Clinical validation of the VIPUN™ gastric monitoring system versus manometry for the evaluation of gastric motility.

BACKGROUND: Gastrointestinal dysmotility is frequently suspected in patients with gastroparesis, functional dyspepsia, and ileus, and in the intensive care unit. Monitoring of gastric motility in clinical practice remains challenging. A novel technology was developed to meet the medical need for a widely available bedside tool to monitor gastric motility continuously. The VIPUN™ Gastric Monitoring System (GMS) comprises a nasogastric feeding tube with intragastric balloon to allow for measuring gastric contractions. AIMS: To compare the performance of the VIPUN GMS versus a reference technique (manometry). METHODS: In this validation study in healthy subjects, the investigational catheter and a solid-state manometry catheter were placed in the stomach concomitantly. Motility was recorded for 2.5 h: 2 h in a fasting state, followed by a 400-kcal liquid meal, and monitoring of the fed state for the remaining half hour. The performance of both systems was compared by automated recognition and manual identification of the contractile activity. Data are presented as mean (standard deviation). KEY RESULTS: The analysis set comprised 13 healthy subjects (6 women, age: 27.5 (8.1) years, BMI: 22.2 (2.46) kg/m2). Automatically-recognized contractility was strongly correlated between the two techniques (endpoint: contraction duration; Spearman ρ = 0.96, p < 0.001). A correlation was also observed between the number of individual contractions identified by expert gastroenterologists on both technologies independently (ρ = 0.71, p = .007) and between the contractions identified by the experts and by the GMS software (ρ = 0.87, p = 0.001). No serious or unanticipated adverse events occurred. CONCLUSIONS & INFERENCES: The observed strong correlations with the gold standard, manometry, validate the performance of the VIPUN GMS as a gastric monitoring system.

Do prokinetic agents provide symptom relief through acceleration of gastric emptying? An update and revision of the existing evidence.

BACKGROUND: Gastroparesis and functional dyspepsia are disorders characterized by upper gastrointestinal symptoms and multifaceted etiologies. One of the main therapeutic approaches is accelerating gastric emptying (GE) by means of prokinetic agents. Their efficacy has been demonstrated, although the association between symptom improvement and acceleration of emptying is less clear. Meta-analyses have found contradictory results. Differences in applied methodology and included trials might drive these contradictions. OBJECTIVE: To provide a transparent meta-analysis update to elucidate the association between symptom improvement and acceleration of GE due to gastroprokinetic agents available for long-term use in patients with gastroparesis. DESIGN: Two approaches from earlier meta-analyses were executed and compared. One analyzed the relative changes on active treatment versus baseline, the other compared the change from baseline on active treatment versus the change from baseline on placebo. Papers that reported sufficient numerical data for both analyses were selected. Both analyses included the same trials. RESULTS: Overall, both approaches yield the same positive direction of association between symptom improvement and acceleration of emptying (0.291 (-0.391, 0.972), p = 0.4 and 0.453 (0.123, 0.782), p = 0.007 for the active-only and placebo-controlled analysis respectively). The association between symptom improvement and GE acceleration for studies using optimal GE tests was either 0.028 (p > 0.9) or 0.463 (p = 0.007), and for sub-optimal GE tests was either 0.370 (p = 0.4) or 0.052 (p > 0.9) depending on the used meta-analysis methodology. CONCLUSIONS: The applied methodology for GE testing, and the meta-analysis substantially impacts the conclusion. When considering the clinically relevant outcome of improvement from baseline, symptoms and emptying improve with prokinetics, but no correlation is found between both aspects. When the change over placebo is considered, limiting the analysis to scientifically more rigorous study approaches, changes in emptying rate and symptom improvement are positively associated.

New Stent Technologies.

Ureteral stents are an indispensable part of any (endo-) urologic practice. Despite the widely demonstrated advantages of stents, they also carry a considerable risk of side effects and complications, such as urinary symptoms, pain, hematuria, decreased quality of life, stent-related infection, and encrustation. Multiple pathways in preventing or mitigating these side effects and complications and improving stent efficacy have been and are being investigated, including stent architecture and design, biomaterials, and coatings. This article provides an update on currently researched and available stents as well as future perspectives.

Supraphysiological effects of pancreatic polypeptide on gastric motor function and nutrient tolerance in humans.

