allopurinol and Alcoholism

Hyperuricemia caused secondly from acquired disorders which affect production or excretion of uric acid is defined as secondary hyperuricemia. Many conditions are associated with this type of hyperuricemia and are classified into three types according to the underlying pathophysiology, including accelerated purine nucleotide degradation, ATP breakdown and purine de novo biosynthesis as overproductive type, use of drugs affecting renal urate handling and renal insufficiency as underexcretion type, or overintake of alcohol or fructose as mixed type. Determining uric acid clearance and urate excretion is important for pointing out original disorder; however, sometimes the result from correcting causal factor should be waited for to fix up a final diagnosis. Anti-hyperuricemia agents are used according to the pathophysiology.

Topics: Adenosine Triphosphate; Alcoholism; Allopurinol; Diuretics; Gout Suppressants; Humans; Hyperuricemia; Hypoxanthine Phosphoribosyltransferase; Purine Nucleotides; Renal Insufficiency; Uric Acid

The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis has been investigated in a series of studies using an ex vivo, perfused canine pancreas preparation. Three models of experimental acute pancreatitis have been developed in this preparation: ischemic pancreatitis, gallstone pancreatitis, and alcohol-induced pancreatitis. In each model, the pancreas becomes edematous, gains weight, and the perfusate develops hyperamylasemia during the 4 hour period of perfusion. Pretreatment with the free radical scavengers superoxide dismutase and catalase significantly ameliorates these manifestations of pancreatic injury in each of the three models. The source of the free radical generation was investigated by pretreating the preparation with allopurinol, a quite specific inhibitor of xanthine oxidase. In each of the three models, this also significantly ameliorated the injury process. These experiments demonstrate that oxygen-derived free radicals, generated by activated xanthine oxidase, appear to play a central role in the pathogenesis of acute pancreatitis in these models. These findings shed light on the fundamental pathophysiology of this disease and may provide the basis for more effective therapy in the future.

Topics: Acute Disease; Alcoholism; Allopurinol; Animals; Catalase; Disease Models, Animal; Free Radicals; Humans; Ischemia; Oxygen; Pancreas; Pancreatitis; Superoxide Dismutase; Xanthine Oxidase

Topics: Adult; Alcoholism; Cholesterol, Dietary; Chylomicrons; Diet, Reducing; Dietary Fats; Female; Gout; Humans; Hyperlipidemias; Purine-Pyrimidine Metabolism, Inborn Errors; Triglycerides; Uricosuric Agents; Xanthine Oxidase

Topics: Alcoholism; Australia; Bloodletting; Gastric Juice; Hemochromatosis; Humans; Intestinal Absorption; Intestinal Mucosa; Iron; Liver Cirrhosis; Metabolic Diseases; Prognosis; Xanthine Oxidase

Topics: Acetaldehyde; Alcohol Oxidoreductases; Alcoholism; Animals; Disulfiram; Drug Tolerance; Humans; Oxygen Consumption; Rabbits; Rats; Succinate Dehydrogenase; Xanthine Oxidase

Topics: Administration, Oral; Alcoholism; Aldehyde Oxidase; Animals; Azetidines; Biotransformation; Cytosol; Febuxostat; Female; Ghrelin; Hepatocytes; Humans; Liver; Mice; Microsomes, Liver; Molybdenum; Raloxifene Hydrochloride; Receptors, Ghrelin; Spiro Compounds; Xanthine Oxidase

This randomized double-blind trial examined the influence of the radical scavengers allopurinol (50 mg per rectum, four times per day) and dimethyl sulfoxide (500 mg per rectum, four times per day) on pancreatic pain treated with intramuscular pethidine hydrochloride (100 mg followed by 50 mg every 4 hours until complete pain relief) in patients given nothing orally and intravenously hydrated. Addition of allopurinol or dimethyl sulfoxide to the analgesic regimen significantly enhanced its efficacy, enabling at least 57% (13 patients receiving allopurinol and 12 patients receiving dimethyl sulfoxide) of 43 patients to be free of pain within 12 hours after admission compared with only four (17%) of 23 controls achieving the same effect. This advantage extended to all patients within 24 hours after admission, leaving 11 controls (48%) still in pain. Consequently, all patients given allopurinol or dimethyl sulfoxide were discharged 3 days after admission, a result realized in only five (22%) of the assessable controls who were discharged after 5 days of hospitalization. The results suggest that oxygen-derived free radicals are implicated in the mechanism of abdominal pain caused by alcohol-induced chronic pancreatitis and that removing them results in a beneficial therapeutic effect.

