Racecadotril in the treatment of acute diarrhea in children: a systematic, comprehensive review and meta-analysis of randomized controlled trials.

BACKGROUND: Racecadotril is a guideline-recommended option for the treatment of acute diarrhea in children but existing guidelines and previous reviews of the field are based on a small fraction of published evidence. Therefore, we have performed a systematic search for randomized controlled trials evaluating racecadotril as add-on or in comparison to other treatments. METHODS: A search was performed in PubMed, Scopus and Google Scholar without limits about country of origin or reporting language. A meta-analysis was conducted for the five most frequently used efficacy parameters. RESULTS: We have retrieved 58 trials, from nine countries including six in comparison to placebo, 15 in comparison to various active treatments and 41 as add-on to various standard treatments (some multi-armed studies allowing more than one comparison). Trials used 45 distinct efficacy parameters, most often time to cure, % of cured children after 3 days of treatment, global efficacy and number of stools on second day of treatment. Racecadotril was superior to comparator treatments in outpatients and hospitalized patients with a high degree of consistency as confirmed by meta-analysis for the five most frequently used outcome parameters. For instance, it reduced time to cure from 106.2 h to 78.2 h (mean reduction 28.0 h; P < 0.0001 in 24 studies reporting on this parameter). Tolerability of racecadotril was comparable to that of placebo (10.4% vs. 10.6% adverse events incidence) or that of active comparator treatments other than loperamide (2.4% in both groups). CONCLUSIONS: Based on a comprehensive review of the existing evidence, we conclude that racecadotril is more efficacious than other treatments except for loperamide and has a tolerability similar to placebo and better than loperamide. These findings support the use of racecadotril in the treatment of acute diarrhea in children.

Racecadotril for acute diarrhoea in children: systematic review and meta-analyses.

OBJECTIVE: Racecadotril is an antisecretory agent that can prevent fluid/electrolyte depletion from the bowel as a result of acute diarrhoea without affecting intestinal motility. An up-to-date systematic review is indicated to summarise the evidence on racecadotril for the treatment of acute diarrhoea in children. DESIGN: A Cochrane format systematic review of randomised controlled trials (RCTs). Data extraction and assessment of methodological quality were performed independently by two reviewers. Methodological quality was assessed using the Cochrane risk of bias tool. PATIENTS: Children with acute diarrhoea, as defined by the primary studies. INTERVENTIONS: RCTs comparing racecadotril with placebo or other interventions. MAIN OUTCOME MEASURS: Duration of illness, stool output/volume and adverse events. RESULTS: Seven RCTs were included, five comparing racecadotril with placebo or no intervention, one with pectin/kaolin and one with loperamide. Moderate to high risk of bias was present in all studies. There was no significant difference in efficacy or adverse events between racecadotril and loperamide. A meta-analysis of three studies with 642 participants showed significantly shorter duration of symptoms with racecadotril compared with placebo (mean difference -53.48 h, 95% CI -65.64 to -41.33). A meta-analysis of five studies with 949 participants showed no significant difference in adverse events between racecadotril and placebo (risk ratio 0.99, 95% CI 0.73 to 1.34). CONCLUSIONS: There is some evidence that racecadotril is more effective than placebo or no intervention in reducing the duration of illness and stool output in children with acute diarrhoea. However, the overall quality of the evidence is limited due to sparse data, heterogeneity and risk of bias. Racecadotril appears to be safe and well tolerated.

[Treatment of diarrhea with loperamide in palliative medicine. A systematic review]. / Behandlung der Diarrhö mit Loperamid in der Palliativmedizin. Eine systematische Literaturübersicht.

