allopurinol and Hemorrhage

The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug-drug interactions (DDIs) in older adults.. All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate.. Amongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%).. DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly.

Topics: Acenocoumarol; Age Factors; Aged; Allopurinol; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hematologic Agents; Hemorrhage; Humans; International Normalized Ratio; Italy; Male; Prevalence; Proton Pump Inhibitors; Warfarin

This study investigated the role of a novel nutrient-rich preservation solution in alleviating intestinal ischemia-reperfusion (IR) injury in a large animal model.. Porcine intestines were treated in vivo with the following intraluminal flush solutions: group 1, none; group 2, University of Wisconsin solution; group 3, an amino acid-based solution, previously shown to be effective in reducing IR injury in rodent models. Intestinal ischemia was induced in vivo for 60 min, followed by 180 min reperfusion. Key metabolic aspects were assessed in relation to two fundamental kinase mechanisms that govern cell fate, AMP kinase, and Jun kinase.. After 180 min reperfusion, groups 1 and 2 exhibited clefting, denudation, and mucosal hemorrhage, whereas injury was markedly reduced in group 3 (median grades 4.5 and 5 vs. 0; P<0.05). In contrast to groups 1 and 2, group 3 tissues exhibited a full recovery of adenylates (ATP, total adenylates) and an effective control of oxidative stress throughout reperfusion. Neutrophil-mediated inflammation was abrogated in group 3. An up-regulation of two key enzymes (glutaminase and alanine aminotransferase) provided a mechanism for the superior recovery of energetics and the preservation of mucosal integrity in group 3. A strong activation of AMP-activated protein kinase resulting in the up-regulation of a primary proapoptotic kinase mechanism, Jun kinase, was evident in groups 1 and 2.. A strategy of intraluminal administration of a nutrient-rich solution represents a potential therapy for alleviating intestinal IR injury; these findings suggest a more effective method for the ischemic storage of intestine.

Topics: Adenosine; Adenylate Kinase; Alanine Transaminase; Allopurinol; Animals; Glutaminase; Glutathione; Hemorrhage; Insulin; Intestinal Mucosa; Intestine, Small; Organ Preservation; Organ Preservation Solutions; Raffinose; Reperfusion Injury; Swine

Extensive and severe hepatic centrilobular hemorrhagic necrosis is a common finding in hepatic vein obstruction and Budd-Chiari syndrome. Some drugs, including allopurinol, can also cause this histopathologic appearance but to our knowledge in this setting the lesions are not so massive. Here we report a case of a 41-year-old female who developed fever, pruritic skin rash, jaundice, eosinophilia, abnormal liver function tests, and acute renal failure 3 weeks after the beginning of allopurinol treatment, complicated with severe hepatocyte necrosis around most terminal hepatic venules suggesting Budd-Chiari syndrome.

Topics: Acute Kidney Injury; Adult; Allopurinol; Antihypertensive Agents; Chemical and Drug Induced Liver Injury; Female; Hemorrhage; Humans; Hypertension; Liver Diseases; Necrosis

L-NAME (N(G)-nitro-(L)-arginine methyl ester), a nitric oxide synthase inhibitor, causes severe limb reduction malformations when gravid rats are treated intraperitoneally on gd-17. Hemorrhages, appearing within hours of L-NAME administration, and defects at term can be significantly reduced by co-treatment with PBN (alpha-phenyl-N-t-butylnitrone), a spin trap antioxidant. We have proposed that limb defects result from ischemia-reperfusion injury. We examine the role of xanthine oxidase and ROS formation in the limb effects of L-NAME.. Gravidas were treated with L-NAME (50 mg/kg) in the presence or absence of allopurinol, a xanthine oxidase inhibitor. Spatial patterns of limb hemorrhage were determined promptly and at term as was digit length at the latter interval. Xanthine oxidase activities were assayed in control and treated limbs with and without allopurinol co-treatment.. Allopurinol significantly reduced hemorrhage severity in a dose-responsive fashion when fetuses were examined at term. Higher doses of allopurinol significantly preserved digit length. Xanthine oxidase activities in fetal limb were significantly increased by L-NAME treatment whereas co-treatment with allopurinol restored activities to near-control levels.. These findings support the role of excess reactive oxygen species (ROS) formation in L-NAME-induced limb reduction. We propose that nitric oxide (NO) depletion by L-NAME interferes with vascular integrity, and causes vasoconstriction. Resultant hypoxia stimulates superoxide formation and nitric oxide formation catalyzed by the inducible isoform of nitric oxide synthase. The reduction products of superoxide or the products of its reaction with nitric oxide oxidize or nitrate endothelial components resulting in limb reduction defects.