Topics: Abdominal Pain; Adult; Aged; Alcoholism; Allopurinol; Chronic Disease; Dimethyl Sulfoxide; Double-Blind Method; Drug Combinations; Female; Free Radicals; Humans; Male; Meperidine; Metoclopramide; Middle Aged; Oxygen; Pancreatitis; Prospective Studies; Recurrence; Time Factors

This study aimed to evaluate the protein and lipid redox status in plasma erythrocytes and erythrocyte ghosts of alcoholics and of patients with non-alcoholic liver disease; we also investigated the relation to glutathione levels and the role of acetaldehyde and xanthine oxidase activity in plasma.. Carbonyl and sulfhydryl proteins, glutathione and malondialdehyde levels and the activity of the circulating xanthine oxidase were determined in: active and abstinent alcoholics, patients with chronic viral hepatitis and healthy controls.. Active alcoholics showed a decrease of sulfhydryl protein and glutathione concentrations in plasma, erythrocytes and ghosts compared to the other groups. Also, an increase of the carbonyl protein and malondialdehyde levels and of the activity of circulating xanthine oxidase (9.2 +/- 1.8 nmol.min.ml, p < 0.001) were observed. Significant correlations between carbonyl protein and malondialdehyde concentrations in plasma (r = 0.775, p < 0.001), as well as between daily alcohol intake and carbonyl protein content in plasma (r = 0.879, p < 0.001) and erythrocytes (r = 0.605, p < 0.01) were observed. However, carbonyl protein levels did not correlate with the degree of liver injury. Incubation of plasma with acetaldehyde, but not with ethanol, significantly increased the carbonyl protein formation. Administration of N-Ethylmaleimide, a thiol depletor, or glutathione significantly increased or delayed, respectively, the carbonyl protein formation.. Proteins are oxidatively modified in plasma and erythrocytes of active alcoholics, whereas no such alterations are detectable in patients with non-alcoholic liver disease. Protein oxidation in alcoholics does not seem to result directly from ethanol; circulating xanthine oxidase, delivered from injured cells, may play a contributory role and glutathione appears to be directly involved in the protection of plasma proteins against acetaldehyde toxicity.

Topics: Acetaldehyde; Adult; Alcoholism; Blood Proteins; Erythrocytes; Glutathione; Humans; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Xanthine Oxidase

With the ex vivo perfused canine pancreas preparation, the infusion of acetaldehyde, the primary metabolite of ethanol oxidation, plus a short period of ischemia to convert xanthine dehydrogenase to xanthine oxidase, results in the physiologic injury response of acute pancreatitis (edema, weight gain, hyperamylasemia). The free radical scavengers superoxide dismutase and catalase and a xanthine oxidase inhibitor, allopurinol, ameliorate this injury response, suggesting that toxic oxygen metabolites generated by xanthine oxidase play an intermediary role.. The isolated ex vivo canine pancreas preparation was perfused for 4 hours, and weight gain of the preparation and amylase activity in the perfusate were monitored. Changes in pancreatic acinar cell architecture were characterized by light and electron microscopy, and intracellular phosphate metabolism was followed by magnetic resonance spectroscopy in control preparations and in glands simulating alcoholic pancreatitis.. Control preparations and preparations with a 1-hour period of ischemia before perfusion gained little weight (7 +/- 3 gm and 8 +/- 1 gm), amylase activity in the perfusate remained normal (933 +/- 513 units/dl and 1537 +/- 553 units/dl), and no changes in architecture were observed. Weight gain (5 +/- 6 gm) and amylase activity (1188 +/- 173 units/dl) were also normal in the preparations receiving acetaldehyde without preceding ischemia, but mild vascular and islet cell injury were observed on electron microscopy. One hour of ischemia followed by acetaldehyde infusion resulted in edema, increased weight gain (21 +/- 12 gm [p < 0.05]), and amylase activity (2487 +/- 1484 units/dl [p < 0.05]). Microscopy showed mild acinar cell damage and greater injury to the capillaries and the islets. The capillary and islet cell changes were reduced by superoxide dismutase and catalase. Intracellular adenosine triphosphate levels remained at baseline levels in the control preparations. Adenosine triphosphate decreased during ischemia but quickly recovered during perfusion without a significant difference whether acetaldehyde was infused after ischemia. An iron chelator desferoxamine ameliorated the injury response in the preparations simulating acute pancreatitis (weight gain, 13 +/- 6 gm [p = 0.09] and amylase activity, 1198 +/- 471 units/dl [p = 0.08]), but a cholecystokinin receptor antagonist L364,718 did not have an effect. A sulfhydryl group protector, dithiothreitol, decreased weight gain (10 +/- 7 gm [p = 0.06]), and amylase activity was not significantly increased over that of the control group (1582 +/- 641 units/dl), but a serine protease inhibitor phenylmethylsulphonylfluoride was ineffective.. In this model simulating acute alcoholic pancreatitis, both the early physiologic injury response and the early morphologic changes are mediated at least in part by free radicals, which are generated by xanthine oxidase converted reversibly from xanthine dehydrogenase. In addition to the superoxide radical, the hydroxyl radical may also be an important early intermediate step, but the cholecystokinin receptor is not.

