Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased small intestinal permeability caused by non-steroidal anti-inflammatory drugs (NSAIDs) is probably a prerequisite for NSAID enteropathy, a source of morbidity in patients with rheumatoid arthritis. This increased small intestinal permeability may be a summation of a local effect during drug absorption, a systemic effect after absorption, and a local effect of the drug excreted in bile, but the relative contribution made by these factors is unknown. We assessed the effect of indomethacin and nabumetone on intestinal permeability. The principal active metabolite of nabumetone, 6-methoxy-2-naphthylacetic acid, is not subject to appreciable enterohepatic recirculation. Twelve volunteers were studied before and after one week's ingestion of indomethacin (150 mg/day) and nabumetone (1 g/day) with a combined absorption/permeability test. Neither drug had a significant effect on the permeation of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose. Indomethacin increased the permeation of radioactive 51chromium ethylenediaminetetra-acetic acid (51Cr EDTA) significantly from baseline (mean (SEM) 0.63 (0.09)% v 1.20 (0.14)%, p less than 0.01) but nabumetone did not (0.70 (0.10)% p greater than 0.1). These results were supported by the 51Cr EDTA/L-rhamnose urine excretion ratios, which reflect changes in intestinal permeability. They suggest that NSAIDs increase intestinal permeability during absorption or after biliary excretion and that the systemic effect is of minor importance.
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PMID:Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man. 190 63

The concentration of 6-methoxy-2-naphthylacetic acid (6-MNA) in plasma, synovial fluid, synovial tissue and fibrous capsule tissue was determined in an open study with 20 patients scheduled for knee joint surgery after oral treatment with nabumetone under steady-state conditions. 6-MNA is the principle metabolite of the prodrug nabumetone arising from an extensive first-pass metabolism in the liver. Patients suffering from rheumatoid arthritis (n = 12) or osteoarthritis stage III or IV (n = 8) received a daily dose of nabumetone 1 g in the evening starting 4 days prior to surgery. On day 1 an additional loading dose of nabumetone 1 g was given in the morning. At the time of surgery (day 5), blood, synovial tissue and fibrous capsule tissue were taken simultaneously. The samples were analysed by high performance liquid chromatography. After 4 days of treatment mean 6-MNA concentration in plasma was 40.76 mg/L, in synovial fluid 34.79 mg/L, in synovial tissue 19.33 mg/g and in fibrous capsule tissue 11.43 mg/g. Under steady-state conditions mean synovial fluid levels of 6-MNA were higher than after administration of a single dose and, in common with levels in synovial tissue, persist in a range sufficient for in vitro cyclo-oxygenase inhibition.
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PMID:Penetration of the active metabolite of nabumetone into synovial fluid and adherent tissue of patients undergoing knee joint surgery. 208 95

Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) of the 2,6-disubstituted naphthylalkanone class. It is a prodrug metabolised to an active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), which preferentially inhibits cyclo-oxygenase-2 (COX-2) and has both anti-inflammatory and analgesic properties. The efficacy of nabumetone is comparable to that of other NSAIDs currently marketed in France for the treatment of rheumatoid arthritis and osteoarthritis. Nabumetone is metabolised to 6-MNA by extensive first-pass metabolism. This active metabolite is subsequently conjugated and excreted in urine. 6-MNA does not undergo enterohepatic recirculation, which may have implications for comparative gastrointestinal toxicity. Substantial concentrations of 6-MNA are achieved and maintained in synovial fluid, which is close to the proposed site of action in chronic arthropathies. The long plasma half-life of 6-MNA (20 to 24 hours) and its persistence in synovial fluid facilitate a once-daily dosage regimen. Nabumetone compares favourably with other NSAIDs with respect to its renal and gastrointestinal adverse effect profile, although increased clinical vigilance of drug-related adverse events relating to these organ systems is still recommended. In addition, in vitro experiments have shown this drug to have a good cartilage tolerability profile. Whether nabumetone has clinical utility in cardiovascular disorders remains to be determined. The unique pharmacokinetic and pharmacodynamic properties of nabumetone make it a welcome addition to the growing arsenal of drugs used in the treatment of chronic arthropathies. There may be clinical advantages in terms of the relative tolerability profile of nabumetone, given that this drug has a low COX-2/COX-1 ratio compared with other nonselective NSAIDs.
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PMID:[Properties and features of nabumetone]. 1084 Oct 70

Nabumetone's position as one of the most commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in the world today is based upon over a decade of clinical experience. The popularity of this drug lies in both its unique pharmacokinetic profile and special safety features in pharmacodynamic terms. This nonacidic prodrug with an active 6-methoxy-2-naphthylacetic acid (6-MNA) metabolite has COX-2 preferential features and is also devoid of enterohepatic recirculation. It is felt that these characteristics have provided the basis for its unique long term tolerability, documented in various at-risk osteoarthritis and rheumatoid arthritis populations. The excellent tolerability of nabumetone and its 24-hour half-life, which provides the advantages of a once-daily dosage regimen, make it uniquely suitable for long term anti-inflammatory therapy in arthritis. The tolerability profile of nabumetone has also demonstrated clear cost-effectiveness advantages, as confirmed by comparative and epidemiological studies. Selective COX-2 NSAIDs are likely to prove more expensive because of the increasing costs and demands of clinical research prior to FDA approval. These higher costs may limit and influence patient access, depending on the healthcare delivery system, and many years of experience will be required to document the putative tolerability advantages of these newer COX-2 inhibitor agents. In the meantime, it is comforting that nabumetone has established such an advantageous tolerability profile together with acknowledged efficacy.
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PMID:[Rationale for using nabumetone and clinical experience]. 1084 Oct 71

