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)

NSAIDs are effective by inhibition of the enzyme cyclooxygenase, which leads to formation of prostaglandins. At the beginning of the 90-ties it became evident, that cyclooxygenase existed in two isoforms (COX-1 and COX-2). COX-1 is found in a number of tissues. In these tissues prostaglandins have several physiological functions. COX-2 is an induceable enzyme involved in inflammation. A new NSAID, rofecoxib, has selective COX-2 inhibition defined as inhibition of COX-2, but not COX-1 in the therapeutic dose range. Trial results have shown pain relief analogous to common NSAIDs (ibuprofen and diclofenac) in patients with osteoarthritis of the hip or knee. The incidence of gastric ulcers was significantly reduced in the rofecoxib treated group compared to the groups treated with common NSAIDs. It is concluded that selective COX-2 inhibition is a promising new treatment. At present it seems appropriate to consider the drug in patients with good indication for an NSAID and simultaneous gastrointestinal risk factors.
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PMID:[Rofecoxib, a new NSAID preparation with selective COX-2 inhibition]. 1104 57

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and effective treatments for pain and inflammation. They have a substantial toxicity profile with side effects mainly affecting the gastrointestinal tract, heart and kidneys. Although they comprise a chemically diverse group of drugs, NSAIDs are unified by a common mode of action the ability to inhibit the enzyme cyclo-oxygenase (COX). This also accounts for much of their toxicity. The enzyme exists in at least 2 isoforms. COX-1 generates prostaglandins with physiological functions, COX-2 is induced by inflammation and its physiologic functions are unclear at present. Conventional NSAIDs, like diclofenac, ibuprofen, and naproxen, are non-selective COX inhibitors, blocking the production of both physiologic and inflammatory prostaglandins. In this chapter, we describe the main predictable gastrointestinal, cardiac and renal toxicities that can be explained by such blockade and review the supporting clinical and epidemiological evidence. In the gastrointestinal tract, the side effects associated with conventional NSAIDs are both local and systemic, and include ulceration, bleeding, perforation, and obstruction. The upper gastrointestinal tract is more commonly affected than the lower. The cardiac and renal side effects are most likely to occur in patients with existing heart or kidney disease, where prostaglandins play an essential role in maintaining the vasoconstrictor/dilator balance necessary for homeostasis. The patients at highest risk of toxicity are the elderly, those with a prior history of ulceration or bleeding, and those with a history of cardiac disease. Among such patients, the decision to prescribe NSAIDs requires careful consideration of the potential benefits and harms.
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PMID:Current problems with non-specific COX inhibitors. 1110 59

The common mechanism of action of aspirin and the chemically unrelated non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of prostaglandin (PG) production due to interference with the enzymatic activity of cyclooxygenase (COX). These agents have long been used as effective treatments for arthritis. The recognition that the inducible isoform COX-2 was associated with inflammation and arthritis led to the hypothesis that PGs produced by a COX-2-dependent pathway were responsible for the inflammation, pain, and tissue destruction. Since the constitutive COX-1 enzyme was identified as responsible for gastroprotection and inhibition of platelet function, the potential for compounds that were both effective and safer than NSAIDs led to rapid development of agents that specifically inhibit COX-2. These agents have now been tested and approved for use by the US Food and Drug Administration for patients with osteoarthritis and rheumatoid arthritis. They have been shown equally effective to comparitor NSAIDs. More importantly, there is a 3.5-fold reduction in the incidence of endoscopic gastroduodenal ulcerations and early data suggesting a similar reduction in clinically significant perforations, symptomatic ulcers, and bleeds. In patients with arthritis at risk for gastrointestinal complications of NSAIDs, specific inhibitors of COX-2 provide an effective and apparently safer form of anti-inflammatory agent.
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PMID:Clinical experience with specific COX-2 inhibitors in arthritis. 1110 60

NSAIDs are widely used and beneficial for patients with inflammatory pain. However, NSAIDs cause significant adverse upper gastrointestinal effects, including increased mortality from serious ulcer complications. NSAIDs exert their anti-inflammatory effects by inhibiting the activity of the COX enzyme, which was recently shown to exist in two isoforms, a constitutive COX-1 and an inducible COX-2. The latter isoform is induced in inflammation, while the former is responsible for prostaglandin effects on platelet function and gastric mucosal defense. Two specific COX-2 inhibitors have recently been introduced into the market. The available data from clinical trials indicate that these new drugs have anti-inflammatory and analgesic effects similar to those of conventional NSAIDs, but reduced rates of adverse upper gastroduodenal effects, which are similar to those observed with placebo. This difference in rates of adverse effects might imply improved safety for patients requiring anti-inflammatory treatment. It has, however, to be kept in mind that specific COX-2 inhibitors lack cardiovascular protective effects. Considering the high consumption rate of NSAIDs to achieve pain relief in arthritis and other musculo-sceletal diseases, the reduced risk of gastrointestinal ulcers and ulcer complications may have a positive impact on population health and health economy.
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PMID:Selective inhibitors of COX-2--are they safe for the stomach? 1114 80

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation but are frequently associated with gastrointestinal side effects, including life-threatening bleeding or perforation of gastroduodenal ulcers. Conventional NSAIDs are nonselective inhibitors of two isoforms of cyclooxygenase (COX): COX-1 and COX-2. The inhibition of COX-1 is believed to be responsible for inducing mucosal injury primarily by impairing prostaglandin-dependent mucosal protective mechanisms. The latest development in reducing the incidence of ulcers and ulcer complications associated with conventional NSAIDs is the use of recently approved COX-2-specific inhibitors (CSIs). This article critically reviews the data on gastrointestinal toxic side effects for conventional NSAIDs without as well as with prevention therapy. In addition, we compare these data with those for the CSIs, namely, celecoxib and rofecoxib. Finally, we offer recommendations on the clinical use of these drugs, emphasizing the need to balance clinical effectiveness with the avoidance of potential gastrointestinal side effects.
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PMID:Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors. 1117 45

