Smecta*60 Sachets. A New Step in Treating Diarrhoea -Powder for Oral Suspension.

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Droylefaix MT, Drouet Y, Schatz B. Sodium glycodeoxycholate and spinability of gastrointestinal mucus-protective effect of smectite. Gastroenterology. 1985;88:1369. Dumitrascu DL, Stanculete M, Mitrea I, Dumitrascu DM, Farcas A. The effect of two antidiarrhoeal drugs on the psychosocial adjustment to illness in chronic functional diarrhoea. Rom J Intern Med Germany. 2004;42:191–7.

The clinical trial was a prospective, open label, non-comparative, multi-center, international study with chronic treatment of diosmectite (Smecta®, 3 g) TID over 5 weeks, whose first purpose was to assess the level of elemental impurities (e.g. lead, arsenic, cadmium) in blood and urine samples after chronic administration of diosmectite. The aim of this ancillary study was to assess the bowel microbiota composition, stools consistency and frequency after chronic administration of diosmectite in subjects with chronic functional diarrhea. Consistency of stools (recorded and rated according to BSS) and frequency were assessed over 24h preceding the stool sample by the subject.

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We have previously demonstrated that NSP4 exerts severe direct enterotoxic effects by modifying the cellular redox state [ 14], and the findings of the present study indicate that DS is effective in reducing NSP4 expression and can thus protect epithelial cells from oxidative stress. We computed the Area Under Curve (AUC) to assess the evolution of an MGS (or higher taxonomic rank) between an initial point \({T}_{initial}\) and a final point \({T}_{final}\), a methodology that has already been used in other studies [ 44, 45]. For each point \(T\) between \({T}_{initial}\) and \({T}_{final}\), each individual \(I\) and each MGS \(M\) we computed the log10 fold change between the abundance of \(M\) at \(T\) and its abundance at \({T}_{initial}\) (D-30 when considering points before the treatment; D-1 when considering points during the treatment). Then we computed the AUC of \(M\) based on the log10 fold change: if the abundance of \(M\) is minimal at \({T}_{initial}\), \(M\) increases and the AUC will be positive; if the abundance of \(M\) is maximal at \({T}_{initial}\), \(M\) decreased and the AUC will be negative. If \(M\) is stable along all considered time points, the AUC will be equal to 0. Diosmectite binds several bacterial and viral toxins [ 6, 7], and this has been postulated to contribute to its antidiarrhoeal effect. Clark et al. [ 8] observed that different clays absorb a bovine RV strain, but the infectivity was actually increased. The authors speculate that this unexpected phenomenon is the result of the more efficient presentation of virus by clays, supporting virus carriage into the cell by the clay, but no studies have been conducted to support this hypothesis. The increased infectivity was observed in kidney epithelial cells, but no information is available regarding the intestinal epithelium. Among the 35 participants, five were missing one or several samples (maximum missing samples: 3 at D-14), leading to a total of 170 samples available for the analysis. DNA extraction and sequencing

Gene richness was computed as the sum of genes whose abundance was strictly positive after downsizing. There were 595,000 ± 131,000 genes in each sample (mean ± sd). Similarly, MGS richness was computed as the sum of the MGS present in one sample. There were 215 ± 49 MGS in each sample. Detailed information about gene and MGS richness in each individual at each time point is available in the Additional file 2 (Supplementary Table 3–4). Statistical analysis The clinical trial was a prospective, open label, non-comparative, multi-center, international study with chronic treatment of diosmectite (Smecta®, 3g) TID over 5weeks, whose first purpose was to assess the level of elemental impurities (e.g. lead, arsenic, cadmium) in blood and urine samples after chronic administration of diosmectite. The aim of this ancillary study was to assess the bowel microbiota composition, stools consistency and frequency after chronic administration of diosmectite in subjects with chronic functional diarrhea. Rateau JG, Morgant G, Droy-Priot MT, Parier JL. A histological, enzymatic and water-electrolyte study of the action of smectite, a mucoprotective clay, on experimental infectious diarrhoea in the rabbit. Curr Med Res Opin. 1982;8:233–41.Dupont C, Foo JLK, Garnier P, Moore N, Mathiex-Fortunet H, Salazar-Lindo E. Oral diosmectite reduces stool output and diarrhea duration in children with acute watery diarrhea. Clin Gastroenterol Hepatol. 2009;7:456–62. We further looked for diosmectite impact at the species level. Considering the 450 MGS that were present in more than 10% of samples, the AUC analysis showed that 18 MGS had a different evolution before and after treatment ( p ≤ 0.05, Wilcoxon signed-rank test). Among them, only 4 and 5 MGS had a significantly different abundance in at least one of the three time points before treatment or during treatment, respectively (p ≤ 0.05, Friedman test). The five MGS whose abundance changed during the treatment had low prevalence at D-1 (32% ± 0.1, see Additional file 1, Supplementary Fig. 2) and accounted for only 0.3% ± 0.5 of the total microbiota. Moreover, we found the same number of MGS ( n = 35) whose abundance changed significantly before the treatment (at D-30, D-14 or D-1, Friedman test, p ≤ 0.05), or during the treatment (at D-1, D8, D35, Friedman test, p ≤ 0.05), suggesting even more random variations instead of an effect of the treatment. Additionally, after correction for multiple testing only one MGS was significantly altered before the treatment, and none during the treatment. Szajewska H, Dziechciarz P, Mrukowicz J. Meta-analysis: Smectite in the treatment of acute infectious diarrhoea in children. Aliment Pharmacol Ther England. 2006;23:217–27. Chang F-Y, Lu C-L, Chen C-Y, Luo J-C. Efficacy of dioctahedral smectite in treating patients of diarrhea-predominant irritable bowel syndrome. J Gastroenterol Hepatol Australia. 2007;22:2266–72. Dupont C, Foo JLK, Garnier P, Moore N, Mathiex-Fortunet H, Salazar-Lindo E. Oral diosmectite reduces stool output and diarrhea duration in children with acute watery diarrhea. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2009;7:456–62 United States.

