Allopurinol
Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats.

Palmer C, Towfighi J, Roberts RL, Heitjan DF.

Department of Pediatrics, Milton S., Hershey Medical Center, Pennsylvania State University, Hershey 17033.

We determined that treatment of immature rats with allopurinol at 15 min after cerebral hypoxia-ischemia reduces brain damage. Seven-d postnatal rats were subjected to right common carotid artery ligation followed by 2.25 h of hypoxia (8% O2). At 15 min of recovery in room air, the rat pups received either allopurinol (135 mg/kg s.c.) or saline. Some of the rats (n = 65) were killed at 42 h of recovery for measurement of cerebral hemispheric water content. Other animals (n = 63) were killed at 30 d for morphologic assessment of the severity of damage. In separate rats, we measured the levels of allopurinol and its metabolites in serum and in the brain around the time of peak serum levels. We also determined the effect of allopurinol on rat pup body temperature. Allopurinol reduced the increase in right hemisphere water content and markedly reduced atrophy. No cavitary lesions were seen in the 31 allopurinol-treated rats, whereas 15 of 32 saline-treated rats had cavitary cerebral lesions. Histologic examination confirmed that the allopurinol-treated rats had less brain injury. Serum allopurinol and oxypurinol peaked between 0.5 and 1 h after allopurinol injection. Their peak serum concentrations at 0.75 h postinjection combined was between 360 and 510 microM. Allopurinol did not lower rectal temperature more than 0.04 degrees C. In conclusion, high-dose allopurinol administered at 15 min of recovery from cerebral hypoxia-ischemia markedly reduces both acute brain edema and long-term cerebral injury in immature rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8479823&dopt=Abstract allopurinol Zyloprim



Allopurinol
Role of xanthine oxidase and prostaglandins in inflammatory-induced bacterial translocation.

Mainous MR, Xu D, Deitch EA.

Department of Surgery, LSU Medical Center, Shreveport 71130-3932.

We have previously documented that a nonlethal dose of zymosan causes gut mucosal injury associated with increased xanthine oxidase activity and bacterial translocation. The current study was performed to investigate the role of xanthine oxidase activation and other potential mediators of intestinal injury in an LD50 zymosan model. Specific pathogen-free rats and mice were pretreated with saline, allopurinol, or ibuprofen prior to intraperitoneal injection of either saline or the LD50 dose of zymosan. Bacterial translocation to the mesenteric lymph node and systemic organs was measured at 6 or 24 hr following injection. In addition, separate animals in each group were followed for 7 days for survival. Pretreatment with allopurinol or ibuprofen reduced both the incidence and the magnitude of translocation at 6 hr in rats and mice (P < 0.05). In the rats pretreated with allopurinol or ibuprofen, no reduction in the incidence or magnitude of translocation occurred at 24 hr. In the mice pretreated with allopurinol or ibuprofen, although the incidence of translocation was not reduced at 24 hr, the magnitude of translocation was reduced (P < 0.05). Pretreatment with allopurinol or ibuprofen also resulted in an improvement in survival, when compared to zymosan alone (P < 0.01). Allopurinol and ibuprofen provide protection against bacterial translocation and improvement in survival following challenge with a lethal dose of zymosan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8508522&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol plus pentoxifilline in hepatic ischaemia/reperfusion injury.

Yildirim S, Tok H, Koksal H, Erdem L, Baykan A.

Sisli Etfal Teaching State Hospital, Istanbul, Turkey. sadikyildirim yahoo.com

OBJECTIVES: Ischaemia/reperfusion injury of the liver is the major cause of liver dysfunction and cellular death in transplantation and in liver resection with hepatic pedicle clamping. Many agents are used to prevent this phenomenon, which occurs following interaction of different mediators during both ischaemia and reperfusion. In this study, we aimed to assess the effects of allopurinol, a xanthine oxidase inhibitor, and pentoxifilline, on liver ischaemia/reperfusion injury when used together and to compare these with the effects of using these agents singly. METHODS: Thirty-two rats were divided into four groups consisting of eight rats: Group C, control; Group P, pentoxifilline; Group A, allopurinol; and Group PA, pentoxifilline + allopurinol. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels were measured before hepatic pedicle clamping, on the 45th minute of ischaemia and 15 and 45 minutes after reperfusion. Group P rats were injected with 50 mg/kg pentoxifilline, Group A rats 50 mg/kg allopurinol and Group PA rats were injected with both agents 15 minutes before hepatic pedicle clamping. RESULTS: Ischaemia/reperfusion injury was produced by hepatic pedicle clamping, as demonstrated by AST, ALT and LDH increase. Injury prevention occurred in Groups P, A and PA. No significantly different (better) prevention was provided by giving allopurinol plus pentoxifilline to the rats. Furthermore, no difference was observed between the allopurinol and pentoxifilline injected groups in terms of preventing ischaemia/reperfusion injury. CONCLUSIONS: Pretreatment with allopurinol or pentoxifilline resulted in significantly lower hepatic enzyme elevation than that in controls in the rat liver ischaemia/reperfusion model. Using both agents does not provide better protection than using either agent alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12376236&dopt=Abstract allopurinol Zyloprim



Allopurinol
Histamine release and SOD, allopurinol and ranitidine pretreatment in haemorrhagic shock in the rat.

