INT261239
From wiki-pain
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Sentences Mentioned In
Key: | Protein | Mutation | Event | Anatomy | Negation | Speculation | Pain term | Disease term |
, 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 | |||||||||||||||
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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). | |||||||||||||||
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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). | |||||||||||||||
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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). | |||||||||||||||
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A recent study in patients with type II diabetes suggests that urate lowering per se does not improve endothelial function.15
Xanthine oxidase (XO) | |||||||||||||||
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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). | |||||||||||||||
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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). | |||||||||||||||
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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. | |||||||||||||||
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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 | |||||||||||||||
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Allopurinol is rapidly metabolized by its target, xanthine oxidase, to its active metabolite oxypurinol, which is also an inhibitor of xanthine oxidase. | |||||||||||||||
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General Comments
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