allopurinol and Leukopenia

Metabolism of thiopurine drugs--azathioprine, 6-mercaptopurine, and 6-thioguanine--has provided a powerful pharmacogenetic model incorporating polymorphism of the enzyme thiopurine methyltransferase (TPMT) and the primary active metabolite, thioguanine nucleotide (TGN). However, a sense of uncertainty about the usefulness of TGNs and other thiopurine metabolites has appeared. This review critically appraises the basis of thiopurine metabolism and reveals the problems and complexities in TGN research. Erythrocyte TGN is used in transplantation medicine and in chronic inflammatory conditions such as Crohn's disease, as a "surrogate" pharmacokinetic parameter for TGN in the target cells: leukocytes or bone marrow. It is not generally appreciated that erythrocytes do not express the enzyme IMP dehydrogenase and cannot convert mercaptopurine to TGN, which explains some of the confusion in interpretation of erythrocyte TGN measurements. TGN routinely measured in erythrocytes derives from hepatic metabolism. Another concern is that TGN are not generally assayed directly: most methods assay the thiopurine bases. Ion-exchange HPLC and enzymatic conversion of TGNs to nucleosides have been used to overcome this, and may reveal undisclosed roles for an unusual cytotoxic nucleotide, thio-inosine triphosphate, and methylated thiopurines. There appear to be additional interactions between xanthine oxidase and TPMT, and folate and TPMT, that could predict leukopenia. Difficult questions remain to be answered, which may be assisted by technological advances. Prospective TGN studies, long overdue, are at last revealing clearer results.

Topics: Azathioprine; Drug Monitoring; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Leukopenia; Mercaptopurine; Methylation; Methyltransferases; Nausea; Thioguanine; Thionucleotides; Xanthine Oxidase

Topics: Acute Kidney Injury; Allopurinol; Antimetabolites, Antineoplastic; Combined Modality Therapy; Female; Fluid Therapy; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukopenia; Middle Aged; Sodium Bicarbonate; Tumor Lysis Syndrome; Vidarabine Phosphate

Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6-MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu-like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu-like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine-induced toxicity.

Topics: Adolescent; Adult; Aged; Asian People; Azathioprine; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Xanthine Oxidase; Young Adult

Azathioprine is an immunosuppressor used with ciclosporin and corticosteroids after organ transplantation. Azathioprine is rapidly transformed into 6-mercaptopurine which in turn is metabolized by three competitive pathways: a) intracellular hypoxanthine guanine phosphoribosyl transferase leads to 6-thioguanine nucleotides which can damage chromosome DNA; b) thiopurine methyltransferase produces inactive methylated derivatives; c) xanthine oxidase produces thiouric acid. Due to inter-individual variations in the later two pathways, azathioprine dose must be adapted to each patient. A 48-year-old female patient underwent renal transplantation in 1994 and was given immunosuppressive therapy combining thymoglobulins, azathioprine and ciclosporin. Severe leukopenia (< 3000/mm3) occurred on day 5 requiring withdrawal of azathioprine. Known hypouricaemia (< 50 mumol/l) suggested xanthine oxidase deficiency. Laboratory results confirmed xanthine oxidase deficiency and also revealed reduced thiopurine methyltransferase activity (14.9 pmol/h/mg Hb). Azathioprine toxicity was confirmed by regression of the leukopenia after withdrawal and recurrence at rechallenge. Xanthine oxidase deficiency occurs in 2% of the general population. Reduced thiopurine methyltransferase activity affects 11% of the population. The combined presence of these two genetic anomalies led to early and sudden intolerance to azathioprine and emphasize the need to develop new immunosuppressor agents degraded by other metabolic pathways.

