Gastric Emptying In Healthy Volunteers Research Articles

Gender Difference of Gastric Emptying in Healthy Volunteers and Patients with Functional Dyspepsia

Background and Aim: Delayed gastric emptying is one of the reasons why functional dyspepsia (FD) occurs. The ¹³C-acetate breath test is widely used to evaluate gastric emptying. Nevertheless, the standard value of ¹³C-acetate breath test has not taken into account the gender difference of gastric emptying among healthy individuals. The main aim of this study was to readjust the standard value of ¹³C-acetate breath test in the light of gender differences. In addition, we clarified the prevalence and clinical characteristics of delayed gastric emptying in patients with FD using the modified standard values of ¹³C-acetate breath test. Methods: Fifty-two healthy individuals and 126 patients with patients with FD were enrolled. Gastric emptying was evaluated by the ¹³C-acetate breath test. The cut-off points of T_max for the diagnosis of delayed gastric emptying were determined on the basis of results from healthy individuals making a distinction of genders. Gastroesophageal reflux symptoms, dyspeptic symptoms, scores of anxiety and depression, age, body mass index (BMI), smoking and alcohol consumption were compared between the delayed gastric emptying group and the non-delayed gastric emptying group. Results: Since gastric emptying was delayed in healthy women compared with that in healthy men (T_max, 53.6 ± 19.3 vs. 42.7 ± 16.9 min, p = 0.04), we set the cut-off points of T_max at 60 min in men and at 75 min in women. In patients with FD, the prevalence of delayed gastric emptying was not different between men and women with the modified standard values of ¹³C-acetate breath test. (31.0 vs. 27.4%, p = 0.68). BMI was lower in the delayed gastric emptying group than in the non-delayed group among the male patients. Reflux symptoms were more severe in delayed gastric emptying group than in the non-delayed group among the female patients. Conclusion: The standard values of ¹³C-acetate breath test should be modified bearing the gender difference in mind. It provides us more appropriate information to understand the mechanisms of FD.

Sex difference in the effects of alcohol on gastric emptying in healthy volunteers:A study using the 13C breath test

Several studies on alcohol and gastric emptying using the (13)C breath test showed that alcohol consumption delayed gastric emptying of meals in healthy male subjects. However, they did not employ female subjects, and the retention time of alcoholic beverages in the stomach has not been examined, yet. We examined the retention time (= gastric emptying rate) of alcoholic beverages in the stomach in healthy male and female subjects. We also examined whether the congeners (nonalcoholic components) of red wine have any effect on gastric emptying. The retention time of 60 mL of red wine, vodka, congeners of red wine, or mineral water, was measured using a (13)C labeled acetic acid breath test. In male subjects, the retention time of wine and vodka was significantly longer than that of congeners and mineral water. In female subjects, although the (13)C content in the breath was slightly but significantly decreased by wine and congeners, but not by vodka, and the parameters for gastric emptying did not differ significantly among the 4 drinks. That is, alcohol hardly influenced the retention time in female subjects. In conclusion, there are sex differences in the gastric emptying rate of alcohol.

RM-131, a Novel Ghrelin Analog, Demonstrates Potent Prokinetic Activity in Phase 1 Single- and Multiple-dose Studies in Healthy Volunteers