Diosmectite reduced the expression of NSP4 and oxidative stress, resulting in a strong inhibition of chloride secretion. Preincubating RV with DS reduced the cytotoxic effect. Finally, the viral load was reduced by DS but not by control clay. This result suggests that DS specifically affects the early events of RV infection protecting the enterocyte, whereas it does not restore already-established cell damage. Conclusion

Considering its importance in the microbiota composition, another limit of the study is the absence of data related to diet apart from the exclusion criteria (artificial feeding or subjects eating shellfish more than two times a week, see Methods).

Reactive oxygen species production was measured using DCFH-DA spectrofluorometry. After stimulation, DCFH-DA (20 µM) was added for 30 min at 37 °C in the dark. Intracellular ROS production was measured in a fluorometer (SFM 25; Kontron Instruments, Japan). For DCF fluorescence imaging, Caco-2 cells were grown on the cover glass for 3 days, fixed and permeabilized with paraformaldehyde 4% and Triton 0.2% for 30 min at 4 °C. Cells were then incubated with DCF-HA 20 µM for 30 min at 37 °C in the dark. Fluorescence images from multiple fields were obtained using a Nikon Eclipse e 80i microscopy. The images were analysed using the NiS Elements D imaging software (Nikon Instruments, Inc., NY, USA). Glutathione assay After a screening period of up to 6weeks including a baseline assessment, each subject was dosed with diosmectite TID over 5weeks (Day 1 to Day 35). Feces samples were collected at screening phase (D-30, D-14), at baseline visit (D-1), and over the treatment period (D8, D35). Collection was performed using a kit provided by INRAE using a stabilizing solution (RNAlater®; ThermoFisher Scientific, Waltham, US) (SOP05_V2 from the International Human Microbiome Standards, IHMS) [ 31] allowing samples to be preserved within 24h to 7days at room temperature before to be handled by laboratory. Szajewska H, Dziechciarz P, Mrukowicz J. Meta-analysis: Smectite in the treatment of acute infectious diarrhoea in children. Aliment Pharmacol Ther. 2006;23:217–27. Rateau et al. [ 20] described the anti-diarrhoeal effects of DS related to increased chloride and magnesium absorption in the rabbit ileal mucosa infected with enterotoxigenic E. coli. These effects were postulated to be due to the inhibition of mucolysis or to the attenuation of damage to the luminal surface of the intestinal mucosa. In addition, DS reduced interleukin-1β (IL-1β) secretion and decreased neutrophil infiltration and monocyte activation, which both contributed to a reduction of the antigenic load in hapten-induced colitis in the rat [ 4]. Since IL-1β induces chloride secretion [ 21], it is possible that this anti-inflammatory effect contributes to the antidiarrhoeal mechanism of DS. However, such a mechanism cannot explain the effects observed with RV diarrhoea, which is not associated with intestinal inflammation.

At lower taxonomic ranks, three families (Streptococcaceae, Eggerthellaceae, and Bifidobacteriaceae) and four genera ( Bifidocbacterium, Parasutterella, Streptococcus, and Turicibacter) evolved differently before and during treatment ( p≤0.05). Friedman tests revealed that the three families and Bifidobacterium changed before treatment (p≤0.05) whereas none of these taxa presented a significant evolution during treatment ( p≥0.1). Mahraoui L, Heyman M, Plique O, Droy-Lefaix MT, Desjeux JF. Apical effect of diosmectite on damage to the intestinal barrier induced by basal tumour necrosis factor-alpha. Gut. 1997;40:339–43. This was a multicentre, placebo-controlled, double-blind, randomized study with parallel groups conducted in 23 centres in Tunisia. Tunisia was chosen for its good medical practice and compliant organization and its prevalence of acute infectious diarrhoea comparable to that of industrialized countries [ 4, 23]. With regards to the primary endpoint, statistical analysis was based on Wilcoxon's test in the intention-to-treat (ITT) population. The ITT population included randomized patients having taken the study drug at least once together with a primary endpoint that was assessable. Per-protocol (PP) population included ITT patients without major protocol deviations as defined after a blind review. PP analyses were supportive only. To assess robustness of the results, it was decided to perform post hoc analyses of primary efficacy data in ITT and PP populations using the “time to event” Gehan-Wilcoxon test, which takes into account censored data and their specific distributions with early events and late censures. Secondary efficacy analyses were conducted in the ITT population.