DOCSLIB.ORG

A Practical Guide to Thiopurine Prescribing and Monitoring in IBD

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Practical Guide to Thiopurine Prescribing and Monitoring in IBD SMALL BOWEL AND NUTRITION Frontline Gastroenterol: first published as 10.1136/flgastro-2016-100738 on 29 August 2016. Downloaded from REVIEW A practical guide to thiopurine prescribing and monitoring in IBD Ben Warner,1 Emma Johnston,2 Monica Arenas-Hernandez,3 Anthony Marinaki,3 Peter Irving,2 Jeremy Sanderson2 11st Floor College House, St ABSTRACT year.3 Thiopurines are commenced ’ Thomas Hospital, London, UK Thiopurines are often the mainstay of treatment earlier in CD, where aminosalicylates 2Department of Gastroenterology, Guy’s and St for many patients with inflammatory bowel play little or no role, and have been Thomas’ NHS Foundation Trust, disease. As such, a general understanding of the demonstrated to reduce the need for London, UK evidence behind their use and of their surgery by 40%.4 The SONIC (Study of 3Purine Laboratory, Viapath, St metabolism is extremely useful in clinical practice. Biologic and Immunomodulator Naive Thomas’ Hospital, London, UK This review gives a practical overview of Patients in CD) trial study showed the Correspondence to thiopurine metabolism, the importance of benefit of thiopurines in addition to anti- Dr Ben Warner, 1st Floor thiopurine S-methyltransferase testing prior to tumour necrosis factor (TNF) agents in College House, St Thomas’ Hospital, Westminster Bridge the start of therapy and the monitoring of the treatment of CD, most likely through Road, London, SE1 7EH, UK; thioguanine nucleotide levels while on reduced formation of antidrug antibodies [email protected] treatment, guiding a personalised approach to against anti-TNF agents.5 optimising thiopurine therapy. Up to a third of patients have to stop Received 27 July 2016 Revised 5 August 2016 thiopurines due to side effects, the main Accepted 8 August 2016 concerns being leucopenia (1.3–12.6%), INTRODUCTION hepatotoxicity (4%), pancreatitis (3%) Inflammatory bowel disease (IBD) is a and gastric intolerance (1.3–6%).67 chronic inflammatory disorder of the gut, Thiopurine S-methyltransferase (TPMT) divided into two main diseases, ulcerative activity influences the incidence of colitis (UC) and Crohn’s disease (CD). adverse effects, particularly bone marrow Over the last decade there has been a toxicity, however, there is no association shift in paradigm of the treatment of IBD with hepatotoxicity or pancreatitis.8 with a ‘top down’ or ‘rapid step-up’ http://fg.bmj.com/ approach aimed at altering the natural history early in the course of the disease. THIOPURINE METABOLISM Newer drugs, especially biologics, are being The prodrug AZA is converted used for the treatment of IBD, and existing non-enzymatically by biogenic thiols, drugs such as thiopurines are being used including glutathione, to MP with the more effectively by guiding individual release of methyl-4-nitro-5-imidazole. on September 29, 2021 by guest. Protected copyright. dosing according to pharmacogenetic data Following uptake by transporters, MP and monitoring of drug metabolite levels. undergoes metabolism by three compet- Sixty per cent of patients with IBD ing pathways (see figure 1) to form the receive thiopurines (azathioprine (AZA), active metabolite, thioguanine nucleo- mercaptopurine (MP) and to a lesser tides (TGNs) which function as rogue extent tioguanine) with proven efficacy in nucleic acids, disrupting the DNA replica- maintaining steroid-free remission.1 tion of the most rapidly dividing cells Although the evidence for the use of such as activated T cell lymphocytes thiopurines in UC is not as strong as in where TGN concentrations have been patients with CD, it has been demon- found to be higher and where genes To cite: Warner B, involved in T cell immunity have been Johnston E, Arenas- strated that in patients with steroid- 9 Hernandez M, et al. Frontline dependent UC, 53% achieved steroid-free shown to be downregulated by AZA. Gastroenterology Published