Purpose: The unique properties of ghrelin offer great potential to treat clinical conditions associated with impaired gastric motility and energy balance. To date, however, therapeutic candidates that influence ghrelin receptor signaling have made limited progress in clinical evaluation. RM-131 is a novel pentapeptide ghrelin analog that in preclinical studies demonstrated significantly greater potency and advantageous pharmaceutical properties than native ghrelin. We aimed to determine if RM-131 showed similar effects in healthy volunteers. Methods: RM-131 was evaluated in a double-blind, placebo (P)-controlled, single ascending dose (SAD) study at 3 to 2400 μg administered by subcutaneous injection (SC) once daily in nine separate cohorts of four healthy volunteers (3 active/1 P). Endpoints included safety, tolerability and the primary pharmacodynamic (PD) endpoints of gastric emptying (GE) by breath test and expected hormonal response (growth hormone [GH] and prolactin [Pr]). RM-131 was also evaluated in a multiple ascending dose (MAD) study at 10 to 300 μg SC once or twice daily for 14 days in four separate cohorts (8 active/2 P) with similar endpoints. Lower gastrointestinal transit time was also evaluated using the SmartPillTM in a subset of subjects. Results: RM-131 was generally well-tolerated in both studies. Accelerated GE was demonstrated after single and multiple doses of ≥10 μg (35 to 55% change from baseline; p<0.05). PK/PD modeling indicated that the EC50 was <0.5 ng/mL. Results on days 1 and 7 of multiple dosing were similar (Table 1) and suggested that 10 μg was on the plateau of the dose response curve for GE. Potent effects of RM-131 were also demonstrated by dose-dependent increases in circulating levels of GH and Pr the first two hours after dosing on day one. These hormonal responses greatly diminished over time, without evidence of a parallel attenuation in GE response. In the subset of patients in the MAD study evaluated with SmartPillTM, RM-131 treatment was associated with a dose-dependent decrease in colonic transit time (˜50% decrease vs. placebo at 80 μg; p<0.07).Table 1: MAD Study: Gastric emptying time (% change from baseline) by gastric emptying breath testConclusion: RM-131 was generally well-tolerated and produced a clear acceleration of GE in healthy volunteers, even at very low doses. The potent effect on GE in healthy volunteers suggests that this compound holds promise for treatment of disease states characterized by delayed GE (gastroparesis) or otherwise slowed gastrointestinal motility, where effective prokinetic agents may be beneficial. Disclosure: Dr. Kaplan - Scientific Advisor Rhythm Pharmaceuticals. Dr. White - Consultant, Rhythm Pharmaceuticals. Ms. Spence - Consultant, Rhythm Pharmaceuticals. Ms. Kennedy - Consultant, Rhythm Pharmaceuticals. Dr. Stoner - Employee, Rhythm Pharmaceuticals. Dr. Noonan - Consultant, Rhythm Pharmaceuticals. Dr. Laken - Employee, Rhythm Pharmaceuticals. Dr. Gottesdiener - Employee, Rhythm Pharmaceuticals. This research was supported by an industry grant from Rhythm Pharmaceuticals.

Stochastic simulations of the exponential-beta function as an assessment of the validity of the choice of the Wagner–Nelson method for the analysis of 13C-octanoic acid breath tests

A compartmental model that generates the exponential-beta function μkβ(1 − e−kt)β − 1 e−kt in order to run stochastic simulations has been constructed. The mathematical considerations that lead to the development of the model and the comparison of its performance with real data sets obtained from the studies of gastric emptying in healthy volunteers using 13C-octanoic acid breath tests are demonstrated. Stochastic simulations have been used to introduce randomness. These confirmed the choice of an exponential-beta function to model the physiological system, as agreement was obtained between experimental and theoretical data. The comparisons were made by visual inspection only, as the intention was to demonstrate that the stochastic exponential-β model would generate the full range of observed curve shapes.

Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans

Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short-term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis during a 6-h infusion in humans. Ghrelin (15 pmol kg(-1) min(-1)) or saline was infused intravenously for 360 min after intake of radio-opaque markers, acetaminophen, and lactulose after a standardized breakfast in 12 male volunteers. Gastric emptying, orocecal transit, colonic transit, postprandial plasma concentrations of glucose, insulin, glucagon-like peptide-1 (GLP-1), and peptide YY were assessed. In vitro studies of gastrointestinal muscle contractility were performed. The gastric emptying rate was faster for ghrelin compared to saline (P = 0.002) with a shorter half-emptying time (50.3 +/- 3.9 vs 59.9 +/- 4.4 min, P = 0.004). There was no effect of ghrelin on orocecal or colonic transit. Postprandial elevations of plasma glucose, insulin, and GLP-1 occurred 15 min earlier and were higher with ghrelin. The insulinogenic index did not change during ghrelin infusion. Basal in vitro contractility was unaffected by ghrelin. The effect of a 6-h ghrelin infusion on gastrointestinal motility is limited to the stomach without affecting orocecal or colonic transit. Plasma glucose, insulin, and GLP-1 are elevated postprandially, probably as a result of the hastened gastric emptying. Changes in glucose homeostasis as a consequence of stimulated gastric emptying and hormone release, need to be taken into account in the use of pharmacological stimulants for the treatment of motility disorders.

