allopurinol and Neutropenia

Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.

Topics: Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Allopurinol; Antimetabolites, Antineoplastic; Dose-Response Relationship, Immunologic; Drug Resistance, Neoplasm; Female; Humans; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Recurrence; Salvage Therapy; Thalidomide; Thrombocytopenia; Tumor Lysis Syndrome; Vidarabine

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL.

Topics: Adolescent; Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Chemical and Drug Induced Liver Injury; Child, Preschool; Drug Evaluation; Female; Guanine Nucleotides; Humans; Hyperbilirubinemia; Hypoxanthine Phosphoribosyltransferase; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methyltransferases; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides; Xanthine Oxidase

We hypothesized that neutralization of TNF-alpha at the time of reperfusion exerts a salubrious role on endothelial function and reduces the production of reactive oxygen species. We employed a mouse model of myocardial ischemia-reperfusion (I/R, 30 min/90 min) and administered TNF-alpha neutralizing antibodies at the time of reperfusion. I/R elevated TNF-alpha expression (mRNA and protein), whereas administration of anti-TNF-alpha before reperfusion attenuated TNF-alpha expression. We detected TNF-alpha expression in vascular smooth muscle cells, mast cells, and macrophages, but not in the endothelial cells. I/R induced endothelial dysfunction and superoxide production. Administration of anti-TNF-alpha at the onset of reperfusion partially restored nitric oxide-mediated coronary arteriolar dilation and reduced superoxide production. I/R increased the activity of NAD(P)H oxidase and of xanthine oxidase and enhanced the formation of nitrotyrosine residues in untreated mice compared with shams. Administration of anti-TNF-alpha before reperfusion blocked the increase in activity of these enzymes. Inhibition of xanthine oxidase (allopurinol) or NAD(P)H oxidase (apocynin) improved endothelium-dependent dilation and reduced superoxide production in isolated coronary arterioles following I/R. Interestingly, I/R enhanced superoxide generation and reduced endothelial function in neutropenic animals and in mice treated with a neutrophil NAD(P)H oxidase inhibitor, indicating that the effects of TNF-alpha are not through neutrophil activation. We conclude that myocardial ischemia initiates TNF-alpha expression, which induces vascular oxidative stress, independent of neutrophil activation, and leads to coronary endothelial dysfunction.

Topics: Animals; Antibodies; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Endothelium, Vascular; Female; Male; Mice; Microcirculation; Muscle, Smooth, Vascular; Myocardial Reperfusion Injury; NADPH Oxidases; Neutropenia; Nitric Oxide; Oxidative Stress; Peroxidase; Peroxynitrous Acid; Reactive Oxygen Species; RNA, Messenger; Superoxides; Tumor Necrosis Factor-alpha; Vasodilation; Xanthine Oxidase

Infection during the induction phase of childhood acute lymphoblastic leukemia (ALL) is a major cause of morbidity and mortality. Several studies have indicated that genetically determined low serum levels of mannose-binding lectin (MBL), a component of innate immunity, are associated with increased risk for infections in patients receiving chemotherapy. Thus, these patients have been proposed to be candidates for MBL replacement therapy.. In a population-based cohort of 137 children with ALL treated at a single pediatric hematology-oncology center with an almost identical chemotherapy regimen, we studied the relationship between polymorphisms in the MBL gene (MBL2) and the MBL2 promoter and the risk of infections during the first 50 d of induction therapy.. No increased frequency of infection was seen for the children with genotypes encoding serum low levels of MBL. A higher incidence of fever (P < 0.004), infectious events (P = 0.025), days with neutropenia (P < 0.001) and a higher frequency of antimicrobial therapy (P = 0.0007) were seen in the young age group (<2.5 yr) compared with the older age group (> or =2.5 yr), independent of the MBL genotype.. MBL deficiency did not influence the frequency of infections in children receiving induction chemotherapy for ALL, not even in the youngest children (<2.5 yr) whom we found to have the highest risk for infections.

Topics: Adolescent; Age Factors; Allopurinol; Anti-Infective Agents; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Candidiasis; Child; Child, Preschool; Cohort Studies; Disease Susceptibility; Doxorubicin; Female; Fever; Fungemia; Genotype; Humans; Immunity, Innate; Immunocompromised Host; Incidence; Infant; Infections; Male; Mannose-Binding Lectin; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Promoter Regions, Genetic; Remission Induction; Vincristine

