Randomized clinical trial: effect of the 5-HT4 receptor agonist revexepride on reflux parameters in patients with persistent reflux symptoms despite PPI treatment.

BACKGROUND: Approximately, 20-30% of patients with gastro-esophageal reflux disease (GERD) experience persistent symptoms despite treatment with proton pump inhibitors (PPIs). These patients may have underlying dysmotility; therefore, targeting gastric motor dysfunction in addition to acid inhibition may represent a new therapeutic avenue. The aim of this study was to assess the pharmacodynamic effect of the prokinetic agent revexepride (a 5-HT4 receptor agonist) in patients with GERD who have persistent symptoms despite treatment with a PPI. METHODS: This was a phase II, exploratory, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in patients with GERD who experienced persistent symptoms while taking a stable dose of PPIs (ClinicalTrials.gov identifier: NCT01370863). Patients were randomized to either revexepride (0.5 mg, three times daily) or matching placebo for 4 weeks. Reflux events and associated characteristics were assessed by pH/impedance monitoring and disease symptoms were assessed using electronic diaries and questionnaires. KEY RESULTS: In total, 67 patients were enrolled in the study. There were no significant differences between study arms in the number, the mean proximal extent or the bolus clearance times of liquid-containing reflux events. Changes from baseline in the number of heartburn, regurgitation, and other symptom events were minimal for each treatment group and no clear trends were observed. CONCLUSIONS & INFERENCES: No clear differences were seen in reflux parameters between the placebo and revexepride groups.

A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson's disease.

BACKGROUND: Lewy bodies and neurites (LN), the two pathological hallmarks of Parkinson's disease (PD), are found in the enteric nervous system (ENS). Previously, we have shown that whole mounts of submucosa obtained after microdissection of colonic biopsies can be used for the detection of LN in the submucosal plexus (SMP) of PD patients. Recent reports suggest that Lewy pathology may extend beyond the submucosa to involve the digestive mucosa. The aim of the present research was to determine whether the analysis of the mucosa obtained after microdissection may help improve the sensitivity of colonic biopsies to detect Lewy pathology in the colon of PD patients. METHODS: Nine PD patients and 10 controls were included. Four biopsies were taken from the sigmoid/descending colon junction during the course of a rectosigmoidoscopy (short colonoscopy) in PD patients and during a total colonoscopy for colorectal screening in controls. Biopsies were microdissected, the mucosa was separated from the submucosa and both structures were analyzed by immunohistochemistry. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein to detect LN and neurofilaments NF200 kDa to label the neuronal structures. KEY RESULTS: Lewy neurites were present in the SMP of four patients and in the mucosa of three patients. Remarkably, among the patients who displayed LN within their mucosa, one was devoid of Lewy pathology in his SMP. No LN were observed in the mucosa and the SMP of controls. CONCLUSIONS & INFERENCES: The parallel analysis of colonic mucosa, along with the SMP, can help detect Lewy pathology in PD.

Endoscopy-negative reflux disease.

Endoscopy-negative reflux disease (ENRD) is more prevalent than reflux esophagitis, especially in a primary care setting. Acid-sensitive esophagus (ie, reflux-related symptoms with normal acid exposure at 24-hour pH monitoring) is part of the gastroesophageal reflux disease spectrum. ENRD is not a mild disease (symptoms return frequently and have an impact on quality of life), but it rarely progresses to the erosive stage. In patients with atypical or extra-esophageal manifestations, pH monitoring remains useful, and symptom analysis (symptom index or symptom-associated probability) is of pivotal importance. A proton pump inhibitor (PPI) test may represent a cost-effective alternative to 24-hour pH monitoring. However, well-designed validation studies are necessary to assess the diagnostic value of PPI tests and improve specificity without reducing sensitivity. Management of ENRD is based on the same principles as that of reflux esophagitis. Restoration of quality of life is the major goal. Proton pump inhibitors are not more (and are sometimes even less) effective in non-erosive reflux disease than in reflux esophagitis. Different long-term strategies (continuous maintenance, intermittent or on-demand therapy) are available, depending on the needs of the patient. Antireflux surgery may be indicated in carefully selected patients. In the future, pharmacologic approaches targeted to transient lower esophageal sphincter relaxation or visceral perception should be developed.

Does the route of feeding modify gastric emptying in rats?

BACKGROUND: It has been shown that the pattern of previous nutrient intake can influence gastric emptying. However, the effect of the absence of enteral stimulation in the setting of a normal energy supply on gastric emptying has not been examined. The aim of this study was to determine whether the absence of enteral stimulation during total parenteral nutrition (TPN) could modify gastric emptying in rats. METHODS: Two experiments were performed. First, gastric emptying of a peptone meal was compared between rats receiving TPN, oral liquid diet (same solution as TPN), or regular diet (control group) for 10 days. In the second experiment, gastric emptying of two test meals (40% peptone and 25% glucose) was studied before and after rats received TPN or intragastric nutrition (same solution as TPN) for 10 to 12 days. RESULTS: In experiment 1, gastric emptying of 40% peptone in the TPN and liquid diet groups was slower than that in the control group. This difference was significant between the TPN group and the control group (p < .01) but not between the liquid diet and control groups (p = .076). Gastric emptying of this meal in the TPN and liquid diet groups was similar. In experiment 2, no difference in gastric emptying of 40% peptone or 25% glucose was found between rats receiving TPN and those receiving intragastric nutrition for 10 to 12 days. CONCLUSIONS: The composition of diet not the route of feeding is important in the modification of gastric emptying by the pattern of previous nutrient intake.

