Disease relevance of Leupurin

• Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study [1].
• Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis [2].
• Treatment of chronic disease with 6-mercaptopurine: what effects on fertility [3]?
• Of the surviving female offspring of mice treated with low doses of 6-mercaptopurine during pregnancy, despite normal body weight and general appearance, many were either sterile or, if they became pregnant, had smaller litters and more dead fetuses as compared to offspring of mothers that had not received the drug [4].
• The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine [5].

Psychiatry related information on Leupurin

• TPMT activity in human tissue is regulated by a common genetic polymorphism, and "pharmacogenetic" variation in TPMT activity is an important factor in individual differences in thiopurine drug metabolism, toxicity and therapeutic efficacy [6].
• The efficacy of this immuno-suppressive therapy is reported in over 70% of patients and the incidence of associated side effects is acceptable, but 6-mercaptopurine and azathioprine act slowly and the long latency period limits the usefulness of these drugs in some patients [7].
• Complications of pregnancy and child development after cessation of treatment with 6-mercaptopurine for inflammatory bowel disease [8].
• The simultaneous determination of 6-mercaptopurine and some of its major metabolites in extracellular fluids may contribute to the monitoring of patient compliance, bioavailability, and individual variation in metabolism and absorption [9].

High impact information on Leupurin

• Pharmacokinetics of mercaptopurine in children with acute lymphocytic leukemia [10].
• Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure [2].
• Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse [2].
• CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait [11].
• Application of pharmacogenetics to optimization of mercaptopurine dosing [12].

Chemical compound and disease context of Leupurin

• Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease [13].
• BACKGROUND & AIMS: Thioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD) [14].
• A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease [15].
• BACKGROUND & AIMS: Clinical experience suggests that 6-mercaptopurine (6-MP) is effective therapy for children with active steroid-dependent Crohn's disease (CD) [15].
• Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial [16].

Biological context of Leupurin

• We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes [11].
• There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49) [11].
• Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations [11].
• Balsalazide and azathiprine or 6-mercaptopurine: evidence for a potentially serious drug interaction [17].
• Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia [18].

Anatomical context of Leupurin

• The immunosuppressant azathioprine (or its metabolite, 6-mercaptopurine) is considered an efficient maintenance therapy for Crohn's, but there is always concern about bone-marrow suppression, liver damage, and other adverse effects [19].
• These data indicate that nutrition and 6-mercaptopurine affect both total RNA, and individual mRNA concentrations at specific sites in the gastrointestinal tract [20].
• Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity [21].
• The intracellular metabolism of 6-mercaptopurine (6-MP) was studied in a murine leukemia cell line, WEHI-3b [22].
• In a small cohort of acute lymphoblastic leukemia patients receiving p.o. 6-mercaptopurine-based maintenance therapy, significant interindividual variation in the accumulation of 6-TG bases into leukocyte DNA was revealed [23].

Associations of Leupurin with other chemical compounds

• Maintenance chemotherapy with 6-mercaptopurine and methotrexate, widely believed an essential contribution to the high cure rates achieved in children with acute lymphoblastic leukaemia (ALL), is thought to work by killing the leukaemia cells that remain after intensive chemotherapy [24].
• The short-term MTT assay was used to assess sensitivity to prednisolone, vincristine, colaspase (asparaginase), daunorubicin, and thioguanine (instead of mercaptopurine which is unstable in vitro) [25].
• Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP) [26].
• Systemic consolidation and maintenance therapy included 6-week cycles of mercaptopurine/methotrexate (6MP/MTX) and vincristine/cyclophosphamide (VCR/CTX), with randomization to intervening pulses of prednisone/doxorubicin (PDN/DOX) or teniposide (VM26)/cytarabine (Ara-C) for a total of 88 weeks [27].
• Its initial uptake in L1210 sublines in vitro was: L1210/0 greater than L1210/cyclophosphamide, L1210/1-beta-D-arabinofuranosylcytosine, L1210/6-mercaptopurine greater than L1210/5-fluorouracil, L1210/Adriamycin greater than L1210/VCR [28].

Gene context of Leupurin

• If they receive standard doses of thiopurine medications (for example, 75 mg/m2 body surface area per day), TPMT-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, which leads to severe and possibly fatal myelosuppression [29].
• OBJECTIVE: To investigate thiopurine enzyme activities for their possible value in predicting the development of azathioprine (AZA)-related toxicity in patients with rheumatoid arthritis (RA) [30].
• Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity [31].
• Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance [32].
• Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs [33].

Analytical, diagnostic and therapeutic context of Leupurin

• Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered [34]?
• Additional discussion on the safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study [35].
• Annual rates of hospitalization decreased in 44% of subjects during 6-mercaptopurine treatment, while increasing in only 22% [36].
• Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis [37].
• Maintenance chemotherapy with 6-mercaptopurine (6MP) and methotrexate was given to four patients starting 100 days after bone marrow transplantation [38].

References