Mais les résultats doivent être attendus longtemps et il n'y a généralement pas de temps azithromycine prix L'autre cas, c'est que l'achat d'un ou d'un autre antibiotique dans une pharmacie classique nécessite des dépenses matérielles considérables et pas toutes les personnes ne peuvent acheter des produits pharmaceutiques aussi coûteux.

Apt_3145 1461.1468

Alimentary Pharmacology & Therapeutics Lactobacillus reuteri therapy to reduce side-effects duringanti-Helicobacter pylori treatment in children: a randomizedplacebo controlled trial E . L I O N E T T I * , V . L . M I N I E L L O * , S . P . C A S T E L L A N E T A   , A . M . M A G I S T A´ * , A . D E C A N I O * , G . M A U R O G I O V A N N I à , E . I E R A R D I § , L . C A V A L L O * , – & R . F R A N C A V I L L A * , – Helicobacter pylori eradication fails in about 25–30% of children, particularly because of the occurrence of resistance to antibiotics and To determine whether adding the Lactobacillus reuteri to an anti-H. pylori regimen could help to prevent or minimize the gastrointestinal ‘B. Trambusti’, Piazza Giulio Cesare, Forty H. pylori-positive children (21 males; median age: 12.3 years) wereconsecutively treated with 10-day sequential therapy [omeprazole + amoxycillin for 5 days, and omeprazole + clarithromycin + tinidazole for other 5 days] and blindly randomized to receive either L. reuteri ATCC 55730 (108 CFU) or placebo. All children completed the Gastroin- testinal Symptom Rating Scale (GSRS) at entry, during and after treat- ment. H. pylori status was assessed after 8 weeks by 13C-urea breath test.
ResultsOverall, in all probiotic supplemented children when compared withthose receiving placebo there was a significant reduction of GSRS scoreduring eradication therapy (4.1 Æ 2 vs. 6.2 Æ 3; P < 0.01) and at theend of follow-up (3.2 Æ 2 vs. 5.8 Æ 3.4; P < 0.009). Overall, childrenreceiving L. reuteri report less symptoms than those receiving placebo.
ConclusionL. reuteri is capable of reducing frequency and intensity of antibiotic-associated side-effects during eradication therapy for H. pylori.
Journal compilation ª 2006 Blackwell Publishing Ltddoi:10.1111/j.1365-2036.2006.03145.x According to the North American Society for Paediat- ric Gastroenterology, Hepatology and Nutrition guide-lines,1 one-week triple therapy represents the current The study enrolled only patients at the first diagnosis most widely used first-line regimen for Helicobacter of H. pylori infection. A total of 42 consecutive symp- pylori infection, but the eradication failure rate is tomatic children [23 males (54.8%), median age more than 30%.2 Today, bacterial resistance and side- 12.3 years (range: 3.3–18 years)] were candidates for effect occurrence represent the second most frequent inclusion in the study at the Department of Paediatric cause for anti-H. pylori treatment failure in clinical Gastroenterology of the University of Bari (Italy) practise.3 Indeed, the high prevalence of antibiotic between November 2004 and December 2005. Exclu- side-effects might induce even motivated dyspeptic sion criteria were one of the following: (i) consumption patients to discontinue therapy, with a consequent of PPI, H2 receptor antagonist, bismuth compounds, treatment failure as well as a possible development antibiotics, probiotics, in the previous 4 weeks, (ii) of antibiotic-resistant strains.4 These manifestations previous gastric surgery, (iii) known allergy to anti- have been related to the quantitative and qualitative biotics and (iv) acute or chronic gastrointestinal changes in the intestinal microflora because of unab- sorbed or secreted antibiotics in the intestinal contentwhich results in a reduction of normal saprophytic flora, bacterial overgrowth and the persistence ofpotentially pathogenic antibiotic resistant indigenous At baseline, patients underwent endoscopy with biop- sies for histology (two samples from the antrum and A strategy targeted to improve the treatment toler- two samples from the corpus), and a rapid urease test ability might increase compliance and eventually raise (one sample from the antrum) (CP test; Yamanouchi eradication rate. The use of probiotics has recently Pharma S.p.A., Carugate, Italy). Endoscopy was per- been proposed in adults to increase patient tolerability formed by the same physician (R.F.) (endoscope model by limiting side-effects of eradicating therapies;4, 6–9 GIF XP20; Olympus, Tokyo, Japan) after sedation with nonetheless, the report from the Maastricht 2000 con- sensus conference on H. pylori include probiotics as were carried out by the same observer using haema- possible useful ‘side tools’ for management of the toxylin–eosin staining for assessment of gastritis and Gram stain for detection of H. pylori. Within 24 h of Lactobacillus reuteri