Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postischemic renal failure is a severe problem following cadaveric renal transplantation, especially if the kidney has been harvested from a non-heartbeating donor, and thereby subjected to periods of both warm and cold ischemia. It is well established that a substantial component of postischemic injury is produced by oxygen-derived free radicals generated from xanthine oxidase at reperfusion. However, the clinical potential of free radical ablative therapy is dependent upon the proportion of the total injury caused by this reperfusion mechanism, compared with the proportion resulting from ischemic injury per se. Therefore, we quantitatively evaluated these proportions in porcine kidneys subjected to various periods of warm (renal artery occlusion in situ), cold (harvest, cold preservation, and allotransplantation), and combined warm and cold ischemia. Experiments were paired, one kidney treated with either superoxide dismutase (SOD) or allopurinol for free radical ablation, the contralateral kidney serving as a control. Creatinine clearance (Ccr) was measured separately for each kidney 48 hr after reperfusion. After 1 and 2 hr of warm ischemia, Ccr dropped to 50% and 36% of normal, respectively. This was improved to 110% and 55% when SOD was given into the renal artery at reperfusion. Similarly, after 24 and 48 hr of cold ischemia, kidney function was significantly improved from 30% and 18% to 72% and 47% of normal, respectively, when allopurinol was added to the preservation solution. SOD used at harvest and again at reperfusion was particularly effective following combined warm and cold ischemia, in a situation mimicking the harvest of cadaver kidneys from a non-heartbeating donor. These findings suggest that the ablation of free radical-mediated reperfusion injury may improve posttransplant renal function sufficiently to allow expansion of the cadaveric donor pool to include non-heartbeating donors.
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PMID:Ablation of free radical-mediated reperfusion injury for the salvage of kidneys taken from non-heartbeating donors. A quantitative evaluation of the proportion of injury caused by reperfusion following periods of warm, cold, and combined warm and cold ischemia. 327 16

Acyclovir (Zovirax) is a highly specific antiherpes virus agent. Extensive investigations of the pharmacokinetics in man have shown it to have a useful half-life of about three hours and to be largely excreted unchanged in the urine. Crystaluria can be avoided provided the patient is well hydrated and attention is paid to the dosing instructions especially in patients with renal failure. In vitro ED50s (the drug concentration inhibiting virus replication by 50%) bear some general relevance to effective plasma levels in man. A new prodrug of acyclovir, 2-amino-9-[2-hydroxyethoxy methyl]-9H-purine (A515U), which is converted to acyclovir by xanthine oxidase is rapidly absorbed from the human gut and converted to acyclovir. This prodrug provides the opportunity to design regimes that are more convenient for the patient and may be more effective than acyclovir itself in the therapy of the less sensitive herpes viruses (e.g. Epstein-Barr virus and the Cytomegalovirus).
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PMID:The clinical pharmacology of acyclovir and its prodrugs. 386 24

We evaluated the hypothesis that postischemic renal failure is caused primarily at reperfusion by oxygen-derived free radicals in a swine model designed to realistically mimick human cadaveric renal transplantation. Both kidneys were removed, flushed with Euro-Collins solution, stored 24 hr at 4 degrees C, and then transplanted to a second pig. Experiments were paired, each pig receiving one treated and one control kidney. All pigs received the optimal conventional regimen of hydration, phenoxybenzamine, furosemide, and mannitol to allow assessment of free radical treatment superimposed thereupon. Two days later creatinine clearance (CCR) was measured from each kidney via separate ureterostomies. Untreated kidneys developed severe functional impairment, CCR falling from a normal level of 25.5 +/- 6.3 ml/min (n = 8) to 7.7 +/- 0.9 ml/min (n = 14, P less than .05 vs. control). The infusion of 20 mg of the free radical scavenger superoxide dismutase (SOD) into the renal artery at reperfusion substantially ameliorated this injury (CCR = 15.9 +/- 1.7 ml/min, n = 18, P less than 0.05 vs. control). A dose-response curve to SOD showed no effect of doses of 0.2 mg (CCR = 8.0 +/- 1.1 ml/min, n = 4) or 2 mg (CCR = 7.7 +/- 0.9, n = 5), and no greater benefit from 100 mg (CCR = 16.1 +/- 2.1 ml/min, n = 3, P less than 0.05 vs. control). Blocking the generation of superoxide radicals from xanthine oxidase with allopurinol (50 mg/kg) afforded similar protection (CCR = 18.2 +/- 1.8; n = 11, P less than 0.01 vs. control). On the other hand, following an 18-hr period of cold ischemia, little damage was sustained by the untreated (control) kidneys (CCR = 22.1 +/- 0.6 ml/min). Consequently, under these conditions the ablation of free radical generation with allopurinol provided no significant benefit. These findings suggest that after a critical period of cold ischemic preservation, metabolic changes take place within the kidney that lead to free radical generation and consequent tissue injury upon reperfusion, despite optimal preservation by conventional methods. This damage can be prevented by simple nontoxic measures--which, therefore, show great promise for use in the prevention of early renal failure following cadaveric renal transplantation.
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PMID:The role of oxygen free radicals in mediating the reperfusion injury of cold-preserved ischemic kidneys. 390 28

