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)

The analysis of drug's influence on peripheral and central sensitisation can give useful information about its mode of action and can lead to more efficacy in the treatment of pain. Peripheral inflammation is associated with peripheral expression and up-regulation of cyclooxygenase 2 (COX-2) in the CNS. The relative contribution of COX-2 mediated central sensitisation may be prominent under inflammatory conditions. In this randomized, double blinded, placebo controlled cross-over trial the effects of multidoses of the COX-2 selective inhibitor rofecoxib on primary and secondary hyperalgesia were evaluated in the UVB pain model. Twenty-four hours after local UVB irradiation at the upper leg of 42 healthy volunteers heat pain perception (HPPT) and heat pain tolerance thresholds (HPTT) were assessed within the inflammation. The area of secondary hyperalgesia was determined by pin prick test. Subjects received oral rofecoxib 50, 250, 500 mg or placebo. Pain testing was repeated after 3 and 6 h. Compared to placebo, rofecoxib significantly increased HPPT (1.55 and 1.08 degrees C, P<0.0001 and P=0.0333), HPTT (1.74 and 1.58 degrees C, P<0.0001 and P<0.0001), and reduced the mean area of secondary hyperalgesia by 15.6% (P=0.007) and 16.8% (P<0.001) after 3 and 6 h. No significant difference between the three dosage groups was observed. These data confirm peripheral effects of rofecoxib in a human inflammatory UV-B pain model and provide circumstantial evidence that even a standard clinical dose of rofecoxib reduces central hyperalgesia in inflammatory pain. We confirm that the effect of single oral dose of rofecoxib plateaus at 50 mg.
Pain 2005 Feb
PMID:Rofecoxib attenuates both primary and secondary inflammatory hyperalgesia: a randomized, double blinded, placebo controlled crossover trial in the UV-B pain model. 1566 39

The mechanisms underlying neuropathic pain caused by nerve injury are not well understood. Inflammatory responses in injured nerves are likely to be key contributing factors in the generation and maintenance of neuropathic pain. The pro-inflammatory cytokine interleukin-6 (IL-6) is up-regulated in invading macrophages and has been implicated in the development of neuropathic pain. We previously demonstrated that invading macrophages up-regulate cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) receptors EP1 and EP4, suggesting that PGE2 may affect macrophage function via autocrine or paracrine mechanisms. This study was undertaken to determine whether PGE2 is involved in the up-regulation of IL-6 in invading macrophages. Two weeks following partial sciatic nerve ligation, numerous IL-6 immunoreactive (IR) cell profiles were present in injured nerves. Colocalization of IL-6 with the invading macrophage marker ED1 or with COX2 was frequently observed. IL-6-IR, COX2-IR and ED1-IR cells were present only in cultures derived from injured nerve segments. PGE2 and IL-6 release from cultured cells derived from injured nerves was increased significantly compared with uninjured nerves. Non-selective and selective COX2 inhibitors suppressed PGE2 and IL-6 release. Treatment with PGE2 further enhanced IL-6 release in a concentration- and time-dependent manner. A selective EP4 receptor antagonist L-161982 was able to suppress IL-6 release, whereas an EP1 receptor antagonist, SC19220, was ineffective. Moreover, a protein kinase C inhibitor, calphostin C, dramatically suppressed IL-6 release, whereas a protein kinase A inhibitor H-89 and a Ca2+ chelator EGTA failed. Taken together, our data suggest that PGE2 is involved in mediating the up-regulation of IL-6 occurring in invading macrophages. This action is mediated through an EP4 receptor and the protein kinase C signaling pathway.
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PMID:Up-regulation of interleukin-6 induced by prostaglandin E from invading macrophages following nerve injury: an in vivo and in vitro study. 1583 25

Non-steroidal anti-inflammatory drugs (NSAIDs) are useful medications for the management of pain. However, Cox-2 NSAIDs have been associated with an increased risk of cardiovascular side-effects and there are now concerns that this increased risk may extend to all NSAIDs. This article outlines the action of NSAIDs and discusses the evidence for a link with increased cardiovascular risk.
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PMID:The practice implications of cardiovascular risks in NSAIDs. 1601 Aug 38

