Yomogi. Saccharomyces cerevisiae HANSEN CBS 5926 (S. boulardii)

Transcription

1 Yomogi Saccharomyces cerevisiae HANSEN CBS 5926 (S. boulardii)

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3 Table of Contents: I Saccharomyces cerevisiae HANSEN CBS 5926 (Medical Synonym: S. boulardii)...4 Discovery of the yeast Saccharomyces boulardii...4 Antimicrobial effect...4 Strengthening the barrier function of the intestinal epithelium...4 Antisecretory effect...4 Effect on intestinal epithelium and immune system...4 II Prophylaxis and Treatment of Diarrhea with Yomogi...5 Acute diarrhea...5 Antibiotic-associated diarrhea (AAD)...6 Co-medication of Helicobacter-pylori triple therapy regimens....7 Further examples of drug-associated diarrhea...8 Traveller s diarrhea...8 Diarrhea associated with irritable bowel syndrome...8 III Dosage and Recommendations for Use...9 Special features....9 Dosage....9 Practical tips...9 IV References...10 Information is current as of June

4 I Saccharomyces cerevisiae HANSEN CBS 5926 (Medical synonym: S. boulardii) The medical synonym for Saccharomyces cerevisiae HANSEN CBS 5926 is Saccharomyces boulardii or S. boulardii for short. We will use this synonym mostly in this brochure. Discovery of the yeast Saccharomyces boulardii This goes back to the French microbiologist Henri Boulard. In the twenties of the last century in Indochina, he observed that the local inhabitants used an infusion beverage obtained from tropical fruits (including lychees) for the treatment of diarrhea, and isolated the yeast from the skin of these fruits. The round-to oval-shaped cells of S. boulardii reproduce by budding. They are eukaryotes which grow both under aerobic and under anaerobic conditions. Antimicrobial actions The effect of S. boulardii in the intestine is based, amongst other things, on an antagonistic effect towards pathogenic bacteria and yeasts which are undesired in the intestines of human beings. Mycocins are made partially responsible for this effect, which are excreted from S. boulardii and have a growthinhibiting effect on these harmful microorganisms. Furthermore, S. boulardii binds pathogens such as Salmonella and certain Escherichia coli which carry fimbriae on their surface, reduces the adherence to the intestinal epithelium and eliminates them from the gut. Bacterial toxins, for example secreted by Clostridium difficile, are neutralised by proteolytic enzymes from S. boulardii. S. boulardii also protects against enteroinvasive pathogenic bacteria, such as Salmonella and Yersinia. Strengthening the barrier function of the intestinal epithelium S. boulardii has a protective effect on the damaged intestinal barrier caused by pathogenic microorganisms by increasing the transepithelial resistance of intestinal cells. 1 In addition, S. boulardii reduces the number of intracellular infective agents and prevents the breakdown of tight junction proteins. 2 The increased intestinal permeability observed in patients with Crohn's disease is lowered in the presence of S. boulardii. 3 Antisecretory effect S. boulardii has an antisecretory effect which normalises the water and electrolyte balance. The uptake of carbohydrates can be improved through the stimulation of disaccharidases. Effect on intestinal epithelia and immune system S. boulardii activates the gut-associated immune system; this is demonstrated by an increased level of protective secretory immunoglobulin A (slga). Summary of the effects of S. boulardii Inhibition of the growth of pathogenic microorganisms Inactivation of bacterial toxins (e. g. Clostridium difficile toxins) Fixation and elimination of pathogenic bacteria Strengthening the barrier function of the intestinal epithelium Protects the intestinal epithelium from invasion by pathogens Antisecretory effect Normalises the transcellular transport of chloride Reduces the loss of sodium and water Immunomodulatory effect Increases siga in the gut Activates the body s own defence system 4