remission on AZA compared with 21% Online First: [please include 2 Day Month Year] on aminosalicylates. Therefore, thiopur- THIOPURINE S-METHYLTRANSFERASE doi:10.1136/flgastro-2016- ines are recommended once a patient has Methylation of MP by TPMT is a critical 100738 required two courses of steroids within a step in thiopurine metabolism. It was first Warner B, et al. Frontline Gastroenterology 2016;0:1–6. doi:10.1136/flgastro-2016-100738 1 SMALL BOWEL AND NUTRITION Frontline Gastroenterol: first published as 10.1136/flgastro-2016-100738 on 29 August 2016. Downloaded from Figure 1 Azathioprine metabolism. AO, aldehyde oxidase; AZA, azathioprine; HPRT, hypoxanthine phosphoribosyltransferase; IBD, inflammatory bowel disease; IMPDH, inosine monophosphate dehydrogenase; ITPase, inosine triphosphatase; MeMP, methylmercaptopurine; MeTIMP, methylthioinosine monophosphate; MP, mercaptopurine; TGMP, thioguanine monophosphate; TGN, thioguanine nucleotide; TGTP, thioguanine triphosphate; TIMP, thioinosine monophosphate; TITP, thioinosine triphosphate; TPMT, thiopurine S-methyltransferase; TUA, thiouric acid; XO, xanthine oxidase. The metabolism of MP involves three competing pathways: the first being degradation to TUA which is then excreted, the second is through methylation by TPMT into MeMP, and the third is the breakdown of MP into TIMP catalysed by HPRT. TIMP is then further metabolised via IMPDH into TGMP. Kinases convert this into the TGNs. Approximately 15–20% of patients with IBD demonstrate hypermethylation when treated with thiopurines. This means that during thiopurine metabolism, methylated thiopurine metabolites are preferentially produced instead of TGNs. noted in the 1980s that differences in TPMT activity completely deficient patients, irrespective of whether help account for the variability in tolerance to thiopur- the patient has a rare or common variant TPMT geno- ines. Rare and common genetic polymorphisms influ- type. Other factors influencing TPMT activity, for ence enzyme function resulting in a trimodal example red cell age, also result in discordance population distribution of activity. In Caucasians, com- between genotype and phenotype, particularly in the plete TPMT deficiency occurs in 1 in 300 individuals. high carrier range.15 Carriers of a deficiency-associated allele (heterozygotes) have around 50% enzyme activity and occur at an THIOGUANINE NUCLEOTIDES approximate frequency of 1 in 10 of the population.10 Although important, TPMT polymorphisms account The majority of cases of TPMT deficiency (∼95%) are for only 10% of overall thiopurine toxicity.16 Indeed, associated with three alleles, TPMT*2, TPMT*3A and 50–75% of all patients developing leucopenia have a TPMT*3C.11 The frequency of these variants depends normal TPMT and only 3% of hypermethylators have 17 on ethnicity with TPMT*3A being more common in ultrahigh TPMT. Measuring TGNs provides a http://fg.bmj.com/ Caucasian populations.12 summary of epigenetic and genetic factors influencing Individuals with complete TPMT deficiency who thiopurine metabolism and, together with measure- receive standard doses of AZA or MP are highly likely ment of MeMP, offers a means for therapeutic drug to develop severe and potentially fatal myelosuppres- monitoring. sion. There is a small case series of patients with IBD Measurement of TGNs and MeMP in red blood treated with around 10% of standard doses, all of cells (RBCs) has been shown to be clinically useful on September 29, 2021 by guest. Protected copyright. whom tolerated this well.13 Heterozygotes are also at after steady state is reached at 4–6 weeks.18 risk of toxicity at standard doses but this is prevented Meta-analyses suggest that a therapeutic range of by initiation at 50% of the conventional dose. Hence, TGN between 235 pmol/8×108 and 450 pmol/8×108 recommended practice is to check TPMT levels prior RBCs correlates best with a good clinical response.19 20 to starting therapy and adjusting the dose according In addition, there is evidence that TGN monitoring in to TPMT status. IBD is associated with improved