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Nicholas E Burgis
Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy)nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5'-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools...
October 22, 2016: Journal of Biomedical Science
Riin Tamm, Reedik Mägi, Roman Tremmel, Stefan Winter, Evelin Mihailov, Alenka Smid, Anja Möricke, Kathrin Klein, Martin Schrappe, Martin Stanulla, Richard Houlston, Richard Weinshilboum, Irena Mlinarič Raščan, Andres Metspalu, Lili Milani, Matthias Schwab, Elke Schaeffeler
Thiopurine-related hematotoxicity in paediatric 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 paediatric ALL-cases...
October 22, 2016: Clinical Pharmacology and Therapeutics
Anastasiya Latushko, Leyla J Ghazi
No abstract text is available yet for this article.
October 20, 2016: Digestive Diseases and Sciences
Gabriella Bröms, Fredrik Granath, Olof Stephansson, Helle Kieler
BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) have been associated with an increased risk of preterm birth. MATERIAL AND METHODS: We identified all 246 singleton preterm births among women with IBD between July 2006 and December 2010 as cases and an equal number of controls with IBD from the Swedish national health registers, matched by maternal age, parity and IBD diagnosis (CD/UC). From register data and medical charts, we obtained information on reproductive history, comorbidity, disease activity and drug treatment (corticosteroids, 5-aminosalicylates, sulfasalazine, thiopurines and anti-TNF) as risk factors for preterm birth...
December 2016: Scandinavian Journal of Gastroenterology
Ray K Boyapati, Gwo-Tzer Ho, Jack Satsangi
No abstract text is available yet for this article.
October 5, 2016: Clinical Gastroenterology and Hepatology
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
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
Makoto Naganuma, Shinta Mizuno, Kosaku Nanki, Shinya Sugimoto, Takanori Kanai
Recently, several medical treatments for ulcerative colitis (UC) have been developed, including 5-aminosalicylic acids (5-ASAs), corticosteroids, thiopurine, calcineurin inhibitors, and anti-tumor necrosis factor (TNF) α treatments. Treatment options including calcineurin inhibitors and anti-TNF treatment for refractory UC are discussed in this article. Furthermore, upcoming treatments are introduced, such as golimumab, vedolizumab, AJM300, tofacitinib. Budesonide foamwill be used as one treatment option in patients with distal colitis...
October 3, 2016: Clinical Journal of Gastroenterology
Wiem Chaabane, Malin Lindqvist Appell
Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are a class of genotoxic drugs extensively used in the treatment of various illnesses including leukemia. Their underlying molecular mechanism of action involves the activation of apoptosis and autophagy but remains widely unclear. Here we present evidence that autophagy induction by thiopurines is a survival mechanism that antagonizes apoptosis and is involved in degrading damaged mitochondria through mitophagy. On the other hand, apoptosis is the main cell death mechanism by thiopurines as its inhibition prohibited cell death...
September 28, 2016: Oncotarget
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
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...
September 1, 2016: Digestive and Liver Disease
Einar S Björnsson, Jiezhun Gu, David E Kleiner, Naga Chalasani, Paul H Hayashi, Jay H Hoofnagle
OBJECTIVE: The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines. BACKGROUND: Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist. METHODS: Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed. RESULTS: Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%)...
June 14, 2016: Journal of Clinical Gastroenterology
Takuya Yoshino, Makoto Sono, Shujiro Yazumi
BACKGROUND: Patients with refractory-ulcerative colitis (UC) require therapy escalation. Sulfasalazine (SASP) could deliver a high concentration of 5-aminosalicylic acid to the colon. The usefulness of SASP for refractory-UC patients, however, is unclear. AIM: The aim was to evaluate the usefulness of SASP for refractory-UC patients. METHOD: We retrospectively analysed 36 (11.4%) of 316 patients with refractory-UC who had been treated with SASP...
2016: BMJ Open Gastroenterology
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
Edward L Barnes, Alison Goldin, Rachel W Winter, Emily Collins, Bonnie Cao, Madeline Carrellas, Anne Marie Crowell, Joshua R Korzenik
BACKGROUND: The benefits of combination therapy with infliximab and azathioprine have been demonstrated in clinical trials of patients with ulcerative colitis (UC) and Crohn's disease (CD). Concerns remain regarding the ideal duration and benefits of adding therapies in a sequential manner. AIMS: We aim to compare long-term outcomes among patients with inflammatory bowel disease (IBD) treated with sequentially added combination therapy or monotherapy strategies ...
November 2016: Digestive Diseases and Sciences
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
Margien L Seinen, Geerten P van Nieuw Amerongen, Nanne K H de Boer, Adriaan A van Bodegraven
The incidence and prevalence of inflammatory bowel disease (IBD) are increasing. Although the etiology of IBD is unknown, it is thought that genetically susceptible individuals display an inappropriate inflammatory response to commensal microbes, resulting in intestinal tissue damage. Key proteins involved in regulating the immune response, and thus in inflammation, are the small triphosphate-binding protein Rac and its regulatory network. Recent data suggest these proteins to be involved in (dys)regulation of the characteristic inflammatory processes in IBD...
September 7, 2016: Molecular Diagnosis & Therapy
Ingolf Cascorbi, Anneke Nina Werk
INTRODUCTION: 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)...
September 16, 2016: Expert Opinion on Drug Metabolism & Toxicology
Justin Côté-Daigneault, Farhad Peerani, Eithne MacMahon, Emmanuel Delaporte, Jean-François Rahier, Jean-Frédéric Colombel
Crohn's disease (CD) and ulcerative colitis (UC), the 2 main clinical phenotypes of inflammatory bowel disease (IBD), are diseases that result from a dysregulated immune response to gut microbiota in genetically susceptible hosts. This aberrant immune response may intrinsically predispose IBD patients to infectious complications. Moreover, immunosuppressive medications used to treat IBD including corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-tumor necrosis factor (anti-TNF) agents and other biologics, further increase patients' susceptibility to opportunistic infections...
October 2016: Inflammatory Bowel Diseases
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...
August 31, 2016: Pediatric Blood & Cancer
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