Angiotensin receptor-neprilysin inhibitor (thiorphan/irbesartan) improved cardiac function in a rat model of myocardial ischemic reperfusion injury.

Mitochondria-mediated apoptosis plays a critical role in myocardial ischemia reperfusion (IR) injury and causes a negative impact on cardiac efficiency and function. The combined angiotensin receptor-neprilysin inhibitor (ARNI) is a promising cardioprotective pharmacological agent that could rescue the heart from IR injury. This study investigated the cardioprotective effect of thiorphan (TH) in combination with three different doses of irbesartan (IRB) on myocardial IR injury and detected the most effective dose combination. Male Wistar rats were used and divided into five groups (10 rats/group): (I) Sham, (II) ischemia-reperfusion I/R, (III) TH/IRB + IR (0.1/5 mg/kg), (IV) TH/IRB + IR (0.1/10 mg/kg), and (V) TH/IRB + IR (0.1/15 mg/kg) groups. Thiorphan and irbesartan were injected intraperitoneally 15 min before IR induction. Mean arterial blood pressure, left ventricular end diastolic pressure (LVEDP), left ventricular maximum rate of pressure (LVdp/dtmax ), and cardiac levels of creatine kinase-MB, malondialdehyde, superoxide dismutase, and endothelin-1 were measured. Cardiac mitochondria complexes activities, histopathological examination of myocardial tissues, immunohistochemistry studies for myocardial apoptosis (Bax and Bcl-2), and electron microscopy examination of left ventricle were performed. TH/IRB combination preserved cardiac functions and mitochondria complex activities and mitigated cardiac damage, oxidative stress, and apoptosis following IR. Also, there was an evident improvement in histopathological changes and electron microscopy examination of left ventricle compared with I/R group. TH/IRB in a dose of 0.1/10 mg/kg showed significant improvement compared with the other treated groups. Thiorphan/irbesartan improved cardiac functions following IR injury. This could be explained by the reported improvement of mitochondria complex activities and reduction of oxidative stress, endothelin-1, and apoptosis.

Can diarrhea affect the pharmacokinetics of racecadotril in neonatal calves?

This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used in the treatment of diarrhea in humans and dogs, following oral administration in both neonatal calves with healthy and neonatal calves with infectious diarrhea. The study was carried out on a total of 24 Holstein calves (2-20 days), of which 6 were healthy and 18 were infectious diarrhea. Calves with infectious diarrhea were divided into 3 groups according to the infectious agent (Escherichia coli, Cryptosporidium parvum, and rotavirus/coronavirus). Racecadotril was administered orally at 2.5 mg/kg dose to calves. The plasma concentrations of racecadotril and its main active metabolite (thiorphan) were determined using HPLC-UV. The pharmacokinetic parameters were analyzed using the non-compartmental method. In healthy calves, the t1/2ʎz , Cmax , Tmax, and AUC0-12 of racecadotril were determined 4.70 h, 377 ng/ml, 0.75 h, and 1674 h × ng/ml, respectively. In the plasma of calves with infectious diarrhea, racecadotril and thiorphan were only detected at the sampling time from 0.25 to 1.5 h. As in calves with infectious diarrhea, thiorphan in plasma was only detected in healthy calves from 0.25 to 1.5 h. Racecadotril showed a large distribution volume, rapid elimination, and low metabolism to thiorphan in healthy calves.

Evaluating the cost utility of racecadotril in addition to oral rehydration solution versus oral rehydration solution alone for children with acute watery diarrhea in four low middle-income countries: Egypt, Morocco, Philippines and Vietnam.

AIM: To evaluate the cost utility of adjunct racecadotril and oral rehydration solution (R + ORS) versus oral rehydration solution (ORS) alone for the treatment of diarrhoea in children under five years with acute watery diarrhoea in four low-middle income countries. METHOD: A cost utility model, previously developed and independently validated, has been adapted to Egypt, Morocco, Philippines and Vietnam. The model is a decision tree, cohort model programmed in Microsoft Excel. The model structure represents the country-specific clinical pathways. The target population is children under the age of five years presenting with symptoms of acute watery diarrhea to an outpatient clinic or general physician practice. A healthcare payer perspective has been analysed with the model parameterised with local data, where available. Most recent cost data has been used to inform the drug, outpatient and inpatient costs. Uncertainty has been explored with univariate deterministic sensitivity. RESULTS: According to the base case models, R + ORS is dominant (cost-saving, more effective) versus ORS alone in Egypt, Morocco, Philippines and Vietnam. The incremental cost-effectiveness ratios in each country fall in the southeast (cost-saving, more effective) quadrant and represent a cost savings of -304,152 EGP per QALY gain in Egypt; -6,561 MAD per QALY gain in Morocco; -428,612 PHP per QALY gain in Philippines and -113,985,734 VND per QALY gain in Vietnam. Univariate deterministic sensitivity analysis shows that the three most influential parameters across all country adaptations are the utility of children without diarrhea; the utility of inpatient children with diarrhea and the cost of one night of inpatient care. CONCLUSION: In keeping with similar findings in upper-middle and high-income countries, the cost utility of R + ORS versus ORS is favourable in low-middle income countries for the treatment of children under five with acute watery diarrhoea.

