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https://www.readbyqxmd.com/read/28346068/institutional-profile-university-of-florida-health-personalized-medicine-program
#1
Larisa H Cavallari, Kristin W Weitzel, Amanda R Elsey, Xinyue Liu, Scott A Mosley, Donald M Smith, Benjamin J Staley, Almut G Winterstein, Carol A Mathews, Francesco Franchi, Fabiana Rollini, Dominick J Angiolillo, Petr Starostik, Michael J Clare-Salzler, David R Nelson, Julie A Johnson
The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations...
March 27, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28321040/whole-exome-sequencing-detects-variants-of-genes-that-mediate-response-to-anticancer-drugs
#2
Sumiko Ohnami, Takeshi Nagashima, Kenichi Urakami, Yuji Shimoda, Fukumi Kamada, Junko Saito, Akane Naruoka, Masakuni Serizawa, Yoko Masuda, Shumpei Ohnami, Masatoshi Kusuhara, Ken Yamaguchi
Certain interindividual differences affecting the efficacy of drug treatment and adverse drug reactions are caused by genetic variants, and their phenotypic effects differ among ethnic groups. In this study, we used whole exome sequencing (WES) systematically to identify germline mutations that influence the activities of drug-metabolizing enzymes, as well as that of a transporter. We analyzed DNA isolated from blood samples from 2,042 Japanese patients with diverse cancers. We identified sequence variants of CYP2B6 (rs3745274), CYP2C9 (rs1057910), CYP2C19 (rs4986893), CYP2C19 (rs4244285), TPMT (rs1142345), NAT2 (rs1799930), NAT2 (rs1799931), UGT1A1 (rs4148323), COMT (rs4680), ABCB1 (rs1045642), and CDA (rs60369023)...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28317081/pharmacogenetic-predictors-of-treatment-related-toxicity-among-children-with-acute-lymphoblastic-leukemia
#3
REVIEW
Rochelle R Maxwell, Peter D Cole
PURPOSE OF REVIEW: The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). RECENT FINDINGS: Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities...
March 20, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28295989/pharmacokinetics-of-two-6-mercaptopurine-liquid-formulations-in-children-with-acute-lymphoblastic-leukemia
#4
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/28277331/nudt15-genotype-distributions-in-the-korean-population
#5
Hyoung-Tae Kim, Rihwa Choi, Hong-Hee Won, Yon Ho Choe, Ben Kang, Kiwuk Lee, Hong Hoe Koo, Keon Hee Yoo, Young-Ho Kim, Soo-Youn Lee
Thiopurines have a narrow therapeutic range because of frequent toxicity (i.e. marrow suppression), which is only partly explained by TPMT genetic polymorphisms, especially within Asian populations. Recent studies have identified NUDT15 variation as another important factor affecting thiopurine metabolism. In this study, a total of four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal) were genotyped in 920 Korean individuals using direct sequencing of NUDT15 for the first time in a Korean population...
March 8, 2017: Pharmacogenetics and Genomics
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
#6
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
#7
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/28172435/p154-complete-sequence-based-nudt15-and-tpmt-variants-for-predicting-thiopurine-induced-leukopenia-in-patients-with-crohn-s-disease
#8
T J Kim, E R Kim, S N Hong, D K Chang, Y-H Kim
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28153823/comparison-of-self-report-and-electronic-monitoring-of-6mp-intake-in-childhood-all-a-children-s-oncology-group-study
#9
Wendy Landier, Yanjun Chen, Lindsey Hageman, Heeyoung Kim, Bruce C Bostrom, Jacqueline N Casillas, David S Dickens, William E Evans, Kelly W Maloney, Leo Mascarenhas, A Kim Ritchey, Amanda M Termuhlen, William L Carroll, Mary V Relling, F Lennie Wong, Smita Bhatia
Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; the accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]), and identify predictors of over-reporting in a cohort of 416 children with ALL in first remission over 4 study months per patient (1,344 patient-months for the cohort) during maintenance therapy...
