Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.
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PMID:A causal role for uric acid in fructose-induced metabolic syndrome. 1623 13

The effects of acacetin (1) and 4,5-O-dicaffeoylquinic acid methyl ester (2), compounds contained in the flowers of Chrysanthemum sinense SABINE, on the serum uric acid level were investigated using the rats pretreated with the uricase inhibitor potassium oxonate as an animal model for hyperuricemia. When administered per orally at doses of 20 and 50 mg/kg, 1 reduced the serum uric acid level by 49.9 and 63.9%, respectively and 2 reduced the level by 31.2 and 44.4%, respectively. On the other hand, when the same doses were given intraperitoneally, both of compounds also exhibited a dose-dependent and more marked reduction of the serum uric acid level (% reduction at 20 and 50 mg/kg were 63.0 and 95.1% in 1, respectively and 66.9 and 86.5% in 2, respectively). Furthermore, the compounds 1 and 2 inhibited the rat liver xanthine oxidase activity with IC(50) values of 2.22 muM and 5.27 muM, respectively. These results demonstrated the hypouricemic action of 1 and 2, which may be attributable to their xanthine oxidase inhibitory activity.
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PMID:Hypouricemic effects of acacetin and 4,5-o-dicaffeoylquinic acid methyl ester on serum uric acid levels in potassium oxonate-pretreated rats. 1632 55

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

In this study, we investigated the effects and mechanisms of Total Saponin of Dioscorea (TSD) on animal experimental hyperuricemia. Mouse and rat hyperuricemic models were made by orally administering yeast extract paste once a day (30 and 20 g/kg, respectively), for 7 days. Yeast would disturb normal purine metabolism by increasing xanthine oxidase (XOD) activity and generating large quantities of uric acid. This model is similar to human hyperuricemia, which is induced by high-protein diets, due to a purine and nucleic acid metabolic disturbance. Another mouse hyperuricemia model was generated by intraperitoneal injection once with uric acid 250 mg/kg or potassium oxonate 300 mg/kg. Potassium oxonate, a urate oxidase inhibitor, can raise the serum uric acid level by inhibiting the decomposition of uric acid. Likewise, injecting uric acid can also increase serum uric acid concentration. The concentration of uric acid in serum or urine was detected by the phosphotungstic acid method, and the activity of XOD was assayed by a test kit. The results showed that TSD (240, 120 and 60 mg/kg, ig) could significantly lower the level of serum uric acid in hyperuricemic mice. TSD (120 and 60 mg/kg, ig) could also lower the level of serum uric acid in hyperuricemic rats, reduce the activity of XOD in the serum and liver of hyperuricemic rats, and increase the level of urine uric acid concentration as well as 24-hour total uric acid excretion. In conclusion, TSD possesses a potent anti-hyperuricemic effect on hyperuricemic animals, and the mechanism may be relevant in accelerating the excretion and decreasing the production of uric acid.
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PMID:Effect and mechanism of total saponin of Dioscorea on animal experimental hyperuricemia. 1643 41

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

Hyperuricemia is a frequent finding in diseases in which the clinical manifestations are thought to be secondary to a state of generalized vascular endothelial dysfunction and related to the cardiovascular disease present in conditions associated with the metabolic syndrome, such as hypertension or diabetes. Traditionally, uric acid has not been given an active role in the pathologic process underlying these conditions. However, there is now a growing body of experimental and clinical evidence that points to a mechanistic role for uric acid in cardiovascular disease. The mechanisms that are most often thought to link uric acid and endothelial dysfunction involve inflammation and generation of oxidative stress in the vasculature. These observations allowed new clinical applications and formulations of therapies, such as the introduction of xanthine oxidase inhibitors in the management of congestive heart failure.
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PMID:Uric acid and the vasculature. 1667 43

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


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