Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model.

摘要: Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use associated with development severe diarrhea in up to 40% patients absence proactive management. We previously developed a rat model neratinib-induced and found inflammation anatomical disruption ileum colon. Here we tested whether anti-diarrheal interventions, budesonide colesevelam, can reduce intestinal pathology. Rats were treated 50 mg/kg neratinib via oral gavage 14 or 28 days (total n = 64). Body weight severity recorded daily. Apoptosis was measured using immunohistochemistry caspase-3. Inflammation multiplex cytokine/chemokine assay. ErbB levels PCR Western Blot. Budesonide co-treatment caused rats gain significantly less than alone from day 4 (P = 0.0418). (P = 0.027) colesevelam (P = 0.033) each reduced amount days moderate compared alone. In proximal colon, had higher apoptosis controls (P = 0.0035). histopathological injury (P = 0.0401) distal colon increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) ileum, while decreased ErbB1 mRNA expression (P = 0.018) (PCR), increase total protein detected (P = 0.0021) (Western Blot). Both show potential as effective interventions against diarrhea.