PLAIN LANGUAGE SUMMARYDecision-makers rely on cost utility models to inform decisions about whether to publicly fund treatments as part of Universal Health Care. In low-middle income countries, the capacity to prepare cost utility models may be limited and using existing validated models is a practical solution to assist decision making. This study uses a cost utility model developed and independently validated for the United Kingdom, and adapts it to Philippines, Egypt, Morocco and Vietnam. The model evaluates the clinical benefit and economic impact of using racecadotril in addition to rehydration solution to treat diarrhoea in children. The results show that racecadotril is cost-saving and improves the quality of life for children in Philippines, Egypt, Morocco and Vietnam.

Angiotensin receptor-neprilysin inhibitior (thiorphan/irbesartan) decreased ischemia-reperfusion induced ventricular arrhythmias in rat; in vivo study.

Ventricular arrhythmias are considered as a major risk of sudden cardiac death. This study was designed to investigate the potential effects of angiotensin receptor neprilysin inhibitor; thiorphan/irbesartan (TH/IRB) combination therapy on myocardial ischemic-reperfusion (I/R)-induced arrhythmia. Fifty male Wistar rats were divided into 5 groups; (I, II): Sham, I/R both received DMSO intraperitoneally before the procedure. (III, IV, V): TH/IRB + IR (0.1/5 mg/kg, 0.1/10 mg/kg and 0.1/15 mg/kg). The drugs were injected intraperitoneally 15 min before I/R induction. Electrocardiograms changes, mean arterial blood pressure, incidence of ventricular tachycardia (VT), incidence of ventricular fibrillation (VF) and arrhythmia score were assessed. Cardiac levels of creatinine kinase-MB (CK-MB), Malondialdehyde (MDA), superoxide dismutase (SOD), endothelin-1 (ET-1), ATP content, and Na+/K+-ATPase pump activity were measured. TH (0.1 mg/kg) in combination with IRB (5, 10 and 15 mg/kg) produced significant decrease in QTc interval duration, ST height, incidence of VT and VF, duration of VT + VF, and arrhythmia score compared to I/R group. All treated groups showed significant decrease in the cardiac levels of: CK-MB, MDA and ET-1 and significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to I/R. TH/IRB + IR (0.1/10 mg/kg) group produced significant decrease in CK-MB, MDA and ET-1 and a significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to other treated groups. In conclusion, angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) decreased arrhythmia score and decreased cardiac damage. These could be explained in part by its ability to decrease oxidative stress and ET-1, increase ATP, and Na+/K+-ATPase pump activity in this rat model of I/R-induced arrhythmia.

Drugs in Focus: The Use of Racecadotril in Paediatric Gastrointestinal Disease.

Acute diarrhoea is a leading cause of morbidity and mortality in the paediatric population. Racecadotril is an antisecretory drug recommended as an adjuvant antidiarrhoeal treatment.In the small bowel, the enzyme neutral endopeptidase (NEP) inhibits the action of enkephalins, which prevent water and electrolyte hypersecretion. By inhibiting NEP, racecadotril allows enkephalins to exhibit their antisecretory effects. Consequently, racecadotril reduces the secretion of water and electrolytes in the small intestine, without having an effect on intestinal motility. No serious adverse events related to racecadotril have been reported.Racecadotril has proven its efficacy as an adjuvant antidiarrhoeal drug with a good safety profile. Its addition to oral rehydration solution (ORS) appears clinically beneficial and potentially leads to health care savings.

Racecadotril for acute diarrhoea in children.

