Oral administration of tannins and flavonoids in children with acute diarrhea: a pilot, randomized, control-case study

Oral administration of tannins and flavonoids in children with acute diarrhea: a pilot,... Background: AG is the most common cause of pediatric consultations among children between 2 and 5 years of age and it still leads to high mortality and morbidity. Its management is based on rehydration therapy, but this treatment is not effective in reducing duration of diarrhea. For this reason, other safer and less expensive interventions, which could be added to oral rehydration therapy, are of great interest. Methods: A pilot, randomized, case-controlled trial was conducted in 60 children affected by AG (< 7 days) with mild-moderate dehydration, according to WHO recommendations, from1 year to 17 years old. Patients were divided into 2 Groups: Group 1 consisting of 30 children treated with Actitan F and standard oral rehydration (SOR); Group 2 consisting of 30 children who received only SOR. Both groups received treatment for seven days, respectively. Patients of Group 1 stopped for their own choice, SOR after the first 24 h and continued only with Actitan F. Results: After 24 h of treatment, the median number of stools was 3.5 for Group 1, and 4 for Group 2. In Group 1 the difference between the number of stools at baseline (n = 5) and after 24 h of treatment (n =3.5) was significant (p <0. 0001). At the end of treatment, the median duration of diarrhea in Group 1 was 5 days, compared with 4 days in the Group 2, this difference was not statically significant (p 0.48). Conclusions: Oral administration of Actitan F associated with SOR seems safe and effective treatment in shortening the duration of AG in children. Further studies confirming these data are needed. Trial registration: NCT03356327 (retrospectively registered). Keywords: Acute gastroenteritis, Treatment, Tannins, Flavonoids Background and less expensive interventions, that could be added to the Acute gastroenteritis (AG) is the most common cause of effect of oral rehydration therapy, are of great interest [3]. pediatric consultations among children between 2 and According to the European Society of Gastroenter- 5 years of age [1]. AG in children still leads to high mor- ology and Hepatology (ESPGHAN) guidelines for diar- tality and morbidity [2].According to current European rhoea [4], probiotics, with evidence of efficacy such as S. guidelines, the main treatment for AG is the oral rehydra- boulardii and L. rhamnosus GG, can be considered as a tion with anhypo-osmolar solution and regular feeding supplement to hypo-osmolar solution. It is known that without dietary changes, including milk consumption. probiotics reduce the mean duration of diarrhoea by However, these treatment, does not reduce severity and about 24 h, but their efficacy on stool amount is not de- duration of symptoms. Considering the burden of AG to scribed [4]. Although the grade of recommendation is children and the high cost for healthcare system, effective very strong, quality of evidences is still low [5]. Other preparations used for treatment of diarrhoea include oral administration of immunoglobulins, antiperistaltic and anti- * Correspondence: staiano@unina.it secretory agents, such as various preparations of bismuth Department of Translational Medical Science, Section of Pediatrics, “Federico subsalicylate, cholestyramine and loperamide [6–10]. Use of II” University of Naples, Via S. Pansini, 5, 80131 Naples, Italy © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 2 of 6 antiperistaltic drugs is not effective and can cause serious consistency in children [14]. On admission, the degree of side effects in children, including lethargy, seizures, dehydration was clinically determined for each patient, Reye’s syndrome, paralytic ileus and respiratory de- based on WHO recommendations and data were recorded pression [11–13]. Use of loperamide, one of the most on a scale from 1 to 3 (1 for mild or < 5%; 2 for moderate common antiperistaltic agents, is not recommended or 5 to 10%; 3 for severe or 10% and more) [15]. in young children and infants. All enrolled children were randomly divided into two In conclusion, an ideal antidiarrheal agent should have groups: Group 1 was treated with Actitan F and standard a high index of safety even when used without close pro- oral rehydration (SOR) and Group 2 was treated with fessional supervisions, and should be compatible with SOR only ad libitum for 7 days (Fig. 1) SOR is a reduced oral rehydration solutions, treating effectively diarrhea of osmolarity oral solution (50/60 mmol/L Na), which is the any etiology with moderate cost. During last years, sev- first line therapy recommended by ESPGHAN guideline eral randomized and controlled studies showed the effi- for Acute Diarrhea [16]. Actitan F, instead, was orally ad- cacy of tannin-rich carob pod for the treatment of ministrated at dose of 1 sack every 4 h, maximum 4 sacks/ acute-onset diarrhea [10]. In 2003,Subbotina et al. dem- day for 7 days. Caregivers were instructed to administer onstrated that tormentil root extract, which has high the daily dose after mixing the contents of the sachet with content of tannins, reduces the duration of rotavirus a small amount of water. The study products used in this diarrhea compared with the control group in a pediatric trial were donated by Aboca® Società Agricola SpA., Loca- population (P < 0.0001) [5].They also demonstrated that lità Aboca, 20, 52,037 Sansepolcro (AR) – Italy. in the group treated with tormentil root extract, 8 of 20 At home, all parents had to fulfil a daily diary to rec- children (40%) were diarrhea-free 48 h after admission ord number and consistency of stools, presence of fever, to the hospital, compared with 1 of 20 in control group vomiting and children compliance with the therapy. (5%, P < 0.0001) [5]. During the final visit, scheduled after 7 days, the interim In this pilot study we aimed to evaluate the efficacy history was assessed, daily diaries were reviewed and dis- and the compliance of a treatment with Actitan-F, a cussed, and a physical evaluation was performed. natural molecular complex of tannins (from Agrimony and Tormentil) and flavonoids (Chamomile), associ- Outcomes ated with SOR, in a pediatric population of children The primary outcome was to evaluate the efficacy of a affected by AG. treatment with Actitan-F, a natural molecular complex of tannins (from Agrimony and Tormentil) and flavo- Methods noids (Chamomile) added to SOR compared to SOR in a We included 60 children (mean age: 3.1 yrs., range 0.3- paediatric population of children affected by AG. 12 years) with a diagnosis of AG, referred between April The secondary outcome was to assess safety, tolerabil- and July 2017 to the Department of Translational Medi- ity and compliance of the study products for short-term cine, section of Pediatric, University of Naples Federico II. treatment. Patients enrolled were children from 3 months to 12 years old, with a diagnosis of acute diarrhoea Endpoints appeared less than 7 days before the admission, capabil- The primary endpoint was the duration of diarrhoea, de- ity to oral rehydration, mild to moderate dehydration. fined as the number of stools after 24 h of treatment or Patients with diarrhoea over 7 days, serious somatic the time needed to normalize number and consistency pathology and severe dehydration were excluded. of stools (compared with the period before the onset of The study was approved by the Institutional Review diarrhoea). Secondary endpoint were the evaluation of Board of the University of Naples “Federico II” with the vomiting, body weight, possible need of hospitalization, protocol number 25/17. At admission, written informed compliance to therapy. consent was obtained from participants’ parents and from all patients older than 10 years. At first visit, a medical history was collected by one of the authors and Statistical analysis all patients underwent clinical evaluation, including body Data were analysed using SPSS version 17.0 (SPSS Inc., weight and body temperature. Chicago, Illinois, USA) for descriptive and frequency re- Frequency of bowel movements, stool consistency mea- sults and presented as median and range for quantitative sured through the Bristol Stool Form Scale (BSFS) and variables and percentiles for categorical variables. Sig- other associated gastrointestinal symptoms, including nificance was defined as P value < 0.05. Comparisons nausea, vomiting, abdominal pain and rectal bleeding, between the two groups used the Fisher’sexact test were accurately recorded. The BSFS is the most com- for categorical variables and the Mann-Whitney U monly standardized instrument used to rate stool test for quantitative variables. χ2testwas used to Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 3 of 6 Fig. 1 Flow-chart of the study determine patients’ acceptance of the products (Acti- continued to take only Actitan F. At the end of treatment, tan F and SOR) we tasted. in Group 1 the primary endpoint was reached after 5 days while in Group 2 after 4 days, this difference was not sta- Results tistically significant (p = 0.48) (Fig. 2). We also showed im- All patients completed the study. Socio-demographic proved stool consistency from baseline to 24 h in the two and clinical characteristics of the study population are groups, from liquid stools in 89.7 and 86.7% for Group 1 showed in Table 1. At baseline, a mean of defecation/ and Group 2, respectively, to 60 and 73.3% (p =0.34). In daily was 5 in both groups (ranged from 3 to 8 in Group particular, regarding stool consistency, we found that at 1 and from 2 to 10 in Group 2) (p = 0.63). The median day 6 in Group 1 76.9% of patients reported formed stools number of stools after 24 h was 3.5 in Group 1 and 4 in compared with 50% in Group 2 (p =0.028). The presence Group 2. The difference in the number of stools the first of vomiting at baseline was 73.3% (22 children of 30) for day of treatment between the two groups was not statis- Group 1 and 43.3% (13 children of 30) for the Group 2; at tically significant (p = 0.4); however, the difference be- 24 h vomiting was present in 46.6% of the Group1 and tween the number of stools at baseline and after 24 h of 16% of the Group 2 with no statistical significant differ- treatment was significant (p = < 0.0001) in the group ence. Bloody diarrhoea was found in only 10 and 6% of treated with Actitan F. After 24 h of treatment, we found patients at baseline for Group 1 and Group 2, respectively; that the most of children (23/30, 76%) in Group 1, by at the end of treatment, no patient presented blood in the their own choice, interrupted the assumption of SOR and stool in both groups. As for weight and fever, we did not Table 1 Demographics and Clinical characteristics at baseline Overall (N=60) Group 