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Bosnian Journal of Basic Medical... Aug 2018The main role of therapy in Crohn's disease (CD) is to achieve long-term clinical remission, and to allow for normal growth and development of children. The... (Review)
Review
The main role of therapy in Crohn's disease (CD) is to achieve long-term clinical remission, and to allow for normal growth and development of children. The immunomodulatory drugs used for the maintenance of remission in CD include thiopurines (azathioprine and 6-mercaptopurine) and methotrexate (MTX). Development of hepatosplenic T-cell lymphoma in some patients with inflammatory bowel disease, treated with thiopurines only or in combination with anti-tumor necrosis factor agents, resulted in a growing interest in the therapeutic application of MTX in children suffering from CD. This review summarizes the literature on the therapeutic role of MTX in children with CD. MTX is often administered as a second-line immunomodulator, and 1-year clinical remission was reported in 25-69% of children with CD after excluding for the use of thiopurines. Initial data on MTX effectiveness in mucosal healing, and as a first-line immunomodulator in pediatric patients with CD, are promising. A definite conclusion, however, may only be made on the basis of additional research with a larger number of subjects.
Topics: Adolescent; Azathioprine; Child; Crohn Disease; Drug Administration Schedule; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Patient Safety; Remission Induction; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 29338679
DOI: 10.17305/bjbms.2018.2792 -
Zhongguo Dang Dai Er Ke Za Zhi =... Sep 2017Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and... (Review)
Review
Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.
Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases
PubMed: 28899477
DOI: 10.7499/j.issn.1008-8830.2017.09.019 -
Saudi Journal of Gastroenterology :... 2022Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it... (Review)
Review
Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it has historically been an important part of pharmacological treatment for patients with inflammatory bowel disease. Despite an increase in therapeutic options, these immunomodulators continue to play important roles in the management of inflammatory bowel disease, used either as a monotherapy in mild to moderate cases or in combination with monoclonal antibodies to prevent immunogenicity and maintain efficacy. In light of data linking the use of thiopurines with the risk of malignancies, methotrexate has regained attention as a potential alternative. In this article, we review data on the pharmacology, safety, and efficacy of methotrexate and discuss options for the positioning of methotrexate alone, or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.
Topics: Azathioprine; Colitis, Ulcerative; Gastroenterologists; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate
PubMed: 35042318
DOI: 10.4103/sjg.sjg_496_21 -
Current Opinion in Pharmacology Dec 2015The management of patients with moderate to severe inflammatory bowel diseases, that is, Crohn's disease and ulcerative colitis, remains challenging. In recent years,... (Review)
Review
The management of patients with moderate to severe inflammatory bowel diseases, that is, Crohn's disease and ulcerative colitis, remains challenging. In recent years, therapeutic goal evolved from clinical remission to mucosal healing and deep remission. In order to achieve remission, it is important to appropriately choose and use available drugs. Therefore, anti-TNFα treatment should be rapidly used for severe and at-risk patients, sometimes in association with thiopurines or methotrexate. The monitoring of through levels and antibodies to anti-TNFα is relevant to optimize the treatment and to reduce drug inefficacy. However, the development of new drugs is required to offer alternative tools to severe and refractory patients.
Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Drug Resistance; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Tumor Necrosis Factor-alpha
PubMed: 26645664
DOI: 10.1016/j.coph.2015.11.003 -
Journal of Crohn's & Colitis Aug 2022Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also...
Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also thioguanine [1950] and azathioprine [1957]) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For her discovery of thiopurines and other antimetabolite drugs, in 1988 Elion was rewarded, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Today thiopurine [based] therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.