outcomes with a Ultrahigh TPMT (>40 pmol/mg Hb/h) is associated negative correlation between RBC TGNs and disease with a skewed drug metabolism in a selection of activity.21 A treatment strategy using TGNs to deter- patients where MP is preferentially metabolised to mine optimal dosing resulted in improved outcomes methylmercaptopurine (MeMP) resulting in lower in 90% of patients compared with 33% in those not TGNs which in turn are associated with a poorer guided by TGNs.18 clinical response and side effects. This preferential metabolism to MeMP or ‘shunting’ is known as HYPERMETHYLATION hypermethylation.14 Approximately 15–20% of patients with IBD demon- TPMT phenotyping by enzyme assay is generally strate hypermethylation when treated with thiopur- preferred to genotyping, as the assay will detect all ines.16 The usual definition of hypermethylation is a 2 Warner B, et al. Frontline Gastroenterology 2016;0:1–6. doi:10.1136/flgastro-2016-100738 SMALL BOWEL AND NUTRITION Frontline Gastroenterol: first published as 10.1136/flgastro-2016-100738 on 29 August 2016. Downloaded from ratio of MeMP to TGN of >11. In this setting, sub- disorders with EBV infection being a further risk therapeutic TGNs risk a poor response to therapy. factor.28 The risk remains small and as yet, avoidance Moreover, MeMP >5700 pmol/8×108 RBCs results of these drugs in seronegative individuals is not in a higher risk of hepatotoxicity.20 advised. European guidelines suggests considering Allopurinol is a xanthine oxidase inhibitor that pre- anti-TNF monotherapy as opposed to combination vents the breakdown of thiopurines into thiouric acid therapy with thiopurines.25 (TUA). It was designed to increase the bioavailability of MP by preventing degradation to TUA. The com- OPTIMISING CLINICAL RESPONSE bination of low dose thiopurine and 100 mg of allo- Measuring TGNs has been proven to improve clinical purinol (LDTA) corrects hypermethylation in patients outcomes.18 We check TGNs in all patients who have who have failed therapy due to hepatotoxicity or who symptoms or active disease. We also check TGNs have had a poor response to treatment in association 4 weeks after starting thiopurines or following a with subtherapeutic TGNs.14 22 When using the com- change in the dose (see figure 2).
Load more

Recommended publications
  • Mitomycin C: Indications for Use and Safe Practice in Ophthalmology Published by American Society of Ophthalmic Registered Nurses
    Mitomycin C: Indications for Use and Safe Practice in Ophthalmology Published by American Society of Ophthalmic Registered Nurses Editor Susan Clouser, RN, MSN, CRNO American Society of Ophthalmic Registered Nurses 655 Beach Street, San Francisco, CA 94109 1 This publication includes independent authors’ guidelines for the safe use and handling of mitomycin C in ophthalmic practices. Readers should use these guidelines as a resource only. These guidelines should never take precedence over manufacturers’ recommended practices, facilities policies and procedures, or compliance with federal regulations. Information in this publication may assist facilities in developing policies and procedures specifc to their needs and practice environment. American Society of Ophthalmic Registered Nurses For questions regarding content or association issues contact ASORN at [email protected] or 1.415.561.8513. Copyright © 2011 by American Society of Ophthalmic Registered Nurses American Society of Ophthalmic Registered Nurses has the exclusive rights to reproduce this work, to prepare derivative works from this work, to publicly distribute this work, to publicly perform this work and to publicly display this work. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of American Society of Ophthalmic Registered Nurses. Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 ACKNOWLEDGMENTS The development of this educational resource would not have been possible without the knowledge and expertise of the ophthalmologists and ophthalmic registered nurses who wrote the content and the subsequent reviewers who provided valuable input.
