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Thiopurine methyltransferase

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https://www.readbyqxmd.com/read/29659353/-genetic-polymorphisms-of-thiopurine-methyltransferase-and-incidence-of-adverse-events-in-patients-with-medical-indication-of-azathioprine
#1
Manuel A Buhl, Graciela Gómez, María Victoria Collado, Elisabet M Oddo, Marina Khoury, Pablo J Azurmendi, Judith Sarano
Azathioprine is a thiopurine which has a narrow therapeutic index and marked hematological and hepatic toxicity. Thiopurine s-methyltransferase is an enzyme involved in the metabolism of thiopurines. Mutations in the gene that encodes the enzyme may augment the risk of adverse events. For that reason, pharmacogenetic determinations prior to the initiation of therapy can provide useful information for the future therapeutic strategy. Nevertheless, its utility in the local environment is not completely established...
2018: Medicina
https://www.readbyqxmd.com/read/29534852/association-between-tpmt-3c-and-decreased-thiopurine-s-methyltransferase-activity-in-patients-with-neuromyelitis-optica-spectrum-disorders-in-china
#2
Xiaoqing Gong, Shenghui Mei, Xindi Li, Xingang Li, Heng Zhou, Yonghong Liu, Anna Zhou, Li Yang, Zhigang Zhao, Xinghu Zhang
Thiopurines (TPRs) are effective drugs in treating neuromyelitis optica spectrum disorders (NMOSD) and other diseases. TPRs' toxicity is mainly imputed to thiopurine S-methyltransferase (TPMT) activity. In Chinese population, the most common and important variation of TPMT is TPMT*3C (rs1142345). This study aims to reveal the association between TPMT activity and genetic polymorphisms of TPMT in patients with NMOSD in China. An LC-MS/MS method was used to evaluate the TPMT activity by using 6-mercapthioprine as substrate in human erythrocyte hemolysate via 1 h incubation at 37 °C to form its methylated product 6-methylmercaptopurine (6-MMP)...
March 10, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/29514826/n-methylation-of-bi-187004-by-thiol-s-methyltransferase
#3
Hlaing H Maw, Xingzhong Zeng, Scot Campbell, Mitchell E Taub, Aaron M Teitelbaum
BI 187004, an 11β-hydroxysteroid dehydrogenase 1 (HSD) inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N-methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite (M1) was 7 fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzyme(s) responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors...
March 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29484155/a-practical-guide-to-thiopurine-prescribing-and-monitoring-in-ibd
#4
REVIEW
Ben Warner, Emma Johnston, Monica Arenas-Hernandez, Anthony Marinaki, Peter Irving, Jeremy Sanderson
Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease. As such, a general understanding of the evidence behind their use and of their metabolism is extremely useful in clinical practice. This review gives a practical overview of thiopurine metabolism, the importance of thiopurine S-methyltransferase testing prior to the start of therapy and the monitoring of thioguanine nucleotide levels while on treatment, guiding a personalised approach to optimising thiopurine therapy...
January 2018: Frontline Gastroenterology
https://www.readbyqxmd.com/read/29470173/preemptive-nudt15-genotyping-redefining-the-management-of-patients-with-thiopurine-induced-toxicity
#5
Swarup A V Shah, Minal U Paradkar, Devendra C Desai, Tester F Ashavaid
BACKGROUND: Thiopurine methyltransferase (TPMT) gene variants have achieved limited success in predicting the outcome of thiopurine therapy, which shows wide inter-individual variations. The literature indicates a strong association between the NUDT15 gene variant and thiopurine-induced toxicity in Asian patients. The present study intends to explore the role of the NUDT15 variant (C415T) in Indian patients on thiopurine therapy. METHODS: NUDT15 and TPMT genotyping were performed using amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) and the restriction fragment length polymorphism (RFLP) technique...
March 28, 2018: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29444714/thiopurine-s-methyltransferase-activity-in-nigerians-phenotypes-and-activity-reference-values
#6
Ayorinde Adehin, Oluseye O Bolaji
OBJECTIVES: This study assessed the activity of thiopurine S-methyltransferase (TPMT) in Nigerians with a view to providing data on susceptibility to thiopurine toxicity, and as well generate reference activity values for clinical use. RESULTS: TPMT activity, expressed as the amount of 6MMP in ng/mL after 1 h incubation at 37 °C per haemoglobin (U/g Hb), varied between 2.34 and 63.50 U/g Hb in the study population. Poor metabolic phenotypes, characterised by an activity values below 8...