Topics: Acetaldehyde; Acute Disease; Alcoholism; Animals; Disease Models, Animal; Dogs; Free Radicals; Ischemia; Pancreas; Pancreatitis; Receptors, Cholecystokinin; Xanthine Oxidase

Acetaldehyde (AA), the first product of ethanol metabolism, has been suggested as an important mediator in alcoholic pancreatitis, but experimental evidence has not been convincing. Prior work using the isolated perfused canine pancreas preparation has suggested that toxic oxygen metabolites generated by xanthine oxidase (XO) may mediate the early injury in pancreatitis. Xanthine oxidase is capable of oxidizing AA, and during this oxidation free radicals are released. The hypothesis that acute alcoholic pancreatitis may be initiated by AA in the presence of active XO (converted from xanthine dehydrogenase [XD]) was tested in the authors' experimental preparation by converting XD to XO by a period of ischemia, and infusing AA. Control preparations remained normal throughout the 4-hour perfusion (weight gain, 7 +/- 4 g; amylase activity, 1162 +/- 202 U/dL). One hour of ischemia or infusion of AA at 25 mg/hr or at 50 mg/hr without ischemia did not induce changes in the preparation. Acetaldehyde at 250 mg/hr induced minimal edema and weight gain (16 +/- 4 g; p less than 0.05), but not significant hyperamylasemia. Changes also were not observed when 1-hour ischemia was followed by a bolus of ethanol (1.5 g) or sodium acetate (3.0 g), or by infusion of 25 mg/hr of AA. One hour of ischemia followed by infusion of AA at 50 mg/hr or at 250 mg/hr induced edema, hemorrhage, weight gain (22 +/- 7 g [p less than 0.05] and 26 +/- 17 g [p less than 0.05]) and hyperamylasemia (2249 +/- 1034 U/dL [p less than 0.05] and 2602 +/- 1412 U/dL [p less than 0.05]). Moreover infusion of AA at 250 mg/hr after 2 hours of ischemia potentiated the weight gain (62 +/- 20 g versus 30 +/- 14 g [p less than 0.05]), but not the hyperamylasemia (3404 +/- 589 U/dL versus 2862 +/- 1525 U/dL) as compared with 2 hours of ischemia alone. Pancreatitis induced by 1 hour of ischemia followed by AA at 50 mg/hr could be inhibited by pretreatment with the free radical scavengers superoxide dismutase and catalase and ameliorated with the XO inhibitor allopurinol. The authors conclude that AA, in the presence of active XO, can initiate acute pancreatitis in the isolated canine pancreas preparation and may be important in the initiation of acute alcoholic pancreatitis in man. Toxic oxygen metabolites appear to play an important intermediary role.

Topics: Acetaldehyde; Acute Disease; Alcoholism; Amylases; Animals; Dogs; Free Radicals; In Vitro Techniques; Organ Size; Oxidation-Reduction; Oxygen; Pancreas; Pancreatitis; Perfusion; Xanthine Oxidase

An oxidative stress has been reported to occur at the hepatic level after ethanol administration. We recently reported that such a stress is also apparent at the cerebellar level during acute ethanol intoxication in rats. Since low molecular weight iron chelates (LMW-Fe) are involved in the biosynthesis of aggressive prooxidant species we presently studied the influence of acute and chronic ethanol administration on hepatic and cerebellar total non-heme iron and LMW-Fe. The results show that an acute ethanol load (50 mmoles/kg b. wt.) administered (i.p.) to male Sprague-Dawley rats elicits altogether a decrease in the non-heme iron content of the serum and a highly significant increase in the hepatic and cerebellar non-heme iron concentration. The LMW-Fe content as well as the percentage of total non-heme iron represented by LMW-Fe are increased at the same time in the cytosolic fraction isolated from hepatic and cerebellar homogenates of the acutely ethanol-treated rats. The ethanol-induced disturbances in the non-heme iron content of liver and cerebellum can be prevented by the administration of allopurinol, which is known to reduce the severity of the oxidative stress observed in these tissues after an acute ethanol load. To study the effects of chronic ethanol administration, rats were given during 4 weeks a 10% (v/v) solution of ethanol in water as sole drinking fluid. The average daily ethanol consumption was 7-9 g. In such alcohol-fed rats the non-heme iron content was decreased by 31% in the serum whereas it was increased by 18% in the liver and by 30% in the cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alcoholism; Allopurinol; Animals; Cerebellum; Iron; Iron Chelating Agents; Liver; Male; Oxidation-Reduction; Rats; Rats, Inbred Strains

