Allopurinol
Role of oxygen-derived free radicals in protease activation after pancreas transplantation in the pig.

Petersson U, Kallen R, Montgomery A, Borgstrom A.

Department of Surgery, University Hospital MAS, University of Lund, Malmo, Sweden.

The role of oxygen-derived free radicals in pancreatitis after pancreas transplantation was examined in a porcine pancreatic transplantation model. Trypsin activation, protease inhibitor consumption, kininogen consumption, and postoperative graft function were investigated in 24 pigs subjected to whole organ pancreaticoduodenal transplantation. The animals were divided into one control group and two groups treated with free radical scavengers. One group was given allopurinol, and one group was treated with superoxide dismutase in combination with catalase. In the early phase (within 1 hr) after reperfusion, no differences were seen between the groups as to protease activation. Neither trypsin-protease inhibitor imbalance nor any signs of kininogen consumption were seen. In a later phase (1-3 days after the transplantation), the trypsin activation, measured as high molecular weight immunoreactive cationic trypsin in plasma, was significantly less pronounced in allopurinol-treated animals. This finding indicates a less severe form of reperfusion pancreatitis in this group compared with the other groups. A tendency toward better function in the allopurinol-treated group was also seen. We conclude that oxygen-derived free radicals seem to be of importance in the development of reperfusion pancreatitis after pancreas transplantation in the pig. We also conclude that allopurinol, but not superoxide dismutase/catalase, possibly due to the administration regimens used in this series, is able to attenuate the trypsin activation and the development of pancreatitis in the later phase in this model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9484764&dopt=Abstract allopurinol Zyloprim



Allopurinol
A new platelet-activating factor antagonist (CV-6209) in preservation of heart and lung for transplantation.

Qayumi KA, English JC, Feeley EJ, Poostizadeh A, Nikbakht-Sangari M.

Department of Surgery, University of British Columbia, Vancouver Hospital, Canada.

The objective of this experimental protocol was to evaluate the protective effect of a new, potent platelet-activating factor (PAF) antagonist CV-6209 and the use of this compound in combination with allopurinol on ischemia-reperfusion injury in a swine model of heart-lung transplantation. Forty-two swine were divided into three groups, with seven donors and seven recipients in each. In group A, the PAF antagonist CV-6209 was administered in a single dosage of 1 mg/kg by slow intravenous injection at 1 hour before crossclamping of the aorta in both donors and recipients. In group B the combination of allopurinol and the PAF antagonist CV-6209 was used. Allopurinol was administered as a pretreatment regime of 50 mg/kg/day for 3 days prior to ischemia. The PAF antagonist dosage and regime of administration were the same as in group A, and both donors and recipients were pretreated with this combination. Group C was the control in which heart-lung transplantations were performed without interventional therapies. Based on the comparison of pre- and post-transplantation assessments of cardiac and pulmonary functional integrity within groups, and post-transplantation among groups, animals in groups A and B were significantly (P < 0.05) better protected from ischemia-reperfusion injury than animals in group C. The difference between groups A and B, however, was insignificant at all times. Morphological findings are in agreement with measures of physiological variation among experimental groups. It is suggested that the new PAF antagonist CV-6209 is effective in the prevention of heart and lung ischemia-reperfusion injury with and without allopurinol pretreatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9512873&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of allopurinol on NMDA receptor modification following recurrent asphyxia in newborn piglets.

Marro PJ, Hoffman D, Schneiderman R, Mishra OP, Delivoria-Papadopoulos M.

Department of Pediatrics, Maine Medical Center, Portland, ME 04102-3134, USA.

The present study tests the hypothesis that repeated episodes of asphyxia will lead to alterations in the characteristics of the N-methyl-d-aspartate (NMDA) receptor in the brain cell membrane of newborn piglets and that pre-treatment with allopurinol, a xanthine oxidase inhibitor, will prevent these modifications. Eighteen newborn piglets were studied. Six untreated and six allopurinol treated animals were subjected to eight asphyxial episodes and compared to six normoxic, normocapneic controls. Brain cell membrane Na+,K+-ATPase activity was determined to assess membrane function. Na+,K+-ATPase activity was decreased from control following asphyxia in both the untreated and treated animals (47.7+/-3.2 vs. 43.0+/-2.2 and 41.0+/-5.3 micromol Pi/mg protein/h, p<0.05, respectively). 3H-MK-801 binding studies were performed to measure NMDA receptor binding characteristics. The receptor density (Bmax) in the untreated asphyxia group was decreased compared to control animals (0.80+/-0.11 vs. 1.13+/-0.33, p<0.05); furthermore, the dissociation constant (Kd) was also decreased (3.8+/-0.7 vs. 9.2+/-2.2, p<0.05), indicating an increase in receptor affinity. In contrast, Bmax in the allopurinol treated asphyxia group was similar to control (1. 06+/-0.37); and Kd was higher (lower affinity) than in the untreated group (6.5+/-1.4, p<0.05). The data indicate that recurrent asphyxial episodes lead to alterations in NMDA receptor characteristics; and that despite cell membrane dysfunction as seen by a decrease in Na+,K+-ATPase activity, allopurinol prevents modification of NMDA receptor-ion channel binding characteristics induced by repeated episodes of asphyxia. Copyright 1998 Elsevier Science B.V.