Diarrhea is a distressing symptom which limits the quality of life in patients receiving palliative care and is associated with high morbidity and mortality. In patients with AIDS, it is a more common problem than for other entities (e.g., cancer). Loperamide is considered the first choice medication for the symptomatic treatment of diarrhea. This literature review examines the efficacy of loperamide in the symptomatic treatment of diarrhea in palliative care. Two databases (Medline and Embase) were searched through June 2012. A total of 286 studies were identified, but only 7 met the inclusion criteria (1 cohort and 6 experimental studies) in which loperamide (alone or in combination) was tested. There is a lack of significant studies which investigate the efficacy of loperamide in the symptomatic treatment of diarrhea. Two trials indicated superiority of loperamide over placebo. In comparison with octreotide, the results were contradictory. The combination of acetorphan with loperamide was more effective than acetorphan alone, but the combination of loperamide with diphenoxylate was inferior to octreotide. The identified studies revealed methodical problems. A definite recommendation for administration of loperamide can, therefore, not be derived from this work.The English full-text version of this article is available at SpringerLink (under "Supplemental").

Prospective randomized double-blind trial of racecadotril compared with loperamide in elderly people with gastroenteritis living in nursing homes.

AIM: Our aim was to compare the efficacy and tolerability of loperamide and racecadotril in elderly patients with acute diarrhea. RESEARCH DESIGN AND METHODS: We performed a randomized, prospective, double-blind, and parallel group design implemented in geriatric nursing homes in Catanzaro, Italy, from February 2008 to March 2009. Patients of both sexes were randomly allocated to receive either one tablet of racecadotril 100 mg every 8 h or two tablets of loperamide 2.0 mg followed by one tablet after each unformed stool, up to four tablets in any 24-h period. Patients were treated until recovery, defined as the production of two consecutive normal stools or no stool production for a period of 12 h. RESULTS: Normal stools were collected 36 +/- 4 h after the beginning of racecadotril and in 63 +/- 6 h from the beginning of loperamide administration (P < 0.01). The median time of abdominal pain in the intent-to-treat (ITT) population was 14 h for racecadotril and 28 h for loperamide. In the per-protocol (PP) population, the median time of abdominal pain was 14 h for racecadotril and 32 h for loperamide (P < 0.01). About the 50% of patients experienced at least one adverse event during the study: 12% in the racecadotril group and 60% in the loperamide group. The most frequently occurring adverse events were nausea and constipation. Genetic analysis did not report the presence of rapid or poor metabolizers. Pharmacoeconomic analysis performed at the end of our study documented an increase in costs in the loperamide group with respect to the racecadotril group (P < 0.01). CONCLUSIONS: Racecadotril is more effective than loperamide-probably due to drug interaction with loperamide-and it is not related to pharmacogenetic susceptibility. Racecadotril is also more cost effective than loperamide.

Systematic review: racecadotril in the treatment of acute diarrhoea in children.

BACKGROUND: Racecadotril (acetorphan) is an antisecretory drug that exerts its antidiarrhoeal effects by inhibiting intestinal enkephalinase. AIM: To summarize studies testing the efficacy and safety of racecadotril for treating children with acute gastroenteritis. METHODS: Reports were gathered by searching electronic databases MEDLINE, EMBASE, the Cochrane Library (all up to April 2007), relevant journals, and bibliographies of reviewed articles. Only randomized-controlled trials were included. RESULTS: Three randomized-controlled trials (471 participants) met the inclusion criteria. Two trials reported stool output, and data suggested less stool output in the racecadotril group than in the control group. The duration of diarrhoea was significantly reduced in the three trials reporting this outcome. Achievement of a cure by day 5 was similar in both groups. Adverse effects were similar in both groups. CONCLUSIONS: The small number of included trials provided some evidence in favour of the use of racecadotril over placebo or no intervention, to reduce the stool output and duration of diarrhoea in children with acute gastroenteritis. However, more data in out-patients are needed. The safety as well as the cost-effectiveness of the therapy should be explored, before routine therapy with racecadotril is recommended.

A blind, randomized comparison of racecadotril and loperamide for stopping acute diarrhea in adults.

