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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
D Zochowska, J Zegarska, E Hryniewiecka, E Samborowska, R Jazwiec, W Tszyrsznic, A Borowiec, M Dadlez, L Paczek
BACKGROUND: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are used in many autoimmune diseases and after solid-organ transplantation. Their properties are mediated by active metabolites, 6-thioguanine nucleotides (6-TGN), and 6-methylmercaptopurine (6-MMP). The most common adverse effects are myelo- and hepato-toxicity. The aim of the study was quantification of 6-TG and 6-MMP, with the use of liquid chromatography combined with tandem mass spectrometry (LC/MS/MS) in solid-organ transplant recipients...
June 2016: Transplantation Proceedings
May Fakhoury, Evelyne Jacqz-Aigrain, Tiphaine de Beaumais, Yves Médard
6-mercaptopurine, a key drug for the treatment of acute lymphoblastic leukaemia in children, is a prodrug metabolized into 6-thioguanine (6-TGN) which are the active compounds and into methylated metabolites, primary by thiopurine S-methyltransferase enzyme (TPMT). This enzyme displays important inter subject variability linked to a genetic polymorphism: when treated with standard doses of thiopurine, TPMT-deficient and heterozygous patients are at great risk for developing severe and potentially life-threatening toxicity (hematopoietic, hepatic, mucositis...
May 2010: Thérapie
Romein W G Dujardin, Berrie Meijer, Nanne K H de Boer, Geert R D'Haens, Mark Löwenberg
BACKGROUND: Thiopurines are commonly used drugs in inflammatory bowel disease. Intracellular levels of thiopurine metabolites [i.e. 6-thioguaninenucleotides (6-TGN)] are associated with efficacy and toxicity. Because 6-TGN measurement is not globally available, the mean corpuscular volume (MCV) has been proposed as a surrogate marker for monitoring thiopurine therapy. AIMS: To analyze the relationship between MCV and efficacy of thiopurines, defined as either response to therapy or 6-TGN levels...
September 2016: European Journal of Gastroenterology & Hepatology
Qiuyuan Liu, Yanyan Wang, Qiao Mei, Wei Han, Jing Hu, Naizhong Hu
OBJECTIVE: It remains controversial whether 6-thioguanine nucleotide (6-TGN)-based dose adjusting can be beneficial in azathioprine (AZA) therapy. This study is designed to assess the role of 6-TGN concentrations in maintaining clinical remission in Chinese patients with Crohn's disease (CD). MATERIAL AND METHOD: We performed a prospective observational study and collected data of CD patients in the First Affiliated Hospital of Anhui Medical University from June 2013 to April 2014...
September 2016: Scandinavian Journal of Gastroenterology
Zhang Fangbin, Gao Xiang, Ding Liang, Liu Hui, Wang Xueding, Chen Baili, Bi Huichang, Xiao Yinglian, Cheng Peng, Zhao Lizi, Chu Yanjun, Xu Feng, Chen Minhu, Huang Min, Hu Pinjin
Up to approximately 40% to 50% of patients discontinue thiopurine therapy during the course of inflammatory bowel disease (IBD). We investigated the role of the metabolite thiopurine in IBD treatment. This was a prospective study. IBD patients receiving azathioprine (AZA) were prospectively included. Thiopurine methyltransferase (TPMT) genotypes were examined before therapy, and thiopurine metabolite levels were examined at weeks 2, 4, 8, 12, 24, and 48. In total, 132 patients were included. The frequency of leucopenia increased at 6-thioguanine nucleotide (6-TGN) levels ≥420  pmol/8 × 10(8) RBC (odds ratio [OR] = 7...
April 2016: Medicine (Baltimore)
Nicole M Giamanco, Bethany S Cunningham, Laura S Klein, Dina S Parekh, Anne B Warwick, Kenneth Lieuw
6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels...
March 2016: Journal of Pediatric Hematology/oncology
Ayumi Asada, Atsushi Nishida, Makoto Shioya, Hirotsugu Imaeda, Osamu Inatomi, Shigeki Bamba, Katsuyuki Kito, Mitsushige Sugimoto, Akira Andoh
BACKGROUND: NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD). METHODS: Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled...
January 2016: Journal of Gastroenterology
Sophie A van den Berg, Marjon de Boer, Andrea E van der Meulen-de Jong, Jeroen M Jansen, Frank Hoentjen, Maurice G V M Russel, Nofel Mahmmod, Adriaan A van Bodegraven, C Janneke van der Woude, Chris J J Mulder, Nanne K H de Boer
BACKGROUND AND AIMS: Conventional thiopurine [azathioprine and mercaptopurine] treatment during pregnancy in patients with inflammatory bowel disease [IBD] is considered to be safe; however data on the safety and teratogenicity of the non-conventional thiopurine tioguanine [TG] in pregnant IBD patients are lacking. We aim to describe the safety and teratogenicity of TG treatment during pregnancy in IBD patients. METHODS: This was a retrospective, multicentre descriptive case series of female IBD patients using TG during pregnancy...
February 2016: Journal of Crohn's & Colitis
N M Heerasing, J F Ng, D Dowling
BACKGROUND: The thiopurine drugs, 6-mercaptopurine and azathioprine, remain the mainstay of immunomodulator therapy for inflammatory bowel disease (IBD). Optimal management depends on achieving therapeutic levels of 6-thioguanine (6-TGN), but measuring thiopurine metabolites is associated with significant cost. Thiopurines cause lymphopenia and an increase in mean corpuscular volume (MCV). It is unclear whether any clinically useful correlation exists between 6-TGN levels and lymphocyte count or MCV...
