Allopurinol
Inhibition of transition metal ion-catalysed ascorbate oxidation and lipid peroxidation by allopurinol and oxypurinol.

Ko KM, Godin DV.

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.

Allopurinol and its metabolite oxypurinol inhibited basal oxidation of ascorbate and exerted comparable concentration-dependent inhibitory effects on the oxidation of ascorbate catalysed by cupric ion, but the stimulation produced by ferric ion was affected minimally. UV spectral analysis suggested the formation of an allopurinol-ascorbate-copper ion complex. The oxidation of erythrocyte membrane lipids by ferric ion and cupric ion-t-butylhydroperoxide was also inhibited by allopurinol and oxypurinol, by the metal chelators EDTA and uric acid, and by the antioxidant butylated hydroxytoluene. The metal chelating actions of allopurinol and oxypurinol may be relevant to their protective actions against ischemia/reperfusion injury.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2117456&dopt=Abstract allopurinol Zyloprim



Allopurinol
Does allopurinol prevent myocardial injury as a result of hypoxia-re-oxygenation in rats?

Miwa-Nishimura N, Kanaide H, Abe S, Nakamura M.

Division of Molecular Cardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

We made use of the xanthine oxidase inhibitor allopurinol and examined changes related to myocardial injury of the rat heart during hypoxia-re-oxygenation. The rat heart was perfused using the Langendorff method. With low-oxygen perfusion for 60 min in a solution saturated with mixed gases of 95% N2 + 5%O2, contractile tension did not develop and tension development was not restored upon re-oxygenation. During hypoxia, the resting tension increased (4.1 g) in the absence of allopurinol. In the allopurinol-administered group (100 microM), contractile tension did not develop during hypoxia; however, the development of tension was restored (18%) upon re-oxygenation. The elevation of resting tension was less (3.2 g) during hypoxia. All events related to the myocardial injury (inhibition of Na+, K(+)-ATPase activities, generation of malondialdehyde, extracellular leakage of creatine kinase) after low-oxygen perfusion for 60 min and re-oxygenating perfusion for 30 min were mild in the allopurinol treated group, compared with findings in the non-administered group. Tissue ATP at 10 min after low-oxygen perfusion was of a significantly high value in the allopurinol treated group (13.2 mumols/g dry weight), compared with findings in the group not given the drug (8.4 mumol/g dry weight). Sixty minutes after low-oxygen perfusion, tissue ATP in the allopurinol group also remained high, compared with the group not given the drug. Although the intensity of the epicardial NADH fluorescence indicated that the extent of inhibition of aerobic energy production during 10 min of low-oxygen perfusion was the same for both groups, lactate was produced in large quantities in the allopurinol treated group, hence energy generation advanced with glycolysis. These observations suggest that allopurinol prevents myocardial injury as a result of hypoxia-re-oxygenation. In the low-oxygen perfusion period, generation of energy is maintained and improved with glycolysis and there is a reduction in the generation of free radicals and an inhibition in lipid peroxidation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2206993&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of ischemia reperfusion or hypoxia reoxygenation on lung vascular permeability and resistance.

Allison RC, Kyle J, Adkins WK, Prasad VR, McCord JM, Taylor AE.

Department of Medicine, College of Medicine, University of South Alabama, Mobile 36688.

The effect of ischemia reperfusion or hypoxia reoxygenation on pulmonary vascular permeability and resistance was studied in 25 isolated blood-perfused dog lungs. Vascular permeability, assessed by determining filtration coefficient (Kf), and vascular resistances were measured at the beginning and end of the experiment. Ischemia reperfusion was produced by occluding blood flow to the lung for 3 h and reperfusing for 1 h, whereas hypoxia reoxygenation was obtained by ventilating the lung with 95% N2-5% CO2 for 3 h and then ventilating with 95% O2-5% CO2 for 1 h with no interruption of perfusion. There was a significant increase in Kf in both ischemia reperfusion and hypoxia reoxygenation groups (51 and 85%, respectively), and total vascular resistance increased greatly in both groups (386 and 532%, respectively). Two additional groups were also studied in which the ischemia reperfusion or hypoxia reoxygenation lungs were pretreated with allopurinol (20 micrograms/ml). The Kf did not significantly increase in either the allopurinol ischemia reperfusion or the allopurinol hypoxia reoxygenation groups (22 and 6%, respectively). However, total vascular resistance significantly increased in both groups (239 and 224%, respectively). Although vascular permeability is modestly increased by both ischemia reperfusion and hypoxia reoxygenation, the predominant change in these conditions is the increased vascular resistance, which predominantly affects the postcapillary resistance and would result in a greater tendency for edema to develop in these slightly damaged lungs. Allopurinol, which inhibits xanthine oxidase, attenuated the permeability changes in both groups and may be useful in preventing ischemia reperfusion injury in certain conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2228871&dopt=Abstract allopurinol Zyloprim



Allopurinol
Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol.

Jaeschke H.

Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Texas.