1 (N=30) Group 2 (N=30) p-value Median age (range), years 3.1 (0.3–12.7) 4.1 (0.5–12.1) 2.7 (0.3–12.7) 0.23 Starting date of diarrhea before consultation in days (range) 1 (1–4) 1 (1–4) 1 (1–3) 0.32 Median number of stools/day at baseline (range) 5 (2–10) 5 (3–8) 5 (2–10) 0.63 Consistency of stools at baseline (%) 0.35 Watery 81.4% 86.2% 76.7% Soft 18.6% 13.8% 23.3% Vomiting at baseline (median and range) 1.5 (0–23) 3 (0–23) 0.5 (0–7) 0.017 Fever (%) 50.0% 50.0% 50.0% 1.0 Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 4 of 6 Fig. 2 Primary Endpoint: Bowel movements/ day find any statistically significant difference between the substances in the treatment of children with AG. The groups. No one was hospitalized. positive clinical effect exerted by this new product on diarrhoea could be related to the tannins. Their action, Compliance and patient acceptance of treatment indeed, is essentially focused on the intestinal mucosa, Concerning compliance with therapy, 8/30 children (26%) favouring its rapid recovery. More specifically, when tan- in Group 1 and 10/30 (30%) in Group 2 refused to take nins meet mucous membranes, they aspecifically inter- Actitan F and SOR, respectively (p = 0.77) (Fig. 3). act with those membranes by making them more Regarding the perception of the treatment efficacy, parents tight and less permeable; this process is called “astrin- of children in Group 1 evaluated the Actitan F treatment gency”. This feature increases protection to the sub- very useful in 50% of cases, while parents of patients in adjacent layers of mucosa from the microorganisms Group 2 evaluated SOR quite effective in 68% of cases, this and irritant chemicals [17]. difference was statistically significant (p < 0.0001). Similar The efficacy and safety of a similar product in treat- trend was present in the perception of improvement after ment of acute diarrhoea in pediatrics have been already 24 h, where we found a tendency to significance in Group demonstrated during the last years. In 2009 Carretero et 1withrespect to Group2(p = 0.07). No adverse events in al. observed a significant decrease in the number of both groups were reported during the study. stools and an improvement in stool consistency in pa- tients treated with oral rehydration solution (SOR) and Discussion gelatin tannate vs. patients treated only with SOR [18]. In this pilot study, we investigated the therapeutic Loeb et al. showed that patients receiving a product con- efficacy of a medical device made of natural complex taining tannate had a normalization of bowel move- ments, body temperature, weight, and ceased to vomit much faster than those receiving placebo [10]. Plein and colleagues studied the effect of tannate on diarrhoea in patients with Crohn’s disease [19]. The re- sults obtained demonstrated that there was a significant reduction in bowel movement frequency at the end of treatment. Another clinical experience was reported by Ziegenhagen and colleagues, who showed the better effi- cacy and safety profile of tannin salts versus activated charcoal. Moreover, in the group receiving tannin salts, the frequency of abdominal pain was lower than in the activated charcoal group (50 versus 82%) [20]. Although our study protocol included the administra- tion of Actitan F plus SOR for a week in Group 1 and Fig. 3 Percentage of patients who complained with flavor of MDSM SOR alone in Group 2, most of the patients in the first (Group1) and Oral solution (Group2) (p = 0.77) Group interrupted the assumption of oral rehydration Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 5 of 6 after the first day of treatment. We can explain this choice Authors’ contributions MR performed data acquisition, analysed the data, wrote the first draft of the considering that after 24 h of combined treatment the re- manuscript, and approved the final version of the paper. VC performed data duction in number of stools in Group 1 was significantly acquisition, critically revised the manuscript and approved the final version different than at baseline (p < 0.0001) (5 vs. 3.5 stools/day). of the paper. VC, RB and AP performed data acquisition, critically revised the manuscript and approved the final version of the paper. EG designed the Due to the high perception of symptom improvement research study, analyzed the data, and approved the final version of the reported by parents of children in Group 1 after the first paper. AS designed the research study, critically revised the manuscript and day of treatment, we can speculate that the rapid approved the final version and the submission. improvement of clinical condition may have induced Ethics approval and consent to participate parents to stop earlier the oral solution and continue The study was approved by the Independent Ethics Committee of the only with Actitan F. “Federico II” University of Naples (reference number: 25/17). As a matter of fact, our results showing that the mean Competing interests duration of diarrhea in both groups after 7 days of ther- The authors declare that they have no competing interests. apy was not statistically significant, should be inter- preted in the light of what we have just described. Publisher’sNote Regarding stool consistency, we showed no statistically Springer Nature remains neutral with regard to jurisdictional claims in significant differences between the two groups, however published maps and institutional affiliations. at day 6 