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Thiopurine metabolites

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https://www.readbyqxmd.com/read/28740837/histological-remission-of-autoimmune-hepatitis-after-the-addition-of-allopurinol-and-azathioprine-dose-reduction
#1
Ana Luiza Vilar Guedes, Adriana Ribas Andrade, Vinicius Santos Nunes, Fabiana Roberto Lima, Evandro Sobroza de Mello, Suzane Kioko Ono, Débora Raquel Benedita Terrabuio, Eduardo Luiz Rachid Cançado
The standard therapy for some autoimmune diseases consists of a combination of corticosteroids and thiopurines. In non-responders to thiopurine drugs, the measurement of the metabolites of azathioprine, 6-thioguanine, and 6-methylmercaptopurine, can be a useful tool. The measurement has been used during the treatment of inflammatory bowel diseases and, less commonly, in autoimmune hepatitis. Many patients preferentially metabolize thiopurines to 6-methylmercaptopurine (6-MMP), which is potentially hepatotoxic, instead of 6-thioguanine, the active immunosuppressive metabolite...
April 2017: Autopsy & case reports
https://www.readbyqxmd.com/read/28731668/-azathioprine-induced-pancytopenia-case-series
#2
Cristina Martínez Faci, Ignacio Ros Arnal, José M Martínez de Zabarte Fernández, Jordi Sorribes Estorch, Mónica López Campos, Carmen Rodríguez-Vigil Iturrate
Azathioprine is an immunosuppressive drug that has shown effectiveness in inflammatory bowel disease treatment. Its metabolite, 6-mercaptopurine, is metabolized through thiopurine methyltransferase. Patients with low enzyme activity may have more frequent and severe side effects. The most common is leukopenia, and rarely pancytopenia. The thiopurine methyltransferase activity monitoring shows an individualized profile of enzymatic activity but it should not replace monitoring by performing serial blood counts...
August 1, 2017: Archivos Argentinos de Pediatría
https://www.readbyqxmd.com/read/28723860/higher-thioguanine-nucleotide-metabolite-levels-are-associated-with-better-long-term-outcomes-in-patients-with-inflammatory-bowel-diseases
#3
Andres J Yarur, Bilal Gondal, Ayal Hirsch, Britt Christensen, Russell D Cohen, David T Rubin
GOALS: The aim of this study was to assess whether sustained 6-thioguaninenucleotide (6-TGN) levels were associated with improved long-term outcomes in patients with inflammatory bowel diseases (IBD). BACKGROUND: Cross-sectional data have shown that thiopurine metabolites are correlated with clinical efficacy in patient receiving thiopurines for IBD but the role for serial measurements through treatment course is unclear. STUDY: We conducted a retrospective cohort study including patients with IBD on thiopurine monotherapy and had serial 6-TGN levels measured...
July 18, 2017: Journal of Clinical Gastroenterology
https://www.readbyqxmd.com/read/28650902/itpa-activity-in-adults-and-children-treated-with-or-without-azathioprine-relationship-between-tpmt-activity-thiopurine-metabolites-and-co-medications
#4
Boulieu Roselyne, Antony Citterio-Quentin, Mustapha Moulsma, Marie-Paule Gustin
BACKGROUND: The implication of inosine triphosphate pyrophosphatase (ITPA) on thiopurine drug response variability has been investigated but little data is available on its role on thiopurine metabolites. ITPA' ability to modify the thiopurine metabolite levels currently used to optimize azathioprine (AZA) therapy in relation to TPMT activity, the aim of this study is to investigate ITPA phenotype in a large population and to evaluate the relation between ITPA and TPMT activities and thiopurine metabolites...
June 22, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28644183/more-dose-dependent-side-effects-with-mercaptopurine-over-azathioprine-in-ibd-treatment-due-to-relatively-higher-dosing
#5
Mark M T J Broekman, Marieke J H Coenen, Corine J van Marrewijk, Geert J A Wanten, Dennis R Wong, Andre L M Verbeek, Olaf H Klungel, Piet M Hooymans, Henk-Jan Guchelaar, Hans Scheffer, Luc J J Derijks, Dirk J de Jong
BACKGROUND: There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy. METHODS: Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care...
June 20, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28623449/differential-effects-of-thiopurine-methyltransferase-tpmt-and-multidrug-resistance-associated-protein-gene-4-mrp4-on-mercaptopurine-toxicity
#6
Chengcheng Liu, Laura J Janke, Jun J Yang, William E Evans, John D Schuetz, Mary V Relling
PURPOSE: Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear. METHODS: We studied the metabolism of and tolerance to mercaptopurine in murine knockout models of Tpmt, Mrp4, and both genes simultaneously...
