Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation and deposition of monosodium urate (MSU) microcrystals in articular and periarticular tissues is the causative agent of acute or chronic inflammatory responses known as gouty arthritis. Mononuclear phagocyte activation is involved in early triggering events of gout attacks. Because stimulated mononuclear phagocytes can constitute an important source of the inducible isoform of cyclooxygenase (COX-2), we evaluated the effects that proinflammatory microcrystals might have on COX-2 protein expression in crystal-stimulated monocytes. We found that MSU crystals, but not calcium pyrophosphate dihydrate (CPPD) crystals, induced COX-2, which correlated with the synthesis of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). Crystal-induced de novo synthesis of COX-2 was dependent on transcriptional and translational events. Inhibition of tyrosine phosphorylation, by herbimycin A, blocked crystal-induced COX-2. Similarly, an inhibitor of the p38 mitogen-activated protein kinase, SB 203580, inhibited the stimulation of COX-2. Colchicine inhibited crystal-induced COX-2. In all cases, prostanoid synthesis was concomitantly inhibited. Taken together, these results implicate COX-2 in the development of MSU-induced inflammation.
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PMID:Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes. 947 45

The authors first briefly review how the concept of COX-2 selectivity was brought to light, then tested against the known gastrotoxicity ranking of currently used NSAIDs, from the old classics to the most recent. One truly selective COX-2 agent--celecoxib--is now being marketed in an ever increasing number of countries. So far it seems to keep its main promises, i.e. high--albeit not total--safety regarding gastrointestinal adverse effects, and undisturbed platelet function. Association with warfarin drugs seems to raise no problems, but one should still be wary of possible renal side-effects. Efficacy, at least as assessed in osteoarthritis and rheumatoid patients, appears satisfactory. However, treatment of intense inflammatory crises, such as gout or ankylosing spondylitis, has not been assessed, as yet. Another COX-2 agent--rofecoxib--is on the brink of being released. Its even more potent COX-2 selectivity raises new issues. What about some COX-1 activity that several authors detected in rheumatic synovitis? On the other hand, in particular circumstances, organs such as the stomach, the kidney and small blood vessels, seem to have their homeostasis partly controlled by COX-2 mechanisms also. These questions should be answered soon, whilst clinical experience with the COX-2 agent builds up.
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PMID:Novel nonsteroidal anti-inflammatory drugs. 1069 73

Gout is an inflammatory response to deposition of monosodium urate crystals in and around joints. It is primarily a disease of adult men. In acute gout, treatment options include non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids, administered either intra-articularly, orally or parenterally. Asymptomatic hyperuricaemia does not require specific treatment, but should prompt screening for atherosclerosis risk factors, and general lifestyle modification to reduce serum urate levels. Gout presents differently in the elderly. Both women and men are affected, attacks are frequently polyarticular and in the upper limbs, and the gout may be associated with diuretic use, hypertension and renal impairment. In patients with peptic ulcer disease, selective COX-2 inhibitors provide another treatment option. In the presence of renal impairment, allopurinol is the treatment of choice for urate lowering therapy, but doses of allopurinol and colchicine must be adjusted. Urate lowering therapy should only be used if recurrent episodes of gout occur despite aggressive attempts to reverse or control the underlying causes. It should not be introduced or discontinued during an acute episode of gout, and gout prophylaxis (NSAIDs or colchicine) should be prescribed during the introduction of urate lowering therapy.
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PMID:Clinical manifestations of gout and their management. 1090 73

Osteoarthritis (OA) and rheumatoid arthritis (RA) are among the most prevalent chronic illnesses and leading causes of disability in the United States. The clinical symptoms of OA and RA, pain and inflammation, are biologic processes mediated in part by prostanoids-prostaglandins, prostacyclin, and thromboxanes. The intermediate enzymes responsible for prostaglandin biosynthesis, cyclooxygenase (COX)-1 and COX-2, have been the target of arthritis therapy using nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). An understanding of the biochemistry and molecular pharmacology of COX enzymes has allowed for the development of agents that specifically inhibit COX-2. COX-2-selective inhibitors have efficacy in OA and RA that is similar to that of NSAIDs but with a lower potential for upper gastrointestinal injury, a serious side effect of nonselective NSAIDs. COX-2-selective inhibitors have been increasingly used in the treatment of OA and RA as well as other inflammatory arthropathies including ankylosing spondylitis and gout. Clinical trials with two currently available drugs, rofecoxib and celecoxib, have demonstrated efficacy comparable to nonselective NSAIDs but with a lower risk of gastrointestinal side effects. In general, these drugs are well tolerated in patients with aspirin-sensitive asthma. Rofecoxib is well tolerated in patients with sulfonamide sensitivities; further studies are needed to fully characterize the utility of celecoxib in these patients. Clinical experience shows that because of their improved GI safety, rofecoxib and celecoxib, and newer COX-2-selective inhibitors (valdecoxib, etoricoxib, parecoxib), represent a significant advance in the treatment of arthritis and other related inflammatory conditions.
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PMID:Development and clinical application of COX-2-selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis. 1208 94

