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Thiopurine methyltransferase

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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
#1
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). Thiopurine S-methyltransferase activity (TPMT), a major determinant of TPDs toxicity, was suggested to be evaluated before TPDs treatment by using 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrate. However, the equivalent of the two substrates in TPMT activity evaluation was unknown, and alternative substrate was required in TPMT activity evaluation in patients who were already taking 6-MP or 6-TG...
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
#2
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, IsoLAIT (Isotope-Labeled, Activity-based Identification and Tracking), designed for bisubstrate systems, 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). Then, this persistent complex is 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
#3
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
#4
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
#5
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/28004405/expert-clinical-management-of-autoimmune-hepatitis-in-the-real-world
#6
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...
December 22, 2016: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27943397/early-prediction-of-thiopurine-induced-hepatotoxicity-in-inflammatory-bowel-disease
#7
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
#8
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...
October 22, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27720019/pharmacogenomics-and-adverse-drug-reactions-primetime-and-not-ready-for-primetime-tests
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/27603572/advances-and-challenges-in-hereditary-cancer-pharmacogenetics
#14
REVIEW
Ingolf Cascorbi, Anneke Nina Werk
Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. Areas covered: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)...
January 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/27577869/nudt15-and-tpmt-genetic-polymorphisms-are-related-to-6-mercaptopurine-intolerance-in-children-treated-for-acute-lymphoblastic-leukemia-at-the-children-s-cancer-center-of-lebanon
#15
Nathalie K Zgheib, Reem Akika, Rami Mahfouz, Carol Al Aridi, Khaled M Ghanem, Raya Saab, Miguel R Abboud, Nidale Tarek, Hassan El Solh, Samar A Muwakkit
BACKGROUND: Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases...
January 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27564568/genomewide-approach-validates-thiopurine-methyltransferase-activity-is-a-monogenic-pharmacogenomic-trait
#16
C Liu, W Yang, D Pei, C Cheng, C Smith, W Landier, L Hageman, Y Chen, J J Yang, K R Crews, N Kornegay, S E Karol, F L Wong, S Jeha, J T Sandlund, R C Ribeiro, J E Rubnitz, M L Metzger, C-H Pui, W E Evans, S Bhatia, M V Relling
We performed a genomewide association study (GWAS) of primary erythrocyte thiopurine S-methyltransferase (TPMT) activity in children with leukemia (n = 1,026). Adjusting for age and ancestry, TPMT was the only gene that reached genomewide significance (top hit rs1142345 or 719A>G; P = 8.6 × 10(-61) ). Additional genetic variants (in addition to the three single-nucleotide polymorphisms [SNPs], rs1800462, rs1800460, and rs1142345, defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype...
March 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27446822/thiopurines-in-the-management-of-crohn-s-disease-safety-and-efficacy-profile-in-patients-with-normal-tpmt-activity-a-retrospective-study
#17
Amine Benmassaoud, Xuanqian Xie, Motaz AlYafi, Yves Theoret, Alain Bitton, Waqqas Afif, Talat Bessissow
Background and Aims. Thiopurines are used in the treatment of Crohn's disease (CD) and thiopurine S-methyltransferase (TPMT) activity can guide thiopurine dosing to avoid adverse events. This retrospective study evaluated the safety and efficacy of starting thiopurines at low dose versus full dose in patients with CD and normal TPMT. Methods. This was a single center retrospective study including adult CD patients with normal TPMT levels (≥25 nmol/hr/g Hgb) who were followed for 1 year. Patients started at full dose of azathioprine (2-2...
2016: Canadian Journal of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/27446285/risk-factors-for-symptomatic-osteonecrosis-in-childhood-all-a-retrospective-study-of-a-slovenian-pediatric-all-population-between-1970-and-2004
#18
Nataša Karas-Kuželički, Simona Mencej-Bedrač, Janez Jazbec, Janja Marc, Irena Mlinarič-Raščan
Treatment induced non-traumatic osteonecrosis (ON) has been reported increasingly in children treated for acute lymphoblastic leukemia (ALL). Several risk factors for ON have been identified in childhood cancer patients; however, their diagnostic and prognostic power is limited and the etiology of the disease remains unclear. Therefore, a continuous effort is focused on the identification of additional ON risk factors. We performed a retrospective study of 313 childhood ALL patients to test the association between the ON occurrence in children receiving ALL therapy and common polymorphisms in potential target genes: Thiopurine S-methyltransferase (TPMT; 460G>A, 719A>G), 5,10-methylenetetrahydrofolate reductase (MTHFR; 677C>T, 1298A>C), estrogen receptor alpha 1 (ESR1; XbaI) and collagen type I, α1 (COL1A1; Sp1)...
August 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27430038/-an-infected-necrosis-of-the-chin
#19
B S Muller, H F van Goor, A J W P Rosenberg
A 51-year-old man was referred by his dentist to a maxillofacial surgeon with complaints of illness and pain in the mandible, associated with a rapidly expanding area of black gingiva and mucosa surrounding the lower front teeth. Clinically and radiographically there was evidence of an infected necrosis of the chin and floor of mouth. Following debridement at the operating room, the patient was treated at the intensive care unit for septic shock leading to prolonged hospitalisation. Investigation of the bone marrow did not provide an explanation for pancytopenia or the severity of the illness...
July 2016: Nederlands Tijdschrift Voor Tandheelkunde
https://www.readbyqxmd.com/read/27416873/nudt15-c415t-variant-as-a-predictor-for-thiopurine-induced-toxicity-in-indian-patients
#20
Swarup A V Shah, Minal Paradkar, Devendra Desai, Tester F Ashavaid
BACKGROUND & AIM: Inter-individual variation seen in the thiopurine metabolism is attributed to the genetic variant in Thiopurine methyltransferase (TPMT) gene leading to myelosuppression. In Asians, the thiopurine-induced toxicity is not completely explained by TPMT variants. Literature indicates that a newer genetic variant in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene is associated with thiopurine intolerance. We aimed to determine the risk allele frequency of NUDT15 genetic variant and it's association with thiopurine-induced toxicity in Indian patients...
July 15, 2016: Journal of Gastroenterology and Hepatology
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