13C-octanoic acid breath test for gastric emptying measurement.

OBJECTIVES: The purpose of this multicentre study was to assess the accuracy and reproducibility of the 13C-octanoic acid breath test compared to scintigraphy for measurement of gastric emptying. METHODS: Sixty-nine healthy subjects (40 men, 29 women; mean age 30 years, range 21-61) were studied at least once by using the 13C-octanoic breath test. In 34 healthy subjects, gastric emptying was simultaneously measured by gastric scintigraphy, and the 13C-octanoic breath test was then repeated in 18 of these cases. Fifty-four patients (30 men, 24 women; mean age 46 years, range 13-74) with dyspeptic or reflux symptoms were studied according to the same procedure. RESULTS: The correlation between breath test and scintigraphic values was highly significant (r = 0.744, P<0.001). The concordance of results of scintigraphy and breath test (normal versus abnormal) and the reproducibility (Bland and Altman method) of the breath test were good (CVinter = 24%, CVintra = 15%). As compared to scintigraphy, breath test detected an abnormal gastric emptying with 67% sensitivity and 80% specificity (ROC analysis). CONCLUSION: These results confirm the value of breath test as an accurate measurement of gastric emptying. Its excellent reproducibility makes it a method of choice for pharmacological studies. However, at least when scintigraphy is considered the gold standard, breath test sensitivity may be insufficient for the detection of gastroparesis in an individual patient.

Proximal gastric tone in gastro-oesophageal reflux disease.

BACKGROUND/OBJECTIVE: Abnormal gastric function may be involved in the pathogenesis of several gastrointestinal functional disorders. This study evaluated gastric tone in gastro-oesophageal reflux disease (GORD). METHODS: Proximal gastric tone was measured with an electronic barostat in fasting conditions and after oral ingestion of a 200 ml/200 kcal liquid meal in 10 patients with GORD, with control groups consisting of 10 patients with dysmotility-like dyspepsia and 16 healthy subjects. RESULTS: Minimal distending pressure was increased in GORD patients compared to dyspeptic patients (P < 0.04) and controls (P< 0.001). Maximal postprandial gastric relaxation was significantly increased in GORD patients (430 +/- 95 ml) compared to dyspeptic patients (200 +/- 152 ml, P < 0.0001) and controls (342 +/- 88 ml, P= 0.05). Endoscopy-negative and mild oesophagitis patients had more profound maximal relaxation than patients with moderate or severe oesophagitis, whereas those with dyspepsia had significantly reduced gastric relaxation compared to GORD patients and controls (P < 0.002). CONCLUSIONS: In GORD, the postprandial gastric relaxation is more pronounced than in normal and dyspeptic patients. The pathophysiological relevance of this abnormal motility pattern remains to be determined.

Inter- and intrasubject variability of solid and liquid gastric emptying parameters. A scintigraphic study in healthy subjects and diabetic patients.

This study was performed to assess: (1) the inter- and intrasubject variability of gastric emptying measurements by a scintigraphic method in 12 healthy subjects and 14 diabetic patients, and (2) the reproducibility of diagnosis of either the presence or absence of gastroparesis. To address this issue, radiolabeled solid-liquid meals were ingested by all subjects on two separate days. High intersubject variability of gastric emptying measurements was shown in both populations. Intrasubject variability was higher in diabetic patients than in healthy subjects. However, there was no significant difference between the means of any parameters obtained on two separate days. The reproducibility of the diagnosis of gastroparesis was excellent for all parameters; the solid half emptying time was the most reproducible parameter (92% in healthy subjects and 93% in diabetic patients). The means +/- SD of the difference between the two separate days' half emptying time results were -10.6 +/- 41.3 min for solids and -4.8 +/- 36.6 min for liquids and were not statistically different from zero. Only one difference between the half emptying time results on two separate days was not in the 95% confidence interval for both solids and liquids; however, this result came from a diabetic patient with obvious gastroparesis on both days. Thus: (1) in spite of high inter- and intrasubject variability, the scintigraphic method of measuring gastric emptying is highly reproducible for the diagnosis of gastroparesis; (2) reproducibility is better in healthy subjects than in diabetic patients; and (3) the knowledge of intrasubject variability allows assessment of the required sample sizes for pharmacological studies using prokinetic medications.

Simultaneous assessment of liquid emptying and proximal gastric tone in humans.

BACKGROUND: Barostat is the only technique that allows assessment of gastric tone in humans. Our aim was to simultaneously assess gastric emptying and relaxation in response to a liquid meal. METHODS: Gastric tone was monitored using an electronic barostat in six healthy subjects after three liquid meals (200 mL, 400 mL, 600 mL, 1 kcal/mL). Scintigraphic imaging was obtained by using double isotopic labeling (technetium 99m for liquid of the 200 mL meal and xenon 133 for air into the barostat). RESULTS: Profound gastric relaxation was detected in every subject. The duration of proximal gastric relaxation increased with meal size. The proximal stomach remained relaxed through the duration of gastric emptying. Gastric tone returned to the fasting values simultaneously with completion of liquid emptying. Repeated measures after the 200-mL meal showed that amplitude (i.e., maximal volume change) and duration of relaxations were reproducible. However, the presence of the bag slightly accelerated gastric emptying and modified the intragastric distribution of the meal. CONCLUSIONS: The barostat is a sensitive and reproducible technique to measure gastric relaxation following liquid meals in humans. The results also suggest that the role of gastric tone as the driving force of gastric emptying of liquids has been overestimated.