AIM: Racecadotril is a specific enkephalinase inhibitor that exhibits intestinal antisecretory activity without affecting intestinal transit. Loperamide is an effective anti-diarrheal agent, but it usually induces constipation. This study is to compare the efficacy, safety, and tolerability of racecadotril versus loperamide in the outpatient treatment of acute diarrhea in adults. METHODS: A two-center, randomized, parallel-group, single-blind study was carried out to compare the efficacy, tolerability, and safety of racecadotril (100 mg thrice daily) and loperamide (2.0 mg 2 twice daily) in 62 adult patients suffering from acute diarrhea. The main efficacy criterion used was the duration of diarrhea after beginning the treatment (in hours). Other signs and symptoms were also evaluated. RESULTS: The clinical success rates for these anti-diarrheal treatments were 95.7% and 92.0% for racecadotril and loperamide respectively. Patients on racecadotril had a median duration of diarrhea of 19.5 h compared with a median of 13 h for patients on loperamide. Rapid improvement in anal burn and nausea was found for each drug. However, more patients on loperamide suffered from reactive constipation (29.0% vs 12.9%). Itching, another adverse event was notably higher in the racecadotril group (28.6% vs 0%). With regard to other adverse events, the two medications showed similar occurrence rates and similar concomitant medication usage rates. CONCLUSION: Racecadotril and loperamide are rapid, equally effective treatments for acute diarrhea in adults, but loperamide treatment is associated with a higher incidence of treatment-related constipation.

Efficacy and tolerability of racecadotril in acute diarrhea in children.

BACKGROUND & AIMS: Oral rehydration therapy is the only treatment recommended by the World Health Organization in acute diarrhea in children. Antisecretory drugs available could not be used because of their side effects, except for racecadotril, which is efficient in acute diarrhea in adults. METHODS: The efficacy and tolerability of racecadotril (1.5 mg/kg administered orally 3 times daily) as adjuvant therapy to oral rehydration were compared with those of placebo in 172 infants aged 3 months to 4 years (mean age, 12.8 months) who had acute diarrhea. The treatment groups were comparable in terms of age, duration of diarrhea, number of stools, and causative microorganism at inclusion. RESULTS: During the first 48 hours of treatment, patients receiving racecadotril had a significantly lower stool output (grams per hour) than those receiving placebo. The 95% confidence interval was 43%-88% for the full data set (n = 166; P = 0.009) and 33%-75% for the per-protocol population (n = 116; P = 0.001). There was no difference between treatments depending on rotavirus status. Significant differences between treatment groups were also found after 24 hours of treatment: full data set (n = 167; P = 0.026) and per-protocol population (n = 121; P = 0.015). Tolerability was good in both groups of patients. CONCLUSIONS: This study demonstrates the efficacy (up to 50% reduction in stool output) and tolerability of racecadotril as adjuvant therapy to oral rehydration solution in the treatment of severe diarrhea in infants and children.

Racecadotril.

Racecadotril is an oral enkephalinase inhibitor used in the treatment of acute diarrhoea. It prevents the degradation of endogenous opioids (enkephalins), thereby reducing hypersecretion of water and electrolytes into the intestinal lumen. 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. Similar results have been obtained in treating castor oil-induced diarrhoea in rats. Racecadotril was significantly more effective than placebo in randomised double-blind studies in adults or children with diarrhoea (of infectious origin or in adults with HIV infection). In well controlled trials, racecadotril had efficacy similar to that of loperamide and was generally as effective as loperamide-oxide. Racecadotril had a similar tolerability profile to placebo, and was better tolerated than loperamide, in adults and children with diarrhoea. It caused significantly less constipation after resolution of diarrhoea than loperamide.

Comparison of racecadotril and loperamide in adults with acute diarrhoea.

