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.

A well-tolerated and rapidly acting thiopurine for IBD?

Thiopurine drugs continue to be a cornerstone of inflammatory bowel disease (IBD) treatment. Thiopurines are economical compared with many newer medical treatments for IBD, other chronic inflammatory diseases and leukaemia, although they are not without their shortcomings. These include a slow-onset therapeutic action and many adverse drug reactions.

Microbial metabolism of thiopurines: A method to measure thioguanine nucleotides.

Thiopurines are anti-inflammatory prodrugs. We hypothesised that bacteria may contribute to conversion to active drug. Escherichia coli strain DH5α was evaluated to determine whether it could metabolise the thiopurine drugs, thioguanine or mercaptopurine, to thioguanine nucleotides.

Smoking behaviour modifies IL23r-associated disease risk in patients with Crohn's disease.

Background And Aim: The etiology of Crohn's disease (CD) implicates both genetic and environmental factors. Smoking behavior is one environmental risk factor to play a role in the development of CD. The study aimed to assess the contribution of the interleukin 23 receptor (IL23R) in determining disease susceptibility in two independent cohorts of CD, and to investigate the interactions between IL23R variants, smoking behavior, and CD-associated genes, NOD2 and ATG16L1.

Inosine triphosphate pyrophosphohydrolase (ITPA) polymorphic sequence variants in adult hematological malignancy patients and possible association with mitochondrial DNA defects.

Background: Inosine triphosphate pyrophosphohydrolase (ITPase) is a 'house-cleaning' enzyme that degrades non-canonical ('rogue') nucleotides. Complete deficiency is fatal in knockout mice, but a mutant polymorphism resulting in low enzyme activity with an accumulation of ITP and other non-canonical nucleotides, appears benign in humans. We hypothesised that reduced ITPase activity may cause acquired mitochondrial DNA (mtDNA) defects.

A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity.

Objective: The anti-leukemic drugs, azathioprine and 6-mercaptopurine (6MP), are important in the treatment of inflammatory bowel disease but an alternative faster-acting, less-allergenic thiopurine, 6-thioguanine (6TG), can cause hepatic veno-occlusive disease/sinusoidal obstructive syndrome (SOS). Understanding of SOS has been hindered by inability to ethically perform serial liver biopsies on patients and the lack of an animal model.

Design: Normal and C57Bl/6 mice with specific genes altered to elucidate mechanisms responsible for 6TG-SOS, were gavaged daily for upto 28d with 6TG, 6MP or methylated metabolites.

Mucins in inflammatory bowel diseases and colorectal cancer.

The gastrointestinal tract is protected by a mucus barrier with both secreted and cell-surface mucins contributing to the exclusion of luminal microbes and toxins. Alterations in the structure and/or quantity of mucins alter the barrier function of mucus and could play roles in initiating and maintaining mucosal inflammation in inflammatory bowel diseases (IBD), and in driving cancer development in the intestine. The aim of this review is to focus on the roles of the mucins in IBD.

The MUC13 cell-surface mucin protects against intestinal inflammation by inhibiting epithelial cell apoptosis.

Background And Aims: The MUC13 transmembrane mucin is highly and constitutively expressed in the small and large intestine. Although MUC13 polymorphisms have been associated with human inflammatory bowel diseases and susceptibility to Escherichia coli infection in pigs, the biological functions of MUC13 are unknown. This study aimed to explore whether MUC13 modulates intestinal inflammation.

A role for B₁₂ in inflammatory bowel disease patients with suppurative dermatoses? An experience with high dose vitamin B₁₂ therapy.

Background: Inflammatory dermatoses in conjunction with inflammatory bowel disease (IBD) comprise a diverse range of disorders. Some but not all of these respond to conventional treatments for the underlying IBD, such as immunomodulating or antibiotic treatments. We describe our experience with high dose vitamin B₁₂, where conventional therapies have failed.

Serious infections in patients with inflammatory bowel disease receiving anti-tumor-necrosis-factor-alpha therapy: an Australian and New Zealand experience.

Background And Aim: Anti-tumor-necrosis-factor-alpha (anti-TNF-α) medications are effective in inflammatory bowel disease (IBD), but have an increased risk of tuberculosis (TB) and serious infections. The aim of this study was to examine the Australian/New Zealand experience of serious infections and TB in IBD patients receiving anti-TNF-α therapy from 1999-2009.

Methods: Serious infections, defined as 'requiring hospital admission' and TB cases in patients receiving, or within 3 months following, anti-TNF-α therapy were analyzed across Australia and New Zealand.

Difficulties and possibilities with thiopurine therapy in inflammatory bowel disease--proceedings of the first Thiopurine Task Force meeting.

