Clinical assessment of gastric emptying and sensory function utilizing gamma scintigraphy: Establishment of reference intervals for the liquid and solid components of the Nottingham test meal in healthy subjects.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study presents the reference intervals of the modular "Nottingham test meal" (NTM) for assessment of gastric function by gamma scintigraphy (GSc) in a representative population of healthy volunteers (HVs) stratified for age and sex. METHODS: The NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and an optional solid component (12 solid agar-beads (0 kcal). Filling and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gamma scintigraphy parameters that describe early and late phase Gastric emptying (GE) were calculated from validated models. KEY RESULTS: Gastric emptying (GE) of the liquid component was measured in 73 HVs (male 34; aged 45±20). The NTM produced normal postprandial fullness (VAS ≥30 in 41/74 subjects). Dyspeptic symptoms were rare (VAS ≥30 in 2/74 subjects). Gastric emptying half-time with the Liquid- and Solid-component -NTM was median 44 (95% reference interval 28-78) minutes and 162 (144-193) minutes, respectively. Gastric accommodation was assessed by the ratio of the liquid-NTM retained in the proximal:total stomach and by Early phase emptying assessed by gastric volume after completing the meal (GCV0). No consistent effect of anthropometric measures on GE parameters was present. CONCLUSIONS AND INFERENCES: Reference intervals are presented for GSc measurements of gastric motor and sensory function assessed by the NTM. Studies involving patients are required to determine whether the reference interval range offers optimal diagnostic sensitivity and specificity.

Development and validation of a large, modular test meal with liquid and solid components for assessment of gastric motor and sensory function by non-invasive imaging.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study introduces the large 'Nottingham Test Meal' (NTM) for assessment of gastric motor and sensory function by non-invasive imaging. METHODS: NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and 12 solid agar-beads (0 kcal) with known breaking strength. Gastric fullness and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gastric emptying (GE) were measured in 24 healthy volunteers (HVs) by gastric scintigraphy (GS) and magnetic resonance imaging (MRI). The contribution of secretion to gastric volume was assessed. Parameters that describe GE were calculated from validated models. Inter-observer agreement and reproducibility were assessed. KEY RESULTS: NTM produced moderate fullness (VAS ≥30) but no more than mild dyspeptic symptoms (VAS <30) in 24 HVs. Stable binding of meal components to labels in gastric conditions was confirmed. Distinct early and late-phase GE were detected by both modalities. Liquid GE half-time was median 49 (95% CI: 36-62) min and 68 (57-71) min for GS and MRI, respectively. Differences between GS and MRI measurements were explained by the contribution of gastric secretion. Breaking strength for agar-beads was 0.8 N/m(2) such that median 25 (8-50) % intact agar-beads and 65 (47-74) % solid material remained at 120 min on MRI and GS, respectively. Good reproducibility for liquid GE parameters was present and GE was not altered by agar-beads. CONCLUSIONS & INFERENCES: The NTM provided an objective assessment of gastric motor and sensory function. The results were reproducible and liquid emptying was not affected by non-nutrient agar-beads. The method is potentially suitable for clinical practice.

Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging.

BACKGROUND: 5-HT(3) antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility. AIM: To assess the effects of ondansetron compared with placebo in healthy volunteers on SBWC and motility in two different groups of subjects, one studied using MRI and another using manometry. METHODS: Healthy volunteers were given either a placebo or ondansetron on the day prior to and on the study day. Sixteen volunteers underwent baseline fasting and postprandial MRI scans for 270 min. In a second study, a separate group of n = 18 volunteers were intubated and overnight migrating motor complex (MMC) recorded. Baseline MRI scans were carried out after the tube was removed. RESULTS: Fasting SBWC was markedly increased by ondansetron (P < 0.0007). Ondansetron reduced the overall antroduodenal Motility Index (P < 0.04). The subjects who were intubated had significantly lower fasting SBWC (P < 0.0002) compared with the group of subjects who were not intubated. CONCLUSIONS: The 5-HT(3) receptor antagonism increased fasting small bowel water. This was associated with reduced fasting antroduodenal Motility Index which may explain the clinical benefit of such drugs.

Effect of a novel 5-HT3 receptor agonist MKC-733 on upper gastrointestinal motility in humans.

