ew-7197 and Peritoneal-Diseases

The relatively low aqueous solubility of EW-7197 that was administered orally may have affected the desired concentration in the systemic circulation for treating peritoneal adhesion. This experimental study aimed to compare the efficacy of different routes of administering EW-7197 (2-fluoro-N-[(5-[6-methylpyridin-2-yl]-4-[(1,2,4)triazolo(1,5-a)pyridin-6-yl]-1H-imidazol-2-yl)methyl]aniline) and EW-7197·hydrobromide (HBr), with improved aqueous solubility, for inhibiting peritoneal adhesion in a rat model.. After peritoneal adhesion induction, 30 male Sprague-Dawley rats were randomly divided into 5 groups with 6 rats in each: group A, sham control; group B, orally administered 25 mg/kg of EW-7197·HBr for 7 days; group C, locally administered 25 mg/kg of EW-7197·HBr; group D, orally administered 20 mg/kg of EW-7197 for 7 days; and group E, locally administered 20 mg/kg of EW-7197. Gross examination, histologic staining (hematoxylin and eosin and Masson's trichrome), and immunohistochemical analyses (Ki-67 and α-smooth muscle actin marker [α-SMA]) were performed to evaluate the efficacy of both drugs.. All procedures were technically successful. All treatment groups, except for group C, showed significantly reduced incidence, quality, tenacity, fibrosis, and collagen deposition scores and lowered expressions of Ki-67- and α-SMA-positive cells compared with group A. When comparing between groups, all scores were significantly lower in group B than in group C (all P < .001), whereas no significant difference was noted in any of the scores between groups D and E and groups B and E (all P > .05).. Orally administering EW-7197·HBr and both orally and locally administering EW-7197 significantly prevented peritoneal adhesion formation, and orally administering EW-7197·HBr was the most effective overall.

Topics: Aniline Compounds; Animals; Fibrosis; Ki-67 Antigen; Male; Peritoneal Diseases; Rats; Rats, Sprague-Dawley

EW-7197 is an oral transforming growth factor β type I receptor kinase inhibitor currently undergoing phase I clinical trials for cancer treatment in the United States. This study evaluates whether EW-7197 prevents peritoneal adhesion formation in a rat model.. Forty-eight female Wistar rats underwent peritoneal adhesion induction by the creation of peritoneal ischemic buttons and were randomly divided into 4 groups of 12 each. The control group received 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The 10 mg and 20 mg groups received 10 or 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The rebound group received 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction followed by 0.3 mL vehicle only by gavage once daily for an additional 21 days. After the respective treatments were completed, the animals were euthanized.. All rats survived until the end of the study without complications. EW-7197 reduced the incidence, quality, and tenacity of peritoneal adhesions in a dose-dependent manner. Fibrosis and collagen production were reduced in EW-7197-treated peritoneal ischemic buttons. Transforming growth factor β/Smad2/3 signaling and mesothelial-to-mesenchymal transition were inhibited in EW-7197-treated peritoneal ischemic buttons. Discontinuation of EW-7197 was not associated with rebound effects.. EW-7197 prevented peritoneal adhesion formation potentially via inhibition of transforming growth factor β1/Smad2/3-induced mesothelial-to-mesenchymal transition in a rat model.

Topics: Administration, Oral; Aniline Compounds; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Epithelial-Mesenchymal Transition; Female; Fibrosis; Humans; Peritoneal Diseases; Peritoneum; Postoperative Complications; Protein Kinase Inhibitors; Rats; Rats, Wistar; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Surgical Procedures, Operative; Tissue Adhesions; Treatment Outcome; Triazoles