A double-blind, randomized, placebo-controlled trial of itopride (100 and 200 mg three times daily) on gastric motor and sensory function in healthy volunteers

Itopride, a dopamine D2 antagonist and acetylcholinesterase inhibitor, significantly improved symptoms in patients with functional dyspepsia in one phase II randomized trial. However, the mechanisms by which itopride may improve symptoms are unknown. We aimed to compare the effects of two doses of itopride and placebo on gastric volumes, gastric emptying, small bowel transit and satiation in female and male healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 7 days of itopride 100 mg (n = 16) or 200 mg (n = 15) or placebo (n = 15) t.i.d. Validated methods were used to study gastric accommodation (single photon emission computed tomography), gastric emptying and orocecal transit and satiation postnutrient challenge. The three arms were comparable with regard to age, gender and body mass index. There were no statistically significant effects of itopride on gastric emptying, orocecal transit, fasting gastric volume, maximum tolerated volume or aggregate symptom score with nutrient drink challenge. Postprandial (PP) change in gastric volume differed in the three groups (P = 0.019): 625[+/-28 (SEM)], 555(+/-26) and 512(+/-33) in placebo, itopride 100 and 200 mg groups, respectively. In healthy subjects, itopride reduced total PP gastric volume without accelerating gastric emptying or significantly altering gastric motor and sensory function in healthy individuals.     

Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women

Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day(-1) micronized progesterone, 0.2 mg day(-1) oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.     

Effect of the NK3 receptor antagonist, talnetant, on rectal sensory function and compliance in healthy humans

Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thus a target for modulation in drug development. Neurokinin (NK) receptors, including NK(3) receptors, are expressed in the motor and sensory systems of the digestive tract. The aim of this study was to compare the effects of two different doses (25 and 100 mg) of the NK(3) receptor antagonist, talnetant (SB223412) with placebo on rectal sensory function and compliance in healthy volunteers studied at two centres. Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days. Studies were performed on three occasions: day 1 immediately prior to 1st dose, day 1 4 h postdose, and after 14- to17-day therapy. Compliance, and pressure thresholds for first sensation, urgency, discomfort and pain were measured using ascending method of limits, and sensory intensity ratings for gas, urgency, discomfort and pain determined during four random phasic distensions (12, 24, 36 and 48 mmHg). Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo. In general, the results obtained at the two centres differed minimally, with intensity scores at one centre consistently somewhat lower. At the doses tested, talnetant has no effect on rectal compliance or distension-induced rectal sensation in healthy participants.     

Risk factors for chronic diarrhoea in the community in the absence of irritable bowel syndrome

Abstract  In contrast to irritable bowel syndrome (IBS), the prevalence and risk factors for diarrhoea in the absence of IBS in the community are unknown. We aimed to evaluate potential risk factors for chronic diarrhoea (non-IBS). A valid questionnaire that recorded gastrointestinal symptoms required for a diagnosis of chronic diarrhoea, self-reported measures of potential risk factors, and a somatic symptom checklist was mailed to an age- and gender-stratified random sample of Olmsted County, Minnesota residents (30–64 year). Chronic diarrhoea was defined as reporting one or more of the following symptoms more than 25% of the time in the past 3 months: ≥3 bowel movements a day, loose or watery stools, or faecal urgency. Subjects with IBS (Rome III) were excluded. Of 892 eligible subjects, 653 (73%) responded. Among 523 respondents not reporting IBS, chronic diarrhoea was reported by 148 (28%); 90 (61%) had chronic painless diarrhoea. Chronic diarrhoea was significantly associated with self-reported food sensitivity (OR = 2.05 [1.31–3.20]) and stress (OR = 1.99 [1.03–3.85]). Both remained significant in the adjusted variable models that excluded subjects with any abdominal pain. Female gender (OR = 0.67 [0.45–0.98]) and higher education level (OR = 0.60 [0.39–0.92]) had smaller odds for chronic diarrhoea. No association was detected for age, marital status, body mass index, cigarette or alcohol use, coffee, analgesics, emotional support, pets or water source. Chronic diarrhoea in the absence of IBS is common; self-reported food sensitivity, male gender and a lower level of education are risk factors.     

Application of magnetic resonance imaging to measure fasting and postprandial volumes in humans

Abstract  Our aims were to measure the gastric volume response in excess of ingested meal volume (i.e. gastric accommodation), contribution of swallowed air to this excess, day-to-day variability of gastric volumes measured by MRI and their relationship to volumes measured by single-photon-emission computed tomography (SPECT). In 20 healthy volunteers, fasting and postprandial gastric volumes were measured after technetium^99m-pertechnetate labeling of the gastric mucosa by SPECT and separately by MRI, using 3D gradient echo and 2D half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences. Ten of these subjects had a second MRI exam to assess intra-individual variation. Thereafter, another 10 subjects had two MRI studies during which they ingested the nutrient in 30 or 150 mL aliquots. During MRI, the postprandial gastric volume change exceeded the ingested meal volume by 106 ± 12 mL (Mean ± SEM). The HASTE and gradient echo sequences distinguished air from fluid under fasting and postprandial conditions respectively. This postprandial excess mainly comprised air (61 ± 5 mL), which was not significantly different when ingested as 30 or 150 mL aliquots. Fasting and postprandial gastric volumes measured by MRI were generally reproducible within subjects. During SPECT, postprandial volumes increased by 158 ± 18 mL; gastric volumes measured by SPECT were higher than MRI. MRI measures gastric volumes with acceptable performance characteristics; the postprandial excess primarily consists of air, which is not affected by the mode of ingestion. Gastric volumes are technique specific and differ between MRI and SPECT.     