is a heterofermentative bacter- the endoscopy, patients completed a standard 13C-urea ium that resides in the gastrointestinal tract of humans breath test (13C-UBT) after overnight fasting. A fatty and animals11 and is considered to be one of the few meal (100 mL) and a solution of 13C urea [75 mg 13C true autochthonous Lactobacillus species in humans.12 urea (AB Analitica srl Padova, Italy)] were fed to each L. reuteri has been shown to exert a beneficial effect patient. Breath samples were collected before and in the prevention and treatment of several intestinal 30 min after the dose of urea. In children <6 years of age, breath samples were collected by using a face- The demonstration that L. reuteri colonizes the mask with a bag (made in house). The ratio of 13C to 12C in the expired air samples was measured using a data that L. reuteri ATCC 55730 is a potent inhibitor dual-inlet-ratio mass spectrometer (Automated Breath of H. pylori growth14 prompted our study in chil- 13Carbon Analyzer; Europa Scientific, Ltd, Crawley, West Sussex, UK). Results were expressed as parts per We investigated, for the first time in a paediatric million of excess of D13CO2 (by subtraction of the population, in a double-blind, randomized, placebo- baseline pretest breath sample). The presence of gastric controlled trial the effect of L. reuteri on antibiotic- urease activity was revealed by a change of 3.5 per associated side-effects during and after H. pylori thousand (or more) related to the baseline signal.15 13C-UBT, as described, had been validated in children ª 2006 The Authors, Aliment Pharmacol Ther 24, 1461–1468Journal compilation ª 2006 Blackwell Publishing Ltd L . R E U T E R I A N D A N T I B I O T I C - A S S O C I A T E D S Y M P T O M S D U R I N G H . P Y L O R I E R A D I C A T I O N of our geographic area by our group.16 In case of anti- All children received a 10-day sequential therapy biotic or antiacid medications, 13C-UBT was deferred comprising of omeprazole (1 mg/kg/die) plus amoxy- to at least 4 weeks. At entry, patients were considered cillin (50 mg/kg/die) for 5 days followed by omepraz- H. pylori positive if two of three tests (histology, rapid ole (1 mg/kg/die) plus clarithromycin (15 mg/kg/die) urease test, 13C-UBT) were positive.
and tinidazole (20 mg/kg/die) for the next 5 days;19omeprazole was prescribed before breakfast and din-ner, the antibiotics were administered after meals.
Patients were randomly assigned to receive either According to current guidelines,1 only symptomatic L. reuteri or placebo both provided by No´os (BioGaia, children deserve anti-H. pylori treatment; therefore, in Sweden) in pills form and included either L. reuteri infancy studying the emergence of anti-H. pylori-rela- (each pill containing 108 CFU of L. reuteri ATCC ted side-effect as performed in adults, is unfeasible 55730 (SD2112), Reuterin, No´os) or placebo which consisted of tablets identical in taste and appearance All children (or family member) attended an inter- to the active study product except for the absence of view to recall history of GI symptoms and the follow- freeze-dried L. reuteri (and cryoprotectants). Boxes ing data were collected: (i) a detailed physical containing placebo had the same shape, dimension, examination, (ii) the 15-item Gastrointestinal Symptom trade mark, indication and contained the same amount Rating Scale (GSRS) to assess severity and frequency of of sachets of boxes containing the viable L. reuteri symptoms17 and (iii) questions to assess other variables and were provided by the probiotic producer. Both that may have affected study results (i.e. intercurrent placebo and probiotics were prescribed one pill once infections, life events). The following symptoms were daily (2 h after lunch) for a period of 20 days.
specifically investigated: epigastric burning and/or An independent physician prescribed either probiotic pain, abdominal pain, acid regurgitation, heartburn, or placebo according to a computer generated rand- sucking sensation in the epigastrium, nausea, vomiting, omization list, blindly to researchers. The code was bloating, abdominal distension, eructation, increased revealed to the researchers once recruitment, data col- flatus, disorders of defecation [decreased/increased pas- lection and laboratory analyses and statistical analyses sage of stools, consistency of stools (loose/hard), urgency, feeling of incomplete evacuation], inappe- Patients were thoroughly instructed and motivated tence, halitosis, taste disturbance and urticaria.
for the therapy. Adherence to treatment was evaluated The symptoms were scored by the child (or family by counting the pills returned by the subject; a mini- member) on a four-point scale: mild (non-interfering mum pill intake of 95% was considered as acceptable.
