allopurinol and Sepsis

Flavopiridol, a cyclin-dependent kinase inhibitor, is cytotoxic to leukemic blasts. In a Phase II study, flavopiridol 50 mg/m(2) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 g/m(2)/72 h ara-C beginning day 6 and 40 mg/m(2) mitoxantrone on day 9 (FLAM) to 45 adults with newly diagnosed acute myelogenous leukemia (AML) with multiple poor-risk features. Thirty patients (67%) achieved complete remission (CR) and 4 (9%) died. Twelve (40%) received myeloablative allogeneic bone marrow transplant (BMT) in first CR. Median OS and DFS are not reached (67% alive 12.5-31 months, 58% in CR 11.4-30 months), with median follow-up 22 months. Sixteen received FLAM in CR, with median OS and DFS 9 and 13.1 months, and 36% alive at 21-31 months. Short OS and DFS correlated with adverse cytogenetics, regardless of age or treatment in CR. The addition of allogeneic BMT in CR translates into long OS and DFS in the majority of eligible patients.

Topics: Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Female; Flavonoids; Follow-Up Studies; Heart Diseases; Humans; Hyperkalemia; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Piperidines; Polyamines; Premedication; Remission Induction; Risk; Sepsis; Sevelamer; Transplantation, Homologous; Treatment Outcome; Tumor Lysis Syndrome; Young Adult

Xanthine oxidase (XO) utilizes molecular oxygen as a substrate to convert purine substrates into uric acid, superoxide, and hydrogen peroxide, which is one of the main enzyme pathways to produce reactive oxygen species (ROS) during septic inflammation and oxidative stress. However, it is not clear whether XO inhibition can improve sepsis-induced renal hypoxia in sepsis-induced acute kidney injury (SI-AKI) mice. In this study, pretreatment with febuxostat, an XO-specific inhibitor, or kidney knockdown of XO by shRNA in vivo significantly improved the prognosis of SI-AKI, not only by reducing the levels of blood urea nitrogen, serum creatinine, tumor necrosis factor-

Topics: Acute Kidney Injury; Animals; Febuxostat; Hypoxia; Inflammation; Ischemia; Kidney; Lipopolysaccharides; Mice; Oxygen; Reactive Oxygen Species; RNA, Small Interfering; Sepsis; Xanthine Oxidase

Topics: Acute Kidney Injury; Alanine Transaminase; Animals; Aspartate Aminotransferases; Cecum; Creatinine; Febuxostat; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Kidney; Ligation; Liver; Liver Diseases; Male; Protective Agents; Rats, Wistar; Sepsis; Urea; Xanthine Oxidase

BACKGROUND Pancytopenia is a hematological condition which is characterized by decreases in all three cellular elements: RBC, WBC, and platelets. As a result, patients with pancytopenia are more prone to anemia, infections, and excessive bleeding. Pancytopenia can be caused by medications or drug interactions that suppress the bone marrow. This case report highlights a drug interaction between allopurinol and mercaptopurine which led to pancytopenia and septic infection, resulting in the patient's death. This could easily have been avoided if a clinical pharmacist had been consulted. CASE REPORT A 55-year-old female patient with a past medical history of gout, depression, back pain, and type 2 diabetes was recently diagnosed with ulcerative colitis and was discharged with a new prescription of mercaptopurine. After 2 months of concurrent use of allopurinol and mercaptopurine, she developed infected foot ulcers, which progressed rabidly to sepsis. At the time, her laboratory findings confirmed pancytopenia. Despite treatment, the patient died. CONCLUSIONS This case illustrates the importance of consulting a clinical pharmacist in order to avoid such medical error. The dose of mercaptopurine should be reduced to 25% of the recommended dose when it is given concurrently with allopurinol to reduce the risk of pancytopenia. Health care providers should think about the significant role of clinical pharmacy services. In our case, there were no clinical pharmacist involved in the care of this patient, and as a result of such negligence, the patient lost her life.

