Introduction
According to WHO, diarrheal disease is rated the second among the leading causes of children under 5-year-old mortality and it accounts for one in nine child deaths worldwide [1,2]. Diarrhea is defined as the passage of loose watery stool at least three times in the 24-h period. According to the cause, pathogenesis, and management, diarrheal diseases are divided into three groups, that is, acute watery, invasive, and persistent diarrhea [3]. A description of diarrheal stool may help indicate the underlying diagnosis. Watery diarrhea may be caused by toxins, gastrointestinal peptides, bile acids, and laxatives that cause malabsorption of carbohydrates, leading to osmosis [4].
The first line for diarrheal-disease treatment is oral rehydration solutions (ORS) that exert its action by replacement of fluid and electrolyte loss. Although ORS has been highly successful, high rates of mortality and morbidity due to diarrheal disease remain recorded worldwide, especially in developing countries [5,6]. As enkephalins were discovered in 1975, their antisecretory role in the gastrointestinal tract was confirmed, hence, a program that was aimed at the development of a drug that would keep these neurotransmitter peptides in the gut by counterfeiting their inactivation. Thus, enkephalinase inhibitor ‘Racecadotril’ emerged because of this research program [7]-[9]. The advantage of Racecadotril over Loperamide is that it did not elongate the small intestine/colon transit time [8]. Also, it does not provoke the overgrowth of the small-intestinal bacteria [10].
When Racecadotril is administered orally, it is rapidly hydrolyzed to the more potent enkephalinase inhibitor ‘Thiorphan in vivo’ [11,12]. As Racecadotril experimental and clinical antidiarrheal activity is performed without any interference with the intestinal motility, this suggested selective antisecretory activity [13,14].
This work aimed to estimate the effect of Racecadotril as an adjunct to ORS in the management of acute watery diarrhea among children under 5 years of age.
Patients and methods
This double-blinded randomized controlled trial study was conducted at Qena General Hospital from June to December 2018. The current research gets approval from the Institutional Review Board (IRB) of the Medical Faculty, Al-Azhar (Asyut Branch) University, before the start of the study, and is registered on the Clinical Trial Registration Website (No. NCT05216822). According to sample calculation using G*Power 3 software, GPower Heinrich-Heine-Universität Düsseldorf, Germany [15], a calculated minimum sample of 50 participants was divided into two equal groups: 25 children received ORS alone for treatment as a control group, and a group of 25 children received ORS, and Racecadotril as treatment (at a dose of 1.5 mg/kg/day, an oral single daily dose for 3 days) was needed to detect an effect size of 0.3 in the mean frequency of diarrheal episodes and duration of hospitalization, with an error probability of 0.05 and 80% power.
Inclusion criteria were all children aged from 6 months to 5 years with acute watery diarrhea and with mild-to-moderate dehydration. Exclusion criteria were patients with severe dehydration (i.e. inability to drink because of drowsiness), patients with any serious concomitant illness that needs antibiotic treatment, those with severe adverse events that occur at any time, and those with chronic diarrhea.
Recruitment and randomization
All caregivers of eligible children were informed about the aims and details of the study. After completion of the baseline data collection, children were randomly assigned to one of the two groups. A biostatistician was responsible for the assignment of respondents, based on a predetermined list generated with blocked randomization with fixed block size. To overcome selection bias, those involved in the data collection and clinical evaluation, as well as the patients’ caregivers, did not have access to the randomization lists and were not aware of the block size.
Moreover, all participants’ caregivers received a written consent form. The informed consent was obvious and indicated the purpose of the study. Furthermore, participants’ confidentiality and anonymity were assured with no effect on the quality of care for those who reject/withdraw participation. The study was concomitant with the guidelines of the Declaration of Helsinki 2013.
All participants underwent full history taking personal history, vaccination history, nutritional history, past and family history, general examination, including general condition, signs of dehydration, vital signs (pulse, blood pressure, heart rate, and respiratory rate), and anthropometric measurements (weight, length/height, and BMI), systemic examination: an examination of the abdomen, chest, heart, and neurological examination. Follow-up and assessment of the outcome measures for three consecutive days: (a) duration of the diarrheal episode (time in which watery stool was normal), (b) frequency of motion per day, (c) clinical assessment, and (d) duration of hospitalization.
Data were revised, coded, processed, and analyzed using the IBM-SPSS program (IBM SPSS Inc., Chicago, US) (Statistical Package for Social Science) for Windows Version 21 [16]. Number and percentages were used for interpretation of the qualitative data where mean, SDs, and ranges were used for quantitative data. The χ2 test was used for the comparison of frequency between groups. For continuous data, an independent-samples t test was used to compare the means between the two groups. For nonparametric data, Mann–Whitney U test was used. For comparison of a quantitative variable with more than two categories, one-way and repeated-measures analysis of variance was used. Significance was considered when P value less than 0.05.
