Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are three stages in the management of gout: (i) treating the acute attack; (ii) lowering excess stores of uric acid to prevent flares of gouty arthritis and to prevent tissue deposition of urate; and (iii) providing prophylaxis to prevent acute flares. It is important to distinguish between therapy to reduce acute inflammation in acute gout and therapy to manage hyperuricaemia in patients with chronic gouty arthritis. During the acute gouty attack nonpharmacological treatments such as topical ice and rest of the inflamed joint are useful. NSAIDs are the preferred treatment in acute gout. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon NSAID therapy is initiated. Other treatments include oral and intravenous colchicine, intra-articular and systemic corticosteroids, and intramuscular corticotropin. Optimal treatment of chronic gout requires long-standing reduction in serum uric acid. The urate-lowering drugs used to treat chronic gout are the uricosuric drugs, the uricostatic drugs, which are xanthine oxidase inhibitors, and the uricolytic drugs. Xanthine oxidase inhibitors such as allopurinol, oxipurinol and febuxastat should be used as first-line treatment in patients with renal calculi, renal insufficiency, concomitant diuretic therapy and ciclosporin (cyclosporine) therapy, and urate overproduction. Uricosuric drugs include probenecid, benzbromarone, micronised fenofibrate and losartan. They are the urate-lowering drugs of choice in allopurinol-allergic patients and underexcretors with normal renal function and no history of urolithiasis. The use of recombinant urate oxidase in patients with chronic gout is limited by the need for parenteral administration, the potential antigenicity and production of anti-urate oxidase antibodies, and declining efficacy. The effectiveness of colchicine prophylaxis as an isolated therapy is still to be confirmed by placebo-controlled trials. Another issue is prophylaxis with NSAIDs. There are no comparative studies with colchicine.
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PMID:Management of acute and chronic gouty arthritis: present state-of-the-art. 1548 99

Blood uric acid levels and purine metabolism are affected in many ways after bone marrow transplantation (BMT). Although BMT is usually performed when patients have a low residual disease burden, a proportion of them are still at risk of tumor lysis syndrome, even with limited disease or after nonmyeloablative conditioning regimens; moreover, an alteration in uric acid turnover can also be observed in patients with persistently normal uric acid blood levels. Apart from this obvious complication, multiple physiopathological events occurring after transplantation may derange uric acid homeostasis. Although there is only indirect evidence (derived from obstetric eclampsia and experimental gout arthritis), a transplant-related increase in cytokine production (particularly TNF, IL-1 and IL-6) may activate xanthine oxidase which, in turn, may be responsible for a further cytokine bout: deranged cytokine homeostasis is involved in the pathogenesis of some of the main acute post-BMT complications, such as hepatic veno-occlusive disease (VOD) and acute graft-versus-host disease (aGVHD). Hyperuricemia is also a well-known side effect of cyclosporine A, the reference drug for the prevention of post-BMT GVHD, which may affect uric acid turnover by reducing glomerular filtration and/or affecting tubular handling; the available evidence favors the former explanation. Hyperuricemia is found in long-term transplanted patients as part of a metabolic pattern reminiscent of the so-called 'X' or 'metabolic'syndrome related to insulin resistance: there is still no precise interpretation of this post-transplant complication nor any definite data concerning its real incidence and outcome. Hyperuricemia is frequently regarded as a marginal finding in the context of X syndrome, but it is pathogenetically linked to the other component of the syndrome and has proved to be autonomously responsible for tissue and vessel damage. Finally, BMT is a possible therapeutic strategy for some inherited forms of hyperuricemia, particularly Lesch- Nyhan disease, although there is still some perplexity concerning the possibility of preventing the development of neurological impairment.
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PMID:Hyperuricemia and bone marrow transplantation. 1560 10

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

The xanthine oxidase (XOD) inhibitory activity of propolis from China and Brazil was measured. The propolis from both place were seen to have XOD inhibitory activity. However, a stronger tendency was shown in the propolis from China. The compounds in each the propolis were measured quantitatively. A great deal of chrysin, galangin, and caffeic acid phenetyl ester were found in the propolis from China, an abundance of p-coumaric acid and artepillin C in the propolis from Brazil. Therefore it was revealed that the propolis compounds are very different depending on their place of origin. The XOD inhibitory activity of these five compounds was measured. Caffeic acid phenetyl ester had the strongest activity, with chrysin and galangin next; p-coumaric acid and artepillin C showed weak XOD inhibitory activity. We evaluated the hypouricemic effect of propolis from China on hyperuricemia induced by the uricase inhibitor, oxonic acid (500 mg/kg p.o., 1 h before the test drugs), and measured plasma uric acid values in rats. Oral propolis had a hypouricemic effect 2 h after its administration to oxonate-pretreated rats. These results suggested that a continuous intake of propolis may be effective for the prevention and the treatment of gout and hyperuricemia.
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PMID:[Xanthine oxidase inhibitory activity and hypouricemia effect of propolis in rats]. 1573 31

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

Hyperuricemia is associated with a number of pathological conditions such as gout. Lowering of elevated uric acid level in the blood could be achieved by xanthine oxidase inhibitors and inhibitors of renal urate reabsorption. Some natural compounds isolated from herbs used in traditional Chinese medicine have been previously demonstrated to possess xanthine oxidase inhibitory activities. In the present investigation, morin (3,5,7,2',4'-pentahydroxyflavone), which occurs in the twigs of Morus alba L. documented in traditional Chinese medicinal literature to treat conditions akin to gout, was demonstrated to exert potent inhibitory action on urate uptake in rat renal brush-border membrane vesicles, indicating that this compound acts on the kidney to inhibit urate reabsorption. Lineweaver-Burk transformation of the inhibition kinetics data demonstrated that the inhibition of urate uptake was of a competitive type, with a K(i) value of 17.4 microM. In addition, morin was also demonstrated to be an inhibitor of xanthine oxidase. Lineweaver-Burk analysis of the enzyme kinetics indicated that the mode of inhibition was of a mixed type, with K(i) and K(ies) values being 7.9 and 35.1 microM, respectively. Using an oxonate-induced hyperuricemic rat model, morin was indeed shown to exhibit an in vivo uricosuric action, which could explain, in part at least, the observed hypouricemic effect of morin in these rats. The potential application of this compound in the treatment of conditions associated with hyperuricemia was discussed.
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PMID:The dual actions of morin (3,5,7,2',4'-pentahydroxyflavone) as a hypouricemic agent: uricosuric effect and xanthine oxidase inhibitory activity. 1616 36

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

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


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