5 Prophylaxis and Therapy of Diarrhea with Yomogi II Acute Diarrhea Acute diarrhea is often caused by bacterial or viral infections. 4 Besides an increased frequency in passing stools and a reduction in their consistency, the loss of water and electrolytes to differing extent may even lead to life-threatening dehydration. This often makes admission to the hospital and the parenteral substitution of fluids by infusion unavoidable. Children and the elderly are particularly vulnerable to dehydration. Oral rehydration therapy in acute diarrhea is therefore fundamental with these patients. However, this symptomatic therapeutic intervention is hardly able to shorten the duration of diarrhea substantially. The treatment of infectious diarrhea in infants using motility-inhibiting preparations (such as loperamide) or secretion inhibitors (e. g. racecadotril) is not recommended, because they suppress intestinal motility, and as a result, delay the excretion of the pathogen responsible for the infection. Thus, damage of the gut mucosa may increase. Treatment of acute diarrhea On the other hand, the value of the active ingredient S. boulardii has been shown time and again in the symptomatic treatment and prevention of acute diarrhea. The efficacy and safety of this probiotic substance has been proven in many clinical studies. Htwe et al. 5 demonstrated in a controlled clinical study that a 5-day treatment period with S. boulardii in addition to administering electrolyte solution to hospitalised children (N = 100; aged between 3 months and 10 years) with acute watery diarrhea significantly reduced the mean duration of diarrhea by 1.5 days (S. boulardii group: 3.08 days, control group: 4.68 days, p < 0.05). Already on day 2, there was a significant reduction in the daily frequency of passing stools in the children in the S. boulardii group, compared to the control group. Stool consistency improved one day later. A study from Höchter et al. 6 confirmed the efficacy of S. boulardii in acute diarrhea in adults. Efficacy of S. boulardii in adults with acute diarrhea 6 Mean frequency of stools/d Meta-analyses confirm the therapeutic efficacy of S. boulardii The meta-analysis of Szajewska et al. 7 comes to a similar result. They evaluated, amongst other things, the data of 944 patients from 7 clinical studies. The main conclusion was that S. boulardii reduced the mean duration of acute diarrhea in children by approximately 1 day compared to placebo. The clinical response to S. boulardii in acute diarrhea in children is currently very much in the news as the meta-analysis of Feizizadeh et al. 8 shows. Here the data from 17 studies with a total of 2102 patients aged between 1 month and 15 years were evaluated. In comparison to controls, S. boulardii significantly reduced the mean duration of diarrhea by about 20 hours Another result of this meta-analysis was that S. boulardii lowered the risk of diarrhea on day 3 by 59 % (relative risk, 0.41; 95 % CI, ) and on day 4 (relative risk, 0.38; 95 % CI, ) by as much as 62 percent Placebo Adults S. boulardii 1.3 Day 5

6 Prophylaxis and Therapy of Diarrhea with Yomogi In its current guideline, the European Society for Paediatrics (ESPGHAN) recommends S. boulardii for the treatment of acute gastro-enteritis in children. 9 As the yeast S. boulardii is insensitive to antibiotics, the prophylactic effect of S. boulardii should be used therapeutically in particular in order to minimise the risk of antibiotic-induced diarrhea. Antibiotic-associated diarrhea (AAD) One of the most common adverse effects of antibiotics is the development of antibiotic-associated diarrhea (AAD). This occurs during antibiotic treatment, and even some weeks afterwards, in up to 25 % of outpatients as well as in up to 60 % of inpatients. For older, immunosuppressed and intensive care patients and/or for those requiring an extended hospital stay, the risk of AAD increases accordingly. 10 The cause of AAD is usually a toxic effect of the antibiotic on the intestinal mucous membrane, as well as an imbalance of the normal gut microbiota. 11 By damaging the intestinal microbiota it is possible that pathogens colonize more easily and thus overgrow the intestine. At the same time, the repeated use of antibiotics promotes the spread of pathogens with increased resistance to therapy with the applied antibiotic. The clinical picture of AAD ranges from simple diarrhea to life-threatening pseudomembranous colitis, associated with an overgrowth of Clostridium difficile in the large bowel. Different antibiotics have a different risk of triggering AAD. There is an increased risk for cephalosporins of the 3 rd generation, broad spectrum penicillins, clindamycin and clarithromycin in higher doses. The therapeutic efficacy of S. boulardii in AAD has been confirmed in clinical trials and meta-analyses. S. boulardii reduces the frequency, the duration and severity of diarrhea associated with antibiotics. S. boulardii prevents and/or reduces the occurrence of AAD in children and adults In the meta-analysis by Szajewska et al. 12, the data of 1076 patients (269 children) with acute diarrhea from 5 clinical, randomised, placebo-controlled studies were evaluated. Accordingly, the risk of AAD could be lowered by using S. boulardii compared to the controls from 17.2 % to 6.7 %. Co-medication with S. boulardii with an antibiotic prevented the risk of an AAD by 61 % ; 13 S. boulardii halves the risk of antibiotic-associated diarrhea AAD (%) without S. boulardii 61 % Risk of AAD with and without S. boulardii treatment The very good data on the efficacy of S. boulardii in the prevention of AAD is also reflected by the positive results of the meta-analysis of McFarland 14. Included in the evaluation were 10 randomised, controlled clinical trials with a total of 1858 patients. 8 studies substantiated a significant anti-diarrheal efficacy of S. boulardii in adults with AAD. The joint analysis of all 10 studies showed a reduction in the risk of diarrhea under S. boulardii by more than a half (54 %) (risk of diarrhea: S. boulardii: 8.4 %; controls: 18.4 % ). 6.7 with S. boulardii 6