with daily activities), moderate (slightly interfering Eight weeks after completion of therapy H. pylori with daily activities), severe (interfering with daily eradication was assessed by using a 13C-UBT. An activities), very severe (continuous and if on therapy, informed consent was obtained by all parents (or producing treatment interruption). Stool consistency guardian). The local Ethical Committee approved the was graded from hard (0) to watery (4). A similar scale has been used in paediatric populations with a 0.84inter-rater reliability in children.18 Data were collected before (1 week before intervention), during (5th and10th day) and after completion of eradicating therapy All data are expressed as median with a range. All (15th and 20th day) and patients were invited to return data analysis was carried out according to a pre-estab- their diaries immediately after the intervention period.
lished analysis plan. The sample size was calculatedstarting from the assumption of having at least oneantibiotic-associated side-effects in at least 80% of the treated children aiming to detect a difference in ameli- In the current study we tested the hypothesis that oration of symptom rate of 35%. Based on a 0.80 L. reuteri would reduce the rate of side-effects power to detect significant difference (P ¼ 0.05, two secondary to the use of antibiotics during H. pylori sided), 20 patients were required for each arm. Propor- tions were compared by using Chi-squared tests with continuity correction or Fisher’s exact test when ª 2006 The Authors, Aliment Pharmacol Ther 24, 1461–1468Journal compilation ª 2006 Blackwell Publishing Ltd appropriate; comparison of continuous variables was was good (>95%) in all enrolled cases, and no patient performed using Mann–Whitney test. The median discontinued therapy because of side-effects. There regression analysis was used to estimate difference were no differences in adherence to treatment sched- between adjusted medians with the baseline value as covariate. A probability (P)-value <0.05 was consid-ered significant. The statistical analysis was performed using the Software Program Stata System (SPSS) v13.0(Chicago, IL, USA) program.
No significant differences were observed between thegroups in the success of H. pylori eradication. Treat-ment was successful in 17 of 20 [85% (95%CI: 68–100)] patients in probiotic supplemented when compared with 16 of 20 patients in placebo group 12.3 years (range: 3.3–18 years)] were recruited while two were excluded (Figure 1). The baseline demogra-phic patients are reported in Table 1. As shown, patients inthe two groups did not differ for age, sex, clinical and Overall, in all probiotic supplemented children when duration of symptoms and baseline GSRS score, as compared with those receiving placebo there was a well as for the endoscopic features detected (Table 2).
significant reduction of GSRS score during eradication At histology, H. pylori was observed in the gastric ant- therapy [4.1 Æ 2 (95%CI: 2.9–5.9) vs. 6.2 Æ 3 (95%CI: rum of all patients. The presence of the bacterium was 5.2–8.3 P < 0.01] which became markedly evident at always associated with chronic gastritis (lymphocytes the end of follow-up [3.2 Æ 2 (95%CI: 2.4–4) vs.
and plasma cells in the lamina propria) with a variable 5.8 Æ 3.4 (95%CI: 4.8–6.9); P < 0.009] (Figure 2). In degree of activity; none had gastric atrophy or intesti- detail, when the frequencies of the symptoms were nal metaplasia (Table 2). In all children, all the three evaluated by taking into account only the occurrence of new or aggravated symptoms during and after theeradication week relative to the baseline, we foundthat children receiving L. reuteri refer less frequently epigastric pain during eradicating treatment (15% vs.
