[Guidelines for the management of chronic cough in adults]. / Recommandations de prise en charge de la toux chronique de l'adulte.

Patients with chronic cough experience major alteration in their quality of life. Given its numerous etiologies and treatments, this disease is a complex entity. To help clinicians involved in patient management of patients, guidelines have been issued by a group of French experts. They address definitions of chronic cough and initial management of patients with this pathology. We present herein the second-line tests that might be considered in patients whose coughing has persisted, notwithstanding initial management. The experts have also put forward a definition of unexplained or refractory chronic cough (URCC), the objective being to more precisely identify those patients whose cough persists despite optimal management. Lastly, these guidelines indicate the pharmacological and non-pharmacological interventions of use in URCC. Amitriptyline, pregabalin, gabapentin or morphine combined with speech and/or physical therapy are mainstays in treatment strategies. Other treatment options, such as P2X3 antagonists, are being developed and have generated high hopes among physicians and patients alike.

STW5 (Iberogast®) for constipation in Parkinson's disease.

BACKGROUND: Chronic constipation is one of the most frequent non-motor symptoms in Parkinson's disease (PD), and impairs patients' quality of life. OBJECTIVE: The aim of this pilot study was to assess the efficacy and the tolerability of STW5, a phytotherapeutic agent composed of nine plant extracts, for the treatment of constipation in patients with PD. METHODS: We carried out an open monocentric study of STW5 in the treatment of constipation in parkinsonian patients. Forty-four PD patients with a mean age of 66.4±7.3 years (range, 35-78), a mean disease duration of 12.6±5.4 years (range, 3-27) and with constipation defined by Rome III criteria for functional constipation were included. Following a two-week laxative-free baseline period, all the patients were treated with 20 drops STW5 t.i.d for 28 days, after a seven-day titration period. Treatment efficacy was defined as marked improvement of stool frequency with an increase of three exonerations during the last week of treatment when compared to the week before the initiation of treatment. Responder rate for stool frequency was estimated at 29/45 patients. RESULTS: An increase of stool frequency≥three eliminations/week was observed in only four out of 44 patients (9.0%) at the end of the study. The only significant difference observed before and after treatment was a decrease in stool consistency (P=0.0272). CONCLUSIONS: Our results suggest that STW5 has a safety profile but is not effective as a phytotherapeutic agent in constipation related to Parkinson's disease.

Expectations of IBS patients concerning disease and healthcare providers: Results of a prospective survey among members of a French patients' association.

BACKGROUND AND AIMS: IBS patients have an impaired quality of life (QoL) and feel dissatisfaction with medical care. We aim to describe the expectations of members of the French Association of IBS patients (APSSII) concerning health care providers (HCPs) and a patients' organization. PATIENTS AND METHODS: From January to June 2013, APSSII members were asked to answer questionnaires on their expectations and experiences concerning IBS and HCP. RESULTS: 222/330 (67%) responded (women: 68.5%, 46.5±17.7 years, disease duration: 8.8±0.7 years, IBS-D 33.6%, IBS-C 26.7%, IBS-M 38.2%. IBS-SSS>300 in 53% and HAD score>19 in 45%). QoL impairment was correlated with disease severity and HAD score (r=-0.707 and r=-0.484, P<0.001 respectively), but not with IBS subtype. Expectations for IBS were "improved health", "better information on causes and treatments" (94%) and "better disease recognition" (86%). A significant gap was observed between expectations and experiences with HCPs. Better information, less isolation, recognition of the disease and a decrease in medical expenses were the main expectations for joining a patients' organization. CONCLUSIONS: French IBS patients have a severe disease with a significant psychological impact and impaired QoL in half of the patients, certain unsatisfied expectations concerning HCP and high expectations in joining a patients' organization.

Hypotonic Low Esophageal Sphincter Is Not Predictive of Gastroesophageal Reflux Disease After Sleeve Gastrectomy.