7 S. boulardii reduces the occurrence of AAD in hospitalised patients In a prospective study, 151 hospitalised adults received S. boulardii in addition to an antibiotic. Only 1.4 % of patients in the S. boulardii group developed of diarrhea, in contrast to 9 % in the placebo group. This difference was statistically significant. 15 S. boulardii reduces the risk of diarrhea in antibiotic therapy. This improves patient compliance and reduces the risk of antibiotic resistance and increases the success of treatment because of fewer treatment discontinuations showed the improvement of eradication rate of Helicobacter as well as a reduction of therapy-associated side- effects, in particular diarrhea. Significantly fewer cases of diarrhea under triple therapy with co-medication using S. boulardii 16 Diarrhea ( %) without S. boulardii 54 % * statistically significant p < * with S. boulardii Co-medication of Helicobacter-pylori triple S. boulardii significantly improves the therapy regimens tolerability of triple therapy In the context of a meta-analysis (5 studies, n = 1307 A significant improvement in the tolerability of triple patients) the data of 1215 patients from 4 studies therapy using adjuvant administration of S. boulardii were evaluated, who received eradication therapy was substantiated by a study from Zojaji et al. 18 (Group due to Helicobacter pylori infection (proton pump inhibitor, clarithromycin or amoxicillin/clarithromycin). clarithromycin (500 mg, b.i.d.), omeprazole (20 mg, A (n = 80) and B (n = 80): amoxicillin (1000 mg, b.i.d.), By the adjuvant administration of S. boulardii in the b.i.d.) for 14 days; co-medication Group A: Yomogi triple therapy regimen, the risk of treatment-related (250 mg, b.i.d.)). diarrhea was lowered from 12.2 % to 5.6 %. A further result of this meta-analysis was that in comparison to controls the eradication rate of Helicobacter by the additional application of S. boulardii was increased (S. boulardii: 80 %; controls: 71 %). For this purpose, 4 studies were evaluated with the data from 915 patients (n = 460 treated with S. boulardii, n = 455 treated with placebo). 16 The therapeutic benefit of adjuvant administration of S. boulardii in patients under classical triple therapy regimen was confirmed in a further clinical trial by Kyriakos et al. 17. This clinical study also Significantly fewer cases with side-effects during triple therapy with co-medication using Yomogi 18 * statistically significant p < 0.05 withouh Yomogi with Yomogi [%] Side-effect frequency in the second week % % % * 22.5 * 52.5 % * * Nausea Diarrhea Abdominal pain Bloating 7

8 Prophylaxis and Therapy of Diarrhea with Yomogi Further drug-associated diarrhea Other medicines can also cause gastrointestinal distress with diarrhea. These include cytostatic drugs (such as methotrexate, cisplatin, 5-fluorouracil) or even high-dosed mineral supplements (such as magnesium) and proton pump inhibitors. Traveller s diarrhea In areas with poor hygiene, foreign travellers are exposed to a higher risk of infection. The most common pathogens which are responsible for enteritis include the enteropathogens E. coli and Salmonella. They exert their diarrhea-causing effect by the secretion of toxins which attack the intestinal wall directly. The main source of infection with pathogens which cause enteritis are the bacterial contamination of water and food. For this reason, hygienic measures are therefore at the top of the list when it comes to preventing traveller s diarrhea, such as the advice to eat only peeled or cooked food and to drink only boiled water ( peel it, cook it or leave it. ). But even following this advice is usually not sufficient. The efficacy of S. boulardii in the prevention of traveller's diarrhea has been substantiated in clinical trials. 19 The efficacy of S. boulardii is based, for example, on the fact that the medicinal yeast inactivates toxins from pathogens which cause diarrhea. Prophylaxis with S. boulardii reduces the risk of traveller s diarrhea 19 Placebo S. boulardii 500 mg/day *statistically significant p < Furthermore, S. boulardii can bind the infectious agent on its surface and thus eliminate it by natural means. Diarrhea associated with irritable bowel syndrome Chronic diarrhea is a major symptom in irritable bowel syndrome. This is often accompanied by abdominal pain, bloating and thus also by a limitation in the quality of life. A new double-blind study from 2014 shows: The active substance in Yomogi, S. boulardii, is also significantly effective in the treatment of diarrhea in irritable bowel syndrome. 20 In this clinical trial with a total of 60 patients, 30 patients received Yomogi over 3 weeks, the other 30 patients received placebo. In addition to the reduction of diarrhea, Yomogi also reduced abdominal pain and bloating in this study. The patients reported that in this way their quality of life had significantly improved. Significant efficacy of the study medication Yomogi in diarrhea associated with irritable bowel syndrome after 3-weeks of treatment 20 Diarrhea (mean Abdominal-Symptom -Score) 2 18 % p = before therapy 3 weeks 3 weeks after therapy Placebo before therapy S. boulardii 250 mg/day after therapy Frequency of diarrhea ( %) % 59 % 40 % * * * North Africa West Africa Middle East 8

