Dersalazine

Clinical trials in ulcerative colitis (UC) rely on certain parameters to evaluate responses that are highly subjective or of low sensitivity. Here, using a select group of genes, we tested the accuracy of gene expression analysis as a biomarker of clinical, endoscopic, and histologic improvements.

Intestinal biopsies were obtained from UC patients included in two cohorts. Cohort 1 was used to select for genes whose expression was modulated in active (vs. inactive) UC. Cohort 2 included patients recruited in a phase II study receiving placebo, mesalazine, or dersalazine sodium for 4 weeks. The expression of 44 genes identified in Cohort 1 was assessed at weeks 0 and 4, and was then correlated with biomarkers, as well as with clinical, endoscopic, and histologic scores.

Significant changes in the expression of 31 of the 44 genes tested were detected in Cohort 2 at week 4. Gene expression (ΔCt) significantly correlated with the total Mayo score, C-reactive protein (CRP), and fecal calprotectin. The number of genes significantly regulated at week 4 was highly associated with histologic and endoscopic responses. Logistic regression analysis identified four separate genes (IFITM1, ITGB2, IL1R2, IL2RA) whose relative change was independently associated with endoscopic remission with high specificity and sensitivity.

Change in the expression of a select set of genes can serve as an early biomarker, one with high specificity and sensitivity to clinical, endoscopic, and histologic responses. This could represent a new tool for identifying early response to treatment in mild to moderately active UC patients.

BACKGROUND AND PURPOSE Dersalazine sodium (DS) is a new chemical entity formed by combining, through an azo bond, a potent platelet activating factor (PAF) antagonist (UR‐12715) with 5‐aminosalicylic acid (5‐ASA). DS has been demonstrated to have anti‐inflammatory effects on trinitrobenzene sulphonic acid (TNBS)‐induced colitis in rats and recently in UC patients in phase II PoC. There is Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to further characterize the anti‐inflammatory effects of DS.EXPERIMENTAL APPROACH Effect of DS (10 or 30 mg·kg−1 b.i.d.) on TNBS‐induced colitis in rats was studied after 2 and 7 days with special focus on inflammatory mediators. Additionally, its anti‐inflammatory properties were analysed in two different models of dextran sodium sulphate (DSS)‐induced colitis, BALB/c and C57BL/6 mice, the latter being dependent on IL‐17.KEY RESULTS DS, when administered for 7 days, showed intestinal anti‐inflammatory effects in TNBS‐induced colitis; these effects were observed both macroscopically and through the profile of inflammatory mediators (TNF, IL‐1β, IL‐6 and IL‐17). Although the 2 day treatment with DS did not induce intestinal anti‐inflammatory effects, it was sufficient to reduce the enhanced IL‐17 expression. DS showed beneficial effects on DSS‐induced colitis in C57BL/6 mice and reduced colonic pro‐inflammatory cytokines IL‐1β, IL‐6 and IL‐17. In contrast, it did not exert intestinal anti‐inflammatory effects on DSS‐induced colitis in BALB/c mice.CONCLUSIONS AND IMPLICATIONS DS exerts intestinal anti‐inflammatory activity in different rodent models of colitis through down‐regulation of IL‐17 expression.