Topics: Allopurinol; Animals; Free Radicals; Hemorrhage; Limb Deformities, Congenital; NG-Nitroarginine Methyl Ester; Nitric Acid; Rats; Rats, Sprague-Dawley; Teratogens; Xanthine Oxidase

Acute lung injury is frequently associated with sepsis or blood loss and is characterized by a proinflammatory response and infiltration of activated neutrophils into the lungs. Hemorrhage or endotoxemia result in activation of cAMP response element-binding protein (CREB) and NF-kappa B in lung neutrophils as well as increased expression of proinflammatory cytokines, such as TNF-alpha and macrophage-inflammatory peptide-2, by these cells. Activation of the extracellular regulated kinase (ERK) pathway occurs in stress responses and is involved in CREB activation. In the present experiments, hemorrhage or endotoxemia produced increased activation of mitogen-activated protein kinase kinase (MEK)1/2 and ERK2 (p42), but not of ERK1 (p44), in lung neutrophils. ERK1, ERK2, and MEK1/2 were not activated in peripheral blood neutrophils after hemorrhage or endotoxemia. Inhibition of xanthine oxidase led to further increase in the activation of MEK1/2 and ERK2 in lung neutrophils after hemorrhage, but not after endotoxemia. Alpha-adrenergic blockade before hemorrhage resulted in increased activation in lung neutrophils of MEK1/2, ERK1, ERK2, and CREB, but decreased activation of NF-kappa B. In contrast, alpha-adrenergic blockade before endotoxemia was associated with decreased activation of MEK1/2, ERK2, and CREB, but increased activation of NF-kappa B. Beta-adrenergic blockade before hemorrhage did not alter MEK1/2 or ERK1 activation in lung neutrophils, but decreased activation of ERK2 and CREB, while increasing activation of NF-kappa B. Beta-adrenergic inhibition before endotoxemia did not affect activation of MEK1/2, ERK1, ERK2, CREB, or NF-kappa B. These data indicate that the pathways leading to lung neutrophil activation after hemorrhage are different from those induced by endotoxemia.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animal Feed; Animals; Cyclic AMP Response Element-Binding Protein; Endotoxemia; Enzyme Activation; Hemorrhage; Injections, Intraperitoneal; Lung; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neutrophil Activation; NF-kappa B; Phentolamine; Propranolol; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Tungsten; Xanthine Oxidase

The transcriptional regulatory factor nuclear factor (NF)-kappaB has a central role in modulating expression of proinflammatory mediators that are important in acute lung injury. In vitro studies have shown that competition between NF-kappaB and cAMP response element binding protein (CREB) for binding to the coactivator CREB-binding protein (CBP) is important in regulating transcriptional activity of these factors. In the present study, we examined in vivo interactions between CBP, CREB, and NF-kappaB in hemorrhage- or endotoxemia-induced acute lung injury. Association of CBP with CREB or the p65 subunit of NF-kappaB increased in the lungs after hemorrhage or endotoxemia. Inhibition of xanthine oxidase before hemorrhage, but not before endotoxemia, decreased p65-CBP interactions while increasing those between CREB and CBP. These alterations in CREB-CBP and p65-CBP interactions were functionally significant because xanthine oxidase inhibition before hemorrhage resulted in increased expression of the CREB-dependent gene c-Fos and decreased expression of macrophage inflammatory protein-2, a NF-kappaB-dependent gene. The present results show that the coactivator CBP has an important role in modulating transcription in vivo under clinically relevant pathophysiological conditions.