Result
This study recruited 50 children randomly divided into two equal groups (group A: 25 patients with watery diarrhea for 5 days or less, with a frequency of three or more diarrheic stools in the past 24 h before admission to the hospital, with no or mild-to-moderate dehydration, received Racecadotril and ORS as treatment, and group B: 25 cases with similar criteria for diarrhea treated with ORS alone).
Table 1 shows that the two studied groups were matched as regards age and sex (P=0.156 and 0.105). In group A, the male/female ratio was 9/16, while in group B, it was 14/11. For age, patients in group A were nonsignificantly older (1.4 years) than group B (1.3 years). Likewise, no difference was found regarding dehydration degree between groups (P>0.05) (Fig. 1).
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Table 1: Comparison between groups as regards baseline data
Figure 1: Degree of dehydration of the two groups.
The effect of treatment on the weight of the child on the 1st, 2nd, and 3rd days was demonstrated in Table 2. There was no difference between the two groups over the 3 days (P>0.05). Also, the weight change over the 3 days in the study group (group B) was insignificant (P=0.414), however, there was a significant decrease in weight from the 1st (10.1 kg) to the 3rd day (9.9 kg) in the control group (P=0.035).
Table 2: Weight of patients on the 1st, 2nd, and 3rd day of the two groups
Likewise, the treatment efficacy in reduction of the stool frequency on the 1st, 2nd, and 3rd days is illustrated in Table 3. There was no difference between the two groups over the 3 days (P>0.05). On the other hand, the frequency of stool over the 3 days in both groups illustrated a significant reduction (P<0.001).
Table 3: Comparison of the mean frequency of stool (1st, 2nd, and 3rd day) between both groups
Moreover, stool consistency was watery on the 1st day (100%) in both groups, this was converted into semisolid in 40% in group A and 25% in group B on the 2nd day. Also, on the 3rd day, further reduction was recorded in both groups, 92% in group A and 52% in group B. These changes were statistically significant (P<0.001) (Table 4).
Table 4: Consistency of stool of patients on 1st, 2nd, and 3rd day of the two groups
Regarding the duration of diarrheal episodes, significantly (P<0.001) shorter duration (2.8 days) was reported for group A compared with group B (3.6 days). Likely, significantly (P<0.001) shorter duration (1.4 days) was reported for group A compared with group B (2.2 days) (Table 5).
Table 5: Duration of the diarrheal episode of the two groups
Discussion
This study included 50 children (23 males and 27 females) with acute watery diarrhea with mild-to-moderate dehydration, they were subdivided into two groups: group A included 25 children treated with Racecadotril and ORS and group B included 25 children who received ORS alone.
There was no significant difference between both groups in their sex, ages, weight on the 1st day, and degree of dehydration. On the other hand, there was a significant difference in the mean weight of patients of group A between the 1st and 3rd days, this revealed that Racecadotril affects the weight of patients significantly as it assists the patient to preserve weight during the 1st, 2nd, and 3rd day of the attack of gastroenteritis through its antisecretory mechanism [5].
Also, there was a significant difference in the frequency and consistency of the stool between the 1st and 3rd day in group A (P<0.001), this supported the findings that Racecadotril is safe and effective as an additional treatment that reduced the frequency, weight, and volume of stool during gastroenteritis [14].
Furthermore, the duration of the diarrheal episode and duration of hospitalization of patients showed statistical differences in both groups with P value less than 0.001. This agreed with another study done by Salazar-Lindo et al. [17] and Asadi et al. [18], who assessed the Racecadotril effect as an adjuvant to ORS in infants/children in a developing country. They found that the mean amount of stool output/48 h was lower in the Racecadotril group (92 g/kg) compared with 170 g/kg in the placebo group (P<0.001), that is, about half the amount (46% of stool output) reduction with Racecadotril.
These results were in line with a study in Peru of 73 male children infected with rotavirus. Stool output was significantly (P<0.001) lower (157 g/kg in total) in the Racecadotril group versus 331 g/kg in the placebo group, that is, Racecadotril exerted a 50% reduction in the total stool amount. There was a significantly (P<0.001) lower median diarrheal duration in the Racecadotril group (47.4 h) than in the placebo group (51.5 h). ORS intake was less evident in the Racecadotril group than in the placebo group (P<0.001). Racecadotril was well-tolerated; only seven patients taking Racecadotril had adverse effects, which were all mild and transient. They concluded that effective and safe outcome results of Racecadotril were found in the management of acute watery diarrhea in male children [17].
