Poliprotect vs Omeprazole in the Relief of Heartburn, Epigastric Pain, and Burning in Patients Without Erosive Esophagitis and Gastroduodenal Lesions: A Randomized, Controlled Trial.

INTRODUCTION: In the treatment of upper GI endoscopy-negative patients with heartburn and epigastric pain or burning, antacids, antireflux agents, and mucosal protective agents are widely used, alone or as add-on treatment, to increase response to proton-pump inhibitors, which are not indicated in infancy and pregnancy and account for significant cost expenditure. METHODS: In this randomized, controlled, double-blind, double-dummy, multicenter trial assessing the efficacy and safety of mucosal protective agent Poliprotect (neoBianacid, Sansepolcro, Italy) vs omeprazole in the relief of heartburn and epigastric pain/burning, 275 endoscopy-negative outpatients were given a 4-week treatment with omeprazole (20 mg q.d.) or Poliprotect (5 times a day for the initial 2 weeks and on demand thereafter), followed by an open-label 4-week treatment period with Poliprotect on-demand. Gut microbiota change was assessed. RESULTS: A 2-week treatment with Poliprotect proved noninferior to omeprazole for symptom relief (between-group difference in the change in visual analog scale symptom score: [mean, 95% confidence interval] -5.4, -9.9 to -0.1; -6.2, -10.8 to -1.6; intention-to-treat and per-protocol populations, respectively). Poliprotect's benefit remained unaltered after shifting to on-demand intake, with no gut microbiota variation. The initial benefit of omeprazole was maintained against significantly higher use of rescue medicine sachets (mean, 95% confidence interval: Poliprotect 3.9, 2.8-5.0; omeprazole 8.2, 4.8-11.6) and associated with an increased abundance of oral cavity genera in the intestinal microbiota. No relevant adverse events were reported in either treatment arm. DISCUSSION: Poliprotect proved noninferior to standard-dose omeprazole in symptomatic patients with heartburn/epigastric burning without erosive esophagitis and gastroduodenal lesions. Gut microbiota was not affected by Poliprotect treatment. The study is registered in Clinicaltrial.gov (NCT03238534) and the EudraCT database (2015-005216-15).

Protective Mechanisms of Liquid Formulations for Gastro-Oesophageal Reflux Disease in a Human Reconstructed Oesophageal Epithelium Model.

Purpose: A novel experimental design based on a human-reconstructed oesophageal epithelium (HO2E) model has been applied to quantitively assess the properties of a set of liquid formulations, Device A (Gerdoff® Protection), Device B (Esoxx® One), and Device C (Marial® gel) developed to form a temporary physical barrier on the oesophageal epithelium and modify epithelial permeability so to protect the oesophageal mucosa from refluxate components. Methods: The formulations were applied to a prewetted HO2E model for 15 min. Then, a 0.5% caffeine solution was applied, and its penetration kinetics was assessed at 1 h and 2 h in acidic environments (pH= 3.3) to mirror exposure of the oesophageal mucosa to acidic reflux in GORD patients. Caffeine permeated into the basolateral compartment (evaluated by HPLC-UV) and Lucifer yellow (LY) permeability were quantified 15 min after application of the caffeine in acidic environments. Results: At the 15 min timepoint, Device A reduced caffeine permeation by 77.2% and LY flux by 30.4% compared to the untreated control and with a faster mode of action than that of the other liquid formulations. Transepithelial caffeine flux was reduced, albeit with different timing and efficiency, by all three compounds up to the end of the 2 hour experiment. At 1 h, Device A reduced the caffeine flux by 79.2%; Device B, by 67.2%; and Device C, by 37%. Conclusion: These results confirm the ability of the medical devices tested to interact with the oesophageal epithelium and create a temporary physical protective film for up to 2 hours after their application. The results underline differences in the mechanism of action of the three medical devices, with Device A performing faster than the other formulations. The overall results support the relevance of the reconstructed mucosal model to investigate oesophageal epithelium-product interactions and precisely differentiate liquid formulation performance.

Medical Devices Made of Substances: Possible Innovation and Opportunities for Complex Natural Products.