Topics: Allopurinol; Colitis, Ulcerative; Diabetic Foot; Drug Interactions; Fatal Outcome; Female; Gout; Gout Suppressants; Humans; Immunosuppressive Agents; Mercaptopurine; Middle Aged; Pancytopenia; Pharmacists; Pharmacy Service, Hospital; Referral and Consultation; Sepsis

Experimental studies indicate that sepsis causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative damage, and inflammation on lung injury, following sepsis model by cecal ligation and puncture, and the effects of quercetin, antioxidant, and anti-inflammatory flavonoid, in the lung tissue were investigated. In the present study, we found that administration of single-dose quercetin before cecal ligation and puncture procedure, while markedly diminishing the levels of YKL-40 and oxidant molecules (xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA)), increases the antioxidant enzymes levels. Quercetin is beneficial to acute lung injury by decreasing the levels of oxidative stress markers and increasing the antioxidant enzyme activities. Quercetin also causes a decrease in the serum levels of YKL-40 and periostin in the oxidative lung injury induced by the experimental sepsis model.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Cecum; Cell Adhesion Molecules; Chitinase-3-Like Protein 1; Disease Models, Animal; Inflammation; Malondialdehyde; Nitric Oxide; Oxidative Stress; Quercetin; Rats; Rats, Wistar; Sepsis; Xanthine Oxidase

Topics: Aged; Allopurinol; Biopsy; Combined Modality Therapy; Fatal Outcome; Female; Glucocorticoids; Gout Suppressants; Herpesvirus 6, Human; Humans; Immunoglobulins, Intravenous; Methylprednisolone; Plasmapheresis; Pulse Therapy, Drug; Roseolovirus Infections; Sepsis; Skin; Stevens-Johnson Syndrome; Time Factors; Treatment Outcome; Virus Activation

To investigate the protection effects of electroacupuncture on injury of lipid peroxidation induced by liver ischemia in septic rats.. Forty-eight male SD rats were subjected to sepsis induced by cecal ligation and puncture (CLP), and were randomly divided into a Sham operation group (group A), a CLP model group (group B), a CLP model plus electroacupuncture at "Zusanli" (ST 36) group (group C), a CLP model plus electroacupuncture at the shame acupoint (group D), a vagotomy plus CLP model group (group E) and CLP model plus electroacupuncture group after vagotomy (group F), 8 rats in each group. CLP was performed in group E and group F after the abdominal vagotomy. Bilateral "Zusanli"(ST 36) points and the shame acupoint were electroacupunctured (2 mA, 2/100 Hz) for 1 hour in group C, group F and group D, respectively. The hepatic blood flow (HBF) was detected by a laser-Doppler flowmetry at 6 h after CLP. The plasma activity of alanine aminotransferase (ALT) was also determined and specimens of liver were harvested for evaluation of malondialdehyde (MDA), xanthine oxidase (XOD) and assessment of the rate of water content.. The blood flow of the liver was (56.97 +/- 11.95) U in group C which was significantly lower than (80.12 +/- 19.57) U in group A but higher than (42.61 +/- 10.97) U in group B, (44.53 +/- 9.23) U in group D, (30.05 +/- 4.46) U in group E and (30.46 +/- 6.38) U in group F (all P < 0.05) 6 h after CLP. Meanwhile, the levels of MDA, XOD, ALT and the rates of water content in liver in group C were all significantly higher than those in group A, but lower than those in the other four groups (all P < 0.05). The levels of MDA, XOD, ALT and the rates of water content in liver in group E and group F were all significantly higher than those in group D (all P < 0.05), while the blood flow of the liver lower than that in group D (P < 0.05), and with no significant differences in all above measurements between group E and group F (all P > 0. 05).. Electroacupuncture at "Zusanli" (ST 36) can promote hepatic blood flow, inhibit lipid peroxidation and alleviate hepatic edema and dysfunction in septic rats, which might be related with the completeness of cranial nerve.