of treatment we found that 76.9% of patients in Received: 30 November 2017 Accepted: 9 May 2018 Group 1 reported formed stools compared with 50% in Group 2, this data showed a tendency to significance with a p = 0,028, maybe do to the small number of pa- References tients enrolled. We can explain this better result on stool 1. Van Damme P. Multicenter prospective study of the burden of rotavirus acute gastroenteritis in Europe, 2004–2005: the REVEAL study. J Infect Dis. consistency comparing to SOR alone, knowing that it 2007;195(Suppl 1):S4–16. has already been demonstrated that tannins and flavo- 2. Ogilvie I. Burden of community-acquired and nosocomial rotavirus noids exerts their action by restoring the physiological gastroenteritis in the pediatric population of Western Europe: a scoping review. BMC Infect Dis. 2012;12:62. function of the intestine barrier and have astringent 3. Szajewska H. Probiotics in gastrointestinal diseases in children: hard and properties [17]. not-so-hard evidence of efficacy. J Pediatr Gastroenterol Nutr. Moreover, in our study any adverse event in children 2006;42:454–75. 4. Guarino A. Probiotics as prevention and treatment for diarrhea. Curr Opin were observed in both groups, and this confirms the Gastroenterol. 2009;25(1):18–23. safety of tannins in the pediatric population. Compliance 5. Subbotina Maria D. Effect of oral administration of tormentil root extract with administration of Actitan F was good; every patient (Potentilla tormentilla) on rotavirus diarrhea in children: a randomized, double blind, controlled trial. Pediatr Infect Dis J. 2003;22:706–10. received 75% of doses according to the patient’s weight. 6. Madkour AA. Cholestyramine in acute infantile diarrhea: a double-blind, This result confirms a good ease of administration. placebo controlled clinical trial in hospitalized infants. Alexandria. J Pediatr. In contrast to other studies, we did not perform stool 1990;4:319–32. 7. Madkour AA. Smectite in acute diarrhea of children: a double-blind cultures at baseline [21, 22]. Nevertheless, ESPGHAN placebocontrolled clinical trial. Gastroenterology. 1991;100:A227. does not recommend performing stool cultures for acute 8. Kaplan MA, Prior MJ, McKonly KI, et al. A multicenter randomized controlled gastroenteritis in primary healthcare, and we did not trial of liquid loperamide product versus placebo in the treatment of acute diarrhea in children. Clin Pediatr. 1999;38:579–91. aim to evaluate the impact of tannins based on the 9. Ebina T. Prevention of rotavirus infection with cow colostrum containing different aetiologies of diarrhoea. antibody against human rotavirus. Lancet. 1983;2:1029–30. 10. Loeb H. Tannin-rich carob pod for the treatment of acute-onset diarrhea. J Pediatr Gastroenterol Nutr. 1989;8:480–5. Conclusion 11. Elaraby II. The use of chlorpromazine as an antisecretory agent in acute Therefore, we can conclude that Actitan F in association diarrhea of childhood. Alexandria J Pediatr. 1989;3:1–8. 12. Kassem AS. Loperamide in acute childhood diarrhoea: a double blind with SOR, may offer a safe and cost-effective approach controlled trial. J Diarr Dis Res. 1983;1:10–6. to AG in infants and children. However, further studies 13. Kassem AS. Effect of antibiotics on the duration of diarrhea and speed of and large trials are required. Because this study showed rehydration. Gazette Egyptian Paediatr Assoc 1983;31:117–118. 14. Lane MM. Reliability and validity of a modified Bristol stool form scale for promising results, it would be worthwhile to perform a children, J Pediatr. 2011;159:437–41.e1. large randomized control trial to unravel the efficacy of 15. World Health Organization. The treatment of diarrhea: A manual for the Actitan F plus SOR in children with AG. physicians and other senior health workers; 2005. 16. Guarino A. European Society for Pediatric Gastroenterology, hepatology, Abbreviations and nutrition/European Society for Pediatric Infectious Diseases Evidence- AG: Acute gastroenteritis; SOR: standard oral rehydration Based Guidelines for the Management of Acute Gastroenteritis in children in Europe: update 2014. JPGN. 2014;59(Issue 1):132–52. Funding 17. Mills S, Bone K. The essential guide to herbal safety. UK: Churchil Aboca® Società Agricola SpA., Località Aboca, 20, 52037 Sansepolcro (AR) – Italy. Livingstone; 2005. 18. Esteban Carretero J. A comparative analysis of ORS (oral rehydration Availability of data and materials solution) vs. ORS + gelatin tannin in two cohorts of pediatric patients with Data will not be shared in accordance to the Department’s policy. acute diarrhea. REV ESP ENFERM DIG (Madrid). 2009;101(1):41–8. Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 6 of 6 19. Plein K. Treatment of chronic diarrhea in Crohn disease. A pilot study of the clinical effect of tannin albuminate and ethacridine lactate. Fortschr Med. 1993;111:114–8. 20. Ziegenhagen DJ. Traveler's diarrhea in Turkey. Prospective randomized therapeutic comparison of charcoal versus tannin albuminate/ethacridine lactate. Med Klin. 1992;87:637–9. 21. Salazar-Lindo E. Racecadotril in the treatment of acute watery diarrhea in children. N Engl Med J. 2000;343:463–7. 22. Cezard J. Efficacy and tolerability of Racecadotril in acute diarrhea in children. Gastroenterology. 2001;120(799–805):13. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Italian Journal of Pediatrics Springer Journals