    [Show full text]
  • Thiopurine Drug Therapy
    Thiopurine Drug Therapy Thiopurine drug therapy is used for autoimmune diseases, inflammatory bowel disease, acute lymphoblastic leukemia, and to prevent rejection after solid organ transplant. The inactivation of thiopurine drugs is catalyzed in part by thiopurine Tests to Consider methyltrasferase (TPMT) and nudix hydrolase 15 (NUDT15). Variants in the TPMT and/or NUDT15 genes are associated with an accumulation of cytotoxic metabolites Thiopurine Methyltransferase, RBC leading to increased risk of drug-related toxicity with standard doses of thiopurine 0092066 drugs, and the effects on thiopurine catabolism can be additive. Method: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry The enzyme activity phenotype of TPMT can also be measured directly when Phenotype test to assess risk for severe performed prior to drug administration. Complementary to pretherapeutic tests, myelosuppression with standard dosing of concentrations of thiopurines and metabolites can be measured after initiation of thiopurine drugs therapy to optimize dose. Use for individuals being considered for thiopurine therapy Must be performed before thiopurine therapy is initiated Disease Overview Can also detect rapid metabolizer phenotype Prevalence TPMT and NUDT15 3001535 Method: Polymerase Chain Very low/absent TPMT activity: ~3/1,000 individuals Reaction/Fluorescence Monitoring Intermediate TPMT activity: ~10% of Caucasian individuals Normal TPMT activity: ~90% of individuals Genotyping test to assess genetic risk for severe myelosuppression
    [Show full text]
  • ULORIC Safely and Effectively
    HIGHLIGHTS OF PRESCRIBING INFORMATION -------------------------WARNINGS AND PRECAUTIONS-------------------­ These highlights do not include all the information needed to use ULORIC safely and effectively. See full prescribing • Cardiovascular Death: In a CV outcomes study, there was a higher information for ULORIC. rate of CV death in patients treated with ULORIC compared to allopurinol; in the same study ULORIC was non-inferior to ULORIC (febuxostat) tablets, for oral use allopurinol for the primary endpoint of major adverse Initial U.S. Approval: 2009 cardiovascular events (MACE). Consider the risks and benefits of WARNING: CARDIOVASCULAR DEATH ULORIC when deciding to prescribe or continue patients on See full prescribing information for complete boxed warning. ULORIC. (1, 5.1) • Gout patients with established cardiovascular (CV) disease • Gout Flares: An increase in gout flares is frequently observed treated with ULORIC had a higher rate of CV death compared to during initiation of anti-hyperuricemic agents, including ULORIC. If those treated with allopurinol in a CV outcomes study. (5.1) a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti- • Consider the risks and benefits of ULORIC when deciding to inflammatory drug [NSAID] or colchicine upon initiation of prescribe or continue patients on ULORIC. ULORIC should only treatment) may be beneficial for up to six months. (2.4, 5.2) be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to • Hepatic Effects: Postmarketing reports of hepatic failure, allopurinol, or for whom treatment with allopurinol is not sometimes fatal. Causality cannot be excluded.
    [Show full text]
  • Identification and Analysis of Single-Nucleotide Polymorphisms in the Gemcitabine Pharmacologic Pathway
    The Pharmacogenomics Journal (2004) 4, 307–314 & 2004 Nature Publishing Group All rights reserved 1470-269X/04 $30.00 www.nature.com/tpj ORIGINAL ARTICLE Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway AK Fukunaga1 ABSTRACT 2 Significant variability in the antitumor efficacy and systemic toxicity of S Marsh gemcitabine has been observed in cancer patients. However, there are 1 DJ Murry currently no tools for prospective identification of patients at risk for TD Hurley3 untoward events. This study has identified and validated single-nucleotide HL McLeod2 polymorphisms (SNP) in genes involved in gemcitabine metabolism and transport. Database mining was conducted to identify SNPs in 14 genes 1Department of Clinical Pharmacy and Pharmacy involved in gemcitabine metabolism. Pyrosequencing was utilized to Practice, Purdue University, W. Lafayette, IN, determine the SNP allele frequencies in genomic DNA from European and 2 USA; Departments of Medicine, Genetics, and African populations (n ¼ 190). A total of 14 genetic variants (including 12 Molecular Biology and Pharmacology, Washington University School of Medicine and SNPs) were identified in eight of the gemcitabine metabolic pathway genes. the Siteman Cancer Center, St Louis, MO, USA; The majority of the database variants were observed in population samples. 3Department of Biochemistry and Molecular Nine of the 14 (64%) polymorphisms analyzed have allele frequencies that Biology, Indiana University School of Medicine, were found to be significantly different between the European and African Indianapolis, IN, USA populations (Po0.05). This study provides the first step to identify markers Correspondence: for predicting variability in gemcitabine response and toxicity. Dr HL McLeod, Washington University The Pharmacogenomics Journal (2004) 4, 307–314.