Sleep disturbances are linked to both upper and lower gastrointestinal symptoms in the general population

Abstract  In tertiary referral patients, there is association between altered sleep patterns, functional bowel disorders and altered gut motor function. Body mass index (BMI) is also associated with gastrointestinal (GI) symptoms including diarrhoea, and with sleep disturbances. Our hypothesis is that sleep disturbances are associated with GI symptoms, and this is not explained by BMI. A 48-item-validated questionnaire was mailed to 6939 community participants in Olmsted County, MN. The survey included GI symptoms, sleep disturbance, daily lifestyle and quality of life (QOL). Independent contributions of sleep disturbance to individual symptoms were assessed using logistic regression adjusting for age, gender, lifestyle and mental health status. The association of an overall sleep score with an overall symptom score was examined and the ability of both scores to predict SF-12 physical and mental functioning scores assessed in multiple linear regression models. Among 3228 respondents, 874 (27%) reported trouble staying asleep. There was a significant correlation of overall sleep scores with overall GI symptom scores (partial r  = 0.28, P  < 0.001). Waking up once nightly at least four times a month was significantly associated with pain, nausea, dysphagia, diarrhoea, loose stools, urgency and a feeling of anal blockage. Trouble falling asleep was significantly associated with rectal urgency. Associations were independent of gender, age, lifestyle factors and BMI. Overall, sleep scores and GI symptom scores were both significant independent predictors of impaired QOL. In the community, reporting poor sleep is associated with upper and lower GI symptoms, but this is independent of BMI.     

Barostat testing of rectal sensation and compliance in humans: comparison of results across two centres and overall reproducibility

We assessed reproducibility of measurements of rectal compliance and sensation in health in studies conducted at two centres. We estimated samples size necessary to show clinically meaningful changes in future studies. We performed rectal barostat tests three times (day 1, day 1 after 4 h and 14-17 days later) in 34 healthy participants. We measured compliance and pressure thresholds for first sensation, urgency, discomfort and pain using ascending method of limits and symptom ratings for gas, urgency, discomfort and pain during four phasic distensions (12, 24, 36 and 48 mmHg) in random order. Results obtained at the two centres differed minimally. Reproducibility of sensory end points varies with type of sensation, pressure level and method of distension. Pressure threshold for pain and sensory ratings for non-painful sensations at 36 and 48 mmHg distension were most reproducible in the two centres. Sample size calculations suggested that crossover design is preferable in therapeutic trials: for each dose of medication tested, a sample of 21 should be sufficient to demonstrate 30% changes in all sensory thresholds and almost all sensory ratings. We conclude that reproducibility varies with sensation type, pressure level and distension method, but in a two-centre study, differences in observed results of sensation are minimal and pressure threshold for pain and sensory ratings at 36-48 mmHg of distension are reproducible.     

Relationship between upper gastrointestinal symptoms and changes in body weight in a population-based cohort

Obesity has been associated with increased reporting of gastrointestinal (GI) symptoms, but whether weight gain or loss causes symptoms is unclear. We studied the association between changes in body weight and changes in upper GI symptoms. Prospective cohort study on random samples of Olmsted County, MN residents. Distinct upper GI symptom complexes [gastro-oesophageal reflux disease (GERD), chest pain, dyspepsia- pain predominant, dyspepsia-dysmotility] were defined. Subjects with persistent, new-onset or disappearing symptoms were identified as cases, subjects with no reported symptoms in any of the surveys served as controls. Associations were studied in a logistic regression model, using age, gender, baseline Body Mass Index and somatic symptom score as covariates. Participants for whom baseline and follow-up data were available (n = 637) had a median time between surveys of 10.5 years. Baseline body weight was associated with GERD, chest pain and dyspepsia-pain predominant symptom complexes. An increase in body weight >10 lb between surveys was associated with new onset of dyspepsia-dysmotility (OR 5.57, 95% CI 1.91, 16.2). No association was found between weight loss >10 lb and the studied symptom complexes. Moderate body weight increases and decreases are generally not associated with upper GI symptom changes over time in the general population.     

Does co‐administration of a non‐selective opiate antagonist enhance acceleration of transit by a 5‐HT4 agonist in constipation‐predominant irritable bowel syndrome? A randomized controlled trial

Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.     

Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion

Abstract  Our aim was to understand the information from differential two-sugar excretion (2-SE) in measuring intestinal permeability. In a crossover study in 12 healthy volunteers, we compared urinary excretion ratios of lactulose (L) to mannitol [(M) LMR] after ingestion in liquid formulation (LF) or in delayed-release, methacrylate-coated capsules (CAP). Both formulations were radiolabelled. Urine was collected every 2 h from 0 to 8 h, and from 8 to 24 h. Two hours after LF, gastric residual was 15.9 ± 6.2% (SEM), and the percentage in colon was 49.6 ± 7.8%; in 11/12 participants, liquid had entered colon within 2 h. Average CAP arrival time in colon was 5.16 ± 0.46 h (mode 6 h). After LF, mannitol was extensively absorbed in the first 8 h; lactulose absorption was low thoughout the 24 h. After the LF, the LMR (geometric mean, 95% CI per h) in the 0–2 h urine was [0.08 (0.05, 0.11)], which was lower than in 8–24 h urine [0.32 (0.16, 0.46); P  < 0.05]. Urine LMRs at 8–24 h were similar after LF or CAP. We concluded that, after LF, sugar excretion in 0–2 h urine may reflect both SI and colon permeability. Colonic permeability is reflected by urine sugar excretion between 6 and 24 h. CAP delivery reduces mannitol excreted at 0–6 h, compared with LF. The 0–5 or 6 h 2-SE urine likely reflects both SI and colon permeability; the higher LMR in the 8–24 h urine relative to 0–2 h urine should be interpreted with caution and does not mean that colon is more permeable than SI.