Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypouricemic effect of a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, TEI-6720, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, was investigated and compared with that of allopurinol in male chimpanzees (n = 3). When allopurinol (10 mg/kg) was administered orally once a day for three consecutive days, it cumulatively reduced serum urate levels by 29.7, 50.1 and 60.2%, 24, 48 and 72 h, respectively, after the initial dose. This effect was dose dependent at doses of 3 and 10 mg/kg. At 3 mg/kg, the mean serum urate levels were 3.1, 2.4, 2.5 and 2.3 mg/dl before and 24, 48 and 72 h, respectively, after the initial dose. Animals treated with 10 mg/kg of allopurinol showed serum urate levels of 3.3, 2.3, 1.6 and 1.3 mg/dl, respectively. The urate-lowering effect of TEI-6720 was then compared with that of allopurinol at a daily dose of 5 mg/kg (n = 3). Both compounds caused striking reductions in serum and urinary uric acid levels accompanied by an increase in urinary xanthine levels. These effects of TEI-6720 were more potent than those of allopurinol. TEI-6720 reduced serum urate levels by 55.9, 69.6 and 73.6%, 24, 48 and 72 h, respectively, after the first dose, whereas the corresponding values after allopurinol were 28.1, 41.6 and 45.1%. These results suggest that the hypouricemic effect of TEI-6720 may be more potent than that of allopurinol in the treatment of hyperuricemia and gout, and that TEI-6720 may become an effective alternative drug.
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PMID:Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees. 811 6

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childhood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.
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PMID:Gout, uric acid and purine metabolism in paediatric nephrology. 843 71

The hypouricemic actions of Biota orientalis (BO) extract and its flavonoid constituents quercetin and rutin, were in vivo examined using oxonate-induced hyperuricemic mice. Quercetin and rutin, when administered three times orally to the oxonate-induced hyperuricemic mice, were able to elicit dose-dependent hypouricemic effects. The effects of quercetin and rutin were more potent than that of Biota orientalis extract at the same dose of 100 mg/kg. At doses of 50 mg/kg of quercetin or above, or at doses of 100 mg/kg of rutin or above, the serum urate levels of the oxonate-pretreated mice were not different from normal mice. In addition, Biota orientalis extract, quercetin and rutin, when tested in vivo on mouse liver homogenates, elicited significant inhibitory actions on the xanthine dehydrogenase/xanthine oxidase (XDH/XO) activities. The effects of quercetin and rutin resulted less potent than that of allopurinol. However, intraperitoneal administration at the same scheme did not produce any observable hypouricemic effect. These hypouricemic effects are partly due to the inhibition of XDH/XO activities in mouse liver. The pharmacological profile of the flavonoids is partly different from that of allopurinol. Such hypouricemic action and inhibition of the enzyme activity of quercetin and rutin may be responsible for a part of the beneficial effects of Biota orientalis extract on hyperuricemia and gout. The effects of quercetin and rutin on serum urate levels in hyperuricemic mice induced by oxonate and the inhibition of enzyme activities in mouse liver are discussed in relation to their absorption and metabolism, and their potential application to treat gout and hyperuricemia.
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PMID:Effects of Biota orientalis extract and its flavonoid constituents, quercetin and rutin on serum uric acid levels in oxonate-induced mice and xanthine dehydrogenase and xanthine oxidase activities in mouse liver. 1518 18

Ermiao wan, which is composed of phellodendri cortex and atractylodis rhizome, is described as eliminating heat, excreting dampness and anti-edema prescription in traditional Chinese medical literatures including Danxi's Experiences in Medicine and State Pharmacopoeia of People's Republic of China. So it is being used clinically in the treatment of gout and hyperuricemia in China. In the present study, the water extracts of Ermiao wan and phellodendri cortex at 840 and 480 mg/kg/day orally for 7 days were demonstrated to possess in vivo potent hypouricemic effects both in hyperuricemic mice pretreated with oxonate and in normal mice, respectively. In the hyperuricemic animals, the effect of Ermiao wan was equal to that of the reference drug allopurinol (at 10 mg/kg/day orally for 7 days), but in the normal mice, the former was weaker than latter. In addition, both Ermiao wan and phellodendri cortex were found to have in vivo relatively inhibitory effects on mouse liver xanthine dehydrogenase (XDH) and xanthine oxidase (XO) activities at the same dose described above. These inhibitory effects were weaker than that observed for allopurinol. Atractylodis rhizome at 340 mg/kg/day orally for 7 days did not show any effects on the above experiments. These results suggested that atractylodis rhizomes assisted and enhanced the effect of phellodendri cortex on reduction of serum uric acid level in hyperuricemic mice, and hypouricemic effects of Ermiao wan and phellodendri cortex may be achieved by other mechanism partly instead of the XDH and XO inhibition.
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PMID:A Chinese herbal medicine Ermiao wan reduces serum uric acid level and inhibits liver xanthine dehydrogenase and xanthine oxidase in mice. 1523 72

FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile, is a novel xanthine oxidoreductase inhibitor that can be used for the treatment of gout and hyperuricemia. We examined the metabolism of FYX-051 in rats, dogs, monkeys, and human volunteers after the p.o. administration of this inhibitor. The main metabolites in urine were pyridine N-oxide in rats, triazole N-glucoside in dogs, and triazole N-glucuronide in monkeys and humans, respectively. Furthermore, N-glucuronidation and N-glucosidation were characterized by two types of conjugation: triazole N(1)- and N(2)-glucuronidation and N(1)- and N(2)-glucosidation, respectively. N(1)- and N(2)-glucuronidation was observed in each species, whereas N(1)- and N(2)-glucosidation was mainly observed in dogs. With regard to the position of conjugation, N(1)-conjugation was predominant; this resulted in a considerably higher amount of N(1)-conjugate in each species than N(2)-conjugate. The present results indicate that the conjugation reaction observed in FYX-051 metabolism is unique, i.e., N-glucuronidation and N-glucosidation occur at the same position of the triazole ring, resulting in the generation of four different conjugates in mammals. In addition, a urinary profile of FYX-051 metabolites in monkeys and humans was relatively similar; triazole N-glucuronides were mainly excreted in urine.
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PMID:Metabolic profile of FYX-051 (4-(5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the rat, dog, monkey, and human: identification of N-glucuronides and N-glucosides. 1691 12

