thioguanine-anhydrous and Chronic-Disease

Thioguanine derivatives, azathioprine and 6-mercaptopurine, represent major drugs in the treatment of chronic active inflammatory bowel disease. They are effective in two-thirds of the patients and safe over the long term in patients who can tolerate them (80-90%). Recent progress in understanding the metabolism of these drugs and its implication in clinical practice have brought up new tools and strategies that are proposed to optimize treatment. In particular, the measurement and characterization of key enzymes and metabolites may have clinical impact. Thus, thiopurine methyl transferase genotyping and activity measurement, as well as erythrocytes, 6-thioguanine nucleotides and 6-methyl mercaptopurine levels, may help in some situations of intolerance or inefficacy with these drugs. Indications for starting and stopping treatment with thioguanine derivatives are also discussed.

Topics: Azathioprine; Chronic Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy.. A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE.. Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG.. In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.

Topics: Adolescent; Adult; Azathioprine; Child; Chronic Disease; Cohort Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Pancreatitis; Retrospective Studies; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Coronary Angiography; Coronary Occlusion; Cytarabine; Daunorubicin; Humans; Percutaneous Coronary Intervention; Podophyllotoxin; Thioguanine; Treatment Outcome

The present study aimed to evaluate the safety and feasibility of a low frame rate protocol for chronic total occlusion (CTO)-percutaneous coronary intervention (PCI).. A total of 192 consecutive patients who underwent CTO-PCI following the low frame rate protocol were analysed. The low frame rate protocol adopted reduced frame rates and the addition of copper and aluminium filters. Procedural outcomes, radiation dose and in-hospital outcomes were ascertained. Meanwhile, a phantom experiment was designed to measure the radiation dose reduction. Overall technical and procedural success rates were 91.1% (175) and 90.6% (174), respectively. The retrograde approach was attempted in 56 (29.2%) lesions. The mean air kerma (AK) radiation exposure, fluoroscopy time and contrast volume were 2.6±2.0 Gy, 50.3±34.3 min and 294.1±131.8 ml, respectively. In-hospital major adverse events occurred in one patient (0.5%) and procedural complications occurred in six patients (3.1%). In the phantom experiment, a remarkable radiation dose reduction could be achieved for AK, dose area product (DAP), simulated first and second operator radiation exposure (reduction of 72.5%, 69.8%, 60.9% and 59.6%, respectively) in cineangiography from this protocol.. Our results provide the primary evidence that it appears to be safe and feasible to carry out the low frame rate protocol for CTO-PCI.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Coronary Angiography; Coronary Occlusion; Cytarabine; Daunorubicin; Feasibility Studies; Humans; Percutaneous Coronary Intervention; Podophyllotoxin; Registries; Thioguanine; Treatment Outcome

Inflammatory bowel diseases (IBD) are chronic relapsing disorders of the gastrointestinal tract. Several mouse models for IBD are available, but the acute dextran sulfate sodium (DSS)-induced colitis model is mostly used for preclinical studies. However, this model lacks chronicity and often leads to significant loss of mice. The aim of this study was to establish a refined and translationally relevant model of DSS chronic colitis in BALB/c mice. In the first part, we compared several standard therapeutic (ST) treatments for IBD in the acute DSS colitis model to identify the optimal treatment control for a DSS colitis model as compared to literature data. In the second part, we tested the two most effective ST treatments in a refined model of chronic DSS colitis. Cyclosporine A (CsA) and 6-thioguanine (6-TG) caused considerable reduction of clinical scores in acute DSS colitis. The clinical outcome was confirmed by the results for colon length and by histopathological evaluation. Moreover, CsA and 6-TG considerably reduced mRNA expression of several pro-inflammatory cytokines in spleen and colon. Both compounds also showed a substantial therapeutic effect in the refined model of chronic DSS colitis with regard to clinical scores and histopathology as well as the expression of inflammatory markers. The refined model of chronic DSS colitis reflects important features of IBD and is well suited to test potential IBD therapeutics.

Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Colitis; Cyclosporine; Dextran Sulfate; Disease Models, Animal; Female; Inflammatory Bowel Diseases; Mice; Mice, Inbred BALB C; Thioguanine

Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD.. We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry.. 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice.. Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.

Topics: Acute Disease; Alanine Transaminase; Analysis of Variance; Animals; Apoptosis; Azathioprine; Chronic Disease; Colitis; Colon; Dextran Sulfate; Female; Interferon-gamma; Interleukin-6; Liver; Mice; Mice, Inbred BALB C; Models, Animal; T-Lymphocytes, Helper-Inducer; Thioguanine; Transforming Growth Factor beta; Weight Loss

The United Kingdom (UK) acute lymphoblastic leukaemia (ALL) 97/99 clinical trial compared 6-mercaptopurine (6MP) with 6-thioguanine (6TG) as maintenance therapy for childhood ALL. Review of interim results has led to discontinuation of the 6TG arm.. We report six children with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6-22) months. All these children were treated in the 6TG-arm.. The median (range) age at presentation was 6.6 (3.2-11.5) years. There were five boys. The presenting features were splenomegaly in all and hepatomegaly in four. AST was abnormal in one (80 IU/l, normal range 10-50). Abdominal sonography showed an altered texture of the liver parenchyma and confirmed splenomegaly. Microscopy showed findings within the spectrum of occlusive venopathy and nodular regenerative hyperplasia (NRH). After a median (range) follow-up of 23 (4-36) months splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension, continue to worsen in all children.. 6TG is associated with chronic hepatic toxicity and progressive portal hypertension on follow-up. Microscopy showed NRH in all patients with features in keeping with an intrahepatic occlusive venopathy and variable parenchymal atrophy and loss.