Forty patients completed the study. No children under- 45%; difference: )30%; P < 0.04) and abdominal dis- went protocol deviation. Compliance to the therapy tension (0% vs. 25%; difference: )25%; P < 0.02), One consumption of antibiotics in the previous 4 weeks; Figure 1. Flow diagram ofparticipants through each ª 2006 The Authors, Aliment Pharmacol Ther 24, 1461–1468Journal compilation ª 2006 Blackwell Publishing Ltd L . R E U T E R I A N D A N T I B I O T I C - A S S O C I A T E D S Y M P T O M S D U R I N G H . P Y L O R I E R A D I C A T I O N Table 1. Baseline demographic and clinical characteristics GSRS
Figure 2. Gastrointestinal Symptom Rating Scale (GSRS)in children receiving the Lactobacillus reuteri or placebobefore, during and after Helicobacter pylori eradication Table 2. Endoscopic and histological findings in the two therapy. Comparison of continuous variables was per- severity of the symptoms. Symptoms which were most positively influenced by L. reuteri were abdominal dis- tension, disorders of defecation, epigastric pain, eruc- The onset of side-effects during anti-H. pylori ther- apy is mainly due to the use of antibiotics in moderate to high-dose or in combination.6 Antibiotic-related side-effects are common and usually affect the gastro- intestinal system. The intestinal microbiota is charac- terized by a high bacterial concentration, up to 1014 CFU/mL in the colon; these bacteria and colonic mucosal cells coexist in a delicate equilibrium that can be easily altered by antibacterial drugs causing the emergence of potentially pathogen species over thesaprophytic flora. Unfortunately, the most frequentlyused antibiotics for H. pylori eradication (amoxycillin, eructation (5% vs. 35%; difference: )30%; P < 0.04), clarithromycin, metronidazole) are frequently accom- disorders of defecation (15% vs. 45%; difference: panied by gastrointestinal side-effects and clarithro- )30%; P < 0.04) and halitosis (5% vs. 35%; difference: )30%; P < 0.04) thereafter (Table 3). No adverse contractility of gastrointestinal smooth muscle, leading Probiotics are ‘living micro-organisms which upon ingestion in certain numbers favourably influence the health of the host by improving the indigenous In this randomized, placebo-controlled study, children microbiota’.21 Many studies have documented the on H. pylori eradication therapy receiving L. reuteri effectiveness of prophylactic probiotics taken with when compared with peers receiving placebo, reported antibiotics in preventing or lowering the antibiotic- a significant reduction of the total symptom score, related gastrointestinal side-effect burden.22–24 It is up which takes into account both the frequency and the to the experts in microbiology, nutritional sciences ª 2006 The Authors, Aliment Pharmacol Ther 24, 1461–1468Journal compilation ª 2006 Blackwell Publishing Ltd Table 3. Frequencies of side-effects reported by the two groups, before, during and after eradication therapy * Assessed before (history of urticaria acute or chronic), during (acute urticaria) and after therapy (in the following 20 days).
have shown that after its administration to healthy vol- requirements for probiotic bacterial strains: bile and unteers, it was possible to detect this strain adhering to acid resistance, adhesion to the mucosa and/or to epithelial cells from corpus and antral gastric biopsies enterocytes, at least temporary colonization of the providing the first clear and direct evidence of colon- human gut, ability to inhibit known gut pathogens ization of the human stomach by L. reuteri.14 and antimicrobial substances, stability and activity Our experience in children on eradication therapy during manufacture and storage, safety in human use showed that L. reuteri is effective in reducing the total and proven health-promoting effects.25 L. reuteri symptom score and the onset of bloating, disorders of shares most of these general characteristics.12, 26–29 defecation and halitosis similarly to adult data after Our choice to use L. reuteri ATCC 55730 derives from the administration of a single strain of Lactobacillus different observations. L. reuteri has been extensively GG (LGG)4 or Bacillus clausii6 or Saccharomyces bou- studied and is widely used as a food additive to lardii or a mixture of Lactobacillus acidophilus, and improve human gastrointestinal health.26 Oral adminis- Bifidobacterium lactis.7 However, what we have found tration delivers L. reuteri ATCC 55730 to the gastroin- more difficult to explain is the effect of L. reuteri on testinal tract, leading to the shedding of live bacteria in symptoms such as eructation and epigastric pain which are more likely related to H. pylori infection.
L. reuteri ATCC 55730 administration is safe both in This is not a novel finding since other authors have adults28, 29 and in children,30 significantly reduces the described a significant reduction of epigastric pain in incidence and the severity of diarrhoea of different ori- the probiotic treated arm during H. pylori eradica- gins and reduces gastrointestinal illness and infec- tion7, 33 although no explanation was advocated. It is tions.27, 31 Being acid resistant, they persist in the of interest a recent evidence that some L. reuteri stomach longer than other bacteria surviving in high strains were able to compete with H. pylori for the proportions (>80%) in the gastric environment for peri- binding to its receptor on gastric epithelial cells ods of 2 h.32 L. reuteri ATCC 55730 adhere to gastric (asialo-GM1 and sulfatide) suggesting that a binding epithelial cells in vitro32 and recently Vauler N, et al.
