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)

Heart failure (HF) is a state of chronic deterioration of oxidative mechanisms due to enhanced oxidative stress and consequent subcellular alterations. In this condition, oxidant-producing enzymes, in particular xanthine oxidase (XO), the major cardiovascular source of reactive oxygen species (ROS), are up-regulated. Growing evidence shows that this impaired oxidative metabolism due to enhanced ROS release is implicated in the development of cardiac hypertrophy, myocardial fibrosis, left ventricular remodelling, and contractility impairment responsible for worsening of cardiac function in CHF. Uric acid (UA) has long been linked with cardiovascular diseases, and hyperuricaemia is a common finding in patients with CHF. Hyperuricaemia is associated with impairment of peripheral blood flow and reduced vasodilator capacity, which relate closely to clinical status and reduced exercise capacity. Recent studies also suggest an association between UA levels and parameters of diastolic function; more importantly, UA has emerged as a strong independent prognostic factor in patients with CHF. In this review, we describe the up-to-date experimental and clinical studies that have begun to test whether the inhibition of XO translates into meaningful beneficial pathophysiological changes. This treatment gives evidence that myocardial energy, endothelial dysfunction, and vasodilator reactivity to exercise are improved by reducing markers of oxidative stress responsible for vascular dysfunction, so it represents an interesting therapeutic alternative for better outcome in CHF patients.
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PMID:Oxidative stress and hyperuricaemia: pathophysiology, clinical relevance, and therapeutic implications in chronic heart failure. 1934 34

The screening of Piperaceous plants for xanthine oxidase inhibitory activity revealed that the extract of the leaves of Piper betle possesses potent activity. Activity-guided purification led us to obtain hydroxychavicol as an active principle. Hydroxychavicol is a more potent xanthine oxidase inhibitor than allopurinol, which is clinically used for the treatment of hyperuricemia.
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PMID:Hydroxychavicol: a potent xanthine oxidase inhibitor obtained from the leaves of betel, Piper betle. 1938 69

Febuxostat (Uloric--Takeda), a xanthine oxidase inhibitor, has been approved by the FDA for chronic management of hyperuricemia in patients with gout. It is the first drug marketed for treatment of gout in 40 years. Febuxostat is structurally unrelated to allopurinol, the only other commercially available inhibitor of xanthine oxidase. Xanthine oxidase inhibitors decrease serum urate concentrations by decreasing urate synthesis.
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PMID:Febuxostat (Uloric) for chronic treatment of gout. 1944 87

Hyperuricemia has recently been recognized to be a risk factor for nephropathy in the diabetic subject. We tested the hypothesis that lowering uric acid with a xanthine oxidase inhibitor might reduce renal injury in the diabetic mouse. Diabetic (db/db) mice were treated with allopurinol or no treatment for 8 wk. Serum uric acid, renal function, and histology were assessed at death. The direct effect of uric acid in human proximal tubular epithelial cells was also evaluated under normal or high glucose condition. We found that db/db mice developed hyperuricemia, albuminuria, mesangial matrix expansion, and mild tubulointerstitial disease. Allopurinol treatment significantly lowered uric acid levels, reduced albuminuria, and ameliorated tubulointerstitial injury, but it did not prevent mesangial expansion. The mechanism for protection was shown to be due to a reduction in inflammatory cells mediated by a reduction in ICAM-1 expression by tubular epithelial cells. Interestingly, allopurinol did not reduce oxidative stress in the kidney. An inflammatory role of uric acid on tubular cells was also confirmed by our in vitro evidence that uric acid directly induced ICAM-1 expression in the human proximal tubular cell. In conclusion, hyperuricemia has a pathogenic role in the mild tubulointerstitial injury associated with diabetic nephropathy but not glomerular damage in db/db mice. Lowering uric acid may reduce tubulointerstitial injury in diabetes.
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PMID:Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice. 1945 27

The prevalence of gout has been increasing in epidemic proportions over the last several decades. Hyperuricemia has been shown to be associated with metabolic syndrome and to be an independent risk factor for cardiovascular disease. Associations between hyperuricemia, obesity and aging have provided an impetus in recent years to develop alternative methods of treating hyperuricemia and gout. Febuxostat is a new non-purine xanthine oxidase inhibitor indicated for chronic gout. Febuxostat has been shown to quickly and effectively lower serum urate levels in patients with chronic gout. This manuscript will review febuxostat, its pharmacokinetics and pharmacodynamics, efficacy and adverse events and use in patients with comorbid conditions. The review will also summarize the phase III trials leading up to the drug's approval by both the European Commission in 2008 and the U.S. FDA in 2009. Possible implications the medication may have in the future on gout and hyperuricemia will also be discussed.
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PMID:Febuxostat: a new agent for lowering serum urate. 1949 90