Nabumetone is a nonsteroidal anti-inflammatory prodrug, which exerts its pharmacological effects via the metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). Nabumetone itself is non-acidic and, following absorption, it undergoes extensive first-pass metabolism to form the main circulating active metabolite (6-MNA) which is a much more potent inhibitor of preferentially cyclo-oxygenase (COX)-2. The three major metabolic pathways of nabumetone are O-demethylation, reduction of the ketone to an alcohol, and an oxidative cleavage of the side-chain occurs to yield acetic acid derivatives. Essentially no unchanged nabumetone and < 1% of the major 6-MNA metabolite are excreted unchanged in the urine from which 80% of the dose can be recovered and another 10% in faeces. Nabumetone is clinically used mainly for the management of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) to reduce pain and inflammation. The clinical efficacy of nabumetone has also been evaluated in patients with ankylosing spondylitis, soft tissue injuries and juvenile RA. The optimum oral dosage of nabumetone for OA patients is 1 g once daily, which is well tolerated. The therapeutic response is superior to placebo and similar to nonselective COX inhibitors. In RA patients, nabumetone 1 g at bedtime is optimal, but an additional 0.5-1 g can be administered in the morning for patients with persistent symptoms. In RA, nabumetone has shown a comparable clinical efficacy to aspirin (acetylsalicylic acid), diclofenac, piroxicam, ibuprofen and naproxen. Clinical trials and a decade of worldwide safety data and long-term postmarketing surveillance studies show that nabumetone is generally well tolerated. The most frequent adverse effects are those commonly seen with COX inhibitors, which include diarrhoea, dyspepsia, headache, abdominal pain and nausea. In common with other COX inhibitors, nabumetone may increase the risk of GI perforations, ulcerations and bleedings (PUBs). However, several studies show a low incidence of PUBs, and on a par with the numbers reported from studies with COX-2 selective inhibitors and considerably lower than for nonselective COX inhibitors. This has been attributed mainly to the non-acidic chemical properties of nabumetone but also to its COX-1/COX-2 inhibitor profile. Through its metabolite 6-MNA, nabumetone has a dose-related effect on platelet aggregation, but no effect on bleeding time in clinical studies. Furthermore, several short-term studies have shown little to no effect on renal function. Compared with COX-2 selective inhibitors, nabumetone exhibits similar anti-inflammatory and analgesic properties in patients with arthritis and there is no evidence of excess GI or other forms of complications to date.
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PMID:Nabumetone: therapeutic use and safety profile in the management of osteoarthritis and rheumatoid arthritis. 1545 29

Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased cardiovascular risk. Finally, there is no particular concern about the nephrotoxic and hepatotoxic potential of nabumetone. Nonetheless, the potential for adverse drug reactions remains, and hence nabumetone, as with any NSAID, should be used at the lowest dose, which is effective for each patient, and for the shortest time necessary to control symptoms.
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PMID:Safety of the nonselective NSAID nabumetone : focus on gastrointestinal tolerability. 1848 83

Diclofenac suppository, a non-steroidal anti-inflammatory drug (NSAID), is used widely in rheumatoid arthritis (RA) patients with severe arthritic pain. As the binding percentage of diclofenac to serum proteins is high, its free (unbound) concentration after rectal administration is low. To increase temporarily the free concentration of diclofenac and to enhance its analgesic effect by inhibiting the protein binding of diclofenac, the analgesic effect of diclofenac was examined before and after the start of an inhibitor administration to RA patients with insufficient control of arthritic pain, and the protein binding capacity of diclofenac was evaluated. Binding experiments were performed by ultrafiltration, and arthritic pain was recorded by the face scale. Free fractions of diazepam and diclofenac were augmented by increasing 6-methoxy-2-naphthylacetic acid (6-MNA; the active metabolite of the NSAID nabumetone) concentrations. The free fraction of diazepam increased after the start of nabumetone administration to RA patients, and arthritic pain relief was observed. These results suggest that 6-MNA has an inhibitory effect on the protein binding of diclofenac and the free fraction of diazepam can be used to evaluate the binding capacity of diclofenac. It is considered that diclofenac suppository-nabumetone combination therapy and the method for protein binding monitoring by diazepam can positively benefit RA patients with insufficient control of arthritic pain.
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PMID:A diclofenac suppository-nabumetone combination therapy for arthritic pain relief and a monitoring method for the diclofenac binding capacity of HSA site II in rheumatoid arthritis. 2322 8