    [Show full text]
  • Caffeine in the Treatment of Pain
    Rev Bras Anestesiol ARTIGOS DE REVISÃO 2012; 62: 3: 387-401 ARTIGOS DE REVISÃO Cafeína para o Tratamento de Dor Cristiane Tavares, TSA 1, Rioko Kimiko Sakata, TSA 2 Resumo: Tavares C, Sakata RK – Cafeína para o Tratamento de Dor. Justificativa e objetivos: A cafeína é uma substância amplamente consumida com efeitos em diversos sistemas e que apresenta farmacoci- nética e farmacodinâmica características, causando interações com diversos medicamentos. O objetivo deste estudo é fazer uma revisão sobre os efeitos da cafeína. Conteúdo: Nesta revisão, são abordados a farmacologia da cafeína, os mecanismos de ação, as indicações, as contraindicações, as doses, as interações e os efeitos adversos. Conclusões: Faltam estudos controlados, randomizados e duplos-cegos para avaliar a eficácia analgésica da cafeína nas diversas síndromes dolorosas. Em pacientes com dor crônica, é necessário ter cautela em relação ao desenvolvimento de tolerância, abstinência e interação medi- camentosa no uso crônico de cafeína. Unitermos: ANALGESIA; DOR; DROGAS, Alcaloide/cafeína. ©2012 Elsevier Editora Ltda. Todos os direitos reservados. INTRODUÇÃO Estrutura química A cafeína foi isolada em 1820, mas a estrutura correta des- A cafeína é um alcaloide presente em mais de 60 espécies ta metilxantina foi estabelecida na última década do século de plantas 4. Sua estrutura molecular pertence a um grupo XIX. Os efeitos não foram claramente reconhecidos até 1981, de xantinas trimetiladas que incluem seus compostos inti- quando o bloqueio de receptores adenosina foi correlacio- mamente relacionados: teobromina (presente no cacau) e nado às propriedades estimulantes da cafeína e de seus teofilina (presente no chá) 1. Quimicamente, esses alcaloides análogos 1. Provavelmente a cafeína é uma das substâncias são semelhantes a purinas, xantinas e ácido úrico, que são psicoativas mais utilizadas no mundo, promovendo efeitos compostos metabolicamente importantes 4.
    [Show full text]
  • Chapter 1.Pdf
    CHAPTER 1 INTRODUCTION AND OUTLINE OF THIS THESIS INTRODUCTION Inflammatory bowel diseases (IBD), comprising Crohn’s disease, ulcerative colitis and IBD- 1 unclassified, are chronic recurrent inflammatory disorders of the (large) intestine with a heterogeneous, but often disabling disease presentation. The prevalence of IBD is increasing worldwide and medical therapies are introduced earlier to improve health-related quality of life and postpone surgical interventions1,2. This has led to the more extensive use of immunosuppressive therapies including biologicals and thiopurines. While the use of tioguanine was soon abandoned due to toxicity concerns3, over the years efficacy data on the use of azathioprine and mercaptopurine for the treatment of IBD has grown4,5. However, due to side effects and ineffectiveness, related to unprofitable metabolism, thiopurine therapy often fails; up to 50% of patients discontinues treatment within 2 years6. Increasing the knowledge on thiopurine metabolism may provide opportunities to further explore the therapeutic usefulness of thiopurines, which both from a patient’s perspective and a pharmacoeconomic perspective is essential. THIOPURINES In the 1950’s Gertrude Elion (1918-1999) worked as an assistant to George Hitchings (1905- 1998), both employees of Burroughs-Wellcome, focussing on the advent of drugs that inhibited cell growth without doing harm to the host cells. They discovered that purine bases are essential components of nucleic acids and vital for cell growth7. Subsequently, they designed the purine antagonists diaminopurine and tioguanine that blocked the synthesis of original nucleic acids and inhibited cell growth8. For the first time a successful treatment of leukaemia became available. Some years later Elion and colleagues also developed mercaptopurine, azathioprine, allopurinol, trimethoprim and acyclovir.
