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Thiopurine methyltransferase

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https://www.readbyqxmd.com/read/28406961/pharmacogenetic-variants-in-tpmt-alter-cellular-responses-to-cisplatin-in-inner-ear-cell-lines
#1
Amit P Bhavsar, Erandika P Gunaretnam, Yuling Li, Jafar S Hasbullah, Bruce C Carleton, Colin J D Ross
Cisplatin is a highly-effective and widely-used chemotherapeutic agent that causes ototoxicity in many patients. Pharmacogenomic studies of key genes controlling drug biotransformation identified variants in thiopurine methyltransferase (TPMT) as predictors of cisplatin-induced ototoxicity, although the mechanistic basis of this interaction has not been reported. Expression constructs of TPMT*3A, *3B and *3C variants were generated and monitored in cultured cells. Cellular TPMT*3A levels were detected at >20-fold lower amounts than the wild type confirming the unstable nature of this variant...
2017: PloS One
https://www.readbyqxmd.com/read/28404197/mercaptopurine-versus-placebo-to-prevent-recurrence-of-crohn-s-disease-after-surgical-resection-toppic-a-multicentre-double-blind-randomised-controlled-trial
#2
Craig Mowat, Ian Arnott, Aiden Cahill, Malcolm Smith, Tariq Ahmad, Sreedhar Subramanian, Simon Travis, John Morris, John Hamlin, Anjan Dhar, Chuka Nwokolo, Cathryn Edwards, Tom Creed, Stuart Bloom, Mohamed Yousif, Linzi Thomas, Simon Campbell, Stephen J Lewis, Shaji Sebastian, Sandip Sen, Simon Lal, Chris Hawkey, Charles Murray, Fraser Cummings, Jason Goh, James O Lindsay, Naila Arebi, Lindsay Potts, Aileen J McKinley, John M Thomson, John A Todd, Mhairi Collie, Malcolm G Dunlop, Ashley Mowat, Daniel R Gaya, Jack Winter, Graham D Naismith, Holly Ennis, Catriona Keerie, Steff Lewis, Robin J Prescott, Nicholas A Kennedy, Jack Satsangi
BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection...
December 2016: Lancet. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28391009/the-promise-of-pharmacogenomics-in-reducing-toxicity-during-acute-lymphoblastic-leukemia-maintenance-treatment
#3
REVIEW
Shoshana Rudin, Marcus Marable, R Stephanie Huang
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity...
April 5, 2017: Genomics, Proteomics & Bioinformatics
https://www.readbyqxmd.com/read/28374975/enrichment-of-genetic-variants-in-the-glucocorticoid-receptor-signalling-pathway-in-autoimmune-hepatitis-with-failure-of-standard-treatment
#4
Peter Lykke Eriksen, Martin Kreutzfeldt, Henning Grønbaek, Kasper Thorsen, Søren Vang, Niels Jessen, Hendrik Vilstrup
The standard treatment for autoimmune hepatitis (AIH) is predniso(lo)ne for remission induction, tapered and followed by azathioprine, which effectively controls the disease in the majority of patients. However, some patients prove to be unresponsive or non-tolerant and require alternative immunosuppressive regimens for disease control. We aimed to investigate whether these AIH patients who experience failure of standard treatment have a genomic basis for their problem in the form of pharmacogenetic variants...
April 4, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28296824/multicentric-case-control-study-on-azathioprine-dose-and-pharmacokinetics-in-early-onset-pediatric-inflammatory-bowel-disease
#5
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/28295989/pharmacokinetics-of-two-6-mercaptopurine-liquid-formulations-in-children-with-acute-lymphoblastic-leukemia
#6
Jaszianne A Tolbert, Shasha Bai, Susan M Abdel-Rahman, Keith J August, Scott J Weir, Gregory L Kearns, Kathleen A Neville
BACKGROUND: A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. METHODS: Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts...