Although paracetamol potently reduces pain and fever, its mechanism of action has so far not been satisfactorily explained. It inhibits both COX-1 and COX-2 weakly in vitro, but reduces prostaglandin synthesis markedly in vivo. In mouse macrophage J774.2 cells, COX-2 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced COX-2. In the rat pleurisy model of inflammation, a second peak of COX-2 protein appears 48 hr after administration of the inflammatory stimulus, during the resolution phase of the inflammatory process. Inhibition of the activity of this late-appearing COX-2 with indomethacin or a selective COX-2 inhibitor, delays resolution and the inflammation is prolonged. Cultured lung fibroblasts also express COX-2 activity after stimulation with IL-1beta which is highly sensitive to inhibition with paracetamol. Thus, evidence is accumulating for the existence of a COX-2 variant or a new COX enzyme which can be inhibited with paracetamol.
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PMID:Paracetamol-inhibitable COX-2. 1119 35

Lumbar disc herniation (LDH) is the disease which is the major cause of radiculopathy. In terms of the pathogenesis of disease, it is reported that prostaglandinE2 (PGE2) plays an important role to induce radiculopathy. Arachidonate cascade, which is the process of PGE2 synthesis, is mainly regulated by two kinds of enzymes, phospholipaseA2 (PLA2) and cyclooxy genase (COX). Previously, PLA2 was recognized as the rate-limiting enzyme of this cascade, and some authors reported the clinical significance of PLA2 at the site of LDH concerning the radicular pain. Recently, COX was elucidated to consist of 2 types of isoform, a constitutive form of COX-1 and an inducible form of COX-2. COX-2 has been focused as a key enzyme to regulate PGE2 synthesis and plays an important role in inflammation, because COX-2 was induced in many types of cells by the stimulation of inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha). However, it is not fully discussed whether or not, COX-2 is induced in lumbar disc tissue and if it plays a significant role in the pathogenesis of LDH. To clarify the role of COX-2 in the pathomechanism of radiculopathy of LDH, we have investigated the expression of COX-2, IL-1 beta and TNF alpha in herniated lumbar disc tissue. Immunohistologically, they were detected in the cytosol of chondrocytes constituting the disc tissue. RT-PCR showed that herniated lumbar disc-derived cells expressed mRNA of COX-2, IL-1 beta and TNF alpha in the presence of inflammatory cytokines in vitro. The disc-derived cells also produced much PGE2 by stimulating of inflammatory cytokines at the same time and this PGE2 production was distinctly suppressed by a selective inhibitor of COX-2, 6-methoxy-2-naphtyl acetic acids (6MNA). These results suggest that COX-2 and inflammatory cytokines might play a causative role in the radiculopathy of LDH through upregulating PGE2 synthesis.
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PMID:The role of cyclooxygenase-2 and inflammatory cytokines in pain induction of herniated lumbar intervertebral disc. 1119

Nimesulide (Aulin) refers to the class of sulphonanilides, which is unique among the non-steroidal antiinflammatory drugs (NSAIDs), being also the first drug on the market of pharmaceuticals, which preferentially inhibits the enzyme cyclooxygenase-2 (COX-2). This enzyme takes part in the synthesis of prostaglandin, which is produced in the course of the cascade of the inflammation process and has relation to the pathogenesis of pain, inflammation and fever, while the COX-1 enzyme forms prostaglandin, which projects the gastro-intestinal mucosis. Many newly found factors, together with the preferential inhibition of COX-2, are also contributing to the therapeutic effects of Nimesulide. The therapeutic concentration of non-combined active substance in blood-circulation reduces the following indicators: the activity of the myeloperoxidase; the release of cytokines; the histamine effects; the synthesis of stromelysin and collagenase, which pull down the proteoglicans and collagen. It is also characteristic of Nimesulide its antioxidant activity and suppression of: the synthesis of superoxidic ions from the neutrophils; also, the synthesis of platelet activating factor. Nimesulide shows good tolerability and is safe with patients having respiratory problems due to treatment with other NSAIDs.
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PMID:[Nimesulide - a non-steroidal anti-inflammatory drug, a preferential cyclooxygenase-2 inhibitor]. 1119 95

The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain has been well established in the treatment of mild pain and also alone or in association with opioids for the treatment of moderate to severe pain. Acutely, NSAIDs may be more than mild analgesics, and may provide additional analgesia when combined with opioids. However, NSAIDs have ceiling effects and there is no therapeutic gain from increasing dosages beyond those recommended. As there is no clearly superior NSAID, the choice should be based on experience and the toxicity profile that probably relates to the COX-1:COX-2 ratio. Among the older drugs, ibuprofen seems to have these properties.Non-steroidal anti-inflammatory drugs have been shown to have an opioid-sparing effect. Although the value of a simple narcotic-sparing effect may be questioned in cancer pain treatment, the use of NSAIDs may be useful when the increase in opioid dosage determine the occurrence of opioid toxicity. Like opioids, NSAIDs should not be considered analgesics for a specific type or cause of pain. There is a lack of evidence for any difference between different routes of NSAIDs administration. The long-term toxicity of NSAIDs in cancer pain is poorly defined due to a lack of studies. A variety of strategies have been used in an attempt to reduce the risks associated with NSAID therapy. Those NSAIDs that are weak COX-1 inhibitors may be preferred. In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications.
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PMID:The use of anti-inflammatory drugs in cancer pain. 1123 77

Rofecoxib (Vioxx, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.
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PMID:Rofecoxib. 1124 95


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