Publications by authors named "Jean-Michel Cardot"

41 Publications

Electrochemical Skin Conductance and Quantitative Sensory Testing on Fibromyalgia.

Pain Pract 2020 04 24;20(4):348-356. Epub 2019 Dec 24.

Biostatistics Unit (DRCI), Clermont-Ferrand University Hospital, Clermont-Ferrand, France.

Background: An impairment of the peripheral nervous system has been suggested in fibromyalgia (FM). Noninvasive distal electrochemical skin conductance (ESC) has been studied little so far when combined with quantitative sensory testing (QST) in patients with FM.

Methods: This study (clinicaltrials.gov NCT03347669) included 50 female patients with FM and 50 matched healthy volunteers (HVs). ESC (measured in microsiemens [µS] with Sudoscan), as well as psychological, quality of life, sleep, and social characteristics, were assessed in both groups. In a subgroup of 24 patients with FM and 24 HVs, QST of cold and warm detection and pain thresholds and diffuse noxious inhibitory controls (DNICs) were explored. Statistical analysis was performed for a 2-sided type I error at 5%.

Results: Between patients with FM and HVs, ESC values differed (71.4 ± 11.2 µS vs. 74.4 ± 10.3 µS, respectively; P = 0.003), especially on the dominant hand (P = 0.03), where more patients with FM had ESC values < 66 µS than did HVs (P = 0.046). No difference was observed on feet. In patients with FM, all collected characteristics were impaired (P < 0.001), DNICs were less functional, detection thresholds occurred later, and pain thresholds occurred earlier. No correlation was observed between ESC and DNICs or with any parameter.

Conclusion: This study shows that the sudomotor function is significantly impaired in patients with FM, especially on the dominant hand. This occurs in parallel with adjustments of detection and pain thresholds in the context of deficient spinal pain modulation. ESC values combined with QST values are relevant in the context of patients with FM and need to be explored further in this nociception-autonomic system intertwining.
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http://dx.doi.org/10.1111/papr.12857DOI Listing
April 2020

Effect of procyanidin on dietary iron absorption in hereditary hemochromatosis and in dysmetabolic iron overload syndrome: A crossover double-blind randomized controlled trial.

Clin Nutr 2020 01 11;39(1):97-103. Epub 2019 Feb 11.

Internal Medicine Department, University Hospital Clermont-Ferrand, F-63003, France; Clermont-Auvergne University, CRNS, SIGMA Clermont, Institute Pascal, F-63000 Clermont-Ferrand, France.

Background & Aims: Type I hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) are the two most prevalent iron overload diseases. Although many food components, particularly polyphenols, reduce iron bioavailability, there is no clinically validated nutritional strategy to reduce food-iron absorption in patients with these diseases. We aimed to determine whether supplementation with 100 mg of procyanidins during a meal reduces dietary iron absorption in patients with HH or DIOS.

Methods: 20 HH and 20 DIOS patients were enrolled in a double-blind three-period crossover randomized study. Basal serum iron level was measured following an overnight fast. Each patient consumed a standardized test iron-rich meal containing 43 mg of iron with two capsules of placebo or procyanidin supplementation. Each period was separated by a 3-day wash-out period. The primary objective was a reduction of dietary iron absorption, assessed by a reduction of serum-iron area under the curve (AUC) corrected for baseline serum iron.

Results: All patients completed the study. The meal and the procyanidin supplements were well tolerated. In both HH and DIOS patients, the iron-rich meal induced a significant increase of serum iron compared with baseline at 120, 180, 240 min, from 8 to 9.1% (p = 0.002, 0.001 and 0.003, respectively) in DIOS and from 15.8 to 25.7% (p < 0.001) in HH. Iron absorption was 3.5-fold higher in HH than in DIOS (p < 0.001). Procyanidin supplementation did not significantly modify iron absorption in DIOS (AUC of added iron 332.87 ± 649.55 vs 312.61 ± 678.61 μmol.h/L, p = 0.916) or in HH (1168.62 ± 652.87 vs 1148.54 μmol.h/L ± 1290.05, p = 0.917).

Conclusions: An iron-rich test meal led to a marked increase in iron absorption in HH but a mild increase in DIOS. Procyanidin supplementation does not significantly reduce dietary iron absorption in either disease. CLINICAL TRIAL REGISTRY: clinicaltrials.gov (NCT03453918).
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http://dx.doi.org/10.1016/j.clnu.2019.02.012DOI Listing
January 2020

Time Scaling for In Vitro-In Vivo Correlation: the Inverse Release Function (IRF) Approach.

AAPS J 2018 08 29;20(6):95. Epub 2018 Aug 29.

Dynakin SL, PTB 801, 48160, Derio, Vizcaya, Spain.

In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world. Level A regression may be complicated due to differences in time scales as well as the lack of coincident times of similar release in vitro and in vivo leading to approximate time-to-time links and subsequent loss of information. Here, a novel method to establish Levy's plot and to provide time scaling for improved IVIVC predictive capacity is presented. The method is mathematically closed and is an inverse release function (IRF) characterizing the single (or more) phases of dissolution/absorption. It uses the complete set of information available from all time points both in vitro and in vivo. An extended-release formulation development situation is presented with three increasing release rate test products compared in a trial versus a reference product. First, the standard level A regression was made. Prediction errors for internal validation were higher than 10% for C. The IRF method was applied to obtain the in vitro times of percentage dissolved equivalent to percentage absorbed. The prediction errors from the IRF level A correlation were nearly negligible.
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http://dx.doi.org/10.1208/s12248-018-0250-5DOI Listing
August 2018

Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study.

Drug Des Devel Ther 2018 10;12:2485-2496. Epub 2018 Aug 10.

Pain Clinic, CHU Clermont-Ferrand, Clermont-Ferrand, France.

