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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tioguanine (LanvisTM), previously thioguanine or 6-thioguanine) is another purine antimetabolite used orally for treating chronic myeloid leukemia and is given at various stages of treatment in short-term cycles (Figure 3.10). It is metabolized to the 9-(1′-ribosyl-5′-phosphate) in cells. However, in contrast to MPRP, this intermediate does not inhibit an enzyme but is further phosphorylated to the triphosphate and then incorporated into DNA as a “false” nucleic acid substrate.
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Tioguanine undergoes extensive metabolism in the liver and other tissues to several active and inactive metabolites. Tioguanine is inactivated mainly by methylation to aminomethylthiopurine; small amounts are deaminated to thioxanthine, and may go on to be oxidised by xanthine oxidase to thiouric acid, but inactivation is essentially independent of xanthine oxidase and is not affected by inhibition of the enzyme. 24–46% of the dose is excreted in the urine within 24 hours. It is excreted in the urine almost entirely as metabolites.
ABCC4, ITPA, NUDT15, TPMT and their interaction as genetic predictors of 6-mercaptopurine intolerance in chinese patients with acute lymphoblastic leukemia
Published in Pediatric Hematology and Oncology, 2022
Paroni O. L. Fan, Kam-Tong Leung, Kathy Y. Y. Chan, Alex W. K. Leung, Grace K. S. Lam, Terry T. W. Chow, Frankie W. T. Cheng, Liz Y. P. Yuen, Takaya Moriyama, Jun J. Yang, Chi-Kong Li
Variants in NUDT15 were revealed as genetic determinants of thiopurine intolerance in genome-wide association studies in patients with ALL.19 Patients with the homozygous mutated TT genotype tolerate only 8.3% of the protocol dose, while patients with CC/CT tolerated 63% of the protocol dose.20 Association between NUDT15 c.415C > T variant with 6-MP intolerance was displayed in studies involving Chinese,12 Singapore (including Chinese, Malays and Indian),5 Japanese,5 and Indian patients.21NUDT15 competes with the kinases and dephosphorylates thioguanine triphosphate (TdGTP), an active metabolite of 6-MP, into 6-TGDP and 6-TGMP and prevents their incorporation into DNA, therefore negatively regulates thiopurine activation and, consequently, the anticancer effect.21 6-TGTP also leads to immunosuppression and inhibition of immune responses by blocking Vav-Rac1 pathway in T-cell.22 Numerous variants of NUDT15 have been revealed to be associated with thiopurine-related myelosuppression.5,23 Interaction of ABCC4 and NUDT15 was also reported by Tanaka that their interaction resulted in lower tolerability of 6-MP in Japanese patients with ALL, all patients with both intermediate NUDT15 activity and ABCC4 c.2128G > A variant suffered from leukopenia.11
Use of medications during pregnancy and breastfeeding for Crohn’s disease and ulcerative colitis
Published in Expert Opinion on Drug Safety, 2021
Robyn Laube, Sudarshan Paramsothy, Rupert W Leong
Thioguanine is a non-conventional thiopurine that is directly converted into active 6-TGN without intermediate metabolites. Thioguanine is rapidly metabolized and taken intracellularly in adults, minimizing the amount of free drug able to traverse the placenta [94]. There are a paucity of studies investigating the safety of thioguanine during pregnancy, however to date no congenital abnormalities or adverse outcomes have been reported. A retrospective multicentre case series of 19 thioguanine-exposed pregnancies (median dose 18 g/day) reported no preterm births or LBW in singletons, one mild congenital abnormality and three spontaneous abortions [95]. Cord blood 6-TGN was measured in four infants, three of which were undetectable, and one was very low (38 pmol/8*108 RBC). No adverse maternal or neonatal outcomes have been reported in three other thiopurine-exposed pregnancies [94,96]. 6-TGN levels were 12-fold lower in cord blood vs. maternal blood and were undetectable in neonates one month post-partum [94]. Therefore, thioguanine is likely to be safe during pregnancy however further data is required, and akin to conventional thiopurines, monitoring of maternal 6-TGN may be considered.
Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients
Published in Scandinavian Journal of Gastroenterology, 2019
Dirk P. van Asseldonk, Melek Simsek, Nanne K. H. de Boer, Bindia Jharap, Elisabeth Bloemena, Gijsbert den Hartog, Dik B. Westerveld, Marco C. Becx, Maurice G. Russel, Birgit I. Lissenberg-Witte, Carin M. van Nieuwkerk, Chris J. J. Mulder, Joanne Verheij, Adriaan A. van Bodegraven
Thioguanine was prescribed in a mean daily dose of 20 mg (SD: 3.5) corresponding with 0.28 mg/kg (range: 0.10–0.38). Median treatment duration between start of TG therapy and the first liver biopsy was 16 months (range: 12–39) and between start of TG and the second liver biopsy was 41 months (13–72). The median time between first and sequential liver biopsy was 25 months (14–54). Adverse events were reported in five out of 25 patients (20%) including hepatotoxicity in three (12%), melanoma in one (4%) and myalgia in another patient (4%). All three patients with hepatotoxicity ceased treatment, whereas the patients with melanoma and the patient with myalgia continued TG. Co-treatments included infliximab in three (12%), budesonide in five (20%) and prednisolone in seven patients (28%) (≤10 mg/d in five and >10 mg/d in two patients).