March 10, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28262261/pharmacogenetics-of-anti-cancer-drugs-state-of-the-art-and-implementation%C3%A2-%C3%A2-recommendations-of-the-french-national-network-of-pharmacogenetics
#7
Sylvie Quaranta, Fabienne Thomas
Individualized treatment is of special importance in oncology because the drugs used for chemotherapy have a very narrow therapeutic index. Pharmacogenetics may contribute substantially to clinical routine for optimizing cancer treatment to limit toxic effects while maintaining efficacy. This review presents the usefulness of pharmacogenetic tests for some key applications: dihydropyrimidine dehydrogenase (DPYD) genotyping for fluoropyrimidine (5-fluorouracil, capecitabine), UDP glucuronosylstransferase (UGT1A1) for irinotecan and thiopurine S-methyltransferase (TPMT) for thiopurine drugs...
January 30, 2017: Thérapie
https://www.readbyqxmd.com/read/28212467/comparison-of-6-mercaptopurine-with-6-thioguanine-for-the-analysis-of-thiopurine-s-methyltransferase-activity-in-human-erythrocyte-by-lc-ms-ms
#8
Shenghui Mei, Xindi Li, Xiaoqing Gong, Xiaoyi Zhang, Xingang Li, Li Yang, Leting Zhu, Heng Zhou, Yonghong Liu, Anna Zhou, Xinghu Zhang, Zhigang Zhao
Thiopurines (TPDs) are first-line drugs in treating neuromyelitis optica spectrum disorders (NMOSD). Evaluation of thiopurine S-methyltransferase activity (TPMT), a major determinant of TPD toxicity, before TPD treatment using 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrate was suggested. However, the equivalent of the two substrates in TPMT activity evaluation was unknown, and an alternative substrate was required in TPMT activity evaluation in patients who were already taking 6-MP or 6-TG. Before evaluating the agreement of 6-MP and 6-TG in TPMT activity measurement in patients with NMOSD, the affinity of the two substrates for the active center of TPMT should be established...
February 17, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28140508/identifying-unknown-enzyme-substrate-pairs-from-the-cellular-milieu-with-native-mass-spectrometry
#9
Kalli C Catcott, Jing Yan, Wanlu Qu, Vicki H Wysocki, Zhaohui Sunny Zhou
The enzyme-substrate complex is inherently transient, rendering its detection difficult. In our framework designed for bisubstrate systems-isotope-labeled, activity-based identification and tracking (IsoLAIT)-the common substrate, such as S-adenosyl-l-methionine (AdoMet) for methyltransferases, is replaced by an analogue (e.g., S-adenosyl-l-vinthionine) that, as a probe, creates a tightly bound [enzyme⋅substrate⋅probe] complex upon catalysis by thiopurine-S-methyltransferase (TPMT, EC 2.1.1.67). This persistent complex is then identified by native mass spectrometry from the cellular milieu without separation...
January 31, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28110955/determination-of-inosine-5-monophosphate-dehydrogenase-activity-in-red-blood-cells-of-thiopurine-treated-patients-using-hplc
#10
Audrey Beringer, Antony Citterio-Quentin, Rebeca Obenza Otero, Clémence Gustin, Rebecca Clarke, Jean-Paul Salvi, Roselyne Boulieu
Thiopurine drugs are commonly used in immune diseases and to a lesser extent, in transplant rejection prophylaxis: however interindividual variability in drug response and in the occurrence of adverse events is observed. Genetic variation in thiopurine S-methyltransferase (TPMT) doesn't completely explain the occurrence of all adverse events and drug response variability. The potential implication of other enzymes involved in thiopurine metabolism, such as ITPA, has been investigated over the last decade but little data is available on inosine 5'-monophosphate dehydrogenase (IMPDH) in patients treated with thiopurine drugs...
February 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28081040/azathioprine-therapy-in-a-pediatric-tpmt-deficient-patient-still-an-option
#11
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
#12
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/28004405/expert-clinical-management-of-autoimmune-hepatitis-in-the-real-world
#13
R Liberal, Y S de Boer, R J Andrade, G Bouma, G N Dalekos, A Floreani, D Gleeson, G M Hirschfield, P Invernizzi, M Lenzi, A W Lohse, G Macedo, P Milkiewicz, B Terziroli, B van Hoek, J M Vierling, M A Heneghan
BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH...