Topics: Alanine Transaminase; Animals; Electroacupuncture; Lipid Peroxidation; Liver Circulation; Male; Rats; Rats, Sprague-Dawley; Sepsis; Xanthine Oxidase

Determine the relation of xanthine oxidase (XO) activity and the outcome of septic patients and its relation to oxidative damage and clinical parameters of sepsis severity.. Patients admitted over a 6-month period were enrolled. Patients were assigned to groups according to the diagnosis of sepsis (n=8), severe sepsis (n=28) or septic shock (n=36). Blood samples were collected to the determination of thiobarbituric acid reactive species (TBARS), protein carbonyls and XO activity.. None of the studied oxidative parameters determined at the time of diagnosis were related to sepsis severity. XO activity, but not oxidative damage parameters, at the time of sepsis diagnosis was significantly higher in non-survival septic patients. In contrast, 24 h after sepsis diagnosis, XO activity was lower in non-survivors septic patients.. XO activity was increased in non-survivors patients and the variations in XO activity could be used for outcome prediction.

Topics: APACHE; Demography; Female; Humans; Male; Middle Aged; Oxidative Stress; Protein Carbonylation; ROC Curve; Sepsis; Severity of Illness Index; Survival Analysis; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

The aim of this study was to elucidate a possible source of oxidant stress in experimental sepsis.. For this aim, 32 Sprague-Dawley type rats were used in the study. After all the animals underwent laparotomy, nonlethal cecum ligation and puncture (CLP) technique was used to create an experimental sepsis model in two groups (CLP-6 and CLP-48 groups). Rats in the other groups (Sham operated) were used as controls. Animals in the control-6 and CLP-6 groups were killed 6 hours after the beginning of the study whereas the other animals were killed 48 hours after the beginning. Part of the terminal ileum of each animal was removed to be used in the measurements of xanthine oxidase and superoxide dismutase enzyme activities.. Xanthine oxidase activity in the CLP-48 group was found to increase significantly as compared with that of the control-48 group, but superoxide dismutase activity did not change. No significant changes, however, were observed between analysis parameters in the terminal ileum tissues when obtained 6 hours after the beginning of sepsis.. Our results suggest that increased xanthine oxidase activity is one of the leading factors for the oxidant stress in the late phase of sepsis.

Topics: Animals; Intestinal Mucosa; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Xanthine Oxidase

Free radicals have been implicated in the etiology of cardiac dysfunction during sepsis, but the actual species responsible remains unclear. We studied the alterations in myocardial nitric oxide (NO), superoxide, and peroxynitrite generation along with cardiac mechanical function and efficiency in hearts from lipopolysaccharide (LPS)-treated rats. Six hours after LPS (4 mg/kg ip) or saline (control) treatment, hearts were isolated and perfused for 1 h with recirculating Krebs-Henseleit buffer and paced at 300 beats/min. Cardiac work, O(2) consumption, and cardiac efficiency were markedly depressed in LPS hearts compared with controls. Plasma nitrate/nitrite level was elevated in LPS rats, and ventricular NO production was enhanced as measured by electron spin resonance spectroscopy, Ca(2+)-independent NO synthase (NOS) activity, and inducible NOS immunohistochemistry. Ventricular superoxide production was also enhanced in LPS-treated hearts as seen by lucigenin chemiluminescence and xanthine oxidase activity. Increased nitrotyrosine staining (immunohistochemistry) and higher lipid hydroperoxides levels were also detected in LPS-treated hearts, indicating oxygen radical-induced stress. Enhanced generation of both NO and superoxide, and thus peroxynitrite, occur in dysfunctional hearts from endotoxemic rats.

