Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease: Effect of N-acetyl transferase polymorphisms

Stocco, Gabriele; Cuzzoni, Eva; Iudicibus, Sara De; Favretto, Diego; Malusà, Noelia; Martelossi, Stefano; Pozzi, Elena; Lionetti, Paolo; Ventura, Alessandro; Decorti, Giuliana

doi:10.3748/wjg.v21.i12.3571

Cited by 13 publications

(20 citation statements)

References 40 publications

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“…On top of the inhibition of multiple inflammatory pathways and the suppression of the nuclear factor kappa B as a main result, amino-salicylates also possess potent anti-oxidant and free-radical-scavenger properties[ 4 ]. Amino-salicylates are mainly used in the induction and maintenance of remission in UC[ 23 ].…”

Section: Aminosalycilatesmentioning

confidence: 99%

“…However, there are studies suggesting a possible role in the postoperative maintenance of remission, as well as in the subgroup of children with mild, localised ileal disease. In addition, adult studies suggest a protective role of 5-ASA in IBD against colon cancer in patients with colonic location[ 23 ].…”

Section: Aminosalycilatesmentioning

confidence: 99%

“…Thiopurines are steroid sparing agents and have been proven effective maintenance treatment in paediatric IBD: studies have shown significantly lower cumulative steroid doses and relapse rates at 18 mo in children on 6-MP compared with placebo (9% vs 47%) as well as a reduced need for surgery in CD[ 3 , 23 ]. Recommended doses are 1.0 to 2.5 mg/kg per day for AZA and 1 mg/d for 6-MP[ 25 ].…”

Section: Thiopurinesmentioning

confidence: 99%

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Treating children with inflammatory bowel disease: Current and new perspectives

Guariso

Gasparetto

2017

WJG

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Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut characterised by alternating periods of remission and relapse. Whilst the mechanism underlying this disease is yet to be fully understood, old and newer generation treatments can only target selected pathways of this complex inflammatory process. This narrative review aims to provide an update on the most recent advances in treatment of paediatric IBD. A MEDLINE search was conducted using “paediatric inflammatory bowel disease”, “paediatric Crohn’s disease”, “paediatric ulcerative colitis”, “treatment”, “therapy”, “immunosuppressant”, “biologic”, “monitoring” and “biomarkers” as key words. Clinical trials, systematic reviews, and meta-analyses published between 2014 and 2016 were selected. Studies referring to earlier periods were also considered in case the data was relevant to our scope. Major advances have been achieved in monitoring the individual metabolism, toxicity and response to relevant medications in IBD including thiopurines and biologics. New biologics acting on novel mechanisms such as selective interference with lymphocyte trafficking are emerging treatment options. Current research is investing in the development of reliable prognostic biomarkers, aiming to move towards personalised treatments targeted to individual patients.

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Section: Aminosalycilatesmentioning

confidence: 99%

Section: Aminosalycilatesmentioning

confidence: 99%

Section: Thiopurinesmentioning

confidence: 99%

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Treating children with inflammatory bowel disease: Current and new perspectives

Guariso

Gasparetto

2017

WJG

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“…These nucleotides act as purine antagonists causing the inhibition of DNA, RNA and protein synthesis, which results in immunosuppression and cytotoxicity. 75 Azathioprine can also generate 6-thioguanine GTP, which has been shown to induce T cell apoptosis through co-stimulation of the CD28 receptor due to blockage of Ras-related C3 botulinum toxin substrate [Rac1] activation of NFκB. 76 Erythrocyte concentrations of thiopurine metabolites are now carefully monitored in many centres, to maintain therapeutic levels and to assess adherence, as increases in blood concentration have been associated with hepatotoxicity.…”

Section: Autophagy and Crohn’s Diseasementioning

confidence: 99%

“…77 Other severe adverse effects associated with thiopurines are pancreatitis and myelosuppression, 3 with 15–20% of patients treated with thiopurines having to discontinue treatment due to these side effects. 75 …”

Section: Autophagy and Crohn’s Diseasementioning

confidence: 99%

Inflammatory Bowel Disease Drugs: A Focus on Autophagy

Hooper

Barlow

Stevens

et al. 2016

ECCOJC

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Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents. This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients.

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No Benefit of Continuing 5-Aminosalicylates in Patients with Crohn’s Disease Treated with Anti-metabolite Therapy

et al. 2021

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Background and Aims 5-aminosalicylates (5-ASA) are frequently used in the management of Crohn's disease (CD). We used a de-identified administrative claims database to compare patterns and outcomes of continuing versus stopping 5-ASA in patients with CD who escalated to anti-metabolite monotherapy. Methods Patients with CD on 5-ASA who were new users of anti-metabolite monotherapy and followed for at least 12 months from OptumLabs® Data Warehouse. Three patterns of 5-ASA use were identified: stopped 5-ASA, short-term 5-ASA (use for < 6 months after starting anti-metabolites), or persistent 5-ASA (use for > 6 months after starting anti-metabolites). Outcomes (need for corticosteroids, risk of CD-related hospitalization and/or surgery, treatment escalation to biologic therapy) were compared using Cox proportional hazard analysis adjusting for key covariates, with a 12-month immortal time period. Results Of 3036 patients with CD who were new-users of anti-metabolite monotherapy, 667 (21.9%), 626 (20.6%), and 1743 (57.4%) stopped 5-ASA, used 5-ASA transiently or persistently, respectively. Compared to patients who stopped 5-ASA after starting anti-metabolites, persistent 5-ASA use was associated with a higher risk of corticosteroid use (HR, 1.24 [1.08-1.42]), without an increase in risk of CD-related hospitalization (HR, 1.21 [0.98-1.49]), CD-related surgery (HR, 1.28 [0.90-1.80]) or treatment escalation (HR,). Sensitivity analyses using a 3-month window after initiation of anti-metabolites to classify patients as continuing vs. stopping 5-ASA showed similar results. Residual confounding by disease severity could not be excluded. Conclusion 5-ASAs are frequently continued long-term even after escalation to anti-metabolite therapy in patients with CD but offer no clinical benefit over stopping 5-ASA.

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Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease: Effect of N-acetyl transferase polymorphisms

Abstract: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study.

Cited by 13 publications

References 40 publications

Treating children with inflammatory bowel disease: Current and new perspectives

Treating children with inflammatory bowel disease: Current and new perspectives

Inflammatory Bowel Disease Drugs: A Focus on Autophagy

No Benefit of Continuing 5-Aminosalicylates in Patients with Crohn’s Disease Treated with Anti-metabolite Therapy

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