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Thiopurine metabolites

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https://www.readbyqxmd.com/read/28211629/editorial-can-we-get-more-clinical-benefit-from-thiopurine-metabolite-testing
#1
EDITORIAL
A G Fraser
No abstract text is available yet for this article.
March 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28211625/editorial-can-we-get-more-clinical-benefit-from-thiopurine-metabolite-testing-authors-reply
#2
EDITORIAL
D R Wong, P M Hooymans
No abstract text is available yet for this article.
March 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28160250/thiopurines-and-methotrexate-use-in-ibd-patients-in-a-biologic-era
#3
REVIEW
Gerassimos J Mantzaris
Although we have been living in the era of biologic therapy for several decades, the use of immunomodulators (primarily thiopurines [azathioprine and mercaptopurine] and less so methotrexate) still remains an important component of the inflammatory bowel disease (IBD) pharmaceutical arsenal. Thiopurines as monotherapy exert corticosteroid-sparing effects and can maintain long-term remission in a considerable proportion of patients who have frequent relapses and are or have become mesalazine and/or corticosteroid intolerant or refractory...
February 3, 2017: Current Treatment Options in Gastroenterology
https://www.readbyqxmd.com/read/28151736/nodular-regenerative-hyperplasia-of-the-liver-in-patients-with-ibd-treated-with-allopurinol-thiopurine-combination-therapy
#4
Margien L Seinen, Dirk P van Asseldonk, Nanne K de Boer, Gerd Bouma, Carin M van Nieuwkerk, Chris J Mulder, Elisabeth Bloemena, Adriaan A van Bodegraven
BACKGROUND: Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination...
March 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28130685/metabolite-monitoring-to-guide-thiopurine-therapy-in-systemic-autoimmune-diseases
#5
Aurélie Chapdelaine, Anne-Marie Mansour, Yves Troyanov, David R Williamson, Maxime Doré
6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases...
January 27, 2017: Clinical Rheumatology
https://www.readbyqxmd.com/read/28081040/azathioprine-therapy-in-a-pediatric-tpmt-deficient-patient-still-an-option
#6
S A W van Moorsel, N Bevers, M Meurs, L K van Rossum, P M Hooymans, D R Wong
We describe the case of a pediatric patient on azathioprine therapy with previously undiagnosed homozygote thiopurine S-methyltransferase (TPMT) deficiency, resulting in myelotoxic thiopurine metabolite levels. The patient was successfully treated with a very low azathioprine dose of 50 mg once a week (4% of standard dose), guided by frequent thiopurine metabolite measurement and a close clinical surveillance. We demonstrate that azathioprine therapy still might be an effective and safe therapeutic option in pediatric thiopurine S-methyltransferase-deficient IBD patients...
February 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28060115/hepatotoxicity-during-maintenance-therapy-and-prognosis-in-children-with-acute-lymphoblastic-leukemia
#7
Maria S Ebbesen, Ulrikka Nygaard, Susanne Rosthøj, Ditte Sørensen, Jacob Nersting, Kim Vettenranta, Finn Wesenberg, Jon Kristinsson, Arja Harila-Saari, Kjeld Schmiegelow
Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered...
January 5, 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/27943397/early-prediction-of-thiopurine-induced-hepatotoxicity-in-inflammatory-bowel-disease
#8
D R Wong, M J H Coenen, L J J Derijks, S H Vermeulen, C J van Marrewijk, O H Klungel, H Scheffer, B Franke, H-J Guchelaar, D J de Jong, L G J B Engels, A L M Verbeek, P M Hooymans
BACKGROUND: Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. AIM: To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment...
February 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27859568/6-methylmercaptopurine-induced-leukocytopenia-during-thiopurine-therapy-in-ibd-patients
#9
Berrie Meijer, Joany E Kreijne, Sofia A W van Moorsel, Luc J J Derijks, Gerd Bouma, Chris J J Mulder, Dennis R Wong, C Janneke van der Woude, Adriaan A van Bodegraven, Nanne K H de Boer
BACKGROUND: Thiopurines have a favorable benefit-risk ratio in the treatment of inflammatory bowel disease (IBD). A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due to toxic concentrations of the pharmacologically active metabolites 6-thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6-methylmercaptopurine (6-MMP). In this case-series, we provide a detailed overview of 6-MMP-induced myelotoxicity in IBD patients...
