect and SC-560 was more potent than rofecoxib. The inhibition of both COX-1 and COX-2 produced a more profound analgesic effect than the inhibition of either COX-1 or COX-2 alone. The present data support the idea that both COX isoforms contribute to the development and maintenance of local inflammatory nociception. Thus, it could be expected that inhibition of both COX-1 and COX-2 is required for non-steroidal anti-inflammatory drugs (NSAID)-induced antinociception in the rat. These findings suggest that the therapeutic effects of NSAIDs may involve, at least in part, inhibition of COX-1 and COX-2.
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PMID:Involvement of peripheral cyclooxygenase-1 and cyclooxygenase-2 in inflammatory pain. 1190 7

Prostaglandins are important modulators of pain and inflammation. Both, pain and inflammation can be inhibited either at the level of the phospholipase A2 by corticosteroids or at the level of the cyclooxygenase (COX) by non steroidal anti-inflammatory drugs (NSAIDs). Formally, "cyclooxygenase" in general was thought to be responsible for the synthesis of prostaglandins involved in pain, inflammation and fever as well as cytoprotection in the stomach, hemostasis and blood flow in the kidneys. Later, two isoenzymes, cyclooxygenase-1 and cyclooxygenase-2 were discovered. It was postulated cyclooxygenase-1 to exist constitutively and to be responsible for cytoprotection and hemostasis whereas cyclooxygenase-2 is inducible and involved in pain, inflammation and fever. In the meanwhile also constitutive cyclooxygenase-2 was discovered in various tissues. Cyclooxygenase-inhibitors may be divided into four groups: non selective ones (ibuprofen, diclofenac etc.), cyclooxygenase-1 selective inhibitors (SC-560), cyclooxygenase-2 preferential ones (meloxicam) and cyclooxygenase-2 selective inhibitors (celecoxib, rofecoxib, parecoxib). Selective cyclooxygenase-2-inhibitors in opposite to classic non steroidal anti-inflammatory drugs are without effect on bleeding time in therapeutic doses. The most important side effects of non steroidal anti-inflammatory drugs are bleeding, ulceration and perforation in the upper gastrointestinal tract and damage in the kidneys. Selective cyclooxygenase-2-inhibitors show less gastroduodenal ulcerations. Risk patients, however, still need gastroprotection during therapy with cyclooxygenase-2-inhibitors. In patients with low dose aspirin prophylaxis cyclooxygenase-2-inhibitors do not show any benefit compared to classic non steroidal anti-inflammatory drugs (CLASS-study). Less gastrointestinal side effects do not mean a higher overall safety benefit. Cardiovascular and thrombotic side effects of rofecoxib are higher than those of naproxen (VIGOR-study). Concerning valdecoxib, hypersensibilities are reported, probably due to its sulfonamidstructure. The same side effects are to be expected with its prodrug, parecoxib. Drug-drug interactions with cyclooxygenase-2-inhibitors and anticoagulant drugs are to be expected as well as other interactions with drugs, metabolised by the cytochrom P450 system.
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PMID:[Pharmacology of cyclooxygenase 2 inhibition]. 1270 61

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

This paper discusses the treatment of pain in the palliative care patient, specifically the use of meloxicam and recent advances in agents with cyclooxygenase-2 (COX-2) selectivity. Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that preferentially inhibits COX-2 more than cyclooxygenase-1 (COX-1), especially at low doses, thereby offering advantages over traditional nonselective NSAIDs. New COX-2 selective agents are discussed, including valdecoxib, parecoxib, etoricoxib, and COX-189.
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PMID:Meloxicam and selective COX-2 inhibitors in the management of pain in the palliative care population. 1291 Oct 75

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents in the treatment of pain, inflammation and fever. They may also have a role in the management of cancer prevention, Alzheimer's disease and prophylaxis against cardiovascular disease. These drugs act primarily by inhibiting cyclooxygenase enzyme, which has two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Selective COX-2 inhibitors provide potent anti-inflammatory and analgesic effects without the side effects of gastric and renal toxicity and inhibition of platelet function. Celecoxib is a potent COX-2 inhibitor being developed for the treatment of rheumatoid arthritis and osteoarthritis. Chemoprevention is the use of pharmacological or natural agents to prevent, suppress, interrupt or reverse the process of carcinogenesis. For this purpose, celecoxib is being used for different cancer types. The effects of NSAIDs on tumor growth remain unclear, but are most likely to be multifocal. In this article, we reviewed COX-2 selectivity, the pharmacological properties of celecoxib, the use of celecoxib for cancer prevention and the mechanisms of chemoprevention.
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PMID:Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention. 1506 37