Pancreatic polypeptide (PP) is known to affect food intake. In this exploratory study, we set out to investigate its supraphysiological effect on food tolerance, gastric accommodation, and emptying. In 12 healthy volunteers, 0, 3, or 10 pmol*kg-1 *min-1 PP was administered intravenously (PP0, PP3 or PP10). Thirty minutes thereafter, nutrient drink infusion (60 ml*min-1 ) through a nasogastric feeding tube was started until maximum satiation. Gastric accommodation was assessed by measuring the intragastric pressure (IGP; nasogastric manometry). In a separate test, the effect of PP0 or PP10 on gastric emptying was tested in 10 healthy volunteers and assessed using the 13 C breath test. Results are presented as mean ± SEM, and p < 0.05 was considered significant. For the IGP test, PP increased ingested nutrient volume: 886 ± 93, 1059 ± 124, and 1025 ± 125 ml for PP0, PP3, and PP10, respectively (p = 0.048). In all groups, Nadir IGP values were reached upon food intake (transformed values: 1.5 ± 0.2, 1.7 ± 0.3, and 1.6 ± 0.3 mmHg for PP0, PP3, and PP10, respectively; NS) to return to baseline thereafter. For the gastric emptying study, volunteers ingested a similar nutrient volume: 802 ± 119 and 1089 ± 128 ml (p = 0.016), and gastric half-emptying time was 281 ± 52 and 249 ± 37 min for PP0 and PP10, respectively (NS). No significant correlation between tolerated nutrient volume and IGP drop (R² < 0.01; p = 0.88 for PP0 vs. PP3 and R² =0.07; p = 0.40 for PP0 vs. PP10, respectively) or gastric half-emptying time (R² = 0.12; p = 0.32) was found. A supraphysiological PP dose enhances food tolerance; however, this effect is not mediated through gastric motility. CLINICAL TRIAL REGISTRY NUMBER: NCT03854708 is obtained from clinicaltrials.gov.

Effect of protein composition of enteral formula on gastric content volume during continuous feeding: A randomized controlled cross-over study in healthy adults.

BACKGROUND & AIMS: Enteral nutrition with polymeric intact protein formula is the preferred medical nutrition strategy in critically ill patients when oral intake is insufficient. Enteral nutrition formulas are often rich in casein protein, which has coagulating properties. Coagulation in the stomach impedes gastric emptying and might result in high gastric residual volumes which are a clinical sign of gastrointestinal intolerance and a major reason to decrease or to discontinue enteral feeding. In this study the impact of protein composition of enteral formula on gastric content volume (GCV) during and after continuous feeding was tested in healthy volunteers in whom gastrointestinal conditions of critically ill patients were mimicked. METHODS: An enteral formula including 4 proteins (P4) with non-coagulating properties was compared to a casein-dominant formula (Cas) with coagulating properties. Esomeprazole and codeine were administered to mimic stress ulcer prophylaxis and induce gastroduodenal motor dysfunction, both being hallmarks of critically ill patients. GCV was measured with magnetic resonance imaging during and after continuous enteral feeding (100 mL/h for 4h) in a randomized single-center cross-over study. Results are provided as mean (SD). Significance level of p < 0.05 was applied. RESULTS: Twenty subjects completed the study (14 women, 6 men, 25.8 (4.6) years old, BMI: 22.5 (1.5) kg/m2). The GCV as change from baseline at T = 240 (primary endpoint) did not differ between study products (P4: 124.3 (83.4) vs. Cas: 137.1 (102.0) mL, 95% CI: -57.4, 27.0, p = 0.457). During feeding and after cessation of feeding, the area under the GCV-curve (AUC0-360 GCV) for P4 and Cas was 44631.1 (15546.1) and 52822.2 (19686.1) mL∗min, respectively (p = 0.061). During feeding the GCV was lower at T = 180 min (175.4 (64.8) vs. 205.2 (75.4) mL, p = 0.038) and after cessation of feeding at T = 300 min (81.3 (71.1) vs. 116.3 (84.3) mL, p = 0.004) and T = 330 min (39.9 (53.9) vs. 73.6 (81.1) mL, p = 0.031). With P4 it took less time to reach half of the GCV at T = 240 min compared to Cas (52.8 (27.6) vs. 65.4 (29.9) min, p = 0.020). CONCLUSIONS: In this study in which healthy volunteers received esomeprazole and codeine to mimic gastrointestinal conditions of critically ill patients, observations of secondary endpoints suggest faster gastric emptying with P4 compared to Cas, and less gastric accumulation, possibly due to the non-coagulating properties of the P4 protein blend. Considering the small effect and the possible clinical relevance of reduced intragastric accumulation of enteral nutrition, the potential impact of protein coagulation should be further investigated in relevant study populations. Registered under Netherlands Trial Register identifier no. NTR6423.