BACKGROUND: Acute diarrhoea is a leading cause of death for children under five years of age. Most deaths are caused by excessive fluid and electrolyte losses. Racecadotril is an anti-secretory drug that has been used for acute diarrhoea in children as an adjunct to oral rehydration therapy. OBJECTIVES: To assess the efficacy and safety of racecadotril for treating acute diarrhoea in children under five years of age. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library Issue 3, March 2019); MEDLINE; Embase; LILACS; ClinicalTrials.gov; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), up to 4 March 2019, for clinical trials regardless of publication language or status. SELECTION CRITERIA: Randomized controlled trials (RCTs) that compared racecadotril to placebo or no intervention in addition to standard care (oral rehydration therapy) in children under five with acute diarrhoea. The primary outcomes were failure of oral rehydration, duration of diarrhoea, and number of stools. The secondary outcomes were stool output, length of the hospital stay, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted the data and assessed risk of bias. We presented dichotomous data with risk ratios (RR) and continuous data with mean difference (MD) or standardized mean difference (SMD). Where appropriate, we combined trials with meta-analysis and used a random-effects model if there was significant heterogeneity (I² ≥ 50%). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Seven RCTs with a total of 1140 participants met the inclusion criteria. The trials were carried out on children aged three months to five years, in outpatient and inpatient facilities from France, Spain, Peru, India, Kenya, and Ecuador. The efficacy and safety of racecadotril were compared to placebo or no treatment. Racecadotril may reduce the risk of rehydration failure (RR 0.41, 95% CI 0.13 to 1.23; 2 RCTs, 192 participants; low-certainty evidence). Data on duration of diarrhoea, number of stools in the first 48 hours are insufficient to reach a conclusion; stool output in the first 48 hours appears to be lower in the two trials measuring this, although the data is not combinable. Length of hospital stay was similar in two studies measuring this, and overall there was no evidence that racecadotril increased overall rate of adverse events (RR 0.90, 95% CI 0.66 to 1.22; 5 RCTs, 688 participants; low-certainty evidence). Most adverse events in the racecadotril group were mild or moderate. AUTHORS' CONCLUSIONS: Racecadotril seems to be a safe drug but has little benefit in improving acute diarrhoea in children under five years of age. Current evidence does not support routine use of racecadotril in management of acute diarrhoea in children under five outside of the context of placebo controlled RCTs. 18 December 2019 Up to date All studies incorporated from most recent search All studies identified during the most recent search (4 Mar, 2019) have been incorporated in the review, and no ongoing studies identified.

Simultaneous inhibition of neprilysin and activation of ACE2 prevented diabetic cardiomyopathy.

BACKGROUND: Neprilysin inhibitors (NEPi) are assisting the renin-angiotensin system (RAS) inhibitors in halting diabetic cardiomyopathy (DCM). Away from conventional tactic, a recent report revealed the renoprotective potential of NEPi and angiotensin-converting enzyme (ACE2) activator combination therapy against diabetic nephropathy. However, this combination so far not evaluated against DCM, thus the present investigation aiming the same. METHODS: Streptozotocin-induced (55 mg/kg, ip) type 1 diabetic (T1D) male Wistar rats were treated with either monotherapy of thiorphan (0.1 mg/kg/day, po) or diminazene aceturate (5 mg/kg/day, po), or their combination therapy, for four weeks. After hemodynamic measurements, all the rats' heart and plasma were collected for biochemistry, ELISA, histopathology, and immunoblotting. RESULTS: Metabolic perturbations and failing cardiac functions associated with diabetes were markedly attenuated by combination therapy. Besides, unfavourable alterations in RAS and natriuretic peptides system (NPS) were corrected by combination therapy. Interestingly, combination therapy significantly increased plasma and heart cGMP levels compared to T1D and monotherapy receiving rats. Moreover, rats receiving combination therapy exhibited significant inhibition of activated NF-κB, TGF-ß and apoptotic signalling, and a notable reduction in cardiac fibrosis when compared to T1D rats. Expressions of posttranslational histone modifications markers; H3K4Me2 and its methyltransferases (SET7/9 and RBBP5) were significantly enhanced in T1D hearts, which were significantly reduced by combination therapy. CONCLUSIONS: The NEPi and ACE2 activator combination therapy effectively prevented DCM by normalising RAS and NPS activities, increasing cGMP, inhibiting inflammatory, pro-fibrotic and apoptotic signalling, and reversing H3K4Me2 and its methyl transferases expressions.

Neprilysin inhibition promotes corneal wound healing.