    [Show full text]
  • How to Manage Acute Promyelocytic Leukemia
    Leukemia (2012) 26, 1743 -- 1751 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu HOW TO MANAGEy How to manage acute promyelocytic leukemia J-Q Mi, J-M Li, Z-X Shen, S-J Chen and Z Chen Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL is changing, from the worst among AML as it used to be, to currently the best. The application of all-trans-retinoic acid (ATRA) to the induction therapy of APL decreases the mortality of newly diagnosed patients, thereby significantly improving the response rate. Therefore, ATRA combined with anthracycline-based chemotherapy has been widely accepted and used as a classic treatment. It has been demonstrated that high doses of cytarabine have a good effect on the prevention of relapse for high-risk patients. However, as the indications of arsenic trioxide (ATO) for APL are being extended from the original relapse treatment to the first-line treatment of de novo APL, we find that the regimen of ATRA, combined with ATO, seems to be a new treatment option because of their targeting mechanisms, milder toxicities and improvements of long-term outcomes; this combination may become a potentially curable treatment modality for APL. We discuss the therapeutic strategies for APL, particularly the novel approaches to newly diagnosed patients and the handling of side effects of treatment and relapse treatment, so as to ensure each newly diagnosed patient of APL the most timely and best treatment. Leukemia (2012) 26, 1743--1751; doi:10.1038/leu.2012.57 Keywords: acute promyelocytic leukemia (APL); all-trans-retinoic acid (ATRA); arsenic trioxide (ATO) INTRODUCTION In this review, we introduce the therapeutic strategies of APL, Acute promyelocytic leukemia (APL) is a distinct subtype of acute including the treatment of newly diagnosed and relapsed myeloid leukemia (AML) characterized by its abnormal promye- patients, as well as the ways to deal with the side effects.
    [Show full text]
  • DRUG NAME: Thioguanine
    Thioguanine DRUG NAME: Thioguanine SYNONYM(S): 2-amino-6-mercaptopurine,1 6-TG, TG COMMON TRADE NAME(S): LANVIS® CLASSIFICATION: antimetabolite, cytotoxic2 Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Thioguanine is a purine antagonist.1 It is a pro-drug that is converted intracellullarly directly to thioguanine monophosphate3 (also called 6-thioguanylic acid)4 (TGMP) by the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT). TGMP is further converted to the di- and triphosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP).5 The cytotoxic effect of thioguanine is a result of the incorporation of these nucleotides into DNA. Thioguanine has some immunosuppressive activity.1 Thioguanine is specific for the S phase of the cell cycle.6 PHARMACOKINETICS: Oral Absorption • incomplete and variable (14-46%)7 • preferably taken on an empty stomach8; may be taken with food if needed • children9: <20% Distribution crosses the placenta10 cross blood brain barrier? negligible11 volume of distribution12 148 mL/kg plasma protein binding no information found Metabolism hepatic10 activation by4: • hypoxanthine-guanine phosphoribosyl transferase (HGPRT) elimination by4: • guanase to 6-thioxanthine • thiopurine methyltransferase (TPMT) to 2-amino-6-methyl thiopurine active metabolites3,4 thiopurine nucleotides inactive metabolites4 6-thioxanthine, 2-amino-6-methyl thiopurine Excretion renal excretion12; initially intact drug, then metabolites urine12
    [Show full text]
  • Is TPMT Testing a Predictor of Duration of Use Or Long-Term Benefit of Thiopurine Agents? Shatoya R
    Grand Valley State University ScholarWorks@GVSU Masters Theses Graduate Research and Creative Practice 12-2018 Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents? Shatoya R. Wilson Grand Valley State University Follow this and additional works at: https://scholarworks.gvsu.edu/theses Part of the Chemical and Pharmacologic Phenomena Commons Recommended Citation Wilson, Shatoya R., "Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents?" (2018). Masters Theses. 914. https://scholarworks.gvsu.edu/theses/914 This Thesis is brought to you for free and open access by the Graduate Research and Creative Practice at ScholarWorks@GVSU. It has been accepted for inclusion in Masters Theses by an authorized administrator of ScholarWorks@GVSU. For more information, please contact [email protected]. Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents? Shatoya Renee Wilson A Thesis Submitted to the Graduate Faculty of GRAND VALLEY STATE UNIVERSITY In Partial Fulfillment of the Requirements For the Degree of Master of Health Science Biomedical Science December 2018 Dedication This is dedicated to my sister and father, for their support and love. I thank you for listening to me when I needed to practice with or vent to someone. I would also like to dedicate this to my thesis committee, who helped me grow as a student and researcher. For your guidance, I am grateful. 3 Acknowledgements I would like to thank my thesis committee, Dr. Debra Burg, David Chesla, and Dr. John Capodilupo for their mentorship and guidance.