Gastric accumulation of enteral nutrition reduces pressure changes induced by phasic contractility in an isovolumetric intragastric balloon.

BACKGROUND: An isovolumetric intragastric balloon to continuously measure gastric phasic contractility was recently developed by us. We aimed to investigate the readout of this technique in relation to gastric content and gastric emptying. METHODS: In this crossover investigation, the VIPUNTM Gastric Monitoring System, which comprises a double lumen nasogastric feeding tube with integrated intragastric balloon, was used to assess phasic gastric contractility by interpretation of the pressure in an isovolumetric balloon in 10 healthy subjects. Balloon pressure was recorded in fasted state, during a 2-hour intragastric nutrient infusion (1 kcal/ml at 25, 75, or 250 ml/h) and 4 hours post-infusion, and quantified as Gastric Balloon Motility Index (GBMI), ranging from 0 (no contractility) to 1 (maximal contractility). Gastric accumulation was quantified with magnetic resonance imaging and gastric emptying with a13 C-breath test. Results are expressed as mean(SD). KEY RESULTS: GBMI was significantly lower during infusion at 250 ml/h compared to baseline (0.13(0.05) versus 0.46(0.12)) and compared to infusion at 25 (0.54(0.21)) and 75 ml/h (0.43(0.20)), all P < 0.005. Gastric content volume was larger after infusion at 250 versus 75 ml/h (P < 0.001). Half-emptying time and accumulation were both negatively correlated with postprandial contractility. Postprandial GBMI was significantly lower when GCV>0 ml compared to when the stomach was empty. CONCLUSIONS AND INFERENCES: Enteral nutrition dose-dependently decreased the contractility readout. This decrease was linked to gastric accumulation of enteral nutrition.

Erythromycin stimulates phasic gastric contractility as assessed with an isovolumetric intragastric balloon pressure measurement.

BACKGROUND: A novel technique to assess gastric motility by measuring the pressure in a low-volume intragastric balloon was developed to monitor (disordered) motility. We previously showed that this technique allows measuring pharmacologically induced inhibition of motility. In this study, we assessed whether it is possible to measure pharmacologically induced stimulation of gastric motility using 200 mg erythromycin. Erythromycin is a highly effective stimulator of gastric emptying and contractility. METHODS: After an overnight fast, a nasogastric balloon catheter was introduced in healthy subjects. After inflation with 120 ml of air, the catheter was connected to a pressure sensor. Intraballoon pressure was continuously recorded for 4 h. After a baseline recording of 2 h, 200 mg erythromycin was infused intravenously over 20 min while the recording continued for 2 h. Epigastric symptoms were surveyed on 100-mm visual analogue scales. Motility was quantified from the pressure recording as a gastric balloon motility index. Wilcoxon signed-rank tests were performed. Data are shown as median (interquartile range). KEY RESULTS: Six subjects were enrolled and five completed the procedures (age: 28 (25-29) years, body mass index: 24.0 (23.8-24.5) kg m-2 ). One subject could not tolerate tube placement. Bloating, nausea, and epigastric sensation scores were 0 (0-3), 0 (0-1), and 1 (0-1) mm, respectively. Erythromycin significantly increased the motility index from 0.48 (0.41-0.51) to 0.79 (0.70-0.82) (p = 0.03). CONCLUSIONS AND INFERENCES: Gastric motility assessed via pressure measurement in a low-volume intragastric balloon is able to detect pharmacologically stimulated motility in healthy subjects, which further validates this technique.

Continuous Assessment of Gastric Motility and Its Relation to Gastric Emptying in Adult Critically Ill Patients.

