Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea
| Autor: | Ying Yu, Brian R. Bond, Jonathan Oliva, Georg Neckermann, Deena Tajfirouz, Marvin J. Meyers, Mary Campbell, Michael J. Prinsen, Stacy D. Arnett, Robert K. M. Choy, Peter G. Ruminski, Yuhua Ji, Eugenio L. de Hostos, David W. Griggs |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug Diarrhea Male Castor Oil Thiorphan media_common.quotation_subject Pharmacology Racecadotril 03 medical and health sciences chemistry.chemical_compound Feces 0302 clinical medicine Endopeptidases medicine Potency Animals Protease Inhibitors Dosing Rats Wistar Antidiarrheals Neprilysin media_common Dose-Response Relationship Drug business.industry fungi Rats Dose–response relationship 030104 developmental biology chemistry Charcoal Molecular Medicine 030211 gastroenterology & hepatology medicine.symptom business Gastrointestinal Motility Gastrointestinal Hepatic Pulmonary and Renal medicine.drug |
| Zdroj: | The Journal of Pharmacology and Experimental Therapeutics |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known antidiarrheal activity in animals and humans; however, in humans, it suffers from shortcomings that might be improved with newer drugs in this class that have progressed to the clinic for nonenteric disease indications. To identify potentially superior NEP inhibitors with immediate clinical utility for diarrhea treatment, we compared their efficacy and pharmacologic properties in a rat intestinal hypersecretion model. Racecadotril and seven other clinical-stage inhibitors of NEP were obtained or synthesized. Enzyme potency and specificity were compared using purified peptidases. Compounds were orally administered to rats before administration of castor oil to induce diarrhea. Stool weight was recorded over 4 hours. To assess other pharmacologic properties, select compounds were orally administered to normal or castor oil–treated rats, blood and tissue samples collected at multiple time points, and active compound concentrations determined by mass spectroscopy. NEP enzyme activity was measured in tissue homogenates. Three previously untested clinical NEP inhibitors delayed diarrhea onset and reduced total stool output, with little or no effect on intestinal motility assessed by the charcoal meal test. Each was shown to be a potent, highly specific inhibitor of NEP. Each exhibited greater suppression of NEP activity in intestinal and nonintestinal tissues than did racecadotril and sustained this inhibition longer. These results suggest that newer clinical-stage NEP inhibitors originally developed for other indications may be directly repositioned for treatment of acute secretory diarrhea and offer advantages over racecadotril, such as less frequent dosing and potentially improved efficacy. |
| Databáze: | OpenAIRE |
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