Mo1236 Early Rebleeding and Mortality in Post HCV Cirrhotic Patients With Esophageal Variceal Bleeding After Band Ligation: Predictive Factors and Value of Vascular Endothelial Growth Factor

and human clinical trials, and is approved for use in ASD in some countries. However, it suffers from shortcomings that might be improved upon with next generation NEPi that have progressed to the clinic for other indications, but which have not been evaluated for anti-diarrheal efficacy. To identify a potentially superior NEPi for future clinical investigation, we tested their activities in a standard rat ASD model and compared the pharmacokinetic and pharmacodynamic (PK/PD) relationships of the most promising compounds. Methods: Racecadotril and 6 other clinical-stage inhibitors of NEP or ACE/NEP were acquired or synthesized for testing. Specificity of NEP inhibition was assessed by determination of IC50 concentrations in an assay panel using commercially available purified peptidase enzymes. Compounds were administered to fasted male Wistar rats by oral gavage at indicated times prior to oral administration of castor oil to induce diarrhea. Stool weight was recorded every 15 minutes up to 4 hours. To assess PK/PD properties, select compounds were administered to healthy or castor oil-treated rats by oral gavage, blood and tissue samples collected at multiple time points, and concentrations of active compound were determined by mass spectroscopy. NEP enzyme activity was measured in tissue homogenates. Results: Three previously untested clinical NEPi significantly delayed diarrhea onset and reduced total stool output. All were shown to be very potent highly specific inhibitors of the NEP enzyme. The three efficacious next generation NEPi exhibited greater suppression of NEP activity in intestinal and non-intestinal tissues than racecadotril, and sustained this inhibition for longer duration. Conclusion: The results suggest newer clinical-stage NEPi inhibitors originally developed as therapies for other indications may offer advantages over racecadotril such as less frequent dosing and potentially improved efficacy for ASD therapy.