INT261239

Context Info Confidence 0.34 First Reported 2008 Last Reported 2010 Negated 1 Speculated 0 Reported most in Body Documents 10 Total Number 10 Disease Relevance 3.16 Pain Relevance 0.31

cytosol (XDH) small molecule metabolic process (XDH) extracellular region (XDH) peroxisome (XDH) cytoplasm (XDH)

Anatomy Link Frequency endothelial cells 1 reticulum 1 XDH (Homo sapiens)

Pain Link Frequency Relevance Heat cINOD 7 98.68 ischemia 12 98.30 adenocard 2 81.92 antagonist 12 63.76 Inflammation 16 62.68 Paracetamol 6 45.60 alcohol 7 27.96 headache 16 5.00 Arthritis 10 5.00 fibrosis 8 5.00

Disease Link Frequency Relevance Heat Myocardial Infarction 80 99.68 Coronary Artery Disease 18 99.26 Diabetes Mellitus 12 99.08 Cv Unclassified Under Development 12 98.30 Crystal Associated Disease 191 96.08 Coronary Heart Disease 6 95.28 Cancer 25 94.60 Increased Venous Pressure Under Development 17 93.22 Stress 134 90.28 Hypoxia 18 88.72

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, lipo-polysaccharides as well as steroid treatment have been shown to upregulate transcription.16 XO is significantly elevated in a variety of conditions including limb ischemia,30 major surgery31 coronary artery disease (CAD)32 and heart failure.33 Circulating XO binds to glycosaminoglycans on the surface of endothelial cells where it is thought it acquires modified kinetics (higher Km and Ki, oxidant producing capacity, and increased stability).34 There are suggestions that this form of induced, circulating and depositing XO appears to be more important in the pathogenesis of endothelial injury compared with XO constitutively produced from endothelial cells.35

XO Binding (binds) of in endothelial cells associated with coronary artery disease, ischemia, injury and myocardial infarction

1) Confidence 0.34 Published 2009 Journal Vascular Health and Risk Management Section Body Doc Link PMC2672460 Disease Relevance 0.63 Pain Relevance 0.05

The molecular mechanism of inhibition of XO activity by febuxostat (Adenuric®, Ipsen, Paris, France) is by high affinity binding to the enzyme in a molecular channel leading to the molybdenum-pterin active site, whereas allopurinol exerts relatively weak competitive inhibition on activity of only the oxidized form of XO (Okamoto et al 2003; Takano et al 2005).

XO Binding (binding) of

2) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2643102 Disease Relevance 0.20 Pain Relevance 0

Febuxostat was shown to inhibit both the oxidized and reduced forms of XO, unlike allopurinol and oxypurinol, each of which binds only to one form of the enzyme (Okamoto et al 2003; Takano et al 2005).

XO Binding (binds) of

3) Confidence 0.27 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2643102 Disease Relevance 0.22 Pain Relevance 0

Mammalian XOR is present in vivo as the dehydrogenase form but is easily converted to XO by oxidation of the sulfhydryl residues or by proteolysis.19 Although XDH has a much greater affinity for NAD+ compared to oxygen (and therefore is practically incapable of directly producing ROS), both XO and XDH can oxidize NADH which results in ROS formation.24 Physiologically, XOR is involved in the hydroxylation of purines, pterins, and aldehydes but its primary role is as the rate-limiting enzyme in the conversion of hypoxanthine to xanthine and xanthine to urate (Figure 1).

XO Binding (affinity) of

4) Confidence 0.26 Published 2009 Journal Vascular Health and Risk Management Section Body Doc Link PMC2672460 Disease Relevance 0.13 Pain Relevance 0

A recent study in patients with type II diabetes suggests that urate lowering per se does not improve endothelial function.15 Xanthine oxidase (XO)

XO Neg (not) Binding (improve) of associated with diabetes mellitus

5) Confidence 0.26 Published 2009 Journal Vascular Health and Risk Management Section Body Doc Link PMC2672460 Disease Relevance 0.33 Pain Relevance 0.06

Mammalian XOR is present in vivo as the dehydrogenase form but is easily converted to XO by oxidation of the sulfhydryl residues or by proteolysis.19 Although XDH has a much greater affinity for NAD+ compared to oxygen (and therefore is practically incapable of directly producing ROS), both XO and XDH can oxidize NADH which results in ROS formation.24 Physiologically, XOR is involved in the hydroxylation of purines, pterins, and aldehydes but its primary role is as the rate-limiting enzyme in the conversion of hypoxanthine to xanthine and xanthine to urate (Figure 1).

XDH Binding (affinity) of

6) Confidence 0.26 Published 2009 Journal Vascular Health and Risk Management Section Body Doc Link PMC2672460 Disease Relevance 0.13 Pain Relevance 0

Mammalian XOR is present in vivo as the dehydrogenase form but is easily converted to XO by oxidation of the sulfhydryl residues or by proteolysis.19 Although XDH has a much greater affinity for NAD+ compared to oxygen (and therefore is practically incapable of directly producing ROS), both XO and XDH can oxidize NADH which results in ROS formation.24 Physiologically, XOR is involved in the hydroxylation of purines, pterins, and aldehydes but its primary role is as the rate-limiting enzyme in the conversion of hypoxanthine to xanthine and xanthine to urate (Figure 1).

XDH Binding (affinity) of

7) Confidence 0.26 Published 2009 Journal Vascular Health and Risk Management Section Body Doc Link PMC2672460 Disease Relevance 0.13 Pain Relevance 0

In dogs with pacing-induced heart failure, allopurinol improved myocardial contractility and eff iciency in oxygen utilization, prevented increases in systemic vasoconstriction and ameliorated reductions in myocardial contractility.65,76,77 In murine post-ischemic cardiomyopathy models, allopurinol attenuated the increase in end-systolic and end-diastolic volumes,78 increased survival, augmented ventricular function as well as reduced products of lipid peroxidation.79 Khan et al found a direct protein-protein interaction between XO and neuronal NOS in the sarcoplasmic reticulum of cardiac myocytes.80 Allopurinol improved myofilament calcium sensitivity as contraction force increased without a concomitant rise in systolic Ca2+ influx.

XO Binding (interaction) of in reticulum associated with coronary heart disease, increased venous pressure under development and myocardial infarction

8) Confidence 0.25 Published 2009 Journal Vascular Health and Risk Management Section Body Doc Link PMC2672460 Disease Relevance 0.46 Pain Relevance 0.06

Distinguishing between serum urate overproducing and underexcreting gout patients may have therapeutic significance but does not need to be routinely performed.15 Concomitant use of colchicine or NSAIDs during the initiation of urate-lowering may be needed to prevent rebound flares.11,16 Xanthine oxidase inhibitors

Xanthine oxidase Binding (rebound) of associated with cinod and crystal associated disease

9) Confidence 0.14 Published 2010 Journal Core evidence Section Body Doc Link PMC2899777 Disease Relevance 0.46 Pain Relevance 0.10

Allopurinol is rapidly metabolized by its target, xanthine oxidase, to its active metabolite oxypurinol, which is also an inhibitor of xanthine oxidase.

xanthine oxidase Binding (target) of

10) Confidence 0.04 Published 2008 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2727789 Disease Relevance 0.48 Pain Relevance 0.04

General Comments

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