Topics: Animals; Chemokine CXCL2; Chemokines; CREB-Binding Protein; Cyclic AMP Response Element-Binding Protein; Endotoxemia; Enzyme Inhibitors; Hemorrhage; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Nuclear Proteins; Proto-Oncogene Proteins c-fos; RNA, Messenger; Trans-Activators; Transcription Factor RelA; Transcription, Genetic; Xanthine Oxidase

Acute inflammatory lung injury occurs frequently in the setting of severe infection or blood loss. Accumulation of activated neutrophils in the lungs and increased pulmonary proinflammatory cytokine levels are major characteristics of acute lung injury. In the present experiments, we examined mechanisms leading to neutrophil accumulation and activation in the lungs after endotoxemia or hemorrhage. Levels of IL-1 beta, TNF-alpha, and macrophage inflammatory protein-2 mRNA were increased in lung neutrophils from endotoxemic or hemorrhaged mice compared with those present in lung neutrophils from control mice or in peripheral blood neutrophils from endotoxemic, hemorrhaged, or control mice. The transcriptional regulatory factors NF-kappa B and cAMP response element binding protein were activated in lung but not blood neutrophils after hemorrhage or endotoxemia. Xanthine oxidase inhibition, achieved by feeding allopurinol or tungsten-containing diets, did not affect neutrophil trafficking to the lungs after hemorrhage or endotoxemia. Xanthine oxidase inhibition did prevent hemorrhage- but not endotoxemia-induced increases in proinflammatory cytokine expression among lung neutrophils. Hemorrhage- or endotoxemia-associated activation of NF-kappa B in lung neutrophils was not affected by inhibition of xanthine oxidase. cAMP response element binding protein activation was increased after hemorrhage, but not endotoxemia, in mice fed xanthine oxidase-inhibiting diets. Our results indicate that xanthine oxidase modulates cAMP response element binding protein activation and proinflammatory cytokine expression in lung neutrophils after hemorrhage, but not endotoxemia. These findings suggest that the mechanisms leading to acute inflammatory lung injury after hemorrhage differ from those associated with endotoxemia.

Topics: Animals; Cell Movement; Chemokine CXCL2; Cyclic AMP Response Element-Binding Protein; Endotoxemia; Enzyme Activation; Hemorrhage; Interleukin-1; Lung; Male; Mice; Mice, Inbred BALB C; Monokines; Neutrophil Activation; Neutrophils; NF-kappa B; Peroxidase; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Xanthine Oxidase

The nuclear regulatory factor (NF)-kappa B is activated in the lungs of patients with acute respiratory distress syndrome (ARDS). In experimental models of acute lung injury, activation of NF-kappa B contributes to the increased expression of immunoregulatory cytokines and other proinflammatory mediators in the lungs. Because of the important role that NF-kappa B activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-kappa B counterregulatory mechanisms in lung mononuclear cells, using a murine model in which inflammatory lung injury develops after blood loss. Sustained activation of NF-kappa B was present in lung mononuclear cells over the 4-h period after blood loss. The activation of NF-kappa B after hemorrhage was accompanied by alterations in levels of the NF-kappa B regulatory proteins I kappa B alpha and Bcl-3. Cytoplasmic and nuclear I kappa B alpha were increased and nuclear Bcl-3 was decreased during the first hour after blood loss, but, by 4 h posthemorrhage, cytoplasmic and nuclear I kappa B alpha levels were decreased and nuclear levels of Bcl-3 were increased. Inhibition of xanthine oxidase activity in otherwise unmanipulated unhemorrhaged mice resulted in increased levels of I kappa B alpha and decreased amounts of Bcl-3 in nuclear extracts from lung mononuclear cells. No changes in the levels of nuclear I kappa B alpha or Bcl-3 occurred after hemorrhage when xanthine oxidase activity was inhibited. These results demonstrate that blood loss, at least partly through xanthine oxidase-dependent mechanisms, produces alterations in the levels of both I kappa B alpha and Bcl-3 in lung mononuclear cell populations. The effects of hemorrhage on proteins that regulate activation of NF-kappa B may contribute to the frequent development of inflammatory lung injury in this setting.

Topics: Allopurinol; Animals; B-Cell Lymphoma 3 Protein; Base Sequence; Cell Nucleus; Cells, Cultured; DNA-Binding Proteins; Genes, Immunoglobulin; Hemorrhage; Homeostasis; I-kappa B Proteins; Inflammation; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; NF-KappaB Inhibitor alpha; Proto-Oncogene Proteins; Transcription Factors

