Diarrhoea is a problem, not only of the developing world, but also of the Western world. Worldwide, diarrhoeal diseases are a leading cause of childhood morbidity and mortality. Acute diarrhoeal diseases rank second amongst all infectious diseases, as a killer in children below 5 years of age worldwide. The most common worldwide cause of diarrhoea is intestinal infection and infants, pre-school children, the elderly, and those with congenital or acquired immunodeficiency run a high risk of contracting such infections.1
Diarrhoeal disease can be classified into three major clinical syndromes: acute watery diarrhoea, bloody diarrhoea, and persistent diarrhoea. Acute infectious diarrhoea can be linked to various pathogens among which viruses are responsible for more than a half cases. Bacterial and viral co-infections are also frequent (up to 15%). A number of different micro-organisms can cause infectious diarrhoea, depending on the clinical setting. Acute diarrhoea may be due to increased intestinal secretion, commonly as a result of infection with enterotoxin-producing organisms (enterotoxigenic Escherichia coli, Vibrio cholerae) or to decreased intestinal absorption from infection with organisms that damage the intestinal epithelium (enteropathogenic E. coli, Shigella sp., Salmonella sp.).
Management of acute diarrhoea is entirely based on clinical presentation of the cases. It includes assessment of the degree of dehydration clinically, rehydration therapy, feeding during diarrhoea, use of antibiotic(s) in selected cases, micronutrient supplementation and use of probiotics.2
Dehydration can be managed with oral rehydration salt (ORS) solution or intravenous fluids. The development of oral rehydration solution has provided a simple approach to rehydration and
maintenance of hydration in patients with acute watery diarrhoea, and has been implemented worldwide under the auspices of the World Health Organization. Antibiotic therapy is not recommended for the treatment of diarrhoea routinely. Only cases of severe cholera and bloody diarrhoea (presumably shigellosis) should be treated with a suitable antibiotics.3
Although oral rehydration therapy has reduced the mortality associated with acute diarrhoea, stool volume often increases during the rehydration process. Besides, rehydration does not treat the diarrhoea itself, which will persist until the infection resolves. Another drawback seen is that the drugs currently used for the treatment of diarrhoea, such as the opiate agents and antibiotics, have limitations.
For more than 20 years, there has been a search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce stool volume.4 Research into antisecretory agents has demonstrated that these class of medications may play a significant role in the future management of acute infectious gastroenteritis.5 There is the possibility for potentiating the proabsorptive effects of endogenous enkephalins by using enkephalinase inhibitors.
Enkephalins (endogenous opiate peptides) act as neurotransmitters along the entire digestive tract where they mediate intestinal absorption without affecting intestinal transit time or motility. They are short-lived peptides rapidly cleaved by 2 membrane peptidases: an enkephalinase and a carboxypeptidase. Enkephalinase
is abundant in the gastrointestinal tract and accounts for over 85% hydrolysis of methionine and leucine enkephalins, providing a potentially novel target for the treatment of acute watery diarrhoea. An approach has concentrated on the antisecretory role of the neurotransmitter, enkephalin, and has resulted in the development of the enkephalinase inhibitor, racecadotril.
Racecadotril is a lipophilic derivative of thiorphan, that interacts specifically with the active site of enkephalinase to produce potent blockade of the enzyme preventing inactivation of endogenous opioid peptides (enkephalins) released by submucosal and myenteric neurons. The encephalins in turn mediate their effect through delta receptor activation that induces a selective increase in chloride absorption by inhibiting adenylate cyclase.5
After oral administration, racecadotril is rapidly absorbed and quickly metabolized to its active metabolite thiorphan, which in turn mediates all further actions. The activity on plasmatic enkephalinase appears 30 min after the administration. The peak plasma concentration of thiorphan is reached 60 min after administration of a single oral dose of racecadotril. The biological half-life of enkephalinase activity is 3 h. The pharmaco kinetic parameters of repeated doses of racecadotril are similar on days 1 and 7 as those observed for a single oral dose. The recommended dose in children is 1.5 mg/kg of racecadotril every 8 hourly.
Racecadotril is the only drug with anti-diarrhoeal properties, with a reduction of the stool output of 50%.7 Unlike loperamide, racecadotril does not prolong transit time in the small intestine or colon. Further experiments have shown that racecadotril does not promote bacterial overgrowth in the small intestine. Racecadotril
lacks any potential for neurotoxicity, and radiolabelled studies have demonstrated that the drug does not enter the brain after oral administration. No potential for abuse or physical dependence has been seen with this drug.8
Experts treated 135 boys, 3 to 35 months of age, who had watery diarrhoea 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 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 (Fig.1).
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) (Fig.2). The median duration of diarrhoea was significantly less in the racecadotril group (28 hours regardless of rotavirus status) than in the placebo group (72 and 52 hours, respectively, for rotaviruspositive and rotavirus-negative patients) (Fig.3). The intake of oral rehydration solution was significantly lower in the racecadotril group than in the placebo group (P<0.001).9
A multicentre, parallel-group, double-blind, double-placebo study was carried out to compare the efficacy, tolerability, and safety of racecadotril and loperamide in children aged 2 to 10 years who were suffering from acute diarrhoea.
Patients on racecadotril passed a mean of 2.7 + 0.4 stools before recovery compared with 2.1 ± 0.4 stools for loperamide. The duration of diarrhoea was similar with both treatments. The incidence of adverse events was lower with racecadotril than with loperamide (11.5% vs. 22%), and significantly more patients on loperamide suffered from constipation (58% vs. 36.5%; P = 0.03). Moreover, significantly more children receiving loperamide required concomitant medication during the study (38% v 19.2%; P = 0.047).10
The aim of this study was to compare the efficacy, safety and tolerability of racecadotril with those of loperamide by assessing their effects on the resolution of the signs and symptoms of diarrhoea in patients living in developing countries who had acute watery diarrhoea of less than 5 days’ duration.
In this study, racecadotril produced a significantly greater reduction in abdominal pain and distension than loperamide. The duration of abdominal distension was significantly shorter with racecadotril (5.4 versus 24.4 h; P=0.0001) and constipation was also significantly less frequent (16% versus 25% ).11
In a randomised double-blind study in 6 adult volunteers with castor oil-induced diarrhoea, racecadotril significantly reduced stool weight and stool number in comparison with placebo. Racecadotril was significantly more effective than placebo in randomised doubleblind studies in adults or children with diarrhoea (of infectious origin or in adults with HIV infection).12