Introduction: Fibromyalgia is characterized by widespread and chronic pain, and its prevalence is increasing worldwide. Milnacipran, an antidepressant, is often prescribed for fibromyalgia with a possible beneficial effect on central pain modulation. The aim of this study was to evaluate if milnacipran could modify the status of conditioned pain modulation (CPM) in patients suffering from fibromyalgia.

Design And Setting: Randomized, double-blind controlled trial.

Subjects And Methods: Women with fibromyalgia received milnacipran 100 mg or placebo. The primary end point was the evolution of CPM with treatments after a 30-second painful stimulus. Secondary outcomes included the predictability of milnacipran efficacy from CPM performance, evolution of global pain, mechanical sensitivity, thermal pain threshold, mechanical allodynia, cognitive function, and tolerance.

Results: Fifty-four women with fibromyalgia (46.7±10.6 years) were included and randomized, and 24 patients were analyzed in each group. At inclusion, CPM was dysfunctional (CPM=-0.5±1.9), and global pain was 6.5±1.8. After treatment, there was a nonsignificant CPM difference between milnacipran and placebo (CPM=-0.46±1.22 vs -0.69±1.43, respectively, =0.55) and 18.8% vs 6.3% (=0.085) patients did reactivate CPM after milnacipran vs placebo. Initial CPM was not a predictor of milnacipran efficacy. Global pain, mechanical and thermal thresholds, allodynia, cognition, and tolerance were not significantly different between both groups.

Conclusion: Milnacipran did not display a significant analgesic effect after 1-month treatment, but the tendency of milnacipran to reactivate CPM in a number of patients must be explored with longer treatment duration in future studies and pleads for possible subtypes of fibromyalgia patients.
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http://dx.doi.org/10.2147/DDDT.S162810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089099PMC
December 2018

Comparative phase I randomized open-label pilot clinical trial of Gynophilus (Lcr regenerans) immediate release capsules versus slow release muco-adhesive tablets.

Eur J Clin Microbiol Infect Dis 2018 Oct 21;37(10):1869-1880. Epub 2018 Jul 21.

Research and Development Department, BIOSE, Aurillac, France.

Gynophilus (Lcr regenerans) is a live biotherapeutic product (LBP) that contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35, which is indicated to restore vaginal health. The aim of the study was to compare the safety, ease of use, and compliance of two formulations (immediate release: IR capsule and slow release: SR muco-adhesive tablets) as well as the colonization of Lcr35 in healthy women. This phase I study (Comprigel) is a parallel, randomized, 4-arm, and open-label clinical trial evaluating an IR daily capsule formulation vs. a SR tablet administered every 3, 4, or 5 days for 21 days. Self-collected vaginal swabs were used to quantify Lcr35 and characterize the composition and structure of the vaginal microbiota. Both LBPs were well-tolerated, and no severe adverse effects were reported. All groups had Lcr35 vaginal concentrations over 10 colony forming unit per milliliter of vaginal secretion on each day in the study. The new Gynophilus slow release tablets administered either every 3, 4, or 5 days provided vaginal concentrations that were not significantly different from those of classic Gynophilus (capsule) once-a-day regimen. The LBPs and the different regimens did not adversely influence the abundance of native Lactobacillus spp. and indeed tended to favor their growth and reduce colonization by non-Lactobacillus spp. This study illustrates that the SR muco-adhesive LBP tablet (Gynophilus SR) administered every 3 or 4 days as a safe, well-tolerated, and efficacious alternative to a more demanding IR daily capsule and could protect women's healthy vaginal microbiome by promoting endogenous Lactobacillus spp.
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http://dx.doi.org/10.1007/s10096-018-3321-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154122PMC
October 2018

An Advanced Formulation of a Magnesium Dietary Supplement Adapted for a Long-Term Use Supplementation Improves Magnesium Bioavailability: In Vitro and Clinical Comparative Studies.

Biol Trace Elem Res 2018 Nov 9;186(1):1-8. Epub 2018 Mar 9.

Pharmacologie Fondamentale et Clinique de la Douleur, Neuro-Dol, Université Clermont Auvergne, Inserm 1107, F-63000, Clermont-Ferrand, France.

While general recommendations are for 300-mg magnesium intake a day, an advanced low-dose formulation of magnesium chloride, ChronoMag®, was designed to provide 100 mg of magnesium element, thus decreasing the risk of gastrointestinal side effects and allowing long-term supplementation in health conditions related to low magnesium levels. The present study aimed to compare magnesium release profile and bioavailability between this patented low-dose continuous-release magnesium chloride tablet (100 mg magnesium element) and a reference tablet at the usually prescribed dose (300 mg magnesium element). Magnesium release profile was determined by dissolving the tablets in solutions simulating the gastrointestinal tract environment. A randomized double-blind crossover controlled trial of ChronoMag® versus reference tablet (3 × 100 mg magnesium element tablets) in 12 normo-magnesemic healthy volunteers was conducted to evaluate the bioavailability of the patented magnesium chloride tablets (two 50 mg magnesium tablets, once-a-day intake). While the reference tablet released 100% of its magnesium within 1 h of dissolution, release from the magnesium chloride formulation was continuous for 6 h. Cumulative urinary magnesium levels compared to those with the reference tablet were 76% (0-5 h), 89% (0-10 h), and 87% (0-24 h). Elimination after 24 h was fairly similar with both supplements. Our results suggest that the new magnesium chloride formulation, providing continuous low-dose magnesium release throughout the gastrointestinal tract, improves absorption and bioavailability. This formulation conforms to the physiological mechanism of magnesium absorption throughout the digestive tract, allowing high absorption, and may improve gastrointestinal tolerance in long-term use.
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http://dx.doi.org/10.1007/s12011-018-1277-2DOI Listing
November 2018

In vivo release of peptide-loaded PLGA microspheres assessed through deconvolution coupled with mechanistic approach.

Eur J Pharm Biopharm 2018 Apr 19;125:21-27. Epub 2017 Dec 19.

