Background/Aims: The Leuven Postprandial Distress Scale (LPDS) is a validated patient reported outcome (PRO) measure for functional dyspepsia (FD)/postprandial distress syndrome (PDS) patients according to Rome III criteria. However, meal-related nausea or epigastric pain, part of PDS in Rome IV, were not addressed in this construct. Also, focus groups identified fatigue as a frequently reported complaint for which the European Medicines Agency requested further analysis. Our aim is to validate the LPDS in FD/PDS as defined by Rome IV criteria and to optimize the model by assessing the value of adding extra items to this questionnaire. Methods: The questionnaire was validated in 3 different Rome IV FD/PDS patient cohorts recruited for controlled clinical trials. Additional questions in the diary regarding symptom relationship to meal and fatigue were evaluated. Anchor scores were the patient assessment of gastrointestinal symptom severity index, Short-form Nepean dyspepsia index, the overall treatment evaluation and overall symptom severity questionnaires. Results: The LPDS Construct validity was confirmed for Rome IV-defined PDS. Psychometric analysis did not support inclusion of fatigue, nausea, meal-related or meal-unrelated, and meal-related epigastric pain, due to low loading or poor model fit. Conclusions The LPDS questionnaire showed good reliability and responsiveness, and can be confidently used as a validated tool in Rome IV PDS populations. Data did not support adding accessory symptoms to the construct, due to low loading or poor model fit.

Functional dyspepsia (FD) is a chronic gastrointestinal disorder without a readily identifiable organic cause, resulting in bothersome upper abdominal symptoms. It is a highly prevalent disorder of which the pathophysiology remains mostly elusive, despite intensive research efforts. However, recent studies have found alterations in the microenvironment of the duodenum in patients with FD. In this review we summarize the duodenal microenvironment in homeostatic conditions and the alterations found in patients with FD, highlighting the similarities and discrepancies between different studies. The most consistent findings, being an impaired duodenal barrier and duodenal immune activation, are reviewed. We discuss the potential triggers for these observed alterations, including psychological comorbidities, luminal alterations and food related triggers. In summary, this review presents the evidence of molecular and cellular changes in patients with FD, with an impaired duodenal barrier and activated mucosal eosinophils and mast cells, challenging the notion that FD is purely functional, and offering different targets for potential future treatments.

Functional dyspepsia (FD) is a chronic gastrointestinal disorder without a readily identifiable organic cause, resulting in bothersome upper abdominal symptoms. It is a highly prevalent disorder of which the pathophysiology remains mostly elusive, despite intensive research efforts. However, recent studies have found alterations in the microenvironment of the duodenum in patients with FD. In this review we summarize the duodenal microenvironment in homeostatic conditions and the alterations found in patients with FD, highlighting the similarities and discrepancies between different studies. The most consistent findings, being an impaired duodenal barrier and duodenal immune activation, are reviewed. We discuss the potential triggers for these observed alterations, including psychological comorbidities, luminal alterations and food related triggers. In summary, this review presents the evidence of molecular and cellular changes in patients with FD, with an impaired duodenal barrier and activated mucosal eosinophils and mast cells, challenging the notion that FD is purely functional, and offering different targets for potential future treatments.

Functional dyspepsia (FD) is a chronic gastrointestinal disorder without a readily identifiable organic cause, resulting in bothersome upper abdominal symptoms. It is a highly prevalent disorder of which the pathophysiology remains mostly elusive, despite intensive research efforts. However, recent studies have found alterations in the microenvironment of the duodenum in patients with FD. In this review we summarize the duodenal microenvironment in homeostatic conditions and the alterations found in patients with FD, highlighting the similarities and discrepancies between different studies. The most consistent findings, being an impaired duodenal barrier and duodenal immune activation, are reviewed. We discuss the potential triggers for these observed alterations, including psychological comorbidities, luminal alterations and food related triggers. In summary, this review presents the evidence of molecular and cellular changes in patients with FD, with an impaired duodenal barrier and activated mucosal eosinophils and mast cells, challenging the notion that FD is purely functional, and offering different targets for potential future treatments.

Manometry, particularly high-resolution manometry is the preferred diagnostic tool used to evaluate esophageal motor function. This investigation is strongly indicated in the setting of dysphagia, but is also useful in gastroesophageal reflux disease (GERD), especially in case of failure of conventional treatment to exclude alternative diagnoses and prior to anti-reflux surgery. Moreover, ineffective esophagogastric junction barrier function and esophageal motor dysfunction are pathophysiological mechanisms in GERD and can be identified by manometry. The recent international guidelines have positioned high-resolution manometry as an important part of functional diagnostic work up in GERD in order to identify the GERD phenotype to guide specific treatment. The proposed manometric identification and measurement is based on the Chicago classification version 4.0 adding with new established metrics for GERD evaluation.

