Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although allopurinol has been available for approximately 50 years, hyperuricemia and its sequelae are not only prevalent, but the incidence and costs associated with this disorder continue to increase. However, several new therapies have been developed. Recombinant urate oxidase has been useful in the treatment of tumor lysis hyperuricemia, and pegylated urate oxidase shows promise in patients with hyperuricemia and gout. Febuxostat and Y-700 are new oral xanthine oxidase inhibitors that are in human clinical trials. Tailoring of antilipid therapy in selected hyperuricemic and hyperlipidemic patients with fenofibrate may be of benefit in lowering blood cholesterol and uric acid levels. Similarly, treatment of selected hyperuricemic patients who also are hypertensive with losartan or amlodipine may be beneficial in lowering blood pressure and hyperuricemia. Despite these advances, new treatments for hyperuricemia are needed.
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PMID:Serum uric acid-lowering therapies: where are we heading in management of hyperuricemia and the potential role of uricase. 1513 5

In order to evaluate the safety, pharmacological properties, and urate-lowering efficacy of febuxostat, a non-purine, selective inhibitor of xanthine oxidase, a Phase 1, 2-week, multiple-dose, placebo-controlled, dose-escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self-limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.
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PMID:Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers. 1557 Dec 11

The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki' values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 muM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout.
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PMID:Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. 1569 61

Febuxostat is a non-purine, selective inhibitor of xanthine oxidase being developed for the management of hyperuricaemia in patients with gout. With febuxostat 10-120 mg, the pharmacokinetics are linear. No dose adjustment appears to be necessary in those with renal insufficiency or mild-to-moderate hepatic impairment. Febuxostat 10-120 mg/day rapidly and sustainably reduces serum uric acid by 25-70% in uric acid underexcretors and overproducers. Prophylaxis with colchicine or a non-steroidal anti-inflammatory drug can mitigate the gout-flare risk from the rapid urate lowering after febuxostat initiation. Febuxostat is well tolerated, the majority of treatment-related adverse events are transient and mild-to-moderate in severity. Febuxostat can broaden the therapeutic options for urate-lowering therapy in those with gout.
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PMID:Febuxostat: a non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. 1602 78

Febuxostat (TEI-6720; TMX-67), an oral non-purine, selective inhibitor of xanthine oxidase (NP-SIXO), is being developed by Teijin, with licensees Ipsen and TAP Holdings, for the potential treatment of gout. In February 2005, it was reported that launch in Japan was expected to be delayed for several years due to the need for additional clinical trials; in May 2005, an EU filing was expected by the end of 2005.
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PMID:Febuxostat (Teijin/Ipsen/TAP). 1631 39

An acute attack of gouty arthritis is one of the most painful experiences reported throughout medical history. Therefore it is paramount to initiate appropriate therapy quickly in order to terminate the acute phase. This goal can be achieved with non-steroidal anti-inflammatory agents, colchicine, or corticosteroid-based therapies. Rarely, because of contraindications to these agents, only symptomatic treatment can be given until the attack subsides. The next step is to lower the serum urate level below the limit of solubility (i.e., below 40.8 mmol/L, or 6.8mg/dL) which reduces recurrences and begins to return the total body urate pool to normal. This equally important goal can be achieved by uricosuric agents or xanthine oxidase inhibitors, although the latter is generally favored. Allopurinol is the agent most commonly preferred because of its safety profile and ease of use, but there are known serious allergic reactions and untoward side effects that occasionally require discontinuation. Febuxostat, a xanthine oxidase inhibitor, and pegylated uricase are new agents under development and may be beneficial in these situations or when other comorbid conditions prevent the use of conventional treatments. Alcohol and dietary consumption are also related to hyperuricemia and acute gout. Recently beer, wine, and liquor were studied and the risk of gout varied according to the alcohol ingested. Furthermore, recent data sheds light on important dietary modifications that may help in the treatment of gout, and dispels certain beliefs about protein ingestion and the occurrence of acute gout. As we learn more about the associated conditions of hypertriglyceridemia, hypertension, and the metabolic syndrome, it may allow the tailoring of medical regimens that directly prevent or reduce recurrent attacks of gouty arthritis. There are specific approved treatments for these common comorbidities that have parallel effects of lowering serum urate levels. These recent findings may be especially important for treating refractory cases. While patient education remains a cornerstone to ensure compliance, other quality indicators for the management of this disease have been reported and should guide the clinician in the treatment of gout and result in improved care.
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PMID:Advances in the management of gout and hyperuricaemia. 1688 87