University of Auvergne, Department of Biopharmacy, EA 4678, 63001 Clermont-Ferrand, France.

In this study, a reevaluation of the in vivo release phases from long-release PLGA-based microspheres is presented, leading to a better characterization of the plasma concentrations/time profile. Microspheres were designed for intramuscular injection releasing a cyclic somatostatin analog over 70 days. Clinical study was performed in 64 healthy subjects receiving a subcutaneous dose of an immediate release solution as reference formulation and an intramuscular injection of microspheres as test formulation. The in vivo input curve was obtained by numerical deconvolution. Results showed that double Weibull function could not fit correctly the tri-phasic (burst, lag, and erosion) in vivo input profile typical for PLGA-based formulations, due to a change in the drug release trend in the terminal phase. Triple Weibull showed a significant improvement in the curve fitting, each term being assigned to one of the following phases: initial (burst/lag), erosion, and terminal phase of drug release. The existence of the additional terminal phase was confirmed by a mechanistic approach as well, which denoted that this phase was, most probably, a consequence of the release mechanism change from erosion to diffusion controlled. The same model demonstrated that the burst release was as well influenced by the polymer swelling, while currently existing theories state that the burst phase is mainly determined by the dissolution of immediately available drug substance and diffusion through surface related pores.
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http://dx.doi.org/10.1016/j.ejpb.2017.12.007DOI Listing
April 2018

Study of the influence of coating methods on lipid spheres manufactured on rotor fluidized bed process.

Pharm Dev Technol 2018 Jul 26;23(6):655-662. Epub 2017 Jul 26.

b Biopharmacy Department, Faculty of Pharmacy , Auvergne University , Clermont-Ferrand , France.

Different previous works have shown that various kinds of spheres can be manufactured by rotor granulation in a 'single-pot process' using a lipid base: hydrogenated castor oil. This single-pot technology is based on wet granulation where all components are placed in the powder form in the rotor bowl; then, they are continuously suspended in a fluidized air, with a tangentially sprayed liquid solution. This process allows the granulation and manufacturing of sphere during the same time. Previous experiments have studied the influence of the formulation and the manufacturing process parameters on spheres in terms of feasibility and dissolution properties. Both the spraying time and the weight of liquid sprayed were found to be the most relevant parameters that govern the final quality of the sphere. Now, in a second part of the work, a first comparison is made with two different fluid bed methods: the tangential rotor spray and the Wurster bottom spray for coating the lipid spheres previously manufactured with the rotor tangential spray. The external aspect of the coated spheres manufactured has been evaluated with an electronic microscopy analysis and a study of dissolution properties of the active ingredient has been done by USP in vitro dissolution tests.
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http://dx.doi.org/10.1080/10837450.2017.1356331DOI Listing
July 2018

Evaluation of different in vitro dissolution tests based on level A in vitro-in vivo correlations for fenofibrate self-emulsifying lipid-based formulations.

Eur J Pharm Biopharm 2017 Mar 16;112:18-29. Epub 2016 Nov 16.

Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, C.I.R.M., University of Liège, 4000 Liège, Belgium.

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http://dx.doi.org/10.1016/j.ejpb.2016.10.030DOI Listing
March 2017

Efficacy of a Standardized Extract of Prunus mume in Liver Protection and Redox Homeostasis: A Randomized, Double-Blind, Placebo-Controlled Study.

Phytother Res 2016 Jun 8;30(6):949-55. Epub 2016 Mar 8.

Stragen Pharma SA, Geneva, Switzerland.

The antioxidant, anti-inflammatory and hepatoprotective effects of Prunus mume (PM) have previously been demonstrated. This double-blind, placebo-controlled study was designed to evaluate the influence of two doses of a food supplement, made of 150 mg of a standardized PM extract on liver transaminases, lipid profile, glycemia, neopterin and reduced and oxidized thiols in plasma and erythrocytes, during a 3-month treatment period, in healthy subjects with transaminases levels between 20 and 40 UI/L. Forty-five subjects (56.0 ± 11.6 years) were enrolled. The results showed a beneficial and statistically significant effect versus placebo of PM extract on liver function, with a decrease versus baseline in alanine aminotransferase (47%), aspartate aminotransferase (7%), gamma-glutamyl transpeptidase (15%) and glycemia (11%). The lipid profile modification was also positive with an increase versus baseline in HDL cholesterol (13%), and a decrease in LDL/HDL ratio (12%) and triglycerides (8%). The antioxidant action of PM translated into a decrease in oxidized glutathione, reduced/oxidized cysteine-glycine, oxidized cysteine (intracellular pro-oxidant) and neopterin (inflammation biomarker), was associated with an increase in reduced glutathione. These results are in favor of the use of a standardized extract of P. mume for the support of liver health and prevention of common metabolic and inflammation-based diseases. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/ptr.5597DOI Listing
June 2016

BCS Biowaivers: Similarities and Differences Among EMA, FDA, and WHO Requirements.

AAPS J 2016 05 4;18(3):612-8. Epub 2016 Mar 4.

Auvergne University, Clermont-Ferrand, France.

The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has enjoyed wide use since 1995 as a mechanism for waiving in vivo bioavailability and bioequivalence studies. In 2000, the US-FDA was the first regulatory agency to publish guidance for industry describing how to meet criteria for requesting a waiver of in vivo bioavailability and bioequivalence studies for highly soluble, highly permeable (BCS Class I) drugs. Subsequently, the World Health Organization (WHO) and European Medicines Agency (EMA) published guidelines recommending how to obtain BCS biowaivers for BCS Class III drugs (high solubility, low permeability), in addition to Class I drugs. In 2015, the US-FDA became better harmonized with the EMA and WHO following publication of two guidances for industry outlining criteria for obtaining BCS biowaivers for both Class I and Class III drugs. A detailed review and comparison of the BCS Class I and Class III criteria currently recommended by the US-FDA, EMA, and WHO revealed good convergence of the three agencies with respect to BCS biowaiver criteria. The comparison also suggested that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators. It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach.
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http://dx.doi.org/10.1208/s12248-016-9877-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256598PMC
May 2016

A proprietary blend of quail egg for the attenuation of nasal provocation with a standardized allergenic challenge: a randomized, double-blind, placebo-controlled study.