Etoricoxib is a cyclo-oxygenase (COX)-2-selective NSAID with a higher COX-1 to COX-2 selectivity ratio than the other COX-2-selective NSAIDs rofecoxib, valdecoxib or celecoxib. In patients with rheumatoid arthritis, improvements in tender and swollen joint counts and patient and investigator global assessment of disease activity were significantly greater in etoricoxib than in placebo recipients in two studies. Etoricoxib was also significantly more effective than naproxen in one of these studies. In patients with osteoarthritis of the hip or knee, etoricoxib was significantly more effective than placebo and had similar efficacy to naproxen with regards to improvements in pain and physical function scores and patient global assessment of disease status scores in two studies. Etoricoxib had similar efficacy to diclofenac in patients with osteoarthritis of the knee. Single-dose etoricoxib relieved pain in patients with postoperative dental pain in two studies. Similar scores assessing total pain relief over 8 hours (TOPAR8) were reported in etoricoxib and naproxen sodium or ibuprofen recipients, and higher TOPAR8 scores were reported with etoricoxib than with paracetamol (acetaminophen)/codeine. Pain relief was significantly better with etoricoxib than placebo in two studies in patients with chronic low back pain. Etoricoxib had similar efficacy to indomethacin in a study in patients with acute gout, and single-dose etoricoxib had similar efficacy to naproxen sodium in a study in women with primary dysmenorrhoea. Compared with non-COX-selective NSAIDs, etoricoxib was associated with significantly fewer upper gastrointestinal (GI) perforations, ulcers or bleeds, and was significantly less likely to result in treatment discontinuation because of NSAID-type GI symptoms or any GI symptoms.
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PMID:Etoricoxib. 1246 2

Advantages and risks related to the use of selective COX-2 inhibitors when treating arthritis are currently being scrutinized by authorities and public. The discussion tends towards exaggerated claims for or against their usefulness. The issue of cardiovascular safety is still not finally settled. In an experimental study using patients with severe coronary disease, administration of celecoxib resulted in improved endothelial function together with reduced CRP levels. Gastrointestinal tolerance was studied in patients who had recently recovered from peptic ulcer bleeding. In this group of high risk patients, celecoxib was as safe as combined therapy using omeprazol and diclofenac when given for 6 months. However, both COX inhibitors caused hypertension and adverse renal effects. The second generation of selective inhibitors is being launched. Etoricoxib--related to rofecoxib--was shown to be as potent as indomethacin in the treatment of acute gout, but it caused fewer adverse reactions. In general, however, any advantage of second generation as compared to first generation COX-2 inhibitors remains to be proven. The Swedish Council on Technology Assessment in Health Care, in its "SBU Alert", has published an appraisal of celecoxib and rofecoxib, in which the need for further long-term safety studies is emphasized.
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PMID:[New studies of COX-inhibitors, yet issues remain]. 1455 11

COX-2 selective inhibitors were developed in order to provide similar efficacy to traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) but with improved upper gastrointestinal safety. This paper presents an overview of randomized clinical trials demonstrating the efficacy of COX-2 selective inhibitors for the treatment of patients with arthritis, particularly osteoarthritis and rheumatoid arthritis. In osteoarthritis and rheumatoid arthritis, COX-2 selective inhibitors have been shown to be more effective than placebo and similarly effective as standard doses of nonselective NSAIDs. There are currently few randomized clinical trials comparing the efficacy of the 2 first-generation COX-2 selective inhibitors, celecoxib and rofecoxib, in osteoarthritis. Of 4 head-to-head studies comparing the 2 agents, 3 indicated similar efficacy, while the other demonstrated superiority of rofecoxib at a dose of 25 mg qd compared with celecoxib at a dose of 200 mg qd. There are no clinical trials comparing the efficacy of different agents for treatment of patients with rheumatoid arthritis. Some studies have also demonstrated efficacy for COX-2 selective inhibitors in patients with ankylosing spondylitis and gout. In aggregate, these data show that COX-2 selective inhibitors provide effective relief of pain in patients with osteoarthritis and rheumatoid arthritis, with efficacy that is similar to traditional NSAIDs. Cost-effectiveness and cost-utility studies suggest, however, that their use should be limited to patients at high risk of serious upper gastrointestinal side effects, including complicated ulcers.
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PMID:COX-2 selective inhibitors in the treatment of arthritis: a rheumatologist perspective. 1597 39