Topics: Azathioprine; Female; Humans; Immune Tolerance; Kidney Diseases; Kidney Transplantation; Leukopenia; Middle Aged; Postoperative Complications; Xanthine Oxidase

This study was conducted with rats to assess the involvement of leukocytes in a model of CO-mediated brain injury. Myeloperoxidase activity, measured as an index of leukocyte sequestration, was found to be increased 10-fold in brain microvessel segments prepared from rats immediately or 90 min after exposure to CO. Fluorescence and light microscopic examinations revealed leukocytes in microvessels taken from CO-poisoned rats, but not in that from control rats. Studies were then conducted with rats that had been made leukopenic or treated with monoclonal anti-CD-18 F(ab')2 fragments to inhibit leukocyte adherence to the vasculature. Neither of these groups of animals exhibited the biochemical changes observed in the brains of sham-treated rats: conversion of xanthine dehydrogenase (XD) to sulfhydryl-irreversible xanthine oxidase (XO), and lipid peroxidation, at 90 min following CO poisoning. Treatment with a synthetic serine protease inhibitor, gabexate mesylate, also prevented these biochemical changes if administered immediately after CO poisoning, but the agent did not inhibit leukocyte sequestration. Rats depleted of XD and XO by a tungsten diet, and those treated with allopurinol to inhibit XD and XO, also exhibited at least a 10-fold increase in myeloperoxidase activity in microvessels immediately after CO poisoning, but only a 5-fold increase at 90 min. In vitro studies demonstrated that B2 integrin-dependent polymorphonuclear leukocyte adherence was impaired immediately following CO poisoning although the adherence molecules were expressed on the membrane surface. Adherence function normalized by 45 min. The results suggest that leukocytes are responsible for the development of biochemical changes in brain following CO poisoning, and the sequence of events is as follows: leukocyte sequestration in the microvasculature, B2 integrin-dependent adherence, protease-mediated conversion of XD to XO, O2 radical-dependent lipid peroxidation.

Topics: Allopurinol; Animals; Brain; Carbon Monoxide Poisoning; Cell Adhesion; Gabexate; Leukocytes; Leukopenia; Male; Microcirculation; Oxidation-Reduction; Peroxidase; Protease Inhibitors; Rats; Rats, Wistar; Xanthine Dehydrogenase; Xanthine Oxidase

Isoproterenol produces myocardial necrosis in rats. To investigate the possible role of oxygen free radicals generated by xanthine oxidase and neutrophils, we examined the effects of the xanthine oxidase inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG) combined and allopurinol, or of irradiation (to induce leukopenia) on isoproterenol-induced myocardial necrosis (ISOMN). The incidence and severity of ISOMN was significantly reduced by 6MP + 6TG but not by the specific inhibitor of xanthine oxidase, allopurinol, indicating that the protective effects of 6MP + 6TG may be due to its free radical scavenging activity rather than its xanthine oxidase inhibitory activity. Irradiation provided complete protection against ISOMN in all rats. Marked leukopenia or other radiation-induced protective factors could play a role in the mechanism of the protection.

Topics: Allopurinol; Animals; Heart Diseases; Isoproterenol; Leukocytes; Leukopenia; Male; Mercaptopurine; Myocardium; Necrosis; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Thioguanine

Topics: Adult; Crohn Disease; Female; Humans; Leukopenia; Mercaptopurine; Xanthine Oxidase

Azathioprine toxicity was examined in 64 consecutively treated patients with various neuromuscular diseases. Reversible leukopenia was seen in 14 patients (22%). Hepatotoxicity developed in six patients (9%), and a systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurred in eight patients (12%). Toxic effects limited the dose of azathioprine in 27 patients (42%) and led to discontinuation of therapy in 13 (20%). Macrocytosis developed in 20% of patients, but did not require an adjustment in the dose. Two patients received allopurinol and azathioprine; both developed reversible leukopenia and macrocytosis. Patients with hematologic and hepatic toxicity, but not those with systemic toxicity, successfully tolerated retreatment with azathioprine. Toxicity was delayed as long as 56 weeks after starting azathioprine in some patients.