Oral administration of tannins and flavonoids in children with acute diarrhea: a pilot, randomized, control-case study

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Abstract

Background: AG is the most common cause of pediatric consultations among children between 2 and 5 years of age and it still leads to high mortality and morbidity. Its management is based on rehydration therapy, but this treatment is not effective in reducing duration of diarrhea. For this reason, other safer and less expensive interventions, which could be added to oral rehydration therapy, are of great interest. Methods: A pilot, randomized, case-controlled trial was conducted in 60 children affected by AG (< 7 days) with mild-moderate dehydration, according to WHO recommendations, from1 year to 17 years old. Patients were divided into 2 Groups: Group 1 consisting of 30 children treated with Actitan F and standard oral rehydration (SOR); Group 2 consisting of 30 children who received only SOR. Both groups received treatment for seven days, respectively. Patients of Group 1 stopped for their own choice, SOR after the first 24 h and continued only with Actitan F. Results: After 24 h of treatment, the median number of stools was 3.5 for Group 1, and 4 for Group 2. In Group 1 the difference between the number of stools at baseline (n = 5) and after 24 h of treatment (n =3.5) was significant (p <0. 0001). At the end of treatment, the median duration of diarrhea in Group 1 was 5 days, compared with 4 days in the Group 2, this difference was not statically significant (p 0.48). Conclusions: Oral administration of Actitan F associated with SOR seems safe and effective treatment in shortening the duration of AG in children. Further studies confirming these data are needed. Trial registration: NCT03356327 (retrospectively registered). Keywords: Acute gastroenteritis, Treatment, Tannins, Flavonoids Background and less expensive interventions, that could be added to the Acute gastroenteritis (AG) is the most common cause of effect of oral rehydration therapy, are of great interest [3]. pediatric consultations among children between 2 and According to the European Society of Gastroenter- 5 years of age [1]. AG in children still leads to high mor- ology and Hepatology (ESPGHAN) guidelines for diar- tality and morbidity [2].According to current European rhoea [4], probiotics, with evidence of efficacy such as S. guidelines, the main treatment for AG is the oral rehydra- boulardii and L. rhamnosus GG, can be considered as a tion with anhypo-osmolar solution and regular feeding supplement to hypo-osmolar solution. It is known that without dietary changes, including milk consumption. probiotics reduce the mean duration of diarrhoea by However, these treatment, does not reduce severity and about 24 h, but their efficacy on stool amount is not de- duration of symptoms. Considering the burden of AG to scribed [4]. Although the grade of recommendation is children and the high cost for healthcare system, effective very strong, quality of evidences is still low [5]. Other preparations used for treatment of diarrhoea include oral administration of immunoglobulins, antiperistaltic and anti- * Correspondence: staiano@unina.it secretory agents, such as various preparations of bismuth Department of Translational Medical Science, Section of Pediatrics, “Federico subsalicylate, cholestyramine and loperamide [6–10]. Use of II” University of Naples, Via S. Pansini, 5, 80131 Naples, Italy © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 2 of 6 antiperistaltic drugs is not effective and can cause serious consistency in children [14]. On admission, the degree of side effects in children, including lethargy, seizures, dehydration was clinically determined for each patient, Reye’s syndrome, paralytic ileus and respiratory de- based on WHO recommendations and data were recorded pression [11–13]. Use of loperamide, one of the most on a scale from 1 to 3 (1 for mild or < 5%; 2 for moderate common antiperistaltic agents, is not recommended or 5 to 10%; 3 for severe or 10% and more) [15]. in young children and infants. All enrolled children were randomly divided into two In conclusion, an ideal antidiarrheal agent should have groups: Group 1 was treated with Actitan F and standard a high index of safety even when used without close pro- oral rehydration (SOR) and Group 2 was treated with fessional supervisions, and should be compatible with SOR only ad libitum for 7 days (Fig. 1) SOR is a reduced oral rehydration solutions, treating effectively diarrhea of osmolarity oral solution (50/60 mmol/L Na), which is the any etiology with moderate cost. During last years, sev- first line therapy recommended by ESPGHAN guideline eral randomized and controlled studies showed the effi- for Acute Diarrhea [16]. Actitan F, instead, was orally ad- cacy of tannin-rich carob pod for the treatment of ministrated at dose of 1 sack every 4 h, maximum 4 sacks/ acute-onset diarrhea [10]. In 2003,Subbotina et al. dem- day for 7 days. Caregivers were instructed to administer onstrated that tormentil root extract, which has high the daily dose after mixing the contents of the sachet with content of tannins, reduces the duration of rotavirus a small amount of water. The study products used in this diarrhea compared with the control group in a pediatric trial were donated by Aboca® Società Agricola SpA., Loca- population (P < 0.0001) [5].They also demonstrated that lità Aboca, 