W2073 Relationships Between Duodenal Contractions and Gastric Emptying in Healthy Volunteers – a Non Invasive, Scintigraphic Study

W2073 Relationships Between Duodenal Contractions and Gastric Emptying in Healthy Volunteers – a Non Invasive, Scintigraphic Study

235 PF-04548043, a Novel Motilin Receptor Agonist, Increases Gastric Emptying in Healthy Volunteers and Does Not Undergo Tachyphylaxis

235 PF-04548043, a Novel Motilin Receptor Agonist, Increases Gastric Emptying in Healthy Volunteers and Does Not Undergo Tachyphylaxis

Lack of Modulation of Gastric Emptying by Dietary Nitrate in Healthy Volunteers

Nitric oxide produced endogenously in vagal neurons modulates gastrointestinal motor activity as an important non-adrenergic and non-cholinergic neurotransmitter. Other than through endogenous biosynthesis, a high concentration of nitric oxide also occurs by chemical reactions within the stomach in the presence of gastric acid through the entero-salivary re-circulation of dietary nitrate. Although dietary nitrate can be a potential source of nitric oxide in the human stomach, there has been no report on the effect of dietary nitrate on gastric motor function. The aim of this study is to investigate the effect of dietary nitrate on gastric emptying, one of the major parameters for the gastric motor function. Fifteen healthy volunteers underwent a placebo-controlled (310 mg sodium nitrate or placebo), double-blind, crossover trial. Since a sufficient amount of gastric acid is essential for dietary nitrate-derived nitric oxide generation in the stomach, the same protocol was repeated after 1-week treatment with a proton pump inhibitor, rabeprazole. Gastric emptying was evaluated by (13)C-octanoate breath test. The sodium nitrate ingestion did not affect gastric emptying either prior to or during rabeprazole treatment, although rabeprazole treatment itself significantly delayed gastric emptying, being independent of the dietary nitrate load. Confirmation of the delayed gastric emptying with rabeprazole indicates the sensitivity of the breath test employed in the present study. In conclusion, despite the potential nitrogen source of exogenous nitric oxide, the ingestion of 310 mg sodium nitrate, which is equivalent to the average daily intake of Japanese adults, does not affect gastric emptying in healthy volunteers.

Role of endogenous opioids in the control of gastric sensorimotor function

Endogenous opioids have been implicated not only in the process of feeding but also in the control of gastric sensitivity and gastric motor responses, and impairment of antinociceptive opioid pathways has been hypothesized to contribute to the pathogenesis of functional dyspepsia. Our aim was to study the effect of suppression of endogenous opioid action by naloxone on gastric sensorimotor function in healthy volunteers. During intravenous administration of saline or naloxone (0.4 mg intravenous bolus followed by continuous infusion 20 microg kg(-1) h(-1)), sensitivity to gastric distension, gastric accommodation and fundic phasic contractility were evaluated by barostat in 15 subjects. Nutrient tolerance and meal-related symptoms were assessed using a satiety drinking test (n = 13), and solid and liquid gastric emptying were evaluated by breath test (n = 14). Naloxone did not influence gastric compliance and sensitivity. No effect on preprandial gastric tone was found but meal-induced accommodation was significantly inhibited by naloxone (P = 0.031). Subjects receiving naloxone demonstrated a higher motility index before (20.8 +/- 2.4 vs 28.0 +/- 1.9 mL s(-1), P = 0.007) and after (15.2 +/- 2.0 vs 22.7 +/- 1.5 mL s(-1), P = 0.0006) the meal. Naloxone significantly decreased the amount of food ingested at maximum satiety (715.4 +/- 77.7 vs 617.3 +/- 61.3 mL, P = 0.03). No effect of naloxone on gastric emptying was observed and intensity of postprandial symptoms was unchanged. These observations suggest that endogenous opioids are involved in the control of gastric accommodation and phasic contractility but not in the control of sensitivity to gastric distension or gastric emptying in healthy volunteers.

