Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Dental pain is encountered daily by clinicians. Nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used for pain management are traditionally cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors, and more recently selective COX-2 inhibitors. This study was designed to identify and quantify COX-1 and COX-2 gene expression level in inflamed rat molar pulps after administration of three NSAIDs: Celebrex, Vioxx, and Advil. Fifty male Wistar rats had their first and second molar pulps exposed and sealed with Cavit for 4 days. Rats were randomly divided into the three drug groups and two control groups. RNA was isolated from the rat pulps. Real Time Quantitative Reverse Transcriptase-Polymerase Chain Reaction assay, a relatively new PCR technique, was used to quantify COX-1 and COX-2 mRNA. Statistical analysis demonstrated no significant differences in COX-1 and COX-2 levels among the drug groups. However, Vioxx and Advil significantly reduced COX-2 expression levels compared to inflamed (positive control) pulps (p < 0.05).
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PMID:A real time quantitative PCR analysis and correlation of COX-1 and COX-2 enzymes in inflamed dental pulps following administration of three different NSAIDs. 1624 22

Prostaglandins (PGs) are generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2) and modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the induction of COX-2 and the generation of PGs has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) that block COX enzymatic activity have been shown to reduce the incidence of AD in various epidemiological studies. While several reports investigated the expression of COX-2 in neurons and microglia, expression of COX-2 in astroglial cells has not been investigated in detail. Here we show that amyloid beta peptide 25-35 (Abeta(25-35)) induces COX-2 mRNA and protein synthesis and a subsequent release of prostaglandin E(2) (PGE(2)) in primary midbrain astrocytes. We further demonstrate that protein kinase C (PKC) is involved in Abeta(25-35)-induced COX-2/PGE(2) synthesis. PKC-inhibitors prevent Abeta(25-35)-induced COX-2 and PGE(2) synthesis. Furthermore Abeta(25-35) rapidly induces the phosphorylation and enzymatic activation of PKC in primary rat midbrain glial cells and in primary human astrocytes from post mortem tissue. Our data suggest that the PKC isoforms alpha and/or beta are most probably involved in Abeta(25-35)-induced expression of COX-2 in midbrain astrocytes. The potential role of astroglial cells in the phagocytosis of amyloid and the involvement of PGs in this process suggests that a modulation of PGs synthesis may be a putative target in the prevention of amyloid deposition.
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PMID:Amyloid beta peptide (25-35) activates protein kinase C leading to cyclooxygenase-2 induction and prostaglandin E2 release in primary midbrain astrocytes. 1654 99

Millions of individuals in the United States take low-dose aspirin for cardioprotection. Physicians face a clinical dilemma when those same patients also have pain from arthritis or another condition. Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of gastrointestinal (GI) complications when used in conjunction with aspirin. In addition, NSAIDs, particularly ibuprofen, may interfere with the antithrombotic benefits of aspirin through competitive interaction with platelet cyclooxygenase-1 (COX-1). Evidence suggests that naproxen has antithrombotic effects; however, as with other NSAIDs, it poses a risk of gastrotoxicity. Selective COX-2 inhibitors reduce the risk of GI side effects, and although they inhibit platelet COX-1, it is to a far lesser extent than COX-2. However, it is unclear to what degree COX-2 inhibitors remain gastroprotective in the presence of aspirin. In addition, recent long-term trials have raised concerns about adverse cardiovascular events with prolonged use of both traditional and selective NSAIDs. Conversely, acetaminophen is well tolerated, has not been shown to contribute to gastrotoxicity when taken with aspirin, and has not been shown to interfere with the inhibition of platelet aggregation produced by aspirin. Acetaminophen is considered a first-line therapy for patients with mild-to-moderate joint pain.
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PMID:Potential for drug-drug interactions in patients taking analgesics for mild-to-moderate pain and low-dose aspirin for cardioprotection. 1667 19

