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)

Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic conditions requiring long-term therapy for pain relief. Currently prescribed non-steroidal anti-inflammatory drugs (NSAIDs) provide symptomatic efficacy, but are frequently associated with gastrointestinal (GI) toxicities such as dyspepsia and ulcerations. In a small but significant number of cases, complications including perforations and massive bleeding develop and these may be fatal. A desirable therapeutic strategy would maintain efficacy while minimizing gastric intolerance. Two potential approaches have been suggested: (i) administration of NSAIDs in combination with gastroprotective compounds; or (ii) administration of potentially safer anti-inflammatory compounds which act via selective inhibition of cyclooxygenase-2 (COX-2). The selective COX-2 inhibitors rofecoxib and celecoxib consistently demonstrate efficacy comparable to conventional NSAIDs in patients with RA and OA, but have a significantly reduced propensity to cause GI toxicity. In many cases, the gastric effects of therapeutically active doses of COX-2 inhibitors are indistinguishable from placebo. The safety benefits of COX-2 inhibitors given alone appear similar to combined therapy with conventional NSAIDs and gastroprotective agents. Findings warrant the consideration of COX-2 inhibitors as first-line therapy in patients requiring long-term pain relief.
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PMID:Clinical experience with cyclooxygenase-2 inhibitors. 1217 76

Preserved human remains, artefacts and works of art contain records of the existence and prevalence of arthropathies, even in the absence of medical texts or formal written accounts, although these also exist for some epochs and cultures. Example objects from the Museum of Medical History in Brussels have been used to illustrate the magnitude of the burden of pain throughout the ages and how rheumatic diseases have indiscriminately afflicted people regardless of their positions in life or occupations. These include both osteoarthritis (OA) and rheumatoid arthritis (RA), as well as the seemingly ubiquitous gout and various skeletal deformities. Adequate pain management has been severely hampered, historically, by obstacles to a comprehensive and systematic classification of diseases posed by the social, religious and philosophical mores of the time, which made differential diagnosis almost impossible to achieve. However, despite this shortcoming, serendipitous events meant that precursors of modern medicines, such as willow bark extracts, were in routine use from the earliest recorded times. It has taken several millennia, however, before empirical treatment has given way to pharmacological rationale. The first clinically acceptable synthetic derivative of the active principle in willow, aspirin, became available only at the turn of the nineteenth century, while non-steroidal anti-inflammatory drugs (NSAIDs) did not arrive on the market until some 60 yr later. At the cusp of the twentieth and twenty-first centuries, physicians have a wider choice of analgesics available than ever before, including the cyclooxygenase-2 inhibitors, which represent the first major advance in NSAID development since the synthesis of the latter compounds themselves.
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PMID:Arthropathy in art and the history of pain management--through the centuries to cyclooxygenase-2 inhibitors. 1217 78

Pain is very common throughout the world and is an increasing problem in the ageing population. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to treat pain and many are also available without prescription, or over the counter. These drugs are effective painkillers, but they can also have severe adverse effects, particularly on the upper gastrointestinal (GI) tract. Therapeutic decisions should be made using the best available evidence and there is a growing body of evidence showing that the new specific cyclooxygenase-2 (COX-2) inhibitors, or coxibs, are effective pain killers that do not cause GI harm. The risks associated with the use of NSAIDs are substantial, with a 1 in 1200 chance of dying from a major GI adverse effect after 2 months of NSAID therapy. These risks increase with age and are avoidable. The costs associated with the prevention and treatment of NSAID-induced GI adverse effects can more than double the cost of the original therapy and should be included when costing NSAID interventions. Taking these costs into account, the expense of switching from a conventional NSAID to a coxib is relatively modest. Compared with other interventions that society may be willing to consider to prevent one death, such as those for the rail (15 million Pounds) and road (100,000 Pounds) networks in the UK, the cost of preventing one death by switching to a coxib is much lower, with a high estimate being 20,000-30,000 Pounds, which is in line with the accepted benchmarks for the cost-effectiveness of medical interventions.
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PMID:The hidden costs of arthritis treatment and the cost of new therapy--the burden of non-steroidal anti-inflammatory drug gastropathy. 1217 80