The novel Regulation 2017/745/EC on medical devices introduces and strengthens the role of "medical devices made of substances", which mostly include substances of natural origin. Natural products may follow different regulations, from food to therapeutics. Concerning their isolated constituents, extracts are characterized by a complexity that is not easily tackled from both a scientific and a regulatory point of view, but more importantly, from a therapeutic point of view. The evidence-based approach applied to isolated molecules requires appropriate evidence of quality, efficacy, and safety. The same needs must be reached for complex substances by finding appropriate methods to generate this evidence, and in addition, defining an appropriate regulatory field for them. From a scientific point of view, new methods, such as those proposed by systems biology, are available and applicable to complex substances. From a regulatory point of view, Directive 2001/83/EC on medicinal products seems to be modeled on single (or combinations of single) molecule products. On the other hand, Regulation 2017/745/EC on medical devices seems to apply to complex substances without derogating on quality, efficacy, and safety. The regulation specifically names and strengthens medical devices that include substances, mostly of natural origin, introducing the official term "medical devices made of substances". This paper discusses and proposes an interpretation of important terms connected to this legislation, regarding both scientific and regulatory issues, and the opportunities the regulation may give for innovation and therapeutic improvement with natural complex substances.

Management of Opioid-Induced Constipation and Bowel Dysfunction: Expert Opinion of an Italian Multidisciplinary Panel.

The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the increasing prevalence of conditions associated with severe pain, the latter being related to population aging. Herein we provide the expert opinion of an Italian multidisciplinary panel on the management of opioid-induced constipation (OIC) and bowel dysfunction. OIC and opioid-induced bowel dysfunction are well-recognised unwanted effects of treatment with opioid analgesics that can profoundly affect quality of life. OIC can be due to additional factors such as reduced mobility, a low-fibre diet, comorbidities, and concomitant medications. Fixed-dose combinations of opioids with mu (µ) opioid receptor antagonists, such as oxycodone/naloxone, have become available, but have limited utility in clinical practice because the individual components cannot be independently titrated, creating a risk of breakthrough pain as the dose is increased. A comprehensive prevention and management strategy for OIC should include interventions that aim to improve fibre and fluid intake, increase mobility or exercise, and restore bowel function without compromising pain control. Recommended first-line pharmacological treatment of OIC is with an osmotic laxative (preferably polyethylene glycol [macrogol]), or a stimulant laxative such as an anthraquinone. A second laxative with a complementary mechanism of action should be added in the event of an inadequate response. Second-line treatment with a peripherally acting µ opioid receptor antagonist (PAMORA), such as methylnaltrexone, naloxegol or naldemedine, should be considered in patients with OIC that has not responded to combination laxative treatment. Prokinetics or intestinal secretagogues, such as lubiprostone, may be appropriate in the third-line setting, but their use in OIC is off-label in Italy, and should therefore be restricted to settings such as specialist centres and clinical trials.

Persistent Systemic Microbial Translocation, Inflammation, and Intestinal Damage During Clostridioides difficile Infection.

BACKGROUND: Clostridioides difficile infection (CDI) might be complicated by the development of nosocomial bloodstream infection (n-BSI). Based on the hypothesis that alteration of the normal gut integrity is present during CDI, we evaluated markers of microbial translocation, inflammation, and intestinal damage in patients with CDI. METHODS: Patients with documented CDI were enrolled in the study. For each subject, plasma samples were collected at T0 and T1 (before and after CDI therapy, respectively), and the following markers were evaluated: lipopolysaccharide-binding protein (LPB), EndoCab IgM, interleukin-6, intestinal fatty acid binding protein (I-FABP). Samples from nonhospitalized healthy controls were also included. The study population was divided into BSI+/BSI- and fecal microbiota transplantation (FMT) +/FMT- groups, according to the development of n-BSI and the receipt of FMT, respectively. RESULTS: Overall, 45 subjects were included; 8 (17.7%) developed primary n-BSI. Markers of microbial translocation and intestinal damage significantly decreased between T0 and T1, however, without reaching values similar to controls (P < .0001). Compared with BSI-, a persistent high level of microbial translocation in the BSI+ group was observed. In the FMT+ group, markers of microbial translocation and inflammation at T1 tended to reach control values. CONCLUSIONS: CDI is associated with high levels of microbial translocation, inflammation, and intestinal damage, which are still present at clinical resolution of CDI. The role of residual mucosal perturbation and persistence of intestinal cell damage in the development of n-BSI following CDI, as well as the possible effect of FMT in the restoration of mucosal integrity, should be further investigated.