9 Dosage and recommendations for use III After taking Yomogi, high counts of non- pathogenic viable yeast cells (S. boulardii) reach the intestine. S. boulardii does not colonise the intestinal tract. For this reason, S. boulardii is no longer detectable in the stools 4 to 6 days after the medication has been discontinued. Special Features The yeast cells in Yomogi are freeze-dried (lyophilisation). This ensures fast revitalisation of the yeast cells as well as a long shelf-life at normal room temperatures. No cooling required Practical tips In order to ensure the full benefit with Yomogi, continue treatment for a few days after the diarrhea has ceased. If microbiological stool examinations are carried out during therapy with Yomogi, this should be communicated to the responsible laboratory to avoid false-positive results. Do not take Yomogi with antimycotics. Yomogi can be combined with antibiotics and is therefore ideal for the treatment of diarrhea associated with antibiotics. Fast revitalisation of the yeast cells, in this way a rapid effect is achieved Furthermore, Yomogi capsules are individually blistered, which is particularly practical and hygienic for taking en route Dosage One Yomogi capsule contains 250 mg dried yeast, corresponding to 2.5 x 10 9 viable non-pathogenic yeast cells of the strain Saccharomyces cerevisiae HANSEN CBS Yomogi is generally dosed as follows: Diarrhea: Take 1 hard gelatine capsule Yomogi 1 2 times daily with a sufficient amount of liquid before meals. For the prophylaxis of traveller s diarrhea: Take 1 hard gelatine capsule Yomogi 1 2 times daily for 5 days prior to departure. NOTE: Children under 6 years Children under 6 years of age should take the hard gelatine capsule Yomogi as follows: open up the two halves of the capsule and stir the contents into food or a liquid (room temperature). Pack sizes 10 Capsules 20 Capsules 50 Capsules 100 Capsules In Germany: Reimbursable only for treating diarrhea in infants and children up to 12 years of age in addition to rehydratation of the patient (Federal Gazette No 133 (p. 3015) dated 03/09/2010) 9