Hemorrhage rapidly increases plasma xanthine oxidase levels as well as the expression of proinflammatory and immunoregulatory cytokines in the lungs. To determine the role of circulating xanthine oxidase (XO), as well as other plasma factors, in affecting pulmonary cytokine expression, we conducted studies in which plasma from hemorrhaged mice was transferred into unhemorrhaged recipient mice. Administration of posthemorrhage plasma to recipient mice increased the levels of mRNA for interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta 1 (TGF-beta 1) in lung mononuclear cells. No enhancement of mRNA levels for these cytokines was found in the lungs of mice given allopurinol-treated posthemorrhage plasma or fed a tungsten-enriched, XO-depleting diet prior to transfer of posthemorrhage plasma. Among the nuclear transcriptional regulatory factors examined, only the cyclic AMP response-element binding protein (CREB) was activated in nuclear extracts from lung mononuclear cells of mice that were given posthemorrhage plasma. No activation of nuclear factor-kappa B (NF-kappa B), nuclear factor interleukin 6 (NF-IL6), activating protein-1 (AP-1), or serum protein-1 (SP-1) was found. These results suggest that the mechanism for hemorrhage-induced increases in pulmonary cytokine expression is by activation of the enhancer CREB through a tissue XO-dependent pathway initiated by plasma-borne mediators.

Topics: Allopurinol; Animals; Base Sequence; Blood Proteins; Cyclic AMP Response Element-Binding Protein; Cytokines; Gene Expression Regulation, Enzymologic; Hemorrhage; Leukocytes, Mononuclear; Lung; Male; Mice; Mice, Inbred BALB C; Molecular Sequence Data; RNA, Messenger; Transcription Factors; Tungsten; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Animals; Dogs; Fetal Tissue Transplantation; Glutathione; Hemorrhage; Hypertonic Solutions; Insulin; Kidney Transplantation; Liver Transplantation; Organ Preservation Solutions; Perfusion; Raffinose; Swine; Swine, Miniature; Transplantation, Heterologous

Hemorrhage rapidly increases the expression of proinflammatory and immunoregulatory cytokines in the lungs. Binding elements for the nuclear transcriptional regulatory factors (NF)-kappa B and NF-IL6 (C/EBP beta) are present in the promoter regions of multiple cytokine genes, including those whose expression is increased after blood loss. In the present experiments, we found increased activation in vivo of NF-kappa B in lung mononuclear cells, but not in splenocytes, taken from mice 1 h after hemorrhage. In contrast, hemorrhage did not activate NF-IL6 in lung cells or splenocytes. Inhibition of xanthine oxidase by prior feeding of a tungsten-enriched diet prevented hemorrhage-induced activation in lung cells of NF-kappa B. Incubating splenocytes in vitro with xanthine oxidase activated NF-kappa B but not NF-IL6. Xanthine oxidase-induced activation of NF-kappa B was inhibited by manganese superoxide dismutase, but not by catalase. These results suggest that xanthine oxidase-mediated superoxide anion-dependent activation of NF-kappa B occurs in vivo and in vitro. This mechanism may contribute to increased lung cytokine responses after hemorrhage.

Topics: Animals; Base Sequence; Catalase; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins; Hemorrhage; Leucine Zippers; Lung; Male; Mice; Mice, Inbred BALB C; Molecular Sequence Data; NF-kappa B; Nuclear Proteins; Oligonucleotide Probes; Spleen; Superoxide Dismutase; Xanthine Oxidase

Treatment of rats with a single carcinogenic dose of CdCl2 (i.e., 30 mumol/kg) caused severe hemorrhagic damage in the testis within the first 12 h after the metal. Subsequently, atrophy with calcification developed in the next 2-3 mo. Atrophied tissues regenerated during the 1 yr after exposure. Twelve hours after exposure to the Cd treatment, lipid peroxidation levels, Fe content, and cellular production of H2O2 were remarkably elevated in testicular Leydig cells, the target cell population for Cd carcinogenesis. At the same time, glutathione peroxidase activity rose, glutathione reductase and catalase activities were reduced, and superoxide dismutase activity was unchanged. Xanthine oxidase activity in Leydig cells was also elevated at 6 and 9 h after the Cd treatment. Reduced glutathione in testes was decreased and oxidized glutathione was increased 12 h after exposure to the metal. These facts suggest that the carcinogenic doses of Cd induced oxidative stress while compromising cellular defense mechanisms against such stress. Therefore, active oxygen species such as H2O2 may have an important role in the initiation of carcinogenesis within the target cell population.