BACKGROUND: Although 5-HT3 antagonists have been used to treat chemotherapy-induced emesis and diarrhoea-predominant irritable bowel syndrome, the effects of 5-HT3 agonists in humans are unknown. AIM: To determine the effect of MKC-733, a selective 5-HT3 receptor agonist, on upper gastrointestinal motility. METHODS: Oral MKC-733 (0.2, 1 and 4 mg) was compared with placebo in three randomized, double-blind, cross-over studies in healthy males. Antroduodenal manometry was recorded for 8 h during fasting and 3 h post-prandially (n = 12). Gastric emptying and small intestinal transit were determined by gamma-scintigraphy (n = 16). Gastric emptying, accommodation and antral motility were determined by echoplanar magnetic resonance imaging (n = 12). RESULTS: MKC-733 (4 mg) increased the number of migrating motor complexes recorded in the antrum and duodenum (P < 0.001), but had no effect on post-prandial motility. MKC-733 delayed scintigraphically assessed liquid gastric emptying (P = 0.005) and accelerated small intestinal transit (P = 0.038). Echoplanar magnetic resonance imaging confirmed the delayed gastric emptying (P < 0.001) and demonstrated a significant increase in cross-sectional area of the proximal stomach (P < 0.01). CONCLUSIONS: MKC-733 delays liquid gastric emptying in association with relaxation of the proximal stomach, stimulates fasting antroduodenal migrating motor complex activity and accelerates small intestinal transit.

Regional differences in quinine absorption from the undisturbed human colon assessed using a timed release delivery system.

PURPOSE: To investigate the regional absorption characteristics of the distal gut using two markers of permeability, quinine (a transcellular probe) and 51CrEDTA (a paracellular probe). METHODS: The permeability markers were delivered to the undisturbed gastrointestinal tract in 39 healthy volunteers using an oral timed-release delivery vehicle which allowed pulsed release within a particular site of the gut. Site of release was identified using gamma scintigraphy. Absorption of quinine and 51CrEDTA was assessed by measuring the percent excretion in the urine using HPLC and gamma counting respectively. Serial plasma samples allowed time-concentration curves for quinine to be plotted. RESULTS: There was a significant trend for diminished absorption with more distal delivery of the transcellular probe, quinine, which was: 6.26 +/- 0.87% (small intestine, n = 10); 4.65 +/- 0.93% (ascending colon, n = 16); and 2.59 +/- 0.52% (transverse colon, n = 10) of the ingested dose excreted respectively (p < 0.001). No such gradient was seen with the paracellular marker, 51CrEDTA. CONCLUSIONS: These results suggest that delayed release formulations should aim for release in the distal small bowel and proximal colon if absorption is to be maximised. Absorption by the transcellular route diminishes in the more distal colon, a fact which has implications for delayed or sustained release formulations.

Night-time quiescence and morning activation in the human colon: effect on transit of dispersed and large single unit formulations.

OBJECTIVES: Controlling the delivery of drugs to different regions of the colon remains an elusive goal. The aim of this study was to define the diurnal variation in colonic transit and show how this influences the colonic distribution and residence time of different formulations given either in the morning or evening. METHODS: Colonic transit of small particulates and a large capsule was measured during nocturnal sleep and daytime wakefulness. Eighteen healthy volunteers participated in a randomised crossover study. 111In-labelled resin (150-300 microm) and a large 99mTc-labelled non-disintegrating capsule (22 x 8 mm) were swallowed at either 0800h or 1700h. MAIN OUTCOME MEASURES: The geometric centre of isotope (range 1-9) was calculated from serial scintiscans allowing comparison of overnight and daytime transit. RESULTS: Transit of resin was delayed in the overnight compared to daytime 8 h periods (change in geometric centres (GCs), mean +/- SEM, 0.59 +/- 0.14 vs 1.46 +/- 0.39 respectively, P < 0.02). Maximal resin movement occurred immediately after awakening, prior to breakfast, in 9/18 studies (P < 0.05). The capsule was more distal than the resin at the end of the study 15 h after dosing (P < 0.001). There was marked inter-individual variability in distribution of both resin and capsule at 15 h, the range of GCs being 2.8-9 and 2.2-9, respectively. CONCLUSION: Sleep delays colonic transit and large capsules travel faster than dispersed small particles. However, substantial inter-individual variability in transit makes targeting specific regions of the human colon unreliable with either dispersed or single unit formulations.