10 IV References 1) Dahan S, Dalmasso G, Imbert V, Peyron JF, Rampal P, Czerucka D. Saccharomyces boulardii interferes with enterohemorrhagic Escherichia coli-induced signaling pathways in T84 cells. Infect Immun. 2003;71(2): ) Czerucka D, Dahan S, Mograbi B, Rossi B, Rampal P. Saccharomyces boulardii Preserves the Barrier Function and Modulates the Signal Transduction Pathway Induced in Enteropathogenic Escherichia coli-infected T84 Cells. Kaufmann SHE, ed. Infection and Immunity. 2000;68(10): ) Garcia Vilela E, De Lourdes De Abreu Ferrari M, Oswaldo Da Gama Torres H, Guerra Pinto A, Carolina Carneiro Aguirre A, Paiva Martins F, Marcos Andrade Goulart E, Sales Da Cunha A. Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn s disease in remission. Scand J Gastroenterol. 2008;43(7): ) Guarino A, Albano F, Ashkenazi S, Gendrel D, Hoekstra JH, Shamir R, Szajewska H. European Society for Paediatric Gastroenterology, Hepatology and Nutrition/ European Society for Paediatric Infectious Diseases: Evidence-based Guidelines for the Management of acute Gastroenteritis in Children in Europe. J Pediatr Gastroenterol Nutr. 2008;46 (Suppl. 2): S81 S122. 5) Htwe K, Yee KS, Tin M, Vandenplas Y. Effect of Saccharomyces boulardii in the treatment of acute watery diarrhea in Myanmar children: a randomized controlled study. Am J Trop Med Hyg. 2008;78(2): ) Höchter W, Chase D, Hagenhoff G. Saccharomyces boulardii bei akuter Erwachsenendiarrhö. Wirksamkeit und Verträglichkeit der Behandlung. Münch Med Wschr. 1990;132: ) Szajewska, H. Skorka, A. Saccharomyces boulardii for treating acute gastroenteritis in children: updated meta-analysis of randomized controlled trials. Aliment Pharmacol Ther. 2009;30(9): ) Feizizadeh S, Salehi-Abargouei A, Akbari V. Efficacy and safety of Saccharomyces boulardii for acute diarrhea. Pediatrics. 2014;134(1): e ) Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir R, Szajewska H. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidencebased guidelines for the management of acute gastroenteritis in children in Europe: update J Pediatr Gastroenterol Nutr. 2014;59(1): ) McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006; 101(4): ) Fuhr R, Stahlmann R. Gastrointestinale Nebenwirkungen von Antibiotika. Der Gastroenterologe. 2006;1: ) Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea. Aliment Pharmacol Ther. 2005;22(5): ) Micklefield G. Saccharomyces boulardii in the treatment and prevention of antibiotic-associated diarrhea [Saccharomyces boulardii bei Antibiotika-assoziierter Diarrhö]. MMW Fortschr Med. 2014;156(1): ) McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol. 2010;16(18): ) Can M, Beşirbellioglu BA, Avci IY, Beker CM, Pahsa A. Prophylactic Saccharomyces boulardii in the prevention of antibiotic associated diarrhea: a prospective study. Med Sci Monit. 2006;12(4):PI ) Szajewska H, Horvath A, Piwowarczyk A. Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment. Aliment Pharmacol Ther. 2010;32(9): ) Kyriakos N, Papamichael K, Roussos A. Theodoropoulos I, Karakoidas C, Smyrnidis A, Archavlis E, Lariou K, Mantzaris GJ. A Lyophilized Form of Saccharomyces Boulardii Enhances the Helicobacter pylori Eradication Rates of Omeprazole-Triple Therapy in Patients With Peptic Ulcer Disease or Functional Dyspepsia. Hospital Chronicles. 2013;8: ) Zojaji H, Ghobakhlou M, Rajabalinia H, Ataei E, Sherafat SJ, Moghimi-Dehkordi B and Bahreiny R. The efficacy and safety of adding the probiotic Saccharomyces boulardiito standard triple therapy for eradication of H.pylori: a randomized controlled trial. Gastroenterol Hepatol Bed Bench. 2013;6(Suppl 1):S99 S ) Kollaritsch HH, Tobüren D, Scheiner O, Wiedermann G. Prophylaxe der Reisediarrhoe. Ergebnisse einer doppelblinden, plazebokontrollierten Studie über die Wirksamkeit von Saccharomyces cerevisiae CBS Münch Med Wschr. 1988;130: ) Akhondi-Meybodi M, Rahimian M, Salmanroghani H, Amirbeigy M, Baghbanian M, Ghelmani SY. Study of the Effect of Probiotic Saccharomyces Boulardii on the Treatment of Irritable Bowel Syndrome. J Biol Today s World. 2014;3(7):

11 Yomogi Active Pharmaceutical Ingredient: Dried yeast of Saccharomyces cerevisiae HANSEN CBS 5926 (Medical synonym: S. boulardii) Qualitative and quantitative composition: 1 hard gelatine capsule contains: 250 mg of yeast from Saccharomyces cerevisiae HANSEN CBS 5926 (Medical synonym: Saccharomyces boulardii) corresponding to at least 2.5 x Excipients: lactose, magnesium stearate (Ph.Eur.), gelatine, purified water, sodium dodecyl sulphate, copper chlorophyll complex, titanium dioxide, iron oxide hydrate. Areas of application: Symptomatic treatment of acute diarrhea, prevention and symptomatic treatment of travel diarrhea as well as diarrhea from enteral feeding, an adjuvant in chronic forms of acne. Contraindications: Not to be used in cases of known hypersensitivity to yeast or to any of the other components of the preparation. This medicinal product should not be given to infants and toddlers under 2 years of age due to a lack of dosage studies. Note: Due to the risk of a generalised colonisation with Saccharomyces cerevisiae HANSEN CBS 5926 which so far is not estimable, patients with severely weakened immune systems (for example, HIV infections, organ transplantations, leukaemia, malignant tumours, radiation, chemotherapy, long term high dose cortisone treatment) and patients with an indwelling central venous catheter should not use this medication. Precaution: due to the widespread application of yeast in food, no evidence of a risk during pregnancy and lactation has arisen so far. Results of experimental studies are not available. For this reason, the drug should not be used in pregnancy and during breastfeeding. Side effects: may cause flatulence when taken. In some cases, intolerance reactions can occur in the form of itching, urticaria and Quincke's oedema, shortness of breath and local or generalized exanthema and anaphylactic shock. No information can be provided about the frequency of these possible side effects. Warning: Contains lactose. Do not store above 25 C. Status: 11/

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