Neprilysin (NEP), an ectoenzyme that modulates inflammation by degrading neuropeptides, was recently identified in the human corneal epithelium. The cornea expresses many NEP substrates, but the function of NEP in homeostatic maintenance and wound healing of the cornea is unknown. We therefore investigated the role of this enzyme under naive and injured conditions using NEP-deficient (NEP-/-) and wild type (WT) control mice. In vivo ocular surface imaging and histological analysis of corneal tissue showed no differences in limbal vasculature or corneal anatomy between naive NEP-/- and WT mice. Histological examination revealed increased corneal innervation in NEP-/- mice. In an alkali burn model of corneal injury, corneal wound healing was significantly accelerated in NEP-/- mice compared to WT controls 3 days after injury. Daily intraperitoneal administration of the NEP inhibitor thiorphan also accelerated corneal wound healing after alkali injury in WT mice. Collectively, our data identify a previously unknown role of NEP in the cornea, in which pharmacologic inhibition of its activity may provide a novel therapeutic option for patients with corneal injury.

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.

Effects of Racecadotril on Weight Loss and Diarrhea Due to Human Rotavirus in Neonatal Gnotobiotic Pigs (Sus scrofa domesticus).

Diarrheal disease is the second leading cause of death in children younger than 5 y, and the most common cause of acute watery diarrhea in young children worldwide is rotaviral infection. Medicines to specifically reduce diarrhea would be a desirable adjunctive treatment to supportive fluid therapy to decrease the mortality rate of diarrheal diseases. In this study, we evaluated the efficacy of an antisecretory drug, racecadotril, in treating human rotavirus (HRV)-induced diarrhea in a neonatal gnotobiotic pig model. In total, 27 gnotobiotic pigs were randomly assigned (n = 9 per group) to receive either racecadotril, chlorpromazine (positive-control drug), or PBS (mock treatment) after inoculation with HRV. Pigs were weighed daily and rectal swabs were collected to determine fecal consistency scores and virus shedding. Rotaviral infection was confirmed by ELISA and cell culture immunofluorescence. Overall, the racecadotril-treated pigs had less severe illness than either the chlorpromazine- or mock-treated groups; this conclusion was supported by the lower fecal-consistency scores, shorter duration of diarrhea, and significant gain in body weight during the course of the study of the racecadotril-treated pigs. Through its influence on decreasing intestinal hypersecretion, racecadotril was better able to control the clinical signs of rotaviral infection in the gnotobiotic pigs. These results lend support for using racecadotril as a treatment for rotaviral diarrhea.

[Consensus paper treatment of acute traveler's diarrhea. Practice recommendation for travel advice]. / Konsensuspapier Therapie der akuten Reisediarrhö : Eine Praxisempfehlung für die Reiseberatung.

BACKGROUND: In times of mass tourism, traveler's diarrhea is one of the most common health problems of long-distance travel. Globally, some 40 million cases occur annually. Travellers to risk areas should therefore be comprehensively advised beforehand, as to what action to take in case of an acute traveler's diarrhea and what drugs to add to their first-aid kit. To date none, or hardly any specific studies or valid specific guidelines for the treatment of traveler's diarrhea are available for Germany. METHOD: Drafting a consensus paper based on results of a specialists' meeting to evaluate therapeutic options in the treatment of acute uncomplicated travelers' diarrhea. The foundation for the present consensus recommendations is current evidence on antidiarrheals available in Germany for symptomatic treatment of gastrointestinal infections, summarized in the S2k guideline for gastrointestinal infections and Whipple's disease. Further taken into account for the present consensus recommendations were Pubmed-listed publications on symptomatic treatment of traveler's diarrhea, practical aspects, and the experts' experience in travel medicine. RESULTS AND CONCLUSION: For the treatment of acute uncomplicated traveler's diarrhea - more than 90 % of all cases - the secretion inhibitor racecadotril is considered first choice, based on our evaluation criteria. The previously usual practice of recommending the antimotility drug loperamide as first choice should be reconsidered, in favor of the recent active ingredient racecadotril. Antibiotics should be used only in complicated cases. A large number of travelers who generally demand antibiotic therapy should be disabused of their expectations. Other therapeutic measures that are currently available for the treatment of acute diarrhea while traveling play a subordinate role.

Racecadotril in the Management of Rotavirus and Non-rotavirus Diarrhea in Under-five Children: Two Randomized, Double-blind, Placebo-controlled Trials.