March 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27943397/early-prediction-of-thiopurine-induced-hepatotoxicity-in-inflammatory-bowel-disease
#14
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/27770449/polymorphic-variation-in-tpmt-is-the-principal-determinant-of-tpmt-phenotype-a-meta-analysis-of-three-genome-wide-association-studies
#15
R Tamm, R Mägi, R Tremmel, S Winter, E Mihailov, A Smid, A Möricke, K Klein, M Schrappe, M Stanulla, R Houlston, R Weinshilboum, Irena Mlinarič Raščan, A Metspalu, L Milani, M Schwab, E Schaeffeler
Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases...
May 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27720019/pharmacogenomics-and-adverse-drug-reactions-primetime-and-not-ready-for-primetime-tests
#16
REVIEW
David A Khan
Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which genetics contributes to ADRs is not entirely clear and varies by drug, as well as the type of ADR. Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively...
October 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27686002/randomized-clinical-trial-a-pilot-study-comparing-efficacy-of-low-dose-azathioprine-and-allopurinol-to-azathioprine-on-clinical-outcomes-in-inflammatory-bowel-disease
#17
Marianne Kiszka-Kanowitz, Klaus Theede, Anette Mertz-Nielsen
BACKGROUND: Treating inflammatory bowel diseases (IBD) using thiopurines is effective; however, a high rate of adverse effects and lack of efficacy limit its use. Retrospective studies have suggested that treatment with low-dose thiopurines in combination with allopurinol is associated with higher remission rates and lower incidence of adverse events. AIM: To compare the rates of clinical remission and the rates of adverse events in IBD patients treated with either standard treatment with azathioprine or low-dose azathioprine in combination with allopurinol...
December 2016: Scandinavian Journal of Gastroenterology
https://www.readbyqxmd.com/read/27665263/frequency-of-thiopurine-methyltransferase-mutation-in-patients-of-mediterranean-area-with-inflammatory-bowel-disease-and-autoimmune-disorders
#18
Angela Di Salvo, Carmelo Fabiano, Vincenza Mannara, Mariangela Dimarco, Ambrogio Orlando, Marco Affronti, Fabio Salvatore Macaluso, Mario Cottone
BACKGROUND AND AIMS: Few studies exist on the frequency of thiopurine methyltransferase (TPMT) mutation in patients from Southern Europe. We aimed to evaluate the frequency of TPMT mutation in a homogeneous Sicilian cohort of patients with inflammatory bowel disease (IBD), autoimmune and hematological disorders, the rate of thiopurine-related adverse events, and its association with the TPMT genotype. RESULTS: Among 105 patients with IBD, 45 with autoimmune disease, and 34 with hematologic diseases, the homozygous TPMT variant genotype was found in one patient only (0...
December 2016: Digestive and Liver Disease
https://www.readbyqxmd.com/read/27640357/measuring-erythrocyte-thiopurine-methyltransferase-activity-in-children-is-it-helpful
#19
Alison L T Ma, Gregory Bale, Helen Aitkenhead, Stephen D Marks
OBJECTIVE: To assess the profile of thiopurine transmethyltransferase (TPMT) enzyme activities in children and discuss the utility of measuring TPMT levels before commencing azathioprine therapy. STUDY DESIGN: Retrospective study in a single pediatric center of all patients who had TPMT enzyme assay measured during a 3-year period before the start of azathioprine therapy. Patients' TPMT enzyme activities were classified as normal (26-50 pmol/h/mgHb), intermediate (10-25 pmol/h/mgHb), and deficient (<10 pmol/h/mgHb)...
September 15, 2016: Journal of Pediatrics
https://www.readbyqxmd.com/read/27604507/nudt15-polymorphisms-are-better-than-thiopurine-s-methyltransferase-as-predictor-of-risk-for-thiopurine-induced-leukopenia-in-chinese-patients-with-crohn-s-disease
#20
X Zhu, X-D Wang, K Chao, M Zhi, H Zheng, H-L Ruan, S Xin, N Ding, P-J Hu, M Huang, X Gao
BACKGROUND: Thiopurine-induced leukopenia is the most common dangerous adverse event in Asians. NUDT15 R139C was recently proposed to be a promising biomarker for leukopenia with thiopurine therapy in Asians, but this has not been replicated in the Chinese population. AIM: To investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), 6-TGN and 6-MMPR on thiopurine-induced leukopenia in Chinese patients with Crohn's disease. METHODS: Clinical and epidemiological characteristics were reviewed from medical records...
November 2016: Alimentary Pharmacology & Therapeutics
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