BACKGROUND/AIMS: This integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. METHODS: Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. RESULTS: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. CONCLUSIONS: Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.
Abdominal Pain/*chemically induced ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group/statistics & numerical data ; Benzofurans/*adverse effects ; Clinical Trials, Phase III as Topic ; Constipation/*drug therapy/ethnology ; Diarrhea/*chemically induced ; Double-Blind Method ; Female ; Headache/*chemically induced ; Humans ; Male ; Middle Aged ; Multicenter Studies as Topic ; Nausea/chemically induced ; Randomized Controlled Trials as Topic ; Regression Analysis

BACKGROUND/AIMS: This integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. METHODS: Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. RESULTS: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. CONCLUSIONS: Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.
Abdominal Pain/*chemically induced ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group/statistics & numerical data ; Benzofurans/*adverse effects ; Clinical Trials, Phase III as Topic ; Constipation/*drug therapy/ethnology ; Diarrhea/*chemically induced ; Double-Blind Method ; Female ; Headache/*chemically induced ; Humans ; Male ; Middle Aged ; Multicenter Studies as Topic ; Nausea/chemically induced ; Randomized Controlled Trials as Topic ; Regression Analysis

BACKGROUND/AIMS: To compare the efficacy and safety of prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC). METHODS: Data of patients with CC, receiving once-daily prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of > or = 3 spontaneous complete bowel movements (SCBMs)/week; average increases of > or = 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining). RESULTS: Overall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the prucalopride group versus placebo experienced an average of > or = 3 SCBMs/week in Asian (34% vs. 11%, P < 0.001) and non-Asian (24.6% vs. 10.6%, P < 0.001) subgroups. The number of patients reporting an increase of > or = 1 SCBMs/week from baseline was significantly higher in the prucalopride group versus placebo among both Asian (57.4% vs. 28.3%, P < 0.001) and non-Asian (45.3% vs. 24.0%, P < 0.001) subgroups. The difference between the subgroups was not statistically significant. Prucalopride significantly reduced the symptom scores for bloating, hard stool, and straining in both subgroups. CONCLUSIONS: Prucalopride 2-mg once-daily treatment over 12-weeks was more efficacious than placebo in promoting SCBMs and improvement of CC-associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non-Asian patients.
Abdominal Pain ; Asian Continental Ancestry Group* ; Constipation* ; Female ; Gastrointestinal Diseases ; Humans ; Serotonin ; Serotonin 5-HT4 Receptor Agonists

BACKGROUND/AIMS: Lack of simple and repeatable tests hampers gastric emptying studies in rats. The aim of this study was to adapt the 14C-octanoate solid gastric emptying breath test for application in rats, and to validate it against radioscintigraphic method. METHODS: After ingestion of a meal containing 3 mCi 99mTc and 2 microCi 14C-octanoate, 23 male Wistar rats were placed on a gamma camera in a airflow container. Scintigraphic images were taken at regular intervals. The amount of 14CO2 in a regularly replaced hyamine hydroxide solution, capturing CO2 in the outflow air, was counted using liquid scintillation spectrometry. 99mTc gastric retention curves and 14CO2-excretion curves were fitted to their respective data. Three rats underwent the same procedures after administration of atropine. RESULTS: Overall Tr10% (time at which 10% of the original amount of 99mTc remained in the stomach) was 355 +/- 64 minutes; Te90% (time at which 90% of total amount of 14CO2 was excreted) was 325 +/- 106 minutes. Their correlation coefficient was 0.71, R-square 0.50 and P < 0.005. Tr1/2 (50% of original amount of 99mTc remained) was 124 +/- 28 minutes; Te1/2 (50% of total amount of 14CO2 excreted) 114 +/- 32 minutes. Their correlation coefficient was 0.83 with R-square of 0.69 and P < 0.00005. In 12 immobilized animals correlation was even better: correlation coefficient 0.84; R-square 0.71 and P < 0.001 (Tr10% was 388 +/- 117 minutes; Te90% 532 +/- 219 minutes; Tr1/2 of 165 +/- 54 minutes; Te1/2 of 175 +/- 67 minutes). Atropine significantly lengthened all emptying times: 904 +/- 307 and 1461 +/- 684 minutes for Tr10% and Te90%, respectively; and 432 +/- 117 minutes for Tr1/2 and 473 +/- 190 minutes for Te1/2. CONCLUSIONS: We adapted and validated the 14C-octanoate gastric emptying breath test for application in rats.
Animals ; Atropine ; Benzethonium ; Breath Tests ; Caprylates ; Eating ; Gamma Cameras ; Gastric Emptying ; Humans ; Hydroxides ; Male ; Meals ; Rats ; Rats, Wistar ; Retention (Psychology) ; Spectrum Analysis

BACKGROUND/AIMS: Type 1 diabetes is often accompanied by gastrointestinal motility disturbances. Vagal neuropathy, hyperglycemia, and alterations in the myenteric plexus have been proposed as underlying mechanism. We therefore studied the relationship between vagal function, gastrointestinal motiliy and characteristics of the enteric nervous system in the biobreeding (BB) rat known as model for spontaneous type 1 diabetes. METHODS: Gastric emptying breath test, small intestinal electromyography, relative risk-interval variability, histology and immunohistochemistry on antral and jejunal segments were performed at 1, 8 and 16 weeks after diabetes onset and on age-matched controls. RESULTS: We observed no consistent changes in relative risk-interval variability and gastric emptying rate. There was however, a loss of phases 3 with longer duration of diabetes on small intestinal electromyography. We found a progressive decrease of nitrergic neurons in the myenteric plexus of antrum and jejunum, while numbers of cholinergic nerve were not altered. In addition, a transient inflammatory infiltrate in jejunal wall was found in spontaneous diabetic BB rats at 8 weeks of diabetes. CONCLUSIONS: In diabetic BB rats, altered small intestinal motor control associated with a loss of myenteric nitric oxide synthase expression occurs, which does not depend on hyperglycemia or vagal dysfunction, and which is preceded by transient intestinal inflammation.
Animals ; Breath Tests ; Carbamates ; Diabetes Mellitus ; Electromyography ; Enteric Nervous System ; Gastric Emptying ; Gastrointestinal Motility ; Hyperglycemia ; Immunohistochemistry ; Inflammation ; Jejunum ; Myenteric Plexus ; Nitrergic Neurons ; Nitric Oxide Synthase ; Organometallic Compounds ; Rats ; Rats, Inbred BB