The effects of 5-hydroxytryptamine (5-HT) on ethanol-induced gastric mucosal damage and on epithelial and vascular integrity were investigated. Male Sprague-Dawley rats were administered with 5-HT (5 or 10 mg/kg, IP) 30 min prior to the challenge with ethanol (40% v/v, 10 ml/kg, PO). 5-HT dose dependently aggravated ethanol-induced injury in the gastric mucosa. Both xanthine oxidase (XO) and myeloperoxidase (MPO) activities in the mucosa were significantly increased with the high dose of 5-HT, which also potentiated the elevation of these enzyme activities by ethanol. However, the mucosal superoxide dismutase activity was left unaltered. In neutropenic (antineutrophil serum-treated) animals, the ethanol-induced gastric mucosal injury was significantly ameliorated, with or without the pretreatment of 5-HT (10 mg/kg). In addition, the effect of 5-HT on the activity of MPO, but not of XO, was also attenuated in these animals. In the ex vivo gastric chamber study on pentobarbital-anesthetized animals, volume of gastric secretion was significantly decreased in the 5-HT-treated groups, with further reduction after ethanol incubation. Transmucosal potential difference (PD) was significantly reduced in 5-HT-treated rats, which also potentiated the ethanol-induced drop in PD. Nevertheless, 5-HT dose dependently increased mucosal vascular permeability and further enhanced during ethanol incubation. These findings suggest that 5-HT adversely affects the defense mechanisms of the gastric mucosa by reducing the secretory function of the mucosal cells and to weaken the epithelial and vascular integrity. Neutrophil activation appears to be responsible for the detrimental effects of 5-HT partly through the elevation in MPO activity. The increase in mucosal XO activity by 5-HT may induce free radical production and possibly modulate the ulcerogenic processes.

Topics: Animals; Capillary Permeability; Drug Synergism; Enzyme Activation; Ethanol; Gastric Lavage; Gastric Mucosa; Male; Membrane Potentials; Neutropenia; Neutrophil Activation; Peroxidase; Rats; Rats, Sprague-Dawley; Serotonin; Superoxide Dismutase; Xanthine Oxidase

Neutrophils contribute to ischemic brain injury in adult animals. The role of neutrophils in perinatal hypoxic-ischemic (HI) brain injury is unknown. Allopurinol reduces neutrophil accumulation after tissue ischemia and is protective against HI brain injury. This study was designed to investigate how neutrophils contribute to perinatal hypoxic ischemic brain injury and how neutropenia compared with allopurinol in its neuroprotective effects. A HI insult was produced in the right cerebral hemisphere of 7-d-old rats by right common carotid artery ligation and systemic hypoxia. Half the rats were rendered neutropenic with an anti-neutrophil serum (ANS). At 15 min of recovery from hypoxia, half the neutropenic and nonneutropenic rats received allopurinol (135 mg/kg, s.c.). The protective effect of the four treatment combinations was determined on brain swelling at 42 h of recovery. Neutropenia reduced brain swelling by about 70%, p < 0.01. Allopurinol alone produced similar protection so that the relatively small number of animals studied did not permit assessment of an additive effect. Neutrophil accumulation in cerebral hemispheres was measured by myeloperoxidase (MPO) activity assay and by neutrophil counts in 6-microm sections stained by MPO and ANS immunostaining. MPO activity peaked between 4 and 8 h of recovery in both hemispheres. Hemispheric neutrophil counts peaked at the end of the HI insult and again at 18 h of recovery. Neutrophils were stained within blood vessels and did not infiltrate the injured brain before infarction had occurred. We conclude that neutrophils contribute to HI brain injury in the neonate and that neutrophil depletion before the insult is neuroprotective.

Topics: Allopurinol; Animals; Animals, Newborn; Brain; Brain Injuries; Brain Ischemia; Chick Embryo; Enzyme Inhibitors; Female; Hypoxia; Immune Sera; Male; Neutropenia; Neutrophils; Peroxidase; Rats; Rats, Wistar; Xanthine Oxidase

It has been widely proposed that conversion of xanthine dehydrogenase (XDH) to its free radical-producing form, xanthine oxidase (XOD), underlies ischemic/reperfusion injury, although the relationship of this conversion to hypoxia and its physiologic control have not been defined. This study details the time course and control of this enzymatic interconversion. In a functionally intact, isolated perfused rat liver model, mean % XOD activity increased as a function of both the duration (25 to 45% in 3 h) and degree (r = 0.97) of hypoxia. This process was markedly accelerated in ischemic liver by an overnight fast (45 vs. 30% at 2 h), and by imposing a short period of in vivo ischemia (cardiopulmonary arrest 72%). Moreover, only under these conditions was there a significant rise in the XOD activity due to the conformationally altered XDH molecule (XODc, 18%), as well as concomitant morphologic injury. Neither circulating white blood cells nor thrombosis appeared to contribute to the effects of in vivo ischemia on enzyme conversion. Thus, it is apparent that conversion to the free radical-producing state, with high levels of XOD activity and concurrent cellular injury, can be achieved during a relatively short period of hypoxia under certain well-defined physiologic conditions, in a time course consistent with its purported role in modulating reperfusion injury. These data also suggest that the premorbid condition of organ donors (e.g., nutritional status and relative state of hypoxia) is important in achieving optimal organ preservation.