BACKGROUND: Critically ill patients frequently develop feeding intolerance, which is difficult to predict. In healthy subjects, gastric motility, assessed by nasogastric balloon tube, correlated with gastric emptying. We now investigated this correlation in critically ill patients, as well as the feasibility and safety of such application in a pilot study. METHODS: Endotracheally intubated adults scheduled to receive enteral nutrition (EN) were included. After insertion of a double-lumen nasogastric balloon tube and radiographic confirmation of position, balloon pressure was recorded for 10 hours after inflation (4 hours fasted, 2 hours during administration of 13 C-labeled EN, and 4 hours postprandially). Gastric motility was expressed as Gastric Balloon Motility Index (GBMI), reflecting the fraction of time in which phasic gastric contractions occurred. Gastric emptying was assessed by 13 C-octanoate breath test and expressed as gastric half-emptying time (GET½). Correlation between GBMI (assessed in different time intervals) and GET½ was investigated by Pearson/Spearman correlation. Feasibility was defined as the success of tube placement and pressure recording. Safety was assessed based on adverse device effects. RESULTS: Thirty patients were enrolled, of whom 19 had paired GBMI and GET½ data. There was no correlation between GBMI and GET½. The tube was successfully placed in 28/30 (93.3%) patients. In 3/28 (10.7%) patients, balloon leakage precluded analysis. Two safety events were directly linked to the device. CONCLUSION: This pilot study showed no significant correlation between balloon-assessed gastric motility and emptying in critically ill patients. The feasibility/safety profile of the balloon tube appears similar to that of standard nasogastric tubes.

Repeated Gastric Motility Measurement Affects Gastric Motility and Epigastric Symptom Sensation.

Background: Gastric motility is an important determinant of gastric emptying, epigastric symptom generation, and intolerance to food. Motility is classically assessed directly using manometry or an intragastric balloon. These diagnostic methods are perceived as stressful and invasive, which, by itself might influence the readout of these assessments. Our hypothesis was that with repeated exposure to an invasive motility test the outcome would be different. Methods: Gastric motility was assessed with a custom-made orogastric balloon catheter in 10 healthy subjects naive to intubation. A motility index ranging from 0 (no motility) to 1 (maximum motility) was calculated in the fasted state for 3.5 h. Symptoms were surveyed with visual analog scales of 100 mm. Results are presented as median (interquartile range). Results: Motility index during visit 1 [0.40 (0.37-0.59)] was lower compared to visit 2 [0.50 (0.45-0.66); not significant] and 3 [0.63 (0.50-0.71); p = 0.016]. Nausea and pain scores were significantly higher during visit 1 (35 (2.8-126) and 103 (88-125) mm, respectively) compared with visit 3 [1 (2.8-26) mm (p = 0.016) and 75 (30-100) mm (p = 0.008), respectively]. No adverse events were observed. Conclusions: Repeated exposure to an invasive method to assess motility resulted in more vigorous motility and lower symptom scores. Caution is warranted when interpreting functional assessments, as prior exposure to invasive tests might confound the obtained results through habituation.

Codeine delays gastric emptying through inhibition of gastric motility as assessed with a novel diagnostic intragastric balloon catheter.

BACKGROUND: The use of opioids as analgesic is on the rise, despite their inhibitory effect on gastric emptying. A novel feeding catheter with integrated intragastric balloon was developed to continuously assess gastric motility, enabling to investigate the effect of opioids on motility and emptying simultaneously. We aimed to discriminate normal and pharmacologically impaired gastric motility and its impact on gastric emptying in healthy adults. METHODS: The VIPUN Gastric Monitoring System comprises a nasogastric balloon catheter and a monitoring unit. In a four-way randomized, single-blinded, cross-over study, subjects received either placebo or 58.8 mg codeine phosphate in combination with either an uninflated or an inflated (180 mL) balloon catheter. Motility-induced pressure changes were recorded for 6 hours. During the first 2 hours, nutrients were infused (225 kcal, 75 mL/h). Gastric emptying was assessed with a 13 C-octanoate breath test and expressed as gastric half-emptying time (GET½). An algorithm, designed to detect phasic contractility, converted pressure changes to a gastric balloon motility index (GBMI). Results are presented as mean(SD). KEY RESULTS: Eighteen subjects completed the investigation (32(13) years, 22(2) kg/m2 ). After codeine, GBMI was lower (0.31(0.16)) and GET½ was longer (233(57) minutes) compared with placebo (GBMI: 0.48(0.15), P < .01 and GET½: 172(12) minutes, P < .001). Within-subject ΔGET½ correlated significantly with ΔGBMI (r = -0.77 and P < .001). CONCLUSIONS AND INFERENCES: The VIPUN Gastric Monitoring System allowed to assess gastric motility safely and continuously. The correlation between pharmacologically decreased gastric emptying and motility indicates a strong link between both. Gastric motility, measured with this innovative device, can be an indicator for gastrointestinal intolerance.