A significant increase in thromboembolic events (i.e. myocardial infarction and stroke) was demonstrated in multicenter studies after several months of treatment with cyclooxygenase 2 (cox-2) inhibitors. In February 2005, the European medical agencies (EMEA) substantially increased the number of contraindications for all cox-2 inhibitors. They are now contraindicated for patients with coronary artery disease. Furthermore, 2 out of 6 cox-2 inhibitors have been withdrawn from the market. In this review, the current state of knowledge on the use of cox-2 inhibitors in perioperative pain therapy is summarized: i) they are equally as potent as other non-opioid analgesics, ii) they decrease opioid consumption, iii) a reduction in postoperative nausea and vomiting (PONV) has not been adequately demonstrated. Regarding side-effects, it can be concluded that i) the incidence of thromboembolic events is increased in patients undergoing coronary artery bypass surgery, ii) perioperative blood loss is not affected, iii) ulcer formation is not promoted, iv) the risk for acute renal failure is probably increased to the same extent as for NSAIDs and v) severe bronchospasm can be triggered in patients with asthma and chronic obstructive pulmonary disease (COPD).
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PMID:[Critical reevaluation of cyclooxygenase two inhibitors in perioperative pain therapy]. 1613 39

Nociception-evoked prostaglandin E2 (PGE2) release in the spinal cord contributes considerably to the development of hyperalgesia and allodynia. Biosynthesis of PGE2 involves the conversion of arachidonic acid to PGH2 by cyclooxygenases (COXs), followed by an isomerization of PGH2 to PGE2 by PGE2 synthases (PGESs). The roles of COX-1, COX-2, and the inducible microsomal PGES-1 have been studied in models of pain and inflammation. In contrast, in nociceptive processes, very little is known about the role of cytosolic PGES (cPGES), which has been described as being functionally coupled to COX-1. Here we show by in situ hybridization and immunohistological analysis that COX-1 and cPGES are constitutively expressed in neuronal and non-neuronal cells of the dorsal and ventral horns in the spinal cord of adult rats. The protein levels of both enzymes were not regulated by nociceptive stimuli; however, reduction of cPGES in rat spinal cord with intrathecal application of cPGES antisense oligonucleotides reduced the nociceptive behavior in zymosan-evoked thermal hyperalgesia and in the formalin assay. The data indicate that cPGES plays an important role in mediating early responses during spinal nociceptive processing.
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PMID:Downregulation of cytosolic prostaglandin E2 synthase results in decreased nociceptive behavior in rats. 1619 91

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used in the treatment of pain, including pain of dental origin, for many years. Even though they are effective in relieving symptoms, they are not without adverse events, most notably upper gastrointestinal toxicity. To prevent this side effect, the pharmaceutical industry developed NSAIDs that selectively inhibit the cyclooxygenase 2 (COX-2) isoenzyme, which is inducible and expressed at sites of inflammation, while sparing the COX-1 isoenzyme, which is associated with gastric protection. On September 30, 2004, the company that produced rofecoxib (Vioxx), a COX-2 inhibitor, voluntarily withdrew this product from the market based on the discovery of its association with increased risk of adverse cardiovascular events reported in an ongoing large clinical trial. This unexpected event caused the medical community to review existing literature regarding this and related medications and also led to the emergence of novel research to improve understanding of the potential mechanisms for this serious side effect. However, instead of clarifying the situation, reports created confusion and controversy regarding the safety of all types of NSAIDs. The major concern is an increase in adverse cardiovascular events with the use of individual drugs as well as the potential for a class effect. In this article, we review recent events and findings and discuss the implications for dentistry.
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PMID:Nonsteroidal anti-inflammatory drugs: confusion, controversy and dental implications. 1620 97

(1) The cardiovascular risks associated with Cox-2 inhibitor therapy were confirmed in early 2005, and measures restricting the use of these drugs were taken in several countries. Yet celecoxib remains on the market. (2) Comparative trials versus other NSAIDs failed to show that celecoxib was any more effective for pain relief. And, following damning revelations that the CLASS study results had been manipulated, it became clear that celecoxib had no tangible advantage in terms of serious gastrointestinal complications. (3) An increase in Cox-2 inhibitor prescriptions, primarily based on their reputation for better tolerability, led to an increase in the absolute number of cases of gastrointestinal haemorrhage. (4) A trial focusing on the prevention of colorectal polyps showed that cardiovascular events occurred two to three times more frequently with celecoxib than with placebo. Another trial showed no significant difference. (5) In a trial involving patients with Alzheimer's disease, overall mortality was higher with celecoxib than in the placebo group. The difference was similar to that observed in placebo-controlled trials of rofecoxib in Alzheimer's disease. (6) The celecoxib affair once again highlights certain failings of the American and European regulatory agencies: celecoxib is still on the market, exposing patients to risks associated with its use without providing any therapeutic advantage.
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PMID:Celecoxib still on the market: but for whose benefit? 1628 73