Ibuprofen belongs to the 2-aryl propionic-acid derivatives and consists of two enantiomers, of which S-ibuprofen is a potent cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitor whereas the R-enantiomer is two to three orders of magnitude less potent to inhibit cyclooxygenases. Beside its positive effects on inflammation and pain several animal studies have shown that ibuprofen also inhibits tumor initiation and proliferation but the molecular mechanisms are not fully understood. To investigate to which extent the antiproliferative effect of ibuprofen depends on COX-inhibition we tested both enantiomers in different human colon carcinoma cell lines (HCA-7 express COX-1, COX-2 and produce high prostaglandin E2 level; HCT-15 express only COX-1 and produce nearly no prostaglandin E2). S- and R-ibuprofen reduced concentration dependently cell survival in both cell lines to a similar extent and caused a G0/G1 phase block as well as apoptosis. The cell cycle block was accompanied by a down regulation of cyclin A and B and an increase of the cell cycle inhibitory protein p27Kip-1. HCA-7 cells were less sensitive against the antiproliferative effects of ibuprofen enantiomers which was probably due to lower ibuprofen concentrations in this cell type. Also in the nude mice model both enantiomers inhibited tumor growth of HCA-7 and HCT-15 xenografts to a similar extent. However, in mice about 54% of R-ibuprofen was unidirectionally inverted to S-ibuprofen, thus the observed antitumorigenic effect of R-ibuprofen in vivo cannot solely be assigned to this enantiomer. In conclusion our data indicate that S- and R-ibuprofen show similar antiproliferative effects in human colon carcinoma cell lines irrespective of its COX-inhibiting potencies.
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PMID:Evidence of COX-2 independent induction of apoptosis and cell cycle block in human colon carcinoma cells after S- or R-ibuprofen treatment. 1673 Jul 2

Non-steroidal anti-inflammatory drugs are widely used for the treatment of pain and inflammation by inhibiting the formation of prostaglandins. However, their use is limited by their side-effects, including gastrointestinal, renal function, cardiovascular and platelet function. Cyclooxygenase activity is the principal target for the action of non-steroidal anti-inflammatory drugs. Two isoforms of cyclooxygenase have been characterized: (i) cyclooxygenase-1, which is found in many tissues and is generally constitutively expressed and synthesizes prostanoids that mediate homeostatic functions; and (ii) cyclooxygenase-2, the inducible isoform, which is mainly expressed at sites of injury or inflammation and synthesizes prostanoids that mediate inflammation, pain and fever. These findings led to the development of selective cyclooxygenase-2 inhibitors, with comparable anti-inflammatory and analgesic properties to traditional non-steroidal anti-inflammatory drugs, but with significantly fewer side-effects. However, these new selective cyclooxygenase-2 inhibitors are not risk free, and care should be taken when using these drugs, especially with elderly patients with multiple medical problems. Finally, the future is bright for the broader usage of these agents in the treatment of diseases other than inflammation and pain, such as Alzheimer's disease, colonic polyp and colon cancer, just to name a few.
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PMID:Cyclooxygenase-2 and antagonists in pain management. 1701 41

The effects of methyleugenol, an essential oil isolated from Asiasari radix, on antinociception were examined using the formalin test in mice. Oral administration of 10 mg/kg methyleugenol significantly decreased the duration of licking and biting behavior in the second phase without affecting that of the first phase, as did diclofenac, a non-steroidal anti-inflammatory drug. Methyleugenol also inhibited pain-related behaviors induced by intrathecal injection of N-methyl-d-aspartic acid (NMDA), while diclofenac did not affect these behaviors. These effects of methyleugenol were suppressed by bicuculline, a gamma-aminobutyric acid(A) (GABA(A)) antagonist. Muscimol, a GABA(A) agonist, displays the same action as methyleugenol with respect to the formalin test and NMDA-induced behaviors. Methyleugenol did not affect cyclooxygenase-1 and -2 activities. These results suggest that the antinociceptive effect of methyleugenol on the second phase of formalin-induced pain may be due to the inhibition of NMDA receptor-mediated hyperalgesia via GABA(A) receptors.
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PMID:Antinociceptive effect of methyleugenol on formalin-induced hyperalgesia in mice. 1704 12