OBJECTIVE: To study the effect of racecadotril on reduction in the duration of acute rotavirus and non-rotavirus diarrhea. DESIGN: Two randomized double-blind placebo-controlled trials. SETTING: Community-based trial in an urban area in Vellore, hospital-based trial at a secondary hospital in Vellore. PARTICIPANTS: 199 and 130 3-59 month old children in the community- and hospital-based trials, respectively. METHODS: Racecadotril (1.5 mg/kg/dose, thrice a day for three days) or placebo were given to manage acute diarrhea in both trials. MAIN OUTCOME MEASURE: Median duration of diarrhea. RESULTS: Among 124 children completing the hospital trial, the median duration of diarrhea was 25 h in both arms (P=0.5); median total stool weight was 74 g/kg and 53.5 g/kg in racecadotril group and placebo group, respectively (P=0.4); and average fluid intake per day was 3.6 mL/kg/h and 3mL/kg/h in racecadotril and placebo arms, respectively (P=0.3). Among rotavirus-positive children, median duration of diarrhea was 26.9 h and 30.2 h in racecadotril and placebo arms, respectively (P=0.7). In the community, 196 completed the trial, the median duration of diarrhea was 2 days for both arms (P=0.8) and rotavirus positive children had similar outcomes with median diarrheal duration of 3 d in both arms (P=0.4). CONCLUSIONS: Treatment with racecadotril did not reduce diarrheal duration, stool volume or the requirement for fluid replacement in children with acute gastroenteritis, both with and without rotavirus infection.

Is racecadotril effective for acute diarrhea in children? -First update. / ¿Es efectivo el racecadotrilo como tratamiento para la diarrea aguda en niños? -Primera actualización.

This article updates the December 2015 Living FRISBEE (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos), based on the detection of two systematic reviews not identified in the previous version. Gastroenteritis or acute watery diarrhea is usually a self-limited disease, but it is still associated to substantial healthcare costs and remains a frequent demand for medical care. Racecadotril, an intestinal enkephalinase inhibitor, has been used as treatment because it would decrease the duration of acute diarrhea and fluid loss. However there is still no evidence supporting its routine use. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including nine randomized trials relevant for our question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded racecadotril probably reduces the duration of acute diarrhea in pediatric patients, without increasing adverse effects.

Este resumen Epistemonikos (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos) es una actualización del resumen publicado en Diciembre de 2015, basado en la detección de dos nuevas revisiones sistemáticas que no habían sido identificadas en la versión anterior. La gastroenteritis o diarrea aguda es una enfermedad habitualmente autolimitada, pero que consume recursos sanitarios y constituye un motivo de consulta frecuente en pediatría. El racecadotrilo, un inhibidor de la encefalinasa intestinal, se ha usado como tratamiento porque disminuiría la duración de la diarrea y la pérdida de líquidos, pero no hay evidencia que justifique su uso rutinario. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos cinco revisiones sistemáticas que en conjunto incluyen nueve estudios aleatorizados relevantes para nuestra pregunta. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que el uso de racecadotrilo probablemente disminuye la duración del cuadro de diarrea aguda en población pediátrica y que no se asociaría a mayor tasa de eventos adversos.

Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea.

Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known antidiarrheal activity in animals and humans; however, in humans, it suffers from shortcomings that might be improved with newer drugs in this class that have progressed to the clinic for nonenteric disease indications. To identify potentially superior NEP inhibitors with immediate clinical utility for diarrhea treatment, we compared their efficacy and pharmacologic properties in a rat intestinal hypersecretion model. Racecadotril and seven other clinical-stage inhibitors of NEP were obtained or synthesized. Enzyme potency and specificity were compared using purified peptidases. Compounds were orally administered to rats before administration of castor oil to induce diarrhea. Stool weight was recorded over 4 hours. To assess other pharmacologic properties, select compounds were orally administered to normal or castor oil-treated rats, blood and tissue samples collected at multiple time points, and active compound concentrations determined by mass spectroscopy. NEP enzyme activity was measured in tissue homogenates. Three previously untested clinical NEP inhibitors delayed diarrhea onset and reduced total stool output, with little or no effect on intestinal motility assessed by the charcoal meal test. Each was shown to be a potent, highly specific inhibitor of NEP. Each exhibited greater suppression of NEP activity in intestinal and nonintestinal tissues than did racecadotril and sustained this inhibition longer. These results suggest that newer clinical-stage NEP inhibitors originally developed for other indications may be directly repositioned for treatment of acute secretory diarrhea and offer advantages over racecadotril, such as less frequent dosing and potentially improved efficacy.

