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World Journal of Gastroenterology Oct 2021Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the...
Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption. Myelosuppression is the most frequent adverse effect; however, approximately 5%-20% of patients develop gastrointestinal toxicity. The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy. In this editorial, we discuss evidence supporting the use of , , and genes, in addition to and as possible biomarkers for thiopurine-related gastrointestinal toxicity.
Topics: Azathioprine; Biomarkers; Humans; Immunologic Factors; Mercaptopurine; Methyltransferases; Pyrophosphatases
PubMed: 34720526
DOI: 10.3748/wjg.v27.i38.6348 -
International Journal of Molecular... May 2020Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent...
Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent inhibitors of the xanthine oxidase (XO)-catalyzed uric acid formation . However, the effects of conjugated flavonoid metabolites are poorly characterized. Furthermore, the inhibition of XO-catalyzed 6-mercaptopurine oxidation is an important reaction in the pharmacokinetics of this antitumor drug. The inhibitory effects of some compounds on xanthine vs. 6-mercaptopurine oxidation showed large differences. Nevertheless, we have only limited information regarding the impact of flavonoids on 6-mercaptopurine oxidation. In this study, we examined the interactions of flavonoid aglycones and some of their conjugates with XO-catalyzed xanthine and 6-mercaptopurine oxidation . Diosmetin was the strongest inhibitor of uric acid formation, while apigenin showed the highest effect on 6-thiouric acid production. Kaempferol, fisetin, geraldol, luteolin, diosmetin, and chrysoeriol proved to be similarly strong inhibitors of xanthine and 6-mercaptopurine oxidation. While apigenin, chrysin, and chrysin-7-sulfate were more potent inhibitors of 6-mercaptopurine than xanthine oxidation. Many flavonoids showed similar or stronger (even 5- to 40-fold) inhibition of XO than the positive control allopurinol. Based on these observations, the extremely high intake of flavonoids may interfere with the elimination of 6-mercaptopurine.
Topics: Allopurinol; Catalysis; Dose-Response Relationship, Drug; Flavonoids; Mercaptopurine; Oxidation-Reduction; Xanthine; Xanthine Oxidase
PubMed: 32380641
DOI: 10.3390/ijms21093256 -
Alimentary Pharmacology & Therapeutics Apr 2002The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid... (Review)
Review
The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid preparations, azathioprine and 6-mercaptopurine, methotrexate, and corticosteroids) are reviewed. On the basis of the reported frequency, severity and timing of side-effects, a practical scheme of monitoring is recommended. This includes a baseline measurement of full blood count, creatinine and liver function tests in all patients. In the absence of worrying symptoms, we recommend the following: (i) no monitoring for sulfasalazine; (ii) for other 5-aminosalicylic acid preparations, the measurement of creatinine at 6 and 12 months and then annually; (iii) for azathioprine/6-mercaptopurine, thiopurine methyltransferase genotype/phenotype determination has no role in treatment monitoring, but a full blood count at 2 weeks, 1 month, 3 months and then every 3 months should be performed; (iv) for methotrexate, a full blood count and liver function tests should be performed every 3 months; (v) for steroids, dual energy X-ray absorptiometry bone scanning should be performed at the start of therapy, every year in which steroids are used if the T score is < 0, and every 3-5 years if the T score is > 0.
Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Azathioprine; Blood Cell Count; Creatinine; Drug Monitoring; Inflammatory Bowel Diseases; Liver Function Tests; Mercaptopurine; Methotrexate
PubMed: 11929382
DOI: 10.1046/j.1365-2036.2002.01216.x -
World Journal of Gastroenterology Apr 2014Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH)... (Review)
Review
Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.
Topics: Animals; Apoptosis; Azathioprine; Glutathione; Glutathione Transferase; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Oxidative Stress; Pharmacogenetics; Polymorphism, Genetic
PubMed: 24707136
DOI: 10.3748/wjg.v20.i13.3534 -
Best Practice & Research. Clinical... Feb 2003Thioguanine derivatives, azathioprine and 6-mercaptopurine, represent major drugs in the treatment of chronic active inflammatory bowel disease. They are effective in... (Review)
Review
Thioguanine derivatives, azathioprine and 6-mercaptopurine, represent major drugs in the treatment of chronic active inflammatory bowel disease. They are effective in two-thirds of the patients and safe over the long term in patients who can tolerate them (80-90%). Recent progress in understanding the metabolism of these drugs and its implication in clinical practice have brought up new tools and strategies that are proposed to optimize treatment. In particular, the measurement and characterization of key enzymes and metabolites may have clinical impact. Thus, thiopurine methyl transferase genotyping and activity measurement, as well as erythrocytes, 6-thioguanine nucleotides and 6-methyl mercaptopurine levels, may help in some situations of intolerance or inefficacy with these drugs. Indications for starting and stopping treatment with thioguanine derivatives are also discussed.