Xanthine dehydrogenase (XDH, EC 1.1.1.204) is a rate-limiting enzyme in the oxidative metabolism of purines and is thought to play a key role in a variety of pathophysiologic processes including ischemiasolidusreperfusion injury, viral pneumonia, and renal failure. We herein report the isolation and characterization of the human XDH gene. The gene is composed of 36 exons and 35 introns and spans at least 60 kb. The exon sizes range from 53 to 279 bp, and the intron sizes range from 0.2 to over 8 kb. Using primer extension and RNase protection analyses, two transcriptional initiation sites were identified 59 and 82 nucleotides upstream of the ATG start codon. One Goldberg-Hogness box (ATTTAT)-like sequence was found 24 bp upstream from the second transcriptional initiation site, and two inverted CCAAT sequences were found 19 and 42 bp upstream from the second transcriptional initiation sites. A relative GC-enriched region was found between -55 and -121. Approximately 2 kb of the 5'-flanking region was sequenced, and a variety of putative regulatory elements were identified including CsolidusEBP binding sites, IL-6 and NF-kappaB sites, and potential TNF-RE, IFN-gamma-RE, and IL-1-RE sites.
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PMID:Molecular cloning and characterization of the human xanthine dehydrogenase gene (XDH). 866 Oct 45

Oxidant injury is considered to be an important mechanism in the pathophysiology of acute renal failure. It has been thought that decrease in extracellular and intracellular fluid and endotoxemia seen in obstructive jaundice may cause an increase in production of oxygen free radicals and impairment in antioxidant defense mechanism. This study is designed to investigate the possible role of oxidant injury in renal failure seen in jaundiced patients. In this study, 28 rats were divided into four groups: Control (C)(N = 7); Renal ischemia (RI)(N = 7); Obstructive jaundice+renal ischemia (OJ+RI)(N = 7); Obstructive jaundice (OJ)(N = 7). All groups were compared with each other according to renal failure findings and enzyme activities, such as Xanthine oxidase (XOD), Superoxide Dismutase (SOD) and Catalase in renal cortex and Glutathione Peroxidase (GSH-Px), in blood at 3rd day after ischemia and reperfusion. Renal failure findings monitored by blood urea and creatinine levels, seemed more evident in OJ+RI than RI group (p < 0.05). When compared with RI, in OJ+RI group, increase in XOD activity at 3rd day was statistically significant [0.259 +/- 0.01 U/g (tissue) and 0.362 +/- 0.03 U/g (tissue) respectively] (p < 0.05). SOD and GSH-Px activities of each ischemic group at 3rd day were decreased compared to non-ischemic groups. This fall was significant (p < 0.05). But there was no statistical difference between jaundiced and non-jaundiced groups. Alterations in catalase activities also had no statistical significance. These findings may suggest that the injury induced by oxygen free radicals at re-oxygenation of tissue after ischemia may also play a role in the pathogenesis of acute renal failure developed in obstructive jaundice.
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PMID:The role of oxygen free radicals in acute renal failure complicating obstructive jaundice: an experimental study. 951 37

In rats with acute renal failure induced by uranyl nitrate, the hepatic microsomal cytochrome P450 (CYP) 2E1 and CYP3A23 increased 2-4- and 4-times, respectively, CYP2C11 decreased to 80% of control, but the levels of CYP1A2 and CYP2B1/2 were not changed. It has been reported that theophylline was metabolized to 1,3-dimethyluric acid by CYP1A2 and CYP2E1 and 1-methylxanthine via CYP1A2, which was metabolized further to 1-methyluric acid via xanthine oxidase in rats. Hence, it was expected that the formation of 1,3-dimethyluric acid would show an increase in rats with renal failure as a result of induction of CYP2E1. The pharmacokinetics of theophylline were compared in control rats and rats with renal failure after intravenous administration of aminophylline, 5 mg kg(-1) as theophylline. In rats with renal failure, the plasma concentrations of theophylline were considerably lower and the resultant total area under the plasma concentration-time curve from time zero to time infinity (AUC(0- infinity )) of theophylline was significantly smaller (2,200 vs 1,550 microg min mL(-1)) compared with control rats. In rats with renal failure, the plasma concentrations of 1,3-dimethyluric acid were considerably higher and the resultant AUC(0-6 h) of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 microg min mL(-1)) compared with control rats. Moreover, the AUC(0-6 h, 1,3-dimethyluric acid)/AUC(0- infinity, theophylline) ratio increased from 2.02% in control rats to 29.4% in rats with renal failure. The in-vitro intrinsic 1,3-dimethyluric acid formation clearance was significantly faster in rats with renal failure (734 vs 529 10(-6) mL min(-1)) compared with control rats using hepatic microsomal fraction. The results led us to conclude that in rats with uranyl nitrate-induced renal failure after the administration of aminophylline, 5 mg kg(-1) as theophylline, there was an increase in the formation of 1,3-dimethyluric acid as a result of an increase in CYP2E1 expression.
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PMID:Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation. 1254