BACKGROUND: Sleeve gastrectomy is the most commonly performed bariatric surgery these days but is associated with de novo reflux. OBJECTIVE: We aimed to study the influence of hypotonic lower esophageal sphincter (LES) on postoperative gastroesophageal reflux disease (GERD). METHODS: Patients with pre- and postoperative esophageal high-resolution manometry (HRM) and 24-h pH monitoring (pHM) were included retrospectively in our study. Preoperative hypotonic LES was defined by a mean residual pressure of the lower esophageal sphincter < 4 mmHg. Postoperative GERD was defined by a DeMeester's score > 14.72. We also evaluated postoperative manometric changes at the esophageal-gastric junction. RESULTS: Sixty-nine patients (54 females and 15 males) had pre- and postoperative HRM and pHM. The mean age was 45.9 ± 9.8 years. The mean body mass index (BMI) was 47.5 ± 7.5 kg/m2. Hypotonic LES concerned 21 patients (30.4%) before sleeve gastrectomy. The mean time between the two esophageal monitorings was 32.1 ± 24.1 months. The sensitivity, specificity, positive predictive value, and negative predictive value of hypotonic LES to predict GERD were 31, 70, 52, and 48% respectively. The LES minimal residual pressure was not statistically decreased after sleeve gastrectomy (p = 0.24). Only the wave speed, esophageal length, and LES length were significantly reduced after SG (p = 0.029, 3.8 × 10-7 and 0.00032). CONCLUSION: Hypotonic LES has a poor predictive value on postoperative GERD. The LES's length is significantly reduced after SG and this could be a factor explaining de novo reflux.

Modulation of VIPergic phenotype of enteric neurons by colonic biopsy supernatants from patients with inflammatory bowel diseases: Involvement of IL-6 in Crohn's disease.

BACKGROUND: Neuroplastic changes in the enteric nervous system (ENS) observed during IBD might participate in physiopathological processes. Vasoactive intestinal polypeptide has been shown to be involved in intestinal inflammation and barrier functions. We aimed to investigate the modulation of VIP expression in colonic biopsies of IBD patient, the ability of soluble factors from biopsies to reproduce in vitro these modulations and identify soluble factors responsible. METHODS: VIP and cytokines mRNA expressions were assessed in colonic biopsies of healthy subjects (HS) and IBD patients from inflamed (I) and non-inflamed areas (NI). Supernatants (SUP) of biopsies were applied to primary culture of ENS and VIP and cytokines mRNA expressions were assessed. The role of cytokines in SUP induced changes in VIP expression was evaluated. KEY RESULTS: VIP mRNA expression was lower in biopsies of patients with Crohn's disease (CD) than Ulcerative Colitis (UC) but unchanged as compared to HS. VIP mRNA and protein expression were lower in primary culture of ENS incubated with SUP-CD than with SUP-UC. Furthermore, in CD but not UC, SUP-I reduced VIP expression in the ENS as compared to SUP-NI. Next, IL-6 but not IL-5, IL-10, IL-17, IFN-γ or TNF-α reduced VIP expression in the ENS. Finally, in CD, SUP-I incubated with anti-IL-6 antibody increased VIP expression as compared to SUP-I alone. CONCLUSIONS & INFERENCES: Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL-6 was identified as a putative soluble factor responsible in part for changes in VIP expression in CD.

Glioplasticity in irritable bowel syndrome.

BACKGROUND: Growing evidence indicates a wide array of cellular remodeling in the mucosal microenvironment during irritable bowel syndrome (IBS), which possibly contributes to pathophysiology and symptom generation. Here, we investigated whether enteric glial cells (EGC) may be altered, and which factors/mechanisms lead to these changes. METHODS: Colonic mucosal biopsies of IBS patients (13 IBS-Constipation [IBS-C]; 10 IBS-Diarrhea [IBS-D]; 11 IBS-Mixed [IBS-M]) and 24 healthy controls (HC) were analyzed. Expression of S100ß and GFAP was measured. Cultured rat EGC were incubated with supernatants from mucosal biopsies, then proliferation and Ca2+ response to ATP were analyzed using flow cytometry and Ca2+ imaging. Histamine and histamine 1-receptor (H1R) involvement in the effects of supernatant upon EGC was analyzed. KEY RESULTS: Compared to HC, the mucosal area immunoreactive for S100ß was significantly reduced in biopsies of IBS patients, independently of the IBS subtype. IBS-C supernatants reduced EGC proliferation and IBS-D and IBS-M supernatants reduced Ca2+ response to ATP in EGC. EGC expressed H1R and the effects of supernatant upon Ca2+ response to ATP in EGC were blocked by pyrilamine and reproduced by histamine via H1R. IBS supernatants reduced mRNA expression of connexin-43. The S100ß-stained area was negatively correlated with the frequency and intensity of pain and bloating. CONCLUSION AND INFERENCES: Changes in EGC occur in IBS, involving mucosal soluble factors. Histamine, via activation of H1R-dependent pathways, partly mediates altered Ca2+ response to ATP in EGC. These changes may contribute to the pathophysiology and the perception of pain and bloating in patients with IBS.

The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.

Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome.

BACKGROUND: Intestinal immune activation is involved in irritable bowel syndrome (IBS) pathophysiology. While most dietary approaches in IBS involve food avoidance, there are fewer indications on food supplementation. Palmithoylethanolamide, structurally related to the endocannabinoid anandamide, and polydatin are dietary compounds which act synergistically to reduce mast cell activation. AIM: To assess the effect on mast cell count and the efficacy of palmithoylethanolamide/polydatin in patients with IBS. METHODS: We conducted a pilot, 12-week, randomised, double-blind, placebo-controlled, multicentre study assessing the effect of palmithoylethanolamide/polydatin 200 mg/20 mg or placebo b.d. on low-grade immune activation, endocannabinoid system and symptoms in IBS patients. Biopsy samples, obtained at screening visit and at the end of the study, were analysed by immunohistochemistry, enzyme-linked immunoassay, liquid chromatography and Western blot. RESULTS: A total of 54 patients with IBS and 12 healthy controls were enrolled from five European centres. Compared with controls, IBS patients showed higher mucosal mast cell counts (3.2 ± 1.3 vs. 5.3 ± 2.7%, P = 0.013), reduced fatty acid amide oleoylethanolamide (12.7 ± 9.8 vs. 45.8 ± 55.6 pmol/mg, P = 0.002) and increased expression of cannabinoid receptor 2 (0.7 ± 0.1 vs. 1.0 ± 0.8, P = 0.012). The treatment did not significantly modify IBS biological profile, including mast cell count. Compared with placebo, palmithoylethanolamide/polydatin markedly improved abdominal pain severity (P < 0.05). CONCLUSIONS: The marked effect of the dietary supplement palmithoylethanolamide/polydatin on abdominal pain in patients with IBS suggests that this is a promising natural approach for pain management in this condition. Further studies are now required to elucidate the mechanism of action of palmithoylethanolamide/polydatin in IBS. ClinicalTrials.gov number, NCT01370720.

Validation of criteria for the definition of transient lower esophageal sphincter relaxations using high-resolution manometry.

BACKGROUND: Criteria for transient lower esophageal sphincter relaxations (TLESRs) are well-defined for Dentsleeve manometry. As high-resolution manometry (HRM) is now the gold standard to assess esophageal motility, our aim was to propose a consensus definition of TLESRs using HRM. METHODS: Postprandial esophageal HRM combined with impedance was performed in 10 patients with gastroesophageal reflux disease. Transient lower esophageal sphincter relaxations identification was performed by 17 experts using a Delphi process. Four investigators then characterized TLESR candidates that achieved 100% agreement (TLESR events) and those that achieved less than 25% agreement (non-events) after the third round. Logistic regression and decision tree analysis were used to define optimal diagnostic criteria. KEY RESULTS: All diagnostic criteria were more frequently encountered in the 57 TLESR events than in the 52 non-events. Crural diaphragm (CD) inhibition and LES relaxation duration >10 seconds had the highest predictive value to identify TLESR. Based on decision tree analysis, reflux on impedance, esophageal shortening, common cavity, upper esophageal sphincter relaxation without swallow and secondary peristalsis were alternate diagnostic criteria. CONCLUSION & INFERENCES: Using HRM, TLESR might be defined as LES relaxation occurring in absence of swallowing, lasting more than 10 seconds and associated with CD inhibition.

Community-acquired Clostridium difficile infections.

OBJECTIVE: To describe the management and treatment of community-acquired C. difficile infections (CDI) and to evaluate family physicians' (FP) knowledge and practice. PATIENTS AND METHODS: Observational study from December 2013 to June 2014. All community-acquired CDI case patients diagnosed in the community or at the University Hospital of Nantes were prospectively included. A questionnaire was mailed to 150 FPs of the area of Nantes. RESULTS: A total of 27 community-acquired CDI case patients were included (incidence: 7.7 case patients/100,000 inhabitants). Mean age was higher among case patients diagnosed at hospital (69years) compared with those diagnosed in the community (44years). Fifteen patients were treated at home (55%) and 22 received a first-line treatment with metronidazole. Only one patient did not receive any prior antibiotic treatment. Amoxicillin-clavulanic acid was mainly prescribed (68%) for respiratory and ENT infections (40%). Twenty-three patients were cured on Day 7 and three had complications (two deaths). Thirty-one of 47 FPs reported to have already managed CDI patients. Twenty-two FPs reported to usually treat patients with uncomplicated CDI at home, 21 to refer patients to a specialist, and three to hospital. Forty-one FPs reported to prescribe a CD toxin test only after recent antibiotic exposure and 30 when patients are at risk of CDI. CONCLUSION: The incidence and impact of community-acquired CDIs may be underestimated and the unjustified use of antibiotics may promote their emergence. FPs are not used to treat CDIs as more than 50% prefer referring patients to hospital or to a specialist.

Randomised clinical trial: transoral incisionless fundoplication vs. sham intervention to control chronic GERD.

BACKGROUND: Until recently only two therapeutic options have been available to control symptoms and the esophagitis in chronic gastro-oesophageal reflux disease (GERD), i.e. lifelong proton pump inhibitor (PPI) therapy or anti-reflux surgery. Lately, transoral incisionless fundoplication (TIF) has been developed and found to offer a therapeutic alternative for these patients. AIM: To perform a double-blind sham-controlled study in GERD patients who were chronic PPI users. METHODS: We studied patients with objectively confirmed GERD and persistent moderate to severe GERD symptoms without PPI therapy. Of 121 patients screened, we finally randomised 44 patients with 22 patients in each group. Those allocated to TIF had the TIF2 procedure completed during general anaesthesia by the EsophyX device with SerosaFuse fasteners. The sham procedure consisted of upper GI endoscopy under general anaesthesia. Neither the patient nor the assessor was aware of the patients' group affiliation. The primary effectiveness endpoint was the proportion of patients in clinical remission after 6-month follow-up. Secondary outcomes were: PPI consumption, oesophageal acid exposure, reduction in Quality of Life in Reflux and Dyspepsia and Gastrointestinal Symptom Rating Scale scores and healing of reflux esophagitis. RESULTS: The time (average days) in remission offered by the TIF2 procedure (197) was significantly longer compared to those submitted to the sham intervention (107), P < 0.001. After 6 months 13/22 (59%) of the chronic GERD patients remained in clinical remission after the active intervention. Likewise, the secondary outcome measures were all in favour of the TIF2 procedure. No safety issues were raised. CONCLUSION: Transoral incisionless fundoplication (TIF2) is effective in chronic PPI-dependent GERD patients when followed up for 6 months. Clinicaltrials.gov: CT01110811.

Chemotherapy-driven dysbiosis in the intestinal microbiome.