Topics: Antimetabolites; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine
PubMed: 35024806
DOI: 10.1093/ecco-jcc/jjac004 -
Current Opinion in Pediatrics Feb 2017Outcomes for children with cancer have improved dramatically. Although the contribution of disease biology and therapy resistance to treatment failure continues to be a... (Review)
Review
PURPOSE OF REVIEW
Outcomes for children with cancer have improved dramatically. Although the contribution of disease biology and therapy resistance to treatment failure continues to be a focus of intense research efforts, the role of medication nonadherence on the part of caregivers or patients has been relatively neglected. Efforts to further improve childhood cancer cure rates must include a focus on improving medication adherence.
RECENT FINDINGS
Recent studies in children with acute lymphoblastic leukemia have conclusively demonstrated that nonadherence to oral antimetabolite therapy is associated with a significant increase in relapse risk. The impact of nonadherence to other oral medications in acute lymphoblastic leukemia and in other childhood cancers remains unknown. Tools by which clinicians can accurately identify nonadherent families are currently being developed but remain suboptimal. Similarly, while current efforts to develop interventions aimed at increasing adherence rates are underway, their feasibility and effectiveness is still unknown.
SUMMARY
Future studies must focus on the development and widespread implementation of methods by which to identify and minimize nonadherence. Doing so will allow for further improve childhood cancer cure outcomes.
Topics: Administration, Oral; Antineoplastic Agents; Child; Humans; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 27798425
DOI: 10.1097/MOP.0000000000000434 -
Expert Opinion on Drug Metabolism &... Oct 2021Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment... (Review)
Review
INTRODUCTION
Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response.
AREAS COVERED
This review gives an overview on gene and function, and discusses the pharmacogenomic implications of variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published since1990, and on PharmGKB.
EXPERT OPINION
To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in heterozygotes and novel individualized TG regimens in maintenance for subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.
Topics: Animals; Antimetabolites, Antineoplastic; Genotype; Humans; Mercaptopurine; Methyltransferases; Molecular Targeted Therapy; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine
PubMed: 34452592
DOI: 10.1080/17425255.2021.1974398 -
Expert Review of Clinical Immunology Sep 2017Thiopurines are central to inflammatory bowel disease (IBD) therapeutics, either as monotherapy or in combination with newer biologic therapies, however it is only... (Review)
Review
Thiopurines are central to inflammatory bowel disease (IBD) therapeutics, either as monotherapy or in combination with newer biologic therapies, however it is only recently that focus has increased on improving effectiveness and tolerability through optimisation. Areas covered: We review the role of thiopurines in IBD and the importance of the timing of initiation of therapy. Drug metabolism and pharmacogenetics have increasingly played a role in determining dosing and dose optimisation and we review the rationale for this in both thiopurine monotherapy and in combination with biologic agents. We also discuss allopurinol co-therapy as a strategy for enhancing both efficacy and tolerability of thiopurine therapy. Although immunomodulators carry safety considerations, we discuss methods of optimisation to minimise side-effects and maximise safety to ensure the broadest number of patients can benefit. Expert commentary: We provide a practical guide to drug initiation and dose optimisation in a clinical setting, and address potential treatment duration. The forward view considers the place for thiopurines in the treatment of IBD, and how the application of the plethora of genetic data may help inform thopurine therapy in the future.
Topics: Allopurinol; Drug Dosage Calculations; Drug Therapy, Combination; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Mercaptopurine; Practice Guidelines as Topic
PubMed: 28678626
DOI: 10.1080/1744666X.2017.1351298 -
Journal of Gastroenterology and... Jun 2016
Topics: Antibodies, Monoclonal, Humanized; Azathioprine; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Hemoglobins; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Remission Induction; Tumor Necrosis Factor-alpha
PubMed: 26990458
DOI: 10.1111/jgh.13345 -
Inflammatory Bowel Diseases Feb 2015The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of... (Review)
Review
BACKGROUND
The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature.
METHODS
A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management.
RESULTS
Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD.
CONCLUSIONS
Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.
Topics: Azathioprine; Disease Management; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Prognosis; Time Factors
PubMed: 25248004
DOI: 10.1097/MIB.0000000000000197