The central role of psychopathology and its association with disease severity in inflammatory bowel disease and irritable bowel syndrome.

BACKGROUND: Biopsychosocial models for both organic and functional gastrointestinal (GI) disorders can be found in the literature. To clarify the role of psychopathological factors and their relationship with GI symptom severity, several studies have examined them in inflammatory bowel disease (IBD) - occasionally distinguishing between ulcerative colitis (UC) and Crohn's disease (CD) - and in irritable bowel syndrome (IBS), leading to unclear results. AIMS: We aimed to evaluate the psychopathological features of IBD and IBS patients in comparison with healthy individuals and assess the association with disease severity. MATERIALS AND METHODS: Sixty-nine IBD outpatients, of which 35 UC and 34 CD, and 75 IBS ones were consecutively recruited at the third level Gastroenterological Center of our University Hospital; 76 healthy controls were also recruited. The psychological status was assessed with the Symptom Checklist-90-Revised (SCL-90-R). RESULTS: IBD and IBS patients showed significantly higher scores on the SCL-90-R Global Severity Index (GSI) and subscales than controls (all p-values<0.001), and IBS patients showed significantly higher GSI, depression, and anxiety scores than IBD patients (all p-values<0.01). Psychopathology was comparable between UC and CD patients. In IBD and IBS patients the SCL-90-R GSI was significantly associated with disease severity (p<0.001). CONCLUSIONS: The presence of chronic bowel symptoms, either organic or functional, is linked to a greater severity of psychopathology compared to the general population, possibly as a consequence of higher loads of stress due to the symptoms affecting everyday life. In both IBD and IBS patients, greater disease severity and worse psychopathological functioning are related.

A risk score system to timely manage treatment in Crohn's disease: a cohort study.

BACKGROUND: Clinical severity and intestinal lesions of Crohn's disease (CD) usually progress over time and require a step up adjustment of the therapy either to prevent or to treat complications. The aim of the study was to  develop a simple risk scoring system to assess in individual CD patients the risk of disease progression and the need for more intensive treatment and monitoring. METHODS: Prospective cohort study (January 2002-September 2014) including 160 CD patients (93 female, median age 31 years; disease behavior (B)1 25%, B2 55.6%, B3 19.4%; location (L)1 61%, L3 31.9%, L2 6%; L4 0.6%; perianal disease 28.8%) seen at 6-12-month interval. Median follow-up 7.9 years (IQR: 4.3-10.5 years). Poisson models were used to evaluate predictors, at each clinical assessment, of having the following outcomes at the subsequent clinical assessment a) use of steroids; b) start of azathioprine; c) start of anti-TNF-α drugs; d) need of surgery. For each outcome 32 variables, including demographic and clinical characteristics of patients and assessment of CD intestinal lesions and complications, were evaluated as potential predictors. The predictors included in the model were chosen by a backward selection. Risk scores were calculated taking for each predictor the integer part of the Poisson model parameter. RESULTS: Considering 1464 clinical assessments 12 independent risk factors were identified, CD lesions, age at diagnosis < 40 years, stricturing behavior (B2), specific intestinal symptoms, female gender, BMI < 21, CDAI> 50, presence of inflammatory markers, no previous surgery or presence of termino-terminal anastomosis, current use of corticosteroid, no corticosteroid at first flare-up. Six of these predicted steroids use (score 0-9), three to start azathioprine (score 0-4); three to start anti-TNF-α drugs (score 0-4); six need of surgery (score 0-11). The predicted percentage risk to be treated with surgery within one year since the referral assessment varied from 1 to 28%; with azathioprine from 3 to 13%; with anti-TNF-α drugs from 2 to 15%. CONCLUSIONS: These scores may provide a useful clinical tool for clinicians in the prognostic assessment and treatment adjustment of Crohn's disease in any individual patient.

