Drug Safety in Crohn’s Disease Therapy

Juillerat, Pascal; Pittet, Valérie; Felley, Christian; Mottet, Christian; Froehlich, Florian; Vader, John‐Paul; Gonvers, Jean‐Jacques; Michetti, Pierre

doi:10.1159/000111031

Cited by 18 publications

(7 citation statements)

References 144 publications

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“…From this in silico study we identified ciprofloxacin, a widely used antibiotic [26], as a potential ligand for the receptor (Figure 3A). Because the structure of GP-BAR1 has not yet been solved experimentally, we have carried out an homology modeling study in order to obtain the three dimensional structure of the receptor [14].…”

Section: Resultsmentioning

confidence: 99%

The Bile Acid Receptor GPBAR-1 (TGR5) Modulates Integrity of Intestinal Barrier and Immune Response to Experimental Colitis

et al. 2011

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Background GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation.AimsTo investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis.MethodsColitis was induced in wild type and GP-BAR1−/− mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies.ResultsGP-BAR1−/− mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1.ConclusionsGP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand.

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Section: Resultsmentioning

confidence: 99%

The Bile Acid Receptor GPBAR-1 (TGR5) Modulates Integrity of Intestinal Barrier and Immune Response to Experimental Colitis

et al. 2011

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“…However, the population as a whole does not seem to experience an excess of either lymphoma 52 or other malignancy 53 and one reviewer estimated that only one in 3500 RA patients treated with methotrexate would develop lymphoma 54 . There is less evidence in the IBD population but early suggestions are that single agent methotrexate therapy does not increase the risk of malignancy in this context 55–57 …”

Section: Risk Of Malignancy With Other Agentsmentioning

confidence: 99%

Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease

Smith

Irving

Sanderson

2010

Aliment Pharmacol Ther

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“…The safety profile of these medications appears to be similar to that of infliximab, especially for fistulizing CD. [82][83][84][85][86][87][88] Another recently introduced agent that has been approved for the management of moderate to severe CD is natalizumab, a humanized monoclonal antibody against the α4 integrin subunit that inhibits leukocyte adhesion and migration to areas of inflammation. However, safety concerns regarding its association with progressive multifocal leukoencephalopathy have limited its use.…”

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confidence: 99%