Topics: Animals; Free Radicals; In Vitro Techniques; Liver; Neutropenia; Oxygen Consumption; Rats; Rats, Inbred Strains; Reperfusion Injury; Xanthine Dehydrogenase; Xanthine Oxidase

We have evaluated, in a controlled study, the modification of the toxicity of a single bolus dose of 5-fluorouracil (5-FU) by allopurinol. Patients first received a single dose of 5-FU and were monitored for toxicity. If a measurable nadir in WBC or platelet count occurred, then the same dose of 5-FU was repeated with concurrent allopurinol, given for four consecutive days at an initial dose of 300 mg twice daily, starting the day before the administration of 5-FU. With this schedule, each evaluable patient received courses of 5-FU with and without allopurinol that could be compared for toxicity. Twenty patients received initial 5-FU doses of either 1,200 mg/m2 or 1,500 mg/m2 and later had the same dose repeated with allopurinol. Nineteen of these patients had a higher WBC count with allopurinol than without it. In several patients who received a further course of 5-FU with 900-mg/d allopurinol, the WBC count was yet higher than with 600-mg/d allopurinol. The myelosuppression produced by 5-FU was characterized by a decrease in granulocyte levels that was much greater than the decrease in lymphocyte levels, and the result of allopurinol treatment was to attenuate this effort on granulocytes. In a second part of the trial, the goal was to establish the maximum tolerated dose of 5-FU given with concurrent allopurinol. In this part of the study, all patients entered were given 5-FU, usually 1,200 mg/m2, with allopurinol, usually 600 mg/d for four days. Escalations of one or the other drugs were made on subsequent treatments. The data for 22 patients showed that 1,800 mg/m2 of 5-FU was well tolerated if given with 600 to 1,200 mg of allopurinol per day, and that the WBC count nadirs were no more severe than those of 1,200-mg/m2 5-FU without allopurinol. Neurotoxicity became limiting in some patients treated at these higher doses. We conclude that allopurinol given in the proper dose and schedule can diminish the granulocytopenia produced by bolus doses of 5-FU, thereby allowing a 50% increase in the maximal tolerated dose of 5-FU.

Topics: Adult; Aged; Allopurinol; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Granulocytes; Humans; Male; Middle Aged; Neoplasms; Nervous System; Neutropenia

In an attempt to decrease the activation of 5-FU by normal cells relative to cancer cells, 20 patients with metastatic cancer were given 72 courses of 5-FU and allopurinol (HPP) in a phase I trial. 5-FU was given daily by iv bolus injection for 5 consecutive days every 4 weeks: HPP, 300 mg orally every 8 hours for 6 consecutive days, was started 24 hours before the first injection of 5-FU. HPP appeared to modulate 5-FU toxicity by allowing higher doses (18-21 mg/kg daily for 5 days) to be given. Unexpectedly, neurotoxicity was the dose-limiting toxicity; it was slowly reversible and manifested primarily as encephalopathy, with some patients having cerebellar signs. Gastrointestinal and hematologic toxic effects were mild and infrequent. Because of the high incidence of neurotoxicity and low response rate, this program does not appear to offer any advantages over conventional dose schedules of 5-FU alone.

Topics: Adenocarcinoma; Aged; Allopurinol; Brain Diseases; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Gastrointestinal Diseases; Humans; Male; Middle Aged; Neutropenia

Topics: Adult; Agranulocytosis; Allopurinol; Female; Humans; Male; Neutropenia; Obesity; Starvation; Uric Acid

In an attempt to convert the bone-marrow population from Philadelphia-chromosome (Ph-1) positivt to partially or wholly Ph-1 negative, thioguanine was used as primary therapy in seven patients with chronic granulocytic leukaemia (C.G.L.). Although eight episodes of neutropenia were induced, prolonged remission or conversion to Ph-1-negativity was not achieved in any patient. However, thioguanine was at least as effective as busulphan for initial therapy in C.G.L., and had the advantage of rapid reversibility of haemopoietic depression when discontinued. Thioguanine merits further evaluation as an agent for the management of C.G.L. in its chronic phase.

Topics: Adult; Alkaline Phosphatase; Allopurinol; Chromosomes, Human, 21-22 and Y; Drug Evaluation; Drug Therapy, Combination; Female; Hematopoietic Stem Cells; Hemoglobins; Humans; Leukemia, Myeloid; Leukocyte Count; Male; Middle Aged; Neutropenia; Neutrophils; Thioguanine