Topics: Animals; Endotoxemia; Heart Diseases; Hydrogen Peroxide; Lipopolysaccharides; Male; Myocardial Contraction; Myocardium; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Oxygen Consumption; Peroxynitrous Acid; Rats; Rats, Sprague-Dawley; Sepsis; Superoxides; Tyrosine; Xanthine Oxidase

The effects of nitric oxide (NO) from calcium-independent NO synthase (iNOS) on microvascular protein leak in acute lung injury (ALI) are uncertain, possibly because of disparate effects of iNOS-derived NO from different cells. We assessed the contribution of iNOS from inflammatory versus parenchymal cells to pulmonary protein leak in murine cecal ligation and perforation-induced ALI. We studied iNOS+/+, iNOS-/-, and two reciprocally bone marrow-transplanted iNOS chimeric mice groups: + to - (iNOS+/+ donor bone marrow-transplanted into iNOS-/- recipient mice) and - to +. Sepsis-induced ALI was characterized by pulmonary leukocyte infiltration, increased pulmonary iNOS activity, and increased pulmonary microvascular protein leak, as assessed by Evans blue (EB) dye. Despite equal neutrophil infiltration, sepsis-induced EB-protein leak was eliminated in iNOS-/- mice and in - to + iNOS chimeras (parenchymal cell-localized iNOS) but was preserved in + to - chimeric mice (inflammatory cell-localized iNOS). EB-protein leak was also prevented by pretreatment with allopurinol and superoxide dismutase. Microvascular protein leak in sepsis-induced ALI is uniquely dependent on iNOS in inflammatory cells with no obvious contribution of iNOS in pulmonary parenchymal cells. Pulmonary protein leak is also dependent on superoxide, suggesting an effect of peroxynitrite rather than NO itself.

Topics: Allopurinol; Animals; Bone Marrow Transplantation; Capillary Leak Syndrome; Chimera; Coloring Agents; Disease Models, Animal; Evans Blue; Free Radical Scavengers; Lung; Male; Mice; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peritonitis; Pilot Projects; Polyethylene Glycols; Respiratory Distress Syndrome; Sepsis; Superoxide Dismutase

The effect of the antioxidant N-acetyl-L-cysteine was studied in a model of polymicrobial sepsis induced in CD-1 mice by cecal ligation and puncture. N-Acetyl-L-cysteine significantly improved survival during the 6 days following sepsis induction and caused lower liver toxicity. This effect was not related to free radicals generated by xanthine oxidase which was significantly induced in liver after cecal ligation and puncture. A specific inhibitor of xanthine oxidase, allopurinol, significantly reduced this enzyme and reduced the early survival rate. The effect of N-acetyl-L-cysteine was not related either to a reduction in tumor necrosis factor production or to a modulation of nitrites or to liver glutathione content. These results show that the induction of xanthine oxidase is not deleterious in this model of sepsis and suggest that N-acetyl-L-cysteine works as a direct antioxidant and scavenger of free radicals generated from other sources.

Topics: Acetylcysteine; Allopurinol; Animals; Cecum; Free Radical Scavengers; Free Radicals; Glutathione; Liver; Male; Mice; Mice, Inbred ICR; Nitric Oxide; Oxidative Stress; Sepsis; Tumor Necrosis Factor-alpha; Xanthine Oxidase

Topics: Animals; Dogs; Dopamine; Escherichia coli Infections; Fluid Therapy; Free Radicals; Hemodynamics; Ibuprofen; Lipid Peroxidation; Nitriles; Oxamic Acid; Sepsis; Shock, Septic; Superoxides; Tromethamine; Xanthine Oxidase

Topics: Allopurinol; Burkitt Lymphoma; Cyclophosphamide; Drug Resistance; Humans; Leukopenia; Retrospective Studies; Sepsis; Thrombocytopenia; Time Factors

Topics: Aged; Allopurinol; Aortic Diseases; Arteriosclerosis; Brain; Catheterization; Chlorothiazide; Diagnosis, Differential; Endocarditis, Bacterial; Female; Heart Failure; Humans; Hypertension; Iatrogenic Disease; Intracranial Aneurysm; Kanamycin; Kidney; Liver; Nephrosclerosis; Sepsis; Staphylococcal Infections; Thromboembolism; Uric Acid