Food Sci Nutr 2014 Nov 20;2(6):655-63. Epub 2014 Jul 20.

Stragen Pharma SA Geneva, Switzerland.

Occasional rhinitis symptoms caused by exposure to pollution or allergens is a growing concern. Based first on empirical observation of a lesser occurrence of allergies in quail farmers and then scientific works on ovomucoids properties, we developed a dietary supplement for the relief of such occasional rhinitis symptoms. The objective of the study was to determine whether one acute oral dose of the study product attenuates nasal provocation and other allergy-related symptoms after exposure to a standardized allergenic challenge as compared to placebo. Healthy subjects were recruited to participate in a randomized, double-blind, two-arm crossover, placebo-controlled, clinical trial. One acute dose of either the active study product (proprietary blend of quail egg) or placebo was given concomitantly to the standardized allergenic challenge. The primary endpoint was peak nasal inspiratory flow (PNIF) measurement and the secondary endpoints were subjects' perceived feelings of well-being based on Visual Analog Scale (VAS) scores for allergy-related symptoms, as well as immunoglobulin E count. Forty-three healthy subjects were enrolled and evaluable in a per protocol analysis. A gradual increase in PNIF from nadir up to Time 120 reflected the normal, gradual recovery from nasal obstruction induced by allergenic challenge for both the active and the placebo groups. At all postchallenge time points, the active group had higher PNIF values compared to the placebo group, indicating that the active product was associated with fewer symptoms and reduced intensity of these symptoms. The active product resulted also in statistically significant improvements of most of the subjects' perceived feelings of well-being based on VAS scores. No adverse events occurred during the study. In conclusion, the dietary supplement consisting of proprietary blend made of quail eggs provides fast and efficient relief of allergic rhinitis symptoms caused by the most common outdoor and indoor allergens, without adverse events.
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http://dx.doi.org/10.1002/fsn3.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256569PMC
November 2014

Use of domperidone as a galactagogue drug: a systematic review of the benefit-risk ratio.

J Hum Lact 2015 Feb 4;31(1):57-63. Epub 2014 Dec 4.

INSERM U1107, NEURO-DOL, Université d'Auvergne, Clermont-Ferrand, France CHU Clermont-Ferrand, Délégation à la Recherche Clinique et à l'Innovation, Clermont-Ferrand, France

Breastfeeding is the optimal method for feeding a newborn. However, some mothers may have difficulties lactating. Domperidone is widely used as a galactagogue but to the best of our knowledge has not been approved by any health authority. The objective of this review was to assess the benefit-risk ratio of domperidone for stimulating lactation. The benefit-risk ratio of domperidone as a galactagogue was assessed following a literature search of the PubMed database up to July 2013. Four studies were selected to assess domperidone efficacy and demonstrated an increased milk production. The limited data (60 mother-baby pairs) and the moderate methodological quality of 1 study remain insufficient to conclude on domperidone efficacy. Regarding the safety of domperidone, 7 studies were selected that exposed 113 infants to domperidone through breastfeeding. No adverse effects were observed in 85 infants, and no information was provided for the remaining 28. The limited data available remain in favor of a safe domperidone profile in infants and mothers. However, in large studies focused on gastrointestinal disorders, domperidone is responsible for drug-induced long QT syndrome and sudden cardiac death. The use of domperidone as a galactagogue is worrisome as drug-induced long QT syndrome occurred mostly in women. In these circumstances, an improvement of breastfeeding practices seems to be more effective and safer than the use of an off-label domperidone treatment.
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http://dx.doi.org/10.1177/0890334414561265DOI Listing
February 2015

Micelle dynamic simulation and physicochemical characterization of biorelevant media to reflect gastrointestinal environment in fasted and fed states.

Eur J Pharm Biopharm 2014 Oct 19;88(2):565-73. Epub 2014 Jun 19.

Clermont-Université, Université d'Auvergne, EA4678, Conception ingénierie et développement de l'aliment et du médicament, Clermont-Ferrand, France. Electronic address:

The characterization of biorelevant media simulating the upper part of the gastrointestinal tract in the fasted and fed states was investigated by classical determination of physicochemical parameters such as pH, osmolality, surface tension and results were compared to in vivo physiological data. Incorporation of fatty material, in order to better simulate the influence of high fat meal was also performed. Stability and characterization of this medium was studied and compared to classical FeSSIF. Micelle characterization and computer dynamic simulation were performed in order to understand the interaction between lecithin and taurocholate and possible interactions between mixed micelle and drugs. The addition of NaTc, lecithin, and/or fatty materials has no influence on pH and osmolality, whereas the presence of fatty material modifies the surface tension. Values of FaSSIF and FeSSIF are in accordance with in vivo parameters and the presence of micelles can simulate the gastrointestinal environment. Modelization of micelles by computer simulation led to a model of mixed micelles in which structures of NaTc interact either by their hydrophilic or hydrophobic phase to give a bilayer stable model in which the lecithin molecule can insert its long carbon chain. The micelle structure is stable and can enhance dissolution of hydrophobic molecules by hydrophobic interaction with the numerous hydrophobic spaces available in the multilayer hydrophilic/hydrophobic layer.
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http://dx.doi.org/10.1016/j.ejpb.2014.05.020DOI Listing
October 2014

Three-stage continuous culture system with a self-generated anaerobia to study the regionalized metabolism of the human gut microbiota.

J Microbiol Methods 2014 Jan 11;96:111-8. Epub 2013 Dec 11.

