Allopurinol
Oxidative stress in distant organs and the effects of allopurinol during experimental acute pancreatitis.

Czako L, Takacs T, Varga IS, Tiszlavicz L, Hai DQ, Hegyi P, Matkovics B, Lonovics J.

First Department of Medicine, Albert Szent-Gyorgyi Medical University, Attila Jozsef University, Szeged, Hungary. czal in1st.szote.u-szeged.hu

BACKGROUND: The present study was aimed at an assessment of the role of oxygen-derived free radicals in the development of local and systemic manifestations of L-arginine (Arg)-induced acute pancreatitis and at an evaluation of the protective effect of the xanthine oxidase inhibitor allopurinol. METHODS: Acute pancreatitis was induced in male Wistar rats by injecting 2 x 250 mg/100 g body weight of Arg intraperitoneally at an interval of 1 h, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. In a third group, 200 mg/kg of allopurinol was administered subcutaneously 30 min before the first Arg injection. Rats were killed at 6, 12, 24, or 48 h following Arg administration. Acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features were observed microscopically. Tissue concentrations of malonyl dialdehyde (MDA), superoxide dismutase (Mn- and Cu,Zn-SOD), glutathione peroxidase (GPx), and catalase were measured in the pancreas, liver, and kidney. RESULTS: The tissue concentration of MDA was significantly elevated in each organ. The activities of Mn-SOD, Cu,Zn-SOD, GPx, and catalase were quickly depleted in the pancreas and kidney, whereas only the Mn-SOD and GPx activities were reduced in the liver after the onset of pancreatitis. Histologic examination revealed acinar cell necrosis in the pancreas, but only mild alterations in the liver and kidney. Allopurinol pretreatment prevented the generation of reactive oxygen metabolites in the pancreas and reduced their formation in the kidney. CONCLUSION: Oxygen-derived free radicals are generated in the pancreas, liver, and kidney at an early stage of Arg-induced acute pancreatitis. The liver and the kidney, but not the pancreas, are able to defend against oxidative stress. The prophylactic application of allopurinol significantly restrains the generation of free radicals in pancreas and kidney.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10952403&dopt=Abstract allopurinol Zyloprim



Allopurinol
The effects of allopurinol in hepatic ischemia and reperfusion: experimental study in rats.

Rhoden E, Pereira-Lima L, Lucas M, Mauri M, Rhoden C, Pereira-Lima JC, Zettler C, Petteffi L, Bello-Klein A.

Course of Post-Graduation in Medical Clinic of the Clinical Hospital of Porto Alegre, Porto Alegre, Brazil.

BACKGROUND/AIMS: Some studies have shown that postischemic hepatic dysfunction is mainly due to oxygen free radicals that are generated by xanthine oxidase. The present study was undertaken to determine the effect of allopurinol, an inhibitor of xanthine oxidase, on oxidative stress, liver injury and histologic alterations induced by hepatic ischemia-reperfusion in rats. METHODS: One hundred and sixty Wistar rats were used and divided into three groups. Group 1: sham operation; group 2: 50 min of ischemia followed by 1 h of reperfusion, and group 3: pretreatment with allopurinol and 50 min of ischemia followed by 1 h of reperfusion. The effect of allopurinol was evaluated by plasma levels of alanine aminotransferase and aspartate aminotransferase, histopathologic studies, and lipid peroxidation measured by the thiobarbituric acid reactive substances method and chemiluminescence initiated by tert-butyl hydroperoxide technique. RESULTS: Ischemia followed by reperfusion promoted an increase in lipid peroxidation of the hepatic cells when compared to the sham-operated group (p<0.05). This increase was attenuated in the group treated with allopurinol (p< 0.05). Allopurinol also showed a protective effect on hepatocellular necrosis (p<0.05), and the plasma levels of liver enzymes returned earlier to the normal range in rats pretreated with allopurinol in comparison to those that did not receive the drug (p<0.05). CONCLUSIONS: Allopurinol exerted a protective effect on hepatic ischemia and reperfusion in rats. The administration of this drug prior to liver operations should be considered to be submitted to trials in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11014922&dopt=Abstract allopurinol Zyloprim



Allopurinol
Electromechanical impairment of human auricle and rat myocardial strip subjected to exogenous oxidative stress.

Ben Abraham R, Matza M, Marmor S, Rudick V, Frolkis I, Shapira I, Weinbroum AA.

Departments of Anesthesiology and Critical Care, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

OBJECTIVE: Animal myocardial dysfunction induced by remote ischemia-reperfusion (IR) was shown to be partly accomplished via a direct effect of the pro-oxidant xanthine oxidase (XO). This direct remote effect was not tested in humans. We now assessed the performance of human auricles in the presence of solutions containing XO and/or allopurinol and compared them to those of rat myocardial strips. METHODS: Human and rat specimens (n=64) were separately exposed for 2h to Krebs-Henseleit solution that either (1) exited from rat livers that were earlier perfused for 2h (control-human or control-rat), (2) exited from livers that were earlier made ischemic for 2h (IR-human, IR-rat), (3) contained xanthine (X) 3.8 microM + XO 3 mU ml(-1) (X+XO-human, X+XO-rat), or (4) exited from post 2h-ischemic livers and contained 100 microM allopurinol (human or rat IR + allopurinol groups). RESULTS: Unlike the unchanged electromechanical performance in the control and IR+allopurinol auricles and strips, the rates of contraction, maximal force of contraction and working index of either preparation were reduced by 75-98% (P<0.01) when exposed to the IR reperfusate or to the X+XO-enriched Krebs. The basal amplitudes of contraction in these four latter groups increased twofold (P<0.01). XO activity was similarly low in the control and in the IR+allopurinol groups, but four- to 45-fold (P<0.001) higher in the IR and the X+XO groups, both in the rat and human organs. The reduced glutathione was reduced by approximately 50% (P<0.01) in either preparation in the IR and the X+XO groups compared to the control and IR+allopurinol groups. CONCLUSIONS: Remotely and exogenously originated oxidative burst directly induces electromechanical dysfunction and disrupts oxidant/antioxidant balance in human auricles as it does in the rat myocardial strip.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12493507&dopt=Abstract allopurinol Zyloprim