Nonsteroidal anti-inflammatory drugs prevent hyperalgesia and inflammation by inhibiting the cyclooxygenase-2 (COX-2) catalyzed oxygenation of arachidonic acid to prostaglandin (PG) H(2). The lipoamino acid N-arachidonylglycine (NAGly) has also been shown to suppress tonic inflammatory pain and is naturally present at significant levels in many of the same mammalian tissues that express COX-2. Here, we report that COX-2 selectively metabolizes NAGly to PGH(2) glycine (PGH(2)-Gly) and hydroxyeicosatetraenoic glycine (HETE-Gly). Site-directed mutagenesis experiments identify the side pocket residues of COX-2, especially Arg-513, as critical determinants of the COX-2 selectivity towards NAGly. This is the first report of a charged arachidonyl derivative that is a selective substrate for COX-2. These results suggest a possible role for COX-2 in the regulation of NAGly levels and the formation of a novel class of eicosanoids from NAGly metabolism.
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PMID:Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2. 1217 25

Prostaglandin E(2) (PGE(2)) is the major prostaglandin produced both centrally and in the periphery in models of acute and chronic inflammation, and its formation in both locations is blocked by cyclooxygenase-2 (COX-2) inhibitors such as celecoxib. In animal models of inflammation, PGE(2) inhibition in the brain may occur secondarily to a peripheral action by inhibiting local PG formation that elicits increased firing of pain fibers and consequent activation of PG synthesis in the central nervous system (CNS). Celecoxib was studied in the kainate-induced seizure model in the rat, a model of direct central prostaglandin induction, to determine whether it can act directly in the CNS. In the kainate-treated rat brain there was increased PGE(2), PGF(2alpha), and PGD(2) production, with COX activity and PGE(2) formation increased about 7-fold over normal. We quantitated mRNA levels for enzymes involved in the prostaglandin biosynthetic pathways and found that both COX-2 and PGE synthase (PGEs) mRNA levels were increased in the brain; no changes were found for expression of COX-1 or PGD synthase mRNA. By Western blot analysis, COX-2 and PGEs were induced in total brain, hippocampus, and cortex, but not in the spinal cord. Immunohistological studies showed that COX-2 protein expression was enhanced in neurons. Dexamethasone treatment reduced the expression of both COX-2 and PGEs in kainate-treated animals. Celecoxib reduced the elevated PGE(2) levels in brain of kainate-treated rats and inhibited induced COX activity, demonstrating the ability of this compound to act on COX-2 in CNS. Doses of celecoxib that inhibited brain COX-2 were lower than those needed for anti-inflammatory activity in adjuvant arthritis, demonstrating a potent direct central action of the compound.
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PMID:Pharmacology of celecoxib in rat brain after kainate administration. 1218 39

We report a case of intra-articular intracortical chondroblastoma of the femoral condyle which radiologically appeared to be osteoid osteoma. A 19-year-old woman presented with a 3-year history of gradually increasing pain in the right knee and had been on nonsteroidal anti-inflammatory drugs for pain relief. Laboratory data were within normal limits. Radiographs showed a well-demarcated lucent lesion in the medial condyle of the right femur. A nidus-like lesion with calcifications and a sclerotic rim located in the cortex was imaged by computed tomography scan. Magnetic resonance imaging revealed bone marrow edema and soft tissue swelling around the lesion, with low signal intensity of the nidus-like lesion on both T1- and T2-weighted images. The lesion was excised en bloc and the histological diagnosis of chondroblastoma was made. A mild inflammatory reaction was observed in the bone marrow and synovium around the tumor. The chondroblastoma cells were shown to express cyclooxygenase-2 with immunohistochemistry.
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PMID:Intracortical chondroblastoma mimicking intra-articular osteoid osteoma. 1232 31

The recent release of the selective cyclooxygenase-2 (COX-2) enzyme inhibitors for the treatment of various inflammatory disorders and pain syndromes has been associated with a clear-cut decrease in adverse gastrointestinal effects. The nephrotoxic effect of selective COX-2 inhibitors has not yet been firmly established. We report a case of reversible acute renal failure due to rofecoxib treatment in an elderly patient with several risk factors associated with traditional nonselective nonsteroidal anti-inflammatory drug (NSAID)-related nephrotoxicity. It is prudent to approach therapy with selective COX-2 inhibitors cautiously and in a fashion similar to traditional NSAID therapy for patients with risk factors that induce prostaglandin-dependent renal function.
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PMID:Acute renal dysfunction associated with selective COX-2 inhibitor therapy. 1245 7