April 2016: Internal Medicine Journal
Shunichi Odahara, Kan Uchiyama, Takahiro Kubota, Zensho Ito, Shinichiro Takami, Hiroko Kobayashi, Keisuke Saito, Shigeo Koido, Toshifumi Ohkusa
Azathioprine (AZA) is frequently used in patients with inflammatory bowel disease (IBD). However, toxic adverse reactions frequently develop and limit the clinical benefits. Currently, the precise mechanisms underlying thiopurine-related toxicity are not well understood. To investigate the relationship between the extent of thiopurine metabolism and adverse reactions in Japanese IBD patients, we prospectively observed 48 IBD patients who received AZA. We analyzed the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) gene mutations and measured the concentrations of 6-thioguanine nucleotide (6-TGN) continuously for 52 weeks...
2015: PloS One
Devaraj Jayachandran, José Laínez-Aguirre, Ann Rundell, Terry Vik, Robert Hannemann, Gintaras Reklaitis, Doraiswami Ramkrishna
6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited...
2015: PloS One
Shi Sum Poon, Rebecca Asher, Richard Jackson, Andrew Kneebone, Paul Collins, Chris Probert, Martyn Dibb, Sreedhar Subramanian
INTRODUCTION: Optimal levels of the thiopurine metabolite, 6-thioguanine nucleotides [6-TGN] correlate with remission of inflammatory bowel disease [IBD]. Apart from variations in the thiopurine methyl transferase [TPMT] gene, little is known about other predictors of 6-TGN levels. Obesity adversely affects response to infliximab and adalimumab and clinical course in IBD, but little is known about the interaction of thiopurines and obesity. We investigated the relationship between body mass index [BMI] and 6-TGN levels and sought to examine other predictors of 6-TGN levels...
August 2015: Journal of Crohn's & Colitis
Joany E Kreijne, Margien L Seinen, Abraham J Wilhelm, Gerd Bouma, Chris J Mulder, Adriaan A van Bodegraven, Nanne K H de Boer
BACKGROUND: The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure...
December 2015: Therapeutic Drug Monitoring
Mi-Na Lee, Ben Kang, So Yoon Choi, Mi Jin Kim, Sook Young Woo, Jong-Won Kim, Yon Ho Choe, Soo-Youn Lee
BACKGROUND: Azathioprine (AZA) is commonly used to treat IBD either alone or in combination with mesalazine. However, there are relatively few studies concerning the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in pediatric patients treated with both AZA and mesalazine. METHODS: We retrospectively investigated the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in 137 pediatric patients with IBD treated with AZA using multilevel analysis...
May 2015: Inflammatory Bowel Diseases
M W Laschke, S Kleer, C Scheuer, D Eglin, M Alini, M D Menger
Adipose tissue-derived microvascular fragments represent promising vascularisation units for implanted tissue constructs. However, their reassembly into functional microvascular networks takes several days, during which the cells inside the implants are exposed to hypoxia. In the present study, we analysed whether this critical phase may be overcome by pre-cultivation of fragment-seeded scaffolds prior to their implantation. Green fluorescent protein (GFP)-positive microvascular fragments were isolated from epididymal fat pads of male C57BL/6-TgN (ACTB-EGFP) 1Osb/J mice...
2015: European Cells & Materials
Andres J Yarur, Maddie J Kubiliun, Frank Czul, Daniel A Sussman, Maria A Quintero, Anjali Jain, Katherine A Drake, Scott I Hauenstein, Steven Lockton, Amar R Deshpande, Jamie S Barkin, Sharat Singh, Maria T Abreu
BACKGROUND & AIMS: In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). METHODS: We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn's and Colitis Center of the University of Miami, FL...
June 2015: Clinical Gastroenterology and Hepatology
Uri Kopylov, Robert Battat, Amine Benmassaoud, Laurence Paradis-Surprenant, Ernest G Seidman
BACKGROUND: Clinical efficacy and risk of complications are associated with intracellular levels of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurines (6-MMP) in patients with Crohn's disease. Therapeutic monitoring of thiopurine metabolites is not widely available. Surrogate markers such as hematologic indices (MCV, leukopenia) have been proposed. AIMS: To evaluate accuracy of hematologic indices for prediction of therapeutic levels of thiopurine metabolites...
February 2015: Digestive Diseases and Sciences
Mi Jin Kim, Soo Youn Lee, Yon Ho Choe
PURPOSE: This study aimed to assess the role of thiopurine S-methyltransferase (TPMT) and 6-thioguanine nucleotide (6-TGN) as predictors of clinical response and side effects to azathioprine (AZA), and estimate the optimal AZA dose in Korean pediatric inflammatory bowel disease (IBD) patients. MATERIALS AND METHODS: One hundred and nine pediatric IBD patients in whom AZA treatment was required were enrolled. Thiopurine metabolites were monitored since September 2010...
September 2014: Yonsei Medical Journal
Matthias W Laschke, Timo E Schank, Claudia Scheuer, Sascha Kleer, Takhirjan Shadmanov, David Eglin, Mauro Alini, Michael D Menger
Undifferentiated adipose-derived mesenchymal stem cell (adMSC) spheroids are attractive vascularization units for tissue engineering. Their osteogenic differentiation further offers the possibility of directed generation of bone constructs. The aim of this study was to analyze how this differentiation affects their in vivo vascularization capacity. Green fluorescent protein (GFP)-positive adMSCs were isolated from C57BL/6-TgN(ACTB-EGFP)1Osb/J mice for the generation of undifferentiated and differentiated spheroids using the liquid overlay technique...
October 2014: Acta Biomaterialia
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