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)

Y-700, a novel xanthine oxidase inhibitor, was recently developed for the treatment of hyperuricemia and gout. Since the major elimination route of this compound is hepatic metabolism and excretion, the aim of the present study was to characterize the uptake mechanism of Y-700 in the liver, which is also the pharmacological target of Y-700. Efficient uptake of Y-700 was observed both in the liver in vivo and in isolated rat hepatocytes. The uptake was Na(+)-dependent, saturable and inhibited both by ATP-depressants and various organic anions. Indomethacin competitively inhibited Y-700 uptake, whereas the inhibitory effect of organic cations and nucleosides was not so remarkable. Saturable and Na(+)-dependent uptake of Y-700 was also observed in freshly isolated human hepatocytes. Uptake of Y-700 by sinusoidal membrane transporters, such as organic anion transporter (Oat) 2 and organic anion transporting polypeptide (OATP)-B, OATP-C, OATP-8, and Oatp1, could not be detected although uptake of Y-700 in the oocytes expressing sodium/taurocholate cotransporting polypeptide (NTCP) was slightly observed. In conclusion, active transport system(s), which specifically recognize certain types of anionic compounds, are involved in the hepatic uptake of Y-700 and, at least partially, relevant to its elimination from the circulation as well as delivery to pharmacological target.
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PMID:Carrier-mediated hepatic uptake of a novel nonrenal excretion type uric acid generation inhibitor, Y-700. 1636 28

Newer approaches to the treatment of gout have included modifications and further attention to aspects of current therapies, and development of interesting new therapies. Colchicine prophylaxis appears to be needed longer than previously recognized after introduction of a urate-lowering agent. Diet has received attention, though most dietary effects are small. New agents under investigation include pegylated formulations of uricase and a new potent xanthine oxidase inhibitor, febuxostat. Some cardiovascular drugs have been shown to be uricosuric.
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PMID:Newer therapeutic approaches: gout. 1650 33

The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades. More recent data indicate that XO also plays an important role in various forms of ischemic and other types of tissue and vascular injuries, inflammatory diseases, and chronic heart failure. Allopurinol and its active metabolite oxypurinol showed considerable promise in the treatment of these conditions both in experimental animals and in small-scale human clinical trials. Although some of the beneficial effects of these compounds may be unrelated to the inhibition of the XO, the encouraging findings rekindled significant interest in the development of additional, novel series of XO inhibitors for various therapeutic indications. Here we present a critical overview of the effects of XO inhibitors in various pathophysiological conditions and also review the various emerging therapeutic strategies offered by this approach.
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PMID:Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. 1650 84

A few clinical trials have evaluated therapeutic agents for crystal-associated arthropathy. Most of the studies are uncontrolled and observational. Management of patients who have acute crystal arthropathies usually is symptomatic with long-term management depending on crystal composition. In trials of gout, studies focus on acute symptomatic treatment, foregoing chronic management, which is aimed at reducing the concentration of serum urate. In those who have calcium crystals, however, there is no definitive or effective long-term treatment in chronic gout. The xanthine oxidase inhibitor and uricosurics are the agents used most commonly. Newer compounds in clinical trials show promise as effective and safe therapeutic options.
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PMID:Clinical trials in crystal arthropathy. 1671 84

First identified by the Egyptians in 2640 BC, podagra (acute gout occurring in the first metatarsophalangeal joint) was later recognized by Hippocrates in the fifth century BC, who referred to it as 'the unwalkable disease'. The term is derived from the Latin word gutta (or 'drop'), and referred to the prevailing medieval belief that an excess of one of the four 'humors'--which in equilibrium were thought to maintain health--would, under certain circumstances, 'drop' or flow into a joint, causing pain and inflammation. Throughout history, gout has been associated with rich foods and excessive alcohol consumption. Because it is clearly associated with a lifestyle that, at least in the past, could only be afforded by the affluent, gout has been referred to as the 'disease of kings'. Although there is evidence that colchicine, an alkaloid derived from the autumn crocus (Colchicum autumnale), was used as a powerful purgative in ancient Greece more than 2000 years ago, its first use as a selective and specific treatment for gout is attributed to the Byzantine Christian physician Alexander of Tralles in the sixth century AD. Uricosuric agents were first used at the end of the 19th century. In the modern era, nonsteroidal anti-inflammatory drugs are usually the drugs of choice for treating acute gout. Perhaps the most important historical advance in the treatment of hyperuricemia was the development of xanthine oxidase inhibitors, which are effective in reducing plasma and urinary urate levels and have been shown to reverse the development of tophaceous deposits.
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PMID:A concise history of gout and hyperuricemia and their treatment. 1682 40

Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.
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PMID:Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. 1682 43

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

The prevalence of gout has increased markedly in the United States in the past two decades, and new treatments for hyperuricemia are being developed. Recent molecular identification of urate transporter-1 (URAT1) as the central mediator of renal urate reabsorption has provided novel understanding of the pathogenesis of hyperuricemia, and the target site for current and possibly future primary uricosuric agents. Recent studies have also highlighted uricosuric effects of several drugs (losartan, atorvastatin, fenofibrate) that are prescribed for primary indications other than hyperuricemia. The niche of these agents in current management of hyperuricemia is discussed. We also review the ongoing development of recombinant uricase preparations and of novel xanthine oxidase inhibitors exemplified by febuxostat. These agents should provide novel options for patients with chronic, refractory gout and hyperuricemia, particularly in association with allopurinol hypersensitivity and renal insufficiency.
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PMID:New developments in clinically relevant mechanisms and treatment of hyperuricemia. 1690 Oct 81

(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

Xanthine oxidase inhibitory activity was assayed from six species belonging to different families traditionally used for the treatment of gout and related symptoms by indigenous people of India. The aqueous, methanol-water mixture and methanolic extract of these plants were used for the experiment. Of the 18 extracts assayed, 14 extracts demonstrated xanthine oxidase inhibitory activity at 100 microg/ml, among which 10 extracts showed an inhibition greater than 50% and IC(50) values below 100 microg/ml. The methanolic extracts of Coccinia grandis, Datura metel, Strychnos nux-vomica and Vitex negundo showed more than 50% inhibition, hence, they were screened for their in vivo hypouricaemic activity against potassium oxonate-induced hyperuricaemia in mice. Methanolic extracts of Coccinia grandis and Vitex negundo showed a significant decrease in the serum urate level (3.90+/-0.07 mg/dl, P<0.001) and (6.26+/-0.06 mg/dl, P<0.01), respectively, when compared to hyperuricaemic control (11.42+/-0.14 mg/dl). This effect is almost similar to the serum urate level of allopurinol (3.89+/-0.07 mg/dl).
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PMID:Xanthine oxidase inhibitory activity of some Indian medical plants. 1701 77


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