June 16, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28618062/examining-maintenance-care-following-infliximab-salvage-therapy-for-acute-severe-ulcerative-colitis
#7
Dean Seah, Matthew C Choy, Alexandra Gorelik, William R Connell, Miles P Sparrow, Daniel van Langenberg, Geoffrey Hebbard, Gregory Moore, Peter De Cruz
BACKGROUND AND AIMS: Data supporting the optimal maintenance drug therapy & strategy to monitor ongoing response following successful infliximab (IFX) induction, for acute severe ulcerative colitis (ASUC), are limited. We aimed to evaluate maintenance & monitoring strategies employed in patients post IFX induction therapy. METHODS: Patients in 6 Australian tertiary centres treated with IFX for steroid-refractory ASUC between April 2014 & May 2015 were identified via hospital IBD & pharmacy databases...
June 15, 2017: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28617756/optimizing-thiopurine-therapy-in-inflammatory-bowel-disease-among-2-real-life-intercept-cohorts-effect-of-allopurinol-comedication
#8
Berrie Meijer, Margien L Seinen, Remco van Egmond, Gerd Bouma, Chris J J Mulder, Adriaan A van Bodegraven, Nanne K H de Boer
BACKGROUND: Thiopurines (azathioprine and mercaptopurine) are frequently used immunosuppressive drugs to maintain remission in patients with inflammatory bowel disease. Half of the conventional thiopurine-derivative users have to discontinue treatment within 5 years, mainly because of intolerable adverse events. Over recent years, different strategies to optimize thiopurine treatment were suggested, yet, studies describing the clinical effectiveness of these strategies remain scarce. The aims of this study were to compare tolerability and sustained clinical benefit of conventional thiopurine derivatives therapy among two 5-year real-life intercept cohorts and to assess the clinical value of specifically allopurinol cotherapy...
June 14, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28552060/thiopurine-s-methyltransferase-as-a-pharmacogenetic-biomarker-significance-of-testing-and-review-of-major-methods
#9
Chingiz Asadov, Gunay Aliyeva, Kamala Mustafayeva
Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of population is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at the high risk of severe adverse drug reactions (ADR) as myelosuppression, gastrointestinal intolerance, pancreatitis and hypersensitivity...
May 28, 2017: Cardiovascular & Hematological Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28489727/pharmacology-of-thiopurine-therapy-in-inflammatory-bowel-disease-and-complete-blood-cell-count-outcomes-a-5-year-database-study
#10
Berrie Meijer, Abraham J Wilhelm, Chris J J Mulder, Gerd Bouma, Adriaan A van Bodegraven, Nanne K H de Boer
BACKGROUND: Thiopurines are the prerequisite for immunomodulation in inflammatory bowel disease (IBD) therapy. When administered in high (oncological) dose, thiopurine metabolites act as purine antagonists, causing DNA-strand breakage and myelotoxicity. In lower IBD dosages, the mode of action is primarily restricted to anti-inflammatory effects. Then, myelosuppression and hepatotoxicity are the most common adverse events of thiopurines. The aim of this study was to assess the effect of thiopurine metabolites on hematologic and hepatic parameters and to determine which patient characteristics are related to generation of thiopurine metabolites...
August 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28452864/azathioprine-with-allopurinol-lower-deoxythioguanosine-in-dna-and-transcriptome-changes-indicate-mechanistic-differences-to-azathioprine-alone
#11
Sally A Coulthard, Phil Berry, Sarah McGarrity, Simon McLaughlin, Azhar Ansari, Christopher P F Redfern
BACKGROUND: Use of azathioprine (AZA) for inflammatory bowel disease is limited by side effects or poor efficacy. Combining low-dose azathioprine with allopurinol (LDAA) bypasses side effects, improves efficacy, and may be appropriate as first-line therapy. We test the hypothesis that standard-dose azathioprine (AZA) and LDAA treatments work by similar mechanisms, using incorporation of the metabolite deoxythioguanosine into patient DNA, white-blood cell counts, and transcriptome analysis as biological markers of drug effect...
June 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28445187/the-effects-of-inherited-nudt15-polymorphisms-on-thiopurine-active-metabolites-in-japanese-children-with-acute-lymphoblastic-leukemia
#12
Takaya Moriyama, Rina Nishii, Ting-Nien Lin, Kentaro Kihira, Hidemi Toyoda, Nersting Jacob, Motohiro Kato, Katsuyoshi Koh, Hiroto Inaba, Atsushi Manabe, Kjeld Schmiegelow, Jun J Yang, Hiroki Hori
Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing...