The effects of bolus and continuous nasogastric feeding on gastro-oesophageal reflux and gastric emptying in healthy volunteers: A randomised three-way crossover pilot study

Nasogastric feeding may result in gastro-oesophageal reflux and, therefore, increase the risk of aspiration. This may be greater when feeds are administered via a bolus than by infusion. We aimed to measure gastric emptying time and quantify gastro-oesophageal reflux in healthy volunteers given a liquid feed via an oral bolus (OB), a nasogastric tube bolus (TB) and a nasogastric tube drip (TD). Twelve male volunteers participated in three separate studies (OB, TB and TD) in random order, each 3 days apart. The feed consisted of 220 ml Ensure Plus (1.5 kcal/ml), labelled with 12 MBq (99m)Tc DTPA. The OB and TB were given over 5 min and the infusion rate for the TD was 55 ml/h. Gastric emptying time was measured using gamma scintigraphy. Gastro-oesophageal reflux was observed continuously until the stomach was empty, using a multichannel intraluminal impedance catheter. Mean (95% CI) T(50) gastric emptying times for the OB and TB studies were 41.3 (36.5-46.2) min and 36.2 (30.6-41.8) min respectively (p=0.19). The stomach emptied at a rate equal to the infusion rate in the TD studies. Median (IQR) number of reflux episodes for the OB, TB and TD studies were 4.5 (2.0-6.0), 3.0 (2.0-4.75) and 2.0 (0.25-6.25) respectively. Median (IQR) total duration of reflux for the OB, TB and TD studies were 38 (20-242), 49 (17-71) and 36 (1-125) s respectively (p=NS). The lack of difference in gastro-oesophageal reflux between bolus and continuous feeding indicates that in healthy volunteers both methods are equally safe with respect to the risk of aspiration.

The effects of bolus and continuous nasogastric feeding on gastro-oesophageal reflux and gastric emptying in healthy volunteers: a randomised three-way cross-over study

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The effects of bolus and continuous nasogastric feeding on gastro-oesophageal reflux and gastric emptying in healthy volunteers: a randomised three-way cross-over study

Summary Background & aims: Nasogastric feeding may result in gastro-oesophageal reflux and, therefore, increase the risk of aspiration. This may be greater when feeds are administered via a bolus than by infusion. We aimed to measure gastric emptying time and quantify gastrooesophageal reflux in healthy volunteers given a liquid feed via an oral bolus (OB), a nasogastric tube bolus (TB) and a nasogastric tube drip (TD). Methods: Twelve male volunteers participated in three separate studies (OB, TB and TD) in random order, each 3 days apart. The feed consisted of 220 ml Ensure Plus (1.5 kcal/ml), labelled with 12 MBq 99m Tc DTPA. The OB and TB were given over 5 min and the infusion rate for the TD was 55 ml/h. Gastric emptying time was measured using gamma scintigraphy. Gastro-oesophageal reflux was observed continuously until the stomach was empty, using a multichannel intraluminal impedance catheter.

Buprenorphine‐associated gastroparesis during in‐patient heroin detoxification

Buprenorphine is a partial mu receptor agonist used in opiate detoxification. It has been shown to cause delayed gastric emptying in healthy volunteers. We describe a case of clinically severe gastroparesis (delayed gastric emptying due to impaired contraction of the stomach) whose onset coincided with the commencement of buprenorphine-assisted detoxification. We review the literature on gastric effects of buprenorphine in healthy volunteers, providing proof of the concept that this was the most probable cause of this patient's gastroparesis.