Topics: Antimetabolites, Antineoplastic; Biopsy; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Chronic Disease; Disease Progression; Female; Follow-Up Studies; Humans; Liver Diseases; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Thioguanine; Ultrasonography

Topics: Adolescent; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Chronic Disease; Female; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Tioguanine may offer an alternative for immunosuppression in chronic active Crohn's disease. Recently, we have shown that tioguanine is effective in inducing rapid remission.. To evaluate the role of tioguanine in the maintenance of remission in chronic active Crohn's disease.. A follow-up study was performed to investigate the long-term efficacy and safety of and tolerance to tioguanine in chronic active Crohn's disease. Sixteen patients who had successfully received 6-tioguanine for remission induction were enrolled. The reasons for immunosuppressive therapy were steroid dependence (n = 10), steroid refractoriness (n = 6) and intolerance (n = 6) or refractoriness (n = 1) to azathioprine. After remission induction therapy for 6 months, patients were treated for another 6 months with a daily dose of 20-40 mg tioguanine. Primary outcomes were remission (Crohn's disease activity index < 150) and complete steroid reduction in steroid-dependent patients at 12 months. Laboratory controls of white blood count and liver enzymes, as well as erythrocyte tioguanine nucleotide levels, were performed regularly.. After 12 months of treatment, 14 of 16 (88%) patients were in remission, and 12 of these were completely free of systemic steroids. Adverse events during maintenance therapy included photosensitivity (one patient), minor viral infections (one), headache (four) and mild alopecia (one). One patient developed elevated liver enzymes, splenomegaly and thrombocytopenia, indicative of nodular regenerative hyperplasia of the liver.. In responders to tioguanine, the drug appears to be very effective in maintaining remission of chronic active Crohn's disease. Unfortunately, long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction. Therefore, to date, tioguanine cannot be recommended for general use outside clinical trials.

Topics: Adult; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Chronic Disease; Crohn Disease; Erythrocytes; Female; Follow-Up Studies; Humans; Male; Methyltransferases; Middle Aged; Phenotype; Steroids; Thioguanine; Treatment Outcome

A salient feature of Hashimoto's thyroiditis (HT) is the T-cell-mediated destruction of the thyroid gland leading to hypothyroidism. In HT, as in other autoimmune diseases, a central premise has been that autoreactive T cells must be dividing in response to autoantigens, accumulating random spontaneous mutations during the activation process. Here, we have examined this hypothesis by using as monitor of somatic cell mutation the hprt gene, encoding the salvage pathway enzyme hypoxanthine-guanine phosphoribosyl transferase. Eleven newly diagnosed patients with HT and 10 patients with chronic disease were selected for the study, whereas 10 healthy individuals were used as controls. Peripheral T cells were cultured under limiting dilution conditions in the presence of 6-thioguanine and the frequency (MF) of surviving mutant hprt(-) T cells was calculated by Poisson statistics. It was observed that the mean MF value of either patient group (6.6 +/- 5.8 per 10(6) cells for the newly diagnosed, and 8.8 +/- 4.0 per 10(6) cells for the patients with chronic disease) was not significantly different (p > 0.05) from that of the control group (6.8 +/- 6.4 per 10(6) cells). These data do not support the concept that patients with HT have an increased number of actively dividing T cells in the circulation compared to healthy controls. Autoreactive T cells may be activated mainly in situ or home readily to the thyroid in the early stages of the disease and reach a nonexpansion stage as the chronic disease is stabilized.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Cell Survival; Cells, Cultured; Chronic Disease; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Lymphocyte Activation; Male; Middle Aged; Mutation; Poisson Distribution; T-Lymphocytes; Thioguanine; Thyroiditis, Autoimmune

Staining with naphthol AS phosphate and Fast Blue BB salt has been used for the estimation of neutrophil alkaline phosphatase (NAP) scores in patients with chronic granulocytic leukaemia (CGL). The very low scores found at diagnosis rise when the disease is treated, and there is some inverse correlation between the NAP score and the absolute neutrophil count. Patients treated intensively developed high NAP scores. Elective splenectomy performed during the chronic phase of CGL is followed by a pronounced but transient neutrophilia and a concurrent striking rise in the NAP score. Similar changes were observed in patients without CGL who underwent splenectomy. These observations can be explained by assuming that newly formed neutrophils in CGL have a normal content of NAP but are rapidly sequestered in non-circulating extramedullary pools, whereas the circulating neutrophil with a typically low NAP content is a relatively aged cell which has lost enzyme activity. In subjects with or without CGL, removal of the spleen, a major site of such pooling, temporarily permits the circulation of newly formed neutrophils but eventually other organs assume the sequestering functions of the spleen. Thus the aberrations of NAP score seen in CGL might be attributable not to an intrinsic cellular defect but to an exaggeration of the granulocyte storage phenomena which also occur in subjects without CGL.

Topics: Alkaline Phosphatase; Bone Marrow Cells; Busulfan; Chronic Disease; Clinical Enzyme Tests; Histocytochemistry; Leukemia, Myeloid; Leukemoid Reaction; Neutrophils; Polycythemia; Primary Myelofibrosis; Splenectomy; Thioguanine; Time Factors

Topics: Adolescent; Adult; Aged; Azathioprine; Blood Cell Count; Blood Platelets; Chronic Disease; Cyclophosphamide; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Male; Mercaptopurine; Middle Aged; Prednisone; Purpura, Thrombocytopenic; Sex Factors; Splenectomy; Thioguanine

Topics: Adolescent; Adult; Antimetabolites; Azaguanine; Azathioprine; Chronic Disease; Cyclophosphamide; Female; Hepatitis; Humans; Liver Cirrhosis; Male; Mercaptopurine; Middle Aged; Prednisone; Thioguanine