Multicentre study and systematic review: Allopurinol exposure during pregnancy

BACKGROUND: Data about the safety of allopurinol in pregnant women are sparsely reported. AIMS: To investigate the risk of adverse pregnancy outcome and congenital abnormalities after in utero exposure to allopurinol in inflammatory bowel disease (IBD) pregnancies and in general. METHODS: We collected safety data of patients with IBD who were treated with allopurinol during pregnancy between January 2013 and March 2022. Additionally, we performed a systematic review about the teratogenic potential of allopurinol. RESULTS: We collected data from 42 allopurinol-exposed pregnancies, including one twin pregnancy; in all women, allopurinol was combined with a thiopurine. Six pregnancies (14.3%) resulted in miscarriage and one in stillbirth at 32 weeks. A congenital anomaly was observed in one newborn (coarctation of the aorta discovered postpartum). Three pregnancies, including the twin pregnancy, ended in moderate preterm delivery and one in very preterm delivery. Five neonates (15.2%) were small for gestational age. From our literature search, we identified an additional 102 allopurinol-exposed pregnancies resulting in 129 live births, including 36 infants from our cohort. Ten infants (7.8%) were born with a congenital anomaly. Two (1.6%) had a comparable pattern of multiple anomalies. The systematic review sub-analysis including only infants born to mothers with IBD (n = 76) revealed that 2.6% of infants had congenital anomalies after in utero exposure to a low dose of allopurinol. CONCLUSIONS: Overall, the teratogenicity of allopurinol remains inconclusive. Children conceived by mothers treated for IBD with allopurinol/thiopurine co-therapy do not seem to have an increased risk of congenital anomalies

Reestablishing Stability and Avoiding a Credit Crunch: Comparing Different Bad Bank Schemes

This paper develops a model to analyze two different bad bank schemes, an outright sale of toxic assets to a state-owned bad bank and a repurchase agreement between the bad bank and the initial bank. For both schemes, we derive a critical transfer payment that induces a bank manager to participate. Participation improves the bank's solvency and enables the bank to grant new loans. Therefore, both schemes can reestablish stability and avoid a credit crunch. However, an outright sale will be less costly to taxpayers than a repurchase agreement only if the transfer payment is sufficiently low

The Thiopurine Tale: An Unexpected Journey

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

Gut Microbiota-driven Drug Metabolism in Inflammatory Bowel Disease

Background and Aims: The gut microbiota plays an important role in the metabolization and modulation of several types of drugs. With this study we aimed to review the literature relating to microbial drug metabolism of medication prescribed in inflammatory bowel disease [IBD] practice. Methods: A systematic literature search was performed in Embase and PubMed from inception to October 2019. The search was conducted with predefined MeSH/Emtree and text terms. All studies regarding drug metabolism by microbiota of medication prescribed in IBD practice were eligible. A total of 1018 records were encountered and 89 articles were selected for full text reading. Results: Intestinal bacterial metabolism or modulation is of influence in four specific drugs used in IBD (mesalazines, methotrexate, glucocorticoids and thioguanine). The gut microbiota cleaves the azo-bond of sulfasalazine, balsalazide and olsalazine and releases the active moiety 5-aminosalicylic acid. It has an impact on the metabolization and potentially on the response of methotrexate therapy. In particular, thioguanine can be converted by intestinal bacteria into the pharmacologically active 6-thioguanine nucleotides without the requirement of host metabolism. Glucocorticoid compounds can be prone to bacterial degradation. Conclusion: The human intestinal microbiota can have a major impact on drug metabolism and efficacy of medication prescribed in IBD practice. A better understanding of these interactions between microbiota and drugs is needed and should be an integral part of the drug development pathway of new IBD medication

The Reliability of Patient-Performed Fecal Calprotectin Testing in Inflammatory Bowel Disease

BACKGROUND: Home use of a buffer-containing extraction device for fecal calprotectin determination can bypass the labor-intensive extraction procedure and potentially prevent degradation at room temperature. METHODS: In this prospective cross-sectional observational study, 2 CALiaGold tubes (extraction device) and one native tube were filled from the same bowel movement by patients with inflammatory bowel disease. Afterwards patients completed a questionnaire including whether they preferred the extraction device or the normal sampling method. All tubes were sent to the laboratory and when they arrived, 2 more CALiaGold tubes were filled at the laboratory from the native sample. The fecal calprotectin concentrations in all tubes were measured by a particle-enhanced turbidimetric immunoassay. RESULTS: Fifty-three patients were included in the study. Fecal calprotectin levels were significantly higher in samples extracted by the patient compared to the analyst-performed extractions. When patients were divided into 3 groups (i.e., fecal calprotectin levels 200 µg/g) a substantial concordance was found (Cohen kappa 0.654). Patients sampling imprecision was higher (P < 0.018, median CV 16%) compared to the analyst. Most patients preferred this extraction device. CONCLUSIONS: Patient-performed fecal calprotectin extraction seems a realistic alternative sampling method and is preferred by most patients

Advances in Thiopurine Drug Delivery: The Current State-of-the-Art

Thiopurines (mercaptopurine, azathioprine and thioguanine) are well-established maintenance treatments for a wide range of diseases such as leukemia, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and other inflammatory and autoimmune diseases in general. Worldwide, millions of patients are treated with thiopurines. The use of thiopurines has been limited because of off-target effects such as myelotoxicity and hepatotoxicity. Therefore, seeking methods to enhance target-based thiopurine-based treatment is relevant, combined with pharmacogenetic testing. Controlled-release formulations for thiopurines have been clinically tested and have shown promising outcomes in inflammatory bowel disease. Latest developments in nano-formulations for thiopurines have shown encouraging pre-clinical results, but further research and development are needed. This review provides an overview of novel drug delivery strategies for thiopurines, reviewing modified release formulations and with a focus on nano-based formulations

Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study

Background: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. Aims: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. Methods: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan–Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman’s correlation coefficient. Results: Of 391 patients with IBD, 233 patients (162 Crohn’s disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. Conclusions: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities