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      A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril

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          Abstract

          Racecadotril, via its active metabolite thiorphan, is an inhibitor of the enzyme neutral endopeptidase (NEP, EC 3.4.24.11), thereby increasing exposure to NEP substrates including enkephalins and atrial natriuretic peptide (ANP). Upon oral administration racecadotril is rapidly and effectively converted into the active metabolite thiorphan, which does not cross the blood–brain-barrier. Racecadotril has mainly been tested in animal models and patients of three therapeutic areas. As an analgesic the effects of racecadotril across animal models were inconsistent. In cardiovascular diseases such as hypertension or congestive heart failure results from animal studies were promising, probably related to increased exposure to ANP, but clinical results have not shown substantial therapeutic benefit over existing treatment options in cardiovascular disease. In contrast, racecadotril was consistently effective in animal models and patients with various forms of acute diarrhea by inhibiting pathologic (but not basal) secretion from the gut without changing gastro-intestinal transit time or motility. This included studies in both adults and children. In direct comparative studies with loperamide in adults and children, racecadotril was at least as effective but exhibited fewer adverse events in most studies, particularly less rebound constipation. Several guidelines recommend the use of racecadotril as addition to oral rehydration treatment in children with acute diarrhea.

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          Most cited references126

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          The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice.

          There is both theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct fropm angiotensin coverting enzyme (ACE), might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional and subcellular distributions as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this enzyme further, we have designed a potent and specific enkephalinase inhibitor. We report here that this compound, thiorphan [(DL-3-mercapto-2-benzylpropanoyl)-glycine; patent no. 8008601] protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration. In addition, thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors.
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            Racecadotril in the treatment of acute watery diarrhea in children.

            Racecadotril (acetorphan), an enkephalinase inhibitor with antisecretory and antidiarrheal actions, is an effective and safe treatment for acute diarrhea in adults and children. Whether treatment with racecadotril and oral rehydration therapy is more effective than treatment with oral rehydration alone in hospitalized children with acute watery diarrhea is not known. We treated 135 boys 3 to 35 months of age who had watery diarrhea of five days' duration or less with racecadotril (1.5 mg per kilogram of body weight orally every eight hours) or placebo, in addition to oral rehydration solution. The primary end point was the 48-hour stool output (measured in grams); the total stool output, duration of diarrhea, and total intake of oral rehydration solution were also measured. The mean (+/-SE) 48-hour stool output was 92+/-12 g per kilogram in the racecadotril group and 170+/-15 g per kilogram in the placebo group (P<0.001), a 46 percent reduction with racecadotril. The results were similar among the 73 boys with rotavirus infections. The total stool output was 157+/-27 g per kilogram in the racecadotril group and 331+/-39 g per kilogram in the placebo group (P<0.001). The median duration of diarrhea was significantly less (P<0.001) in the racecadotril group (28 hours regardless of rotavirus status) than in the placebo group (72 and 52 hours, respectively, for rotavirus-positive and rotavirus-negative patients). The intake of oral rehydration solution was significantly lower in the racecadotril group than in the placebo group (P<0.001). Racecadotril was well tolerated; only seven patients taking racecadotril had adverse effects, which were all mild and transient. In young boys with acute watery diarrhea, racecadotril is an effective and safe treatment.
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              European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe.

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                Author and article information

                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Research Foundation
                1663-9812
                30 May 2012
                2012
                : 3
                : 93
                Affiliations
                [1] 1simpleDepartment of Medical Affairs Germany, Boehringer Ingelheim Pharma GmbH & Co KG Ingelheim, Germany
                [2] 2simpleDepartment of Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co KG Ingelheim, Germany
                Author notes

                Edited by: Angelo A. Izzo, University of Naples Federico II, Italy

                Reviewed by: Hemant Kulkarni, Texas Biomedical Research Institute, USA; Luca Gallelli, School of Medicine University of Catanzaro, Italy

                *Correspondence: Martin C. Michel, Department of Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma Gmbh & Co KG, Binger Str. 173, 55216 Ingelheim, Germany. e-mail: martin.michel@ 123456boehringer-ingelheim.com

                This article was submitted to Frontiers in Gastrointestinal Pharmacology, a specialty of Frontiers in Pharmacology.

                Article
                10.3389/fphar.2012.00093
                3362754
                22661949
                a18579d2-f1fd-4895-98cd-60a6152d067f
                Copyright © 2012 Eberlin, Mück and Michel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 11 April 2012
                : 27 April 2012
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 131, Pages: 16, Words: 15090
                Categories
                Pharmacology
                Review Article

                Pharmacology & Pharmaceutical medicine
                loperamide,analgesia,racecadotril,congestive heart failure,neutral endopeptidase,hypertension,diarrhea

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