Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease

Chande, Nilesh; Townsend, Cassandra M; Parker, Claire E; MacDonald, John K

doi:10.1002/14651858.cd000545.pub3

Cited by 262 publications

(91 citation statements)

References 78 publications

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“…Thiopurine drugs, namely azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are immunosuppressive agents that are, due to their low cost and high effectiveness, widely used in the treatment of inflammatory bowel diseases (IBD), but also in other autoimmune diseases, some hemopoetic disorders and some solid organ transplant [1][2][3][4][5]. However, the occurrence of adverse drug reactions limits the use of these drugs.…”

Section: Indroductionmentioning

confidence: 99%

Determination of thiopurine S -methyltransferase activity by hydrophilic interaction liquid chromatography hyphenated with mass spectrometry

Pecher

Dokupilová

Zelinková

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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Determination of thiopurine S-methyltransferase activity by hydrophilic interaction liquid chromatography hyphenated with mass spectrometry, Journal of Pharmaceutical and Biomedical Analysishttp://dx.doi.org/10. 1016/j.jpba.2017.05.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Highlights New HILIC-HPLC-MS method was developed for determination of TPMT activity  HILIC-HPLC-MS combination was approved by excellent performance parameters  HILIC-HPLC-MS was compared to traditional RP-HPLC-UV as well as advanced RP-HPLC-MS  Conventional approaches were surpassed in terms of selectivity, LOD, analysis time  HILIC-HPLC-MS is favorable for routine assay of 6-MMP/6-MP ratio in RBC lysates List of abbreviations6-MMP -6-methylmercaptopurine, 6-MP -6-mercaptopurine, 6-TG -6-thioguanine, AZA -azathioprine, Cl-P -6-chloropurine, DTT -dithiothreitol, IBD -inflammatory bowel diseases, RBC -red blood cells, SAM -S-adenosyl-L-methionine, TGN -thioguanine nucleotides, TPMT -thiopurine-S-methyl transferase. IndroductionThiopurine drugs, namely azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are immunosuppressive agents that are, due to their low cost and high effectiveness, widely used in the treatment of inflammatory bowel diseases (IBD), but also in other autoimmune diseases, some hemopoetic disorders and some solid organ transplant [1][2][3][4][5]. However, the occurrence of adverse drug reactions limits the use of these drugs. Up to 15 % of IBD patients discontinue this type of treatment due to adverse events that include nausea, skin reactions, pancreatitis, hepatotoxicity or myelotoxicity [6,7].Thiopurine drugs are prodrugs, so their biological activity is preceded by extensive metabolism. Briefly, after absorption, AZA is metabolized in the liver to 6-MP which then can be metabolized to active thioguanine nucleotides (TGN) and to inactive methylated product 6-methylmercaptopurine (6-MMP) by the thiopurine-S-methyl transferase (TPMT) enzyme [8]. TPMT (EC 2.1.1.67), a key enzyme involved in the thiopurine drug metabolism, is subject to common genetic polymorphism that leads to trimodial distribution of the TPMT activity in population [9]. Individuals with lower TPMT activity might have an increased risk of developing thiopurine-induced myelosuppression. On the contrary, individuals with high TPMT activity have lower concentrations of active TGN metabolites resulting in reduced therapeutic efficacy of the drug [10]. In addition, high TPMT activity leads to accumulation of the hepatotoxic methylated metabolites [11]. Therefore, some scientific committees advise to determine the TP...

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Section: Indroductionmentioning

confidence: 99%

Determination of thiopurine S -methyltransferase activity by hydrophilic interaction liquid chromatography hyphenated with mass spectrometry

Pecher

Dokupilová

Zelinková

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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“…A meta-analysis by Pearson et al [57] reported an odds ratio of 3.09 for response to therapy over placebo. In the more recent meta-analyses conducted for the Cochrane database, a pooled effi cacy of 54% and 71% for induction and maintenance of CD remission was reported for AZA [58,59]. Although the data are less robust for UC, AZA was shown to be superior for the maintenance of remission compared to placebo (failure to maintain remission: OR 0.41; 95% CI 0.24 to 0.70) [60].…”

Section: Thiopurinesmentioning

confidence: 99%

Therapeutic Drug Monitoring in Inflammatory Bowel Disease

2017

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Tumor necrosis factor (TNF)-α inhibitors and thiopurines are among the most important classes of medications utilized in the clinical management of Crohn's disease and ulcerative colitis. A signifi cant proportion of patients loses response to these agents or develops adverse eff ects during the course of the treatment. Monitoring of drug levels and anti-drug antibodies (for TNF-α inhibitors) and metabolite levels (for thiopurines) can provide valuable insight into the possible etiology of unfavorable outcomes and allow for an appropriate management strategy for these patients. Th is review summarizes the current knowledge on the clinical implications of therapeutic drug monitoring in infl ammatory bowel disease patients treated with TNF-α inhibitors and thiopurines.

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“…4,5 However, the treatment effect of thiopurines for Crohn's disease has continued to be inconsistent. The most recent Cochrane Library meta-analyses reported that thiopurines are not effective for induction of remission 6 , but are effective for maintenance of remission and for steroid sparing 7 , and another meta-analysis reported efficacy of thiopurines for prevention of post-operative recurrence. 8 Given the inconsistency of treatment effects, controversy has persisted regarding the appropriate role of thiopurines in the treatment of Crohn's disease.…”

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confidence: 99%

“…6 Third, the most recent Cochrane Library meta-analysis demonstrated that thiopurines are modestly effective for maintenance of steroid induced remission 7 , and another meta-analysis demonstrated a modest effect for prevention of post-operative recurrence. 8 With regard to these two indications, it must be kept in mind that when thiopurines are combined with corticosteroids, the relative risks of serious infection and mortality from infection are markedly increased.…”

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confidence: 99%

“…8 With regard to these two indications, it must be kept in mind that when thiopurines are combined with corticosteroids, the relative risks of serious infection and mortality from infection are markedly increased. 21,22 Thus, the two remaining indications for primary therapy with thiopurines are maintenance of steroid induced remission/steroid sparing in patients with CD which is not newly diagnosed 7 , and prevention of post-operative recurrence 8 , each of which has a modest effect size that must be weighed against the risks of the medications. Two comparative effectiveness trials have demonstrated unequivocal superiority of combination therapy with thiopurines and TNF antagonist therapy with infliximab as compared with thiopurines alone, with no incremental increase in toxicity.…”

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