February 14, 2018: BMC Research Notes
https://www.readbyqxmd.com/read/29425801/analytical-and-clinical-validation-of-an-lc-ms-ms-method-to-measure-thiopurine-s-methyltransferase-activity-by-quantifying-d3-6-mmp
#7
Jing Ma, Christiaan W Sies, Linda S Pike
BACKGROUND: Identification of patients with thiopurine S-methyltransferase (TPMT) deficiency prior to thiopurine drug therapy has become routine clinical practice worldwide. To measure TPMT activity, traditional radiochemical assays have been replaced by chromatographic methods. METHOD: Inspired by the increasing number of isotope labelled sources that may be of benefit for the TPMT assay, a new LC-MS/MS method for TPMT activity was developed and validated. Isotope labelled d3-S-adenosyl-l-methionine (d3-SAM) was selected for the enzymatic methylation of mercaptopurine during sample incubation; d3-6-methylmercaptopurine (d3-6-MMP) with d2-2, 8-hypoxanthine as the internal standard was quantified to ascertain individual TPMT activity...
February 6, 2018: Clinical Biochemistry
https://www.readbyqxmd.com/read/29421584/effective-long-term-solution-to-therapeutic-remission-in-inflammatory-bowel-disease-role-of-azathioprine
#8
REVIEW
Lyla Adam, Alisa Phulukdaree, Prashilla Soma
Azathioprine (AZA) is a well-known immunosuppressant used for many years for its ability to ensure long term disease remission in inflammatory bowel diseases (IBD) at an affordable cost to the public. However, the side effect profile has raised many concerns with numerous investigations into the risk, cause and prevention of these effects. Much of the side effect profile of AZA can be linked to a single nucleotide polymorphism (SNP) in the thiopurine methyltransferase (TPMT) gene which ensures the breakdown and efficacy of AZA...
February 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29387964/role-of-tpmt-and-itpa-variants-in-mercaptopurine-disposition
#9
Tina Gerbek, Maria Ebbesen, Jacob Nersting, Thomas L Frandsen, Malin Lindqvist Appell, Kjeld Schmiegelow
PURPOSE: To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. METHODS: Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen...
February 1, 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29373914/genetic-polymorphism-of-thiopurine-s-methyltransferase-in-children-with-acute-lymphoblastic-leukemia-in-jordan
#10
Mervat Alsous, Al-Motassem Yousef, Mariam Abdel Jalil, Mohammed Zawiah, Shorouq Yacoub, Deema Momani, Alia Gharabli, Suha Omar, Rawad Rihani
Background and Aims: It has been demonstrated that homozygote and heterozygote mutant allele carriers for thiopurine S-methyltransferase (TPMT) are at high risk of developing myelosuppression after receiving standard doses of 6-mercaptopurine (6-MP). The aim of this study was to determine the frequency of TPMT deficient alleles in children with acute lymphoblastic leukemia (ALL) in Jordan and to compare it with other ethnic groups. Methods: We included 52 ALL childhood cases from King Hussein Cancer Research Center in Jordan...
January 27, 2018: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/29370945/-usefulness-of-thiopurine-methyltransferase-polymorphism-study-and-metabolites-measurement-for-patients-treated-by-azathioprine
#11
V Guillotin, G Galli, J-F Viallard
Azathioprine is widely used in internal medicine and frequently implicated in occurrence of adverse events. Among these adverse events the bone marrow suppression, a dose-related one, is the most serious because of is potential morbidity and mortality. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism that results in a high variability of its activity with 89% of patients with a normal activity, 11% with an intermediate activity, and 0...
January 19, 2018: La Revue de Médecine Interne
https://www.readbyqxmd.com/read/29357999/recommendations-of-the-spanish-working-group-on-crohn-s-disease-and-ulcerative-colitis-geteccu-on-the-use-of-tiopurines-in-inflammatory-bowel-disease
#12
Fernando Bermejo, Mariam Aguas, María Chaparro, Eugeni Domènech, Ana Echarri, Esther García-Planella, Iván Guerra, Javier P Gisbert, Antonio López-Sanromán
Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects...
March 2018: Gastroenterología y Hepatología
https://www.readbyqxmd.com/read/29351371/implementation-of-standardized-clinical-processes-for-tpmt-testing-in-a-diverse-multidisciplinary-population-challenges-and-lessons-learned
#13
Kristin W Weitzel, D Max Smith, Amanda R Elsey, Benjamin Q Duong, Benjamin Burkley, Michael Clare-Salzler, Yan Gong, Tara A Higgins, Benjamin Kong, Taimour Langaee, Caitrin W McDonough, Benjamin J Staley, Teresa T Vo, Dyson T Wake, Larisa H Cavallari, Julie A Johnson
Although thiopurine S-methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme)...