Prostaglandin H2 synthase (PGHS) synthesizes PGH2, a prostaglandin precursor, from arachidonic acid and was the first monotopic enzyme to have its structure experimentally determined. Both isozymes of PGHS are inhibited by nonsteroidal antiinflammatory drugs, an important class of drugs that are the primary means of relieving pain and inflammation. Selectively inhibiting the second isozyme, PGHS-2, minimizes the gastrointestinal side-effects. This had been achieved by the new PGHS-2 selective NSAIDs (i.e., COX-2 inhibitors) but it has been recently suggested that they suffer from additional side-effects. The design of these drugs only made use of static structures from x-ray crystallographic experiments. Investigating the dynamics of both PGHS-1 and PGHS-2 using classical molecular dynamics is expected to generate new insight into the differences in behavior between the isozymes, and therefore may allow improved PGHS-2 selective inhibitors to be designed. We describe a molecular dynamics protocol that integrates PGHS monomers into phospholipid bilayers, thereby producing in silico atomistic models of the PGHS system. Our protocol exploits the vacuum created beneath the protein when several lipids are removed from the top leaflet of the bilayer. The protein integrates into the bilayer during the first 5 ns in a repeatable process. The integrated PGHS monomer is stable and forms multiple hydrogen bonds between the phosphate groups of the lipids and conserved basic residues (Arg, Lys) on the protein. These interactions stabilize the system and are similar to interactions observed for transmembrane proteins.
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PMID:A computational protocol for the integration of the monotopic protein prostaglandin H2 synthase into a phospholipid bilayer. 1663 99

Arthritis is the leading cause of disability in the United States. Osteoarthritis, the most common form of arthritis, is a degenerative joint disease affecting both whites and African Americans similarly. African Americans have a high incidence rate of comorbidities, including hypertension, cardiovascular disease (CVD) risk factors and diabetes. Treatment of osteoarthritic pain in patients with comorbidities is often complicated by potential safety concerns. Traditional nonsteroidal antiinflammatory drugs (NSAIDs) and cyclooxygenase 2 (COX-2) specific NSAIDs have been shown to increase blood pressure in hypertensive patients taking antihypertensive medications. Patients with CVD risk factors taking low-dose aspirin for secondary prevention may be at increased risk for gastrointestinal bleeding with NSAIDs. Diabetics face an increased risk of renal complications. Because NSAIDs are associated with adverse renal effects, they should be used cautiously in patients with advanced renal disease. Acetaminophen is the most appropriate initial analgesic for African Americans with chronic osteoarthritic pain and concurrent hypertension, CVD risk factors or diabetes, and is recommended by the American College of Rheumatology as first-line treatment. Many of the adverse effects commonly associated with NSAIDs are not associated with acetaminophen. Safety concerns surrounding pharmacologic treatment of osteoarthritis in African Americans are reviewed.
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PMID:Safe pharmacologic treatment strategies for osteoarthritis pain in African Americans with hypertension, and renal and cardiac disease. 1689 83

Bioactive materials have previously been used to coat implants. In a new development for bioactive materials, a silica-ceramic mixture was found to alleviate pain (Lee, Poster presented at the Ninth World Congress of Gynecological Endocrinology, Hongkong, 2001. Poster session (p47)). Here, we hypothesized that silica-ceramic can reduce the expression and activity of cyclooxygenase 2 (COX2) or cytokines associated with inflammation. The production of COX2 and proinflammatory cytokines was investigated by reverse transcriptase (RT)-PCR and ELISA assay in macrophages stimulated by lipopolysaccharide (LPS). Silica-ceramic had no effect of COX2 expression and prostaglandin production in macrophages. However, silica-ceramic suppressed the synthesis of cytokines involved in inflammation, in particular, the expression of IL-1beta and IL-6 was reduced at the transcriptional and translational levels. The involvement of NF-kappaB in the suppression of cytokines by silica-ceramic was examined by luciferase reporter assay. The NF-kappaB activity stimulated by LPS was inhibited by 20-60% with silica-ceramic compared with treatment with LPS alone. We suggest that inhibition of NF-kappaB activity by silica-ceramic might cause the attenuation of proinflammatory cytokine expression in macrophages. In conclusion, silica-ceramic could be an alternative approach to regulate the inflammation process.
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PMID:Silica-ceramic suppresses the expression of proinflammatory cytokines induced by lipopolysaccharide in macrophages. 1713 51


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