METHODS: A multicentre, randomized, double-blind, double-placebo, parallel-group study was carried out to compare the efficacy, tolerability, and safety of racecadotril (100 mg three times daily) and loperamide (2 mg after each diarrhoeic stool) in 157 adults with acute diarrhoea. Patients were treated for 7 days or until recovery, if this took place earlier. RESULTS: Both groups of patients passed similar numbers (mean +/- S.E.M.) of stools before recovery (3.5 +/- 0.5 for racecadotril vs. 2.9 +/- 0.4 for loperamide), and the duration of diarrhoea (mean +/- S.E.M.) was similar in both groups (14.9 +/- 2.0 h for racecadotril and 13.7 +/- 2.2 h for loperamide). Both treatments reduced the incidence of associated symptoms and signs during the study, and both were similarly well tolerated. However, more patients on loperamide reported rebound constipation during treatment (18.7% vs. 9.8% with racecadotril). CONCLUSIONS: The enkephalinase inhibitor, racecadotril, and the intestinal transit inhibitor, loperamide, were similarly and rapidly effective in resolving the symptoms and associated signs of diarrhoea.

Racecadotril versus placebo in the treatment of acute diarrhoea in adults.

METHODS: A two-centre, double-blind, parallel-group, randomized study was carried out to compare the efficacy and tolerability of racecadotril (100 mg three times daily) and placebo in 70 adult patients with acute diarrhoea. An objective criterion of antisecretory activity, stool weight, was used. RESULTS: Racecadotril produced a significant (P = 0.025) decrease in stool weight during the first day of treatment compared with placebo, and was also associated with significantly fewer diarrhoeic stools than placebo after 1 day of treatment (p = 0.027). Racecadotril and placebo were equally well tolerated, and the frequency of symptoms and signs was similar in both groups after 4 days of treatment. Fewer patients on racecadotril suffered from abdominal distension following treatment (5.6% vs. 18.2% on placebo). CONCLUSIONS: Racecadotril acts rapidly to resolve acute diarrhoea and has an incidence of adverse events similar to that of placebo.

Comparison of racecadotril and loperamide in children with acute diarrhoea.

METHODS: 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 received racecadotril (1.5 mg/kg) or loperamide (0.03 mg/kg) three times daily plus matching placebo until recovery. Fifty-two children received racecadotril and 50 loperamide. RESULTS: Patients on racecadotril passed a mean (+/- S.E.M.) 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). Measurement of abdominal circumference at the final consultation, 6 days after entry to the study, revealed no significant differences between treatments. CONCLUSIONS: Racecadotril and loperamide were equally effective in treating acute diarrhoea in these children, and racecadotril had a superior tolerability and safety profile.

Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment.

PURPOSE: Irinotecan (CPT-11), a camptothecin derivative, has shown efficacy against colorectal cancer. Delayed-onset diarrhea is its main limiting toxicity. The aim of this study was to determine the pathophysiology of CPT-11-induced delayed-onset diarrhea and assess the efficacy of combined antidiarrheal medication in a phase II, prospective, successive-cohorts, open study. PATIENTS AND METHODS: Twenty-eight patients with advanced colorectal cancer refractory to fluorouracil (5-FU) therapy received CPT-11 350 mg/m2 every 3 weeks. The first cohort of 14 consecutive patients explored for the mechanism of diarrhea received acetorphan (a new enkephalinase inhibitor) 100 mg three times daily; the second 14-patient cohort received, in addition to acetorphan, loperamide 4 mg three times daily. Before treatment, and if late diarrhea occurred, patients underwent colon mucosal biopsies for CPT-11 and topoisomerase I levels; intestinal transit time; fecalogram; fat and protein excretion; alpha1-antitrypsin clearance; D-xylose test; blood levels for vasoactive intestinal polypeptide, glucagon, gastrin, somatostatin, prostaglandin E2, and carboxylesterase; CPT-11/SN-38 and SN-38 glucuronide pharmacokinetics; and stool cultures. RESULTS: Delayed-onset diarrhea occurred during the first three treatment cycles in 23 patients (82%). Electrolyte fecal measurements showed a negative or small osmotic gap in nine of nine patients and an increased alpha1-antitrypsin clearance in six of six patients. There were no modifications in stool cultures or hormonal dysfunction. Four of 11 patients (36%) with delayed-onset diarrhea in the first cohort responded to acetorphan, whereas nine of 10 patients (90%) responded to the combination of acetorphan and loperamide (P < .02). CONCLUSION: CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.