Allopurinol is an inhibitor of xanthine oxidoreductase (XOR) and inhibits the generation of uric acid (UA) as the final product of purine catabolism, as well as the resulting generation of superoxide (O2(-)), in humans. Elevation of the serum UA (SUA) level, referred to as hyperuricemia (HU), eventually leads to gout and allopurinol has been used for the treatment of HU and gout. Studies have revealed the role of elevated SUA levels and the associated oxidative stress (OS) in a broad spectrum of pathological conditions and it is anticipated that these findings would also expand the use of allopurinol as a therapeutic drug. This article presents a review of reports, mainly of recent studies, on the efficacy of allopurinol in various diseases and explores novel potential uses of the drug. Important novel and potential uses of great interest include metabolic syndrome (MetS) and related disorders, chronic kidney disease (CKD), nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Ischemia-reperfusion injury and mucositis, encountered as adverse effects of cancer treatment, have also been under investigation as potential targets for allopurinol.
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PMID:Allopurinol, an inhibitor of uric acid synthesis--can it be used for the treatment of metabolic syndrome and related disorders? 1958 65

Our previous study identified 2-[2-(2-methoxyethoxy)ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4] triazol-3-yl]benzonitrile (2)[corrected]as a safe and potent xanthine oxidoreductase (XOR) inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) [corrected] to be one of the most potent XOR inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial.
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PMID:Discovery of 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051 - a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia [corrected]. 1978 39

Allopurinol as an effective inhibitor of the enzyme xanthine oxidase (XO) has been used for several decades for the treatment of patients with gout and hyperuricemia. Because the inhibition of XO limits the formation of radical oxygen species as well as uric acid (UA) production, allopurinol has been used experimentally for the treatment of conditions associated with ischemia and reperfusion (I/R) injury.Although there have been many ischemic organs treated in the laboratory with allopurinol, the heart has been of particular interest. Therefore, we emphasize our attention to the administration of XO inhibitors such as allopurinol on cardiac I/R as well as cardiac failure. Experimental data also support allopurinol as a possible consideration for biochemical support after acute myocardial infarction. Anker and associates (Circulation. 2003;107:1991-1997) have observed a direct correlation between uric acid levels and mortality in treated heart failure patients. Anker and associates showed a 100% mortality rate in patients with UA levels 800 micromol/L or less over a period of 3 years. Comparing this to a 27% mortality rate in patients with UA levels 400 micromol/L or less over a period of 10 years, it seems that the suppression of XO activity ameliorates myocardial inefficiency, and poor vascular flow may present innovative contributions to the future treatment of I/R heart failure patients. Our review focuses on the role of allopurinol on ischemic hearts as well as those with added chronic heart failure.
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PMID:Allopurinol, xanthine oxidase, and cardiac ischemia. 1979 15

Our objective was to examine the effect of orange juice and hesperetin on serum total antioxidant capacity (TAC), lipid peroxidation (MDA), uric acid and hepatic xanthine oxidase (XO) and xanthine dehydrogenase (XDH) activity in hyperuricemic rats. Experimentally hyperuricemia in rats was induced by intraperitoneal injection of potassium oxonate (250 mg/kg). Orange juice (5 ml/kg) and hesperetin (5 mg/kg) was given by oral gavage to rats for 2 weeks and biochemical data was measured. Data showed that orange juice supplementation increased serum TAC and decreased MDA concentration (p</=0.05). Orange juice also inhibited hepatic XO and XDH activity and decreased serum uric acid levels. Hesperetin, which is the main flavanone constituent in orange juice, also exhibited antioxidative and antihyperuricemic properties, but its effect was weaker than that of orange juice. Although the hypouricemic effect of allopurinol (5 mg/kg), as a positive control, was much higher than that of orange juice and hesperetin, it could not significantly change biomarkers of oxidative stress. These features of orange juice and hesperetin make them an attractive candidate for the prophylactic treatment of hyperuricaemia, particularly if these compounds are to be taken on a long-term basis.
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PMID:Orange juice and hesperetin supplementation to hyperuricemic rats alter oxidative stress markers and xanthine oxidoreductase activity. 1990 18

Gout is the most common inflammatory arthritis in an elderly population, and can be diagnosed with absolute certainty by polarization microscopy. However, diagnosis may be challenging because atypical presentations are more common in the elderly. Management of hyperuricemia in the elderly with gout requires special consideration because of co-medication, contra-indications, and risk of adverse reactions. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used sensibly in the elderly, especially when renal function impairment is present. However, if used at the lowest dose that maintains the serum urate level below 5.0 to 6.0 mg/dL (0.30 to 0.36 mmol/L), the excess urate in the body will eventually be eliminated, acute flares will no longer occur, and tophi will resolve. Febuxostat, a new xanthine oxidase inhibitor, is welcomed, as few alternatives for allopurinol are available. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment. Its antihyperuricemic efficacy at 80 to 120 mg/day is better than "standard dosage" allopurinol (300 mg/day). Long-term safety data and efficacy data on tophus diminishment and reduction of gout flares have recently become available. Febuxostat may provide an important option in patients unable to use allopurinol, or refractory to allopurinol.
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PMID:Management of hyperuricemia in gout: focus on febuxostat. 2016 38


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