Protective Role of Postbiotic Mediators Secreted by Lactobacillus rhamnosus GG Versus Lipopolysaccharide-induced Damage in Human Colonic Smooth Muscle Cells.

BACKGROUND: Some beneficial effects of probiotics may be due to secreted probiotic-derived factors, identified as "postbiotic" mediators. The aim of this study was to evaluate whether supernatants harvested from Lactobacillus rhamnosus GG (LGG) cultures (ATCC53103 strain) protect colonic human smooth muscle cells (HSMCs) from lipopolysaccharide (LPS)-induced myogenic damage. MATERIALS AND METHODS: LGG was grown in de Man, Rogosa, Share medium at 37°C and samples were collected in middle and late exponential, stationary, and overnight phases. Supernatants were recovered by centrifugation, filtered, and stored at -20°C. The primary HSMCs culture was exposed for 24 hours to purified LPS of a pathogen strain of Escherichia coli (O111:B4) (1 µg/mL) with and without supernatants. Postbiotic effects were evaluated on the basis of HSMCs morphofunctional alterations and interleukin-6 (IL-6) production. Data are expressed as mean±SE (P<0.05 significant). RESULTS: LPS induced persistent, significant, 20.5%±0.7% cell shortening and 34.5%±2.2% decrease in acetylcholine-induced contraction of human HSMCs. These morphofunctional alterations were paralleled to a 365.65%±203.13% increase in IL-6 production. All these effects were dose-dependently reduced by LGG supernatants. Supernatants of the middle exponential phase already partially restored LPS-induced cell shortening by 57.34%±12.7% and IL-6 increase by 145.8%±4.3% but had no effect on LPS-induced inhibition of contraction. Maximal protective effects were obtained with supernatants of the late stationary phase with LPS-induced cell shortening restored by 84.1%±4.7%, inhibition of contraction by 85.5%±6.4%, and IL-6 basal production by 92.7%±1.2%. CONCLUSIONS: LGG-derived products are able to protect human SMCs from LPS-induced myogenic damage. Novel insights have been provided for the possibility that LGG-derived products could reduce the risk of progression to postinfective motor disorders.

Pathophysiological approach to chronic diarrhoea.

Chronic diarrhoea disrupts everyday life because of urgency, incontinence and frequent bowel movements. Non-inflammatory diarrhoea may be secondary to altered process of absorption, secretion or digestion. The most prevalent functional diarrhoea is due to altered gut-brain interaction and often after an acute gastroenteritis. Microscopic colitis, rare cases of eosinophilic colitis, congenital diarrhoeal disorders and bile acid malabsorption have been more frequently reported and their pathophysiology elucidated.

Intestinal mucus barrier in normal and inflamed colon.

Intestinal bacteria are usually regarded as harmless commensals in healthy intestine but are pathogens, if these invade the tissues. The mucus gel separates the luminal bacteria from the epithelial surface throughout the colon in healthy individuals. This viscoelastic mucus gel is protective against adhesion and invasion by microorganisms, bacterial toxins, and antigens. The mucus viscosity increases progressively toward the distal colon, separating bacteria selectively in the proximal colon and completely in the distal colon. Mucus in normal subjects is usually intact and devoid of bacteria, by contrast mucus barrier is broken and penetrated by bacteria and inflammatory cells in patients with colonic inflammation. The immune inclusion hypothesis postulates that the host mucosa maintains an adherent bacterial biofilm that develops immune tolerance with specific immune mechanisms. The bacterial biofilm, growing in the mucus matrix, would prevent contact of pathogenic bacteria with the intestinal mucosal wall. On the contrary, recent evidence indicates that bacteria are absent in mucus from healthy individuals and present in mucus from patients with inflammatory bowel disease. In inflammatory bowel disease alteration in the types of mucins or, alternatively, the altered mucus layer as a response to inflammation contributes to the underlying pathology by affecting the mucus barrier function.