Allopurinol
Allopurinol prevents early alcohol-induced liver injury in rats.

Kono H, Rusyn I, Bradford BU, Connor HD, Mason RP, Thurman RG.

Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Free radical formation caused by chronic ethanol administration could activate transcription factors such as nuclear factor-kappaB (NF-kappaB), which regulates production of inflammatory cytokines. Xanthine oxidase is one potential source of reactive oxygen species. Therefore, the purpose of this study is to determine whether allopurinol, a xanthine oxidase inhibitor and scavenger of free radicals, would affect free radical formation, NF-kappaB activation, and early alcohol-induced liver injury in rats. Male Wistar rats were fed a high-fat diet with or without ethanol (10-16 g/kg/day) continuously for up to 4 weeks with the Tsukamoto-French enteral protocol. Either allopurinol or saline vehicle was administered daily. Allopurinol had no effect on body weight or the cyclic pattern of ethanol in urine. Mean urine ethanol concentrations were 271 +/- 38 and 252 +/- 33 mg/dl in ethanol- and ethanol + allopurinol-treated rats, respectively. In the control group, serum aspartate aminotransferase and alanine aminotransferase levels were approximately 40 I.U./l and 25 U/l, respectively. Administration of enteral ethanol for 4 weeks increased serum transaminases approximately 5-fold. Allopurinol blunted these increases significantly by approximately 50%. Ethanol treatment also caused severe fatty infiltration, mild inflammation, and necrosis. These pathological changes also were blunted significantly by allopurinol. Furthermore, enteral ethanol caused free radical adduct formation, values that were reduced by approximately 40% by allopurinol. NF-kappaB binding was minimal in the control group but was increased significantly nearly 2.5-fold by ethanol. This increase was blunted to similar values as control by allopurinol. These results indicate that allopurinol prevents early alcohol-induced liver injury, most likely by preventing oxidant-dependent activation of NF-kappaB.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10734182&dopt=Abstract allopurinol Zyloprim



Allopurinol
Nephrotoxic effects of allopurinol in dinitrofluorobenzene-sensitized mice: comparative studies on TEI-6720.

Horiuchi H, Ota M, Kaneko H, Kasahara Y, Ohta T, Komoriya K.

Pharmacological Research Department, Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan. h.horiuchi teijin.co.jp

Allopurinol is widely used and generally well-tolerated. However, when used in patients with renal insufficiency it may have life-threatening toxic effects known as allopurinol hypersensitivity syndrome (AHS). We previously found that allopurinol increased ear swelling and mortality in a DNFB-induced contact hypersensitivity mouse model. In the present study, we investigated the toxic effect of allopurinol on DNFB-sensitized mice in order to clarify the mechanism responsible for the lethal effect of allopurinol. Allopurinol increased plasma GPT and GOT in DNFB-sensitized mice and markedly increased plasma creatinine and BUN. The increase in plasma GPT and GOT was moderate and declined time-dependently. In contrast, the increase in plasma creatinine and BUN was striking and continued until 18 hr after administration of allopurinol at 100 mg/kg/day. Although allopurinol increased GOT and GPT in DNFB-sensitized mice, no effect was observed in non-sensitized mice even at 100 mg/kg/day, indicating that allopurinol essentially has no toxic effect on the liver. A high dose of allopurinol induced renal impairment even in non-sensitized mice. These observations indicate that there is some biological interaction between allopurinol and DNFB, and suggest that allopurinol may modulate or enhance the inflammatory reactions induced by DNFB, and/or that DNFB may cause metabolic changes via inflammation, leading to the enhanced toxicity of allopurinol. In contrast, TEI-6720, a newly synthesized XOD/XDH inhibitor, had almost no effect on DNFB-sensitized mice. TEI-6720 at 1 mg/kg, in terms of hypouricemic effect, appeared to be more potent than allopurinol at 3 mg/kg. Therefore, the nephrotoxic effect of allopurinol observed in the present study may not be related to XOD/XDH inhibitory activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10741380&dopt=Abstract allopurinol Zyloprim



Allopurinol
A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats.

Horiuchi H, Ota M, Kobayashi M, Kaneko H, Kasahara Y, Nishimura S, Kondo S, Komoriya K.

Pharmaceuticals Development Research Laboratories, Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan. h.horiuchi teijin.co.jp

In this study, the hypouricemic efficacy of a novel xanthine oxidase/xanthine dehydrogenase inhibitor, TEI-6720, was compared with that of allopurinol in a hyperuricemic rat model established by feeding the animals oxonate, a uricase inhibitor. In addition, using normal rats, the changes in xanthine concentration in plasma and the concentrations and absolute quantities of uric acid, allantoin and xanthine in urine were analyzed during a 28-day period of repeated administration of TEI-6720 to determine the changes occurring during this period and the conditions required for the formation of xanthine crystals and calculi in comparison with allopurinol. TEI-6720 and allopurinol caused a significant dose-dependent decrease in plasma uric acid levels in the hyperuricemic rat model and the ED50 of TEI-6720 was lower than that of allopurinol, indicating that in terms of hypouricemic efficacy TEI-6720 is more potent than allopurinol. TEI-6720 also showed more potent activity than allopurinol in decreasing urinary uric acid and allantoin levels in normal rats. In addition, TEI-6720 and allopurinol showed similar dose-response curves for the decrease in uric acid or allantoin concentration, and the associated increase in xanthine concentration, indicating that TEI-6720 and allopurinol have similar pharmacological characteristics although the dosage required differs. The efficacy of TEI-6720 in increasing plasma and urinary xanthine levels in normal rats was approximately 10- to 30-fold greater than that of allopurinol. However, with respect to renal xanthine calculus formation, there was only about a 3-fold difference in dosage comparing TEI-6720 and allopurinol. This difference suggests that there may be another factor independent of xanthine, and dependent on the drug itself, involved in renal calculus formation caused by allopurinol. The daily excretion of purine metabolites per body weight was about 20-fold higher in rats than in humans. From these results, it is concluded that TEI-6720 has potent hypouricemic activity and that, compared to allopurinol, administration of TEI-6720 is not likely to result in a higher incidence of calculus formation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10741381&dopt=Abstract allopurinol Zyloprim



Allopurinol
The role of allopurinol and deferoxamine in preventing pressure ulcers in pigs.