The prostaglandins are lipid mediators, discovered in the 1930s by von Euler in Sweden and Goldblatt in the United Kingdom. They are made by the bifunctional enzyme, cyclooxygenase, which has both cyclooxygenase and peroxidase activities in the same molecule. Prostaglandins are involved in physiological functions such as protection of the stomach mucosa, aggregation of platelets and regulation of kidney function. They also have pathological functions such as their involvement in inflammation, fever and pain. Vane in 1971 elegantly showed that the pharmacological actions of aspirin and similar drugs were due to the inhibition of cyclooxygenase. Thus, aspirin-like drugs exert their anti-inflammatory, antipyretic and analgesic effects by inhibition of cyclooxygenase. In 1991, Simmons and his colleagues identified a second cyclooxygenase enzyme, designated cyclooxygenase-2, derived from a separate gene from cyclooxygenase-1. Cyclooxygenase-2 is upregulated by inflammatory mediators and forms prostaglandins which intensify the inflammatory response. Cyclooxygenase-1 is, therefore, a 'housekeeping' enzyme making prostaglandins, which are important for maintaining physiological functions and cyclooxygenase-2 makes prostaglandins which are important in inflammation. The discovery of cyclooxygenase-2 and the establishment of its structure led to the development of selective inhibitors of this enzyme, such as celecoxib and rofecoxib, with potent anti-inflammatory actions but with reduced gastrotoxic effects. A putative cyclooxygenase-3, has also been characterised and cloned. This enzyme is a product of the cyclooxygenase-1 gene, but retains intron 1 after transcription and translates into a cyclooxygenase enzyme with 34 additional amino acids. It is more sensitive to inhibition by paracetamol, aspirin and some other non-steroid anti-inflammatory drugs than cyclooxygenase-1 or cyclooxygenase-2. A cyclooxygenase enzyme induced in cultured cells by some non-steroid anti-inflammatory drugs is also more sensitive to inhibition by paracetamol than cyclooxygenase-2 induced by bacterial lipopolysaccharide.
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PMID:Inhibitors of cyclooxygenases: mechanisms, selectivity and uses. 1721 63

Zeel comp. N (Zeel) is a homeopathic medication that has been widely used for many years for the treatment of arthritic disorders in a large number of countries worldwide. In recent years, a growing body of clinical and molecular evidence has been accumulating that shed light on the possible antiarthritic effects of this preparation. A number of studies report anti-inflammatory effects from Zeel. In vitro studies have indicated Zeel-mediated inhibition of the pathways involving the enzymes cyclooxygenase-1 and -2, and also the 5-lipoxygenase pathways, affecting levels of both eicosanoids and leukotrienes. Thus, Zeel may reduce the main two classes of molecules responsible for arthritic pain and inflammation. This review describes recent research on Zeel and discusses the need for further studies to clarify the role of the compound in the antiarthritic armamentarium of complementary medicine.
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PMID:The homeopathic antiarthitic preparation Zeel comp. N: a review of molecular and clinical data. 1723 64

Inhibitors of cyclooxygenases (COXs) are the most widely used drugs. They reduce discomfort and fever, inhibit peri-operative and inflammatory pain. These effects are largely mediated by inhibition of cyclooxygenase-1 and -2 (COX-1 and COX-2)-enzymes found throughout the body producing prostaglandins, which are important mediators of pain and fever, but also adaptive and protective reactions in many organs. A first step to reduce the overall toxicity and to increase the anti-inflammatory activity of these drugs was achieved with the development of acidic 'non-selective' (traditional) non-steroidal anti-inflammatory drugs (tNSAIDs). These agents distribute unequally throughout the body, reaching effective concentrations in inflamed tissue (effect compartment) for prolonged time periods. They can also reach effective concentrations in the bloodstream, kidney and gastrointestinal (GI) mucosa, where they can cause unwanted effects, such as GI toxicity, kidney dysfunction and cardiovascular impairment. All these effects are particularly prominent with compounds which are eliminated slowly [half-life (T((1/2))) >12 h] and thus also block prostaglandin production permanently outside the effect compartment. A second step towards improving safety was achieved with selective COX-2 inhibitors. These agents reduce the incidence of GI toxicity, pseudo-asthmatic reactions and blood loss following surgical interventions. However, they may be more toxic to the cardiovascular and renal systems than some tNSAIDs, possibly because they distribute homogeneously throughout the body and inhibit COX-2 in the endothelial layer of the vessels and the kidney permanently due to their slow elimination. Another step towards improvement in safety appears possible by combining both enzyme specificity and tissue selectivity, to achieve a further reduction of unwanted drug effects while maintaining the anti-inflammatory/analgesic efficacy.
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PMID:Combining enzyme specificity and tissue selectivity of cyclooxygenase inhibitors: towards better tolerability? 1745 58

Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966-2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966-2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous.
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PMID:Tolerance to coxibs in patients with intolerance to non-steroidal anti-inflammatory drugs (NSAIDs): a systematic structured review of the literature. 1749 55


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