Many patients with rheumatic diseases have their management complicated by renal problems. Renal failure modifies the metabolism of many drugs, especially by retention. Questions often arise about the effects of renal failure on the handling of drugs commonly used in rheumatology. For which drugs must we be especially concerned about increased toxicity? Patients on chronic dialysis may also need a variety of drugs for rheumatic disease. How are our drugs dialyzed, and which of these can be safety used and how best to use them?Decisions about dosing of rheumatic drugs are often required for the patients with chronic renal insufficiency or on long-term dialysis, although many drugs have not been formally studied in these settings. Patients with renal insufficiency are excluded from most drug trials. Data for some of these drugs have to be extrapolated based on the information available about the pharmacokinetics of the drug.This review addresses dosing of commonly used drugs in rheumatology in patients with chronic renal insufficiency or failure. It is compiled from a MEDLINE search of papers dealing with renal handling of antirheumatic drugs and suggestions for dose adjustments for these drugs. Drugs reviewed include commonly used disease-modifying antirheumatic drugs (DMARDS), drugs used for treatment of gout, commonly used nonsteroidal antnflammatory drugs (NSAIDS) and the newer COX-2 inhibitors.
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PMID:Dosing of antirheumatic drugs in renal disease and dialysis. 1704 8

We determined the anti-inflammatory activity of standardized extracts of four medicinal plant species (Baccharis incarum, B. boliviensis, Chuquiraga atacamensis, Parastrephia lucida) that grow in the Argentine Puna (3800 m above sea level) and that are used to reduce oxidative stress and alleviate gout and arthritic pain. The extracts of plant aerial parts were standardized in terms of total phenolic compounds and flavone/flavanone content and free radical scavenging activity. All extracts showed high phenolic compound concentration (0.5-1.6 mg/mL), mainly flavones and flavonols (0.1-0.8 mg/mL). The extracts showed hydrogen donating ability (DPPH and ABTS) and reactive oxygen species scavenging activity (O2-, OH-, H2O2). The ability of the extracts to inhibit cyclooxygenase enzymes (COX-1 and COX-2) was determined by calculating percent inhibition of PGE2 production measured by enzyme immunoassay. All extracts inhibited both enzymes with IC50 values of 2.0 to 16.7 microg/mL. The anti-inflammatory activity of B. incarum and C. atacamensis extracts was higher than that of B. boliviensis and P. lucida. The IC50 values obtained for indomethacin were 0.11 and 0.78 microM for COX-1 and COX-2, respectively. The present results are consistent with the anecdotal use of these species in phytotherapic preparations.
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PMID:Inhibition of cyclooxygenase activity by standardized hydroalcoholic extracts of four Asteraceae species from the Argentine Puna. 1973 84

The prevalence of gout increases with age. Up to 7% of men > 65 and 3% of women > 85 have gout. Risk of gout increases significantly with increasing serum uric acid levels. Alcohol consumption and purine-rich foods such as red meat and seafood increase the risk of incident gout significantly. Loop and thiazide diuretics are also associated with increased risk. Gout is frequently associated with the metabolic syndrome. Dehydration, increasing creatinine levels, and surgery are also known to precipitate flares. Acute gout manifests as severe joint pain, of rapid onset, reaching maximal intensity within a few hours. Gout has a predilection for lower extremity joints. It often starts at the first metatarsophalangeal joint, a condition termed podagra. Other common sites of gouty flares include: tarsal and subtalar joints; ankle; knee; wrist; small joints of the hands; Achilles tendon; and olecranon bursae. The joint affected is usually hot, red, swollen and very painful. This is often associated with skin erythema. Identification of MSU crystals in the synovial fluid of an inflamed joint or from tophi allows a definite diagnosis of gout to be made. Hyperuricaemia does not confirm or exclude gout as most people with hyperuricaemia are asymptomatic, while serum uric acid levels tend to decrease during acute attacks. Short-acting NSAIDs should be used at maximal dose as first drug of choice if not contraindicated. In patients at risk of GI complications, co-prescription of a proton pump inhibitor or the use of COX-2 selective agents should be considered. Colchicine can be particularly useful in patients with heart failure in whom NSAIDs are contraindicated but should be avoided in patients with severe renal impairment. Joint aspiration and injection of intra-articular steroids is one of the most effective ways of treating acute monoarthritic gout. Uric acid lowering therapy is initiated if a patient suffers two or more attacks in one year. Many rheumatologists will start this therapy in hyperuricaemic patients whose first attack is very severe or in polyarticular gout.
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PMID:Diagnosis and treatment of gout in primary care. 2227 26


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