thioguanine-anhydrous and Colitis

Topics: Colitis; Colitis, Ulcerative; Humans; Thioguanine

Topics: Colitis; Colitis, Ulcerative; Drug Development; Humans; Inflammatory Bowel Diseases; Thioguanine

Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease [IBD] patients. Prospective effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD.. IBD patients who previously failed azathioprine or mercaptopurine and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (Harvey-Bradshaw Index [HBI] ≤ 4 or Simple Clinical Colitis Activity Index [SCCAI] ≤ 2). The primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment [PGA] and quality of life [QoL].. Sustained corticosteroid-free clinical remission at 3, 6 or 12 months was observed in 75 [69%], 66 [61%] and 49 [45%] of 108 patients, respectively. Thioguanine was continued in 86 patients [80%] for at least 12 months. Loss of response [55%] included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6%, and portal hypertension in 1% of patients.. Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD.

Topics: Azathioprine; Colitis; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Prospective Studies; Quality of Life; Thioguanine

Chronic bowel inflammation increases the risk of colon cancer; colitis-associated cancer (CAC). Thiopurine treatments are associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/β-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/β-catenin signalling. Autophagy is implicated in colonic tumors, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms.. Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harboring intestinal epithelial cell-specific deletion of autophagy related 7 gene (Atg7. Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemoprophylactic approaches.

Topics: Administration, Rectal; Animals; Autophagy; Autophagy-Related Protein 7; Azoxymethane; beta Catenin; Caco-2 Cells; Colitis; Colitis-Associated Neoplasms; Colon; Dextran Sulfate; Gene Knockdown Techniques; HCT116 Cells; Humans; Intestinal Mucosa; Mercaptopurine; Mice; Mice, Transgenic; Neuropeptides; rac1 GTP-Binding Protein; Thioguanine; Wnt Signaling Pathway

Thiopurines are analogues of endogenous purines. They are pro-drugs which require the purine salvage pathway to convert them to the active drug nucleotides (TGN). These drugs are used to maintain clinical remission in patients with inflammatory bowel diseases. In our recent Gut paper, we showed that thioguanine worked quickly to improve colitis in the absence in the host animal of the key guanine salvage enzyme, hypoxanthine-guanine-phosphoribosyltransferase (HPRT). Current evidence favours the proposition that active drug delivery to the host lacking HPRT requires translocation of TGN-loaded bacteria across the inflamed mucosal barrier, and most likely delivery by phagocytosis. Alternatively, the efficacy of thioguanine in treating colitis could be mediated by modulation of the community of the microbiota in the intestine, or there are novel host pathways for conversion of the thioguanine pro-drug to TGN.

Topics: Administration, Oral; Administration, Rectal; Animals; Autophagy; Colitis; Colon; Disease Models, Animal; Gene Knockout Techniques; Host-Pathogen Interactions; Humans; Hypoxanthine Phosphoribosyltransferase; Inflammatory Bowel Diseases; Mice; Microbiota; Prodrugs; Thioguanine

Inflammatory bowel diseases (IBD) are chronic relapsing disorders of the gastrointestinal tract. Several mouse models for IBD are available, but the acute dextran sulfate sodium (DSS)-induced colitis model is mostly used for preclinical studies. However, this model lacks chronicity and often leads to significant loss of mice. The aim of this study was to establish a refined and translationally relevant model of DSS chronic colitis in BALB/c mice. In the first part, we compared several standard therapeutic (ST) treatments for IBD in the acute DSS colitis model to identify the optimal treatment control for a DSS colitis model as compared to literature data. In the second part, we tested the two most effective ST treatments in a refined model of chronic DSS colitis. Cyclosporine A (CsA) and 6-thioguanine (6-TG) caused considerable reduction of clinical scores in acute DSS colitis. The clinical outcome was confirmed by the results for colon length and by histopathological evaluation. Moreover, CsA and 6-TG considerably reduced mRNA expression of several pro-inflammatory cytokines in spleen and colon. Both compounds also showed a substantial therapeutic effect in the refined model of chronic DSS colitis with regard to clinical scores and histopathology as well as the expression of inflammatory markers. The refined model of chronic DSS colitis reflects important features of IBD and is well suited to test potential IBD therapeutics.

Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Colitis; Cyclosporine; Dextran Sulfate; Disease Models, Animal; Female; Inflammatory Bowel Diseases; Mice; Mice, Inbred BALB C; Thioguanine

Mercaptopurine (MP) and pro-drug azathioprine are 'first-line' oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG).. C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed.. Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt. Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation.

Topics: Administration, Oral; Administration, Rectal; Animals; Autophagy; Bacteroides thetaiotaomicron; Cells, Cultured; Colitis; Colon; Cytokines; Dextran Sulfate; Enterococcus faecalis; Epithelial Cells; Escherichia coli; Female; Fibroblasts; Gastrointestinal Microbiome; Host-Pathogen Interactions; Hypoxanthine Phosphoribosyltransferase; Immunosuppressive Agents; Intestinal Mucosa; Macrophages; Male; Mercaptopurine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucin-2; RNA, Messenger; T-Lymphocytes; Thioguanine

Although acute dextran sodium sulphate (DSS)-induced colitis in mice is frequently used as a preclinical model for testing drugs involved in inflammatory bowel disease (IBD), only limited data is available that compares the efficacy of established drug treatments and combinations employed in IBD. We have therefore compared the efficacy of aminosalicylates (mesalazine, olsalazine), corticosteroids (budesonide), thiopurines (6-thioguanine (6-TG)) and cyclosporine A (CsA) and combinations thereof as well as the EP4 agonist AGN205203 in the acute DSS-colitis model.. Female BALB/c mice were challenged with 4% DSS in drinking water for 7 days to induce colitis and treated daily with different drugs/combinations orally. Disease scores (diarrhoea, bleeding, disease activity index), systemic (body weight loss, serum amyloid A levels) and colonic (myeloperoxidase activity, length and histopathology) inflammation parameters were analysed.. Mesalazine, olsalazine (100mg/kg) and budesonide (0.5mg/kg) were only weakly active or even worsened colitis. 6-TG dose-dependently reduced systemic and colonic inflammation parameters with estimated ED50 values between 0.5-4 mg/kg. CsA (10, 25 and 50mg/kg) dose-dependently reduced colitis with high efficacy on systemic inflammation. A combination of CsA 25mg/kg+olsalazine 100mg/kg produced a more pronounced anti-inflammatory effect than the compounds given alone. AGN205203 (3, 10 and 30 mg/kg BID) was the most efficacious compound and almost completely inhibited colitis.. 6-TG and CsA are suitable reference compounds in the DSS mouse model. CsA+olsalazine, as a combination, was more efficacious than the compounds given alone, supporting combination treatments in IBD.

Topics: Aminosalicylic Acids; Animals; Anti-Inflammatory Agents; Budesonide; Colitis; Colon; Cyclosporine; Dextran Sulfate; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Mesalamine; Mice; Mice, Inbred BALB C; Receptors, Prostaglandin E, EP4 Subtype; Thioguanine

Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD.. We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry.. 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice.. Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.

Topics: Acute Disease; Alanine Transaminase; Analysis of Variance; Animals; Apoptosis; Azathioprine; Chronic Disease; Colitis; Colon; Dextran Sulfate; Female; Interferon-gamma; Interleukin-6; Liver; Mice; Mice, Inbred BALB C; Models, Animal; T-Lymphocytes, Helper-Inducer; Thioguanine; Transforming Growth Factor beta; Weight Loss

Topics: Antineoplastic Combined Chemotherapy Protocols; Colitis; Colon; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Gastrointestinal Hemorrhage; Humans; Immunohistochemistry; Infant; Leukemia, Myeloid, Acute; Leukemic Infiltration; Leukocyte Common Antigens; Peroxidase; Sigmoidoscopy; Thioguanine