Omeprazole delays gastric emptying in healthy volunteers: an effect prevented by tegaserod

Proton-pump inhibitors effectively suppress stomach acidity. They are widely used for treating gastro-oesophageal reflux disease and related conditions. While generally safe, omeprazole and other proton-pump inhibitors can delay gastric emptying. To test the hypothesis that tegaserod can normalize or prevent omeprazole-induced delay in gastric emptying. This was a randomized, double-blind, placebo-controlled, parallel group study in 40 healthy male volunteers. After informed consent and screening, qualified volunteers were treated with unblinded omeprazole 20 mg b.d. and either blinded tegaserod 6 mg t.d.s. (active treatment group) or placebo-matching tegaserod t.d.s. (control group) for 14 days. Gastric emptying was assessed before and after treatment, using a scintigraphy method. Omeprazole monotherapy significantly delayed gastric emptying expressed by duration of lag-phase (P < 0.007), time to gastric half-emptying (P < 0.003), and gastric retention of the meal at 60 (P < 0.002) and 120 min (P < 0.04) after its ingestion. Tegaserod taken together with omeprazole effectively prevented development of the above effects. Combined treatment was safe and well tolerated. Concomitant administration of tegaserod 6 mg t.d.s. prevented development of the delayed gastric emptying induced by omeprazole monotherapy.

Dietary protein precipitation properties have effects on gastric emptying in healthy volunteers

Background & aims: Strategies that reduce the size of particles in the stomach accelerate gastric emptying. Partial dephosphorylation of casein reduces the size of protein precipitates (curds) in acid conditions and facilitates peptic digestion. We hypothesized that changing the precipitation properties of casein by partial dephosphorylation would accelerate gastric emptying. Methods: Eight healthy male volunteers entered a prospective, double blind, randomized study with crossover design. Gastric emptying of milk based formula containing either unmodified or dephosphorylated casein was assessed by scintigraphy. Gastric pH measurements were acquired concurrently. Results: A trend to faster gastric emptying was observed for the unmodified preparation, with lower median half time (unmodified 133; dephosphorylated 214 min, P=0.09) and area under the curve (unmodified 8425 min%; dephosphorylated 9135 min%, P=0.08). A positive correlation was found between half time for the dephosphorylated preparation and the treatment effect ( r 2=0.81, P<0.02). Gastric pH was unaffected. Conclusions: The study hypothesis was rejected; indeed gastric emptying tended to be faster for the unmodified than the dephosphorylated protein. This effect was more pronounced in subjects with slow gastric emptying on the dephosphorylated preparation. Properties other than the size of protein precipitates determine the rate of gastric emptying for milk based formula.

Analysis of gastric accommodation and gastric emptying in healthy volunteers by magnetic resonance imaging (MRI)

Analysis of gastric accommodation and gastric emptying in healthy volunteers by magnetic resonance imaging (MRI)

Functional Dyspepsia and Gastric Acid: Any Relation?