The status of xanthine oxidase in ethanol-induced liver injury has been investigated in the rat, by acute and chronic ethanol treatments. A 38% increase of the enzyme O-form was observed after repeated ethanol administration. Chronic intoxication caused a significant decrease of total xanthine oxidase activity after both prolonged ethanol feeding and life span ethanol ingestion. The intermediate D/O-form of xanthine oxidase (that can act either as an oxidase or as a dehydrogenase, being able to react with O2 as well as with NAD+ as electron acceptor) increased 5.5-fold after prolonged ethanol feeding.

Topics: Alcoholic Intoxication; Alcoholism; Animals; Female; Liver; Male; Rats; Rats, Inbred Strains; Xanthine Oxidase

The hypothesis is presented that lipid peroxidation is responsible for the damage in skeletal and cardiac muscle of chronic alcoholic subjects. The enhanced lipid peroxidation is caused by the accumulation of oxygen radicals. Both excessive production and decreased disposal of oxygen radicals can arise from the acetaldehyde formed in the oxidation of ethanol. Although acetaldehyde from hepatic sources may contribute, muscle itself can generate significant amounts of acetaldehyde through the action of muscle catalase. The effects of alcohol on other tissues, and its known long-term effects on membranes lend support to this hypothesis. The ultrastructural features of the alcoholic myopathies provide further support. The resemblance between vitamin E-deficiency myopathy and the alcoholic myopathies is strong additional evidence in favor of this hypothesis.

Topics: Acetaldehyde; Alcohol Oxidoreductases; Alcoholism; Animals; Cardiomyopathy, Alcoholic; Catalase; Ethanol; Free Radicals; Glutathione Peroxidase; Humans; Lipid Peroxides; Liver; Liver Diseases, Alcoholic; Muscles; Muscular Diseases; Oxygen; Superoxide Dismutase; Xanthine Oxidase

Examination of hearts and livers of rats fed ethanol for 25-30 weeks showed significant increases in catalase and glutathione peroxidase activity. Further examination revealed that the xanthine dehydrogenase/oxidase activity ratio in both tissues were decreased, suggesting that an interconversion of the dehydrogenase into oxidase might have occurred. Such an interconversion would be expected to enhance the formation of superoxide anions during acetaldehyde metabolism by xanthine oxidase. Since a role of oxidative or free radical damage in the etiology of ethanol-induced liver pathology is becoming increasingly apparent, the observation that the biochemical changes in the heart and liver are comparable suggests that oxidative damage is involved in alcoholic pathology of the heart as well as liver.

Topics: Alcoholism; Animals; Catalase; Free Radicals; Glutathione Peroxidase; Humans; Liver; Male; Myocardium; Rats; Rats, Inbred Strains; Xanthine Oxidase

Topics: Aged; Alcoholism; Allopurinol; Arrhythmias, Cardiac; Chloral Hydrate; Colchicine; Digoxin; Drug Synergism; Gastrointestinal Hemorrhage; Gout; Hospitals, Teaching; Humans; Liver Diseases; Male; Middle Aged; Nitroglycerin; Patient Care Team; Pharmacists; Pharmacy Service, Hospital; Quinidine; Warfarin; Washington

Topics: Alcoholism; Animals; Humans; Liver; Rats; Xanthine Oxidase

Topics: Acute Kidney Injury; Alcoholism; Allopurinol; Chemical and Drug Induced Liver Injury; Granuloma; Humans; Liver; Liver Function Tests; Male; Middle Aged

Topics: Aged; Alcoholism; Allopurinol; Ammonia; Humans; Liver Diseases; Male; Middle Aged

Topics: Alcoholism; Anemia, Hypochromic; Bicarbonates; Diagnosis, Differential; Enzyme Therapy; Gout; Humans; Indomethacin; Lead Poisoning; Male; Middle Aged; Xanthine Oxidase