June 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28348471/role-of-allopurinol-in-optimizing-thiopurine-therapy-in-patients-with-autoimmune-hepatitis-a-review
#13
REVIEW
Shivani Deswal, Anshu Srivastava
Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes...
March 2017: Journal of Clinical and Experimental Hepatology
https://www.readbyqxmd.com/read/28333183/machine-learning-algorithms-for-objective-remission-and-clinical-outcomes-with-thiopurines
#14
Akbar K Waljee, Kay Sauder, Anand Patel, Sandeep Segar, Boang Liu, Yiwei Zhang, Ji Zhu, Ryan W Stidham, Ulysses Balis, Peter D R Higgins
Background and Aims: Big data analytics leverage patterns in data to harvest valuable information, but are rarely implemented in clinical care. Optimising thiopurine therapy for inflammatory bowel disease [IBD] has proved difficult. Current methods using 6-thioguanine nucleotide [6-TGN] metabolites have failed in randomized controlled trials [RCTs], and have not been used to predict objective remission [OR]. Our aims were to: 1) develop machine learning algorithms [MLA] using laboratory values and age to identify patients in objective remission on thiopurines; and 2) determine whether achieving algorithm-predicted objective remission resulted in fewer clinical events per year...
March 14, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28296824/multicentric-case-control-study-on-azathioprine-dose-and-pharmacokinetics-in-early-onset-pediatric-inflammatory-bowel-disease
#15
Gabriele Stocco, Stefano Martelossi, Serena Arrigo, Arrigo Barabino, Marina Aloi, Massimo Martinelli, Erasmo Miele, Daniela Knafelz, Claudio Romano, Samuele Naviglio, Diego Favretto, Eva Cuzzoni, Raffaella Franca, Giuliana Decorti, Alessandro Ventura
BACKGROUND: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers...
April 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28278299/combination-treatment-with-6-mercaptopurine-and-allopurinol-in-hepg2-and-hek293-cells-effects-on-gene-expression-levels-and-thiopurine-metabolism
#16
Sofie Haglund, Svante Vikingsson, Sven Almer, Jan Söderman
Combination treatment with low-dose thiopurine and allopurinol (AP) has successfully been used in patients with inflammatory bowel disease with a so called skewed thiopurine metabolite profile. In red blood cells in vivo, it reduces the concentration of methylated metabolites and increases the concentration of the phosphorylated ones, which is associated with improved therapeutic efficacy. This study aimed to investigate the largely unknown mechanism of AP on thiopurine metabolism in cells with an active thiopurine metabolic pathway using HepG2 and HEK293 cells...
2017: PloS One
https://www.readbyqxmd.com/read/28276819/is-there-a-role-for-thioguanine-therapy-in-ibd-in-2017-and-beyond
#17
Kirstin M Taylor, Mark G Ward, Paul A Blaker, Miles P Sparrow
Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use...
May 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28264514/excited-state-dynamics-of-the-thiopurine-prodrug-6-thioguanine-can-n9-glycosylation-affect-its-phototoxic-activity
#18
Brennan Ashwood, Steffen Jockusch, Carlos E Crespo-Hernández
6-Thioguanine, an immunosuppressant and anticancer prodrug, has been shown to induce DNA damage and cell death following exposure to UVA radiation. Its metabolite, 6-thioguanosine, plays a major role in the prodrug's overall photoreactivity. However, 6-thioguanine itself has proven to be cytotoxic following UVA irradiation, warranting further investigation into its excited-state dynamics. In this contribution, the excited-state dynamics and photochemical properties of 6-thioguanine are studied in aqueous solution following UVA excitation at 345 nm in order to provide mechanistic insight regarding its photochemical reactivity and to scrutinize whether N9-glycosylation modulates its phototoxicity in solution...
February 28, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28211629/editorial-can-we-get-more-clinical-benefit-from-thiopurine-metabolite-testing
#19
EDITORIAL
A G Fraser
No abstract text is available yet for this article.
March 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28211625/editorial-can-we-get-more-clinical-benefit-from-thiopurine-metabolite-testing-authors-reply
#20
EDITORIAL
D R Wong, P M Hooymans
No abstract text is available yet for this article.
March 2017: Alimentary Pharmacology & Therapeutics
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