A comparison of various intragastric balloons for the assessment of gastric motility.

BACKGROUND: There is a clear need for a novel method to readily assess gastric motility in daily clinical practice. METHODS: In a crossover design, 10 noncompliant balloons of different shape and volume (25-350 mL), attached to a classic feeding tube, were introduced in the stomach of eight healthy volunteers. In the same experiment, a High-Resolution Manometry (HRM) catheter was positioned throughout the stomach. Gastric motility was recorded during fasting (2 hours) and liquid nutrient administration (30 minutes). Motility was quantified using a peak detection algorithm. Symptoms were recorded throughout the experiment using visual analog scales (100 mm). Results are presented as mean ± SD. KEY RESULTS: The % time during which motility-induced pressure increments could be detected with HRM but not by the balloon varied from 42 ± 24% in the smallest (25 mL) balloon to 1 ± 1% in the 330 mL balloon. On the other hand, bloating, discomfort and nausea scores were 0 ± 0, 0 ± 0 and 2 ± 5 mm, respectively, for the smallest balloon (25 mL) while these scores were 28 ± 38, 13 ± 30, and 38 ± 30 mm, respectively, for the largest balloon (350 mL). A phase III contraction pattern was consistently evoked in balloons with a volume >200 mL. CONCLUSION: Gastric motility could be assessed more accurately with larger volume balloons, while epigastric symptoms were evoked with increasing balloon volume. The optimal balloon to measure gastric motility has a 5 cm diameter and is 11 cm long (210 mL). A nasogastric balloon catheter can now be developed that enables relatively easy monitoring of gastric motility in patients with epigastric symptoms.

Comparison of Functional Outcome after Extended versus Super-Extended Pelvic Lymph Node Dissection during Radical Prostatectomy in High-Risk Localized Prostate Cancer.

BACKGROUND: Urinary continence and erectile function (EF) are best preserved when meticulous dissection of prostate and nerve sparing technique are used during radical prostatectomy (RP). However, extent of lymph node dissection (LND) may also adversely affect functional results. OBJECTIVE: To determine whether performing a super-extended LND (seLND) has a significant effect on recovery of urinary continence and EF after RP. DESIGN SETTING AND PARTICIPANTS: All patients who underwent RP from January 2007 until December 2013 were handed questionnaires assessing continence and EF. All patients in whom at least an extended LND (eLND) was performed were selected. This search yielded 526 patients. 172 of these patients had filed out 2 or more questionnaires and were included in our analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All questionnaires were reviewed. We used Kaplan-Meier analyses and multivariate Cox analysis to assess the difference in recovery of continence and EF over time for eLND/seLND. Primary endpoints were full recovery of continence (no loss of urine) and full recovery of EF (successful intercourse possible). Patients who did not reach the endpoint when the last questionnaire was filled out were censored at that time. Median follow-up was 12.43 months for continence, and 18.97 months for EF. RESULTS AND LIMITATIONS: Patients undergoing seLND have a lower chance of regaining both urinary continence [hazard ratio (HR) 0.59, 95% CI 0.39-0.90, p = 0.026] and EF (HR 0.28, 95% CI 0.13-0.57, p = 0.009). Age at surgery had a significant influence on both continence and EF in multivariate analysis. Major limitation of the study was that no formal preoperative assessment of continence and potency was done. CONCLUSION: Extending the LND template beyond the eLND template may cause at least a significant delay in recovery of urinary continence and leads to less recovery of EF.

Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers.