Zollei I, Asakawa H, Karacsonyi S.

Department of Surgery of Szent-Gyorgyi Albert Medical University, Szeged, Hungary.

Histamine release have been demonstrated in haemorrhagic shock. There are some observations that oxygen free radicals can cause histamine release. Oxygen free radicals play a role in the pathogenesis of gastric mucosal lesions. The goal of this study was to determine whether ranitidine or SOD and allopurinol pretreatment modify the histamine release during and after the haemorrhagic shock in the rat. In the anaesthetized rat 0.1 N HCl was instilled into the stomach and the rat was bled to reduce the blood pressure to 30 mmHg for 20 min. The shed blood was reinfused. Twenty min later the stomach was removed. The area of gastric mucosal lesions were measured, histological grading was made. Blood samples taken from the carotid artery were examined by radioimmunoassay (IMMUNOTECH) to determine the plasma histamine level. Plasma histamine level did not change significantly during the preparative surgery, but there was a significant increase of histamine level by the end of shock period. After the reinfusion of the blood the plasma histamine remained essentially at the same level for five min. Oxygen free radicals did not cause an important histamine release. By the end of the experiment the histamine level decreased dramatically. Ranitidine, allopurinol and SOD pretreatment provided significant protection against the gastric mucosal lesions. Allopurinol and SOD did not influence significantly the histamine level. Ranitidine caused significant histamine release immediately after the injection and every histamine value was significantly higher in this group except for the final value which was lower than the control one. The oxygen free radicals were not found as endogenous histamine releasers in this study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1285366&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol challenge test in children.

Burlina AB, Ferrari V, Dionisi-Vici C, Bordugo A, Zacchello F, Tuchman M.

Department of Pediatrics, University of Padua, Italy.

The allopurinol challenge test was performed on 44 healthy subjects (28 children and 16 adolescents) in order to establish normal values of urinary orotic acid excretion following allopurinol ingestion in the paediatric population. The subjects were divided into three groups according to their age: 6 months to 6 years; 6 years to 10 years; and 10 years to 17 years. They were given 100 mg, 200 mg, or 300 mg of allopurinol, respectively (based on age) in a single oral dose. Maximum peak urinary orotic acid levels following ingestion of allopurinol were 13.0 (n = 14), 9.3 (n = 14), and 10.2 (n = 16) mumol/mmol creatinine in the three groups, respectively. In all children tested the peak orotic acid level was 3.1 +/- 2.7 mumol/mmol creatinine (mean +/- SD, n = 44). This allopurinol challenge test was also performed in six children with urea-cycle disorders, including five females with ornithine transcarbamylase (OTC) deficiency, all of whom demonstrated abnormally elevated levels of urinary orotic acid (peak levels of 26-134 mumol/mmol creatinine) following allopurinol ingestion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1434508&dopt=Abstract allopurinol Zyloprim



Allopurinol
Preserved mitochondrial function by allopurinol despite deteriorated hemodynamics in warm ischemia-damaged canine liver.

Nakano M, Sugano M, Terasaki M, Morimoto T, Mashima S, Mitsuyoshi A, Sasaki H, Kumada K, Ozawa K.

Second Department of Surgery, Faculty of Medicine, Kyoto University, Japan.

To investigate the pathophysiology of warm ischemia (WI) of the liver, the changes in hemodynamics and energy metabolism were studied during and after 60-min complete WI induced by total hepatic vascular exclusion (HVE) in the canine model. Hepatic arterial blood flow after WI was maintained at 76% of the pre-ischemic level, while portal blood flow was only 27% of the pre-ischemic level associated with increased portal vein pressure, which was twice the pre-ischemic level, resulting in a decrease of total hepatic blood flow to 46% of the pre-ischemic level. Concentration of tissue lipid peroxide increased after WI. Arterial blood ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state, could not recover to the pre-ischemic level after termination of WI. However, when 100 mg/kg of allopurinol (xanthine oxidase inhibitor) was administered intravenously 10 min prior to initiating WI, AKBR was restored to the pre-ischemic level at 30 min after WI in spite of the fact that allopurinol administration to one group produced no remarkable changes in the hepatic hemodynamics compared with the group without allopurinol treatment. Concentration of adenine nucleotides was significantly higher for the treated group at the end of and after WI than for the group without allopurinol treatment and was maintained at a higher level even after WI. Lipid peroxide production was suppressed. Electron microscopic examination revealed that allopurinol treatment could not prevent mitochondrial swelling. It is suggested that WI causes injury primarily to the portal sinusoidal circulation, resulting in portal congestion concomitant with high portal pressure after the release of WI. Allopurinol could prevent the deterioration of mitochondrial ATP metabolism, and was able to inhibit lipid peroxide production, resulting in the rapid recovery of mitochondrial redox state in spite of the fact that it produced no amelioration of hepatic hemodynamics and morphological alterations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1480816&dopt=Abstract allopurinol Zyloprim