November 16, 2016: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/27787512/weight-and-body-composition-compartments-do-not-predict-therapeutic-thiopurine-metabolite-levels-in-inflammatory-bowel-disease
#10
Darcy Q Holt, Boyd Jg Strauss, Gregory T Moore
OBJECTIVES: Thiopurine drugs are the most commonly used steroid-sparing therapies in moderate-to-severe inflammatory bowel disease (IBD). Their complex metabolism and their narrow therapeutic windows means that optimal dosing is difficult. However, weight-based dosing is the norm. Similar antimetabolites are dosed by body composition parameters. In IBD, treatment response and toxicity has been shown to correlate with thiopurine metabolite levels. We sought to determine whether weight or body composition parameters predicted therapeutic 6-thioguanine nucleotide (6TGN) or toxic 6-methylmercaptopurine (6MMP) levels...
October 27, 2016: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/27530327/nudt15-hydrolyzes-6-thio-deoxygtp-to-mediate-the-anticancer-efficacy-of-6-thioguanine
#11
Nicholas C K Valerie, Anna Hagenkort, Brent D G Page, Geoffrey Masuyer, Daniel Rehling, Megan Carter, Luka Bevc, Patrick Herr, Evert Homan, Nina G Sheppard, Pål Stenmark, Ann-Sofie Jemth, Thomas Helleday
Thiopurines are a standard treatment for childhood leukemia, but like all chemotherapeutics, their use is limited by inherent or acquired resistance in patients. Recently, the nucleoside diphosphate hydrolase NUDT15 has received attention on the basis of its ability to hydrolyze the thiopurine effector metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP, thereby limiting the efficacy of thiopurines. In particular, increasing evidence suggests an association between the NUDT15 missense variant, R139C, and thiopurine sensitivity...
September 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27458036/xanthine-oxidoreductase-in-drug-metabolism-beyond-a-role-as-a-detoxifying-enzyme
#12
REVIEW
Maria Giulia Battelli, Letizia Polito, Massimo Bortolotti, Andrea Bolognesi
The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs...
2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27447547/maintenance-therapy-of-childhood-acute-lymphoblastic-leukemia-revisited-should-drug-doses-be-adjusted-by-white-blood-cell-neutrophil-or-lymphocyte-counts
#13
Kjeld Schmiegelow, Jacob Nersting, Stine Nygaard Nielsen, Mats Heyman, Finn Wesenberg, Jon Kristinsson, Kim Vettenranta, Henrik Schrøeder, Richard Weinshilboum, Katrine Lykke Jensen, Kathrine Grell, Susanne Rosthoej
BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. PROCEDURE: To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1...
December 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27402913/early-assessment-of-thiopurine-metabolites-identifies-patients-at-risk-of-thiopurine-induced-leukopenia-in-inflammatory-bowel-disease
#14
Dennis R Wong, Marieke J H Coenen, Sita H Vermeulen, Luc J J Derijks, Corine J van Marrewijk, Olaf H Klungel, Hans Scheffer, Barbara Franke, Henk-Jan Guchelaar, Dirk J de Jong, Leopold G J B Engels, André L M Verbeek, Piet M Hooymans
BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials...
February 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/27399027/-azathioprine-induced-pancytopenia-case-series
#15
Cristina Martínez Faci, Ignacio Ros Arnal, José M Martínez de Zabarte Fernández, Jordi Sorribes Estorch, Mónica López Campos, Carmen Rodríguez-Vigil Iturrate
Azathioprine is an immunosuppressive drug that has shown effectiveness in inflammatory bowel disease treatment. Its metabolite, 6-mercaptopurine, is metabolized through thiopurine methyltransferase. Patients with low enzyme activity may have more frequent and severe side effects. The most common is leukopenia, and rarely pancytopenia. The thiopurine methyltransferase activity monitoring shows an individualized profile of enzymatic activity but it should not replace monitoring by performing serial blood counts...