Some pyrazolo[3,4-d]pyrimidines, structurally related with allopurinol, a well known xanthine oxidase inhibitor, clinically used in the therapy of gout, have also been reported as potent inhibitors of xanthine oxidase and the growth of several human tumour cell lines. Considering the potential interest of this family of compounds, the aim of the present study was to synthesise and provide a full chemical characterization of new N-aryl-5-amino-4-cyanopyrazole derivatives and their corresponding pyrazolo[3,4-d]pyrimidines. Their biological activity pertaining to the xanthine oxidase inhibition and effect on the growth of three tumour cell lines (MCF-7, NCI-H460, and SF-268) are also provided. With only one exception, the synthesised compounds showed no effect on the growth of the three tumour cell lines. However, a strong xanthine oxidase inhibitory activity was observed for almost all pyrazolo[3,4-d]pyrimidines tested, revealing some of them IC(50) values below 1 microM. The results of the molecular docking studies of these compounds, against xanthine oxidoreductase are also described, providing an atomistic explanation of the differences in the inhibitory efficiency. MEP calculations were used to explain different inhibitory efficiency of similar inhibitors.
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PMID:Synthesis of N-aryl-5-amino-4-cyanopyrazole derivatives as potent xanthine oxidase inhibitors. 1769 32

The aim of this review is to examine clinical aspects of the use of the hypouricemic drug allopurinol. Allopurinol is a moderately active hypouricemic drug. Its activity is largely the result of the inhibition of xanthine oxidoreductase by oxypurinol, the active metabolite of allopurinol. The activity of allopurinol may be limited by oxypurinol, reducing the renal clearance of urate. Optimal use of allopurinol involves individualization of dose to attain a sufficient decrease in plasma urate concentrations. This may require a dose greater than recommended based on creatinine clearance. The initial use of an anti-inflammatory drug or low-dose colchicine decreases but does not eliminate the development of acute attacks of gout during the initiation of therapy with allopurinol. Monitoring of oxypurinol concentrations has shed some light on the efficacy of allopurinol but more data are required particularly in patients with renal impairment. Probenecid increases the hypouricemic effect of allopurinol but the favorable interaction may be significant only in patients with glomerular filtration rates greater than about 50 mL/min.
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PMID:Optimizing therapy with allopurinol: factors limiting hypouricemic efficacy. 1834 96

Inhibitors of xanthine oxidoreductase decrease production of uric acid, thus they act as hypouricemic drugs. Allopurinol, a prototypical xanthine oxidoreductase inhibitor, has been widely prescribed for treatment of gout and hyperuricemia. However, severe side effects of allopurinol may occur in patients with renal insufficiency. Recently, novel nonpurine selective inhibitors of xanthine oxidoreductase have been developed as potential alternatives to allopurinol. They have different inhibition mechanisms, utilizing the enzyme structure and the reaction mechanism. Such variation of the inhibition mechanism affects/in vivo/hypouricemic effects of the inhibitors.
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PMID:[Inhibitors of xanthine oxidoreductase]. 1840 26

An inhibitor of xanthine dehydrogenase (XDH), allopurinol, and uricosuric agents, probenecid and benzbromarone, have been used for more than 20 years in the treatment of hyperuricemia and gout. However, they are inconvenient in some situations. With regard to allopurinol, the dosage reduction is recommended in patients with renal insufficiency for preventing from rare adverse effect, bone marrow depression. Benzbromarone also has quite rare adverse effect, fulminant hepatitis. Recently several new therapies have been developed such as new XDH inhibitors urate transporter (URAT) 1 inhibitor, and a modified recombinant uricase. The dosage reduction of the new XDH inhibitors, febuxostat and FYX-051, is not necessary in patients with renal insufficiency because renal excretion is not main excretory pathway. JTT-552 is a first medicine targeting on URAT1. Polyethylene glycol (PEG) conjugation with recombinant uricase sufficiently reduces the immunogenicity to permit repeated dosing and the clinical trials are ongoing for patients with treatment-failure gout and hyperuricemia.
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PMID:[New antihyperuricemic medicine: febuxostat, Puricase, etc]. 1840 28

Inhibitors of xanthine oxidoreductase block conversion of xanthine to uric acid and are therefore potentially useful for treatment of hyperuricemia or gout. We determined the crystal structure of reduced bovine milk xanthine oxidoreductase complexed with oxipurinol at 2.0 A resolution. Clear electron density was observed between the N2 nitrogen of oxipurinol and the molybdenum atom of the molybdopterin cofactor, indicating that oxipurinol coordinated directly to molybdenum. Oxipurinol forms hydrogen bonds with glutamate 802, arginine 880, and glutamate 1261, which have previously been shown to be essential for the enzyme reaction. We discuss possible differences in the hypouricemic effect of inhibitors, including allopurinol and newly developed inhibitors, based on their mode of binding in the crystal structures.
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PMID:Mechanism of inhibition of xanthine oxidoreductase by allopurinol: crystal structure of reduced bovine milk xanthine oxidoreductase bound with oxipurinol. 1860 May 58


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