Exploring the role of oxidative stress and the effect of N-acetylcysteine in thiopurine-induced liver injury in inflammatory bowel disease: A randomized crossover pilot study.

Thiopurine treatment is regularly complicated by drug-induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine-induced liver injury coincides with increased oxidative stress and whether co-administration with N-acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine-induced increased serum liver tests.

Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

Background: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth.

Methods: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included.

Electronic Nose Sensor Drift Affects Diagnostic Reliability and Accuracy of Disease-Specific Algorithms.

Sensor drift is a well-known disadvantage of electronic nose (eNose) technology and may affect the accuracy of diagnostic algorithms. Correction for this phenomenon is not routinely performed. The aim of this study was to investigate the influence of eNose sensor drift on the development of a disease-specific algorithm in a real-life cohort of inflammatory bowel disease patients (IBD).

Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn's disease: a cross-sectional study.

Background: Methotrexate is an immunomodulatory drug for patients with Crohn's disease. Erythrocyte MTX-polyglutamates (MTX-PG) may be used for therapeutic drug monitoring (TDM) as MTX-PG is thought to mediate MTX's efficacy. Information on determinants of the concentration of MTX-PG in patients with Crohn's disease is lacking.

A three-dimensional analysis of the development of cranial nerves in human embryos.

To increase our understanding of the etiology of specific neurological disorders (e.g., Duane syndrome, glossoptosis in Pierre Robin sequence), proper knowledge of anatomy and embryology of cranial nerves is necessary.

The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review.

: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (.

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies.

Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy.

Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy.

Methods: In this nationwide, multicentre study, medical records of tioguanine- using IBD patients were retrospectively reviewed.

Key insights from therapeutic drug monitoring in Crohn's disease patients.

The incidence and prevalence of Crohn's disease are increasing causing a significant disease burden. Therapeutic drug monitoring (TDM) is advocated as a promising tool for personalized or individual-tailored therapy strategies and has been welcomed as a new means to improve current therapy strategies. Nevertheless, pharmacokinetic-based TDM has limitations, and straightforward target concentrations for most therapies are lacking.

Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease.

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype.

Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs).

High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients.

Objectives: Thiopurines play an essential role in the management of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis).

Optimizing Thiopurine Therapy in Inflammatory Bowel Disease Among 2 Real-life Intercept Cohorts: Effect of Allopurinol Comedication?

Background: Thiopurines (azathioprine and mercaptopurine) are frequently used immunosuppressive drugs to maintain remission in patients with inflammatory bowel disease. Half of the conventional thiopurine-derivative users have to discontinue treatment within 5 years, mainly because of intolerable adverse events. Over recent years, different strategies to optimize thiopurine treatment were suggested, yet, studies describing the clinical effectiveness of these strategies remain scarce.

Nodular Regenerative Hyperplasia of the Liver in Patients with IBD Treated with Allopurinol-Thiopurine Combination Therapy.

Background: Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver.

Rac Attack: Modulation of the Small GTPase Rac in Inflammatory Bowel Disease and Thiopurine Therapy.

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing. Although the etiology of IBD is unknown, it is thought that genetically susceptible individuals display an inappropriate inflammatory response to commensal microbes, resulting in intestinal tissue damage. Key proteins involved in regulating the immune response, and thus in inflammation, are the small triphosphate-binding protein Rac and its regulatory network.

Rac1 as a Potential Pharmacodynamic Biomarker for Thiopurine Therapy in Inflammatory Bowel Disease.

Background: Azathioprine and mercaptopurine (MP) are effective in treating patients with inflammatory bowel disease (IBD). Immunosuppressive effects of thiopurines involve T-cell apoptosis after inhibition of GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1). This study aimed to assess whether expression and activity of Rac1 or phosphorylated ezrin-radixin-moesin (pERM) in patients with IBD could provide a useful biomarker for the pharmacodynamic thiopurine effect and might be related to clinical effectiveness.

Clinical Value of Mercaptopurine After Failing Azathioprine Therapy in Patients With Inflammatory Bowel Disease.

Background: Thiopurines have been widely accepted as immunosuppressive therapy in inflammatory bowel disease. However, many patients have to discontinue thiopurines due to intolerance or ineffectiveness. A therapeutically beneficial effect of switching from azathioprine (AZA) to mercaptopurine (MP) after developing adverse events (AEs) has been reported.

Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease.

Background: The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure.

The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients.

Background And Aims: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement.

Methods: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included.

Sustained clinical benefit and tolerability of methotrexate monotherapy after thiopurine therapy in patients with Crohn's disease.

Background & Aims: Methotrexate is an immunosuppressant that is used to treat patients with Crohn's disease (CD). However, there are few data on the long-term effects of methotrexate maintenance therapy for these patients. We assessed the sustained clinical benefits and tolerability of methotrexate monotherapy after thiopurine therapy in patients with CD.

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study.

Introduction: Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes.