J. Tack

Effect of the GABA B agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors

Background and aims: A subset of patients with gastro-oesophageal reflux disease (GORD) with refractory symptoms during therapy with proton pump inhibitors (PPIs), have persistent non-acid duodeno-gastro-oesophageal reflux (duodenal reflux). The aim of the present study was to investigate the effect of the GABAB receptor agonist baclofen, which was shown to inhibit the occurrence of transient lower oesophageal sphincter relaxations (TLOSRs) in patients with persistent non-acid duodenal reflux during PPI therapy. Methods: Patients were eligible for the study if they had persistent reflux symptoms, normal pH monitoring, and pathological Bilitec monitoring during PPI treatment. Upper gastrointestinal endoscopy and reflux symptom score were performed at the beginning of the study. Baclofen 5 mg three times daily was associated with treatment, and was increased by 5 mg every fourth day until a maintenance dose of 20 mg three times daily was reached. A reflux symptom questionnaire, ambulatory pH monitoring, and Bilitec monitoring were repeated four days later while PPI and baclofen were continued. All data are given as mean (SEM) or median (interquartile range) and were compared using the Student’s t test or the Mann-Whitney U test. Results: Sixteen patients (11 women, mean age 46 (3) years) with persistent heartburn or regurgitation for at least three months, in spite of PPI therapy, were included in the study. Erosive oesophagitis was present in seven patients (five with grade 1, two with grade 2). Under PPI therapy alone, all patients had normal acid exposure (0.3 (0.05; 2.2)% of the time) but pathological duodenal reflux exposure (13.8 (11.8; 15.5)% of the time). After addition of baclofen 20 mg three times daily, acid exposure was similar (0.4 (0.15; 2.3)% of the time; NS) but duodenal reflux had significantly decreased (6.1 (0.8; 10.3)% of the time; p<0.05). The number of duodenal reflux episodes and the number of longlasting duodenal reflux episodes (>5 minutes) was decreased, respectively, from 23 (14.5; 34) to 12 (5; 21) (p = 0.06) and from 5 (3; 8) to 2 (0.5;4.5) (p<0.05). The cumulative severity score for 14 reflux symptoms decreased from 10.3 (1.7) to 5.8 (1.3) (p<0.01). Four patients reported mild side effects of nausea or drowsiness. Conclusions: The GABAB receptor agonist baclofen improves duodenal reflux and associated reflux symptoms that persist during PPI therapy.

Systematic review: Cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders

The nonselective 5‐HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs).

Immune dysfunction in patients with functional gastrointestinal disorders

Abstract  There is increasing evidence for involvement of the immune system in functional gastrointestinal disorder (FGID), including onset after acute gastrointestinal infections, genotypes resulting in altered cytokine expression and abnormal presence of immune cells. Our aim was to assess cellular and humoral immune responses in (i) FGIDs, compared to healthy subjects and (ii) acute vs unspecified onset FGIDs. Lymphocytic [interleukin (IL)‐5, IL‐10, IL‐13 and interferon γ (IFN‐γ)] and monocytic [IL‐10, IL‐12, tumour necrosis factor (TNF)‐α] cytokine production was characterized at baseline and after stimulation with phytohemagglutinine and anti‐CD28 or lipopolysaccharide (LPS) in controls (n = 32), irritable bowel syndrome (IBS) (n = 30), functional dyspepsia (FD) (n = 23) and non‐cardiac chest pain (NCCP) (n = 15). Serum IL‐6 and IL‐10 concentrations were compared, and the immunophenotype was assessed using fluorescent‐activated cell sorter. Findings were compared for acute vs unspecified onset FGID. Compared to controls, stimulated lymphocyte expression of IL‐5 and IL‐13 was enhanced in IBS, FD and NCCP (all P < 0.05). Conversely, the stimulated monocytic IL‐12 and lymphocytic IL‐10 expression were reduced in IBS and FD, while IFN‐γ expression was also reduced in FD patients. Except for an increase in the numbers of CD3+CD45RA+CD45RO+ cells, no distinct cellular profile was detected. Patients with a presumed acute onset of their symptoms had higher serum IL‐10 levels and more CD3+CD45RA+CD45RO+ cells, while TNF‐α levels following stimulation with LPS were higher in FD patients reporting an acute onset. A shift towards a Th2 cytokine profile is present in FGID, while the cellular immunophenotype remains largely unchanged. Further research is indicated and could provide new therapeutic strategies for these disorders.

Randomised clinical trials: linaclotide phase 3 studies in IBS‐C – a prespecified further analysis based on European Medicines Agency‐specified endpoints

Treatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS‐C) are lacking.

Diagnosis and management of non-erosive reflux disease--the Vevey NERD Consensus Group.

Background/Aims: Although considerable information exists regarding gastroesophageal reflux disease with erosions, much less is known of non-erosive reflux disease (NERD), the dominant form of reflux disease in the developed world. Methods: An expert international group using the modified Delphi technique examined the quality of evidence and established levels of agreement relating to different aspects of NERD. Discussion focused on clinical presentation, assessment of clinical outcome, pathobiological mechanisms, and clinical strategies for diagnosis and management. Results: Consensus was reached on 85 specific statements. NERD was defined as a condition with reflux symptoms in the absence of mucosal lesions or breaks detected by conventional endoscopy, and without prior effective acid-suppressive therapy. Evidence supporting this diagnosis included: responsiveness to acid suppression therapy, abnormal reflux monitoring or the identification of specific novel endoscopic and histological findings. Functional heartburn was considered a separate entity not related to acid reflux. Proton pump inhibitors are the definitive therapy for NERD, with efficacy best evaluated by validated quality-of-life instruments. Adjunctive antacids or H2 receptor antagonists are ineffective, surgery seldom indicated. Conclusions: Little is known of the pathobiology of NERD. Further elucidation of the mechanisms of mucosal and visceral hypersensitivity is required to improve NERD management.

Intragastric distribution of a standardized meal in health and functional dyspepsia: correlation with specific symptoms.

Abstract  In functional dyspepsia, abnormal intragastric distribution of a test meal has been identified but has never been correlated to any symptom pattern. The aim of this study was to compare the intragastric distribution of a meal between functional dyspepsia patients and controls, and to correlate distribution with symptom patterns, using scintigraphic gastric emptying studies. In forty patients with functional dyspepsia and 29 healthy volunteers, scintigraphic planar images were obtained immediately after ingestion of a mixed radiolabelled test meal and every 20 min for 2 h. The images of the stomach were divided into proximal and distal compartments. The mean intragastric distribution was similar in patients and controls. Over the whole test, 18 (45%) and 20 (50%) patients had a distal redistribution of the solid and liquid phase of the meal, respectively, while proximal retention of these phases was found in 13 (33%) and 9 (23%) patients. Early satiety was associated with early distal redistribution of the liquid phase and fullness was associated with late proximal retention. This study shows similar intragastric distribution of a test meal in health and functional dyspepsia. Within the patient group, an association between abnormal intragastric distribution patterns and symptom profiles was found, which might be related to different pathophysiological mechanisms.

On the existence and location of cardiac mucosa: an autopsy study in embryos, fetuses, and infants

Background: The incidence of gastric cardiac adenocarcinoma has increased in the last decades. Gaining insight into the pathogenesis of this lesion is hampered by the limited knowledge of the origin and histology of cardiac mucosa (CM). Currently, the location, extent, and even the existence of CM are controversial. Aims: We studied the development of the gastro-oesophageal junction (GOJ) in embryos, fetuses, and infants to clarify if CM is a normal structure at birth and where it is located. Subjects: Twenty one autopsy cases were evaluated ranging in age from 13 weeks’ gestational age (GA) to seven months. Methods: The distal oesophagus and proximal part of the stomach were embedded entirely. Serial sections were stained with haematoxylin-eosin and alcian blue/periodic acid-Schiff. The following parameters were measured: length of abdominal oesophagus; length of columnar lined oesophagus; length of CM; and distance from CM to angle of His. Results: CM was present in all evaluated sections. Its mean length varied throughout gestation. A maximum value was reached at a GA of 16 weeks (1.2 mm). After term delivery it was very short (0.3–0.6 mm). CM was proximal to, or straddled, the angle of His in all cases. During gestation, the mucin staining pattern of the CM was to a high degree similar to that of the developing pyloric mucosa. Conclusions: CM develops during pregnancy and is present at birth as a normal structure. If the angle of His is taken as a landmark for the GOJ, CM is located in the distal oesophagus.

Intestinal immune activation in presumed post-infectious functional dyspepsia.

Abstract  Functional dyspepsia (FD) symptoms may develop after an acute gastroenteritis. In post‐infectious (PI) irritable bowel syndrome, persisting low‐grade colonic inflammation and increased enterochromaffine cells (EC) counts have been reported. The aim was to compare signs of inflammation and EC hyperplasia on duodenal biopsies in presumed PI‐FD and unspecified‐onset (U‐)FD. Duodenal biopsies were obtained in 12 U‐FD and 12 PI‐FD (on average 13 months after the acute event) patients. The presence of intra‐epithelial, intravillar, and the number of CD3, CD4, CD8 and CD68+ cells per crypts, and the mean number of Chromogranine A (CA) positive cells per villus were compared. We also measured gastric emptying and assessed proximal stomach function with a barostat. Data are shown as mean ± SEM. Focal aggregates of T cells and focal CD8+ aggregates, were found in PI‐FD but not in U‐FD patients (respectively 5/12 vs 0/12, P = 0.02 and 5/9 vs 0/11, P < 0.01). In patients with focal aggregates, gastric emptying was delayed (189 ± 37 min vs 98 ± 11 min, P = 0.002). The number of CD4+ cells per crypt (0.52 ± 1.6 vs 1.22 ± 2.18, P = 0.04), and the number of intravillar CD4+ cells (0.5 ± 0.2 vs 2.7 ± 0.7, P = 0.01) were reduced, while the number of CD68+ cells per crypt was increased (0.64 ± 0.13 vs 0.40 ± 0.05, P = 0.03) in PI‐FD. The number of EC and CA were comparable. PI‐FD is associated with persisting focal T‐cell aggregates, decreased CD4+ cells and increased macrophage counts surrounding the crypts. This may indicate impaired ability of the immune system to terminate the inflammatory response after acute insult.

Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome

Aliment Pharmacol Ther 2011; 34: 432–442

Acotiamide hydrochloride (Z-338), a novel prokinetic agent, restores delayed gastric emptying and feeding inhibition induced by restraint stress in rats.

Abstract  Acotiamide hydrochloride (Z‐338) is a member of new class prokinetic agents currently being developed for the treatment of functional dyspepsia (FD). DNA microarray analysis showed that acotiamide altered the expressions of stress‐related genes such as γ‐aminobutyric acid (GABA) receptors, GABA transporters and neuromedin U (NmU) in the medulla oblongata or hypothalamus after administration of acotiamide. Therefore, effects of acotiamide on stress‐related symptoms, delayed gastric emptying and feeding inhibition, in rats were examined. Acotiamide significantly improved both delayed gastric emptying and feeding inhibition in restraint stress‐induced model, but did not affect both basal gastric emptying and feeding in intact rats, indicating that acotiamide exerted effects only on gastric emptying and feeding impaired by the stress. On the other hand, mosapride showed significant acceleration of gastric emptying in intact and restraint stress‐induced model, and itopride showed no effect on restraint stress‐induced delayed gastric emptying. In addition, gene expression of NmU increased by restraint stress was suppressed by administration of acotiamide, while acotiamide had no effect on delayed gastric emptying induced by an intracerebroventricular administration of NmU, suggesting that the suppressive effect of acotiamide on gene expression of NmU might be important to restore delayed gastric emptying or feeding inhibition induced by restraint stress. These findings suggest that acotiamide might play an important role in regulation of stress response. As stress is considered to be a major contributing factor in the development of FD, the observed effects may be relevant for symptom improvement in FD.