Pharmacotherapy Of Inflammatory Bowel Disease Research Articles

Targeting Lineage-Specific Transcription Factors and Cytokines of the Th17/Treg Axis by Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Attenuates TNBS-Induced Experimental Colitis

The pharmacotherapy of inflammatory bowel disease (IBD) is still not fully effective and safe. Attempts to search for new IBD drugs remain an incessant research aim. One of the novel approaches is targeting the developmental pathway molecules and effector cytokines of Th17/Treg axis. This study aimed to elucidate the impact of new pyrrolo[3,4-d]pyridazinone derivatives, compounds 7b, 10b, or 13b, on the course of experimental colitis in rats and to assess whether these new compounds may influence Th17/Treg axis. Rats were pretreated with studied compounds intragastrically before intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid used for colitis induction. Body weight loss, disease activity index, colon index, and colon tissue damage were analyzed to evaluate the severity of colitis. The colonic levels of RORγt, STAT3, CCR6, Foxp3, IL-6, IL-10, IL-17, TNF-α, IL-23, and PGE2 were assessed. Pretreatment with compounds 7b and 13b alleviated the severity of colitis and concomitantly counteracted the increased levels of RORγt, STAT3, CCR6, IL-6, IL-17, IL-23, TNF-α, and PGE2. The beneficial effect of compounds 7b and 13b may be due to the decrease in the levels of Th17-specific transcription factors and cytokines. The studied compounds might therefore constitute a promising therapeutic strategy in Th17/Treg imbalance-driven inflammatory conditions such as IBD.

Cornelian Cherry Iridoid-Polyphenolic Extract Improves Mucosal Epithelial Barrier Integrity in Rat Experimental Colitis and Exerts Antimicrobial and Antiadhesive Activities In Vitro.

Background and Aims Inflammatory bowel disease pharmacotherapy, despite substantial progress, is still not satisfactory for both patients and clinicians. In view of the chronic and relapsing disease course and not always effective treatment with adverse effects, attempts to search for new, more efficient, and safer substances are essential and reasonable. This study was designed to elucidate the impact of cornelian cherry iridoid-polyphenolic extract (CE) and loganic acid (LA) on adherent-invasive E. coli growth and adhesion in vitro and to assess the effect of pretreatment with CE or LA on the course of intestinal inflammation in rat experimental colitis compared with sulfasalazine. Methods Antibacterial and antiadhesive activities of CE and LA were assessed using microdilution, Int407 cell adherence, and yeast agglutination assays. The colitis model was induced by 2,4,6-trinitrobenzenesulfonic acid. Studied substances were administered intragastrically for 16 days prior to colitis induction. Body weight loss; colon index; histological injuries; IL-23, IL-17, TNF-α, and chemerin levels; and STAT3, Muc2, and TFF3 mRNA expression were evaluated. Results Only CE exerted antimicrobial and antiadhesive activities in vitro and alleviated colonic symptoms. CE coadministrated with sulfasalazine was more effective than single compounds in reversing increased concentrations of TNF-α, IL-17, and chemerin and decreased Muc2 mRNA expression. Conclusions CE exerted a protective effect against experimental colitis via impaired mucosal epithelial barrier restoration and intestinal inflammatory response attenuation and given concomitantly with sulfasalazine counteracted colitis in a more effective way than sulfasalazine alone, which indicates their synergistic interaction. The beneficial effect of CE may also be due to its bacteriostatic and antiadhesive activities.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease

According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.

Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis

BackgroundThe magnitude of risk of serious infections due to available medical therapies of inflammatory bowel disease (IBD) remains controversial. We conducted a systematic review and network meta-analysis of the existing IBD literature to estimate the risk of serious infection in adult IBD patients associated with available medical therapies.MethodsStudies were identified by a literature search of PubMed, Cochrane Library, Medline, Web of Science, Scopus, EMBASE, and ProQuest Dissertations and Theses. Randomized controlled trials comparing IBD medical therapies with no restrictions on language, country of origin, or publication date were included. A network meta-analysis was used to pool direct between treatment comparisons with indirect trial evidence while preserving randomization.ResultsThirty-nine articles fulfilled the inclusion criteria; one study was excluded from the analysis due to disconnectedness. We found no evidence of increased odds of serious infection in comparisons of the different treatment strategies against each other, including combination therapy with a biologic and immunomodulator compared to biologic monotherapy. Similar results were seen in the comparisons between the newer biologics (e.g. vedolizumab) and the anti-tumor necrosis factor agents.ConclusionsNo treatment strategy was found to confer a higher risk of serious infection than another, although wide confidence intervals indicate that a clinically significant difference cannot be excluded. These findings provide a better understanding of the risk of serious infection from IBD pharmacotherapy in the adult population.Prospero registrationThe protocol for this systematic review was registered on PROSPERO (CRD42014013497).

Anti-inflammatory effect of novel analogs of natural enkephalinase inhibitors in a mouse model of experimental colitis.

The pharmacotherapy of inflammatory bowel disease is difficult and currently available treatments bring mostly poor and unsatisfactory results. The purpose of this work was the synthesis of opiorphin, sialorphin, spinorphin and a series of their analogs and the in vitro characterization of their effect on degradation of enkephalin by neutral endopeptidase and aminopeptidase N. Consequently, we investigated in vivo the anti-inflammatory effect of the most active inhibitors selected in the in vitro studies (Pal-KKQRFSR & Pal-KKQHNPR). Putative inhibitor - enzyme (neutral endopeptidase or aminopeptidase N) complexes are also presented and their binding interfaces are identified. Our results suggest that Pal-KKQHNPR has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of GI tract inflammation.