Background: Thiopurines, such as azathioprine and mercaptopurine, are of pivotal importance in the treatment of inflammatory bowel disease. Although these drugs have been used for several decades, still many questions remain unanswered.

Aim: To provide an overview of clinically and scientifically challenging topics concerning thiopurine therapy in inflammatory bowel disease treatment.

Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria.

Objectives: Mucosa-associated bacteria are increased in inflammatory bowel disease (IBD), which suggests the possibility of an increased source of digestible endogenous mucus substrate. We hypothesized that mucolytic bacteria are increased in IBD, providing increased substrate to sustain nonmucolytic mucosa-associated bacteria.

Methods: Mucolytic bacteria were characterized by the ability to degrade human secretory mucin (MUC2) in pure and mixed anaerobic cultures.

KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand population.

Objectives: Crohn's disease (CD; MIM 266600) is one of the most common forms of inflammatory bowel disease (IBD), and represents a significant burden to health care in developed countries. Our aim was to determine whether a gene in the IBD linkage region on chromosome 19q13, with a role in Paneth cell secretion and T-cell activation, conferred genetic susceptibility to the development of CD.

Methods: In total, 792 CD cases and 1,244 controls of Australian origin (Caucasian) were genotyped for seven single-nucleotide polymorphisms (SNPs) in the gene encoding the intermediate conductance calcium-activated potassium channel protein (KCNN4) at 19q13.

MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy.

The bacterium Helicobacter pylori can cause peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. The cell-surface mucin MUC1 is a large glycoprotein which is highly expressed on the mucosal surface and limits the density of H. pylori in a murine infection model.

Mucin dynamics in intestinal bacterial infection.

Background: Bacterial gastroenteritis causes morbidity and mortality in humans worldwide. Murine Citrobacter rodentium infection is a model for gastroenteritis caused by the human pathogens enteropathogenic Escherichia coli and enterohaemorrhagic E. coli.

Intestinal barrier dysfunction in inflammatory bowel diseases.

The etiology of human inflammatory bowel diseases (IBDs) is believed to involve inappropriate host responses to the complex commensal microbial flora in the gut, although an altered commensal flora is not completely excluded. A multifunctional cellular and secreted barrier separates the microbial flora from host tissues. Altered function of this barrier remains a major largely unexplored pathway to IBD.

Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis.

Background: MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis.

Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population.

Background: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD.

IgG antibodies against common gut bacteria are more diagnostic for Crohn's disease than IgG against mannan or flagellin.

Introduction: Antibodies to baker's yeast (mannan) have been widely used to aid in diagnosis of Crohn's disease. Recently, there has been interest in antibodies against a flagellin from Clostridium coccoides subphylum. We hypothesized that reactivity with these antigens is a surrogate marker for a generalized increased IgG response against intestinal microbiota in Crohn's disease.

Relationship between disease severity, quality of life and health-care resource use in a cross-section of Australian patients with Crohn's disease.

Background And Aim: New treatments for Crohn's disease are expensive and place economic strain upon health-care systems, and 'value-for-money' needs to be confirmed. This study aimed to correlate disease severity with health-related quality of life and with health-care resource use, to allow evaluation of the cost effectiveness of these treatments.

Methods: A cross-sectional, non-interventional, pharmacoeconomics study was performed with patients completing questionnaires comprising demographic, disease and health-care utilization questions, together with the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ) and the Assessment of Quality of Life (AQoL) multi-attribute utility instrument.

Clinically active Crohn's disease in the presence of a low C-reactive protein.

Objective: Clinical interest in C-reactive protein (CRP) -- a component of the innate immune system -- has focused mainly on its worth as an indicator of disease activity. There has been a resurgence of interest in CRP in the Crohn's disease (CD) literature because several trials of new treatments for active CD have been characterized by both a large proportion of patients with low CRP (<10 mg/l) at entry to the trials and by a negative therapeutic outcome. It is therefore of interest to study the clinical characteristics of patients who are thought to have at the same time both active CD and a low CRP.

Thiopurine therapies: problems, complexities, and progress with monitoring thioguanine nucleotides.

Metabolism of thiopurine drugs--azathioprine, 6-mercaptopurine, and 6-thioguanine--has provided a powerful pharmacogenetic model incorporating polymorphism of the enzyme thiopurine methyltransferase (TPMT) and the primary active metabolite, thioguanine nucleotide (TGN). However, a sense of uncertainty about the usefulness of TGNs and other thiopurine metabolites has appeared. This review critically appraises the basis of thiopurine metabolism and reveals the problems and complexities in TGN research.