BACKGROUND: Chemotherapy is commonly used as myeloablative conditioning treatment to prepare patients for haematopoietic stem cell transplantation (HSCT). Chemotherapy leads to several side effects, with gastrointestinal (GI) mucositis being one of the most frequent. Current models of GI mucositis pathophysiology are generally silent on the role of the intestinal microbiome. AIM: To identify functional mechanisms by which the intestinal microbiome may play a key role in the pathophysiology of GI mucositis, we applied high-throughput DNA-sequencing analysis to identify microbes and microbial functions that are modulated following chemotherapy. METHODS: We amplified and sequenced 16S rRNA genes from faecal samples before and after chemotherapy in 28 patients with non-Hodgkin's lymphoma who received the same myeloablative conditioning regimen and no other concomitant therapy such as antibiotics. RESULTS: We found that faecal samples collected after chemotherapy exhibited significant decreases in abundances of Firmicutes (P = 0.0002) and Actinobacteria (P = 0.002) and significant increases in abundances of Proteobacteria (P = 0.0002) compared to samples collected before chemotherapy. Following chemotherapy, patients had reduced capacity for nucleotide metabolism (P = 0.0001), energy metabolism (P = 0.001), metabolism of cofactors and vitamins (P = 0.006), and increased capacity for glycan metabolism (P = 0.0002), signal transduction (P = 0.0002) and xenobiotics biodegradation (P = 0.002). CONCLUSIONS: Our study identifies a severe compositional and functional imbalance in the gut microbial community associated with chemotherapy-induced GI mucositis. The functional pathways implicated in our analysis suggest potential directions for the development of intestinal microbiome-targeted interventions in cancer patients.

[Gastro-esophageal reflux and chronic respiratory diseases]. / Reflux gastro-œsophagien et pathologies respiratoires chroniques.

Gastroesophageal reflux disease (GERD) frequently occurs in association with chronic respiratory diseases although the casual link is not always clear. Several pathophysiological and experimental factors are considered to support a role for GERD in respiratory disease. Conversely, respiratory diseases and bronchodilator treatment can themselves exacerbate GERD. When cough or severe asthma is being investigated, GERD does not need to be systematically looked for and a therapeutic test with proton pump inhibitors is not always recommended. pH impedance monitoring is now the reference diagnostic tool to detect non acid reflux, a form of reflux for which proton pump inhibitor treatment is ineffective. Recent data have shown a potential role of GERD in idiopathic pulmonary fibrosis and bronchiolitis obliterans following lung transplantation, leading to discussions about the place of surgery in this context. However, studies using pH impedance monitoring are still needed to better understand and manage the association between GERD and chronic respiratory diseases.

Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications.

BACKGROUND: Gastrointestinal mucositis is defined as inflammation and/or ulcers of the gastrointestinal tract occurring as a complication of chemotherapy and radiation therapy, and affects about 50% of all cancer patients. AIM: To assess the role of gut microbiota in the pathogenesis of gastrointestinal mucositis and the potential for manipulations of the microbiota to prevent and to treat mucositis. METHODS: Search of the literature published in English using Medline, Scopus and the Cochrane Library, with main search terms 'intestinal microbiota', 'bacteremia', 'mucositis', 'chemotherapy-induced diarrhoea', 'chemotherapy-induced mucositis', 'radiotherapy-induced mucositis'. RESULTS: The gut microbiota plays a major role in the maintenance of intestinal homoeostasis and integrity. Patients receiving cytotoxic and radiation therapy exhibit marked changes in intestinal microbiota, with most frequently, decrease in Bifidobacterium, Clostridium cluster XIVa, Faecalibacterium prausnitzii, and increase in Enterobacteriaceae and Bacteroides. These modifications may contribute to the development of mucositis, particularly diarrhoea and bacteraemia. The prevention of cancer therapy-induced mucositis by probiotics has been investigated in randomised clinical trials with some promising results. Three of six trials reported a significantly decreased incidence of diarrhoea. One trial reported a decrease in infectious complications. CONCLUSIONS: The gut microbiota may play a major role in the pathogenesis of mucositis through the modification of intestinal barrier function, innate immunity and intestinal repair mechanisms. Better knowledge of these effects may lead to new therapeutic approaches and to the identification of predictive markers of mucositis.