EA 4678 CIDAM, Clermont-Université, Université d'Auvergne, BP 10448, F-63000 Clermont-Ferrand, France. Electronic address:

The technical and ethical difficulties in studying the gut microbiota in vivo warrant the development and improvement of in vitro systems able to simulate and control the physicochemical factors of the gut biology. Moreover, the functional regionalization of this organ implies a model simulating these differences. Here we propose an improved and alternative three-stage continuous bioreactor called 3S-ECSIM (three-stage Environmental Control System for Intestinal Microbiota) to study the human large intestine. Its main feature compared with other in vitro systems is the anaerobic atmosphere originating directly from the microbiota metabolism, leading to different gas ratios of CO2 and H2 in each compartment. Analyses of the metabolic and microbiological profiles (LC-MS and a phylogenetic microarray) show different profiles together with a maintenance of this differentiation between the three compartments, simulating respectively a proximal, a transversal and a distal colon. Moreover, the last reactor presents a high similarity with the initial fecal sample, at the microbiological diversity level. Based on our results, this in-vitro process improvement is a valuable alternative tool to dynamically study the structure and metabolism of gut microbiota, and its response to nutrients, prebiotics, probiotics, drugs or xenobiotics.
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http://dx.doi.org/10.1016/j.mimet.2013.11.015DOI Listing
January 2014

Efficacy of mucoadhesive hydrogel microparticles of whey protein and alginate for oral insulin delivery.

Pharm Res 2013 Mar 24;30(3):721-34. Epub 2012 Oct 24.

Univ Clermont 1, UFR Pharmacie, ERT 18 Laboratoire de Biopharmacie, Clermont-Ferrand, 63001, France.

Purpose: To evaluate the efficacy of mucoadhesive insulin-loaded whey protein (WP) /alginate (ALG) microparticles (MP) for oral insulin administration.

Methods: Insulin-loaded microparticles (ins-MP) made of whey protein and alginate were prepared by a cold gelation technique and an adsorption method, without adjunction of organic solvent in order to develop a biocompatible vehicle for oral administration of insulin. In vitro characterization, evaluations of ins-MP in excised intestinal tissues and hypoglycaemic effects after intestinal administration in healthy rats were performed

Results: The release properties and swelling behaviors, investigated in different pH buffers, demonstrated a release based on diffusion mechanism following matrix swelling. Mucoadhesion studies in rabbits and insulin transport experiments with excised intestinal rat tissues revealed that encapsulation in microparticles with mucoadhesive properties promotes insulin absorption across duodenal membranes and bioactivity protection. In vivo experiments reinforced the interest of encapsulation in whey protein/alginate combination. Confocal microscopic observations associated with blood glucose levels bring to light duodenal absorption of insulin biologically active following in vivo administration.

Conclusions: Insulin-loaded WP/ALG MP with high quantities of drug entrapped, in vitro matrix swelling and protective effect as well as excellent mucohadesive properties was developped. Improvement of intestinal delivery of insulin and increased in bioavailability were recorded.
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http://dx.doi.org/10.1007/s11095-012-0913-3DOI Listing
March 2013

Development and in vitro characterization of insulin loaded whey protein and alginate microparticles.

Int J Pharm 2012 Dec 11;439(1-2):136-44. Epub 2012 Oct 11.

Université d'Auvergne, UFR Pharmacie, Equipe de Recherche Technologique Conception, Ingénierie et Développement de l'Aliment et du Médicament (ERT CIDAM), Clermont-Ferrand F-63001, France.

Insulin was encapsulated into microparticles (MP) made of denaturized whey proteins (WP) and alginate (ALG) using an extrusion/cold gelation process with calcium ions. High encapsulation efficiency of 85% was obtained. Influence of insulin on polymeric viscosity and on microparticle behavior was evaluated. Insulin seemed to interact with WP chains by non covalent binding and steric hindrance. This influence was balanced by ALG addition. Nevertheless, insulin was released rapidly by diffusion at both acidic and intestinal dissolution media. Despite this fast in vitro release, WP/ALG MP showed an important enzymatic inhibition effect on trypsin and alpha-chymotrypsin. Thus, WP/ALG MP contributed to an effective insulin protection towards enzymatic degradation. The aforementioned results suggested that WP based microparticles are a promising carrier for improving oral delivery of insulin.
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http://dx.doi.org/10.1016/j.ijpharm.2012.10.003DOI Listing
December 2012

Efficacy and safety profile of LCR35 complete freeze-dried culture in irritable bowel syndrome: a randomized, double-blind study.

World J Gastroenterol 2012 May;18(17):2067-75

Médecine Digestive, Centre Hospitalier Universitaire-CHU Estaing, CHU Clermont-Ferrand, Clermont Université, Inserm UMR 766, 63001 F-Clermont-Ferrand, France.

Aim: To assess the effects and safety of Lactobacillus casei rhamnosus LCR35 complete freeze-dried culture (LCR35) in patients suffering from irritable bowel syndrome (IBS).

Methods: A randomized, double-blind pilot study was performed in 50 patients complaining of IBS symptoms complying with Rome III criteria. Patients were allocated to receive either LCR35 (n = 25) at a minimum daily dose of 6 × 10(8) colony forming units or placebo (n = 25) for 4 wk. At inclusion, after treatment and 2 wk later, patients completed the IBS severity scale. Change from baseline in the IBS severity score at the end of treatment was the primary efficacy criterion. Changes were compared between groups in the whole population and in IBS subtypes (IBS with predominance of constipation, IBS with predominance of diarrhoea, mixed IBS, unsubtyped IBS). The presence of lactobacillus casei rhamnosus in stools was investigated at inclusion and at the end of treatment. The gastrointestinal quality of life questionnaire and the hospital anxiety and depression (HAD) scale were also completed.

