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Thiopurine metabolites

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https://www.readbyqxmd.com/read/28445187/the-effects-of-inherited-nudt15-polymorphisms-on-thiopurine-active-metabolites-in-japanese-children-with-acute-lymphoblastic-leukemia
#1
Takaya Moriyama, Rina Nishii, Ting-Nien Lin, Kentaro Kihira, Hidemi Toyoda, Nersting Jacob, Motohiro Kato, Katsuyoshi Koh, Hiroto Inaba, Atsushi Manabe, Kjeld Schmiegelow, Jun J Yang, Hiroki Hori
Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing...
April 25, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28348471/role-of-allopurinol-in-optimizing-thiopurine-therapy-in-patients-with-autoimmune-hepatitis-a-review
#2
REVIEW
Shivani Deswal, Anshu Srivastava
Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes...
March 2017: Journal of Clinical and Experimental Hepatology
https://www.readbyqxmd.com/read/28333183/machine-learning-algorithms-for-objective-remission-and-clinical-outcomes-with-thiopurines
#3
Akbar K Waljee, Kay Sauder, Anand Patel, Sandeep Segar, Boang Liu, Yiwei Zhang, Ji Zhu, Ryan W Stidham, Ulysses Balis, Peter D R Higgins
Background and Aims: Big data analytics leverage patterns in data to harvest valuable information, but are rarely implemented in clinical care. Optimising thiopurine therapy for inflammatory bowel disease [IBD] has proved difficult. Current methods using 6-thioguanine nucleotide [6-TGN] metabolites have failed in randomized controlled trials [RCTs], and have not been used to predict objective remission [OR]. Our aims were to: 1) develop machine learning algorithms [MLA] using laboratory values and age to identify patients in objective remission on thiopurines; and 2) determine whether achieving algorithm-predicted objective remission resulted in fewer clinical events per year...
March 14, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28296824/multicentric-case-control-study-on-azathioprine-dose-and-pharmacokinetics-in-early-onset-pediatric-inflammatory-bowel-disease
#4
Gabriele Stocco, Stefano Martelossi, Serena Arrigo, Arrigo Barabino, Marina Aloi, Massimo Martinelli, Erasmo Miele, Daniela Knafelz, Claudio Romano, Samuele Naviglio, Diego Favretto, Eva Cuzzoni, Raffaella Franca, Giuliana Decorti, Alessandro Ventura
BACKGROUND: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers...
April 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28278299/combination-treatment-with-6-mercaptopurine-and-allopurinol-in-hepg2-and-hek293-cells-effects-on-gene-expression-levels-and-thiopurine-metabolism
#5
Sofie Haglund, Svante Vikingsson, Sven Almer, Jan Söderman
Combination treatment with low-dose thiopurine and allopurinol (AP) has successfully been used in patients with inflammatory bowel disease with a so called skewed thiopurine metabolite profile. In red blood cells in vivo, it reduces the concentration of methylated metabolites and increases the concentration of the phosphorylated ones, which is associated with improved therapeutic efficacy. This study aimed to investigate the largely unknown mechanism of AP on thiopurine metabolism in cells with an active thiopurine metabolic pathway using HepG2 and HEK293 cells...
2017: PloS One
https://www.readbyqxmd.com/read/28276819/is-there-a-role-for-thioguanine-therapy-in-ibd-in-2017-and-beyond
#6
Kirstin M Taylor, Mark G Ward, Paul A Blaker, Miles P Sparrow
Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use...
February 20, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28264514/excited-state-dynamics-of-the-thiopurine-prodrug-6-thioguanine-can-n9-glycosylation-affect-its-phototoxic-activity
#7
Brennan Ashwood, Steffen Jockusch, Carlos E Crespo-Hernández
6-Thioguanine, an immunosuppressant and anticancer prodrug, has been shown to induce DNA damage and cell death following exposure to UVA radiation. Its metabolite, 6-thioguanosine, plays a major role in the prodrug's overall photoreactivity. However, 6-thioguanine itself has proven to be cytotoxic following UVA irradiation, warranting further investigation into its excited-state dynamics. In this contribution, the excited-state dynamics and photochemical properties of 6-thioguanine are studied in aqueous solution following UVA excitation at 345 nm in order to provide mechanistic insight regarding its photochemical reactivity and to scrutinize whether N9-glycosylation modulates its phototoxicity in solution...
February 28, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28211629/editorial-can-we-get-more-clinical-benefit-from-thiopurine-metabolite-testing
#8
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
#9
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
#10
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...
March 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
#11
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
#12
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
#13
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
#14
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...
April 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/27943397/early-prediction-of-thiopurine-induced-hepatotoxicity-in-inflammatory-bowel-disease
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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