Background: Denatonium benzoate (DB) has been shown to influence ongoing ingestive behavior and gut peptide secretion.Objective: We studied how the intragastric administration of DB affects interdigestive motility, motilin and ghrelin plasma concentrations, hunger and satiety ratings, and food intake in healthy volunteers.Design: Lingual bitter taste sensitivity was tested with the use of 6 concentrations of DB in 65 subjects. A placebo or 1 µmol DB/kg was given intragastrically to assess its effect on fasting gastrointestinal motility and hunger ratings, motilin and ghrelin plasma concentrations, satiety, and caloric intake.Results: Women (n = 39) were more sensitive toward a lingual bitter stimulus (P = 0.005) than men (n = 26). In women (n = 10), intragastric DB switched the origin of phase III contractions from the stomach to the duodenum (P = 0.001) and decreased hunger ratings (P = 0.04). These effects were not observed in men (n = 10). In women (n = 12), motilin (P = 0.04) plasma concentrations decreased after intragastric DB administration, whereas total and octanoylated ghrelin were not affected. The intragastric administration of DB decreased hunger (P = 0.008) and increased satiety ratings (P = 0.01) after a meal (500 kcal) in 13 women without affecting gastric emptying in 6 women. Caloric intake tended to decrease after DB administration compared with the placebo (mean ± SEM: 720 ± 58 compared with 796 ± 45 kcal; P = 0.08) in 20 women.Conclusions: Intragastric DB administration decreases both antral motility and hunger ratings during the fasting state, possibly because of a decrease in motilin release. Moreover, DB decreases hunger and increases satiety ratings after a meal and shows potential for decreasing caloric intake. This trial was registered at clinicaltrials.gov as NCT02759926.

High School Football and Late-Life Risk of Neurodegenerative Syndromes, 1956-1970.

OBJECTIVE: To assess whether athletes who played American varsity high school football between 1956 and 1970 have an increased risk of neurodegenerative diseases later in life. PATIENTS AND METHODS: We identified all male varsity football players between 1956 and 1970 in the public high schools of Rochester, Minnesota, and non-football-playing male varsity swimmers, wrestlers, and basketball players. Using the medical records linkage system of the Rochester Epidemiology Project, we ascertained the incidence of late-life neurodegenerative diseases: dementia, parkinsonism, and amyotrophic lateral sclerosis. We also recorded medical record-documented head trauma during high school years. RESULTS: We identified 296 varsity football players and 190 athletes engaging in other sports. Football players had an increased risk of medically documented head trauma, especially if they played football for more than 1 year. Compared with nonfootball athletes, football players did not have an increased risk of neurodegenerative disease overall or of the individual conditions of dementia, parkinsonism, and amyotrophic lateral sclerosis. CONCLUSION: In this community-based study, varsity high school football players from 1956 to 1970 did not have an increased risk of neurodegenerative diseases compared with athletes engaged in other varsity sports. This was from an era when there was a generally nihilistic view of concussion dangers, less protective equipment, and no prohibition of spearing (head-first tackling). However, the size and strength of players from previous eras may not be comparable with that of current high school athletes.

The motilin receptor agonist erythromycin stimulates hunger and food intake through a cholinergic pathway.

BACKGROUND: Motilin-induced phase III contractions have been identified as a hunger signal. These phase III contractions occur as part of the migrating motor complex (MMC), a contractility pattern of the gastrointestinal tract during fasting. The mechanism involved in this association between subjective hunger feelings and gastrointestinal motility during the MMC is largely unknown, however, as is its ability to stimulate food intake. OBJECTIVES: We sought to 1) investigate the occurrence of hunger peaks and their relation to phase III contractions, 2) evaluate whether this relation was cholinergically driven, and 3) assess the ability of the motilin receptor agonist erythromycin to induce food intake. DESIGN: An algorithm was developed to detect hunger peaks. The association with phase III contractions was studied in 14 healthy volunteers [50% men; mean ± SEM age: 25 ± 2 y; mean ± SEM body mass index (BMI; in kg/m(2)): 23 ± 1]. The impact of pharmacologically induced phase III contractions on the occurrence of hunger peaks and the involvement of a cholinergic pathway were assessed in 14 healthy volunteers (43% men; age: 29 ± 3 y; BMI: 23 ± 1). Last, the effect of erythromycin administration on food intake was examined in 15 healthy volunteers (40% men; age: 28 ± 3 y; BMI: 22 ± 1). RESULTS: The occurrence of hunger peaks and their significant association with phase III contractions was confirmed (P < 0.0001). Pharmacologically induced phase III contractions were also significantly associated with hunger peaks (P < 0.05), and this association involved a cholinergic pathway. Administering erythromycin significantly stimulated food intake compared with placebo (53% ± 13% compared with 10% ± 5%; P < 0.05). CONCLUSIONS: Motilin-induced phase III contractions induced hunger feelings through a cholinergic pathway. Moreover, erythromycin stimulated food intake, suggesting a physiologic role of motilin as an orexigenic signal from the gastrointestinal tract. This trial was registered at www.clinicaltrials.gov as NCT02633579.