Topics: Allopurinol; Azathioprine; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Leukopenia; Liver; Male; Neuromuscular Diseases; Time Factors

In clinical oncology emergency situations are either manifestations of the underlying disease or effects of the treatment. The successful treatment of emergency situations is not only important in diseases in which cure is possible. It contributes also essentially to an optimal palliation for not curable disease states in oncology. Some special examples from the point of view of internal medicine are briefly discussed.

Topics: Allopurinol; Bacterial Infections; Bleomycin; Cyclophosphamide; Emergencies; Fever; Fluid Therapy; Granulocytes; Humans; Hypercalcemia; Leukopenia; Lymphoma; Neoplasms; Spinal Cord Compression; Spinal Injuries; Spinal Neoplasms; Tetracyclines

Azathioprine metabolite concentrations were studied in 54 kidney transplant recipients. Thirty-seven of these patients were studied over a 6 month period to investigate the intrapatient variation in metabolite concentrations. All patients had stable functioning grafts and normal peripheral white blood cell counts. The metabolites measured were plasma 6-mercaptopurine and red blood cell 6-thioguanine nucleotide. There was no correlation between azathioprine dose and plasma 6-mercaptopurine concentration but there was a significant correlation between dose and red blood cell 6-thioguanine nucleotide concentration (rs = 0.41, P less than 0.005). The individual transplant recipient showed little variation in metabolite concentrations over several months. Using this group as a control we studied metabolite concentrations in patients with kidney transplants who developed leucopenia. Our preliminary findings indicate that elevated red cell 6-thioguanine nucleotide concentrations, above the control range, can be associated with bone marrow depression.

Topics: Adult; Allopurinol; Azathioprine; Dose-Response Relationship, Drug; Female; Guanine Nucleotides; Humans; Individuality; Kidney Transplantation; Leukocyte Count; Leukopenia; Male; Sex Factors; Thionucleotides

Topics: Allopurinol; Anemia, Macrocytic; Azathioprine; Drug Interactions; Female; Humans; Leukopenia; Middle Aged; Myasthenia Gravis

Topics: Allopurinol; Humans; Leukopenia; Male; Middle Aged; Syndrome; Thrombocytopenia

Topics: Allopurinol; Blood Platelets; Blood Transfusion; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukopenia; Middle Aged; Patient Isolation; Thrombocytopenia; Uric Acid

Topics: Allopurinol; Drug Therapy, Combination; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leukopenia; Stomatitis

Immunoblastic lymphadenopathy is a recently described lymphoproliferative disorder, presumably of B-cell origin. It is characterized by regional or generalized lymphadenopathy, usually associated with hypergammaglobulinemia or dysproteinemia. Other findings may be hepatosplenomegaly, dermatitis, fever, malaise, weight loss, and various altered immunologic reactions. Histologically, the involved lymph nodes show immunoblast, plasmacytoid, and plasma cell proliferation. This may be extranodal as well. The case reported here is one of the few followed up prospectively. The patient's purpuric eruption was an apparent manifestation of a type II mixed cryoglobulinemia. Differing from what has usually been reported, we noted hypogammaglobulinemia and findings in part of altered cell-mediated immunity. Despite leukopenia and anemia there were no infectious episodes. Although a satisfactory treatment regimen has not been established, there was beneficial response to prednisone and short courses of melphalan.

Topics: Allopurinol; Anemia; B-Lymphocytes; Cryoglobulins; Female; Humans; Leukopenia; Lymphatic Diseases; Melphalan; Middle Aged; Paraproteinemias; Prednisone; Purpura, Hyperglobulinemic

Topics: Adult; Allopurinol; Anemia, Aplastic; Antineoplastic Agents; Bone Marrow; Cyclophosphamide; Depression, Chemical; Drug Synergism; Female; Hematopoiesis; Humans; Leukopenia; Male; Thrombocytopenia; Time Factors

Topics: Allopurinol; Antineoplastic Agents; Bone Marrow; Drug Synergism; Leukopenia; Thrombocytopenia

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