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.

[Efficacy of racecadotril vs. smectite, probiotics or zinc as an integral part of treatment of acute diarrhea in children under five years: A meta-analysis of multiple treatments]. / Eficacia del racecadotrilo versus smectita, probióticos o zinc como parte integral del tratamiento de la diarrea aguda en menores de cinco años: meta-análisis de tratamientos múltiples.

RATIONALE: Despite major advances in treatment, acute diarrhea continues to be a public health problem in children under five years. There is no systematic approach to treatment and most evidence is assembled comparing active treatment vs. placebo. OBJECTIVE: Systematic review of evidence on efficacy of adjuvants for treatment of acute diarrhea through a network meta-analysis. METHODS: A systematic search of multiple databases searching clinical trials related to the use of racecadotril, smectite, Lactobacillus GG, Lactobacillus reuteri, Saccharomyces boulardii and zinc as adjuvants in acute diarrhea was done. The primary endpoint was duration of diarrhea. Information is displayed through network meta-analysis.The superiority of each coadjutant was analyzed by Sucra approach. RESULTS: Network meta-analysis showed race cadotril was better when compared with placebo and other adjuvants. Sucra analysis showed racecadotril as the first option followed by smectite and Lactobacillus reuteri. INTERPRETATION: Considering a strategic decision making approach, network meta-analysis allows us to establish the therapeutic superiority of racecadotril as an adjunct for the comprehensive management of acute diarrhea in children aged less than five years.

Travellers' diarrhoea.

INTRODUCTION: It is estimated that approximately 30% to 70% of international travellers will develop diarrhoea during their travels or after returning home. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 24 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (empirical), antibiotics plus antimotility agents, antimotility agents, bismuth subsalicylate, diet, oral rehydration solutions, and racecadotril for travellers' diarrhoea.

Pediatric gastroenteritis in the emergency department: practice evaluation in Belgium, France, The Netherlands and Switzerland.

BACKGROUND: Based on European recommendations of ESPGHAN/ESPID from 2008, first line therapy for dehydration caused by acute gastroenteritis (AGE) is oral rehydration solution (ORS). In case of oral route failure, nasogastric tube enteral rehydration is as efficient as intra-venous rehydration and seems to lead to fewer adverse events. The primary objective was to describe rehydration strategies used in cases of AGE in pediatric emergency departments (PEDs) in Belgium, France, The Netherlands, and Switzerland. METHODS: An electronic survey describing a scenario in which a toddler had moderate dehydration caused by AGE was sent to physicians working in pediatric emergency departments. Analytical data were analyzed with descriptive statistics and Kruskal -Wallis Rank test. RESULTS: We analyzed 68 responses, distributed as follows: Belgium N = 10, France N = 37, The Netherlands N = 7, and Switzerland N = 14. Oral rehydration with ORS was the first line of treatment for 90% of the respondents. In case of first line treatment failure, intravenous rehydration was preferred by 95% of respondents from France, whereas nasogastric route was more likely to be used by those from Belgium (80%), The Netherlands (100%) and Switzerland (86%). Serum electrolyte measurements were more frequently prescribed in France (92%) and Belgium (80%) than in The Netherlands (43%) and Switzerland (29%). Racecadotril was more frequently used in France, and ondansetron was more frequently used in Switzerland. No respondent suggested routine use of antibiotics. CONCLUSION: We found variations in practices in terms of invasiveness and testing. Our study supports the need for further evaluation and implementation strategies of ESPGHAN/ESPID guidelines. We plan to extend the study throughout Europe with support of the Young ESPID Group.

What place for ▾racecadotril?

Worldwide, there are about two billion cases of diarrhoeal disease every year and it is the second leading cause of death in children under 5 years of age, killing 1.5 million children annually.(1) The most severe threat posed by diarrhoea is dehydration. In the UK, the incidence of diarrhoea is about one episode per person per year,(2) and approximately 10% of children younger than 5 years old present to healthcare services with gastroenteritis each year.(3) ▾Racecadotril (Hidrasec) is the first in a new class of antidiarrhoeal drug ('enkephalinase inhibitor') that has an antisecretory mechanism and is licensed in adults, children and infants (over 3 months of age) for symptomatic treatment of acute diarrhoea or as complementary treatment when causal treatment is possible.(4-6) Here we review the evidence for racecadotril and its place in the management of acute diarrhoea.