Selective inhibition of cyclooxygenase-2 (COX-2) leads to relief of pain and inflammation with reduced gastrointestinal side effects relative to nonsteroidal anti-inflammatory drugs. 2-Acetoxyphenylhept-2-ynyl sulfide (APHS) is a selective COX-2 inhibitor that covalently modifies the protein by acetylating Ser-530. We utilized site-directed mutants in the COX-2 active site to probe the molecular determinants of APHS acetylation of COX-2. Incorporation of acetyl groups into Ser-530 was monitored by HPLC and mass spectrometry. Mutations that introduce steric bulk into a channel at the top of the active site (e.g., G533A, G533V) lead to a significant reduction in APHS acetylation. Reduction in acetylation is also observed by mutation of the active-site tyrosine (Tyr-385) to phenylalanine. Mutations in the side-pocket region, into which diarylheterocycle inhibitors insert, do not affect the ability of APHS to acetylate COX-2. Surprisingly, mutation of Arg-120, which is located on the floor of the active site, strongly reduces acetylation. Based on these results, we propose that the heptynyl side chain of APHS inserts into the top channel and acetylates Ser-530 with the assistance of hydrogen bonding from Tyr-385. Arg-120 is proposed to fix the conformation of the active site to one that favors acetylation.
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PMID:Functional analysis of the molecular determinants of cyclooxygenase-2 acetylation by 2-acetoxyphenylhept-2-ynyl sulfide. 1246 51

During dermal injury and the associated trauma a number of compounds are released that can mediate the inflammatory response. Determining the cellular mechanisms that initiate the inflammatory responses to acute keratinocyte damage is important for understanding the regulation of epidermal inflammation. The recently cloned vanilloid receptor-1 (VR1) is a polymodal receptor, responding to thermal, pH, or vanilloids such as capsaicin stimulation. Although VR1 has been localized only on sensory neurons and within the central nervous system, recent evidence suggests a functional VR1 is expressed in human skin and epidermal cells. Using reverse transcription-polymerase chain reaction and immunoblotting we report that human keratinocytes and the human keratinocyte cell line HaCaT express VR1. Consistent with neuronal VR1, activation of epidermal VR1 by capsaicin induced a calcium influx. Treating HaCaT cells with capsaicin resulted in a dose-dependent expression of cyclooxygenase-2 (COX-2), whereas pretreatment with the VR1 receptor antagonist capsazepine abolished the capsaicin-stimulated increase in COX-2 expression. Furthermore, the capsaicin-induced expression of COX-2 was dependent on extracellular calcium. Activation of the epidermal VR1 by capsaicin also resulted in an increased release of interleukin-8 and prostaglandin E2, and the stimulated release was attenuated by capsazepine. The finding that VR1 is expressed by keratinocytes is of great importance because it expands the putative role of VR1 beyond that of pain perception. Our results suggest that VR1 expression in keratinocytes may have a role in the inflammation that occurs secondary to epidermal damage or insult, and thus may function as a sensor for noxious cutaneous stimulation.
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PMID:Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. 1249 May 94

Synergism has been used to obtain analgesia at doses at which side effects are minimal. In addition, it has been demonstrated that inhibition of cyclooxygenase-2 is responsible for the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to evaluate the antinociceptive interaction between the preferential COX-2 inhibitor, rofecoxib and morphine. Several combinations were evaluated using the pain-induced functional impairment model (PIFIR), a rat model of arthritic pain. Surface of synergistic interaction (SSI) analysis and an isobolographic method were used to detect the antinociceptive potency of the drugs, given either individually or in combination. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Male rats received orally morphine alone (10, 17.8, 31.6, 56.2 and 100.0 mg/kg), rofecoxib alone (3.2, 5.6, 10, 31.6, 56.2 and 74.0 mg/kg) or 12 different combinations of morphine and rofecoxib. Three combinations exhibited potentiation of antinociceptive effects (10 mg/kg of morphine with either 5.6, 10 or 31.6 mg/kg of rofecoxib), whereas the other nine combinations showed additive antinociceptive effects. The combination of morphine, 56.2 mg/kg (p.o.), and rofecoxib, 31.6 mg/kg (p.o.), produced the maximum antinociceptive effect (P<0.05). This combination caused gastric injuries less severe than those observed with indomethacin, i.e. it reduced ulcers and erosion formation. The synergistic antinociceptive effects of rofecoxib and morphine are important and suggest that combinations with drugs may decrease the side effects associated with the use of nonselective NSAIDs. Furthermore, the present results suggest that combinations containing opioid drugs and selective COX-2 inhibitors may have clinical utility in pain therapy.
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PMID:Enhancement of antinociception by co-administration of an opioid drug (morphine) and a preferential cyclooxygenase-2 inhibitor (rofecoxib) in rats. 1255 69


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