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Allopurinol
An ultrastructural study to investigate the effect of allopurinol on cerulein-induced damage to pancreatic acinar cells in rat.

Brunelli A, Scutti G.

Department of Research Nino Masera and University of Ancona School of Medicine, Italy.

CONCLUSION: Subcellular organelles and membranes were the structures most protected by allopurinol, indirectly demonstrating their role of main and early target of oxygen-derived free radicals in the pathogenesis of acute pancreatitis. BACKGROUND: The present work evaluates the ultrastructural changes during cerulein-induced acute pancreatitis in rat, with and without treatment with allopurinol. METHODS AND RESULTS: Supramaximal doses of cerulein, injected intraperitoneally (50 microg/kg) twice, at 1-h interval, caused severe subcellular alterations, including zymogen distribution, pathological vacuoles, and damage to organelles and membranes. Cotreatment (40 mg/kg ip twice with 1-h interval; n = 10 rats) and, most of all, pretreatment (40 mg/kg ip allopurinol, 1 h; 20 mg/kg ip allopurinol + 50 microg/kg ip cerulein, 30 min; 40 mng/kg ip allopurinol, 30 min; 50 microg/kg ip cerulein; n = 10 rats) with allopurinol showed significant morphological improvement.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9520088&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effects of allopurinol on free-radical-induced reduction of the proliferation of retinal pigment epithelial cells.

Augustin AJ, Grus FH, Hunt S.

Department of Ophthalmology, University of Bonn, Germany.

PURPOSE: To investigate the effects of allopurinol on free-radical-induced reduction of growth of retinal pigment epithelial (RPE) cells. METHODS: Bovine RPE cells were seeded at a density of 1 x 10(5) cells/Petri dish (60 x 15 mm) containing 4 ml MEM-Earle plus 15% FCS plus antibiotics. Twenty-four hours after seeding, cultures were exposed to a free radical generating system hypoxanthine(HX)/xanthine oxidase (XO) (HX: 0.1 micromol/l; XO: 700 microU/ml) for 10 or 60 min. Thereafter, the cells were washed. After washing the cells, allopurinol was added at 500 or 1000 micromol. To evaluate the effect of the radical generating system one group was not washed after treatment ('no wash'). The cultures were divided into eight groups: (1) no treatment (control); (2) HX/XO, no wash; (3,4) HX/XO, washed after 10 or 60 min; (5,6) HX/XO, washed after 10 or 60 min, application of 500 micromol of allopurinol; (7,8) HX/XO, washed after 10 or 60 min, application of 1000 micromol of allopurinol. Cell counts were carried out 96 h post-seeding. The values are expressed as means +/- SE. RESULTS: After 72 h (HX/XO, no wash), the radical generating system resulted in a significant decrease in cell growth as compared to controls. When being eliminated after 10 or 60 min, the radical generating system also led to significant decrease in the values as compared to controls. Allopurinol treatment: All therapy (scavenger) groups (4,5) were significantly different from the respective control group; following exposition to the radical generating system for 60 min, allopurinol showed significantly higher values when given at 1000 micromol as compared to 500 micromol. CONCLUSIONS: The results demonstrate that allopurinol, when given at a scavenger dose (500-1000 micromol), can prevent free-radical-induced cell damage and stop chain reactions. Thus, the possible beneficial value of allopurinol on diseases with involvement of oxidative tissue damage, such as age-related macular degeneration, should be investigated further.

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Allopurinol
Attenuation of renal ischemia-reperfusion injury in rats by allopurinol and prostaglandin E1.

Gupta PC, Matsushita M, Oda K, Nishikimi N, Sakurai T, Nimura Y.

First Department of Surgery, Nagoya University School of Medicine, Japan.

50 Sprague-Dawley rats were used to study the effect of allopurinol and prostaglandin E1 (PGE1) on renal ischemia-reperfusion injury. They underwent left renal ischemia for 1 h and reperfusion. A right nephrectomy was performed, and 5 groups were made. Group AP received allopurinol 50 mg/kg and PGE1 20 micrograms/kg; group A, allopurinol; group P, PGE1; group C, control, and group S, sham group. Five animals from each group were used to study renal functions and 5 for renal histology. The serum creatinine values were lower in the treatment groups compared to the controls on days 1-3 and 7 (p < 0.05). The blood urea nitrogen values showed a similar trend. Maximum histological damage was seen in group C, followed by groups A, P and AP, in this order. We conclude that allopurinol and PGE1 attenuate renal ischemia-reperfusion injury in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9565743&dopt=Abstract allopurinol Zyloprim