Results: Both groups were balanced for baseline characteristics. In 85% of patients, stool analyses showed that lactobacillus casei rhamnosus able to survive in the digestive tract. In the whole population, improvements in the IBS severity score did not differ significantly between treatments with a 25% decrease after 4-wk treatment, and a 15% decrease from baseline 2 wk later in both groups. In IBS subgroups, statistical analysis could not be performed due to small sample size, but a clinical response in favour of LCR35 was observed in IBS patients with predominance of diarrhoea: no change in the symptom severity score was seen with the placebo after 4 wk treatment, whereas a clinically relevant decrease occurred with LCR35 (-37% vs -3%). Furthermore, in spite of an increase in symptom intensity, the IBS severity score was maintained below the baseline value 2 wk later with LCR35 (-19% from baseline), whilst a slight 5% increase from baseline was observed with placebo. In the IBS subgroup with predominance of diarrhoea only, a clinically relevant decrease in abdominal pain severity score (-36%) was observed with LCR35, whereas no change occurred with placebo. In mixed IBS patients, the 20% and 30% decreases in the IBS severity score observed after treatment with LCR35 and placebo, respectively, were maintained 2 wk later in both groups. A clinical response slightly in favour of placebo was observed at the end of the treatment period in IBS patients with predominance of constipation (-41% vs -20%) and unsubtyped IBS patients (-47% vs -17%), with the same value maintained 2 wk later. In both groups, no clinically relevant changes were observed either for the gastrointestinal quality of life index or HAD score. Thus, these results suggest that sub-grouping of IBS patients may be important for optimizing treatment responses by the physician.

Conclusion: This pilot study suggests that LCR35 could have some efficacy in IBS patients complaining of diarrhoea. These preliminary results need to be confirmed in larger studies.
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http://dx.doi.org/10.3748/wjg.v18.i17.2067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342605PMC
May 2012

Cisplatin pharmacokinetics in nontumoral pig liver treated with intravenous or transarterial hepatic chemoembolization.

Cardiovasc Intervent Radiol 2012 Dec 24;35(6):1467-74. Epub 2012 Apr 24.

Pôle de Radiologie, CHU Clermont-Ferrand, 58 Rue Montalembert, 63000, Clermont-Ferrand, France.

Purpose: To evaluate cisplatin (CDDP) pharmacokinetics after its intravenous (IV) or intrahepatic arterial administration (IHA) in healthy pigs with or without embolization by absorbable gelatine.

Material And Methods: We analysed plasmatic and hepatic drug concentration in four groups of six mini-pigs each according to the modality of administration of CDDP (1 mg/kg): IV, IHA, IHA with partial embolization using absorbable gelatine (IHA-Pe), and IHA with complete embolization (IHA-Te). Unbounded plasmatic and hepatic platinum concentrations were measured. Concentration and pharmacokinetics parameters were compared using analysis of variance.

Results: For all groups, there was a rapid and biexponential decrease in free platinum concentration. Plasmatic terminal half-life (T(1/2)) was significantly decreased after embolization at 191, 178, 42, and 41 min after IV, IHA, IHA-Pe, and IHA-Te administration, respectively. Maximal plasmatic concentration and systemic exposure to CDDP (AUC(24)) values were significantly decreased after embolization (C(max) p = 0.0075; AUC(24) p = 0.0053). Hepatic CDDP concentration rapidly peaked and then decreased progressively. After 24 h, the residual concentration represented 45, 47, 60, and 63 % of C(max), respectively, after IV, IHA, IHA-Pe, and IHA-Te. Hepatic T(1/2) and AUC(∞) values were increased after embolization, but the differences were not statistically significant.

Conclusion: This preliminary study confirms the feasibility of a pig model to study systemic and hepatic CDDP pharmacokinetics. Systemic exposure is lower after embolization, which could minimize systemic toxicity. Hepatic T(1/2) elimination and hepatic exposition values are increased with IHA compared with IV administration.
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http://dx.doi.org/10.1007/s00270-012-0386-0DOI Listing
December 2012

Development and characterization of coated-microparticles based on whey protein/alginate using the Encapsulator device.

Drug Dev Ind Pharm 2013 Jan 7;39(1):128-37. Epub 2012 Mar 7.

Université Clermont, UFR Pharmacie, Centre de Recherche en Nutrition Humaine, Clermont-Ferrand, France.

The aim of this study is to prepare whey protein (WP)-based microparticles (MP) using the Encapsulator(®) device. The viscosity dependence of the extrusion device required to mix WP with a food-grade and less viscous polymer. Mixed WP/ALG MP were obtained with the optimized WP/alginate (ALG) ratio (62/38). These particles were further coated with WP or ALG using non-traumatic and solvent-free coating process developed in this study. Size and morphology of coated and uncoated MP were determined. Then, swelling and degradation (WP release) of formulations were investigated in pH 1.2 and 7.5 buffers and in simulated gastric and intestinal fluids (SGF, SIF) and compared to pure ALG and pure WP particle behaviours. At pH 1.2, pure ALG shrank and pure WP swelled, whereas the sizes of mixed WP/ALG matrix were stable. In SGF, WP/ALG MP resisted to pepsin degradation compare to pure WP particles due to ALG shrinkage which limited pepsin diffusion within particles. Coating addition with WP or ALG slowed down pepsin degradation. At pH 7.5, WP/ALG particles were rapidly degraded due to ALG sensitivity but the addition of a WP coating limited effectively the swelling and the degradation of MP. In SIF, pancreatin accelerated MP degradation but ALG-coated MP exhibited interesting robustness. These results confirmed the interest and the feasibility to produce coated WP-based MP which could be a potential orally controlled release drug delivery system.
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http://dx.doi.org/10.3109/03639045.2012.660950DOI Listing
January 2013

Teenagers as a moving target: how can teenagers be encouraged to accept treatment?

J Pers Med 2012 Dec 11;2(4):277-86. Epub 2012 Dec 11.