March 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29350448/clinical-and-genetic-associations-for-carboplatin-related-ototoxicity-in-children-treated-for-retinoblastoma-a-retrospective-noncomparative-single-institute-experience
#14
Sameh E Soliman, Crystal N D'Silva, Helen Dimaras, Irakli Dzneladze, Helen Chan, Brenda L Gallie
BACKGROUND: Children with retinoblastoma treated with carboplatin chemotherapy risk moderate to severe, irreversible hearing loss. Based on published evidence, we hypothesized that ototoxicity risk is associated with clinical parameters and variants in candidate genes in drug metabolism pathways (methyltransferases [thiopurine S-methyltransferase, TPMT] and [catechol-O-methyltransferase, COMT], and drug transporter ABCC3). PROCEDURE: We retrospectively reviewed clinical records of patients with retinoblastoma treated with carboplatin chemotherapy regarding age (at diagnosis and chemotherapy initiation), chemotherapy sessions (cycles number, drug doses, and cumulative carboplatin dose), and hearing loss (defined as ototoxicity ≥grade 2 by at least one classification system)...
May 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29321348/influence-of-thiopurine-methyltransferase-gene-polymorphism-on-egyptian-children-with-acute-lymphoblastic-leukaemia
#15
Azza A G Tantawy, Fatma S E Ebeid, Amira A M Adly, Eman El-Ghoroury, Mai Mostafa
Thiopurine methyltransferase (TPMT) gene polymorphism regulates thiopurine therapeutic efficacy and toxicity. The aim of this study was to determine the influence of TPMT gene polymorphism in Egyptian children with acute lymphoblastic leukaemia (ALL). Sixty-four patients with ALL, T lineage (27%) and pre-B phenotype (73%), who were treated with BFM 90 or CCG 1991 standard risk protocol, and who also experiencedmyleosuppresion toxicity and required interruption and/ormodification of thiopurine chemotherapy were recruited over a year period...
December 2017: Journal of Genetics
https://www.readbyqxmd.com/read/29194039/validation-of-a-high-performance-liquid-chromatography-method-for-thiopurine-s-methyltransferase-activity-in-whole-blood-using-6-mercaptopurine-as-substrate
#16
Hannah Rieger, Patrik Schmidt, Elke Schaeffeler, Manabu Abe, Mira Schiffhauer, Matthias Schwab, Nicolas von Ahsen, Gabriela Zurek, Hartmut Kirchherr, Maria Shipkova, Eberhard Wieland
BACKGROUND: Variation in metabolism, toxicity and therapeutic efficacy of thiopurine drugs is largely influenced by genetic polymorphisms in the thiopurine S-methyltransferase (TPMT) gene. Determination of TPMT activity is routinely performed in patients to adjust drug therapy. METHODS: We further optimized a previously established high-performance liquid chromatography (HPLC) method by measuring TPMT activity in whole blood instead of isolated erythrocytes, which is based on conversion of 6-mercaptopurine to 6-methylmercaptopurine using S-adenosyl-methionine as methyl donor...
December 1, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/29192347/pharmacogenetics-of-thiopurines-for-inflammatory-bowel-disease-in-east-asia-prospects-for-clinical-application-of-nudt15-genotyping
#17
REVIEW
Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa
The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations...
February 2018: Journal of Gastroenterology
https://www.readbyqxmd.com/read/29191122/association-between-tpmt-3c-and-decreased-thiopurine-s-methyltransferase-activity-in-patients-with-neuromyelitis-optica-spectrum-disorders-in-china
#18
Xiaoqing Gong, Shenghui Mei, Xindi Li, Xingang Li, Heng Zhou, Yonghong Liu, Anna Zhou, Li Yang, Zhigang Zhao, Xinghu Zhang
AIM OF THE STUDY: Thiopurines are effective drugs in treating neuromyelitis optica spectrum disorders and other diseases. Thiopurines' toxicity is mainly imputed to thiopurine S-methyltransferase activity. In Chinese population, the most common and important variation of thiopurine S-methyltransferase is TPMT*3C (rs1142345). This study aims to reveal the association between thiopurine S-methyltransferase activity and genetic polymorphisms of thiopurine S-methyltransferase in patients with neuromyelitis optica spectrum disorders in China...
December 1, 2017: International Journal of Neuroscience
https://www.readbyqxmd.com/read/29147133/allopurinol-in-combination-with-thiopurine-induces-mucosal-healing-and-improves-clinical-and-metabolic-outcomes-in-ibd
#19
Brigitte Moreau, Pierre Clement, Yves Theoret, Ernest G Seidman
Background: Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD...
November 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/29065511/novel-tetra-primer-arms-pcr-assays-for-thiopurine-intolerance-susceptibility-mutations-nudt15-c-415c-t-and-tpmt-c-719a-g-tpmt-3c-in-east-asians
#20
Chi-Chun Ho, Wai-Ying Fong, Yuen-Hon Lee, Wing-Tat Poon
Thiopurines are clinically useful in the management of diverse immunological and malignant conditions. Nevertheless, these purine analogues can cause lethal myelosuppression, which may be prevented by prospective testing for variants in the thiopurine S-methyltransferase ( TPMT ) and, in East Asians, Nudix hydrolase 15 ( NUDT15 ) genes. Two single-tube, tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR) assays were developed to genotype the common loss-of-function variants NUDT15 c...
October 23, 2017: Genes
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