Conclusion and recommendations
In conclusion, Racecadotril is an antisecretory drug that exerts its antidiarrheal effect by inhibiting intestinal enkephalinase. It is effective in reducing the volume and frequency of stool output. Racecadotril is well-tolerated and safe by providing symptomatic relief and reducing the severity of diarrhea as an adjuvant therapy during the acute attack of gastroenteritis. It is recommended that the new generations of already-discovered drugs for control of secretory diarrhea should be studied to discover the ones with fewer side effects to other systems in the body.
Study strengths and limitations
This study had several strength points, that is, using double-blinded randomized clinical trial design and examining the main effect of adding Racecadotril to ORS. However, several limitations were recorded, that is, this study did not investigate the effect of Racecadotril alone. Also, no control (placebo) group was assigned to detect the Racecadotril-attributable effect alone. Further, the side effects of Racecadotril were not fully studied.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. WHO. Diarrheal disease global burden. 2017
https://www.who.int/news-room/fact-sheets/detail/diarrhoeal-disease. Accessed 17th August 2021.
2. GBD Diarrheal Diseases Collaborators (2017). . Estimates of global, regional, and national morbidity, mortality, and etiologies of diarrheal diseases: a systematic analysis for the Global Burden of Disease Study 2015 Lancet Infect Dis. 2017;17:909–948
3. Harris JB Approach to the child with diarrhea, Hunter’s tropical medicine & emerging infection disease. 202010th ed. Netherland Elsevier Inc.:169–183
4. Veereman-Wauters G, Taminiau JWyllie R, Hyams J. Diarrhea Pediatric gastrointestinal and liver disease. 2015ed. 5 Philadelphia WB Saunders:64
5. Thiagarajah J, Ko E, Tradtrantip L, Donowitz M, Verkman A. Discovery and development of anti secretory drugs for treating diarrheal diseases Clin Gastroenterol Hepatol. 2014;12:204–209
6. Thompson K, Ray R, Alli S, Ge W, Boler A, Shannon McCool W, et al Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100 Exp Biol Med (Maywood). 2018;243:1056–Rx1065
7. Schwartz J. Racecadotril: a new approach to the treatment of diarrhea Antimicrob Agents. 2000;14:75–79
8. Liang Y, Zhang L, Zeng L, Gordon M, Wen J. Racecadotril for acute diarrhea in children Cochrane Database Syst Rev. 2019;12:CD009359
9. Eberlin M, Chen M, Mueck T, Däbritz J. Racecadotril in the treatment of acute diarrhea in children: a systematic, comprehensive review and meta-analysis of randomized controlled trials BMC Pediatr. 2018;18:124
10. Fischbach W, Andresen V, Eberlin M, Mueck T, Layer P. A comprehensive comparison of the efficacy and tolerability of racecadotril with other treatments of acute diarrhea in adults Front Med (Lausanne). 2016;3:44
11. Xu Y, Huang J, Liu F, Gao S, Guo Q. Quantitative analysis of Racecadotril metabolite in human plasma using a liquid chromatography/tandem mass spectrometry J Chromatogr B Analyst Technol Biomed Life Sci. 2007;852:101–107
12. Wang B, Yang L, Wang B, Luo C, Wang Y, Wang H, et al Development, in vitro and in vivo evaluation of racecadotril orodispersible films for pediatric use AAPS Pharma Sci Technol. 2021;22:15
13. Primi MP, Bueno L, Baumer P, Berard H, Lecomte J. Racecadotril demonstrates intestinal anti secretory activity in vivo Aliment Pharmacol Ther. 1999;13(Supp 6):3–7
14. Alam N, Ashraf H, Khan W, Karim M, Fuchs G. Efficacy and tolerability of Racecadotril in the treatment of cholera in adults: a double-blind, randomized, controlled clinical trial Gut. 2003;52:1419–1423
15. Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences Behav Res Methods. 2007;39:175–191
16. IBM_SPSSz. Statistical Package for Social Science. Ver.21. Standard version. 2012 NY, USA SPSS Inc.:2011–2012 Copyright ©
17. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M. Racecadotril in the treatment of acute watery diarrhea in children N Engl J Med. 2000;343:463–467
18. Asadi M, Mohammadi-Khanaposhtani M, Hosseini F, Gholami M, Dehpour A, Amanlou M. Design, synthesis, and evaluation of novel racecadotril-tetrazole-amino acid derivatives as new potent analgesic agents Respir Pharma Sci. 2021;16:341–357
