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Thiopurine metabolites

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https://www.readbyqxmd.com/read/29140288/capillary-electrophoresis-hyphenated-with-mass-spectrometry-for-determination-of-inflammatory-bowel-disease-drugs-in-clinical-urine-samples
#1
Katarína Maráková, Juraj Piešťanský, Zuzana Zelinková, Peter Mikuš
Azathioprine is the main thiopurine drug used in the treatment of immune-based inflammations of gastrointestinal tract. For the purpose of therapy control and optimization, effective and reliable analytical methods for a rapid drug monitoring in biological fluids are essential. Here, we developed a separation method based on the capillary electrophoresis (CE) hyphenated with tandem mass spectrometry (MS/MS) for the simultaneous determination of azathioprine and its selected metabolites (6-thioguanine, 6-mercaptopurine, and 6-methylmercaptopurine) as well as other co-medicated drugs (mesalazine, prednisone, and allopurinol)...
November 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29120908/patients-beliefs-about-medicine-are-associated-with-early-thiopurine-discontinuation-in-patients-with-inflammatory-bowel-diseases
#2
Mark M T J Broekman, Marieke J H Coenen, Geert J Wanten, Corine J van Marrewijk, Wietske Kievit, Olaf H Klungel, André L M Verbeek, Dennis R Wong, Piet M Hooymans, Henk-Jan Guchelaar, Hans Scheffer, Luc J J Derijks, Marcel L Bouvy, Dirk J de Jong
BACKGROUND: Patients' beliefs about medicine may either reflect the necessity for treatment or concerns regarding the treatment. We explored the extent to which these beliefs have an effect on thiopurine metabolite levels and premature discontinuation in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Patients enrolled in the 'Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory Bowel Disease Clinics' (TOPIC) trial were asked to complete the Beliefs about Medicine Questionnaire (BMQ) 4 weeks after thiopurine initiation...
November 8, 2017: European Journal of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/29051993/treatment-related-sinusoidal-obstruction-syndrome-in-children-with-de-novo-acute-lymphoblastic-leukemia-during-intensification
#3
Casey L McAtee, Netta Schneller, Julienne Brackett, M Brooke Bernhardt, Eric S Schafer
PURPOSE: Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, has been described following treatment of acute lymphoblastic leukemia (ALL) with the anti-metabolite 6-thioguanine (6-TG). Previous studies incorporating daily 6-TG into maintenance chemotherapy demonstrated a high incidence of SOS, typically presenting after prolonged exposures to 6-TG. 6-TG continues to be used as a single, 14-day burst during intensification; however, SOS associated with brief courses of 6-TG is poorly described...
October 19, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29040228/analytical-pitfalls-of-therapeutic-drug-monitoring-of-thiopurines-in-patients-with-inflammatory-bowel-disease
#4
Melek Simsek, Berrie Meijer, Chris J J Mulder, Adriaan A van Bodegraven, Nanne K H de Boer
The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD...
December 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28914560/thiopurine-metabolite-levels-in-patients-with-atopic-dermatitis-and-or-chronic-hand-foot-eczema-treated-with-azathioprine
#5
F M Garritsen, J van der Schaft, C A F Bruijnzeel-Koomen, R H van Schaik, M de Graaf, M P H van den Broek, M S de Bruin-Weller
BACKGROUND: Azathioprine is frequently used in severe eczema. It is converted in the liver into active metabolites, including 6-thioguanine nucleotide (6-TGN) and methylated 6-methylmercaptopurine (6-MMP). In the past, the therapeutic potential of azathioprine may have not been fully utilized. Recent investigations on inflammatory bowel disease have led to a better understanding of azathioprine metabolism and optimizing treatment. OBJECTIVE: To investigate whether measuring thiopurine metabolites in circulation can improve the effectiveness and safety of azathioprine treatment in patients with atopic dermatitis and/or chronic hand/foot eczema...