[Enteric nervous system and Parkinson's disease]. / Système nerveux entérique et maladie de Parkinson.

It has become increasingly evident over the last years that Parkinson's disease is a multicentric neurodegenerative disease that affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. The aims of the present article are to discuss the role of the enteric nervous system lesions in pathology spreading (Braak's hypothesis) and in the gastrointestinal dysfunction encountered in Parkinson's disease. Owing to its accessibility to biopsies, we further discuss the use of the enteric nervous system as an original source of biomarker in Parkinson's disease.

Wireless pH capsule--yield in clinical practice.

Wireless pH monitoring is one of the recent technologies that focus on improving the diagnosis of gastroesophageal reflux disease (GERD). The capsule, which is fixed within the esophagus, transmits data via telemetry to an external receiver. The capsule is usually inserted 6 cm above the squamocolumnar junction during an upper endoscopy. The standard recording duration is 48 hours but this can be extended to 96 hours. The wireless capsule has been shown to be at least as accurate as the conventional catheter for the monitoring of esophageal pH. Normal pH values have been established in three different series. The use of a wireless capsule provides an increased diagnostic yield for GERD compared with the conventional catheter. The increased yield is the result of higher sensitivity to detect both abnormal acid esophageal exposure and positive symptom-reflux association. This may be related both to the prolonged recording duration and to fewer dietary modifications and restrictions on activities. Several studies have shown that the pH capsule was better tolerated by patients than the conventional pH catheter. Mild-to-moderate chest pain represents the main side effect of the pH capsule: severe chest pain requiring endoscopic removal of the capsule is rare. The main indication for wireless capsule application is monitoring of distal esophageal pH for diagnostic purpose, particularly in patients with a normal endoscopic examination. The capsule technique has some limitations: costs are higher than conventional pH monitoring, misplacement may occur, and the sampling rate is lower. Finally, compared with pH-impedance monitoring, only acid reflux events can be evaluated.

Parkinson disease: the enteric nervous system spills its guts.

Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as "the brain in the gut" because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.

Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease.

BACKGROUND: ADX10059, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, has been shown to reduce gastro-oesophageal reflux events and oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GERD) and healthy subjects. AIM: To evaluate the effects of ADX10059 monotherapy for 2 weeks on symptom control in patients with GERD. METHODS: This was a double-blind, placebo-controlled, multi-centre trial in GERD patients who were responders to proton pump inhibitors (PPIs). Following PPIs withdrawal, a 2-week baseline washout period was followed by 2-week treatment with either ADX10059 120 mg or placebo b.d. The primary clinical efficacy endpoint was the number of GERD symptom-free days in treatment week 2 compared with the last 7 days of baseline. The effect on reflux events using 24-h impedance-pH monitoring was also determined in a subset of 24 patients. RESULTS: The full analysis set comprised 103 patients ADX10059 (N= 50), Placebo (N=53). In treatment week 2, ADX10059 significantly increased GERD symptom-free days (P=0.045) and heartburn-free days (P=0.037), reduced antacid use (P=0.017), improved total symptom score (P=0.048) including subscale heartburn/regurgitation (P=0.007) and sleep disturbance because of GERD (P= 0.022). ADX10059 significantly reduced total (P=0.034) and acidic reflux events (P=0.003). ADX10059 was well tolerated. Most common adverse events for ADX10059 were mild to moderate dizziness 16% and vertigo 12% (placebo 4% and 2%). CONCLUSIONS: Inhibition of mGluR5 with ADX10059 monotherapy reduces reflux events and improves symptoms in GERD patients. This mechanism has promise for the management of GERD.