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Thiopurine methyltransferase

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https://www.readbyqxmd.com/read/29867468/nudt15-r139c-variants-increase-the-risk-of-azathioprine-induced-leukopenia-in-chinese-autoimmune-patients
#1
Xiang Fei, Qing Shu, Huaijun Zhu, Bingzhu Hua, Shiying Wang, Ling Guo, Yun Fang, Weihong Ge
The aim of this study was to investigate the influence of NUDT15 R139C , thiopurine S-methyltransferase ( TPMT ), and 6-TGN on azathioprine (AZA) induced leukopenia in Chinese autoimmune patients. Among 87 enrolled patients, 23 (26.4%) had leukopenia. The NUDT15 R139C variant was associated with leukopenia ( p = 1.86 × 10-7 ; OR: 7.59; 95% CI: 3.16-18.21). However, TPMT genotype was not shown to be correlated with the incidence of leukopenia ( p = 0.95). There was no significant difference of 6-TGN concentration between patients with or without leukopenia ( p = 0...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29843045/drug-metabolizing-enzymes-and-their-inhibitors-role-in-cancer-resistance
#2
REVIEW
Shelly Pathania, Rohit Bhatia, Ashish Baldi, Randhir Singh, Ravindra K Rawal
Despite continuous research on chemotherapeutic agents, different mechanisms of resistance have become a major pitfall in cancer chemotherapy. Although, exhaustive efforts are being made by several researchers to target resistance against chemotherapeutic agents, there is another class of resistance mechanism which is almost carrying on unattended. This class of resistance includes pharmacokinetics resistance such as efflux by ABC transporters and drug metabolizing enzymes. ABC transporters are the membrane bound proteins which are responsible for the movement of substrates through the cell membrane...
May 26, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29801578/the-pharmacogenetics-of-immune-modulating-therapy
#3
Ingolf Cascorbi
Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies-depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC efflux transporters were investigated, however, with partly contradicting results...
2018: Advances in Pharmacology
https://www.readbyqxmd.com/read/29752633/clinical-pharmacokinetic-and-pharmacodynamic-considerations-in-the-treatment-of-ulcerative-colitis
#4
REVIEW
Sophie E Berends, Anne S Strik, Mark Löwenberg, Geert R D'Haens, Ron A A Mathôt
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology, probably caused by a combination of genetic and environmental factors. The treatment of patients with active UC depends on the severity, localization and history of IBD medication. According to the classic step-up approach, treatment with 5-aminosalicylic acid compounds is the first step in the treatment of mild to moderately active UC. Corticosteroids, such as prednisolone are used in UC patients with moderate to severe disease activity, but only for remission induction therapy because of side effects associated with long-term use...
May 12, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29742281/analyzing-the-clinical-actionability-of-germline-pharmacogenomic-findings-in-oncology
#5
Rebecca Wellmann, Brittany A Borden, Keith Danahey, Rita Nanda, Blase N Polite, Walter M Stadler, Mark J Ratain, Peter H O'Donnell
BACKGROUND: Germline and tumor pharmacogenomics impact drug responses, but germline markers less commonly guide oncology prescribing. The authors hypothesized that a critical number of clinically actionable germline pharmacogenomic associations exist, representing clinical implementation opportunities. METHODS: In total, 125 oncology drugs were analyzed for positive germline pharmacogenomic associations in journals with impact factors ≥5. Studies were assessed for design and genotyping quality, clinically relevant outcomes, statistical rigor, and evidence of drug-gene effects...
May 9, 2018: Cancer
https://www.readbyqxmd.com/read/29720911/association-between-thiopurine-s-methyltransferase-tpmt-genetic-variants-and-infection-in-pediatric-heart-transplant-recipients-treated-with-azathioprine-a-multi-institutional-analysis
#6
Dionna J Green, Son Q Duong, Gilbert J Burckart, Tristan Sissung, Douglas K Price, William D Figg, Maria M Brooks, Richard Chinnock, Charles Canter, Linda Addonizio, Daniel Bernstein, David C Naftel, Adriana Zeevi, James K Kirklin, Steven A Webber, Brian Feingold
OBJECTIVES: Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine S -methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection...
March 2018: Journal of Pediatric Pharmacology and Therapeutics: JPPT: the Official Journal of PPAG
https://www.readbyqxmd.com/read/29659353/-genetic-polymorphisms-of-thiopurine-methyltransferase-and-incidence-of-adverse-events-in-patients-with-medical-indication-of-azathioprine
#7
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/withdrawn-association-between-tpmt-3c-and-decreased-thiopurine-s-methyltransferase-activity-in-patients-with-neuromyelitis-optica-spectrum-disorders-in-china
#8
Xiaoqing Gong, Shenghui Mei, Xindi Li, Xingang Li, Heng Zhou, Yonghong Liu, Anna Zhou, Li Yang, Zhigang Zhao, Xinghu Zhang
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
March 11, 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
#9
Hlaing H Maw, Xingzhong Zeng, Scot Campbell, Mitchell E Taub, Aaron M Teitelbaum
BI 187004, an 11 β -hydroxysteroid dehydrogenase 1 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 [ N -methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes 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...
June 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
#10
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
#11
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
#12
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
#13
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...
April 2018: Clinical Biochemistry
https://www.readbyqxmd.com/read/29421584/effective-long-term-solution-to-therapeutic-remission-in-inflammatory-bowel-disease-role-of-azathioprine
#14
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...
April 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29387964/role-of-tpmt-and-itpa-variants-in-mercaptopurine-disposition
#15
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...
March 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
#16
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
#17
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
#18
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
#19
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
#20
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
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