September 26, 2017: Journal of Dermatological Treatment
https://www.readbyqxmd.com/read/28877179/adherence-to-6-mercaptopurine-in-children-and-adolescents-with-acute-lymphoblastic-leukemia
#6
Mervat Alsous, Rana Abu Farha, Eman Alefishat, Suha Al Omar, Deema Momani, Alia Gharabli, James McElnay, Robert Horne, Rawad Rihani
OBJECTIVE: Studies on children with Acute Lymphoblastic Leukemia (ALL) reported non-adherence in 2-54% of cases. The primary objective of this study was to assess rates of adherence to 6-MP using two different methods in children and adolescents with ALL. Secondary aim was to identify factors that influence adherence to 6-MP in children with ALL. METHODS: All eligible children with ALL who are (≤ 19) years old and receive 6-MP therapy for at least 1 month were approached to participate in the study...
2017: PloS One
https://www.readbyqxmd.com/read/28839871/monitoring-thiopurine-metabolites-in-inflammatory-bowel-disease
#7
REVIEW
Yago González-Lama, Javier P Gisbert
Thiopurines (azathioprine and mercaptopurine) are one of the immunosuppressive mainstays for the treatment of inflammatory bowel disease. In spite of its widespread use, thiopurine metabolism is still not fully understood, and a significant proportion of patients suffer toxicity or lack of efficacy. Different enzymatic pathways with individual variations constitute a pharmacogenetic model that seems to be suitable for monitoring and therapeutic intervention. This review is focused on current concepts and recent research that may help clinicians to rationally optimise thiopurine treatment in patients with inflammatory bowel disease...
October 2016: Frontline Gastroenterology
https://www.readbyqxmd.com/read/28811125/pharmacokinetics-and-pharmacodynamics-of-thiopurines-in-an-in%C3%A2-vitro-model-of-human-hepatocytes-insights-from-an-innovative-mass-spectrometry-assay
#8
Marco Pelin, Elena Genova, Laura Fusco, Monzer Marisat, Ute Hofmann, Diego Favretto, Marianna Lucafò, Andrea Taddio, Stefano Martelossi, Alessandro Ventura, Gabriele Stocco, Matthias Schwab, Giuliana Decorti
AIM: To apply an innovative LC-MS/MS method to quantify thiopurine metabolites in human hepatocytes and to associate them to cytotoxicity. METHODS: Immortalized human hepatocytes (IHH cells) were treated for 48 and 96 h, with 1.4 × 10(-4) M azathioprine and 1.1 × 10(-3) M mercaptopurine, concentrations corresponding to the IC50 values calculated after 96 h exposure in previous cytotoxicity analysis. After treatments, cells were collected for LC-MS/MS analysis to quantify 11 thiopurine metabolites with different level of phosphorylation and viable cells were counted by trypan blue exclusion assay to determine thiopurines in vitro effect on cell growth and survival...
September 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28774547/american-gastroenterological-association-institute-technical-review-on-the-role-of-therapeutic-drug-monitoring-in-the-management-of-inflammatory-bowel-diseases
#9
REVIEW
Niels Vande Casteele, Hans Herfarth, Jeffry Katz, Yngve Falck-Ytter, Siddharth Singh
Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels and anti-drug antibodies, is a promising strategy that can be used to optimize inflammatory bowel disease therapeutics. It is based on the premise that there is a relationship between drug exposure and outcomes, and that considerable inter-individual variability exists in how patients metabolize the drug (pharmacokinetics) and the magnitude and duration of response to therapy (pharmacodynamics). Therefore, the American Gastroenterological Association has prioritized clinical guidelines on the role of TDM in the management of inflammatory bowel disease...
September 2017: Gastroenterology
https://www.readbyqxmd.com/read/28740837/histological-remission-of-autoimmune-hepatitis-after-the-addition-of-allopurinol-and-azathioprine-dose-reduction
#10
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
#11
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
#12
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
#13
Antony Citterio-Quentin, Mustapha Moulsma, Marie-Paule Gustin, Roselyne Boulieu
BACKGROUND: The implication of inosine triphosphate pyrophosphatase (ITPA) on thiopurine drug response variability has been investigated but little data are available on its role on thiopurine metabolites. The ability of ITPA to modify the thiopurine metabolite levels is currently used to optimize azathioprine (AZA) therapy in relation to thiopurine S-methyltransferase (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...
October 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
#14
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...
October 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
#15
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...
August 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28618062/examining-maintenance-care-following-infliximab-salvage-therapy-for-acute-severe-ulcerative-colitis
#16
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
#17
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...
November 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
#18
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
#19
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
#20
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
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