Acetaminophen (500 mg/kg i.p.) induced hepatotoxicity in fasted ICR mice in vivo. Acetaminophen also caused a long-lasting 50% reduction of the hepatic ATP content, an irreversible loss of hepatic xanthine dehydrogenase activity and a transient increase of the xanthine oxidase activity. All effects occurred before parenchymal cell damage, i.e., the release of cellular enzymes. The hepatic content of GSH and GSSG was initially depleted by acetaminophen without affecting the GSSG:GSH ratio (1:200), however, during the recovery phase of the hepatic GSH levels the GSSG content increased faster than GSH, resulting in a GSSG:GSH ratio of 1:18 24 h after acetaminophen administration. The mitochondrial GSSG content increased from 2% in controls to greater than 20% in acetaminophen-treated mice. The extremely elevated tissue GSSG levels were accompanied by a 4-fold increase of the plasma GSSG concentrations but not by an enhanced biliary efflux, although hepatic GSSG formation and biliary excretion were not affected by acetaminophen. Allopurinol protected dose-dependently against acetaminophen-induced cell injury, the loss of ATP and the increase of the GSSG content in the total liver and in the mitochondrial compartment without inhibiting reactive metabolite formation. High, protective as well as low, nonprotective doses of allopurinol almost completely inhibited hepatic xanthine oxidase and dehydrogenase activity, but only high doses prevented the increase of the mitochondrial GSSG content. The data indicate a long-lasting, primarily intracellular oxidant stress during the progression phase of acetaminophen-induced cell necrosis. The protective effect of allopurinol is unlikely to involve the inhibition of reactive oxygen formation by xanthine oxidase but could be the result of its antioxidant property.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2262912&dopt=Abstract allopurinol Zyloprim



Allopurinol
Simultaneous determination of allopurinol and oxypurinol by liquid chromatography using immobilized xanthine oxidase with electrochemical detection.

Eisenberg EJ, Conzentino P, Liversidge GG, Cundy KC.

Department of Drug Delivery, Sterling Research Group, Great Valley, PA 19355.

A novel liquid chromatographic method using an immobilized xanthine oxidase reactor and an electrochemical detector was developed for the simultaneous determination of allopurinol and oxypurinol in rat plasma, intestinal wash and bile. Xanthine oxidase was immobilized on 5-microns aldehyde silica (prepacked into a 2 mm x 10 mm cartridge) in a simple procedure. Allopurinol eluted from an analytical column was converted to oxypurinol in the enzyme reactor with the eluent as the reaction medium and detected with high selectivity using an amperometric detector with a glassy carbon electrode at the applied potential of +0.85 V. High specificity of the enzymatic reaction combined with selectivity of the electrochemical detection eliminated the need for an extensive sample preparation. The assay was linear in the range 15-500 ng/ml of rat plasma, intestinal wash and bile with a low limit of detection of 10 pg on-column (signal-to-noise ratio = 4) for both allopurinol and oxypurinol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2277120&dopt=Abstract allopurinol Zyloprim



Allopurinol
Prolonged survival and decreased mucosal injury after low-dose enteral allopurinol prophylaxis in mesenteric ischemia.

Megison SM, Horton JW, Chao H, Walker PB.

Department of Surgery, University of Texas Southwestern Medical Center, Dallas 75235-9031.

Previous studies demonstrating protective effects of allopurinol in intestinal ischemia have evaluated intravenous allopurinol (presently unavailable for human use) or enteral allopurinol at supranormal doses and, therefore, have questionable clinical relevance. To address this problem, we evaluated the protective effects of clinically used doses of enteral allopurinol in rats with intestinal ischemia. Forty male Sprague-Dawley rats (weighing 300 to 400 g) received enteral allopurinol (10 mg/kg) or water daily for 1 week. Rats were then subjected to superior mesenteric artery occlusion with interruption of collateral flow for 20 minutes to produce ischemic injury to the intestine. Segmental small bowel resections were performed in 10 control rats and 10 allopurinol-treated rats before and after reperfusion to identify histopathologic evidence of reperfusion injury. Mucosal injury was quantitated using a grading scale of 0 to 5 (5 being most severe). The remaining 20 rats (10 in each group) were observed for mortality (death within 7 days) after reperfusion. Mucosal injury after reperfusion was graded at 4.4 +/- 0.20 in controls versus 2.3 +/- 0.23 in the treated group (P less than .001). In addition, there was a significant increase in mucosal damage in the control group when postreperfusion specimens were compared with specimens taken before reperfusion (2.8 +/- 0.19 before and 4.4 +/- 0.20 after reperfusion, P less than .001). Injury score for the allopurinol-treated group did not significantly increase after reperfusion. Survival was 50% in the water-fed control group compared with 100% survival in allopurinol-treated rats (P = .016). We conclude that enteral allopurinol in the presently available form and dose is effective in reducing mesenteric reperfusion injury.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2401948&dopt=Abstract allopurinol Zyloprim