Biopharmaceutical Department, UFR Pharmacie, University d'Auvergne, 28, Place H. Dunant, B.P. 38, F-63001 Clermont-Ferrand, France.

Pediatric patients exhibit their own needs and problems and are now considered as a real patient group in which downsizing the adult formulation is not the best choice and may result in problems. Adolescence (between 12 and 18 years) is a transitional period of life from puberty to adulthood and, in this pediatric subgroup population, complex problems are observed in compliance with chronic treatments. Heterogeneity exists in this group which follows very different and sometimes short trends and tendencies and where illness can be a problem leading to stigmatization. Influence of social environment as well as friends is complex in this period of life. Teenagers have to take care of themselves and be part of the treatment including all the features of the social code of this group. Particular attention has to be paid to formulation and packaging in order to increase compliance and to suit the specific needs of this pediatric subgroup. Some examples are given for different drug forms.
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http://dx.doi.org/10.3390/jpm2040277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251378PMC
December 2012

Use of artificial digestive systems to investigate the biopharmaceutical factors influencing the survival of probiotic yeast during gastrointestinal transit in humans.

Pharm Res 2012 Jun 9;29(6):1444-53. Epub 2011 Nov 9.

Centre de Recherche en Nutrition Humaine Auvergne, ERT 18 Conception Ingénierie et Développement de l'Aliment et du Médicament, Clermont Université, Université d'Auvergne, BP 10448, 63000, Clermont-Ferrand, France.

Purpose: To evaluate the influence of the main biopharmaceutical factors on the viability of a new probiotic yeast strain, using dynamic in vitro systems simulating human gastric/small intestinal (TIM) and large intestinal (ARCOL) environments.

Methods: The viability of Saccharomyces cerevisiae CNCM I-3856 throughout the artificial digestive tract was determined by microbial counting. We investigated the effects of galenic formulation, food intake, dose, mode and frequency of administration on yeast survival rate.

Results: In both fasted and fed states, yeast viability in the upper digestive tract was significantly higher when the probiotic was administered in hydroxypropylmethylcellulose (HPMC) capsules compared to tablets. Food intake led to a delay in yeast release and a two-fold increase in strain survival. Whatever the dose, yeasts were particularly sensitive to the large intestinal environment. High concentrations of probiotic could only be maintained in the colon when it was inoculated twice a day over a 5-h-period.

Conclusions: TIM and ARCOL are complementary in vitro tools relevant for screening purposes, supplying valuable information on the effects of galenic form, food intake and dose regimen on the viability of probiotics throughout the human digestive tract.
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http://dx.doi.org/10.1007/s11095-011-0620-5DOI Listing
June 2012

Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial.

Magnes Res 2011 Jun;24(2):28-35

CHU Clermont-Ferrand, Centre de Pharmacologie Clinique, Clermont-Ferrand, France.

Studies in animals and in patients have suggested that magnesium (Mg), a physiological blocker of N-methyl-D-aspartate receptor, could have an antinociceptive effect in painful situations. This randomised, double-blind, controlled trial in two parallel groups aims at studying oral Mg effects in patients with neuropathic pain. It explores the impact of Mg (6x419 mg Mg chloride/capsule per day for a month), versus placebo (lactose) on pain [Neuropathic Pain Symptom Inventory (NPSI) and numerical scale (NS)], and on quality of life indicators after 4 weeks treatment, in 45 patients suffering from neuropathic pain. After 4 weeks, NPSI, NS and quality of life are not different in the Mg and placebo groups, while the frequency of pain paroxysms diminishes and the emotional component improves in the Mg group compared to baseline. This clinical trial displays a large placebo response and could not demonstrate any significant difference in pain alleviation after a month of oral treatment between Mg and placebo in patients suffering from neuropathic pain. Frequency of pain paroxysms and emotional impact will be explored in future studies as they constitute major aspects of pain alleviation in chronic pain conditions.
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http://dx.doi.org/10.1684/mrh.2011.0282DOI Listing
June 2011

Validation of a transient pain monitor in healthy volunteers.

Reg Anesth Pain Med 2011 Mar-Apr;36(2):110-5

CHU Clermont-Ferrand, Centre de Pharmacologie Clinique(Inserm CIC 501), F-63003 Clermont-Ferrand Cedex 1, France.

Background And Objectives: Transient pain in humans is usually quantified using visual analog or numeric rating scales, but no assessment method has yet been validated in real time during such stimulation.

Methods: To validate a transient pain monitor, healthy volunteers submitted to stimulations generated by a CO(2) laser at graded levels of stimulation were trained to close the dominant hand around a handgrip dynamometer as strongly as they felt the pain, and the signal was computerized.The parameters recorded for each response were the peak intensity, the area under the curve, and pain expressed on a visual analog scale as a control. The volunteers underwent a second session 1 week later to assess reproducibility.

Results: The 3 parameters studied had a similar capacity to report the intensity of stimulation. The peak intensity showed many similarities with the visual analog scale, although a downward drift of the values throughout the session was observed. The area under the curve displayed a greater interindividual variability than other parameters, but it was better to assess low-intensity stimulation; a better fit for crossover designs was also suggested with the area under the curve.

Conclusions: This study validates in human volunteers under a laser stimulation of skin the metrological properties of an electronic handgrip device to assess the intensity of transient punctuate pain (compared with visual analog scale). The transient pain monitor validated here should now be tested in the clinical context.
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http://dx.doi.org/10.1097/aap.0b013e3182030811DOI Listing
December 2011

Characteristics of the neuropathy induced by thoracotomy: a 4-month follow-up study with psychophysical examination.

Clin J Pain 2011 Jul-Aug;27(6):471-80

CHU Clermont-Ferrand, Pôle Anesthésie-Réanimation-SAMU-SMUR, Hôpital Gabriel-Montpied, Centre de Pharmacologie Clinique, CHU Clermont-Ferrand, France.