20, 52,037 Sansepolcro (AR) – Italy. in the group treated with tormentil root extract, 8 of 20 At home, all parents had to fulfil a daily diary to rec- children (40%) were diarrhea-free 48 h after admission ord number and consistency of stools, presence of fever, to the hospital, compared with 1 of 20 in control group vomiting and children compliance with the therapy. (5%, P < 0.0001) [5]. During the final visit, scheduled after 7 days, the interim In this pilot study we aimed to evaluate the efficacy history was assessed, daily diaries were reviewed and dis- and the compliance of a treatment with Actitan-F, a cussed, and a physical evaluation was performed. natural molecular complex of tannins (from Agrimony and Tormentil) and flavonoids (Chamomile), associ- Outcomes ated with SOR, in a pediatric population of children The primary outcome was to evaluate the efficacy of a affected by AG. treatment with Actitan-F, a natural molecular complex of tannins (from Agrimony and Tormentil) and flavo- Methods noids (Chamomile) added to SOR compared to SOR in a We included 60 children (mean age: 3.1 yrs., range 0.3- paediatric population of children affected by AG. 12 years) with a diagnosis of AG, referred between April The secondary outcome was to assess safety, tolerabil- and July 2017 to the Department of Translational Medi- ity and compliance of the study products for short-term cine, section of Pediatric, University of Naples Federico II. treatment. Patients enrolled were children from 3 months to 12 years old, with a diagnosis of acute diarrhoea Endpoints appeared less than 7 days before the admission, capabil- The primary endpoint was the duration of diarrhoea, de- ity to oral rehydration, mild to moderate dehydration. fined as the number of stools after 24 h of treatment or Patients with diarrhoea over 7 days, serious somatic the time needed to normalize number and consistency pathology and severe dehydration were excluded. of stools (compared with the period before the onset of The study was approved by the Institutional Review diarrhoea). Secondary endpoint were the evaluation of Board of the University of Naples “Federico II” with the vomiting, body weight, possible need of hospitalization, protocol number 25/17. At admission, written informed compliance to therapy. consent was obtained from participants’ parents and from all patients older than 10 years. At first visit, a medical history was collected by one of the authors and Statistical analysis all patients underwent clinical evaluation, including body Data were analysed using SPSS version 17.0 (SPSS Inc., weight and body temperature. Chicago, Illinois, USA) for descriptive and frequency re- Frequency of bowel movements, stool consistency mea- sults and presented as median and range for quantitative sured through the Bristol Stool Form Scale (BSFS) and variables and percentiles for categorical variables. Sig- other associated gastrointestinal symptoms, including nificance was defined as P value < 0.05. Comparisons nausea, vomiting, abdominal pain and rectal bleeding, between the two groups used the Fisher’sexact test were accurately recorded. The BSFS is the most com- for categorical variables and the Mann-Whitney U monly standardized instrument used to rate stool test for quantitative variables. χ2testwas used to Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 3 of 6 Fig. 1 Flow-chart of the study determine patients’ acceptance of the products (Acti- continued to take only Actitan F. At the end of treatment, tan F and SOR) we tasted. in Group 1 the primary endpoint was reached after 5 days while in Group 2 after 4 days, this difference was not sta- Results tistically significant (p = 0.48) (Fig. 2). We also showed im- All patients completed the study. Socio-demographic proved stool consistency from baseline to 24 h in the two and clinical characteristics of the study population are groups, from liquid stools in 89.7 and 86.7% for Group 1 showed in Table 1. At baseline, a mean of defecation/ and Group 2, respectively, to 60 and 73.3% (p =0.34). In daily was 5 in both groups (ranged from 3 to 8 in Group particular, regarding stool consistency, we found that at 1 and from 2 to 10 in Group 2) (p = 0.63). The median day 6 in Group 1 76.9% of patients reported formed stools number of stools after 24 h was 3.5 in Group 1 and 4 in compared with 50% in Group 2 (p =0.028). The presence Group 2. The difference in the number of stools the first of vomiting at baseline was 73.3% (22 children of 30) for day of treatment between the two groups was not statis- Group 1 and 43.3% (13 children of 30) for the Group 2; at tically significant (p = 0.4); however, the difference be- 24 h vomiting was present in 46.6% of the Group1 and tween the number of stools at baseline and after 24 h of 16% of the Group 2 with no statistical significant differ- treatment was significant (p = < 0.0001) in the group ence. Bloody diarrhoea was found in only 10 and 6% of treated with Actitan F. After 24 h of treatment, we found patients at baseline for Group 1 and Group 2, respectively; that the most of children (23/30, 76%) in Group 1, by at the end of treatment, no patient presented blood in the their own choice, interrupted the assumption of SOR and stool in both groups. As for weight and fever, we did not Table 1 Demographics and Clinical characteristics at baseline Overall (N=60) Group 1 (N=30) Group 2 (N=30) p-value Median age (range), years 