ABSTRACT
BACKGROUND: The administration of parnaparin sodium as oral colon-release tablets (CB-01-05 MMX) has been proposed as a novel approach for the treatment of ulcerative colitis (UC). AIM: To assess the efficacy and the tolerability of 8 weeks' oral daily administration of 210 mg of parnaparin sodium compared with placebo in subjects treated with stable-doses of oral aminosalicylates. METHODS: This multicenter, randomized, double-blind proof of concept trial compared the efficacy of CB-01-05 MMX 210 mg tablets to placebo in 141 subjects with mild to moderately active left-sided UC treated with stable-doses of aminosalicylates. The efficacy was assessed by clinical activity index (CAI), endoscopic index (EI) and histological score (HS). RESULTS: A total of 121 subjects (61 in test group and 60 in control group) formed the per protocol (PP) population. After 8 weeks of treatment, clinical remission was achieved in 83.6% of the CB-01-05 MMX group, and in 63.3% in the comparator group (P = 0.011). This effect was also significantly evident in the test group at week 4 (P = 0.028). A significant difference was also detected in rectal bleeding, (disappeared respectively in 75.4% and 55.0%; P = 0.018), and in mucosal friability (recovered respectively in 80.3% and in 56.7%; P = 0.005). CONCLUSIONS: CB-01-05 MMX was safe and significantly effective in treating subjects with mild-to-moderate left-sided UC treated with stable-doses of aminosalicylates.
Subject(s)
Anticoagulants/administration & dosage , Colitis, Ulcerative/drug therapy , Colon/drug effects , Heparin, Low-Molecular-Weight/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Anticoagulants/adverse effects , Colitis, Ulcerative/physiopathology , Colon/physiopathology , Delayed-Action Preparations , Dose-Response Relationship, Drug , Double-Blind Method , Female , Heparin, Low-Molecular-Weight/adverse effects , Humans , Male , Middle Aged , Treatment Outcome , Young AdultABSTRACT
Recent studies have suggested that 5-aminosalicylic acid (5-ASA) inhibits colorectal cancer (CRC) development. However, the mechanism underlying the antineoplastic effect of 5-ASA remains unknown. We here examined the effect of 5-ASA on epidermal growth factor receptor (EGFR) activation, a pathway that triggers mitogenic signals in CRC cells. We show that 5-ASA inhibits EGFR activation, through a mechanism that does not rely on CRC cell death induction. 5-ASA enhances the activity, but not expression, of phosphorylated (p)-EGFR-targeting phosphatases (PTPs), and treatment of cells with PTP inhibitors abrogates the 5-ASA-mediated EGFR dephosphorylation. Both SH-PTP1 and SH-PTP2 interact with EGFR upon 5-ASA treatment. However, knockdown of SH-PTP2 but not SH-PTP1 by small interference RNAs prevents the 5-ASA-induced EGFR dephosphorylation. Finally, we show that 5-ASA attenuates p-EGFR in ex vivo organ cultures of CRC explants. Data indicate that 5-ASA disrupts EGFR signalling by enhancing SH-PTP2 activity, and suggest a mechanism by which 5-ASA interferes with CRC growth.