Topics: Animals; Atrophy; Cadmium; Cadmium Chloride; Calcium; Cells, Cultured; Chlorides; Glutathione; Hemorrhage; Hydrogen Peroxide; Iron; Leydig Cells; Lipid Peroxidation; Male; Oxidation-Reduction; Rats; Rats, Inbred Strains; Regeneration; Testicular Neoplasms; Testis; Xanthine Oxidase; Zinc

The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis was studied by evaluating the effects of catalase, allopurinol, and dimethylsulfoxide on diet-induced acute hemorrhagic pancreatic necrosis in mice. The mortality rate and degree of hyperamylasemia associated with this model of pancreatitis were reduced by catalase but a similar result followed the administration of heat-denatured catalase, suggesting that the apparent protective effect of catalase was not the result of reductions in free radical levels. Neither allopurinol nor dimethylsulfoxide reduced mortality or degree of hyperamylasemia. The increased pancreatic content of amylase and the necrosis that characterize this model of pancreatitis were not altered by any of the agents tested. In contrast, both allopurinol and dimethylsulfoxide reduced peripancreatic edema formation, suggesting that edema, but not the other features that characterize this model of pancreatitis, may result from generation of oxygen-derived free radicals.

Topics: Acute Disease; Allopurinol; Amylases; Animals; Catalase; Choline Deficiency; Diet; Dimethyl Sulfoxide; Edema; Ethionine; Female; Free Radicals; Hemorrhage; Mice; Necrosis; Oxygen; Pancreatitis

Older patients with type I glycogen storage disease (GSD) develop hepatic adenomas that may undergo malignant transformation. Despite their similarity to oral contraceptive-related hepatic tumors, only one previous report has even mentioned hemorrhage in GSD-related hepatic tumors. We recently followed a 20-year-old patient with type Ia GSD and a 10 cm focal defect in the left lobe of the liver; angiography suggested that this was a benign adenoma. At 22 years of age, after an acute symptomatic episode, repeat studies (ultrasonography and angiography) revealed a 2 cm increase in diameter of the hepatic mass. Imminent tumor rupture was of grave concern; thus the patient was admitted to the hospital and given 2 weeks of constant glucose administration by central venous line in the hope of improving her metabolic abnormalities. After resolution of the coagulopathy and metabolic disorders, the patient safely underwent surgical enucleation of the tumor. Pathologic examination of the tumor revealed that the patient had indeed hemorrhaged into a typical hepatic adenoma that had focuses of hepatocellular dysplasia. She has done well without evidence of tumor recurrence for 3 years since the operation. We conclude that hemorrhage and malignant transformation are potential complications of GSD-related hepatic adenomas. This conclusion underscores the importance of following these patients closely as they age. Nocturnal nasogastric feeding should be considered in the hope of preventing a tumor or inducing regression. Acute symptomatic attacks should be evaluated promptly for possible tumor hemorrhage.

Topics: Adenoma; Adolescent; Adult; Allopurinol; Child; Follow-Up Studies; Glucose; Glycogen Storage Disease Type I; Hemorrhage; Humans; Infant; Infusions, Parenteral; Liver Diseases; Liver Neoplasms; Time Factors

Acute renal failure may be a contributory cause of death in patients with acute leukemia. The purpose of this study was to define the causes and course of acute renal failure in group of patients with acute leukemia in order to identify preventive measures and reversible aspects of the renal insufficiency. Among 88 patients with acute leukemia whose courses were followed to the time of death, ten developed acute renal failure. Etiologic factors of the renal failure were uric acid nephropathy, sepsis with complicating hypotension and hypovolemia, and the administration of nephrotoxic antibiotics. In one patient ureteral obstruction from clots was responsible for renal failure, while in another patient disseminated aspergillosis led to renal failure. Other causes of acute renal failure in persons with acute leukemia, but not observed in this patient group, are hypercalcemia and leukemic infiltration of the kidneys.

Topics: Acute Disease; Acute Kidney Injury; Adult; Allopurinol; Female; Hemorrhage; Humans; Kidney Diseases; Kidney Tubular Necrosis, Acute; Leukemia; Male; Middle Aged; Uric Acid

Topics: Allopurinol; Blood Cell Count; Cell Movement; Colchicine; Diet; Drug Synergism; Gastrointestinal Diseases; Gout; Hemorrhage; Humans; Indomethacin; Leukocytes; Mercaptopurine; Phenylbutazone; Probenecid; Purines; Uric Acid

Topics: Aged; Allopurinol; Blood Cell Count; Dehydration; Erythrocytes; Fever; Hemoglobins; Hemorrhage; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphocytes; Male; Monocytes; Pharyngitis; Prednisone; Reticulocytes