Targeting extra-oral bitter taste receptors modulates gastrointestinal motility with effects on satiation.

Bitter taste receptors (TAS2Rs) are present in extra-oral tissues, including gut endocrine cells. This study explored the presence and mechanism of action of TAS2R agonists on gut smooth muscle in vitro and investigated functional effects of intra-gastric administration of TAS2R agonists on gastric motility and satiation. TAS2Rs and taste signalling elements were expressed in smooth muscle tissue along the mouse gut and in human gastric smooth muscle cells (hGSMC). Bitter tastants induced concentration and region-dependent contractility changes in mouse intestinal muscle strips. Contractions induced by denatonium benzoate (DB) in gastric fundus were mediated via increases in intracellular Ca(2+) release and extracellular Ca(2+)-influx, partially masked by a hyperpolarizing K(+)-efflux. Intra-gastric administration of DB in mice induced a TAS2R-dependent delay in gastric emptying. In hGSMC, bitter compounds evoked Ca(2+)-rises and increased ERK-phosphorylation. Healthy volunteers showed an impaired fundic relaxation in response to nutrient infusion and a decreased nutrient volume tolerance and increased satiation during an oral nutrient challenge test after intra-gastric DB administration. These findings suggest a potential role for intestinal TAS2Rs as therapeutic targets to alter gastrointestinal motility and hence to interfere with hunger signalling.

Effect of pancreatic polypeptide on gastric accommodation and gastric emptying in conscious rats.

Pancreatic polypeptide (PP) is an anorexigenic hormone released from pancreatic F cells upon food intake. We aimed to determine the effect of PP on gastric accommodation and gastric emptying in conscious Wistar HAN rats to investigate whether effects on motor function could contribute to its anorexigenic effects. Intragastric pressure (IGP) was measured through a chronically implanted gastric fistula during the infusion of a nutrient meal (Nutridrink; 0.5 ml/min). Rats were treated with PP (0, 33 and 100 pmol·kg(-1)·min(-1)) in combination with N(G)-nitro-L-arginine methyl ester (L-NAME; 180 mg·kg(-1)·h(-1)), atropine (3 mg·kg(-1)·h(-1)), or vehicle. Furthermore, the effect of PP was tested after subdiaphragmal vagotomy of the stomach. Gastric emptying of a noncaloric and a caloric meal after treatment with 100 pmol·kg(-1)·min(-1) PP or vehicle was compared using X-rays. PP significantly increased IGP during nutrient infusion compared with vehicle (P < 0.01). L-NAME and atropine significantly increased IGP during nutrient infusion compared with vehicle treatment (P < 0.005 and 0.01, respectively). The effect of PP on IGP during nutrient infusion was abolished in the presence of L-NAME and in the presence of atropine. In vagotomized rats, PP increased IGP compared with intact controls (P < 0.05). PP significantly delayed gastric emptying of both a noncaloric (P < 0.05) and a caloric (P < 0.005) meal. PP inhibits gastric accommodation and delays gastric emptying, probably through inhibition of nitric oxide release. These results indicate that, besides the well-known centrally mediated effects, PP might decrease food intake through peripheral mechanisms.

The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis.

OBJECTIVES: The relationship between symptom improvement (SI) and acceleration of gastric emptying (GE) for different drugs used in the treatment of idiopathic and diabetic gastroparesis is uncertain. In this paper we examined the study-specific correlations between SI and GE, and we performed a meta-regression analysis of the association across multiple studies. METHODS: The MEDLINE database (1,946 to present) was searched, and only controlled trials or trials with an established effective comparator that compared both SI and GE were included. RESULTS: Studies were identified for metoclopramide (n=6), domperidone (n=6), cisapride (n=14), erythromycin (n=3), botulinum toxin (n=2), and levosulpiride (n=3). Even though most drugs concomitantly improved symptoms and accelerated GE, no study reported a significant correlation between SI and GE. Moreover, a correlation analysis over all studies using meta-regression did not show a significant relationship between SI and GE. Our findings need to be qualified by inconsistencies in study methods, which is a limitation but also suggests that our findings are robust to methodological factors. CONCLUSIONS: In this review, no evidence of a relationship between SI and GE was identified for different drugs used for the treatment of gastroparesis. This finding questions the use of GE measurement to direct drug development for gastroparesis.