February 2, 2017: Blood
https://www.readbyqxmd.com/read/28140508/identifying-unknown-enzyme-substrate-pairs-from-the-cellular-milieu-with-native-mass-spectrometry
#10
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
#11
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
#12
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
#13
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/27941536/lc-ms-ms-analysis-of-erythrocyte-thiopurine-nucleotides-and-their-association-with-genetic-variants-in-patients-with-neuromyelitis-optica-spectrum-disorders-taking-azathioprine
#14
Shenghui Mei, Xindi Li, Xiaoqing Gong, Xingang Li, Li Yang, Heng Zhou, Yonghong Liu, Anna Zhou, Leting Zhu, Xinghu Zhang, Zhigang Zhao
BACKGROUND: Azathioprine (AZA) is a first-line drug in treating neuromyelitis optica spectrum disorders (NMOSD). To exhibit its bioactivity, AZA needs to be converted to thiopurine nucleotides (TPNs) including 6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-MMPNs) that are affected by genetic polymorphisms. This study aims to develop an LC-MS/MS method for the analysis of erythrocyte concentrations of TPNs and to evaluate their associations with variants of various genes (MTHFR, TPMT, HLA, SLC29A1, SLC28A2, SLC28A3, ABCB1 and ABCC4) in patients with NMOSD...
November 29, 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27920553/meta-analysis-of-the-impact-of-thioprine-s-methyltransferase-polymorphisms-on-the-tolerable-6-mercaptopurine-dose-considering-initial-dose-and-ethnic-difference
#15
Myeong Gyu Kim, Minoh Ko, In-Wha Kim, Jung Mi Oh
A meta-analysis was conducted to decide whether to reduce an initial 6-mercaptopurine (6-MP) dose in TPMT heterozygote in the case of an initial 6-MP dose of <75 mg/m(2)/d and to compare the tolerable 6-MP dose among different ethnic groups. The study was undertaken according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The differences in mean values of the tolerable 6-MP dose were calculated by using Comprehensive Meta-Analysis version 3. The results of the meta-analysis indicated that the tolerable 6-MP dose was significantly lower in the TPMT heterozygote group (difference in mean values =11...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27809554/mercaptopurine-and-inflammatory-bowel-disease-the-other-thiopurine
#16
Fernando Bermejo San José, Alicia Algaba, Sergio López Durán, Iván Guerra, Marta Aicart, María Hernández-Tejero, Elena Garrido, María de Lucas, Daniel Bonillo, Antonio López Sanromán
BACKGROUND: Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited. AIMS: To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease. METHODS: Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease. RESULTS: One hundred and fifty-two patients received mercaptopurine, 15...
January 2017: Revista Española de Enfermedades Digestivas
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
#17
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/27729156/analysis-of-genetic-and-non-genetic-risk-factors-for-cisplatin-ototoxicity-in-pediatric-patients
#18
Yüksel Olgun, Safiye Aktaş, Zekiye Altun, Günay Kırkım, Deniz Çakır Kızmazoğlu, Ayşe Pınar Erçetin, Banu Demir, Dilek İnce, Kamer Mutafoğlu, Bengü Demirağ, Hülya Ellidokuz, Nur Olgun, Enis Alpin Güneri
OBJECTIVE: The aim of this study was to analyse the genetic and non genetic risk factors for cisplatin ototoxicity. METHODS: This study was conducted on 72 children who received cisplatin based chemotherapy. Brock and Muenster classifications were used to evaluate ototoxicity seen in these children. 6 single nucleotide polymorphisms (SNP); ERCC1 rs 11615, GSTP1 rs1138272, GSTP1 rs1695, LRP2 rs 2075252, TPMT rs 12201199, COMT rs 9332377, were evaluated as genetic factors by real time PCR...
November 2016: International Journal of Pediatric Otorhinolaryngology
https://www.readbyqxmd.com/read/27703193/genes-implicated-in-thiopurine-induced-toxicity-comparing-tpmt-enzyme-activity-with-clinical-phenotype-and-exome-data-in-a-paediatric-ibd-cohort
#19
Tracy Coelho, Gaia Andreoletti, James J Ashton, Akshay Batra, Nadeem Ahmad Afzal, Yifang Gao, Anthony P Williams, Robert M Beattie, Sarah Ennis
The aim of our study was to assess the utility of next generation sequencing (NGS) for predicting toxicity and clinical response to thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data for 100 patients were assessed against biochemically measured TPMT enzyme activity, clinical response and adverse effects. The TPMT gene and a panel of 15 other genes implicated in thiopurine toxicity were analysed using a gene based statistical test (SKAT-O test). Nine patients out of 100 (Crohn's disease- 67, ulcerative colitis- 23 and IBDU-10) had known TPMT mutations associated with deficient enzyme activity...
October 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27665263/frequency-of-thiopurine-methyltransferase-mutation-in-patients-of-mediterranean-area-with-inflammatory-bowel-disease-and-autoimmune-disorders
#20
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
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