3.1 (0.3–12.7) 4.1 (0.5–12.1) 2.7 (0.3–12.7) 0.23 Starting date of diarrhea before consultation in days (range) 1 (1–4) 1 (1–4) 1 (1–3) 0.32 Median number of stools/day at baseline (range) 5 (2–10) 5 (3–8) 5 (2–10) 0.63 Consistency of stools at baseline (%) 0.35 Watery 81.4% 86.2% 76.7% Soft 18.6% 13.8% 23.3% Vomiting at baseline (median and range) 1.5 (0–23) 3 (0–23) 0.5 (0–7) 0.017 Fever (%) 50.0% 50.0% 50.0% 1.0 Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 4 of 6 Fig. 2 Primary Endpoint: Bowel movements/ day find any statistically significant difference between the substances in the treatment of children with AG. The groups. No one was hospitalized. positive clinical effect exerted by this new product on diarrhoea could be related to the tannins. Their action, Compliance and patient acceptance of treatment indeed, is essentially focused on the intestinal mucosa, Concerning compliance with therapy, 8/30 children (26%) favouring its rapid recovery. More specifically, when tan- in Group 1 and 10/30 (30%) in Group 2 refused to take nins meet mucous membranes, they aspecifically inter- Actitan F and SOR, respectively (p = 0.77) (Fig. 3). act with those membranes by making them more Regarding the perception of the treatment efficacy, parents tight and less permeable; this process is called “astrin- of children in Group 1 evaluated the Actitan F treatment gency”. This feature increases protection to the sub- very useful in 50% of cases, while parents of patients in adjacent layers of mucosa from the microorganisms Group 2 evaluated SOR quite effective in 68% of cases, this and irritant chemicals [17]. difference was statistically significant (p < 0.0001). Similar The efficacy and safety of a similar product in treat- trend was present in the perception of improvement after ment of acute diarrhoea in pediatrics have been already 24 h, where we found a tendency to significance in Group demonstrated during the last years. In 2009 Carretero et 1withrespect to Group2(p = 0.07). No adverse events in al. observed a significant decrease in the number of both groups were reported during the study. stools and an improvement in stool consistency in pa- tients treated with oral rehydration solution (SOR) and Discussion gelatin tannate vs. patients treated only with SOR [18]. In this pilot study, we investigated the therapeutic Loeb et al. showed that patients receiving a product con- efficacy of a medical device made of natural complex taining tannate had a normalization of bowel move- ments, body temperature, weight, and ceased to vomit much faster than those receiving placebo [10]. Plein and colleagues studied the effect of tannate on diarrhoea in patients with Crohn’s disease [19]. The re- sults obtained demonstrated that there was a significant reduction in bowel movement frequency at the end of treatment. Another clinical experience was reported by Ziegenhagen and colleagues, who showed the better effi- cacy and safety profile of tannin salts versus activated charcoal. Moreover, in the group receiving tannin salts, the frequency of abdominal pain was lower than in the activated charcoal group (50 versus 82%) [20]. Although our study protocol included the administra- tion of Actitan F plus SOR for a week in Group 1 and Fig. 3 Percentage of patients who complained with flavor of MDSM SOR alone in Group 2, most of the patients in the first (Group1) and Oral solution (Group2) (p = 0.77) Group interrupted the assumption of oral rehydration Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 5 of 6 after the first day of treatment. We can explain this choice Authors’ contributions MR performed data acquisition, analysed the data, wrote the first draft of the considering that after 24 h of combined treatment the re- manuscript, and approved the final version of the paper. VC performed data duction in number of stools in Group 1 was significantly acquisition, critically revised the manuscript and approved the final version different than at baseline (p < 0.0001) (5 vs. 3.5 stools/day). of the paper. VC, RB and AP performed data acquisition, critically revised the manuscript and approved the final version of the paper. EG designed the Due to the high perception of symptom improvement research study, analyzed the data, and approved the final version of the reported by parents of children in Group 1 after the first paper. AS designed the research study, critically revised the manuscript and day of treatment, we can speculate that the rapid approved the final version and the submission. improvement of clinical condition may have induced Ethics approval and consent to participate parents to stop earlier the oral solution and continue The study was approved by the Independent Ethics Committee of the only with Actitan F. “Federico II” University of Naples (reference number: 25/17). As a matter of fact, our results showing that the mean Competing interests duration of diarrhea in both groups after 7 days of ther- The authors declare that they have no competing interests. apy was not statistically significant, should be inter- preted in the light of what we have just described. Publisher’sNote Regarding stool consistency, we showed no statistically Springer Nature remains neutral with regard to jurisdictional claims in significant differences between the two groups, however published maps and institutional affiliations. at day 6 of treatment we found that 76.9% of patients in Received: 