An antioxidant metal-organic framework with functional coatings for oral anti-TNF-α antibody delivery in inflammatory bowel disease treatment.

The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn's disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease. Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function. The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.

Baseline Disease Activity and Steroid Therapy Stratify Risk of COVID-19 in Patients With Inflammatory Bowel Disease

To explore the effects and mechanisms of the Xianhecao-Huanglian drug pair on autophagy-mediated intervention in acute inflammatory bowel disease (IBD) via the JAK2/STAT3 pathway. The study examined the underlying mechanisms of action of Xianhecao (APL) and Huanglian (CR) using a mouse model of dextran sodium sulfate (DSS)-induced acute inflammatory bowel disease (IBD) and in an in vitro model of IBD induced by lipopolysaccharide (LPS). The assessment of the therapeutic efficacy of the Xianhecao-Huanglian drug combination in a mouse model of IBD caused by DSS included the following parameters: Assessment of weight loss or gain. Measurement of the disease activity index (DAI). Assessment of histological damage. Determination of organ index. Measurement of colon length. Ascertain the levels of inflammatory cytokines in the intestinal tissues and serum of mice. Immunohistochemistry (IHC) for the measurement of tight junction protein concentrations in the colon mucosa, including ZO-1, claudin-1, and occludin. Measurement of mucin levels, specifically Mucin 2 (Muc2). Hematoxylin and eosin (HE) staining for the observation of histopathological alterations in colonic tissues. Examining the effect on goblet cells using periodic acid-Schiff (PAS) labeling. Application of Western blot and immunofluorescence techniques for the detection of autophagy-related markers in colonic tissues and proteins associated with the JAK2/STAT3 pathway. A cell inflammation model of IBD was induced through LPS stimulation, and a serum containing the Xianhecao-Huanglian drug pair (referred to as ACHP-DS) was formulated. Cell viability, anti-proinflammatory cytokines, tight junction proteins, mucins, autophagy-related markers, and the JAK2/STAT3 signaling pathway were assessed. The Xianhecao-Huanglian drug pair significantly ameliorated the symptoms and survival quality of acute IBD mice, reducing the disease activity index score, raising MUC2 secretion and tight junction protein expression to improve the integrity of the intestinal barrier, and preserving goblet cell function; thus, protecting the intestines. It effectively restrained triggering the signaling pathway that involves JAK2 and STAT3, leading to the suppression of inflammation and amelioration of colonic inflammation damage. Additionally, it induced autophagy in mouse colonic tissues.The in vitro experiments demonstrated that the Xianhecao-Huanglian drug combination enhanced the viability of LOVO and NCM460 cells when exposed to LPS stimulation. Furthermore, it suppressed the production of inflammatory cytokines such as IL-6, IL-1β, as well as TNF-α, whilst increasing the production of IL-10, ZO-1, along with MUC2. These effects collectively led to the alleviation of inflammation and the restoration of mucosal integrity. The results were consistent with what was shown in the in vivo trial. Moreover, the medication demonstrated effectiveness in reducing JAK2 along with STAT3 phosphorylation levels in the LPS-induced inflammatory model of IBD cells. The intervention with either the Xianhecao-Huanglian drug combination-containing serum or the JAK2/STAT3 pathway inhibitor AG490 reversed the pro-inflammatory effects and increased autophagy levels in the LPS-stimulated cells. The Xianhecao-Huanglian drug combination modulates the JAK2/STAT3 pathway, leading to the induction of autophagy, which serves as an intervention for IBD.

Multi-detector CT-colonography in inflammatory bowel disease: Prospective analysis of CT-findings to high-resolution video colonoscopy

Selective Glucocorticoid Receptor Agonists for Treatment of Inflammatory Bowel Disease – in vitro studies