Minor hypersensitivity reactions to allopurinol presenting as skin rash occur in approximately 2% of patients. A more severe, albeit rare, hypersensitivity reaction with fever, eosinophilia, dermatitis, renal failure, vasculitis and hepatic dysfunction carries a mortality of up to 20%. The incidence of this severe reaction can probably be reduced by adjusting the dose of allopurinol in patients with impaired renal function. Azathioprine and mercaptopurine are metabolised by xanthine oxidase, the enzyme that is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by approximately 75%. The uricosuric agent benzbromarone has recently been withdrawn from the market because of several cases of fulminant hepatic failure with subsequent death of the patient or liver transplantation.
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PMID:[Life-threatening adverse effects of pharmacologic antihyperuricemic therapy]. 1549 19

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5-10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non-recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost-effective option in the management of hyperuricemia.
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PMID:Management of hyperuricemia with rasburicase review. 1557 Dec 72

This study was carried out to determine if Ginkgo Biloba Extract (GBE or Egb 761) exerts a beneficial effect against cisplatin-induced renal failure in rats. Sprague Dawley rats were divided into four groups. The first group (control) received orally 1 mL/kg/day of 0.9% saline by an oral carrier vehicle on days 1 to 10. The second group was injected with 7 mg/kg cisplatin intraperitoneally (i.p.) on the fourth day, once only. The third group (vit E+cisplatin) was administered 10 mg/kg/day i.p. vit E on 1 to 10 days with one dose of i.p. cisplatin (7 mg/kg) injection on the fourth day. The fourth group (GBE+cisplatin) was given GBE orally at 100 mg/mL/kg started on the first day up to the tenth day with one dose of cisplatin (7 mg/kg) injection on the fourth day. Cisplatin was found to lead a statistically significant increase in plasma BUN and creatinine levels, as well as urine micro total protein (MTP) levels, leading to acute renal failure (ARF) in rats. Renal xanthine oxidase (XO) activities increased in all groups (statistically significant in cisplatin + GBE-treated rats; P < 0.001). Adenosine deaminase (AD) activities were increased in cisplatin-treated rats, and decreased in cisplatin+GBE-treated (P < 0.041) and cisplatin+vit E-treated (P < 0.005) rats, compared to controls. Malondialdehyde (MDA), nitric oxide (NO) levels and myeloperoxidase (MPO) activities were increased in the kidney tissue of cisplatin-treated rats. Vit E improved plasma creatinine and urine MTP levels, together with tissue MDA, NO levels, and MPO activities. But GBE had no statistically significant effect on those parameters. These results indicate that increased XO, AD and MPO activities, as well as MDA and NO levels play a critical role in cisplatin nephrotoxicity. GBE has been shown to protect against cisplatin-induced nephrotoxicity.
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PMID:The effects of ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malondialdehyde, and nitric oxide in cisplatin-induced nephrotoxicity. 1671 42

Adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency is an enzymopathy of purine metabolism, which is inherited as an autosomal recessive trait. APRT is a salvage enzyme that normally catalyzes the conversion of adenine to adenosine monophosphate. APRT deficiency results in adenine accumulation with oxidation by xanthine dehydrogenase (XDH; EC 1.1.1.204) to 2,8-dihydroxyadenine (2,8-DHA) then excreted in urine. This compound is extremely insoluble and its crystallization can lead to stone formation and renal failure. The diagnosis of the disease is based on stone analysis by infrared spectroscopy or microscopic examination of urine, which may reveal typical 2,8-DHA crystals. The enzyme activity measurements in erythrocyte lysates will identify both homozygotes and heterozygotes for APRT deficiency. Molecular approach can identify mutations which are responsible of this inherited disease. Two types of deficit are commonly distinguished, depending on the level of residual APRT activity: type I, mainly observed in Caucasian subjects, in whom the enzyme activity is undetectable in homozygous patients and type II, found in Japanese patients who are able to form APRT but the enzyme activity is strikingly reduced because a low affinity for phosphoribosylpyrophosphate. The crystallization of 2,8-DHA and subsequent renal damages may be prevented with allopurinol therapy, a xanthine oxidase inhibitor. The role of the laboratory is crucial to detect APRT deficiency and to assess the efficacy of therapy, the objective being to avoid 2,8-DHA crystal formation.
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PMID:[2,8-dihydroxyadenine nephrolithiasis: from diagnosis to therapy]. 1803 2


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