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease.

Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.

Colon-specific delivery of budesonide from microencapsulated cellulosic cores: evaluation of the efficacy against colonic inflammation in rats.

Budesonide (BDS) is a potent corticosteroid that has important implications in the pharmacotherapy of inflammatory bowel disease, especially in the treatment of ulcerative colitis and Crohn's disease. BDS is available on the market in the form of enteric-coated preparations. However these products, similar to other available site-specific dosage forms, are not sufficiently selective to treat colonic inflammatory bowel disease. The objective of this study was to evaluate the efficacy of a new microparticulate system containing BDS, to treat experimentally induced colitis in rats. This microparticulate system consisted of BDS-containing hydrophobic cores, microencapsulated within an enteric polymer, which solubilizes at above pH 7, thus combining pH-sensitive and controlled-release properties. Colonic injury and inflammation were assessed by measuring colon/bodyweight ratio, myeloperoxidase (MPO) activity, and by scoring macroscopic and histological damage in colitic rats. Rats were treated orally with BDS, included in the developed system, once a day for 4 days after the induction of inflammation. A BDS suspension and BDS-containing enteric microparticles were included as control formulations in the experimental design. The administration of the new BDS delivery system significantly reduced the colon/bodyweight ratio compared with the administration of control formulations. Similarly, MPO activity and macroscopic and histological damage of the inflamed colonic segments decreased significantly when the BDS formulation was administered, compared with the results obtained after oral administration of the drug suspension. There were no significant differences, however, when the new treatment was compared with the control formulation consisting of simple enteric microparticles.

The Pharmacotherapy of Inflammatory Bowel Disease in Child and Adolescence

The importance of pediatric inflammatory bowel disease (IBD) has grown significantly, for the incidence of pediatric inflammatory bowel disease in Korea has been rapidly increasing in recent years. One quarter of the new IBD patients has been known to be presented in childhood. Growth and pubertal delay are one of key factors in the management of pediatric IBD. The focus of treatment in children should be to reduce or eliminate symptoms, optimize nutritional status and growth, and prevent complications. This review will deal with the evidence supporting the treatments currently used in children with inflammatory bowel disease.

Review article: thiopurines in inflammatory bowel disease

In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity. To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy. To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'. Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such. Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.

New developments in the pharmacotherapy of inflammatory bowel disease.

In this article the clinical features and aetiology of inflammatory bowel diseases are described and current pharmacotherapeutic possibilities are explored. Also reviewed are recent developments and future prospects for the pharmacotherapy of inflammatory bowel diseases, including aminosalicylates, corticosteroids, immunosuppressants, lipoxygenase inhibitors, fish oil, sucralfate, bismuth compounds, free radical scavengers, (hydroxy)chloroquine, sodium cromoglycate and methotrexate.

Pharmacotherapy of inflammatory bowel disease. Part 2. Metronidazole.

Studies have shown metronidazole to be useful in the treatment of colonic Crohn's disease, especially for perineal complications. It appears to equal sulfasalazine in effectiveness and to offer hope to patients who fail to respond to that drug. However, exacerbation of perineal disease is to be expected on discontinuation of therapy. The only troublesome side effect is paresthesia, which apparently is dose-related and not progressive. Although no studies exist showing the drug to be mutagenic, teratogenic, or carcinogenic in humans, animal and laboratory tests raise concern of this possibility. For this reason, metronidazole therapy should be stopped in two to six months if ineffective and stopped periodically when disease is controlled to see if it can be discontinued.

Pharmacotherapy of inflammatory bowel disease. Part 1. Sulfasalazine.

Published studies suggest that sulfasalazine is effective in treating mild to moderate attacks of ulcerative colitis. Its usefulness in severe attacks has not been adequately tested. Published reports also justify the use of sulfasalazine to prevent recurrence of ulcerative colitis. It is not clear how long maintenance therapy should be continued, but evidence to date favors prolonged treatment in the absence of side effects. In treatment of Crohn's disease, sulfasalazine has been shown to be effective when disease involves the colon or the colon and small intestine. Maintenance therapy does not prevent relapse. Recent studies have indicated that 5-aminosalicylic acid (5-ASA) may be the therapeutic moiety of sulfasalazine, and sulfapyridine (SP) may be related to most of the side effects. Therefore, research is under way to develop a product that contains 5-ASA without the sulfonamide component and that is capable of reaching the colon without being absorbed in the upper small intestine.

Pharmacotherapy of inflammatory bowel disease

The etiology, pharmacotherapy and management of the two major types of inflammatory bowel disease--ulcerative colitis and Crohn's disease--are reviewed. Sulfasalazine and topical corticosteroids (i.e., hydrocortisone, hydrocortisone acetate or methylprednisolone acetate) are effective in many patients with mild distal ulcerative colitis. Maintenance sulfasalazine therapy significantly reduces the relapse rate in ulcerative colitis. Systemic corticosteroids (i.e., prednisone, prednisolone or methylprednisolone) have improved the survival rate of patients with moderate and severe ulcerative colitis. Antacids should be given regularly during high-dose steroid therapy to prevent gastritis. If oral steroids are ineffective, the use of parenteral corticosteroids (hydrocortisone sodium succinate or methylprednisolone sodium succinate) is suggested. Both sulfasalazine and corticosteroids appear to be effective in the treatment of Crohn's disease but require further investigation, however, if patients fail to respond to this therapy, oral corticosteriods, in low dosages, given concomitantly with azathioprine (currently under evaluation) is suggested.