August 1, 2016: Archivos Argentinos de Pediatría
https://www.readbyqxmd.com/read/27362994/liquid-chromatography-mass-spectrometry-for-measuring-deoxythioguanosine-in-dna-from-thiopurine-treated-patients
#16
Sally A Coulthard, Phil Berry, Sarah McGarrity, Azhar Ansari, Christopher P F Redfern
Adverse reactions and non-response are common in patients treated with thiopurine drugs. Current monitoring of drug metabolite levels for guiding treatment are limited to analysis of thioguanine nucleotides (TGNs) in erythrocytes after chemical derivatisation. Erythrocytes are not the target tissue and TGN levels show poor correlations with clinical response. We have developed a sensitive assay to quantify deoxythioguanosine (dTG) without derivatisation in the DNA of nucleated blood cells. Using liquid chromatography and detection by tandem mass spectrometry, an intra- and inter-assay variability below 7...
August 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27333713/an-epidemiological-study-of-thiopurine-methyltransferase-variants-in-a-croatian-inflammatory-bowel-disease-patient-cohort
#17
Agata Ladić, Nada Božina, Vladimir Borzan, Marko Brinar, Boris Vucelić, Silvija Cuković-Cavka
Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. Over 20 variant TPMT-encoding alleles, which cause reduced enzymatic activity, have been discovered so far. Our aim was to investigate the frequencies of variant alleles, i.e. genotypes in inflammatory bowel disease (IBD) patients and healthy individuals and to compare these frequencies with selected world populations. The most common variant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C were analyzed with polymerase chain reaction-based assays and allele-specific polymerase chain reaction-based assays in 685 participants including 459 IBD patients and 226 healthy volunteers...
March 2016: Acta Clinica Croatica
https://www.readbyqxmd.com/read/27271488/long-term-safety-and-efficacy-of-low-dose-azathioprine-and-allopurinol-cotherapy-in-inflammatory-bowel-disease-a-large-observational-study
#18
Polychronis Pavlidis, Panagiotis Stamoulos, Answar Abdulrehman, Patrick Kerr, Claire Bull, John Duley, Azhar Ansari
BACKGROUND: Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling...
July 2016: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/27257870/usefulness-of-mean-corpuscular-volume-as-a-surrogate-marker-for-monitoring-thiopurine-treatment-in-inflammatory-bowel-disease
#19
Romein W G Dujardin, Berrie Meijer, Nanne K H de Boer, Geert R D'Haens, Mark Löwenberg
BACKGROUND: Thiopurines are commonly used drugs in inflammatory bowel disease. Intracellular levels of thiopurine metabolites [i.e. 6-thioguaninenucleotides (6-TGN)] are associated with efficacy and toxicity. Because 6-TGN measurement is not globally available, the mean corpuscular volume (MCV) has been proposed as a surrogate marker for monitoring thiopurine therapy. AIMS: To analyze the relationship between MCV and efficacy of thiopurines, defined as either response to therapy or 6-TGN levels...
September 2016: European Journal of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/27112707/designer-thiopurine-analogues-for-optimised-immunosuppression-in-inflammatory-bowel-diseases
#20
Imke Atreya, Alexandra Diall, Radovan Dvorsky, Raja Atreya, Christian Henninger, Mathias Grün, Ute Hofmann, Elke Schaeffeler, Rocío López-Posadas, Ilse Daehn, Stefanie Zenker, Michael Döbrönti, Clemens Neufert, Ulrike Billmeier, Sebastian Zundler, Gerhard Fritz, Matthias Schwab, Markus F Neurath
BACKGROUND AND AIMS: The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD]. METHODS: Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients...
October 2016: Journal of Crohn's & Colitis
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