(1) Febuxostat is a selective inhibitor of xanthine oxidase. Its use in the management of hyperuricemia and gout is being studied. (2) In a 52-week, phase III randomized clinical trial, febuxostat was superior to allopurinol for lowering uric acid levels. Its efficacy in preventing gout attacks was similar to that of allopurinol. Despite a similar rate of adverse effects, individuals on febuxostat were more likely to stop treatment than those on allopurinol. (3) The most commonly observed adverse effects with febuxostat include liver function test abnormalities, diarrhea, headache, nausea, vomiting, abdominal pain, and dizziness. (4) Given that renal dysfunction is a risk factor for hyperuricemia and gout, the safety and efficacy of febuxostat in this population should be considered, but only limited data are available. (5) The diffusion of febuxostat may be limited by its price relative to that of allopurinol, regardless of whether febuxostat proves to have advantages in specific populations.
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PMID:Febuxostat for prevention of gout attacks. 1695 89

We investigated whether xanthine oxidase inhibition with febuxostat enhances left ventricular (LV) function and improves myocardial high energy phosphates (HEP) in dogs with pacing-induced heart failure (CHF). Febuxostat (2.2 mg/kg over 10 minutes followed by 0.06 mg/kg/min) caused no change of LV function or myocardial oxygen consumption (MVO2) at rest or during treadmill exercise in normal dogs. In dogs with CHF, febuxostat increased LV dP/dtmax at rest and during heavy exercise (P < 0.05), indicating improved LV function with no change of MVO2. Myocardial adenosine triphosphate (ATP) and phosphocreatine (PCr) were examined using 31P nuclear magnetic resonance spectroscopy in the open chest state. In normal dogs, febuxostat increased PCr/ATP during basal conditions and during high workload produced by dobutamine + dopamine (P < 0.05). PCr/ATP was decreased in animals with CHF; in these animals, febuxostat (given after completing basal and high workload measurements with vehicle) tended to increase PCr/ATP during basal conditions with no effect during catecholamine stimulation. Thus, febuxostat improved LV performance in awake dogs with CHF, but caused only a trend toward increased PCr/ATP in the open chest state. It is possible that the antecedent high workload condition prior to drug administration blunted the effect of febuxostat on HEP in the CHF animals. Alternatively, beneficial effects of febuxostat on LV performance in the failing heart may not involve HEP.
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PMID:Acute effects of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in pacing induced heart failure. 1711 Aug 8

Gout is a common chronic arthritis that can lead to significant disability. Gout is one of the few rheumatological conditions that can be diagnosed with certainty, has a known cause and can be cured with appropriate therapy. Hypouricaemic agents reduce uric acid concentrations through inhibiting uric acid production (allopurinol) or enhancing uric acid excretion (probenecid, benzbromarone). Allopurinol is the most commonly used hypouricaemic agent but at recommended doses often fails to reduce adequately uric acid concentrations and prevent acute attacks of gout. The use of probenecid is limited by lack of efficacy in renal impairment. In the last few years, new agents in the management of hyperuricaemia and gout have become available. Febuxostat, a new xanthine oxidase inhibitor, is an effective hypouricaemic agent although further data are required for patients with renal impairment and other significant medical conditions. Rasburicase, a recombinant uricase (which catalyses the conversion of uric acid to the more readily excreted allantoin) is available for prevention of tumour lysis syndrome. However, its repeated use, as would be required in chronic gout, is limited by antigenicity. A less antigenic PEGylated uricase can rapidly reduce serum uric acid concentrations and promote resorption of tophi. However, further information with regard to the long-term risks and benefits of these agents is required. These agents may ultimately be used in the short term to rapidly deplete urate stores (induction therapy) followed by long-term therapy with an alternative hypouricaemic agent to prevent subsequent accumulation of uric acid (maintenance therapy).
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PMID:Emerging therapies in the long-term management of hyperuricaemia and gout. 1738 67

Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once-daily oral febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and >or=65 years. Although unbound peak concentration (C(max,u)) and area under the concentration-time curve (AUC(24,u)) for febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P <or= .01, and 62.8 vs 53.9 ng x h/mL, P <or= .05, for C(max,u) and AUC(24,u), respectively), the differences were not considered clinically significant and could be largely accounted for by weight differences between male and female subjects. For pharmacodynamic parameters, even though the percentage decrease in serum uric acid 24-hour mean concentration was slightly greater in women than in men (59% vs 52%, P <or= .01), this difference was not considered clinically meaningful. Febuxostat was well tolerated in male and female subjects in both age groups. Age or gender had no clinically significant effect on the pharmacokinetics, pharmacodynamics, or safety of febuxostat. Therefore, febuxostat does not require any dose adjustments based on age or gender.
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PMID:The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. 1863 56


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