The tachykinin NK2 receptor antagonist SR 48968 inhibits citric acid-induced airway hyperresponsiveness in guinea pigs.

Airway hyperresponsiveness is a main feature of asthma, and several lines of evidence suggest that tachykinins might be involved in the pathogenesis of airway hyperresponsiveness in rodents. We conducted a study designed to describe an original model of airway hyperresponsiveness induced by citric acid administered as aerosol to guinea pigs, and to investigate the effects of the nonpeptide neurokinin1 (NK1) and neurokinin2 (NK2)-receptor antagonists, SR 140333 and SR 48968, respectively, on the development of this airway hyperresponsiveness. Animals received thiorphan 1 mg/kg intraperitoneally and 30 min later were exposed to an aerosol of citric acid 0.4 M for 1 h. After 24 h, the animals were anesthetized and ventilated. Airway hyperresponsiveness was evidenced by significant shifts to the left of dose-response curves for intravenous acetylcholine (ACh) without a change in maximum responses to ACh. Exposure to citric acid induced an airway hyperresponsive that was abolished by chronic pretreatment with capsaicin (120 mg/kg, 5 d before citric acid exposure). SR 48968 1 mg/kg intraperitoneally, given once at 30 min before the citric acid exposure, inhibited airway hyperresponsiveness, whereas SR 140333 1 mg/kg or codeine 30 mg/kg given under similar conditions did not. The inhibition of airway hyperresponsiveness by SR 48968 did not result from functional antagonism, since SR 48968 did not affect ACh-induced bronchoconstriction, nor did it result from inhibition of tachykinin, which could have been released under the influence of ACh in hyperresponsive animals, since SR 48968 given after the exposure to aerosolized citric acid failed to inhibit airway hyperresponsiveness. In conclusion, these results show that inhaled citric acid can induce the development of an airway hyperresponsiveness in the guinea pig through a release of tachykinins, and also demonstrate that NK2-receptor stimulation plays a predominant role in the development of airway hyperresponsiveness.

Effects of acetorphan, an antidiarrhoeal enkephalinase inhibitor, on oro-caecal and colonic transit times in healthy volunteers.

Acetorphan is a potent enkephalinase inhibitor displaying antidiarrhoeal activity attributable to its intestinal antisecretory action mediated by endogenous enkephalins. The effect of acetorphan on digestive motility was studied in 12 healthy volunteers. Oro-caecal transit time was evaluated using the sulphasalazine/sulphapyridine method and colonic transit times using radiopaque markers. These measurements were successively performed after one week treatment with an antidiarrhoeal dose of acetorphan (100 mg t.d.s.) or placebo. There was no significant modification in transit time linked to acetorphan treatment: total oro-caecal times were 303 +/- 32 min vs. 287 +/- 27 min and colonic transit times 25.8 +/- 5.8 h vs. 31.3 +/- 5.5 h after acetorphan and placebo, respectively (means +/- S.E.M.). There was no significant modification either in right colonic, left colonic or rectosigmoid segmental transit times, or in the mean number of stools. These results, consistent with those from animal studies, confirm that, unlike classical antidiarrhoeal mu opiate receptor agonists, which act by delaying intestinal transit, acetorphan does not affect the transit. Antidiarrhoeal activity not accompanied by a delayed intestinal transit could have beneficial therapeutic consequences in the management of infectious diarrhoea. In addition, we show that the sulphasalazine and radiopaque markers methods can be simultaneously applied in the same study.