    [Show full text]
  • Recent Topics on the Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 May 2019 doi:10.20944/preprints201905.0358.v1 Peer-reviewed version available at Int. J. Mol. Sci. 2019, 20, 3210; doi:10.3390/ijms20133210 1 of 39 1 Review 2 Recent topics on the mechanisms of 3 immunosuppressive therapy-related neurotoxicities 4 Wei Zhang 1, Nobuaki Egashira 1,2,* and Satohiro Masuda 1,2 5 1 Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 6 Kyushu University, Fukuoka 812-8582, Japan 7 2 Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan 8 * Correspondence: [email protected], Tel.: 81-92-642-5920 9 Abstract: Although transplantation procedures have been developed for patients with end-stagec 10 hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. 11 Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin 12 inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly 13 increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is 14 commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. 15 The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability 16 or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in 17 electrophysiological state. Other immunosuppressants can also induce neuropsychiatric 18 complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces 19 depression and headache; methotrexate affects the central nervous system; mouse monoclonal 20 immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and 21 patients using corticosteroids usually experience cognitive alteration.
    [Show full text]
  • Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A
    Case Report DOI: 10.4274/tjh.2013.0082 Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A/*3C Polymorphisms in a Patient with Pediatric Leukemia and the Effect of Steroid Therapy Pediatrik Bir Lösemi Olgusunda Tiyopurin S-Metiltransferaz *3A/*3C Polimorfizmi ile İlişkili Ağır Miyelotoksisite-Steroid Tedavisinin Etkisi Burcu Fatma Belen1, Türkiz Gürsel1, Nalan Akyürek2, Meryem Albayrak3, Zühre Kaya1, Ülker Koçak1 1Gazi University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey 2Gazi University Faculty of Medicine, Department of Pathology, Ankara, Turkey 3Kırıkkale University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey Abstract: Myelosuppression is a serious complication during treatment of acute lymphoblastic leukemia and the duration of myelosuppression is affected by underlying bone marrow failure syndromes and drug pharmacogenetics caused by genetic polymorphisms. Mutations in the thiopurine S-methyltransferase (TPMT) gene causing excessive myelosuppression during 6-mercaptopurine (MP) therapy may cause excessive bone marrow toxicity. We report the case of a 15-year-old girl with T-ALL who developed severe pancytopenia during consolidation and maintenance therapy despite reduction of the dose of MP to 5% of the standard dose. Prednisolone therapy produced a remarkable but transient bone marrow recovery. Analysis of common TPMT polymorphisms revealed TPMT *3A/*3C. Key Words: Myelosuppression, Thiopurine S-methyl transferase, Acute leukemia Özet: Miyelosupresyon,
    [Show full text]
  • List of Drugs Not Repackaged by Safecor Health
    Drugs Not Repackaged by Safecor Health The following tables list specific medications that are not repackaged by Safecor Health due to regulatory restrictions or specific manufacturer requirements. The items not repackaged are alphabetically listed below, both by brand name (table 1) and generic name (table 2). Please note: Safecor Health cannot repackage any beta lactam antibiotics (such as penicillins, amoxicillin and cephalosporins) or potent chemotherapeutic agents. Also, due to FDA restrictions, we cannot repackage half- or quarter-tabs, compounded or diluted drugs, powders, and ointments or creams. Safecor Health can repackage most hazardous drugs on the NIOSH list. Contact us for a complete list of hazardous drugs repackaged by Safecor Health. Table 1. Do Not Repackage Drugs Sorted Alphabetically by Brand Name Brand Name(s) Generic Name(s) Reason Item Cannot Be Repackaged Adrucil Fluorouracil Potent chemotherapy agent Aspirin and Extended-Release Specific manufacturer recommendations for very Aggrenox Dipyridamole limited expiration dating Albenza Albendazole Cost per dose prohibitive Alkeran Melphalan Potent chemotherapy agent Augmentin Amoxicillin and Clavulanate Potassium Safecor Health does not repackage this drug class Manufacturer states, "dispense in original container," Belsomra Suvorexant on the drug label Manufacturer states, "dispense in original container," Biktarvy Bictegravir, Emtricitabine and Tenofovir Alafenamide on the drug label Bion Tears Dextran, Hypromellose Ophthalmic Drops Sterile and unpreserved CeeNU Lomustine
    [Show full text]