Sundin BM, Hussein MA, Glasofer S, El-Falaky MH, Abdel-Aleem SM, Sachse RE, Klitzman B.

Department of Cell Biology, Duke University Medical Center, Durham, NC 27710-3906, USA.

Ischemia and reperfusion may be important in the pathogenesis of pressure ulcers. On the basis of this hypothesis, the effects of intermittent pressure and the anti-free radical agents allopurinol and deferoxamine were studied in a pig model in which a pressure of 150 mmHg was applied intermittently to the scapulae. Cutaneous blood flow, transcutaneous oxygen tension, skin and muscle damage, and muscle levels of adenosine triphosphate were quantified. A control group of pigs (n = 6) was untreated, the allopurinol group (n = 6) received oral allopurinol beginning 2 days before the experiment, and the deferoxamine group (n = 6) received an intramuscular injection of deferoxamine 2 hours before the experiment. Pressure (150 mmHg) was applied to the scapulae for 210 minutes, and it was relieved for 30 minutes. This 4-hour cycle was repeated continuously for 48 hours, and it resulted in pressure injuries in all animals. Allopurinol and deferoxamine improved cutaneous blood flow and tissue oxygenation, but only deferoxamine could significantly reduce cutaneous and skeletal muscle necrosis (p < 0.001). This study suggests a future role for anti-free radical agents in the reduction of pressure-induced injury.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10744232&dopt=Abstract allopurinol Zyloprim



Allopurinol
Inhibition of xanthine oxidase does not influence immunosuppression after hemorrhagic shock.

Pinault GC, Sanson AJ, Malangoni MA.

Department of Surgery, Case Western Reserve University School of Medicine, MetroHealth Medical Center, Cleveland, Ohio 44109-1998, USA.

BACKGROUND: Resuscitated hemorrhagic shock causes global ischemia reperfusion with generation of toxic oxygen metabolites. We hypothesized that the immunosuppression that follows hemorrhagic shock may be linked to this process. METHODS: Forty-five male Sprague-Dawley rats (weight, 250-300 g) were bled to a mean arterial pressure of 30 mm Hg for 60 minutes, then were resuscitated with three times the maximum blood loss of lactated Ringer's solution. Immune response was assessed by splenocyte proliferation and interleukin-2 (IL-2) production 72 hours after hemorrhage. Allopurinol (50 mg/kg) was given after hemorrhage and immediately before resuscitation. RESULTS: Hemorrhagic shock caused significant decreases in splenocyte proliferation (cpm: (157,880 +/- 22,068 (mean +/- SD) vs. 37,787 +/- 15,849) and IL-2 production (1/2 max U/ml: 79.6 +/- 7.9 vs. 48.0 +/- 7.7) (both p < 0.05). Hepatic xanthine oxidase was significantly increased with hemorrhage and resuscitation. Hepatic xanthine oxidase activity after hemorrhage and resuscitation was significantly decreased after treatment with allopurinol (74.2 +/- 41.7 vs. 9.2 +/- 9.40). Allopurinol did not affect splenocyte proliferation (cpm: 21,875 +/- 9,316) or IL-2 production (1/2 max U/ml: 45.0 +/- 7.1). CONCLUSIONS: These results demonstrate that inhibition of xanthine oxidase by allopurinol after hemorrhagic shock did not affect splenocyte proliferation or IL-2 production. We conclude that the immunosuppression after hemorrhagic shock is not dependent on xanthine oxidase-induced production of toxic oxygen metabolites.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9420104&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol blocks shock-wave-induced rises in cytosolic calcium levels in MDCK cells.

Jan CR, Chen WC, Lee YH, Huang JK, Ou HC, Tseng CJ.

Department of Medical Education and Research, Veterans General Hospital-Kaohsiung, Taiwan, Republic of China. crjan isca.vghks.gov.tw

Allopurinol has been reported to ameliorate the side effects in patients following shock wave lithotripsy (SWL); however, the mechanism has not been studied. We have examined the protective effect of allopurinol on Madin-Darby canine kidney (MDCK) cells after shock wave exposure (SWE) by determining the release of aspartate aminotransferase (ASAT) and lactate dehydrogenase (LD), and the resting cytosolic Ca2+ concentration ([Ca2+]i). In SWE-treated cells, the release of ASAT and LD increased immediately, but largely transiently, by approximately 23% and 5-fold over control, respectively. Within 1-6 h after SWE there was a gradual rise in the resting [Ca2+]i of 16-137% above control. Allopurinol did not affect the transient enzyme release but blocked the long-term rises in the resting [Ca2+]i. The transient changes in [Ca2+]i evoked by two hormones, ATP and bradykinin, and a drug that releases Ca2+ from internal Ca2+ stores, thapsigargin, were only slightly affected in allopurinol-treated cells. We conclude that the protection conferred by allopurinol on patients treated with SWL might involve a direct protection of the kidney cells by maintaining a normal resting [Ca2+]i.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9443653&dopt=Abstract allopurinol Zyloprim