ª 2006 The Authors, Aliment Pharmacol Ther 24, 1461–1468Journal compilation ª 2006 Blackwell Publishing Ltd L . R E U T E R I A N D A N T I B I O T I C - A S S O C I A T E D S Y M P T O M S D U R I N G H . P Y L O R I E R A D I C A T I O N surface.34 Therefore, it is possible that the concomitant symptoms. Our data demonstrate that symptoms relief, use of a probiotic along with eradication therapy may although in the short term, is better achieved by the decrease more rapidly the bacterial load thus amelior- concomitant administration of L. reuteri together with ating symptoms such as epigastric pain. Indeed, we antibiotics; in our experience, the use of L. reuteri have demonstrated that L. reuteri ATCC 55730 is cap- does not improve the eradication rate, however, the able of decreasing the bacterial load when adminis- small sample size of our series does not allow to draw tered to untreated patients (R.F., personal unpublished firm conclusion, although in line with previous studies data) as shown for other probiotic strains.35 Moreover, in adults.6, 7, 33 Finally, similar to previous experien- it is documented that probiotics have an anti-inflam- ces,6, 7, 33 the overall compliance of patients was not matory effect that might contribute to reduce gastric increased by L. reuteri, however, the treatment tolerab- inflammation when given to H. pylori colonized ani- mals.36, 37 Despite the suitability of this hypothesis, In Italy a box of L. reuteri costs 11.00 euros for 10 caution should be used in attributing symptomatic pills that makes 1.1 euro for each treatment day, benefits to probiotic oral therapy until the mechanistic therefore, its use would increase the overall costs of bases of action of probiotics are fully understood.
approximately 20 euros. Moreover, we have to consi- A possible confounding factor in our study may be der that often, after an antibiotic treatment, sympto- that all enrolled children were symptomatic, reason for matic children receive a probiotic that it is usually which these children were tested and treated since in what the family have at home and rarely one with childhood there is no indication for either in the proved efficacy for a particular indication.
absence of symptoms.1 However, taking into account In conclusion, our study shows, for the first time in only the occurrence of new or aggravated symptoms the paediatric population, that probiotic supplementa- during and after the eradication therapy when com- tion, during and after a sequential treatment for pared with baseline we have demonstrated the superi- H. pylori eradication, may positively affect therapy- ority of L. reuteri when compared with placebo at related symptoms and overall treatment tolerance.
Dealing with children, we always have a double aim when we decide to eradicate the H. pylori, being theelimination of the bacterium and the resolution of No external funding was received for this study.
8 Gotteland M, Brunser O, Cruchet S. Sys- Sjostedt S, Edlund C. Comparative effects 1 Gold BD, Colletti RB, Abbott M, et al.
controlling gastric colonization by Heli- gastric and intestinal microflora in Heli- cobacter pylori-infected patients. J Anti- microb Chemother 1999; 44: 629–40.
Helicobacter pylori infection. Int J Anti- 6 Nista EC, Candelli M, Cremonini F, et al.
2 Oderda G, Marinello D, Lerro P, et al.
10 Malfertheiner P, Megraud F, O’Morain blind randomized multicentre trial. Heli- 3 Deltenre M, Ntounda R, Jonas C, et al.
et al. Effect of different probiotic prepa- 11 Mitsuoka T. The human gastrointestinal does it fail? Ital J Gastroenterol Hepatol rations on anti-Helicobacter pylori ther- 4 Megraud F. H. pylori antibiotic resist- 12 Reuter G. The Lactobacillus and Bifido- intestine: composition and succession.
ª 2006 The Authors, Aliment Pharmacol Ther 24, 1461–1468Journal compilation ª 2006 Blackwell Publishing Ltd 21 Lewis SJ, Freedman AR. Review article: 14 Valeur N, Engel P, Carbajal N, et al.
23 Cremonini F, Di Caro S, Nista EC et al.
32 Conway PL, Gorbach SL, Goldin BR.
et al. Carbon 13-labeled urea breath test nal cells. J Dairy Sci 1987; 70: 1–12.
24 Arvola T, Laiho K, Torkkeli S, et al. Pro- 16 Rutigliano V, Ierardi E, Francavilla R, ized study. Pediatrics 1999; 104: e64.
dyspepsia in childhood: clinical pattern, 25 de Vrese M, Schrezenmeir J. Probiotics and non-intestinal infectious conditions.
Br J Nutr 2002; 88 (Suppl. 1): 59–66.
34 Mukai T, Asasaka T, Sato E, et al. Inhi- 17 Svedlund J, Sjodin I, Dotevall G. GSRS: a clinical rating scale for gastrointesti- ease. Dig Dis Sci 1988; 33: 129–34.
25–29 Global access available at http:// inal pain in children. Pediatr Clin North 36 Michetti P, Dorta G, Wiesel PH, et al.
et al. Bacteriotherapy with Lactobacillus 19 Francavilla R, Lionetti E, Castellaneta reuteri in rotavirus gastroenteritis. Pedi- atr Infect Dis J 1997; 16: 1103–7.
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ª 2006 The Authors, Aliment Pharmacol Ther 24, 1461–1468Journal compilation ª 2006 Blackwell Publishing Ltd

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Epilim® - data sheet

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