Allopurinol
Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease.

Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SP, Rees L, Van'T Hoff W, Mansell M, Pattison J, Goldsmith DJ, Simmonds HA.

Purine Research Unit GKT, Guy's Hospital, London, UK.

BACKGROUND: The efficacy of allopurinol in autosomal dominant familial juvenile hyperuricaemic nephropathy (FJHN) has been disputed. AIM: To address this question, in the absence of controlled trials. DESIGN:Retrospective long-term follow-up study. METHODS: All kindreds were biochemically screened. Measurements included uric acid clearance, creatinine clearance, serum creatinine, and glomerular filtration rate (GFR). We used five siblings who had died or progressed to transplantation, ten other deceased relatives, and two index cases (one untreated, one non-compliant) as controls to assess the effects of allopurinol. RESULTS: Of eight families with FJHN, six had a strong history of renal disease and early parental death (mean age 41 years, n=10). Of 27 patients started immediately on allopurinol and treated uninterruptedly, 21 responded well, including three children born subsequently. Eight siblings (mean age 19 years) with a normal plasma creatinine at start (<120 micromol/l, mean GFR 80 ml/min/1.73 m(2)) retained stable renal function (mean 14.5 years, mean age 34 years, GFR 85 ml/min/1.73 m(2)). Of the 13 other responders, treated for up to 34 years, 10 with a creatinine <200 micromol/l at diagnosis (mean age 28 years, mean creatinine 137 micromol/l at start) now have a mean creatinine of 210 micromol/l. In contrast, five patients (mean age 26 years) with a creatinine >200 micromol/l (GFR <35 ml/min/1.73 m(2)) when allopurinol commenced, plus one untreated index case, all progressed rapidly (mean 6 years) to end-stage renal failure. In two others (one non-compliant, one initially untreated), GFR fell by >50% in 7 years. Introduction of allopurinol in the latter has stabilized GFR. DISCUSSION: Allopurinol reduced the morbidity and mortality from renal failure seen in untreated siblings and previous generations of these families. Early diagnosis of FJHN is important, so that treatment can begin before irreversible renal damage has developed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12205338&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of allopurinol, superoxide-dismutase, and hyperbaric oxygen on flap survival.

Prada FS, Arrunategui G, Alves MC, Ferreira MC, Zumiotti AV.

Section of Reconstructive Microsurgery, Division of Traumatology and Orthopaedic Surgery, Hospital das Clinicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil. fsprada unisys.com.br

The effect of allopurinol, superoxide-dismutase, and hyperbaric oxygen was compared on axial pattern skin flap survival. An abdominal flap based on the inferior epigastric pedicle was raised in rats for this purpose. Three experimental groups were studied. In the first group, adult male Wistar rats received 50 mg/kg I.P. of allopurinol. The second received 20,000 I.U./kg of superoxide-dismutase. The third group was submitted to hyperbaric oxygen therapy. The flaps were exposed to 8-h warm ischemia. Flap survival was evaluated on postoperative day 7. All flaps survived, and the mean survival areas were 63.53%, 83.03%, and 55.98%, respectively, in the allopurinol, superoxide-dismutase, and hyperbaric groups. The percentage of flap necrosis was significantly smaller in all experimental groups when compared to controls (P < 0.05). It was clear that the superoxide-dismutase group had better results on axial pattern ischemic skin flap survival, under the tested conditions. The tested methods improved flap survival to ischemic injury, and the flap designed is a reliable model for further investigations. Copyright 2002 Wiley-Liss, Inc. MICROSURGERY 22:352-360 2002

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12497572&dopt=Abstract allopurinol Zyloprim



Allopurinol
A review of inpatients with adverse drug reactions to allopurinol.

Khoo BP, Leow YH.

Raffles Surgicentre, Singapore.

Allopurinol is still an effective uric-acid lowering drug since its introduction in 1963. However it has been frequently incriminated for severe adverse drug reactions. From our retrospective review of 13 inpatients with allopurinol adverse reactions seen over 3 years, fever and rash were the commonest presenting symptoms, occurring several weeks after initiation of the drug. Other associated abnormalities included leukocytosis (62% of patients), eosinophilia (54%), renal impairment (54%) and liver dysfunction (69%). Although 12 patients (92%) met the criteria for allopurinol hypersensitivity syndrome, there was no mortality recorded. The indications for initiating allopurinol therapy were frequently unclear. In view of the severe adverse reactions experienced with allopurinol, we propose that it should only be prescribed when truly indicated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11063179&dopt=Abstract allopurinol Zyloprim