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.
Highlights
Acute diarrhea is an alteration of normal bowel movements characterized by an increase in the water content, volume, or frequency of stools
Racecadotril was consistently effective in animal models and patients with various forms of acute diarrhea by inhibiting pathologic secretion from the gut without changing gastro-intestinal transit time or motility
In line with the above studies, as an addition to oral rehydration treatment, racecadotril is being recommended for the treatment of acute diarrhea in children by recent guidelines, e.g., from the World Gastroenterology Organisation (World Gastroenterology Association, 2008), the European Society of Pediatric Gastroenterology, Hepatology and Nutrition/European Society for Pediatric Infectious Diseases (Guarino et al, 2008), a guideline panel from Spain and Latin America (Gutierrez Castrelion et al, 2010), and the German Society for Pediatric Gastroenterology and Nutrition (Koletzko and Lentze, 2008)
Summary
Acute diarrhea is an alteration of normal bowel movements characterized by an increase in the water content, volume, or frequency of stools. Oral rehydration is the cornerstone of treatment, and a standardized glucose-electrolyte solution has been developed under the auspices of the World Health Organization and is being used with great success While this has significantly improved the prognosis of acute diarrhea, it remains a clinical problem in both the developing world and in industrialized countries and, in developing countries, acute diarrhea is still responsible for the death of two to three million individuals per year worldwide (Farthing, 2006). Μ-opioid receptor agonists such as codeine, loperamide, and morphine are being employed, among which loperamide has become most frequently used (Baldi et al, 2009) Their main mechanism of action is a reduction of gut motility and they can cause secondary constipation, abdominal pain, and abdominal distension. Racecadotril has been reviewed in the past (Lecomte, 2000; Matheson and Noble, 2000; Schwartz, 2000) but those articles had a more limited scope and more than 40 new studies have been published since
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