Gastric acid and upper gastrointestinal disorders are closely connected, and antacids and acid secretion inhibitors are commonly used in the treatment of such disorders. Gastro-oesophageal ree ux disease (GERD) and peptic ulcer disease are undoubtedly acid-related disorders (although Helicobacter pylori might be more important in patients with ulcer disease), but the relation between acid and functional dyspepsia (FD) (or non-ulcer dyspepsia) has been questioned for many years (1). Previous discussions have been hampered by poor dee nition of FD and different diseases in the upper gastrointestinal tract were in part mixed in. Although the different disease entities have been better dee ned with less overlap, the role of gastric acid in patients with FD remains obscure. The uncertainty is ree ected in the treatment. There are well-documented and effective treatments (medical and surgical) for patients with peptic ulcer disease and GERD, whereas the treatment for patients with FD remains controversial. Symptomatic improvement following treatment with acid secretion inhibitors indicates a relation between acid and FD. Numerous studies have evaluated the symptomatic effect of antacids, H2-receptor antagonists and proton-pump inhibitors in patients with FD, and meta-analyses sum up the results (2, 3). Bolling-Sternevald et al. present one further study in this issue of the Scandinavian Journal of Gastroenterology (4). Most reviews and meta-analyses, like the study by Bolling-Sternevald et al., conclude that acid secretion inhibitors are effective, but the therapeutic gain above placebo is small (in the range of 10%‐20%) and the clinical signie cance of the effect is poorly documented. The clinical benee t is also mentioned in the study by Bolling-Sternevald et al. (4). The e nding that mild abdominal pain/discomfort compared to moderate/severe symptoms was indicative of a favourable outcome, and that the PGWB index (quality of life) could not detect any signie cant differences between the treatment groups, questions the clinical usefulness of the treatment in all patients. Most studies indicate that the effect is restricted to a subset of patients (5). If the effect is restricted to a subgroup with an impressive effect, the therapeutic effect might be highly valuable to this group. With the exception of an effect in patients with ree ux-like symptoms (who might have GERD and not FD), it has been dife cult to characterize the responder. Accordingly, the ‘trial and error’ method has been used to tailor the optimal therapy for the individual patient. Various pathophysiological mechanisms in the oesophagus, stomach and duodenum might bring about acid-induced FD. A characteristic pattern of acid ree ux to the oesophagus might in some patients cause dyspepsia (without ree ux symptoms), which is effectively treated with acid secretion inhibitors (6). Acid in the stomach might also provoke symptoms. Direct installation of acid in the stomach and increased acid secretion after injection of pentagastrin provoke symptoms in patients with dyspepsia, and rebound hypersecretion after withdrawal of acid secretion inhibitors induces dyspepsia in healthy volunteers (7‐9). Sensitivity and motility in the upper GI tract are often altered in patients with FD, and acid affects both gastric and duodenal sensitivity and motility. HCl increases the sensitiveness of mucosal mechanoreceptors in the gastric wall, and acid suppressants delay gastric emptying in healthy volunteers (10, 11). Patients with FD, but not healthy volunteers, report nausea after infusion of acid in the duodenum (12, 13). Motility studies after infusion of acid in the duodenal bulb in the fasting period demonstrate decreased clearance of exogenous acid from the duodenal bulb and decreased duodenal motor activity in dyspeptic patients compared to controls (12‐14). Acid secretion inhibitors alter the antropyloroduodenal motor response to acid infusion (14). This variety of pathophysiological disturbances in patients with FD explains the dife culties in predicting response to acid secretion inhibitors in the individual patient and in characterizing the responder. Inall, it is likely that acid provokes symptoms in a subset of patients with FD through various mechanisms in the upper gastrointestinal tract. Non-acid related disturbance is the cause of symptoms in other patients. Further research should aim at expanding our understanding of the pathophysiology in patients with FD and improve the methods for predicting response to treatment in the individual patient.

Comparison of two mathematical programmes in evaluation of the 13C-octanoic acid breath test for gastric emptying in healthy volunteers

Comparison of two mathematical programmes in evaluation of the 13C-octanoic acid breath test for gastric emptying in healthy volunteers

Comparison of two mathematical programmes in evaluation of the 13C-octanoic acid breath test for gastric emptying in healthy volunteers

Comparison of two mathematical programmes in evaluation of the 13C-octanoic acid breath test for gastric emptying in healthy volunteers

Effect of L-NMMA on postprandial transient lower esophageal sphincter relaxations in healthy volunteers.

In a previous study we showed that nitric oxide (NO) synthesis inhibition by NG-monomethyl-L-arginine (L-NMMA) reduced the number of transient lower esophageal sphincter relaxations (TLESRs) triggered by gastric balloon distention. The role of NO in postprandial TLESRs and gastroesophageal reflux, however, is unknown. Therefore, we studied the effect of L-NMMA on meal-induced TLESRs and reflux episodes with simultaneous recording of esophageal peristalsis, intraesophageal and intragastric pH, and gastric emptying in healthy volunteers. Ingestion of a solid meal resulted in an increase in TLESRs [8.5 (6.3-11.0) 60 min] which was significantly inhibited by L-NMMA [6.0 (4.0-8.8) 60 min, P < 0.05]. In addition, the total number of reflux episodes was reduced. L-NMMA had no effect on intragastric meal distribution and gastric emptying, but attenuated the postprandial increase in intragastric pH. These results confirm the involvement of NO in the neurocircuitry underlying the triggering of TLESRs. The reduction in reflux by L-NMMA has to be confirmed in patients with gastroesophageal reflux disease. NO may be involved in the regulation of gastric acid secretion.