Topics: Azathioprine; Chronic Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine
PubMed: 12617881
DOI: 10.1053/bega.2002.0346 -
Expert Opinion on Drug Discovery Sep 20186-Mercaptopurine (6-MP) and 6-thioguanine (6-TG), two anticancer drugs, have high systemic toxicity due to a lack of target specificity. Therefore, increasing target... (Review)
Review
6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG), two anticancer drugs, have high systemic toxicity due to a lack of target specificity. Therefore, increasing target selectivity should improve drug safety. Areas covered: The authors examined the hypothesis that new prodrug designs based upon mechanisms of kidney-selective toxicity of trichloroethylene would reduce systemic toxicity and improve selectivity to kidney and tumor cells. Two approaches specifically were investigated. The first approach was based upon bioactivation of trichloroethylene-cysteine S-conjugate by renal cysteine S-conjugate β-lyases. The prodrugs obtained were kidney-selective but exhibited low turnover rates. The second approach was based on the toxic mechanism of trichloroethylene-cysteine S-conjugate sulfoxide, a Michael acceptor that undergoes rapid addition-elimination reactions with biological thiols. Expert opinion: Glutathione-dependent Michael addition-elimination reactions appear to be an excellent strategy to design highly efficient anticancer drugs. Targeting glutathione could be a promising approach for the development of anticancer prodrugs because cancer cells usually upregulate glutathione biosynthesis and/or glutathione S-transferases expression.
Topics: Animals; Antineoplastic Agents; Drug Design; Glutathione; Glutathione Transferase; Humans; Kidney; Mercaptopurine; Molecular Targeted Therapy; Neoplasms; Prodrugs; Thioguanine
PubMed: 30101640
DOI: 10.1080/17460441.2018.1508207 -
Life Science Alliance Mar 2023PACSIN2 variants are associated with gastrointestinal effects of thiopurines and thiopurine methyltransferase activity through an uncharacterized mechanism that is...
PACSIN2 variants are associated with gastrointestinal effects of thiopurines and thiopurine methyltransferase activity through an uncharacterized mechanism that is postulated to involve autophagy. This study aims to clarify the role of PACSIN2 in autophagy and in thiopurine cytotoxicity in leukemic and intestinal models. Higher autophagy and lower PACSIN2 levels were observed in inflamed compared with non-inflamed colon biopsies of inflammatory bowel disease pediatric patients at diagnosis. PACSIN2 was identified as an inhibitor of autophagy, putatively through inhibition of autophagosome formation by a protein-protein interaction with LC3-II, mediated by a LIR motif. Moreover, PACSIN2 resulted a modulator of mercaptopurine-induced cytotoxicity in intestinal cells, suggesting that PACSIN2-regulated autophagy levels might influence thiopurine sensitivity. However, PACSIN2 modulates cellular thiopurine methyltransferase activity via mechanisms distinct from its modulation of autophagy.
Topics: Humans; Child; Mercaptopurine; Inflammatory Bowel Diseases; Intestines; Autophagy; Adaptor Proteins, Signal Transducing
PubMed: 36596605
DOI: 10.26508/lsa.202201610 -
World Journal of Gastroenterology Aug 2004Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire... (Review)
Review
Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is not the only choice for UC treatment and medical management should be as a comprehensive whole. Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-aminosalicylic acid (5-ASA), which is the topical anti-inflammatory ingredient. Pentasa is more commonly used in treating Crohn's ileitis because Pentasa capsules release more 5-ASA into the small intestine than Asacol tablets. Pentasa can also be used for treating mild to moderate UC. Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis. The sulfa-free 5-ASA agents (Asacol, Pentasa, Dipentum and Rowasa) have fewer side effects than sulfa-containing Azulfidine. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds, systemic (oral) corticosteroids should be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.) are potent and fast-acting drugs for treating UC, Crohn's ileitis and ileocolitis. Systemic corticosteroids are not effective in maintaining remission in patients with UC. Serious side effects can result from prolonged corticosteroid treatment. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved. In patients with corticosteroid-dependent or unresponsive to corticosteroid treatment, surgery or immunomodulator is considered. Immunomodulators used for treating severe UC include azathioprine/6-MP, methotrexate, and cyclosporine. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.
Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Medicine, Chinese Traditional; Mercaptopurine
PubMed: 15285010
DOI: 10.3748/wjg.v10.i16.2311 -
Taiwanese Journal of Obstetrics &... Sep 2023Azathioprine, a prodrug of 6-mercaptopurine (6-MP), is used in the treatment of inflammatory bowel disease and may be continued during pregnancy. Acute cholestatic liver... (Review)
Review
OBJECTIVE
Azathioprine, a prodrug of 6-mercaptopurine (6-MP), is used in the treatment of inflammatory bowel disease and may be continued during pregnancy. Acute cholestatic liver injury has been reported to occur with azathioprine. We aimed to examine azathioprine related cholestasis effect on pregnancy complications and outcome.
CASE REPORT
We present a unique case of 6-MP-induced severe intrahepatic cholestasis of pregnancy (ICP) that required meticulous combined therapy including plasma exchange. The symptoms resolved following 6-MP withdrawal. A literature review revealed 11 pregnancies complicated by early-induced severe ICP among women treated with azathioprine or 6-MP.
CONCLUSION
We recommend weekly bile acid level tests for pregnant women treated with azathioprine or 6-MP, beginning early in the second trimester of pregnancy, and the prompt discontinuation of treatment upon establishment of an ICP diagnosis.
Topics: Pregnancy; Female; Humans; Azathioprine; Mercaptopurine; Cholestasis, Intrahepatic; Pregnancy Complications
PubMed: 37679010
DOI: 10.1016/j.tjog.2023.07.023 -
Genomics, Proteomics & Bioinformatics Apr 2017Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in... (Review)
Review
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and potentially inosine triphosphatase (ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) and dihydrofolate reductase (DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1) and thymidylate synthetase (TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.
Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Female; Humans; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 28391009
DOI: 10.1016/j.gpb.2016.11.003