The antinociceptive, anti-inflammatory, antipyretic effects along with gastric safety profile of parecoxib, a novel, potent selective cyclooxygenase-2 inhibiting prodrug, and those of ketorolac, a nonselective cyclooxygenase inhibitor, were evaluated in various animal models. Parecoxib (up to 20 mg/kg, i.v.) had no effect in two acute pain models, namely, the acetic acid-induced writhing (visceral pain) and the formalin test (tonic pain). However, ketorolac (up to 10 mg/kg, i.v.) showed marked antinociceptive effects in these models. In the models of carrageenan-provoked inflammatory hyperalgesia and inflammation, and in lipopolysaccharide-induced pyrexia, parecoxib significantly reversed all the behavioral changes and it was found to be more potent than ketorolac. Further, ketorolac (10 mg/kg, i.v.) produced visible gastric lesions with prominent petechiae and hemorrhagic streaks. However, parecoxib was without any effect on gastric mucosa. The present results showed that the cyclooxygenase-2 inhibitor, parecoxib, when administered parenterally, has potent antihyperalgesic, anti-inflammatory, antipyretic effects and has a better safety profile than with ketorolac, with sparing of cyclooxygenase-1 in the stomach in these animal models.
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PMID:Pharmacological profile of parecoxib: a novel, potent injectable selective cyclooxygenase-2 inhibitor. 1510 35

Vanilloid receptor 1 was recently reported to play an important role in hyperalgesia, but the mechanisms by which this receptor is activated by endogenous inflammatory mediators, such as bradykinin and nerve growth factor, are not yet fully understood. Here, we investigated whether bradykinin, which is a pain-producing inflammatory mediator, sensitizes vanilloid receptor 1 by inducing the activation of cyclooxygenases, phospholipase C and phospholipase A2 in rat dorsal root ganglion cells. We demonstrated this using 45Ca2+ uptake and inositol phosphates accumulation assays, bradykinin activates phospholipase C and cyclooxygenase-1 through the bradykinin B2 receptor. The bradykinin B2 receptor then sensitizes vanilloid receptor 1 activity by facilitating non-selective Ca2+ channel activity, increasing the intracellular Ca2+ concentration from the extracellular pool. These methods would be useful for screening new drugs for activity at vanilloid receptor 1. These data suggest that endogenous substances produced by several enzymes may be capable of producing a synergistic response involving the vanilloid receptor 1.
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PMID:Sensitization of vanilloid receptor 1 induced by bradykinin via the activation of second messenger signaling cascades in rat primary afferent neurons. 1536 73

Enzyme cyclooxygenase plays an important role in many cellular processes. It is necessary for a synthesis prostaglandines, which belong to the most important mediators of inflammatory and pain processes. Many studies show an importance of this enzyme not only in periphery but in central nervous system as well. The main unsolved question is, if the cyclooxygenase-1 or cyclooxygenase-2 play the main role in synaptic transmission. In this review we try to summarise the current overview in relation to this topic.
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PMID:[The role of cyclooxygenase in pain processing in CNS]. 1570 42

The aim of this study was to compare the in vivo effects on free radical metabolism of 2 non-steroidal anti-inflammatory drugs (NSAIDs): tenoxicam, an oxicam preferentially cyclooxygenase-1 (COX-1) inhibitor, and celecoxib, a sulfonamide selective COX-2 inhibitor. The serum levels of oxidative stress-related enzymes (ie, xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)), of a lipid peroxidation marker (malondialdehyde (MDA)), and of nitric oxide (NO) in patients with knee osteoarthritis were studied at baseline and after a 4-wk course of treatment with celecoxib (n = 11) and tenoxicam (n = 12). Celecoxib-treated patients had significant decrease in nitrite levels (p = 0.043), whereas SOD, XO, GSH-Px enzyme activities, and MDA levels did not change significantly compared to baseline. Tenoxicam-treated patients had significant decrease in nitrite levels (p = 0.036) and XO activity (p = 0.01), but their SOD, GSH-Px enzyme activities, and MDA levels were unchanged from baseline. There was significant correlation between the patients' (n = 23) Western Ontario and McMaster Universities (WOMAC) LK3.0 Osteoarthritis Index, WOMAC-pain scores, and MDA levels (r = 0.50, p = 0.014) and the patients' WOMAC-stiffness scores and XO enzyme activity (r = 0.46, p = 0.027) at baseline. Significant improvement was found in pain-VAS, patients' global assessment, and WOMAC pain, stiffness, and physical function scores in celecoxib and tenoxicam-treated groups. In summary, our study revealed that tenoxicam may have antioxidant effects, and that celecoxib and tenoxicam may reduce nitrite levels, indicating an alteration of NO pathways.
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PMID:In vivo effect of celecoxib and tenoxicam on oxidant/ anti-oxidant status of patients with knee osteoarthritis. 1594 76

Selective inhibitors of cyclooxygenase-2 (COX-2, 'coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non-steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myo cardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX-2 on the cardiovascular system. Although COX-2, in contrast to the cyclooxygenase-1 (COX-1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX-2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX-2-dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin (PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX-2, and its levels are reduced to less than half of normal when COX-2 is inhibited. This review outlines the rationale for the development of selective COX-2 inhibitors and the pathophysiological consequences of selective inhibition of COX-2 with special regard to vasoactive prostaglandins. It describes coxibs that are current ly available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights.
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PMID:Selective COX-2 inhibitors and risk of myocardial infarction. 1597 6


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