Objectives: To explore the role of neuropathy in persistent pain after thoracotomy, combining a clinical follow-up and a psychophysical examination of the operated area.

Methods: Seventy-three patients were followed and examined at their discharge from hospital, 6 weeks and 4 months after pneumonectomy under thoracotomy. Spontaneous and evoked pain was assessed by clinical examination, a 7-day pain score, and the Neuropathic Pain Symptom Inventory. At the fourth month follow-up, pain and tolerance thresholds to pinprick, heat, and warm sensation threshold were measured on both sides of the thorax.

Results: The rate of spontaneous pain was 40% at discharge and went up to 59% at the sixth week follow-up. Evoked pain was rare at discharge (11%), most cases appearing at the sixth week follow-up (47%). The evolution profiles of pain between the sixth week and the fourth month follow-up were heterogeneous with a tendency to decrease. Young age, female sex, and spontaneous pain observed at discharge from hospital were identified as early predictive factors of spontaneous pain persisting at the fourth month follow-up. On the side of operation, thresholds tended to increase for warm and hot stimuli, and to decrease for mechanical stimuli. At the fourth month follow-up, spontaneous pain and evoked pain were associated to static hyperalgesia, persisting hypoesthesia, low mechanical thresholds, altered sensation of heat, and impaired quality of life.

Discussion: Peripheral neuropathy is common after thoracotomy, with variant characteristics, ranging from subclinical disturbances to severe pain. The process seems to develop between the discharge from hospital and the sixth week after thoracotomy.
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http://dx.doi.org/10.1097/AJP.0b013e31820e12d4DOI Listing
October 2011

Developing drugs for children and the adjustment of medication-is it a new challenge or an adaptation of past ideas?

J Pers Med 2011 Dec 6;1(1):5-16. Epub 2011 Dec 6.

University Clermont 1, UFR Pharmacie, Biopharmaceutical Department, 28, Place H. Dunant, B.P. 38, F-63001 Clermont-Ferrand, France.

Nowadays the adjustment of medication for each patient is at the center of health strategy. Children can be considered as specific targets with their own specificities. In the oral route field some examples of drugs especially adapted to children can be found. Design is introduced in drug formulation to offer a better choice of products and now, children can be considered as partners in their own treatment. Enhanced comprehension of children's requirements can also lead to creation of drugs that improve compliance.
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http://dx.doi.org/10.3390/jpm1010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251352PMC
December 2011

Development of a New Type of Prolonged Release Hydrocodone Formulation Based on Egalet® ADPREM Technology Using In Vivo-In Vitro Correlation.

Pharmaceutics 2011 Mar 9;3(1):73-87. Epub 2011 Mar 9.

Egalet Denmark, Lejrvej 37-41, DK-3500 Værløse, Denmark.

A novel abuse deterrent, prolonged release tablet formulation of Hydrocodone for once-daily dosing has been developed, based on the novel proprietary Egalet® ADPREM technology. The tablet is an injection molded polymer system consisting of an erodible matrix in which the Active Pharmaceutical Ingredient (API), such as Hydrocodone, is dispersed. The matrix is partly covered with a water-impermeable, non-erodible shell which leaves both ends of the cylindrical tablet exposed to erosion by the gastrointestinal (GI) fluid. In vivo-in vitro correlation (IVIVC) was initiated and validated with three formulations. A good internal predictability was observed for the three formulations. How the changing conditions in the GI tract influenced in vivo performance of an erosion based product was discussed. The validated IVIVC could be used to optimize the tablet formulation and to obtain a desired profile. In addition, this technique could help to establish the dissolution limits in which a certainty of bioequivalence is calculated. Based on this validated level A IVIVC, dissolution can be used as surrogate of bioequivalence for development, but also scale up post approval changes.
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http://dx.doi.org/10.3390/pharmaceutics3010073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857038PMC
March 2011

Single process for manufacturing spheres with a lipid base (HCO).

Pharm Dev Technol 2012 May-Jun;17(3):303-14. Epub 2010 Dec 22.

Biopharmacy Department, Faculty of Pharmacy, Place Henri Dunant, Clermont-Ferrand, France.

Pellets and spheres are manufactured in the pharmaceutical industry by various processes which are not always easily automated. In this paper, a 'single pot process' is described using rotary fluid bed granulation with lipid fillers. This technology is based on wet granulation of powder components, continuously suspended in a fluidized air with a tangentially sprayed liquid solution. After a previous work devoted to selection of matrix filler, this work focuses on lipid component: hydrogenated castor oil, used as matrix filler associated with theophylline as tracer. Spheres manufactured can be introduced either directly into a hard gelatine capsule or compressed as tablets. The influence of the formulation and process parameters on the sphere manufacture in terms of feasibility is studied with in vitro tests. Spraying time and weight of liquid sprayed are found to be the most relevant parameters that governed the final quality of the sphere.
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http://dx.doi.org/10.3109/10837450.2010.535827DOI Listing
August 2012

Effect of a new probiotic Saccharomyces cerevisiae strain on survival of Escherichia coli O157:H7 in a dynamic gastrointestinal model.

Appl Environ Microbiol 2011 Feb 3;77(3):1127-31. Epub 2010 Dec 3.

Clermont Université, Centre de Recherche en Nutrition Humaine Auvergne, ERT 18, Conception Ingénierie et Développement de l'Aliment et du Médicament, BP 10448, F-63000 Clermont-Ferrand, France.

Survival of Escherichia coli O157:H7 was investigated using a dynamic gastrointestinal model. A high bacterial mortality was observed in the stomach and duodenum. In contrast, bacteria grew in the distal parts of the small intestine. The coadministration of Saccharomyces cerevisiae CNCM I-3856 led to a significant reduction of bacterial resumption, maybe through ethanol production.
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http://dx.doi.org/10.1128/AEM.02130-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028742PMC
February 2011