Rationale: Anti-tumor necrosis factor (TNF) therapy is a very effective way to treat inflammatory bowel disease. However, systemic exposure to anti-TNF-α antibodies through current clinical systemic administration can cause serious adverse effects in many patients. Here, we report a facile prepared self-assembled supramolecular nanoparticle based on natural polyphenol tannic acid and poly(ethylene glycol) containing polymer for oral antibody delivery.Method: This supramolecular nanoparticle was fabricated within minutes in aqueous solution and easily scaled up to gram level due to their pH-dependent reversible assembly. DSS-induced colitis model was prepared to evaluate the ability of inflammatory colon targeting ability and therapeutic efficacy of this antibody-loaded nanoparticles.Results: This polyphenol-based nanoparticle can be aqueous assembly without organic solvent and thus scaled up easily. The oral administration of antibody loaded nanoparticle achieved high accumulation in the inflamed colon and low systemic exposure. The novel formulation of anti-TNF-α antibodies administrated orally achieved high efficacy in the treatment of colitis mice compared with free antibodies administered orally. The average weight, colon length, and inflammatory factors in colon and serum of colitis mice after the treatment of novel formulation of anti-TNF-α antibodies even reached the similar level to healthy controls.Conclusion: This polyphenol-based supramolecular nanoparticle is a promising platform for oral delivery of antibodies for the treatment of inflammatory bowel diseases, which may have promising clinical translation prospects.

Management of Patients With Crohn’s Disease and Ulcerative Colitis During the Coronavirus Disease-2019 Pandemic: Results of an International Meeting

The treatment of inflammatory bowel disease (IBD) possesses numerous difficulties owing to the unclear etiology of the disease. This article overviews the drugs used in the treatment of IBD depending on the intensity of clinical symptoms (Canine Inflammatory Bowel Disease Activity Index and Canine Chronic Enterophaty Clinical Activity Index). Patients demonstrating mild symptoms of the disease are usually placed on an appropriate diet which may be combined with immunomodulative or probiotic treatment. In moderate progression of IBD, 5-aminosalicylic acid (mesalazine or olsalazine) derivatives may be administered. Patients showing severe symptoms of the disease are usually treated with immunosuppressive drugs, antibiotics and elimination diet. Since the immune system plays an important role in the pathogenesis of the disease, the advancements in biological therapy research will contribute to the progress in the treatment of canine and feline IBD in the coming years.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract (GIT). Glucagon-like peptide-2 (GLP-2) analogs possess high potential in the treatment of IBD by enhancing intestinal repair and attenuating inflammation. Due to the enzymatic degradation and poor intestinal absorption, GLP-2 analogs are administered parenterally, which leads to poor patient compliance. This work aims to develop IBD-targeted nanoparticles (NPs) for the oral delivery of the GLP-2 analog, Teduglutide (TED). Leveraging the overproduction of Reactive Oxygen Species (ROS) in the IBD environment, ROS-sensitive NPs are developed to target the intestinal epithelium, bypassing the mucus barrier. PEGylation of NPs facilitates mucus transposition, but subsequent PEG removal is crucial for cellular internalization. This de-PEGylation is possible by including a ROS-sensitive thioketal linker within the system. ROS-sensitive NPs are established, with the ability to fully de-PEGylate via ROS-mediated cleavage. Encapsulation of TED into NPs resulted in the absence of absorption in 3D in vitro models, potentially promoting a localized action, and avoiding adverse effects due to systemic absorption. Upon oral administration to colitis-induced mice, ROS-sensitive NPs are located in the colon, displaying healing capacity and reducing inflammation. Cleavable PEGylated NPs demonstrate effective potential in managing IBD symptoms and modulating the disease's progression.

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.

The incidence of inflammatory bowel disease (IBD) with a poor prognosis is increasing, and a single field is not capable of fully diagnosing and comprehensively treating IBD. The purpose of the current study was to explore the role of a multidisciplinary team (MDT) in the diagnosis and treatment of IBD. Subjects were 55 patients with IBD who underwent surgery at this hospital before the establishment of a MDT (before June 2016) and 276 patients who were discussed by a MDT; 72 of the latter patients underwent surgery. The preoperative rate of diagnosis, preoperative basic nutritional status, frequency of emergency surgery, and surgical complications in the two groups were compared to determine whether the MDT significantly affected the diagnosis and treatment of IBD and to explore trends in the types of patients with IBD and treatment decision-making since the establishment of MDT. Results revealed that the MDT significantly improved preoperative diagnostic accuracy for patients with IBD who underwent surgery (p < 0.005), and the frequency of elective surgery decreased significantly (p < 0.005). There were significant differences in the rate of clinical recurrence (p < 0.005) and the rate of additional surgery (p < 0.01) between the two groups, with higher rates in the control group. In terms of preoperative nutritional status, the proportion of decreased serum albumin and hemoglobin in the experimental group was significantly lower than that in the control group (p < 0.05). MDT plays a positive role in accurate preoperative diagnosis, improvement of preoperative preparations, and a reduction in postoperative adverse events for patients with IBD undergoing surgery.

Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis

BackgroundBiologics are used for the treatment of inflammatory bowel diseases, Crohn´s disease and ulcerative colitis refractory to conventional treatment. In order to allocate healthcare spending efficiently, costly biologics for inflammatory bowel diseases are an important target for cost-effectiveness analyses. The aim of this study was to systemically review all published literature on the cost-effectiveness of biologics for inflammatory bowel diseases and to evaluate the methodological quality of cost-effectiveness analyses.MethodsA literature search was performed using Medline (Ovid), Cochrane Library, and SCOPUS. All cost-utility analyses comparing biologics with conventional medical treatment, another biologic treatment, placebo, or surgery for the treatment of inflammatory bowel diseases in adults were included in this review. All costs were converted to the 2014 euro. The methodological quality of the included studies was assessed by Drummond’s, Philips’, and the Consolidated Health Economic Evaluation Reporting Standards checklist.ResultsAltogether, 25 studies were included in the review. Among the patients refractory to conventional medical treatment, the incremental cost-effectiveness ratio ranged from dominance to 549,335 €/Quality-Adjusted Life Year compared to the incremental cost-effectiveness ratio associated with conventional medical treatment. When comparing biologics with another biologic treatment, the incremental cost-effectiveness ratio ranged from dominance to 24,012,483 €/Quality-Adjusted Life Year. A study including both direct and indirect costs produced more favorable incremental cost-effectiveness ratios than those produced by studies including only direct costs.ConclusionsWith a threshold of 35,000 €/Quality-Adjusted Life Year, biologics seem to be cost-effective for the induction treatment of active and severe inflammatory bowel disease. Between biologics, the cost-effectiveness remains unclear.

Background: Inflammatory bowel disease (IBD) is the common cause of chronic gastrointestinal signs in dogs. The treatment possesses numerous difficulties due to the idiopathic nature of the disease. Conventional steroid therapy usually produces side effects on long term usage. Thus, there is a need for alternative therapies. When compared to human medicine, there is no published data on the use of budesonide and probiotic in the treatment of canine IBD in India. The present study was proposed to compare oral prednisolone, budesonide and probiotics in the management of canine inflammatory bowel disease. Methods: Thirty dogs with idiopathic IBD were selected and randomly grouped. They were subjected to therapy involving prednisolone, budesonide or probiotics. Clinical assessment was performed by calculation of the post treatment Clinical Inflammatory Bowel Disease Activity Index (CIBDAI) score, faecal score and endoscopy. Biochemical analysis of alkaline phosphatase and alanine transaminase were done to record side effects of steroid administration. Result: It was observed from the present study that both prednisolone and budesonide are equally effective in the management of IBD in dogs. Probiotics were found to be less effective when compared to prednisolone and budesonide in the treatment of IBD.

SIRS, The Review Article by Drs Creed and Probert discusses steroid resistance in inflammatory bowel disease (IBD) - mechanisms and therapeutic strategies. 1 They underline the use of alternative immunosuppressants for the treatment of steroid-resistant IBD, but do not discuss a potential role for cyclophosphamide. Based on previous observations in autoimmune diseases (i.e., vasculitides), cyclophosphamide can be the primary cytotoxic drug and pulse intravenous cyclophosphamide is probably equally effective as oral cyclophosphamide at inducing and maintaining remission. 2-4 Cyclophosphamide can be administered intravenously at 500-1000 mg/m 2 pulses monthly. The optimal duration of treatment has not been determined for IBD, but treatment for 6 months with monthly pulses would be typical, followed by maintenance therapy with azathioprine or methotrexate. Recently, we reported an uncontrolled prospective study with pulse cyclophosphamide therapy for IBD patients.5' 6 The aim of this study was to examine the effect of this therapy both on UC and CD. Patients entered into remission after the second/third cyclophosphamide pulse, disease activity decreased without side effects and toxicity. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/week) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/day). This study and others' indicates that cyclophosphamide-induced remission is long-lasting under standard immunosuppressive therapy.7'8 Because cyclophosphamide is effective for other inflammatory conditions and is relatively less expensive than some other agents, it is considered in the treatment of IBD. Intravenous pulse cyclophosphamide therapy may be a safe and effective treatment for patients with severe IBD unresponsive to conventional treatment as a first-line adjunct to or replacement of systemic corticosteroids in the treatment of IBD. However, larger placebo-controlled studies in more diverse patient population are warranted. 7