30 November 2017 Accepted: 9 May 2018 Group 1 reported formed stools compared with 50% in Group 2, this data showed a tendency to significance with a p = 0,028, maybe do to the small number of pa- References tients enrolled. We can explain this better result on stool 1. Van Damme P. Multicenter prospective study of the burden of rotavirus acute gastroenteritis in Europe, 2004–2005: the REVEAL study. J Infect Dis. consistency comparing to SOR alone, knowing that it 2007;195(Suppl 1):S4–16. has already been demonstrated that tannins and flavo- 2. Ogilvie I. Burden of community-acquired and nosocomial rotavirus noids exerts their action by restoring the physiological gastroenteritis in the pediatric population of Western Europe: a scoping review. BMC Infect Dis. 2012;12:62. function of the intestine barrier and have astringent 3. Szajewska H. Probiotics in gastrointestinal diseases in children: hard and properties [17]. not-so-hard evidence of efficacy. J Pediatr Gastroenterol Nutr. Moreover, in our study any adverse event in children 2006;42:454–75. 4. Guarino A. Probiotics as prevention and treatment for diarrhea. Curr Opin were observed in both groups, and this confirms the Gastroenterol. 2009;25(1):18–23. safety of tannins in the pediatric population. Compliance 5. Subbotina Maria D. Effect of oral administration of tormentil root extract with administration of Actitan F was good; every patient (Potentilla tormentilla) on rotavirus diarrhea in children: a randomized, double blind, controlled trial. Pediatr Infect Dis J. 2003;22:706–10. received 75% of doses according to the patient’s weight. 6. Madkour AA. Cholestyramine in acute infantile diarrhea: a double-blind, This result confirms a good ease of administration. placebo controlled clinical trial in hospitalized infants. Alexandria. J Pediatr. In contrast to other studies, we did not perform stool 1990;4:319–32. 7. Madkour AA. Smectite in acute diarrhea of children: a double-blind cultures at baseline [21, 22]. Nevertheless, ESPGHAN placebocontrolled clinical trial. Gastroenterology. 1991;100:A227. does not recommend performing stool cultures for acute 8. Kaplan MA, Prior MJ, McKonly KI, et al. A multicenter randomized controlled gastroenteritis in primary healthcare, and we did not trial of liquid loperamide product versus placebo in the treatment of acute diarrhea in children. Clin Pediatr. 1999;38:579–91. aim to evaluate the impact of tannins based on the 9. Ebina T. Prevention of rotavirus infection with cow colostrum containing different aetiologies of diarrhoea. antibody against human rotavirus. Lancet. 1983;2:1029–30. 10. Loeb H. Tannin-rich carob pod for the treatment of acute-onset diarrhea. J Pediatr Gastroenterol Nutr. 1989;8:480–5. Conclusion 11. Elaraby II. The use of chlorpromazine as an antisecretory agent in acute Therefore, we can conclude that Actitan F in association diarrhea of childhood. Alexandria J Pediatr. 1989;3:1–8. 12. Kassem AS. Loperamide in acute childhood diarrhoea: a double blind with SOR, may offer a safe and cost-effective approach controlled trial. J Diarr Dis Res. 1983;1:10–6. to AG in infants and children. However, further studies 13. Kassem AS. Effect of antibiotics on the duration of diarrhea and speed of and large trials are required. Because this study showed rehydration. Gazette Egyptian Paediatr Assoc 1983;31:117–118. 14. Lane MM. Reliability and validity of a modified Bristol stool form scale for promising results, it would be worthwhile to perform a children, J Pediatr. 2011;159:437–41.e1. large randomized control trial to unravel the efficacy of 15. World Health Organization. The treatment of diarrhea: A manual for the Actitan F plus SOR in children with AG. physicians and other senior health workers; 2005. 16. Guarino A. European Society for Pediatric Gastroenterology, hepatology, Abbreviations and nutrition/European Society for Pediatric Infectious Diseases Evidence- AG: Acute gastroenteritis; SOR: standard oral rehydration Based Guidelines for the Management of Acute Gastroenteritis in children in Europe: update 2014. JPGN. 2014;59(Issue 1):132–52. Funding 17. Mills S, Bone K. The essential guide to herbal safety. UK: Churchil Aboca® Società Agricola SpA., Località Aboca, 20, 52037 Sansepolcro (AR) – Italy. Livingstone; 2005. 18. Esteban Carretero J. A comparative analysis of ORS (oral rehydration Availability of data and materials solution) vs. ORS + gelatin tannin in two cohorts of pediatric patients with Data will not be shared in accordance to the Department’s policy. acute diarrhea. REV ESP ENFERM DIG (Madrid). 2009;101(1):41–8. Russo et al. Italian Journal of Pediatrics (2018) 44:64 Page 6 of 6 19. Plein K. Treatment of chronic diarrhea in Crohn disease. A pilot study of the clinical effect of tannin albuminate and ethacridine lactate. Fortschr Med. 1993;111:114–8. 20. Ziegenhagen DJ. Traveler's diarrhea in Turkey. Prospective randomized therapeutic comparison of charcoal versus tannin albuminate/ethacridine lactate. Med Klin. 1992;87:637–9. 21. Salazar-Lindo E. Racecadotril in the treatment of acute watery diarrhea in children. N Engl Med J. 2000;343:463–7. 22. Cezard J. Efficacy and tolerability of Racecadotril in acute diarrhea in children. Gastroenterology. 2001;120(799–805):13.

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Italian Journal of PediatricsSpringer Journals

Published: Jun 4, 2018

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