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Racecadotril is an enkephalinase inhibitor, presented as a purely antisecretory agent with advantages over the opiate-receptor agonist loperamide in the treatment of diarrhea. A critical review of the literature and the models used was performed. Although pretreatment with high doses of racecadotril reduced cholera toxin-induced secretion and although clinical efficacy was demonstrated in young infants-a population characterized by 10-fold higher plasma enkephalin concentrations compared with adults, the analysis calls into question the peripheral antisecretory selectivity and relative clinical efficacy. Conversely, loperamide can be proposed as an antisecretory agent at therapeutic concentrations. Its efficacy is well established in acute and chronic diarrhea. Current experimental and clinical comparative studies of both drugs have problems with regard to the selection of the doses, the validity of models, and/or the trial design. The conclusion is that more research is needed before reliable conclusions can be drawn on the place of racecadotril in diarrhea treatment.
KEY WORDS: diarrhea; antidiarrheal; racecadotril; loperamide; antisecretory.
Racecadotril, also called acetorphan, is an enkephalinase inhibitor, presented as a purely antisecretory therapy with advantages over loperamide (Table 1) (1-14), in particular because it does not slow gut transit (15). Loperamide is a peripheral opiate-receptor agonist, with antisecretory and motility-inhibiting properties (16). This review examines the literature on the mode of action and the clinical efficacy of racecadotril in comparison to loperamide. Medline, reviews, and manufacturer's information were used as sources for racecadotril and complemented with relevant literature of loperamide. Because enkephalinase inhibition results in enhanced enkephalin levels, information relevant to the physiology of enkephalins and their actions on the gut is briefly summarized. The objective is to contribute to antidiarrheal research and therapy.
PHYSIOLOGY OF ENKEPHALINS
Natural enkephalins are pentapeptides of L-amino acids. These opioid peptides and their synthetic (mainly D) analogs, have a wide range of pharmacological actions. They play a role in analgesia, gastrointestinal motility, fluid absorption, olfaction, respiration, cognitive function, and mood (17, 18).
Although enkephalins are often proposed to act selectively on + or --opiate receptors in the gut, thereby reducing the mucosal cyclic AMP levels and decreasing the hypersecretion of water and electrolytes (1, 2, 7, 10), it is recognized that they also bind 1-opiate receptors and influence the motor function and transit of the gut (13, 18, 19)....